STANDARD TREATMENT GUIDELINES ORGAN TRANSPLANT: LIVER Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 Treatment Guidelines for liver diseases and transplantation 4 2

Group Head Coordinator of Development Team Dr Subash Gupta Consultant Liver Surgeon, Indraprastha Apollo Hospital New Delhi 3

Treatment Guidelines for liver diseases and transplantation 1. Diagnosis of chronic liver disease Algorithm for management of icterus: 1. Patients presenting first time with jaundice from a liver disease should have the following tests: a) Liver function tests, b)INR c) CBC d) Ultrasound of the abdomen. 2. Raised INR over 1.7 has ominous portents and will require referral to a higher centre 3. Patients should then be separated in to obstructive (SOJ) or medical jaundice.

4. Patients with SOJ should be referred to gastroenterologist/GI surgeon. 5. Patients with medical jaundice should be then further divided in to acute hepatitis or chronic liver disease. Additional tests such as HBsAg, anti HCV, and anti Hep E IgM may be conducted to define this further. 6. Patients with chronic liver disease should then undergo testing in a tertiary centre to see if they have a treatable liver condition such as HVOO (Budd Chiari Syndrome), autoimmune hepatitis or Wilson’s disease.

7. Patients with advanced chronic liver disease should then be categorized in to Child’s A, B or C disease. Those with Child’s C disease should be referred to a transplant centre. Patients with Child’s A and B cirrhosis should be advised to see a transplant hepatologist at some point to discuss future treatment possibilities. 2) Guidelines for management of Liver disease: a) Alcoholic liver disease: The mainstay of treatment is alcohol abstinence. May require help from a psychiatrist.

However it may not be clear whether alcohol has caused liver damage or there has been another associated factor such as NASH, hepatitis C or hemachromatosis or diabetes. Management principles are in accordance with general measures to manage chronic liver disease. Patients presenting with acute severe alcoholic steatohepatitis are usually not considered for transplant especially in a predominant cadaver program. The treatment of these

patients is with intensive care including dialysis and ventilatory support. Nutrition is an important component. It poses an ethical issue whether these patients should have the option of LRLT. The treating clinicians are under immense pressure from the family for this treatment option. At this moment, till a consensus is reached, a case-by-case decision should be taken after counseling the family and the potential donor and after an opinion from a psychiatrist. b) Hepatitis B 4

1) Evaluation of patients newly diagnosed with chronic HBV infection should include history, physical examination and laboratory testing as outlined below: • History and physical examination • Complete blood counts with platelets, liver function tests and prothrombin time/INR • Tests for HBV replication—HBeAg/anti-HBe, HBV DNA • Tests to rule out viral co-infections—anti-HCV, and anti-HIV in those at risk • Ultrasound upper abdomen • Upper gastrointestinal endoscopy

• Tests to screen for HCC–AFP and ultrasound • Liver biopsy in those with suspected chronic hepatitis 2) Patients are classified in the following groups for treatment purpose: inactive carrier state, chronic hepatitis B (HBeAg positive or HBeAg negative groups) and cirrhosis. Once cirrhosis is diagnosed, all attempts should be made to identify its complications such as ascites, GI bleed, hepatic encephalopathy, renal dysfunction, spontaneous bacterial peritonitis, and hepatocellular carcinoma.

3) HBeAg-positive patients: HBeAg-positive patients with persistently normal ALT should be tested for ALT at 3-6 month intervals. ALT along with HBV DNA should be tested more often when ALT levels become elevated. HBeAg status should be checked every 6-12 months. 4) HBeAg-negative patients: a) HBeAg-negative patients with normal ALT and HBV DNA <2,000 IU/ml should be tested for ALT every 3 months during the first year to verify that they are truly in the “inactive carrier state” and then every 6-12 months.

b) Use of interferon for hepatitis B should be limited to higher centres with extensive experience. 5) In those who need treatment, options include oral antivirals such as entecavir, tenofovir, telbivudine or pegylated interferon in selected subgroup of patients. 6) Patients with decompensated cirrhosis: treatment should be initiated with an oral antiviral agent, which has high viral suppression and low risk of resistance. a. Entecavir or tenofovir would be an appropriate treatment in this setting.

b. IFN should not be used in patients with decompensated cirrhosis. c. Treatment is indicated even if HBV DNA level is low. 7) Treatment of patients awaiting Liver Transplantation. a. In those who are being considered for liver transplantation, aim is to make the patient HBV DNA negative or achieve at least 2 log reduction in HBV DNA load prior to transplantation. b. Treatment of patients with advanced liver disease is advised in order to reduce

the risk of HBV recurrence in graft in those who undergo liver transplantation. 8) Patients with hepatitis B related cirrhosis with complications should be referred to a liver transplant centre. c) Hepatitis C: The hepatitis C virus (HCV) has a prevalence of 1 to 2% in India. 5

1. 55% to 85% of individuals who develop acute hepatitis C infection will develop chronic hepatitis. 2. The risk of developing cirrhosis in them is up to 25% over periods of 25 years. 3. The diagnosis of acute or chronic HCV infection generally requires testing of serum for both antibody to HCV (anti-HCV) and for HCV RNA. Treatment • Treatment decisions should be individualized based on 1) the severity of liver disease, 2) the potential for serious side effects, 3) the likelihood of treatment

response and 4) the presence of comorbid conditions. • Treatment decisions are often based on liver biopsy findings. • HCV RNA should be tested (quantitative assay) at the initiation of treatment and at regular intervals there after. • The optimal therapy for chronic HCV infection is the combination of peginterferon and ribavirin. • For genotype 1 and 4, treatment with peginterferon plus ribavirin should be administered for 48 weeks.

• For genotypes 2 and 3, treatment with peginterferon plus ribavirin should be administered for 24 weeks. • 50% of patients with genotype 1 and 4 and 80% with genotype 2 and 3 remain persistently HCV RNA negative after stopping therapy. • The most common adverse events are influenza like side effects (fatigue, headache, fever and rigors), psychiatric symptoms (depression, anxiety), anemia and neutropenia. • Patients with HCV-related compensated cirrhosis (CTP class A) can be treated with

the standard regimen of pegylated interferon and ribavirin but will require close monitoring for adverse events. • Patients with HCV-related decompensated cirrhosis should be referred for consideration of liver transplantation. 6

• Interferon-based therapy may be initiated at a lower dose in patients with decompensated cirrhosis (CTP class B and C), as long as experienced clinicians administer treatment with vigilant monitoring for adverse events. • Treatment can be initiated with half doses that are increased incrementally as tolerated at 2-week intervals (referred to as a LADR, low accelerating dose regimen), supplemented with growth factors if required. d) Wilson's Disease

Patients with cirrhosis with neuro-psychiatric manifestations should be evaluated for Wilson's disease. However, the type of the liver disease can be highly variable, ranging from asymptomatic with only biochemical abnormalities to acute liver failure. It should be suspected in any patient presenting with acute hepatic failure with Coombs- negative intravascular hemolysis, modest elevations in serum aminotransferases, or low serum alkaline phosphatase and ratio of alkaline phosphatase to bilirubin of <2.

If Wilson's disease is suspected, patients should undergo Kayser-Fleischer ring examination by slit-lamp. Other tests include estimation of serum ceruloplasmin and basal 24 hrs urinary excretion of copper. An extremely low serum ceruloplasmin level (<50 mg/L or <5 mg/dL) should be taken as strong evidence for the diagnosis of Wilson's disease. Penicillamine challenge studies may be performed for the diagnosis of Wilson's disease in selected cases.

In occasional cases, estimation of hepatic parenchymal copper content by liver biopsy may be necessary. The drugs used for its treatment include D-penicillamine, Trientine and Zinc. Patients with acute liver failure due to Wilson's disease should be referred for liver transplantation urgently as without transplant, mortality is very high. e) Hemochromatosis As this is a genetic disease and progression to cirrhosis can be prevented, screening of target population is important. i) Symptomatic patients

Unexplained manifestations of liver disease or a presumably known cause of liver disease with abnormality of one or more indirect serum iron markers Type 2 diabetes mellitus, particularly with hepatomegaly, elevated liver enzymes, atypical cardiac disease or early-onset sexual dysfunction Early-onset atypical arthropathy, cardiac disease, and male sexual dysfunction ii) Asymptomatic patients First-degree relatives of a confirmed case of hemochromatosis

Individuals with abnormal serum iron markers discovered during routine testing 7

Individuals with unexplained elevation of liver enzymes or the serendipitous finding of asymptomatic hepatomegaly or radiologic detection of enhanced computed tomography attenuation of the liver Investigations Serum iron Total iron binding capacity % saturation Serum ferritin Percent saturation greater than 45% and serum ferritin greater than 150ng/ml suggests hereditary hemochromatosis / iron overload states, and patient should be evaluated further.

Patients should undergo genetic testing for HFE mutations (C282Y and H63D). Sometimes, liver biopsy may be necessary to evaluate for cirrhosis and iron overload. Patients with proven hemochromatosis should undergo therapeutic phlebotomy. For those with advanced liver disease, therapeutic phlebotomy should be stopped as liver transplantation will offer definitive treatment f) Autoimmune Hepatitis • Autoimmune hepatitis (AIH) is an unresolving inflammation of the liver of unknown

cause affecting women more frequently. • An acute onset of illness is common (40%), and a fulminant presentation, characterized by hepatic encephalopathy within 8 weeks of disease onset, is possible. Diagnostic Criteria • Diagnosis of Autoimmune Hepatitis (AIH) often represents a clinical challenge • Interface hepatitis is the histologic hallmark of the syndrome,2 and portal plasma cell infiltration typifies the disorder.

• Neither histologic finding is disease specific, and the absence of portal plasma cells does not preclude the diagnosis • Liver biopsy examination is essential to establish the diagnosis and evaluate disease severity to determine the need for treatment. • A scoring system has been proposed to assess the strength of the diagnosis Diagnostic Scoring System • A value of 6 or more points makes the diagnosis of AIH very likely, a value of 7 or 8 points demonstrates definite AIH 8

Sub-classifications • Three types of AIH have been proposed based on differences in their immunoserologic markers • They do not have distinctive etiologies or responses to corticosteroid therapy Treatment Indications: • Treatment may not be indicated in patients with inactive cirrhosis, preexistent comorbid conditions, or drug intolerances • The indications for treatment are shown in Table 2 Treatment Regimens: • Two treatment regimens are comparable with each other and superior to

nonsteroidal therapies in the management of severe AIH in adults (Table 3) • Prednisone in combination with azathioprine or a higher dose of prednisone alone is the appropriate treatment for severe AIH in adults • Sixty-five percent of patients enter remission within 18 months, and 80% achieve remission within 3 years (mean duration of treatment to remission, 22 months) Liver biopsy assessment prior to termination of treatment is preferred and

recommended, but not essential, in the management of patients who satisfy clinical and laboratory criteria for remission g) HCC; HCC oftens coexists with cirrhosis and with hep B liver disease. Screening interval should be 6 months using ultrasound. Nodules < less than 1 cm, follow up scans every 3 months for 2 years, if no growth, revert to 6 m sans 9

Nodules greater than 1 cm, CT/MRI, typical features, treat like HCC, atypical second contrast scan, biopsy if not clear Management recommendations • Single lesion, resection if good liver function, HVPG <10 mmHg. No pre or post adjuvant therapy. • Liver Transplant if within UCSF criteria • Preoperative therapy if wait list is likely to exceed 6 months • Local ablation if resection/transplant can not be done. • Alcohol injection for HCC less than 2 cm, otherwise RFA

• TACE is rcommened as firt line non curative therapy for non surgical patients with large multifocal HCC without vascular or extrahepatic spread. • Sorefinib for those who can not have surgery, TACE, local ablation and still have preserved liver function. • Radioactive particles may be useful but enough data has not accrued to give guidelines. h) Pregnancy & Jaundice Jaundice in pregnancy can either be due to a. Exacerbation of a preexisting liver disease,

b. Coincidental liver disease acquired during pregnancy or c. Pregnancy related liver disorder. A preexisting liver disease as well as coincidental liver disease acquired/detected during pregnancy should be managed as in a non pregnant state, the choice of medications are dictated by the safety profile for the fetus. Interferon is not to be used in pregnancy. A pregnant female on therapy for Chronic Hepatitis B should be continued on the

medication she is on Lamivudine and tenofovir have the best safety profile in pregnancy with emerging evidence for entecavir as well. Hepatitis E in pregnancy This can run a very fulminant course, with a higher risk of developing acute liver failure compared to non-pregnant population as well as higher risk of death if ALF develops. There is no evidence that termination of pregnancy decreases incidence of acute liver failure or

mortality in patients with acute viral hepatitis. Termination of pregnancy after development 10

of ALF has also not shown to decrease mortality. Management of the patient with acute viral hepatitis is supportive, and viral hepatitis is not an indication for termination of pregnancy, caesarean section, or discouragement for breastfeeding. Chronic liver disease and pregnancy Chronic liver disease like autoimmune hepatitis (AIH) and Wilson’s disease may flare up during pregnancy. These patients should be maintained on the medications they were on

before pregnancy, with flares being treated with steroids in AIH. Gallstones and biliary disease is treated in the same way as in without pregnancy. Surgery is avoided if possible in 1st and 3rd trimester, for increased risk of abortion and premature labor, respectively. Choledocholithiasis is treated with ERCP and papillotomy/stone extraction irrespective of the trimester. Pregnancy related liver disease For pregnancy related liver disorders, evaluation of jaundice in pregnancy depends on the

type of symptoms and the time of onset of symptoms in relation to the week of gestation. a) Hyperemesis gravidarum Severe nausea and vomiting are the key features of hyperemesis gravidarum, which occurs predominantly in the first trimester. It occurs most often in women less than 25 years of age who are overweight, multiparous, and with multiple births. Treatment is symptomatic. If nausea and vomiting is accompanied by headache and peripheral edema, it may indicate

preeclampsia and, if accompanied by abdominal pain with or without hypotension in late pregnancy, may indicate hepatic rupture. b) Preeclampsia and HELLP syndrome usually occurs after 20 weeks of gestation and is characterized by hypertension, proteinuria, and edema. It is generally a disease of primigravidas. Jaundice is usually not a feature of preeclampsia, but is seen with HELLP syndrome (Hemolysis, elevated liver enzymes and low platelets) as well as hepatic rupture.

Both these conditions are associated with preeclampsia. Treatment for all three conditions is delivery after stabilization of the mother. c) Pruritus is the characteristic feature of intrahepatic cholestasis of pregnancy. It typically involves the palms of the hands and soles of the feet initially and then affects the rest of the body. Jaundice typically follows the pruritus. It is most common in third trimester of pregnancy but may occur in second and rarely in first also. Maternal outcome is benign,

pruritus resolves quickly after delivery. In the fetus, maternal intrahepatic cholestasis has been associated with an increased incidence of prematurity, perinatal deaths, fetal distress, and meconium staining of amniotic fluid. Treatment is symptomatic. Antihistaminics are not of much help. Cholestyramine and UDCA have been used with some success. d) Acute fatty liver of pregnancy (AFLP) is a rare and potentially fatal disease that generally

occurs in the last trimester of pregnancy. AFLP occurs more commonly during first pregnancies, with multiple gestations, and with male fetuses. They present with prodromal symptoms of abdominal pain and then jaundice. More severe manifestations include progressive liver failure, coagulopathy, encephalopathy and renal dysfunction with oliguria or uremia. 11

AFLP has a very poor prognosis for both mother and fetus unless early diagnosis and prompt termination of pregnancy is done. Early delivery is the mainstay of therapy. Orthotopic liver transplantation may be required in patients with AFLP and fulminant hepatic failure who do not improve despite delivery and intensive supportive care 2) Management of complications of cirrhosis: Frequency of blood tests in Chronic liver disease

Patients with chronic liver disease need to be monitored so that they can be transplanted before they deteriorate. Further organ availability may not be immediate. MELD score Status rectification Lab values not older than >25 Every week 48 h 18 to 24 Every month 7 days 11 to 18 Every 3 months 14 days 0 to 10 Every 12 months 30 days i) Gastrointestinal bleeding Endoscopy: Patients with upper GI bleed should have an endoscopy done within 8

hours of presentation. The initial management is with somatostatin infusion. If on Endoscopy, varices are identified, they should be placed on regular endoscopic band ligation. Endoscopic management is the mainstay and failure of endoscopic management should lead to consideration of TIPS procedure. Surgical shunts are generally not indicated in cirrhotics. If shunt surgery is to be done, a Mesocaval shunt is the shunt of choice. Recommendations for Endoscopy

a) At the time the diagnosis of cirrhosis is made. b) Repeat every 2 years if no varices at initial screening and no decompensation, if decompensation, at time of decompensation and every year. c) Small varices which have not bled, EGD every 1 year or put them on beta blockers and no follow up EGD. d) Patients on beta-blockers, adjust dose to the maximal tolerated dose, if treated with EVL, repeat every 1 -2 weeks till obliteration and then surveillance EGD at 1-3

months later and then every 6-12 months for recurrence. ii) Ascites: Salt and fluid restriction 12

Bed rest Daily weight record Diuretics to be started; however if there is development of renal impairment, hyponatremia or encephalopathy, patient should be advised liver transplantation. Large volume paracentesis should be advised if the patient is not a fit candidate for transplant. TIPS may be considered if the liver function is good. There is no role for peritoneovenous shunt because of the high occlusion rate and LIMITED EFFICACY. Indications for TIPS • Refractory variceal bleeding

• Ascites intolerant to LVP • Hepatic hydrothorax • Hepatorenal syndrome • Budd Chiari Syndrome TIPS not indicated for GAVE iii) SBP a) hospital admission b) ascitic tap and cell count c) Injection albumin d) I/v antibiotics e) observe renal function f) prophylaxis with quinolones iv) Hepatic Hydrothorax Defined as a significant pleural effusion, usually >500 mL, in a patient with cirrhosis of liver but no primary cardiac or pulmonary disease o Occurs usually with alcoholic cirrhosis

o Develops in roughly 4% to 10% of ESLD patients o HH can occur even in the absence of ascites o Liver transplantation is the most definitive cure o Uncommon presentation of HH is spontaneous bacterial empyema (SBEM) Conservative Management Protocol o restrict daily sodium intake to 90 mEq 13

o a trial of diuretics (spironolactone and furosemide) – Increase doses until the pleural effusion is controlled or side effects preclude greater doses o No more than 1.5 liters of fluid should be aspirated during therapeutic thoracentesis – risk of unilateral pulmonary edema or hypotension Send the fluid for o SAAG o Cytology for malignant cells o Biochemistry o ADA o PCR for TB After aspiration, confirm lung expansion with an X-ray lung. If there is no expansion even

after tapping to dryness, then obtain a CT scan of the chest to rule out any underlying lung fibrosis. Hepatic hydrothorax and liver transplantation In patients with cirrhosis and hydrothorax who are planned for liver transplantation, it is essential demonstrate lung expansion prior to the transplantation. If there is no reason for the lungs not to expand other than re-accumulating intrapleural fluid or the patient needs multiple aspirations to prevent re-accumulation, then temporarily

place an ICD prior to planned date of operation v) Renal impairment in cirrhotics a) Judicious use of nephrotoxic drugs, avoid when possible b) Avoid IV contrast during pre-transplant imaging, however it may be essential to image the portal vein prior to a high risk LRLT c) Optimization of extracellular fluid volume and vasoconstriction: Albumin / d)Terlipressin/noradrenaline/octreotide and midodrine e) Treat sepsis, such as SBP, f) If albumin is indicated, then reassess the need for albumin every 48 hrs

vi) Encephalopathy: Hepatic encephalopathy (HE) is a common manifestation seen in both acute and chronic liver failure. Several factors influence its outcome such as infection, hypoxemia, GI hemorrhage, or electrolyte disturbances. It is classified in to following clinical stages: Grade 1. Trivial lack of awareness. Shortened attention span. Hypersomnia, insomnia, or inversion of sleep pattern. Asterixis can be detected. Grade 2. Lethargy or apathy. Disorientation. Inappropriate behavior. Slurred

speech. Obvious asterixis. Grade 3. Gross disorientation. Bizarre behavior. Semistupor to stupor. Asterixis generally absent. Grade 4. Coma. 14

Several precipitating factors for HE have been identified such as: GI hemorrhage, infections, electrolyte disturbances, use of sedatives, constipation, and excessive dietary protein. Treatment guidelines: Avoidance and prevention of precipitating factors Nutrition. Improve protein intake by feeding dairy products and vegetable- based diets. Lactulose. Dosing aims at two to three soft bowel movements per day. Use of antibiotics such as metronidazole, ampicillin or rifaximin

Refer for liver transplantation in appropriate candidates. Patients in deeper stages of HE may need prophylactic tracheal intubation. A nasogastric tube is placed for patients in deep encephalopathy. Avoid sedatives whenever possible. Lactulose can be administered via enema or nasogastric tube in deep encephalopathy. Dosing every hour until stool evacuation appears optimizes oral dosing. vii) Hepatopulmonary Syndrome (HPS) Patients with chronic liver disease should be evaluated for Hepatopulmonary

syndrome if they have dyspnoea, cyanosis or clubbing, and arterial blood gases show low PaO2 (<80mmHg). Patients may complain of platypnea and have orthodeoxia. HPS may be present with minimal symptoms of chronic liver disease. HPS is defined by the triad of liver disease, increased alveolar-arterial oxygen gradient ≥15mmHg while breathing room air, and intrapulmonary vascular dilatations. The diagnosis is usually based on positive bubble contrast echocardiography and

99mTc labeled macroaggregated albumin scan (MAA scan). It is important that other cardio-pulmonary causes should be excluded before labelling a patient as having HPS. Mainstay of therapy is supplemental oxygen. Patients with troublesome HPS should be referred to a liver transplant centre as HPS may regress completely following liver transplantation. viii) Porto-pulmonary hypertension (PPH) Portopulmonary hypertesion should be looked for in patients with liver disease who complain of exertional dyspnoea.

Based on degree of elevation in mPAP, it can be classified as mild (mPAP = 25 to 35 mm Hg), moderate (mPAP = 35 to 50 mm Hg) and severe (mPAP > 50 mm Hg). 15

Transthoracic echocardiography and, sometimes, right heart catheterization are needed to establish the diagnosis of PPH. Prostacyclin (epoprostenol) is a potent vasodilator and platelet aggregation inhibitor that results in clinical improvement in PPH. Bosentan and Sildenafil are orally available drugs that improve pulmonary hemodynamics in primary pulmonary hypertension. Moderate to severe PPH (mean pulmonary artery pressure >50 mm Hg) is a

contraindication to liver transplantation because of perioperative mortality of approximately 40% and lack of reversibility of pulmonary hypertension. Non transplant surgery in cirrhosis: In general surgery is poorly tolerated in patients with advanced cirrhosis and therefore should be taken up for surgery with caution. They often present with hernias and this should be managed by controlling ascites first. Cholelithiasis and cirrhosis:

In patients with cirrhosis, category Child’s B and C, elective surgery should be avoided, as risk of decompensation is very high with consequent mortality. Safe medicines in cirrhosis: NSAIDs should not be given as it may cause GI bleeding. Anti TB drugs should be prescribed with caution and with regular monitoring of liver function tests every 2 weeks. Aminoglycosides to be avoided as they may cause nephrotoxicity when used with diuretics.

Diabetes in decompensated cirrhosis should be treated with Insulin rather than with OHAs. The antiepileptic valproate should be avoided. In general caution must be exercised in prescribing medicines in patients with chronic liver disease as quite often these medicines are metabolized in the liver. Indigenous medicines and in particular Ayurvedic medicines should be avoided. Liver Transplantation 1. Indication for transplantation a) Chronic liver disease i) Child’s C cirrhosis

ii) Child’s B cirrhosis with an episode of life threatening decompensation such as SBP, renal dysfunction, refractory ascites, recurrent GI bleeding refractory to endoscopic management or recurrent HE. iii) Cholestatic liver disease: impairing quality of life such as severe itching, osteoporosis and recurrent cholangitis, presence of a dominant stricture without evidence of cholangiocarcinoma 16

b) Tumours: i) HCC a. If within UCSF criteria (UCSF criteria is a. Single nodule less than 6.5 cm in size, b. not more than 3 nodules with cumulative diameter less than 8 cms) ii) Neuroendocrine tumours To be considered for transplantation under exceptional circumstances such as no evidence of extrahepatic disease, and evidence of slow progression of disease. A period of waiting to assess biological behaviour of tumour would be desirable. iii) Cholangiocarcinoma

Although the Mayo group has successfully transplanted patients with cholangiocarcinoma, in general they should not be considered for transplantation, as the results are poor. iv) Pediatric tumours a. Hepatoblastoma post three cycles of chemotherapy if not resectable and absence of extrahepatic disease with the exception of stable pulmonary metastasis b. HCC in children can be transplanted beyond UCSF criteria provided they are Hep B and C negative. c. Indication in acute liver failure: Pediatrics:

In general, patients for ALF in this age group have been selected for transplant based on Kings College criteria. However the current evidence from King’s College group suggests that patients should be considered for transplant, once the INR is greater than 4 with or without encephalopathy. It is also realised that symptoms of encephalopathy can be easily missed in an irritable child. Outcome of transplant in children with grade III or IV coma is not good and

therefore these children should be transplanted only in exceptional circumstances. Adults: The King’s College criteria are a good guide. However large volumes centres have accumulated enough experience to decide on their own the indication for transplant in a particular patient. i) Listing for transplant as is prevalent in the West has little meaning in India where organ harvesting and allocation is not yet a regular feature. ii) Patients with non hyperacute liver failure in Grade III or IV coma should be

transplanted early as without transplant the outcome is dismal. iii) INR should be monitored without FFP support, as the use of FFP has not been shown to improve survival. iv) A progressive worsening INR or deterioration in sensorium are good indicators for need of transplant. v) Patients of ALF in renal or multiorgan failure such as requirement for high FiO2 do not do well after transplant and therefore should only be considered for transplant

under exceptional conditions. Paracetamol overdose could be one exception as renal failure can be an early feature. 2. Management of ALF: a) Nurse in a quiet room with head elevation. b) I/v fluids and measures to reduce cerebral edema such as i/v Mannitol, 3% hypertonic saline and hypothermia. c) Watch for hypoglycemia d) Renal support; Institute dialysis early, role of MARS is controversial e) Antibiotics and antifungal prophylaxis should be started.

f) Elective ventilation should be done if the patient is Grade III or more of coma g) No FFP should be given, unless an invasive procedure is planned. h) Should be referred to a transplant centre if the INR> 2.5. All patients of ALF should be managed in consultation with a Liver Transplant centre so that smooth transfer can be organized if the patient is not recovering. i) Intracranial pressure measurement is generally not practiced in India because unequivocal advantages of this has not been shown

3. Acute on chronic liver disease: a. These patients with should be referred for transplant as soon as the diagnosis is made, as the prognosis is dismal otherwise. Those with encephalopathy should be transplanted early. b. Alcoholic steatohepatitis is usually acute on chronic liver disease and alcohol abstinence may improve prognosis. This situation is different from other causes of ACLF 4 Renal Dysfunction and Liver Transplantation i) High Risk Groups who need renal protection during Liver Transplantation

Creatinine > 1.5 at the time of transplant Duration of renal failure (Cr. > 1.5) > 2 weeks in the preceding 6 months GFR < 40 ml/min Renal dysfunction requiring dialysis in the preceding 6 months Pre-Transplant renal dysfunction: medical renal disease with proteinuria >500 mg/24 hours indicative of nephropathy ii). Indications for combined liver and kidney transplant Serum creatinine > 2 mg/dL in patients who also have chronic renal disease Dialysis > 8 weeks GFR < 30 mL/minute

Kidney biopsy: (usually not possible because of low platelet and deranged INR) > 30% glomerulosclerosis > 30% interstitial fibrosis, or both Irreversible kidney damage Primary Hyperoxaluria iii). Contra indications and delisting criteria for liver transplantation Absolute Contraindications: a) Extrahepatic malignancy (unless patients meet standard oncologic criteria for cure – as in certain neuro-endocrine malignancies metastatic to the liver with proof of treatment of primary disease).

b) Hepatocellular cancers known to be radiologically / macroscopically involving a major intra-hepatic vascular structure. c) Primary severe pulmonary artery hypertension d) Sepsis unresponsive to treatment. e) Coma with evidence of irreversible brain injury (particularly relevant in patients with acute liver failure and may also be relevant to a select few patients with chronic liver disease). f) Severe, uncorrectable congenital anomalies

g) Major disease in other organ system (diffuse coronary artery disease that is uncorrectable, endstage COPD, etc) h)Current substance abuse (narcotics). Relative Contraindications (if ameliorated before transplantation, the transplant operation can proceed) a) Cholangiocarcinoma b) Age: Generally > 70 years preclude the benefits of transplantation. However, chronologic age is not uniformly indicative of the status of health and marginal

exceptions can be made on a case by case basis keeping in view the overall state 19

of health and possibilities of being able to lead a fruitful & satisfactory life subsequent to transplant. c) Respiratory failure requiring > 50% O2 d) Advanced malnutrition e) Inability to understand or adhere to post-operative regimen f) Alcoholics in recovery and other prior substance abusers who have documented abstinence for a minimum of three months and have undergone a thorough multidisciplinary assessment (including social and psychiatric evaluation) may be

considered for liver transplantation if they possess appropriate psychosocial support systems so that they can comply with lifelong immunosuppressive therapy and be expected to maintain permanent abstinence from all addictive substances. g) Individuals with alcohol consumption where reasonable doubt exists regarding its contribution to the genesis of end stage liver disease or those individuals with alcoholism who were unaware of their chronic liver disease presenting with an acute

on chronic liver disease unlikely to survive the minimum abstinence period, can be considered on a case by case basis for transplantation if appropriate psycho-social support and motivation and insight for abstinence is certified by the psychiatrist designated for the transplant program. h) HIV infection may not be a contraindication if the viral load is negative and CD4+ T cell counts are >250 cells/dl and the patient does not suffer from opportunistic

infections. The history of Pnuemocystis Carinii pneumonia is not a contraindication for transplantation. 2. Live liver donor selection: 18-55, blood group compatible, BMI < 33 1st or 2nd degree relatives, Govt. Auth Committee in case the donor is not a near relative Healthy, no addictions, Detailed systemic work up HBsAg, HCV, HIV negative Triphasic CT scan of abdomen, for Liver Attenuation index (steatosis), volumetry, vascular map MRCP, for mapping biliary tree Ideal GRWR 0.8, remnant 30%

Contraindications Steatosis > 30% Abnormal LFT (transaminases x 2) Inadequate graft or remnant volume Abnormal anatomy Systemic disease 3. Immunosuppression 20

The standard immunosuppression in liver transplant is a triple drug regimen begun within 24 hours of transplantation. In patients with renal failure, IL2 receptor antagonists may be used based on centre’s preference. Low dose CNI could be another alternative. At the moment, there is no strong evidence for tailoring immunosuppression based on etiology of the liver disease except that steroid boluses should be avoided in patients transplanted for hepatitis C.

Cyclosporine may increase SVR in transplanted patients who are given treatment with IFN. Sirolimus may have a role in patients undergoing transplant for HCC. Most centres taper steroids between 3 to 6 months post transplant. However in some patients, renal impairment may be an issue and these patients may be given long term steroids together with either MMF or azathioprine. The standard regimen is as follows: a) CNI, either Tacrolimus or Cyclosporine

Tacrolimus trough levels in first month should be between 5 to 10 ng/ml and later maintained between 5 to 8 ng/ml. Cyclosporine trough level in the first month should be between 200 to 300 ng/ml and later reduced to 100 to 200 ng/ml. Centres may choose to adjust dose based on C2 level as well. b) MMF or azathioprine: MMF is given in the dose 500 mg twice a day or the equivalent Myfortic 360 mg twice a day. In selected patients except those with AIH, PSC, PBC, MMF can be discontinued after 1 year

Azathioprine should be given in dose 1 mg/kg body weight once a day. TLC should be monitored frequently and the drugs stopped if the TLC is less than 3500. c) Steroids: Steroids are given at the time of transplantation during the anhepatic phase in the dose of 500 mg and then gradually tapered in the next few days to 20 mg per day. In the next few months the steroids are gradually tapered off unless the preoperative diagnosis was an autoimmune condition d) Renal sparing protocol:

MMF + steroids + delayed CNI, may consider IL2 receptor blockade, May also be used in those with neurological toxicity e) Treatment of Acute rejection: Steroid boluses usually 500 mg of methyl prednisolone for three days is given preferably after a liver biopsy. Steroid resistant rejection should be confirmed by a review of liver biopsy slides and by ruling out biliary, vascular and infective issues. ATG/Thymoglobulin is the standard drug to

be used for steroid resistant rejection in the dose of? 5-15 mg / kg/day, (ATG) or Thymoglobulin 0.5 to 2 mg/kg/day infused over 4 to 6 hours after premedication for 7 to 14 21

days depending on the response. f) Monitoring adverse effects: Renal function should be monitored closely in patients receiving CNIs. It may lead to either dose reduction or even stopping altogether in case of significant renal impairment. The options at this stage can be MMF monotherapy, Azathioprine with steroids, MMF with steroids or Sirolimus alone or with steroids. Sirolimus: in case of CNI intolerance, not to be used in the first 4 weeks as may impair healing and result in hepatic artery thrombosis.

The use of Sirolimus will require monitoring of proteinuria and lipid profile. When used with Tacrolimus, the combined level should be kept below 15 ng/ml. In general all patients on immunosuppression will require monitoring of their metabolic status such as diabetes, lipid profile and atherosclerosis. Currently there is no recommendation for screening for development of malignancy. However as it is known that there is a higher incidence of malignancy, clinicians should be alert to this possibility.

No guidelines can be given for stopping immunosuppression as the goal of tolerance is yet to be achieved. Post transplant surveillance blood tests: for rejection, nephrotoxicity, atherosclerosis, diabetes, leucopenia In the first few months post transplant, blood tests (CBC, LFT, Renal, CNI level) should be done every 1 to 2 weeks. When on stable dose of immunosuppression every 2 months and within 1 week post change in dose of medication.

Monitor hepatitis C post transplant by blood tests and liver biopsy every 6 months. Hep B recurrence by DNA measurement every 3 months. HCC recurrence by AFP and ultrasound every 3 months for the first two years and then every 6 months for 5 years. Alogorithm for management of graft dysfunction: Ultrasound, doppler, CNI level and relevant microbiology first Liver biopsy if answer is not clear. Biliary obstruction is difficult to diagnose in the transplanted liver, as IHBR dilatation

may not be present. MRCP/ERCP/HIDA should be carried out to define this further. 22

Monitoring disease recurrence post transplant: HCC: No adjuvant treatment is recommended for HCC post transplant to prevent recurrence. It should be monitored with 6 monthly AFP levels and ultrasound of the liver. Hep C: Post transplant liver biopsy should be done every 6 to 12 months post transplant and treated with interferon if there is any evidence of disease recurrence. Hep B: Disease recurrence can be prevented by use of a combination of HBIg and antiviral

medications. However it may be appropriate to use antiviral medicines alone in patients who have been negative for hepatitis B DNA. Alcoholic liver disease: Drinking and smoking should not be permitted post transplant. NASH: Weight gain should be curbed. Diabetes should be managed with exercise and metformin/+insulin. 6. Monitoring donor complications i). Right lobe adult-to-adult liver transplantation is a very complex surgery with requirement

for excellent surgical skills and teamwork. Donor deaths have been reported. ii). At the time of inspection for grant of license for transplant to a particular hospital, the team must satisfy itself that standards for donor safety are met prior to granting license for conducting right lobe adult to adult transplantation. Consideration for licensing should include evaluation of infrastructure for cadaveric donation and transplantation.

iii) All donors must be followed up and complications should be documented. iv) It may be advisable to have a national donor registry to monitor complications Nutrition: a)`Patients with cirrhosis are usually advised bland, low protein non fatty diet. This is a myth and harmful to the patient. Apart from salt and fluid restriction, diet should have sufficient proteins and fat in much the same way as in the diet of healthy people.

b) Post transplant diet should be directed to reduce weight gain and atherosclerosis. Uncooked sea food is not allowed. Fruits should be washed and peeled prior to eating. Timing of medication with food should be such that bioavailability is there. PRETRANSPLANT For ESLD patients, highly individualized, aggressive nutrition support is usually necessary to minimize catabolism and slow the deterioration of nutritional status while awaiting a donor

organ, preferably with the guidance of an experienced dietitian S.NO NUTRIENTS 23

1 Calories 120 – 140% of BEE 2 Protein 1– 1.5g / kg / day, For patients with hepatic encephalopathy - 0.6 – 1 g/kg/day 3 Carbohydrate 50 – 70% of calories 4 Fat 30% of calories 5 Sodium (salt) 1-2g/day or less 6 Vitamins& Minerals According to RDA levels Small, frequent feedings, including high calorie, high-protein supplements, are often necessary to ensure adequate nutrients orally. If oral intake is inadequate then nasoenteric

tube feeding is suggested either nocturnally or over 24hours according to the oral intake. Daily calorie counts are useful in assessing readiness to wean from supplemental nutrition support. POST TRANSPLANT NUTRIENTS SHORT TERM LONG TERM Calories 120 – 130% of BEE Maintenance: 120 – 130% BEE Protein 1.3 – 2g / kg / day Based on activity level Carbohydrate 50 – 70% of calories 50 – 70% of calories Fat 30% of calories <30% of total calories Calcium 1200mg / day 1500mg / day

Vitamins & Minerals According to RDA levels According to RDA levels • Estimated energy requirements in the immediate post operative stage are similar to those preoperatively, and the same guidelines may be used. Avoid over feeding. • Protein catabolism is increased after liver transplantation and positive nitrogen balance may be difficult to achieve in the first week or longer post operatively. Administration of to 2g / kg / day is suggested as an initial estimate in patients without significant azotemia.

• Fluid administration must be individualized. • Ideally, patients would move quickly to an oral diet after transplant. Nasoenteric tube feeding is recommended as soon as the patient is hemodynamically stable. 24

• TPN is considered only when enteral route cannot be used. This is usually possible within the first 18 to 24 hours post operatively. • An oral diet is resumed when the patient’s mental and physical state allows. A liquid to solid diet progression is implemented according to patient tolerance. Small, frequent feedings, including high calorie, high-protein supplements, are often necessary until the patient is reliably able to consume adequate nutrients orally. Daily

calorie counts are useful in assessing readiness to wean from supplemental nutrition support. Advice on discharge Discharge diet instruction may include education involving: o therapeutic or modified diets o food- drug interactions o nutritional care for certain diagnoses/conditions o post liver transplant diet protocol Brain death Identification As per THOA 1994. Multiorgan retrieval: All hospitals, which have a neurosurgery department and a trauma centre, should have provision for organ retrieval.

At the current moment, organ retrieval can only be conducted in hospitals, which are licensed for transplantation. 1. Each hospital doing organ or tissue transplantation should draw up an SOP and deposit with Organ Coordinating agency to facilitate organ retrieval. 2. Each hospital should also ensure ready availability of organ retrieval personnel, items, drugs/storage fluids, containers for organ transport and blood sampling to start at short notice.

3. Each hospital should examine the donor patient /records available and satisfy themselves on the organ acceptance criteria. 4. Each hospital to inform Organ coordinating agency on priority if organ is not being utilized/unfit for utilization. 5. Each hospital will be responsible for retrieving and storage of the organ concerned ensuring optimal utilization. 25

Role of the coordinator: a) Will liaise with the donor and recipient team and will be the communication conduit with Organ Facilitating Agency b) Medico legal clearance if necessary c) Arrangement of post mortem if required d) Responsible for overseeing documentation of the case. e) Responsible winding up after donor team leaves with organs. f) Will be responsible for ensuring that all donors are tested for HIV Ab, HBsAg, HBcAb, HCV Ab, CMV Ab, Toxoplasma Ab, VDRL. Team leader:

a) Check risk of transfer of infection malignancy b) brain death diagnosis in accordance with THOA, c) cause of death d) Consent in accordance with THOA A proposal is underway for a team to move from a licensed hospital to another hospital for retrieval. As yet, no major progress has been made. Till a government proposal does not materialize frequent multi organ retrieval will not become a reality. The order of retrieval of organs will be as follows: a) Heart, heart/lung b) liver c) pancreas d) kidneys

e) corneas ICU management of prospective donor a) Consent b) Maintenance of therapy, as standard medical therapy c) Liaise with Local Transplant Coordinator d) Change of therapy from the aim of preserving brain function to optimizing transplantable organ function, mainly correcting hypovolemia Supporting the donor: a) Goals: 26

MAP 60 to 80 mmHg Preload CVP, 4-10 mmHg, PA occlusion pressure, 10-15 mmHg Heart rate 60 to 100 beats/min Rhythm sinus rhythm Cardiac output CI > 2.1 l/min/m Inotropes: high dose adrenaline may cause detrimental vasoconstriction Dobutamine may cause vasodilatation and lead to undesirable hypotension and tachycardia Vasopressin less likely to cause metabolic acidosis or pulmonary hypertension and may be more appropriate than noradrenaline for the cardiovascular collapse phase Endocrine support

Diabetes insipidus Maintain Na+ = 155 mmol/l with 5% dextrose, Urine output to be maintained 1-2 ml/kg/hr with vasopressin 1 U bolus and 0.5 – 4.0 U/h infusion. If vasopressin fails to control diuresis, intermittent desmopressin (DDAVP) may be required Hyperglycemia Insulin infusion to maintain plasma glucose 4-9 mmol/l, maintain K >4.0 mmol/l Hypothyroidism T3 4 mcg bolus and then infusion at 3 mcg/h, debate over its necessity, however most units use it

High dose methylprednisolone as part of the hormone package Respiratory support: a) Fio2 to be kept below 0.4 b) Peep <5 cmH20 c) Physiotherapy, gentle inflation of lungs every hour and side to side turning every 2 hours Mode of ventilation: i) pressure control ii) SMV not possible 27

iii) very sensitive triggers may allow cardiac cycle induced pressure changes to trigger ventilation leading to erroneous diagnosis of spontaneous breathing Renal support: Donor preconditioning with dopamine may help kidney function post transplant Hematology: Keep Hb over 9 g/dl, deranged coagulation should be treated wih FFP/platelets Antifibirinolytics should be avoided. Temp support: Avoid hypothermia Nursing Keep family members well informed and demonstrate good nursing skills Nurses:

Must have knowledge of donation, transplantation and ethical issues Diagnosis of death by brain stem testing and its certification Continued clinical management of potential donor Communication skills Ability to support families during a stressful time Awareness of religious and cultural issues Role of donor transplant coordinator. Splitting of liver This technique should be encouraged as one liver can save two persons. All liver cannot be split as I may compromise graft function

Ideal liver donors from young patients and those who are not on major inotropic support and with a short ICU stay should be split. Ethical issues in split liver transplantation a) The transplant team has an ethical obligation to maximize the number of patients transplanted b) Patients have the clear and unequivocal right to effuse an offered organ including a liver segment c) The transplant physician must inform potential recipient of current practices of their program regarding split liver transplant. 28

d) All parties involved in the transplant process must understand that there is no claim of ownership of an organ by a potential recipient, transplant centre or transplant surgeon. Each individual involved in the process is a guardian than owner of that organ. e) The team conducting the split should have the right to both split organs. This will provide an impetus for splitting and may justify the added risk of split organ transplant. Allocation and sharing of donor organs

Cadaver transplant is in infancy in this country, though a major advance has been made in Tamil Nadu and in AP. The MELD scoring system has been used in North America for organ allocation. Currently the system in place in the two southern states is as follows: Patients need to be registered in the city where transplant is going to be done and they then come in the waiting list. The centre maintains its list of recipients and decides who should

get the organ. If it does not have a suitable recipient, the organ is offered to another hospital in the state. If there are no suitable recipients in the state, the organ is offered outside. Only when no suitable Indian recipient is available, can the organ be used for a foreign recipient. 29

id4229031 pdfMachine by Broadgun Software - a great PDF writer! - a great PDF creator! - http://www.pdfmachine.com http://www.broadgun.com CHIKUNGUNYA FEVER Facts  Chikungunya (chik(cid:146)-en-GUN-yah), also called chikungunya virus disease or chikungunya fever, is a viral illness that is spread by the bite of infected mosquitoes. The disease resembles dengue fever, and is characterized by severe, sometimes persistent, joint pain (arthiritis), as well as fever and rash. It is rarely life-threatening.

 Chikungunya occurs in Africa, India and Southeast Asia. It is primarily found in urban /peri-urban areas.  There is no specific treatment for chikungunya.  Prevention centers on avoiding mosquito bites in areas where chikungunya virus may be present, and by eliminating mosquito breeding sites. 1. What is chikungunya Chikungunya (also known as chikungunya virus disease or chikungunya fever) is a debilitating, but non-fatal, viral illness that is spread by the bite of infected mosquitoes. It

resembles dengue fever. 2. Which are the states affected by chikungunya? The states affected by chikungunya are Andhra Pradesh, Karnataka, Maharasthra, Tamil Nadu, Madhya Pradesh, Gujarat, Kerala, A&N Island, GNCT of Delhi, Rajasthan, Pondicherry, Goa. The number of suspected chikungunya fever cases reported by these states till 30.10.2006 are given below :- 1

Sr. Total fever cases State No. suspected No. of Districts Chikungunya No. of confirmed Affected fever cases cases 1 Andhra Pradesh 23 77533 248 2 Karnataka 27 760513 294 3 Maharashtra 31 263268 679 4 Tamil Nadu* 35 64155 116 5 Madhya Pradesh 21 60098 70 6 Gujarat 25 72589 170 7 Kerala 8 65434 38 8 A&N Island 2 4469 0 9 GNCT of Delhi 12 356 32 10 Rajasthan 1 102 24 11 Pondicherry 1 542 9 12 Goa 2 260 2 Total 188 1369319 1682 3. When was chikungunya epidemic outbreak occurred in the past?

In India a major epidemic of Chikungunya fever was reported during the last millennium viz.; 1963 (Kolkata), 1965 (Pondicherry and Chennai in Tamil Nadu, Rajahmundry, Vishakapatnam and Kakinada in Andhra Pradesh; Sagar in Madhya Pradesh; and Nagpur in Maharashtra) and 1973, (Barsi in Maharashtra). Thereafter, sporadic cases also continued to be recorded especially in Maharasthra state during 1983 and 2000. 4. What is the infectious agent that causes chikungunya?

Chikungunya is caused by the chikungunya virus, which is classified in the family Togaviridae, genus Alphavirus. 2

5. How is chikungunya spread? Chikungunya is spread by the bite of an Aedes mosquito, primarily Aedes aegypti. Humans are thought to be the major source, or reservoir, of chikungunya virus for mosquitoes. Therefore, the mosquito usually transmits the disease by biting an infected person and then biting someone else. An infected person cannot spread the infection directly to other persons (i.e. it is not a contagious disease). Aedes aegypti mosquitoes bite during the day time. TRANSMISSION CYCLE 3

6. Where is chikungunya found? Chikungunya occurs mainly in Africa, India, and Southeast Asia. There have been a number of outbreaks (epidemics) in the Philippines and on islands throughout the Indian Ocean. Epidemics are sustained by the human-mosquito-human transmission cycle. The Aedes mosquitoes that transmit chikungunya breed in a wide variety of manmade containers which are common around human dwellings. These containers collect water,

and include discarded tyres, flowerpots, old oil drums, animal water troughs, water storage vessels, and plastic food containers. Lack of public health infrastructure and all factors that promote uncontrolled mosquito breeding are conducive to outbreaks of chikungunya, or other mosquito borne diseases. 7. What are the symptoms of chikungunya? Chikungunya usually starts suddenly with fever, chills, headache, nausea, vomiting, joint

pain, and rash. In Swahili, (cid:147)chikungunya(cid:148) means (cid:147)that which contorts or bends up(cid:148). This refers to the contorted (or stooped) posture of patients who are afflicted with the severe joint pain (arthritis) which is the most common feature of the disease. Frequently, the infection causes no symptoms, especially in children. While recovery from chikungunya is the expected outcome, convalescence can be prolonged and persistent joint pain may

require analgesic (pain medication) and long-term anti-inflammatory therapy. Infection appears to confer lasting immunity. 8. How soon after exposure do symptoms appear? The time between the bite of a mosquito carrying chikungunya virus and the start of symptoms ranges from 1 to 12 days. 4

9. How is chikungunya diagnosed? Chikungunya is diagnosed by blood tests (ELISA). Since the clinical appearance of both chikungunya and dengue are similar, laboratory confirmation is important especially in areas where dengue is present. Such facilities are, at present, available at National Institute of Virology (NIV), Pune & National Institute of Communicable Diseases (NICD), Delhi. 10. Who is at risk for chikungunya? Anyone who is bitten by an infected mosquito can get chikungunya.

11. What is the treatment for chikungunya? There is no specific treatment for chikungunya. Supportive therapy that helps ease symptoms, such as administration of non-steroidal anti-inflammatory drugs, and getting plenty of rest, may be beneficial. Infected persons should be isolated from mosquitoes in as much as possible in order to avoid transmission of infection to other people. 12. How common is chikungunya? The first recognized outbreak occurred in East Africa in 1952-1953. Soon thereafter

epidemics were noted in the Philippines (1954,1956 & 1968), Thailand, Cambodia, Vietnam, India, Burma and Sri Lanka. Since 2003, there have been outbreaks in the islands of the Pacific Ocean, including Madagascar, Comoros, Mauritius, and Reunion Island. In January 2006, in an epidemic that is currently ongoing on Reunion Island, over ten thousand cases have been reported. It is suspected that many cases of chikungunya are either misdiagnosed or go unreported. 5

13. How can chikungunya be prevented? There is neither chikungunya virus vaccine nor drugs are available to cure the infection. Prevention, therefore, centers on avoiding mosquito bites. Eliminating mosquito breeding sites is another key prevention measure. To prevent mosquito bites, do the following:  Use mosquito repellents on skin and clothing  When indoors, stay in well-screened areas. Use bed nets if sleeping in areas that are not screened or air-conditioned.

 When working outdoors during day times, wear long-sleeved shirts and long pants to avoid mosquito bite. 14. How can Aedes mosquito breeding be controlled? (a) Source reduction Method (i) By elimination of all potential vector breeding places near the domestic or peri- domestic areas. (ii) Not allowing the storage of water for more than a week. This could be achieved by emptying and drying the water containers once in a week.

(iii) Straining of the stored water by using a clean cloth once a week to remove the mosquito larvae from the water and the water can be reused. The sieved cloth should be dried in the sun to kill immature stages of mosquitoes. (b) Use of larvicides (i) Where the water cannot be removed but used for cattle or other purposes, Temephos can be used once a week at a dose of 1 ppm (parts per million). (ii) Pyrethrum extract (0.1% ready-to-use emulsion) can be sprayed in rooms (not

outside) to kill the adult mosquitoes hiding in the house. (c) Biological control (i) Like introduction of larvivorous fish, namely Gambusia and Guppy in water tanks and other water sources. 6

1 1 egaP Contents Page S.No. Topic No. 1 ACUTE DISSEMINATED ENCEPHALOMYELITIS: TREATMENT GUIDELINES 2 2 AIAN GUIDELINES FOR MANAGEMENT OF COMMON NEUROLOGICAL DISORDERS 7 ASSESSMENT AND MANAGEMENT OF ORTHOSTATIC HYPOTENSION IN 3 PARKINSON’S DISEASE 8 4 BELL’S PALSY: TREATMENT GUIDELINES 10 5 CEREBRAL MALARIA AND BACTERIAL MENINGITIS 13 6 CONSTIPATION IN PARKINSON’S DISEASE 18 7 DEMENTIA IN PARKINSONISM 20 GUIDELINES FOR THE USE OF BOTULINUM TOXIN IN MOVEMENT DISORDERS AND 8 SPASTICITY 24

GUIDELINES ON THE DIAGNOSIS AND THE CURRENT MANAGEMENT OF 9 HEADACHE AND RELATED DISORDERS 28 10 GUIDELINES FOR MANAGEMENT OF ESSENTIAL TREMOR 48 11 INITIATION OF TREATMENT IN EARLY PD (EVIDENCES BASED) 52 12 MOTOR FLUCTUATIONS AND DYSKINESIAS (DIAGNOSIS AND MANAGEMENT) 57 13 PARKINSON’S DISEASE 60 14 PSYCHOSIS IN PARKINSON’S DISEASE 65 15 SLEEP DISORDERS IN PARKINSON’S DISEASE: DIAGNOSIS AND MANAGEMENT 67 16 STROKE MANAGEMENT 70 17 TREATMENT OF MULTIPLE SCLEROSIS 85

18 TREATMENT GUIDELINES FOR GUILLAIN–BARRÉ SYNDROME 90 19 TREATMENT IN LATE PARKINSON’S DISEASE 99

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S60 Acute disseminated encephalomyelitis: Treatment guidelines Alexander M., J. M. K. Murthy1 Department of Neurological Sciences, Christian Medical College, Vellore, 1The Institute of Neurological Sciences, CARE Hospital, Hyderabad, India For correspondence:

Dr. Alexander Mathew, Professor of Neurology, Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India Annals of Indian Academy of Neurology 2011;14:60-4 Introduction of intracranial space occupying lesion, with tumefactive demyelinating lesions.[ 13-17] Acute disseminated encephalomyelitis (ADEM) is a Certain clinical presentations may be specific with certain monophasic, postinfectious or postvaccineal acute inflammatory

infections: cerebellar ataxia for varicella infection, myelitis demyelinating disorder of central nervous system (CNS).[1,2] The for mumps, myeloradiculopathy for Semple antirabies pathophysiology involves transient autoimmune response vaccination, and explosive onset with seizures and mild directed at myelin or other self-antigens, possibly by molecular pyramidal dysfunction for rubella.[18,19] Acute hemorrhagic mimicry or by nonspecific activation of autoreactive T-cell

leukoencephalitis and acute necrotizing hemorrhagic clones.[3] Histologically, ADEM is characterized by perivenous leukoencephalitis of Weston Hurst represent the hyperacute, demyelination and infiltration of vessel wall and perivascular spaces by lymphocytes, plasma cells, and monocytes.[4] fulminant form of postinfectious demyelination.[20] Diagnosis The annual incidence of ADEM is reported to be 0.4–0.8 per 100,000 and the disease more commonly affects children

Cerebrospinal fluid (CSF) is abnormal in about two-thirds and young adults, probably related to the high frequency of of patients and shows a moderate pleocytosis with raised exanthematous and other infections and vaccination in this age proteins.[21] Oligoclonal band in CSF is usually absent in ADEM group.[5-9] There seems to be no gender predominance.[10] Box 1: Acute disseminated encephalomyelitis: Clinical Clinical Features syndromes

In ADEM, neurologic deficits develop 3–6 weeks following Most common—polysymptomatic presentation an antecedent event. The onset can be abrupt or may Site restricted syndromes evolve over a period of several days. Prodromal illness Acute cerebellar ataxia may precede the neurologic symptoms.[10] ADEM can affect Transverse myelitis any part of the neuraxis and thus the clinical presentation Brainstem syndromes is variable and usually polysymptomatic [Box 1]: altered Optic neuritis (bilateral)

mental status, pyramidal dysfunction, cerebellar ataxia, Myeloradiculitis brainstem syndromes, optic neuritis, myelitis, and rarely myeloradiculopathy and extrapyramidal syndromes.[11,12] Seizures are not uncommon, can be focal or generalized. Box 2: Common clinical and laboratory features of Encephalitic illness is more common in children younger than ADEM 3 years. [Box 2][12] Rarely ADEM may present with features Clinical Mostly monophasic Access this article online Antecedent infection/vaccination

Abrupt onset with prodromal symptoms Quick Response Code: Website: More common in children and no gender preference www.annalsofian.org Polysymptomatic Encephalopathy features are more common Laboratory DOI: Mild to moderate lymphocytic pleocytosis 10.4103/0972-2327.83095 Oligoclonal band usually uncommon or transient Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

3 3 egaP Alexander and Murthy: Management updates S61 whereas it is a common finding in the CSF in patients with Table 1].[15,16] In addition, MRI features may be diagnostic of multiple sclerosis (MS).[22] MS or ADEM. Differentiating ADEM from the first attack of MS is of therapeutic importance as early institution of disease Magnetic resonance imaging (MRI) is the imaging modality modifying drugs will modify the course of MS. of choice to demonstrate white matter lesion in ADEM and

MS. A recent study in children suggested the presence of any Site restricted syndromes of ADEM may have to be differentiated 2 of the MRI features: (1) absence of bilateral diffuse pattern; from Clinical Isolated Syndrome (CIS) [Table 2]. CIS is (2) presence of black holes; and (3) presence of 2 or more characterized by the occurrence of a single, clinical (monofocal periventricular lesions help to differentiate MS from ADEM. presentation), demyelinating event with no clinical evidence of

The sensitivity and specificity of these criteria was 81% and MS lesion in space and time. The most common presentation 95%. respectively. In this study the total number of lesions includes optic neuritis, partial myelitis, brainstem syndromes, did not differentiate ADEM from MS but periventricular or multifocal abnormalities.[29] lesions were more frequent in MS.[23] A study done to compare the MRI pattern of lesions, which could help to differentiate

The patient with a CIS would have sustained a first ever clinical ADEM from MS found the following characteristics: solitary demyelinating event, and has 2 clinically silent lesions on T2- lesion, unilateral large lesion, cortical lesions, and subcortical weighted brain MRI, with a size of at least 3 mm, at least one grey matter (basal ganglia and thalamus) involvement.[24] of which is ovoid or periventricular or infratentorial in the first Other studies suggested that bilateral thalamic lesion may be

imaging. The revised MS diagnostic criteria are of great value diagnostic of ADEM.[15,16,25-28] as it enables one to make an earlier diagnosis of MS, based on the development of new lesions on MRI brain, despite the Differential Diagnosis absence of a new clinical event. The MRI brain can predict the conversion to clinical definite MS (CDMS) one cohort study had Monophasic ADEM has to be differentiated from the first shown that 88% of patients with an abnormal scan experienced

attack of MS. In the absence of a biological marker, the a second event, whereas only 19% of patients with a normal distinction between ADEM and MS cannot be made with initial scan converted to MS.[30] Most patients with CIS develop certainty at the time of first presentation.[15] However, certain either CDMS or new brain MRI-confirmed lesions within a very clinical features are more indicative of ADEM [Box 1 and short period of 18 months, and the presence of gadolinium-

enhancing lesions or meeting MS MRI diagnostic criteria Table 1: Differential diagnosis: Acute disseminated further increases this likelihood.[31] The diagnostic criteria of encephalomyelitis vs multiple sclerosis CIS are heavily weighted on imaging features. Features Acute Multiple sclerosis In the Optic Neuritis Treatment Trial, the risk of conversion to disseminated encephalomyelitis MS at 10 years is 22% in patients who have a normal imaging of

the brain, and 56% in patients with an abnormal brain imaging. Antecedent events Infections or No recognizable O’ Riordan et al found that in patients presenting with optic vaccination infection or vaccination neuritis, transverse myelitis, and brain stem syndromes, along Clinical Meningism, stupor Focal signs with an abnormal MRI of brain, had a risk of 83% going on to characteristics focal signs develop MS at 10 years, while those with a normal brain MR Course Nonprogressive, Relapsing and

monophasic Remitting and/or had only a 11% risk.[32] progressive CSF oligoclonal bands (OCBs) in CIS showed a sensitivity MRI features Diffuse, bilateral Periventricular of 91.4% and specificity of 94.1%.[33] Masjuan et al found that symmetrical lesions black holes 32/33 patients with OCBs went on to develop MS in 6 years, Prognosis Recovery is rapid Recovery variable whereas only 3/19 patients without OCBs went on to and often complete develop MS.[31]

Table 2: Site restricted syndromes of acute disseminated encephalomyelitis and clinically isolated syndrome Acute disseminated encephalomyelitis Clinically isolated syndrome Postinfectious/vaccineal No antecedent events Polysymptomatic Mostly monosymptomatic Restricted forms can occur Restricted form Bilateral optic nerve involvement Unilateral optic nerve PNS involvement No PNS involvement Long segment of spinal cord involvement Restricted partial cord CSF: lymphocytic pleocytosis with raised Not often

Protein Usually monophasic Risk for subsequent MS is high Could have relapse/recurrence (multiphasic ADEM) Risk for MS PNS, Peripheral nervous system; ADEM, Acute disseminated encephalomyelitis; Bilateral, CSF, Cerebrospinal fluid.

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S62 Alexander and Murthy: Management updates Treatment Spontaneous improvement has been documented in patients with ADEM.[34] However, the recovery is incomplete in patients with ADEM not receiving any form of immune modulation treatment. No therapy has been established by controlled trials in ADEM. Use of high-dose steroids, plasma exchange,

and intravenous immunoglobulin are based on the analogy of pathogenesis of ADEM with that of MS.[35,36] Treatment of ADEM includes: (1) supportive, and (2) specific— high-dose intravenous methyl prednisolone, intravenous immunoglobulin (IVIg), and plasma paresis, and (3) physical Figure 1: Treatment algorithm—acute disseminated encephalomyelitis and rehabilitation therapy [Figure 1]. the second-line treatment, when corticosteroids fail. The choice Supportive Care

of second-line treatment should be individualized, depending on the severity of the disease, complications, and comorbidities. Supportive care includes airway protection in patients with For example, autonomic dysfunction and hypotension would altered mental status and mechanical ventilation if required. preclude the use of PE.[42] Anecdotal reports suggest that IVIg Patients with cervical myelitis may require mechanical may be more effective in patients with peripheral nervous

ventilation. Other supportive includes: antiseizure medication system involvement and PE in patients with tumefactive in patients with seizures, correction of fluid and electrolyte demyelination. Methyl prednisolone along with IVIg has been disturbances, and prophylactic anticoagulation for prevention successfully used in patients with atypical features and could of deep vein thrombosis in patients with high risk. be tried for fulminant, aggressive, and atypical disease.[48]

Immunomodulation Cyclophosphamide[10] and hypothermia[49] have been used with success in patients with fulminant ADEM. Decompressive Intravenous methyl prednisolone is the first-line drug (10–30 hemi-craniectomy has been reported to be life saving in patients mg/kg/day, up to a maximum of 1 g/day) for 3–5 days are with massive life-threatening cerebral edema refractory to being used (Class IV).[3,4,12,37,38] With this modality of treatment, conventional medical management.[50,51]

full recovery has been reported in 50%–80% of patients. Methylprednisolone-treated patients had significantly better Relapsing/Recurrence/Multiphasic Acute outcome with respect to disability status when compared Disseminated Encephalomyelitis with those treated with dexamethasone.[39] Oral corticosteroid treatment is continued with gradual tapering over 6 weeks Although ADEM is typically a monophasic illness, occasionally to reduce the risk of relapses. However, these regimens are

it can have biphasic or multiphasic course. Different not based on controlled randomized trials. The role of terminologies have been used for an event that occurs within corticosteroids in patients presenting late in the course of the 4 weeks of treatment or within the first 3 months, relapsing disease is questionable. Any type of vaccination should be avoided during the first 6 months following recovery. ADEM. However, some researchers view new event temporally

related to the initial disease process, and thought to be related to early steroid withdrawal and hence terminology steroid If high-dose corticosteroids fail, the next step will be plasma dependent or pseudo-relapsing ADEM. exchange (PE) and there is Class Ib evidence for PE.[40-42] A course of 4–6 PEs have been shown to be associated with moderate to marked and sustained improvement. One could If there is another event 4 weeks after steroid withdrawal

remove a large volume of plasma per exchange if there are or 3 months after the first episode, and if both clinically and no problems of autonomic dysfunction. Predictors associated radiologically, the same site is involved, this entity is called with improvement include male sex, preserved reflexes, and recurrent ADEM.[52] But there needs to be a prerequisite that early initiation of treatment.[39,40] In centers that do not have this this patient was in complete remission or as in a stable plateau

facility for conventional PE, one could modify and improvise phase of incomplete remission. If one or more ADEM relapses to do a small volume manual plasma exchange—by doing a occur, including encephalopathy and multifocal deficits occur, phlebotomy, centrifuging the blood, remove 250–300 mL of involving new areas of the neuraxis on MRI and neurologic plasma and return the cells. One could do this twice a day for examination, this entity is multiphasic ADEM.[53] If only the

7–10 days.[43] imaging criteria are used these entities would fulfill the criteria for MS and hence these patients need to be referred Intravenous immunoglobulin (IVIg) (0.4 gm/kg/day for 5 to a tertiary center with expertise in management of these days) is another option, but there is a constraint of high cost problems. The present evidence suggests that these episodes and the evidence for this modality of treatment in ADEM is are probably related to the ongoing active disease and the

Class IV.[44] The improvement is seen within 2–3 days.[45-47] autoimmune disease is probably due to persistent antigen/ In the absence of randomized controlled trials and with the epitope progression and these episodes occur in relation to available evidence, either plasma exchange or IVIg, could be the initial episode. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

5 5 egaP Alexander and Murthy: Management updates S63 Prognosis linkage. Eur J Neurol 2003;10:537-46. 14. Singh S, Alexander M, Sase N, Korah IP. Solitary Hemispheric Demyelination in Acute Disseminated Encephalomyelitis. Earlier studies reported a mortality rate of 20% with a high Australas Radiol 2003;47:29-36. incidence of neurologic sequelae in those who survived 15. Murthy JM. Acute disseminated encephalomyelitis. Neurol India probably it was related to high incidence of postmeasles 2002;50:238-43.

ADEM. [8] However, recent studies suggest a favorable 16. Murthy JM, Yangala R, Meena AK, Jaganmohan Reddy J. Acute prognosis.[2,24,54] Prolonged altered mental state was associated disseminated encephalomyelitis: Clinical and MRI study from with both mortality and morbidity. Multiple or single extensive South India. J Neurol Sci 1999;132:133-8. lesions on MRI lesions may be associated with disability.[18] 17. Krivickas LS, Hochberg FH, Freeman S. Chronic inflammatory

demyelinating polyradiculoneuropathy with tumefactive central demyelination. Muscle Nerve 2006;33:283-8. The long-term prognosis of this entity depends on the etiology, 18. Murthy SK, Faden HS, Cohen ME, Bakshi R. Acute disseminated with postmeasles patients having a higher mortality rate and encephalomyelitis in children. Pediatrics 2002;110:e21. significant morbidity in survivors. The prognosis of nonmeasles 19. Noorbaksh F, Johnson RT, Emery D, Power C. Acute Disseminated

cases is favorable and most studies report a full recovery Encephalomyelitis: Clinical and Pathogenesis features. Neurol Clin in 50%–75% of patients, in a period of 1–6 months after the 2008;26:759-80. illness.[3,4] The most common sequelae are focal motor deficits, 20. Kuperan S, Ostrow P, Landi MK, Bakshi R. Acute Hemorrhagic could range from mild ataxia to hemiparesis. The principal Leukoencephalitis vs ADEM: FLAIR MRI and neuropathology findings. Neurology 2003:2:721-2.

determinants for the extent of neuronal and axonal damage 21. Francis GS, Deguette P, Antel JP. Inflammatory demyelinating are duration and severity of inflammation in brain and spinal disease of the central nervous system. In: Bradely WG, Daroff cord. A hyperacute onset, severe neurologic deficits as a result RB, Fenichel GM, editors. 2nd ed. Boston: Butterworth Heinemann. of aggressive disease, and unresponsiveness to steroids are Neurol Clin Prac 1995;2:1307-43.

poor prognostic indicators. 22. Rust RS, Dodson W, Prensky A. Classification and outcome of acute disseminated encephalomyelitis. Ann Neurol 1997;42:491. References 23. Callen DJ, Shroff MM, Branson HM, Li DK, Lotze T, Stephens D, et al. Role of MRI in the differentiation of ADEM from MS in children. Neurology 2009;72:961-7 1. Tenembaum S, Chitnis T, Ness J, Hahn JS; International Pediatric 24. Singh S, Prabhakar S, Korah IP, Warade SS, Alexander M. MS Study Group. Acute Disseminated Encephalomyelitis.

Acute Disseminated Encephalomyelitis and Multiple Sclerosis. Neurology 2007;68:S23-36. Magnetic Resonance Imaging Differentiation. Australas Radiol 2. Krupp LB, Banwell B, Tenembaum S. The International Pediatric 2000;44:404-11. MS Study Group. Consensus definitions proposed for pediatric 25. Kesselring J, Miller DH, Robb SA, Kendall BE, Moseley IF, multiple Sclerosis and related childhood disorders. Neurology Kingsley D, et al. Acute disseminated encephalomyelitis. Brain 2007;68:S7-12. 1990;113:291-302.

3. Hynson JL, Kornberg AJ, Coleman LT, Shield L, Harvey AS, Kean 26. Andreula CF, Recchia Luciana NM, Milella D. Magnetic resonance MJ. Clinical and neuroradiologic features of acute disseminated imaging in the diagnosis of acute disseminated encephalomyelitis. encephalomyelitis in children. Neurology 2001;56:1308-12. Int J Neuroradiol 1997;3:21-34. 4. Dale RC, de Sousa C, Chong WK, Cox TC, Harding B, Neville BG. 27. Baum PA, Barkovich AJ, Koch TK, Berg BO. Deep gray matter

Acute disseminated encephalomyelitis, multiphasic disseminated involvement in children with acute disseminated encephalomyelitis. encephalomyelitis and multiple sclerosis in children. Brain AJNR Am J Neuroradiol 1994;15:1275-83. 2000;123:2407-22. 28. Okumura A, Hayakawa M, Watanabe K, Kito M, Negoro T, 5. Ascherio A, Munger K. Epidemiology of Multiple Sclerosis. From Kawamura M. Two cases of acute disseminated encephalomyelitis Risk factors to Prevention. Semin Neurol 2008;28:17-28.

with lesion in the thalamus or basal ganglia. No to Hattatsu 6. Panicker JN. Acute Disseminated Encephalomyelitis: Clinical 1992;24:278-82. Profile and Predictors of Outcome (dissertation). Bangalore: 29. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses National Institute of Mental Health and Neurosciences, NIMHANS and Progression of disability in multiple sclerosis. N Engl J Med (Deemed University); 2004 2000;343:1430-8. 7. Menge T, Hemmer B, Nessler S, Wiendl H, Neuhaus O, Hartung

30. Brex PA, Ciccarelli O, O’Riordan JI, Sailer M, Thompson AJ, Miller HP, et al. Acute disseminated encephalomyelitis: An update. Arch DH. A longitudinal study of abnormalities on MRI and disability Neurol 2005;62:1673-80. from multiple sclerosis. N Engl J Med 2002;346:158-64. 8. Anlar B, Basaran C, Kose G, Guven A, Haspolat S, Yakut A, et 31. CHAMPS Study Group. MRI predictors of early conversion to al. Acute disseminated Encephalomyelitis in Children: Outcome

clinically definite MS in the CHAMPS placebo group. Neurology and Prognosis. Neuropediatrics 2003;34:194-9. 2002;59:998-1005. 9. Tenembaum S, Chamoles N, Fejerman N. Acute disseminated 32. O’Riordan JI, Thompson AJ, Kingsley DP, MacManus DG, encephalomyelitis: A long-term follow-up study of 84 pediatric Kendall BE, Rudge P, et al. The prognostic value of Brain MRI patients. Neurology 2002;59:1224-31. in Clinically Isolated Syndromes of the CNS : 10 year follow up.

10. Schwarz S, Mohr A, Knauth M, Wildemann B, Storch-Hagenlocher Brain 1998;121:495-503 . B. Acute Disseminated Encephalomyelitis: A followup study of 40 33. Masjuan J, Alvarez-Cermeño JC, García-Barragán N, Díaz- adult patients. Neurology 2001;56:1313-8. Sánchez M, Espiño M, Sádaba MC, et al. Clinically Isolated 11. Wingerchuk DM, Weinshenker BG. Multiple Sclerosis: Epidemiol- Syndromes: A new oligoclonal band test accurately predicts ogy, genetics, classification, natural history and clinical outcome

conversion to MS. Neurology 2006;66:576-8. measures. Neuroimaging Clin North Am 2000;10:611-24. 34. Rust RS, Dodson W, Prensky A. Classification and outcome of 12. Singh S, Alexander M, Korah IP. Acute Disseminated acute disseminated encephalomyelitis. Ann Neurol 1997;42:491. Encephalomyelitis: Pictorial Essay. Am J Roentgenol 35. Barkhof F, Filippi M, Miller DH, Scheltens P, Campi A, Polman 1999;173:1101-7. CH, et al. Comparison of MRI Criteria at first presentation to

13. Idrissova ZR, Boldyreva MN, Dekonenko EP, Malishev NA, predict conversion to clinically definite Multiple Sclerosis. Brain Leontyeva IY, Martinenko IN, et al. Acute disseminated 1997;120;2059-69. encephalomyelitis in children: Clinical features and HLA-DR 36. Noseworthy JH, Hartung HP. Multiple Sclerosis and Related

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S64 Alexander and Murthy: Management updates Conditions. Neurological Therapeutics. Principles and Practice. clinical and CSF response to intravenous gamma globulin in 2nd Ed, Vol 1. 2006. p. 1225-50. acute disseminated encephalomyelitis. Eur J Neurol 2001;8:725.

37. Wingerchuk DM. Current Evidence and Therapeutic Strategies in 48. Straussberg R, Schonfeld T, Weitz R, Karmazyn B, Harel L. Multiple Sclerosis. Semin Neurol 2008;28:56-68. Improvement of atypical acute disseminated encephalomyelitis 38. Straub J, Chofflon M, Delavelle J. Early high-dose intravenous with steroids and intravenous immunoglobulins. Pediatr Neurol methylprednisolone in acute disseminated encephalomyelitis: A 2001;24:139-43.

successful recovery. Neurology 1997;49:1145-7. 49. Takata T, Hirakawa M, Sakurai M, Kanazawa I. Fulminant form 39. Sakakibara R, Hattori T, Yasuda K, Yamanishi T. Micturitional of acute disseminated encephalomyelitis: Successful treatment disturbance in acute disseminated encephalomyelitis (ADEM). J with hypothermia. J Neurol Sci 1999;165:94-7. Auton Nerv Syst 1996;60:200-5. 50. Von Stuckrad-Barre S, Klippel E, Foerch C, Lang JM, du Mesnil

40. Weinshenker BG, O’Brien PC, Petterson TM, Noseworthy de Rochemont R, Sitzer M. Hemicraniectomy as a successful JH, Lucchinetti CF, Dodick DW, et al. A randomized trial of treatment of mass effect in acute disseminated encephalomyelitis. plasma exchange in acute central nervous system inflammatory Neurology 2003;61:420-1. demyelinating disease. Ann Neurol 1999;46:878-86. 51. Refai D, Lee MC, Goldenberg FD, Frank JI. Decompressive

41. Keegan M, Pineda AA, McClelland RL, Darby CH, Rodriguez M, hemicraniectomy for acute disseminated encephalomyelitis: Case Weinshenker BG. Plasma exchange for severe attacks of CNS report. Neurosurgery 2005;56:E872. demyelination: Predictors of response. Neurology 2002;58:143-6. 52. Cohen O, Steiner-Birmanns B, Biran I, Abramsky O, Honigman S, 42. Miyazawa R, Hikima A, Takano Y, Arakawa H, Tomomasa T, Steiner I. Recurrence of ADEM at previously affected brain site.

Morikawa A. Plasmapheresis in fulminant acute disseminated Arch Neurol 2001;58:797-801. encephalomyelitis. Brain Dev 2001;23:424-6. 53. Singhi PD, Ray M, Singhi S, Khandelwal NK. Acute disseminated 43. Kumar S. Manual (small) volume Plasmapheresis: An effective encephalomyelitis in North Indian children: Clinical profile and and safe therapeutic procedure in Acute Neurological Illness. Ann follow-up. J Child Neurol 2006;21:851-73.

Indian Acad Neurol 2004;7:439-40. 54. Kesselring J, Miller DH, Robb SA, Kendall BE, Moseley IF, 44. Brekke OH, Sandlie I. Therapeutic antibodies for human diseases Kingsley D, et al. Acute disseminated encephalomyelitis. Brain at the dawn of the twenty-first century. Nat Rev Drug Disc 1990;113:291-302. 2003;2:52-62. 45. Sahlas DJ, Miller SP, Guerin M, Veilleux M, Francis G. Treatment of acute disseminated encephalomyelitis with intravenous How to cite this article: Alexander M, Murthy J. Acute disseminated

immunoglobulin. Neurology 2000;54:1370-2. encephalomyelitis: Treatment guidelines. Ann Indian Acad Neurol 46. Kleiman M, Brunquell P. Acute disseminated encephalomyelitis: 2011;14:60-4. Response to intravenous immunoglobulin? J Child Neurol Received: 26-01-11 1995;10:481-3. Source of Support: Nil. Conflict of Interest: None declared. 47. Pittock SJ, Keir G, Alexander M, Brennan P, Hardiman O. Rapid Author Help: Online submission of the manuscripts

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7 7 egaP Behari, et al.: Parkinson's disease S1 Editorial AIAN guidelines for management of common neurological disorders Why guidelines? This may be the question many people Kameshwar Prasad, Ravishankar and Uday Muthani. The would ask. The fact is many common neurological diseases Editor of AIAN, Dr. Sanjeev Thomas, has been kind enough are commonly treated by primary care physicians, eg. Stroke, to give the finishing touches to the various articles and bring

headache, Neuroinfections, Parkinson’s disease, etc. Often, it up as per the requirement of the journal. I also thank Dr. C it is not possible for them to keep up with the changing Meshram, Honorary Secretary of IAN, for his cooperation and trends, both in the diagnosis and management. It would interest in bringing out this issue. benefit both the patients and treating physicians if they have

updated information with the current practice guidelines. The entire guidelines are being published as a special issue With this thought in mind, it was planned, during my which can be a ready reckoner for the practicing neurologists tenure as President of IAN, to bring out the “Guidelines for and physicians. Finally guidelines remain just that – as management of common neurological disorders.” Fortunately, guidelines – not as a gospel truth! They only guide the physician

IAN already has subsections in various disciplines, wherein to take appropriate decision for that individual patient. a group of dedicated people have taken interest in the topic and are updated with the advances. The guidelines have been H. V. Srinivas contributed by experts in respective fields. The guidelines for Supplement Editor epilepsy are already published by Indian Epilepsy Society as Sagar Hospital, 30th Cross, Tilaknagar, Jayanagar, “Guidelines for Epilepsy Management in India” (Gemind).

Bangalore 560 041. Email: hvsrinivas@vsnl.com Hence, this topic is not covered here. I thank all the contributors for their cooperation, interest and the hard work they have put in bringing out this issue. I thank all the convenors of How to cite this article: Srinivas HV. AIAN guidelines for management of common neurological disorders. Ann Indian Acad Neurol 2011;14:1. subsections - Drs. Madhuri Behari, J M K Murthy, U K Mishra, Access this article online Quick Response Code: Website: www.annalsofian.org

[[DDoowwnnllooaaddeedd ffrreeee ffrroomm hhttttpp::////wwwwww..aannnnaallssooffiiaann..oorrgg oonn MMoonnddaayy,, FFeebbrruuaarryy 0066,, 22001122,, IIPP:: 111155..111133..5566..222277]] |||| CClliicckk hheerree ttoo ddoowwnnllooaadd ffrreeee AAnnddrrooiidd aapppplliiccaattiioonn ffoorr tthhiiss jjoou Behari, et al.: Parkinson's disease S17 disturbs the spouse or companion sharing the bed. Visual which have no psychotomimetic action of their own. Finally,

hallucinations in PD psychosis take form of people, friends levodopa is reduced. If the hallucinations still persist on and relatives from past. Solitary figures are seen repeatedly withdrawing the offending drugs and further reduction but do not speak. Animals running across floor appearing in dopaminergic drugs is not possible without hampering through closed window or door are seen. Inanimate objects the mobility of the patient, then only addition of atypical

grow legs and walk. Miniature people are seen. Ceiling and antipychotic is considered. floors appear to be in motion. Often hallucinations are benign and nonthreatening. They occur in the evening hours and Several atypical antipsychotic agents (i.e. clozapine, commonly are visual, rarely auditory, thus differentiating them olanzapine) have been shown to be efficacious in reducing from other causes such as schizophrenia. Paranoid psychotic symptoms in PD; however, use of clozapine

delusions are common. Anticholinergic drugs produce requires regular monitoring due to the side effects such toxic delirium, confusion, agitation, and are associated with as agranulocytosis, worsening of confusion, tachycardia, tachycardia, unformed hallucination and lack a theme. dizziness, sweating. Regular WBC monitoring every 2 Other behavior manifestations in patients with PD include weeks is required. Olanzepinein in smaller doses may help

delusions, punding, hypersexuality, gambling, obsessive– but also has the side effects such as worsening of confusion, compulsive disorders, euphoria, anxiety, anticholinergics – somnolence, balance impairment, lipid abnormalities, toxic confusional state. weight gain, impaired sugar control in diabetics. Caution in warranted in glaucoma, prostatic hypertrophy, seizure Treatment of Psychosis disorder, hypovolemia and dehydration. This drug leads to motor worsening in higher doses. Ziprasidone and

aripiprazole are proven to be efficacious in open-label trials Papapetropoulos et al. concluded that virtually all anti- and have shown limited efficacy. Quetiapine is a common Parkinsonian drugs are able to induce psychotic symptoms.[2] first-line treatment for PD psychosis because of its tolerability, It is controversial that some of the dopaminergic drugs do ease of use although it has failed to demonstrate its efficacy

have a higher potential to induce psychosis than others. In in double-blind trials. A common side effect in the elderly a study by Aarsland et al., the authors found no correlation is sedation. Cholinesterase inhibitors may prove to be more at all between anti-Parkinsonian drugs (levodopa and dopamine agonist (DA)) and hallucinations.[3] Possible beneficial than antipsychotics. Donepezil has not shown significant reductions in psychotic symptoms, perhaps due

correlations between dopaminergic treatment with different to methodological limitations. However, results from an drugs and the risk for PD patients to develop psychosis were open-label study and a double-blind, placebo-controlled analyzed. In randomized, double-blind trials investigating trial involving PD patients with hallucinations support the different DAs, the incidence of hallucinations was 8.1% for efficacy of rivastigmine. Non-pharmacological interventions

priribedil, 2.8% for bromocriptine, 4% for rotigotine, 5% for such as electroconvulsive therapy in isolated case reports ropinirole, 7–9.3% for pramipexole, 4.8% for cabergoline, have shown the potential to reduce psychotic symptoms and 3.4% for pergolide, and 0–4.4% for levodopa. All DAs are may be considered in cases involving concurrent depression effective D2 agonists and, to a lower extent, D3 agonists. and/or medication-refractory psychosis. Antidepressants (i.e.

These drugs also have D4 receptor affinity which may play ap s ryoclheo. s Lise ivno dthoep par e–s etnhte i ndvreusgt i gwaittiho n t –h eh also wonelsyt lroiwsk a fffiorn i t y c sloommiep draemprienses e adn pda tciietnaltos.p ram) may improve psychosis in to D4 receptors. Dopamine agonists with α2 receptor affinity, such as pergolide, may have higher incidence of psychosis. References Cabergoline behaves as a strong antagonist at α2 receptors,

whereas ropinirole and pramipexole are mostly inactive. 1. Freidman JH. Stewart Factor Atypical antipsychotics in the Thus, the treatment of psychosis is focused on withdrawing treatment of drug induced psychosis in Parkinsons disease. Mov the drugs which have higher incidence of inducing psychosis Disord 2000;15:201-11. 2. Papapetropoulos S, Mash DC. Psychotic symptoms in and less antiparkinsonian effect. Thus, the following order Parkinsons disease: From description to etiology. J Neurol

of withdrawing the offending drugs is suggested, that is 2005;252:753-64. tapering and stopping, if necessary, the drugs with the highest 3. Aarsland D, Bronnick K, Ehrt U, De Deyn PP, Tekin S, Emre M, et risk-to-benefit ratio first. Anticholinergics are stopped first, al. Neuropsychiatric symptoms in patients with Parkinsons disease followed by selegiline, dopamine agonists, amantadine, and and dementia: Frequency, profile and associated care giver stress.

finally catechol-O-methyltransferase (COMT) inhibitors, J Neurol Neurosurg Psychiatry 2007;78:36-42. Assessment and management of orthostatic hypotension in Parkinson’s disease The autonomic nervous system controls vital body functions, functions, through the sympathetic and parasympathetic namely, the heart rate, blood pressure, bladder and genital nervous systems. Dysfunction of the autonomic nervous

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[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S18 Behari, et al.: Parkinson's disease system in Parkinson’s disease (PD) presents as postural or Testing orthostatic hypotension (OH) or impaired urinary, genital, bowel or sweating functions. OH is the hallmark of failure of OH is tested at the bedside by recording a change in BP of

the sympathetic nervous system. The sympathetic nervous the patients while they are standing for 3 minutes after they system maintains the blood supply to the brain by keeping are in the supine position for 3 minutes.[2] If the patient has the blood pressure (BP) against gravitational stress while difficulty to stand, change in BP can be checked on changing standing. Autonomic failure occurs in different Parkinsonian from supine to sitting positions. OH is tested in the laboratory

disorders, namely, PD, multiple system atrophy and diffuse using a tilt table. OH is defined as a fall of SBP by >20 mm Lewy body disease. Hg or DBP by >10 mm Hg or both. An increase in heart rate in the presence of OH suggests a normal parasympathetic Definition of Orthostatic Hypotension nervous system. OH is defined as fall in systolic blood pressure (SBP) of 20 mm Management[3] Hg or more or diastolic blood pressure (DBP) of 10 mm Hg or

more on standing or head-up tilt to at least 60°. Measuring BP It is important to recognize and manage OH as doing this in supine position alone can be misleading, as patients with Parkinson's Disease reduces morbidity and mortality in PD. It OH can misleadingly have supine hypertension. is essential to educate patients, their family, and caregivers to reduce falls occurring because of OH. In patients with mild OH, Clinical Profile non-pharmacological methods like avoiding sudden standing

after prolonged rest in the supine position might be enough. OH occurs in 50.3% of PD patients with the Posture and Gait Elderly PD patients should be advised not to pass urine while instability (PIGD) phenotype. It is also common in older standing. Alcohol and medicines might worsen OH; therefore, it patients taking large doses of dopaminergic medications. is important to check all medicines they are taking. They should

Parkinsonian patients with OH should be asked for avoid foods rich in carbohydrates. It is helpful to increase the head presence of bladder and erectile dysfunction. Patients with end of bed by 20° while sleeping. Taking small meals at frequent OH complain of postural dizziness and light-headedness intervals will avoid postprandial OH. Patients with OH should because of transient fall in cerebral blood flow, but these take 5 g of common salt divided through the day. Exercising

orthostatic symptoms are poor indicators of OH in PD. This the calf muscles by walking or cycling can help to prevent BP makes it mandatory that all PD patients should undergo BP falls. In the presence of severe OH, calf muscle exercises using recording in lying and standing positions even when they a reclining bicycle can be helpful. Elastic stockings are helpful do not complain of orthostatic symptoms.[1] OH in PD is but could be uncomfortable in warm weather.

often asymptomatic as autonomic failure possibly because it develops gradually. Pharmacological methods It is essential to check and adjust dopaminergic medicines Drugs used to treat PD including l-Dopa and other as they can worsen OH. The first choice of drug to use is dopaminergic medications can both cause or worsen BP falls Fludrocortisone. The next choice is sympathomimetic drugs in the supine [Levodopa-induced Supine Hypotension (LISH)] like ephedrine or midodrine. It is important to start them at

and standing positions [Levodopa-induced orthostatic a low dose and increase the dose slowly. hypotension (LOH)]. References Access this article online Quick Response Code: 1. Jamnadas-Khoda J, Koshy S, Mathias CJ, Muthane UB, Ragothaman M, Dodaballapur SK. Are current recommendations to diagnose orthostatic hypotension in Parkinson's disease Website: satisfactory? Mov Disord 2009;24:1747-51. www.annalsofian.org 2. Mathias CJ. Autonomic disorders and their recognition. N Engl J Med 1997;36:721-4.

3. Mathias CJ. Autonomic diseases: Management. J Neurol Neurosurg Psychiatry 2003;74:42-7. Sleep disorders in Parkinson’s disease: Diagnosis and management A large majority (upto 96%) of patients with Parkinson’s The main factors responsible for disturbed sleep in PD disease (PD) suffer from various sleep-related problems.[1,2] have been classified by Barone et al, into the following four Sleep

disturbances, as assessed by validated scales like the subcategories:[5] 1) PD-related motor symptoms, including Parkinson’s disease sleep scale (PDSS)[3] usually correlate with nocturnal akinesia, early-morning dystonia, painful cramps, disease severity and the Hoehn and Yahr staging.[4] tremor and difficulty turning in bed; 2) treatment-related Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S70 Bell’s palsy: Treatment guidelines J. M. K. Murthy, Amrit B. Saxena Department of Neurology, The Institute of Neurological Sciences, CARE Hospital, Hyderabad, India For correspondence: Dr. J K. Murthy, The Institute of Neurological Sciences, CARE Hospital, Hyderabad - 500034, India. E-mail: drjmk@sol.net.in

Annals of Indian Academy of Neurology 2011;14:70-2 The most common cause of acute onset unilateral peripheral (peripheral facial palsy with zoster oticus), sarcoidosis, facial weakness is Bell’s palsy. The incidence of Bell’s palsy is Sjogren’s syndrome, parotid-nerve tumors, leprosy, 20-30 cases for 100,000[1] and accounts for 60-70% of all cases polyarteritis nodosa and amyloidosis, by its rapid onset over

of unilateral peripheral facial palsy.[2] Either sex is affected several hours. Facial palsy secondary to other causes equally and may occur at any age, the median age is 40 years. progresses over days to months. The incidence is lowest under 10 years of age and highest in people over the age of 70. Left and right sides are affected Diagnostic Workup equally.[3] Diagnosis of Bell’s palsy in a patient with unilateral peripheral Clinical Characteristics

facial weakness of unknown cause is purely clinical. However, electrodiagnostic testing done within 14 days of onset may Bell’s palsy is an acute peripheral facial weakness of unknown provide prognostic information. cause and the diagnosis can be established without difficulty in patients with unexplained unilateral isolated facial weakness. The nerve excitability test determines the excitation threshold The onset is sudden and symptoms typically peak within a few

by recording the minimum electrical stimulus required to days. Additional symptoms may include pain in or behind the produce visible muscle contraction. A difference greater than ear, numbness or tingling in the affected side of the face usually 3.5 mA between affected and unaffected sides is considered without any objective deficit on neurological examination, to be significant in terms of poorer outcome. Measuring the hyperacusis and disturbed taste on the ipsilateral anterior

peak-to-peak amplitude of the evoked compound action part of the tongue.[1] Bilateral idiopathic facial palsy occurs less potential of the involved side compared to the normal side has frequently than unilateral involvement. About 7% of patients prognostic importance. If there is a 90% or greater reduction with history of Bell’s palsy may experience recurrence. The mean interval to first recurrence is reported at 9.8 years after in the amplitude of the affected side, the prognosis is poor.[4]

the first episode. Currently the trigeminal blink reflex is the only test to measure Diagnosis intracranial pathway of the facial nerve and also useful test to study various postparalysis sequelae such as synkinesis The first step in the diagnosis is to determine whether facial and hemifacial spasms. With recovery of facial function the weakness is central or peripheral. Peripheral facial palsy ipsilateral R1 latency becomes less prolonged and the amount

involves all the facial muscles ipsilateral to the side of facial of initial prolongation of this response correlates with greater nerve involvement where as central weakness involves lower loss of facial motor function. facial muscles contralateral to the lesion in the brain stem above pons and cerebral hemisphere. Gadolinium contrast magnetic resonance (MRI) study reveals enhancement of internal acoustic meatal segment on the

Bell’s palsy is differentiated from other causes of facial palsy affected side; however, this is a non-specific finding. MRI such as diabetes mellitus, human immunodeficiency virus should not be done routinely and should be the investigation (HIV) infection, Lyme disease, Ramsay Hunt syndrome to look for other possible causes for acute facial paralysis especially if there is little or no recovery of function. Access this article online Treatment Quick Response Code:

Website: The aims of treatment in the acute phase of Bell’s palsy www.annalsofian.org include strategies to speed recovery and to prevent corneal complications. Eye care includes eye patching and lubrication, lubricating drops should be applied frequently during the day DOI: and a eye ointment should be used at night.[5] Strategies to 10.4103/0972-2327.83092 speed recovery include physical therapy, corticosteroids and antiviral agents [Figure 1]. 10

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Murthy and Saxena.: Bells palsy S71 Figure 1: Bell’s Palsy: Treatment algorithm Prednisolone efficacy any of these therapies, is lacking. Cochrane systemic The rationale for the use of corticosteroids in acute phase of review of the efficacy of physical therapies, electrostimulation

Bell’s palsy is that inflammation and edema of the facial nerve and exercises, on outcome of Bell’s palsy concluded that there are implicated in causing Bell’s palsy and corticosteroids have a was no significant benefit or harm from any of these physical potent anti-inflammatory action which should minimise nerve therapies for Bell’s palsy. There was limited evidence that damage and thereby improve the outcome. improvement began earlier in the exercise group.[14] Another

systematic review examined the effects of facial exercises associated either with mirror or electromyogram biofeedback Randomized, double-blind, placebo-controlled trials have with respect to complications of delayed recovery in Bell’s provided compelling evidence that treatment with prednisolone palsy and concluded that because of the small number of improves outcome in patients with Bell’s palsy and shortens the randomized controlled trials, it was not possible to analyze if

time to complete recovery.[6-8] Prednisolone should be used in the exercises, were effective.[15] However, that the possibility all patients with facial palsy of less than 72 h duration who do that facial exercise reduces time to recover and sequelae needs not have contraindications to steroid therapy. The prednisolone dose used was 60 mg per day for 5 days then reduced by 10 confirming with good quality randomised controlled trials.[14] mg per day (for a total treatment time of 10 days)[8] and 50 mg

per day (in two divided doses) for 10 days.[7] The reported Prognosis adverse rates were low. Treatment with prednisolone is likely to be cost-effective.[9] About 71% of patients with Bell’s palsy have motor function recovery completely within 6 months without treatment.[16,17] Antiviral Agents By 6 months all patients with Bell’s palsy should show some improvement.[17] Poor prognostic factors include: old age, The rationale for the use of antiviral agents is the evidence

hypertension, diabetes mellitus, impairment of taste and that the inflammation of the facial nerve in Bell’s palsy might complete facial weakness.[18] About one-third of patients be related to the herpes simplex virus (HSV). In an autopsy may have incomplete recovery and residual effect. Among study latent HSV type-1 has been isolated from the majority the residual effects include post-paralytic hemifacial spasm, of the geniculate ganglia samples.[10] HSV-1 genome was

co-contracting muscles, synkinesis, sweating while eating or detected in 79% of facial nerve endoneurial fluid in patients during physical exertion. The two most common abnormal with Bell’s palsy, but not in the controls.[11] However, the regeneration patterns are: ‘crocodile tears’ - lacrimation of the benefit of acyclovir or valacyclovir, either as single agents ipsilateral eye during chewing and ‘jaw-winking’ - closure of or in combination with prednisolone in Bell’s palsy has not

the ipsilateral eyelid when the jaw opens. been definitively established.[6-8,12,13] Thus with the available evidence acyclovir or valacyclovir should not be routine and References treatment with acyclovir is highly unlikely to be considered cost-effective.[9] 1. Hauser WA, Karnes WE, Annis J, Kurland LT. Incidence and prognosis of Bell’s palsy in the population of Rochester, Minnesota. Physical Therapy Mayo Clin Proc 1971;46:258-64.

In Bell’s palsy various physical therapies, such as exercise, 2. Adour KK, Byl FM, Hilsinger RL Jr, Kahn ZM, Sheldon MI. The biofeedback, laser, electrotherapy, massage and thermotherapy true nature of Bell’s palsy: Analysis of 1,000 consecutive patients. are used to hasten recovery. However, the evidence for the Laryngoscope 1978;88:787-801. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S72 Murthy and Saxena.: Bells palsy 3. Katusic SK, Beard CM, Wiederholt WC, Bergstralh EJ, Kurland 12. De Diego JI, Prim MP, De Sarria MJ, Madero R, Gavilan J. LT. Incidence, clinical features, and prognosis in Bell’s palsy, Idiopathic facial paralysis: A randomized, prospective, and

Rochester, Minnesota 1968-1982. Ann Neurol 1986;20:622-7. controlled study using single-dose prednisone versus acyclovir 4. Brackmann DE, Fetterman BL. Cranial nerve VII: Facial nerve. three times daily. Laryngoscope 1998;108:573-5. In: Goetz GC, editor. Textbook of clinical neurology. Philadelphia: 13. Kawaguchi K, Inamura H, Abe Y, Koshu H, Takashita E, Muraki Saunders Elsevier; 2007. p. 185-98. Y, et al. Reactivation of herpes simplex virus type 1 and varicella-

5. Hughes GB. Practical management of Bell’s palsy. Otolaryngol zoster cirus and therapeutic effects of combination therapy Head Neck Surg 1990;102:658-63. with prednisolone and valacyclovir in patients with Bell’s palsy. 6. Grogan PM, Gronseth GS. Practice parameter: Steroids, acyclovir, Laryngoscope 2007;117:147-56. and surgery for Bell’s palsy (an evidence-based review): Report 14. Teixeira LJ, Soares BG, Vieira VP, Prado GF. Physical therapy

of the Quality Standards Subcommittee of the American Academy for Bell’s palsy (idiopathic facial palsy). Cochrane Database Syst of Neurology. Neurology 2001;56:830-6. Rev 2008;3:CD006283. 7. Sullivan FM, Swan IR, Donnan PT, Morrison JM, Smith BH, 15. Cardoso JR, Teixeira EC, Moreira MD, Fávero FM, Fontes McKinstry B, et al. Early treatment with prednisolone or acyclovir SV, Bulle de Oliveira AS. Effects of exercise on Bell’s palsy:

in Bell’s palsy. N Engl J Med 2007;357:1598-607. Systematic review of randomized controlled trials. Otol Neurotol 8. Engstrom M, Berg T, Stjernquist-Desatnik A, Axelsson S, 2008;29:557-60. Pitkäranta A, Hultcrantz M, et al. Prednisolone and valacyclovir 16. Peitersen E. The natural history of Bell’s palsy. Am J Otol in Bell’s palsy: A randomized, double-blind, placebo-controlled, 1982;4:107-11. multicentre trial. Lancet Neurol 2008;7:993-1000. 17. Peitersen E. Bell’s palsy: The spontaneous course of 2500

9. Hernández RA, Sullivan F, Donnan P, Swan I, Vale L; BELLS peripheral facial nerve palsies of different etiologies. Acta Trial Group. Economic evaluation of early administration of Otolaryngol 2002;549:4-30. prednisolone and/or acyclovir for the treatment of Bell’s palsy. 18. Gilden DH. Bell’s palsy. N Engl J Med 2004;351:1323-31. Fam Pract 2009;26:137-44. 10. Furuta Y, Takasu T, Sato KC, Fukuda S, Inuyama Y, Nagashima

K. Latent herpes simplex virus type 1 in human geninulate ganglia. How to cite this article: Murthy J, Saxena AB. Bell's palsy: Treatment Acta Neuropathol 1992;84:39-44. guidelines. Ann Indian Acad Neurol 2011;14:70-2. 11. Murakami S, Mizobuchi M, Nakashiro Y, Doi T, Hato N, Yanagihara Received: 27-12-10 N. Bell’s palsy and herpes simplex virus: Identification of viral DNA Source of Support: Nil. Conflict of Interest: None declared. in endoneurial fluid and muscle. Ann Intern Med 1996;124:27-30. 12

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S35 Cerebral malaria and bacterial meningitis U. K. Misra, J. Kalita, S. Prabhakar1, A. Chakravarty2, D. Kochar3, P. P. Nair Department of Neurology, SGPGIMS, Lucknow, 1PGIMER, Chandigarh, 2Vivekananda Institute of Medical Sciences, Kolkata, 3Department of Medicine, S.P. Medical College, Bikaner, Rajasthan, India For correspondence:

Dr. UK Misra, Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareily Road, Lucknow- 226 014, India E-mail: drukmisra@rediffmail.com / ukmisra@sgpgi.ac.in Annals of Indian Academy of Neurology 2011;14:35-9 Malaria is one of the most common treatable and preventable (70%) compared to adults (20%), and some patients may have infectious diseases in the world; and 300–500 million malaria status epilepticus. Rarely meningismus, focal neurologic

cases occur annually, leading to 1.5–2.7 million deaths in signs (aphasia, hemiplegia, ataxia, chorea, and tremor), and tropical countries. About one-third of these cases occur in Asia. neuro-ophthalmologic signs (gaze deviation, oculomotor In hyperendemic area, most of the children acquire infection palsy, nystagmus, and ocular bobbing) may be present. Retinal by the age of 5 years. Children younger than 6 months enjoy hemorrhage may occur in 15% of patients. The systemic

immunity from their mothers. In India the disease occurs in manifestations of severe malaria complicate the clinical picture all the agegroups. and include severe anemia, renal failure, jaundice, pulmonary edema, adult respiratory distress syndrome, hypoglycemia, Most clinicians would consider any manifestation of cerebral hemoglobinuria, secondary infection, and septicemia. The dysfunction in a patient with malaria as cerebral malaria. These presence of mult-iorgan dysfunction adversely affect the

manifestations include impairment of consciousness (confusion, prognosis. delirium, obtundation, stupor, or coma), convulsions, focal neurologic deficit, and psychosis. These abnormalities can The cerebral malaria has a mortality of 20%–50%, which is as well be due to hypoglycemia or high fever only. Hence a higher in children. Poor prognostic predictors are the level precise definition has been recommended, which has been of consciousness and presence of other organ dysfunction.

summarized in Box 1. Recurrent seizures, absent corneal reflex, decerebration, retinal hemorrhage, age < 3 years, heavy parasitemia, Clinical Picture (>20%), peripheral leukocytosis presence of pigmented polymorphonuclear leucocytes (>5%), lactic acidosis, elevated CSF lactate and serum transaminase, and low antithrombin III The mean incubation period is 12 days but it may be as short level are associated with poor prognosis. Those who survive as 6–12 h in children and non immune person. The prodrome

usually have complete recovery. Transient neurologic sequelae comprises of malaise, headache, and myalgia; chill usually occur in 10%–18% being higher in children and include precedes the fever. High fever of 104–105°F, shaking chills, ataxia, hemiparesis, memory disturbance, visual field defects, rigors, and sweating are typical of malaria but the patient may cognitive impairment, and behavioral abnormalities, which have irregular pattern or continuous fever as well. Rarely a

patient may have hypothermia due to shock and endotoxemia. Fever in P. falciparum malaria occurs every 3rd day but may not Box 1: Definition of cerebral malaria be obvious because of multiple exposures and several cycles of Practical definition parasitemia. Nausea, vomiting, abdominal pain, tachycardia, arthralgia, weakness, muscle tenderness, hepatosplenomegaly, Any impairment of consciousness or convulsion in a patient of malaria. and chest rales may occur in some patients. Seizures may be

focal or generalized, occurring more commonly in children Research defini(cid:1)on (requires 1 − 3 + 4). 1. Unarousable coma, Glasgow Coma Scale < 10/14 in adults and Blantyre coma scale <_ 2 in children (and not after a generalized convulsion and not reversed by correction of Access this article online hypoglycemia.) Quick Response Code: 2. Asexual forms of P. falciparum in blood smear. Website: www.annalsofian.org 3. Exclusion of other causes of coma by history (eg,

encephalitides, metabolic encephalopathy, septic encephalopathy, intracranial mass lesion, toxicity, and trauma) by cerebrospinal fluid (CSF) and other relevant examinations. DOI: 10.4103/0972-2327.83101 4. Fatal cases only: confirmation of typical brain histopathology sequestrated infected RBCs in postmortem needle biopsy. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S36 Misra, et al.: Cerebral malaria generally reverse in 4–8 weeks. A postmalaria neurological hypoglycemia, disseminated intravascular coagulation, and syndrome characterized by acute onset of confusion, seizure, shock, need special attention. Corticosteroids are not beneficial

ataxia, myoclonus, tremor, and aphasia is described in patients and although phenobarbitone reduces the seizures, it increases successfully treated for cerebral malaria in the absence of mortality specifically in children. Intensive care management parasitemia. This syndrome is attributed to immunologic using artificial ventilation, hemofiltration or hemodialysis may mechanisms as it responds to corticosteroids. significantly improve the outcome. Bacterial Meningitis Diagnosis

Diagnosis of cerebral malaria requires demonstration of asexual form of P. falciparum in peripheral blood smear, in thick and Acute bacterial meningitis (ABM) refers to inflammatory thin blood smear films stained by Giemsa stain. Absence of response to bacterial infection of pia-arachnoid and CSF of the subarachnoid space. In view of the continuity of subarachnoid parasites in some patients may be due to sequestration of space over the brain, spinal cord, nerve roots, and nerves,

parasitized RBCs in cerebral circulation or earlier treatment these structures may also be affected. ABM occurs throughout with antimalarial drugs. In such a situation, atleast 3 smears 6 h the world, although its precise figures are not available in apart should be examined. At least 3 smears should be negative various Asian countries, its mortality and morbidity is likely to before excluding cerebral malaria. The rapid diagnostic test be higher in the developing countries. Worldwide there are 3

(antigen detection test) and PCR may be helpful. main pathogens responsible for ABM: Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis, which CSF examination is necessary to exclude other causes of febrile account for 75%–80% patients with ABM after the neonatal encephalopathy. CSF is generally normal in cerebral malaria, period. During the neonatal period, the major pathogens however, mild pleocytosis (10–50 cells/mm3) and protein

responsible for ABM are group B streptococci, Escherichia coli, rise up to 200 mg/dL may be seen. CT and MRI are usually and other enteric bacilli and Listeria monocytogenes. normal or show edema and cortical or subcortical infarcts in watershed zone in 15%–20% patients. EEG shows nonspecific The most common organisms causing bacterial meningitis are abnormalities, such as diffuse slowing, spike wave discharges, S. pneumoniae, S. meningitidis, and H. influenzae, which spread by

and burst suppression pattern. Cerebral malaria may occur droplet or exchange of saliva. Microbial adherence to mucosa, rarely with negative blood smear; therefore a high index of invasion of mucosal barrier, bacteremia, tissue tropism, and suspension is required. host defence mechanisms determine the invasive nature of the microbial disease. The pathogens colonizing the nasopharynx Treatment when cause bacteremia and breach the blood–brain barrier,

Cerebral malaria is a neurologic emergency requiring urgent it results in bacterial meningitis. Meningitis can also occur intervention. In endemic area, treatment should be started due to parameningeal infection, after traumatic or surgical without waiting for confirmation of the diagnosis. The disruption of blood–brain barrier and rupture of cerebral treatment includes specific antimalarial therapy, supportive therapy for multiorgan dysfunction, and management of

Box 2: Treatment of severe falciparum malaria associated complications. The drug of choice for cerebral (WHO 2010)[1] malaria is parenteral artemisinin derivatives or quinine because 1. Severe malaria is a medical emergency. After rapid clinical of widespread resistance to chloroquine. Artesunate has been assessment and confirmation of the diagnosis, full doses of reported to reduce mortality by 34.7% compared to quinine in a parenteral antimalarial treatment (artesunate or quinine) should

randomized controlled trial in Asian adults. It also reduced the be started without delay. occurrence of convulsion, coma and hypoglycemia. The dose 2. For adults, artesunate 2.4 mg/kg (reconstitute with 5% schedule of antimalarial drugs is presented in Box 2. In patients bicarbonate immediately before infusion) IV or IM given with cardiac disease and in older people, QTc interval should be on admission, then at 12 h and 24 h, then once a day.

monitored and quinine should be discontinued if QTc interval Artemether, or quinine, is an acceptable alternative if exceeds 25% of the basal value. Once the patient can swallow parenteral artesunate is not available: artemether 3.2 mg/kg orally he can be switched to oral therapy In renal and hepatic IM given on admission then 1.6 mg/kg per day; or quinine 20 dysfunction the dose of antimalarial should be reduced after mg salt/kg on admission (IV infusion given in 4 hrs), then 10 mg/kg every 8 h.

48 h. In patients undergoing hemodialysis or hemofiltration, dose adjustment is not necessary. 3. Once the patient can take oral therapy the further treatment should be as below a. Patient receiving parental quinine should be treated with Artemether and artesunate are advantageous because of oral quinine 10mg/kg three times a day to complete a low toxicity, ease of administration, and greater efficacy. course of seven days along with doxycycline 3mg/kg/

Artesunate, which is water soluble has the advantage of i.v. day for 7 days (Doxycycline is contraindicated in pregnant or i.m. administration and does not produce hypotension or women and children under 8 years of age and they should hypoglycemia. In cerebral malaria mafloquine is not preferred receive clindamycin 10mg/kg every 12 h for 7 days ). because of neuropsychiatric complications. In patients with b. Patient receiving artemisinine derivative should get full

hyperparsitemia more than 20%, exchange transfusion is course of oral ACT (artemether plus lumifantrine, or recommended. artesunate plus sulfadoxine-pyrimethamine ) for 3 days. 4. In pregnant women IV quinine is drug of choice for first Complications of malaria, such as adult respiratory distress trimester whereas IV artesunate is drug of choice in 2nd and syndrome, renal failure, convulsions , jaundice, severe anemia, 3rd trimester. 14

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Misra, et al.: Cerebral malaria S37 abscess into the subarachnoid space. The leptomeningeal CT or MRI may be normal or reveal meningeal enhancement, inflammation results in hyperemia of meningeal venules and cerebral edema, communicating or obstructive hydrocephalus,

capillaries and increases permeability of these vessels, resulting infarction or venous sinus thrombosis. in exudation of protein and migration of neutrophils into pia- and subarachnoid spaces. The patients with bacterial meningitis should be differentiated from viral, tubercular, fungal or parasitic meningitis, Clinical features subarachnoid hemorrhage and carcinomatous meningitis. If the meningeal signs are less prominent cerebral or epidural abscess,

The classical clinical picture of adult bacterial meningitis subdural empyema and viral encephalitis should be considered. includes headache, fever, neck stiffness, and often with cerebral dysfunction in 65% patients. Nausea, vomiting, myalgia, and Treatment photophobia are also common. The meningeal sings (neck stiffness, Kernig’s or Brudzinski’s) are present in 50% adult Antibiotic therapy should be started promptly because

patients and less commonly in neonates and older people. delay results in poor outcome of ABM. The selection of Absence of meningeal signs does not rule out the diagnosis antibiotics depends on local resistance pattern, clinical of bacterial meningitis. Cerebral dysfunction manifests with setting in conjunction with allergies, and CSF results. When lumbar puncture is delayed or Gram stain results are confusion, delirium, and declining consciousness ranging

inconclusive, empiric therapy is indicated, which is presented from lethargy to coma. Seizures occur in 40% patients. Focal in Table 1. Ampicillin, penicillin G or third-generation neurologic deficit (hemiparesis, monoparesis, or aphasia) cephalosporin are typical first-line agents. Ampicillin covers may develop due to cortical or subcortical infarction or most pneumococcus, meningococcus, and Listeria and third- ischemia, increased intracranial pressure (ICP), or associated

generation cephalosporins cover gram-negative organisms subdural empyema. Neurologic deficit and seizures are more and ampicillin-resistant H. influenzae. In patients with common in pneumococcal compared with H. influenzae or head injury or after neurosurgical procedures, vancomycin meningococcal meningitis. Papilledema is rare and should should replace ampicillin. Ceftazidime should be reserved suggest an alternative diagnosis, such as brain abscess. In

for pseudomonas meningitis. When the CSF Gram stain or neonates, classical features of meningitis may be replaced culture reports are available, the specific antibiotic should be by listlessness, shrill cry, refusal to feed, irritability or other started. If S. pneumoniae is of unknown antibiotic sensitivity, nonspecific manifestations. In older people, the onset may vancomycin should be added to third-generation cephalosporin be gradual with lethargy and obtundation with or without

to overcome the emerging penicillin-resistant pneumococcus. meningeal signs or fever. A high index of suspicion and low Gram-positive cocci are treated with vancomycin and third- threshold for performing lumbar puncture is recommended. generation cephalosporins, gram-negative cocci with penicillin G, gram-positive bacilli with ampicillin and aminoglycoside, Certain clinical features suggest specific diagnosis, such as and gram-negative bacilli with third-generation cephalosporins

prominent rash in extremities in meningococcemia, and aminoglycoside. The duration of therapy is 7–10 days for Staphylococcus aureus, Acinetobacter spp., and rickettesioses. meningococcal and H. influenzae, 10–14 days for pneumococcal, Pneumonia and otitis media or sinusitis is found in 30% patients 14–21 days for L. monocytogenes and group B streptococci, and 21 with pneumococcal or H. influenzae. S. pneumoniae is the causative days for gram-negative bacilli other than H. influenzae.

organism for bacterial meningitis due to CSF rhinorrhea or otorrhea. Listeria, gram-negative bacilli and group B streptococci Treatment of bacterial meningitis sometimes may extend to may result in encephalitis in extremes of age. include family members, medical personnel, and other Diagnosis Table 1: Treatment of bacterial meningitis Diagnosis of bacterial meningitis is based on CSF examination. Prompt blood culture and CSF examination are indicated in all Age group Etiology Antibiotics

the patients with suspected meningitis. Cranial CT scan before 0–12 Group B streptococci Ceftriaxone 150 mg/ lumbar puncture is indicated when focal findings, altered weeks Escherichia coli kg/d 6 hourly + sensorium, or evidence of raised intracranial pressure are Listeria monocytogenes Ampicillin 50–100 mg/ present. When CT scan is not available, blood culture should Streptococcus pneumoniae kg/d 4–6hourly be drawn and empiric antibiotic therapy should be started. Haemophilus influenzae

3 mo to S. pneumoniae Ceftriaxone 100 mg/ CSF examinations 50 y Neisseria meningitidis kg/d i.v. 12 hourly H. influenzae + vancomycin 1 g 8 Bacterial meningitis reveals raised CSF pressure (20–50 cm hourly, for children of water); protein (100-1000 mg/dl), marked pleocytosis 60 mg/kg/day in 4 (1000–10,000/mm3, >60% neutrophils) and reduced glucose divided doses. (<40% of serum glucose). CSF Gram stain is positive in at >60 years S. pneumoniae Ceftriaxone 2 g 12 h

least 60% of patients and CSF culture in 75%, which may be L. monocytogenes + ampicillin 3 g 4–6 reduced to 5%–40% if antibiotics were administered before Anerobic gram-negative bacilli hourly + vancomycin 1 lumbar puncture. For rapid specific diagnosis, latex particle g 8 hourly agglutination or counter immunoelectrophoresis may be used Postsurgical Staphylococcus aureus Ceftazidime 2 g 8 if available. A careful Gram stain of CSF is usually sufficient or post- Anerobic gram-negative bacilli hourly

and should be encouraged in developing countries where PCR head injury S. pneumoniae Vancomycin 1 g 8 hourly and other tests may not be available. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S38 Misra, et al.: Cerebral malaria contacts who may require chemoprophylaxis and notification malignancies, malaria, and toxoplasma should be excluded in to authorities. appropriate clinical settings. Despite the modern antibacterial therapy, the morbidity Treatment

and mortality of bacterial meningitis is unacceptably high. Four-drug antitubercular treatment with RHZE (rifampicin, Corticosteroid has a beneficial effect in bacterial meningitis isoniazide, pyrazinamide, ethambutol) should be initiated as as it inhibits the synthesis of proinflammatory cytokines at soon as the diagnosis of TBM is suspected. One should start mRNA level, decrease CSF outflow resistance, and stabilize the therapy without waiting for confirmation [Table 2].

blood–brain barrier. If the organism is known, corticosteroid co- administration results in greater survival and lower morbidity, In adults ethambutol and in children streptomycin may be especially in H. influenzae and pneumococcal meningitis in preferred. Ethambutol is preferred to streptomycin because both children and adults. In a recent meta-analysis, adjunctive of ototoxicity in adults. Four drugs are recommended for

dexamethasone in the treatment of ABM, however, did not seem initial 2 months; and INH and rifampicin for a total of 9–12 to significantly reduce death or neurological disability. There months. In patients who come late or have had incomplete were no significant treatment effects in any of the prespecified treatment may be treated for 12–18 months. Some patients subgroups. The benefit of adjunctive dexamethasone for all or with tuberculoma may need longer treatment. DOTS (Directly

any subgroup of patients with bacterial meningitis thus remains observed therpay short course ahs not been sufficiently evaluate unproven. Seizure and status epilepticus should be promptly in TB meningitis . treated with phenytoin, lorazepam, or diazepam. Corticosteroids are recommended on the basis of randomized Tuberculous Meningitis controlled trial (RCT) and meta-analysis. Corticosteroids are recommended in patients without HIV infection. A large RCT-

recommended dexamethasone treatment for 4 weeks (0.4 mg/ Tuberculous meningitis (TBM) is the most severe form of kg/day for 1 week, 0.3 mg/kg/day in week 2, 0.2 mg/kg/day in tuberculosis and is an important cause of death and disability week 3, and 0.1 mg/kg/day in week 4) followed by oral taper in adults and children, especially in HIV-infected patients. The (4, 3, 2, and 1 mg/day for 1 week each). Thus patients received diagnosis of TBM is based on clinical, CSF, and radiological

2 months of corticosteroids. Lower doses of prednisolone 40 (CT/MRI) findings, evidence of extra-CNS TB, and additional mg/day, tapered after 1 month may also be considered. But laboratory findings. before administering corticosteroids one must be sure of the diagnosis (exclude cryptococcal, syphilis, toxoplasma, and The clinical findings of TBM are nonspecific in the early partially treated septic meningitis) and exclude the patients stage and include fever, headache, irritability, neck stiffness,

with HIV, diabetes, bedsore, septicemia, and so on. vomiting, and focal neurologic signs. Altered sensorium, cranial nerve palsies, and limb paralysis are more commonly Baseline investigations found in advanced disease. The symptom onset to the time All the patients after the diagnosis of TBM should be tested of presentation ranges from 7 to 30 days. History of close for HIV and if positive, CD4 count should be done. High-risk contact with TB or extrapulmonary TB should be considered

individuals for hepatitis should undergo serology for hepatitis suggestive of TBM. B and C. Baseline serum bilirubin, liver enzymes, platelet, and creatinine should be done. Patients on ethambutol should The diagnosis of TBM depends on CSF examination but CT undergo vision testing and red–green color discrimination scan should be done before lumbar puncture if a patient has test. On subsequent follow-up, routine liver and renal function papilledema, focal signs, altered sensorium, or history of seizure

tests are not needed unless there are baseline abnormalities or to exclude a pressure cone and avoid possible herniation. CSF symptoms related to liver dysfunctions. On monthly follow- in TBM is typically clear, has lymphocytic pleocytosis (10–1000 up, the patient should be enquired about visual disturbances cells/mm3 with lymphocytic predominance), elevated protein (blurring or scotoma) and red–green discrimination if patient

(0.5–3 g/L), and low glucose (CSF to plasma glucose ratio < 50%). is on ethambutol therapy for more than 2 months. CT or MRI findings are commonly seen in stage 2 and 3 of TBM. Table 2: Chemotherapeutic options of tuberculous Basal meningeal enhancement, hydrocephalus, granuloma, meningitis in adults and infarction are common findings and are found in various combinations. Drugs Dose (mg) Frequency Low probability of drug resistance

Evidence of extra-CNS TB is obtained by a radiograph of Isoniazide 300 Daily the chest, or a cervical or abdominal lymphadenopathy (on Rifampicin 600 Daily abdominal ultrasonography). Diagnostic sampling of lung, Pyrazinamide 15–30/kg Daily lymph node, liver, bone marrow, ascitic fluid, and gastric High probability of drug resistance aspirate add confidence to the diagnosis of TBM. HIV serology INH 300 Daily should be undertaken in all patients with TBM. Rifampicin 600 Daily Pyrazinamide 15–30/kg Daily

Other diagnoses, such as cryptococcal meningitis (CSF India Streptomycin 1000 Daily Ink and cryptococcal antigen), treponema pallidum (treponema Ethionamide 15/kg Daily pallidum hemagglutination assays), cytologic tests for 16

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Misra, et al.: Cerebral malaria S39 Surgery At times intracranial tuberculoma may require biopsy and Surgery has limited but definite role in the management of CNS surgery when response to ATT is not adequate or diagnosis tuberculosis for secondary complications and when diagnosis is in doubt. is not clear. Reference Hydrocephalus

Mild to moderate hydrocephalus responds well to medical 1. World Health Organization. Guidelines for the treatment of malaria. treatment but surgery is indicated when there is raised Second edition. 2010. intracranial pressure, leading to alteration in sensorium. In a patient with hydrocephalus, ventriculoperitoneal shunt is the treatment of choice. Results of shunt surgery in deeply How to cite this article: Misra UK, Kalita J, Prabhakar S, Chakravarty A,

comatose patients who are decerebrating are poor. In such Kochar D, Nair PP. Cerebral malaria and bacterial meningitis. Ann Indian patients, a preliminary trial of external ventricular drainage Acad Neurol 2011;14:35-9. may help to distinguish the patients who are likely to benefit Received: 07-10-10 from surgery. Source of Support: Nil. Conflict of Interest: None declared. New features on the journal’s website Optimized content for mobile and hand-held devices

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Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Behari, et al.: Parkinson's disease S15 iii. Add COMT inhibitor Neurology 1993;43:S34-5. iv. Add rasagiline 3. Fahn S. How do you treat motor complications in Parkinson’s v. Change to liquid preparation of LD:[15] disease: Medicine, surgery, or both? Ann Neurol 2008;64:S56-64. 4. Waters C.H. Treatment of advanced stage patients with

Daily liquid preparation of LD needs to be prepared by Parkinson’s disease. Parkinson Relat Disord 2002;9:15-21 crushing ten tablets of standard (immediate release) 5. The Parkinson Study Group. Entacapone improves motor 100/25 levodopa/carbidopa, 2 g of ascorbic acid and fluctuations in levodopa-treated Parkinson’s disease patients. dissolving in 1 L of water. This solution need to be Ann Neurol 1997;42:747-55.

administered every 60-90 min intervals, the dose being 6. Rinne UK, Larsen JP, Siden A, Worm-Petersen J; Nomecomt adjusted according to the response and side effects. Study Group. Entacapone enhances the response to levodopa vi. Redistribute dietary protein in parkinsonian patients with motor fluctuations. Neurology vii.Subcutaneous apomorphine 1998;51:1309 -14. 7. Ahlskog JE, Muenter MD, McManis PG, Bell GN, Bailey PA. f. Freezing (motor blocks) Controlled-release Sinemet (CR-4): A double-blind crossover

i. Only in “OFF” state study in patients with fluctuating Parkinson’s disease. Mayo Clin Proc 1988;63:876-86. 1. Management strategies as like in patients with 8. Koller WC, Pahwa R. Treating motor fluctuations with controlled wearing-off release levodopa preparations. Neurology 1994;44:S23-8. 2. Manage anxiety, if present, by appropriate drugs 9. Rascol O, Brooks DJ, Melamed E, Oertel W, Poewe W, Stocchi

or behavioural therapy and nonpharmacologic F, et al. Rasagiline as an adjunct to levodopa in patients with techniques that involve the use of sensory or mental Parkinson’s disease and motor fluctuations (LARGO, Lasting imagery, cues, or devices.[11,16] effect in Adjunct therapy with Rasagiline Given Once daily, ii. Both in “OFF” and “ON” stages study): a randomised, double-blind, parallel-group trial. Lancet 1. Increase LD to make optimal “ON” 2005;365:947-54.

2. Sensory cues 10. Fahn S, Isgreen WP. Long-term evaluation of amantadine and levodopa combination in Parkinsonism by double-blind crossover 3. Assistive devices analyses. Neurology 1975;25:695-700. 4. Manage anxiety, if present, by appropriate drugs or 11. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) behavioural therapy for the management of Parkinson’s disease (2001): Treatment iii Only “ON” freezing guidelines. Neurology 2001;56:S1-88.

12. Metman LV, Del Dotto P, LePoole K, Oertel W, Poewe W, Stocchi It is very difficult to manage and patients sometimes benefit F, et al. Amantadine for levodopa-induced dyskinesias: A 1-year by reducing the dose of LD. follow-up study. Arch Neurol 1999;56:1383-6. 13. Antonini A. New strategies in motor parkinsonism. Parkinson Relat In summary, medical management of motor fluctuations in PD Disord 2007;13:S446-9.

is challenging. Surgical treatment of PD may be a better option 14. Durif F, Debilly B, Galitzky M, Morand D, Viallet F, Borg M, et al. Clozapine improves dyskinesias in Parkinson disease: A double- for carefully selected patients. blind, placebo controlled study. Neurology 2004;62:381-8. 15. Kurth MC, Tetrud JW, Irwin I, Lyness WH, Langston JW. Oral References levodopa/carbidopa solutions versus tablets in Parkinson’s disease with severe fluctuations: A pilot study. Neurology

1. Chase TN, Mouradian MM, Engber TM. Motor response 1993;43:1036-9. complications and the function of striatal efferent systems. 16. Dietz MA, Goetz CG, Stebbins GT. Evaluation of a modified Neurology 1993;43:S23-6. inverted walking stick as a treatment for parkinsonian freezing 2. Stern MB. Sinemet CR. Rationale and clinical experience. episodes. Mov Disord 1990;5:243-7. Constipation in Parkinson’s disease Introduction occurring in about 50–60% of patients and may occur even

before the motor symptoms appear.[1] Various mechanisms Constipation is a common problem in Parkinson’s disease (PD), causing it are degeneration of neurons in myenteric plexus of colon with presence of Lewy bodies, weakness and Access this article online incoordinated contraction of muscles of pelvic floor and abdominal muscles which is unable to straighten, anorectal Quick Response Code: angle preventing passage of stool, dystonic contractions of muscles, megacolon and volvulus.[2,3] Website:

www.annalsofian.org Principles of management are the following. In early stages, simple measures may be tried, but later on, combinations may be needed. • Dietary modifications include increased intake of fluids Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S16 Behari, et al.: Parkinson's disease (6–8 glasses of water/day), high fiber diet, and plenty of raw mechanical nerve root distribution pain/paresthesia coldness/ vegetables/salads, and bran can be added to increase the bulk. numbness, arthritis and pain due to bursitis. • Exercise should be increased.

• Medicines that can be helpful include milk of magnesia, The management of these symptoms[8] is by introduction of Cisapride, Mosapride (5HT4 agonist/partial 5HT3 dopaminergic therapy with dopamine agonist or levodopa, antagonist), enemas, suppositories, stool softeners such passive and active exercise and DBS (in advanced stages). as lactulose. References Pain/Dysesthesia in PD 1. Abbott RD, Ross GW, White LR, Sanderson WT, Burchfiel CM,

Pain is a common problem in PD and occurs in about 50% of Kashon M, et al. Environmental, life-style, and physical precursors patients. It occurs both in early phase and in advanced stage of clinical Parkinson’s disease: Recent findings from the Honolulu- of disease – more often in off period, but also in on period.[4,5] Asia Aging Study. J Neurol 2003;250:III30-9. 2. Edwards LL, Quigley EM, Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease: Frequency and pathophysiology.

The exact mechanism of pain and dysesthesia is not known, Neurology 1992;42:726-32. but several mechanisms are proposed. These are:[6,7] abnormal 3. Singaram C, Ashraf W, Gaumnitz EA, Torbey C, Sengupta A, firing in afferent nerves in dystonic muscles, impaired ability Pfeiffer R, et al. Dopaminergic defect of enteric nervous system of basal ganglia to modulate sensory information, alteration in Parkinson’s disease patients with chronic constipation. Lancet

in serotonergic pathways, decreased activity of dopaminergic 1995;346:861-4. fibers on dorsal horn and intermediolateral column of spinal 4. Waseem S, Gwinn-Hardy K. Pain in Parkinson’s disease. Common cord and reduced pain threshold due to dopamine deficiency yet seldom recognized symptom is treatable. Postgrad Med by action on frontal, insular and cingulated gyrus (limbic 2001;110:33-4,39-40,46.

system) and reduced nociceptive flexion reflex threshold by 5. Ford B, Louis ED, Greene P, Fahn S. Oral and genital pain syndromes in Parkinson’s disease. Mov Disord 1996;11:421–6 the same mechanism. 6. Sandyk R. Pineal melatonin and sensory symptoms in Parkinson disease. Ital J Neurol Sci 1989;10:399-403. The presentation of pain/dysesthesia includes: painful “frozen 7. Chudler EH, Dong WK. The role of the basal ganglia in nociception shoulder” usually on the side of first symptom, especially

and pain. Pain 1995;60:3-38. before treatment is started (usually early in the disease), off- 8. Drake DF, Harkins S, Qutubuddin A. Pain in Parkinson’s disease: period limb pain, off-period painful foot dystonia, pain and Pathology to treatment, medication to deep brain stimulation. dysesthesia on chest or abdomen. Some patients may have NeuroRehabilitation 2005;20:335-41. Psychosis in Parkinson’s disease

Psychosis in Parkinson’s disease (PD) appears in the later intrinsic, disease-related components. The most important stages of the disease. It affects 5–8% of the treated patients,[1] extrinsic factor is use of dopaminergic medication, which more often as the disease advances. The clinical features plays a prominent role in PD psychosis. Intrinsic factors include prominent visual hallucinations with clear sensorium seen in PD patients with hallucination consist of duration

and retained insight. The risk factors for the development of illness, old age, visual processing deficits such as lower of psychosis in PD are anti-PD medications (particularly, visual acuity, difficulty in recognizing color and contrast, dopamine receptor agonists), duration of disease, older age, ocular pathology and functional brain abnormalities. Sleep disease severity, sleep disturbance, cognitive impairment, disturbances are reported early and include fragmentation of

dementia and/or depression.M sleep and vivid dreams. The intrinsic factors include altered neurochemicals (dopamine, serotonin, acetylcholine, etc.) and structural abnormalities involving Lewy body deposition The pathophysiology of PD psychosis is now known to in specific regions of brain. Genetic predisposition such as involve an interaction between extrinsic, drug-related and presence of apolipoprotein E epsilon 4 allele and tau H1H1 genotype may also play a role. Deep brain stimulation surgery

Access this article online resulted in reduction of anti-PD medication, but this failed to improve psychosis, thus leading to some insights to the Quick Response Code: intrinsic factors where reduction in anti-PD medications to the lowest tolerated dose did not improve psychosis. Initial Website: manifestation of chronic dopaminergic medication may www.annalsofian.org be sleep disturbances in the form of dreams, night terrors. Dreams are vivid, real, featuring people and events from

past and nightmares, where the patient screams and thrashes. The patient is commonly unaware of these symptoms but Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Behari, et al.: Parkinson's disease S21 Dementia in Parkinsonism Movement disorders originate from malfunctioning of the basal halo, and are difficult to see under routine staining conditions. ganglia, whereas dementia is the result of cortical aberrations. Moreover, brains of PDD and DLB patients have pathological

Therefore, conceptually, these two disorders are due to findings of AD, which is more common than in healthy controls. involvement of different anatomical areas of brain. But with the Biochemically, dopamine deficiency due to nigral degeneration passage of time, newer concepts have come up, which eventually has been implicated for the pathogenesis of dementia. explain the co-occurrence of these two seemingly divergent However, loss of noradrenergic input from locus ceruleus and

clinical problems. On one hand, with the demonstration of cholinergic input from nucleus of basalis of Meynert are also basal ganglia circuit it is now evident that this area has got important for the development of dementia. It is interesting to rich connections with cerebral cortex, particularly prefrontal note that there is more cholinergic deficiency in PDD than AD. cortex, through thalamus. On the other hand, newly discovered

circuits for cognition have stressed on the role of basal ganglia, Frequency of dementia in PD varies from 0% to 81% in particularly the caudate nucleus and thalamus, in different different studies depending on the associated comorbidity, aspects of cognition. The central point in the understanding methodology used, and the criteria used to define dementia. of dementia in movement disorders is the prefrontal network Brown and Marsden in a seminal paper in Lancet estimated

for attention and the prefrontal cortex, caudate nucleus, and that it is in the order of 15%–20%, the inordinately high dorsomedial thalamus that form the different components of values being attributed to serious methodological flaws. [1-3] this network. This network subserves behavioral aspects that The cognitive disturbances range from specific deficits, require an integration of thought with emotion and motivation, demonstrated by formal neuropsychological tests, to overt

personality, and attention. In terms of the concept of network dementia and there is a continuous spectrum between these theory dysfunctions restricted to subcortical components can two extremes.[4] There is some evidence of a preclinical phase of present with frontal lobe-like features even when the frontal lobe dementia, and tests of verbal fluency may be a good predictor has not been pathologically involved. Apart from this anatomical of later development of dementia.[5] The risk factors for the

explanation, there are other possible explanations of dementia in development of dementia in PD are advanced age, treatment- movement disorders. Moreover, biochemically it has been seen induced visual hallucination, more severe motor symptoms that not only are these related to dopaminergic system, but other (Unified Parkinson’s Disease Rating Scale > 25), development of neurotransmitters, such as acetylcholine and serotonin are also at mania, agitation, disorientation, or psychosis when treated with

fault, which explain the cognitive and psychiatric disturbances levodopa, exposure to psychological stress, low socioeconomic in movement disorders. status, low education level, and clinical presentation as postural instability gait difficulty variety. Facial masking at presentation The different parkinsonian syndromes where dementia is a has also been observed as a risk factor by some workers.[6] It prominent feature include the following: has been found that the relative risk of developing dementia

with PD is 1.7 as compared with patients without PD. Severity Parkinson’s Disease of dementia has been related to bradykinesia, postural and gait disturbances, atypical neurological features of PD, such When James Parkinson first described the “shaking palsy” as early autonomic failure, symmetrical onset, and poor in 1817, it was considered as a purely motor system disease. response to levodopa. Some investigators have been able to

In recent times Parkinson’s disease with dementia (PDD) correlate the severity of disability and the extent of the disease along with dementia with Lewy body (DLB), collectively on one hand and the degree of intellectual impairment on the called Cortical Lewy Body Disease comprises 10%–15% of other.[7-9] Duration of illness has often been implicated in the all degenerative dementia and is only second to Alzheimer’s development of dementia,[10] although others believe that this

disease (AD) in terms of prevalence. is an inconsistent association.[11] Lieberman et al[7] showed that those who were demented, were at least 5 years older than Lewy body, an intracytoplasmic inclusion containing α- the nondemented ones, developed the disease later in life synuclein, is the pathological hallmark of PD and is found in and the illness was of brief duration. Importantly, they were

nigral cells. However, it is found in neocortical and paralymbic poorly responsive to levodopa as well. What emerged from regions in PDD and DLB as well. In contrast to their brainstem this study was that possibly there are two subsets of patients, counterpart, the neocortical Lewy bodies are smaller, lack where one group suffers predominantly from motor disabilities and are young in age where the progression of the disease is rather slow and the therapeutic response to levodopa is good;

Access this article online the other subset is often termed the motor–cognitive group whose predominant feature is cognitive impairment. Errea Quick Response Code: et al showed that cognitive decline correlated well with low educational level.[12] Website: www.annalsofian.org The clinical profile of PDD is one of frontostriatal in nature.[13,14] Dysphasia, dysphoria, apraxia, and agnosia, which characterize AD, are classically lacking in PDD, while executive dysfunction,

visuospatial deficit, large fluctuation in attention, and frequent Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S22 Behari, et al.: Parkinson's disease visual hallucination are the significant features. Executive MRI voxel-based morphometry reveals that DLB has little dysfunction is characterized by mental inflexibility and cortical involvement but does show a discrete cluster of gray

impaired set sifting, whereas visuospatial deficits are in the matter loss in basal forebrain and dorsal midbrain. Occipital domain of block designing, picture arrangement, and line hypoperfusion in SPECT study is found in both PDD and DLB. orientation.[15] Visuoperceptual matching, a feature disturbed in PDD, is retained in AD and selective impairment in the dating Progressive Supranuclear Palsy of historical photographs is impaired in PD in contradistinction

to the inability even to recognize the scenes as well, a feature It is grouped under the rubric of parkinsonism plus syndrome. found in AD.[16,17] Memory sphere is less involved as compared The cardinal manifestations are symmetric bradykinesia with AD and when involved it is more of a retrieval deficit in and rigidity (axial > appendicular) without tremor with declarative memory and procedural memory. Patients perform predominant vertical supranuclear gaze palsy. Cognitive

better in recognition tasks. Mild language dysfunction may be decline, although less stressed upon, is present in 22% cases at there and it is characterized by “tip of the tongue” phenomenon, presentation and around 80% in life time. It is predominantly decreased naming and fluency, impaired comprehension of of the frontal subcortical in variety with involvement of syntactically difficult questions and decreased melody of executive function and attention.[21] Executive dysfunction speech.

is characterized by impaired set sifting, motor inhibition, verbal fluency, and abstract thinking. Atypical cases are Dementia with Lewy Body not uncommon who present predominantly with cognitive decline simulating progressive aphasia or frontotemporal Cortical Lewy bodies are found in different types of degeneration (FTD). Pathologically it is characterized by degenerative dementia, which are collectively called as LBD. neurofibrillary tangles, which are composed of aggregates

Clinicopathologically, it encompasses PDD, DLB, and Lewy of tau-protein. body variant of Alzheimer’s disease (LBV). The last of the three is characterized by cortical Lewy bodies and Alzheimer’s type Management of Dementia in Parkinsonism neuropathological changes in the brain and constitutes about The management of dementia and related problems in 70% of LBD. In different literatures the terms LBD and DLB Parkinsonism is difficult. One of the chief reasons is that

have been used interchangeably and the term diffuse LBD has any attempt to ensure mobility with levodopa and related been used to denote classical DLB. Because 25%–30% of PD drugs is fraught with the danger of exacerbating mental and patients develop dementia (PDD) and most DLB patients have behavioral problems and the physician is almost always parkinsonism, it has been hypothesized that PD, PDD, and DLB caught in the cleft stick in order to determine which classes

are not distinct entities, but may exist along the spectrum of of drugs need to be augmented and which should be LBD. A DLB/PDD Working Group recently proposed the use of restricted so that the subject can lead an optimally healthy life. LBD as an umbrella for studying the biology of these disorders, However, conventional antipsychotics do not work well for although they also suggested that the three individual terms the management of the behavioral problems in Parkinsonism

should be maintained for clinical needs. Consensus criteria and they significantly worsen the motor problems as well.[22] artificially divide patients with PDD and DLB by the “one year Of all the atypical antipsychotics clozapine has been shown rule” where dementia appears within 1 year of appearance of to superior to others in various placebo-controlled studies. It parkinsonian features in the latter condition. reduces the positive symptoms of psychosis and there is no

worsening of the motor symptoms or global cognition and a DLB is the second most common cause of degenerative recent structured review and meta-analysis concluded that dementia in the elderly with prevalence up to 30.5% among dementia patients. Pathologically three types of DLB are Table 1: Revised criteria for the clinical diagnosis of recognized—brain stem predominant, limbic (transitional), dementia with Lewy bodies (DLB) and neocortical.[18] The areas that are particularly vulnerable

Central feature (essential for a diagnosis of possible or to cortical Lewy bodies are hypothalamus, basal forebrain, probable DLB) amygdala, and temporal neocortex. Additionally, Aβ42 • Dementia defined as progressive cognitive decline of sufficient amyloid plaques are abundant with paucity of tau-positive magnitude to interfere with normal social or occupational neuritis as opposed to what is found in AD. Both dopamine function. Prominent or persistent memory impairment may not

and acetylcholine deficiency are implicated in the genesis of necessarily occur in the early stages but usually is evident with dementia in this condition. progression. Deficits on tests of attention, executive function, and visuospatial ability may be especially prominent. DLB consensus criteria has been put forward by McKeith et • Core features (two core features are sufficient for probable and one for possible DLB) al.[19] see Table 1.. Fluctuating cognition, Recurrent vivid visual hallucination,

Spontaneous features of Parkinsonism Impaired visual construction and attention with preserved • Suggestive features (one core feature +‡ one suggestive memory and naming skills distinguish DLB from AD.[20] Few feature = probable DLB; ‡ one suggestive feature= possible features are helpful in the diagnosis of probable DLB. Visual DLB) hallucination is most specific (90%) for DLB, but its sensitivity REM sleep behaviour disorder is low (22%). Intersecting pentagon test is helpful in mild to

Severe neuroleptic sensitivity moderate dementia (MMSE > 13) to differentiate DLB from AD. Low dopamine transporter uptake in the basal ganglia Intrusions are more common in DLB. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Behari, et al.: Parkinson's disease S23 only clozapine can be recommended for the management of features associated with dementia in Parkinson’s disease. drug-induced psychosis in Parkinsonism.[23-25] Olanzepine, Neurology 1993;43:1690-2.

on the other hand, led to significant worsening of the motor 7. Lieberman A, Dziatolowski M, Coopersmith M, Cerb M, Goodgold A, Lorein J, et al. Dementia in Parkinson’s disease. Ann Neurol symptoms.[26,27] Trials on quetiapine have not shown any 1979;6:355-9. worsening of the symptoms, although some works have 8. Martilla RJ, Rinne UK. Dementia in Parkinson’s disease. Arch doubted the efficacy of this compound for the management Neurol Scand 1976;54:431-41.

of psychosis in Parkinsonism.[28,29] Aripiprazole, an atypical 9. Mjones H. Paralysis Agitans. Acta Psych et Neurol 1949;54:1-95. antipsychotic with partial agonism at D receptors, showed 10. Mathews CG, Haaland KY. The effect of symptoms duration on 2 promise as an antipsychotic in Parkinsonism when it cognitive and motor performances in parkinsonism. Neurology was first introduced, but two small open-label studies at 1979;29:951-6. 11. Mortimer JA, Christensen KJ, Wekster DD. Parkinsonian dementia.

varying dosages reported worsening of symptoms or lack In: Frederiks JA, editor. Handbook of clinical neurology. Vol. 46 of improvement in psychosis.[30,31] Another recently (Revised series 2). Neurobehavioral disorders. Amsterdam: introduced compound, ziprasidone showed significant overall Elsevier; 1985. p. 371-84. improvement in total Neuropsychiatric Inventory score and 12. Errea JM, Ara JR. Cognitive deterioration in Parkinson’s disease:

no change in the Unified Parkinson’s Disease Rating Scale Associated risk factors. Revista de Neurologia 1999;28:439-43. motor score.[32] 13. Channon S, Jones MC, Stephenson S. Cognitive strategies and hypothesis testing during discrimination learning in Parkinson’s There is some evidence that cholinesterase inhibitors may have disease. Neuropsychologica 1993;31:75-82. antipsychotic properties for the management of behavioral 14. Owen AM, James M, Leigh PN, Summers BA, Marsden CD, Quinn

symptoms in Parkinsonism. A number of open-label studies NP, et al. Frontostriatal cognitive deficits at different stages of Parkinson’s disease. Brain 1992;115:1727-51. have documented the beneficial effects of donepezil and 15. Growdon JH, Corkin S. Cognitive impairment in Parkinson’s rivastigmine in the management of dementia in Parkinsonism. disease. Adv Neurol 1986;45:383-92. A large placebo-controlled study of rivastigmine found that 16. Sahakian BJ, Morris RG, Evenden JL, Heald A, Levy R, Philpot

the rivastigmine group had significant improvement of the M, et al. A comparative study of visuospatial memory and learning neuropsychiatric symptoms than the control group and were in Alzheimer’s-type dementia and Parkinson’s disease. Brain less likely to develop hallucinations.[33] Furthermore, patients 1988;111:695-718. who suffered from visual hallucination at the time of initiation 17. Sagar HJ, Cohen NJ, Sullivan EV, Corkin S, Growdon JH. Remote

of treatment benefited the most.[34] memory function in Alzheimer’s disease and Parkinson’s disease. Brain 1988;111:185-206. 18. Calderon J, Perry RJ, Erzinclioglu SW, Barrios GE, Dening The management of psychosis in DLB is equally frustrating TR, Hodges JR. Perception, attention, and working memory and only a prospective randomized study in this regard has are disproportionately impaired in dementia with Lewy bodies

been reported to date.[35] Rivastigmine led to significant compared with Alzheimer’s disease. J Neurol Neurosurg improvement in delusions, hallucinations, depression, Psychiatry 2001;70:157-64. and apathy; and therefore, cholinesterase inhibitors are 19. McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, et al. Consensus guidelines for the clinical and pathological now recommended as the first line of management for this diagnosis of dementia with Lewy bodies: Report of the consortium

condition. Mementine has also been found useful in one small on DLB international workshop. Neurology 1996;47:1113-24. retrospective study.[36] However, cholinesterase inhibitors 20. McKeith IG, Dickson DW, Lowe J, Emre M, O’Brian JT, Feldman can increase tremor in Parkinsonism by their procholinergic H. Lewy bodies: Third report of the DLB Consortium. Neurology actions.[35] 2005;65:1863-72. 21. Litvan I, Mega MS, Cummings JL, Fairbanks F. Neuropsychiatric aspects of progressive supranuclear palsy.

One of the major problems of management of psychosis and Neurology 1996;47:1184-9. related problems in Parkinsonism is that stopping drugs often 22. Henderson MJ, Mellers JD. Psychosis in Parkinson’s disease: lead to worsening of symptoms.[37] However, some trials show “between a rock and a hard place.” Int Rev Psychiatry that patients can be switched from clozapine to quetiapine after 2000;12:319-34.

stability has been earned, provided they responded earlier to 23. French Clozapine Parkinson Study Group: Clozapine in drug- the latter agent.[38] induced psychosis in Parkinson’s disease. Lancet 1999;353:2041-2. 24. Parkinson Study Group: Low-dose clozapine for the treatment References of drug-induced psychosis in Parkinson’s disease. N Engl J Med 1999;340:757-63. 25. Frieling H, Hillemacher T, Ziegenbein M, Neundörfer B, Bleich

1. Aarsland D, Tandberg E, Larsen JP, Cummings JL. Frequency of S. Treating dopamimetic psychosis in Parkinson’s disease: dementia in Parkinson’s disease. Arch Neurol 1996;58:538-42. Structured review and meta-analysis. Eur Neuropsychopharmacol 2. Hobson P, Merara J. Risk and incidence of dementia in a cohort 2007;17:165-71. of older subject with Parkinson’s disease in the United Kingdom. 26. Breier A, Sutton VK, Feldman PD, Kadam DL, Ferchland I, Wright

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1986;22:163-70. 2002;17:1031-5. 5. Jacobs D, Marder K, Côté LJ, Sano M, Stern Y, Mayeux R. 28. Ondo WG, Tintner R, Voung KD, Lai D, Ringholz J. Double-blind, Neuropsychological characteristics of preclinical dementia in placebo-controlled, unforced titration parallel trial of quetiapine for Parkinson’s disease. Neurology 1995;45:1691-6. dopaminergic-induced hallucinations in Parkinson’s disease. Mov 6. Stern Y, Marder K, Tang MS, Mayeux R. Antecedent clinical Disord 2005;20:958-63.

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A double-blind labeled study of 3 months’ duration. Mov Disord 35. McKeith I, Del Ser T, Spano P, Emre M, Wesnes K, Anand R, 2007;22:313-8. et al. Efficacy of rivastigmine in dementia with Lewy bodies: A 30. Friedman JH, Berman RM, Goetz CG, Factor SA, Ondo WG, randomised, double-blind, placebo-controlled international study. Wojcieszek, et al. Open-label flexible-dose pilot study to Lancet 2000;356:2031-6.

evaluate the safety and tolerability of aripiprazole in patients 36. Sabbagh M, Hake A, Ahmed S, Farlow MR. The use of memantine with psychosis associated with Parkinson’s disease. Mov Disord in dementia with Lewy bodies. J Alzheimers Dis 2005;7:285-9. 2006;21:2078-81. 37. Fernandez HH, Trieschmann ME, Okun MS. Rebound psychosis: 31. Fernandez HH, Trieschmann ME, Friedman JH. Aripiprazole Effect of discontinuation of antipsychotics in Parkinson’s disease.

for drug-induced psychosis in Parkinson’s disease: Preliminary Mov Disord 2004;20:104-15. experience. Clin Neuropharmacol 2004;27:4-5. 38. Fernandez HH, Lannon MC, Friedman JH, Abbott BP. Clozapine 32. Gómez-Esteban JC, Zarranz JJ, Velasco F, Lezcano E, Lachen placement by quetiapine for the treatment of drug-induced MC, Rouco I, et al. Use of ziprasidone in Parkinsonian patients psychosis in Parkinson’s disease. Mov Disord 2000;15:579-81. with psychosis. Clin Neuropharmacol 2005;28:111-4.

33. Emre M, Aarsland D, Albanese A, Byrne EJ, Deuschl G, D Deyn How to cite this article: Behari M, Bhattacharyya KB, Borgohain R, Das PP, et al. Rivastigmine for dementia associated with Parkinson’s SK, Ghosh B, Kishore A, et al. Parkinson's disease. Ann Indian Acad disease. N Engl J Med 2004;351:2509-18. Neurol 2011;14:2-24. 34. Burn D, Emre M, McKeith I, De Deyn PP, Aarsland D, Hsu C, Source of Support: Nil. Conflict of Interest: None declared.

et al. Effects of rivastigmine in patients with and without visual Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S31 Guidelines for the use of botulinum toxin in movement disorders and spasticity Afshan Jabeen, Rukmini M Kandadai, Meena A Kannikannan, Rupam Borgohain Department of Neurology, NIMS, Punjagutta, Hyderabad, Andhra Pradesh, India For correspondence: Dr. Rupam Borgohain, Department of Neurology, NIMS, Punjagutta, Hyderabad,

500082 Andhra Pradesh, India. E-mail: b_rupam@hotmail.com Ann Indian Acad Neurol 2011;14:31-4 Introduction analysis for later comparative evaluation. Patient education and counseling are essential and treatment goals should be Botulinum neurotoxin (BoNT) has proved to be a remarkably agreed and documented. Consent should be obtained and effective therapy for numerous movement disorders associated BoNT should be prescribed. Secondary causes of treatable

with muscle overactivity such as dystonia and related disorders, dystonia such as drugs or Wilson’s disease should be ruled as well as spasticity [Table 1]. Additional therapeutic benefits out. Physicians administering BTX should have a good accrue from actions such as blockade of acetylcholine release understanding of both the anatomy of affected muscles and at autonomic nerve analysis as well as the blockade of release the resultant movement disorder. EMG monitoring helps

of nonacetylcholine transmitters at peripheral nerve endings. diagnose the underlying disorder and identify appropriate muscles for injection. Three broad categories of undesirable side effects are seen with BoNT. These are[1] diffusion of toxin into neighboring Goals for Treatment muscles and nerve endings,[2] sustained neuro-transmission blockade producing effects akin to anatomic denervation, Dystonia and[3] development of antibodies to BoNT with subsequent

Treatment of focal dystonia with BoNT is designed to improve immunoresistance.[1] the patients’ postures and function and to relieve associated pain. BoNT temporarily weakens dystonic muscles, thereby Indications allowing more normal posture and function. The benefits that BONT conveys to a particular patient depend on the Most appropriate conversion factor between Botox and Dysport localization and relative degree of severity of the dystonic

units is less than 3 in cervical dystonia.[7] muscles being injected. The decision to combine injections of BTX-A with other forms of treatment for dystonia is based on Relative Contraindications associated factors and individual decision. These include any excessive weakness, fixed contractures Blepharospasm and neuromuscular disease such myasthenia gravis, Eaton- Blepharospasm may be idiopathic or induced by drugs such

Lambert syndrome, and motor neuron disease. Other relative l-dopa or neuroleptics. It needs to be differentiated from facial contraindications include pregnancy and lactation and the tics in patients with Tourette’s syndrome and apraxia of eyelid concurrent use of aminoglycosides. opening. Assessment The injections are done on an outpatient basis. Intradermal This would include a detailed clinical examination and a video injection with a 27--30-gauge needle is recommended. Typically

3--5 points around each eye are injected. The principle is to avoid the midportion of the upper eyelid to avoid inadvertent Access this article online diffusion into the levator palpebrae superiors, which would Quick Response Code: lead to undesirable ptosis. Website: www.annalsofian.org Focal hand dystonia Among these, Writer’s cramp is the most common form of DOI: occupational dystonia. However, these has been described in

10.4103/0972-2327.83099 those professional whose work involves frequent and repetitive movements such as musicians, typists, milkers, cashiers, Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jo S32 Borgain: Botulinum toxin Table 1: Dosage of botulinum toxin for various indications Indication Dosage References Dystonia Blepharospasm 12.5--25 units/eye Botox [2-6] 50--90 units/eye Dysport [5] Cervical dystonia (Torticollis) 60--374 units Botox [7-9] 125--1200 units Dysport [9-11] 579--19853 units Myobloc [9], [12-14]

Oromandibular – facial – lingual dystonia Up to 50 units Botox in each muscle masseters and temporalis [15] Spasmodic dysphonia Adductor 15 unilat or 2.5--5 units bilat/TA [16-20] Abductor 3.75 units/PCA (unilat) serially [21] Focal limb dystonia (including Writer’s cramp) Individualized dosages [22--28] Hemifacial spasm 17.5 units Botox [5] 70 units Dysport Dystonic tics Individualized dosages [29] Tremors Hand and neck 50-100 units Botox [30--32]

cobblers, ticket collectors, and seamstresses. Neurologic EMG guidance, and percutaneous injections of BTX are evaluation and nerve conduction studies are required to rule administered through the cricothyroid membrane. Bilateral out radiculopathy or peripheral nerve involvement such as injection approach is the most common technique for adductor ulnar neuropathy or median entrapment neuropathy at the rest. dysphonia, while for the rarer abductor variety unilateral

Doses used for writer’s cramps are 5 U for small muscles and injections are done serially into the posterior cricoarytenoid 10–20 U for muscles in the forearm. Benefit has been reported muscles. in as many as 80%--90% patients and is usually apparent 5--7 days after injection. Hemifacial spasm This can be a very disabling disease because severely affected Cervical Dystonia individuals are socially handicapped and functionally blind. This can involve any combination of orbicularis oculi, frontalis,

risorius, zygomaticus major, and platysma muscles. Injections The movements of the neck – rotation, anterior, and posterior of BTX are given according to the muscles in spasm which differ flexion, tilt, and shift in the antero--posterior or lateral planes from patient to patient. – can occur in any combination in cervical dystonia. This can be associated with shoulder involvement as well as jerky or Palatal Tremor (myoclonus) tremulous movements and also pain. Muscles involved in

the abnormal posturing are isolated using standard anatomic landmarks. The most commonly injected muscles include This may be idiopathic or symptomatic. BTX injection of sternocleidomastoid, trapezius, splenius capitis, levator the tensor veli palitini muscle may reduce the symptom by scapulae, and scalene complex. Usually 2--6 muscles are reducing the amplitude of myoclonic jerk. injected at muscle sites. The BTX should be injected along the belly of the muscle to allow for adequate diffusion. Bruxism

Comella et al.[33] reported a significantly greater magnitude of improvement in those cases where the treated neck muscles This is an involuntary chewing such as rhythmic jaw movement were selected by clinical and electromyographic guidance than occurring especially at night, with grinding of the teeth. In this the cases in which only clinical examination was used. disease, BoNT is injected into the most sore part of the muscle, weakening the most spastic part of the masseter muscle without

Oromandibular dystonia affecting the ability to chew. This typically involves the masticatory, lower facial, and tongue muscles and is associated with jaw deviation and spasm. BTX Tics should be injected into the inappropriately contracting muscles These can be either motor or phonic tics. Both of these can in different combinations including masseter, temporalis lateral be simple or complex and also classified as clonic, tonic, and

pterygoids, and submental muscles. The lingual muscles need dystonic. BoNT produces significant decrease in both tic to be injected carefully. frequency and urge to tic. It improves the quality of life as reported by the patients. One has to be cautious of producing Laryngeal dystonia hypophonia. They are three types---adductor spasmodic dysphonia (strained strangled voice), abductor spasmodic dysphonia (whispering Outcome measurement and follow up

voice), and adductor breathing dysphonia (paradoxical vocal Measurement methods include the use of physical measures, fold motion). The thyroaarytenoid muscles are located with techniques to quantify individual symptoms or benefits, such Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Borgain: Botulinum toxin S33 as visual analogs scales and verbal scales as well as other rating toxin preparations in the treatment of essential blepharospasm. scales. Follow-up appointment should be at approximately Gracfes Arch Clin Exp Ophthalmol 1997;235:197-9.

3--17 weeks post injection using the same assessment as pre 5. Sampaio C, Ferreira JJ, Simões F, Rosas MJ, Magalhães M, Correia AP, et al. DYSBOT: A single-blind, randomized parallel injection. It should be assessed again 4--6 months interval. study to determine w4hether any differences can be detected in the efficacay and tolerability of two formulations of botulinum toxin Spasticity type A-Dysport and Botox - assuming a ratio of 4:1. Mov Disord

Symptomatic improvement decreases spasm frequency and 1997;12:1013-8. relief of pain. There is a reduction of generalized spasticity 6. Yoshimura DM, Aminoff MJ, Tami TA, Scott AB. Treatment – it facilitates sitting, and positioning or standing and also of hemifacial spasm with Botulinum toxin. Muscle Nerve 1992;15:1045-9. allows wearing of orthosis. In functional improvement it 7. Ranoux D, Gury C, Fondarai J, Mas JL, Zuber M. Respective improves mobility in terms of speed, quality or endurance of

potencies of Botox and Dysport: A double blind, randomised, gait, endurance of wheel chair propulsion, improves ease and crossover study in cervical dystonia. J Neurol Neurosurg safety of transfers, dexterity and reaching. There is decrease Psychiatry 2002;72:459-62. in burden on care givers such as positioning (e.g., feeding) 8. Garcia Ruiz PJ, Martínez Castrillo JC, Burguera JA, Campos

care and hygiene, e.g., washing and catheterization, dressing, V, Castro A, Cancho E, et al. Evolution of dose and response decreases care time to allow quality time. In prevention of to botulinum toxin A in cervical dystonia: A multicenter study. J complications, it prevents unnecessary use of antispasmodic Neurol 2011 Jan 1. 9. Chapman MA, Barron R, Tanis DC, Gill CE, Charles PD. and others medications, and also prevents pressure sores and Comparison of botulinum neurotoxin preparations for the treatment

contractures. It prevents or delays surgery. Cosmetically, it of cervical dystonia. Clin Ther. 2007 Jul;29:1325-37. improves body image. 10. Poewe W, Deuschl G, Nebe A, Feifel E, Wissel J, Benecke R, et al. What is the optimal dosse of botulinum toxin A in the treatment BoNT injection of cervical dystonia? Results of a double blind, placebo controlled, BoNT should be offered as a treatment option to reduce muscle dose ranging study using Dysport. German Dystonia Study Group.

J Neurol Neurosurg Psychiatry 1998;64:13-7. tone and improve passive function in adults with spasticity 11. Truong D, Duane DD, Jankovic J, Singer C, Seeberger LC, (Level A) and should be considered to improve function Comella CL, et al. Efficacy and safety of Botulinum type A (Level B).[34] Patient should be selected for BoNT depending toxin (Dysport) in cervical dystonia: Results of the first US

on the focal spasticity, dynamic spastic component, clearly randomized, double-blind, placebo-controlled study. Mov Disord identified goals for treatment and anticipated functional gains. 2005;20:783-91. Patient and their families/care givers should be given adequate 12. Brashear A, Lew MF, Dykstra DD, Comella CL, Factor SA, information, prior to treatment and should agree goals before Rodnitzky RL, et al. Safety and efficacy of NeuroBloc (Botulinum

treatment is given. Informed consent should be obtained toxin type B) in type A-responsive cervical dystonia. Neurology 1999;53:1439-46. from patients prior to injection. If the patient does not have 13. Brin MF, Lew MF, Adler CH, Comella CL, Factor SA, Jankovic J, the mental capacity to concern current policies for obtaining et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) consent should be followed. The maximum dose used in a in type A-resistant cervical dystonia. Neurology 1999;53:1431-8.

single treatment should not exceed 1500 mu Dysport (Ipsen), 14. Lew MF, Adornato BT, Duane DD, Dykstra DD, Factor SA, 400 U Botox (Allergan) or 10,000 U Myobloc. The dose of BoNT Massey JM, et al. Botulinum toxin type B: A double-blind, placebo- injected intramuscularly depends on the muscle size. Small controlled, safety and efficacy study in cervical dystonia. Neurology muscles such as the open cords receive 0.75 U, whereas larger 1997;49:701-7.

15. Jankovic J, Schwartz K, Donovan DT. Botulinum toxin treatment neck muscles may require 100--150 U and lower limb muscles of cranial-cervical dystonia, spasmodic dysphonia, other may require 200--300 U to exert a desirable effect. focal dystonias and hemifacial spasm. J Neurol Neurosurg Psychiatry. 1990;53:633-9. Other services 16. Troung DD, Rontal M, Rolnick M, Aronson AE, Mistura K. Double-

BoNT injection must be a part of rehabilitation program blind controlled study of Botulinum toxin in adductor spasmodic involving postinjection exercise, muscle stretch and/splinting, dysphonia. Laryngoscope 1991;101:630-4. to achieve an optimal beneficial clinical effect. Clinical should 17. Murry T, Woodson GE. Combined-modality treatment of adductor spasmodic dysphonia with botulinum toxin and voice therapy. J have access to facilities to aid in assessment, selection and Voice 1995;9:460-5.

treatment planning, e.g., electromyography (EMG). Clinical 18. Wong DL, Adams SG, Irish JC, Durkin LC, Hunt EJ, Charlton MP. should familiarize themselves with a single agent to avoid Effect of neuromuscular activity on the response to Botulinum toxin confusion over dose. injections in apasmodic dysphonia. J Otolaryngol 1995;24:209-16. 19. Warrick P, Dromey C, Irish JC, Durkin L, Pakiam A, Lang A. References Botulinum toxin for essential tremor of the voice with multiple

anatomical sites of tremor: A crossover design study of unilateral versus bilateral injection. Laryngoscope 2000;110:1366-74. 1. Simpson LL. Identification of the major steps in Botulinum toxin 20. Adler CH, Bansberg SF, Hentz JG, Ramig LO, Buder EH, Witt K, action. Ann Rev Pharmacol Toxicol 2004;44:167-93. et al. Botulinum toxin type A for treating voice tremor. Arch Neurol 2. Girlanda P, Quartarone A, Sinicropi S, Nicolosi C, Messina C. 2004;61:1416-20.

Unilateral injection of botulinum toxin in blepharospam: Single 21. Blitzer A, Brin MF. The evaluation and management of abductor fiber electromyography and blink reflex study. Mov Disord laryngeal dystonia. Therapy with Botulinum toxin. In: Jankovic J, 1996;11:27-31. Hallet M, editors. New York: Marcel Dekker, Inc.; 1994. p. 451-9. 3. Jankovic J, Orman J. Botulinum A toxin for cranial-cervical 22. Kruisdijk JJ, Koclman JH, Ongerboer de Visscr BW, de Haan RJ,

dystonia: A double-blind, placebo-controlled study. Neurology Speelman JD. Botulinum toxin for writer’s cramp: A randomized, 1987;37:616-23. placebo-controlled trial and 1-year follow-up. J Neurol Neurosurg 4. Nussgens Z, Roggenkamper P. Comparison of two Botulinum- Psychiatry 2007;78:264-70. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S34 Borgain: Botulinum toxin 23. Yoshimura DM, Aminoff MJ, Olney RK. Botulinum toxin therapy 31. Brin MF, Lyons KE, Doucette J, Adler CH, Caviness JN, Comella for limb dystonias. Neurology 1992;42:627-30. CL, et al. A randomized, double masked, controlled trial of

24. Tsui JK, Bhatt M, Calne S, Calne DB. Botulinum toxin in the botulinum toxin type A in esssential hand tremor. Neurology treatment of writer’s cramp: A double-blind study. Neurology 2001;56:1523-8. 1993;43:183-5. 32. Pahwa R, Busenbark K, Swanson-Hyland EF, Dubinsky RM, 25. Cole R, Hallett M, Cohen LG. Double-blind trial of Botulinum toxin Hubble JP, Gray C, et al. Botulinum toxin treatment of essential for treatment of focal hand dystonia. Mov Disord 1995;10:466-71. head tremor. Neurology 1995;45:822-4.

26. Chen R, Karp BI, Goldstein SR, Bara-Jimenez W, Yaseen Z, 33. Comella CL, Buchman AS, Tanner CM, Brown-Toms NC, Goetz Hallett M. Effect of muscle activity immediately after botulinum CG. Botulinum toxin injection for spasmodic torticollis: Increased toxin injection for writer’s cramp. Mov Disord 1999;14:307-12. magnitude of benefit with electromyographic assistance. 27. Geenen C, Consky E, Ashby P. Localizing muscles for botulinum Neurology 1992;42:878-82

toxin treatment of focal hand dystonia. Can J Neurol Sci 34. Simpson DM, Gracies JM, Graham HK, Miyasaki JM, Naumann 1996;23:194-7. M, Russman B, et al. Assessment: Botulinum neurotoxin for the 28. Molloy FM, Shill HA, Kaelin-Lang A, Karp BI. Accuracy of muscle treatment of spasticity (an evidence-based review). Report of the localization without EMG: Implications for treatment of limb Therapeutics and Technology Assessment Subcommittee of the

dystonia. Neurology 2002;58:805-7. American Academy of Neurology. Neurology 2008;70;1691-8. 29. Marras C, Andrews D, Sime E, Lang AE. Botulinum toxin for simple motor tics: A randomized, double-blind, controlled clinical How to cite this article: Jabeen A, Kandadai RM, Kannikannan MA, trial. Neurology 2001;56:605-10. Borgohain R. Guidelines for the use of botulinum toxin in movement 30. Jankovic J, Schwartz K, Clemence W, Aswad A, Mordaunt J. A disorders and spasticity. Ann Indian Acad Neurol 2011;14:31-4.

randomized, double-blind, placebo-conrolled study to evaluate Received: 15-05-10 Botulinum toxin type A in essential hand tremor. Mov Disord Source of Support: Nil. Conflict of Interest: None declared. 1996;11:250-6. Staying in touch with the journal 1) Table of Contents (TOC) email alert Receive an email alert containing the TOC when a new complete issue of the journal is made available online. To register for TOC alerts go to www.annalsofian.org/signup.asp. 2) RSS feeds

Really Simple Syndication (RSS) helps you to get alerts on new publication right on your desktop without going to the journal’s website. You need a software (e.g. RSSReader, Feed Demon, FeedReader, My Yahoo!, NewsGator and NewzCrawler) to get advantage of this tool. RSS feeds can also be read through FireFox or Microsoft Outlook 2007. Once any of these small (and mostly free) software is installed, add www. annalsofian.org/rssfeed.asp as one of the feeds.

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S40 Guidelines on the diagnosis and the current management of headache and related disorders K. Ravishankar, Ambar Chakravarty1, Debashish Chowdhury2, Rakesh Shukla3, Sumit Singh4 The Headache and Migraine Clinic, Jaslok and Lilavati Hospitals, Mumbai, 1Department of Neurology, Vivekananda

Institute of Medical Science, Kolkata, 2Department of Neurology, G.B.Pant Hospital, New Delhi, 3Department of Neurology, CSM Medical University, Lucknow, 4Department of Neurology, Medanta – The Medicity Gurgaon, Haryana, India. For correspondence: Dr. K. Ravishankar, A/64, Kalpataru Residency, Sion East, Mumbai – 400 022, Mumbai, India. E-mail: dr.k.ravishankar@gmail.com Annals of Indian Academy of Neurology 2011;14:40-59

There are at present no existing guidelines on “headache” that to a specialist has also been included. Common entities have pertain to the Indian setting. With a view to standardizing been described in greater detail while rare conditions that are headache diagnosis across the country and keeping in mind seen less often are only mentioned in passing. treatment issues peculiar to our setting, these Guidelines have been evolved to help primary care physician’s deal

The following is a brief listing of the headache conditions with headache patients. These Guidelines have been drawn that are included in the second edition of The Classification up by neurologists with a special interest in headache. With of Headache Disorders of the International Headache society- limited evidence in literature regarding headache practice ICHD2 (2004). The rubrics employed in all the chapters will and treatment in India, these guidelines are more experience

be the same that is used in ICHD2. based than evidence based. Quick Reference to the ICHDs All contributors have adhered to the second edition of the International Classification of Headache Disorders (ICHD2- 2nd edition-(2004) 2004). In ICHD2, the first four categories deal with the a. Primary headache disorders primary headaches.[1-5] The next eight categories deal with • Migraine headaches due to identifiable secondary causes.[6-13] The last • Tension-type headache

two categories deal with cranial neuralgias and other causes • Cluster headache and other trigeminal autonomic of facial pain.[14-17] cephalalgias • Other primary headaches It is well accepted that no practice guidelines can cover all situations. Some headaches need to be handled by a b. Secondary headache disorders neurologist but for the most part, primary care physicians are • Headache attributed to head and/or neck trauma the ones who should be ideally handling headaches and these

• Headache attributed to cranial or cervical vascular guidelines are targeted toward that end. These guidelines disorder reflect current clinical practice trends in India. Every chapter • Headache attributed to non-vascular intracranial has a brief introduction, followed by the salient diagnostic disorder features, the way to investigate and treatment options. A • Headache attributed to a substance or its withdrawal summary of important practice points regarding when to refer

• Headache attributed to infection • Headache attributed to disorder of homeoeostasis Access this article online • Headache or facial pain attributed to disorder of Quick Response Code: cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, Website: or other facial or cranial structures www.annalsofian.org • Headache attributed to psychiatric disorder c. Cranial Neuralgias and facial pains DOI: • Cranial neuralgias and central causes of facial pain 10.4103/0972-2327.83100

• Other headache, cranial neuralgia central, or primary facial pain Before going into the actual details, it is important to Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Ravishankar, et al: Headache disorders S41 emphasize that the primary physicians should know intensity of migraine attacks continue to progress. when to get a neuroimaging in a headache patient to rule out the secondary causes of headache. Also, they should Treatment

know when to refer the patient to a specialist or higher Management needs to be individualized. The basic principles centre. These have been tabulated in Tables 1 and 2. are as follows. Establish the diagnosis correctly; educate migraine sufferers about their condition and discuss the Primary Headache Disorders treatment plan; establish realistic patient expectations by setting appropriate goals; choose the drug treatment based Migraine Diagnosis Table 3: Sub-classification of migraine according to

the ICHD2 (2004) Migraine is divided into two broad categories, namely migraine without aura and migraine with aura. The spectrum of migraine Migraine without aura has now expanded [Table 3]. Most patients suffer from attacks Migraine with aura of migraine without aura. The ICHD2 diagnostic criteria for Typical aura with migraine headache Typical aura with non-migraine headache migraine without and with aura are included in Tables 4 Typical aura without headache

and 5. Migraine with aura includes a transient neurological Familial hemiplegic migraine dysfunction that may be visual, sensory or may involve speech Sporadic hemiplegic migraine and language. Migraine attacks in children are of shorter Basilar-type migraine duration (usually 1–2 h only); the accompanying symptoms Childhood periodic syndromes that are precursors of migraine are different and may include syndromes such as abdominal Cyclical vomiting

migraine or periodic syndromes like cyclic vomiting. Abdominal migraine Benign paroxysmal vertigo of childhood Retinal migraine Investigations Complications of migraine Neuroimaging in migraine patients is advocated only when Chronic migraine patients present with an unexpected abnormal finding on Status migrainosus neurologic examination, when patients present with atypical Persistent aura without infarction features, when attacks with migrainous features occur for the Migrainous infarction

first time after the age of 40 years, or when the frequency or Migraine-triggered seizure Probable migraine Probable migraine without aura Table 1: When do we ask for a CTscan/ MR scan in a Probable migraine with aura headache patient? Probable chronic migraine Neuroimaging should be considered in patients with headache and an unexplained abnormal finding on the neurologic examination. Table 4: Diagnostic criteria of migraine without aura-- In any headache that is worsened by Valsalva maneuver -ICHD2

With new headaches or progressively worsening headaches At least five attacks fulfilling criteria B–D In patients with atypical headache patterns Headache lasting 4–72 h (untreated or unsuccessfully treated) When it is the “first and worst” headache Headache has at least two of the following characteristics: Unilateral location Headache that is persistently on the same side Pulsating quality Headache that is not responding to treatment Moderate or severe pain intensity

New onset headache in a patient who has cancer or is human Aggravation by or causing avoidance of routine physical activity immunodeficiency virus (HIV) positive (e.g. walking or climbing stairs) Headache with fever, stiff neck, nausea, vomiting. During headache at least one of the following: Headache associated with papilledema, cognitive impairment, Nausea and/or vomiting personality change, or seizures. Photophobia and phonophobia Not attributed to another disorder

Table 2: When does one refer or hospitalize a Table 5: Diagnostic criteria for migraine with aura--- headache patient? ICHD 2 When a severe headache presents as a medical emergency A There have been at least two attacks fulfilling criterion B listed associated with intractable nausea and vomiting producing below dehydration or postural hypotension. B At least three of the following characteristics are present:

When backup medications do not work. There are one or more fully reversible aura symptoms indicating When dealing with migraine complications or variants (e.g. focal cerebral cortical or brain stem dysfunction hemiplegic migraine, suspected migrainous infarction, basilar Either at least one aura symptom develops gradually over more migraine with serious neurolgic symptoms such as syncope, than 4 min, or two or more symptoms occur in succession

confusional migraine, etc) No aura symptom lasts more than 60 min; if more than one aura When a diagnosis has not been established during a previous symptom is present, accepted duration is proportionally increased similar occurrence. Headache follows aura with a free interval of less than 60 min (it may also begin before or simultaneously with the aura) When there is a diagnostic suspicion of an infectious disorder No evidence of organic disease history, physical examination, and

involving the central nervous system (e.g. brain abscess and diagnostic tests exclude a secondary cause meningitis) Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S42 Ravishankar, et al: Headache disorders on the frequency and severity of attacks and the presence of maximum of 100 mg per dose to a maximum of 300 mg per day. associated symptoms such as nausea and vomiting; consider Patients with nausea and vomiting may be given subcutaneous

comorbid and coexisting conditions when choosing drugs for (SC) sumatriptan. A SC injection of 1/2 cc = 6 mg may be used prophylaxis; encourage patients to identify and avoid triggers. for severe attacks with vomiting. Both sumatriptan injection and intranasal sumatriptan are available in India. Sumatriptan Migraine-abortive treatment should not be taken within 24 h of the administration of The basic principles of abortive treatment of migraine are as DHE or ergotamine. Caution must be exercised when using

follows. Tailor the treatment choice to suit individual needs sumatriptan in patients with cardiac risk factors, cardiac disease, (e.g. based on their severity of illness, co-morbidity / co- or uncontrolled hypertension. Rizatriptan is given orally in a existing conditions and prior response to medications); use dose of 5 or 10 mg to treat attacks of moderate severe migraine. A migraine-specific agents (ergotamine, dihydroergotamine lower dose is recommended for patients who are on betablockers.

(DHE), triptans) in patients with more severe migraine and Naratriptan is long acting and is used in a dose of 1 mg or 2.5 in those whose headaches respond poorly to non-steroidal mg. Recurrence is less with naratriptan. anti-inflammatory drugs (NSAIDs) or combination analgesics Other medications such as aspirin plus acetaminophen or caffeine; select a non-oral route of administration for migraines associated Corticosteroids (dexamethasone or hydrocortisone) are options

with nausea or vomiting; guard against medication overuse for rescue therapy in patients with status migrainosus. headache (MOH) (rebound headache). Frequent use of Migraine-preventive treatment acute medications like ergotamine, opiates, triptans, simple The basic principles of abortive treatment of migraine are analgesics, and combination analgesics containing caffeine/ as follows. Preventive therapy should be employed in those codeine are thought to cause rebound headache; preventive

patients in whom migraine has a high frequency, severity, therapy given simultaneously will help reduce the need for substantial impact, and in those who have not responded repeated acute medications. to acute care. Use the least amount of the medication with the fewest side effects to gain control of the symptoms until Nonspecific medications for acute treatment preventive treatment can be reduced or stopped. Initiate Antiemetics therapy with medications that have the highest level of

Oral antiemetics such as metoclopramide and domperidone are efficacy. Increase the dose slowly until clinical benefits are an adjunct to treat nausea associated with migraine. achieved without adverse events. Give each drug an adequate trial of at least 2 to 3 months. Use a long acting formulation, it NSAIDs, nonopiate analgesics, and combination analgesics will help improve compliance. Monitor the patient’s headache

NSAIDs (oral) and combination analgesics containing caffeine frequency using a headache diary. Select a drug that will are a reasonable first-line treatment choice for mild to moderate treat the coexistent condition and migraine. When using migraine attacks or severe attacks that have been responsive in prophylactics, direct special attention to women who are the past to similar NSAIDs or nonopiate analgesics. Overuse of pregnant or desire to conceive. Preventive medications may

combination medications is considered to be one of the most have teratogenic effects. prominent causes of rebound headache. Fortunately, analgesics containing butalbital and opioids are not easily available in our Beta–blockers country and so their overuse is limited. Not all beta-blockers are effective in migraine. Those that are efficacious include propranolol, atenolol, and metoprolol. Beta- Opiate analgesics blockers are contraindicated in patients with asthma, chronic

Parenteral opiates should only rarely be used as rescue therapy obstructive pulmonary disease, insulin-dependent diabetes for acute migraine. The risk of sedation and habituation will mellitus, heart block or failure, or peripheral vascular disease. have to be addressed. When prescribing beta-blockers, start with a low dose and titrate upward as required. Once the attacks are controlled, Specific medications for acute treatment the medication should be tapered. Propranolol can be started

Ergot alkaloids and derivatives in a dose of 10 mg twice daily and gradually increased to a maximum of 80-120 mg per day. Doses in Indian patients are Ergotamine oral 1 mg (available in combination with caffeine) much less than in the western population. may be considered in the treatment of patients with moderate to severe migraine. Rectal suppositories are not available in India. Safe usage limits the consumption to between 6 to 10 Calcium-channel blockers

mg per week but ergotamine should not be used on a long- Of the available agents in this group, flunarizine is most term basis. DHE, a nonselective 5-HT receptor agonist, is commonly used for migraine prophylaxis. Flunarizine is useful 1 effective in relieving headache when used intramuscularly or as a first line prophylactic and can be started in a smaller intravenously. Unfortunately, DHE is not available in India. dose of 5 mg at night and gradually increased to 10 mg daily.

This will help avoid sedation. Flunarizine is to be avoided Triptans (5 HT receptor agonists): As of 2011, sumatriptan, in patients with depression. Calcium-channel blockers are 1B/1D rizatriptan, naratriptan, and zolmitriptan are the only four contraindicated in patients with hypotension, congestive heart triptans available in India. Initial treatment with any triptan is failure, or arrhythmia. a reasonable choice when the headache is moderate to severe.

The recommended starting dose for sumatriptan is 25 mg orally. Tricyclic antidepressants If needed one may increase the dose in increments of 50 mg to a Amitriptyline is useful in migraine, especially in patients Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jo Ravishankar, et al: Headache disorders S43 with associated TTH.10 mg orally each night should be Fortunately, most pregnant migraineurs experience less or given at first, followed by an increase of 10 mg every week, even no migraine attacks. When migraine attacks occurs

up to 25-50 mg/day; a higher dosage may be required in the during pregnancy, only paracetamol should be administered. presence of comorbid depression. Contraindications include NSAIDs can be given in the second trimester. Triptans and cardiac, kidney, liver, prostate and thyroid disease, glaucoma, ergot alkaloids are contraindicated. Propranolol and hypotension, seizure disorder, and use of monoamine oxidase amtriptlyline are the prophylactics that can be used if

inhibitors. Tricyclic drugs should be used with caution in necessary elderly patients because of anticholinergic side effects. When to refer to a specialist? Anti-epileptic drugs The patient should be referred to a specialist when migraine Sodium valproate, valproic acid, divalproex sodium, and transforms to a chronic daily headache or becomes refractory, topiramate have been found to be effective for migraine when migraine is comorbid with severe depression or other

prophylaxis. Side effects of divalproex include nausea, alopecia, psychiatric comorbidity, when there is associated medication tremor, and weight gain, and their use has been associated with overuse, and parenteral treatment becomes necessary. hepatotoxicity, particularly in children. They may also cause neural tube defects and should not be given to women who Tension type headache are pregnant or considering pregnancy or young women with Diagnosis

polycystic ovarian disease (PCOD). Divalproex is started in a TTH are recurrent episodes of headache lasting minutes to small dose of 250-500 mg per day and the dose is gradually weeks. The pain is typically pressing or tightening in quality, increased up to 1500 mg per day with continuous monitoring of mild to moderate intensity, and bilateral in location, and for side-effects. Topiramate should be started in a small dose does not worsen with the routine physical activity. Nausea and

of 25 mg per day in adults and the dose should be gradually vomiting is usually absent, but photophobia or photophobia increased in 25 mg weekly increments to a maximum of 100 may be present. mg twice daily. Doses of topiramate for migraine in Indian patients are less than that in westerners. Topiramate should not The diagnosis of TTH is essentially clinical and relies only on be used in the presence of glaucoma, renal stones and tingling symptoms and signs [Table 6].

and numbness, diarrhea, and confusional state are some of the temporary side effects. Topiramate has the advantage of TTH has been divided into two forms, episodic (ETTH) and weight loss and can be used in preference to divalproex when chronic (CTTH) in ICHD 2. Episodic tension type headache has treating obese patients. been divided into two groups, namely infrequent and frequent. TTH is the least distinct of all headache types. Diagnosis

Non-Pharmacologic Therapy is based chiefly on negative features (i.e. the absence of Nonpharmacologic treatment may be combined with symptoms that characterize other primary or secondary preventive therapy to achieve additional clinical improvement headaches). However, many of the secondary headaches for migraine relief. Behavioral treatments are classified into such as MOH chronic posttraumatic headaches, sinus/ eye

three broad categories: relaxation training, biofeedback disease related headaches, temporo-mandibular joint disorder therapy, and cognitive-behavioral training (stress-management related headaches, brain tumor related headaches, psychiatric training). Physical treatment includes acupuncture, cervical disorder-related headaches, and cervical spondylosis may manipulation, and mobilization therapy. mimic TTH at some stage of their clinical evolution. Therefore,

atypical history or abnormal clinical examination in patients Specific situations that warrant different treatment of suspected TTH indicates the need for further investigation. strategies Migraine in children and adolescents Treatment The only analgesics with evidence of efficacy for the acute Acute abortive treatment migraine treatment in childhood and adolescents are ibuprofen • Simple analgesics and NSAIDSs are the mainstays in the

10 mg/kg body weight and paracetamol 15 mg/kg body weight. acute therapy. Domperidone is the antiemetic of choice in children. Ergot alkaloids should not be used in children and adolescents. Table 6: Tension type Headache---core features Menstrual migraine Duration 30 min to 7 days Different drug regimes have been studied to treat this Two out of four Bilateral location menstrual migraine. Naproxen sodium (250 mg twice daily) has following headache Pressing/tightening quality (non-pulsating)

features Mild to moderate intensity been shown to reduce pain including headache in menstrual Not aggravated by routine physical activity migraine. In patients who have clearly predictable menstrual Associated No nausea and vomiting (anorexia may cycles, one can plan a short 8-day course of peri-menstrual symptoms occur) prophylaxis starting 5 days prior to and for 3 days during No more than one of photophobia or periods. phonophobia Not attributed to by Other disorders to be excluded by clinical

Migraine in pregnancy another disorder history and examination or by suitable Most migraine drugs are contraindicated in pregnancy. investigation if necessary Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S44 Ravishankar, et al: Headache disorders • Care should be taken to avoid overuse. cranial autonomic symptoms with increased parasympathetic • Opiates should to be avoided. and decreased sympathetic activity. The TACs include the • Nonpharmacologic treatment in the form of relaxation following individual headache entities: cluster headache (CH);

training can be of benefit in recurrent ETTH paroxysmal hemicranias (PH); short lasting neuralgiform headache with conjunctival injection and tearing (SUNCT). Preventive treatment Cluster Headache • Tricyclic antidepressants: Amtriptlyline has been found to be most effective for the treatment of CTTH. Amtriptlyline should be started on low dose (10 mg to 25 mg per day) Diagnosis and titrated by 10-25 mg weekly till the therapeutic effect An important feature of CH is the circadian periodicity

or the side effects appear. The common side effects of the with attacks occurring in a clustered form daily exactly at drug are dry mouth and drowsiness. Serious side effects nearly the same time for several days and with variable like cardiac arrhythmias, precipitation of glaucoma, and periods of remission in between---hence the name CH. urinary retention can occur in predisposed, especially Severe head pain that is unilateral and orbital, supraorbital

elderly subjects. or temporal in location, lasting for 15--180 min duration if • Mirtazepine: can be given in situations where amtriptlyline is untreated. The headache may be associated with one of the either ineffective or contraindicated. Other antidepressants following symptoms: ipsilateral conjunctival injection and/or lacrimation; ipsilateral nasal congestion/rhinorrhea; like SSRI and tetracyclics have been found to be not so ipsilateral miosis, ptosis; ipsilateral eyelid edema; ipsilateral useful.

• Recently, Botulinum Toxin Type A injection has been tried forehead and facial sweating; sense of restlessness, or agitation during headache. Attack frequency may range from in CTTH with variable results. Currently, this is reserved 1 to 8 per day. CH may be classified as episodic or chronic for refractory patients. depending on duration. • Relaxation training and biofeedback training are also helpful. • Usually, preventives are continued for 6 months following Investigation

which withdrawal is attempted. Upon withdrawal, some Although most cases of CH seen in practice are primary in patients continue to remain headache free while others start nature, CH may be a rare manifestation of an underlying to have headaches again. These patients usually require space-occupying lesion, (especially pituitary tumors). Hence long-term treatment. neuroimaging studies of all cases of CH are recommended. Patient education Treatment

Many patients of frequent ETTH and CTTH have grave concerns Abortive treatment about possibility of a serious disease such a brain tumor. Correct To terminate the acute attack. explanations can allay these concerns. Physicians should refrain • SC sumatriptan: Given as ½ cc = 6 mg SC injection. The from using such terms like “psychosomatic” or “depression” injection is available in a preloaded autoinjector format

which might be perceived negatively by the patient. which the patient himself can administer. If the injection is not available, sumatriptan can be given as a nasal spray Headache diary containing 20 mg per puff. This often is very helpful for the physicians. They can measure • Oxygen: Inhalation of 100% oxygen at 6-7 L/min for 15 min the progression of the frequency and severity. is effective in 60% cases. Higher flow rate (12 L/min) may benefit some patients

When to refer to a specialist? • DHE: Dihydroegotamine injection or nasal spray is also The patient should be referred to a specialist when the diagnosis effective but the drug is not available in India is uncertain (Multiple headache diagnoses possible), when there is a recent change in character and response pattern Preventive treatment in a diagnosed patient, with refractory headaches that are To reduce the frequency and severity of the attacks.

unresponsive to first and second line drugs, with medication • Verapamil: Pretreatment ECG is essential and this drug overuse problems including opioid dependence, with should be avoided in conjunction with beta-blockers. It depression and anxiety not responding to standard drugs, is given in a starting dose of 120 mg long acting daily when non-pharmacological treatment like relaxation training, increased to three times daily. Constipation is the main and biofeedback training are required. side effect.

• Lithium: Given in a starting dose of 300 mg to be gradually Cluster Headache and Trigeminal Autonomic increased to a max of 900 mg. Pre-check of thyroid and Cephalgias renal profile is necessary and lithium levels need to be monitored periodically. Trigeminal autonomic cephalgias (TACs) are uncommon, most • Steroids: Prednisolone in a dose of 60 mg daily to start with often primary headache disorders which are usually short lasting followed by gradual tapering. Normal precautions as while

and associated with cranial autonomic features. The general administering steroids. diagnostic characteristics of this group are unilateral head pain • Ergotamine: Useful as adjunctive therapy. For reasons still predominantly affecting the first division of trigeminal nerve, unknown, ergotamine when used in CH on a daily basis namely the eye, periorbital region, and forehead associated with does not usually lead to MOH. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Ravishankar, et al: Headache disorders S45 Surgical Options pain in the head that occur in the absence of organic disease Surgery as a treatment option for CH is to be considered of underlying structures or of the cranial nerves. Stabs last

only in medically intractable situations when there is no for a few seconds and there are no accompanying symptoms, improvement with verapamil, lithium, and methysergide. exclusively or predominantly in the distribution of the trigeminal nerve (orbit, temporal, parietal). These headaches Paroxysmal Hemicrania are not accompanied by autonomic symptoms. Migraine is a common association. Diagnosis Treatment Paroxysmal hemicrania (PH) is similar to CH clinically but

differs from CH in that it occurs predominantly in females, the Indomethacin in a 25-50 mg per day dosage is the most effective attack duration is shorter, number of attacks is more per day, treatment option. and this headache is exquisitely responsive to indomethacin. The gender bias for PH is the reverse of CH. (M: F 1:2.4). The Primary Cough Headache usual onset is 20--50 years (range 6--81 years). Most cases are primary. The attacks are of 2--30 min duration. PH has been Diagnosis

divided along the same lines as CH into two categories: episodic The headache is sudden, short, and bilateral and brought and chronic PH. on by coughing or straining and generally not present at other times. Headache induced by cough or straining may Investigations be primary (or benign) and secondary. Most cases of Neuroimaging is seldom needed unless unusual features occur symptomatic or secondary cough headaches are due to

and an underlying secondary structural cause needs ruling Arnold – Chiari Malformation Type 1 (herniation of cerebellar out. Indomethacin responsiveness must be tested in all cases tonsil through the foramen magnum). Intracranial neoplasms of suspected PH to differentiate from CH and SUNCT. or vascular diseases including aneurysms may also cause symptomatic cough headache. Treatment Oral indomethacin is the drug of choice---starting at 25 mg Investigation

TID and increasing to 75 mg TID if GI symptoms do not occur. Primary cough headaches must occur in the absence of an Gastroprotective agents may be used concurrently. Withdrawal intracranial pathology and hence neuroimaging (preferably of indomethacin once every 6 months may be attempted. MRI) must be done in all cases. Short Lasting Neuralgiform Attacks with Treatment Conjunctival Injection and Tearing Smoking should be stopped. Some patients respond well to indomethacin. Diagnosis

The attacks are associated with severe to very severe pain that Primary Exertional Headache is strictly unilateral, neuralgic in character (short and sharp) located in the ophthalmic---trigeminal distribution attack, Diagnosis duration is short and in seconds (5-200), attack frequency is Any form of exercise precipitates the headache. The headache very high (1/day – 60/h). Autonomic features are dominant- lasts from 5 to 48 h. --lacrimation, conjunctival injection are usually seen. Other

features may or may not be present and include rhinorrhea, Primary Headache Associated with Sexual Activity nasal blockage, eye lid edema, ptosis, facial flushing, and facial sweating. There is no refractory period in between attacks. Rarely SUNCT may be caused by posterior fossa tumors and Diagnosis pituitary adenomas. SUNCT needs to be differentiated from These are headaches precipitated by sexual activity usually trigeminal neuralgia (TN). start as a dull bilateral ache as sexual excitement increases and

suddenly become intense at orgasm. The headaches occur in Treatment the absence of any intracranial disorder. At presentation, the • Lamotrigine (100--400 mg/day); Topiramate (50--400 mg/ causal relationship to sexual activity (often suppressed by day); Gabapentin (600--3600 mg/day) and IV Lidocaine in patients) must be elicited for diagnosis. intractable cases (1.3 – 3.3 mg/kg/h). • Greater occipital nerve blockade may also help in some. Investigation

Hypothalamic deep brain stimulation is now being It is known that sexual activity may cause an intracranial bleed evaluated as a preventive measure. (aneurysmal subarachnoid hemorrhage or even intracerebral hemorrhage) and hence a detailed history must be obtained. Other Primary Headaches Other conditions must be excluded by appropriate investigations Primary stabbing headache (neuroimaging or CSF study), with any “thunderclap” Diagnosis headache where exclusion of subarachnoid hemorrhage is of

This entity is characterized by transient and localized stabs of paramount importance. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S46 Ravishankar, et al: Headache disorders Treatment Headache Attributed to Head And/Or Neck Trauma Some may obtain relief with indomethacin (50 mg) prior to the sex act. Post-traumatic headache Post-traumatic headache (PTH) may be accompanied by Hypnic Headache somatic, psychologic, or cognitive disturbances. It can simulate

the clinical characteristics of several primary headaches and is defined as a new onset headache resulting from injury to the Diagnosis brain, head, and neck. Attacks of dull headache (sometimes severe) occur at night often awakening the patient from sleep. The headache may Diagnosis occur several times per month, generally lasting for 15--30 min PTH can present after mild, moderate, or severe head injury. If after waking. There are no accompanying autonomic features

headache, without any typical characteristics, develops within (differentiation from CH). 7 days after head trauma or after regaining consciousness following head trauma and resolves within 3 months or 3 Investigations months have not yet elapsed, it is termed “acute PTH.” If it Exclusion of intracranial disorder is important and hence the persists for more than 3 months after head trauma, it is termed need for neuroimaging. “chronic PTH.” The distinction of 3 months between acute and

chronic PTH is rather arbitrary and not based on any clear Treatment clinical or biological evidence. • A hot cup of strong coffee at bedtime helps many patients. • Some patients benefit from may need lithium carbonate 300 Investigation mg at night or flunarizine 10 mg at bedtime. • The investigation of choice for PTH is cranial computed tomography (CT) with bone window images. Primary Thunderclap Headache • Cranial magnetic resonance imaging (MRI) is more sensitive

for detecting non-hemorrhagic focal contusions. • With accompanying neck injury, plain x-rays cervical spine Diagnosis on flexion and extension are necessary to identify fracture, High intensity headache of abrupt onset mimic that of ruptured subluxation, or ligamentous injury of spine. cerebral aneurysm. “True” primary thunderclap headaches are uncommon. Aneurysmal rupture must be excluded. Other conditions include bleeding from cerebral AVM, cerebral Treatment

venous sinus thrombosis, and pituitary apoplexy. Treatment guidelines are based on clinical experience and there are few controlled studies. Treatment Pharmacological All cases of thunderclap headaches must be referred urgently • Abortive treatment for acute PTH provides short-term relief to specialized units for full work-up and treatment. and includes NSAIDs (naproxen 500 mg bd, ibuprofen 400 mg tds). Use of these drugs should be limited to prevent Hemicrania Continua rebound.

• Preventive treatment should be considered if there are Diagnosis more than two attacks of headache per week or headache Hemicrania continua (HC) is a strictly unilateral headache severity or duration are high. Tricyclic antidepressants responsive to indomethacin, usually unremitting, but rare cases (amtriptlyline 10-75 mg hs, nortriptyline 25-75 mg hs). of remission have been reported. The diagnostic criteria for HC • The chronic, frequent use of opioids or benzodiazepines

are as follows. Unilateral pain without side shift; pain is daily and should be avoided because of the potential for habituation. continuous, without pain free periods; moderate severity, but • Management of PTH should be tailored to the class of with exacerbations of severe pain; autonomic features occurring non-traumatic primary headache (chronic tension-type, during exacerbations and ipsilaterally to the pain side include migraine, etc) into which it fits.

conjunctival injection and/or lacrimation, nasal congestion and/ or rhinorrhea and ptosis and/or miosis. Complete response to Non-pharmacological therapeutic doses to indomethacin confirms the diagnosis. • Psychological evaluation is a generally accepted intervention to identify factors for delayed recovery and for cognitive Treatment assessment. Indomethacin in a progressively increasing dose of up to 100 • This along with patient education, reassurance, trigger

mg daily orally gives complete response. Maintenance doses identification, biofeedback, physical therapy, joint of indomethacin are smaller. manipulation therapy, and other occupational therapy may be considered if functional overlay is documented. Secondary Headache Disorders Headache Attributed to Whiplash Injury Eight categories deal with headaches due to identifiable secondary causes.[5-12] These are detailed as follows. Acute and chronic whiplash injury (WI) headaches are new

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Ravishankar, et al: Headache disorders S47 diagnostic entities in the ICHD2 classification. WI is produced Headache Attributed to Subarachnoid Hemorrhage when acceleration and deceleration forces act on the neck, resulting in hyperextension, hyperflexion, and occasionally Subarachnoid hemorrhage (SAH) is by far the most common

hyperrotation of the cervical spine. Rear end or side-impact cause of intense and incapacitating headache of abrupt onset motor collisions are responsible for about 85% of all WI. Up (thunderclap) headache and remains a serious condition (50% to 80% of patients complain of headaches following a WI. of patients die following SAH, often before arriving at hospital and 50% of survivors are left disabled). 80% of patients with Diagnosis SAH have saccular aneurysms. SAH or the warning leak for

If headache, without any typical characteristics, develops saccular aneurysm or AVM should be suspected in any patient within 7 days after whiplash injury (sudden and significant with abrupt and new onset, severe, and unremitting headache. acceleration/deceleration movement of the neck) and resolves This suspicion is heightened when headache is associated with within 3 months or 3 months have not yet elapsed, it is termed neck rigidity, vomiting, and altered mentation.

“acute headache attributed to whiplash injury.” If it persists for more than 3 months after whiplash, it is termed “chronic Investigation headache attributed to whiplash injury.” • CT head scan (without contrast): It is the initial investigation of choice to detect SAH with a sensitivity of >90% during Investigation first 24 h. The pattern of hemorrhage can also suggest the Plain x-rays of cervical spine on flexion and extension are location of the ruptured aneurysm.

necessary to identify fracture, subluxation, or ligamentous • MRI (Flair) is more sensitive than CT scan from 3 to 14 days injury of spine. CT scan has improved sensitivity for detecting after the hemorrhage. fracture and has been shown to be faster and cost-effective • Cerebrospinal fluid examination is advised if neuroimaging in moderate and high risk trauma patients. 3D CT images is normal and the suspicion for SAH is high. RBCs are are of excellent quality. A cervical spine MRI is indicated in

present in nearly all the cases but usually clear from 4 to patients with abnormal neurological examinations suggesting 21 days. Xanthochromia is present due to the presence the possibility of radiculopathy or myelopathy. CT scan/ of oxyhemoglobin, methhemoglobin, and bilirubin. myelography may be more sensitive than MRI in some cases Oxyhemoglobin is released from the breakdown of RBCs for nerve root compression. Electromyogram and nerve after 2 to 12 h of the SAH and degrades into bilirubin by

conduction studies may provide evidence of radiculopathy 3rd to 4th day. or brachial plexopathy. • Angiography: Digital subtraction angiography (DSA), MRA, and CT angiography are required for detection Treatment and demonstration of the aneurysm. DSA is essential Pharmacological preoperatively to know the morphology. • Short-term use of simple analgesics (acetaminophen 1000 mg, aspirin 500--1000 mg), muscle relaxants (tizanidine 2-8 Treatment mg tds), or NSAIDs (naproxen 500 mg bd, ibuprofen 400

• Complete bed rest is advised, any kind of exertion should mg tds) is recommended. be avoided, and stool softeners should be given. • Headache due to greater occipital neuralgia may respond • Headache should be treated with opioids or acetaminophen to local anesthetic blocks with or without an injectable and mild sedation. NSAIDs are relatively contraindicated corticosteroid. because of the risk of gastrointestinal bleeding. • Persistent headaches and neck pain may benefit from

• Vasospasm is treated or prevented by the “triple H” therapy tricyclic antidepressants (amtriptlyline 10--75 mg hs, (hydration, hypertension and hemodilution) along with nortriptyline 25--75 mg hs). nimodipine. • Surgical clipping or endovascular coiling of the aneurysm Non- pharmacological to prevent re-rupture is the definite treatment, and allows • Short-term active exercise and physiotherapy are measures to prevent and treat vasospasm. recommended. • SAH is a neurosurgical emergency. The patient should

be referred as soon as possible to a specialist when the • Soft collar, immobilization, and more than 3 to 5 days of diagnosis is suspected. rest should not be advised • The mortality is 45% in the first month even in hospitalized patients and 50% of survivors are left with serious Headache Attributed to Cranial or Cervical neurological complications. Vascular Disorders Headache Attributed to Giant Cell Arteritis When a new headache occurs for the first time in close temporal

relation to a vascular disorder, it is coded as a secondary Among the arteritides and collagen vascular diseases, giant cell headache attributed to the vascular disorder. A diagnosis of arteritis (GCA) is most conspicuously associated with headache headache attributed to vascular disorder usually becomes (which is due to inflammation of cranial vasculature, mostly definite only when the headache resolves or greatly improves branches of the external carotid artery). It is seen after the

within a specified time after its onset. These include many fifth decade. GCA has variable clinical manifestations. Recent entities of which the ones that are important to recognize are repeated attacks of amaurosis fugax associated with headache described in the following. are very suggestive of GCA. Any recent persisting headache in Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S48 Ravishankar, et al: Headache disorders a patient over 60 years of age should suggest GCA and lead to one of the many conditions that can cause angiitis. Second step appropriate investigations. Patients may have swollen tender is to find the underlying condition (inflammatory, infectious,

scalp artery. Steroids should be started promptly without malignant, toxic) in a patient presenting with CNS angiitis. waiting for the biopsy. The major risk is of blindness due to anterior ischemic optic neuropathy, which can be prevented Investigation by immediate steroid treatment. Investigations are directed to establish systemic vasculitis. It is imperative to make the diagnosis of the CNS angiitis as well Investigation etiological diagnosis of the underlying systemic vasculitis.

• The ESR and C-reactive protein are high. It is used to monitor disease activity during corticosteroid therapy. Treatment • The diagnosis is confirmed by a biopsy of the temporal Treatment is directed toward the management of the underlying artery. Since involvement of the vessel may be segmental, systemic vasculitis e.g. corticosteroids and immunosuppressant positive yield is increased by obtaining a biopsy segment of (azathioprine and cyclophosphamide).

3–5 cm together with serial sectioning of biopsy specimens. Headache Attributed to Cerebral Venous Treatment Thrombosis • Treatment should be started immediately without waiting for the biopsy result. Headache is the most frequent and the most common presenting • Typically prednisolone is started in a dose of 40--60 mg/ symptom of cerebral venous thrombosis (CVT). It has no specific day and continued for a month. characteristic. It is usually accompanied by focal neurological

• Many cases of GCA are chronic and may require steroids deficit, seizures, or signs of raised intracranial tension. Headache for many years. resolves within 1 month after appropriate treatment • The disease activity is monitored by ESR and clinical assessment. Investigation • The single best non-invasive diagnostic tool is MRI along Headache Attributed to Primary Central Nervous with MRV, and in doubtful cases invasive venography System Angiitis should be done.

• Etiology of the CVT is established by investigations Headache is the dominant symptom in central nervous system relevant to the clinical setting. In general, investigations (CNS) angiitis (either primary or secondary). It is present include complete blood count, coagulation profile, anti- in 50--80% of cases. Nevertheless, it has no specific features phospholipid antibodies, protein C, protein S, etc. and is therefore of little diagnostic value until other signs are

present such as focal deficits, seizures, altered cognition, or Treatment disorders of consciousness. The pathogenesis of the headache is • Intravenous heparin should be started as possible. It is multifactorial: inflammation, stroke (ischemic or hemorrhagic), safe even in the presence of hemorrhagic infarct. Weight- raised intracranial pressure, and/or SAH. adjusted heparin nomograms for patients with venous thromboembolism are available.

Investigation • An initial bolus of 5000 units or 80 units/kg of unfractionated • Complete blood count: TLC is greater than 10,000/mm3 heparin followed by an infusion of 18 units/kg/h is given. without eosinophilia in 50% of case. • Treatment with oral anticoagulants (warfarin/acitrom) is • ESR is normal or mildly elevated. started along with heparin. When PT/INR value in the range • CSF often shows lymphocytic pleocytosis and elevated of 2--3 is achieved, heparin is discontinued. Warfarin is

proteins. continued indefinitely, if there is underlying coagulopathy, • Neuroimaging shows nonspecific multifocal ischemia. otherwise stopped after 3 to 6 months. • Cerebral angiography is abnormal in 75% of cases but is • When present, seizures are controlled with anticonvulsants. not pathognomonic. It shows segmental narrowing of the • Intracranial hypertension is treated with mannitol, medium sized vessels. diuretics, and acetazolamide.

• Meningeal and brain biopsy is abnormal in only three- • Adequate hydration should be maintained fourths of cases due to patchy involvement. Primary CNS • Appropriate antibiotics are given in cases of septic angiitis is the diagnosis of exclusion which is confirmed on thrombosis.. meningeal and the brain biopsy. • ANA or other markers are absent. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Treatment

Patients are treated with the combination of prednisone 40--60 Cerebral Autosomal dominant arteriopathy with subcortical mg/day and cyclophosphamide 100 mg/day. The response to infarcts and leukoencephalopathy (CADASIL) is an autosomal the treatment is far less dramatic than giant cell arteritis. dominant (with some sporadic cases) small artery disease of the brain characterized clinically by recurrent small deep infarcts, Headache Attributed to Secondary CNS Angiitis

subcortical dementia, mood disturbances, and migraine with aura. It is due to mutations of Notch-3 gene. Attacks of migraine First step is to diagnose CNS angiitis in a patient known to have with aura, with or without other neurological signs are present. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Ravishankar, et al: Headache disorders S49 It is a progressive disorder and presents with migraine with with a primary headache disorder or in close temporal relation aura and stroke. As a rough guideline, migraine appears in to a non-vascular intracranial disorder. A majority of patients

third to fourth decade, stroke in the fourth to fifth decade and have papilledema, but IIH without papilledema is also dementia in sixth to seventh decade. observed. Other symptoms may include tinnitus, transient visual obscurations, and diplopia. Investigation • MRI is always abnormal with striking white matter changes The various conditions that can be associated with IIH are on T2WI. enumerated in Table 7. • The diagnosis is made on a simple skin biopsy with

immunostaining of Notch-3 antibodies. The disease Diagnosis involves the smooth muscle cells in the media of small Progressive headache with at least one of the following arteries and it is due to mutations of Notch-3 gene. characteristics and fulfilling criteria C and D: (1) Daily • Genetic testing for Notch-3 gene mutation can also be done. occurrence, (2) diffuse and/or constant (non-pulsating) pain, (3) aggravated by coughing or straining. Intracranial

Treatment hypertension fulfils the following criteria. Neurological • The treatment is largely symptomatic. examination is normal or demonstrates any of the following • Patients are treated as for migraine. Triptans and abnormalities: papillodema; enlarged blind spot; visual field defect (progressive if intreated); sixth nerve palsy. Increased ergotamine should however be avoided because of their CSF pressure (> 200 mm HO in non-obese, > 250 mm HO vasoconstrictive property. 2 2

• Antiplatelet agents are used for lacunar infarcts. in obese) is measured by lumbar puncture in the recumbent position or by epidural or intraventricular pressure monitoring. Normal CSF chemistry (low CSF protein is acceptable) and Headache Attributed to Non-Vascular Intracranial cellularity. Headache improves after withdrawal of CSF to Disorder reduce pressure to 120--170 mm HO and resolves within 72 h 2 of persistent normalization of intracranial pressure. Idiopathic intracranial hypertension

Idiopathic intracranial hypertension (IIH) is the persistent Investigation increase in intracranial pressure in the absence of any • Ophthalmologic assessment is done to look for papilledema intracranial lesions such as intracranial tumor, hydrocephalus, and atrophy. Visual field charting and assessment intracranial infections, dural sinus thrombosis or hypertensive (perimetry) are performed to chart the blind spot.

encephalopathy. The term benign intracranial hypertension • CT scan or MRI is done to show normal cranial and cerebral is not used anymore because the development of the disease characteristics and exclude a venous thrombosis. A high can entail complications like vision loss. IIH is a diagnosis quality ≥ 1.5 T MRI and MRV are mandatory to rule out of exclusion. Careful detailed history is essential. IIH most mass lesions, dural venous sinus thrombotic occlusion,

commonly occurs in young obese women. It can occur along and dural and parenchymal arterio-venous, fistula or AV malformation. • If required, a DSA may be performed to rule out a vascular Table 7. Conditions associated with IIH malformation. Obstruction to venous drainage • CSF examination is done by lumbar puncture after Cerebral venous sinus thrombosis excluding the possibility of an intracranial space occupying Jugular vein tumor lesion as it is imperative to measure CSF pressure.

Superior vena cava syndrome Increased right heart pressure Treatment Endocrine disorders • Primary goal is to prevent vision loss and symptom control. Addison’s disease Hypoparathyroidism Patients without papilledema are not at risk of visual loss. Obesity, recent weight gain • Papilledema improves over a period of 6 months after Exogenous agents reduction of ICP. Amiodarone • No treatment is required if the patient has minimal Cytarabine symptoms and visual function is normal. However, all

Corticosteroids (particularly withdrawal) patients require serial monitoring of visual function, Cyclosporine especially field charting for signs of visual impairment. Growth hormone Levothyroxine (children) • Weight reduction---weight loss improves papilledema Lithium carbonate by reduction of intracranial pressure. Weight loss may Levonorgestrel (Norplant) also be beneficial for comorbid medical conditions like Tetracycline and related compound hypertension and sleep apnea. Minocycline

• Reduction of CSF pressure: Doxycycline • Drugs---Medical treatment includes carbonic anhydrase Vitamin A inhibitors (e.g. acetazolamide and topiramate) and Vitamin supplements, liver Infectious or post-infectious conditions loop diureties such as frusemide. The usual dose of HIV infection Lyme disease acetazolamide is 250--500 mg tds (up to 4 g/day may After varicella be needed) alone or in combination with a loop diuretic Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S50 Ravishankar, et al: Headache disorders such as frusemide 40--120 mg/day. Corticosteroids are • Oral or intravenous caffeine and theophylline have also reserved for urgent management of patients with visual been used by the virtue of their constrictive effect on

loss and should not be used for the routine treatment intracranial arteries, leading to increased CSF pressure and of IIH. reduction in headache. • Lumbar puncture---Repeated LPs have been used to • One to two cups of coffee provide good amount of caffeine. lower ICP but have not been systematically studied. The • Epidural blood patch is given in patients who have failed procedure is uncomfortable, and usually not acceptable initial treatment.

to the patient. • Epidural infusion of dextran, fibrin glue, or intrathecal fluid • Surgery---Surgery should be considered when medical infusion has also been tried. treatment fails or when visual function deteriorates. The • Surgery is considered when conservative and less invasive main procedures performed include lumbo-peritoneal approaches fail. shunt, ventriculo-peritoneal shunt, optic nerve sheath Medication Overuse Headache fenestration, and venous stenting.

• Tricyclic antidepressants, valproate, and calcium channel blockers should be used cautiously because MOH is an interaction between therapeutic agents used. of the fear of weight gain and fluid retention. Simple MOH should be suspected in a patient not responding to analgesics/NSAIDS are adequate for patients with only standard prophylactic drugs. Diagnosis is important as both symptom is headache. Serial LPs may also be performed acute and prophylactic drugs become ineffective as long as

for relief of headache. patient is overusing these analgesic medications. Maintenance of a headache diary is important for diagnosis, and both When to refer to a specialist? physicians and patients need to be educated about its use. A patient needs to be referred to a headache specialist or a neurologist if there is no improvement of headache after Diagnosis withdrawal of CSF to reduce pressure between 120 and 170 According to the IHCD2 criteria, the diagnosis of MOH can

mm HO within 72 h, persistent headache despite adequate be made in any patient who is having headache for more than 2 medications or progressive visual loss. 15 days per month and is regularly overusing medications for more than 3 months. Overuse is said to be present, if Spontaneous Low Pressure Headache ergots, triptans, opioids, and combination analgesics are taken for more than 10 days per month. For simple analgesics

This condition was first recognized in 1930s. More has been the duration has to be more than 15 days per month. The diagnostic criteria of MOH are based on the number of tablets learned about it since the early 1990s when MRI became taken per month as well as the number of days per month for widely available and after pachymeningeal gadolinium which the drug is used. They are difficult to use in our country enhancement was seen in MRI of headache patients. A much

as very few patients are in the habit of maintaining a diary. broader clinical and imaging spectrum of the disease is now recognized and a substantially larger number of patients Treatment are diagnosed. Headache that occurs upon standing and is relieved by lying down occurs typically in low pressure • Patient education and proper counseling is very important headaches. It remains commonly misdiagnosed when there as it helps to motivate the patient for withdrawal of

is no history of a spinal tap. Headache aggravated by valsalva overused medication, to tolerate the withdrawal symptoms, maneuver is suggestive of spontaneous low pressure CSF and also prevent the patient from returning back to the overused drug. headache. It should be considered an important and relatively • The next step is to discontinue the offending medication. frequent cause of new daily persistent headache in young and It can be done either suddenly or gradually either as an

middle aged individual. However, it is important to note that outpatient or inpatient. Abrupt withdrawal is the treatment not all orthostatic headaches are due to CSF leak and not all of choice. Withdrawal symptoms usually last 3--4 days. CSF leak headaches are orthostatic. Cervical or interscapular They include withdrawal headache, nausea, vomiting, pain may precede orthostatic headache (by days or weeks). arterial hypotension, tachycardia, sleep disturbances,

Lingering non-orthostatic headache may precede orthostatic restlessness, anxiety, and nervousness. headache (by days, weeks, or months). CSF rhinorrhea and • Bridge therapy is required to treat withdrawal symptoms. CSF otorrhea do not cause positional headache. NSAIDs, chlorpromazine, valproate, steroids, or clonidine Investigation may be used. Most experts recommend steroids for • CSF examination: opening pressure is typically low, outpatient withdrawal, while IV sodium valproate can be

sometimes unmeasurable. CSF protein---normal or elevated used for in-patient withdrawal. Oral steroids 60--100 mg up to 100 mg/ kg and normal glucose and cells. have been used for 5--6 days in a tapering dose. IV DHE • CT brain scan is usually normal. 1--2 mg 8 hourly is preferred as it has a very low likelihood • MRI may show the following signs: diffuse pachymeningeal of development of medication overuse but unfortunately

enhancement and descent (sagging/ sinking) of brain this drug is not available in India. (cerebellar tonsils) • Patient should be instructed about the proper use of acute medications. He should be advised to take it only if he has Treatment severe headache. They should be told not to take the drug • Bed rest and avoidance of upright position. in anticipation. NSAIDS such as naproxen are preferred as • Adequate hydration should be maintained. they rarely cause MOH.

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Ravishankar, et al: Headache disorders S51 • Migraine preventive medications are an important Headache Attributed To Infection component of withdrawal treatment strategy and should start as soon as possible during the withdrawal process. Headache is a common accompaniment of intracranial infections

Topiramate and divalproex sodium have been shown to and systemic viral infections. It is also common with sepsis be beneficial. and rarely may it accompany other systemic infections. In • Relapse following successful withdrawal is a major intracranial infections, headache is usually the first and the most problem. frequently encountered symptom. The occurrence of a new type • Prevention of development of MOH can be done by of headache which is diffuse, pulsating, and associated with a

using drugs which rarely cause MOH such as NSAIDs general feeling of illness and fever should raise the suspicion or have a low probability of causing MOH such as of an intracranial infection even in the absence of a stiff neck. aspirin, acetaminophen, and triptans and these should Headache Attributed to Bacterial Meningitis be preferred for acute treatment. Use of combination analgesics, tranquilizers, and opioids should be avoided

in the treatment of headache. Adequate prophylaxis can Bacterial meningitis usually presents with a triad of headache, help to reduce the overuse of acute medications. fever, and altered sensorium. Diagnosis Headache Attributed to Substance Withdrawal Headache is the most common and may be the first symptom of bacterial meningitis. Fever and vomiting may be associated. The Headache may be produced on withdrawal of few substances history is usually of short duration. There may be associated

after chronic use like caffeine, opioid, and estrogen. They history of an ear discharge, or throat infection. may be diagnosed if there is temporal relationship between headache and withdrawal of substance known to produce Investigation withdrawal headache. • The hemogram shows polymorphoneuclear leuckocytosis and positive acute phase reactants indicative of infection Headache Attributed to Withdrawal From Chronic • A cerebrospinal fluid examination (CSF) is the confirmatory use of Other Substances test.

• CSF exhibits polymorphonuclear leuckocytosis with markedly decreased sugars and increased proteins. It has been suggested but without sufficient evidence that • CSF samples should also be sent for gram stain, culture, withdrawal of the following substances may cause headache: and sensitivity to look for the causative organism. corticosteroids, tricyclic antidepressants, selective serotonin • Chest x-ray, blood culture, and culture from throat, ear reuptake inhibitors (SSRIs), NSAIDs.

discharge, skin lesions (if any) should also be done. • Imaging of the brain with a CT scan or MRI is not usually Investigation required for confirmation. • No specific investigations are needed as the diagnosis is based on history of temporal relation between headache Treatment and withdrawal of offending agent. • Systemic antibiotics are the mainstay of treatment and the • If there is any doubt about diagnosis then investigations choice of antibiotics depends upon the causative organism

are required to rule out a secondary cause. grown on the CSF culture/blood culture. • In many cases, culture reports are either not contributory or Treatment are negative, in which case empirical antibiotics [Table 8] are • Treatment is directed toward total withdrawal of the started assuming the most common organism (depending offending drug because after total withdrawal headache upon the age of the patient). subsides within 1 week period. • The incidence of resistance to antimicrobials is gradually

• Acute symptomatic drugs like NSAIDs may be used if increasing and therefore patients should be closely headache is problematic. Specific treatment for the opioid monitored, and if there is no clinical response observed in withdrawal should be undertaken. the first few days, antibiotics should be changed. Table 8: Antimicrobials in bacterial meningitis Age Likely organism Antimicrobial drug 0--12 weeks Group B Streptococcus, Listeria III Generation cephalosporin + Ampicillin

3 months--50 years S. pneumoniae, H. influenzae N. Meningitidis III Generation cephalosporin ± Vancomycin 50 years S. Pneumonia, Listerea, gram-negative Bacilli As above + Ampicillin Skull fractures S. aureus, S. pneumoniae As above Post surgery As above Vancomycin + Ceftazidime Dosage of antibiotics Ceftriaxone 4 g/day Cefotaxime 8--12 g/day Ceftazidime 8 g/day Vancomycin 3 g/day Ampicillin 12 g/day Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S52 Ravishankar, et al: Headache disorders • Steroids are not indicated in acute bacterial meningitis toxoplasmosis, systemic vasculitis), mildly reduced except in children or in conditions where patients develop (tubercular meningitis, viral meningitis) or significantly septicemic shock. reduced (cryptococcal meningitis). Proteins in the CSF are

high in almost all cases except with chemical meningitis Headache Attributed to Lymphocytic Meningitis and cryptococcal meningitis. • The CSF should also be evaluated for cryptococci using India ink and for cryptococcal antigens (in cases of suspected A variety of organisms cause a lymphocytic reaction on fungal meningitis), acid fast bacillus (TB meningitis), PCR infecting the subarachnoid space and cause lymphocytic (TB meningitis, viral meningitis), toxoplasma antigen

meningitis. Headache is a common manifestation of these (toxoplasmosis). Specialized investigation are required as conditions. Causes of lymphocytic meningitis include: and when needed according to the individual case. infections: tuberculosis, viral infections, borrelia, brucella, • HIV serology should be done in all patients with ameobic meningoencephalitis, toxoplasmosis, fungal meningitis; malignancy: leukemic meningitis, systemic cancer lymphocytic meningitis as it has an important bearing on

the management. with meningeal seedlings; chemical meningitis: drug induced, contrast material induced; and systemic causes: vascultits/ Treatment connective tissue disorders • The treatment of various forms of lymphocytic meningitis is individualized. Diagnosis • There are no specific guidelines for many of these treatments Headache, photophobia, and nuchal rigidity are the main and there are no studies in the Indian population to decide symptoms of lymphocytic or non-bacterial meningitis.

what regimen is ideal and correct. Fever may or may not be an accompanying feature to begin with, but is almost invariably seen at some time during the Tubercular Meningitis course of the disease. Headache is usually generalized, associated with stiffness of the neck and altered sensorium • Patients with tubercular meningitis (TBM) require in advanced cases. The onset of the symptoms may be acute anti-tuberculous drug treatment in the standard doses.

as in viral infections or may be subacute or gradual as in Treatment should ideally be started as early as possible chronic situations like fungal meningitis, tuberculosis, or for better results. toxoplasmosis. In chronic meningitis, patients usually have • There are no studies to recommend which drug a history of prolonged constitutional symptoms like weight combination is ideal. Rifampicin (R) (15 mg/kg),

loss, malaise, and evening rise of temperature. A history of isoniazid (H) (10 mg/kg), pyrizinamide (Z) (30--50 mg/ prolonged immunosuppression, steroid intake, diabetes could kg), ethambutol (E) (15--20 mg/kg), streptomycin (1.25 be contributory in some patients. Patients with viral meningitis mg/kg) (M) are the usually prescribed drugs. At least have an acute onset of these symptoms but the clinical course four drugs should be given at the start of the treatment

of the disease is milder and recovery can be spontaneous. (RHEZ/RHEM). • It is recommended that these four drugs be given for at least Investigation 3 months and thereafter at least three drugs be continued • The hemogram might be normal or may show a lymphocytic for at least 1 year or 15 months. pleocytosis with a raised ESR. • In the initial phase of treatment steroids (dexamethasone---2 • X-ray of the chest might reveal tuberculosis which might mg/kg or prednisolone 1 mg/kg) are strongly recommended.

be clinically silent; it may show evidence of vasculitis or Steroids need to be given for at least a month before tapering sarcoidosis. them off. • Unlike in acute meningitis, here imaging of the brain is • Periodic checks of liver function tests should be carried out usually the first investigation. in all patients as the chances of developing drug induced • The contrast enhanced CT scan head in patients with hepatitis after starting anti-tuberculous treatment (ATT) in

chronic meningitis shows evidence of basal exudates patients with TBM is very high. usually in the cisternal spaces, and/or evidence of vascular • Patients should be reassessed periodically for improvement. compromise of perforator arteries due to these exudates If they fail to show improvement or develop persistent causing infarcts. headache or start worsening or show focal neurological • CT scans also show tuberculomas, cryptococcomas, deficits, a repeat evaluation including neuroimaging should

and toxoplasma granulomas which are evident as ring be done. Hydrocephalus needs to managed by doing a enhancing lesions on imaging. Evidence of hydrocephalus ventriculoperitoneal shunt. if present can also be seen. • Drug resistance is frequently observed with TBM and needs • MRI of the brain is required in cases where it is difficult to to be managed by giving second line drugs like capreomycin, differentiate between various inflammatory granulomas kanamycin, or quinolones. If patients develop features of

in the brain. non-responsiveness or worsen in their clinical condition • MRI of the spine is needed if there is a suspicion of they are best referred to specialists for further management. arachnoiditis. • CSF examination is required in all cases. All patients with Fungal Meningitis lymphocytic meningitis show lymphocytic pleocytosis in • Cryptococcal meningitis is the commonest fungal meningitis. the CSF. Depending upon the cause the CSF sugars might They should be treated with antifungals. Amphotericin B,

be normal (chemical meningitis, lymphocytic meningitis, flucytosine, fluconazole are the ones that can be used. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Ravishankar, et al: Headache disorders S53 • When diagnosed correctly, such patients are better head injury, or history of recent head surgery should heighten managed at major hospitals with adequate experience in clinical suspicion. The most common organisms causing

the management of fungal meningitis. brain abscess include streptococcus, Staphylococcus aureus, bacteroides species, and enterobacter. Viral Meningitis Diagnosis • Headache is the most important feature. Viral meningitis is almost always self limiting and except in • Fever may or may not be present, and if present is usually some cases no specific treatment apart from general treatment associated with chills. is required. Some patients with extremely severe meningitis

• Patients may have focal deficits on neurological examination with herpes simplex virus might require acyclovir. depending upon the area of the brain where the abscess is located. Headache Attributed to Encephalitis • Approximately 50% will have seizures and vomiting and nausea, more so in the morning. Most common causes of encephalitis are the viral infections. • Neck rigidity is usually not seen.

Herpes simplex virus, arbovirus, and mumps are known causes • Predisposing factors include infections of paranasal sinuses, of encephalitis. Except for HSV encephalitis, the causative virus ears, jaws, teeth or lungs. is identified in fewer than half of cases of encephalitis even at referral centers. Investigation • Routine hemogram might be normal; CSF examination is Diagnosis contraindicated in suspected or proven brain abscess.

Patients with encephalitis usually present with high grade fever, • Imaging of the brain clinches the diagnosis. headache, and altered sensorium. The headache is like any other • In the early stage of cerebritis, the abscess appears as an intracranial infection and the fever is usually high grade with area of hypodensity in the CT scan or hyperintensity on chills and rigors. Patients with encephalitis characteristically an MRI scan.

do not have neck rigidity. Behavioral problems are common, • In later stages, the abscess presents as a ring enhancing particularly in patients with herpes simplex encephalitis lesion with a thick ring which enhances on contrast scans. who present with apathy, aphasia, or generalized irritability. Seizures are common in viral encephalitis. Treatment • Intravenous antibiotics are required in all, and surgery in Investigation most cases with brain abscess.

• The CSF in encephalitis demonstrates a lymphocytic • A judicious combination of antibiotics, depending pleocytosis with normal or mildly reduced sugars and upon the likely organism, is to be given for a long time. normal proteins. Most regimens include penicillin or a third-generation • Herpes virus antigen can be detected in the CSF and PCR cephalosporin and metronidazole. In case the abscess for viral DNA may be positive; however these tests are follows a surgery, or head injury, vancomycin should be

available only in referral centers. added to the regimen. • The CT scan may show changes with hypointense areas in • Antibiotics should be continued for at least 6 to 8 weeks. the temporofrontal region. In non-responders, or in patients with multiloculated • MRI is a better modality of investigation and shows areas abscesses or in patients with large abscesses, early surgery of hypointensity in the frontotemporal region, even in cases is recommended.

where the CT scan may be normal. • Surgery might be in the form of a thick needle aspiration • EEG shows abnormal lateralized discharges in the region or a decortication of the abscess. of the frontotemporal region. • Anticonvulsants are usually given for about 3 months after surgical excision. Recurrence is common and therefore repeat imaging after 6 months after a successful treatment Treatment of the brain abscess is recommended. • Acyclovir is the drug of choice and is given in 10 mg/kg

every eight hourly for at least 14 days or till the CSF PCR comes negative (whichever is earlier). Headache Attributed to Subdural Empyema • If the treatment begins in time the response to treatment can be very rewarding and a clinical cure might be expected. Subdural empyema is often secondary to sinusitis or otitis • Anitepileptics might be required if there are associated media. It may also be a complication of meningitis, seizures. osteomyelitis of the bones of the skull, or head injury.

Headache Attributed to Brain Abscess Diagnosis Patients usually present with headache which evolves acutely. Headache is a common finding in patients with brain abscess. The presence of a febrile encephalopathy with focal Investigation neurological deficits is indicator of an evolving brain abscess. • Early diagnosis is best made by CT or MRI which The presence of an associated ear discharge, frontal sinusitis, demonstrates pus accumulating in the subdural space.

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S54 Ravishankar, et al: Headache disorders Treatment Since there are disorders not commonly seen in practice and • Untreated subdural hematomas are uniformly fatal. therefore they have not been discussed in detail. • Combined medical and surgical treatment is definitely

required. Posterior fossa empyemas usually require Headache or Facial Pain Attributed to Disorder of a craniotomy, others might benefit with burr whole Cranium, Neck, Eyes, Ears, Nose, Sinuses, Teeth, evacuation. Mouth or Other Facial or Cranial Structures • Antibiotics should be given for at least 6--8 weeks. The disorders of the structures in and around the neck and Headache Attributed to Systemic Infection head region have long been held responsible for headache.

Degenerative disorders of the cervical spine, temporomandibular Headache in systemic infections is usually a relatively joints, and diseases of the paranasal sinuses are so commonly inconspicuous symptom and diagnostically unhelpful. These reported to be “associated” with headaches that headache is conditions are mostly dominated by fever, general malaise, and often said to be the caused by these disorders. These associations systemic symptoms. Nevertheless, some systemic infections,

have not been supported by evidence as many people who have particularly influenza, have headache as a prominent symptom these disorders do not have headaches and vice versa. Therefore along with fever and other symptoms. they are not discussed in detail here. Headache Attributed to HIV/AIDS Headache Attributed to Disorder of Eyes Headache in patients with HIV infection could be manyfold. Headache attributed to acute glaucoma At the time of seroconversion, patients with HIV infection

Acute angle closure glaucoma presents with a painful red eye may have associated aseptic meningitis. These patients, with blurring of vision and occasionally sudden blindness. A because of diminished immunity, are prone to many cranial closure of this angle due to any reason tends to precipitate an infections---like tubercular meningitis, cryptococcal meningitis, attack of acute glaucoma as the intra-ocular pressure increases toxoplasmosis, etc. Effective treatment of these infections

to very high levels in a few hours. Pain is severe, boring, and usually resolves the headache. Prophylaxis might be required in located in or around the eyes. most such infections, if the CD 4 count is low in AIDS patients. Diagnosis Diagnosis Pain in the eye and behind or above it, fulfilling criteria C Headache is dull and bilateral, reminiscent of tension-type and D. Raised intraocular pressure, with at least one of the headache. The confirmation of HIV infection is essential to

following: conjunctival injection; clouding of cornea; or visual discriminate headache caused by additional intracranial disturbances. Pain develops simultaneously with glaucoma. condition that are associated with HIV infections (e.g., Pain resolves within 72 h of effective treatment of glaucoma cryptococcal meningitis). Therefore, it is crucial to obtain neuroimaging studies and CSF examination to distinguish Investigation between headache as a general symptom of systemic HIV

• High index of suspicion in a patient with red fiery eye infection and one that is caused by CNS infection or conditions • Raised intraocular pressure in excess of 28 mmHg that accompany HIV disease. Headache in AIDS can also be caused by CNS tumors like primary CNS lymphoma and Treatment metastatic systemic lymphoma. • Pilocarpine or other mitotic drugs---to make the iris cornea angle wider Treatment • Mannitol to reduce intraocular pressure. • The pain of HIV AIDS usually responds to routine • Steroids.

analgesics. • Surgery when condition stabilizes. • Management of other primary headaches remains the same in patients with HIV. Headache Attributed to Refractive Errors • Opportunistic infections in AIDS should be managed accordingly, and this results in improvement of the headache of HIV patients. Refractive errors are very commonly thought to be associated with headache, to the extent that in every individual with

Headache Attributed to Disorder of Homoeostasis any type of headache a visual acuity testing is advised. It is actually a misconception since refractive error is an uncommon cause of headache. Patients rarely complain of Included in this segment are headaches attributed to abnormal headache, they usually have a heaviness of the head or eye blood circulation in the brain. Previously these were called as soreness on times when they are awake and watching events

Headache associated with metabolic or systemic disease. Headaches like television or reading. can be caused by sudden alteration in the arterial pressure as in pheochromocytoma, and by myocardial ischemia are included in this section. In addition, disorders of homoeostatic Headache Attributed to Ocular Inflammatory mechanisms affecting a variety of organ systems, including disorder altered arterial blood gases, volume disturbances as in dialysis,

and disorders of endocrine function, are covered in the ICHD2. Ocular inflammations are categorized in a variety of ways Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Ravishankar, et al: Headache disorders S55 including by anatomic location (cornea, iris, sclera, choroid, etc), Diseases of the Paranasal Sinuses type of inflammatory response found (e.g., nongranulomatous or granulomatous), temporal profile of symptoms (acute, Acute Sinusitis subacute, chronic), and cause (e.g., viral, bacterial, fungal,

• Inflammation of the nasal membrane, sinuses, and their autoimmune) vicinity cause the symptoms of sinusitis. • Purulent discharge and headache develop with acute nasal Diagnostic Criteria sinusitis, following an upper respiratory tract infection. • Nasal polyps can also cause similar symptoms due to Pain in the eye and behind or around it, fulfilling criteria C and obstruction of the meatus of the sinuses. Maxillary sinusitis

D. Ocular inflammation diagnosed by appropriate investigation. also may be caused by inflammations of dental gin, such Headache develops during inflammation. Headache resolves as periapical abscesses, or of iatrogenic origin as a result within 7 days after relief of the inflammatory disorder of dental surgery. • Allergies, hypothyroidism, cystic fibrosis, immune suppression, and diabetes mellitus predispose to the Treatment • Treatment of the underlying cause---antiviral, antibacterials.

development of sinusitis. Trauma to the nasal sinus with fractures also may give rise to nasal sinusitis. • Steroids in cases of autoimmune uveitis. • Systemic steroids in severe cases. • Maxillary sinusitis-pain felt over the sinuses may radiate to the ear and teeth. Skin over the sinuses is tender to • Cycloplegics to abolish the associated ciliary spasm. percussion. There is purulent discharge from the middle meatus with mild anosmia. Referral • Frontal sinusitis-Pain is behind the eyes and in and around

The patients should be referred to an ophthalmologist as soon the centre of the head. Maximum on getting up in the as the diagnosis is made, as most of these conditions can be morning and improves on ambulation. There is tenderness severe and require expert management. over the sinus and the supraorbital nerve, and there is purulent discharge from the nasofrontal duct. Headache Attributed to Rhinosinusitis • Ethmoidal and sphenoidal sinusitis-the pain in both the

cases is poorly localized but is usually retro-orbital and Headache is commonly attributed to diseases of the nose and the eyes are sensitive to pressure. There is presence of paranasal sinuses. As the nerve supply of the nasal sinuses is post-nasal discharge. the same as that of the frontal and temporal regions, the pain • Chronic Sinusitis-chronic inflammation of the nasal sinus of the sinuses is often referred to the skin in the region of the mucous membranes, which become hypertrophy and cause

scalp and face. Infection/inflammation of the nose and the nasal a permanent disturbance of nasal ciliary action and altered sinuses tend to worsen the primary headaches. The diseases of function of the mucous glands. the following structures can cause headache Diagnosis Diseases of the Nose • Frontal headache accompanied by pain in one or more • Nasal Septum-Deviation of the nasal septum may cause regions of the face, ears or teeth, and fulfilling criteria C

acute disease of the nasal sinuses that causes facial pain. and D Acute or chronic sinusitis can complicate the picture. • Clinical, nasal endoscopic, CT and/or MRI imaging and/ • Septal Hematoma and Septal Abscess-presents with a or laboratory evidence of acute or acute-on-chronic purulent and swollen nasal septum, pain is localized and rhinosinusitis;[1,2] severe, marked sensitivity to local pressure, reddening • Headache and facial pain develop simultaneously with

of the tip of the nose. Seen in granulomatous disease, onset or acute exacerbation of rhinosinusitis polychondritis, or other autoimmune disorders. • Headache and/or facial pain resolve within 7 days after • Inflammatory Rhinosinusitis-rhinorrhea, elevated remission or successful treatment of acute or acute-on- temperature, pain affecting the middle part of the face and chronic rhinosinusitis the area of distribution of the first and second trigeminal

braches, and symptoms of an infection of the upper Investigation respiratory tract are the symptoms. • Polymorphonuclear leukocytosis raised ESR. • Allergic Rhinitis---does not cause primary pain but facial • Culture from the pus/purulent discharge to isolate the pain may occur as a secondary development. It is typically organism responsible seasonal presenting with nasal obstruction, nasal pain, and • A transillumination examination can reveal pus levels in rhinitis. sinusitis.

• Vasomotor Rhinitis---is due to excessive reactivity of the • Plain radiographs of the nasal sinuses may show shadows mucous membrane. The nasal discharge is clear, and the or fluid levels. It is not possible to differentiate chronic nasal mucous membrane is swollen and displays a slight from acute sinusitis by means of radiologic examination; reddening compared with inflammatory rhinitis. this must be done on the basis of clinical features and the

• Atrophic Rhinitis---there is reduced reactivity of the nasal examination findings. mucous membrane. Mucous production is reduced, and • A CT or magnetic resonance tomogram may be helpful the nasal mucous membrane is dry, encrusted, inflamed, in differentiating between a cystic and a solid lesion or a and irritated. fluid level. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S56 Ravishankar, et al: Headache disorders Treatment other causes of compression of trigeminal nerve leading to • Antibiotics and oral decongestants---depending upon the symptomatic trigeminal neuralgias in 5% to 7% of patients. organism and the sensitivity of the cultures. These groups of patients are classified as symptomatic

• Decongestants to be given for not more than 3 days. trigeminal neuralgias. In these cases, clinically some atypical • Steam inhalation, warm compresses. features may be found such as the presence of sensory • Irrigation of the sinuses by saline and by antibiotics. impairment, bilaterality (like in MS), and the presence of non- • Removal of the obstruction, like polyps, deposits can be paroxysmal pain. cleared surgically. • Drainage improved surgically by increasing the size of the Investigation

orifices draining the sinuses. • All patients of trigeminal neuralgia should undergo MRI, • Correction of the deviated nasal septum. preferably using 3D reconstruction techniques to assess the relationship of nerve with the neighborhood blood vessels Headache Attributed To Psychiatric Disorder and to rule out causes other than the vascular compression. Patients with psychosis seldom complain of headache, in fact Treatment

it is considered that these patients perceive lesser pain than The management of trigeminal neuralgia includes normal individuals. Patients who have a delusion that they pharmacotherapy and neurosurgical intervention through have a lesion in the brain like a space occupying mass, or a various neuroablative procedures. delusion that someone has implanted a machine inside their head which causes the headache is an example of the condition Pharmacotherapy

when headache can occur in patients with psychosis. • Carbamazepine was tested by many double-blind placebo- controlled randomized trials and has been found to be Cranial Neuralgias and Central Causes of Facial efficacious in 75% of patients. • Treatment is usually started with low dose carbamazepine Pain (100-200 mg/day), which is then up-titrated gradually. Usually the maintenance dose of 400-1200 mg per day is Diagnosis required. Neuralgias are defined as sharp, intense, electric shock like

• Physicians have to be cautious about various side effects of pain abrupt in onset and termination limited to the distribution carbamazepine especially in the elderly patients. of one or more divisions of a cranial nerves or cervical roots • Other second line drugs used for treating trigeminal or nerves. The facial pain syndromes have the common neuralgia include oxcarbazepine, phenytoin, baclofen, denominator of pain in the face which may be localized to either lamotrigine, and gabapentin [Table 9].

one or more divisions of trigeminal nerve. Unlike neuralgias, they are diffused and are more long-lasting. These diverse Surgical Treatment conditions can be divided into three broad groups as follows. • Surgical intervention is required for patients who are • Primary neuralgias refractory to medical treatment and continue to have • Pain of cranial and cervical nerve origin other than primary significant pain despite adequate trial of medications. Also, neuralgias

specific secondary causes may be amenable to surgical • Central pain in the face and head treatment such as tumors. • Primary Neuralgias • Following surgical options are available for refractory primary (classical) trigeminal neuralgias. Trigeminal Neuralgia • Micro-vascular decompression (MVD) is the most definitive treatment for trigeminal neuralgia in younger patients. In Diagnosis MVD, the trigeminal nerve is exposed, the offending blood

Trigeminal neuralgia is a unilateral disorder characterized vessel(s) identified, and decompressed. Most common by electric shock like pains, abrupt in onset and termination finding is a segment of superior cerebral artery compressing (seconds to up to 2 min), limited to the distribution of one the nerve at the root entry zone. After decompressing it, the or more divisions of trigeminal nerve. Most commonly, the operator places a piece of felt between it and the nerve to

second and third divisions of trigeminal nerve get affected. ensure a permanent separation. In less than 5% of patients, the first division is affected. Pain • Pain relief following MVD is almost always immediate and is commonly evoked by trivial stimuli including washing, its long-term results are impressive. shaving, smoking, talking, and/or brushing the teeth which • Around 80% of patients remain pain-free up to 2 years and

are known as trigger factors. Frequently, however, it occurs up to 64% patients remain pain-free up to 10 years post- spontaneously. Trigeminal neuralgia runs a chronic course; the MVD. In expert hands, operating complications are low. pains usually remit for variable periods of time to recur again. • For elderly patients or those with medical complications Despite severe pain, clinically no neurologic (sensory) deficit where MVD is not possible, percutaneous radiofrequency

is seen in primary trigeminal neuralgias. thermocoagulation of trigeminal nerve sensory root as it leaves the Gasserian ganglion is the procedure of choice. Etiology • Alcohol block of the peripheral branch of the division of Compression of the trigeminal nerve by a blood vessel at root the trigeminal nerve that is painful can be attempted. Initial entry zone is the cause of trigeminal neuralgia in majority pain relief is good but the recurrence rates are high within

of patients. In many, no cause can be found. There may be 6 months to 1 year. The procedure can be repeated. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Ravishankar, et al: Headache disorders S57 Table 9: Drugs for trigeminal neuralgia Drug Initial dose Maintenance dose Important and common adverse effects Carbamazepine 100-200 mg 600-1200 mg Sedation, dizziness, mental slowing, rash, hyponatremia, drug interactions

Oxcarbazepine 150-300 mg 600-1200 mg Better tolerated than Carbamazepine but hyponatremia is slightly more. Spectrum of adverse effect is same Gabapentin 100-300 mg 600-2400 mg Sedation, memory impairment, peripheral edema Phenytoin 100- 300 mg 300-400 mg Sedation, ataxia, dizziness, mental slowing, rash, drug interactions, gum hypertrophy, lymphadenopathy, folate deficiency, osteopenia, acne Lamotrigine 25-50 mg 200-400 mg Rash, sedation, ataxia, dizziness

Baclofen 10 mg 30-80 mg Sedation, ataxia, fatigue, GI symptoms, muscle weakness. • Other upcoming procedures for refractory trigeminal densely interwoven dilator veins, U-shaped arterial loops, or neuralgia include percutaneous balloon compression of angiomas. Neuroimaging including x-rays, CT, meylo-CT, and the trigeminal ganglion and stereotaxic radiosurgery with MRI usually are reported to be normal. The most important

gamma knife. However, early recurrences are still a problem. diagnostic procedure is the complete relief of pain following local anesthetic blockade of the C 2 spinal nerves. Glossopharyngeal Neuralgia Treatment Diagnosis • Pharmacotherapy is usually known to be non-rewarding • Glossopharyngeal neuralgia is a severe transient stabbing in C2 neuralgia. pain experienced in the ear, in the base of tongue, in the • Surgical approach remains the definitive treatment.

tonsillar fossa, or beneath the angle of jaw. Decompression of the entrapped nerves (due to scarring) • The pain is therefore felt in the distribution of the can be done. auricular and the pharyngeal branches of the vagus and glossopharyngeal nerves. Rare cranial neuralgias • It is commonly provoked by swallowing, talking, coughing, • Nervous intermedius neuralgia (brief paroxysms of pain and may remit and relapse similar to trigeminal neuralgia. are felt deeply in the auditory canal).

• Glossopharyngeal neuralgia is in many ways similar to • Superior laryngeal neuralgia (pain paroxysms in throat, trigeminal neuralgia. submandibular region and under ear and is relieved by • The diagnosis of glossopharyngeal neuralgia is essentially local anesthetic block of superior laryngeal nerve). clinical, based on the history of characteristic paroxysms • Nasociliary neuralgia (touching the outer aspect of one of lancinating or aching pain. nostril causes stabbing pain lasting minutes to hours on

• Neurologic, dental, and imaging studies are normal. that side of nose radiating up to the medial frontal region), • Supra-orbital neuralgia (pain in the region of supraorbital Treatment notch and medial aspect of forehead). • Pharmacotherapy of glossopharyngeal neuralgia includes • Nummular neuralgia pain in a rounded or elliptical area similar drugs as those used in trigeminal neuralgia. of about 2-6 mm diameter, most commonly in the parietal

Carbamazepine, oxcarbazepine, baclofen, phenytoin, region that is now considered to be localized terminal gabapentin, and lamotigine either alone or in combination branch neuralgia of the trigeminal nerve. have been used. Pain of Cranial and Cervical Nerve Origin other Other Cranial Neuralgias Than Primary Neuralgia Occipital neuralgia Acute Herpes zoster Diagnosis It results from reactivation of latent infection by varicella virus.

It refers to paroxysmal stabbing pain with or without Essentially it is a disease of dorsal root ganglia characterized by persistent aching between the paroxysms in the distribution vesicular eruptions in the affected dermatome. About 13% of the of greater or lesser and/or third occipital nerve, sometimes patients have involvement of trigeminal nerve. The ophthalmic accompanied by diminished sensation or dysesthesias in the division is affected in majority (80%) of these patients.

affected area. It is commonly associated with the tenderness over the nerve concerned and is blocked by local anesthetic Diagnosis injection of the nerve. The frequency of attacks varies from 4 to The onset of acute Herpes zoster is usually heralded by pain 5 per day to 2 to 7 per week. Intervening pain-free periods may which precedes the vesicular eruption by a few days. The last up to days weeks or months. Because of the associated condition becomes evident once the visible eruption is seen.

feature of lacrimation and ciliary injection and periodicity, this The initial rash of herpes zoster may mimic that of herpes pain syndrome can be confused with cluster like headaches. simplex. The vesicles usually dry out within about 1 week and Occipital localization and neuralgic character distinguish it within a month they heal. The most important complication from cluster like headaches. In most cases, the abnormalities is post-herpetic neuralgia which may occur in about 10% to

found to compress the C2 and its roots include single or 15% of patients. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S58 Ravishankar, et al: Headache disorders Treatment causative lesion of painful ophthalmoplegia. • Acute herpes zoster is treated by using anti-viral agents • As a first step, neuroimaging, preferably contrast enhanced such as acyclovir, valacyclovir, or famciclovir. Anti-viral MRI, is required to detect cavernous sinus and other

therapy also decreases the subsequent incidence of post- pathologies. herpetic neuralgia by about 80%. • This is then followed up by various tests like blood • In addition to the anti-viral agents, tramadol (an opioid chemistry (ESR, blood sugar, connective tissue profile, derivative), and tricyclic antidepressants like amitriptyline serology for various infections), CSF studies, cerebral have been found to relieve the residual pain. angiography and biopsy depending on suspected etiology.

• Systemic steroids, particularly for ophthalmic herpes have 2. For example, if a glaucomatous lesion is seen in cavernous been used. They usually do not reduce the pain but may sinus, further investigations for various infections by improve the quality of life. serology and CSF studies are indicated. In contrast, if a lesion suspicious of aneurysm is seen, angiography is Post-herpetic neuralgia indicated. Post-herpetic neuralgia is a neuralgic pain that persists in the

affected the dermatome long after the vesicular eruption of Ophthalmoplegic Migraine acute herpes zoster has healed. The pain is typical of neuralgia. Jabs of shooting, lancinating pain on a background of constant This is now considered to be a rare disorder. Recurrent attacks burning, or aching pain are characteristically reported. The of headache with migrainous characteristics associated with skin of the affected dermatome is hypoaesthetic. However, the

paresis of one or more ocular nerves (commonly the third zones of hyperesthesia from which the attacks of pain may be nerve) in the absence of a demonstrable intracranial lesion triggered by light touch or brushing are present around the on MRI define the clinical syndrome. Only finding on MRI hypoaesthetic zone. at times may be the enhancement of third cranial nerve with Treatment gadolinium. The diagnosis is that of exclusion. All other

• Tricyclic antidepressants, pregabalin, gabapentin, opioids causes of painful ophthalmoplegia need to be excluded. are effective in postherpetic neuralgia. • Of these, amtriptlyline and related tricyclic antidepressants Central Pain in the Face and Head have been most widely used and most thoroughly studied agents for the treatment of post herpetic neuralgia. Characteristically, central pain is constant and spontaneous, • For pain resistant to tricyclic antidepressants and

although they can be evoked. Occasionally, paroxysmal gabapentin, opioids may be tried. pain can also occur. Central pain may have a predominantly • Intravenous lidocaine and intravenous morphine may dysesthetic character. The term thalamic pain denotes pain be used in an attempt to interrupt the persistent pain due to lesions or dysfunction of thalamus. Pseudothalamic unrelieved by other medications. central pain is sometimes used for central pain caused by

• There are many surgical interventions that have been extrathalamic lesions. Central post-stroke pain is the central used for trigeminal post-herpetic neuralgia. These include pain resulting from a cerebrovascular lesion affecting the trigeminal rhizotomy, avulsion, alcohol injection, or quintothalmic pathways or thalamus. Anesthesia dolorosa cryoinjection of the supraorbital nerve, alcohol injection of consists of persistent painful anesthesia in the distribution

the trigeminal ganglia, and trigeminal tractotomy. While of the trigeminal nerve or one of its divisions or of occipital some of these procedures may be useful in an individual nerves. Despite the sensory loss, the patients feel pain which patient, none has been found to produce consistently good may become unbearable. Persistent idiopathic facial pain is results for achieving prolonged pain relief. of unknown cause occurring predominantly in middle-aged

females and is a diagnosis of exclusion. The pain is usually Tolosa Hunt Syndrome and Painful unilateral, occasionally can be bilateral and is commonly felt Ophthalmoplegia around chin or nasolabial fold which may spread to wider areas of face and neck. They are usually deep, poorly localized, Diagnosis occur continuously throughout day and night, and worsen One or more episodes of unilateral orbital pain persisting for with time. Although many patients have overt depression,

weeks if untreated associated with paresis of one or more of the not all are depressed. Burning mouth syndrome is a condition third, fourth, and/or sixth cranial nerves and/or demonstration characterized by burning sensation in the mouth without a of granuloma by MRI or biopsy suggests diagnosis of Tolosa medical or dental cause. Oral mucosa is normal on examination. Hunt Syndrome. Paresis usually coincides with the onset of Occasionally pain may be limited to tongue only (glossodynia).

pain or follows it within 2 weeks. Pain and paresis resolve within 72 h when treated adequately with corticosteroids. Etiology of Central Pain This condition is however should be considered as only one of the etiologies out of many diverse conditions which have been grouped under the broad heading of “painful Vascular lesions in the brain and the spinal-cord, multiple ophthalmoplegia.” sclerosis, spinal injuries, and neurosurgical procedures like cordotomies are common conditions causing central pain.

Investigation In contrast brain tumors and traumatic brain injuries seldom • Clinical examination alone is not sufficient to find out the cause central pain. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Ravishankar, et al: Headache disorders S59 Diagnosis and second line drugs. • The diagnosis of central pain rests on the total clinical • When surgical treatment is contemplated. picture, in which history, symptoms, and signs indicate disease process in the CNS and the pain characteristics of References which are compatible with central pain.

• The pain usually starts after the onset of the CNS disease 1. Headache Classification Subcommittee of the International and often the onset is delayed. Pain occurs in a regional Headache Society. The International Classification of Headache distribution and is usually lateralized in contrast to Disorders. Cephalalgia 2004;24:1-160. dermatomal or nerve distribution. 2. Silberstein SD. Report of the Quality Standards Subcommittee

• Characteristically, the pain is burning, aching, pricking, of the American Academy of Neurology. Practice parameter: Evidence-based guidelines for migraine headache (an evidence- lacerating, or lancinating type. Quite often, patients report based review). Neurology 2000;55:754-63. a mixture of such types of pain occurring simultaneously. 3. Pryse-Phillips WE, Dodick DW, Edmeads JG, Gawel MJ, Nelson Clinical examination usually reveals sensory abnormalities

RF, Purdy RA, et al. Guidelines for the diagnosis and management in the form of hypoesthesia, hyperesthesia, and dysesthesias. of migraine in clinical practice. CMAJ 1997;156:1273-87. • Non-sensory symptoms and signs may or may not be 4. Lance JW, Goadsby PJ. Mechanisms and management of present. Central pain is almost always chronic usually headaches. 7th ed. Oxford: Butterworth – Heinemann; 2005. lasting for many years. 5. Chakravarty A, Mukherjee A, Roy D. Trigeminal autonomic

• Anesthesia dolorosa is most commonly seen as a surgical cephalgias and variants: Clinical profile in Indian patients. Cephalgia 2004;24:859-66. complication of rhizotomy and thermocoagulation done to 6. Ashina S, Bendtsen L, Ashina M. Pathophysiology of tension-type treat trigeminal neuralgia. headache. Curr Pain Headache Rep 2005;9:415-22 • Persistent idiopathic facial pain and burning mouth 7. Fumal A, Schoenen J. Tension-type headache: Current research

syndrome are diagnoses of exclusion. and clinical management. Lancet Neurol 2008;7:70-83. 8. Bendtsen L. Drug and nondrug treatment in tension-type Treatment headache. Therap Adv Neurol Disord 2009;2:155-61. Current treatment of central pain includes pharmacotherapy 9. Holroyd KA, O’Donnell FJ, Stensland M, Lipchik GL, Cordingley GE, Carlson BW. Management of chronic tension-type headache and neurostimulation. with tricyclic antidepressant medication, stress management

therapy, and their combination: A randomized controlled trial. Pharmacotherapy JAMA 2001;285:2208-15. • The first group of drugs is those which reduce CNS 10. Somand D, Meurer W. Central nervous system infections. Emerg hyperactivity. These include carbamazepine, lamotrigine, Med Clin North Am 2009;27:89-100. gabapentin, pregabalin, clonazepam, and baclofen. 11. Tyler KL. Neurological infections: Advances in therapy, outcome,

• The second group of drugs increases the activity of and prediction. Lancet Neurol 2009;8:19-21. 12. Bigal ME, Gladstone J. The metabolic headaches. Curr Pain endorphin-related pain inhibiting systems by influencing Headache Rep 2008;12:292-5. the reuptake of serotonin and noradrenalin. The classic 13. Smitherman TA, Baskin SM. Headache secondary to psychiatric example is antidepressant drug, amitriptyline. disorders. Curr Pain Headache Rep 2008;12:305-10

• The third group includes alpha-2-agonist like clonidine and 14. Zebenholzer K, Wober C, Vigl M, Wessely P, Wöber-Bingöl C. direct opiate receptor antagonists. Facial pain and the second edition of the international classification • Sometimes, intravenous lidocaine and intravenous of headache disorders. Headache 2006;46:259-63. morphine may be used in an attempt to interrupt the 15. Cranial neuralgias and central causes of facial pain. Mechanism

persistent pain unrelieved by other medications. and management of headache. In: Lance JW, Goadsby PJ, editors. Philadelphia, PA: Elsevier Butterworth Heinemann; 2005. p. 333. Neurostimulation 16. Tasker RR, Watson CP. The treatment of central pain. Neurological • Transcutaneous electrical stimulation has been found to be therapeutics: Principles and practice. In: Noseworthy JH, editor. effective in central pain syndrome. London, New York: Martin Dunitz; 2003. p. 214.

• Thalamic stimulation also appears promising. 17. Sadosky A, McDermott AM, Brandenburg NA, Strauss M. A review • Excellent results have been reported following surface of the epidemiology of painful diabetic peripheral neuropathy, postherpetic neuralgia, and less commonly studied neuropathic stimulation of the motor cortex in central post-stroke pain conditions. Pain Pract 2008;8:45. pain. All these however require expertise and are usually available in larger centers.

When to refer to a specialist? How to cite this article: Ravishankar K, Chakravarty A, Chowdhury • When the diagnosis is uncertain. D, Shukla R, Singh S. Guidelines on the diagnosis and the current • When there is a neuralgias with atypical features management of headache and related disorders. Ann Indian Acad Neurol 2011;14:40-59. • When there is neuralgia with prominent neurological Received: 12-01-11 deficits.

• Refractory neuralgias and headaches unresponsive to first Source of Support: Nil. Conflict of Interest: None declared. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S25 Guidelines for management of essential tremor Pramod Kumar Pal Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India For correspondence: Dr. Pramod Kumar Pal, Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India. E-mail: palpramod@hotmail.com

Annals of Indian Academy of Neurology 2011;14:25-8 Essential tremor (ET) is a common movement disorder, and can increase the symptoms. An outline of the management of approximately 50% of the cases are inherited as an autosomal ET is given in Figure 1. dominant trait.[1] The incidence of ET increases with age, may manifest at any age (childhood to adulthood), and those Behavioral Techniques and Physical Therapy with a positive family history have an earlier age of onset.[2]

The tremor involves mainly the upper limbs distally and is Not all patients with ET will need treatment with drugs. postural or kinetic type. The less common parts involved with Treatment depends on the severity of tremor, the body part tremor are the head, lower limbs, voice, tongue, face, and the affected, and the occupation of the patients. It is also trunk. The tremor amplitude increases with time, and patients determined by the degree of social disability. In patients

experience difficulty in writing, eating, holding objects and with less disabling tremor, certain behavioral techniques and doing fine motor tasks, dressing, and speaking.[3] Although physical therapy may be useful. These include relaxation ET usually does not reduce life expectancy or cause other therapies and reducing emotional stress, using the less disabled symptoms, many patients have severe psychosocial disability. hand to write or eat, using wrist weights[2] and minimizing

[3] Tremor often increases with anxiety, stress, and in situations exposure to tremorogenic foods (eg, caffeine) and drugs (eg, involving interaction with others. Patients with head and voice sympathomimetics). tremor often suffer severe embarrassments, and may develop depression. Medical Treatment ET should be differentiated from the other types of tremors, Treatment schedules especially tremor of Parkinson’s disease, tremor associated with When it is decided to start medical treatment, it can be of 2

hyperthyroidism, and dystonic tremor of head in patients with types: isolated head tremor. Once a diagnosis is made, the severity 1. Intermittent treatment: On an as-needed or scheduled of functional and psychosocial disabilities should be assessed basis. This is recommended when the patient is distressed by objective scales, which will help to determine the need for mainly in social gatherings or prior to an important social pharmacotherapy. activity. A half to 2 tablets of propranolol (20 mg) can

be administered 30 min to 1 h before a social activity or The management of a patient with ET includes (a) behavioral the anxiety-provoking event, which increases tremor. techniques and physical therapy, (b) medical therapy, and (c) Alternatively, a benzodiazepine, such as lorazepam or surgical treatment. The patient should be explained about the clonazepam can be administered prophylactically. disease, the long-term outcome, and what the therapies can

However, as the benzodiazepines can cause central nervous achieve. All therapies are essentially symptomatic and will not system adverse events and also have abuse potential, they cure or change the course of the disease. If there is minimal need to be administered judiciously. Although routine use functional disability, the patient need not take treatment. Even of alcohol is not recommended, in patients with alcohol if the tremor is controlled by medical therapy, stress and anxiety

responsive tremors, judicial use of a small amount of alcohol prior to select social activities, such as social dinner, can be considered. Access this article online 2. As long-term suppressive therapy: In patients who need Quick Response Code: long-term therapy, the following drugs have proved to be Website: www.annalsofian.org useful with varied efficacy and levels of recommendations, based on the class of evidence. DOI: Drugs of choice

10.4103/0972-2327.83097 β-Blockers, most commonly propranolol, and primidone are the drugs of choice for treatment of ET. Both these agents have level Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jour S26 Pal.: Guidelines for management of essential tremor Figure 1: A flow chart showing the steps in the management of essential tremor A recommendation, and either can be used for initial treatment in 3 divided dosages. In India, since only 250 mg tablets are

of ET,[4] depending on the concurrent medical conditions, and available, the treatment is usually started with one-quarter of potential side effects. a tablet (or even smaller if feasible) at bedtime, and gradually increased by one-quarter every week, till the tremor control is Propranolol (β-2 blocker) achieved (the final dose may be given in 3 divided dosages). Treatment should be initiated at 10 mg once daily and gradually When the patient cannot tolerate any increment of dosage, he

titrated (eg, every 3–7 days) to 20 mg twice daily. Elderly may continue the previous dosage for a longer time, and then individuals may need a lower dose (eg, 10 mg twice daily), try further increment of dosage. while for those who are tolerating well, propranolol can be increased up to 240 mg/day in divided doses. Improvement The most common side effect of primidone is sedation and occurs in approximately 50%–60% of the patients, the greatest drowsiness, and the other common side effects being nausea,

improvement being for hand tremor, and the least for head vomiting, dizziness, ataxia, confusion, vertigo, and acute or voice tremor. Long-acting preparations of propranolol also toxic reaction. Patients on primidone should have a complete have a similar efficacy. Ten to 15 percent of the responders may blood count before starting the treatment and again every 6–12 develop tolerance after a year of treatment.[5] Side effects include months, as it has been reported, although rarely, to cause red

light headedness, fatigue, impotence, bradycardia, and reduced cell hypoplasia, aplasia, agranulocytosis, and megaloblastic blood pressure. Relative contraindications to propranolol are anemia. It is contraindicated during pregnancy, lactation, and in severe heart failure, conduction blocks, hyperactive airway patients having porphyria and hepatic and renal dysfunctions. disease, depression, and diabetes. Combination therapy Primidone When monotherapy with propranolol or primidone does not

The efficacy of primidone for managing ET appears to be similar adequately control limb tremor, these 2 drugs can be used in to propranolol[5] and it can be an initial therapy, although most combination. It has been shown that there may be an added often this is started after the failure of propranolol to control beneficial effect without an increase in side effects.[4] ET satisfactorily. Currently, this drug is not easily available in

India. The treatment is initiated at the lowest possible dose and Other drugs gradually titrated up to avoid side effects, which often appear. The following drugs have lower level (level B or C) When a 50 mg tablet or an oral suspension preparation (50 mg/ recommendations for treating ET, and should be tried (add mL) is available (not available in India), it can be started at 12.5 on or monotherapy) in patients not adequately responding

mg at bedtime and slowly titrated upward (increments by 12.5 to propranolol or primidone, or when there are prominent mg every week) to the dose when desirable tremor control is side effects: achieved without significant side effects. Most patients achieve an optimal tremor control at 250 mg/day, although higher Benzodiazepines doses up to 750–1000 mg/day may sometimes be required. This group of drugs, which probably augments GABA activity,

When a patient requires a lower dose, once daily dosing may can be used as add-on treatment for ET. Alprazolam (0.125–3 be adequate; with higher dosage, the drug should be given mg/day), clonazepam (0.5–6 mg/day), lorazepam (1–10 mg/ Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Pal.: Guidelines for management of essential tremor S27 day), and diazepam (1–10 mg/day) can be considered in therapy. Contralateral thalamotomy (VIM nucleus) or deep patients with significant worsening of tremor due to anxiety brain stimulation (DBS) of the thalamus are highly effective in

or emotional stress. Clonazepam may be particularly useful for reducing tremor.[21-22] In India, the choice between thalamotomy treatment of orthostatic tremor, a rare variant of ET.[6] The drugs and DBS is primarily dictated by the availability of expertise should be used with caution because of their abuse potential, and the cost of DBS. Bilateral thalamotomy is not recommended side effects of drowsiness and fatigue, and possible withdrawal due to its adverse side effects. Therefore, in those who cannot

symptoms following abrupt discontinuance. afford DBS, unilateral thalamotomy contralateral to the most severely affected side is recommended. In patients who can afford DBS, bilateral DBS is recommended to suppress tremor Gabapentin of both sides. There is contradictory evidence that bilateral DBS Gabapentin (structure similar to GABA) can be used as a may be useful for suppressing head and voice tremor. Side monotherapy or as an add-on therapy for treatment of ET.[7-9] It

effects are more frequent with bilateral DBS. is started at 300 mg 3 times daily, and titrated up to 1200–1800 mg/day. The drug is usually well tolerated with few side effects In summary, ET is a disorder, which can lead to a significant (sedation, irritability, ataxia, weight gain). morbidity in some patients, especially functional disability. The approach to management should be guided by the severity Topiramate of tremor, the parts of the body involved, occupation of the

Topiramate (blocks sodium channels and potentiates GABA patient, and physical and social disability. activity) has been shown to be effective in reducing ET (monotherapy or add-on therapy).[10-12] It is started at 25–50 mg References at bedtime and titrated up to 400 mg/day. Side effects include suppression of appetite, weight loss, and paresthesias. Further 1. Findley LJ, Koller WC. Definitions and behavioral classifications. studies are required to prove its efficacy in ET.

In: Findley LJ, Koller WC. editors. Handbook of Tremor Disorders. New York, NY: Marcel Dekker; 1995. p. 1-5. Zonisamide 2. Chen JJ, Swope DM. Essential tremor. J Pharma Pract Zonisamide (acts on sodium and calcium channels) has been 2007;20:458. 3. Koller WC, Biary N, Cone S. Disability in essential tremor: Effect reported to be useful in ET, especially for tremors of voice, of treatment. Neurology 1986;36:1001-4. face, tongue, and head.[13] It is initiated at 25 mg at bedtime

4. Zesiewicz TA, Elble R, Louis ED, Hauser RA, Sullivan KL, Dewey and gradually increased to 200 mg/day. Side effects include RB Jr, et al. Practice Parameter: Therapies for essential tremor sleepiness, fatigue, headache, and paresthesias. The drug can Report of the Quality Standards Subcommittee of the American be used as monotherapy or add-on therapy of ET in those who Academy of Neurology. Neurology 2005;64:2008-20.

have unsatisfactory response to other antitremor medications 5. Koller WC, Vetere-Overfield B. Acute and chronic effects of at maximally tolerated dosage. Further studies are required to propranolol and primidone in essential tremor. Neurology determine the efficacy of zonisamide in ET. 1989;39:1587-8. 6. Papa SM, Gershanik OS. Orthostatic tremor: An essential tremor variant. Mov Disord 1988;3:97-108. Other drugs 7. Pahwa R, Lyons K, Hubble JP, Busenbark K, Rienerth JD, Pahwa

There are reports of possible beneficial effects of pregabalin A, et al. Double-blind controlled trial of gabapentin in essential (starting at 50 mg/day and escalated to 600 mg/day), atenolol tremor. Mov Disord 1998;13:465-7. (50-150 mg/day) , sotalol (75–200 mg/day), nadolol (120–240 8. Gironell A, Kulisevsky J, Barbanoj M, López-Villegas D, Hernández G, Pascual-Sedano B. A randomized placebo-controlled mg/day), clozapine (6–75 mg/day), and nimodipine (120 mg/

comparative trial of gabapentin and propranolol in essential tremor. day) in ET. Clozapine is recommended only for refractory cases Arch Neurol 1999;56:475-80. of limb tremor in ET[14,15] and patients should be monitored 9. Ondo W, Hunter C, Vuong KD, Schwartz K, Jankovic J. for agranulocytosis. Further studies are required to prove the Gabapentin for essential tremor: A multiple-dose, doubleblind, efficacy of these drugs. placebo-controlled trial. Mov Disord 2000;15:678-82.

10. Connor GS. A double-blind placebo-controlled trial of topiramte treatment for essential tremor. Neurology 2002;59:132-4. Botulinum Toxin 11. Ondo WG, Jankovic J, Connor GS, Pahwa R, Elble R, Stacy MA, et al. Topiramate in essential tremor: A double-blind, placebo- In medically refractory cases of ET, injections of Botulinum controlled trial. Neurology 2006;66:672-7. Toxin-A in the tremorogenic muscles (preferably under 12. Frima N, Grunewald RA. A double-blind, placebo controlled,

electromyographic guidance for selecting the muscles) crossover trial of topiramate in essential tremor. Clin Neurophar- macol 2006;29:94-6. may be useful[4] . The injection has been shown to be useful 13. Morita S, Miwa H, Kondo T. Effect of zonisamide on essential for limb, head, and voice tremor.[16-20] Side effects include tremor: A pilot crossover study in comparison with arotinolol. temporary weakness of the injected muscles and breathlessness, Parkinsonism Relat Disord 2005;11:101-3.

dysphagia, and hoarseness following treatment for voice 14. Ceravolo R, Salvetti S, Piccini P, Lucetti C, Gambaccini G, tremor. Botulinum toxin injection should be performed only Bonuccelli U. Acute and chronic effects of clozapine in essential by a trained and experienced neurologist. tremor. Mov Disord 1999;14:468-72. 15. Pakkenberg H, Pakkenberg B. Clozapine in the treatment of tremor. Acta Neurol Scand 1986;73:295-7. Surgical Treatment 16. Brin MF, Lyons KE, Doucette J, Adler CH, Caviness JN, Comella

CL, et al. A randomized, double masked, controlled trial of Surgical treatment for ET is reserved for those selected patients botulinum toxin type A in essential hand tremor. Neurology who have severe tremor not adequately controlled by medical 2001;56:1523-8. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S28 Pal.: Guidelines for management of essential tremor 17. Pahwa R, Busenbark K, Swanson-Hyland EF, Dubinsky RM, 21. Zirh A, Reich SG, Dougherty PM, Lenz FA. Stereotactic Hubble JP, Gray C, et al. Botulinum toxin treatment of essential thalamotomy in the treatment of essential tremor of the upper

head tremor. Neurology 1995;45:822-4. extremity: Reassessment including a blinded measure of outcome. 18. Wissel J, Masuhr F, Schelosky L. Quantitative assessment of J Neurol Neurosurg Psychiatry 1999;66:772-5. botulinum toxin treatment in 43 patients with head tremor. Mov 22. Pahwa R, Lyons KL, Wilkinson SB, Carpenter MA, Tröster AI, Disord 1997;12:722-5. Searl JP, et al. Bilateral thalamic stimulation for the treatment of

19. Warrick P, Dromey C, Irish JC, Durkin L, Pakiam A, Lang A. essential tremor. Neurology 1999;53:1447-50. Botulinum toxin for essential tremor of the voice with multiple anatomical sites of tremor: A crossover design study of unilateral How to cite this article: Pal PK. Guidelines for management of essential versus bilateral injection. Laryngoscope 2000;110:1366-74. tremor. Ann Indian Acad Neurol 2011;14:25-8. 20. Hertegard S, Granqvist S, Lindestad PA. Botulinum toxin Received: 14-01-11

injections for essential voice tremor. Ann Otol Rhinol Larnygol 2000;109:204-9. Source of Support: Nil. Conflict of Interest: None declared. Author Help: Reference checking facility The manuscript system (www.journalonweb.com) allows the authors to check and verify the accuracy and style of references. The tool checks the references with PubMed as per a predefined style. Authors are encouraged to use this facility, before submitting articles to the journal.

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possible articles in PubMed will be given. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S6 Behari, et al.: Parkinson's disease 1993;43:962-5. 46. Becker G, Seufert J, Bogdahn U, Reichmann H, Reiners K. 43. Wenning GK, Shephard B, Hawkes C, Petruckevitch A, Lees A, Degeneration of substantia nigra in chronic Parkinson’s disease

Quinn N. Olfactory function in atypical parkinsonian syndromes. visualized by transcranial color-coded real-time sonography. Acta Neurol Scand 1995;91:247-50. Neurology 1995;45:182-4. 44. Suchowersky O, Reich S, Perlmutter J, Zesiewicz T, Gronseth G, 47. Berg D, Godau J, Walter U. Transcranial sonography in movement Weiner WJ. Practice parameter: Diagnosis and prognosis of new disorders. Lancet Neurol 2008;7:1044-55

onset Parkinson disease (an evidence-based review). Report of 48. Walter U, Niehaus L, Probst T, Benecke R, Meyer BU, Dressler D. the Quality Standards Subcommittee of the American Academy Brain parenchyma sonography discriminates Parkinson’s disease of Neurology. Neurology 2006;66:968-75. and atypical Parkinsonian syndromes. Neurology 2003;60:74-7. 45. Yoshita M. Differentiation of idiopathic Parkinson’s disease 49. Walter U, Dressler D, Probst T, Wolters A, Abu-Mugheisib M,

from striatonigral degeneration and progressive supranuclear Wittstock M, et al. Transcranial brain sonography findings in palsy using iodine- 123 meta-iodobenzylguanidine myocardial discriminating between parkinsonism and idiopathic parkinson scintigraphy. J Neurol Sci 1998;155:60-7. disease. Arch Neurol 2007;64:1635-40. Initiation of treatment in early PD (evidences based) Treatment of early Parkinson’s disease (PD) may be divided IU of vitamin E/day or placebo (with or without selegiline) and

into neuroprotective therapies, symptomatic therapies and followed for 14 ± 6 months did not show any difference between various non-standard pharmacologic or non-pharmacologic the vitamin E and placebo groups in the average time to require therapies. Practical guides to direct treatment depend on the levodopa (hazard ratio 0.91, 95% CI 0.74–1.12).[2] patients’ symptoms, the degree of functional impairment, the expected benefits and risks of available therapeutic agents. The Coenzyme Q10

treatment of PD needs to be individualized, since patients often Several open and controlled pilot studies on the symptomatic present with a unique set of signs and symptoms, response to effects of coenzyme Q10 (CoQ10) revealed inconsistent results. medications and a multitude of other non-socioeconomic factors. The study of the Parkinson Study Group investigating possible protective effects of CoQ10 in early PD demonstrated that In this communication, we shall present the different agents

high doses of CoQ10 slow the progressive deterioration of which have been used in PD subjects with level of evidence of functions in PD measured by the total score on the Unified efficacy in different research studies. Then, we shall put our Parkinson’s Disease Rating Scale (UPDRS), but neither improve recommendation at the end. motor functions nor postpone the initiation of levodopa Neuroprotective Therapies of PD treatment.[3] Due to the lack of a washout phase and the fast

and predominant effects of CoQ10 on activities of daily living (ADL) scores, it is not yet fully clear whether these effects might Neuroprotective therapy in PD implies that it would delay be a consequence of functional or antidepressive effects rather decline of motor symptoms and preserve the quality of life. In practical sense, one has to judge the effect of neuroprotective than neuroprotective actions.[3-5] therapy by clinical markers. Potential clinical surrogate markers Riluzole

include ratings of motor impairment, general disability, quality A single Class I, randomized, double-blind, placebo-controlled, of life measures, delay for the initiation of symptomatic therapy 6-month trial evaluated riluzole 50 mg BID compared to placebo and time to a specific event, motor fluctuations, or death. with a primary outcome of change in UPDRS. This pilot and Potential neuroprotective therapies include the following. extension study showed that riluzole (100 mg/day) was well

tolerated in patients with early PD. No evidence of symptomatic Vitamin E effect of riluzole was observed. Because of the exploratory nature Although one unblinded and nonrandomized study of the design and small size of the study, it was not possible to without independent assessment suggested a slower rate of determine whether riluzole affected the natural history of PD.[6] progression in early PD patients treated with vitamin E (3200

IU/day) combined with vitamin C (3000 mg/day),[1] another MAO-B inhibitors randomized, blinded study with 800 patients treated with 2000 Selegiline Access this article online The Deprenyl and Tocopherol Antioxidative Therapy for Parkinson’s Disease (DATATOP) study[7] examined the Quick Response Code: ability of selegiline to delay the need for levodopa therapy in 800 patients with early PD who were not taking any PD Website: medication. After 1 year, 97 subjects (24%) receiving selegiline

www.annalsofian.org versus 176 subjects (44%) not receiving selegiline experienced disability significant enough to require levodopa therapy. In addition, patients in the selegiline group had significantly better motor function scores compared with those taking Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Behari, et al.: Parkinson's disease S7 placebo. Given the observed symptomatic effect of selegiline, correlate, the absence of a placebo control and the potentially however, conclusions could not be drawn regarding any different regulatory effects of levodopa or dopamine agonists

disease-modifying effects of the drug. Dry mouth was the only (DAs) on the imaging marker preclude conclusions on any adverse event that occurred more commonly with selegiline disease-modifying effects of pramipexole on the progression than with placebo. of PD. Rasagiline To find out long-term effect of initiating pramipexole versus In early monotherapy for PD patients (TEMPO) study,[8] a 26- levodopa in early PD, the policies of initial pramipexole and

week study of rasagiline in early PD, patients were randomized initial levodopa use followed by open-label levodopa use to receive 1 mg rasagiline daily, 2 mg rasagiline daily, or placebo. resulted in similar self-reported disability, 6 years after Motor function significantly improved with both doses of randomization. Persistent differences favoring initial rasagiline compared with placebo. After the first 6 months of pramipexole were seen in the rates of dopaminergic motor

the study, those receiving placebo were switched to rasagiline 2 complications, with less severe somnolence favoring initial mg daily and patients in the initial rasagiline groups (1 or 2 mg levodopa.[14] This study also ruled out any neuroprotective daily) remained on their initial rasagiline doses for an additional effect of pramipexole. 6 months. Significantly better motor function scores were noted in those initially treated with rasagiline than in those who were Ropinirole

treated with placebo followed by 6 months of rasagiline.[9] A pilot study examined 45 subjects in a prospective cohort Long-term follow-up of 306 of the 360 subjects who completed treated with up to 1200 mg of levodopa and ropinirole up the initial 6-month study indicated that after up to 6.5 years, to 24 mg/day, followed for 2 years, and evaluated with the group that initially received rasagiline continued to have fluorodopa Positron Emission Tomography (PET), which

significantly better motor function scores compared with the revealed no difference between the two groups. Completion delayed-start group (16% difference between groups).[10] Results rate was 82%.[15] of a larger, 9-month delayed-start study that was designed to further investigate this finding showed that early treatment REAL-PET was a parallel-group prospective levodopa- with rasagiline at a dose of 1 mg per day provided benefits controlled 2-year RCT conducted to assess the effect of

that were consistent with a possible disease-modifying effect, ropinirole in 186 untreated patients with early PD. The primary but early treatment with rasagiline at a dose of 2 mg per day endpoint to measure disease progression was percent reduction did not. Because the two doses were associated with different in bilateral putaminal uptake of levodopa on fluorodopa PET.[16] outcomes, the authors concluded that the study results must One hundred and sixty-two patients eligible for analysis were

be interpreted with caution.[11] treated with ropinirole (up to 24 mg/day) or levodopa (up to 1000 mg/day) for up to 24 months. Both the groups could Dopa Agonists also be supplemented with levodopa or with stable doses of amantadine or anticholinergics throughout the study. Pramipexole Completion rate was 63%. The reduction in the ropinirole group A randomized controlled trial (RCT) of 301 patients with early was 13.4% as compared to 20.3% in the levodopa group (P <

PD assessed treatment effects of levodopa versus pramipexole. 0.001), but the same limits as discussed for the pramipexole Fewer patients receiving initial treatment for PD with study preclude any firm conclusions on the effect of ropinirole pramipexole developed dopaminergic motor complications on PD progression. than with levodopa therapy. Despite supplementation with open-label levodopa in both groups, the levodopa-treated Other DAs

group had a greater improvement in total UPDRS compared There are several DAs such as bromocryptine, pergolide, with the pramipexole group making it inconclusive to say that apomorphine, cabergoline, lisuride, piribedil, and rotigotine. pramipexol has any neuroprotective effect in PD.[12] In a study Among these, bromocryptine and cabergoline are available of dopamine transporter brain imaging to assess the effects of in India. Both are ergot derivatives. Bromocryptine is the

pramipexole vs levodopa on Parkinson disease progression, weakest clinically in relation to others. Cabergoline is costly. eighty-two patients with early PD who were recruited were Choosing a DA depends on how much it can be tolerated randomly assigned to receive pramipexole, with levodopa by the patients and its efficacy. Adverse effects may be the placebo (n = 42), or carbidopa/levodopa, with pramipexole deciding factor regarding a selection. Non-ergot compounds

placebo (n = 40). Clinical severity of PD was assessed using should be preferred to ergot derivatives because of fibrotic the UPDRS 12 hours off anti-PD medications,[13] The primary adverse reactions and the risk of restrictive heart valve outcome was change in UPDRS score and change in SPECT changes. with 2-beta-carboxymethoxy-3beta(4-iodophenyl)tropane (beta-CIT) labeled with iodine 123. At 46 months, there was Levodopa no difference in the change from baseline in the UPDRS

scores between the two treatment groups. At 46 months, a A randomized, double-blind, placebo-controlled ELLDOPA reduction of beta-CIT uptake of 16 ± 13.3 (pramipexole) trial[17] evaluated 361 patients with early PD who were versus 25.5 ± 14.1 in levodopa-treated patients (P = 0.01) was assigned to receive carbidopa–levodopa at a dailydose of 37.5 seen. However, many of the patients on pramipexole had and 150 mg, 75 and 300 mg, or 150 and 600 mg, respectively,

concomitant levodopa treatment. The lack of a clinical or a matching placebo for a period of 40 weeks, and then to Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S8 Behari, et al.: Parkinson's disease undergo withdrawal of treatment for 2 weeks. The primary MAO-B inhibitors outcome was a change in UPDRS scores at baseline and at 42 Selegiline[22] and rasagiline[8] have both been compared with

weeks. Neuroimaging studiesof 142 subjects were performed placebo in good quality RCTs and they were seen to improve at baseline and at week 40 to assess striatal dopamine- parkinsonism better than placebo. They can therefore be transporter density with the use of 123I β -CIT uptake [imaging considered efficacious. of the presynaptic dopamine transporters using (123I) beta-CIT used Dopa agonist as monotherapy as a diagnostic marker for nigro-striatal degeneration]. Patients

randomized to all levodopa doses had significantly better A meta-analysis of RCTs of DA as monotherapy for the early UPDRS scores than patients on placebo, with the greatest treatment of PD showed superior efficacy but more frequent improvement seen on the highest dose. Change in UPDRS on adverse events compared to placebo. However, the clinical placebo was 7.8 (SD ±9), at a dose of 150 mg levodopa was 1.9 benefit is often delayed and the potency is lower than l-dopa.

(SD ±6), at 300 mg was 1.9 (SD ±6.9), and at 600 mg was −1.4 The use of DA is an effective treatment option for the treatment (SD ±7.7). These results suggest that patients on a higher dose of early PD.[23] of levodopa had sustained functional improvement compared Levodopa to their baseline even after a 2-week washout. However, it is Standard levodopa has been tested in a placebo-controlled possible that this washout period was not sufficient to exclude

RCT, which confirmed its long-established antiparkinsonian a persistent symptomatic effect. Patients on the highest dose of levodopa did develop more dyskinesias, but it is unclear efficacy in early PD.[17] whether this reflects a dose effect or disease progression. Apomorphine There was no significant difference in beta-CIT uptake across It is being only used subcutaneously and has never been tested the groups. In a post-hoc analysis that included only patients

as monotherapy for the treatment of PD at this early stage. with abnormal baseline beta-CIT scans, patients on high dose levodopa had greater reduction on beta-CIT uptake. These COMT inhibitors results are inconsistent and do not allow one to conclude definitely on the impact of levodopa on PD progression. These drugs are only active when combined with levodopa and are therefore not efficacious as monotherapy in the treatment of untreated patients with early PD. Other neuroprotective therapies

Due to nonrandomized design and nonindependent outcome DAs versus levodopa assessment, the potential role of thalamotomy[18] and On up to 2 years of open extended follow-up of the CALM- amantadine[19] as neuroprotective agents is difficult to assess. PD subjects,[14] it was concluded that the policies of initial There are certain trophic factors which promote survival of pramipexole and initial levodopa use followed by open-label DA neurons, such as glial cell line–derived neurtotrophic

levodopa use resulted in similar self-reported disability, 6 factor (GDNF) and neuroimmunophilins. Inflammations years after randomization. Persistent differences favoring mediated nerodegeneration by the production of cytokines initial pramipexole were seen in the rates of dopaminergic and prostaglandins have been advocated in PD and role of motor complications, with less severe somnolence favoring minocycline as an anti-inflammatory agent has not been found initial levodopa.

effective. Certain agents have been used as apoptotic agents, but have not been successful in the experimental stage. Two recent meta-analyses[23,24] confirm that motor complications are reduced with DAs compared to levodopa, but also establish Symptomatic Therapies for PD that other important side effects are increased and symptom control is poorer with agonists. Larger, long-term comparative Amantadine trials assessing patient-rated quality of life are needed to assess

Rigorous analysis of the six randomized controlled trials of more reliably the balance of benefits and risks of DAs compared amantadine reveals insufficient evidence of its efficacy and to levodopa. safety in the treatment of idiopathic PD.[20] Amantadine is more helpful in managing dyskinesia associated with dopaminergic Controlled release levodopa versus levodopa therapy. Despite the progressive nature of PD, both the immediate- release and sustained-release carbidopa/levodopa formulations

Anticholinergics maintained a similar level of control in PD after 5 years As monotherapy or as an adjunct to other antiparkinsonian compared with baseline in a blinded randomized parallel drugs, anticholinergics are more effective than placebo study of 618 patients in 36 centers worldwide. Additionally, in improving motor function in PD. Neuropsychiatric the low incidence of motor fluctuations or dyskinesia was not

and cognitive adverse events occur more frequently on significantly different between the treatment groups and may anticholinergics than on placebo and are a more common be partly attributed to the relatively low doses of levodopa reason for withdrawal than lack of efficacy. Results regarding used throughout the 5-year study.[25] a potentially better effect of the anticholinergic drug on tremor than on other outcome measures are conflicting and Agonist Monotherapy versus Another Agonist

data do not strongly support a differential clinical effect on individual Parkinsonian features. Data are insufficient to There is no convincing evidence of clinically relevant allow comparisons in efficacy or tolerability between differences in the efficacy of the currently available DAs when individual anticholinergic drugs.[21] used for the treatment of early PD. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Behari, et al.: Parkinson's disease S9 Levodopa/Carbidopa/Entacapone versus include functional disability, disease severity, age, employment Levodopa/Carbidopa status, lifestyle, cognitive and psychiatric status, handedness, predominantly affected side, the presence of comorbid

One recent multicenter, randomized, double-blind study[26] conditions and economic status. Once the decision has been made to start symptomatic treatment, the best choice for investigated whether treatment with levodopa/carbidopa/ each individual patient must be identified. Moreover, drugs entacapone when compared with levodopa/carbidopa available locally are also important. improves the quality of life in PD patients with no or minimal, nondisabling motor fluctuations. One hundred and eighty-four

However, in an ideal situation, an effective evidence-based patients on three to four equal doses of 100/25 to 200/50 mg guideline will be as follows: levodopa/carbidopa or levodopa/benserazide, 0–3 hours of 1. At this point of time, there is no definite neuroprotective nondisabling OFF time over a 48-hour period and no dyskinesia therapy available for PD. were randomized to levodopa/carbidopa/entacapone or 2. Mild symptoms and signs without functional impairment

levodopa/carbidopa treatment for 12 weeks. The primary should be observed till mild functional impairment starts outcome measure was quality of life as assessed by the PDQ- appearing. 8. Secondary outcome measures were the UPDRS parts I–IV 3. In a patient with mild functional impairment, it is preferable and the wearing off card. Treatment with levodopa/carbidopa/ to initiate with an MAO-B inhibitor (Level 1 evidence). entacapone resulted in significantly greater improvements in

4. If or when MAO-B inhibitor is insufficient or symptoms PDQ-8 scores compared to treatment with levodopa/carbidopa worsen, the subject should be switched to or add levodopa/ (mean difference 1.4 points, P = 0.021). Statistically significant carbidopa or non-ergot dopa agonist (pramipexol or improvements were seen predominantly in nonmotor domains ropinirole). (depression, personal relationships, communication, stigma, all P < 0.05; dressing P = 0.056). Patients who were randomly

In a patient older than 65 years, who has cognitive or psychiatric assigned to levodopa/carbidopa/entacapone also showed issues, or significant comorbidities, initiation of a low dose of significantly greater improvement in UPDRS part II scores levodopa and carbidopa preparation which is to be slowly (P = 0.032), with UPDRS part III scores showing borderline increased as clinically necessary is recommended with or significance. Differences in UPDRS part I and IV and wearing without an MAO-B inhibitor.

off card scores were not significant. They concluded that treatment with levodopa/carbidopa/entacapone results in In a patient younger than 65 years, the choice is a DA or improved quality of life compared with levodopa/carbidopa anticholinergics or amantidine which could be initiated or in PD patients with mild or minimal, nondisabling motor added to an MAO-B inhibitor. Dose is to be escalated as required fluctuations. But long-term studies are required to evaluate the

and tolerated. Then, l-dopa and carbidopa preparation should potential long-term benefits of this treatment strategy. be added when agonist monotherapy becomes insufficient or is not tolerated (Level 1 evidence). Various Non-standard Pharmacologic or Non- 1. Use of anticholinergics and amantidine in early PD has pharmacologic Therapies of PD however lower level of evidence. 2. Evidence is still required to recommend starting levodopa/

Use of complementary medication and treatment is common carbidopa/entacapone instead of levodopa/carbidopa when in patients with PD; 40% of patients in the United States and indicated. 54% of patients in the United Kingdom use treatments such as References herbs, vitamins, massage and acupuncture.[27,28] Among these, food therapy,[29-34] vitamin therapy,[35-37] acupuncture 1. Fahn S. A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parkinson’s disease. Ann Neurol 1992;32:S128-32.

therapy,[38] manual therapy,[39-41] exercise therapy[42,43] and speech 2. The Parkinson Study Group. Effects of tocopherol and deprenyl therapy[44,45] have been tried in various trials. on the progression of disability in early Parkinson’s disease. The Parkinson Study Group. N Engl J Med 1993;328:176-83. For patients with PD, exercise therapy may be considered to 3. Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S, et

improve the function (Level C), but this effect persists as long al. Effects of coenzyme Q10 in early Parkinson disease: Evidence as the patient continues with exercise. For patients with PD of slowing of the functional decline. Arch Neurol 2002;59:1541-50. complicated by dysarthria, speech therapy may be considered 4. Muller T, Buttner T, Gholipour AF, Kuhn W. Coenzyme Q10 supplementation provides mild symptomatic benefit in patients to improve speech volume (Level C).

with Parkinson’s disease. Neurosci Lett 2003;341:201-4. Indian Guidelines for Treatment of Early PD 5. Horstink MW, van Engelen BG. The effect of coenzyme Q10 therapy in Parkinson disease could be symptomatic. Arch Neurol 2003;60:1170-2. Based on the above evidences, Indian guidelines for treatment 6. Jankovic J, Hunter C. A double-blind, placebo-controlled and of early PD are as follows. longitudinal study of riluzole in early Parkinson’s disease. Parkinsonism Relat Disord 2002;8:271-6.

7. Parkinson Study Group. Effect of deprenyl on the progression Until agents with proven neuroprotective or disease-modifying of disability in early Parkinson’s disease. The Parkinson Study effects become available, the choice of initial treatment must Group. N Engl J Med 1989;321:1364-71. be tailored to each patient’s requirements. Several factors 8. Parkinson Study Group. A controlled trial of rasagiline in

should be considered when determining whether to initiate early Parkinson disease: the TEMPO Study. Arch Neurol treatment and which treatment option to use. These factors 2002;59:1937-43. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S10 Behari, et al.: Parkinson's disease 9. Parkinson Study Group. A controlled, randomized, delayed- 2001;57:790-4. start study of rasagiline in early Parkinson disease. Arch Neurol 28. Ferry P, Johnson M, Wallis P. Use of complementary therapies and 2004;61:561-6. non-prescribed medication in patients with Parkinson’s disease.

10. Hauser RA, Lew MF, Hurtig HI, Ondo WG, Wojcieszek J, Fitzer- Postgrad Med J 2002;78:612-4. Attas CJ; TEMPO Open-label Study Group. Long-term outcome 29. Nagashayana N, Sankarankutty P, Nampoothiri MR, Mohan of early versus delayed rasagiline treatment in early Parkinson’s PK, Mohanakumar KP. Association of L-DOPA with recovery disease. Mov Disord 2009;24:564-73. following Ayurveda medication in Parkinson’s disease. J Neurol

11. Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, Sci 2000;176:124-7. et al. A double-blind, delayed-start trial of rasagiline in Parkinson's 30. Vaidya AB, Rajagopalan TG, Mankodi NA, Antarkar DS, Tathed disease N Engl J Med 2009;361:1268-78. PS, Purohit AV, et al. Treatment of Parkinson’s disease with the 12. Parkinson Study Group. Pramipexole vs levodopa as initial cowhage plant-Mucuna pruriens Bak. Neurol India 1978;26:171-6.

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disease progression. JAMA 2002;287:1653-61. natural source of L-dopa--prolongs ”on” periods in patients with 14. Parkinson Study Group CALM Cohort Investigators. Long-term Parkinson’s disease who have ”on-off” fluctuations. Mov Disord effect of initiating pramipexole vs levodopa in early Parkinson’s 2000;15:164-6. Disease. Arch Neurol 2009;66:563-70. 33. Rabey JM, Vered Y, Shabtai H, Graff E, Harsat A, Korczyn AD.

15. Rakshi JS, Pavese N, Uema T, Ito K, Morrish PK, Bailey DL, et al. Broad bean (Vicia faba) consumption and Parkinson’s disease. A comparison of the progression of early Parkinson’s disease in Adv Neurol 1993;60:681-4. patients started on ropinirole or L-dopa: An 18F-dopa PET study. 34. Rabey JM, Vered Y, Shabtai H, Graff E, Korczyn AD. Improvement J Neural Transm 2002;109:1433-43. of parkinsonian features correlate with high plasma levodopa

16. Whone AL, Watts RL, Stoessl AJ, Davis M, Reske S, Nahmias C, et values after broad bean (Vicia faba) consumption. J Neurol al. Slower progression of Parkinson’s disease with ropinirole versus Neurosurg Psychiatry 1992;55:725-7. levodopa: The REAL-PET study. Ann Neurol 2003;54:93-101. 35. Reilly DK, Hershey L, Rivera-Calimlim L, Shoulson I. On-off effects 17. Parkinson Study Group. Levodopa and the progression of in Parkinson’s disease: a controlled investigation of ascorbic acid

Parkinson’s disease. N Engl J Med 2004;351:2498-508. therapy. Adv Neurol 1983;37:51-60. 18. Tasker RR, DeCarvalho GC, Li CS, Kestle JR. Does 36. McGeer PL, Zeldowicz L, McGeer EG. A clinical trial of folic acid thalamotomy alter the course of Parkinson’s disease? Adv Neurol in Parkinson's disease. Can Med Assoc J 1972;106:145-6. 1996;69:563-83. 37. Schwarz J, Trenkwalder C, Gasser T, Arnold G, Oertel WH. Folinic

19. Uitti RJ, Rajput AH, Ahlskog JE, Offord KP, Schroeder DR, Ho acid therapy fails to improve early Parkinson‘s disease: A two MM, et al. Amantadine treatment is an independent predictor week placebo controlled clinical trial. J Neural Transm Park Dis of improved survival in Parkinson‘s disease. Neurology Dement Sect 1992;4:35-41. 1996;46:1551-6. 38. Shulman LM, Wen X, Weiner WJ, Bateman D, Minagar A, Duncan

20. Crosby N, Deane KH, Clarke CE. Amantadine in Parkinson’s R, et al. Acupuncture therapy for the symptoms of Parkinson’s disease. Cochrane Database Syst Rev 2003;2:CD003468. disease. Mov Disord 2002;17:799-802. 21. Katzenschlager R, Sampaio C, Costa J, Lees A. Anticholinergics 39. Stallibrass C, Hampson M. The Alexander technique: Its for symptomatic management of Parkinson’s disease. Cochrane application in midwifery and the results of preliminary research

Database Syst Rev 2003;:CD003735 into Parkinson’s. Complement Ther Nurs Midwifery 2001;7:13-8. 22. Parkinson Study Group. Impact of deprenyl and tocopherol 40. Stallibrass C. An evaluation of the Alexander Technique for the treatment of Parkinson’s disease in DATATOP subjects not management of disability in Parkinson’s disease: A preliminary requiring levodopa. Ann Neurol 1996;39:29-36. study. Clin Rehabil 1997;11:8-12.

23. Baker WL, Silver D, White CM, Kluger J, Aberle J, Patel AA, et al. 41. Stallibrass C, Sissons P, Chalmers C. Randomized controlled trial Dopamine agonists in the treatment of early Parkinson‘s disease: of the Alexander technique for Parkinson’s disease. Clin Rehabil A meta-analysis. Parkinsonism Relat Disord 2009;15:287-94. 2002;16:695-708. 24. Stowe RL, Ives NJ, Clarke C, van Hilten J, Ferreira J, Hawker 42. de Goede C, Keus S, Kwakkel G, Wagenaar R. The effect of

RJ, et al. Dopamine agonist therapy in early Parkinson’s disease. physical therapy in Parkinson’s disease: A research synthesis. Cochrane Database Syst Rev 2008;16:CD006564. Arch Phys Med Rehabili 2001;82:509-15. 25. Koller WC, Hutton JT, Tolosa E, Capildeo R, Carbidopa/ 43. Deane KH, Jones D, Playford ED, Ben-Shlomo Y, Clarke CE. Levodopa Study Group. Immediate-release and controlled-release Physiotherapy for patients with Parkinson’s disease: A comparison

carbidopa/levodopa in PD: A 5-year randomized multicenter study. of techniques. Cochrane Database Syst Rev 2001:CD002817. Neurology 1999;53:1012-9. 44. Deane KH, Whurr R, Playford ED, Ben-Shlomo Y, Clarke CE. 26. Fung VS, Herawati L, Wan Y. Movement Disorder Society of A comparison of speech and language therapy techniques for Australia Clinical Research and Trials Group; QUEST-AP Study dysarthria in Parkinson’s disease. Cochrane Database Syst Rev

Group. Quality of life in early Parkinson’s disease treated with 2001:CD002814. levodopa/carbidopa/entacapone. Mov Disord 2009;24:25-31. 45. Deane KH, Whurr R, Playford ED, Ben-Shlomo Y, Clarke CE. 27. Rajendran PR, Thompson RE, Reich SG. The use of alternative Speech and language therapy for dysarthria in Parkinson’s therapies by patients with Parkinson‘s disease. Neurology disease. Cochrane Database Syst Rev 2001:CD002812. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Behari, et al.: Parkinson's disease S13 Bilateral deep brain stimulation vs best medical therapy for patients 20. Trepanier LL, Kumar R, Lozano AM, Lang AE, Saint-Cyr JA. with advanced Parkinson disease: A randomized controlled trial. Neuropsychological outcome of GPi pallidotomy and GPi or

JAMA 2009;301:63-73. STN deep brain stimulation in Parkinson’s disease. Brain Cogn 14. Lang AE, Widner H. Deep brain stimulation for Parkinson’s disease: 2000;42:324-47. Patient selection and evaluation. Mov Disord 2002;17:S94-101 21. Gross RE. What happened to posteroventral pallidotomy 15. Bronstein JM, Tagliati M, Alterman RL, Lozano AM, Volkmann for Parkinson’s disease and dystonia? Neurotherapeutics J, Stefani A, et al. Deep brain stimulation for Parkinson disease: 2008;5:281-93.

an expert consensus and review of key issues. Arch Neurol 22. Stocchi F, Vacca L, Ruggieri S, Olanow CW. Intermittent vs 2011;68:165. continuous levodopa administration in patients with advanced 16. Morgante L, Morgante F, Moro E, Epifanio A, Girlanda P, Ragonese Parkinson disease: A clinical and pharmacokinetic study. Arch P, et al. How many parkinsonian patients are suitable candidates Neurol 2005;62:905-10.

for deep brain stimulation of subthalamic nucleus? Results of a 23. Eggert K, Schrader C, Hahn M, Stamelou M, Rüssmann A, questionnaire. Parkinsonism Relat Disord 2007;13:528-31. Dengler R, et al. Continuous jejunal levodopa infusion in patients 17. Anderson VC, Burchiel KJ, Hogarth P, Favre J, Hammerstad with advanced Parkinson disease: Practical aspects and outcome JP. Pallidal vs subthalamic nucleus deep brain stimulation in of motor and non-motor complications. Clin Neuropharmacol

Parkinson’s disease. Arch Neurol 2005;62:554-60. 2008;31:151-66. 18. Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P, et al. 24. Stocchi F, Vacca L, De Pandis MF, Barbato L, Valente M, Ruggieri Pallidal versus subthalamic deep-brain stimulation for Parkinson’s S. Subcutaneous continuous apomorphine infusion in fluctuating disease. N Engl J Med 2010;362:2077-91. patients with Parkinson’s disease: Long-term results. Neurol Sci 19. Starr PA, Vitek JL, Bakay RA. Ablative surgery and deep 2001;22:93-4.

brain stimulation for Parkinson’s disease. Neurosurgery 25. Fabbrini G, Brotchie JM, Grandas F, Nomoto M, Goetz CG. 1998;43:989-1015. Levodopa-induced dyskinesias. Mov Disord 2007;22:1379-89. Motor fluctuations and dyskinesias (diagnosis and management) Motor complications appear in approximately 50% of patients periods when not on medications or after the effect of on levodopa (LD) therapy for more than 5 years. Chase et al[1] medicine goes away, and a predictably good “ON”

reported that 28--84% of LD-treated patients develop motor response about 45 min to an hour after intake of LD (or fluctuations after an average of 4.1 years after starting LD other dopaminomimetics). therapy. These occur as a result of progression of the disease process (increased neuronal degeneration) and the cumulative However, as the disease progress, the “ON” response may be effect of prolonged treatment with dopaminergic drugs, suboptimal or erratic, and patient can develop unpredictable

especially LD. “ON”--“OFF” motor fluctuations. These “motor shifts” occur as a result of loss of presynaptic dopamine terminals and from The Motor Complications include fluctuating neurotransmitter level.[1] iii. Nighttime deterioration: In moderate to advanced disease, a. Motor fluctuations patients wake up in the night with motor symptoms, i. Wearing off effects (end-of-dose deterioration): This difficulty in rolling over in bed, muscular discomfort, is the most common initial manifestation of motor

and frequent urination. fluctuation. The patient starts to feel the reappearance of iv. Early morning deterioration: This can often be associated motor symptoms before the next dose. It is predictable and occurs 2--4 h after a dose of LD.[2] In the initial with painful foot dystonia.[3] stages, the symptoms great promptly alleviated after b. Dyskinesias/ dystonias. the same dose of dopaminergic medications. However, later the dose needs to be increased or another medicine

These can be of the following types:[3,4] i. At peak-dose, more often dyskinesias for PD needs to be added. ii. During “OFF” periods, more often dystonias ii. “ON” and “OFF” phenomena which can be predictable or iii. A combination of peak-dose and “OFF” period unpredictable: Gradually, the patient starts having “OFF” (biphasic), patients often cycling in these two phases Access this article online Diagnosis Quick Response Code: a. Diagnosis is based on meticulous history from the patient

Website: and caregivers. Patients need prolonged observation before www.annalsofian.org and after a dose of medications for PD. Patients are often not concerned about the minor dyskinesias and therefore may deny this symptom. However, the caregivers are in a better position to confirm the presence of dyskinesias. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S14 Behari, et al.: Parkinson's disease b. When in doubt about the presence or degree of motor a. If patient is on CR preparation of LD, switch complications, patients should be given 24 h diaries to be over to immediate release one[11] completed at home, marking the OFF, ON stages, time and b. Reduce individual dose of LD and give more

severity of dyskinesias, and temporal relationship with the frequent medications. If necessary, patients and caregivers should be c. If patient is on a COMT inhibitor, stop the drug shown video clippings of patients with dyskinesias. d. Reduce the total daily dose of LD and add a c. Finally, patients may need a short admission in the hospital dopamine agonist (ropinirole or pramipexole) or and evaluated in OFF and ON stages with UPDRS scales increase the dose of dopamine agonist if patient

and scales for dyskinesias. is already taking one e. Reduce dosage of LD and add amantadine. The Principles of Management dose of amantadine need to be 300-400 mg/day and the benefits tend to be short lived[12] a. Suboptimal clinical response, wearing-off phenomenon, f. Reduce LD and add anticholinergic drugs (e.g. delayed “ON” or no “ON” without dyskinesias or minimal trihexyphenidyl) dyskinesias g. Remove selegiline or rasagiline

i. Optimize the current dosage of anti-PD medications h. Continuous drug delivery such as subcutaneous (increase the strength of each dose or give more apomorphine or duodenal LD may be frequently) without causing side effects. considered[13] ii. If already on optimal dosage of levodopa-carbidopa i. Atypical neuroleptics such as clozapine may (LD) preparation only, try be of help[14] 1. adding COMT-inhibitor-entacapone (200 mg with j. Consider surgery for PD (deep brain stimulation

each dose of LD, up to 1600 mg/day,[5,6] of bilateral subthalamic nucleus is most preferred 2. changing over to controlled-release (CR) preparation target)[3] of LD or add CR preparation to the standard LD preparation (especially a bedtime dosage of 200/50 2. Biphasic dyskinesias: It is difficult to treat this mg CR preparation of LD for nighttime wearing- condition, but the following strategies may be off),[7,8] tried.[11]

3. adding MAO-B inhibitor, e.g. selegiline (5 mg at a. If patient is on a CR preparation of LD, change morning and afternoon) or rasagiline (0.5 mg at over to immediate release one morning, later can be increased to 1.0 mg at b. Increase the total dose of LD morning),[9] c. Restrict use of LD to several early and/or mid- 4. adding amantadine, 100 mg once daily, increased day doses to twice a day,[10] d. Add or increase the dose of dopamine agonist

5. adding a dopamine agonist (e.g. ropinirole or e. ubcutaneous apomorphine injections can be pramipexole),[3] tried at selected times iii. If already on an optimal dosage of dopamine agonist f. Try continuous drug delivery (as mentioned only, try above) 1. switching over to another agonist (e.g. from g. Assess for psychiatric problems and treat when pramipexole to ropinirole and vice versa) present 2. adding LD preparation (immediate or CR h. Try behavioural management preparation)

i. Consider surgery for PD 3. adding MAO-B inhibitor or amantadine iv. redistribute dietary protein ii. Dystonias v. consider surgery for PD 1. Peak-dose dystonia a. Reduce dose of LD b. Nighttime deterioration: The following strategies may be b. Add or increase dose of dopamine agonists tried: c. Consider surgery for PD i. A CR preparation of LD at bedtime 2. Early-morning / OFF-period dystonia ii. An extra dose of standard LD around midnight when a. Add CR preparation of LD at bedtime

patients wakes up b. Add dopamine agonist at bedtime iii. Addition of dopamine agonist or entacapone if patient c. Add COMT inhibitor is not on these drugs. d. Early morning immediate release LD may be tried 1--2 h before getting up from bed c. Early morning deterioration: Often patients are relieved by e. Other drugs such as baclofen, diazepam, or a standard preparation of LD, which can be given crushed anticholinergic drugs can be tried and with carbonated drink or on empty stomach, if patient

f. In focal dystonia, injection of botulinum toxin can tolerate. type A in the dystonic muscles can be tried d. Patients with disabling dyskinesias e. Unpredictable “ON-OFF” periods: The following options i. Choreiform dyskinesias may be considered. 1. Peak dose dyskinesias: The following strategies i. Adjust time and dose of LD can be tried: ii. Add dopamine agonist Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

Daily liquid preparation of LD needs to be prepared Parkinson’s disease. Parkinson Relat Disord 2002;9:15-21 by crushing ten tablets of standard (immediate release) 5. The Parkinson Study Group. Entacapone improves motor 100/25 levodopa/carbidopa, 2 g of ascorbic acid and fluctuations in levodopa-treated Parkinson’s disease patients. dissolving in 1 L of water. This solution need to be Ann Neurol 1997;42:747-55.

i. Only in “OFF” state study in patients with fluctuating Parkinson’s disease. Mayo Clin 1. Management strategies as like in patients with Proc 1988;63:876-86. 8. Koller WC, Pahwa R. Treating motor fluctuations with controlled wearing-off release levodopa preparations. Neurology 1994;44:S23-8. 2. Manage anxiety, if present, by appropriate drugs 9. Rascol O, Brooks DJ, Melamed E, Oertel W, Poewe W, Stocchi or behavioural therapy and nonpharmacologic

F, et al. Rasagiline as an adjunct to levodopa in patients with techniques that involve the use of sensory or mental Parkinson’s disease and motor fluctuations (LARGO, Lasting imagery, cues, or devices.[11,16] effect in Adjunct therapy with Rasagiline Given Once daily, ii. Both in “OFF” and “ON” stages study): a randomised, double-blind, parallel-group trial. Lancet 1. Increase LD to make optimal “ON” 2005;365:947-54. 2. Sensory cues 10. Fahn S, Isgreen WP. Long-term evaluation of amantadine and

3. Assistive devices levodopa combination in Parkinsonism by double-blind crossover analyses. Neurology 1975;25:695-700. 4. Manage anxiety, if present, by appropriate drugs or 11. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) behavioural therapy for the management of Parkinson’s disease (2001): Treatment iii Only “ON” freezing guidelines. Neurology 2001;56:S1-88. 12. Metman LV, Del Dotto P, LePoole K, Oertel W, Poewe W, Stocchi It is very difficult to manage and patients sometimes benefit

F, et al. Amantadine for levodopa-induced dyskinesias: A 1-year by reducing the dose of LD. follow-up study. Arch Neurol 1999;56:1383-6. 13. Antonini A. New strategies in motor parkinsonism. Parkinson Relat In summary, medical management of motor fluctuations in PD Disord 2007;13:S446-9. is challenging. Surgical treatment of PD may be a better option 14. Durif F, Debilly B, Galitzky M, Morand D, Viallet F, Borg M, et al.

for carefully selected patients. Clozapine improves dyskinesias in Parkinson disease: A double- blind, placebo controlled study. Neurology 2004;62:381-8. 15. Kurth MC, Tetrud JW, Irwin I, Lyness WH, Langston JW. Oral References levodopa/carbidopa solutions versus tablets in Parkinson’s disease with severe fluctuations: A pilot study. Neurology 1. Chase TN, Mouradian MM, Engber TM. Motor response 1993;43:1036-9.

complications and the function of striatal efferent systems. 16. Dietz MA, Goetz CG, Stebbins GT. Evaluation of a modified Neurology 1993;43:S23-6. inverted walking stick as a treatment for parkinsonian freezing 2. Stern MB. Sinemet CR. Rationale and clinical experience. episodes. Mov Disord 1990;5:243-7. Constipation in Parkinson’s disease Introduction occurring in about 50–60% of patients and may occur even before the motor symptoms appear.[1] Various mechanisms

Constipation is a common problem in Parkinson’s disease (PD), causing it are degeneration of neurons in myenteric plexus of colon with presence of Lewy bodies, weakness and Access this article online incoordinated contraction of muscles of pelvic floor and abdominal muscles which is unable to straighten, anorectal Quick Response Code: angle preventing passage of stool, dystonic contractions of muscles, megacolon and volvulus.[2,3] Website:

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S2 Behari, et al.: Parkinson's disease ) Parkinson’s disease Madhuri Behari, Kalyan Brata Bhattacharyya1, Rupam Borgohain2, Shyamal Kumar Das3, Bhaskar Ghosh4, Asha Kishore5, Syam Krishnan5, K Rukmini Mridula2, Uday Muthane6, Pramod Kumar Pal7, Charulata Sankhla8, Garima Shukla

Department of Neurology, All India Institute of Medical Sciences, 1Amrapali Point, Kolkata, 2Nizam's Institute of Medical Sciences, 3Bangur Institute of Neurosciences, Kolkata, 4BR Singh Hospital and Center for Medical Education and Research, Kolkata, 5Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, 6Parkinson and aging research Foundation, Bengalure, 7National Institute for Mental Health and Neurosciences, Bengalure, 8PD Hinduja National Hospital, Mumbai For correspondence:

Prof. Madhuri Behari, Department of Neurology, All India Institute of Medical Sciences and Technology, New Delhi, India. Annals of Indian Academy of Neurology 2011;14:02-24 The diagnosis of Parkinson’s disease (PD) is clinical and tremor appears immediately on assuming the posture. Typically, there are no biological markers to confirm it during life. [1] rest tremor of the hands in PD has a pill rolling appearance and

Confirmation is possible only post mortem. There are no abates during action. In the head region, tremor occurs in the accepted neuropathological criteria for PD[2] and there is an lips, chin, and jaw but is infrequent in the neck. About 75% of ongoing debate on whether PD is a single entity.[3,4] This is PD patients have tremor during the course of their illness.[13] because of the description of genetic forms of PD with

clinical features typical of sporadic PD but pathological Rigidity (resistance offered to passive flexion-extension or features distinct from it.[5] Early accurate diagnosis of PD rotation movement of major joints with the patient sitting may be important for institution of disease course -modifying relaxed. It does not include cog-wheel rigidity caused by treatments when they become available, for prognostication tremor). Rigidity in PD is lead pipe-like, is present throughout

and for research purposes.[6] Recognizing early PD is not easy. the range of movement, and is not velocity dependent. In PD, It is also well known that in the early stages of the disease, PD rigidity involves both neck and limbs while in progressive and other forms of degenerative parkinsonism share common supranuclear palsy (PSP) there is a disproportionate axial features and clinical distinction may be difficult.[7] The certainty preponderance of rigidity.[14]

of diagnosis increases as the disease advances and in specialist clinics.[8] Even though PD is considered as a predominantly Bradykinesia (slowness of initiation of voluntary movements motor disorder, non-motor symptoms occur at all stages of with progressive reduction in speed and amplitude of repetitive the disease[9] and may even antedate it.[10,11] However, the actions). It is tested by asking the patient to do repeated finger

diagnosis of PD rests on motor signs. The three cardinal motor taps, alternate pronation and supination of forearm, opening manifestations of PD which are essential to make a diagnosis and closing of fist and foot taps. Look for speed, regularity, are rest tremor, rigidity, and bradykinesia. arrests of ongoing movement and slowness. Fatiguing or gradual reduction in amplitude during continued activity and Rest tremor (4-6 Hz) tremor occurring when the limb is fully arrests are typical of true bradykinesia.

supported). It can be brought out by mental stress, during Postural instability (not due to cerebellar, vestibular, posterior walking, or while performing alternating finger taps with column or visual dysfunction). In the clinic this may be the opposite hand. Some patients have postural tremor but demonstrated by the “pull test.” This is assessed from the appears only after a latency of seconds to a minute of assuming response to the sudden strong posterior displacement produced

the outstretched posture of arms (re-emergent tremor).[12] This by a pull on shoulders while the patient stands erect with eyes feature, if present, helps to differentiate PD tremor from postural open and feet slightly apart. The patient is prepared for the test tremor due to other causes, e.g. essential tremor (ET) in which and can have a few practice runs. Many experts do not consider postural instability by itself for the early diagnosis of PD as

Access this article online it is seldom present in early stages and is nonspecific. Onset Quick Response Code: with postural instability and gait disturbance (PIGD) tends to Website: be more often due to atypical parkinsonism.[15] www.annalsofian.org Although several clinical criteria have been proposed for PD, most have not been evaluated for reliability and validity. DOI: The United Kingdom Parkinson’s disease Society Brain

10.4103/0972-2327.83083 Bank Clinical Diagnostic Criteria[16] [Table 1] is based on a retrospective clinico- pathological study and has been tested Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Behari, et al.: Parkinson's disease S3 in autopsy confirmed cases and found to have an accuracy tremor, rigidity, bradykinesia, or impaired postural of around 75% to 80%.[17] The misdiagnosis in the remaining reflexes are required to make this diagnosis. Alternatively,

cases was from conditions such as multiple system atrophy asymmetrical rest tremor, asymmetrical rigidity, or (MSA), progressive supranuclear palsy (PSP), vascular asymmetrical bradykinesia alone may be sufficient. parkinsonism and Alzheimer’s disease. These criteria are useful 3. Clinically definite PD: A combination of three of the for improving diagnostic accuracy but may not be useful in features - rest tremor, rigidity, bradykinesia or impairment

monosymptomatic and early stages of PD.[18] Early PD can in postural reflexes - is required to make the diagnosis of have a wide variety of presentations including non-specific PD clinically definite. Alternatively, two of the features symptoms like generalized stiffness, pain and paresthesia, are sufficient if one of the first three displays asymmetry. reduced appetite, constipation, sleeplessness, shoulder pain, Laboratory support for the diagnosis could be applied

and reduction in volume of voice or more specific ones like to each category. However, these criteria have not been tremor during anxiety, sense of inner tremor, reduced arm validated in pathologically confirmed cases. swing, reduced facial expression, personality changes noticed by others, slowness, monotonous speech, micrographia, There are certain conditions which are commonly mistaken problems with fine motor task, dragging of leg, dystonia of for PD, especially in the early stages of PD. ET can have

limbs (especially in young onset PD due to Parkin mutations), rest tremor[25] and also cogwheel type of rigidity. ET can be mood changes, decreased smell, and increased salivation.[19-21] asymmetric; however, long-duration asymmetric postural Response to treatment may support the diagnosis. Excellent tremor is more likely to be due to PD than ET.[26] The response to levodopa and levodopa-induced chorea are seen distinguishing features between the tremor of PD and ET

more often in PD but can occur in MSA[22] where it wanes with are shown in Table 2. The other conditions producing rest time. Orofacial dystonia, spontaneous or levodopa induced, is tremor include dystonic tremor (tremor in a dystonic body often seen in MSA. Partial response to levodopa can be seen in part, irregular and abolished in certain positions), tardive PSP[23] and other atypical parkinsonism. tremor related to neuroleptic exposure, and Wilson’s disease.

The slowness of activities seen in hypothyroidism may be In order to address the issue of improving the early diagnosis mistaken for bradykinesia. The slowness of activities and of PD, Calne et al. proposed a designation of escalating levels reduced facial expression in depression can resemble PD. of diagnostic confidence [Table 2].[24] Three categories were Slowness of activities, slow gait, instability, and hypomimia defined. of the elderly may also resemble PD. Diagnosis of PD should

1. Clinically possible: Presence of any one of tremor, rigidity, be made carefully in very old people in whom the presence of or bradykinesia could qualify for clinically possible PD. a rest tremor may be the most specific sign.[27] Impairment in postural reflexes was not included. Tremor must be of recent onset and may be rest or postural. PD needs to be differentiated from the secondary causes of

2. Clinically probable: Two of the cardinal features of rest parkinsonism. Vascular parkinsonism results from infarcts Table 1: UK Parkinson’s disease society brain bank clinical diagnostic criteria[16] Inclusion criteria Exclusion criteria Supportive criteria Bradykinesia (slowness History of repeated strokes with stepwise progression of parkinsonian features. (Three or more required for of initiation of voluntary History of repeated head injury diagnosis of definite PD)

movement with History of definite encephalitis Unilateral onset progressive reduction in Oculogyric crises Rest tremor present speed and amplitude of Neuroleptic treatment at onset of symptoms Progressive disorder repetitive actions) More than one affected relative Persistent asymmetry affecting And at least one of the Sustained remission side of onset most following: Strictly unilateral features after 3 years Excellent response (70--100%) Muscular rigidity Supranuclear gaze palsy to levodopa

4-6 Hz rest tremor Cerebellar signs Severe levodopa-induced Postural instability not Early severe autonomic involvement chorea caused by primary visual, Early severe dementia with disturbances of memory, language, and praxis Levodopa response for 5 yr or vestibular, cerebellar, or Babinski sign more proprioceptive dysfunction Presence of cerebral tumor or communicating hydrocephalus on CT scan Clinical course of 10 yr or Negative response to large doses of levodopa (if malabsorption excluded) more

MPTP exposure Table 2: Distinguishing features between tremor of Parkinson’s disease and essential tremor Feature PD ET Tremor type Predominantly rest; re-emergent postural tremor Predominantly postural (immediate) Tremor frequency 4-6 Hz 8--12 Hz Tremor characteristics Supination--pronation Flexion--extension Unilateral/bilateral Usually unilateral to begin with Usually bilateral Areas involved Head and voice tremor not usually seen Head and voice tremor are usually seen Response to alcohol No Common

Positive family history Rare (less than 10%) Usual (17--100% of patients in various series) Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S4 Behari, et al.: Parkinson's disease involving frontal lobe, deep subcortical white matter, and than appendicular rigidity, behavioral and cognitive changes, basal ganglia. The patients are more likely to present with early dysphagia, and dysarthria.[37] MRI may be supportive.

gait difficulty and postural instability rather than tremor. They Cortico-basal degeneration (CBD) results in progressive cortical usually have a history of stroke and report risk factors for dysfunction such as asymmetric ideomotor or constructional stroke. Focal signs like pyramidal signs and vascular dementia apraxia, alien limb phenomenon, cortical sensory loss, may co-exist. The patients usually have a more upright posture, focal myoclonus, apraxia of speech, or nonfluent aphasia.

wide based stance, and well-preserved arm swing compared to Extrapyramidal dysfunction such as asymmetric appedicular PD. Response to levodopa therapy is usually poor.[28] A variety rigidity that is levodopa unresponsive and asymmetric of drugs including neuroleptics, dopamine receptor blocking appendicular dystonia is also part of the clinical picture.[38] agents, dopamine depletors (tetrabenazine), and calcium MRI findings may support the diagnosis. Dementia with Lewy

channel blockers can cause drug-induced parkinsonism bodies (DLB) is a dementia syndrome associated with visual (DIP). This could develop 1 to 3 months after introduction of hallucinations, fluctuating levels of attention, and spontaneous a D2 receptor blocker neuroleptic or an increase in dose and parkinsonism. Dementia precedes motor symptoms or occurs generally resolves in weeks to months after discontinuation. within 1 year. The parkinsonism is symmetric with early gait

Freezing and festination are rare in DIP. DIP is often difficult and postural instability.[39] Moderate L-dopa response may be to differentiate from PD; useful clues for differentiation seen. In Alzheimer’s disease, parkinsonism follows dementia, include parkinsonism associated with tardive dyskinesia or is symmetric, and rest tremor is rare. Dementia of AD is akathisia , symmetric signs, action greater than resting tremor dominated by early and severe memory impairment. Clinical

and presence of a low-frequency, high-amplitude jaw tremor features which suggest an alternative diagnosis other than PD (“Rabbit syndrome”).[29-31] The classical features of normal in a patient presenting with parkinsonism are listed in Table 3. pressure hydrocephalus include gait disturbance, urinary incontinence and cognitive changes; however the triad is seen There is no diagnostic test which can reliably differentiate PD

only in advanced cases.[32] Bradykinesia of upper limbs is seen from other causes of parkinsonism. Acute levodopa challenge in around 50% and frank parkinsonism, usually symmetrical, (with 250 mg/25 mg of levodopa/carbidopa) and assessment in less than 15% of patients.[33] Rest tremor and upper limb for changes in Unified Parkinson’s Disease Rating Scale Part III rigidity are rare. Gait is more wide-based and apractic in (UPDRS-III) score of 30% or more have a sensitivity of around

NPH. Gait difficulty is not usually overcome by stepping over 70% and specificity of around 80% for predicting an eventual examiners foot as it happens in PD. Wilson’s disease is yet diagnosis of PD.[40] Around 30% will have false positive or false another cause for parkinsonism; most cases also have other negative results. Subcutaneous apomorphine challenge (1-4.5 signs like coarse “wing beating” tremor, dystonia, a “mixed” mg of apomorphine given subcutaneously)[41] has similar utility

dysarthria, and neurobehavioral disturbances. Investigations but apomorphine is not freely available in India. Patients need like serum copper and ceruloplasmin measurement, slit lamp to be pre-treated with domperidone for 2-3 days to prevent examination for Kayser–Fleischer ring, 24 h urinary free copper dopaminergic side effects. estimation, and liver biopsy are helpful in establishing the Decreased smell in standardized smell identification tests diagnosis in suspected cases. Infections (SSPE, mycoplasma

(like the University of Pennsylvania Smell Identification Test - pneumonia, HIV, viral encephalitis), metabolic disturbances UPSIT) may be useful to discriminate PD from PSP and CBD. (hyperparathyroidism), toxins (MPTP, manganese, carbon The smell is preserved in these conditions unlike PD in which monoxide, cyanide, methanol), anoxia, and structural lesions there is moderate to severe impairment of smell. MSA and PD (frontal, temporal, brainstem and posterior fossa space

occupying lesions causing hydrocephalus) are relatively rare have overlapping levels of impairment.[42,43] causes of secondary parkinsonism. Significant overlap in levels of impairment does not allow reliable distinction between PD and atypical parkinsonism Differentiation of PD from other neurodegenerative causes based on neuropsychological testing, electro-oculogram, of Parkinsonism is important from the treatment and sphincter and urethral EMG or autonomic function tests.[44]

prognostication point of view. MSA is characterized by a combination of varying degrees of parkinsonism, early and Conventional and advanced MR modalities may help prominent autonomic dysfunction, and cerebellar distinguish PD from atypical parkinsonism. However, the dysfunction. Parkinsonism is predominant in MSA-P and cerebellar dysfunction is more prominent in MSA-C.[34] Red Table 3: Baseline features that suggest an alternative

flags that suggest MSA are disproportionate anterocollis diagnosis other than PD (chin on chest), severe lateroflexion of trunk, head and neck • Mild or no tremor, particularly absence of rest tremor (Pisa syndrome), orofacial dystonia that are spontaneous • Severe bradykinesia at onset or L-dopa induced, irregular action and postural tremor of • Symmetric signs and rapid progression

hands, severe hypophonic quivering high pitched dysarthria, • Postural instability, gait difficulty and freezing at onset or early emotional incontinence, nocturnal strider, or excessive snoring. in the disease (within 3 years) • Falls at presentation or early in the course Dementia and behavioral changes are not usually seen.[35] • Slowing of saccades or supranuclear palsy(other than upgaze MRI may be supportive. Patients with PSP present with restriction)

progressive unexplained and unexpected falls or tendency • Dementia preceding motor symptoms or in the first year to fall (backwards or in any direction) within 1 year of onset • Hallucinations unrelated to medicines early in the disease of parkinsonism.[36] Vertical supranuclear gaze paresis (any • Severe and symptomatic dysautonomia unrelated to medicines downward or moderate to severe upgaze) is characteristic. *A combination of features is more suggestive of an alternative diagnosis than

The parkinsonism is generally symmetric with axial more a single odd feature. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Behari, et al.: Parkinson's disease S5 evidence is insufficient and MRI has low sensitivity. [44] 20. Stephenson R, Siderowf A, Stern MB. Premotor Parkinson’s Iodine-123 meta-iodobenzylguanidine (MIBG) cardiac disease: Clinical features and detection strategies. Mov Disord imaging is normal in multiple system atrophy and PSP, 2009;24:S665-70.

21. Wolters EC, Francot C, Bergmans P, Winogrodzk A, Booij J, while it is abnormal in PD.[45] However, the level of evidence Berendse HW, et al. Preclinical (premotor) Parkinson’s disease. is currently not considered high enough to recommend for J Neurol 2000;247:II/103-9. routine diagnostic purposes. Hyperechogenicity of substantia 22. Hughes AJ, Colosimo C, Kleedorfer B, Daniel SE, Lees AJ. The

nigra detected by brain ultrasonography has been shown to dopaminergic response in multiple system atrophy. J Neurol differentiate PD from atypical parkinsonism.[46-49] Evidence is Neurosurg Psychiatry 1992;55:1009-13. not strong to recommend it for routine diagnostic purposes. 23. O’Sullivan SS, Massey LA, Williams DR, Silveira-Moriyama L, Beta CIT and IBZM SPECT can differentiate PD from ET[44] but Kempster PA, Holton JL, et al. Clinical outcomes of progressive

are not freely available. supranuclear palsy and multiple system atrophy. Brain 2008;131:1362-72. 24. Calne DB, Snow BJ, Lee C. Criteria for diagnosing Parkinson’s References disease. Ann Neurol 1992;32:S125-7. 25. Cohen O, Pullman S, Jurewicz E, Watner D, Louis ED. Rest 1. Rao G, Fisch L, Srinivasan S, D’Amico F, Okada T, Eaton tremor in patients with essential tremor: Prevalence, clinical

C, et al. Does this patient have Parkinson disease? JAMA correlates, and electrophysiologic characteristics. Arch Neurol 2003;289:347-53. 2003;60:405-10. 2. Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday 26. Chaudhuri KR, Buxton-Thomas M, Dhawan V, Peng R, Meilak C, GM, et al. Neuropathological assessment of Parkinson’s disease: Brooks DJ. Long duration asymmetrical postural tremor is likely

refining the diagnostic criteria. Lancet Neurol 2009;8:1150-7. to predict development of Parkinson’s disease and not essential 3. Calne DB. Is “Parkinson’s disease” one disease? J Neurol tremor: Clinical follow up study of 13 cases. J Neurol Neurosurg Neurosurg Psychiatry 1989;52:18-21. Psychiatry 2005;76:115-7. 4. Weiner WJ. There is no Parkinson disease. Arch Neurol 27. Prettyman R. Extrapyramidal signs in cognitively intact elderly 2008;65:705-8. people. Age Ageing 1998;27:557-60.

5. Mori H, Kondo T, Yokochi M, Matsumine H, Nakagawa-Hattori Y, 28. Winikates J, Jankovic J. Clinical correlates of vascular Miyake T, et al. Pathologic and biochemical studies of juvenile parkinsonism. Arch Neurol 1999;56:98-102. parkinsonism linked to chromosome 6q. Neurology 1998;51:890-2. 29. Quinn NP. Parkinsonism: Recognition and differential diagnosis. 6. Becker G, Muller A, Braune S, Buttner T, Benecke R, Greulich BMJ 1995;310:447-52.

W, et al. Early diagnosis of Parkinson’s disease. J Neurol 30. Diederich NJ, Goetz CG. Drug-induced movement disorders. 2002;249:III/40-8. Neurol Clin 1998;16:125-40. 7. Jankovic J, Rajput AH, McDermott MP, Perl DP for the Parkinson 31. Montastruc JL, Llau ME, Rascol O, Senard JM. Drug-induced Study Group. The evolution of diagnosis in early Parkinson Parkinsonism: A review. Fundam Clin Pharmacol 1994;8:293-306.

disease. Arch Neurol 2000;57:369-70. 32. Relkin N, Marmarou A, Klinge P, Bergsneider M, Black PM. 8. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of Diagnosing idiopathic normal-pressure hydrocephalus. diagnosis of parkinsonian syndromes in a specialist movement Neurosurgery 2005;57:S4-16. disorder service. Brain 2002;125:861-70. 33. Krauss JK, Regel JP, Droste DW, Orszagh M, Borremans J,

9. Chaudhuri KR, Schapira AHV. Non-motor symptoms of Vach W. Movement disorders in adult hydrocephalus. Mov Disord Parkinson’s disease: Dopaminergic pathophysiology and 1997;12:53-60. treatment. Lancet Neurol 2009;8:464-74. 34. Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias DJ, 10. Webster Ross G, Petrovitch H, Abbott RD, Tanner CM, Popper Trojanowski JQ, et al. Second consensus statement on the

J, Masaki K, et al. Association of olfactory dysfunction with risk of diagnosis of multiple system atrophy. Neurology 2008;71:670-6. future Parkinson’s disease. Ann Neurol 2008;63:167-73. 35. Wenning GK, Ben-Shlomo Y, Hughes A, Daniel SE, Lees A, Quinn 11. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of NP. What clinical features are most useful to distinguish definite a Parkinsonian disorder in 38% of 29 older men initially diagnosed multiple system atrophy from Parkinson’s disease? J Neurol

with idiopathic rapid eye movement sleep behavior disorder. Neurosurg Psychiatry 2000;68:434-40. Neurology 1996;46:388-93. 36. Litvan I, Mangone CA, McKee A, Verny M, Parsa A, Jellinger 12. Jankovic J, Schwartz KS, Ondo W. Re-emergent tremor of K, et al. Natural history of progressive supranuclear palsy Parkinson’s disease. J Neurol Neurosurg Psychiatry (Steele-Richardson-Olszewski syndrome) and clinical predictors 1999;67:646-50. of survival: A clinicopathological study. J Neurol Neurosurg

13. Hughes AJ, Daniel SE, Blankson S, Lees AJ. A clinicopathologic Psychiatry 1996;61:615-20. study of 100 cases of Parkinson’s disease. Arch Neurol 37. Nath U, Ben-Shlomo Y, Thomson RG, Lees AJ, Burn DJ. Clinical 1993;50:140-8. features and natural history of progressive supranuclear palsy: A 14. Lubarsky M, Juncos JL. Progressive supranuclear palsy: A current clinical cohort study. Neurology 2003;60:910-6. review. Neurologist 2008;14:79-88. 38. Gibb WR, Luthert PJ, Marsden CD. Corticobasal degeneration.

15. Wenning GK, Ebersbach G, Verny M, Chaudhuri KR, Jellinger Brain 1989;112:1171-92. K, McKee A, et al. Progression of falls in postmortem-confirmed 39. Geser F, Wenning GK, Poewe W, McKeith I. How to diagnose parkinsonian disorders. Mov Disord 1999;14:947-50. dementia with Lewi bodies: State of the art. Mov Disord 16. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical 2005;20:S11-20. diagnosis of idiopathic Parkinson’s disease: A clinico-pathological

40. Merello M, Nouzeilles MI, Arce GP, Leiguarda R. Accuracy of acute study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181-4. levodopa challenge for clinical prediction of sustained long-term 17. Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ. What features levodopa response as a major criterion for idiopathic Parkinson’s improve the accuracy of clinical diagnosis in Parkinson’s disease: disease diagnosis. Mov Disord 2002;17:795-8. A clinicopathologic study. Neurology 1992;42:1142-4.

41. Rossi P, Colosimo C, Moro E, Tonali P, Albanese A. Acute 18. Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson’s challenge with apomorphine and levodopa in Parkinsonism. Eur disease. Lancet Neurol 2006;5:75-86. Neurol 2000;43:95-101. 19. Siderowf A, Stern MB. Premotor Parkinson’s disease: Clinical 42. Doty RL, Golbe LI, McKeown DA, Stern MB, Lehrach CM, features, detection and prospects for treatment. Ann Neurol Crawford D. Olfactory testing differentiates between progressive 2008;64:S139-47.

supranuclear palsy and idiopathic Parkinson’s disease. Neurology Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jour S6 Behari, et al.: Parkinson's disease 1993;43:962-5. 46. Becker G, Seufert J, Bogdahn U, Reichmann H, Reiners K. 43. Wenning GK, Shephard B, Hawkes C, Petruckevitch A, Lees A, Degeneration of substantia nigra in chronic Parkinson’s disease

high doses of CoQ10 slow the progressive deterioration of which have been used in PD subjects with level of evidence of functions in PD measured by the total score on the Unified efficacy in different research studies. Then, we shall put our Parkinson’s Disease Rating Scale (UPDRS), but neither improve recommendation at the end. motor functions nor postpone the initiation of levodopa treatment.[3] Due to the lack of a washout phase and the fast Neuroprotective Therapies of PD

and predominant effects of CoQ10 on activities of daily living (ADL) scores, it is not yet fully clear whether these effects might Neuroprotective therapy in PD implies that it would delay be a consequence of functional or antidepressive effects rather decline of motor symptoms and preserve the quality of life. In [3-5] than neuroprotective actions. practical sense, one has to judge the effect of neuroprotective therapy by clinical markers. Potential clinical surrogate markers Riluzole

IU/day) combined with vitamin C (3000 mg/day),[1] another MAO-B inhibitors randomized, blinded study with 800 patients treated with 2000 Selegiline The Deprenyl and Tocopherol Antioxidative Therapy for Access this article online Parkinson’s Disease (DATATOP) study[7] examined the Quick Response Code: ability of selegiline to delay the need for levodopa therapy in 800 patients with early PD who were not taking any PD Website: medication. After 1 year, 97 subjects (24%) receiving selegiline

system) and reduced nociceptive flexion reflex threshold by 5. Ford B, Louis ED, Greene P, Fahn S. Oral and genital pain the same mechanism. syndromes in Parkinson’s disease. Mov Disord 1996;11:421–6 6. Sandyk R. Pineal melatonin and sensory symptoms in Parkinson disease. Ital J Neurol Sci 1989;10:399-403. The presentation of pain/dysesthesia includes: painful “frozen 7. Chudler EH, Dong WK. The role of the basal ganglia in nociception

shoulder” usually on the side of first symptom, especially and pain. Pain 1995;60:3-38. before treatment is started (usually early in the disease), off- 8. Drake DF, Harkins S, Qutubuddin A. Pain in Parkinson’s disease: period limb pain, off-period painful foot dystonia, pain and Pathology to treatment, medication to deep brain stimulation. dysesthesia on chest or abdomen. Some patients may have NeuroRehabilitation 2005;20:335-41. Psychosis in Parkinson’s disease

resulted in reduction of anti-PD medication, but this failed Access this article online to improve psychosis, thus leading to some insights to the Quick Response Code: intrinsic factors where reduction in anti-PD medications to the lowest tolerated dose did not improve psychosis. Initial Website: manifestation of chronic dopaminergic medication may be www.annalsofian.org sleep disturbances in the form of dreams, night terrors. Dreams are vivid, real, featuring people and events from

hallucinations in PD psychosis take form of people, friends levodopa is reduced. If the hallucinations still persist on and relatives from past. Solitary figures are seen repeatedly withdrawing the offending drugs and further reduction in but do not speak. Animals running across floor appearing dopaminergic drugs is not possible without hampering the through closed window or door are seen. Inanimate objects mobility of the patient, then only addition of atypical

grow legs and walk. Miniature people are seen. Ceiling and antipychotic is considered. floors appear to be in motion. Often hallucinations are benign and nonthreatening. They occur in the evening hours and Several atypical antipsychotic agents (i.e. clozapine, commonly are visual, rarely auditory, thus differentiating olanzapine) have been shown to be efficacious in reducing them from other causes such as schizophrenia. Paranoid psychotic symptoms in PD; however, use of clozapine

delusions are common. Anticholinergic drugs produce requires regular monitoring due to the side effects such as toxic delirium, confusion, agitation, and are associated with agranulocytosis, worsening of confusion, tachycardia, tachycardia, unformed hallucination and lack a theme. dizziness, sweating. Regular WBC monitoring every 2 Other behavior manifestations in patients with PD include weeks is required. Olanzepinein in smaller doses may help

aripiprazole are proven to be efficacious in open-label trials Papapetropoulos et al. concluded that virtually all anti- and have shown limited efficacy. Quetiapine is a common Parkinsonian drugs are able to induce psychotic symptoms.[2] first-line treatment for PD psychosis because of its tolerability, It is controversial that some of the dopaminergic drugs do ease of use although it has failed to demonstrate its efficacy have a higher potential to induce psychosis than others. In

in double-blind trials. A common side effect in the elderly a study by Aarsland et al., the authors found no correlation is sedation. Cholinesterase inhibitors may prove to be more at all between anti-Parkinsonian drugs (levodopa and dopamine agonist (DA)) and hallucinations.[3] Possible beneficial than antipsychotics. Donepezil has not shown significant reductions in psychotic symptoms, perhaps due correlations between dopaminergic treatment with different

to methodological limitations. However, results from an drugs and the risk for PD patients to develop psychosis were open-label study and a double-blind, placebo-controlled analyzed. In randomized, double-blind trials investigating trial involving PD patients with hallucinations support the different DAs, the incidence of hallucinations was 8.1% for efficacy of rivastigmine. Non-pharmacological interventions priribedil, 2.8% for bromocriptine, 4% for rotigotine, 5% for

such as electroconvulsive therapy in isolated case reports ropinirole, 7–9.3% for pramipexole, 4.8% for cabergoline, 3.4% for pergolide, and 0–4.4% for levodopa. All DAs are have shown the potential to reduce psychotic symptoms and effective D2 agonists and, to a lower extent, D3 agonists. may be considered in cases involving concurrent depression These drugs also have D4 receptor affinity which may and/or medication-refractory psychosis. Antidepressants (i.e.

play a role. Levodopa – the drug with the lowest risk for clomipramine and citalopram) may improve psychosis in psychosis in the present investigation – has only low affinity some depressed patients. to D4 receptors. Dopamine agonists with α2 receptor affinity, such as pergolide, may have higher incidence of psychosis. References Cabergoline behaves as a strong antagonist at α2 receptors, whereas ropinirole and pramipexole are mostly inactive. 1. Freidman JH. Stewart Factor Atypical antipsychotics in the

Thus, the treatment of psychosis is focused on withdrawing treatment of drug induced psychosis in Parkinsons disease. Mov the drugs which have higher incidence of inducing psychosis Disord 2000;15:201-11. and less antiparkinsonian effect. Thus, the following order 2. Papapetropoulos S, Mash DC. Psychotic symptoms in of withdrawing the offending drugs is suggested, that is Parkinsons disease: From description to etiology. J Neurol 2005;252:753-64.

tapering and stopping, if necessary, the drugs with the highest 3. Aarsland D, Bronnick K, Ehrt U, De Deyn PP, Tekin S, Emre M, et risk-to-benefit ratio first. Anticholinergics are stopped first, al. Neuropsychiatric symptoms in patients with Parkinsons disease followed by selegiline, dopamine agonists, amantadine, and and dementia: Frequency, profile and associated care giver stress. finally catechol-O-methyltransferase (COMT) inhibitors, J Neurol Neurosurg Psychiatry 2007;78:36-42.

Assessment and management of orthostatic hypotension in Parkinson’s disease The autonomic nervous system controls vital body functions, functions, through the sympathetic and parasympathetic namely, the heart rate, blood pressure, bladder and genital nervous systems. Dysfunction of the autonomic nervous Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

often asymptomatic as autonomic failure possibly because it develops gradually. Pharmacological methods It is essential to check and adjust dopaminergic medicines Drugs used to treat PD including l-Dopa and other as they can worsen OH. The first choice of drug to use is dopaminergic medications can both cause or worsen BP falls Fludrocortisone. The next choice is sympathomimetic drugs in the supine

[Levodopa-induced Supine Hypotension (LISH)] like ephedrine or midodrine. It is important to start them at and standing positions [Levodopa-induced orthostatic a low dose and increase the dose slowly. hypotension (LOH)]. References Access this article online Quick Response Code: 1. Jamnadas-Khoda J, Koshy S, Mathias CJ, Muthane UB, Ragothaman M, Dodaballapur SK. Are current recommendations to diagnose orthostatic hypotension in Parkinson's disease Website: satisfactory? Mov Disord 2009;24:1747-51.

www.annalsofian.org 2. Mathias CJ. Autonomic disorders and their recognition. N Engl J Med 1997;36:721-4. 3. Mathias CJ. Autonomic diseases: Management. J Neurol Neurosurg Psychiatry 2003;74:42-7. Sleep disorders in Parkinson’s disease: Diagnosis and management A large majority (upto 96%) of patients with Parkinson’s The main factors responsible for disturbed sleep in PD have disease (PD) suffer from various sleep-related problems.[1,2] been classified by Barone et al, into the following four

Sleep disturbances, as assessed by validated scales like the subcategories:[5] 1) PD-related motor symptoms, including Parkinson’s disease sleep scale (PDSS)[3] usually correlate with nocturnal akinesia, early-morning dystonia, painful cramps, disease severity and the Hoehn and Yahr staging.[4] tremor and difficulty turning in bed; 2) treatment-related Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Behari, et al.: Parkinson's disease S19 nocturnal disturbances with drugs like levodopa, other Diagnosis of individual sleep problems and their dopamine agonists, antidepressants; 3) psychiatric symptoms, management including hallucinations, vivid dreams, depression, RLS and / or PLMD

dementia, insomnia, psychosis and panic attacks; 4) other RLS is diagnosed by specific criteria laid down by the sleep disorders, including insomnia, rapid eye movement international RLS study group:[8] behavioral disorder (REM-BD), restless legs syndrome (RLS), periodic leg movements (PLMS) and excessive daytime Essential Criteria: sleepiness (EDS). Other common problems among these • Urge to move legs, usually accompanied or caused by

patients like poor sleep hygiene, nocturia and pain further uncomfortable and unpleasant sensations in the legs. worsen sleep quality. • Symptoms begin or worsen during periods of rest or inactivity such as lying or sitting. Objective Assessment of PD Patients for Sleep • Symptoms are partially or totally relieved by movement, Problems such as walking or stretching, at least as long as the activity continues.

Over the last few years, a bedside scale, the PDSS for sleep • Symptoms are worse in the evening or at night than during disturbances specifically for PD has been developed, validated the day or only occur in the evening or night. and employed for screening.[3] The following sleep-related issues are included in this scale: The diagnosis of PLMD can be suspected clinically, typically • Overall quality of night’s sleep (item 1) with the bed partner complaining of jerky limb movements

• Sleep onset and maintenance insomnia (items 2 and 3) occurring periodically every few seconds or minutes. This • Nocturnal restlessness (items 4 and 5) does, however, need to be confirmed through an overnight • Nocturnal psychosis (items 6 and 7) polysomnography.[9] • Nocturia (items 8 and 9) • Nocturia motor symptoms (items 10-13) Treatment: • Sleep refreshment (item 14) Although treatment strategies essentially remain the same • Daytime dozing (item 15)

for RLS and PLMD in PD as in other patients, with dopamine agonists and Levodopa, the main challenge often is to control This, along with the widely accepted sleepiness scale, the symptoms, when patients are already on high doses of these Epworth Sleepiness Scale is an ‘easy to apply’ instrument for agents for PD. Improvement of RLS symptoms following identifying sleep-related problems in PD.[6] In addition, for bilateral subthalamic nucleus stimulation in patients with PD,

specific assessment for RBD, the RBD clinical questionnaire has been reported.[10] can be used.[7] [Table 1] RBD: Table 1: Approach to sleep-related problems in patients with PD RBD is a disorder manifesting with elaborate motor activity with dream mentation during REM sleep with intermittent Poor night time sleep/Insomnia Excessive daytime loss of REM sleep atonia. The following the diagnostic criteria sleepiness laid down in the International Classification of Sleep disorders

Sleep initiation problems: • Maintenance of good (ICSD-R) and criteria B and C are the minimal, required for Poor sleep hygiene: sleep hygiene RBD diagnosis:[11] regular sleep and activity schedules • Addressing all causes a. The patient has a complaint of violent or injurious behavior RLS / PLMD: of disturbed nighttime during sleep. adjust dopaminergics, opioids sleep, especially sleep Hallucinations and psychosis: apnea b. Limb or body movement is associated with dream

reduce Levodopa, quetiapine/ • Treatment of depression mentation. clozapine with non-sedating c. At least one of the following occurs: Pain, dyskinesias, dystonia: antidepressants, if 1. Harmful or potentially harmful sleep behaviors adjust timing of dopaminergic therapy night time sleep is 2. Dreams appear to be “acted out” Sleep maintenance problems: satisfactory 3. Sleep behaviors disrupt sleep continuity Depression: SSRIs, Buproprion • Adjusting dosage of

d. Polysomnographic monitoring demonstrates at least one Sleep apnea: CPAP dopaminergic therapy of the following electrophysiological measures during RBD: Clonazepam • Use of Modafinil Nocturia: Oxybutynin, tolterodine REM sleep: Pain: NSAIDs / other analgesics 1. Excessive augmentation of chin electromyography (EMG) tone 2. Excessive chin or limb phasic EMG twitching, Access this article online irrespective of chin EMG activity and one or more Quick Response Code:

of the following clinical features during REM sleep: a. Excessive limb or body jerking b. Complex, vigorous or violent behaviors Website: www.annalsofian.org c. Absence of epileptic activity in association with the disorder Upto half of all patients with RBD can progress to develop Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S20 Behari, et al.: Parkinson's disease PD and other neurodegenerative conditions (multiple system cause disrupted nighttime sleep, as discussed above should be atrophy, diffuse lewy body dementia) nearly 10-50 years after the main target. Sleep apnea should especially be looked for. onset of RBD symptoms.[12,13]

The following table summarizes a brief approach toward Treatment: diagnosis and management of sleep disorders: Treatment of RBD is relatively simple since a vast majority References (>90%) of patients show good response to small doses (0.25-3 mg) of Clonazepam.[14] Another agent which can be useful is 1. Garcia-Borreguero D, Larrosa O, Bravo M. Parkinson’s disease melatonin; however, the purity of available preparations of this and sleep. Sleep Med Rev 2003;7:115-29.

drug remains an issue. 2. Happe S, Ludemann P, Berger K. The association between disease severity and sleep-related problems in patients with Parkinson’s disease. Neuropsychobiology 2002;46:90-6. Sleep apnea 3. Chaudhari KR, Pal S, DiMarco A, Whately-Smith C, Bridgman Studies have shown that sleep apnea is not commoner in K, Mathew R, et al. The Parkinson’s disease sleep scale: A patients with PD than in the general population.[15] However, new instrument for assessing sleep and nocturnal disability

this being a common disorder, especially in the elderly, who in Parkinson’s disease. J Neurol Neurosurg Psychiatry may also suffer from cardiovascular comorbidities. The 2002;73:629-35. diagnosis is suspected from a history of excessive snoring, 4. Tse W, Liu Y, Barthlen GM, Hälbig TD, Tolgyesi SV, Gracies JM, et al. Clinical usefulness of the Parkinson’s disease sleep scale. excessive daytime somnolence and witnessed apneas and needs Parkinsonism Relat Disord 2005;11:317-21.

to be established by polysomnography studies. 5. Barone P, Amboni M, Vitale C. Treatment of nocturnal disturbances and excessive daytime sleepiness in Parkinson’s Treatment, as in all patients with obstructive sleep apnea, is disease. Neurology 2004;26:S35-8. with continuous positive airway pressure (CPAP). 6. Johns MW. A new method for measuring daytime sleepiness: The Epworth sleepiness scale. Sleep 1991;14:540-5. 7. Scaglione C, Vignatelli L, Plazzi G, Marchese R, Negrotti A, Rizzo

Disorders of circadian sleep rhythm G, et al. REM sleep behaviour disorder in Parkinson’s disease: A The main problems related to circadian sleep rhythms are questionnaire-based study. Neurol Sci 2005;25:316-21. irregular sleep wake patterns, mainly resulting from the 8. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, widely prevalent problem of EDS in patients with PD, which Montplaisi J; et al. Restless legs syndrome: Diagnostic criteria,

results in multiple naps in the daytime and disrupted and special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop inadequate nighttime sleep. Dopaminergic therapy has been at the National Institutes of Health. Sleep Med 2003;4:101-19. shown to be related with activity rest rhythm alterations, 9. Kushida CA, Littner MR, Morgenthaler T, Alessi CA, Bailey D,

mainly early morning awakenings among patients with PD.[16] Coleman J Jr, et al. Practice parameters for the indications for The other rhythm disorder which could be encountered is polysomnography and related procedures: An update for 2005. advanced sleep phase syndrome, in which sleep onset shifts to Sleep 2005;28:499-521. much earlier than usual with very early morning awakening. 10. Driver-Dunckley E, Evidente VG, Adler CH, Hillman R, Hernandez

This can result from an exaggeration of the propensity for the J, Fletcher G, et al. Restless legs syndrome in Parkinson’s disease patients may improve with subthalamic stimulation. Mov elderly to develop some advancement in sleep phase. Disord 2006;21:1287-9. 11. American Academy of Sleep Medicine. International Classification These problems can be addressed by stressing the need for of Sleep Disorders, Revised: Diagnostic and Coding

proper sleep hygiene with fixed sleep schedules and minimal Manual. American Academy of Sleep Medicine, Rochester, allowance for daytime napping. Minnesota, 2001. 12. Iranzo A, Molinuevo JL, Santamaría J, Serradell M, Martí MJ, Valldeoriola F, et al. Rapid-eye-movement sleep behaviour Insomnia disorder as an early marker for a neurodegenerative disorder: A Nearly 30% patients with PD may suffer from insomnia, descriptive study. Lancet Neurol 2006;5:572-7.

resulting from the general tendency of the elderly to lose 13. Claassen DO, Josephs KA, Ahlskog JE. REM sleep behavior a continuous consolidated period of sleep every night, disorder preceding other aspects of synucleinopathies by up to compounded by motor problems of PD, nocturia, medication half a century. Neurology 2010;75:494-9. effect, any other primary sleep disorders and most of all 14. Schenck CH, Mahowald MW. Polysomnographic, neurologic, psychiatric, and clinical outcome report on 70 consecutive

coexistent depression.[17] cases with the REM sleep behavior disorder (RBD): Sustained clonazepam efficacy in 89.5% of 57 treated patients. Cleve Clin Treatment should be targeted firstly toward improving physical J Med 1990;57:S10-24. activity with regular sleep schedules, improving sleep hygiene. 15. Trotti LM, Bliwise DL. No increased risk of obstructive sleep apnea Simultaneously, a good history should always be taken to look in Parkinson’s disease. Mov Disord 2010;25:2246-9.

16. Santiago PL, Rossi M, Cardinali DP, Merello M. Activity-rest for primary sleep disorders and causes of secondary insomnia, rhythm abnormalities in Parkinson’s disease patients are related mainly depression. to dopaminergic therapy. Int J Neurosci 2010;120:11-6. 17. Larsen JP, Tandberg E. Sleep disorders in patients with EDS Parkinson’s disease: Epidemiology and management. CNS Drugs EDS in PD can be multifactorial. The various causes which may 2001;15:267-75.

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S82 Stroke management Kameshwar Prasad, Subhash Kaul1, M.V. Padma, S.P. Gorthi2, Dheeraj Khurana3, Asha Bakshi Department of Neurology, All India Institute of Medical Sciences, New Delhi, 1Nizam's Institute of Medical Sciences, Hyderabad, 2Command Hospital, Central Command, Lucknow, 3Postgraduate Institute of Medical Education and

Research, Chandigarh, India For correspondence: Dr. Kameshwar Prasad, Department of Neurology, Room No.704, 7th Floor, Neurosciences Centre, Ansari Nagar, AIIMS, New Delhi - 110 029, India. E-mail: drkameshwarprasad@gmail.com Annals of Indian Academy of Neurology 2011;14:82-96 Introduction areas where gaps in knowledge or lack of evidence exist and to stimulate research in each area. Scope of the guidelines

These National Clinical Guidelines for stroke cover the The guidelines are concerned with the management of management of patients with acute stroke and the secondary patients who present with a new clinical event that might be prevention of stroke. Primary prevention of stroke, rehabilitation stroke. Stroke in this context is defined as ‘a clinical syndrome and subarachnoid hemorrhage are excluded from the scope of characterized by rapidly developing signs and symptoms of

these guidelines. These guidelines cover the management of focal or at times global loss (as in subarachnoid hemorrhage stroke in adults (over 18 years) from onset to chronic care or brain stem involvement) of cerebral brain functions, lasting and focus on patients with a new clinical event (first stroke or more than 24 hours or leading to death, with no apparent cause recurrent stroke). other than of vascular origin.’ Goal and objectives of the guidelines

While appraisal of evidence forms the basis of the development The primary goal of the guidelines is to continuously improve of these guidelines, we wish to clarify some points: the quality of care in patients with stroke nationally. Our • Evidence related to drugs is generally stronger, because it is intention is closing the gap between best practice and actual methodologically easier to study each intervention in contrast practice. to studying complex intervention like occupational therapy,

health education or nursing care. These do not necessarily The objective of the guidelines is to provide clinicians and mean that interventions with so called strong evidence are administrators with explicit statements, where evidence is more important than those where the evidence is weak. available, on the best way to manage specific problems. Local • We believe that highest level of evidence is not always health service facilities (e.g. hospitals, nursing homes, etc.) will

required to make strong recommendation. If the intervention need to add detail. is safe, logic is strong and effect is obvious, the level of evidence desirable to make strong recommendation may The guidelines are directed primarily at practising clinicians be lower than the highest. involved in management of patients with stroke. Their aim is to • We recognize that many areas of clinical importance may help clinicians, at any level – primary, secondary or tertiary – to

not have evidence available to construct guidelines, and the make the best decisions for each patient, using the evidence recommendations represent a consensus from the working currently available. The focus is on the more common clinical group on such areas. questions faced in day-to-day practice. The guidelines may be used by all health professionals or health care planners involved in the management of the patients with stroke. The working group is aware of recent developments in

evaluating levels of evidence and strength of recommendations, The secondary objectives of the guidelines are to identify and also that the GRADE methodology has been adopted by more than 25 organizations around the world including the WHO. The group endorses the use of GRADE methodology Access this article online (Guyatt and Oxman)[1] for this purpose and will incorporate Quick Response Code: this in the next version of the guidelines. Website: www.annalsofian.org Context and use

These guidelines should be taken as statements to inform the DOI: clinician, not as rigid rules. Practitioners may need to deviate 10.4103/0972-2327.83084 from the guidelines in individual cases but such deviations should be justifiable and justified. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Prasad, et al.: Stroke management guidelines S83 The guidelines may be used to inform decisions on standards • ED personnel should undergo educational activities related of good practice and are likely to be used for audit of stroke to stroke diagnosis and management at least twice a year.

services. Before the guidelines are used as ‘standards’, it is important to ensure that the relevance and appropriateness of Stroke unit the guidelines are discussed in the context proposed. • Should consist of a hospital unit with specially trained staff and a multidisciplinary approach to treatment and care of These guidelines do not cover specific management of stroke patients. associated illnesses like diabetes mellitus, cardiac problems • Should be able to admit patients in the unstable phase,

and others as these may addressed by guidelines from related monitor the vital and neurological parameters, diagnose organizations or are generally expected from a physician. the etiology and subtype, treat and discharge patients with advice on physiotherapy and secondary prevention. Guidelines for Organization of Services for Stroke • Should transfer severely ill and stuporous patients Care including those with raised intracranial pressure (ICP) and with unstable cardiopulmonary status to intensive care.

• Should consider using telemedicine to improve access to Stroke care may be organized at three levels - a basic stroke treatment in rural and remote areas. care facility, a primary stroke care facility and a comprehensive stroke care facility. The basic stroke care facility should be the minimum setup at district hospitals; primary stroke care facility Neurosurgical services should be mandatory for all medical colleges and multispeciality • Comprehensive stroke care facilities should have 24 × 7 on

hospitals; and well-equipped hospitals including some medical call neurosurgeon to evaluate and operate in cases requiring colleges should develop comprehensive stroke care facilities. such consultation and neurosurgery. The basic stroke facility may not have artificial ventilators, • A primary stroke care facility should have neurosurgical echocardiography and carotid Doppler facility, primary stroke care available as early as possible (<2 hours). The patient

care facilities may have these facilities but not neurosurgery, should either be transferred to a neurosurgical care facility MRI or angiography. Comprehensive stroke care facilities or should be able to call in a neurosurgeon within 2 hours. should have all these facilities. • A written protocol for transfer plan should be available. • The hospital with neurosurgical facility should be having 24 Recommendations hours operating facility and support personnel (anesthesia,

radiology, laboratory services, etc.). Patient care services Acute stroke team Support services • At a minimum, includes a physician and another health • Neuroimaging: All levels of stroke care facilities should care professional (i.e., nurse, physician). In addition, a have the capability of performing or access to either a cranial physiotherapist is essential for rehabilitation. computed tomography (CT scan) or magnetic resonance

• Team personnel should have experience, expertise and imaging (MRI) scan within 30 minutes of the order being special interest in diagnosis and treatment of stroke written with experienced physicians or a radiologist to patients. interpret the imaging reports. • Team should be available 24 × 7 and a member of the team • Laboratory services to perform routine blood tests, should be at patient bedside within 15 minutes of being coagulation studies, ECG and chest roentgenograms with

called. 24-hour services. The lab results should be available within 45 minutes of being ordered. • Commitment and Support of the Organization/Institution Written care protocols should be available toward the stroke care facility and the • Protocols should be made available for rt-PA use in acute stroke unit should have a designated medical director/ stroke. incharge with expertise in stroke. • Protocols for emergency care, diagnostic tests, stabilization

• Educational programs periodically and annual programs of vital functions and use of medication should be made for the stroke team should be instituted and public available. education about prevention, recognition and management • Protocols should be reviewed and updated at least once of stroke should be carried out. a year. Emergency medical services (EMS) should be developed and Evidence: Albers,[2] Alberts,[3] Audebert,[4] Calvet,[5] Evans,[6]

upgraded for stroke care at the hospital or district level to Intercollegiate Stroke Working Party,[7] Katzan,[8] Koton,[9] include transport and triage of patients from peripheral LaMonte,[10] Prabhakaran,[11] Purroy,[12] Ronning,[13] Silva,[14] medical centers. Stavem,[15] Stroke Unit Trialists’ Collaboration.[16] Emergency department Acute Phase Care • ED personnel should be trained to diagnose and treat all types of stroke. Admission to hospital

• ED should have good communication with the EMS and Most patients with stroke should be admitted to a hospital the acute stroke team because their neurological condition may worsen over the first Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S84 Prasad, et al.: Stroke management guidelines few days, they may develop non-neurological complications Evidence: Bray,[17] Cucchiara,[18] Lavallee,[19] Rothwell.[20] (e.g., aspiration pneumonia), and urgent investigations (like CT scan) may be required. Diagnosis of acute persistent cerebrovascular event

The aims of emergent evaluation are to: Recommendations • Separate stroke (a vascular event) from other causes of rapid Patients with acute stroke (onset within last 72 hours or altered onset neurological dysfunction (stroke mimics); consciousness due to stroke) should be admitted to hospital for • Provide information about pathology (hemorrhage vs. initial care and assessment. Circumstances where a physician ischemia);

might reasonably choose not to admit selected patients with • Give clues about the most likely etiology; stroke include the following: • Predict the likelihood of immediate complications; and • Individuals with severe pre-existing irreversible disability • Plan appropriate treatment. (e.g., severe untreatable dementia), or terminal illnesses • It should be recognized that ‘stroke’ is primarily a clinical

(e.g., cancer), who have options to be cared at lower level diagnosis and that the diagnosis should be made with health care facility. special care: • Alert patients with mild neurological deficits (not • In the young; secondary to ruptured saccular aneurysm) who are • If the sensorium is altered in presence of mild to identified more than 72 hours after onset of symptoms, moderate hemiparesis; who can be evaluated expeditiously as outpatients, and • If the history is uncertain; or

who are unlikely to require surgery, invasive radiological • If there are other unusual clinical features such as procedures or anticoagulation; gradual progression over days, unexplained fever or • Patients with mild neurological deficits in whom a papilloedema. history and examination is consistent with lacunar stroke syndrome, and a CT scan that either is normal or shows History, physical examination and common old lacunar infarcts. However, they should be evaluated investigations

expeditiously as outpatients. • History should follow usual routine. Special attention should be paid to onset of symptoms, recent stroke, myocardial Diagnosis and management of resolved or rapidly infarction, seizure, trauma, surgery, bleeding, pregnancy resolving acute neurological event and use of anticoagulation/insulin/antihypertensive, • Patients who are first seen after fully resolved or rapidly history of modifiable risk actors: Hypertension, diabetes,

resolving neurological symptoms need diagnosis to smoking, heart disease, hyperlipidemia, migraine and determine whether in fact the cause is vascular (about 50% history of headache or vomiting, recent child birth and are not) and then to identify treatable causes that can reduce risk of dehydration. the risk of stroke (greatest in first 7-14 days). • Physical examination should be on usual lines with

• Any patient who presents with transient symptoms special attention to ABC (airway, breathing, circulation), suggestive of a cerebrovascular event should be considered temperature, oxygen saturation, sign of head trauma to have had a transient ischemic attack (TIA), unless (contusions), seizure (tongue laceration), carotid bruits, neuroimaging reveals an alternative diagnosis. peripheral pulses, cardiac auscultation, evidence of

• All such patients except those with transient monocular petechiae, purpura or jaundice. blindness should have imaging of brain, either CT scan • Validated stroke scales like NIHSS may be used to or MRI. Patients presenting with transient monocular determine the degree of neurological deficit. blindness (amaurosis fugax) must have a complete • All patients should have neuroimaging, complete blood ophthalmological examination to exclude primary count, blood glucose, urea, serum creatinine, serum

disorders of the eye before diagnosis of TIA. electrolytes, ECG and markers of cardiac ischemia. Selected • Patients who have had a TIA should be assessed as soon as patients may require liver function tests, chest radiography, possible for their risk of subsequent stroke using a validated arterial blood gases, EEG, lumbar puncture, blood alcohol scoring system, such as ABCD2 (Refer to Appendix -1). level, toxicology studies or pregnancy test.

• All patients with history of TIA should be started on • All patients should have their clinical course monitored aspirin 150 or 300 mg daily or Clopidogrel (75 mg) once and any patient whose clinical course is unusual for stroke a day in case of aspirin allergy; and those at high risk of should be reassessed for possible alternative diagnosis. stroke (ABCD2 score of 4 or above) should be assessed at

primary or comprehensive stroke care facility within 24 Brain imaging should be performed immediately for patients hours for further management (as indicated under heading with persistent neurological symptoms if any of the following ‘Secondary Prevention’). Those at lower risk should be apply: assessed within 1 week of onset of symptoms. • Indication for thrombolysis or early anticoagulation. • Patients with crescendo TIA (two or more TIAs in a week) • On anticoagulant treatment.

should be treated as being at high risk of stroke, even • A known bleeding tendency. though they may have ABCD2 score of 3 or below. • A depressed level of consciousness (GCS below 13). • Patients who have had a TIA but who present more than • Severe headache at onset of stroke symptoms. one week after their last symptom has resolved should be • Papilloedema, neck stiffness, subhyaloid hemorrhage treated as those with ABCD2 score of 3 or below. or fever.

• All patients with TIA should be managed as indicated under the heading ‘Secondary Prevention’. Patients with acute stroke without the above indications for Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Prasad, et al.: Stroke management guidelines S85 immediate brain imaging, scanning should be performed management of patients with acute ischemic stroke. within 24 hours after onset of symptoms. • No neuroprotective drug is recommended outside the setting of randomized clinical studies.

Evidence: Intercollegiate stroke working party,[7] Wardlaw.[21] Evidence: Davalos,[31] Muir,[32] Shuaib.[33] Immediate specific management of ischemic stroke All patients with disabling acute ischemic stroke who can Immediate specific management of intracerebral be treated within 3 hours (4.5 hours as soon as approved by hemorrhage (ICH) the Drug Controlling authority) after symptom onset should ICH related to antithrombotic or fibrinolytic therapy

be evaluated without delay to determine their eligibility for • ICH related to intravenous heparin requires rapid treatment with intravenous tissue plasminogen activator normalization of a-PTT by protamine sulphate (1 mg/100 (alteplase). U of heparin) with adjustment of dose according to time • Please see Appendix - 2 for detailed recommendation on elapsed since the last heparin dose: For 30 to 60 min : 0.5 thrombolytic therapy. to 0.75 mg; for 60 to 120 min: 0.375 to 0.5 mg, for >120 min

• All acute stroke patients should be given at least 150 mg 0.25-0.3/mg). Protamine sulfate is given by slow i.v. not to of aspirin immediately after brain imaging has exceed 5 mg/min (maximum of 50 mg). Protamine sulfate excluded intracranial hemorrhage (In patients with t-PA, may also be used for ICH related to use of subcutaneous aspirin should be delayed until after the 24-hour post- low molecular weight heparin. thrombolysis). • Patients with warfarin related ICH should be managed

• In patients with large hemispheric infarct (malignant MCA with vitamin K, fresh frozen plasma (FFP) and wherever territory infarct), aspirin may be delayed until surgery or available prothrombin complex concentrate. Vitamin K decision is made not to operate. (10 mg i.v.) should not be used alone because it takes • In dysphagic patients, aspirin may be given by enteral tube. at least 6 hours to normalize the INR. FFP (15-20 ml/

• Aspirin (at least 150 mg) should be continued until 2 weeks kg) is an effective way of correcting INR, but there is after the onset of stroke symptoms, at which time any risk of volume overload and heart failure. Prothrombin antiplatelet or anticoagulant agent is started as indicated complex concentrate and factor IX complex concentrate in ‘secondary prevention’. require smaller volumes of infusion than FFP (and

• Any patient with acute ischemic stroke who is known to correct the coagulopathy faster but with greater risk of have dyspepsia with aspirin should be given a proton thromboembolism). pump inhibitor in addition to aspirin (also see ‘secondary • Patients with ICH related to thrombolysis should be treated prevention’). with infusion of platelets and cryoprecipitate as indicated in Appendix-2. Evidence: CAST,[22] ECASS III - Hacke,[23] Hill,[24] IST-3 Whiteley,[25]

National Institute for Health and Clinical Excellence,[26] Evidence: Cartmill,[34] Goldstein,[35] Huttner,[36] Fredriksson,[37] NINDS.[27] Yasaka.[38] Surgery for ischaemic stroke Patients with middle cerebral artery (MCA) infarction who meet Restarting warfarin all of the criteria below should be considered for decompressive • Patients with a very high risk of thromboembolism (those hemicraniectomy and operated within a maximum of 48 hours: with mechanical heart valves), warfarin therapy may be

• Age 60 years or below. restarted at 7-10 days after onset of the index ICH. Those • NIHSS score of above 15. with lower risk may be restarted on antiplatelet therapy. • Decrease in the level of consciousness to give a score of 1 or more on item 1a of NIHSS, or GCS score between 6 and 13. Evidence: Gubitz 4,[39] Phan.[40] • CT scan showing signs of an infarct of at least 50% of the MCA territory, with or without infraction in the territory Surgery for ICH

of anterior or posterior cerebral artery on the same side or • Patients with cerebellar hemorrhage (>3 cm in diameter) diffusion-weighted MRI showing infarct volume >145cm3. who are deteriorating neurologically or who have signs of brain stem dysfunction should have suboccipital Patients with large cerebellar infarct causing compression craniectomy and surgical evacuation of hematoma. of brainstem and altered consciousness should be surgically • Patients with supratentorial ICH causing midline shift

managed with suboccipital craniectomy. and/or herniation with impairment of consciousness or deteriorating neurologically should have surgical Symptomatic hydrocephalus should be treated surgically with evacuation of hematoma within 72 hours of onset of ventriculostomy. symptoms, unless they were dependent on others for activities of daily living prior to the event or their GCS is Evidence: DECIMAL, DESTINY, HAMLET - Gupta,[28] Jüttler,[29] <6 (unless this is because of hydrocephalus).

Vahedi.[30] • Patients with hydrocephalus who are symptomatic from ventricular obstruction should undergo ventriculostomy. Hemodilution and neuroprotection: • Hemodilution therapy is not recommended for the Evidence: Auer 1989,[41] Mendelow,[42] Prasad,[43] Prasad.[44] Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S86 Prasad, et al.: Stroke management guidelines Acute arterial dissection medication should be recommended only if there is a • Any patient suspected of having arterial dissection should hypertensive emergency with one or more of the following be investigated with appropriate imaging (MRI and MRA). serious concomitant medical issues:

• People with stroke secondary to arterial dissection should • hypertensive encephalopathy be treated with either anticoagulants or antiplatelet agents. • hypertensive nephropathy In selected patients, stenting may be indicated. • hypertensive cardiac failure/myocardial infarction • aortic dissection Evidence: Arauz,[45] Desfontaines,[46] Han,[47] Lyrer.[48] • pre-eclampsia/eclampsia • intracerebral hemorrhage with systolic blood pressure Cardioembolic stroke (SBP) over 200 mmHg.

• Patients with disabling ischemic stroke who are in atrial fibrillation should be treated with aspirin 300 mg for the • Antihypertensive medication should be withheld in first 2 weeks before starting anticoagulation. ischemic stroke patients unless SBP is >220 mmHg or • In patients with prosthetic valves who have disabling the mean arterial blood pressure (MAP) is >120 mmHg. cerebral infarction and who are at significant risk of Lowering by approx 15% during the first 24 hours is

hemorrhage transformation, anticoagulation treatment recommended. should be stopped for one week and aspirin 150-300 mg • Except in hypertensive emergency, lowering of blood should be substituted. • Some experts, despite lack of evidence, recommend starting pressure should be slow and with use of oral medications. • Sublingual use of antihypertensives is not recommended. heparin within 48 hours of onset of cardioembolic stroke, • Blood pressure reduction to 185/110 mmHg or lower

except in patients with large infarctions. should be considered in people who are candidates for Evidence: Butler,[49] Evans,[50] Hart,[51] Intercollegiate Stroke thrombolysis. Working Party,[7] Scottish Intercollegiate Guidelines Network.[52] Intracranial hemorrhage Cerebral venous thrombosis • If SBP is >200 mmHg or MAP is >150 mmHg (recorded twice, • Patients suspected to have stroke due to cerebral venous two or more minutes apart), then blood pressure should

thrombosis should be investigated by MRI/MRV/CTV only be aggressively treated with parenteral antihypertensives if not diagnosed by CT scan. (e.g., labetolol or nitroglycerin). • Patients diagnosed with stroke due to cerebral venous • If SBP is >180 mmHg or MAP is >130 mmHg (up to 150 thrombosis (with or without hemorrhagic infarct or mm Hg), then a modest reduction is advised with rapidly secondary cerebral hemorrhage) should be given full-dose acting oral or parenteral medication or nitroglycerin patch.

anticoagulation (initially heparin and then warfarin [INR • Target BP should be 160/90 or MAP of 110 mmHg. 2-3]) unless there are contraindications. Evidence: Bousser,[53] Stam.[54] Evidence: Ahmed,[61] Bath,[62] Horn,[63] Schrader.[64] Physiological Homeostasis (Oxygen, temperature, Management of blood glucose blood pressure, glucose) Recommendation • The blood glucose level should be maintained between 70 Supplemental oxygen therapy and 190 mg/dL. Elevated blood glucose >140 mg/dL should

• Patients should receive supplemental oxygen if their oxygen be managed with insulin administration using the sliding saturation drops below 95%. scale in the first week of stroke onset. • Hypoglycemia should be monitored and accordingly 20% Evidence: Chiu,[55] Ronning.[56] glucose (50 ml bolus) should be administered. Management of body temperature Evidence: Bruno,[65] Gray,[66] National Institute for Health and Recommendation Clinical Excellence.[67] • Temperature should be monitored every 4 hours for at

least first 48 hours and preferably as long as the patient is Cerebral edema and increased intracranial pressure in the ward. Until more data are available • Fever (>37.5ºC) should be treated with paracetamol. The • Corticosteroids are not recommended for the management search for possible infection (site and cause) should be of cerebral edema and increased ICP following stroke. made. • In patients whose condition is deteriorating secondary to

• Hypothermia <34ºC should be avoided as it can lead to increased ICP, including those with herniation syndromes, coagulopathies, electrolyte imbalance, infection and cardiac various options include: Hyperventilation, mannitol, arrhythmias. furosemide, CSF drainage and surgery. If CT scan (first or repeat one after deterioration) suggests hydrocephalus as Evidence : Castillo,[57] Fukuda,[58] Hajat,[59] Reith.[60] the cause of increased ICP, then continuous drainage of CSF can be used.

Management of blood pressure • Initial care includes mild restriction of fluids, elevation of Ischemic stroke head end of the bed by 20 to 30 degrees and correction of • In acute ischemic stroke, paraenteral antihypertensive factors that might exacerbate increased ICP (e.g. hypoxia, Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Prasad, et al.: Stroke management guidelines S87 hypercarbia and hyperthermia). and use the appliance(s). • Hyperventilation acts immediately (reduction of the pCO 2 • An appropriate oral care protocol should be used for every by 5-10 mmHg lowers ICP by 25-30%) but should be patient with stroke, including those who use dentures. The

followed by another intervention to control brain edema oral care protocol should address areas including frequency and ICP. Hyperventilation can cause vasoconstriction that of oral care (twice per day or more), types of oral care might aggravate ischemia. An intravenous bolus of 40 mg products (toothpaste, floss and mouthwash) and specific furosemide may be used in patients whose condition is management for patients with dysphagia.

rapidly deteriorating. If required, furosemide 20 mg (once • If concerns are identified with oral health and/or appliances, daily) may be continued for the first week, Acetazolamide patients should be referred to a dentist for consultation and 250 mg (BD) may be added in those not responding to other management as soon as possible. treatment methods. • Strict intake-output chart must be maintained to avoid Evidence: Brady.[78] dehydration.

• Mannitol (0.5 gm/kg IV given over 20 minutes) can be given Early mobilization every 6-8 hours. If clinically indicated, dose frequency may • Passive full-range-of-motion exercises for paralyzed limbs be increased to every 4 hours, but then the central venous can be started during the first 24 hours. pressure should be monitored and kept between 5 and 12 • All patients should be referred to a physiotherapist/

mmHg to prevent hypovolemia. This may be continued rehabilitation team as soon as possible, preferably within for 3-5 days. 48 hours of admission. • The patient’s need in relation to moving and handling Evidence: Bereczki,[68] Broderick,[69] Qizilbash,[70] Tyson.[71] should be assessed within 48 hours of admission. General Early Supportive Care Evidence: Fang,[79] Richards.[80] Position Nutrition • Patients should be advised to undertake activities like • Every patient should have his/her nutritional status

sitting, standing or walking only with caution. An determined using valid nutritional screening method occasional patient, who deteriorates on assuming sitting within 48 hours of admission. or standing posture, should be advised bed rest. • Nutritional support should be considered in any • Non-ambulatory patient should be positioned to minimize malnourished patient. the risk of complications such as contractures, respiratory

complications, shoulder pain and pressure sores etc. Evidence: Davalos,[81] Gariballa,[82] Milne,[83] National Institute for Health and Clinical Excellence.[84] Evidence : Turkington,[72] Tyson.[71] Management of seizures Swallowing • Patients with seizure, even single should be treated with • Please see Appendix- 3 for detailed recommendation on loading dose of phenytoin (15-20 mg/kg) followed by bedside swallowing assessment. maintenance dose 5 mg/kg per day for a period of at least

• All conscious patients should have assessment of the ability 3 months. If needed, carbamazepine or sodium valproate to swallow. A water swallow test performed at the bedside may be added. Status epilepticus should be treated as per its is sufficient (e.g. 50 ml water swallow test ) guidelines. At present there is insufficient data to comment • Testing the gag reflex is invalid as a test of swallowing. on the prophylactic administration of anticonvulsants to

• Patients with normal swallow should be assessed for the patients with recent stroke. most suitable posture and equipment to facilitate feeding. Any patient with abnormal swallow should be fed using Evidence: Meierkord,[85] Passero,[86] Vespa.[87]. a nasogastric tube. • Gastrostomy feeding should be considered for patients who Venous thromboembolism are unable to tolerate nasogastric tube. Prophylaxis

• Patients with altered sensorium should be given only • Patients with paralyzed legs (due to ischemic stroke) intravenous fluids (Dextrose saline or normal saline) for should be given standard heparin (5000 units subcutaneous at least 2-3 days. b.d.) or low-molecular weight heparin (with appropriate prophylactic doses as per agent) to prevent deep vein Evidence: Dennis,[73] Hamidon,[74] Norton,[75] Paciaroni,[76] thrombosis (DVT). Smithard.[77] • For those who cannot tolerate heparin, aspirin given for

treatment is of some prophylactic value. Oral care • In patients with paralyzed legs (due to ICH), routine • All stroke patients should have an oral/dental assessment physiotherapy and early mobilization should be carried including dentures, signs of dental disease, etc., upon or out to prevent leg vein thrombosis. soon after admission. • Early mobilization and optimal hydration should be • For patients wearing a full or partial denture, it should be maintained for all acute stroke patients.

determined if they have the neuromotor skills to safely wear • CLOTS trial data does not support the routine use of thigh Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S88 Prasad, et al.: Stroke management guidelines length graduated compression stockings for prevention Evidence: Grasel,[93] Langhorne,[94] Larsen.[95] of DVT. Secondary Prevention Treatment • Standard heparin (5000 U i.v.) or low molecular weight This includes measures to reduce the risk of recurrence of

heparin (with appropriate therapeutic doses as per agent) stroke in patients who have had TIA or stroke. These should be started initially. When standard heparin is used, guidelines apply to vast majority of patients with TIA or a prior baseline complete blood count and a-PTT should be stroke, although some of the recommendations may not be done and a rebolus (80 U/kg/h) and maintenance infusion appropriate for those with unusual causes of stroke, like

(18 U/kg/h) should be given (target a-PTT of 1.5 times the trauma, infections, etc. control value). • Anticoagulation (warfarin 5 mg once daily) should be Every patient should be evaluated for modifiable risk factors started simultaneously unless contraindicated and the dose within one week of onset. This includes: should be adjusted subsequently to achieve a target INR of • Hypertension 2.5 (range 2.0-3.0), when heparin should be stopped. • Diabetes mellitus • Smoking

Evidence: Berge,[88] CLOTS,[89] Gubitz.[39] • Carotid artery stenosis (for those with non-disabling stroke) • Atrial fibrillation or other arrhythmias Bladder care • Structural cardiac disease • An indwelling catheter should be avoided as far as possible and if used, indwelling catheters should be assessed daily In any patient where no risk factor is found, consideration for and removed as soon as possible. investigating for rare causes may be given. The investigations

• Intermittent catheterization should be used for urinary may include anti-phospholipid antibodies, protein C,S and retention or incontinence. anti-thrombin III. • The use of portable ultrasound is recommended as preferred non-invasive method for assessing post-void Evidence: Coull,[96] Johnston,[97] Koton,[98] Lovett.[99] residual urine. Antiplatelet therapy Evidence: Thomas[90] • All patients with ischemic stroke or TIA should receive antiplatelet therapy unless there is indication for Bowel care

anticoagulation. • Patient with bowel incontinence should be assessed for • Aspirin (30-300 mg/day) or combination of aspirin (25 other causes of incontinence including impacted feces with mg) and extended release dipyridamole (200 mg) twice spurious diarrhea. or clopidogrel (75 mg OD) are all acceptable options for • Patients with severe constipation should have a drug review initial therapy. The clinician should be guided by his own

to minimize use of constipating drugs, be given advice on preference coupled with the affordability and tolerance of diet, fluid intake and exercise (as much as possible), be the patient. offered oral laxatives and be offered rectal laxatives only • In children, the maintenance dose of aspirin is 3-5 mg/kg if severe problems remain. per day. • Combined aspirin-extended release dipyridamole as well Evidence: Coggrave[91] as clopidogrel is marginally more effective than aspirin in preventing vascular events.

Infections • The combination of aspirin and clopidogrel increases the • Development of fever after stroke should prompt a search risk of hemorrhage and is not recommended unless there for pneumonia, urinary tract infection or DVT. is indication for this therapy (i.e., coronary stent or acute • Prophylactic administration of antibiotics is not coronary syndromes). recommended. • Addition of proton pump inhibitor should not be routine

• Appropriate antibiotic therapy should be administered and should only be considered when there is dyspepsia early (after taking relevant culture specimens). or other significant risk of gastrointesinal bleeding with aspirin. Evidence: Chamorro.[92] Evidence: CAPRIE,[100] CHARISMA Bhatt et al,[101] ESPS,[102] ESPS- Discharge planning 2,[103] ESPIRIT,[104] MATCH – Fisher.[105] • Discharge planning should be initiated as soon as a patient is stable. Anticoagulation

• Patients and families should be prepared and fully involved. • Anticoagulation should be started in every patient • Care givers should receive all necessary training in caring with atrial fibrillation (valvular or non-valvular) unless for it. contraindicated, if they are likely to be compliant with • Patients should be given information about discharge the required monitoring and are not at high risk for

issues and explained the need for and timing of follow up bleeding. Aspirin also provides some protection if there after discharge. are constraints to the use of oral anticoagulation. [Table 1]. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Prasad, et al.: Stroke management guidelines S89 • Anticoagulation should be considered for all patients who Evidence: Cina,[116] ECST,[117] Ederle,[118] Fairhead,[119] NASCET - have ischemic stroke associated with mitral valve disease, Eliasziw,[120] Inzitari,[121] Paty,[122] Rothwell.[123]

prosthetic heart valves, or within 3 months of myocardial infarction. Lipid lowering therapy • Anticoagulation should not be started until brain imaging • All patients with history of TIA or ischemic stroke should has excluded hemorrhage, and 14 days have passed from be treated with a statin if they have a total cholesterol of > the onset of a disabling ischemic stroke (except when a 200 mg%, or LDL cholesterol > 100 mg%.

demonstrable intracardiac thrombus is present). • The treatment goals should be a total cholesterol of <200 • Anticoagulation should not be used for patients in sinus mg%, and LDL cholesterol of <100 mg% (<70 mg% for very rhythm unless cardiac embolism is suspected. high risk individuals). • For effective anticoagulation target, INR is 2.5 (range 2.0-3.0) • Treatment with statin therapy should be avoided or used

except for mechanical cardiac valves (3.0: range 2.5-3.5). with caution in patients with history of hemorrhgic stroke. Evidence: Antithrombotic Trialists’ Collaboration,[106] De Evidence: Baigent,[124] Collins,[125] HPS,[126] SPARCL - Amarenco. Schryver,[107] ESPRIT,[104] Hankey,[108] Ringleb,[109] Saxena.[110] [127,128] Lifestyle measures Blood pressure lowering • Blood pressure lowering treatment is recommended

for all patients with history of TIA or stroke. The • All patients who smoke should be advised to stop smoking benefit extends to persons with or without a history of and to avoid environmental smoke. hypertension. The treatment should be initiated (or • All patients who can do regular exercise should be advised to do so for at least 30 minutes each day. They should be modified) prior to discharge from hospital in hospitalized advised to start with low intensity exercise and gradually

and at the time of first medical assessment in non- increase to moderate levels (sufficient to become slightly hospitalized patients. • An optimal target for these patients is 130/80 mmHg, breathless). • All patients should be advised to use low fat dairy products but for patients known to have bilateral severe (>70%) and products based on vegetable and plant oils, and reduce internal carotid artery stenosis, SBP of 150 mmHg may be intake of red meat. appropriate.

• Patients’ body mass index or waist circumference should be • The optimal drug regimen is uncertain; however the measured, and those who are overweight or obese should available data supports the use of diuretics or the be offered advice and support to lose weight. combination of diuretics and an ACEI. • All patients, but especially those with hypertension, should be advised to reduce their salt intake by not adding extra Evidence: ALLAHAT,[111] Blood Pressure Lowering Treatment

table salt to food, using as little as possible in cooking, and Trialists’ Collaboration,[112] EXPRESS – Rothwell,[113] HOPE,[114] avoiding preserved foods, pickles etc. and choosing low PROGRESS.[115] salt foods. • Patients who drink alcohol should be advised to keep Carotid intervention within recognized safe drinking limits of no more than three • Patients with TIA or non-disabling stroke and ipsilateral units per day for men and two units per day for women.

70-99% internal carotid artery stenosis (measured by two concordant non-invasive imaging modalities or on Evidence: Brunner,[129] He,[130] Hooper,[131] Lancaster,[132] Rice,[133] a catheter angiogram) should be offered carotid Silagy,[134] Toole,[135] Wang.[136] endarterectomy or stenting (see below) within 2 weeks of the incident event unless contraindicated. Appendix-1 • Carotid intervention is recommended for selected patients

with moderate (50-69%) stenosis in symptomatic patients. ABCD and ABCD2 Prognostic score to identify people at high • Carotid ultrasound / angiogram should be performed risk of stroke after a TIA. It is calculated based on: on all patients who would be considered for carotid endarterectomy or angioplasty. A – age (≥60 years, 1 point). • Carotid endarterectomy should be performed by a surgeon with a known perioperative morbidity and mortality of B – blood pressure at presentation (≥140/90 mmHg, 1 point).

<6%. • Carotid angioplasty and/or stenting should be considered C – clinical features (unilateral weakness, 2 points or speech for patients who are not operative candidates for technical, disturbance without weakness, 1 point). anatomic or medical reasons or when adequate surgical expertise is not available. D – duration of symptoms (≥60 minutes, 2 points or 10–59 • Carotid intervention is not recommended for patients with minutes, 1 point). mild (<50%) stenosis.

• All those with carotid stenosis should receive all secondary The calculation of ABCD2 also includes the presence of prevention measures, whether or not they receive carotid diabetes (1 point). Total scores range from 0 (low risk) to 7 intervention. (high risk). Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S90 Prasad, et al.: Stroke management guidelines Appendix - 2 is still on) and obtain emergency CT scan. 5. Measure blood pressure every 15 minutes for the first 2 Recommendation on thrombolytic therapy hours and subsequently every 30 minutes for the next 6

Prerequisites and criteria for inclusion: hours, then hourly until 24 hours after treatment. 1. Diagnosis of acute ischemic stroke. 6. Increase the frequency of blood pressure measurements 2. No evidence of hemorrhage on plain CT scan (NCCT) of if a systolic blood pressure is ≥ 180 mmHg or if a diastolic blood pressure is ≥ 105 mmHg; administer antihypertensive brain. 3. Measurable neurological deficit (NIHSS 4-25) medications to maintain blood pressure at or below these

4. Neurological deficits of low NIHSS score but significant levels. 7. Delay placement of nasogastric tubes, bladder catheters or functional disability: • Aphasias intra-arterial (IA) pressure catheters. • Hemineglect 8. Obtain a follow-up CT scan at 24 hours before starting • Hemianopia anticoagulants or antiplatelet agents. 5. Neurological signs should not be clearing up spontaneously in the evaluation period. Catheter-Based or intra-arterial (IA) thrombolysis or reperfusion

6. Onset of symptoms within 4.5 hours of beginning treatment. strategies: IA thrombolysis is still under investigation and 7. Absence of major head trauma or major stroke in the should be used in well-equipped centers within a framework previous 3 months. of research protocol. 8. No myocardial infarction requiring hospitalization in the past 3 months (to prevent hemopericardium) Indications 9. No major gastrointestinal or urinary tract hemorrhage in the past 3 weeks.

• A significant neurologic deficit expected to result in long- 10. No major surgery in the previous 14 days. term disability. 11. No history of previous intracranial hemorrhage due to • Deficits attributable to large vessel occlusion (basilar, aneurysm, angioma or arterio-venous malformations. vertebral, internal carotid or MCA M1 or M2 branches). 12. Diagnosed brain tumor. • Non-contrast CT scan without hemorrhage or showing 13. Blood pressure should be less than 185/110 mm Hg. well-established infarct

14. No evidence of acute bleeding from any site or acute fracture • Acute ischemic stroke symptoms with known onset. on examination. Treatment initiated within 6-8 hours of established, non- 15. Not taking oral anticoagulants or if anticoagulants are being fluctuating deficits due to Anterior Circulation (carotid/ taken, INR to be ≤ 1.7 MCA) stroke. The window of opportunity for treatment 16. If receiving heparin in last 48 hours, a-PTT is to be is less well-defined in posterior circulation (Vertebral/

performed and should be normal ( < 35 secs). Basilar) ischemia and patients may have fluctuating, 17. Platelet count to be assessed if there is clinical suspicion of reversible ischemic symptoms over many hours or even thrombocytopenia. Platelet count should be ≥ 1,00,000 /μl. If days and still be appropriate candidates for therapy. there is no clinical suspicion, platelet count test is ordered, but need not wait for result to start thrombolysis. Contraindications

18. Arterial puncture at a non-compression site < 7 days. 19. Blood glucose concentration ≥ 50 mg % and ≤ 300 mg%. 20. Seizure at onset to be ascertained whether due to stroke. If 1. Intracranial hemorrhage (ICH, SAH, subdural hematoma, there is clinical suspicion of non-vascular postictal deficit, etc.) magnetic resonance imaging (MRI) with diffusion-weighted 2. Well-established acute infarct on CT/MRI in the territory imaging (DWI) to CT with CT angiography (CTA) to be to be reperfused ***

performed to document stroke. 3. Major infarction. *** 21. NCCT head should not show a large or multilobar • [e.g. > 1/3 cerebral hemisphere] hypodensity involving more than 1/3 rd of arterial territory 4. CNS lesion with high likelihood of hemorrhage s/p chemical (limited literature suggests increased risk of hemorrhagic thrombolytic agents (e.g., brain tumors, abscess, vascular transformation). malformation, aneurysm, contusion) ***

22. Informed consent from patient or responsible care giver. 5. Suspicion of subarachnoid hemorrhage The items marked with *** are not contraindications for mechanical clot lysis. Treatment regime for IV thrombolysis with rt-PA in acute ischemic stroke 1. Infuse 0.9 mg/Kg (maximum dose of 90 mg) over 60 minutes Warnings with 10% of the dose given as a bolus over 1 minute. 2. Admit the patient to an intensive care unit or a dedicated These conditions may increase the risk of unfavorable outcomes

stroke unit for monitoring. but are not necessarily a contraindication to treatment: 3. Perform neurological assessments every 15 minutes during 1. Recent surgery/trauma (< 15 days) *** the infusion and every 30 minutes thereafter for next 6 2. Recent intracranial or spinal surgery, head trauma, or stroke hours, then hourly until 24 hours after treatment. (< 3 months) *** 4. If the patient develops severe headache, acute hypertension, 3. History of intracranial hemorrhage or brain aneurysm or

nausea or vomiting, discontinue the infusion (if the infusion vascular malformation or brain tumor *** Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Prasad, et al.: Stroke management guidelines S91 • [may consider IA catheter-based repurfusion in patients • Systolic > 185 mmHg or diastolic > 110 mmHg with CNS lesions that have a very low likelihood of • Labetalol 10-20 mg IV over 1-2 min

bleeding such as small unruptured aneurysms or benign • If labetalol is not available, oral captopril ( 12. 5 mg) tumors with low vascularity] and repeat at intervals of 15 minutes or clonidine 4. Active internal bleeding (< 22 days) *** ( 0.1 mg) • [including arterial puncture at a non-compressible site] • if still elevated, 5. Platelets less than 100,000/μl, PTT > 40 sec after heparin use, • May repeat or double labetalol every 10 min to

or PT > 15 or INR > 1.7, or known bleeding diathesis *** maximum dose of 300 mg, or give initial labetalol 6. Left heart thrombus documented *** dose, then start labetalol drip at 2-8 mg/min 7. Increased risk of bleeding due to any of the following: *** • Nicardipine 5 mg/h IV infusion as initial dose and • Acute pericarditis titrate to desired effect by increasing 2.5 mg/h every • Subacute bacterial endocarditis (SBE) 5 min to maximum of 15 mg/h

• Hemostatic defects including those secondary to severe • If blood pressure is not controlled by labetolol or hepatic or renal disease nicardipine, consider sodium nitroprusside or rule • Pregnancy (relative contraindication) out other cause of acute hypertension such as • Diabetic hemorrhagic retinopathy, or other hemorrhagic hypertensive urgency ophthalmic conditions • Septic thrombophlebitis or occluded AV cannula at • During/after treatment seriously infected site • Monitor blood pressure

• Patients currently receiving oral anticoagulants, e.g., • Check blood pressure every 15 min for 2 h, then every Warfarin sodium and INR > 1.7 30 min for 6 h, and finally every hour for 16 h • Advanced age • Diastolic > 140 mmHg • Status - post-full dose IV tPA • Sodium nitroprusside 0.5 mcg/kg/min IV infusion as 8. Life expectancy less than 1 year or severe comorbid illness initial dose and titrate to desired blood pressure The items marked with *** are not contraindications for

• Systolic > 230 mmHg or diastolic >121 – 140 mmHg mechanical clot lysis. • Option 1 • Labetalol 10 mg IV for 1-2 min Prethrombolysis management • May repeat or double labetalol every 10 min to 1. Start supplementary oxygen if unable to maintain O 2 maximum dose of 300 mg, or give initial labetalol saturation > 92%. Treat any fever with acetominophen. NPO dose, then start labetalol drip at 2-8 mg/min for any oral intake (e.g., food, medication, etc.).

2. Do not place Foley, nasogastric tube, arterial line or central • Option 2 • Nicardipine 5 mg/h IV infusion as initial dose and venous line unless it is necessary for patient safety. 3. Do not place any femoral catheters (venous or arterial). titrate to desired effect by increasing 2.5 mg/h every 4. Do not lower blood pressure unless it is causing myocardial 5 min to maximum of 15 mg/h; if blood pressure is

ischemia or exceeds 220/120. Use labetolol iv (5-20 mg iv not controlled by labetolol or nicardipine, consider q 10-20 mins). Monitor with non-invasive cuff pressures sodium nitroprusside. every 15 mins or continuous arterial pressure monitoring. • Systolic 180 – 230 mmHg or diastolic 105 - 120 mmHg 5. Do not administer heparin unless recommended by the • Labetalol 10 mg IV for 1 - 2 min Acute Stroke Team. • May repeat or double labetalol every 10 - 20 min to

6. Alert interventional neuroradiology and anesthesia about maximum dose of 300 mg or give initial labetalol possible case. dose, then start labetalol drip at 2 - 8 mg/min 7. Alert neuro-ICU and check for bed availability. • Consider bypassing CT Angio if risk is increased (e.g., For acute stroke onset during or immediately after renal failure, acute CHF) and it is unlikely to change diagnostic or therapeutic angiography/ or coronary and treatment decision. Hold metformin 48 hrs after cardiac interventions

iodinated contrast. If a femoral arterial sheath is still in place, DO NOT REMOVE • Check MRI exclusions (e.g., Severe claustrophobia, IT. The sheath should remain sutured in place while t-PA is implanted pacemaker, metal fragments, shrapnel). given. Consider IA urokinase if the sheath can be accessed • Review CT/CTA with interventionalist and stroke team. and the Interventional Neuroradiology staff is available. If not,

• Obtain written or verbal informed consent for consider giving t-PA i.v. at full dose 0.9 mg/kg. In all cases, endovascular procedure and general anesthesia from leave the sheath in place and check STAT a-PTT. Observe the patient or appropriate caregiver. If no individual is groin site closely and follow hematocrit and vital signs for available for consent, consider emergency consent evidence of acute blood loss. If a hematoma forms or there procedures.

is evidence of blood loss, notify vascular surgery and apply • If time permits, obtain STAT DWI-MR imaging but do pressure until hemostasis is achieved. If bleeding continues, not delay time to treatment. t-PA can be reversed with FFP, cryoprecipitate and platelets. Vascular surgery may choose to surgically repair the artery. Guidelines for management of blood pressure prior and If no bleeding occurs, the sheath can be removed after 24

perithrombolysis: hours. If heparin cannot be held for sheath removal, vascular • Pretreatment surgery will surgically close the vessel in the operating room. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S92 Prasad, et al.: Stroke management guidelines Bleeding after t-PA Laryngeal (Aah/ee) (Normal = 1, weak = 2, [ ] 1. For suspected symptomatic hemorrhage after t-PA or other function absent =3 plasminogen activator has been given: Voluntary (Normal = 1, weak = 2, absent = 3) [ ] • Hold administration of IV t-PA if still infusing until cough

Brain CT completed and shows no evidence of bleeding. Stage 1: Give a teaspoon (5 mL) of water three times • Exclude other possible causes of neurologic worsening Dribbles (None /once = 1, > once = 2) [ ] or acute hemodynamic instability. water Laryngeal (Yes = 1, no = 2) [ ] 2. For confirmed symptomatic hemorrhage on head CT: movement • Consult neurosurgery for possible intervention. on attempted • Check STAT values: CBC, PT, a-PTT, platelets, fibrinogen swallow

and D-dimer. “Repeated (None/once = 1, > once = 2) [ ] • If fibrinogen < 100 mg/dL, then give cryoprecipitate 0.15 movements” units/kg rounded to the nearest integer. If still bleeding felt ? at 1 hr and fibrinogen level still less than 100 mg/dL, Cough on (None/once = 1, > once = 2) [ ] repeat cryoprecipitate dose. swallowing • Institute frequent neurochecks and therapy of acutely Stridulous on (No = 1, yes = 2) [ ] elevated ICP, as needed. swallowing

• Additional options or considerations. Laryngeal (Normal = 1, weak/wet =2, absent [ ] • If platelet dysfunction suspected, give platelets 4 U. function after =3) • If heparin has been administered in the past 3 hours: Swallowing • Discontinue the heparin infusion and order protamine Stage 2: If the swallow is normal in stage 1 (two of three attempts), try 60 mL of water in a glass or beaker. sulfate. Calculate total amount of heparin received over Able to finish [ ] the preceding 3 hours. in seconds

• If initiated within 30 minutes of last heparin dose: Give No of sips [ ] 1 mg protamine per 100 U heparin. • If initiated within 30-60 minutes: Give 0.5-0.75 mg Cough during (No = 1, yes = 2) [ ] or after protamine per 100 U heparin. swallowing • If initiated within 60-120 minutes: Give 0.375-0.5 mg Stridor (No = 1, yes = 2) [ ] protamine per 100 U heparin. during • If heparin stopped greater than 120 minutes ago: Give or after 0.25-0.375 mg protamine per 100 U heparin. swallowing

• Give by slow IV injection, not to exceed 5 mg/min, with Laryngeal (Normal = 1, weak/wet = 2, [ ] total dose not to exceed 50 mg. function after • Monitor for signs of anaphylaxis; the risk is higher in swallowing diabetics who have received insulin. Do you feel (No = 1, possible =2, yes =3) [ ] • Follow-up with STAT a-PTT q1 hour for the next 4 hours, aspiration is then q4 hours through 12 hours of hospitalization. present? • Serious systemic hemorrhage should be treated in a

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102. The European Stroke Prevention Study (ESPS). Principal end- Ozsvath KJ, et al. Early carotid endarterectomy after acute stroke. points. The ESPS Group. Lancet 1987;2:1351-4. J Vasc Surg 2004;39:148-54. 103. Second European Stroke Prevention Study. ESPS-2 Working 123. Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJ. Group. J Neurol 1992;239:299-301. Endarterectomy for symptomatic carotid stenosis in relation to

104. Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin clinical subgroups and timing of surgery. Lancet 2004;363:915-24. plus dipyridamole versus aspirin alone after cerebral ischaemia 124. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino of arterial origin (ESPRIT): Randomised controlled trial. Lancet C, et al. Efficacy and safety of cholesterol-lowering treatment: 2006;367:1665-73. Prospective meta-analysis of data from 90,056 participants in 14

105. Fisher M, Davalos A. The MATCH study results in the context of randomised trials of statins. Lancet 2005;366:1267-78. secondary stroke prevention. Stroke 2004;35:2609. 125. Collins R, Armitage J, Parish S, Sleight P, Peto R. Effects of 106. Collaborative meta-analysis of randomised trials of antiplatelet cholesterol-lowering with simvastatin on stroke and other major therapy for prevention of death, myocardial infarction, and stroke vascular events in 20536 people with cerebrovascular disease or

in high risk patients. BMJ 2002;324:71-86. other high-risk conditions. Lancet 2004;363:757-67. 107. De Schryver EL, Algra A, van Gijn J. Dipyridamole for preventing 126. MRC/BHF Heart Protection Study of cholesterol lowering with stroke and other vascular events in patients with vascular disease. simvastatin in 20,536 high-risk individuals: A randomised placebo- Cochrane Database Syst Rev 2007;3:CD001820. controlled trial. Lancet 2002;360:7-22.

108. Hankey GJ, Sudlow CL, Dunbabin DW. Thienopyridine derivatives 127. Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, (ticlopidine, clopidogrel) versus aspirin for preventing stroke Hennerici M, Rudolph AE, et al. High-dose atorvastatin after stroke and other serious vascular events in high vascular risk patients. or transient ischemic attack. N Engl J Med 2006;355:549-59. Cochrane Database Syst Rev 2000;2:CD001246. 128. Amarenco P, Goldstein LB, Szarek M, Sillesen H, Rudolph AE,

109. Ringleb PA, Bhatt DL, Hirsch AT, Topol EJ, Hacke W. Benefit of Callahan A 3rd, et al. Effects of intense low-density lipoprotein clopidogrel over aspirin is amplified in patients with a history of cholesterol reduction in patients with stroke or transient ischemic ischemic events. Stroke 2004;35:528-32. attack: The Stroke Prevention by Aggressive Reduction in 110. Saxena R, Koudstaal PJ. Anticoagulants for preventing stroke Cholesterol Levels (SPARCL) trial. Stroke 2007;38:3198-204.

in patients with nonrheumatic atrial fibrillation and a history of 129. Brunner EJ, Rees K, Ward K, Burke M, Thorogood M. Dietary stroke or transient ischaemic attack. Cochrane Database Syst advice for reducing cardiovascular risk. Cochrane Database Syst Rev 2004;2:CD000185. Rev 2007;4:CD002128. 111. Major outcomes in moderately hypercholesterolemic, hyper- 130. He FJ, Nowson CA, MacGregor GA. Fruit and vegetable

tensive patients randomized to pravastatin vs usual care: The consumption and stroke: Meta-analysis of cohort studies. Lancet Antihypertensive and Lipid-Lowering Treatment to Prevent Heart 2006;367:320-6. Attack Trial (ALLHAT-LLT). JAMA 2002;288:2998-3007. 131. Hooper L, Bartlett C, Davey SG, Ebrahim S. Advice to reduce 112. Turnbull F. Effects of different blood-pressure-lowering regimens dietary salt for prevention of cardiovascular disease. Cochrane

on major cardiovascular events: Results of prospectively-designed Database Syst Rev 2004;1:CD003656. overviews of randomised trials. Lancet 2003;362:1527-35. 132. Lancaster T, Stead LF. Individual behavioural counselling for 113. Rothwell PM, Giles MF, Chandratheva A, Marquardt L, Geraghty smoking cessation. Cochrane Database Syst Rev O, Redgrave JNE, et al. Effect of urgent treatment of transient 2002;3:CD001292.

ischaemic attack and minor stroke on early recurrent stroke 133. Rice VH, Stead LF. Nursing interventions for smoking cessation. (EXPRESS study): A prospective population-based sequential Cochrane Database Syst Rev 2004;1:CD001188. comparison. Lancet 2007;370:1432-42. 134. Silagy C, Lancaster T, Stead L, Mant D, Fowler G. Nicotine 114. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. replacement therapy for smoking cessation. Cochrane Database

Effects of an angiotensin-converting-enzyme inhibitor, ramipril, Syst Rev 2002;4:CD000146. on cardiovascular events in high-risk patients. The Heart 135. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S96 Prasad, et al.: Stroke management guidelines LC, Howard VJ, et al. Lowering homocysteine in patients with systematic review. Am J Clin Nutr 2006;84:5-17. ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: The Vitamin Intervention for Stroke Prevention (VISP)

How to cite this article: Prasad K, Kaul S, Padma MV, Gorthi SP, randomized controlled trial. JAMA 2004;291:565-75. Khurana D, Bakshi A. Stroke management. Ann Indian Acad Neurol 136. Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, 2011;14:82-96. Kupelnick B, et al. n-3 Fatty acids from fish or fish-oil supplements, Received: 26-01-11 but not alpha-linolenic acid, benefit cardiovascular disease

outcomes in primary- and secondary-prevention studies: A Source of Support: Nil. Conflict of Interest: None declared. AUTHOR INSTITUTION MAP FOR THIS ISSUE Map will be added after issue gets online**** Please note that not all the institutions may get mapped due to non-availability of requisite information in Google Map. For AIM of other issues, please check Archives/Back Issues page on the journal’s website. Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S65 Treatment of multiple sclerosis Lekha Pandit, J. M. K. Murthy1 Department of Neurology, KS Hegde Medical Academy, Nitte University, Mangalore, Karnataka, 1The Institute of Neurological Sciences, CARE Hospital, Hyderabad, India For correspondence:

Dr. Lekha Pandit, Professor of Neurology, KS Hegde Medical Academy, Nitte University, Mangalore-575018, Karnataka. Email: panditmng@gmail.com Annals of Indian Academy of Neurology 2011;14:65-9 Multiple sclerosis (MS) is a chronic autoimmune inflammatory Diagnosis disorder of the central nervous system (CNS). There has been an increase in the prevalence of MS worldwide. There are no The core requirements for the diagnosis of MS are dissemination

epidemiological studies available from India in the last three of lesions in space and time [Table 1]. The currently accepted decades. The prevalence of 3 per 100,000 for India, quoted classification for MS is the McDonald Diagnostic Criteria[3] by the Multiple Sclerosis International Federation (MSIF), is which is heavily biased in favor of MRI. Evoked potential likely to be a gross under estimation. Natural history studies studies and cerebrospinal fluid (CSF) evaluation have become

have shown that 10 years after disease onset, approximately less important in the diagnosis of MS and are recommended 50% of patients are using a cane to walk and 15% require a when evaluating a case of CIS or there is clinical or radiological wheel chair.[1] A significant number of patients with “benign uncertainty [Table 2]. MS” develop cognitive dysfunction into the course of their disease.[2] The revised criteria for diagnosis of MS include the following:

• At least two attacks with objective clinical evidence of at Clinical Features least two lesions. • At least two attacks with objective clinical evidence of one Most of the patients have initial demyelinating events referred lesion plus dissemination in space1 shown on MRI or two to as clinically isolated syndromes (CISs) such as optic neuritis, or more MRI lesions consistent with MS plus positive CSF partial cord syndrome, or an acute brainstem event. If the finding or second clinical attack.

magnetic resonance imaging (MRI) shows multifocal disease • One attack with objective clinical evidence of at least two at the time of CIS, nearly half to two-third develop recurrent lesions plus dissemination in time2 on MRI or second events and transform into clinically definite MS. Based on the clinical attack. type of presentation, MS is classified into: • One attack with objective clinical evidence of one lesion,

1. Clinically isolated syndromes (CISs) plus dissemination in space shown on MRI or two or more 2. Relapsing and remitting multiple sclerosis (RRMS) MRI lesions consistent with MS plus positive CSF findings 3. Secondary progressive multiple sclerosis (SPMS) and dissemination in time shown on MRI or second clinical 4. Primary progressive multiple sclerosis—progressive from attack. the onset (PPMS) • Insidious neurologic progression suggestive of MS plus

5. Primary relapsing multiple sclerosis (PRMS) one year of disease progression determined retrospectively or prospectively and two of the following: Positive brain MRI results (nine T2 lesions or at least four T2 lesions with An acute relapse refers to an episode of neurological positive visual evoked potential), positive spinal cord MRI disturbance, of the kind seen in MS that lasts for at least 24 h, results with two focal T2 lesions, and positive CSF findings.

and which was not precipitated by intercurrent infection or stress. Typically relapses evolve over days, reach a plateau, Treatment of multiple sclerosis and gradually remit over a variable period of time. Treatment of MS includes treatment of acute relapses, disease- modifying drugs, and treatment of various symptoms and Access this article online complications associated with MS [Table 3 and Figure 1]. Quick Response Code: Website: Note

www.annalsofian.org 1. The revised MRI criteria for dissemination in space are three of the following: One or more gadolinium-enhancing lesions or nine T2 hyperintense lesions; one or more infratentorial lesions; one or DOI: more juxtacortical lesions; or three or more periventricular lesions. 10.4103/0972-2327.83094 2. The revised MRI criteria for dissemination in time are detection of gadolinium enhancement at least 3 months after the onset of the

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S66 Pandit and Murthy: Treatment of MS Table 1: Diagnostic criteria for multiple sclerosis (Revised Mc Donald criteria) Clinical presentation Additional Data Needed 2 or more attacks None; clinical evidence will suffice 2 or more objective clinical lesions (additional evidence desirable and must be consistent with MS)

2 or more attacks Dissemination in space, demonstrated by: 1 objective clinical lesion • MRI • 1 Gd-enhancing or 9 T2 hyperintense lesions if no Gd-enhancing lesion • 1 or more infratentorial lesions • 1 or more juxtacortical lesions • 3 or more periventricular lesions • (I spinal cord lesion =I brain lesion) • or a positive CSF and 2 or more MRI lesions consistent with MS • or further clinical attack involving different site 1 attack Dissemination in time, demonstrated by:

2 or more objective clinical lesions MRI or second clinical attack 1 attack Dissemination in space by demonstrated by: 1 objective clinical lesion • MRI (monosymptomatic presentation) • or positive CSF and 2 or more MRI lesions consistent with MS and Dissemination in time demonstrated by: MRI A Gd-enhancing lesion demonstrated in a scan done at least 3 months following onset of clinical attack at a site different from attack, or

In absence of Gd-enhancing lesions at 3 month scan, follow-up scan after an additional 3 months showing Gd-lesion or new T2 lesion. or second clinical attack Insidious neurological progression Positive CSF suggestive of MS and (primary progressive MS) Dissemination in space demonstrated by: • MRI evidence of 9 or more T2 brain lesions • or 2 or more spinal cord lesions • or 4-8 brain and 1 spinal cord lesion • or positive VEP with 4-8 MRI lesions

• or positive VEP with <4 brain lesions plus 1 spinal cord lesion and Dissemination in time demonstrated by: • MRI A Gd-enhancing lesion demonstrated in a scan done at least 3 months following onset of clinical attack at a site different from attack, or In absence of Gd-enhancing lesions at 3 month scan, follow-up scan after an additional 3 months showing Gd-lesion or new T2 lesion. • or continued progression for 1 year

Attack – neurological disturbance consistent with MS and lasting more than 24 hours. Time between attacks not less than 30days, Positive CSF - Oligoclonal IgG bands in CSF (and not serum) or elevated IgG index, Positive VEP (visual evoked potential)- Delayed but well-preserved wave form. Attack – neurological disturbance consistent with MS and lasting more than 24 hours. Time between attacks not less than 30days, Positive CSF - Oligoclonal IgG bands in CSF (and not serum) or

elevated IgG index, Positive VEP (visual evoked potential)- Delayed but well-preserved wave form. first clinical event or detection of a new T2 lesion appearing at any for the treatment of disabling relapses such as optic neuritis, time compared with a reference scan done at least 30 days after the significant motor disability, acute ataxia, etc. The exact onset of the initial clinical event. mechanism of action is not clear, but some of the possible

mechanisms include: antiedema effects, stabilization of blood– Treatment of acute relapse brain barrier, reduction of proinflammatory cytokines, and Prevention apoptosis of T cells.[4] Several factors may trigger relapses or may exacerbate existing symptoms and MS patients should be educated about The optic neuritis treatment trial (OPTT) established the preventive measures. Infections especially of the urinary tract standard of care.[5] High dose intravenous (IV) methyl

should be anticipated and aggressively controlled. It is safe prednisolone in a dose of 1 g/day for 3 days followed by a to vaccinate these patients. Stressful life events and physical short course of oral steroids in tapering dose was shown to be trauma may also cause relapse. significantly better than oral corticosteroids in the hastening rate of recovery following mono ocular optic neuritis. Time Steroids to next relapse was also prolonged in those who received

Not all relapses need to be treated. Steroids are best indicated parenteral steroids though this effect was not significant Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Pandit and Murthy: Treatment of MS S67 Table 2: Diagnostic work up for suspected multiple sclerosis Source Test Reason for testing MRI with contrast Brain and spinal cord Diagnosis of white matter disease. In MS, in addition, to establish dissemination in space and time Blood (essential) ESR,ANA, ANCA,RF Vasculitis, Systemic autoimmune disorder

Vitamin B12 Vitamin B12 deficiency Serology for HIV, Syphilis, HTLV1 Blood (optional) ACE Sarcoidosis, whipples disease Lactate, pyruvate,CK Mitochondrial encephalomyopathy Very long chain fatty acids Leukodystrophy Arylsulfatase Paraneoplastic syndrome Anti neuronal nuclear antibody 1&11 CSF (optional) IgG index, Oligoclonal bands (paired samples) MS, SSPE, HIV, neurosyphilis Lactate,pyruvate Mitochondrial encephalopathy PCR for infections HSV, CMV, HTLV1, other

Cerbral angiography Vasculitis, vasculopathy, (optional) Biopsy Skin SLE, Vasculitis (optional) Conjunctiva Sarcoidosis Brain Atypical (non MS) white matter lesions ESR- Erythrocyte sedimentation ratio, ANA- Antinuclear antibody, ANCA-Anti nutrophil cytoplasmic antibody, RF-Rheumatoid factor, ACE-Angiotensin converting enzyme, CK-Creatine phosphokinase, HSV-Herpes simplex virus, CMV-Cytomegalo virus, SSPE-Subacute sclerosing panencephalitis

Table 3: Treatment recommendations in multiple after the first 10 years following OPN. Most neurologists use Sclerosis IV methyl prednisolone in doses of 1 g/day for 3–5 days.[6] Oral taper with corticosteroids is a controversial area in MS 1. Acute relapse : Specific treatment ;Oral or Intravenous methylprednisolne therapeutics, with many neurologists preferring to avoid (preferably Intravenous) 1 gram per day for 3 days, not more it. In some situations when patients do not respond well to

than 3 times in a year. initial 3–5 days of parenteral methyl prednisolone, the course 2. Disease modifying therapy: may be repeated once again. It is also advisable to give not RRMS : In all patients newly diagnosed to have RRMS by Mc more than three courses of steroids per year in MS patients.[7] Donald Criteria Transient hyperglycemia and hypertension should be looked SPMS : In all patients with SPMS and having superimposed out for and so also worsening of preexisting acid peptic

relapses during their progressive disease course. disease. The specific precaution to be taken before steroid PPMS: Not indicated administration is to exclude infections particularly urinary. Choice of therapy : Plasmapheresis and intravenous immunoglobulin are not RRMS - Either Interferon Beta or Glatiramir acetate can be standard recommendations in the treatment of MS relapse. started. Frequent and higher dosing with Interferon Beta more superior to once a week treatment.

SPMS – Interferon Beta to be started Disease-modifying drugs in multiple sclerosis The disease-modifying drugs (DMDs) [Table 4] are used for the relapsing forms of MS and have multiple benefits:[8,9] (1) decreases in the frequency and severity of relapses or no relapses: (2) less development of disability or sustained improvement; (3) well maintained or improved quality of life; and (4) less MRI lesion burden and less development of CNS atrophy. Although a variety of DMDs has become available for the

treatment in MS, only interferon-beta (IFN-b), glatiramir acetate, mitoxantrone, and the very recently launched Natalizumab (Tysabri) are currently available in India. Interferon-b Interferons are produced naturally in human lymphocytes and modulate the immune system by influencing the production of protein products. Avonex and Rebif are forms of interferon b-1a, but the strength of the individual doses and the injection routes differ. Avonex is prepackaged as a 30-mg dose that is

given once a week intramuscularly. Rebif is provided in two dose strengths, 22 mg and 44 mg, and is injected subcutaneously three times a week, beginning therapy with the lower dose. Figure 1: Treatment algorithm for multiple sclerosis Betaseron, interferon b-1b, is given subcutaneously every other Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S68 Pandit and Murthy: Treatment of MS Table 4: Disease modifying drugs in multiple Table 5 Symptomatic treatment of MS sclerosis Symptom Treatment Agent Dose Major side effects Pharmacological Non IFNB 1b 250 ug SC every Flue like illness, liver pharmacological other day function and thyroid Drug Dosage

function abnormalities Spasticity Baclofen 10-150 Physiotherapy IFNB 1a (IM) 30 ug IM weekly Same as above mg/d. IFNB 1a (SC) 44 ug thrice weekly Same as above Tizanidine 2-24 mg/d Treat Glatirmaer 20 mg SC daily Injection site concurrent acetate reactions, urticaria, infections lymphadinopathy Diazepam 5- 30 Mitoxantrone 12 mg/m2 IV every Cardiomyopathy, mgm/d. 3 months (max 140 leucopenia, Gabapentin 300-3600 mg/m2) treatment-related- mg/d. leukemia. infections Botulium Toxin infertility

Fatigue Amantadine 200-400 Exclude mg/d depression day. In several class I studies, interferon-b has been shown to Modafanil 200-400 Exclude reduce the attack rate in RRMS patients and also reduce T2 mg/d Hypothyroidism lesion load on MRI.[9,10] However, there is little evidence from Cooling of body long-term follow-up studies that it slows down sustained Pain (MS Amitryptylline 25-150 disability progression.. Related) mg/d Carbamazepine 200-1600 Glatiramer acetate mg/d

Glatiramer acetate (Copaxone) is a synthetic drug that interferes Gabapentin 300-2400 with antigen presentation.[11] It is given as a single, daily, 20-mg mg/d subcutaneous injection. In several class I studies, glatiramer Lamotrigine 200-400 acetate has been shown to reduce the attack rate in patients mg/d with RRMS, reduce lesion load on T2W MRI and possibly Pregabalin 150-600 mg/d also slows sustained disability progression. It is appropriate

to consider glatiramer acetate for treatment in any patient Tremor Occupational who has RRMS. Although it may be that glatiramer acetate therapy Intention Propranolol 40-120 Physiotherapy also is helpful in patients with progressive disease, there is no mg/d convincing evidence to support this hypothesis. Gabapentin 300-2400 mg/d Mitoxantrone Cerebellar Carbamazepine 200-1600 VIM It is an anthrocenedione chemotherapeutic agent (similar mg/d thalamotomy

to adriamycin) that has been approved for the treatment of Topiramate 25-150 VIM deep brain relapsing remitting and secondary progressive MS. Three mg/d stimulation clinical trials including a large phase III study support the use Clonazepam 3-6mg/d of mitoxantrone in RRMS.[12-14] However, its use is associated Paroxysmal Carbamazepine 200-1000 with cardio-toxicity and leukemia in some patients who were mg/d in remission five or more years after treatment.[15] At present Symptoms Gabapentin 300-1500

the best indication for mitroxantrone would be in patients mg/d with aggressive RRMS (more than two relapses in a year or Lamotrigine 200-400 worsening lesion load while on a primary disease modifying mg/d agent) and probably patients with poor response to IFN-b. Cognitive Donepezil 10 mg/d Attention However, in view of dosing limitations, at best, mitoxantrone training can be used as an inducer of remission in RRMS.[16] Maintenance Impairment memory

therapy with other DMDs is required. The best combination training perhaps would be short course of mitoxantrone combined with a DMD with a good safety profile such as b-interferon or activity, and the drug is very well tolerated. Natalizumab glatiramir acetate. There is no robust evidence to support the is given once a month as infusion. The major concern with use of mitoxantrone in primary PPMS, or in the later stages of natalizumab is the development of progressive multifocal

SPMR (EDSS > 6). leukoencephalopathy (PML).[17] By February 2011, at the time of writing this article the reported cases were 95, 20 of whom Natalizumab have died. The risk of PML rises with duration of treatment It is a humanized monoclonal antibody directed against from, <1/1000 in the first year to a little more than 1/1000 after a-integren, an adhesion molecule expressed on all leukocytes the second year. except neurtrophils.[16] The drug has been shown to be

effective in suppression of relapses, disability, and MRI lesion Other drugs used in the treatment of MS include azothiaprine, Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Pandit and Murthy: Treatment of MS S69 methotrexate, cyclophosphamide, and mycophenolate moftil. 4. Gold R, Buttgereit F, Toyka KV. Mechanism of action of However, none of them have been established for use by phase glucocorticosteroid hormones: Possible implications for therapy

III studies. of neuroimmunological disorders. J Neuroimmunol 2001;117:1-8. 5. Beck RW. The optic neuritis treatment trial: Three-year follow-up results. Arch Ophthalmol 1995;113:136-7. Pregnancy 6. Tremlett HL, Luscombe DK, Wiles CM. Use of corticosteroids During pregnancy relapse rates are low but it definitely increases in multiple sclerosis by consultant neurologists in the United in the immediate 3 months postpartum.[18] Ideally women with Kingdom. J Neurol Neurosurg Psychiatry 1998;65:362-5.

MS should plan their pregnancy and stop disease-modifying 7. Alam SM, Kyriakides T, Lawden M, Newman PK. agents 3 months prior to conception and restart the same after Methylprednisolone in multiple sclerosis: A comparison of oral with breast feeding is over. IFN-b and natalizumab are Category C intravenous therapy at equivalent high dose. J Neurol Neurosurg Psychiatry 1993;56:1219-20. pregnancy drugs (where potential benefits may warrant the 8. Goodin DS, Frohman EM, Garmany GP Jr, Halper J, Likosky

use of the drug in pregnant women despite potential risks), WH, Lublin FD, et al. Disease modifying therapies in multiple glatiramer acetate is a Category B (no demonstrable side effects sclerosis. Report of the Therapeutics and Technology Assessment in the fetus during any trimester) and mitoxantrone is a Category Subcommittee of the American Academy of Neurology and D (positive evidence of human fetal risk based on adverse the MS Council for Clinical Practice Guidelines. Neurology

reaction data, but potential benefits may warrant use of the drug 2002;58;169-78. in pregnant women despite potential risks) drug. There are no 9. Goodin DS. Disease-modifying therapy in multiple sclerosis: contraindications for breast feeding while on DMD. Update and clinical implications. Neurology 2008;71:S8-S13. 10. Kappos L, Traboulsee A, Constantinescu C, Erälinna JP, Forrestal Role of disease-modifying agents in clinically isolated F, Jongen P, et al. Long-term subcutaneous interferon beta-

syndromes 1a therapy in patients with relapsing-remitting MS. Neurology 2006;67:944-53. Several placebo-controlled phase III clinical trials (class I 11. Neuhaus O, Farina C, Wekerle H, Hohlfeld R. Mechanisms of evidence) have studied patients with CIS and evidence of action of glatiramer acetate in multiple sclerosis. Neurology silent lesions on MRI. There was substantial reduction in new 2001;56:702-8.

MRI lesions and risk of subsequent exacerbations in patients 12. Edan G, Miller D, Clanet M, Confavreux C, Lyon-Caen O, Lubetzki treated with interferon b-1a (Avonex or Rebif),[19] interferon C, et al. Therapeutic effect of mitoxantrone combined with b-1b (Betaseron), and more recently with glatiramer acetate methylprednisolone in multiple sclerosis: A randomised multicentre (Copaxone). Patients initially treated with placebo and later study of active disease using MRI and clinical criteria. J Neurol

converted to active treatment never achieved the magnitude of Neurosurg Psychiatry 1997;62:112-8. 13. Edan G, Morrissey S, Le Page E. Rationale for the use of benefit seen in the patients who received early treatment with mitoxantrone in multiple sclerosis. J Neurol Science 2004;223:35-9. disease modifying therapy. 14. Millefiorini E, Gasperini C, Pozzilli C, D’Andrea F, Bastianello S, Trojano M, et al. Randomized placebo-controlled trial of

Symptomatic treatment of multiple sclerosis mitoxantrone in relapsing-remitting multiple sclerosis: 24-month Spasticity, fatigue, tonic spasms, parasthesia, depression, clinical and MRI outcome. J Neurol 1997;244:153-9. sexual, and voiding dysfunctions are some of the symptoms 15. Ellis R, Boggild M. Therapy related acute leukemia with that require pharmacological interventions[20] [Table 5]. Mitoxantrone: What is the risk and can we minimize it ? Mult Scler 2009;15:505-8.

16. Calabresi PA, Giovannoni G, Confavreux C, Galetta SL, Havrdova Conclusions E, Hutchinson M, et al. The incidence and significance of anti- natalizumab antibodies: Results from AFFIRM and SENTINEL. The key to successful management of MS is early diagnosis and Neurology 2007;69:1391-403. early initiation of treatment with disease-modifying agents. 17. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab

Creating awareness among primary care doctors especially and interferon beta-1a for multiple sclerosis. N Engl J Med ophthalmologists, pediatricians, and physicians with interest 2005;353:369-74. in neurology, go a long way in achieving an early diagnosis. 18. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire The exorbitant cost of DMD makes it unaffordable to vast P, Moreau T. Rate of pregnancy-related relapse in multiple

majority of patients with MS in India. The necessity is now to sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med have well-designed clinical trials which could re-examine the 1998;339:285-91. role of cheaper drugs such as azathioprine, in the Indian setting. 19. Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically References

isolated syndromes. Neurology 2006;67:1242-9. 20. Henze T, Riekmann P, Toyka KV. Symptomatic Treatment of 1. Weinshenker BG, Bass B, Rice PA, Noseworthy J, Carriere W, Multiple Sclerosis-Multiple Sclerosis Therapy Consensus Group Baskerville J, et al. The natural history of Multiple Sclerosis: A (MSTCG) of the German Multiple Sclerosis Society. Eur Neurol geographically based study . Clinical course and disability. Brain 2006;56:78-105. 1989;112:133-46.

2. Amato MP, De Stefano N. Longitudinal follow-up of benign Multiple Sclerosis at 20 years. Neurology 2007;69:938-9. How to cite this article: Pandit L, Murthy J. Treatment of multiple 3. McDonald WI, Compston A, Edan G. Recommended diagnostic sclerosis. Ann Indian Acad Neurol 2011;14:65-9. criteria for multiple sclerosis: Guidelines from the International Received: 26-01-11 Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol 2001;50:121-7. Source of Support: Nil. Conflict of Interest: None declared.

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S73 Treatment guidelines for Guillain–Barré Syndrome Meena A. K., S. V. Khadilkar1, J. M. K. Murthy2 Department of Neurology Nizam’s Institute of Medical Sciences, Hyderabad, 1Grant Medical College, Mumbai, 2The Institute of Neurological Sciences, CARE Hospital, Hyderabad, India For correspondence:

Dr. A. K. Meena, Professor Department of Neurology Nizam’s Institute of Medical Sciences Hyderabad – 500082 Email: meenaak@hotmail.com Annals of Indian Academy of Neurology 2011;14:73-81 Introduction Clinical Features Guillain–Barré syndrome (GBS) is an acute onset, usually Most often an unremarkable infection, such as upper monophasic immune-mediated disorder of the peripheral respiratory infection, often predates the onset of GBS by 14

nervous system. The term GBS is often considered to be days.[2,5] Many antecedent infections have been identified, synonymous with acute inflammatory demyelinating including Campylobacter jejuni, cytomegalovirus (CMV), polyradiculoneuropathy (AIDP), but with the increasing Mycoplasma pneumonia, Epstein–Barr virus, influenza virus, recognition of variants over the past few decades, the number JEV.[13,14] Surgery, immunization, and parturition have also

of diseases that fall under the rubric GBS have grown to been associated with GBS. GBS usually begins abruptly with include axonal variants and more restricted variants, such as distal, relatively symmetrical onset of paraesthesias and quickly Miller Fisher syndrome (MFS) [Table 1].[1] followed by progressive limb weakness. Progression is rapid, with 50% of patients reaching clinical nadir by 2 weeks and more than 90% by 4 weeks. The current diagnostic criteria Epidemiology

include <4 weeks of progression to clinical nadir. Approximately 80%–90% of patients with GBS become nonambulatory during The reported incidence rates for GBS are 1–2 per 100,000 the illness.[15,16] Pain is prominent in 50% of patients.[16,17] population.[2-4] The lifetime likelihood of any individual Neurological examination is characterized by distal and often acquiring GBS is 1:1000.[5] The subtypes of GBS have different proximal, relatively symmetrical, weakness. Although GBS is

incidence rates in different parts of the world. In Europe and essentially a motor neuropathy, sensory dysfunction is seen North America AIDP is dominant contributing to 90% of in a few patients. It is seen more in a demyelinating form of the cases. In contrast in China and Japan AMAN being the GBS.[12,18] Sensory examination is often normal in the early most common subtype.[6,7] The picture is intermediate when phase of disease. Facial or pharyngeal weakness is commonly

we look at other population. In Indian series the incidence seen in GBS. Diaphragmatic weakness due to phrenic nerve of AIDP and AMAN are virtually equal although AMAN involvement is also common. Approximately one third of is more common in younger patients.[8] There seems to be a hospitalized GBS patients require mechanical ventilation slight preponderance of AIDP in studies by Gupta et al[9] and due to respiratory muscle or oropharyngeal weakness.[18,19]

by Meena et al (unpublished data from NIMS, Hyderabad). Tachycardia is common but more serious autonomic nervous Available Indian literature indicates a peak incidence between system dysfunction may occur, including life-threatening June–July and Sept–October.[10] In western countries, GBS is arrhythmias, hypotension, hypertension, and gastrointestinal common in the 5th decade,[11] but in India it occurs more dysmotility. The incidence is between 27% and 55% and is more

commonly at a younger age.[10,12] GBS is equally common in common in demyelinating than axonal form.[12,20] men and women and can occur at any age. There is a male preponderance among the hospitalized population.[10,12] Pathogenesis Major advances have been made in understanding the Access this article online mechanisms of some of the subtypes. The histological appearance of the AIDP subtype resembles experimental Quick Response Code: Website: autoimmune neuritis, which is predominantly caused by T

www.annalsofian.org cells directed against peptides from the myelin proteins P0, P2, and PMP22. The role of T-cell-mediated immunity in AIDP remains unclear and there is evidence for the involvement of DOI: antibodies and complement. Strong evidence now exists that 10.4103/0972-2327.83087 axonal subtypes of Guillain–Barré syndrome, acute motor axonal neuropathy (AMAN), and acute motor and sensory Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S74 Meena, et al.: Treatment guidelines for Guillain–Barré syndrome Table 1: Guillain–Barré syndrome—clinical variants Acute inflammatory demyelinating polyradiculoneuropathy [Predominantly motor, bilateral facial and pharyngeal, occasional sensory, and autonomic disturbances] Acute motor axonal neuropathy [Only motor neuropathy]

Acute motor sensory axonal neuropathy [Motor and sensory neuropathy] Miller Fisher syndrome [Ophthalmoplegia, ataxia, areflexia] Acute pandysautonomia [Pure autonomic neuropathy—both sympathetic and parasympathetic] Pure sensory Guillian Barré syndrome [Pure sensory neuropathy] Cervico-brachial-pharyngeal [Motor weakness predominantly affecting cervico-brachial and pharyngeal muscles] Bi-brachial [Motor weakness confining to both the upper limbs with areflexia] Distal limb variant

[Motor weakness confined to distal muscles of upper and lower limbs with no sensory and cranial nerve involvement] Oculopharyngeal [Motor weakness predominantly affecting ocular and pharyngeal muscles] Paraparetic variants [Motor weakness predominantly confined to lower limbs] Pure ophthalmoplegia [Weakness of bilateral ocular muscles] Bilateral facial palsy with paresthesias [Weakness of bilateral facial muscles with paresthesias] Ropper’s variant [Bilateral sixth and seventh cranial nerve palsy]

Pure generalized ataxia [Symmetrical limb and axial ataxia] Polyneuritis cranialis [Symmetrical or asymmetrical multiple cranial neuropathy] axonal neuropathy (AMSAN), are caused by antibodies to count) is only found on initial CSF analysis in 50% of patients; gangliosides on the axolemma that target macrophages to elevated CSF protein concentration occurs in more than 90% invade the axon at the node of Ranvier. About a quarter of of patients at the peak of the disease. CSF pleocytosis is an

patients with Guillain–Barré syndrome have had a recent C. important red flag, which raises the question of infectious jejuni infection, and axonal forms of the disease are especially (HIV, CMV, Lyme, sarcoid), carcinomatous, or lymphomatous common in these people. The lipo-oligosaccharide from the C. polyradiculoneuropathy [Table 2]. jejuni bacterial wall contains ganglioside-like structures and its injection into rabbits induces a neuropathy that resembles Electrodiagnosis

acute motor axonal neuropathy.[21-23] Antibodies to GM1, GM1b, GD1a, and GalNac-GD1a are in particular implicated Electrodiagnostic (EDX) testing is performed to support in acute motor axonal neuropathy and, with the exception of the clinical impression. EDX testing of GBS patients often GalNacGD1a, in acute motor and sensory axonal neuropathy. demonstrates features of demyelination, such as temporal dispersion, significantly slow conduction velocities, and

Diagnosis prolonged distal and F-wave latencies.[24] Electrodiagnostic testing features of acquired demyelination (eg, conduction Progressive weakness in both upper and lower extremities block, temporal dispersion, nonuniform slowing of conduction within 4 weeks along with areflexia is essential requirement velocities) are particularly helpful because these findings for the diagnosis. Supportive ancillary testing for GBS includes are characteristic of immune-mediated demyelinating

CSF analysis and electrodiagnostic testing, both of which may neuropathies. In early GBS, prolonged distal compound muscle be normal in the early phase of GBS. The limitations of ancillary action potential (CMAP) latencies and temporal dispersion are testing in the early phase combined with the importance of more commonly demonstrated than are slow motor conduction prompt treatment of GBS mandates that the clinician at times velocities and conduction block. [27] Another electrodiagnostic

make the diagnosis based solely on history and examination. testing hallmark of GBS is the “sural sparing” pattern; that is, An elevated CSF protein concentration (with normal cell the finding of a normal sural sensory nerve response in the Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Meena, et al.: Treatment guidelines for Guillain–Barré syndrome S75 setting of abnormal upper extremity sensory nerve results.[27] China and more sporadically elsewhere.[44] It mostly affects This pattern is very unusual for neuropathies other than children and young people, usually from rural areas. Onset

GBS. Sural sparing, a marker of demyelinating neuropathy, of motor weakness is abrupt. In addition to acute pure motor is more commonly seen in later than in early stages of AIDP. paralysis, many patients have transient neck and back stiffness Other electrodiagnostic testing abnormalities are frequently early in the course with resolution within day. Recovery encountered in early GBS but they are less specific to GBS. usually begins within 3 weeks and is often complete and may

These include absent H-reflexes, low motor nerve CMAP take longer. Mortality rate is roughly 3%–5%. Sensory nerve amplitudes on distal stimulation, and prolonged F-wave conduction studies are normal and motor nerve studies are responses.[25-27] It is reported that the H-reflex was absent in remarkable for low or absent CMAP amplitudes with normal 97% of GBS patients within the first week of symptom onset. It conduction velocities. Denervating potentials are seen on

should also be pointed out that motor electrodiagnostic testing needle electromyography.[6] findings are more often abnormal than sensory nerve results in early GBS. Blink reflex studies are often abnormal when AMSAN shares many pathological features with acute there is facial nerve involvement.[26] Phrenic nerve conduction motor axonal neuropathy but differs clinically from it in studies can be used to predict respiratory failure and the need patient age of onset (usually adults rather than children),

for ventilation.[28] Reduced CMAP amplitudes of 0%–20% of geographic distribution (can occur anywhere), time of onset the lower limit of normal carry a poor prognosis.[29] (not only summertime), involvement of sensory nerves, course (protracted), and outcome (usually severe residual The diagnostic yield of various neurophysiological criteria may disability).[40-44] It has an abrupt onset and rapid progression

vary in different subforms of Guillain–Barré syndrome, whose with most patients requiring mechanical ventilation within prevalence varies in different geographical areas. In a recent a few days of symptom onset. Motor nerves are electrically study the diagnostic sensitivity of Albers et al,[30] Cornblath,[31] inexcitable early in the disorder. Sensory nerve conduction Ho et al,[32] Dutch GBS Study Group,[33] Italian GBS Study studies are also abnormal. Widespread denervation is seen

Group,[34] and Albers and Kelly criteria[35] were evaluated and on needle examination. The course is protracted and outcome correlated with clinical subtypes of GBS, duration, severity, poor, with only 20% ambulating at 1 year. and outcome.[36] The sensitivity of nerve conduction study in the diagnosis of GBS and in different clinical subtypes of GBS Table 2: Guillian–Barré syndrome—red flags raising was highest using Albers criteria (88.2%) and lowest using other diagnostic possibilities

Cornblath criteria (39.2%). As per Ho et al, patients could be Clinical categorized into AIDP (86.3%), AMAN (7.8%), and AMSAN (5.9%). Electrophysiological findings necessary to diagnose • Fever at onset GBS is in Table 3. • Severe pulmonary dysfunction with limited weakness at onset • Severe sensory signs with limited weakness at onset • Persistent bladder or bowel dysfunction or bladder or bowel Incidence of antiganglioside antibodies in GBS has varied dysfunction at onset

widely in different published series.[37,38] Its much more • Sharp sensory level common in AMAN variant than AIDP. The incidence was • Marked persistent asymmetry of weakness found to be 58% in a study of 60 patients of GBS by Meena et al (Unpublished data from NIMS, Hyderabad). Although Laboratory antiganglioside antibodies have been implicated in the • Increased number of mononuclear cells in CSF pathogenesis of GBS, assaying antiganglioside values in a • Polymorphonuclear cells in CSF

patient with GBS other than MFS at the present time has no diagnostic value in routine practice. Table 3: Electrodiagnostic findings in Guillain–Barré syndrome[32] Variants of Guillain–Barré syndrome Commonly recognized variants include those with axonal Electrodiagnostic features suggestive of acquired forms, variants based on particular fiber-type involvement demyelinating neuropathy (sensory or autonomic), and MFS. Variants with regional Conduction velocity reduced in two or more nerves

or a markedly asymmetric distribution also occur.[1] There CMAP conduction block or abnormal temporal dispersion in 1 or are also differences in abruptness of onset and time to reach more nerves nadir, which can complicate diagnosis and decisions about Prolonged distal motor latencies in 2 or more nerves treatment. For example, some patients have clinical features Prolonged minimum F-wave latency or absent F-wave and disease course similar to GBS except for a slower

Electrodiagnostic features suggestive of axonal neuropathy progression (ie, progression that lasts longer than 4 weeks); No evidence of significant reduction in conduction velocity. this disease is sometimes referred to as subacute inflammatory No evidence of abnormal temporal dispersion. demyelinating polyradiculoneuropathy (SIDP);[39,40] however, Prolonged distal latency NOT considered demyelination if in many respects SIDP is like GBS and often should be treated amplitude < 10% LLN.

as such. AMSAN and AMAN are two variants characterized Decrease in CMAP (AMAN) and SNAP (AMSAN) to <80% of LLN by immune attack directed at axons rather than Schwann or inexcitable (absent evoked response) in 2 or more nerves. cells and myelin.[41-44] CMAP, Compound muscle action potential; AMAN, Acute motor axonal neuropathy; AMSAN, Acute motor and sensory axonal neuropathy; SNAP, Sensory AMAN occurs in large epidemics during summer in northern nerve action potential; LLN, Lower limits of normal

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S76 Meena, et al.: Treatment guidelines for Guillain–Barré syndrome MFS: The more recognizable and distinct regional variant of GBS. Mortality is due to disease-related issues or secondary GBS is MFS.[1,45,46] Like GBS, the onset of MFS often follows complications developed in hospital due to prolonged disease

an infection, for example C. jejuni.[47] MFS patients classically course. Meticulous and attentive care of these patients are present with external ophthalmoparesis, areflexia, and ataxia,[2] essential in reducing the mortality. Supportive care consensus although MFS patients often present with fewer components guidelines have been published.[59] of the classical clinical triad[1,46,48,49] or with additional clinical

features (facial weakness, oropharyngeal weakness, internal Management of respiratory failure ophthalmoparesis, central nervous system involvement). GBS is the most common peripheral neuropathy causing Bickerstaffs brainstem encephalitis (BBE) is a related syndrome respiratory paralysis. Despite advances in respiratory in which alteration of consciousness or conticospinal tract signs management and immunotherapy, mortality from GBS is as

are seen in addition to ophthalmoparesis and ataxia. Many high as 20% for ventilated patients. Mechanical ventilation is patients with MFS or BBE also have “overlapping GBS” with usually required by one third of the patients.[59] Clinical signs flaccid quadriparesis.[46,50] Anti-GQ1b antibodies are present like tachypnea, tachycardia, brow sweating asynchronous in 95% of patients with acute MFS[51] and in approximately movements of chest and abdomen and a vital capacity < 20

two-thirds of patients with BBE. The recognition of various mL/kg, maximal inspiratory pressures < 30 mm HO, maximal clinical presentations and the high sensitivity and specificity of 2 expiratory pressure < 40 cm HO predicts imminent respiratory anti-GQ1b antibody testing suggest rubric name of “anti-GQ1b 2 failure.[59] Time from onset to admission of less than 1 week, antibody syndrome.” facial weakness, bulbar paresis, and neck weakness are other

Anti-GT1a antibody without anti-GQ1b reactivity is found in factors associated with respiratory failure. [59,60,61] Simple patients presenting with the pharyngeal–cervical–brachial (PCB) bedside single breath count, which correlates well with vital variant of GBS.[52,53] More than half of MFS patients will have capacity than phrenic nerve conduction studies is a good cytoalbuminological dissociation on CSF analysis performed predictor of respiratory failure (Unpublished data by Meena

within the first 3 weeks of disease onset.[54] In MFS, motor nerve et al from NIMS, Hyderabad). Percutaneous dilatational conduction studies in the limbs are usually normal or only mildly tracheostomy may be advantageous over traditional tracheostomy by allowing less risk of accidental extubation abnormal with slight reductions in compound muscle action potential amplitudes and conduction velocities.[55] Conduction and a better cosmetic outcome. In general it takes 2–6 weeks

to wean out of ventilatory support.[62] Tracheostomy may be block and temporal dispersion are not a feature of MFS. Sensory performed 2 weeks following intubation and should be based nerve action potential amplitudes are usually moderately to severely reduced, more so in the upper extremity sensory nerves on status of an individual. It is comfortable and provides (eg, median) than the sural nerve. Blink reflex R1 delayed or airway safety but is associated at times with life-threatening

absent. MRI of the brain frequently demonstrates cranial nerve complications and disfiguration.[59] If pulmonary function enhancement (eg, occulomotor nerves) in MFS[56] and high- is improving, it may be preferable to wait 1 more week to intensity abnormalities in the posterior fossa, white matter, or attempt at weaning from ventilator. thalami in patients with BBE.[50] MFS is generally a benign, self- limiting conduction. Almost all treated and untreated patients Management of Dysautonomia

return to normal activities within 6 months of disease onset, usually with resolution of ophthalmoplegia within 1–2 months Acute dysautonomia is a significant cause of death in patients and ataxia within 3–4 months.[57] with GBS. Cardiac and hemodynamic disturbance manifesting as hypertension, postural hypotension, and tachycardia Other regional variants of GBS are those that affect other occur in a majority of GBS patients.[69] This is due to excessive

specific areas of the body, such as only the face or the afferent sympathetic over activity and parasympathetic under activity. sensory and autonomic systems.[58] Severe dysautonomia occurs usually in severe cases at the Management peak of the deficit.[69] Tachycardia is most common, usually in the range of 100–120/min, which does not require treatment. Patients with GBS who are symptomatic but are able to

walk unaided for more than 5 m and who are stable can be Approach to inserting a pacemaker for serious bradycardia or managed conservatively at peripheral centers. However, they sinus arrest has varied widely because of the uncertainty that should be observed for progression of the disease, especially exists in anticipating such events at the bed side by different if they are still within the first week of the onset of the disease. ways. However, the presence of tachycardia, increased

Blood pressure and heart rate fluctuations, clinical signs of daily variation in systolic blood pressure, reduced normal respiratory failure should be carefully and meticulously respiratory-induced heart rate variation, and first episode of monitored. Clinical signs of ileus should be watched. If any of severe bradyarrhythmia reduce the threshold for insertion of these signs are detected they should be immediately shifted to pacemaker.[70,71] Endotrachial suction may provoke bradycardia

specialized centers for further management. In the acute phase or systole, and this can be reduced by hyperoxygenation. in bed-bound adult patients require both supportive therapy Hypertension is seen in one third of patients with GBS and can and immunotherapy can be used taking into consideration the be labile or be followed by hypotension.[63-65] If hypertension cost factors and the clinical status (staging, complications, and is severe (mean pressure greater than approximately 125

other comorbid conditions) of individual patients. mmHg) and sustained, specific therapy may be necessary. Antihypertensives with short half-lives (labetolol, esmolol, Supportive Care or nitroprusside infusions) should be considered.[65] Beta- adrenergic or calcium channel blockers should be used with Immunotherapy therapy has not reduced the mortality in caution, especially if episodes of hypertension alternate with Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Meena, et al.: Treatment guidelines for guillain–Barré syndrome S77 hypotension. Hypotension can be managed by maintaining recovery after 1 year, and severe sequelae after 1 year. Time intravascular volume and avoid using diuretics. Patients with to onset of motor recovery in mildly affected patients was

a risk of hypotension should not be left unattended in a sitting significantly shortened in the PE group. However, the cost or upright position. Pronounced and persistent hypotension of PE has been shown to be offset by the savings of shorter should warrant search for other causes, such as sepsis hospital stay.[74] myocardial infarction and pulmonary thromboembolism or use of narcotics or positive pressure ventilation. Gastrointestinal The volume of plasma removed and the optimum number of

motility disorders occur in 15% of severely affected GBS PE has not been established and it varies in different trials, but patients. Ileus is associated with other features of dysautonomia many physicians use the protocol of North American trial in (tachycardia and hypertension). Dysmotility can be effectively which a total of 200–250 mL/kg was exchanged over 7–10 days managed by suspension of enteral feeds, nasogastric suctioning, all over the world.[75] There is evidence that the number of PE

and erythromycin or neostigmine.[59,69] in GBS should be adjusted to disease severity and that also patients with mild symptoms do benefit from PE.[76] Hyponatremia is the common electrolyte abnormality in GBS and is due to SIADH (in majority of the cases) and natriuresis. In mild GBS, two sessions of PE are superior to none. In The treatment is different for both. Both require replenishment moderate GBS, 4 sessions are superior to 2. In severe GBS, 6

of sodium but SIADH need fluid restriction and in case of sessions are no better than 4. In line with these findings, Yuki et natriuresis requires intravascular volume expansion. The best al reported that at least 2 PE are needed to significantly reduce way to differentiate these two conditions is by measuring the circulating immunoglobulin complexes.[77] In developing central venous pressure. countries where cost is the limiting factor, small volume PE

may be used. In India small volume PE was used by Tharakan Deep vein thrombosis prophylaxis et al with comparable results.[78] They used 15 mL/kg body All patients should be given subcutaneous fractionated or weight/day to be continued till the progression of the disease unfractionated heparin and support stockings until they got arrested or recovery started. This protocol is still performed are able to walk independently to prevent deep vein in various centers in developing countries with good results.

thrombosis.[59 ] If a prolonged bedridden period is anticipated and a tracheostomy has already been performed, institute oral Type of Plasma Exchange anticoagulant treatment with warfarin coumadin. Continuous flow PE is superior to intermittent flow exchanges. Pain and sensory symptoms are reported in majority of The replacement fluids do not affect the outcome of PE according patients with GBS and should be treated effectively with opioid to the French Study Group.[79] Although albumin was found to

analogues. Sedation and bowel hypomotility may become a be superior to fresh frozen plasma as the exchange fluid. problem. Other drugs, such as gabapentin, carbamazepine acetaminophen, NSAIDs, and tricyclic antidepressants also When to use PE? A better outcome was demonstrated with PE can be tried. in French Study Group when compared with North American Study Group.[79] This is due to the fact that treatment was Nutrition initiated within 2 weeks in the former study group and within

Nasogastric or gastric tube feeding should be instituted early 4 weeks in the latter. Hence PE is more beneficial when started and slowly. High energy (40–45 nonprotein kcal) and high within 7 days after disease onset rather than later, but was still protein diet (2–2.5 g/kg) have been recommended so has beneficial in patients treated up to 30 days after disease onset. to reduce muscle wasting and assist respiratory weaning.

Continuous enteral feeding seems to be better tolerated than Who should be offered PE? All patients with mild, moderate, and bolus feeding in these patients. severe GBS benefit from treatment. Patients who need even minimum assistance for walking, who are steadily progressing Surveillance for infections with weekly or more frequent sputum and those who are bed- and ventilator-bound should be advised

and urine cultures and blood count may be useful but the use PE. The value of PE in children younger than 12 years is not of these tests should be guided by clinical circumstances. known. Immunotherapy AAN in 2003 concluded that PE hastens recovery in Both plasma exchange and IVIg are effective immunotherapies nonambulant patients who get treatment within 4 weeks of for adult and pediatric patients with GBS if given during the onset, and PE hastens recovery of ambulant patients with GBS

first few weeks of disease. who are examined within 2 weeks. PE is usually administered as one plasma volume, 50 mL/kg, on 5 separate occasions over Plasmapheresis 1–2 weeks.[72] In a meta-analysis of 6 class II trails comparing plasma exchange (PE) to supportive care alone for adults with GBS, it Slightly more complications were observed in PE group than was found that PE reduced the risk of developing respiratory the IVIg group. Significant adverse events of PE include

failure.[72,73] Patients treated with PE fared significantly better hypotension, septicemia, pneumonia, abnormal clotting, and in the following secondary outcome measures: Time to recover hypocalcemia. Major hemostatic disorders, unstable walking without aid, percentage of patients requiring artificial cardiovascular state, active infection, and pregnancy are ventilation, duration of ventilation, full muscle strength contraindications to PE.

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S78 Meena, et al.: Treatment guidelines for Guillain–Barré syndrome Immunoadsorption therapy is an alternative technique to PE. This recovery. Patients with mild or uncomplicated MFS may form of therapy removes Ig from the circulation without the perhaps be treated conservatively. Patients with more severe

need for replacement with albumin or FFP because of loss of or complicated anti-GQIB antibody syndrome, an overlapping albumin. Evidence says that there is no difference in outcomes GBS, should probably receive immunotherapy. between patients treated with immunoadsorption and PE or double filtration plasmapheresis.[80,81] Treatment of patients who deteriorate in spite of therapy Some patients with GBS continue to deteriorate after PE or Steroids a standard course of IVIg. In these cases, the best option is

unknown. Whether these patients need PE after they have In a Cochrane systematic review of 6 trials with 587 patients been treated with IVIg has not been investigated, but the it has been shown that corticosteroid therapy is ineffective for combination of PE followed by IVIg is no better than PE or treating GBS.[82] IVIg alone. PE after IVIg is also not advised, because PE would probably wash out the IVIg previously administered. A study

Intravenous Immunoglobulins in a small series of patients investigated the effect of a second course of IVIg in severe unresponsive patients with GBS.[90] This uncontrolled study suggested that a repeated course of The first RCT on the use of IVIg was published in 1992, and IVIg could be effective. About 5%–10% of patients with GBS showed that IVIg is as effective as PE.[83] Since the deteriorate after initial improvement or stabilization following

publication of these results, IVIg, in a regimen of 0·4 g/kg IVIg treatment.[91] Although no RCTs have assessed the effect bodyweight daily for 5 consecutive days, has replaced PE as of a repeated IVIg dose in this condition, it is common practice the preferred treatment in many centers, mainly because of to give a second IVIg course (2 g/kg in 2–5 days). These its greater convenience and availability. The Cochrane review patients are thought to have a prolonged immune response

on the use of IVIg in GBS contained 4 additional trials.[84] No that causes persistent nerve damage that needs treatment for difference was found between IVIg and PE with respect to the a longer period of time.[92] A longer interval between onset and improvement in disability grade after 4 weeks, the duration treatment and longer time to nadir may be associated with a of mechanical ventilation, mortality, or residual disability. greater chance of relapse.

The combination of PE followed by IVIg was not significantly better than PE or IVIg alone. The combination of IVIg and Cost-effectiveness of PE and IVIg in GBS intravenous methyl prednisolone was not more effective than IVIg alone, although there might be a short-term effect of this When faced with restrictions in financial resources, especially combined treatment when a correction is made for known in developing countries cost-effectiveness of any treatment

prognostic factors.[85,86] becomes a major issue in treatment decision making. This is very true in GBS in which the currently approved treatment has shown equal efficacy. There are a few available cost In general in patients with renal dysfunction the rate of infusion analysis studies addressing this issue and the results are should be decreased to half of the normal infusion rate. controversial.[93,94] However, in developing countries use of small volume PE may bring down the cost when compared

Timing of treatment to IVIg. Hence the decision to use PE or IVIg must be based Most RCTs have included only patients who are treated within on multiple factors. The main limitations for use of PE would the first 2 weeks from onset of weakness and who are unable be availability of the technical expertise and support. Lack of to walk without assistance. If these criteria are met, there is no these, ease of administration, and fewer side effects with IVIg

doubt that patients with GBS should be treated with IVIg or PE. may dictate use of IVIg as the first line of therapy. The question remains as to what to do in patients with rapidly progressive limb weakness or impaired pulmonary function Prognosis but who are still able to walk. Although not proven effective, it seems logical to treat these patients with IVIg. GBS has a serious long-term impact on the patients’ work and

Treatment of mildly affected patients private life, even 3–6 years after the onset of illness. Recovery These patients are able to walk with some support or no can be slow and take years. . Persistent disability is seen in 20%– support. A retrospective study showed that these patients often 30% of adult patients but is less common in children.[2,95] Severe have residual disabilities.[87] RCTs that have assessed the effect fatigue is a sequel of GBS in two thirds of adult patients. In an

of IVIg have not studied the effect in mildly affected patients. RCT of amantidine, it was not superior to placebo.[96] Twelve It should be kept in mind that no RCTs have assessed the effect weeks bicycle extensive training program had positive effects of PE or IVIg in these mildly affected patients with GBS. on fatigue, anxiety, depression, and functional outcome.[97] Miller Fisher syndrome Conclusions No RCTs have studied the effect of PE or IVIg in patients with

MFS.[88] Observational studies have suggested that the final GBS is a monophasic immune-mediated neuropathy outcome in patients with MFS is generally good. In a large characterized by acute onset of predominantly motor uncontrolled observational study,[89] IVIg slightly hastened the weakness and is a common cause of respiratory paralysis. amelioration of ophthalmoplegia and ataxia. The investigators There are many variants described with different prognosis

concluded that IVIg and PE did not influence the outcome and manifestations. Electrodiagnosis aids in the diagnosis. of patients with MFS, presumably because of good natural Immunotherapy definitely makes a difference in the recovery Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Meena, et al.: Treatment guidelines for Guillain–Barré syndrome S79 of GBS patients and both PE and IVIg are equally effective. IVIg et al. Campylobacter jejuni lipopolysaccharides in Guillain–Barré may be preferred because of its low side-effect profile and ease syndrome: Molecular mimicry and host susceptibility. Neurology

of administration. However, small volume PE can be used with 1998;51:371-8. 23. Vriesendorp FJ, Mishu B, Blaser MJ, Koski CL. Serum antibodies equal efficacy due to cost constraints. Attentive anticipatory to GM1, GD1b, peripheral nerve myelin, and Campylobacter jejuni supportive treatment is equally important in reducing the in patients with Guillain–Barré syndrome and controls: Correlation morbidity and mortality in GBS. and prognosis. Ann Neurol 1993;34:130-5.

24. Albers JW, Kelly JJ Jr. Acquired inflammatory demyelinating References polyneuropathies: Clinical and electrodiagnostic features. Muscle Nerve 1989;12:435-51. 25. Albers JW, Donofrio PD, McGonagle TK. Sequential 1. Levin KH. Variants and mimics of Guillain–Barré syndrome. electrodiagnostic abnormalities in acute inflammatory demyelinating Neurologist 2004;10:61-74. polyradiculoneuropathy. Muscle Nerve 1985;8:528-39. 2. Chiò A, Cocito D, Leone M, Giordana MT, Mora G, Mutani R.

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92. Visser LH, van der Meché FG, Meulstee J, van Doorn PA. Risk quality of life in Guillain-Barré syndrome and CIDP. Neurology factors for treatment related clinical fluctuations in Guillain-Barré 2004;63:2393-5. syndrome. Dutch Guillain-Barré Study Group. J Neurol Neurosurg Psychiatry 1998;64:242-4. How to cite this article: Meena AK, Khadilkar SV, Murthy J. Treatment 93. Nagpal S, Benstead T, Shumak K, Rock G, Brown M, Anderson guidelines for Guillain-Barré Syndrome. Ann Indian Acad Neurol

DR. Treatment of Guillain–Barré syndrome: A cost –effectiveness 2011;14:73-81. analysis. J Clin Apher 1999;14:107-13. Received: 26-01-11 94. Tsai CP, Wang KC, Liu CY, Sheng WY, Lee TC. Pharmacoeconomics Source of Support: Nil. Conflict of Interest: None declared. of therapy for Guillain–Barré syndrome: Plasma exchange and Announcement Android App A free application to browse and search the journal’s content is now available for Android based

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[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou Behari, et al.: Parkinson's disease S11 Treatment in late Parkinson’s disease It is almost 200 years since James Parkinson described the initiated, alone or in addition to dopaminergic agonists, the major symptoms of idiopathic Parkinson’s disease (IPD). Since time duration from the onset of levodopa therapy to

then, our treatment armamentarium has slowly increased, occurrence of dyskinesias was the same in both groups. providing effective treatment to many patients, but the Similarly, addition of entacapone to levodopa/carbidopa management of the late stage of the disease is still a huge theoretically should cause less dyskinesias, but the evidence challenge. Levodopa is the most effective pharmacological is still lacking. A recent review and guidelines by AAN

treatment available for IPD.[1] In late stages of the disease, identified amantadine as a safe and effective pharmacological however, it is difficult to maintain a stable therapeutic therapeutic agent for dyskinesias.[4] Various studies have response with pharmacological therapy. Motor complications shown that amantadine significantly reduces dyskinesias such as wearing off fluctuations[2] and dyskinesias[3] develop by about 50%. However, there are still confounding results

with increasing frequency in patients after 5–6 years of on whether the antidyskinetic effect of amantadine wears dopaminergic therapy. off after a year or there is a long-standing effect.[9-11] Though clozapine has also shown reduction in dyskinesias, the side Pharmacological Therapy effect profile, especially the occurrence of agranulocytosis, restricts its usage.[4] Thus, in late stage of PD, there is limited Motor complications are often managed in the initial stages with efficacy of medical therapy.

adjustment in levodopa dosage. Motor off time can be reduced by the addition of various dopaminergic agonists including Surgical Therapy pergolide, pramipexole, ropinirole, cabergoline, and drugs such as monoamine oxidase (MAO) inhibitors (rasagiline) and catechol-O-methyl transferase (COMT) inhibitors (entacapone). The recent progress in functional neurosurgery probably [4] A recent Cochrane review demonstrated that all the three marks the second most important therapeutic advance in PD

groups of adjuvant drugs – dopaminergic agonists, MAO-B after the introduction of levodopa. In the last 15 years, there inhibitors (MAOBI) and COMT inhibitors (COMTI) – reduced have been many Class III and Class IV studies suggesting off time, levodopa dose, and improved Unified Parkinson the effectiveness of deep brain stimulation (DBS).[4] With the Disease Rating Scale (UPDRS) scores in Parkinson’s disease results of the recently concluded two large-scale randomized

(PD) patients with motor complications but at the cost of clinical trials involving 156 patients with PD[12] and 255 increased dyskinesias and numerous other side effects. In the patients with PD[13] with severe motor complications, the same review, indirect comparisons suggested that dopamine evidence has become more robust. DBS is more effective than agonist therapy may be more effective than COMTI and the best medical therapy in improving “on” time without

MAOBI therapy. However, there is lack of direct evidence and troubling dyskinesias by 4.6 h/day, motor function in 71% head to head comparison trials between these drugs.[5] compared to 36% in medical therapy, and quality of life at 6 months after surgery.[13] There was, however, an increased Management of troublesome dyskinesias is a major challenge in risk of side effects related to the procedure.[13] Thus, while

late stages of the disease. Studies have shown that dyskinesias DBS is the most effective therapy in patients with motor occur in about 50% of elderly and almost 100% of younger complications, it is important to select the correct patients patients under the age of 40 years after 6 years of levodopa who are eligible for the procedure.[14] therapy.[6] PD patients with at least 5 years disease duration, UPDRS-

The exact pathophysiology of dyskinesias is still not clear. III off score of 30 or more, H and Y score of ≤3, significant As fluctuations in the dopamine levels may contribute to the response to syndopa with troublesome dyskinesias and normal appearance of dyskinesias, reducing the dose and increasing cognition are eligible for DBS.[14] Best results have been reported the frequency of levodopa, addition of MAOBI or COMTI in patients with advanced PD with at least 5 years of disease

and addition of dopaminergic agonists can be tried in the duration and (a) excellent levodopa response, (b) younger age, initial phases. There is strong evidence that initial therapy (c) no or few axial non-levodopa responsive motor symptoms, with dopamine agonists in early stages of the disease results (d) no or very mild cognitive impairment, and (e) absence of in delay in the appearance of dyskinesias compared to that or well-controlled psychiatric disease.[15] Unfortunately, these

with levodopa.[7,8] However, once levodopa treatment is stringent criteria imply that only a small percentage of PD patients are eligible for DBS.[16] Access this article online Various sites have been proposed but the effect is maximally Quick Response Code: seen with stimulation of bilateral subthalamic nucleus (STN) and globus pallidum interna (GPi) for most features of IPD. Website: Similar benefits for both STN and GPi DBS have been reported

www.annalsofian.org in only a few randomized studies.[17] The recent co-op study addressed this issue.[18] Two hundred ninety-nine patients with PD were randomized to STN or GPi DBS with the primary outcome of UPDRS-III assessed in a blinded manner. Similar Annals of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

[Downloaded free from http://www.annalsofian.org on Monday, February 06, 2012, IP: 115.113.56.227] || Click here to download free Android application for this jou S12 Behari, et al.: Parkinson's disease improvements were found at 2-year follow-up for both Late PD surgical sites. Dopaminergic medication was decreased more for the STN group but visuomotor processing speed declined less after GPi DBS. Furthermore, subjects who had GPi DBS showed improvement in depression, whereas subjects who

Add MAO-B Wearing Dyskinesias Add had STN DBS worsened. Taken together, both STN and GPi or COMT off amantadine DBS improve motor function, but the target selection should inhibitor be individualized considering the differences in nonmotor outcomes.[18] Various complications can occur with DBS, Modify Add Bilateral Continuous Modify including risk of intracranial hemorrhage (<2%), lead fracture levodopa dopaminergi STN/GPI dopaminergics levodopa

and migration and hardware infection, but the rates have dose agonist DBS timulation dose come down markedly with improvement in technology and operative procedures. Figure 1: Algorithm for management of late stage PD Ablative Surgery Although few patients improve with modifications in levodopa dosage and addition of dopaminergic agonists, MAOBI Although thalamotomy and pallidotomy have largely been and COMTI, many develop troublesome dyskinesias. Best

abandoned and replaced by DBS, ablative therapies may therapy available is bilateral DBS of STN or GPi. Continuous yet have a role in certain patients such as those with an dopaminergic stimulation with duodopa or apomorphine may increased risk of infection or a history of recurrent infection be considered [Figure 1]. of their DBS systems, economic reasons and in patients with predominantly unilateral symptoms. Ablative surgeries are References not preferred because of significant side effects including

dysphagia, dysarthria and cognitive deficits. Disadvantages of 1. Goetz CG, Poewe W, Rascol O, Sampaio C. Evidence-based ablative surgery include mistargeted lesions with permanent medical review update: Pharmacological and surgical treatments neurological deficits and suboptimal and unilateral benefits of Parkinson’s disease: 2001 to 2004. Mov Disord 2005;20:523-39. even in well-targeted approach.[19-21] 2. Mouradian MM, Juncos JL, Fabbrini G, Schlegel J, Bartko JJ,

Chase TN. Wearing-off fluctuations in Parkinson’s disease: central pathophysiology mechanisms, Part II. Ann Neurol 1988;24:372-8. Newer Treatment Modalities 3. Nutt JG. Levodopa-induced dyskinesia: Review, observations and speculations. Neurology 1990;40:340-5. Continuous dopaminergic stimulation 4. Pahwa R, Factor SA, Lyons KE, Ondo WG, Gronseth G, Bronte- Intrajejunal constant-rate infusions of levodopa are a newer Stewart H, et al. Practice parameter: Treatment of Parkinson

therapeutic option to provide a constant dopaminergic level in disease with motor fluctuations and dyskinesia (an evidence- the blood. Studies have shown that with this approach, motor based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:983-95. fluctuations, and particularly, the intractable dyskinesias of 5. Stowe R, Ives N, Clarke CE, Deane K, van Hilten, Wheatley K, patients with advanced PD are substantially reversed even

et al. Evaluation of the efficacy and safety of adjuvant treatment as the total daily levodopa dose and corresponding “on” to levodopa therapy in Parkinson s disease patients with motor time are increased. The carboxymethylcellulose formulation complications. Cochrane Database Syst Rev 2010;7:CD007166. of levodopa, provided in a gel formulation (duodopa) at 6. Schrag A, Quinn N. Dyskinesias and motor fluctuations in

a concentration of 20 mg/mL and delivered through an Parkinson’s disease: A community-based study. Brain intrajejunal pump system, is approved in most countries of 2000;123:2297-305. Europe.[22,23] Studies are being conducted to further validate the 7. Hauser RA, Rascol O, Korczyn AD, Jon Stoessl A, Watts RL, results of this procedure and look at its technical liabilities for Poewe W, et al. Ten year follow-up of Parkinson’s disease patients randomized to initial therapy with ropinirole or levodopa. Mov

long-term therapy (e.g., potential percutaneous gastrostomy Disord 2007;22:2409-17. infections, dislocation, kinking and occlusion of catheters, high 8. Parkinson Study Group. CALM Cohort Investigators: Long-term cost) to assess the overall efficacy. effect of initiating pramipexole vs levodopa in early Parkinson disease. Arch Neurol 2009;66:563-70. Similarly, mini pumps with continuous subcutaneous delivery 9. Verhagen ML, Del Dotto P, van den Munckhof P, Fang J,

of the dopamine agonist apomorphine have been shown to Mouradian MM, Chase TN. Amantadine as treatment for reverse fluctuations and dyskinesias.[24] dyskinesias and motor fluctuations in Parkinson’s disease. Neurology 1998;50:1323-6. 10. Thomas A, Iacono D, Luciano AL, Armellino K, Di Iorio A, Newer molecules like glutamate receptor antagonists (that Onofrj M. Duration of amantadine benefit on dyskinesia of reduce D1 output), cannabinoid receptor antagonists, a2-

severe Parkinson’s disease. J Neurol Neurosurg Psychiatry adrenergic receptor antagonists (that inhibit GPe), adenosine 2004;75:141-3. A2A-receptor antagonist, and 5-HT1A-receptor agonists are 11. Wolf E, Seppi K, Katzenschlager R, Hochschorner G, Ransmayr being evaluated for reducing dyskinesias.[25] G, Schwingenschuh P, et al. Long-term antidyskinetic efficacy of amantadine in Parkinson’s disease. Mov Disord 2010;25:1357-63. Conclusions 12. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schäfer

H, Bötzel K, et al. A randomized trial of deep-brain stimulation for Late stages of PD are characterized by the development of Parkinson’s disease. N Engl J Med 2006;355:896-908. motor complications including wearing off and dyskinesias. 13. Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ Jr, et al. Annals of Indian Academy of Neurology, July 2011, Vol 14, SupplemeAntn 1n als of Indian Academy of Neurology, July 2011, Vol 14, Supplement 1

JAMA 2009;301:63-73. STN deep brain stimulation in Parkinson’s disease. Brain Cogn 14. Lang AE, Widner H. Deep brain stimulation for Parkinson’s disease: 2000;42:324-47. Patient selection and evaluation. Mov Disord 2002;17:S94-101 21. Gross RE. What happened to posteroventral pallidotomy for 15. Bronstein JM, Tagliati M, Alterman RL, Lozano AM, Volkmann Parkinson’s disease and dystonia? Neurotherapeutics J, Stefani A, et al. Deep brain stimulation for Parkinson disease: 2008;5:281-93.

especially LD. “ON”--“OFF” motor fluctuations. These “motor shifts” occur as a result of loss of presynaptic dopamine terminals and from The Motor Complications include fluctuating neurotransmitter level.[1] iii. Nighttime deterioration: In moderate to advanced disease, a. Motor fluctuations patients wake up in the night with motor symptoms, i. Wearing off effects (end-of-dose deterioration): This difficulty in rolling over in bed, muscular discomfort,

is the most common initial manifestation of motor and frequent urination. fluctuation. The patient starts to feel the reappearance of iv. Early morning deterioration: This can often be associated motor symptoms before the next dose. It is predictable with painful foot dystonia.[3] and occurs 2--4 h after a dose of LD.[2] In the initial stages, the symptoms great promptly alleviated after b. Dyskinesias/ dystonias. the same dose of dopaminergic medications. However, These can be of the following types:[3,4]

later the dose needs to be increased or another medicine i. At peak-dose, more often dyskinesias for PD needs to be added. ii. During “OFF” periods, more often dystonias ii. “ON” and “OFF” phenomena which can be predictable or iii. A combination of peak-dose and “OFF” period unpredictable: Gradually, the patient starts having “OFF” (biphasic), patients often cycling in these two phases Access this article online Diagnosis Quick Response Code: a. Diagnosis is based on meticulous history from the patient

Website: and caregivers. Patients need prolonged observation before www.annalsofian.org and after a dose of medications for PD. Patients are often not concerned about the minor dyskinesias and therefore may deny this symptom. However, the caregivers are in a better position to confirm the presence of dyskinesias.

STANDARD TREATMENT GUIDELINES GASTROINTESTINAL SURGERY Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 ACUTE PANCREATITIS 4 2 PORTAL HYPERTENSION 12 3 CHOLEDOCHOLITHIASIS 24 4 CARCINOMA STOMACH 31 5 GALLBLADDER CARCINOMA (GBC) REQUIRING HOSPITALIZATION 38 6 CARCINOMA RECTUM 46 2

Group Head Coordinator of Development Team Dr. V.P. Bhalla Department of Surgical Gastroenterology, Bariatric & Minimal Access Surgery BLK Superspeciality Hospital 3

Acute Pancreatitis Dr. V.P. Bhalla Dr. Deep Goel Department of Surgical Gastroenterology, Bariatric & Minimal Access Surgery BLK Superspeciality Hospital New Delhi Peer Reviewer- Dr Samiran Nundy, Chairman, Surgical Gastro and Liver Transplant, Sir Ganga Ram Hospital 1. When to suspect/recognize a) Introduction Acute pancreatitis is an important cause of acute upper abdominal pain associated with vomiting. The common causes include gall bladder stone disease, alcoholism and idiopathic-

where no obvious cause is discernible. Fortunately the majority of cases of acute pancreatitis are mild and respond to conservative treatment. In less than 10% the disease is more severe and follows a vicious course with immense clinical and socio economic implications. These guidelines will help in the initial management of these patients at the secondary district level hospital and also at the more advanced tertiary metro super specialty centre. b) Case definition

A typical patient presents with severe agonizing upper abdominal pain which may radiate to the back and is associated with retching and vomiting. The patient may be a known case of gall bladder stone disease or give a history of chronic alcohol consumption or a recent alcoholic binge. Clinical examination early in the disease process may reveal upper abdominal tenderness guarding and later the patient will show all the features of hypovolaemia including shock as third spacing of fluids sets in.

I. A 3-4 fold increase in serum amylase level within 48 hours of onset of pain is highly suggestive of the diagnosis of acute pancreatitis. Initial management is aimed at relieving pain and administration of IV fluids to maintain core perfusion as evidenced by good urine output. Subsequently management of containing pancreatitis is best done in tertiary multi super specialty hospitals with expertise in dealing with such patients. II. Incidence of the condition

The exact incidence of acute pancreatitis in India is unknown as no hard data is available. The incidence is rising world wide with the United Kingdom reporting an incidence range of 150-420 cases per million population. The experience of senior clinicians from personal experience seems to suggest that even in India incidence of Acute Pancreatitis appears to be rising and patients are being seen frequently. 4

III. Differential diagnosis The differential diagnosis of acute pancreatitis include all the differentials of the syndrome of sudden onset severe epigastric pain associated with vomiting. These are: 1. Severe acute gastritis 2. Peptic ulcer perforation 3. Liver abscess 4. Enteric perforation 5. Biliary colic 6. Acute cholecystitis 7. Acute gastroentertitis 8. Acute episode of chronic pancreatitis 9. Acute mesenteric ischaemia 10. Myocardial infarction IV. Prevention and counselling

In a known case of alcohol induced pancreatitis the patient must be counselled about the role of alcohol and that abstaining from it will prevent a further episode of pancreatitis. Similarly avoidance of fatty food and early cholecystectomy in a known case of biliary or gall stone induced pancreatitis will prevent further attacks. V. Optimal diagnostic criteria, investigations, treatment and referral criteria Diagnosis of acute pancreatitis is based on the presentation with severe acute upper and

abdominal pain and a three to four fold increase in the level of serum amylase within 48 hours of onset of pain. Investigation to confirm the diagnosis and exclude other possibilities is a contrast enhanced CT examination of the abdomen. An early CT (within the first few hours or day 1-2) will be helpful if no diagnosis has been made in 48 hours. The best time for CECT abdomen to establish the diagnosis of acute pancreatitis and extent of necrosis is 5-7 days.

Further investigations need to be done to document severity of acute pancreatitis. These include CBC, BUN & serum creatinine, blood gas analysis, C-reactive protein. Chest X-ray PA and ultrasound to demonstrate pleural effusion. Other investigations to help establish the cause of acute pancreatitis include, MRCP- Magnetic Retrograde Cholangio Pancreaticography, ultrasound and increasingly endo- ultrasound. V. Referral criteria

Criteria have been developed to predict mortality in Acute Pancreatitis. These can be used to identify patients who will do well to be referred to tertiary centres for further management. 5

Facilities in the peripheral or district level hospitals may not be adequate to do APACHE scoring. Hence a simpler bedside index may be more relevant and suitable to our condition. The BISAP – Bedside index for severity of Acute Pancreatitis is ideally suited to our needs. It is simple, clinically oriented severity scoring system that can predict mortality of Acute Pancreatitis. Individual components of the BISAP scoring system are: BUN > 25 mg/dl Impaired mental status (Glasgow coma scale score < 15)

SIRS as defined by two or more: Temperature <36 or 38°C Respiratory rate > 20/min (PaCO < 32 mm Hg) 2 Pulse > 90/ minute WBC <4000 or >12000 /cumm or > 10% immature bands Age > 60 years Pleural effusion detected on X ray or ultrasound One point is assigned for each variable within 24 hours of presentation and then added for a composite score of 0-5 . Chances of mortality BISAP Score Mortality 0 0 1 0 2 2% 3 10% 4 50% 5 35% (Singh et al Am J Gastro 2009: 104: 966-971)

It would be reasonable that based on the above the following referral recommendations can be made: BISAP 0-2 Admit in District Secondary Hospital BISAO 3-5 Admit in Tertiary Care Facility 6

Situation 1 At secondary hospital/ non metro situation optimal standards of treatment in situation where technology and resources are limited. Clinical Diagnosis Abdominal pain and vomiting together with 3-4 times raised plasma concentration of amylase and lipase with 3-4 days of onset of pain is diagnostic of Acute Pancreatitis. The half life of amylase is shorter compared to lipase. Therefore lipase levels remain elevated longer

as compared to amylase. Also because the pancreas is the only source of lipase it has superior sensitivity and specificity and greater overall diagnostic accuracy than amylase. Investigations Plain X ray abdomen and ultrasonography (USG) may not directly aid in the diagnosis of Acute pancreatitis but are important investigations to demonstrate gall stones and rule out other causes of acute abdomen like enteric or upper GI perforation.

A plain x ray of the chest and USG together may demonstrate pleural effusion which will be an aid in the BISAP scoring. Treatment at secondary hospital 1. Prompt and adequate crystalloid infusion to maintain core perfusion as evidenced by catheterising the patient and maintaining an urine output of 1 ml/kg/hour. 2. Adequate oxygenation to maintain an sPO above 95%. 2 3. Nutritional support – unless nausea and vomiting are troublesome. Oral intake should nbe

encouraged. Enteral feeding by nasogastric tube is as effective as nasojejunal tube feed. A blenderised low fat low protein kitchen tube feed supplying 2400 kcal/ day is sufficient for a 50 kg adult patient. Prolonged ileus more than 5 days necessitate total parenteral nutrition, which will fall in the purview of treatment at the superspecialty centre. 4. Drug therapy a. Pain relief can be provided by any available analgesic. Alkaloid opiates eg morphine

should be avoided as it causes increase sphincter of oddi spasm. b. Routine use of antibiotics is not recommended. For patients being transferred to a tertiary centre a stat dose of ciprofloxacin and metrogyl can be given and repeated after 8 hours if the travel time is more than 8 hours. 7

5. Referral criteria Criteria have been developed to predict mortality in Acute Pancreatitis. These can be used to identify patients who will do well to be referred to tertiary centres for further management. Facilities in the peripheral or district level hospitals may not be adequate to do APACHE scoring. Hence a simpler bedside index may be more relevant and suitable to our condition. The BISAP – Bedside index for severity of Acute Pancreatitis is ideally suited to our needs. It is simple, clinically

oriented severity scoring system that can predict mortality of Acute Pancreatitis. Individual components of the BISAP scoring system are: BUN > 25 mg/dl Impaired mental status (Glasgow coma scale score < 15) SIRS as defined by two or more: Temperature <36 or 38°C Respiratory rate > 20/min (PaCO < 32 mm Hg) 2 Pulse > 90/ minute WBC <4000 or >12000 /cumm or > 10% immature bands Age > 60 years Pleural effusion detected on X ray or ultrasound

One point is assigned for each variable within 24 hours of presentation and then added for a composite score of 0-5 . Chances of mortality BISAP Score Mortality 0 0 1 0 2 2% 3 10% 4 50% 5 35% (Singh et al Am J Gastro 2009: 104: 966-971) It would be reasonable that based on the above the following referral recommendations can be made: BISAP 0-2 Admit in District Secondary Hospital BISAO 3-5 Admit in Tertiary Care Facility 8

Situation 2 At Super Specialty facility in Metro location where higher end technology is available Clinical Diagnosis As in situation 1. Record history of known gall stone disease, alcohol intake, drug intake, exposure to known viral causes Investigations Aims of investigations at super speciality facility are 1. Confirm diagnosis 2. Confirm aetiology 3. Confirm presence of pancreatic necrosis and infected pancreatic necrosis 4. Confirm developing complications of Acute Pancreatitis

a. Peri pancreatic fluid collection b. Peri pancreatic abscess c. Bowel ischemia and gangrene d. Bleeding Investigations to be done at the super speciality centre Blood tests 1. CBC – serial complete blood counts to look for the trends of neutrophilic leucocytosis which will indicate both severe pancreatitis and infected pancreatic necrosis 2. Serum pancreatic enzymes- amylase and lipase are not helpful after 4-5 days 3. LFT 4. Blood urea and serum creatinine

5. Serial monitoring of blood sugar and serum calcium 6. Fasting serum lipid profile 7. Viral antibody titres Radiological tests 1. Ultrasound 2. CECT scan not earlier than 5-7 days will demonstrate areas of necrosis. It is now believed that the extent of radiologically demonstrated necrosis does not correlate with the outcome and mortality. The important factor determining outcome is organ failure. The more the number of failing organs as demonstrated by the SIRS criteria of BISAP scoring

the worse the prognosis 3. ERCP – a. Urgent therapeutic ERCP should be performed in patients with acute pancreatitis of suspected or proven gall stone aetiology which satisfy the criteria for predicted or actual severe pancreatitis or when there is cholangitis , jaundice or a dilated common bile duct. b. The procedure is best carried out within the first 72 hours after the onset of pain 9

c. All patients will with severe gall stone pancreatitis will require endoscopic sphincterotomy whether or not stones are found in the bile duct d. Patients with signs of cholangitis may require duct drainage by stenting to ensure relief of biliary obstruction 4. EUS ( endoscopic ultrasound) – EUS has proven superiority over conventional abdominal ultrasound for the detection of CBD stones. It is of particular benefit in the evaluation of patients with recurrent acute pancreatitis.

5. MRCP – is an effective non invasive means of delineating biliary and pancreatic ductal anatomy. In patients with recurrent pancreatitis it can show CBD stones, ampullary strictures and presence of pancreatic divisium. 6. Image guided FNAC of pancreatic necrosis to confirm infected pancreatic necrosis. Treatment Continuing treatment at the tertiary centre is aimed at early detection and treatment of complications due to acute pancreatitis. Infected pancreatic necrosis is perhaps the most significant

such complication. Antibiotics Role of antibiotics in preventing infected pancreatic necrosis continues to be controversial. Prophylactic antibiotics combining metronidazole with imipenem or a quinolone if used must be administered for 14 days. Recent data presented in the Dutch National PANTER trial seems to suggest that antibiotics alone maybe sufficient to treat a subset of patients with infected pancreatic necrosis. Enteral nutrition

The acute inflammatory response is associated with impaired gut mucosal barrier function. Nutritional support helps preserve mucosal function and limit the stimulus to systemic inflammatory response. Enteral feeding is safer than parenteral feeding and has fewer septic complications. It also makes for better financial sense. In patients with severe disease oral intake is often inhibited by nausea. When enteral feeding is

limited by the presence of ileus and nausea for more than five days, parenteral nutrition should be initiated. Surgical intervention 1. All patients with biliary pancreatitis should undergo definitive management of gall stones during the same hospital admission in the form of cholecystectomy. 2. Patients with established infected pancreatic necrosis who continue to remain febrile three to four weeks after the onset of pain must be considered for intervention to drain the infected necrosis.

3. Intervention should ideally be delayed into the fourth week of pancreatitis. Earlier interventions are associated with poor outcomes. 10

4. A stepped up approach starting with radiological guided needle aspirations, endoscopic guided lesser sac aspiration and going on to video assisted retro peritoneal endoscopic drainage maybe preferred to open conventional necrosectomy if all facilities are available at the tertiary hospital. 5. Conventional necrosectomy is acceptable treatment if the above facilities are not available. It is recommended that a cholecystectomy be added during the necrosectomy particularly in

patients with biliary pancreatitis. 6. A feeding jejunostomy must always be added in our Indian patients. Tertiary treatment centre for patients with acute pancreatitis 1. Every tertiary hospital receiving patients with pancreatitis should have a nominated clinical team to manage these patients. 2. Components of team a. Clinicians : a multidisciplinary team of specialists including surgical and medical gastroenterologists, intensivists, nutritionists and other support staff of the intensive care unit.

b. Facilities for dynamic multislice C.T., percutaneous needle aspiration and drainage procedure and MR imaging. c. Facilities for ERCP and EUS. Further reading 1. UK guidelines for the management of acute pancreatitis UK working party on acute pancreatitis Gut 2005;54;1-g 2. Singh VK et al A prospective evaluation of the bedside index for severity in acute pancreatitis score in assessing mortality and intermediate markers of severity in acute pancreatitis Am J Gastro, 2009;104;966-971 3. Hirota M et al

Fundamental and intensive care of acute pancreatitis J Hepatobiliary Pancreat Sci (2010) 17:45-42 4. Acute pancreatitis: Problems in adherence to guidelines 2009:76.12;697-703 5. Wu Bu et al, The early prediction of mortality in acute pancreatitis: A large population- based study, Gut 2008: 57:1698-1703 11

Portal hypertension S Thiagrajan Sorabh Kapoor Samiran Nundy Department of Surgical Gastroenterology and Liver Transplantation Sir Ganga Ram Hospital New Delhi I. When to suspect / recognise a)Introduction Portal hypertension may manifest as variceal bleeding, ascites, splenomegaly, hepato renal syndrome and hepatopulmonary syndrome.The management of Portal Hypertension (PHTincludes treating acute bleeding from varices in the oesophagus and

stomach, preventing recurrent bleeding (secondary prophylaxis), preventing the first bleeding episode (primary prophylaxis) and controlling ascites and liver failure. In these guidelines we will only deal with the management of bleeding varices in both cirhhotic and non cirrhotic portal hypertension [EHPVO(extra hepatic portal venous obstruction), NCPF (non cirrhotic portal fibrosis) etc.,]. The management of ascites and liver failure is

mainly by drugs and liver transplants. In addition management of left sided portal hypertension usually accompanying chronic pancreatitis is also dealt separately b) Case definition Portal hypertension is defined as elevated pressure in portal venous system due to resistance to portal blood flow. The site of resistance may be prehepatic (EHPVO), hepatic (cirrhosis and NCPF which is presinusoidal) and post hepatic (Hepatic venous

outflow tract obstruction – HVOTO). The normal portal pressure is 5-10 mmHg. Pressure more than 10 mmHg is defined as portal hypertension. Since portal pressure or HVPG is normally measured in specialized Gastroenterology /Hepatology units, presence of varices along with evidence of liver cirrhosis or portal vein thrombosis / HVOTO in the presence /absence of ascites and splenomegaly is considered sufficient for diagnosis of portal hypertension. II. Incidence of portal hypertension in our country

The true incidence of the condition is unknown. However variceal bleeding is one of the common causes of Upper gastrointestinal haemorrhage , accounting for almost half of cases (depending on referral pattern). Variceal haemorrhage is also the commonest complication of liver cirrhosis. Almost 90% of patients with cirrhosis will have variceal formation and 30% of all patients with varices are likely to bleed. Most patients with EHPVO and NCPF are also diagnosed after evaluation for splenomegaly and variceal

bleeding. In children, variceal bleeding is most common cause of UGI bleeding in India, accounting for almost 90% cases with EHPVO responsible for the majority and NCPF and cirrhosis responsible for the rest. III. Differential diagnosis 12

a) Variceal hemorrhage has to be differentiated from GI bleed due to Peptic ulcer disease, esophagitis, Dieulafoy’s lesion, Mallory Weiss tear NSAID induced ulcers Arteriovenous malformations/ telengectasias b) Ascites due to portal hypertension has to differentiated from ascites due to Renal disease Malignant ascites Tuberculosis Pancreatic ascites, etc c) Similarly splenomegaly and hypersplenism have to be differentiated from hematological and other infiltrative causes of splenic enlargement

IV. Prevention and counseling Since the etiology of EHPVO and NCPF are not fully known the prevention is mainly prophylaxis of bleeding or rebleeding. Simiarly, if HVOTO is diagnosed then etiology of probable hypercoagulable state needs to be evaluated for prevention of further thrombosis of other hepatic veins or re occlusion after interventional radiological management / shunt / transplant. The prevention of cirrhosis involves essentially involves counseling in alcoholics, vaccination for

Hepatitis B, and precautions for Hepatitis C and treatment of patients with NAFL (to prevent progression to NAFLD). In addition, all patients diagnosed with viral hepatitis( B, C and D) or chronic liver disease due to any etiology require management by specialized gastroenterogy / hepatology units with the aim of halting the progression of disease and early management of complications. Prevention of Variceal haemorrhage

The prevention of index bleeding in cirrhotics or other causes of PHT in patients who are diagnosed prior to bleeding is important. 13

Primary Prophylaxis Primary prophylaxis is administered to patients at high risk of bleeding. These patients have large varices, red wale markings on the varices, and severe liver failure. Pharmacotherapy Propranolol Individualize dose. 40 mg PO bid average dose; initiate 20 mg PO q12h, adjusting dose q3-4d until heart rate is reduced by 25%, provided it does not drop below 55 bpm or systolic arterial pressure does not drop below 90 mm Hg. Administering more than 320 mg/d is not recommended Nadolol

Individualize dose. 20 mg PO bid average dose; initiate 10 mg PO q12h, adjusting dose q3-4d until heart rate is reduced by 25%, provided it does not drop below 55 bpm or systolic arterial pressure does not drop below 90 mm Hg . 14

Response to treatment is monitored by a reduction of the portal pressure gradient by more than 20% of the baseline value or less than 12 mm Hg. Checking the HVPG response in primary prophylaxis is not mandatory because 60% of patients who do not achieve these targets do not bleed at 2-year follow-up evaluations. Propranolol is contraindicated in patients with asthma, chronic obstructive pulmonary disease (COPD), atrioventricular (AV) block, intermittent claudication, and psychosis. Beta-blockers are best

continued for the patient's lifetime because the risk of variceal hemorrhage returns to that of the untreated population once beta-blockers are withdrawn. Vasodilators Available evidence does not support the use of Isosorbide mononitrate ISMN as monotherapy for primary prophylaxis, even in patients with contraindications or intolerance to beta-blockers. Combination therapy This involves both beta-blockers and ISMN. Combination therapy cannot be recommended presently until further studies prove efficacy.

Prophylactic sclerotherapy and Surgery No role in primary prophylaxis except perhaps in patients with EHPVO who have ‘dangerous’ varices and live far from tertiary medical centres. Prophylactic endoscopic variceal ligation Prophylactic EVL currently cannot be recommended as a routine measure for primary prevention but may be an option for patients with grade 3-4 varices who have contraindications to or cannot tolerate beta-blockers.

V. Optimal diagnostic criteria, investigations, treatment and referral criteria Situation 1. At secondary hospital /Non metro situation : Optimal standards of treatment in situations where technology and resources are limited Clinical diagnosis Variceal hemorrhage is diagnosed when patients present with upper gastrointestinal hemorrhage in the background of preexisting chronic liver disease or cirrhosis or in patients in 1st decades of life for EHO and 2nd and 3rd decade who present with UGI

bleeding associated with splenomegaly usually in the absence of any associated features of chronic liver disease. Investigations The initial investigations are aimed at guiding and assessing the adequacy of resuscitation by checking Hemogram , liver and renal function 15

Treatment Initial resuscitation with replacement of blood volume loss Secure respiratory tract patency, if needed endotracheal intubation may be done. Place two wide bore 16G intravenous lines preferably in the antecubital fossae and consider central venous line insertion. Assess severity of bleeding, monitor vitals. Blood sample for hemoglobin and cross matching. Volume replacement with colloids/blood, guided initially, by blood pressure and urine

output and central venous pressure(CVP) if possible. It is important to avoid under- than over-transfuse to avoid excessive intravascular volume and variceal expansion and consequent rebleeding. Blood should be replaced at a modest target of HCT (hematocrit) of 25-30%. Place a nasogastric tube Prevention of complications (eg, hepatic encephalopathy, bronchial aspiration, renal failure, systemic infections, Spontaneous Bacterial Peritonitis)

All patients with cirrhosis and upper GI bleeding are at a high risk of developing severe bacterial infections, which are associated with early rebleeding. The use of prophylactic antibiotics has been demonstrated to decrease the rate of bacterial infections and increase survival rates, thus prophylactic antibiotic use (norfloxacin 400 mg PO bid for 7 d; ciprofloxacin and other broad-spectrum antibiotics) in the setting of acute bleeding is recommended. Pharmacological therapy

This acts by decreasing splanchnic blood flow Octreotide is a synthetic analogue of somatostatin that is usually administered at a constant infusion of 50 mcg/h. Terlipressin,a synthetic analogue of vasopressin which is also useful during an acute bleeding episode. Dosage 0.5 mg to 2mg QID by slow IV infusion The use of vasopressin is limited by adverse effects related to splanchnic vasoconstriction (eg, bowel ischaemia) and systemic vasoconstriction (eg, hypertension,

myocardial ischemia). Continuous infusion of 0.2-0.4 IU/min (not exceeding 0.8 IU/min) is recommended. Vasopressin always should be accompanied by intravenous nitroglycerin at a dose of 40 mcg/min (not to exceed 400 mcg/min) to maintain systolic blood pressure greater than 90 mm Hg. Adding nitrates to vasopressin therapy improves its efficacy, although the adverse effects of combination therapy are higher than those associated with terlipressin or somatostatin. Subsequent Management

If the bleeding continues the Endoscopic therapy with sclerotherapy or band ligation should be attempted. In the absence of expertise or rebleeding after initial control Balloon tamponade should be instituted and the patient referred to higher center. Situation 2. At superspeciaity facility in metro location where higher end technology is available Clinical diagnosis Variceal hemorrhage is diagnosed when patients present with upper gastrointestinal

hemorrhage in the background of preexisting chronic liver disease or cirrhosis or in patients in 1st decades of life for EHO and 2nd and 3rd decade who present with UGI bleeding associated with splenomegaly usually in the absence of any associated features of chronic liver disease. Investigations The definitive diagnosis of variceal haemorrhage is done by demonstrating varices on esophagogastroscopy which should be done after adequate resuscitation and

stabilization. Imaging of liver by ultrasound or CT scan is also done after initial resuscitation. Following emergent treatment, the etiology of portal hypertension or cirrhosis needs to be identified. EHPVO is diagnosed by clinical presentation with preserved liver functions and splenomegaly with varices along with demonstration on USG Doppler of portal vein thrombosis or portal cavernoma formation. Similarly aforementioned presentation with

normal liver function and normal portal vein with normal liver on ultrasound is considered sufficient for diagnosis of NCPF. Doppler is also used for diagnosis of HVOTO which may be supplemented by venography. Etiology of cirrhosis is identified by history of alcoholism , liver functions and viral serology, PCR, autoantibodies and tests for Wilsons disease and hemochromatosis. Liver biopsy may be needed in various situations. Emergency Treatment Bleeding from esophageal varices

Following resuscitation, treatment of acute variceal bleeding includes control of bleeding (24 h without bleeding within the first 48 h after starting therapy) and prevention of early recurrence. Initial resuscitation with replacement of blood volume loss Secure respiratory tract patency, if needed endotracheal intubation may be done. Place two wide bore 16G intravenous lines preferably in the antecubital fossae and consider central venous line insertion. Assess severity of bleeding, monitor vitals. 17

Blood sample for hemoglobin and cross matching. Volume replacement with colloids/blood, guided initially, by blood pressure and urine output and central venous pressure(CVP) if possible. It is important to avoid under- than over-transfuse to avoid excessive intravascular volume and variceal expansion and consequent rebleeding. Blood should be replaced at a modest target of HCT (hematocrit) of 25-30%. Place a nasogastric tube

Prevention of complications (eg, hepatic encephalopathy, bronchial aspiration, renal failure, systemic infections, Spontaneous Bacterial Peritonitis) All patients with cirrhosis and upper GI bleeding are at a high risk of developing severe bacterial infections, which are associated with early rebleeding. The use of prophylactic antibiotics has been demonstrated to decrease the rate of bacterial infections and increase survival rates, thus prophylactic antibiotic use (norfloxacin 400 mg PO bid for 7

d; ciprofloxacin and other broad-spectrum antibiotics) in the setting of acute bleeding is recommended. Pharmacological therapy This acts by decreasing splanchnic blood flow Octreotide is a synthetic analogue of somatostatin that is usually administered at a constant infusion of 50 mcg/h. Terlipressin,a synthetic analogue of vasopressin which is also useful during an acute bleeding episode. Dosage 0.5 mg to 2mg QID by slow IV infusion Vasopressin The use of

vasopressin is limited by adverse effects related to splanchnic vasoconstriction (eg, bowel ischaemia) and systemic vasoconstriction (eg, hypertension, myocardial ischemia). Continuous infusion of 0.2-0.4 IU/min (not exceeding 0.8 IU/min) is recommended. Vasopressin always should be accompanied by intravenous nitroglycerin at a dose of 40 mcg/min (not to exceed 400 mcg/min) to maintain systolic blood pressure greater than 90 mm Hg. Adding nitrates to vasopressin therapy improves its

efficacy, although the adverse effects of combination therapy are higher than those associated with terlipressin or somatostatin. . Endoscopic therapy Endoscopic therapy is a very effective emergency treatment for acute oesophageal variceal bleeding (though not optimal for patients bleeding from gastric fundal varices). Failures of endoscopic treatments may be managed by a second session of endoscopic treatment, but no more than two sessions should be undertaken before deciding to

insert a transjugular intrahepatic portosystemic shunt(TIPS) or perform surgery. Endoscopic variceal ligation (EVL) is achieved by a banding device attached to the tip of the endoscope. The varix is aspirated into the banding chamber, and a trip wire dislodges the carried rubber band, ligating the entrapped varix. One to three bands are applied to each varix, resulting in thrombosis. EVL is less prone to complications than 17

injection sclerotherapy. However it has the same limitations of availability, cost, and difficulty in treating gastric varices as sclerotherapy. Endoscopic injection sclerotherapy - Injecting a sclerosant solution into the bleeding varix, obliterating the lumen by thrombosis, or into the overlying submucosa. Sclerosants include 5% sodium morrhuate, 1% to 3% sodium tetradecyl sulphate, and 5% ethanolamine oleate. The typical volume used per injection is 1-2 mL of sclerosant, with

the total volume ranging from 10-15 mL. Although ligation is being considered the treatment of choice for esophageal varices, the choice of technique should be left up to the experience of the operator, as well as the particular circumstances found during endoscopic therapy. Other interventions Balloon-tube tamponade should be used only in massive bleeding as a temporizing measure (less than 48 hours) until definitive treatment can be instituted. Continued

bleeding during balloon tamponade indicates an incorrectly positioned tube or bleeding from another source. The Sengstaken-Blakemore (S-B) tube has three lumens - one for gastric aspiration and two to inflate the gastric and esophageal balloons.. The tube is inserted through the mouth, and its position within the stomach is checked by auscultation while injecting air through the gastric lumen. The gastric balloon is inflated with 200 mL of air. Once fully

inflated, the gastric balloon is pulled up against the oesophagogastric junction, using approximately 0.5 kg of traction, compressing the submucosal varices. Oesophageal balloon inflation however is rarely required. A plain X ray of the abdomen is performed to confirm the position of the inflated gastric balloon. The tube is usually removed before 48 h to permit definite evaluation by UGIE. The Minnesota tube is an adaptation

of the SB tube, the difference is that it has and additional oesophageal suction port to prevent aspiration. Endoscopic administration of cyanoacrylate monomer (superglue) is indicated in gastric varices. TIPS TIPS is a useful procedure for bleeding which continues despite medical and endoscopic treatment in Child’s C patients and selected patients with Child class B disease. Under local anaesthesia with sedation, the hepatic vein is cannulated with a needle via the

internal jugular vein and a tract is created through the liver parenchyma from the hepatic to the portal vein. This is performed under ultrasonographic and fluoroscopic guidance. The tract is dilated, and an expandable metal stent is introduced, connecting the hepatic and portal systems. Blood from the hypertensive portal vein and sinusoidal bed is shunted to the hepatic vein. Accepted indications include (1) active variceal bleeding despite emergency endoscopic and/or pharmacological treatment, and 18

(2) recurrent variceal bleeding despite adequate endoscopic treatment. Potential indications include (a) isolated bleeding from gastric fundal varices and (b) refractory ascites. TIPS is a viable option and is less invasive for those whose bleeding is not controlled. However, if TIPS is not available, then staple transection of the esophagus is an option when endoscopic treatment and pharmacological therapy have failed. Emergency Surgery

Patients with PHT may require emergency surgical intervention when endoscopic and/or pharmacotherapy and SBT fail to arrest acute variceal bleeding. The objective of emergency surgery is to control bleeding from the varices. The most important factor in choosing the surgical option in patients with uncontrolled variceal bleeding is the experience of the surgeon and the underlying etiology of PHT. Shunt procedures have high control rates of bleeding and low rebleeding rates,

therefore should be an option of choice in experienced hands in patients a with suitable venous anatomy. Patients with unshuntable anatomy and poor liver function (Child's B or C) should only be subjected to nonshunt procedures such as gastroesophageal devascularization with or without gastroesophageal transection, partial esophagogastrectomy and transthoracic ligation of varices. These procedures however are associated with a higher rebleeding rates.2 19

Algorithm for management of emergent bleeding Elective Treatment / Secondary Prophylaxis Nonselective beta-blockers Propranolol and nadolol significantly reduce the risk of rebleeding and are associated with prolongation of survival. Endoscopic sclerotherapy This usually is performed at weekly intervals.Approximately 4-5 sessions are required for eradication of varices, which is achieved in nearly 70% of patients. Endoscopic variceal ligation

EVL is considered the endoscopic treatment of choice in the prevention of rebleeding. Sessions are repeated at 7- to 14-day intervals until variceal obliteration (usually 2-4 sessions). Major complications of EST are retrosternal discomfort (30%), esophageal ulcerations (18-30%o) and 20

strictures (6-16%); and transient pyrexia (39%). Serious complications like esophageal perforation and mediastinitis can rarely occur. Combination of EVL and pharmacologic therapy EVL plus nadolol plus sucralfate is more effective in preventing variceal rebleeding than EVL alone. Combination of EVL with beta-blockers seems to be reasonable for patients in whom pharmacological therapy has failed. Surgical Care For prevention of rebleeding, when pharmacological therapy and/or endoscopic therapy have failed,

consider surgery. Failure is defined as a single episode of clinically significant rebleeding (transfusion requirement of 2 U of blood or more within 24 h, a systolic blood pressure <100 mm Hg or a postural change of >20 mm Hg, and/or pulse rate greater than 100 bpm). When the patient lives far from tertiary medical care cannot come for regular follow up with endoscopy there is a role for early shunt procedures in those with non cirrhotic portal hypertension

with documented massive hematemesis and especially when there is growth retardation . These patients have normal liver function therefore, no risk of post- shunt hepatic decompensation and encephalopathy; and tolerate surgery well. Indications of surgery in this group of children with EHPVO would be failure to control acute variceal bleeding by non- surgical methods, gastric varices (bleeding or large size), significant hypersplenism,

bleeding ectopic varices and isolated splenic vein thrombosis. Each patient with EHPVO needs to be individualized for appropriate therapy. Children with PHT due to other non- cirrhotic conditions like congenital hepatic fibrosis and non- cirrhotic portal fibrosis may be managed on similar guidelines of EHPVO as these cases are expected to have well preserved liver function. Operations have the added advantages of being one time procedures, they reverse the problems associated with splenomegaly

and improve post-operative growth parameters. Surgical procedures performed are shunt and nonshunt operations. Decompressive Shunts The shunt procedures are designed to divert blood from the high-pressure portal venous to the low pressure systemic system. They have been divided into non-selective shunts; selective shunts, partial shunts and the more recently introduced "Rex shunt"(mesenterico-left portal bypass). Total portal systemic shunts

These include any direct anastomosis between shunt between the portal vein (or one of its main tributaries) and the IVC (or one of its tributaries).The non-selective shunts completely decompress the entire portal venous system and divert all portal blood flow away from the liver. These are end- to-side and side-to-side portacaval shunts; central lienorenal shunts, mesocaval shunts and the large 21

diameter interposition portacaval or mesocaval shunts. These shunts achieve effective control of bleeding. However a major concern with them is that they may precipitate encephalopathy (rate of 40-50% in cirrhotics) and progressive liver failure. The procedure has relatively limited indications, which include massive variceal bleeding with ascites or acute Budd-Chiari syndrome without evidence of liver failure. Splenectomy with a central lienorenal shunt has not been found to be

associated with an increased risk of post- splenectomy sepsis. The "Rex shunt" restores the physiological hepatopetal flow by interposing a jugular venous allograft between the superior mesenteric vein and the intrahepatic left portal vein. This shunt has been initially used for treating portal vein thrombosis after liver transplantation and its application has been extended to primary portal vein thrombosis. Partial portal systemic shunts

These reduce the size of the anastomosis of a side-to-side shunt to 8 mm in diameter. Portal pressure is reduced to 12 mm Hg, and portal flow is maintained in 80% of patients. The operative approach is similar to side-to-side portacaval shunts, except the interposition graft must be placed between the portal vein and the IVC. Selective shunts The selective shunts compartmentalize the portal venous system into a decompressed gastrosplenic

and hypertensive superior mesenteric circuit, thus maintaining portal perfusion. For instance a distal splenorenal shunt (Warren shunt) is a selective shunt used primarily in patients who present with refractory bleeding and continue to have good liver function. This shunt provides the best long- term maintenance of some portal flow and liver function with a lower incidence of encephalopathy (10-15%) compared to total shunts. The operation produces ascites because the retroperitoneal

lymphatics are diverted. Non shunt operations A subgroup(approximately 5-10%) of patients with EHPVO have no suitable veins for shunting due to extensive thrombosis of the splenoportal axis, prior splenectomy or a previously performed but failed shunt procedure. This group poses special management problems. They merit non-surgical management and in case of its failure would necessitate non-shunt surgical procedures. Devascularization Procedures

These include splenectomy, gastroesophageal devascularization, and, occasionally, esophageal transection. The incidence of liver failure and encephalopathy is low following devascularization procedures, presumably because of better maintenance of the portal flow. 22

Splenectomy This should not be performed except in patients with gastric varices and isolated left sided portal hypertension following splenic vein thrombosis(usually following chronic pancreatitis. In them it is a curative procedure. The spleen is one of the major inflow paths to gastroesophageal varices. Gastroesophageal devascularization (Sugiura procedure) In this the whole greater curve of the stomach from the pylorus to the esophagus and the upper two

thirds of the lesser curve of the stomach; the esophagus is devascularized for a minimum of 7 cm via a thoracic approach upto the level of the inferior pulmonary vein. Follow-up Further Outpatient Care To prevent recurrent variceal hemorrhage, these patients should have EVL sessions scheduled until complete obliteration of varices is achieved. EVL sessions are repeated at 7- to 14-day intervals. These usually require 2-4 sessions for complete obliteration of varices. Patients should be included

in an on-demand endoscopic program of varices eradication for postoperative follow-up as opposed a prophylactic program. 1. Chang YW. Indication of treatment for esophageal varices: who and when?. Dig Endosc. Jan 2006;18(1):10-5. 2. Uchiyama M, Iwafuchi M, Ohsawa Yet al. Long term results after non-shunt operations for esophageal varices in children. J Pediatr Surg 1994; 29 : 1429-1433 3. Dite P, Labrecque D,Michael F et al. World Gastroenterology Organisation practice

guideline: Esophageal varices June 2008 4. Alvarez F, Bernard O, Brunelle F et al. Portal obstruction in children. II. Results of surgical portosystemic shunts. J Pediatr 1983; 103 : 703-707 5. Prasad AS, Gupta S, Kohli V, Pande GK, Sahni P, Nundy S. Proximal Splenorenal shunts for extrahepatic portal venous obstruction in children. Ann Surg 1994; 219 : 193-196 6. Bambin/DA, Superina R, Almond PS, Wh/tington PF, Alonso E. Experience with the Rex

(Mesenterico-Left portal Bypass) in children with Extrahepatic portal hypertension~ J Pediatr Surg 2000; 35 : 13-19 Garcia-Tsao G. Portal hypertension. Curr Opin stroenterol. May 2000;16:282-9 23

CHOLEDOCHOLITHIASIS Anand Bharathan V Sitaram Department of Hepatic Pancreatic & Biliary (HPB) Surgery Christian Medical College Vellore. I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Choledocholithiasis is suspected in patients presenting with colicky upper abdominal pain that may or may not radiate to back (biliary colic). This may be associated with jaundice. About 8-20% of patients who have gallbladder stones were found to have choledocholithasis in published

literature1. About 5% of common bile duct stones found during an operation may be unsuspected preoperatively2. Case definition: Choledocholithiasis is occurrence of stones within the common bile duct or common hepatic duct. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY Published data on the incidence of choledocholithiasis is limited. III. DIFFERENTIAL DIAGNOSIS a. Gallbladder stone disease b. Mirrizzi syndrome c. Choledochal cyst d. Benign biliary stricture

e. Malignant obstruction of extra-hepatic biliary tree IV. PREVENTION AND COUNSELING No specific primary or secondary preventive measures are known. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT AND REFERRAL CRITERIA History: Abdominal pain is the most common symptom. Jaundice with or without cholestatic features like pruritus and clay colored stools, fever with chills due to cholangitis, acute pancreatitis may also form part of history. (Physical examination is usually non-contributory). 24

Diagnosis: Elevated levels of serum bilirubin and alkaline phosphatase indicate biliary obstruction but are not sensitive or specific for choledocholithiasis. Normal levels of bilirubin, alkaline phosphatase or liver enzymes like aspartate transaminase and alanine transaminase will not rule out choledocholithiasis. Ultrasound scan abdomen is usually the first imaging modality to raise the suspicion of choledocholithiasis. Sensitivity and specificity of ultrasound scan for diagnosis are 30% and close

to 100% respectively3. Magnetic resonance cholangio pancreatography (MRCP) has demonstrated sensitivity and specificity of 91% and 100% respectively. Sensitivity of MRCP decreases to about 71% for stones less than 5 mm4. Endoscopic ultrasound (EUS) scan of bile duct has been shown to have sensitivity and specificity of 84-100% and 96-100% respectively. Positive predictive values of MRCP and EUS for diagnosis were 0.87 and 0.93 respectively.

Corresponding negative predictive values were 0.92 and 0.96. All these are in comparison to endoscopic retrograde cholangio pancreatography (ERCP) which has been given up as a diagnostic modality. It is currently recommended only for therapeutic use to remove bile duct stone after a reasonable diagnosis of choledocholithiasis has been arrived at3. Treatment In patients who have undergone cholecystectomy earlier and diagnosis of choledocholithiasis,

endoscopic retrograde cholangio pancreatography (ERCP) and extraction of bile duct stones using endoscopic techniques is the preferred approach. If this fails, open or laparoscopic common bile duct exploration should be performed. A possibility that dilated common bile duct with calculi is a choledochal cyst must be kept in mind as treatment & long term follow up of the latter is different. In patients with gall bladder stones and high risk of choledocholithiasis, ERCP and stone retrieval

followed by laparoscopic cholecystectomy is the preferred treatment. If endoscopic therapy fails, they may undergo laparoscopic or open common bile duct exploration along with cholecystectomy. A cautious decision to withhold cholecystectomy after endoscopic treatment of choledocholithiasis may be made in patients with unacceptable surgical risk. If there is intermediate risk of choledocholithiasis in those with gallstones this should be confirmed with MRCP or EUS. Thereafter treatment is as outlined above.

Patients with low risk of choledocholithiasis and gallstones may undergo intraoperative cholangiogram (IOC). If choledocholithiasis if diagnosed, and the bile duct is of normal caliber, exploration is not advised. Post operative endoscopic therapy is an option. If the common bile duct is dilated options are: laparoscopic common bile duct exploration / conversion to open operation and common bile duct exploration. Patient must be referred to higher centers if either of MRCP, EUS or intraoperative

Situation 1 At secondary hospital / non-metro situation: optimal standards of treatment in situations where technology and resources are limited Clinical diagnosis: The most common presentation is with colicky upper abdominal pain (biliary colic) with or without jaundice. Fever with chills would indicate cholangitis. Pruritus and clay colored stools may be present if biliary obstruction is high grade. Fever and icterus may be present on general examination. There

are no specific abdominal signs that would indicate choledocholithiasis. Presence of distended gallbladder will be a pointer against the diagnosis of choledocholithiasis in most cases. Investigations Haemogram, liver function test, ultrasound scan abdomen. MRCP should preferably be available even in this situation. Treatment We recommend two treatment protocols depending on whether cholecystectomy has been performed earlier. These protocols have been given in the form of two algorithms along with this

document. It would be acceptable not to have high end technology like endoscopic ultrasound scan (EUS), laparoscopic ultrasound scan or instrumentation for laparoscopic common bile duct exploration in a secondary referral hospital setting. Standard operating procedure (please see the two algorithms) Most of the investigations may be performed as an outpatient. Cholangitis would make admission mandatory during the initial evaluation itself. Referral criteria

Patients with cholangitis unresponsive to antibiotic therapy should be referred to a tertiary (super specialty) hospital. Patients with failed papillary access / biliary cannulation (at ERCP and attempt at 26

stone extraction) should also be considered for referral to tertiary care centers before decision to perform open common bile duct exploration. Situation 2 At super specialty facility in metro location where high end technology is available Clinical diagnosis: Careful review of symptoms and signs must be done. Investigations: If cholangitis was the indication for referral, complete blood count, coagulation profile and blood

culture and sensitivity must be done at admission. Liver function tests and ultrasound scan abdomen to confirm the diagnosis and to look for cholangitic abscess should be performed. Parenteral vitamin K supplementation must be initiated during the period of evaluation. After initiation of appropriate antibiotic therapy, it may be reasonable to proceed to ERCP and attempt at endoscopic retrieval of bile duct stones. Treatment:

Our suggested treatment protocol is in the form of algorithms attached with this document. Standard Operating procedure All investigations can be done as outpatient/day care procedures. However, if cholangitis is present, patient should be hospitalized. All surgical procedures require hospitalization. Referral criteria None. 27

References 1. Blumgart LH. Stones in the common bile duct-Clinical features and open surgical approaches and techniques. In: Blumgart LH, Fong Y eds. Surgery of the liver and biliary tract. Saunders Elsevier; 2000:528-547. 2. McFadden DW, Nigam A. Choledocholithiasis and cholangitis. In: Zinner MJ, Ashley SW eds. Maingot's Abdominal operations. McGraw Hill Medical; 2007:865-888. 3. Williams EJ, Green J, Beckingham I, Parks R, Martin D, Lombard M. Guidelines on the

management of common bile duct stones (CBDS). Gut 57, 1004-1021. 2008. Ref Type: Journal (Full) 4. Sugiyama M, Atomi Y, Hachiya J. Magentic resonance cholangiography using half-Fourier acquisition for diagnosing choledocholithiasis. American Journal of Gastroenterology 93, 1886- 1890. 1998. Ref Type: Journal (Full) 30

CARCINOMA STOMACH Gen RP Chaubey (retd) Formerly from the Armed Forces Medical Services Sri Balaji Action Medical Institute New Delhi I. WHEN TO SUSPECT /RECOGNIZE? a) Introduction Carcinoma Stomach remains a common disease worldwide with dismal prognosis. It represents the fourth most common malignancy and the second leading cause of cancer related death. In Japan gastric cancer remains the most common type of cancer among

men. Its incidence, however, has been declining globally since World War II. Gastric cancer is one of the least common cancers in North America. The incidence of proximal gastric cancer is on the increase while the distal gastric cancer is declining in North America. The five year survival rate of gastric carcinoma is low (10-20%). b) Case Definition Gastric Cancer refers to the malignant growth arising from the epithelial lining of the

stomach. It is an aggressive tumor with vague early symptoms and spreads to the adjoining structures early in its course. II. INCIDENCE IN INDIA India falls in low incidence zone of gastric cancer. It is the fifth commonest cancer in males and seventh commonest in females in India. Age adjusted rate (AAR) of gastric cancer in six urban registries from India have reported the incidence 3.0- 13.2/1,00,000 population which is lower to the world incidence of 4.1-15.5/1,00,000 population.

There is a regional variation in its incidence. It occurs four times more commonly in south India as compared to north India and also a decade earlier. Gastric cancer follows the global trend of declining incidence in India as well. III. DIFFERENTIAL DIAGNOSIS 31

• Lower Esophageal Cancer • Lower Esophageal Stricture • Lower Esophagitis • Gastric Ulcers • Acute Gastritis • Atrophic Gastritis • Chronic Gastritis • Bacterial Gastroenteritis • Viral Gastroenteritis • Non-Hodgkin Lymphoma • Malignant Neoplasms of the Small Intestine IV. PREVENTION AND COUNSELING Vast majority of Gastric Cancers are attributed to environmental factors, the most common being infection with Helicobacter Pylori. This organism has been found in

almost 70% of the patients with Antral gastric cancer and is associated with nine fold increased risk of developing gastric cancer. Inoculation most likely occurs in childhood through the oro-fecal pathway and is transmitted from person to person. Intake of certain food contents is also thought to be contributory; preserved diets with high salt contents, smoked foods and diets with low fresh fruits and vegetable contents have also been attributed to the increased incidence of gastric cancer.

Smoking and prolonged consumption of alcohol have also been attributed to the increased occurrence of gastric cancer. Better living standard, better dietary habits, eradication of Helicobacter Pylori infection, giving up of smoking and alcohol consumption may decrease the occurrence of gastric cancer. 1-3% of gastric cancers are associated with inherited gastric cancer predisposition syndromes. E-cadherin mutations occur in approximately 25% of

families with an autosomal dominant predisposition to diffuse gastric cancers also called hereditary diffuse gastric cancer. This subset of persons may benefit from genetic counseling and prophylactic gastrectomy. 32

V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA a) Clinical Diagnosis Clinical diagnosis of Gastric Cancer, like all other diseases is based on astute history taking and thorough physical examination. There are no pathognomic symptoms of early gastric cancer; rather they are vague and non-specific often mimicking peptic ulcer disease. Commonest complaint is epigastric discomfort. Patient often present with Aneamia, weight loss (Aesthenia)

and loss of appetite (Anorexia), early satiety and rarely upper GI bleed. Physical examination of early gastric cancer is usually uninformative. In late stage they may present with palpable epigastric mass, cachexia, bowel obstruction, ascites and pedal oedema. In advance cancers peritoneal seedling may involve ovaries leading to Krukenberg tumor, pelvic cul-de-sac (Blumer’s shelf) palpable on digital rectal examination, left supra clavicular lymphadenopathy (Virchow node), left

anterior axillary lymphadenopathy (Irish’s node) or a periumbilical lymph node (Sister Mary Joseph node). b) Investigations Upper GI Endoscopy is the mainstay of diagnosis, accounting for > 90% of Gastric Cancer diagnosis. Typically gastric cancer appears as irregular ulcer with raised margins or a polypoidal or fungating mass lesion. Multiple, at least 6 or more biopsies are to be taken for the best yield. Barium UGI series is hardly required these days, though it may prove diagnostic in

patient with Linitis Plastica, who have undistensible stomach. Contrast Enhanced Computed Tomography (CECT), is required to stage the disease and evaluate the metastatic status. 33

Endoscopic Ultrasound (EUS) is used to asses the tumor depth and the adjacent lymphadenopathy. EUS guided FNAC of adjacent lymph nodes can also be performed. Staging laparoscopy is the latest addition to the investigation armamentarium for carcinoma stomach. PET scan is not routinely recommended to evaluate Gastric Cancer. Tumor Markers: There are no specific tumor markers for Gastric cancer hence their assessment is not routinely advocated. c) Treatment

Multi-disciplinary treatment planning is mandatory for a better outcome of this rather dismal disease. Patients with Gastric cancer should be managed by an experienced team of Surgeons, Onco-physicians, Gastroenterologist, Radiation- Oncologist. Nutrion Specialist and Onco –Nurses. Surgery remains the mainstay of treatment of gastric cancer. It is the only single modality treatment capable of curing the disease. The goal of surgical cure requires

complete resection (R0). The standard recommendations for respectable gastric cancer are free margin surgery (at least 5 cm clearance) with at least D1 lymph node dissection removing minimum of 15 lymph nodes. Type of Gastectomy depends upon tumor location and its extent and consists of partial ( ProximaL/ Distal) or Total Gastrectomy addition of Splenectomy and distal Pancreatectomy significantly increases post operative mortality without significant

Lymph Node Excision: Extent of lymph node dissection though an important issue, remains controversial. Results of D1 lymphadenectomy ( Perigastric nodes along the lesser and greater curvature) are comparable with D2 lymhadenectomy ( nodes along the coeliac trunk and its 3 branches), however more centres in even western world are now resorting to D2 gastrectomy for better post operative outcome. Laparoscopic Surgery For Gastric Cancer:

Laparoscopy –assisted distal gastectomy(LADG) first developed by Kitano et al in Japan in 1991, has now become the standard of care in Japan for respectable Gastric Cancer. Neo-Adjuvant/Adjuvant Therapy: Large number of randomized phase 3 studies have shown the efficacy of perioperative (pre & post operative) chemotherapy and post operative chemoradiotherapy in combination with R0 tumor resection and D1/D2 LN dissection. Early Gastric Cancer: Endoscopic Mucosal Resection (EMR), and Endoscopic Sub-

Mucosal dissection are the latest surgical option in the management of early gastric cancer (T1NoMo)., however such cancers are rarity in India and the western world. Advanced Gastric Cancer: In the treatment of advanced gastric Cancer (Unresectable, metastatic), surgery has no role except as palliative gastrojejunostomy for gastric Outlet Obstruction, control of bleeding or placement of feeding jejunostomy tube. Multi disciplinary team, so necessary for the successful management of patients

with Gastric Carcinoma, may not be available even in most of Indian Metro 35

Hospitals; their management at secondary Hospital/ Non-Metro situation is not advisable. Referral Criteria: All patients of gastric cancer, who are deemed respectable at secondary hospitals, must be referred to super-specialty facility for a better post therapy outcome; however patients with advanced disease requiring palliation or emergency surgery can be tackled at secondary hospitals only. VI. FURTHER READING/ REFERNCES 1) James McLoughlin, MD .Adenocarcinoma of the stomach: a review –

Baylor University Medical Centre Proceedings, Vol -17 (4), October 2004, 391- 399 2) Bryan J. Dicken,MD, David L. Bigam,MD, FRCS©, Carol Cass, I Mackey, MD, FRCS©, Anil A. Joy, MD, FRCS©, and Stewart M,FRCS(C) Gastric Adencarcinoma : Review and considerations for Future Directions- Ann Surg. 2005, January; 241(1):27-39 3) Farhat Aziz Khan, Aditya Nath Shukla .Pathogenesis and treatment of gastric carcinoma: “An update with brief review” –. J Cancer Res Ther; December 2006- Vol 2 (4), 196-199

4) Eric Van Cutsem, Cornelius Van de Velde, Arnaud Roth, Florian Lordick, Claus- Henning Kohne, Stefano Cascinu, Matti Aapro . Expert opinion on management of gastric and gastro-oesophegeal junction adenocarcinoma on behalf of the 36

European Organisation for Research and Treatment of Cancer (EORTC) – gastrointestinal cancer group -, European Journal of Cancer 44 (2008) 182-194 5) NCCN Clinical Practice Guidelines in Oncology : Gastric Cancer- V.2.2009 6) Keechalat Pavithran, Dinesh C.Doval and Kamal K. Pandey Gastric Cancer in India- Gastric Cancer. 2002;5(4):240-3. 7) Atul Sharma, Venkataraman Radhakrishnan. Gastric Cancer in India- Indian J of Med & Paediatr Oncol 2011; Vol 32: 12-16

8) Naro Shiraishi, Tsuyashi Etoh, Seigo Kitano. Laparoscopic Surgery in Gastric Cancer, Laparoscopic Gastrointestinal Surgery, ECAB Clinical Update: Surgical Gastroenterology and Liver Transplantation,113-129 9) Elwyn C Cabebe, MD, Vivek K Mehta, MD, George Fisher Jr, MD, Michael Perry, MD, MS, MACP, Francisco Talavera, PharmD, PhD, Benjamin Movsas, MD, Rajalaxmi McKenna, MD, FACP, Jules E Harris, MD: emedicine.medscape.com/article/278744-overview 37

Gallbladder carcinoma (GBC) requiring hospitalization Anil K Aggarwal Department of Surgical Gastroenterology and Liver Transplantation GB Pant Hospital New Delhi Introduction The gallbladder is a distensible pear-shaped structure located in a fossa on the undersurface of the right lobe of the liver. It is a storage reservoir that allows bile acids to be delivered in a high concentration and a controlled manner to the duodenum for the solubilization of dietary lipid.

Gallbladder has a storage capacity of approximately 30 to 50 mL in a normal adult. The portions of the gallbladder are the fundus, body, infundibulum, and neck. Case definition (for situation 1 and 2) (cid:216) The term Gallbladder carcinoma (GBC) refers to malignant tumor arising from epithelial lining of gallbladder. It is an aggressive tumor which can spread to adjacent organs, lymph nodes and metastasize to distant sites resulting in death if left untreated.

(cid:216) Incidental GBC - GBC that is not suspected before or at operation and even on gross examination of the opened gallbladder specimen by the surgeon, but is detected for the first time on histopathological examination (HPE) of a gallbladder removed for presumed (clinical, ultrasound, operative) diagnosis of gallstone disease (GSD). Incidence in our country (cid:216) GBC is more common in Northern and Eastern India compared to other regions.

(cid:216) Age standardized incidence rate in males ranged from 0.3 /1,00,000 men in low incidence areas to 5.3/1,00,000 men in high incidence areas. (cid:216) Age standardized incidence rate in females ranged from 0.4/1,00,000 in low incidence areas to 14.3/1,00,000 in high incidence areas. (cid:216) GBC is becoming one of the most common cancers among women in north and northeast India. Diagnosis Situation 1 Clinical : Clinical diagnosis is based on evaluation of symptoms and examination.

(cid:216) Right upper abdominal pain – colicky or continuous with or without radiation to shoulder or back (cid:216) Abdominal lump Symptoms due to adjacent organ involvement (cid:216) Jaundice (bile duct involvement) (cid:216) Vomiting (gastroduodenal involvement) (cid:216) Intestinal obstruction (colonic involvement) Constitutional symptoms (cid:216) Anorexia (cid:216) Weight loss Symptoms due to metastasis (cid:216) Bone pain (bone metastasis)

(cid:216) Abdominal distension (peritoneal dissemination with ascites) (cid:216) Dyspnoea (lung metastasis) Situation 2 Clinical : Same as in situation 1 Differential diagnosis Presentation with upper abdominal pain (cid:216) Cholelithiasis and cholecystitis (cid:216) Pancreatitis (cid:216) Peptic ulcer disease Presentation with jaundice (cid:216) Choledocholithiasis (CBD stones) (cid:216) Periampullary carcinoma (cid:216) Carcinoma head of pancreas Presentation with vomiting 39

(cid:216) Benign gastric outlet obstruction (peptic ulcer disease related) (cid:216) Carcinoma stomach (cid:216) Duodenal tuberculosis Presentation with abdominal lump (cid:216) Hepatocellular carcinoma (cid:216) Periampullary/carcinoma head of pancreas with palpable gallbladder (cid:216) Hydatid cyst (cid:216) Carcinoma hepatic flexure Management (situation 1) Investigations : Ultrasound abdomen: Features suggestive of GBC are (cid:216) Irregular /focal GB wall thickening

(cid:216) Large intraluminal polypoidal mass (cid:216) GB mass with liver infiltration. Treatment Situation 1 Out patient (cid:216) Patients with clinical findings suggestive of GBC should be evaluated with Ultrasound abdomen. (cid:216) If ultrasound findings are suggestive of GBC patient should be referred to tertiary centre with expertise in management of GBC. In patient (cid:216) Patients with clinical findings suggestive of GBC should be evaluated with Ultrasound abdomen.

(cid:216) If ultrasound findings are suggestive of GBC patient should be referred to tertiary centre with expertise in management of GBC Intra-op 40

Patient taken up for cholecystectomy for suspected gall stone disease (cid:224) Intraoperative findings suggestive of mass in gallbladder (cid:224) If no expertise in management (cid:224) it is preferable to refer the patient to tertiary centre with expertise in management of GBC instead of performing simple cholecystectomy Post-op (cid:216) All cholecystectomy specimens performed for gallstone disease should be sent for histopathological examination (HPE)

(cid:216) If HPE suggestive of GBC patient should be referred to tertiary centre with expertise in management of GBC Management (situation 2) Investigations For diagnosis and staging Ultrasound with Doppler abdomen : Doppler to assess vascular involvement Contrast enhanced computed tomography (CECT) abdomen or Magnetic resonance imaging (MRI) abdomen with Magnetic Resonance Cholangio Pancreatography (MRCP) (cid:216) Both CECT and MRI abdomen are more sensitive for diagnosis and staging compared to

ultrasound abdomen (cid:216) MRI preferred in patients with jaundice Whole body Positron emission tomography (PET) (cid:216) Not required in all patients (cid:216) In selected cases (locally advanced disease) with no evidence of metastasis on CECT/MRI abdomen to detect metastatic disease Upper GI endoscopy : In patients with suspected gastroduodenal involvement Tumor markers (CEA,CA 19-9, CA 125, CA 242) (cid:216) Not required for diagnosis (cid:216) Prognostic value (cid:216) Useful in follow up

Pathological diagnosis (image guided FNAC or biopsy) Not required in all patients 41

Required in selected cases (cid:216) Planned for neoadjuvant therapy in view of locally advanced disease (cid:216) Planned for palliative therapy in view of metastatic disease To assess fitness for surgery (cid:216) Hemogram (cid:216) Serum electrolytes (cid:216) Kidney function test (cid:216) Liver function test (cid:216) ECG (cid:216) Chest x-ray Treatment Outpatient (cid:216) Patients with clinical findings suggestive of GBC and fit for surgery should be evaluated with Ultrasound abdomen.

(cid:216) If ultrasound findings are suggestive of GBC further evaluation with CECT/MRI abdomen for diagnosis and staging. (cid:216) Early admission and surgical intervention should be advised In patient Staging laparoscopy should be preferably done in all patients prior to laparotomy T1b –T2 GBC (cid:216) Radical cholecystectomy is the standard treatment. (cid:216) Radcical cholecystectomy includes – liver resection with lymphadenectomy

(cid:216) Liver resection - cholecystectomy with 2cm wedge or anatomical segment IVb-V resection (cid:216) Lymphadenectomy – Extent of lymphadenectomy varies from clearance of only nodes along the hepatoduodenal ligament skeletonizing the vascular structures and the bile ducts to 42

additional clearance of nodes anterior and posterior to the head of the pancreas and the hepatic artery till its origin from the celiac axis. T3 GBC (cid:216) Radical cholecystectomy is the standard treatment. (cid:216) Extended right hepatectomy in patients with extensive liver infiltration T4 GBC (cid:216) Radical cholecystectomy with resection of adjacent involved organs if deemed resectable IGBC Completion radical cholecystectomy for all cases with stage T1b and above.

Contraindications for curative surgery (absolute and relative) (cid:216) Distant metastasis - liver metastasis and peritoneal deposits (cid:216) Vascular involvement (main portal vein, common hepatic artery) (cid:216) Extensive nodal disease or multiple adjacent organ involvement (cid:216) Extensive biliary involvement. Adjuvant chemoradiotherapy It can be considered in patients with (cid:216) Advanced stage disease (stage III and IV) (cid:216) Nodal positive disease

(cid:216) Non curative resection (R1 and R2 resection) Post-operative care (cid:216) Analgesics (cid:216) Antibiotics – duration depends upon postoperative course (cid:216) Intravenous fluid supplementation till oral feeds are started (cid:216) Wound care (cid:216) DVT prophylaxis in high risk patients 43

Complications (cid:216) Wound infection (cid:216) Chest infection (cid:216) Bleeding (cid:216) Bile leak (cid:216) Anastomotic leak in patients with resection of adjacent organs (cid:216) Liver failure following major hepatectomy Prevention Risk factors for GBC (cid:216) Female gender (cid:216) Increasing age (cid:216) Dietary factors (higher consumption of mustard oil contaminated with argemone oil, high cholesterol intake, intake of red meat, drinking water contaminated with pesticides)

(cid:216) Exposure to potential carcinogens (methylcholanthrene, aflatoxin B) (cid:216) Cholelithiasis and chronic cholecystitis (cid:216) Gallbladder polyps (cid:216) Choledochal cysts (cid:216) Anomalous pancreaticobiliary duct junction (cid:216) Genetic factors (p53 and K-ras mutations) Further reading/references 1. D’Angelica M, Dalal KM, DeMatteo RP, et al. Analysis of the extent of resection for adenocarcinoma of the gallbladder. Ann Surg Oncol. 2009;16(4): 806–816.

2. NCCN practice guide lines in Oncology 2011 3. Sikora SS, Singh RK. Surgical strategies in patients with gallbladder cancer: nihilism to optimism. J Surg Oncol. 2006 Jun 15;93(8):670-81. Review. 44

4. Nishio H, Ebata T, Yokoyama Y, Igami T, Sugawara G, Nagino M. Gallbladderm cancer involving the extrahepatic bile duct is worthy of resection. Ann Surg. 2011 May;253(5):953- 60. 5. Agarwal AK, Mandal S, Singh S, et al. Biliary obstruction in gall bladder cancer is not sine qua non of inoperability. Ann Surg Oncol. 2007;14(10):2831–2837. 6. Regimbeau JM, Fuks D, Bachellier P, Le Treut YP, Pruvot FR, Navarro F, Chiche L, Farges O.

Prognostic value of jaundice in patients with gallbladder cancer by the AFC-GBC-2009 study group. Eur J Surg Oncol. 2011 Jun;37(6):505-12. 7. Agarwal AK, Mandal S, Singh S, Sakhuja P, Puri S. Gallbladder cancer with duodenal infiltration: is it still resectable? J Gastrointest Surg. 2007 Dec;11(12):1722-7. 8. Hirano S, Tanaka E, Shichinohe T, Saitoh K, Takeuchi M, Senmaru N, Suzuki O, Kondo S. Feasibility of en-bloc wedge resection of the pancreas and/or the duodenum as an

alternative to pancreatoduodenectomy for advanced gallbladder cancer. J Hepatobiliary Pancreat Surg. 2007;14(2):149-54. 9. Mekeel KL, Hemming AW. Surgical management of gallbladder carcinoma: a review.J Gastrointest Surg. 2007 Sep;11(9):1188-93. Review. 10. Pilgrim C, Usatoff V, Evans PM. A review of the surgical strategies for the management of gallbladder carcinoma based on T stage and growth type of the tumour. Eur J Surg Oncol. 2009 Sep;35(9):903-7. Epub 2009 Mar 4. Review. 45

CARCINOMA RECTUM Ameet Kumar Peush Sahni Department of GI Surgery and Liver Transplantation All India Institute of Medical Sciences New Delhi I. WHEN TO SUSPECT/ RECOGNIZE? b) Introduction: Colorectal cancer is common in developed countries such as the USA and Japan, and lower in frequency in developing countries like Africa and Asia. The incidence is slightly higher in men than women, and is highest in African American men. Colon and rectal cancer is the third most

common cancer in both women and men in the US. Incidence rates range from 25.3 per 100,000 in Eastern Europe to 45.8 per 100,000 in Australia. The crude incidence of rectal cancer in the European Union is ∼35% of the total colorectal cancer incidence, i.e. 15–25/100 000 per year. The mortality is 4–10/100 000 per year with lower figures in women and the higher ones for men. Case definition: A patient with bleeding per rectum and/or tenesmus with or without change in bowel habit who

on rectal examination/proctoscopy or sigmoidoscopy is found to have a mass which on biopsy is a cancer. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY The incidence rates of colorectal cancers in India are low––about 2 to 8 per 100,000. The incidence of rectal cancer in India has been constant over the past few years. Hospital- and population-based data also show that the incidence rates for rectal cancer are higher than colon

cancer in all parts of India. However, a high incidence of these cancers is seen in the urban population. Data is limited. III. DIFFERENTIAL DIAGNOSIS a. Haemorrhoids b. Ulcerative colitis c. Solitary rectal ulcer d. Rectal prolapse e. Radiation proctitis IV. PREVENTION AND COUNSELING No specific intervention for primary prevention is known. However, the following dietary and lifestyle changes may play a role in prevention: physical activity, folate, fruits and vegetables, 46

calcium, vitamin D, high fiber diet, weight reduction, avoidance of red and processed meat, stopping smoking. For secondary prevention, 2 broad groups have been identified a. High risk individuals (those with a history of adenomas or cancers, family history or genetic syndrome, or inflammatory bowel disease) b. Average risk individuals (all others) Among the high risk groups: a colonoscopy 3 years after removal of an adenoma/polyp and if this is normal then after 5 years.

Previous Colorectal Cancer and Family History of Colorectal Cancer - The first surveillance colonoscopy at 1 year following cancer resection - If normal, the interval can be increased to 3 years. However, if additional disease is noted on postoperative colonoscopy, more frequent examinations are warranted. Patients with a family history of colorectal cancer or adenoma, including affected first-degree relatives - should undergo screening with colonoscopy beginning at 40 years of age or earlier, when

they are 10 years younger than their affected family member(s) were at age of initial diagnosis. Patients with long-standing IBD - In patients with pancolitis surveillance colonoscopy should begin after 8 years of symptoms. Surveillance can start later in those patients with left-sided colitis, generally after 12 to 15 years of disease. Colonoscopy should be performed every 1 to 2 years. Patients from FAP families who have not been tested for an APC mutation should begin routine

screening at puberty with annual flexible sigmoidoscopy. If polyps are not identified by age 40 years, then the frequency of examinations can be decreased to every 3 years. On the other hand, individuals who express the phenotype require upper endoscopy to examine the periampullary region. Patients with a known genetic mutation or members of an FAP kindred should undergo colectomy when they develop polyps, because stage-specific survival of colorectal cancer appears to

be the same for polyposis patients as for those who have sporadic bowel cancers. Colorectal screening for patients with HNPCC - endoscopy should thus be performed every 1 to 2 years. For individuals with known mutations or family history consistent with the Amsterdam Criteria, screening should begin at 21 years of age. Screening for extracolonic disease should be performed as well, including urine cytology, pelvic ultrasound, and periodic endometrial biopsy. a. Average risk individuals

Combination of fecal occult blood test (FOBT) with flexible sigmoidoscopy at 5-year intervals after the age of 50 years V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT AND REFERRAL CRITERIA 47

Diagnosis History: Rectal bleeding is the commonest symptom. Other symptoms include tenesmus, altered bowel habits and mucus discharge, weight loss and loss of appetite. Diagnosis: A digital rectal examination, proctoscopy and/or sigmoidoscopy with biopsy for histopathological examination. Tumours with distal extension to ≤15 cm (as measured by rigid sigmoidoscopy) from the anal margin are termed rectal tumours, while more proximal ones are called colonic.

Staging: Complete blood count, liver and renal function tests and a full colonoscopy to evaluate for synchronous lesions (present in up to 5% of colorectal cancers), rigid proctoscopy (to define the level of the tumour), abdominal CT and chest X-ray to evaluate for metastases, and baseline serum carcinoembryonic antigen (CEA) level. A PET-CT may be done to evaluate suspected extrahepatic metastasis. The depth of penetration can be estimated by digital rectal

exam (superficial tumours are mobile, whereas fixed lesions have deeper infiltration), and endorectal ultrasound (ERUS) or MRI with endorectal coil can provide a good assessment of the extent of invasion of the bowel wall. ERUS for early tumours (T1–T2) or rectal MRI for all tumours, including the earliest ones, is usually suggested prior to planning treatment and extent of surgery. Histopathological examination of the surgical specimen should assess the proximal, distal

and circumferential margins and regional lymph nodes (at least 12 lymph nodes should be examined). Also, vascular and neural invasion should be assessed. Treatment Localized disease Low anterior resection or abdominlperineal resection as required Advanced disease Locally advanced disease may require neoadjuvant therapy in an attempt to downstage the tumour and attempt sphincter preservation. Preoperative radiotherapy (short course or long course) may be used. Situation 1

At Secondary Hospital/Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited 48

Clinical diagnosis: In a patient who presents with bleeding per rectum, a thorough history and clinical examination should be undertaken especially in the elderly. A history of tenesmus, change in bowel habits, anorexia and weight loss should be asked as also a family history of colorectal cancer. Next, a rectal examination/proctoscopy and if necessary a sigmoidoscopic examination should be done and if found to have a mass, a punch biopsy should be done. If on pathology this shows a malignancy then

it confirms the diagnosis. Investigations Haemogram, liver function test, CEA levels, sigmoidoscopy, chest X-ray, CT abdomen and pelvis. Treatment All patients who have confirmed rectal cancer should have a surgical resection (anterior resection or abdomino-perineal resection). Neoadjuvant therapy if required for sphincter preservation may be used. Standard Operating procedure All investigations can be done as outpatient/day care procedures. However, if the general condition

of patient is not good, hospitalization may be needed. All surgical procedures require hospitalization. Referral criteria All patients with borderline resectability or where a low/ultralow anterior resection is required, or those with metastatic liver disease may benefit by referral to GI Surgery centres for complete evaluation and definitive management. Situation 2 At Super Specialty Facility in Metro location where higher-end technology is available Clinical Diagnosis: 49

Patients with rectal bleeding along with a suggestive history should be evaluated for colorectal cancer. All patients referred as cases of rectal cancer should have their diagnosis confirmed. Investigations: Review of all previous investigation including blocks and slides followed by colonoscopy to rule out synchronous lesions. Haemogram, liver function test, CEA levels, Sigmoidoscopy, chest X-ray, CT abdomen, MRI pelvis/ERUS, PET-CT. Treatment: Operable/potentially operable

Anterior resection or abdominoperineal resection Advanced disease If both primary and metastatic tumours are considered resectable, multidisciplinary teams should consider initial systemic treatment followed by surgery. If not resectable, consider palliative chemotherapy along with a palliative resection/diverting colostomy. Standard Operating procedure All investigations can be done as outpatient/day care procedures. However, if the general condition of patient is not good, hospitalization may be needed.

All surgical procedures require hospitalization. Referral criteria May require referral if neoadjuvant therapy is planned and if facilities for radiotherapy/chemotherapy are not available. 50

STANDARD TREATMENT GUIDELINES INTERVENTIONAL RADIOLOGY Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 BRONCHIAL ARTERY EMBOLIZATION IN MASSIVE HAEMOPTYSIS 4 2 Fallopian Tube Recanalization in Infertility Due to Proximal Tubal Obstruction 15 3 INTRACRANIAL ANEURYS 22 4 Extra Cranial Carotid Stenosis 30 5 Acute Cerebral Ischemic Stroke Due to a Major Vessel Occlusion 36 6 UTERINE FIBROID EMBOLISATION 42 7 Chemoembolization for unresectable hepatocellular carcinoma(HCC) 47 8 Radiofrequency Ablation (RFA) in Hepatocellular carcinoma and liver metastases 51

9 PERIPHERAL ARTERIAL DISEASE 54 10 RENOVASCULAR HYPERTENSION 63 11 VERTEBROPLASTY 71 2

Group Head Coordinator of Development Team Dr. Chander Mohan Dr. B.L. Kapur Hospital New Delhi 3

BRONCHIAL ARTERY EMBOLIZATION IN MASSIVE HAEMOPTYSIS I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Massive hemoptysis constitutes a significant and often life-threatening respiratory emergency and carries a poor prognosis when treated conservatively, with mortality rates ranging from 50% to 80% (1). The cause of death is usually asphyxiation, not exsanguination (2). Bronchial artery embolisation (BAE) as well as embolisation of a few

relevant systemic arteries have become the established procedure in the management of massive and recurrent haemoptysis since 1973 (3). The efficacy, safety, and utility of BAE in controlling massive hemoptysis have been well documented in many subsequent reports (4-11).Moreover, because of poor pulmonary reserve and other medical co-morbid conditions, most patients with massive hemoptysis are not surgical candidates (1,2) The

reported mortality rates for surgery performed for massive hemoptysis range from 7.1% to 18.2% (12). However, the mortality rate increases significantly, up to about 40%, when the surgery is undertaken as an emergency procedure (12).BAE is effective in an elective surgery(12). However, surgery is indicated in massive haemoptysis due to hydatid cyst, thoracic vascular injury, bronchial adenoma, and aspergilloma which are resistant to other therapies.

Case definition: For both situations of care (mentioned below*) Massive haemoptysis has been described as the expectoration of an amount of blood ranging from 100 ml to more than 1,000 ml over a period of 24 hours, and the most widely used criterion is the production of 300–600 ml per day (1,2,12,13). A life-threatening condition may be caused by even a rather small amount of hemorrhage depending on the ability of the patient to maintain a patent airway. Thus, interventional management should

be undertaken whenever the amount of hemorrhage has the potential to cause a life- threatening condition (13,14) II. INCIDENCE OF THE CONDITION IN OUR COUNTRY Pulmonary tuberculosis has been the commonest cause of haemoptysis in India for more than four decades (15). It had been shown to be present in 79.2% of haemoptysis cases in the year 2009 (16). 4

III. DIFFERENTIAL DIAGNOSIS After confirming the presence of blood, an initial task is to differentiate between haemoptysis, pseudo haemoptysis (i.e., the spitting of blood that does not come from the lungs or bronchial tubes), and haematemesis (i.e., the vomiting of blood). In the non-Western world, pulmonary tuberculosis and tubercular bronchiectasis, are the most common underlying causes of massive haemoptysis(17-20) whereas bronchogenic

carcinoma and chronic inflammatory lung diseases due to bronchiectasis, cystic fibrosis, or aspergillosis are the more prevalent causes of haemoptysis in Western countries (1,2,13). Other relatively common causes include lung abscess, pneumonia, chronic bronchitis, pulmonary interstitial fibrosis, pneumoconiosis, congenital cardiac or pulmonary vascular anomalies such as arterio-venous malformation, pulmonary embolism, elevated pulmonary venous pressure (mitral stenosis), systemic coagulopathy,

use of anticoagulants or thrombolytic agents IV. PREVENTION AND COUNSELING Since pulmonary tuberculosis, bronchiectasis and malignancy are common etiologic causes in our country, creating awareness about importance of their early detection and seeking early medical attention( for cough more than 3 weeks, unexplained fever, weight loss, chronic purulent sputum, haemotysis) at appropriate medical facility is an effective preventive strategy.

Proper counseling of the patient should be done by explaining various treatment options including non-surgical treatments such as bronchoscopy guided interventions and bronchial artery embolization and their outcome. The importance of cessation of smoking to reduce risk of haemoptysis due to chronic bronchitis should also be duly emphasized. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of

Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: After establishing true haemoptysis, the rate and volume of blood loss should be assessed. Historical evaluation must include important risk factors such as history of fever, weight loss, smoking, chronic obstructive pulmonary disease, exposure to asbestos, arsenic, chromium, nickel and certain ethers, anticoagulant use, heart disease, known malignancy

elsewhere in the body, nausea, vomiting, malena, alcoholism, chronic use of non steroidal anti-inflammatory drugs, history of chronic purulent sputum production and frequent pneumonias including past history of pulmonary tuberculosis. 5

Physical Examination General Physical examination: Recording of vital signs, pulse oximetry levels, fever, tachycardia, tachypnea, weight changes and hypoxia. Constitutional signs such as cachexia and level of patient distress, cyanosis, pallor, clubbing, ecchymoses, telangiectasia, gingivitis, evidence of bleeding from the oral or nasal mucosa, lymph node enlargement in neck, supraclavicular region, and axillae. Examination of chest and lungs for signs of consolidation, wheezing, rales and trauma.

Cardiovascular examination includes evaluation for jugular venous distention, abnormal heart sounds and edema. b) Investigations: Haematological & Biochemical Haemoglobin & haematocrit Total & differential blood count Platelet count Erythrocyte sedimentation rate Prothrombin time, International Normalized Ratio, partial thromboplastin time Blood group and cross-matching Sputum Gram stain, culture, acid-fast bacillus smear and culture Human immunodeficiency virus test Sputum cytology Arterial Blood gases

Imaging work up Chest radiograph Chest radiography may provide the diagnosis in only 50% of cases (19) and could demonstrate lesions which suggest either a localized pneumonia, acute or chronic pulmonary tuberculosis, healed tuberculosis, bronchogenic cancer or lung abscess (21). Chest computed tomography (CT) The role of CT in the evaluation of patients with hemoptysis has been validated (20,21). CT has proved to be of considerable value in diagnosing bronchiectasis,

bronchogenic carcinoma, and aspergilloma in patients with massive hemoptysis (19,22). CT may demonstrate lesions that may not be visible on conventional radiographs, and contrast material–enhanced CT may help detect vascular lesions that cause massive hemoptysis. CT findings can suggest a specific diagnosis in 50% of patients in whom CT can also help localize the site of bleeding in 63%–100% of patients with haemoptysis (14,18). c) Treatment: Standard Operating procedure a) In Patient- 6

The management of a patient with haemoptysis has three objectives – cessation of bleeding, prevention of aspiration and treatment of the underlying cause. As with any potentially serious condition, the initial approach would involve evaluation of the airway, breathing, and circulation (ABC). Massive haemoptysis warrants a more aggressive approach, sometimes requiring intensive care and early consultation with a pulmonologist. Reassurance and reduction of

anxiety are beneficial. In cases of massive or life threatening haemoptysis, diagnosis and therapy must occur simultaneously. Maintenance of the airway is vital because the primary mechanism of death is asphyxiation, not exsanguination (2). Other measures include -supplemental oxygen, fluid resuscitation, hypotensive agents in adults if significantly hypertensive, blood transfusion, correction of coagulopathy, if necessary and intravenous antibiotics.

b) Out Patient- This is not applicable as all patients with massive haemoptysis should be admitted c) Day Care- This is not applicable as all patients with massive haemoptysis should be admitted d) Referral criteria: If facilities for bronchial artery embolization or bronchoscopic intervention are not available, patient must referred to a hospital where these facilities are available. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available

a) Clinical Diagnosis: same as above b) Investigations: Multidetector CT is the investigation of choice for stable patients to show whether there are any hypertrophied bronchial arteries suitable for embolization and should be arranged as soon as possible after admission in a patient with massive haemoptysis. If hypertrophied bronchial arteries are (> 2mm in adults, significant chances are that these are responsible for haemoptysis. Multidetector CT allows rapid scanning, making timely

examination feasible in critically ill patients. In addition, hypertrophied non bronchial systemic feeder vessels can be detected which contribute to the recurrence of haemoptysis after successful embolization of bronchial arteries(23). CT versus Bronchoscopy 7

The overall diagnostic accuracy of fiberoptic bronchoscopy (FOB) in evaluating patients with haemoptysis is reported to be 10%–43% (18, 21).Bronchoscopy is unnecessary in patients with hemoptysis of known cause if the site of bleeding can be determined on conventional radiographs(21). Bronchoscopy may have disadvantage in massive, active haemoptysis as it is difficult to localize the bleeding site if there is excessive blood in the

bronchi. ronchial therapies are not effective in most cases of massive haemoptysis (13). Bronchoscopy guided interventions are not effective in most cases of massive haemoptysis (13). Other disadvantages of bronchoscopy include possible airway compromise due to sedation, delay in treatment, hypoxemia and extra cost. CT should be performed prior to bronchoscopy in all patients with haemoptysis (13,20,21,24). c) Treatment: Standard Operating procedure a.In Patient- Initial management. Nurse upright

Humidified Oxygen A review of the patient's previous medical records and value of the forced expiratory volume (FEV1) may help in determining the feasibility of surgery. The interventional radiologist and the thoracic surgeon should be informed about admission of patient with severe haemoptysis. Further management. Appropriate antibiotics IV Tranexamic Acid - 10mg/kg/td. Daily for 7 days if repeated bleeding occurs over a short period. If more than 100ml haemoptysis occurs on the third day, addition of

intravenous Terlipressin (2mg bolus, followed by 1mg to 2mg every 4-6 hours (for a maximum duration of 72 hours) to control bleeding may be considered. However, this should not to be used in pregnancy. Further investigations. Bronchoscopic interventions are rarely useful in the acutely bleeding patient. In massive haemoptysis, rigid bronchoscopy, though technically difficult, may sometimes allow clot removal (with the additional risk of precipitating further bleeding), temponade of bleeding

site using a Fogarty catheter or achieving haemostasis with thrombin glue or cold saline/ vasoconstrictor lavage. Selective bronchial angiography and embolisation 8

In unstable patients, bronchial artery and embolization may be performed following chest radiograph, haematological & coagulation profile and renal function tests. Rationale The source of massive haemoptysis is usually the bronchial circulation (90% of cases) rather than the pulmonary circulation (5%) (25,26). In a minority of cases (5%), massive haemoptysis may originate from non bronchial systemic arterial supply to the lungs

(27,28,29). In many acute and chronic lung diseases, the pulmonary circulation is reduced or occluded at the level of the pulmonary arterioles because of hypoxic vasoconstriction, intravascular thrombosis, and vasculitis (30). As a result, bronchial arteries proliferate and enlarge to replace the pulmonary circulation. The enlarged bronchial vessels, which exist in an area of active or chronic inflammation, may be ruptured due to erosion by a bacterial

agent or due to elevated regional blood pressure. The arterial blood under systemic arterial pressure subsequently extravasates into the respiratory tree, resulting in massive haemoptysis (30). Results Previous studies have shown that BAE is very effective in controlling acute massive haemoptysis with initial non-recurrence rates reported to be 73%–98% (5-11,33,34). Recurrence of bleeding may be caused by recanalization of embolized vessels,

incomplete embolization, revascularization by the collateral circulation, inadequate treatment of the underlying disease, progression of basic lung disease, or non bronchial systemic arterial supply (1,2,31,37).Recurrent bleeding is more common in patients with chronic tuberculosis, aspergilloma, or neoplasm. Long-term recurrence rates have been reported to be 10%–52% (1,2). However, the long- term success rate can be improved with repeat BAE. Haemoptysis may recur after

successful BAE if the disease process is not controlled with drug therapy or surgery because embolization treats the symptom but not the underlying disease. Complications Chest pain is the most common complication, with a reported prevalence of 24%–91% (10,35,36). Chest pain is likely related to an ischemic phenomenon caused by 9

embolization and is usually transient. Transient dysphagia due to embolization of esophageal branches may be seen sometimes with a prevalence of 0.7%–18.2% (10, 35). The most serious complication of BAE is spinal cord ischemia due to the inadvertent occlusion of spinal arteries. The prevalence of spinal cord ischemia after BAE is reported to be 1.4%–6.5% (11,32, 35, 37). The visualization of radicular branches on bronchial or intercostal angiograms is not an

absolute contraindication for BAE. However, when the anterior medullary artery (artery of Adamkiewicz) is visualized at angiography, embolization should not be performed. Other rare complications include aortic and bronchial necrosis, bronchoesophageal fistula, non–target organ embolization (eg, ischemic colitis), pulmonary infarction, referred pain to the ipsilateral forehead or orbit, and transient cortical blindness (38-43). Non bronchial Systemic Arterial Supply

Non bronchial systemic arteries can be a significant source of massive haemoptysis especially in patients with pleural involvement caused by an underlying disease. In the presence of pleural thickening, non bronchial systemic feeder vessels that originate from various arteries, for example, intercostal artery, branches of the subclavian and axillary arteries , internal mammary artery, inferior phrenic artery (2,8, 32.44) may develop along

the pleural surface and become enlarged as a result of the inflammatory process. Use of CT to predict the presence of non bronchial systemic vessels that supply a parenchymal lesion is important prior to BAE because it helps in localizing the site of bleeding and in selecting systemic vessels for the interventional approach. a. Out Patient- This is not applicable as all patients with massive haemoptysis should be admitted for management.

b. Day Care – This is not applicable as all patients with massive haemoptysis should be admitted for management. b) Referral criteria: In case, haemoptysis is not controlled, repeat embolization may be performed. However, in case of no significant clinical improvement, option of Surgery in the form of resection of diseased part of the lobe or lung may be considered by thoracic surgeon. VI. WHO DOES WHAT? and TIMELINES a. Doctor - Supportive management by physician/pulmonologist immediately

Bronchial Artery Embolization (BAE) by interventional radiologist as early as feasible 10

b. Nurse – Assisting during the procedure as well as before and after interventional treatment. a. Technician- Performing the CT scan and assisting in the BAE procedure. VII. FURTHER READING / REFERENCES 1. Najarian KE, Morris CS. Arterial embolization in the chest. J Thorac Imaging 1998;13:93-104 2. Marshall TJ, Jackson JE. Vascular intervention in the thorax: bronchial artery embolization for haemoptysis. Eur Radiol 1997; 7:1221-1227

3. Remy J, Voisin C, Ribet M, et al. Treatment, by embolization, of severe or repeated haemoptysis associated with systemic hypervascularization. Nouv Presse Med 1973; 2:2060-2068 4. Wholey MH, Chamorro HA, Rao G, Ford WB, Miller WH. Bronchial artery embolization for massive haemoptysis. JAMA 1976; 236:2501-2504 5. Remy J, Arnaud A, Fardou H, Giraud R, Voisin C. Treatment of haemoptysis by embolization of bronchial arteries. Radiology 1977; 122:30-32

6. Uflacker R, Kaemmerer A, Neves C, Picon PD. Management of massive haemoptysis by bronchial artery embolization. Radiology 1983; 146:627-634. 7. Uflacker R, Kaemmerer A, Picon PD, et al. Bronchial artery embolization in the management of haemoptysis: technical aspects and long-term results. Radiology 1985; 157:637-644 8. Keller FS, Rosch J, Loflin TG, Nath PH, McElvein RB. Nonbronchial systemic collateral arteries: significance in percutaneous embolotherapy for haemoptysis. Radiology 1987;164:687-692

9. Hayakawa K, Tanaka F, Torizuka T, et al. Bronchial artery embolization for haemoptysis: immediate and long-term results. Cardiovasc Intervent Radiol 1992; 15:154-159 10. Ramakantan R, Bandekar VG, Gandhi MS, Aulakh BG, Deshmukh HL. Massive haemoptysis due to pulmonary tuberculosis: control with bronchial artery embolization. Radiology1996;200:691-694 11. Mal H, Rullon I, Mellot F, et al. Immediate and long-term results of bronchial artery

embolization for life-threatening haemoptysis. Chest 1999; 115:996-1001 12. Fernando HC, Stein M, Benfield JR, Link DP. Role of bronchial artery embolization in the management of haemoptysis. Arch Surg 1998; 133:862-866 13. Jean-Baptiste E. Clinical assessment and management of massive haemoptysis. Crit Care Med 2000; 28:1642-1647 14. Hsiao EI, Kirsch CM, Kagawa FT, Wehner JH, Jensen WA, Baxter RB. Utility of fiberoptic bronchoscopy before bronchial artery embolization for massive haemoptysis.

Am J Roentgenol 2001; 177:861-867 15. Rao PU. Hemoptysis as a symptom in a chest clinic. Indian J Chest Dis. 1960;2:219 16. Rajendra Prasad, Rajiv Garg, Sanjay Singhal, and Piyush Srivastava. Lessons from 11

patients with haemoptysis attending a chest clinic in India. Ann Thorac Med. 2009;4(1): 10– 12 17. Ashraf O. Hemoptysis: A developing world perspective. BMC Pulmonary Med 2006;6:1 18. Abal AT, Nair PC, Cherjan J. Hemoptysis: Aetiology, evaluation and outcome. a prospective study in a third-world country. Respir Med. 2001;95:548–52 19. Hirshberg B, Biran I, Glazer M, Kramer MR. Hemoptysis: etiology, evaluation and outcome in a tertiary referral hospital. Chest 1997; 112:440-444

20. McGuinness G, Beacher JR, Harkin TJ, Garay SM, Rom WN, Naidich DP Hemoptysis: prospective high-resolution CT/bronchoscopic correlation. Chest 1994; 105:1155-1162 21. Tak S, Ahluwalia G, Sharma SK, Mukhopadhya S, Pande JN. Haemoptysis in patients with a normal chest radiograph: bronchoscopy-CT correlation. Australas Radiol 1999; 43:451-455 22. Millar AB, Boothroyd AE, Edwards D, et al. The role of computed tomography (CT) in the investigation of unexplained haemoptysis. Respir Med 1992; 86:34-38

23. Hidenori Mori, Yasushi Ohno, Yusuke Tsuge, Masanori Kawasaki, Fumitaka Ito, Junki Endo, Norihiko Funaguchi, Bu Lin Bai La, Masayuki Kanematsu, Shinya Minatoguch.Use of Multidetector Row CT to Evaluate the Need for Bronchial Arterial Embolization in haemoptysis Patients. Respiration 2010;80:21-28 24. Naidich DP, Harkin TJ. Airways and lung: correlation of CT with fiberoptic bronchoscopy. Radiology 1995; 197:1-12 25. Remy J, Remy-Jardin M, Voisin C. Endovascular management of bronchial bleeding. In:

Butler J, eds. The bronchial circulation. New York, NY: Dekker, 1992; 667-723 26. Woong Yoon, Jae Kyu Kim,Yun Hyun Kim,Tae Woong Chung, Heoung Keun Kang. Bronchial and Nonbronchial Systemic Artery Embolization for Life-threatening Hemoptysis: A Comprehensive Review. RadioGraphics 2002; 22: 1395-1409 27. MacIntosh EL, Parrott JCW, Unrhu HW. Fistulas between the aorta and tracheobronchial tree. Ann Thorac Surg 1991; 51:515-519 28. Hakanson E, Konstantinov IE, Fransson SG. Management of life-threatening

haemoptysis. Br J Anaesth 2001; 88:291-295 29. Pearse EO, Bryan AJ. Massive haemoptysis 27 years after surgery for coarctation of the aorta. J R Soc Med 2001; 94:640-641 30. Deffenbach ME, Charan NB, Lakshminarayan S, Butler J. The bronchial circulation: small, but a vital attribute to the lung. Am Rev Respir Dis 1987; 135:463-481 31. White RI, Jr. Bronchial artery embolotherapy for control of acute haemoptysis: analysis of outcome. Chest 1999; 115:912-915

32. Tanaka N, Yamakado K, Murashima S, et al. Superselective bronchial artery embolization for haemoptysis with a coaxial microcatheter system. J Vasc Intervent Radiol 1997; 8:65- 70 33. Hashimoto M, Heianna J, Okane K, Izumi J, Watarai J. Internal mammary artery embolization for haemoptysis. Acta Radiol 1999; 40:187-190 34. Kato A, Kudo S, Matsumoto K, et al. Bronchial artery embolization for haemoptysis due to benign diseases: immediate and long-term results. Cardiovasc Intervent Radiol 2000; 23:351-357.

35. Cremashi P, Nascimbene C, Vitulo P, et al. Therapeutic embolization of the bronchial artery: a successful treatment in 209 cases of relapse haemoptysis. Angiology 1993; 44:295-299 36. Cohen AM, Doershuk CF, Stern RC. Bronchial artery embolization to control haemoptysis in cystic fibrosis. Radiology 1990; 175:401-405 37. Tonkin ILD, Hanissian AS, Boulden TF, et al. Bronchial arteriography and embolotherapy for haemoptysis in patients with cystic fibrosis. Cardiovasc Intervent Radiol 1991; 14:241-246

38. Wong ML, Szkup P, Hopley MJ. Percutaneous embolotherapy for life-threatening haemoptysis. Chest 2002; 121:95-102 39. Girard P, Baldeyrou P, Lemoine G, Grunewald D. Left main stem bronchial artery stenosis complicating bronchial artery embolization. Chest 1990; 97:1246-1248 40. Munk PL, Morris C, Nelems B. Left main bronchial-esophageal fistula: a complication of bronchial artery embolization. Cardiovasc Intervent Radiol 1990; 13:95-97

41. Lemoigne F, Rampal P, Petersen R. Fatal ischemic colitis after bronchial embolization. Nouv Presse Med 1983; 12:2056-2057 42. Remy-Jardin M, Wattinne L, Remy J. Transcatheter occlusion of pulmonary arterial circulation and collateral supply: failures, incidents, and complications. Radiology 1991; 180:699-705 43. Ramankantan R, Ketkar M, Maddali K, Deshmukh H. Referred pain to the ipsilateral forehead and orbit: an unusual phenomenon during bronchial artery embolization.

Cardiovasc Intervent Radiol 1999; 22:275-277 44. Liu SF, Lee TY, Wong SL, Lai YF, Lin AS. Transient cortical blindness: a complication of bronchial artery embolization. Respir Med 1998; 92:983-986. 13

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 Physician -1 1. Routine blood 1. Local Pulse oxymeter/ Radiologists-1 examination anaesthetic & non invasive Anaesthetist -1 Hb, TLC, DLC , ESR sedatives monitor Radiographer etc. 2. Mist cough Crash cart

Technicians –2 2. Sputum for AFB, Linctus. containing Nurses – 2 malignant cells Oxygen cylinder laryngoscope and Orderly / Ward 3. Serum HIV with masks endotracheal tube Boy – 2 4. Renal function Capsules and tests Injection of 5. Blood sugar Tranexamic acid 6. Chest Radiograph 7. CT Chest Life saving drugs 2 Doctors – 2 same as above Same as mentioned Digital (Radiologists- 2. CT Angiography above Subtraction 2(at least one of chest Angiographic Angiography

interventional 3. BAE catheters, arterial equipment and radiologist) sheath, guide wires, Anaesthesia Anaesthetist -1 microcatheter, equipment Physician embolic material, (preferably puncture needles, pulmonologist)- X ray 1) Documentation- Technicians –2 films/CD/DVD Nurses – 2 Dressing material Orderly / Ward Boy – 2 14

Fallopian Tube Recanalization in Infertility Due to Proximal Tubal Obstruction VII. WHEN TO SUSPECT/ RECOGNIZE? Infertility is defined as the inability to conceive after 1 year of contraceptive-free intercourse. Since the reasons for infertility may be due to multiple factors, a systematic approach is required diagnosis and management. It may be due to factors relating to fallopian tubes in 30-40%, mucus hostile to sperms in 15-20% and factors relating to males in 40% (1). a) Introduction:

A large number of pathologic conditions can affect the proximal fallopian tube . Infection and subsequent inflammation or fibrosis is leading causes of proximal tubal obstruction. These are frequently consequent to chlamydial or gonococcal salpingitis or postpartum endometritis. About half of patients with bilateral proximal tubal obstruction (PTO)have very localized disease with no pelvic adhesions (2,3), making them ideal candidates for an attempt at tubal catheterization for

establishing patency. Moreover, PTO often occurs because of the accumulation of mucus or debris, which forms an impacted plug in the interstitial or proximal isthmic portion of the tube . fallopian tube recanalization (FTR) is a minimally invasive procedure used to recanalize blocked fallopian tubes in patients with a history of infertility and confirmed proximal tubal obstruction. b) Case definition: For both situations of care (mentioned below*)

Proximal tubal obstruction is defined as obstruction in either the intramural segment or the uterotubal junction, diagnosed as cornual block on hysterosalpingogram with normal fallopian tubes on , hysterocoposy or laparoscopy during work up of female infertility. INCIDENCE OF THE CONDITION IN OUR COUNTRY The exact incidence of female infertility due to proximal tubal disease in our country is not known. The incidence in United states has been reported to be 15-20%.In India, proximal tubal

obstruction due to tubal spasm or transient occlusion by mucus plugs or debris has been reported in 10-40% of women in 2009(4,5). DIFFERENTIAL DIAGNOSIS Proximal, distal and peritubal damage can be caused by a number of disease processes, such as inflammation, endometriosis and surgical trauma . Bacteriological examination of tubal fluid detects pathologic micro flora in the oviducts of 36.6% women with PTO. Most common cause

of fallopian tube obstruction is infection such as pelvic inflammatory disease (PID). The tubal infertility has been reported to be around 12% after one, 23% after two, and 53% after three episodes of PID (6). Inflammatory etiology seems to be important in isthmic tubal occlusion, especially due to chlamydial infection which causes muscular hypertrophy leading to salpingitis isthmica nodosa. Other factors such as uterine curettage, pelvic inflammatory disease,

endometritis, infections after childbirth or abortions and intraabdominal infections including appendicitis and peritonitis and intrauterine devices may all influence PTO infertility . 15

VIII. PREVENTION AND COUNSELING (a) Awareness about sexually transmitted infections and its early treatment. Since tubal infertility may be the consequence of chronic pelvic inflammatory disease (PID), which can lead to tubal scarring. The latter can be prevented by early detection and treatment of sexually transmitted infections particularly Chlamydia infection (7). (b) Avoidance of tobacco , smoking and obesity. These lifestyle factors can cause fertility

impairment during the reproductive years (8). Tobacco products not only cause infertility but also interfere with its treatment (8). Hence tobacco screening and cessation is an important component of infertility care (9). Obesity may be associated with ovulatory and menstrual dysfunction and subsequent infertility, increased risk of miscarriage, and decreased effectiveness of Assisted Reproductive Therapy (10). (c) Regular treatment. Proper & regular of the metabolic disorder associated with the polycystic

ovary syndrome due to the link between overeating, insulin resistance, and the endocrine changes that reduce fertility in women with polycystic ovary syndrome (11). (d) Avoidance of excessive and repeated exposure to radiation (e) Proper diet and exercise. Optimal reproductive functioning requires both proper diet and appropriate levels of exercise. Women who are significantly overweight or underweight may have difficulty in becoming pregnant.

(f) Assisted reproductive therapy (ART)- In cases, where tubal recanalization is not possible in spite of various techniques, couples should be advised for Assisted reproductive therapy (ART) IX. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: Women with unilateral or bilateral proximal tube obstruction confirmed

by hysterosalpingography (HSG) or laparoscopy are candidates for fallopian tube recanalization. Proper historical evaluation, general physical and gynaecological examination and exclusion of infective etiology should precede (HSG) b) Investigations: Sonography Sonography should be performed for evaluation of uterus and adnexae to exclude uterine abnormalities, hydrosalpinx, polycystic ovaries, endometriosis and fluid in Pouch of Douglas. Hysterosalpingography (HSG)

Hysterosalpingography (HSG) should be performed to demonstrate endometrial cavity, uterine abnormalities, fallopian tubes with peritoneal spill, level of blockage(proximal, mid or distal) in case of blocked fallopian tubes, presence or absence of hydrosalpinx. About 10% of patients with apparent bilateral blocked fallopian tubes on HSG become pregnant without further therapy 16

and may demonstrate patent tubes on repeat HSG. However, HSG is contraindicated in acute pelvic inflammatory disease, active uterine bleeding, recent curettage and intrauterine adhesions. Diagnostic criteria of PTO Hysterosalpingography shows persistent unilateral or bilateral tubal occlusion in spite of administration of anticholinergic drugs or spasmolytics. c) Treatment: Standard Operating procedure a. In Patient- This is not applicable as admission is not required for these investigations

b. Out Patient- Sonography and HSG are performed as OPD procedures c. Day Care – This is not applicable as admission is not required for these investigations d) Referral criteria: Infertile women with detection of persistent unilateral or bilateral proximal tubal obstruction within the first 0-4 cm of the fallopian tube on HSG should be referred to a tertiary care centre having interventional and Assisted Reproductive Treatment (ART) facility.

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available c) Clinical Diagnosis: Women with unilateral or bilateral proximal tube obstruction confirmed by hysterosalpingography (HSG) or laparoscopy are candidates for fallopian tube recanalization. Proper historical evaluation, general physical and gynaecological examination and exclusion of infective etiology should precede (HSG) d) Investigations: Hysterosalpingography (HSG)

A repeat study may be performed if not performed earlier or earlier study was not satisfactory. Hysteroscopy or Laparoscopy Hysteroscopy or laparoscopy can be considered depending on the availability and local expertise in the referred tertiary centre. Combined Hysteroscopy and Laparoscopy Procedure Patients with previous history of pelvic inflammatory disease, proximal tubal obstruction may be evaluated by combined hysteroscopy & laparoscopy especially if laparoscopy had

not been performed previously. Moreover in patients with uterine mass, hystroscopically guided removal may be preferred over fallopian tube recanalization 17

e) Treatment: Fallopian catheterization The procedure may be best carried out with use of fluoroscopic guidance if patient has had prior laparoscopy that showed either no or minimal pelvic disease. Small tapered catheters and wires can be easily advanced fluoroscopically if the obstruction is in the isthmic part of the tube, 3-5 cm from the tubal ostium. Diagnostic Selective Salpingography and Therapeutic fallopian Tube Recanalization

It should be performed in case of non filling of fallopian tubes to differentiate technically inadequate hysterosalpingography or spasm from true obstruction or tubal disorder such as salpingitis isthmica nodosa (SIN).The other indications include discordance between HSG and laparoscopy, prior to recanalization of PTO and persistent hypofertility after surgical tubocornual anastomosis. Tubal cannulation can be used effectively to restore tubal patency in sub fertility due to

isolated PTO, thus helps to avoid expensive assisted reproductive techniques. Tubal cannulation also eliminates or postpone the need for laparoscopic or hysteroscopic interventions by identifying patients with proximal and distal occlusion (bipolar tubal occlusion) and differentiating between true and false diagnoses of PTO.This procedure is reported to be successful in 62%–90% of patients. Recanalization is possible but potentially less successful in women who have occluded tubes

after surgical anastomosis for reversal of tubal ligation. The success rates depend upon postoperative scarring at the anastomosis and range from 44% (12) to 77% (13). In patients with fallopian tube occlusion related to salpingitis isthmica nodosa, recanalization is successful in 77%–82% of tubes (14, 15). The average pregnancy rates are reported to be about 30% following the procedure (16-19). Alternative Therapies Alternative therapies such as microsurgical tubocornual anastomosis, hysteroscopic tube

cannulation or falloscopic tube cannulation and in vitro fertilization should be reserved for failed fluoroscopic transcervical fallopian tube recanalization. Standard Operating procedure a. In Patient- This is not applicable as fallopian tube recanalization procedure is carried out as day care procedure. 18

b. Out Patient- Follow up in OPD c. Day Care- Fluoroscopic transcervical procedure is carried out as day care procedure f) Referral criteria: Not applicable X. WHO DOES WHAT? and TIMELINES a. Doctor- mentioned below b. Nurse- -do- c. Technician- - do- Designation Responsibility Gynaecologist Clinical Evaluation & diagnostic work up Diagnostic Radiologist Perform Sonography, HSG , MRI(if required) Gynaecologist trained in Performs laparoscopy or laparoscopy & hysteroscopy or both hysteroscopy

Interventional IR Procedures –Diagnostic selective Radiologist salpingography and fluoroscopic transcervical fallopian tube recanalization Nursing Staff Assist in managing the patient RadiographerTechnician Assist in imaging of patient and during interventional procedure Lab Technician Haematological & biochemical (Haematologist & evaluation Biochemist) XI. FURTHER READING / REFERENCES 1. Laven JSE, Velde ER, Haans LCF, Wensing CJG, Mali WPTM, Eimers JM. Effects of

varicocele treatment in adolescents: a randomized study. Fertil Steril 1992; 58: 758-762 2. Wilshire G, Bohrer M, Blomer M. Bilateral corneal tubal occlusion is not associated with an increased risk of distal tubal pathology. Presented at the American Fertility Society annual meeting, New Orleans, November 1992. 19

3. Thurmond AS, Rosch], Parton PE, et al. Fluoroscopic transcervical fallopian tube catheterization for diagnosis and treatment of female infertility caused by tubal obstruction. Radiographies 1988;8, 621-640. 4. Bhattacharya S, Logan S: Evidence-based management of tubal factor infertility. In: The Fallopian Tube. Allahbadia GN, Djahanbakhch O, Saridogan E (Eds). Anshan Publishers, UK 215–223 (2009) 5. Allahbadia GN, Naik P, Allahbadia SG: Should tactile-guided trans-uterine cannulation always

be the first line treatment for all proximal tubal blocks or are there exceptions? In: The Fallopian Tube. Allahbadia GN, Djahanbakhch O, Saridogan E (Eds). Anshan Publishers, UK 236–245 (2009 6. Yen SSC, Jaffe RB, Barbieri RL. Reproductive Endocrinology, 4th Ed.. W. B. Saunders Co, 1999 7. Scholes D, Stergachis A, Heidrich FE, Andrilla H, Holmes KK, Stamm WE. Prevention of pelvic inflammatory disease by screening for cervical chlamydial infection. N Engl J Med 1996; 334: 1362–6.

8. Augood C, Duckitt K, Templeton AA. Smoking and female infertility: a systematic review and meta-analysis. Hum Reprod 1998;13: 1532–9. 9. American Society for Reproductive Medicine. Smoking and infertility. Fertil Steril 2006; 86:S172–7 10. Pasquali R, Patton L, Gambineri A. Obesity and infertility. Curr Opin Endocrinol Diabetes Obes 2007;14: 482–7. 11. Nestler JE, Clore JN, Blackard WG. The central role of obesity (hyperinsulinemia) in the

pathogenesis of the polycystic ovary syndrome. Am J Obstet Gynecol 1989;161: 1095–7. 12. Millward SF, Claman P, Leader A, Spence JE. Technical report: fallopian tube recanalizationa simplified technique. Clin Radiol 1994; 49:496-497 13. Thurmond AS, Brandt KA, Gorrill MJ. Tubal obstruction after ligation reversal: results of catheter recanalization. Radiology 1999; 210:747-780 14. Houston JG, Machan LS. Salpingitis isthmica nodosa: technical success and outcome of

fluoroscopic transcervical fallopian tube recanalization. Cardiovasc Interv Radiol 1998; 21:31-35 15. Thurmond AS, Burry K, Novy MJ. Salpingitis isthmica nodosa: results of transcervical fluoroscopic catheter recanalization. Fertil Steril 1995; 63:715-722. 16. Confino E, Friberg J, Gleicher N. Preliminary experience with transcervical balloon tuboplasty. Am J Obstet Gynecol 1988; 59:370-375 17. Maubon A, Rouanet JP, Cover S, Courtieu C, Mares P, Lopez FM. Fallopian tube

recanalization by selective salpingography: an alternative to more invasive techniques? Hum Reprod 1992; 7:1425-1438 18. Thurmond AS, Rosch J. Nonsurgical fallopian tube recanalization for treatment of infertility. Radiology 1990; 174:371-374 19. Woolcott R, Petchpud A, O'Donnel P, Stanger J. Differential impact on pregnancy rate of selective salpingography, tubal catheterization, and wire-guide recanalization in the treatment of proximal fallopian tube obstruction. Hum Reprod 1995; 10:1423-1426 20

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) SITUAT HUMAN INVESTIGATI DRUGS & EQUIPMENT(S) ION RESOURCES ONS CONSUMABLES 1. Doctors – Hemoglobin, 1. Drugs: Injection Color Doppler Gynaecologist – 1, Random Blood Buscopan, Atropine Ultrasound (1) Diagnostic Radiologist -1 Sugar, total & Diazepam/ X ray machine with

X ray Technicians –1, differential blood Midazolam image intensifier (1) Lab technician -1 count, platelet Doxycycline Vaginal speculum, Nurses - 2 count, ESR , capsules, introducer HIV, urine Non ionic catheter/canula for analysis, vaginal radiographic contrast, HSG smear, chest radiograph, 2. Gynaecologist trained in Hemoglobin, Drugs: Injection Color Doppler laparoscopy & Random Blood Buscopan, Atropine Ultrasound (1) hysteroscopy-1 Sugar, total & Diazepam/ X ray machine with

Interventional radiologist differential blood Midazolam image intensifier (1) -1 count, platelet Doxycycline Vaginal speculum, X ray Technicians – 1 count, ESR , capsules, introducer catheter/ Lab technician -1 HIV, urine Recanalization set canula for HSG Nurses - 2 analysis, vaginal (Cook) or smear, Chest 5 French and 3 radiograph, French catheters. 0.018 inch and 0.035 inch hydrophilic guidewire Non ionic radiographic contrast, 21

INTRACRANIAL ANEURYSM When to suspect or recognize? Intracranial aneurysms are focal outpouching from intracranial arteries with weak walls as compared to normal arteries and therefore have propensity to present with intracranial bleed, usually subarachnoid hemorrhage (SAH). Clinically, these cases present with sudden severe headache (‘thunderclap headache’) in case of bleed (1-6). Occasionally, these lesions may grow

to significant size without bleeding and manifest clinically because of compression of adjoining brain parenchyma or cranial nerves (2-4). a) Introduction The word aneurysm comes from the Latin word ‘aneurysma’, which means dilatation. Aneurysm is an abnormal focal dilatation in the wall of a blood vessel, usually an artery, due to a defect, disease, or injury (5,6). Aneurysms can be true or false. A false aneurysm is a cavity lined by blood clot. The 3 major

types of intracranial aneurysms are saccular, fusiform, and dissecting (1,6). b) Case definition Any patient presenting with or suspected to have non traumatic subarachnoid hemorrhage (SAH) or uncommonly, focal neurological deficit with demonstration of aneurysm on Imaging should be suspected of harboring an aneurysm (3-6). I. Incidence of the condition in our country It is underdiagnosed, undertreated, and much more common than previously thought. Incidence

of the condition in our country is not exactly known due to lack of organized data. International literature suggests incidence between 1-6% in general population. Differential Diagnosis Clinically, other causes of ‘thunderclap headache’ merit consideration (1-6). These include cerebral venous thrombosis, cervical dissection, migraine, pituitary bleed, reversible cerebral vasoconstriction (Call Flemming syndrome). Radiologically, other causes of subarachnoid

hemorrhage need consideration which are trauma, brain arteriovenous malformations (AVMs), bleeding disorders and other rare causes. II. Prevention and Counselling At this time, a routine screening test to discover brain may not be required without clinical symptoms. However, certain modifiable risk factors as follows should be adequately controlled to prevent bleed: i. Cigarette smoking – increases the risk of an aneurysm rupture. Smokers are three times more likely to have an SAH than non-smokers. 22

ii. Alcohol & drugs use - It is unclear if alcohol use increases the risk of developing an aneurysm, but moderate to heavy drinking is considered a risk factor for the rupture of an aneurysm if present. Similarly, drug use, particularly cocaine, may increase the risk of rupture. iii. High Blood Pressure – several studies found that having high blood pressure increases the risk for developing an aneurysm and for rupture of existing aneurysms (7).

III. Optimal Diagnostic Criteria, Investigations, Treatment & Referral Criteria - Diagnostic Criteria Aneurysm should be considered in the following clinical setting (1,5,6) : i) Sudden severe headache (‘thunderclap headache’) in the absence of obvious head injury ii) Presence of SAH on imaging (CT/MRI) iii) Demonstration of aneurysm on imaging during evaluation for any neurologic problem. Investigations i) CT Scan CT scan should be sought on any patient with non-traumatic SAH. Large Aneurysms or their wall

calcification may also be at times seen on NCCT. ii) CT Angiogram (CTA) Conventional angiography like images of the cerebral vasculature can be obtained using rapid contrast infusion and thin-section dynamic CT scanning (CTA). Various 3-dimensional display techniques, including shaded surface display, volume rendering, and maximum intensity projection, are used to complement the conventional transaxial images. It has very high diagnostic accuracy with sensitivity and specificity of >95% (8-10).

iii) MR Angiogram (MRA) MRA should be usually performed only if there is some contraindication to CTA or CT cannot be easily performed. The sensitivity and specificity is lower as compared to CTA (11). iv) Digital Subtraction Angiogram (DSA) It remains the gold standard for diagnosis, particularly in delineating small aneurysms. DSA is usually always required in case any endovascular or surgical treatment is planned (6,8). Treatment Two major strategies for treatment are:

(1) To closely follow up in case of incidentally detected asymptomatic aneurysms by clinical and radiological re assessment periodically. (2) In symptomatic group, treatment options include endovascular coiling of the sac or surgical clipping of the aneurysm neck Referral Criteria 23

*Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited: 1. Clinical diagnosis I. Subarachnoid hemorrhage: The most common presentation of intracranial aneurysm is subarachnoid hemorrhage (SAH) in non traumatic background. On presentation, patients typically report experiencing the worst headache of their lives (thunderclap headache). The association of meningeal signs should increase suspicion of SAH.

II. Mass effect: The so-called giant aneurysms (diameter >2.5 cm) are more often symptomatic because of their mass effect. Some intracranial aneurysms produce cranial neuropathies. A common example is the third nerve palsy that is secondary to posterior communicating artery aneurysm or III/IV/VI nerve palsy seen in giant cavernous ICA aneurysms. Rarely, even visual loss caused by an ophthalmic artery aneurysm that compresses the optic nerve has been reported.

III. Other symptoms: Other, less common, symptoms include seizures, headaches, and transient ischemic attacks or cerebral infarction secondary to emboli (usually associated with large or giant partially thrombosed aneurysms). Severe vasospasm associated with SAH is often the leading cause of death. 2. Investigations i) CT – to confirm SAH or to look for diagnostic possibility of aneurysm as a cause for focal neurologic deficit

ii) CTA/MRA – if available, to confirm the diagnosis before referring to higher center. 3. Treatment Based on the available literature, the management of aneurysm differs in ruptured and unruptured patients (1, 5,6, 12,13). Ruptured aneurysms should be treated urgently (within 72 h of hemorrhage) to prevent rebleeding and to permit aggressive Management of vasospasm. Unruptured aneurysms are generally treated electively and may even be followed up if small (<7mm) and incidentally detected.

i) Initial management for Ruptured Aneurysms : a. Administer calcium channel blockers (nimodipine for 21 d) to all patients; this has been shown to improve outcome (6,14). b. Anticonvulsant use is controversial, but is generally given (levetiracetam or phenytoin), particularly for patients undergoing craniotomy or those with focal cerebral hematomas in addition to the SAH. ii) Ventricular drainage: Blood in the subarachnoid space obliterates the arachnoidal villi /

ventricular foramina, causing acute hydrocephalus. In life threatening state, a ventriculostomy catheter should be emergently placed (6). 24

iii) Definite Management: Endovascular coiling or Surgical Clipping - To be done at higher center with expertise and infrastructure. i. Referral criteria A diagnosed or suspected case of aneurysm which warrants urgent or early intervention due to presentation (SAH or neurological deficits) should be referred to tertiary care center with facilities for endovascular treatment or neurosurgery as early as possible. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is

available b. Case Definition (tertiary care) 1. Clinical diagnosis: i) Subarachnoid hemorrhage: The most common presentation of intracranial aneurysm is subarachnoid hemorrhage (SAH) in non traumatic background. On presentation, patients typically report experiencing the worst headache of their lives (thunderclap headache). The association of meningeal signs should increase suspicion of SAH. ii) Mass effect: The so-called giant aneurysms (diameter >2.5 cm) are more often

symptomatic because of their mass effect. Some intracranial aneurysms produce cranial neuropathies. A common example is the third nerve palsy that is secondary to posterior communicating artery aneurysm or III/IV/VI nerve palsy seen in giant cavernous ICA aneurysms. Rarely, even visual loss caused by an ophthalmic artery aneurysm that compresses the optic nerve has been reported. iii) Other symptoms: Other, less common, symptoms include seizures, headaches, and

transient ischemic attacks or cerebral infarction secondary to emboli (usually associated with large or giant partially thrombosed aneurysms). Severe vasospasm associated with SAH is often the leading cause of death. 2. Investigations: i) CT Scan - to confirm SAH or to look for diagnostic possibility of aneurysm as a cause for focal neurologic deficit Large Aneurysms or their wall calcification may also be at times seen on NCCT.

ii) CT Angiogram (CTA) – Angiography like images of the cerebral vasculature can be obtained using rapid contrast infusion and thin-section dynamic CT scanning (CTA). Various 3- dimensional display techniques, including shaded surface display, volume rendering, and maximal intensity projection, are used to complement the conventional transaxial images (8-10). iii) MR Angiogram (MRA)- MRA should be usually performed only if there is some contraindication to CTA or CT cannot be easily performed (6,11). 25

iv) Digital Subtraction Angiogram (DSA)- It remains the gold standard for diagnosis, particularly small aneurysms. DSA is usually always required in case any endovascular or surgical treatment is planned (1,5,6). 3. Treatment i) Initial treatment and evaluation: As outlined above. If not already started, supportive treatment should be started immediately. ii) Definite Management: Endovascular coiling or Surgical Clipping

Obliteration of an aneurysm can be done by either putting metallic (usually titanium) clips at the aneurysm neck (‘clipping’) or by packing the aneurysm sac from inside by using platinum coils (‘coiling’) through endovascular (transarterial) route. While clipping is a major surgical procedure, coiling is a minimally invasive technique and therefore appears more attractive. However, the choice of procedure depends on various other factors and needs to be decided

carefully. Recent evidence suggests that coiling is highly effective and in certain conditions (eg posterior circulation aneurysms) much more favored option (13,17-20). ii. Referral criteria A diagnosed or suspected case of aneurysm which warrants urgent or early intervention due to presentation (SAH or neurodeficts) should be refered to tertiary care center with facilities for endovascular treatment or neurosurgery. Who does what? And Timelines Designation Clinical Role Timeline

Physician (Internist) Clinical Evaluation Screening on presentation to OP General Surgeon (GS) Clinical Evaluation & supervising Specialist Consultant who vascular evaluation becomes the primary care Physician once diagnosis is established Performs Vascular Surgery When indicated or when IR procedures fail. Biochemist Biochemical evaluation After evaluation by and on the request of GS Diagnostic Radiologist Evaluate NCCT, CTA or MRA After evaluation by and on the request of GS

Neurosurgeon Neurologic evaluation After consultation by and on the request of GS Management of SAH and surgical If necessary, following GS clipping consult and on the request of GS Interventional IR Procedures – Endovascular coiling, Referring Specialist for IR 26

Radiologist parent artery occlusion if safe, procedures on the request of endovascular bypass device (flow GS/ NS diverters) Nursing Staff Assist in managing the patient In-patient or Day Care in Vascular Surgery facility, Dialysis facility and Interventional Radiology facility Technician Assist in Imaging the patient In CT,MR and Interventional Radiology facility after Radiology & IR consultation RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS)

(Units to be specified for human resources, investigations, drugs & consumables and equipment. Quantity to also be specified) SITUATI HUMAN INVESTIGATIONS DRUGS & EQUIPMENT(S) ON RESOURCES CONSUMABLES 1. Doctors – Hemoglobin, 1. Drugs: MDCT or MRI with (Internist – 1, Random Blood Nimodipine, Heparin facility for Vascular General Surgeon – 1, Sugar, PT, APTT Imaging Diagnostic Radiologist or INR, Platelet -1, Count, Se. Technician(s) – 3, Creatinine, Nursing - 2 HBsAg, HIV

2. Doctors – Hemoglobin, 1. Drugs: Vascular Doppler(1) (Internist – 1, Random Blood Nimodipine, Heparin, Operation Theatre Vascular Surgeon with Sugar, PT, APTT Non Ionic (1) – 1, Diagnostic or INR, Platelet radiographic contrast Radiologist -1, Count, Se. media Color Doppler Interventional Creatinine, 2. Consumables: Ultrasound (1) Radiologist – 1, HBsAg, HIV Arterial access device, Anaesthetist -1) Diagnostic Catheter, MDCT or MRI with Technician(s) – 3 to 4 Guiding catheter, Vascular Imaging (1)

Nurses – 3 to 4 for all balloon or self the units expanding Stent, Digital Subtraction GDC platinum coils Angiography System (1) Sterile Suite Multichannel 27

invasive monitor (1) Resuscitation equipment (1) Crash Trolley (1) References: 1. Biousse V, Newman NJ. Aneurysms and subarachnoid hemorrhage. Neurosurg Clin N Am. Oct 1999;10(4):631-51. 2. Juvela S, Porras M, Poussa K. Natural history of unruptured intracranial aneurysms: probability of and risk factors for aneurysm rupture. J Neurosurg. Sep 2000;93(3):379-87. 3. Juvela S, Porras M, Heiskanen O. Natural history of unruptured intracranial aneurysms: a

long-term follow-up study. J Neurosurg. Aug 1993;79(2):174-82. 4. Juvela S, Porras M, Poussa K. Natural history of unruptured intracranial aneurysms: probability and risk factors for aneurysm rupture. Neurosurg Focus. 2000;8(5):Preview 1. 5. Goldman. Cecil Textbook of Medicine. ed. Philadelphia, Pa: W B Saunders Co; 1999. 6. Greenberg MS. Handbook of Neurosurgery. 4th ed. Lakeland, Fl: Theme Medical Pub; 1997 7. Inci S, Spetzler RF. Intracranial aneurysms and arterial hypertension: a review and

hypothesis. Surg Neurol. Jun 2000;53(6):530-40; discussion 540-2. 8. Anderson GB, Steinke DE, Petruk KC, et al. Computed tomographic angiography versus digital subtraction angiography for the diagnosis and early treatment of ruptured intracranial aneurysms. Neurosurgery. Dec 1999;45(6):1315-20; discussion 1320-2. 9. Sahel M, Ourrad E, Zouaoui A, et al. [3D-CT angiography with volume rendering technique in the intracerebral aneurysms]. J Radiol. Feb 2000;81(2):127-32.

10. Velthuis BK, Van Leeuwen MS, Witkamp TD, et al. Computerized tomography angiography in patients with subarachnoid hemorrhage: from aneurysm detection to treatment without conventional angiography. J Neurosurg. Nov 1999;91(5):761-7. 11. Bendel P, Koivisto T, Könönen M, Hänninen T, Hurskainen H, Saari T, et al. MR imaging of the brain 1 year after aneurysmal subarachnoid hemorrhage: randomized study comparing surgical with endovascular treatment. Radiology. Feb 2008;246(2):543-52.

12. [Guideline] Bederson J, Connolly E, Batjer H, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage : a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. Mar;40(3) 2009;994-1025. 13. Subarachnoid Hemorrhage. In: Goldstein L. A Primer on Stroke Prevention and Treatment - An Overview based on AHA/ASA Guidelines. Dallas, TX: Wiley-Blackwell; April 2009. 28

14. Barker FG 2nd, Ogilvy CS. Efficacy of prophylactic nimodipine for delayed ischemic deficit after subarachnoid hemorrhage: a metaanalysis. J Neurosurg. Mar 1996;84(3):405- 14. 15. Molyneux A, Kerr R, Stratton I, et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet. Oct 26 2002;360(9342):1267-74.

16. Cloft HJ, Kallmes DF. Aneurysm packing with HydroCoil Embolic System versus platinum coils: initial clinical experience. AJNR Am J Neuroradiol. Jan 2004;25(1):60-2. 17. De Oliveira JG, Beck J, Ulrich C, Rathert J, Raabe A, Seifert V. Comparison between clipping and coiling on the incidence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. Neurosurg Rev. Jan 2007;30(1):22-30; discussion 30-1.

18. Gonzalez N, Murayama Y, Nien YL. Treatment of unruptured aneurysms with GDCs: clinical experience with 247 aneurysms. AJNR Am J Neuroradiol. Apr 2004;25(4):577- 83. 19. Karmonik C, Strother CM, Chen X. Stent-assisted coiling of intracranial aneurysms aided by virtual parent artery reconstruction. AJNR Am J Neuroradiol. Oct 2005;26(9):2368-70. 20. Kurre W, Berkefeld J. Materials and techniques for coiling of cerebral aneurysms: how

much scientific evidence do we have?. Neuroradiology. Nov 2008;50(11):909-27 29

Extra Cranial Carotid Stenosis I. WHEN TO SUSPECT / RECOGNIZE? a) Introduction: This is a common condition, predominantly affecting the elderly, as atherosclerosis is the commonest etiology. Most common site affected are carotid bifurcation and origins of carotid and vertebral arteries. It can also occur following radiation / trauma and can also be seen in connective tissue disorders and arteritis. It causes focal or diffuse narrowing of the

carotid artery depending on etiology. It often presents with transient / permanent neurological deficits. Transient Ischemic Attack, Cerebral stroke, local bruit, amaurosis fugax, previous history of neck surgery or radiation therapy are some of the clues to clinical diagnosis. b) Case definition : The diagnosis is established by vascular imaging such as color Doppler / CT angiography / MR angiography / catheter angiography. Doppler is the first screening tool. However, catheter

angiography remains the gold standard in this situation. The degree of stenosis is defined in comparison with the normal distal artery diameter (NASCET Criteria / ECST CRITERIA). Symptomatic Stenosis or stenosis more than 60% is of clinical significance. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY: Cerebral ischemic stroke is the third leading cause of death, and carotid artery stenosis is the commonest cause of cerebral

ischemic stroke. The incidence of intracranial intracranial carotid disease is also on the rise in our country and high index of suspicion and proper imaging is often helpful in detecting the disease burden. III. DIFFERENTIAL DIAGNOSIS: The carotid stenosis may be caused by: Atherosclerosis Fibro muscular dysplasia Arteritis Radiation Trauma Dissection Secondary to involvement in malignant tumour in the neck IV. PREVENTION AND COUNSELLING

Preventive measures as advised for atherosclerosis should be followed. These include: Avoidance of smoking Low fat diet Regular exercise Control of blood pressure 30

Control of Diabetes V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA: Diagnostic criteria / investigations – Stenosis greater than 60% by NASCET criteria in symptomatic individuals and greater than 70% in asymptomatic individuals are presently considered as indications for interventional treatment. The imaging modalities used are 1. Color Doppler 2. CT Angiography 3. MR Angiography 4. Catheter angiography

Treatment - It can be treated by endovascular stenting or surgical endarterectomy. Both modalities have shown similar results. However in non atherosclerotic etiology / difficult surgical access / high risk cases for surgery, stenting is of choice. Recent cerebral infarction is a relative contraindication. The procedure may need to be deferred for 3 weeks in such cases. Follow up – Color Doppler is the preferred imaging modality for follow up.

* Situation 1: At Secondary Hospital / Non-Metro situation: Optimal Standards of Treatment in situations where technology and resources are limited. a) Clinical Diagnosis: Transient Ischemic Attack, Cerebral stroke, local bruit, amaurosis fugax, previous history of neck surgery or radiation therapy are some of the clues to clinical diagnosis. b) Investigations: Hemoglobin, Total and Differential Leucocyte counts, ESR, Blood Sugar, INR, Platelet count, Serum Creatinine,

Imaging : Diagnostic criteria / investigations – Stenosis greater than 60% by NASCET criteria in symptomatic individuals and greater than 70% in asymptomatic individuals are presently considered as indications for interventional treatment. The imaging modalities used are 1. Color Doppler 2. CT Angiography 3. MR Angiography 4. Catheter angiography c) Treatment : It can be treated by endovascular stenting or surgical endarterectomy. Both modalities have shown similar results. However in non 31

atherosclerotic etiology / difficult surgical access / high risk cases for surgery, stenting is of choice. Recent cerebral infarction is a relative contraindication. The procedure may need to be deferred for 3 weeks in such cases. Standard operating procedure a. In Patient - All cases should be treated as in patients b. Out Patient - Not applicable c. Day Care - Not applicable d. Referral criteria : Stenosis greater than 60% by NASCET criteria in symptomatic individuals and

greater than 70% in asymptomatic individuals are presently considered as indications for interventional treatment. If facilities for standard treatment are not available, patient is referred to super specialty hospital where these facilities are available. * Situation 2 : At super specialty facility in metro location where higher-end technology is available. a) Clinical Diagnosis: Transient Ischemic Attack, Cerebral stroke, local bruit,

amaurosis fugax, previous history of neck surgery or radiation therapy are some of the clues to clinical diagnosis b) Investigations: Hemoglobin, Total and Differential Leucocyte counts, ESR, Blood Sugar, INR, Platelet count, Serum Creatinine, Imaging : Diagnostic criteria / investigations – Stenosis greater than 60% by NASCET criteria in symptomatic individuals and greater than 70% in asymptomatic individuals are presently considered as indications for interventional treatment.

The imaging modalities used are 5. Color Doppler 6. CT Angiography 7. MR Angiography 8. Catheter angiography c) Treatment : It can be treated by endovascular stenting or surgical endarterectomy. Both modalities have shown similar results. However in non atherosclerotic etiology / difficult surgical access / high risk cases for surgery, stenting is of choice. Recent cerebral infarction is a relative contraindication. The procedure may need to be deferred for 3 weeks in such cases.

a. In Patient - All cases are to be treated as in patients. They should be treated in centers equipped with Digital Subtraction Angiography equipment (DSA) with roadmap facility, facility of ICU care. b. Out Patient - Not applicable c. Day Care - Not applicable d. Referral criteria : Stenosis greater than 60% by NASCET criteria in symptomatic individuals and greater than 70% in asymptomatic individuals are presently considered as indications for interventional treatment. VI. WHO DOES WHAT ? and TIMELINES

a. Doctor: Diagnosis & interventional treatment. b. Nurse: Assistance in pre, during & post interventional clinical care. c. Technician: Assistance in pre, during & post interventional imaging. VII. FURTHER READING / REFERENCES 1. Handbook of Interventional Radiologic Procedures. Authors: Lee Fox, James Benenati, Edited by: Krishna Kandarpa, John E. Aruny, Publishers: Wolters Kluwer/ Lippincott, Williams & Wilkins 2. Quality assurance guidelines for the performance of carotid stenting:

European Standards adopted and modified by CIRSE in cooperation with the Society of Interventional Radiology (SIR) Standards of Practice Committee. Sumaira Macdonald. Trevor J Cleveland, Peter A. Gaines. 3. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/ SVM/SVS Guidelines on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease: Executive Summary A Report of the American College of Cardiology

Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery,

Society for Vascular Medicine, and Society for Vascular Surgery Developed in Collaboration With the American Academy of Neurology and Society of Cardiovascular Computed Tomography . Brott et al JACC Vol. 57, No. XX, 2011. 33

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situat- HUMAN DRUGS & EQUIPMENT INVESTIGATIONS ion RESOURCES CONSUMABLES 1. Doctors – 3 Hemoglobin, Digital (Radiologists Total and Differential 1. Drugs: Aspirin, subtraction (specialist trained Leucocyte counts, Clopidogrel, angiography in Neuro - ESR, Blood Sugar, Nitroglycerine, system (DSA)

interventional INR, Platelets, Serum Nimodipine, procedures-1, Creatinine Heparin, Non-Ionic Colour Doppler Anaesthetist -1, Iodinated contrast Ultrasound Neurologist for media clinical 2. Consumables: Multiparameter management – 1) Arterial access patient monitor sheath, 90 cm long Technicians –1 sheath, Guiding Resuscitation Nurses – 1 catheter, Self equipment expanding carotid stent, Pre and post dilatation angioplasty balloon catheter, diagnostic angiography catheter, appropriate 0.014” & 0.035”

guidewires, exchange length 0.035” guidewire, Tuhoy SBorst Y connector, Indeflator, saline Pressure flush bag, distal (or proximal) protection device 34

2. Minimum Same Same as mentioned Same as mentioned Same as as mentioned above above mentioned above. In above. addition, In addition ACT Intensivist – machine ( for 1(desirable) activated clotting time determination) is desirable. 35

Acute Cerebral Ischemic Stroke Due to a Major Vessel Occlusion I. WHEN TO SUSPECT / RECOGNIZE? a) Introduction: Cerebral Stroke is a sudden onset neurological deficit due to neurovascular pathological conditions. Ischemic stroke due to a major vessel occlusion forms an important group in cerebral stroke. This is a common condition, predominantly affecting the elderly, as atherosclerosis with/without thrombo-embolism is the commonest etiology. It can also occur due to embolism

from cardiac or neck vessel source, vasculitis and arteritis, traumatic or spontaneous dissection and other causes. It usually presents with stroke leading to transient / permanent neurological deficits. c) Case definition: The diagnosis is established by CT, MRI supplemented with vascular imaging such as CT angiography / MR angiography / catheter angiography. CT Perfusion or MR perfusion may be necessary. Cerebral ischemic stroke cases due to acute occlusion of a major intracranial vessel

like ICA, A1/Proximal A2, M1/Proximal M2 and Basilar artery presenting in the recommended therapeutic time window period are suitable for intra arterial therapeutic recanalization procedures. Stroke due to a small vessel involvement as seen in atherosclerosis or vasculitis leading to lacunar infarction are not considered for intra arterial recanalization procedures. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY: Cerebral ischemic stroke is one of the important causes of death/disability in the elderly

population. III. DIFFERENTIAL DIAGNOSIS: Cerebral ischemic stroke involving a major intracranial vessel may be caused by: Atherothrombosis Embolism Dissection Trauma Clinically however stroke like picture may be due to a variety of causes including small vessel involvement as in atherosclerosis or vasculitis, and tumors, infection, demyelination etc. 36

IV. PREVENTION AND COUNSELLING Preventive measures as advised for atherosclerosis should be followed. These include – - Avoidance of smoking - Low fat diet - Regular exercise - Control of blood pressure and diabetes V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA: Diagnostic criteria / investigations – Cerebral ischemic stroke due to acute occlusion of a major intracranial vessel like ICA,

A1/Proximal A2, M1/Proximal M2 and Basilar artery presenting in the recommended therapeutic time window period are suitable for intra-arterial therapeutic recanalization procedures. For anterior circulation upto 6-8 hrs from the onset of occlusion of vessel is the recommended therapeutic time window. A longer window period is available for posterior circulation and central retinal artery occlusion. Similarly further deferred therapeutic window period is available for cerebral venous sinus recanalization.

Intracranial hemorrhage, hypertension, deranged clotting parameters, low platelet counts, CT demonstrable infarction occupying more than a third of the hemispheric territory are some of the absolute and relative contraindications. The imaging modalities used are 5. CT and/or MRI 6. CT Angiography 7. MR Angiography 8. Catheter angiography 9. CT or MR Perfusion imaging 10. Transcranial Doppler Treatment - It can be treated by endovascular intra arterial thrombolysis and/or clot

retrieval/aspiration. Adjuvant intracranial angioplasty/stenting may be required. Follow up – CT, MRI and non-invasive angiographic techniques are generally used for follow up and monitoring. 37

*Situation 1: At Secondary Hospital / Non-Metro situation: Optimal Standards of Treatment in situations where technology and resources are limited. a) Clinical Diagnosis: Cerebral Stroke is a sudden onset neurological deficit due to neurovascular pathological conditions. Lacunar ischemic stroke and hemorrhagic strokes conditions need to be excluded. After clinical evaluation suitable imaging will be required to establish correct diagnosis. b) Investigations:

Hemoglobin, Total and Differential Leucocyte counts, ESR, Blood Sugar, INR, Platelets, Serum Creatinine, Imaging as mentioned in diagnostic criteria c) Treatment: It can be treated by endovascular intra arterial thrombolysis and/or clot retrieval/aspiration. Adjuvant intracranial angioplasty/stenting may be required. Standard operating procedure e. In Patient - All cases should be treated as in patients f. Out Patient - Not applicable g. Day Care - Not applicable h. Referral criteria :

Cerebral ischemic stroke cases due to acute occlusion of a major intracranial vessel like ICA, A1/Proximal A2, M1/Proximal M2 and Basilar artery presenting in the recommended therapeutic time window period are suitable for therapeutic recanalization procedures. If facilities for standard treatment are not available, patient is referred to super specialty hospital where these facilities are available. * Situation 2 : At super specialty facility in metro location where higher-end technology is available.

a) Clinical Diagnosis: Cerebral Stroke is a sudden onset neurological deficit due to neurovascular pathological conditions. Lacunar ischemic stroke and hemorrhagic strokes conditions need to be excluded. After clinical evaluation suitable imaging will be required to establish correct diagnosis. 38

b) Investigations: Hemoglobin, Total and Differential Leucocyte counts, ESR, Blood Sugar, INR, Platelets, Serum Creatinine, Cerebral ischemic stroke due to acute occlusion of a major intracranial vessel like ICA, A1/Proximal A2, M1/Proximal M2 and Basilar artery presenting in the recommended therapeutic time window period are suitable for intra-arterial therapeutic recanalization procedures. For anterior circulation up to 6-8 hrs from the onset of occlusion of vessel is the recommended

therapeutic time window. A longer window period is available for posterior circulation and central retinal artery occlusion. Similarly further deferred therapeutic window period is available for cerebral venous sinus recanalization. Intracranial hemorrhage, hypertension, deranged clotting parameters, low platelet counts, CT demonstrable infarction occupying more than a third of the hemispheric territory are some of the absolute and relative contraindications. The imaging modalities used are

11. CT and/or MRI 12. CT Angiography 13. MR Angiography 14. Catheter angiography 15. CT or MR Perfusion imaging 16. Trans cranial Doppler c) Treatment : It can be treated by endovascular intra arterial thrombolysis and/or clot retrieval/aspiration. Adjuvant intracranial angioplasty/stenting may be required. Standard operating procedure e. In Patient - All cases are to be treated as in-patients. They should be treated in centers equipped with DSA, with roadmap facility and facility of ICU care.

f. Out Patient - Not applicable g. Day Care - Not applicable h. Referral criteria: Cerebral ischemic stroke cases due to acute occlusion of a major intracranial vessel like ICA, A1/Proximal A2, M1/Proximal M2 and Basilar artery presenting in the recommended therapeutic time window period are suitable for therapeutic recanalization procedures. If facilities for standard treatment are not available, patient is referred to super specialty hospital where these facilities are available.

d. Doctor: Diagnosis & Interventional treatment. e. Nurse: Assistance in pre, during & post interventional clinical care. f. Technician: Assistance in pre, during & post interventional imaging. RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) SITUA HUMAN DRUGS & EQUIPMENT INVESTIGATIONS TION RESOURCES CONSUMABLES 1. Doctors – 3 Hemoglobin, Digital

(Radiologists/spe Total and Differential 1. Drugs: Aspirin, subtraction cialist trained in Leucocyte counts, Clopidogrel, angiography neurointervention ESR, Blood Sugar, Nitroglycerine, system al procedures.-1, INR, Platelets, Serum Nimodipine, Anaesthetist -1, Creatinine Heparin, Non Ionic Multiparameter Neurologist - 1 Iodinated contrast patient monitor ) media, Technicians –1 Urokinase/rTPA Resucitation Nurses – 1 2. Consumables: equipment Arterial access sheath, Guiding catheter, diagnostic Transcranial

angiography Doppler catheter, preferable. appropriate guidewires, microcatheter/ microwire, infusion pump, clot removal devices like Merci, Penumbra, Solitaire AB stent device, intracranial angioplasty balloon and balloon mounted stent 2. Minimum Same Same as mentioned Same as mentioned Same as as mentioned above above mentioned above. In above. addition, In addition Intensivist – ACT machine 40

1(desirable) ( for activated clotting time determination) is desirable. FURTHER READING / REFERENCES 1. Handbook of Interventional Radiologic Procedures. Authors: David Kumpe Edited by: Krishna Kandarpa, John E. Aruny, Publishers: Wolters Kluwer/ Lippincott, Williams & Wilkins 2. Guidelines for the Early Management of Patients With Ischemic Stroke A Scientific Statement From the Stroke Council of the American Stroke Association Harold P. Adams Jr, MD et al

3. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation. 2007;115:e478-e534

4. Imaging-Guided Acute Ischemic Stroke Therapy: From "Time Is Brain" to "Physiology Is Brain" R.G. Gonzáleza, American Journal of Neuroradiology 27:728-735, April 2006 41

UTERINE FIBROID EMBOLISATION I. WHEN TO SUSPECT/ RECOGNIZE? Whenever a woman of child bearing age presents with menorrhagia (excessive bleeding during menstruation), dysmenorrhea (painful menses), or recurrent abortion. 1a Introduction: Uterine fibroid is a common benign tumour smooth muscle cells and fibrous connective tissue that develop within the walls of the uterus. It generally affects the middle-aged women and present with menorrhagia and pressure effects

on the urinary bladder and or the rectum. Women with fibroids may also have dysmenorrhea. When occurring in the child bearing age, these fibroids may interfere with pregnancy and the lady is either unable to conceive or unable to carry the pregnancy till completion. Uterine fibroid embolisation (UFE) is a minimally invasive, percutaneous, endovascular (interventional radiological) therapy to treat the fibroids, by blocking the arteries supplying the fibroid. 1b Indications:

It is indicated for treatment of symptomatic uterine fibroids, causing menorrhagia /dysmenorrhea / pressure effects on rectum or urinary bladder. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY: Fibroids is a common ailment of the middle aged women, occurring in up to 20%. III. DIFFERENTIAL DIAGNOSIS: Other causes of uterine masses could be cancer cervix, endometrial cancer. Occasionally ovarian cancer may mimic a uterine fibroid. Imaging with Ultrasound / MRI and histopathological studies can give the

correct diagnosis. IV. PREVENTION AND COUNSELING: Menorrhagia / lower abdominal masses should be evaluated by imaging and histopathology, to arrive at the correct diagnosis, and early appropriate treatment should be implemented. The middle aged women should be always evaluated with a PAP smear to rule out any malignancy of uterine cervix. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA / FOLLOW UP Diagnostic Criteria:

• Ultrasound: Reveals a spherical mass with heterogeneous middle level echoes. Most fibroids are intramural. Occasionally they may be pedunculated 42

and apparently detached from the uterus or they could be subendometrial There is always an accompanied displacement of the endometrial echo, which also serves an indirect indicator for the isoehoic fibroids. • MRI: Reveals a uterine mass that is heterogeneously hyperintense on T2 and isointense on T1 images. There is hypertrophy of the uterine arteries. Investigations: • Ultrasound Pelvis • MRI Pelvis • PAP smear from Cervix • Endometrial biopsy, if there is suspicion of endometrial Ca

• Blood - Hb, TLC, DLC, ESR • Blood – Platelets count • Blood – PT(INR) and APTT • Blood Creatinine Treatment: Uterine fibroid embolisation – The uterine artery is accessed endovascularly and the tip of the catheter / microcatheter is placed distal to the ovarian / cystic / cervical branch, and embolised with Poly Vinyl alcohol particles, till the flow becomes very sluggish. Referral criteria: Patients meeting the criteria for UFE should be referred to centers equipped with capability to perform UFE.

Follow up: Patient would be admitted a day prior to the embolisation and managed as inpatient till 2-3 days till the pain and nausea gets tolerable. There after Clinical follow up is done at 2 week, 6 weeks, 3 months and 6 months. During these follow up ultrasound could be done to assess the size of the fibroid. *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited b) Clinical Diagnosis: As above

c) Investigations: As above d) Treatment: Standard Operating procedure: Patient would be assessed and evaluated by the primary gynecologist to rule out any other gynecological problems. Thereafter patient will be assessed by the interventional radiologist for the feasibility of embolisation. Most of the times the procedure would be done under local anesthesia and if required the anesthesiologist’s consultation can be taken. The patient’s uterine artery would then be accessed by endovascular 43

approach; the catheter tip will be placed beyond the branches to the ovary, urinary bladder and uterine cervix. Then polyvinyl alcohol particle would be injected for embolisation of the artery till the flow becomes sluggish. a. In Patient: UFE is to be done as inpatient. b. Out Patient: no. c. Day Care: no e) Referral criteria: As above *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available g) Clinical Diagnosis: As above h) Investigations: As above

i) Treatment: As above Standard Operating procedure: As above. a. In Patient – The procedure will be done as an inpatient therapy b. Out Patient – No c. Day Care - No j) Referral criteria: As above. VI. WHO DOES WHAT? and TIMELINES Designation Clinical Role Timeline Gynecologist Clinical Evaluation and assessment of Screening on presentation to the gynecologic status of the patient. OP till the embolisation is To rule out any other malignancy by performed. PAP smear. Pharmacological control

of bleeding and symptomatic Post embolisation, to be management of pain till the followed up by gynecologist embolisation is done. Patient to be and interventional informed about option of UFE and radiologist referred to interventional radiologist. Following this the patient should decide between hysterectomy / myomectomy / UFE Pathologist To assess the PAP smear or any other As soon as possible 44

histopathology examination Diagnostic Radiologist Imaging of the uterine pathology by As soon as possible. USG or MRI Interventional Assessment for feasibility for uterine As soon as possible. Radiologist fibroid embolisation Biochemist Biochemical evaluation As soon as possible Cardiologist Cardiac evaluation After consultation by and on the request of interventional radiologist for patients who are high risk for cardiac status Interventional Performs the uterine fibroid After the patient is declared

Radiologist embolisation fit for the procedure by the above timelines Nursing Staff Assist in managing the patient as In- NA patient in ward and in Interventional Radiology Suite Technician Assist in Imaging the patient, assist NA the IR specialist in the IR suite, and manage the DSA images also. VII. FURTHER READING / REFERENCES 1. Quality improvement guidelines for uterine artery embolisation for symptomatic leomyomata. DM Hovesepian, GP Siskin, J Bonn et al. CIRSE website.

2. Leiomyomata treated with uterine artery embolisation Factors Associate with successful symptom and Imaging outcome. JB Spies, AR Roth, BS Reena C Jha, Jackeline Gomez-Jorge, EB Levy, TC Chang, SA Ascher. Radiology 2002; 222:45-52. 3. Embolic Agents Used for Uterine Fibroid Embolization. GP Siskin, Meridith Englander, BF Stainken, JAhn, K Dowling, EG Dolen. AJR:175, Sept 2000, 767-773 4. Limited uterine artery embolisation with Trisacryl Gelatin Microspheres for Uterine

fibroids. JP Pelage, O Le Dref, JP Beregi, M Nonent, Y Robert, M cosson, D Jacob, JB Turc. JVIR 2003; 14: 15-20 5. A multi-centre retrospective cohort study comparing the efficacy, safety and cost-effectiveness of hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids. The HOPEFUL study. A Hirst, S Dutton, O Wu, A Briggs, C Edwards, L Waldenmaier, M Maresh, A Nicholson and K McPherson. Health Technology Assessment 2008; Vol. 12: No. 5

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) 45

(Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) SITUATI HUMAN INVESTIGATIONS DRUGS & EQUIPMENT(S) ON RESOURCES CONSUMABLES 1. Doctors – Hemoglobin, 1. Drugs: MRI Ultrasound (1) (Gynaecologist– 1, Random Blood contrast media, MRI Interventional Sugar, PT, APTT Lignocaine, Digital Subtraction Radiologist – 1, or INR, Platelet Nitroglycerine, , Angiography Diagnostic Radiologist Count, Se. Heparin, Non Ionic

-1, Creatinine, radiographic contrast Technician(s) – 1, HBsAg, HIV media Nursing - 1 2. Consumables: Angiographic catheters – pigtail - 1, Cobra / sim2/uterine -1, Guidewire 0.035”– 1 Vascular sheath – 1 PVA particles – 2 vials 2. Doctors – Hemoglobin, 1. Drugs: Ultrasound (1) (Gynaecologist– 1, Random Blood Lignocaine, MRI Interventional Sugar, PT, APTT Nitroglycerine, , Digital Subtraction Radiologist – 1, or INR, Platelet Heparin, Non Ionic Angiography

Diagnostic Radiologist Count, Se. radiographic contrast System (1) -1, Creatinine, media Sterile Suite Technician(s) – 1, HBsAg, HIV 2. Consumables: Multichannel Nursing - 1 Angiographic invasive monitor (1) catheters – pigtail - 1, Resuscitation Cobra / sim2/uterine equipment (1) -1, Crash Trolley (1) Guidewire 0.035”– 1 Vascular sheath – 1 Microcatheter and guidewire – 1 each, PVA particles – 2 vials 46

Chemoembolization for unresectable hepatocellular carcinoma(HCC) I. WHEN TO SUSPECT / RECOGNIZE ? a) Introduction : The treatment of choice for HCC remains surgical resection or liver transplanation, however, in a non-surgical case a variety of percutaneous therapeutic interventional palliative treatment techniques such as transcatheter arterial chemoembolization (TACE), transcatheter arterial radio- embolization (TART)

and percutaneous ablative therapies like radiofrequency ablation (RFA) are available (1- 3). d) Case definition : For both situations of care (mentioned below*) A clinically or radiologically suspected, biopsy or laboratory proved case of hepatocellular carcinoma. II. INCIDENSE OF THE CONDITION IN OUR COUNTRY : HCC is one of the common cancer and the cause of cancer related death in the world. It’s incidence in India is also increasing due to increase in incidence of cirrhosis and hepatitis B&C.

III. DIFFERENTIAL DIAGNOSIS: Liver metastasis, benign hepatic lesion. IV. PREVENTION AND COUNSELLING: Since HBV is the most common etiologic agent in our country, the vaccination against hepatitis B may be an effective preventive strategy. The other cause such as alcohol induced cirrhosis may be avoided by avoidance of alcohol. Proper counseling of patient by explaining him various non-surgical interventional treatment options and their outcome should be explained to every patient.

V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA : Diagnostic criteria / investigations – 47

17. Clinical - features of cirrhosis & palpable mass. 18. Biochemical – Serum alpha fetoprotein (AFP), viral markers (HBV & HCV) 19. Radiological – Imaging features on US, CT & MR. 20. Histological – Fine needle aspiration cytology or biopsy as & when required. Treatment - Chemoembolization for unresectable tumour with child’s class A & B. 1. Tumour size > 5 cm in diameter. 2. Tumour size > 3 cm in diameter and 2 or 3 in number. 3. Treatable size tumour with ipsilateral portal vein invasion.

Referral criteria – Patient fit for chemoembolization is treated with angiographic treatment. If angiographic facility is not available at the hospital, patient is referred to the hospital with such treatment facilities. * Situation 1 : At Secondary Hospital / Non-Metro situation : Optimal Standards of Treatment in situations where technology and resources are limited. a) Clinical Diagnosis: Clinical features of cirrhosis &/or palpable mass. b) Investigations :

Biochemical – Serum alpha fetoprotein (AFP), viral markers (HBV & HCV) Radiological – Imaging features on US, CT & MR. Histological – Fine needle aspiration cytology or biopsy as & when required. c) Treatment : chemoembolization for unresectable tumour with Child’s class A & B. Standard operating procedure i. In Patient - Chemoembolization is performed as indoor case j. Out Patient - Not applicable k. Day Care - Not applicable l. Referral criteria :

If facilities for standard treatment are not available, patient is referred to super specialty hospital where these facilities are available. * Situation 2 : At super specialty facility in metro location where higher-end technology is available. a) Clinical Diagnosis : Clinical features of cirrhosis &/or palpable mass. b) Investigations : 48

Biochemical – Serum alpha fetoprotein (AFP), viral markers (HBV & HCV) Radiological – Imaging features on US, CT & MR. Histological – Fine needle aspiration cytology or biopsy as & when required. c) Treatment : Chemoembolization for unresectable tumour with Child’s class A & B. Standard operating procedure i. In Patient - Chemoembolization is performed as indoor case j. Out Patient - Not applicable k. Day Care - Not applicable l. Referral criteria : Not applicable VI. WHO DOES WHAT ? and TIMELINES

g. Doctor : Physician performs clinical management. Radiologist performs imaging and interventional radiologist performs the interventional treatment. h. Nurse : Assists in clinical management, during & post interventional treatment. i. Technician : performs imaging and assists during interventional treatment. VII. FURTHER READING / REFERENCES 1. Gu YK, Luo RG, Huang JH et al.Transarterial embolization ablation of HCC with lipiodal – ethanol mixture.World J. Gast. Roenterology 2010 ; 16 (45) : 5766 – 72.

2. Srivastava DN, Thulkar S, Sharma S, et al.Therapeutic radiological interventional procedures in hepatocellular carcinoma.Indian J. Gastroenterology 2002 ; 21 : 96 – 98. 3. Kumar R, Saraswat MK, Sharma BC et al.Characteristics of hepatocellular carcinoma in India : a retrospective analysis of 191 cases. Oxford J. Medicine 2008 ; 101 (6) : 479 – 485. RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and

Situat- HUMAN DRUGS & EQUIPMENT INVESTIGATIONS ion RESOURCES CONSUMABLES 1. 1. Routine blood 1. Doxorubicin Digital (Radiologists-2 examination 50 – 100 mg. subtraction Anaesthetist -1 Hb, TLC, DLC etc. 2. Other chemo- angiography Clinician - 1) 2. S. alfa feto protein therapeutic drugs equipment Technicians –2 3. Serum HBV & as per case with life Nurses – 2 HCV 3. Lipiodol 20 ml saving devices Orderly / Ward 4. Liver function 4. Angiographic and Boy - 2 tests catheters (4 –5 F) Ultrasound

5. Blood sugar etc 5. Microcatheter (colour (3F) Doppler) 6. Gel foam equipment 7. PVA 3/4 vials 2. Same as Same as mentioned Same as Same as mentioned above above mentioned above mentioned above 50

Radiofrequency Ablation (RFA) in Hepatocellular carcinoma and liver metastases I. WHEN TO SUSPECT / RECOGNIZE? a) Introduction: The best treatment for hepatocellular carcinoma (HCC)is either surgical resection of the tumour or transplantation of the liver. However, in a patient who is unsuitable for surgery, a variety of percutaneous interventional treatment options are available to treat HCC or liver metastases like transcatheter arterial chemoembolization

(TACE), transcatheter arterial radio- embolization (TART) and ablative therapies like radiofrequency ablation (RFA) (1,2). b) Case definition: A clinically suspected case of hepatocellular carcinoma or colorectal liver metastases which has been proven by imaging, biopsy and laboratory parameters. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY: HCC and metastases form the commonest group of malignancies involving the liver. These are the leading causes of deaths due to

malignancy. It’s incidence in India is increasing due to the increase in the prevalence of liver cirrhosis and liver infections caused by hepatitis viruses B and C (3). III. DIFFERENTIAL DIAGNOSIS: Benign hepatic lesions. These can be differentiated in most cases by imaging findings. IV. PREVENTION AND COUNSELLING: Since the Hepatitis B virus is a common cause of HCC in our country, an effective preventive strategy could be vaccinations against hepatitis B. Alcohol

induced liver cirrhosis could be prevented by avoiding alcohol and de-addiction programs. Counseling of the patient by explaining various non-surgical interventional treatment options and their outcome would be beneficial. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT AND REFERRAL CRITERIA: Diagnostic criteria/investigations: 1. Clinical – Finding suggestive of liver cirrhosis and its complications. Sometimes a liver mass is palpable.

2. Biochemical – Serum alpha fetoprotein (AFP), viral markers (HBV & HCV) 3. Radiological – Imaging features on US, CT and MR. 4. Histological – Fine needle aspiration cytology or biopsy as required. Treatment: Radiofrequency ablation of HCC and metastases (4,5) 1. A single tumour sized less than or equal to 5 cm in diameter. 2. Multiple tumours sized less than 3 cm in diameter and two to three in number. Referral criteria: A patient found suitable for treatment with radiofrequency ablation is best

treated with radiofrequency ablation (6). If this facility is not available at the hospital, patient should be referred to another hospital having such treatment facilities. 51

* Situation 1 : At a secondary hospital or non-metro situation where technology and resources for optimal standards of treatment are limited. 45. Clinical Diagnosis : Finding suggestive of liver cirrhosis and its complications. Sometimes a liver mass is palpable. 46. Investigations: Biochemical – Serum alpha fetoprotein (AFP), viral markers (HBV & HCV) Radiological – Imaging features on US, CT and MR Histological – Fine needle aspiration cytology or biopsy as required

47. Treatment: Radiofrequency ablation of HCC and Metastases • A single tumour size less than or equal to 5 cm in diameter. • Multiple tumours size less than 3 cm in diameter and two to three in number. Standard operating procedures a. In patient- Radiofrequency ablation should be performed as indoor case.. b. Out patient- not applicable c. Day care- not applicable. d. Referral criteria: If this facility for RFA is not available at the hospital, patient

should be referred to another hospital having such treatment facilities. * Situation 2: At a super specialty facility in a metro location where high-end technology is available. 1. Clinical Diagnosis : Finding suggestive of liver cirrhosis and its complications. Sometimes a liver mass is palpable. 2. Investigations: Biochemical – Serum alpha fetoprotein (AFP), viral markers (HBVand HCV). Radiological – Imaging features on US, CT & MR. Histological – Fine needle aspiration cytology or biopsy as required.

3. Treatment: Radiofrequency ablation of HCC and colorectal metastases to the liver • A single tumour sized less than or equal to 5 cm in diameter. • Multiple tumours sized less than 3 cm in diameter and two to three in number. Standard operating procedures II. In patient – Radiofrequency ablation should be performed as indoor case. III. Out patient - Not applicable IV. Day care - Not applicable V. Referral criteria- Not applicable VI. WHO DOES WHAT? and TIMELINES

b. Nurse: Assistance in patient care before, during and after interventional treatment. c. Radiography technologist: Assistance in imaging of the patient before, during and after interventional treatment. RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 Kg) Situat HUMAN INVESTIGATIONS DRUGS & EQUIPMENT ion RESOURCES CONSUMABLES 1. Doctors – 4 1. Routine blood Local anaesthetic Radiofrequency ( Clinician - 1 examination- Hb, and sedatives. equipment (1),

Anaesthetist -1 TLC, DLC etc. Ultrasound Radiologists-2 out 2. S. alfafetoprotein scanning of which at least 3. Se HBV & HCV machine (1), one should be an 4. Liver function Anesthesia and interventional tests monitoring radiologist) 5. Blood sugar equipment (1), Radiography Resuscitation technologists –2 equipment with Nurses – 2 crash trolley (1) Orderly/ward Boys – 2 2. Same as Same as mentioned Same as mentioned Same as mentioned above above above mentioned above VII. REFERENCES

1. Srivastava DN, Thulkar S, Sharma S. Therapeutic radiological interventional procedures in hepatocellular carcinoma. Indian J. Gastroenterology 2002 ; 21: 96 – 98 2. Morsi A, Moharram H, Hamed I Radiofrequency Ablation in Unresectable Hepatocellular Carcinoma. Journal of the Egyptian Nat. Cancer Inst., Vol. 15, No. 4, December: 293-302, 2003 3. Kumar R, Saraswat MK, Sharma BC Characteristics of hepatocellular carcinoma in India :

a retrospective analysis of 191 cases. Oxford J. Medicine 2008 ; 101 (6): 479 – 485 4. Curley SA. New Approaches to the Treatment of Hepatic Malignancies - Radiofrequency Ablation of Malignant Liver TumorsAnn Surg Oncol, Vol. 10, No. 4, 2003 5. Yao-Jun Zhang and Min-Shan Chen. Role of radiofrequency ablation in the treatment of small hepatocellular carcinoma. World J Hepatol. 2010 April 27; 2(4): 146–150 6. Galandi D, Antes G. Radiofrequency thermal ablation versus other interventions for

hepatocellular carcinoma. Cochrane Database of Systematic Reviews 2004, Issue 2 53

NAME OF THE CONDITION: PERIPHERAL ARTERIAL DISEASE IV. When to suspect or recognize? Peripheral Arterial Disease should be suspected for adults 50 years and older who have atherosclerosis risk factors. Likewise for adults 70 years and older with complaints of fatigue, aching, numbness or pain in the lower extremity or any history of walking impairment (suggesting exertional limitation of the lower extremity muscles), pain at rest localized to the

lower leg or foot and its association with the upright or recumbent positions and poorly healing or non-healing wounds of the legs or feet(1). c) Introduction The term “Peripheral Arterial Disease (PAD)” broadly encompasses the vascular diseases caused primarily by atherosclerosis and thromboembolic pathophysiological processes that alter the normal structure and function of the aorta, iliac and the arteries of the lower extremity. Patients

with PAD have an increased risk of mortality, myocardial infarction, and cerebrovascular disease. They also suffer from significant functional limitations in their daily activities, and the most severely affected are at risk of limb loss. d) Case definition Peripheral arterial disease (PAD) is the preferred clinical term that should be used to denote stenotic and occlusive diseases of the aorta and its branch arteries, exclusive of the coronary arteries. V. Incidence of the condition in our country

It is underdiagnosed, undertreated, and much more common than previously thought. Incidence of the condition in our country is not exactly known due to lack of organized data. A strong association exists between advancing age and the prevalence. Almost 20% of adults older than 70 years have PAD. An American survey of 2174 patients older than 40 years of age used the Ankle-Brachial Index (ABI) as a screening tool, and showed a PAD prevalence of 0.9% between

the ages of 40 and 49 years, 2.5% between the ages of 50 and 59 years, 4.7% between the ages of 60 and 69 years, and 14.5% for the ages of 70 years and older(2). Differential Diagnosis Differential Diagnosis of Intermittent Claudication Condition Location of Characteristic Onset Effect of Effect of Other Pain Discomfort Relative Rest Body Characteris or Discomfort to Exercise Position tics Intermittent Buttock, thigh, Cramping, After same Quickly None Reproducibl

claudication or aching, fatigue, degree of relieved e calf muscles weakness, or exercise and rarely the frank pain 54

foot Nerve root Radiates down Sharp Soon, if not Not Relief may be History of compression leg, usually lancinating immediately quickly aided by back (e.g., posteriorly pain after onset relieved adjusting problems herniated (also back disc) often position present at res Spinal stenosis Hip, thigh, Motor After walking Relieved Relief by Frequent buttocks weakness or by lumbar history of (follows more standing for stopping spine flexion back dermatome) prominent variable only (sitting or problems,

than pain lengths of if position stooping provoked by time changed forward) intra- abdominal pressure Arthritic, Foot, arch Aching pain After Not May be Variable, inflammatory variable quickly relieved may processes degree of relieved by not relate to exercise (and bearing activity may be weight level present at rest) Hip arthritis Hip, thigh, Aching After Not More Variable, buttocks discomfort, variable quickly comfortable may usually degree of relieved sitting, relate to

localized to exercise (and weight activity hip and gluteal may be taken off legs level, region present at weather rest) changes Symptomatic Behind knee, Swelling, With Present at None Not Baker’s cyst down calf soreness, exercise rest intermittent tenderness Venous Entire leg, but Tight, bursting After walking Subsides Relief History of claudication usually worse pain slowly speeded by iliofemoral in thigh and elevation deep vein groin thrombosis, signs of venous congestion, edema

Chronic Calf muscles Tight, bursting After much Subsides Relief Typically compartment pain exercise very speeded by occurs in syndrome (e.g., slowly elevation heavy jogging) muscled athletes Adapted from J Vasc Surg, 31, Dormandy JA, Rutherford RB, for the TransAtlantic Inter-Society Consensus (TASC) Working Group, Management of peripheral arterial disease. (PAD), S1–S296, Copyright 2000 VI. Prevention and Counselling 55

Individuals at risk for lower extremity disease should undergo a vascular review of symptoms to assess walking impairment, claudication, ischemic rest pain and/or the presence of non - healing wounds. Aggressive lifestyle modification to reduce underlying risk factors (e.g. atherogenic diet, overweight or obesity, physical inactivity), to control risk factors such as diabetes, hypertension and hyperlipidemia are recommended for individuals with asymptomatic lower extremity PAD.

VII. Optimal Diagnostic Criteria, Investigations, Treatment & Referral Criteria - Diagnostic Criteria PAD is considered in the following clinical setting - iv) Adults 50 years and older who have atherosclerosis risk factors and v) Adults 70 years and older with the following symptoms - - Fatigue, aching, numbness or pain in the lower extremity or any history of walking impairment (suggesting exertional limitation of the lower extremity muscles)

- Pain at rest localized to the lower leg or foot and its association with the upright or recumbent positions. - Poorly healing or non-healing wounds of the legs or feet. Acute limb ischemia (ALI) - refers to a rapid decrease of perfusion in the affected extremity that requires urgent revascularization to preserve tissue viability. Complications include rhabdomyolysis and renal failure. Chronic Limb Ischemia (CLI) - refers to a chronic, severely compromised arterial blood supply in

the affected extremity that manifests as ischemic pain at rest, ulcers or gangrene in various combinations. Investigations 1. Measurement of Ankle-Brachial Index (ABI) 2. Color Doppler evaluation – Color flow and pulsed wave Doppler allows an estimation of the stenosis severity on the basis of Doppler-derived velocity criteria. It is an accurate method for determining the degree of stenosis or length of occlusion of the arteries supplying the lower extremity. It is also useful in

the follow-up of patients who have undergone endovascular (percutaneous transluminal angioplasty/stent) or surgical revascularization. 3. Magnetic Resonance Angiography (MRA) - Magnetic resonance angiography (MRA) of the aorta and peripheral vasculature can be performed rapidly with excellent image quality. Being noninvasive, it is virtually replacing invasive diagnostic angiography as the primary modality for vascular imaging. Determining the 56

type of intervention is feasible on a technically adequate MRA study. However, availability of the scanners with capability for peripheral vascular imaging and patients with relative contraindications to MR evaluation limits the utilization. 4. Computed Tomographic Angiography (CTA) - Higher spatial resolution, absence of flow-related phenomena that may distort MRA images and the capacity to visualize calcification and metallic implants such as endovascular stents or stent

grafts is an advantage with CTA when compared with MRA. Its advantages over invasive angiography include volumetric acquisition, improved visualization of soft tissues and other adjacent anatomic structures, less invasiveness and thus fewer potential complications. Exposure to ionizing radiation and the need for iodinated contrast medium limits its utilization as also availability of scanners with capability for peripheral vascular imaging. 5. Digital Subtraction Angiography (DSA) -

Vascular imaging with ultrasonography, CTA, and MRA has replaced catheter-based techniques in the initial diagnostic evaluation in most circumstances. The major advantage of DSA is the ability to selectively evaluate individual vessels, obtain physiologic information such as pressure gradients and as a platform for percutaneous intervention. Exposure to ionizing radiation, use of iodinated contrast agents, and risks related to vascular access and catheterization are limitations of this technique. Treatment

Two major strategies for treatment are: (3) To improve symptoms and quality of life with medical therapy alone or with percutaneous / surgical revascularization and (4) To prevent cardiovascular events with a comprehensive program that includes smoking cessation, an exercise program, control of blood pressure, achievement of goal LDL-C, antiplatelet therapy, and control of diabetes. Asymptomatic Lower Extremity PAD - 1. Smoking cessation, lipid lowering, diabetes and hypertension treatment.

2. Antiplatelet therapy - to reduce the risk of adverse cardiovascular ischemic events. 3. Angiotensin-converting enzyme (ACE) inhibition. Symptomatic Lower extremity PAD – Medical Management- Best medical treatment is considered the main therapeutic pillar in patients with PAD. These patients are at increased risk for major adverse cardiovascular events (MACE) and cardiovascular death. Antithrombotic, antihypertensive and lipid lowering therapy has been 56

shown to reduce the relative risk by 25% each. Medication should only be used in combination with aggressive lifestyle modification to reduce underlying lifestyle risk factors as mentioned above. Revascularization Before offering revascularization, a predicted or observed lack of adequate response to exercise therapy and claudication pharmacotherapies must be considered. Three clear indications for revascularization in patients with PAD are ischemic rest pain, ischemic ulcers or gangrene, and

claudication that interfere with the patient's lifestyle. Revascularization by endovascular or surgical means, will be guided by the lesion morphology based on TASC II (Trans Atlantic Society Consensus) document criteria, where TASC A & B lesions are treated by endovascular approach and type D lesion are treated surgically. TASC C lesions can be attempted by endovascular approach and if the same fails, surgery is resorted to.

Endovascular procedures for revascularization depend upon whether the clinical presentation is acute or chronic and whether it is because of thrombotic occlusion or steno-occlusive lesion. Acute thrombotic occlusions are treated by Catheter directed thrombolysis, whereas chronic occlusions may require mechanical thrombectomy. Stenosis and short length occlusions (TASC A & B) are treated by Angioplasty & Stenting. Diffuse atheromatous plaques causing stenosis

require Plaque Excisional Atherectomy. Long length occlusions in Iliac and SFA may yield to subintimal angioplasty followed by stent insertion if needed. Referral Criteria *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited: a) Clinical Diagnosis: Same diagnostic criteria as above. b) Investigations: Following thorough clinical evaluation, following investigations are required -

- Measurement of Ankle-Brachial Index (ABI) & hand held vascular doppler - Color Doppler Sonography - Magnetic Resonance Angiography (MRA) or Computed Tomographic Angiography (CTA) c) Treatment: Asymptomatic Lower Extremity PAD - Smoking cessation, lipid lowering, diabetes and hypertension treatment. Antiplatelet therapy - to reduce the risk of adverse cardiovascular ischemic events (10, 11). Symptomatic Lower extremity PAD – Best medical treatment is considered the main therapeutic

pillar in patients with PAD. These patients are at increased risk for major adverse cardiovascular events (MACE). Symptomatic Lower extremity PAD: 57

c) Modification of lifestyle to improve diet and physical activity and to control obesity, diabetes, hypertension and hyperlipidemia. d) Medical treatment with antithrombotic, antihypertensive and lipid lowering drugs. e) Revascularization, either endovascular or surgical (12). Standard Operating Procedure a. Out Patient / Day Care – Asymptomatic and symptomatic patients with less severe symptoms are treated on an Outpatient or Day Care basis.

ii) Referral criteria: Patients may be referred to higher medical facility based upon - - Worsening of symptoms despite adequate medical management including aggressive lifestyle modification or - Patient presents with acute limb ischemia (ALI) where immediate limb salvage is required. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available Clinical Diagnosis: Same diagnostic criteria as above. Investigations:

1. Measurement of Ankle-Brachial Index (ABI) & hand held vascular doppler 2. Color Doppler Sonography 3. Magnetic Resonance Angiography (MRA) or 4. Computed Tomographic Angiography (CTA) 5. Digital Subtraction Angiography (DSA) Treatment: Asymptomatic Lower Extremity PAD – 1. Smoking cessation, lipid lowering, diabetes and hypertension treatment. 2. Antiplatelet therapy - to reduce the risk of adverse cardiovascular ischemic events. Symptomatic Lower extremity PAD –

1. Aggressive lifestyle modification to reduce underlying lifestyle risk factors (e.g. atherogenic diet, overweight/obesity, physical inactivity) to control risk factors such as diabetes, hypertension and hyperlipidemia. 58

2. Medical treatment with antithrombotic, antihypertensive and lipid lowering therapy is given to reduce the relative risk of adverse events. 3. Revascularization – endovascular or surgical Standard Operating procedure a) Out Patient - Asymptomatic and symptomatic patients with less severe symptoms are treated on an Outpatient or Day Care basis. b) In Patient - Symptomatic patients requiring revascularization will need hospitalization for

minimum duration depending upon endovascular or surgical approach, where the former approach requires shorter hospital stay. Similarly patients with major adverse cardiovascular events will need hospitalization to treat the adverse events. Referral Criteria: 1. Worsening of symptoms despite adequate medical management including aggressive lifestyle modification or patient presents with acute limb ischemia where immediate limb salvage is required. Who does what? And Timelines

Designation Clinical Role Timeline Physician (Internist) Clinical Evaluation Screening on presentation to OP Vascular Surgeon (VS) Clinical Evaluation & supervising vascular Specialist Consultant who evaluation becomes the primary care Physician once diagnosis is established Performs Vascular Surgery When indicated or when IR procedures fail. Biochemist Biochemical evaluation After evaluation by and on the request of VS Diagnostic Radiologist Perform Duplex Doppler Sonography, After evaluation by and on the

Evaluate CTA or MRA request of VS Cardiologist Cardiac evaluation After consultation by and on the request of VS Management of MACE If necessary, following VS consult and on the request of VS Interventional IR Procedures – PTRA & Stenting, Referring Specialist for IR Radiologist Thrombolysis, Mechanical procedures on the request of VS thrombectomy, Subintimal Angioplasty 59

etc. Nursing Staff Assist in managing the patient In-patient or Day Care in Vascular Surgery facility, Dialysis facility and Interventional Radiology facility Technician Assist in Imaging the patient In CT,MR and Interventional Radiology facility after Radiology & IR consultation RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs & consumables and equipment. Quantity to also be specified)

SITUATI HUMAN INVESTIGATIONS DRUGS & EQUIPMENT(S) ON RESOURCES CONSUMABLES 1. Doctors – Hemoglobin, 1. Drugs: Vascular (Internist – 1, Random Blood Aspirin, Clopidogrel, Doppler(1) Vascular Surgeon – 1, Sugar, PT, APTT Nitroglycerine, Color Doppler Diagnostic Radiologist or INR, Platelet Nimodipine, Heparin Ultrasound (1) -1, Count, Se. MDCT or MRI Technician(s) – 3, Creatinine, with facility for Nursing - 2 HBsAg, HIV Vascular Imaging (1) 2. Doctors – Hemoglobin, 1. Drugs: Vascular

(Internist – 1, Random Blood Aspirin, Clopidogrel, Doppler(1) Vascular Surgeon with Sugar, PT, APTT Nitroglycerine, Operation – 1, Diagnostic or INR, Platelet Nimodipine, Heparin, Theatre (1) Radiologist -1, Count, Se. Non Ionic Interventional Creatinine, radiographic contrast Color Doppler Ultrasound (1) Radiologist – 1, HBsAg, HIV media Anaesthetist -1) 2. Consumables: Technician(s) – 3 to 4 Arterial access MDCT or MRI Nurses – 3 to 4 for all device, Diagnostic with Vascular

the units Catheter, Guiding Imaging (1) catheter, Self expanding or balloon Digital expanding Stent, Pre Subtraction and post dilatation Angiography angioplasty System (1) balloon(s), Compatible Sterile Suite guidewire (s) Multichannel 60

invasive monitor (1) Resuscitation equipment (1) Crash Trolley (1) References: 48. White C. Clinical practice: intermittent claudication. NEJM 2007;356(12):1241-1250 49. Hirsch AT, Criqui MH, Treat-Jacobson D et al: Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001; 286(11):1317-1324 50. Dormandy JA, Rutherford RB, for the TransAtlantic Inter-Society Consensus (TASC) Working Group, Management of peripheral arterial disease. Vasc Surg (2000) 31, S1– S296

51. Koshy CG, Chacko BR, Keshava SN, Agarwal S. Diagnostic Accuracy of Color Doppler Imaging in the Evaluation of Peripheral Arterial Disease as Compared to Digital Subtraction Angiography. Vascular Disease Management. January/ February 2009, Vol. 6(1):171-8 52. Fleischmann D, Hallett RL, Rubin GD: CT angiography of peripheral arterial disease. J Vasc Interv Radiol. 2006;17(1):3-26 53. Sun Z, Diagnostic accuracy of multislice CT angiography in peripheral arterial disease. JVIR 2006;17(12):1915-1921

54. Hirsch AT, Haskal ZJ, Hertzer NR et al:. ACC/AHA 2005 Practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic) Circulation. 2006;113(11):e463-e654 55. Hiatt WR: Medical treatment of peripheral arterial disease and claudication. NEJM 2001; 344(21):1608-1621 56. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, TASC II

Working Group: Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg. 2007;45:S5-S67 57. Hiatt WR, Hoag S, Hamman RF, San Luis Valley Diabetes Study. Effect of diagnostic criteria on the prevalence of peripheral arterial disease. Circulation 1995;91(5):1472-1479 61

58. Pickett CA, Jackson JL, Hemann BA, Atwood JE: Carotid bruits as a prognostic indicator of cardiovascular death and myocardial infarction: a meta-analysis. Lancet 2008;371(9624):1587-1594 59. Gray BH, Conte MS, Dake MD, et al. Atherosclerotic peripheral vascular disease symposium II: lower-extremity revascularization: state of the art. Circulation 2008;118(25):2864-2872 62

NAME OF THE CONDITION: RENOVASCULAR HYPERTENSION When to suspect or recognize? Renovascular hypertension should be suspected or recognized whenever there is any of the following(1) - - Onset of hypertension occurring in patients younger than 30 years without risk factors - Abrupt onset of severe hypertension in patients older than 55 years - Severe or resistant hypertension despite appropriate antihypertensive therapy - Abrupt increase in blood pressure over previously stable baseline in patients with

previously well-controlled essential hypertension as well as patients with known RAS - Negative family history for hypertension - History of smoking tobacco products - Symptoms of atherosclerotic disease elsewhere in the presence of moderate-to-severe hypertension, particularly in patients older than 50 years - Recurrent flash pulmonary edema in the setting of moderate-to-severe hypertension Introduction: Although hypertension is most often “essential” or idiopathic in origin, renovascular disease is an

important and potentially remediable cause of both hypertension and progressive renal insufficiency. The coexistence of renal arterial vascular disease and hypertension defines this type of nonessential hypertension. Renal artery stenosis may be caused by a heterogeneous group of conditions, but > 90% of cases is accounted for by atherosclerotic renovascular disease or fibromuscular dysplasia of the renal artery. Takayasu’s arteritis is a less common cause.

Thrombosis, embolism and dissection of the renal artery are rare causes(2). Case definition: Renovascular hypertension (RVHT) is the hypertension secondary to renal artery stenosis. It denotes the causal relationship between anatomically evident arterial occlusive disease and elevated blood pressure. Hemodynamically significant RAS should be defined as either: 1) Severe (> 70%) angiographically confirmed stenosis, or 2) moderate (50–70%) stenoses as

determined by angiography that are accompanied by hemodynamic evidence of renal ischemia documented by either a hyperemic systolic gradient > 20 mmHg, or renal fractional flow reserve of < 0.8. Incidence of the condition in our country: It is the most common type of secondary hypertension, accounting for 1-5% of cases in unselected populations and as many as 30% of cases in selected populations. The prevalence may

be up to 60% in patients older than 70 years. In general, the prevalence of atherosclerotic RAS increases with age, particularly in patients with diabetes, aortoiliac occlusive disease, coronary artery disease or hypertension. Differential Diagnosis: Prevention and Counselling: Preventing atherosclerosis may prevent the development of rental artery stenosis. Lifestyle changes may reduce risk of high blood pressure. Cessation of smoking, maintenance of healthy 63

weight, low cholesterol and lipid levels, regular exercise and diet with low protein, low sodium and high fiber content helps control blood pressure(3). Optimal Diagnostic criteria, Investigations, Treatment & Referral Criteria - Diagnostic Criteria: Clinical presentation is protean. In addition to elevated systemic blood pressure, renovascular hypertension usually produces symptoms common to hypertensive states, such as headache,

palpitations, tachycardia, anxiety, light-headedness, decreased tolerance of temperature extremes, retinopathy, and mental sluggishness. Significant complications include heart failure, myocardial infarction, stroke and, occasionally, renal failure. A high index of clinical suspicion may help in picking-up such patients. In particular, hypertensive patients with extensive atherosclerotic disease in other areas are prime candidates.

Hypokalaemia, an abdominal bruit, the absence of a family history of essential hypertension, duration of hypertension of less than one year, and the onset of hypertension before the age of 50 years are suggestive. Investigations: Investigations comprise tests to assess overall renal function, perfusion studies to assess differential renal blood flow, and imaging studies to identify renal artery stenosis. Imaging

studies establish the diagnosis; assess the location and severity of the clinically suspected RAS. Hematological Studies – To assess overall renal function, blood urea, serum creatinine, creatinine clearance and e GFR studies are needed. Duplex renal artery sonography - following clinical and laboratory evaluation, Duplex Doppler Sonography is the first line of imaging. It helps direct visualization of the renal arteries with

measurement of various hemodynamic changes in the main renal artery with Doppler, providing both structural and functional assessment of renovascular hypertension. Additional information regarding kidney size and presence of hydronephrosis can be obtained by ultrasound. Doppler for renal artery evaluation is limited by operator dependency, obesity and bowel gas artifacts. Captopril Scintigraphy adds valuable information regarding revascularization. The study relies

on the effect of captopril,an angiotensin-converting enzyme inhibitor, to reduce glomerular fi ltration in an ischemic kidney and increase it in the contralateral normal kidney. This difference can be imaged under a gamma camera. Asymmetry of flow or unilateral delayed isotope appearance but good bilateral renal concentration and excretion are strongly suggestive of large renal artery vascular occlusive disease that might be cured by revascularization. Test results may

be falsely negative in the presence of bilateral disease. Magnetic Resonance Angiography – Magnetic resonance angiography (MRA) is a noninvasive test for assessing renal artery stenosis, especially among patients with renal insufficiency at higher risk for contrast nephropathy. Evaluates not only the main renal arteries but also the accessory renal arteries and distal stenosis. The reliability of magnetic resonance angiography is

not affected by the presence of bilateral renovascular disease unlike scintigraphy. MRA may overestimate the severity of stenosis relative to angiography. 64

Computed Tomographic Angiography – CT angiography (CTA) especially with MDCT is a valuable noninvasive study for assessing renal artery stenosis. If the patient has normal renal function, this probably represents the best screening test. It is much faster to perform than MRA, is less prone to false positive results, and has superior spatial resolution. It is not limited by flow related artifacts and presence of mural calcification. Evaluates not only the main renal artery but

also the accessory renal arteries and distal stenosis. Subset of patients not suitable for MRA can be evaluated by CTA. Digital Subtraction Angiography - remains the gold standard to determine the degree and location of renal artery stenosis. With the availability of noninvasive imaging, DSA is reserved to confirm the diagnosis, often as a prelude to percutaneous intervention. However, it is limited in providing information about the functional role and thus the clinical significance of the lesion.

Use of Iodinated contrast and related nephropathy limit its use(4). Treatment: Management of RAS should ideally control hypertension, restore renal function (renal salvage) and ultimately reduce cardiovascular mortality in the long term. Revascularization of the ischemic kidney helps to preserve renal function as well as lower blood pressure. Once the lesion is found and proved to be functionally significant, three modalities of management are available: 1. Medical therapy 2. Angioplasty and stenting

3. Surgery Relative merits of the different types of treatment depend on a variety of factors such as the age of the patient, the etiology and severity of the renal artery stenosis, and the presence or absence of concomitant disease(3). Medical Management: ACE inhibitors are widely accepted as being superior to other antihypertensive drugs in controlling renovascular hypertension. Furthermore, ACE inhibitors have been associated with improved survival of these patients, many of whom carry a heavy

burden of generalized atherosclerotic disease. Endovascular Management: Percutaneous Transluminal Renal Angioplasty & Stenting (PTRA) - For patients with symptomatic, hemodynamically significant RAS, reperfusion by angioplasty and stent placement is the treatment of choice (4-10). Patients with significant RAS who benefit most are those with: 1) Poorly controlled hypertension on adequate medical therapy - with hemodynamically

significant renal artery stenosis and accelerated hypertension, resistant hypertension, and malignant hypertension. 2) Ischemic nephropathy in a viable kidney with declining renal function - with renal artery stenosis and progressive chronic kidney disease with bilateral renal artery stenosis or a stenosis to a solitary functioning kidney. 65

3) Cardiac destabilization syndromes, i.e., flash pulmonary edema, recurrent congestive heart failure or refractory unstable angina - with hemodynamically significant renal artery stenosis (i.e,>70% stenosis on angiography) and recurrent, unexplained congestive heart failure or sudden, unexplained pulmonary edema. Referral Criteria: *Situation 1: At Secondary Hospital / Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited: Clinical Diagnosis:

Clinical presentation is protean. In addition to elevated systemic blood pressure, renovascular hypertension usually produces symptoms common to hypertensive states, such as headache, palpitations, tachycardia, anxiety, light-headedness, decreased tolerance of temperature extremes, retinopathy, and mental sluggishness. Significant complications include heart failure, myocardial infarction, stroke and, occasionally, renal failure.

A high index of clinical suspicion may help in picking-up such patients. In particular, hypertensive patients with extensive atherosclerotic disease in other areas are prime candidates. Hypokalaemia, an abdominal bruit, the absence of a family history of essential hypertension, duration of hypertension of less than one year, and the onset of hypertension before the age of 50 years are suggestive. Investigations: 1. Biochemical studies to assess overall renal function.

2. Imaging studies to identify renal artery stenosis and to assess the location and severity of the clinically suspected RAS. Hematological Studies – To assess overall renal function, blood urea, serum creatinine, creatinine clearance and e GFR studies are needed. Duplex renal artery Sonography - First line of imaging following clinical and laboratory evaluation. It helps by direct visualization of the renal arteries with measurement of various

hemodynamic changes in the main renal artery with Doppler, providing both a structural and a functional assessment. Once suspected, the patient can be referred to tertiary care center for further evaluation and management. Treatment: Medical Management: ACE inhibitors are widely accepted as being superior to other antihypertensive drugs in controlling renovascular hypertension. Furthermore, ACE inhibitors have been associated with improved survival of these patients, many of whom carry a heavy

burden of generalized atherosclerotic disease. Standard Operating Procedure 66

Out Patient: Medical management for RVHT without complications can be done on an outpatient basis. Day Care: If patient is on maintenance hemodialysis, day care is needed. In Patient: To manage complications of RVHT such as heart failure, myocardial infarction, stroke and, occasionally, renal failure patients may require hospitalization. Referral criteria: Poorly controlled hypertension on adequate medical therapy, Ischemic nephropathy in a viable

kidney with declining renal function, Cardiac destabilization syndromes, i.e., flash pulmonary edema, recurrent congestive heart failure or refractory unstable angina are the indications for referring for further aggressive management. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available Clinical Diagnosis: Criteria same as in Situation 1 Investigations: Required to establish the diagnosis, assess the location and severity of the clinically suspected RAS.

1. Studies to assess overall renal function 2. Physiological studies to assess the renin – angiotensin system 3. Perfusion studies to assess differential renal blood flow and 4. Imaging studies to identify renal artery stenosis Biochemical evaluation Duplex Doppler Sonography of renal artery Captopril Scintigraphy Magnetic Resonance Angiography (MRA) Computed Tomographic Angiography (CTA) Digital Subtraction Angiography (DSA) Treatment:

Medical Management: ACE inhibitors are widely accepted as being superior to other antihypertensive drugs in controlling renovascular hypertension. Endovascular Management (Percutaneous Transluminal Renal Angioplasty & Stenting) - For patients with symptomatic, hemodynamically significant RAS, reperfusion by angioplasty and stent placement is the treatment of choice. Patients with significant RAS who have 1) poorly controlled hypertension despite adequate medical therapy, 2) Ischemic nephropathy in a viable

kidney with declining renal function, 3) Cardiac destabilization syndromes, i.e., flash pulmonary edema, recurrent congestive heart failure or refractory unstable angina are the subset who will benefit from revascularization. Standard Operating procedure 67

In Patient: For revascularization procedures, such as Percutaneous Transluminal Renal Angioplasty & Stenting (PTRA), patient needs admission into the hospital for minimum three to four days. To manage complications of RVHT such as heart failure, myocardial infarction, stroke and occasionally, renal failure the duration of stay may be longer. Day Care: If patient is on maintenance hemodialysis, day care is needed. Out Patient: Medical management is done on an outpatient basis. Referral criteria:

Poorly controlled hypertension on adequate medical therapy, Ischemic nephropathy in a viable kidney with declining renal function, Cardiac destabilization syndromes, i.e., flash pulmonary edema, recurrent congestive heart failure or refractory unstable angina are the indications for referring for further aggressive management. Who does what? And Timelines Designation Clinical Role Timeline Physician (Internist) Clinical Evaluation Screening on presentation to OP

Biochemist Biochemical evaluation Following evaluation by Physician Nephrologist Specific management including Dialysis, if Specialist Consultant who needed becomes the primary care Physician once diagnosis is established Diagnostic Radiologist Perform Duplex Doppler Sonography, Evaluate Following evaluation by CTA or MRA Nephrologist Cardiologist Management of Cardiac complications When indicated Interventional PTRA & IR management of vascular Referring Specialist for IR

Radiologist complications, if any procedures on the request of Nephrologist Nursing Staff Assist in managing the patient In-patient or Day Care in Nephrology or Dialysis facility and Interventional Radiology facility Technician Assist in Imaging the patient In CT,MRI and Interventional Radiology facility after Radiology & IR consultation CTA=CT Angiography, MRA=MR Angiography, PTRA=Percutaneous Transluminal Renal Angioplasty, IR =

Interventional Radiology, CT=Computed Tomography, MR=Magnetic Resonance Imaging RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) 68

Situa HUMAN INVESTIGATIONS DRUGS & CONSUMABLES EQUIPMENT tion RESOURCES 1 Doctors - 6 Hematological -Antihypertensive drugs - Hematological (Physician, Imaging laboratory Biochemist, -Duplex Doppler - Color Doppler Nephrologist, Sonography Ultrasound (1) Diagnostic Radiologist, Cardiologist, Interventional Radiologist) Nursing – 6 - 8 Technician – 4 - 6 2 Doctors - 4 Hematological -Antihypertensive -Hematological Nursing - 4 Imaging: drugs laboratory

Technician – 6 - Duplex Doppler -Anticoagulants -Color Doppler Sonography -Vasodilators Ultrasound (1) - Radionuclide -Radioisotopes -SPECT (1) Scintigraphy -Radiographic Contrast -CT or MRI Scanner - CTA or MRA medium (1) - DSA (PTRA with -Parenteral fluids etc. -DSA equipment (1) Stenting) -Vascular access devices -Catheters for diagnostic angiography -Compatible guiding catheter -Compatible guidewire -Stent -Inflatable infusion bag(s) Further Reading / References:

VI. Ashish Bhalla, Sanjay D’Cruz, SS Lehl, Ram Singh: Renovascular hypertension – its evaluation and management: JIACM 2003; 4(2): 139-46 VII. Olin JW, Melia M, Young JR, Graor RA, Risius B. Prevalence of atherosclerotic renal artery stenosis in patients with atherosclerosis elsewhere. Am J Med 1990; 88:46N– 51N VIII. Vesna D. Garovic, Garvan C. Kane, Gary L. Schwartz: Renovascular hypertension: Balancing the controversies in diagnosis and treatment: Cleveland Clinic Journal of Medicine 72(12) 2005

IX. Rees C. Renovascular interventions. JVIR1996(suppl);7(1):311-314. 69

X. Cicuto KP, McLean GK, Oleaga JA, Freiman DB, Grossman RA, Ring EJ. Renal artery stenosis: anatomic classification for percutaneous transluminal angioplasty. AJR 1981; 137:599–601. XI. Safian RD, Textor SC. Renal-artery stenosis. N Engl J Med 2001;344:431–442 XII. Cooper CJ, Murphy TP. Case for Angioplasty and Stenting of Atherosclerotic Renal Artery Stenosis. Circulation 2007;115:263-270 XIII. Canzanello VJ, Millan VG, Spiegel JE Percutaneous transluminal renal

angioplasty in management of atherosclerotic renovascular hypertension: results in 100 patients. Hypertension 1989,13:163–172 XIV. Fang BR, Lin CY. Reversible renin-dependent renovascular hypertension successfully treated with percutaneous transluminal renal angioplasty and stenting. Int Heart J. 2005 Mar;46(2):339-45 XV. VJ Canzanello, VG Millan, JE Spiegel, PS Ponce, RI Kopelman and NE Madias. Percutaneous transluminal renal angioplasty in management of atherosclerotic

renovascular hypertension: results in 100 patients. Hypertension,1989,Vol 13, 163-172 70

VERTEBROPLASTY VIII. WHEN TO SUSPECT/ RECOGNIZE? 1a Introduction: Vertebroplasty is injection of bone cement into a diseased vertebra, Percutaneously, under image guidance. This is done to provide pain relief and to strengthen the diseased vertebra. 1b Indications: It is indicated under the following conditions for near immediate pain relief / where prolonged bed rest is contraindicated / pain relief is inadequate with analgesics: 1. Painful osteoporotic collapse vertebra

2. Painful metastatic collapse vertebra 3. Painful Hemangioma of vertebra 4. Post traumatic painful partial collapse in a non osteoporotic vertebra without retropulsion causing cord compression IX. INCIDENCE OF THE CONDITION IN OUR COUNTRY: Osteoporosis and malignancy have a world wide distribution. Cancer is the leading cause of death. Osteoporosis is inevitable with age. X. DIFFERENTIAL DIAGNOSIS N/A XI. PREVENTION AND COUNSELING: Early diagnosis of osteoporosis and

malignancy and their appropriate treatment will reduce the incidence of osteoporotic collapse vertebrae and of metastases. This can reduce the incidence of vertebral collapse. XII. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA / FOLLOW UP Diagnostic Criteria: • Vertebral tenderness • Radiograph Spine – shows partial collapse of vertebral body that s tender 71

• MRI – shows marrow edema in the vertebral body • Radiograph and MRI – Not suggestive of infective etiology • Bone biopsy to be done along with vertebroplasty if MRI suggests metastatic possibility Investigations: • Radiograph of Spine – AP and Lateral views • MRI Spine • Blood - Hb, TLC, DLC • Blood – Platelets count • Blood – INR • Blood Creatinine Treatment: Vertebroplasty As required for etiology of partial collapse, such as for malignancy or Osteoporosis Referral criteria:

Patients meeting the criteria for vertebroplasty should be referred to centers equipped with capability to perform vertebroplasty Follow up: Clinical after 1 week Subsequent follow up should be if there is recurrence of symptoms. *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited f) Clinical Diagnosis: Back ache with local tenderness on the spinous process of the vertebra.

g) Investigations: i. Radiograph Spine AP and lateral views, ii. MRI Spine iii. Blood – Hb, TLC, DLC, ESR, Platelets, INR, Glucose fasting and post prandial, Creatinine h) Treatment: Standard Operating procedure : Based on the clinical condition of the patient, the procedure can be done under Local anesthesia / Conscious sedation / General Anesthesia. The patient is positioned on a Fluoroscopy unit, in a prone position for 72

dorsal and lumbar vertebrae and supine for cervical vertebrae. A patient who cannot lie prone or supine may lie in a decubitus position. A biplane DSA unit is preferable. However the procedure can be done in a single plane fluoroscopy unit. Appropriate anesthesia / sedation is given. The Needle approved for Vertebroplasty is positioned into the anterior half of the vertebral body Under Image guidance with Image intensifier. Opacified bone cement approved for Vertebroplasty is injected into the

vertebral body under live fluoroscopy, so as to diffuse into the affected vertebral body. Care be taken to avoid cement passage out of the vertebral body. The needle is removed. The patient is on bed rest for a minimum period of 3 hours. Additional restrictions are as per the anesthesia. a. In Patient: If necessitated by the general condition of the patient. b. Out Patient: Can be treated as outpatient. c. Day Care: Can be treated as outpatient. i) Referral criteria: As above

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available k) Clinical Diagnosis: As above l) Investigations: As above m) Treatment: As above Standard Operating procedure: As above a. In Patient b. Out Patient c. Day Care n) Referral criteria: As above XIII. WHO DOES WHAT? and TIMELINES a. Doctor – Patient evaluation, Informed Consent, Procedure b. Nurse – Assists the Doctor 73

c. Technician – Manages the C Arm XIV. FURTHER READING / REFERENCES 1. J. Kevin McGraw, MD, John Cardella, MD, John Dean Barr, MD, John M. Mathis, MD, Orestes Sanchez, MD, Marc S. Schwartzberg, MD, Timothy L. Swan, MD, and David Sacks, MD, for the Society of Interventional Radiology Standards of Practice Committee. Society of Interventional Radiology. Quality Improvement Guidelines for Percutaneous Vertebroplasty. J Vasc Interv Radiol 2003; 14:S311– S315

2. Quality assurance guidelines for performance of Percutaneous Vertebroplasty. A Gangi, T Sabharwal, RG Irani et al. CIRSE – Cardiovascular and Interventional Radiology Web site. 3. ACR–ASNR–ASSR–SIR–SNIS PRACTICE GUIDELINE FOR THE PERFORMANCE OF VERTEBROPLASTY. Revised 2009 vide resolution no. 25. American College of Radiology website. RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and

consumables and equipment. Quantity to also be specified) Situat HUMAN INVESTIGATIONS DRUGS & EQUIPMENT ion RESOURCES CONSUMABLES 1 Interventional Blood Hb, TLC, Vertebroplasty C Arm. Preferably Radiologist -1 DLC Set -1 Biplane Nurse -1 Blood Platelet Local Anesthetic Muti parmeter count – 10ml monitor X Ray Technitian Blood – INR Sedative Oxygen trained in C Arm - 1 Anesthetist if Blood Creatinine Analgesic Defibrillator required Suction Machine 2 Same as above Same as above Same as above Same as above 74

RABIES IS 100 PERCENT FATAL BUT PREVENTABLE Rabies can be caused by bite or scratch of rabid animal such as dogs, cats etc Do not apply chillies, mustard oil or any other National Rabies Control Programme irritant on the bite wounds Wash the wound immediately with plenty of soap & water National Guidelines Do not apply dressing & Do not get the wound stitched on Rabies Prophylaxis Consult your doctor immediately or rush to nearest antirabies clinic Complete the course of antirabies vaccination,

as advised by your doctor In severe bites, combined antirabies serum and vaccine therapy is recommended Vaccinate your pets against rabies every year NATIONAL CENTRE FOR DISEASE CONTROL NATIONAL CENTRE FOR DISEASE CONTROL (Directorate General of Health Services) (Directorate General of Health Services) 22-SHAM NATH MARG, DELHI - 110 054 22-SHAM NATH MARG, DELHI - 110 054 hp://www.ncdc.gov.in hp://www.ncdc.gov.in 2015 2015

National Rabies Control Programme National Guidelines on Rabies Prophylaxis

Contents List of abbreviations and acronyms Page No. 1. Introduction 7 2. Post-Exposure Prophylaxis 8 2.1 Decision to treat 8 2.2 Approach to Post-Exposure Prophylaxis 11 2.2.1 Management of Animal Bite Wound 12 2.2.2 Rabies Immunoglobulin (RIG) 13 2.2.3 Anti-Rabies Vaccines 16 2.2.3.1 Intradermal (ID) Regimen 17 2.2.3.2 Intramuscular (IM) Regimen 21 2.3 Management of re-exposure in previously vaccinated person 22 3. Pre-Exposure Prophylaxis 23 4. List of Experts 24 5. Annexures 25

1. Table 1: Equine rabies immunoglobulin currently manufactured in India 25 Table2: Currently available human rabies immunoglobulin in India. 25 Table3: Currently available anti-rabies vaccines in India. 26 2. Proforma for management of animal bite case at an anti-rabies centre/clinic (ARC) 27 6. Decision Tree: Guide to Post-Exposure Prophylaxis (PEP) 28 7. Frequently Asked Questions 29

List of Abbreviations and Acronyms AEFI Adverse events following immunization AIDS Acquired Immunodeficiency Syndrome ARC Anti-Rabies Centre/Clinic ARV Anti-Rabies Vaccine CCV Cell Culture Vaccine DCGI Drug Controller General of India ERIG Equine Rabies Immunoglobulin HDCV Human Diploid Cell Vaccine HIV Human Immunodeficiency Virus HRIG Human Rabies Immunoglobulin IAP Indian Association of Pediatrics ICMR Indian Council of Medical Research ID Intradermal IM Intramuscular IU International Units

NCDC National Centre for Disease Control NICD National Institute of Communicable Diseases NRCP National Rabies Control Programme NSAID Non-Steroidal Anti-Inammatory Drug NTV Nerve Tissue Vaccine PCEC Purified Chick Embryo Vaccine PDEV Purified Duck Embryo Vaccine PEP Post-Exposure Prophylaxis PrEP Pre-Exposure Prophylaxis PVRV Purified Vero Cell Vaccine RIG Rabies Immunoglobulin WHO World Health Organization ºC Degree Centigrade

4 National Guidelines on Rabies Prophylaxis National Guidelines on Rabies Prophylaxis 5

1.Introduction Rabies is an acute viral disease that causes fatal encephalomyelitis in virtually all the warm-blooded animals including man. The virus is found in wild and some domestic animals, and is transmitted to other animals and to humans through their saliva (following bites, scratches, licks on broken skin and mucous membrane). In India, dogs are responsible for about 97% of human rabies, followed by cats (2%), jackals, mongoose and others (1%). The disease is mainly

transmitted by the bite of a rabid dog. Rabies has terrified man since antiquity. The fear is by no means unfounded since the disease is invariably fatal and perhaps the most painful and dreadful of all communicable diseases in which the sick person is tormented at the same time with thirst and fear of water (hydrophobia). Fortunately, development of rabies can be prevented to a large extent if animal bites are managed appropriately and in time. In this regard the post-exposure treatment of animal

bite cases is of prime importance. National Centre for Disease Control (formerly National Institute of Communicable Diseases), Delhi, WHO Collaborating Centre for Rabies Epidemiology, organized an expert consultation in 2002 to formulate national guidelines for rabies prophylaxis to bring out uniformity in post-exposure prophylaxis practices. These guidelines were revised in an expert consultation in 2007 and again in 2013, after Nerve Tissue Vaccine (NTV) production was

stopped (2004) in the country and modern cell culture vaccines (CCVs) were recommended for use for post exposure prophylaxis. Higher cost of intra- muscular administration of CCV is a limiting factor for its wider use. And hence, in February 2006, as per WHO recommendations, results of clinical trials on safety, efficacy and feasibility, Drug Controller General of India (DCGI) approved the use of safe, efficacious and economical Intra-dermal (ID) route of inoculation of CCVs.

Under the 12th five year plan National Rabies Control Programme (NRCP) has been approved. The NRCP has both human and animal health components. The human health component is being implemented throughout the country. The NCDC is the nodal centre for its implementation and the focus of human health component is on providing timely and appropriate animal bite management to all animal bite victims. This can be attained by creating awareness in general

community to seek Post Exposure Prophylaxis (PEP), train doctors in appropriate animal bite management and implement ID route of inoculation of CCVs for wider coverage in available quantity of vaccines. Hence, need was felt to review national guidelines and disseminate them widely for uniformity in PEP. 6 National Guidelines on Rabies Prophylaxis National Guidelines on Rabies Prophylaxis 7

2.Post-Exposure Prophylaxis (PEP) Bite by rodents: Exposure to domestic rodents, squirrel, hare and rabbits do not ordinarily require PEP. 2.1Decision to treat Bat rabies: Bat rabies has not been conclusively proved in India and hence, at In a rabies endemic country like India where there is sustained dog-to-dog present, exposure to bats does not warrant PEP. transmission, every animal bite is suspected as a potentially rabid animal bite,

and treatment should be started immediately after exposure. Bite by all warm Post-exposure prophylaxis of immune-compromised patients: Several blooded animals necessitates post-exposure prophylaxis. As rabies is practically studies of patients with HIV/AIDS have reported that those with low CD4 (<200 100% fatal, bites by dogs and cats in particular must be considered as a “medical counts) will mount a significantly lower or no detectable neutralizing antibody

emergency” and the “life-saving” post exposure prophylaxis must be provided response to rabies. In such patients and those in whom the presence of immediately. immunological memory is no longer assured as a result of other causes (patients on chemotherapy, long term steroid therapy, cancer patients, etc) proper and Observation of biting dog/cat: The PEP should be started immediately after thorough wound management and antisepsis accompanied by local infiltration

the bite. The observation period of 10 days is valid for dogs and cats only. The of rabies immunoglobulin followed by complete course of anti-rabies vaccination natural history of rabies in mammals other than dogs and cats is not fully by intramuscular route in both category II and III exposures are of utmost understood and therefore the 10-day observation period is not applicable. importance. Preferably, if the facilities are available, anti-rabies antibody

estimation should be done 14 days after the completion of course of vaccination The treatment may be modified if dog or cat involved remains healthy to assess the need of additional doses of vaccine. throughout the observation period of 10 days by converting post-exposure prophylaxis to pre-exposure vaccination by skipping the vaccine dose on day 14 Human-to-human transmission: The risk of rabies transmission to other and administering it on day 28 while using Essen Schedule. While using ID

humans from a human rabies case is very minimal and there is no well- administration complete course of vaccination should be given irrespective of documented case of human-to-human transmission, other than the few cases status of animal. resulting from organ/tissue (cornea) transplant. However, people who have been exposed closely to the secretions of a patient with rabies may be offered Vaccination status of the biting animal: Although unvaccinated animals

PEP as a precautionary measure. Organ/tissue (cornea) for transplantation, are more likely to transmit rabies, vaccinated animals can also do so if the should never be collected from suspected/confirmed rabies or rabies like vaccination of the biting animal was ineffective for any reason. A history of encephalitis cases. rabies vaccination in an animal is not always a guarantee that the biting animal is not rabid. Animal vaccine failures may occur because of improper

Contraindications and precautions: As rabies is nearly 100% fatal disease, administration or poor quality of the vaccine, poor health status of the animal, there is no contraindication to PEP. Pregnancy, lactation, infancy, old age and and the fact that one vaccine dose does not always provide long-lasting concurrent illness are no contraindications for rabies PEP in the event of an protection against rabies infection in dogs/cats. Hence, appropriate

exposure. PEP against rabies takes preference over any other consideration as it documentation of vaccination status of dog/cat and proper history should be is a lifesaving treatment. Moreover, rabies vaccine does not have any adverse elicited before deciding to defer post-exposure prophylaxis after bite by effect on pregnant woman, course of pregnancy, fetus or lactating mother. vaccinated dog/cat. Hence, complete PEP should be given depending on the category of the exposure.

Provoked versus unprovoked bite: A provoked dog bite should also be managed as an exposure and PEP started immediately. A provoked bite does not People taking chloroquine for malaria treatment or prophylaxis may have a mean that the biting animal is not rabid. It is difficult to understand what reduced response to ID rabies vaccination. These patients should receive the provokes a dog so it is prudent to start PEP at the earliest. rabies vaccine intramuscularly.

Bite by wild animals: Bite by all wild animals should be treated as category III exposure. All animal bites in forest or in the wild should be treated as category III exposure. 8 National Guidelines on Rabies Prophylaxis National Guidelines on Rabies Prophylaxis 9

As with all other immunizations, vaccinated persons should be kept under Table 1: Type of contact, exposure and recommended post-exposure medical supervision for at least 15–20 minutes following vaccination. Previous prophylaxis reaction to any component of a vaccine is a contraindication to the use of the Category Type of contact Recommended post-exposure prophylaxis same vaccine for PEP or Pre-exposure prophylaxis (PrEP). I Touching or feeding of animals None, if reliable case history is

Licks on intact skin available Because of long and variable incubation period, which is typical of most cases of Contact of intactskin with secretions/excretions of rabid animal/human case human rabies, it is possible to institute PEP to protect the individual. This must be started at the earliest to ensure that the individual is immunized or protected II Nibbling of uncovered skin Wound management

before the rabies virus reaches the nervous system. However, people who Minor scratches or abrasions without bleeding Anti-rabies vaccine present for treatment even months or years after a possible rabies exposure should be evaluated and treated as if the event had occurred recently. Risk assessment of potential rabies exposure can be complex and confusing. When in doubt post exposure prophylaxis should be initiated and the attending physician should consult specialist at Anti Rabies Centres.

To bring out uniformity globally, the classification of animal bite for post- III Single or multiple transdermal bites or Wound management exposure prophylaxis has been based on WHO recommendations (WHO TRS scratches, licks on broken skin Rabies immunoglobulin Anti-rabies vaccine 2013) (Table 1). Contamination of mucous membrane with saliva (i.e. licks) It is re-emphasized that PEP should be started as early as possible after exposure. However, PEP should not be denied to person reporting late for

treatment as explained previously. 2.2. Approach to Post-Exposure Prophylaxis (PEP) The post-exposure prophylaxis is a three-pronged approach. All three carry equal importance and should be done simultaneously as per the category of exposure Management of animal bite wound(s) Passive immunization with Rabies Immunoglobulin (RIG) Active immunization with Anti-Rabies Vaccines (ARV) 10 National Guidelines on Rabies Prophylaxis National Guidelines on Rabies Prophylaxis 11

2.2.1 Management of animal bite wound(s) Wound(s) toilet can be done by prompt and gentle thorough washing with soap Wound(s) toilet: Since the rabies virus enters the human body through a bite or detergent and ushing the wound(s) with running water. If soap and or scratch, it is imperative to remove as much saliva, and thereby the virus, from detergent are not immediately available wash with running water. The

the wound(s) as is possible by an efficient wound(s) toilet that should not involve maximum benefit of the wound(s) washing is obtained when fresh wound(s) is additional trauma. Washing of wound(s) should be carried out as soon as cleaned immediately. Considering the importance of this step all health possible with soap and water. Since the rabies virus can persist and even facilities should have wound washing facilities. multiply at the site of bite for a long time, wound(s) toilet must be performed

even if the patient reports late. (Table 2) The application of irritants (like chilies, oil, turmeric, lime, salt, etc) is unnecessary and damaging. In case irritants have been applied on the wound(s), Table 2: Wound(s) Management enough gentle washing with soap or detergent to remove the external applicant/s should be done followed by ushing with copious amount of water Do's immediately. Physical Wash with running water Mechanical removal of virus from

the wound(s) It should be noted that the immediate washing of the wound(s) is a priority. However, the victim should not be deprived of the benefit of wound(s) toilet as long as there is an unhealed wound(s) which can be washed even if the victim reports late. The maximum benefit of the wound(s) washing is obtained when fresh wound(s) is cleaned immediately. Application of antiseptics: After thorough washing and drying the wound(s),

any one of the available chemical viricidal agents should be applied, such as povidone iodine, alcohol, etc. Chemical Wash the wound(s) with soap and water Inactivation of the virus Apply disinfectant Local infiltration of rabies immunoglobulin: In category III exposures rabies immunoglobulin should be infiltrated in the depth and around the wound(s) to neutralize the locally present virus as described in section 3.2. Suturing of wound(s) should be avoided as far as possible. If surgically

unavoidable, after adequate cleansing, rabies immunoglobulin should be infiltrated in the depth and around the wound(s) and suturing should be delayed by a few hours. The delay in suturing allows diffusion of antibodies in the tissues. Minimum loose sutures should be applied for arresting the bleeding in life threatening situations. Cauterization of wound(s) is no longer recommended as it leaves bad scar, and Biological Infiltrate immunoglobulin into the depth and Neutralization of the virus

does not confer any additional advantage over washing the wound(s) with water around the wound(s) in Category III exposures and soap. Tetanus and antibiotic prophylaxis should be given if required. To prevent sepsis in the wound(s), a suitable course of an antibiotic may be recommended. 2.2.2 Rabies Immunoglobulin (RIG) Dont's Touch the wound(s) with bare hand The anti-rabies serum/Rabies Immunoglobulin (RIG) provides passive Apply irritants like soil, chilies, oil, lime, herbs, chalk, betel leaves, etc.

12 National Guidelines on Rabies Prophylaxis National Guidelines on Rabies Prophylaxis 13

immunity in the form of ready-made anti-rabies antibodies, before it is injection at a site distant from the vaccine injection site. physiologically possible for the victim to begin producing his/her own antibodies following anti-rabies vaccination. Anti-rabies serum or RIG has the property of Animal bite wounds inicted can be severe and multiple, especially in small

binding with the rabies virus, thereby resulting in neutralization and thus loss children. In such cases, the calculated dose of the rabies immunoglobulin may of infectivity of the virus and hence it is most logical to infiltrate RIG locally at not be sufficient to infiltrate all wounds. In these circumstances, it is advisable the site of exposure. Two types of RIGs are available: to dilute the calculated volume of RIG in sterile normal saline to a volume

sufficient to infiltrate all the wounds. However, the total recommended dose of Equine Rabies Immunoglobulin (ERIG): ERIG is of heterologous origin RIG must not be exceeded as it may suppress the antibody production produced by hyper-immunisation of horses. Currently manufactured ERIGs are stimulated by the anti-rabies vaccine. highly purified Fab 2' fragments and the occurrence of adverse events has been

significantly reduced. These are produced in the country in public and private Rabies immunoglobulin for passive immunization is administered only once, sectors. (Annexure 1: Table 1: ERIG currently manufactured in India) preferably within 24 hours after the exposure (on day 0 along with the first dose of anti-rabies vaccine). If RIG was not administered when ARV was begun, it

Since, ERIG are of heterologous origin, they carry a small risk of anaphylactic can be administered up to the seventh day after the administration of the first reaction (1/150,000). However, literature supports that there is no scientific dose of ARV. Beyond the seventh day(after 3 doses of vaccine have been ground for performing a skin test prior to administering ERIG because testing administered), RIG is not indicated since an antibody response to ARV would

does not predict reactions, and ERIG should be given irrespective of the result of have occurred and administration of RIG at this stage can suppress the immune the test. The treating physician should be prepared to manage anaphylaxis, response of the patient to the ARV received. which, although rare, could occur during any stage of administration, even

when the skin test did not show any reaction (WHO TRS 2013, pg 43). However, Infected bite wound is no contraindication to infiltration of immunoglobulin. Tip some manufacturers of ERIG still recommend performing a skin test. of finger(s) and toe(s), ear lobe(s) or bites on nose or around the eye can be safely injected with RIG provided the injection is not done with excessive pressure, Human Rabies Immunoglobulin (HRIG): HRIG are of homologous origin and which can cause compression syndrome.

are relatively free from the side effects encountered in a serum of heterologous origin. However, it is expensive and is imported from other countries. (Annexure Rabies Immunoglobulin should never be administered in the same syringe or at 1: Table 2: Currently available HRIG in India). Because of their longer half-life, the same anatomical site as vaccine. they are given at half the dose of equine anti-rabies serum. Animal bite victim should be kept under observation for at least half–an–hour

Indication: RIG should be administered to all category III exposures. However, after administration of ERIG. There is no need to admit the patient. in immune compromised individuals, RIG should be administered in both category II and III exposures. Physicians administering ERIG should always be ready to treat anaphylactic reactions with adrenalin. The dose is 0.5 ml of 0.1 percent solution (1 in 1000,

Dose of rabies immunoglobulin: The dose of ERIG is 40 IU per kg body 1mg/ml) for adults and 0.01ml/kg body weight for children, injected weight of patient. The ERIG produced in India contains 300 IU per ml. The dose subcutaneously or IM. Other emergency drugs and supportive therapy should of the HRIG is 20 IU per kg body weight. HRIG preparation is available in also be available. concentration of 150 IU per ml. Administration of full dose of RIG intramuscularly into the gluteal region or

Administration of rabies immunoglobulin: The RIG should be brought to infiltration of half the dose of RIG locally and half intramuscularly is not room temperature (25ºC to 30ºC) before administration to the patient. recommended. As much of the calculated dose of RIG as is anatomically feasible should be infiltrated into and around the wound/s. Multiple needle injections into the Tolerance and side effects: There may be transient tenderness at the

wound(s) should be avoided. After all the wound(s) has been infiltrated, if any injection site and a brief rise in body temperature that does not require any volume of RIG is remaining, it should be administered by deep intramuscular treatment. Anaphylactic reactions are extremely rare. RIG must never be given 14 National Guidelines on Rabies Prophylaxis National Guidelines on Rabies Prophylaxis 15

intravenously. but at the maximum, within 8 hours. Serum sickness is rare and occurs usually 7 to 10 days after injection of ERIG, While using IM administration the vaccine should be used immediately after but it has not been reported after treatment with HRIG. reconstitution. However, in case of unforeseen delay it should not be used after 8 hours of reconstitution. A full course of ARV should follow thorough wound cleansing and passive

immunization. All vaccines which are reconstituted and not used thereafter should be discarded after 8 hours of reconstitution. 2.2.3 Anti-Rabies Vaccines Active immunization is achieved by administration of safe and potent cell Adverse effects following administration of CCVs: The CCVs are widely culture vaccines (CCVs) or purified duck embryo vaccine (PDEV). Currently accepted as the least reactogenic rabies vaccines available today. However, few

available CCVs could be administered by IM regimen and CCVs approved for ID studies have now shown that adverse effects can be either general in nature or use shall be administered by ID regimen. allergic in origin. Mild systemic adverse events following immunization (AEFI) include headache, malaise, nausea and fever. Symptomatic treatment may be Anti-rabies vaccines are produced as one single intramuscular dose with needed. Minor and transient erythema, pain and/or swelling may occur at the

potency of > 2.5IU per IM dose for post exposure and pre-exposure prophylaxis. site of injection, particularly following intradermal administration. Serious It is absolutely essential that every batch of CCVs have minimum potency of AEFIs mainly of allergic or neurological nature rarely occur. 2.5IU per IM dose, irrespective of whether the vaccine is administered by IM or ID route. Switch over from one brand/type of vaccine to the other: Shifting from

one brand/type of CCV to other brand/type should not be encouraged in routine Indications: All animal bite victims of Category II and III exposures practice. However, under unavoidable circumstances, available brand/type may irrespective of age and body weight require the same number of injections and be used to complete PEP. dose per injection. All Category III exposures and Category II exposures in immuno-compromised individuals, in addition, require administration of RIG Duration of immunity

as discussed previously in section 2.2. The development of immunological memory after vaccination with CCVs and PDEV is critical for the establishment of long lasting immunity against rabies in Storage and transportation: Though most CCVs are marketed in freeze humans. Individuals who had received their primary series 5–21 years dried (lyophilized) form, it is recommended that these vaccines should be kept previously showed good anamnestic responses after booster vaccination. Long-

and transported at a temperature range of 2-8ºC and protected from sunlight. term immunity is also achieved with intradermal immunization, and may Temperature monitoring device should be used while storage or transportation persist even when antibodies are no longer detectable. The ability to develop an of vaccine. Freezing does not damage the lyophilized vaccine but there are anamnestic response to a booster vaccination is related neither to the route of

chances of breakage of ampoule containing the diluent. Liquid (adsorbed) rabies administration of the initial series (intramuscular or intradermal) nor to vaccines should never be frozen. whether the patient completed a pre-exposure or post-exposure series. Reconstitution and storage: The lyophilized rabies vaccine should be Protective level of anti-rabies antibody: Humoral antibodies play an

reconstituted with the diluent provided with the vaccine immediately prior to important role in protection against rabies. Anti-rabies neutralizing antibody use. Some vaccines have 0.5ml diluents and others have 1ml diluents as per the titre of 0.5 IU/ml or more in serum is considered as protective. This level is approval of the brand, which cannot be altered. It is imperative that the achieved in most healthy individuals by day 14 of a post-exposure regimen, with

information literature accompanying the vaccine is carefully read and the or without simultaneous administration of rabies immunoglobulin. instructions given are adhered to. 2.2.3.1 Intra-dermal (ID) Regimen While using ID administration, the vaccine vial should be stored at 2-8ºC after Current anti-rabies vaccines are produced as one single intramuscular dose.

reconstitution. The total content of the vial should be used as soon as possible, Intradermal regimens consist of administration of a fraction of intramuscular 16 National Guidelines on Rabies Prophylaxis National Guidelines on Rabies Prophylaxis 17

dose of rabies vaccines which is also approved for use by ID route on one or more Only the anti-rabies vaccines (lyophilized vaccine along with the than one site in the layers of the dermis of the skin. The vaccines used are same; diluent of specified volume) approved by DCGI for ID administration however route, dose and site of administration differ. should be used for ID route. The vaccine package leaet should include a statement indicating that the potency as well as immunogenicity and safety

The use of intra-dermal route leads to considerable savings in total amount of allow safe use of vaccine by both the IM and ID routes for post-exposure and pre- vaccine needed for full pre- or post- exposure vaccination, thereby reducing the exposure prophylaxis. cost of active immunization. Single dose (0.5ml or 1ml) of anti-rabies vaccine when given by IM route gets deposited in the muscle. Potency of approved vaccines The vaccines should have stated potency of ≥ 2.5 IU per IM dose, irrespective of

There after the antigen is absorbed by the blood vessels and is presented to reconstituted volume. (The volume of the diluent remains the same as that of antigen presenting cells which triggers the immune response. Whereas, while the IM dose) using ID route, small amount (0.1ml) of anti-rabies vaccine is deposited in the The same vaccine is used for ID administration as per stated schedule. A dose of layers(dermis) of the skin at one or more than one site, the antigen is carried by

0.1ml of vaccine, irrespective of reconstituted volume (0.5ml or 1 ml for IM antigen presenting cells via the lymphatics to the regional lymph nodes and route), is administered per ID site as per the stated schedule. reticulo-endothelial system eliciting a prompt and protective antibody response. Immunity is dependent mainly upon the CD 4 + T-cell dependent neutralizing Regimen antibody response to the G protein. The cell-mediated immunity is also an Post-exposure regimen

important part of the defense against rabies. Cells presenting the fragments of Updated Thai Red Cross Schedule (2-2-2-0-2). G protein are the targets of cytotoxic T- cells and the N protein induced T helper cells. The immune response induced by ID administration of anti-rabies vaccine This involves injection of 0.1ml of reconstituted vaccine per ID site and on two is adequate and protective against rabies. sites per visit (one on each deltoid area, an inch above the insertion of deltoid

muscle) on days 0, 3, 7 and 28. The day 0 is the date of first dose administration of Use of intradermal route of administration of anti-rabies vaccine allows wider anti-rabies vaccine and may not be the date of rabies exposure/animal bite. coverage of PEP in available quantity of vaccines and hence makes it cost effective. WHO recommended use of ID route for administration of anti-rabies Maintenance of vaccine vial in use

vaccines in 1992.Based on WHO recommendation and results of various safety, Use aseptic technique to withdraw the vaccine. efficacy studies and feasibility trial conducted by ICMR, Drug Controller General of India (DCGI) approved the use of intra-dermal vaccination regimen Store in a refrigerator at 2ºC to 8ºC. Do not freeze the vaccine. Do not expose for rabies post-exposure prophylaxis. the vaccine to sunlight.

Vaccines and regimen approved for ID use in the country Use reconstituted vaccine as soon as possible or within 8 hours if kept at 2ºC to 8ºC. Discard all unused reconstituted vaccine at the end of 8 hours. Currently, the following vaccines have been approved by DCGI for use by intra- dermal route. Materials required A vial of anti-rabies vaccine along with its diluent that is approved by the PCECV - Rabipur, Chiron Behring, Vaccines Pvt. Ltd DCGI for ID administration. - Vaxirab N, ZydusCadila

2 ml disposable syringe with 24 G needle for reconstitution of vaccine. PVRV - Verorab, Aventis Pasteur (Sanofi Pasteur) India Pvt. Ltd - Pasteur Institute of India, Coonoor Disposable 1 ml (insulin) syringe (with gradations upto 100 units) with a - Abhayrab, Human Biologicals Institute fixed (self-mounted) (28 G or more) needle (Fig-1), Syringes with detachable - Indirab, Bharat BiotechInternational Ltd. needles should not be used as they contribute to wastage of vaccine.

18 National Guidelines on Rabies Prophylaxis National Guidelines on Rabies Prophylaxis 19

Disinfectant swabs (e.g. 70% ethanol, isopropyl alcohol) for cleaning the top Advise to the vaccinated person: of the vial and the patients' skin. Do not rub the injection site Do not apply anything to the injection site Complete the course of vaccination Adverse reactions following ID administration of anti-rabies vaccine: Adverse events may include mild itching, erythema, rarely body ache and fever that are usually self-limiting. Sometimes symptomatic management using

analgesics and antihistamines may be needed. Fig-1: 1ml syringe with self-mounted needle (Insulin syringe) Logistic requirements for giving antirabies vaccine at health facility: Have adequately trained staff to give ID inoculation of anti-rabies vaccine. ID injection technique Have adequate cold chain facility for vaccine storage. Using aseptic technique, reconstitute the vial of lyophilized vaccine with the Ensure adequate supply of suitable self-mounted syringes for ID

diluent supplied by the manufacturer. administration. With 1 ml syringe draw 0.2 ml (up to 20 units in a 100 units syringe) of Are well versed in management of open vial and safe storage practices. vaccine needed for one patient (i.e. 0.1 ml per ID site for 2 sites). Expel the air bubbles carefully from the syringe thereby removing any dead Animal bite victims on chloroquine therapy should be given ARV by space in the syringe. intramuscular route.

Using the technique of BCG inoculation, stretch the surface of the skin and insert the tip of the needle with bevel upwards, almost parallel to the skin Switch over from IM to ID route of administration or vice versa during PEP: surface (Fig-2) and slowly inject half the volume of vaccine in the syringe Shifting from one route to other i.e. IM to ID or vice-versa during post exposure (i.e. 0.1ml; 10 units) into the uppermost dermal layer of skin, over the

prophylaxis is not recommended as there is no sufficient scientific deltoid area an inch above the insertion of deltoid muscle. If the needle is evidence/study on vaccine immunogenicity following changes in the route of correctly placed inside the dermis, resistance is felt while injecting the vaccine administration during PEP. vaccine. A raised bleb should begin to appear immediately causing a peau d' orange (orange peel) appearance (Fig-3). 2.2.3.2 Intra-muscular (IM) Regimen

Inject the remaining volume of vaccine (i.e. 0.1ml; 10 units) on the opposite The currently available vaccines and regimen in India for IM administration are deltoid area. described below. If the vaccine is injected too deeply into the skin (subcutaneous), bleb (Peau de orange) is not seen. Then the needle should be withdrawn and reinserted Vaccines at an adjacent site and ID vaccine given once more. 1. Cell Culture Vaccines If for some reason the deltoid region cannot be used for injection, then the

Human Diploid Cell Vaccine (HDCV), Liquid (Adsorbed), 1ml: Produced alternative sites are the suprascapular area or the anterolateral thigh. locally in private sector Purified Chick Embryo Cell Vaccine (PCECV), 1ml: Produced locally in private sector Purified Vero Cell Rabies Vaccine (PVRV), 0.5ml and 1ml: Imported and also produced locally in public & private sectors 2. Purified Duck Embryo Vaccine (PDEV), 1ml: Produced locally in private sector and is currently being exported.

Fig-2: Insertion of needle for Fig-3: Bleb raised on ID inoculation Regimen ID inoculation Essen regimen (1-1-1-1-1): Five dose intramuscular schedule - The course for 20 National Guidelines on Rabies Prophylaxis National Guidelines on Rabies Prophylaxis 21

post-exposure prophylaxis consists of intramuscular administration of five 3.Pre-Exposure Prophylaxis (PrEP) injections, one dose each given on days 0, 3, 7, 14 and 28. Day 0 indicates date of administration of first dose of vaccine. Pre-exposure vaccination may be offered to high risk groups like laboratory staff handling the virus and infected material, clinicians and persons attending to Site of injection: The deltoid region is ideal for the administration of these

human rabies cases, veterinarians, animal handlers and catchers, wildlife vaccines. Gluteal region is not recommended because the fat present in this wardens, quarantine officers and travelers from rabies free areas to rabies region retards the absorption of antigen and hence impairs the generation of endemic areas. The Indian Academy of Pediatrics (IAP) has recommended pre- optimal immune response. In case of infants and young children antero-lateral

exposure prophylaxis of children. This may be considered on voluntary basis. part of the thigh is the preferred site. Schedule of vaccination: Pre-exposure vaccination is administered as one (Annexure 1: Table 3: Currently available ARVs in India) full dose of vaccine intramuscularly or 0.1 ml intra-dermally on days 0, 7 and either day 21 or 28. 2.3 Management of re-exposure in previously vaccinated individuals Laboratory staff and others at high continuing risk of exposure should have

their neutralizing antibody titres checked every 6 months during the initial two Priming of immune system and the development of immunological memory years period after the primary vaccination. If it is less than 0.5 IU/ml a booster after complete pre-exposure vaccination or post-exposure vaccination with dose of vaccine should be given. Subsequently, sero-monitoring is recommended

potent cell culture vaccines is an important factor in the establishment of long every two years. Because vaccine-induced immunological memory persists in lasting immunity against rabies. most cases for years, a booster would be recommended only if rabies virus neutralizing antibody titers have dropped to less than 0.5IU/ml. Such Several studies have indicated that persons who have previously received individuals on getting exposed to rabies virus after successful pre-exposure

complete pre- or post-exposure prophylaxis will elicit an anamnestic response to immunization require only two booster injections of vaccine given on days 0 and one or more booster doses of rabies vaccine even if the initial series of 3 and no RIG vaccination was administered several years previously. This response will occur whether: the initial vaccination regimen was administered IM or ID; the booster dose is given IM or ID the previously vaccinated person has detectable rabies virus neutralizing

antibodies or not. Based on the above if re-exposed persons who have previously received and documented full pre- or post-exposure prophylaxis (either by IM or ID route) with a cell-culture vaccine or PDEV should now be given only two booster doses intramuscularly (0.5ml/1ml) or CCVs intra-dermally (0.1 ml at 1 site) on days 0 and 3. Proper wound toilet should be done. Treatment with RIG is not required. Persons who have previously received full post-exposure treatment with NTV or

vaccine of unproven potency or cannot document previous pre- or post-exposure treatment should be treated as fresh case and given treatment as per merits of the case. 22 National Guidelines on Rabies Prophylaxis National Guidelines on Rabies Prophylaxis 23

4.List of Experts 5.Annexures Annexure 1 Dr. N S Dharamshaktu Dr. S Venkatesh Dr. Veena Mittal Table1: Equine rabies immunoglobulin currently manufactured in Addl DGHS,Dte GHS Director Addl Director & Head, India New Delhi NCDC, Delhi Zoonosis Division, NCDC, Delhi Pharmaceutical 1. Central Research Institute, Kasauli, Himachal Pradesh 2. Bharat Serums and Vaccines, Limited, Mumbai Dr. B. J Mahendra Dr. G. Sampath Dr. Indu Grewal 3. VINS Biopharma, Hyderabad.

Director & Dean Deputy Civil Surgeon Head, Health promotion Kodugu Institute of Medical Sciences Institute of Preventive Medicine and Education Division, CHEB 4. Human Biologicals Institute, Hyderabad Medikeri Hyderabad 5. Virchow Biotech Pvt Ltd, Qutubullapur, Telengana 6. Haffkine Biopharmaceutical Corp Ltd, Pimpri 7. Premium Serums & Vaccines Pvt Ltd, Pune Dr. Gyanendra Gongal Dr. Manju Rahi Mr. Rahul S Shakhapure

Zoonosis Focal Point Scientist-E Asst. Drug Controller India, 8. Serum Institute of India, Pune WHO Regional Office for Indian Council of Medical Research DSCO, DCGI Office, New Delhi South East Asia Region, New Delhi New Delhi Table 2: Currently available human rabies immunoglobulin in India Brand Product Pharmaceuticals Dr. Veena Dhobhal Dr. HK Gohil Dr. Naveen Gupta CMO Incharge , CMO Incharge Joint Director 1 Berirab-P Human Rabies Immunoglobulin, ZLB Behring AG,

Anti-rabies clinic ARV Centre CRI, Kasauli 150IU/ml;2 ml (300 IU) ampoule and5 Marburg,Germany/ HinduRao Hospital, Delhi MVID Hospital Delhi ml (750 IU) ampoule Bharat Serums and Vaccines Ltd., Mumbai. Dr. Yogesh Gautam Dr. Shati Kolhapure Dr. S Balakrishnan 2 Imogamrab Human Rabies Immunoglobulin, Sanofi Pasteur, Medical Officer, Casualty Head Medical affairs Head Institutional Business 150IU/ml;2 ml (300 IU) ampoule and France

VMMC & SJH , New Delhi Novartis Vaccines India Novartis Vaccines, India 5 ml (750 IU) ampoule 3 Plasmarab Human Rabies Immunoglobulin, Kamada Ltd., 150IU/ml;2 ml (300 IU) vial and Beit-Kama, Israel 5 ml (750 IU) vial Dr. Dipesh Bhattacharya Dr. Simmi Tiwari Dr. Monil Singhai Addl Director, NCDC, Delhi Assistant Director, NCDC, Assistant Director, NCDC, Delhi Delhi Dr. Mala Chhabra Joint Director NCDC, Delhi 24 National Guidelines on Rabies Prophylaxis National Guidelines on Rabies Prophylaxis 25

Table 3: Currently available anti-rabies vaccines in India# Annexure 2 : Proforma for management of animal bite case at an antirabies centre/clinic(ARC) Brand Product Pharmaceuticals Name: Age : Gender : 1 Abhayrab Purified Vero cell Rabies Human Biologicals Residential address : Vaccines (PVRV) Institute, Hyderabad Telephone/Mobile Nos.: 2 Indirab Chromatographically purified Bharat Biotech Occupation: Monthly income ( in Rupees )

(PVRV) International Ltd, Previous anti- rabies vaccination Status( with dates ): Not vaccinated( ) Vaccinated ( ) : Hyderabad Record available ( ) Not available/Not applicable ( ) DD/MM/YY(doses) 3 PVRV* Purified Vero cell Rabies Pasteur Institute of Date of animal bite: Time of bite: Vaccine(PVRV) India,Coonoor, Tamilnadu Address/ Place where bite took place: Interval between bite and reporting to ARC ( in hours/days ) : 4 Rabipur Purified Chick Embryo Cell Novartis Vaccines,

Site of bite/s: Number of wounds: Superficial …....Deep …..... Total ……. Vaccine (PCECV) Mumbai Biting Animal- species: Dog/Cat/Monkey/Mongoose/Others ( specify) 5 Rabivax Human Diploid Cell Culture Serum Institute of India, Type: Pet/Stray/Wild Vaccine (HDCV) (Liquid) Pune Vaccination Status of Animal: Vaccinated/Not vaccinated /Not known 6 Vaxirab Purified Duck Embryo Zydus Health Care ltd., If vaccinated: number of doses received: Vaccination card : not available( )available( )( show it )

Vaccine(PDEV) Ahmedabad Bite: Provoked/unprovoked Type of provocation: 7 Vaxirab-N Purified Chick Embryo Cell Zydus Health Care Ltd, Fate of animal: Alive/Killed/Died/Unknown/Untraceable: Vaccine (PCECV) Ahmedabad No. of other persons bitten by same animal within one week of the bite: Not known() 8 Verorab Purified Vero cell Rabies Sanofi Pasteur/ Zuventus Outcome in other persons bitten: Not Applicable( )

Vaccines (PVRV) Health Care, Mumbai Type of exposure: WHO category – Category I ( ) Category II ( ) Category III ( ) a)Licks on intact skin * Limited production, since July 2001. b)Nibbling of uncovered skin c)Minor scratches or abrasions without bleeding # A few other vaccines are being used in the country in limited quantities d)Licks on broken skin e)Single or multiple bites with bleeding f)Contamination of mucus membrane with saliva Remedy taken before coming to anti-rabies centre/ clinic: a)None ( )

b)Washed with water…………………………………………………………………………......…….. c)Washed with soap and water…………………………………………………………….………….. d)Antiseptic application……………………………………………………………………….………… e)Any other specify: application of oil/salt/chilies/lime/herbs/any other (specify)……….……….. Duration between bite & Local treatment of wound: Who advised you to come to anti-rabies clinic: Treatment given at the anti-rabies clinic: a)Wound washed in the clinic…………………………………………………………………..………

b)RIG (Name) given………….Local (mL)...…..…Systemic (mL)………..Total(mL)…....………… c)Wound suturing (if done, details). …………………………………………………………...……… d)Vaccine (Name): IM/ID: on days 0/3/7/14/28 (as applicable) (dates)…………………...………. e)Injection TT………………………………………………………………………………….…………. f)Record/Report adverse events to vaccine or RIG: ………………………………….…………….. g)Antibiotics……………………………………………………………………………………………… h)Analgesics/NSAID/Antihistamines………………………………………………….....…………….

i)Other drugs/treatment given (if any)…………………………………………………………………. 26 National Guidelines on Rabies Prophylaxis National Guidelines on Rabies Prophylaxis 27

6.Decision Tree: Guide to Post-Exposure 7.Frequently Asked Questions Prophylaxis Question 1: Is there any vaccine which can protect against rabies with one or two doses? Answer: No such vaccine exists in the world which can induce protective immunity against rabies with only 1 or 2 injections. A complete course comprises of administration of DCG (I) approved vaccine (Lyophilized vaccine with specified amount of diluent) as per recommended schedule i.e. 0.1 ml of vaccine on 2 sites on days 0, 3, 7 & 28.

Question 2: Application of chillies, lime, salt and mustard oil to animal bite wound is common practice. Does it confer any advantage over washing with soap and water? Answer: Application of any of these does not confer any advantage. On the contrary, irritation produced by any of these may provide more avenues to the virus to gain entry into nerves and spread to brain. This also gives a false sense of security that some treatment has been administered.

Question 3: Are there any dietary restrictions for animal bite victims receiving anti-rabies vaccination? Answer: No dietary restriction need be imposed on the vaccinee. However, excessive intake of alcohol should be discouraged. Question 4: Can a vaccinated dog transmit rabies? Answer: A dog effectively vaccinated against rabies cannot suffer and transmit the disease. However in the absence of laboratory documentation of protection, it cannot be presumed that a vaccinated dog is actually protected, given

the variable efficacy of various anti-rabies vaccines in animals and/or health status of animals. Hence, irrespective of the vaccination status of the biting dog, the PEP is given. Question 5: If I am bitten by a rat do I require post-exposure prophylaxis (PEP)? Answer: Rat rabies has been reported from some Asian countries but is extremely rare. It is not necessary to take PEP in bite cases by house rats. However, it is prudent to take PEP in consultation with an infectious disease physician when

bitten by wild rats/rodents. 28 National Guidelines on Rabies Prophylaxis National Guidelines on Rabies Prophylaxis 29

Question 6: Can consumption of meat from an infected animal transmit Question 10: DCG (I) approved vaccine is being used in anti-rabies centre rabies? which reconstitutes to 0.5ml volume. Is it advisable to add extra diluent to this and use it for ID inoculation using 0.1 Answer: The consumption of raw meat from infected animals ml per site at 2 sites on days 0,3,7 &28. requires PEP. Cooking kills the virus and hence

consumption of cooked meat does not transmit rabies. Answer: No, this should never be done. However, it is not advisable to consume meat from an infected animal. Question 7: Do we need to consider specific vaccine potency for ID vaccination? Answer: There has been concern as single IM doses are reconstituted in different volumes depending on manufacturers. The recommended minimum potency of all anti-rabies vaccine is > 2.5 IU per IM dose. The recommended volume of a single

dose of rabies vaccine administered per ID site is 0.1 ml. The DCG(I) approved vaccine (pack containing i.e. lyophilized vaccine and specified amount of diluent) with a potency of > 2.5 IU/IM dose should be used for ID inoculation. The recommended dose is 0.1 ml at 2 sites on day 0, 3, 7 & 28. Question 8: It is necessary to perform an antibody test following anti- rabies vaccination in all animal bite victims? Answer: No, it is not required in all cases. When human rabies

vaccines are given according to the approved schedule in a healthy individual it is not necessary to do antibody titre estimation. It is recommended only under special circumstances such as for immunocompromised patients, patients receiving immunosuppressive therapy or patients who have not taken vaccination as per recommended schedule. Question 9: Is there any possibility of failure after PEP? Answer: There are occasional human rabies cases reported despite

PEP, due to various factors related to negligence and individual health status. Most cases have been reported due to delayed vaccination, or non-use of rabies immunoglobulin in category III exposure, or incomplete course of vaccination. Some cases are related to immunocompromised status such as HIV/AIDS, cirrhosis or use of chloroquine, long term steroids, or anti-cancer drugs. Unexplained failure in cases where everything was apparently done correctly have also been documented, however, are very rare.

30 National Guidelines on Rabies Prophylaxis National Guidelines on Rabies Prophylaxis 31

STANDARD SIDDHA TREATMENT GUIDELINES FOR NON COMMUNICABLE DISEASES (June 2014) Prepared By NATIONAL INSTITUTE OF SIDDHA (Dept. of AYUSH, Govt. of India) TAMBARAM SANATORIUM CHENNAI-600047 0

THAMARAGA NOI (CARDIOVASCULAR DISEASES) INTRODUCTION In modern science cardiac diseases were classified as following types Hypertensive heart disease, ischemic heart diseases, Myocardial infarction, valvular heart disease, inflammatory / congestive cardiac failure, arrhythmic heart diseases and congenital heart diseases. In our siddha system cardiac diseases is caused by deranged vatha humour. It is classified into four types 1. Vali, 2.Azhal, 3.Iyyam & 4. Mukkutram, apart

from this one more type, which is caused by intestinal worms. This four types of cardiac diseases (Thamaraga noi) symptoms were correlated with modern cardiac diseases. Vali thamaraga noi: Symptoms correlataed with rheumatic valvular heart diseases Azhal thamaraga noi Symptoms correlataed with hypertensive heart / ischemic heart diseases Iyya thamaraga noi Symptoms correlataed with myocardial infraction Mukkura thamaraga noi Symptoms correlataed with congestive cardiac failure/ arrhythmia.

Our siddha system contributes to prevent and cure the cardiac diseases through life style modification and rejuvenation drugs. DEFINITION It denotes a combination of symptoms such as proximal, nocturnal dyspnoea, difficult to breathing, chest pain, palpitation, Retro-sternal discomfort, restlessness, syncope, heartburn, heaviness on chest, pedal oedema and followed by sudden death. ETIOLOGY Cardiac diseases occurs due to excessive intake of vatha diet, bad habits,

sexually transmitted disease, aggravation of uthanavayu (Mel nokkunkal), Viyanavayu(Paravukal) and another one is congenital causes ,and cardiac diseases followed by rheumatism. CLINICAL DESCRIPTION In siddha system cardiac diseases were classified into 5 types and has symptoms like Ocassional dyspnoea, palpitation, chestpain, syncope, semiorientation, centralcyanosis, insominia, proxysmalnocturnal dyspnoea, nocturnal cough, restleesness, edema. TYPES 1. Vali thamaraga noi 2. Azhal thamaraga noi

3. Iyyam thamaraga noi 4. Mukkutram thamaraga noi 5. Puzhu thamaraga noi 1

VALI THAMARAGA NOI:  It occurs increase in vatha humour prominent in the age between 14 to 40 years.  It also comes at any age and it produces following symptoms like sore throat, fever, anemia, edema, palpitation, heaviness of the chest, breathing difficulty, cough & vomiting.  The symptoms resembling with Valvular heart diseases. AZHAL THAMARAGA NOI:  It occurs in middle age  Chestpain, palpitation, breathlessness, dyspnoea, sweating, giddiness are the symptoms of this thamaraga noi.

 It is curable type.  It resembles Ischaemic heart disease & Hypertensive cardiac disease. IYYA THAMARAGA NOI:  It comes in the old age, it comes suddenly by denoting a combination of symptoms.Heaviness of chest, difficulty to breath.  It cures after life threatening treatment, the following symptoms comes one by one like chest pain, sweating pain radiating to left upper limb to fingertip , dyspnoea, restlessness and followed by sudden death.

 The symptoms of this disease resembles with Myocardial Infarction. MUKKUTRA THAMARAGA NOI:  It comes under secondary cardiac diseases , followed by other diseases like rheumatism, rheumatic fever, hypertension, diabetic, renal diseases it also comes like fever(kabavatha suram) and followed by sudden death.  The symptoms resembles with Congestive cardiac failure and Arrythmia. PUZHU THAMARAGA NOI:  It does not comes under cardiac disease, but the symptoms are related to chest

region, so they classified under cardiac disease. MUKKUTRAVERPADU( PATHOGENESIS)  The deranged Vatham has become the predominiant cause for the occurrence of cardiac disease.  Another one is Kabam has become the predominiant cause for the occurrence of cardiac disease.  The combined Vatha and Kabam humours leads to the development of cardiac disease. CLINICAL MANAGEMENT FOR DIFFERENTSTAGE OF DISEASES CONDITION: STAGE -1 Hypertensive and rheumatic valvular heart diseases (Azhal Thamaraga Noi)

is treated in the stage 1 OPD level. This diseases is treated with following internal and external medication LINE OF TREATMENT Purgation – three humours are neutralized 2

Internal medicine Kudineer Chooranam Mathirai Manapagu Rasayanam vadagam Extrernal medicine Oil bath STAGE II Ischemmic heart diseases (Azhal Thamaraga Noi) is treated after patient taken vasodilator treatment from modern side in the stage 2 OPD/IPD level. This diseases is treated with following internal and external medication LINE OF TREATMENT Purgation – three humours are neutralized Internal medicine Kudineer Chooranam Vadagam Mathirai Rasayanam Manapagu Parpam Chendooram Extrernal medicine Oil bath

STAGE III Myocardial infarction (Iyyathamaraga Noi) is treated after patient taken vasodilator treatment from modern side in the stage 3 OPD/IPD level. This diseases is treated with following internal and external medication LINE OF TREATMENT Laxative Medication (three humours are neutralized) Internal medicine Kudineer Chooranam Mathirai Rasayanam Manapagu Parpam Chendooram Mezhugu Thravagam Kattu Extrernal medicine Oil bath STAGE IV 3

CCF, Inflammatory heart diseases, arrthymic heart diseases is treated after patient taken vasodilator treatment from modern side in the stage 4 OPD/IPD level. If this patient goes critical stage, patients are referred to higher centre for further management. Laxative Medication (three humours are neutralized) Internal medicine Kudineer Chooranam Mathirai Rasayanam Manapagu Parpam Chendooram Mezhugu Thravagam Kattu Extrernal medicine Oil bath DIET  Advice to take salt free foods  Take haematinic diet

 Easily digestible diet  To take barley gruel diet  Tender vegetables  Vegetable soups  Greens and vegetables AVOID  Sour and pungent taste diet  Oily foods  Non-vegeterian DIET CHART As per WHO guidelines every cardiac patients should take following 1200 - 1800 Calorie Diet plan. Early morning (6.00 am) 1 cup of green tea. Breakfast (8.00am) 1 cup of oats or 3 idlies or 2 rotti with veg chutney or sambar Pre noon (11.00 am) Lime juice or 1 cup of vegetable salad (tomatoes,onion,cabbage,raddish)

Lunch(1.00 pm) 1 cup of steamed rice with sambar ,1 cup boiled vegetables ,1 cup of skimmed butter milk Evening(4.00 pm) 1 cup of lemon tea or 2 slice of wheat bread 4

Dinner (8.00 pm) Two Chappathies or Two ragi dosas without oil and One cup of Veg curry Oils used for cooking Sunflower oil Rice bran oil Gingely oil Fruits Pappaya Apple Guava Orange Pear Grapes Vegetables Brinjal Cucumber Bottle goard Beans Lady‗s finger Flowers Lotus flower Banana flower Drumstick flower Grains Unpolished rice Wheat Millets Clear soups Bitter goard soup Drumstick soup Amaranthus tricolor soup Sessile plant soup Thumbe soup Greens Amaranthus blitum Indian acalypha Palak

Amaranthus tricolor Cock‘s comb greeens Centalla asiatica Black night shade DO’S AND DON’T  Maintain the blood cholesterol level  Maintain the blood pressure level within normal range  Aim for a healthy weight  Manage diabetes  Reduce stress  Limit alcohol 5

 Mild exercise Patient adviced for a peaceful life  Comfortable sleep  Regular medication  Rest after taking food  Avoid taking full stomach diet  Avoid smoking Approximate Cost for Procedures, Medicines Etc during treatment and Post Treatment STAGE –I Medicine- Rs. 60/day Rs. 1800/Month Investigation first visit Blood routine Rs. 200 ECG Rs. 50 X-Rays Rs. 30 USG Abdomen Rs. 200 STAGE –II MEDICINE/FOOD IN IPD- Rs-90/day / Rs100/day Rs-5700/Month Investigation first visit Blood routine- Rs. 200

ECG Rs. 50 X-Rays Rs. 30 USG ABDOMEN Rs. 200 STAGE –III/IV MEDICINE/FOOD IN IPD- Rs-150/day / Rs100/day Rs-7500/month Investigation first visit Blood routine Rs. 200 ECG Rs. 50 X-Rays Rs. 30 USG ABDOMEN Rs. 200 6

PAKKAVATHAM (Stroke / Hemiplegia) Definition: A stroke can be caused by an obstruction in the blood flow, or the rupture of an artery that feeds the brain. The patient may suddenly lose the ability to speak, there may be memory problems, or one side of the body can become paralyzed. When to suspect/recognize:  Heaviness of body, sudden weakness or numbness of the face, arm or leg, most often on one side of the body  Giddiness, confusion, difficulty speaking or understanding speech

 Increased pulse rate, loss of balance or coordination; severe headache with no known cause; fainting or unconsciousness Epidemiology: It is common in children to old age people. Ilavenil (early summer), Muthuvenil (late summer) aggravates occurrence of the disease. Envagai thervugal (Eight fold system of clinical assessments): S. Siddha Investigation parameters Findings No 1. Naa thervu-examinaion of tongue i. Niram(Colour) Pale ii. Thanmai (Character) Coated/dry/furrowed iii. Pulan (Sense) Sour & bitter

2. Niram thervu – examination of colour Pale/black 3. Mozhi thervu – examination of speech Slurred/depressive 4. Vizhi thervu-examination of eye: i. Niram (Colour) Pale ii. Thanmai (Character) Dry iii. Pulan (Sense) Diminished 5. Malam thervu – examination of stool: i. Niram (Colour) Darkened ii. Nurai (Froth) Absent iii. Elagal/Erugal (Consistency) Erugal (Dry & hard) 6. Moothiram thervu – examination of urine: (a) Neerkuri: (i) Niram (Colour) Yellow

(ii) Adarthi (Specific gravity) Decreased/Increased comorbid condition of disease (iii) Manam (Odour) Tamarind (iv) Nurai (Froth) Increased (v) Enjal (Deposits) Present (b)Neikkuri: Slow, spread in the form of snake 7

7. Sparisam thervu – examination by touch Cold 8. Naadi thervu – examination of pulse: (i) Thanmai (Character) Thin and rapid (ii) Naadai (Pattern) Vali naadi Diff erential diagnosis:  Arunavatham - Diplegia  Aegavatham – Monoplegia Referral criteria:  Semiconsious/unconscious patients  Uncontrolled hypertension  Abnormal Orientation Laboratory Investigation: Routine blood (Complete Heamogram) Rs. 60.00 Routine urine investigation Rs. 25.00 Glucose (FP / PP) Rs.50.00 Lipid profile Rs. 275.00

Liver function test Rs. 220.00 Renal function test Rs. 400.00 HbA1C Rs. 25.00 Other investigation: In acute condition to evaluate site of lesion CT- Rs. 200.00, MRI Rs. 3000/- ECG – Rs.50.00/- ECHO- to rule out valvular heart disease and to find ejection fraction - Investigation for stroke in young: Along with above mentioned investigation, ANA-Rs. 50.00 Anti phspholipid antibody &Anti cardiolipin antibody- Rs. 250.00 Line of Treatment:

Kalichal maruthuvam to neutralize vitiated vaatham: Rs. 400.00 (Initial) INTERNAL MEDICINE (PER DAY): Choornam (Medicinal powder) Rs. 10.00 Ilagam (Electuary) Rs. 10.00 Thylum (Medicated oil) Rs. 100.00 Parpam(Calcined oxide) Rs.6.00 Chendooram(Calcined red Oxides/Sulphide) Rs. 10.00 Mezhugu Rs. 8.00 Pathangam(Sublimate) Rs. 20.00 Mathirai(Tablet) Rs. 10.00 8

EXTERNAL MEDICINE Thokkanam: Rs. 1000.00 (per session) Oils which posses anti Vaatham properties may be applied over the affected region with following procedures : Azhthudhal (Pressing) Izhuthal (Pulling) Pidithal (Grasping/gripping) Varmam Rs. 300/- (per day) Specific varmam (Vital Points) may be given to fasten the prognosis. Medicated Bundle Rs. 700.00 (per day) Application of Medicated Bundle contains herbs which possess antivatham properties may be advised Steam Bath: Rs. 600.00 (per day)

Precaution should be taken if patient is hypertensive. DIETARY REGIMEN (PATHIYAM): Advised to take:  Kaththari Pinchu (Solanum melongena)  Avarai Pinchu (Dolichos lablab)  Aththi pinchu (Ficus racemosa)  Mudakkarran (Cardiospermum halicacabum) GREENS: 1. Mudakkarran Keerai (Cardiospermum halicacabum) 2. Ponnakaanik Keerai (Alternanthera sessilis) 3. Thoothuvealaik Keerai (Solanum trilobatum) 4. Mookkirattai Keerai (Boerhaavia diffusa) 5. Vealaik Keerai (Cleome viscosa) Advised to avoid (AAGAP PORUTGAL)

1. Surai (Lagenaria siceraria) 2. Poosunai (Luffa acutangula) 3. Vellari (Cucumis sativus) 4. Pudalai (Trichosanthes cucumerina) 5. Peerkku (Luffa acutangula) 6. Kaaramani (Vigna unguiculata) 7. Ulunthu (Vigna mungo) 8. Kollu (Macrotyloma uniflorum) 9

9. Kadugu (Brassia juncea) DO’S &Dont’s:  Avoid stress and strain  Avoid humid floor  Do pranayamam  Keep regular bowel movements 10

PUTTRU (CANCER) INTRODUCTION Puttru (Cancer) is one of the fatal diseases next to Cardiac diseases in the developed countries. According to WHO 5 million people die due to Cancer. In India 50,000 people die because of Cancer. Vai Puttru (Oral Cancer), Marbaga Puttru (Breast Cancer) and Karuppai Puttru (Utrine Cancer) are more predominantly in India. DEFINITION: Cancer refers to a group of illness that result from cells in the body growing

abnormally. These cells divide and produce new cells in an uncontrolled way that can spread throughout the body and cause damage to essential organs ETIOLOGY: 1. Excess intake of Tubers 2. Excessive intake of Salt & Sour 3. Excessive intake of Non-Vegetable food stuffs 4. Sexual Indulge 5. Contaminated food 6. Obesity 7. Sedentary life 8. Habit of Smoking 9. Genetics 10. Radiation 11. Chemical dyes 12. Environmental factors 13. Virus 14. Immunodeficiency 15. Chronic irradiations CLINICAL DESCRIPTION:

 Loss of Weight  Loss of Appetite  Difficulty in Swallowing  Sore Throat  Colour changes in Skin  Persistent Cough  Altered Bowel and Bladder Habits  Haemoptysis 11

 Fever  Nodule and Organs  Edema  Hardness of breast  Non Healing Ulcer  Wart Moles SIDDHA TYPES: 1. Vatha vippuruthi 2. Santhu vippuruthi 3. Oodu vippuruthi 4. Sethuma vippuruthi 5. Piththa vippuruthi 6. Kuvalai vippuruthi 7. Karba vippuruthi PATHOGENESIS ON THE BASIS OF THIRITHODAM Due to Intrinsic and Extrinsic factors Vatha humour (Paravukaal) gets altered (increased), its activity also gets increased and affects the thathukkal and organs of the

body which leads to proliferation of tissues. This is followed by the derangement of Kabham which also affects Udal thathukkal one by one. Due to altered Kabham, there will be excessive cell growth (Valarthal), hypertrophy of cells (Kanaththal), increased cell division (Pilaththal). Finally the function of Vatham and Kabham gets altered resulting in derangement of normal structure and functions of the seven thathus. Clinical Management for Different Stages of Disease Condition STAGE I

Stage 1 usually means a cancer is relatively small and contained within the organ it started in. Purgation Oleation Internal medicines External medicines STAGE II Stage 2 usually means the cancer has not started to spread into surrounding tissue, but the tumour is larger than in stage 1. Sometimes stage 2 means that cancer cells have spread into lymph nodes close to the tumour. This depends on the particular type of cancer. Purgation Oleation Internal medicines 12

External medicines STAGE 3 Stage 3 usually means the cancer is larger. It may have started to spread into surrounding tissues and there are cancer cells in the lymph nodes in the area Purgation Oleation Internal medicines External medicines STAGE 4 - REFERAL CRITERIA  If the patient shows discomfort such as grimacing or moaning,  If the patient not wants to eat/drink at all  If the patient have noisy breathing  Complete loss of consciousness  Loss of bowel and bladder habits

 There is need to refer the patient immediately for further treatment  Cancers have often metastasized, or spread to other organs or throughout the body. Stage IV cancer can be treated by chemo, radiation, or surgery ASANAS : Pujangasanam Dhanurasanam Hiruthayasanam Paathahasthasanam Vibarithakarani Machasanam Yogamudra Naadi sudhi Shanthiasanam 1800 Calories diet plan for cancer patiens  7.00 am : A glass of warm water.  7.30 am : 1 glass of Wheat Grass Juice.

 8.00 am :1 glass warm milk (without sugar) + Papaya/Chickoo(1 bowl) or veg halwa.  11.00 am : 1 bowl of Veg Soup or 1 glass of coconut water + 5-6 pc Almond/Walnut.  1.00 pm : 1 bowl Salad/ Boiled Vegetables/ Raita + 1 bowl Curd/ 1 glass Buttermilk/ Milk Kheer without sugar. 13

 4.00 pm : 1 glass of warm milk (without sugar) + Dates/figs  Kurmura / Roasted chana/ chikki.  6.00 pm : 1 glass of fresh fruit juice/ Sugarcane juice/ Raw vegetable juice.  8.00 pm : 1 bowl Salad/ Boiled vegetables/ Raita + 1 bowl Curd / 1 glass Butter milk/ Milk kheer without sugar.  10.00 pm : 1 glass warm milk(without sugar) DIET : Vegetables : Carrot, Tomato, Cabbage, Beetroot, Brinjal, Cucumber, Lady‘sfinger, Onion Greens : Vallarai, Thoothuvalai, Murungai, Pannai keerai

Fruits : Guava, Orange, Apple, Grapes, Lemon, Dates, Banana Pulses : Wheat, Maize, Groundnut, Unpolished rices Dairy products : Cows milk Non-veg diet : Fish, Mushroom Herbs : Kodiveli, Vembu, Nithyakalyani, Kadukkai, Thulasi DO’S AND DON’TS Do’s  Partial fasting by eating only once every day  Take Tender Coconut water in abundance  Hip bath & Sun bath should be taken in abundance  Drink Ash gourd juice & arugam, wheat grass juice on alternative days  Milk should not be avoided

 If the external parts like breasts etc have been affected by cancer give mud bath.  Choose non fat dairy products.  Use brown rice instead of white rice. Don’ts  Smoking, Liquor Drinking, Pan masala etc,  Oily foods  Ghee  Egg  Pickles  Buttermilk  Dry fish(Aromatic Hydro carbons) 14

 Contraceptives  Spicy foods.  Cooking oils at high heat. STAGE I Purgation Cost Rs 400 Oleation Cost Rs 500/month Internal medicines Cost Rs 68.50 ,Rs 2054/month External medicines Cost Rs 30/day, Rs 900/month Lab Investigation CBC Rs 65 FBS Rs 30 PPBS Rs 30 Urine routine Rs. 30 Bl.urea Rs 25 Sr creatinine Rs 25 Lipid profile Rs 75 LFT Rs 220 X Ray Chest Rs 30 ECG Rs 50 USG Abdomen Rs 200 Histopathology Rs 15 CA Markers Rs 200 Total cost Rs 995

Stage I Clinical management & Lab investigations Total cost Rs 4849 STAGE II Purgation Cost Rs 400 Oleation Cost Rs 500/month Internal medicines Cost Rs 96.40/day, Rs 2893/month External medicine Cost Rs 60/day, Rs 1800/month Investigation first visit Rs 995 Stage II Clinical management & Lab investigations Total Cost Rs 6588 STAGE III Purgation Cost Rs 400 Oleation Cost Rs 500/month Internal medicines Cost Rs 115.80/day, Rs 3476/month External medicines : Attai Vidal Cost Rs 1000/day, Rs 2000/month

Pugai Cost Rs 500/day,Rs 2000/month Investigation first visit Cost Rs. 995 Stage III Clinical management & Lab investigations Total cost Rs 9371 15

NEERIZHIVU (DIABETES MELLITUS) MADHUMEGAM (INIPPU NEER) INTRODUCTION : According to siddhars the imbalance of mukkuram causes totally 4448 diseases to human being. Among them megarogam is considered to be the emperor of diseases. Based on the text ―Yugi Vaithya Chimdhamani‖, mega noi is classified into 20 types, Madhumegam one among them under pitha type . DEFINITION : It denotes a disease characterized by polyuria, presence of honey odour in

urine on heating. It ultimately affects all the seven udal thaathus (seven fundamental tissues of the body). ETIOLOGY : Excessive indulgence in sex – depletion of total body strength Increased body heat (pitham) Excessive hunger Excessive food intake like ghee fish milk,toddy Physical inactivity Psychosomatic stress Genetic factors CLINICAL FEATURES : Excessive thirst, dry mouth, polyuria, nocturia polyphagia, tiredness, fatigue,

irritability, recent changes in weight. pruritis vulvae,balanitis,muscular cramps.  Blurring of vision, nausea, headache  Passing of urine in large quantity at frequent intervals.  Burning and spasmodic pain in urethra and dull pain in testis.  urine may be cold, slimy to touch, brownish yellow in colour and produces white sediments  Skin is pale and there is generalized tenderness.  Ants and flies are attracted to the site of voided urine.  When the urine is heated it gives honey odour.

PATHOGENESIS : Due to intrinsic and extrinsic factors body iyam thathu gets altered this is followed by the derangement of vatha (particularly keelnokku kaal) which affects udal kattukal one by one. Finally the function of vatham, and pitham also altered resulting in derangement of normal structure and functions of the seven thathus. LINE OF TREATMENT : Regulating of affected kutram (oil bath and then purgation)After that internal medication given. STAGE I CLINICAL FEATURES : 16

Poly urea Polydypsia Polyphagia Purgation Internal medicines External medicines ; Oleation STAGE II CLINICAL FEATURES : Numbness in both palms and soles Pricking sensation in both palms and soles (peripheral neuropathy) Purgation Internal medicines External medicines ;Oleation STAGE III CLINICAL FEATURES Ulceration of feet Peripheral vascular disease (neuropathy ) Nephropathy Blurred vision (Retinopathy) Severe ketoacidosis Purgation Internal medicines External medicines ;Oleation REFERRAL CRITERIA :

Dyspnoea Chestpain Skin lesions AASANAS : Pranayaamam Padmaasanam Sugaasanam Salabaasanam Dhanuraasanam Halasanam Patchimothasanam 17

Sarvangasanam Mayuraasanam Artha machaendhrasanam DIET : Rice or kanji : Clear Soup, Lemon juice without sugar Unripped vegetables : Atthi, Murungai Surai, Vendai, Kathari, Chinna Vengayam Greens : Manathakkali, Ponmusuttai, Pasali, Keeraithandu, Puliaarai, Neeraarai keerai, Puthina, Curry Veppilai, Kothumalli leaves Fruits : Nelli, Pappali, Madhulai, Koiyya Pulses : Ulunthu Dairy products : Cows butter milk Nonvegetarien diet : Ayirai meen DO’S and DONT’S : DO’S :

Sunbath and pranayamam must be practiced over day Diabetes patients should take adequate rest They should avoid mental tension During night it is better to have only half the quantity or food needed DONT’S Sweets, bakery products such as cream biscuits, cakes, pastries, concentrated milk preparations such as beda and burfees etc.,  Ice-creams, soft drinks,fruit juices,  Tubers like potato, sweet potato,yam,carrot,beetroot and colachasia  Saturated fats like vanaspathi, dalda, ghee,and butter.

 Nuts, dryfruits like pista, badham and mundhiri  Fatty meat cuts, organ meat such as heart, liver, kidney, brain, eggyolk.  Polished rice, tinned foods, starchy foods, sugar are should be avoided.  Fruits such as banana, mango fruits, sapotta, pineapple, jack fruits should be avoided DIET CHART (2200 cal diet plan with low fat) MORNING;- 6 a.m : Coriander seed kasayam or Seeraga kasayam -200ML 6.30 a.m to7.00 am Walking ;- 3km 18

BREAKFAST; 8.30a.mto9.00a.m- Two idlies or two dhosa with sambar or green chutney or Oats meal –one cup or Wheat rava uppuma with plenty of carrot and beans MIDMORNING;- Take 200 ml lime juice or With-one small cup of Fruits (Options- Apple, Papaya) LUNCH;- Start with soup Clear rasam Or Veg soup One cup rice with one cup boiled vegetable 1 Cup of skimmed butter milk EVENING;- Tea or coffee without sugar with two oats biscuits DINNER;- Take two chappaties with dhal Or Take two wheat dhosa STAGE I

Purgation Cost Rs 400 Internal medicines Cost Rs 57.50/day, Rs 1712/month External medicines; Oleation Rs 500/month Lab Investigation CBC Rs 65 FBS Rs 30 PPBS Rs 30 Urine routine Rs.30 Bl.urea Rs 25 Sr creatinine Rs 25 Lipid profile Rs 75 LFT Rs 220 HbA1C Rs 25 X Ray Chest Rs 30 ECG Rs 50 Investigation first visit Rs 705 Stage I Clinical management & Lab investigations Total cost Rs 3317 STAGE II Purgation Cost Rs 400 Internal medicines Cost Rs103.20 /day, Rs 3097/month

Investigation first visit Rs 705 Doppler Studies Rs 700 Stage II Clinical management & Lab investigations Total cost Rs 5402 STAGE III Purgation Cost Rs 400 Internal medicines Cost Rs 146.60/day, Rs 4400/month External medicines; Oleation Cost Rs 500/month Investigation first visit Rs 705 DOPPLER STUDIES Rs 700 Stage III Clinical management & Lab investigations Total cost Rs 6705 20

PRIMARY OBESITY Introduction: Obesity raises the risk of morbidity from hypertension, dyslipidemia, type 2 diabetes mellitus (diabetes), coronary heart disease (CHD), stroke, gallbladder disease, osteoarthritis, sleep apnea and respiratory problems, and some cancers. Obesity is also associated with increased risk in all-cause and cardiovascular disease (CVD) mortality. The biomedical, psychosocial, and economic consequences of

obesity have substantial implications for the health and well-being of the population. Obesity is most commonly caused by a combination of excessive food energy intake, lack of physical activity and genetic susceptibility, although a few cases are caused primarily by genes, endocrine disorders, medications or psychiatric illness. Evidence to support the view that some obese people eat little yet gain weight due to a slow metabolism is limited. On average obese people have greater energy

expenditure than their thin counterparts due to the energy required to maintain an increased body mass. According to the 1998 Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—The Evidence Report, overweight is defined as a body mass index (BMI) of 25 kg/m2 to 29.9 kg/m2 and obesity as a BMI of >30 kg/m2. Current estimates are that 69% of adults are either overweight or obese with approximately 35% obese. These latest data from the

National Health and Nutrition Examination Surveys report that for both men and women, obesity estimates for 2009–2010 did not differ significantly from estimates for 2003–2008 and that the increases in the prevalence rates of obesity appear to be slowing or leveling off. Yet, overweight and obesity continue to be highly prevalent especially in some racial and ethnic minority groups as well as in those with lower incomes and less education. Overweight and obesity are major contributors to chronic

diseases and present a major public health challenge. Definition: Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have a negative effect on health, leading to reduced life expectancy and/or increased health problems. People are considered obese when their body mass index (BMI), a measurement obtained by dividing a person's weight by the square of the person's height, exceeds 30 kg/m2. Etiology:

At an individual level, a combination of excessive food energy intake and a lack of physical activity are thought to explain most cases of obesity. A limited number of cases are due primarily to genetics, medical reasons, or psychiatric illness. In contrast, increasing rates of obesity at a societal level are felt to be due to an easily accessible and palatable diet, increased reliance on cars and mechanized manufacturing. Most cases of obesity are caused by eating too much and moving too little. If

you consume high amounts of energy from your diet but do not burn off the energy through exercise and physical activity, the surplus energy is turned into fat. 21

a. Calories: The energy value of food is measured in units called calories. The average physically active man needs 2,500 calories to maintain a healthy weight, and the average physically active woman needs 2,000. This may sound high, but it can be easy to reach this limit if you eat certain types of food. For example, eating a large take away hamburger, fries and a milkshake can add up to 1,500 calories of your intake. Another problem is that many people are not physically active, so lots of the

calories they consume end up being "wasted" and converted into fat cells. b. Lifestyle choices: Obesity does not just happen overnight – it develops gradually from poor diet and lifestyle choices.For example, unhealthy food choices could include:  eating processed or fast food high in fat  not eating fruit, vegetables and unrefined carbohydrates, such as wholemeal bread and brown rice  drinking too much alcohol – alcohol contains a lot of calories, and heavy drinkers are often overweight

 eating out a lot – you may have a starter or dessert in a restaurant, and the food can be higher in fat and sugar  eating larger portions than you need – you may be encouraged to eat too much if your friends or relatives are also eating large portions  comfort eating – if you feel depressed or have low self-esteem, you may comfort eat to make yourself feel better Unhealthy eating habits tend to run in families, as you learn bad eating habits

from your parents. Childhood obesity can be a strong indicator of weight-related health problems in later life, showing that learned unhealthy lifestyle choices continue into adulthood. c. Lack of physical activity: Lack of physical activity is another important factor related to obesity. Many people have jobs that involve sitting at a desk most of the day. They also rely on their cars rather than walking or cycling. When people relax, they tend to watch TV,

browse the internet or play computer games, and rarely take regular exercise. If you are not active enough, you do not use the energy provided by the food you eat and the extra calories are stored as fat instead. The Department of Health recommends adults do at least 150 minutes (2 hours and 30 minutes) of moderate-intensity aerobic activity such as cycling or fast walking every week. However, if you are obese and trying to lose weight, you may need to do

more exercise – in some cases, up to 300 minutes (five hours) may be recommended. d. Genetics: Some people claim there is no point in losing weight because "it runs in my family" or "it's in my genes". While there are some rare genetic conditions that can cause obesity, such as Prader -Willi syndrome, there is no reason why most people cannot lose weight. It may be true that certain genetic traits inherited from your parents – such as taking longer to burn up calories (having a slow metabolism) or 22

having a large appetite – can make losing weight more difficult, but it certainly does not make it impossible. Many cases where obesity runs in families may be due to environmental factors, such as poor eating habits learned during childhood. e. Medical reasons: Medical conditions that can cause weight gain include:  Cushing's syndrome, a rare disorder that causes the over-production of steroid hormones  an underactive thyroid gland (hypothyroidism), where your thyroid

gland does not produce enough thyroid hormone Certain medicines, including some corticosteroids and antidepressants, can also contribute to weight gain. Weight gain can also be a side effect of taking the combined contraceptive pill and from quitting smoking. Clinical Description: Being a little overweight may not cause many noticeable problems. However, once you are carrying a few extra kilograms (or pounds), you may develop symptoms that affect your daily life. a. Short-term problems:

Obesity causes day-to-day problems such as:  breathlessness  increased sweating  snoring  difficulty sleeping  inability to cope with sudden physical activity  feeling very tired every day  back and joint pains b. Long-term problems: Obesity can also cause changes you may not notice that can seriously harm your health, such as:  high blood pressure (hypertension)  high cholesterol levels (fatty deposits blocking your arteries)

Both conditions significantly increase your risk of developing a cardiovascular disease, such as:  coronary heart disease, which may lead to a heart attack  stroke, which can cause significant disability and can be fatal Another long-term problem that can affect obese people is type 2 diabetes. It is estimated that just under half of all cases of diabetes are linked to obesity. The main symptoms of diabetes are:  feeling very thirsty 23

 going to the toilet a lot, especially at night  extreme tiredness c. Psychological problems: In addition to the day-to-day problems of obesity, many people may also experience psychological problems, such as:  low self-esteem  low confidence levels  feeling isolated in society These can affect relationships with family members and friends and may lead to depression. Pathogenesis on the basis of Thirithodam: Due to intake of high calorie food, conception of alcohol, lack of physical

activity the vatham vitiated it leads to vitiate the kabam humour . Finally the vitiated vatham and kabam causing to increase body weight by stimulating fat deposition in different areas. Clinical Management for different stages of disease condition:  To suppress the increased vatham humour medicated Ennai kuliyal (oil bath) is the first choice of treatment  To reduce the increased vatham humour the viresanam (purgation) inducing medicines are more effective because “Viresanathal vatham Thalum”

 To reduce the vitiated kabam , herbal steam bath can be advised  The internal medicines can be administered in the form of chooranam , mathirai, kudineer, parpam and karppam  The external therapies like yogam and piranayamam to be advised. Approximate cost for the treatment of Obesity: Primary obesity can be classified in to two stages based on the BMI. Stage I: (BMI = 25 to 29.9) For oil bath - Rs.300.00 For purgation - Rs.400.00 For internal medicine - Rs.725.00 For Yogam and Piranayamam - Rs. 450.00

For Investigation - Rs. 410.00 (Complete blood count- 175/-, Lipid profile- 125/-, Sugar (F& PP)-60/-, ECG- 50/-) Total - Rs.2285.00/Month Stage II: For oil bath - Rs. 300.00 For Purgation - Rs. 400.00 For internal medicine - Rs. 1200.00 24

For Yogam and Piranayam - Rs. 650.00 For Investigation - Rs. 410.00 (Complete blood count- 175/-, Lipid profile- 125/- Sugar (F& PP)-60/-, ECG- 50/-) Total - Rs. 2960.00 The choice of medicine can be decided by physician based on the patient condition and BMI level. Dietary regimen:  Reducing the intake of fats and calories is a must and one of the first steps to reduce weight  Make sure that you drink warm water mostly. Siddha recommends this remedy

because people with kabam thodam feel hungry often. At such time, do not consume cold drinks. Warm water stimulates metabolism and also quenches thirst.  Low Calorie Vegetables like Ash gourd , Bottle gourd, Cluster beans , Colocasia stem , Cucumber , Ghosala , Kovai , Parwal, Ridge guard ,Snake guard are recommended.  Radish and banana stem juice(120ml) can be drink in empty stomach  Add more Garlic and Fenugreek in diet  Add horse gram in diet as kanjii or rasam

 Instead of tamarind, Garcinia should be added in curries  Consume plenty of greens like pasalai, vallarai, sirukeerai  Bilimbi , Jamb safed, Musk melon ,Water melon , Orange juice , Tomato ripe is advisable  Amla juice , Aloe juice are recommended daily  Take small meals after every few hours instead of three huge meals  Practice breathing exercises every morning. Breathing exercises help in stimulating digestive power and clean the system from impurities as well.

 Control the craving for foods high in carbohydrates and fats. They are the biggest sources of fats  Non veg food should be avoided strictly  Junk foods like cream biscuit , samosa, burger, pizza, chips and aerated items should be avoided  Salty food like Pickle , papadam , dry fish should be avoided  Consume a lot of citrus fruits like oranges and grapes as they help in dispensing fats.  Include foods rich in VitmainB12 in your diet. It helps in building tissues

 One should avoid alcohol. Alcohol is high on calories and also stimulates hunger. It also leads to failing of physiological mechanism that makes us feel full.  What we need to realize is the importance of physical activities and exercises in reducing weight. Morning walk or running help in burning the excessive fats and calories and also improve the endurance of the body.  A balanced diet is always helpful but overeating is not.  Do not eat late dinners.  Do not change your diet timings too often

 Do not skip any meals.  Avoid intake of dairy products like milk, cheese, ghee and ice cream.  Sleeping during daytime is highly advised against  Do not consume too many sweets and chocolates, as they are rich in carbohydrates.  Do not eat fast foods DIET CHART: Morning: 6.00 to 6.30 am : Green tea -30ML 6.30 a.m to7.15am : Walking and physical exercise 7.15 a.m to7.45 am : Radish or Banana stem juice – 60 ml Breakfast; 8.30 a.m to 9.00 a.m Two idlies or two dhosa with sambar or green chutney or

Oats meal –one cup or Wheat rava uppuma 1 cup with plenty of carrot and beans Midmorning Take 200 ml lime juice/ amla juice or With-one small cup of Fruits/ vegetable salad (options-Guava, Apple, Papaya) Lunch;- Clear rasam Or Veg soup One cup rice with one cup boiled vegetable 1 Cup of skimmed butter milk Evening;- Tea or coffee with minimum sugar or one cup sundal DINNER;- Two chappaties with dhal or Two wheat dhosa 26

PIRUKKA NOI (Chronic Kidney Disease) DEFINITION: It denotes a chronic kidney disease characterised by Oliguria, Anuria and reduced function. CLINICAL FEATURES:  Anuria  Giddiness  Breathlessness  Dizziness  Vomiting  Diarrhoea  Pre-comatic stage  Cramps  Tiredness  Constriction of pupils  Dryness of Tongue  Haematuria  Perspiration with injury odour EPIDEMIOLOGY: 1. Pirukka noi is more common in man and the age of onset is 3rd to 4th decade.

2. Elavenil, mudhuvenil(early and late summer) aggravate the disease 3. Paalai(Arid tract), neithal(coastal tract) and mullai(sylvant tract) reportedly higher compared to their areas. CAUSES:  Renal Calculus and other primary renal diseases  Stricture urethra  Congenital obstruction of urethra  Toxicosis  Complication of Diabetes  Tumours in Urethra  Haemorrhage in urethra due to trauma PATHOGENESIS: The imbalance in one‘s diet and fluid intake increase the azhal kutram. This

azhal kutram dries up the body fluid and urine resulting in concentration of salts, this further affects the keezh nokku kaal. One of the function of the keezh nokku kaal is to excrete urine. So when this keezh nokku kaal is affected the urine will be obstructed within urinary tract according to Siddha concepts. MANAGEMENT: STAGE – 1 Slightly diminished function; kidney damage with normal or relatively high GFR (≥90 mL/min/1.73 m2). Kidney damage is defined as pathological abnormalities

or markers of damage, including abnormalities in blood or urine test or imaging studies. Purgation Cost Rs 400 Internal medicines Cost Rs 22.50/day, Rs 675/month External medicines; Oleation Rs 500/month 27

Lab Investigation CBC Rs 65 FBS Rs 30 PPBS Rs 30 Urine routine 30 Bl. urea Rs 25 Sr creatinine Rs 25 X Ray KUB Rs 30 ECG Rs 50 Creatinine clearance test Rs 50 Investigation first visit Rs 335 Stage I Clinical management & Lab investigations Total cost Rs. 1910 STAGE– 2: Mild reduction in GFR (60–89 mL/min/1.73 m2) with kidney damage. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine test or imaging studies. Purgation Cost Rs 400

Internal medicines Cost Rs 27.50/day, Rs 825/month External medicines; Oleation Rs 500/month Lab Investigation CBC Rs 65 FBS Rs 30 PPBS Rs 30 Urine routine 30 Bl. urea Rs 25 Sr creatinine Rs 25 Lipid profile Rs 75 X Ray KUB Rs 30 ECG Rs 50 Creatinine clearance Test Rs 50 Investigation first visit Rs 410 Stage II Clinical management & Lab investigations Total cost Rs 2135 STAGE– 3: Moderate reduction in GFR (30–59 mL/min/1.73 m2).[1] British guidelines

distinguish between stage 3A (GFR 45–59) and stage 3B (GFR 30–44) for purposes of screening and referral Purgation Cost Rs 400 Internal medicines Cost Rs 28.50/day, Rs 855/month External medicines; Oleation Rs 500/month 28

Treatment given is for spacing the dialysis to be performed in modern treatment set up. Lab Investigation CBC Rs 65 FBS Rs 30 PPBS Rs 30 Urine routine 30 Bl.urea Rs 25 Sr creatinine Rs 25 X Ray KUB Rs 30 ECG Rs 50 LFT Rs 200 Creatinine clearance test Rs 50 Investigation first visit Rs 535 Stage III Clinical management & Lab investigations Total cost Rs 2290 STAGE– 4: Severe reduction in GFR (15–29 mL/min/1.73 m2)[1] Preparation for renal replacement therapy Purgation Cost Rs 400

Internal medicines Cost Rs 32.50/day, Rs 975/month External medicines; Oleation Rs 500/month Treatment given is for spacing the dialysis to be performed in modern treatment set up. Lab Investigation CBC Rs 65 FBS Rs 30 PPBS Rs 30 Urine routine 30 Bl.urea Rs 25 Sr creatinine Rs 25 Lipid profile Rs 75 X Ray KUB Rs 30 ECG Rs 50 Creatinine clearance test Rs 50 LFT Rs 200 Investigation first visit Rs 610 Stage IV Clinical management & Lab investigations Total cost Rs.2485 STAGE – 5:

Established kidney failure (GFR <15 mL/min/1.73 m2, permanent renal replacement therapy (RRT),[1] or end stage renal disease (ESRD) 29

If it is medical management failure or symptoms persists. Referral Criteria Breathlessness Dysnoea Ascites Relentless rise of creatinine nearing 8 mg/dL 2000 calories Diet plan for Chronic kidney disease: 6 gm salt, 40gms protein, 1.2 litres of liquid, 10 ml of cooking oil recommended. Low potassium diet is advised, avoid Tender coconut, Mangoes, Banana, Mint leaves, tubers. Vegetables should be leeched, MORNING 6.00 a.m : 100ml of tea with skimmed milk BREAKFAST

8.00 a.m : 2 idlies or 2 dosas with vegetable chutney MID MORNING 10.00 a.m : 100 ml of skimmed butter milk LUNCH 1.00 p.m : 150 gms of steamed rice, 1 cup of leeched and boiled vegetables, 1 cup of clear rasam. EVENING 4. 00 p.m : 100 ml of green tea DINNER 7.00 p.m : 2 chappathies, 1 cup of oat gruel 10.00 p.m : 100 ml of skimmed milk. DIET: Rice or kanchi – barley rice, double boiled rice, Kaar rice, Karuvai rice, Manakkathai Rice kanchi Tender vegetables – Aavarai Vendai Vazhaippu and thandu Kovai

Vellari Greens: Pasalai Kodi pasalai Siru pasalai Vendaya Keerai 31

ERAIPPU NOI (BRONCHIAL ASTHMA) I. INTRODUCTION Bronchial Asthma is characterized by chronic airway inflammation and increased airway responsiveness resulting in symptoms of Wheeze, cough, chest tightness and dyspnoea. In Siddha System of Medicine the Disease Eraippu Noi comes under Kaba diseases which may be correlated with Bronchial Asthma in Modern Medicine.It is an episodic disease with acute exacerbation interspersed with symptoms - free

periods.The Kaar (earlyrainy),Koothir(late rainy),Munpani(early winter),Pinpani(late winter) aggravated the disease especially at vaigarai(early morning). Siddha system contributes to control and prevent the Bronchial asthma symptoms through internal and external medications, life style modification and rejuvenation drugs. II. DEFINITION Eraippu Noi is characterized by paroxysmal dyspnoea associated with discomfort in the chest. There is difficulty in the process of inspiration and

expiration.Usually the respiration is associated with some musical sounds called wheezing. The patient may find with difficult to expel the sputum. III. AETIOLOGY  Allergic food items  Excessive intake of Cold food items  Various fumes , dusts  Inhaling irritable smelling substances  Excessive smoking  More exposure to cold air IV. CLINICAL DESCRIPTION  Rhinorrhoea  Sneezing  Discomfort in chest  Wheezing  Dryness of tongue  Prolonged Expiration  Cough without expectoration

 Pain in the chest and ribs  Excessive Sweating  Flatulence of abdomen 32

V. TYPES According to the text book ―Siddha Maruthuvam (Pothu)‖ Eraippu Noi is classified into 5 types. 1. Vali Eraippu Noi (Gastro- Oesophageal Reflux and Asthma) 2. Iya Eraippu Noi (Bronchial Asthma) 3. Iya Vali Eraippu Noi (Complications of Bronchial Asthma-Cardiac and renal symptoms) 4. Mukkutra Eraippu Noi (Chronic Bronchial Asthma) 5. Melnokku Eraippu Noi (Acute Severe Asthma) I ) Vali Eraippu Noi ( Gastro- oesophageal Reflux and Asthma )

Intake of indigestible foods and tubers, exposure to hot summer which promotes Vatham and causes decreased body strength leads to difficulty to breath. This type of Eraippu noi is curable. II) Iya Eraippu Noi (Bronchial Asthma) Intake of excessive kaba promoting foods like cold food items,sweet tasted foods exposure to rain and cold air which also promotes Iyam and causes running nose, nasal obstruction. These symptoms relived spontaneously followed by tightness

of chest, wheezing with unproductive cough. In this case, when the sputum is expelled by cough, the symptoms are relived, otherwise dyspnoea will be severe.Sweating in the forehead, darkness of the face , chillness of the limbs , protrusion of eyeballs , dryness of the tongue, tremor , labored breathing, unable to lie in the bed also occurs. III) Iya Vali Eraippu Noi (Complications of Bronchial Asthma - Cardiac & Renal symptoms) In this type the deranged Kabam and Vatham affects the Uthaanan (Air of

upward motion) and produces the following symptoms. Wheezing, constipation, oliguria, flatulence, dryness of the tongue, redness of the eyes, sweating, blabbering speech , fearfulness, restlessness, giddiness. IV) Mukkutra Eraippu Noi (Chronic Bronchial Asthma) In this type all the thirithodams, Uthaanan (Air of upward motion), Abaanan (Air of downward motion), viyananl (Air which spreads throughout) , samananl (Air with upward and downward motion), seven body constituents are affected. Severe

dyspnoea, tremor, fearfulness, high pitched wheezing, tightness of chest, giddiness, constipation, oliguria, flatulence, slurring speech, weakness of five sensory organs , body pain, excessive sweating in forehead. V)Melnokku Eraippu Noi ( Acute severe Asthma) When the above types were not responded to any kind of the treatment, it may weakens the Uthaanan and leads to severe persistent dyspnoea associated with dryness of the tongue , protrusion of eyes, unable to speak and gasping. If it is treated

VI. PATHOGENESIS ON THE BASIS OF THIRITHODAM In Eraippu Noi Kabam is accompanied with vitiated Vatham or Pitham and produces the clinical symptoms. Excess of Kabam in the respiratory organs affects the Melnokkungal ( Air with upward motion) and uyirkaal ( Air of life ).So the air is not able to reach the terminal point of respiration , which produces gasping and laboured breathing. VII.CLINICAL MANAGEMENT FOR DIFFERENT STAGES OF DISEASE CONDITION Stage I (Mild to Moderate)

Symptoms of the disease are managed completely by Siddha herbal preparations such as Kudineer, Chooranam, Vadakam, Saaru, Lehiyam, Manappaaku. Vali Eraippu Noi (Gastro- Oesophageal Reflux and Asthma), Iya Eraippu Noi (Bronchial Asthma) is treated in the stage 1 OPD level. This diseases is treated with following internal and external medication. DIAGNOSIS ENVAGAI THERVUGAL (Eight fold system of clinical assessments): 1. Naa thervu (Examination of tongue)

(i) Niram (Colour) Pale/cyanosis in acute severe condition. (ii) Thanmai (Character) Coated / denuded. (iii) Pulan (Sense) Salaiva tend to taste sweet / sour. (iv) Salivary secretion Decreased 2. Niram thervu (Examination of colour) Pale / red / pink 3. Mozhi thervu (Examination of speech) Low pitched Wheezing sound heard (Snake‘s snort) along with speech. 4. Vizhi thervu (Examination of eye) (i) Niram (Colour) Pale / black (ii) Thanmai (Character) Normal. (iii) Pulan (Sense) Normal.

5. Malam thervu (Examination of stool) (i) Niram (Colour) Pale (ii) Nurai (Froth) Present (iii) Elagal/Erugal (Consistancy) Elagal (loose stools) 6. Moothiram thervu (Examination of urine) (a) Neerkuri: (i) Niram (Colour) Straw coloured 34

(ii) Adarthi (Density) Decreased (iii) Manam (Odour) Flesh smell (iv) Nurai (Froth) Increased (v) Enjal (Deposits) Absent (b) Neikkuri: Iya neer- Oil stands in the form of pearl. In severe stage: The oil drops spreads the shape of the sieve, betle leaf, irregular margin and flower shapes. 7. Parisam thervu (Examination by touch) Cold / clammy / pain in throat / tenderness. 8. Naadi thervu (Examination of pulse) (i) Thanmai (Character) Rapid and thin. (ii) Nadai (Pattern) Iya Naadi and Vali Iya Naadi

INVESTIGATIONS  Blood & Urine – routine  Serum Ig E  Pulmonary function test  Sputum for AFB  X ray – Chest  ECG TREATMENT FOR STAGE I : In this stage, initially Vali Eraippu Noi patients are treated with purgation & Iya Eraippu Noi patients are treated with Purgation / emetic therapy to normalize the altered Uyirthaathukkal (Vali,Azhal,Iyam) and this stage I is followed with internal and external medications. Drugs for disease: Internal Medicines:

Chooranam, Vadakam, Theeneer, Ilakam, Rasayanam, Nei, Karpam, Maathirai types of Internal medicines are used in Stage I EXTERNAL MEDICINES Puha i(Fumigation) Vedhu (Vapour bath) : Thokanam & Otradam (Oil massage & Fomentation) Oleation Stage II (Moderate to Severe ) Symptoms are treated with medicines managed prepared from Ulokam (Metals), Uparasam ( Minerals), Kaarasaaram (Salts) and from Animal origin. 35

Iya Vali Eraippu Noi(Complications of Bronchial Asthma – Cardiac & renal symptoms), Mukkutra Eraippu Noi (Chronic Bronchial Asthma) is treated in the stage 2 OPD / IPD level. TREATMENT FOR STAGE II : In this stage, patients are treated directly with internal and external medications. INTERNAL MEDICINES Parpam, Chendooram types of Internal medicines are used in Stage-II EXTERNAL MEDICINES Puhai (Fumigation) Vedhu (Vapour bath) : Thokanam & Otradam (Oil massage & Fomentation) Oleation

Stage III (Very Severe to Advanced disease ) The level 3 usually recommended to be carried out at in – patient care. At this level, symptoms are treated with specific potent medicines including Muppu , Kattu, Neeru, Pathangam and strong medicines – Paadanam (Arsenic preparations ) , pancha sootham (Mercurial preparations) Melnokku Eraippu Noi (Acute Severe Astma ) is treated in the stage 3 IPD / OPD level. TREATMENT FOR STAGE III: In this stage , patients are treated only with Internal medicines.

INTERNAL MEDICINES Karuppu, Chunnam types of medicines & copper, silver, gold preparations are used in stage III. Diet Rice or kanji - Chukku mudikanji Nerpori kanji Barlie kanji Rice boiled hot water REFERRAL CRITERIA  Marked increase in intensity of symptoms, such as sudden development of resting dyspnoea, Cyanosis, drowsiness and confusion.  Retention of urine, constipation. DIET CHART Morning:  7.00 am- Ginger/ Dry ginger/ Turmeric/ Pepper mixed milk Break fast:

 Chukku mudi kanji/ Steamed foods like Idly / Idiyappam / Puttu 36

 11.00 am – Pepper mixed vegetable soup/ crab soup Lunch:  Boiled rice, Green gram sambar, pepper rasam, Thuthuvalai thuvaiyal (Solanum trilobatum.linn)  Vegetable curry of Drumstick/ Carrot/ Ridge guard/Indian butter beans/ Solanum Torvum (Sundai)  Green vegetables like solanum nigrum (Manathakkali) /Alternanthera Sessilis (Ponnanganni)/Moringa Oleifera (Murungai)  Non-veg: Crab / Egg with Pepper / Fish gravy like loach(Ayirai),Turkey, Goat‘s meat  Fruits like Papaya / Apple / Strawberry Evening:

 5.00 pm – Green tea / Chukku coffee  Musumusukkai adai (Mukia madaraspatana,linn)/ Kalyana murungai adai (Erythrena variegata,linn) Dinner:  Steamed foods like Idly / Idiyappam / Puttu VIII. DO’S AND DONT’S DIETS TO BE ADDED: The following diets are advised to take in Asthmatics. 1.Green Leafy Vegetables like  Spinach (Pasalai)  Solanum Nigrum (Manathakkali)  Alternanthera Sessilis (Ponnanganni)  Moringa Oleifera (Murungai)  Centella Asiatica (Vallarai)  Solanum Trilobatum (Thoothuvalai)

 Cissus Quadrangularis (Pirandai)  Mukia Scavrilla (Mookirattai)  Erythrina variegate(Kalyana murungai)  Mukia maderaspatana(Musumusukkai)  Amaranthus tristis(Arukerai)  Amaranthus tricolor(sirukerai)  Gisekia pharnaceiodes(Manalikerai)  Melochia corchorifoliatim(Pinnakku kerai) 2. Sproutted Seeds and Grains 3. Fresh tender Vegetables like 37

 Indian butter beans  Unripe Fig  Ridge Gourd  Stem of Plantain  Drumstick  Solanum Torvum (Sundai)  Indian Goose Berry (Nellikkai)  Bottle Gourd  Radish  Carrot  Ladies finger 4. Add sufficiently in diet  Garlic  Onion  Ginger  Pepper  Turmeric  The Bhisopsweed (Omum)  Fenugreak  Coriander Seeds  Anet Seeds (Sathakuppai)  Asafoetida  Cardamom seeds  Dried ginger 5. Fresh Fruits Like  Apple  Papaya  Strawberrys 6. Non Vegetable Diet like  Crab  Turkey  Rabbit  White rat

Dies to be avoided  Fried Foods  Difficult to digest Foods  Refrigerated Foods  All refined & processed Foods  Food Preservatives & Food Coloring  Allergic foods.  Food Additives (sulfites)  Curd Preparations  Cool Drinks, ice Creams, Chocolates, Sweets  Strong tea & Coffee  Alcoholic Beverages  Condiments Pickles, Sauces  Citrus Fruits like lemon, orange.  Other fruits like pine apple, grapes, jackfruit, mango, pomegranate Principles and Advice (or) Guidelines for in Advices Asthmatics

Asthmatics should follow the following principles and advice in their diet and daily life.  Intake of Hot water and hot Foods.  Taking Bath strictly in hot water  Avoidance of Chill weather  Avoidance of polluted area and dust.  Avoidance of Allergic Factors  Avoidance of smoking and snuff  Avoidance of stress, emotion  Avoidance of factors which causes digestive disturbances.  Evening meal should preferably be finished before sundown (or) atleast 3 hours before bed time.

 Avoid cycling, mountain Biking, Long distance, Running, Weight lifting.  Advice to practice Pranayamam and Yogasanam like buyangasanam, sarvangasanam, patchimothasanam, halasanam, badhmasanam.  Remove Carpets from bedrooms and vacuum regularly. 39

 Keep the house clean and keep food in containers and out of bedrooms. XI. APPROXIMATE COST FOR PROCEDURES, MEDICINES ETC DURING TREATMENT AND POST TREATMENT STAGE –I INTERNAL MEDICINES Purgation treatment (kalichal) Rs.400 Therapeutic Emesis(vamanam) Rs.500 Drugs for disease Rs. 35 /day Rs. 1085 /month Rs. 13020 /year EXTERNAL THERAPIES- Puhai(Fumigation) – One sitting Rs.500 Therapeutic inhalation (Vedhu) Rs.500 Therapeutic manipulation (Thokkanam) for specific regions of the body Rs.400

Yogasanam Rs.500 Investigation Blood routine- Rs. 90 ECG Rs. 100 Chest X Ray Rs. 30 Serum Ig E Rs. 100 Pulmonary Function Test Rs. 250 STAGE –II INTERNAL MEDICINES Rs. 122 /day Rs. 3,782 /month Rs. 45,384 /year EXTERNAL THERAPIES- Puhai(Fumigation) – One sitting Rs.500 Therapeutic inhalation (Vedhu) Rs.500 Therapeutic manipulation (Thokkanam) for specific regions of the body Rs.400 Yogasanam RS.500 Investigation Blood routine Rs. 90 ECG Rs. 100 Chest X Ray Rs.30 Serum Ig E Rs. 100

STAGE –III/IV INTERNAL MEDICINES Rs- 85/day Rs- 2635/month Rs- 31620/year Investigation Before and After Treatment Blood routine Rs. 90 ECG Rs. 100 Chest X Ray Rs. 30 Serum Ig E Rs. 100 Pulmonary Function Test Rs. 250 Allergy Test – Intradermal test Rs. 1500 41

OVVAMAI (ALLERGIC DISORDERS) Introduction: Allergies are pretty common. Both genes and environment play a role. The immune system normally protects the body against harmful substances, such as bacteria and viruses. It also reacts to foreign substances called allergens, which are generally harmless and in most people do not cause a problem. But in a person with allergies, the immune response is oversensitive. When it recognizes an allergen, the immune system launches a response. Chemicals such as

histamines are released. These chemicals cause allergy symptoms. Common allergens are drug, dust, food, insect venom, mold, pet and other animal dander and pollen. Allergy is an interaction between the immune system and a substance foreign to the body. There are two important effects of allergy on the body. One is the classic "allergic reaction" that can cause sudden tissue swelling, itching, sneezing, increased mucous production, and in the lungs, wheezing and shortness of breath. In food

allergic reactions, the intestinal tract can also be acutely inflamed and cause nausea, vomiting and diarrhoea. In a "whole body" allergic reaction, including anaphylaxis, low blood pressure and shock can occur. The other part of the "allergic response" is persistent inflammation that is important in nasal allergy, asthma and eczema. In allergy of the airway, inflammation can occur and cause some symptoms without the sneezing, itching and wheezing. Diagnosis and effective treatment of allergic

disorders requires consideration of both of these effects. In Siddha system the allergic disorders can be correlated with Ovvamai, is unsuitability to the constitution. Altered Pitham along with Kabam by various factors causes the allergic reaction in the body. The common allergic reactions are follows 1. Kaanakadi (Urtecari) 2. Kann thinayu (Allergic conjunctivitis) 3. Kulir erumal (Allergic cough) 4. Neer mookkadaippu (Allergic rhinitis) 42

KAANAKADI (URTECARIA) Introduction: Saint Ugi munivar classified the skin diseases in to 18 types. Thadippu kuttam is one of them which is characterised by wheel formation, itching, swelling of the body, increased body heat and burning sensation .It is caused by deranged Pitham. It is described under curable varieties. The name Kaanakadi derived from its unknown aetiology and unknown bite. The kaanakadi can be correlated with urtecaria of modern science.

Urtecaria and angioedema occurs more frequently after adolescence with high incidence in young adults. There are two types of urtecaria, acute (below6week) and chronic (above6week).chronic urtecaria is less common than acute urtecaria and is common in women than male. The urtecaria affects 15-20% of population. Definition: Kaanakadi is characterised by itching and wheel formation, which may be localised or generalised in the body. This can disappear within short period. In some

people it is chronic in nature. The impure blood causes the vitiation of Pitham from its normal range and can cause wheel formation and itching in the body. Causative factors: The triggers of short-term (acute) urticaria are unknown in around half of all cases. Recognised triggers include: 1. A food allergy to foods such as peanuts, shellfish, eggs and cheeses 2. An allergic reaction to environmental factors such as pollen, dust mites or chemicals

3. An allergic reaction to latex, which can be a common problem in healthcare workers 4. Infections, which can range from relatively trivial, such as a cold to very serious, such as HIV 5. Insect bites and stings 6. Emotional stress 7. Certain medications that can cause urticaria as a side effect, including antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin 8. Physical triggers, such as pressure to the skin, changes in temperature, sunlight, exercise or water Chronic urticaria

1. Chronic urticaria may occur when the body's immune system attacks its own tissues. This is known as an autoimmune reaction. 2. Antibodies (proteins that usually fight bacteria and viruses) then trigger the release of histamine, resulting in urticaria. 3. About a third to half of all chronic cases of urticaria are thought to be autoimmune related. 43

4. it‘s not known why autoimmune urticaria develops, although it can sometimes occur in combination with other autoimmune conditions, such as:  Rheumatoid Arthritis  lupus 5. Chronic urticaria can also be linked to other chronic illnesses and infections, such as viral hepatitis , intestinal parasites, hypothyroidism or an hyperthyroidism. Chronic urticaria tends to come and go. Many people find that certain things make it reappear or make existing symptoms worse. Triggers include:  Stress  Alcohol

 Caffeine  Warm temperatures  Prolonged pressure on the skin – this can happen by wearing tight clothing  Medications – such as NSAIDs, and the painkiller codeine  Certain food additives – such as salicylates, which are found in tomatoes, orange juice and tea  Insect bites and stings  Exposure to heat, cold, pressure or water Causes of urtecaria mentioned in siddha literature: 1. eating of unhygienic chicken and sea foods like fish 2. Eating of uncooked and undigested food

3. Practising the Yogam immediately after heavy meals. 4. Excessive heat and excessive cold 5. Increased sexual activity 6. Stress and worriessect bite 8. Genitic and family history 9. Drugs The above mentioned causes can toxicified the blood which cause the vitiation of Pitham and produce the diseases Clinical description: It characterised by the appearance of elevated wheals and itchy erythematous swelling which may vary from a few millimetre\ to several centimetres in size. In

some the itching will be very severe. These lesions can disappear spontaneously. In a variation, itching is absent instead angioedema of the eyelids, earlobes and mucous membrane of the throat occurs and disappears. At times, this oedema affects the larynx and obstructs breathing. 44

A variation called vasculitic urtecaria occurs in some number of cases. In this condition the wheals lasts more than 24 hrs .they are often painful, may become dark red and may leave red mark. Pathogenesis on the basis of Thirithosam Deranged Pitham(Vitiated Pitham) by internal and external causative factor will join with Kapam and produce the disease in the skin. Paraukal kaal of Vatham is also affected by vitiated Pitham and produce the diseases.

Pirasaka pitham of Pitham and Avalampakam of Kapam are also affected. Udal thathukkal affected by the Kaanakadi are Saram, Senneer,and Oon. Investigation 1. Skin prick testing 2. Serum allergen-specific Ig E testing 3. Full blood count. 4. Thyroid antibody testing. 5. Skin biopsy is only rarely required, if urticarial vasculitus is suspected. Sign and symptoms are staged from I to IV for treatment purpose  Stage-I –up to50 small wheals or less than 10 large wheals with or without itching

 Stage-II-greater than 50 small wheals or 10 to 50 large wheals with itching and with or without angioedema  Stage-III almost the whole body is covered with or without angioedema and vasculitis  Stage-IV (referral criteria) urtecaria with angioedema associated with difficulty in  Breathing, hypotension, abdominal pain, vomiting etc. Line of Treatment Step-1. Normalisation of the altered Uyir thathukkal Step-2. Internal medicine Step-3 External medicine Step-4 Special therapy

Step-1.Normalization of altered Uyirthathukal The altered Uyirthathukal should be normalised by the following procedure. Pitham will be normalized by Vomiting Kapam will be normalized by Nasiyam and Anjanam Vatham will be normalised by Purgation Step-2. Internal medicine 45

Level -1 : The level-1 contain the following form of medicine 1. Chooranam 2. Mathirai 3. Kasayam 4. Karkam Level -2 : The level-2 contain the following form of medicine Parpam Level- 3 : The level-3 contain the following form of medicine Chenthuram Level- 4 : The level-4 contain the following form of medicine 1. Mezhuku 2. Pathangam 3. Chunnam Step -3 External medicines Step-3 contain the following form of medicine 1. Thylam 2. Vennai 3. Poochu Step 4 special therapy Iyamam and Niyamam Karpa Asanam

Santhi asanam Virutchsasanam Makrasanam Sarvangasanam Utthanapathasanam Pranayamam Natichuthi pranayamam Kabalapathy Seethalapathy and seethari Meditation Treatment for different stage of diseases:  Stage-1 of disease – chooses the suitable medicine from step- 1, step -2(level- 1), step- 3 and step-4  Stage-2 of disease – choose the suitable medicine from step- 2(level- 1 and level- 2), step -3 and step-4  Stage-3 of disease – choose the suitable medicine from step- 2(level- 1, level-3

or Level-4), step -3 and step-4  Stage-4 of disease – referral criteria 46

Approximate cost for different stage of treatment Stage -1 Cost for step- 1 – Rs.1200 Cost for step- 2 – Rs.10 Cost for step -3 – Rs.25 Cost for step - 4 – Rs.300 Total cost for stage-1 treatment/day= Rs.1535 Total cost for stage-1 treatment/month= Rs.2550 Stage-2 Cost for step- 1 – Rs.1200 (Not necessary if given in step-1) Cost for step- 2 – Rs. 17 Cost for step -3 – Rs.25 Cost for step - 4 – Rs.300 Total cost for stage-2 treatment/day= Rs.1542 Total cost for stage-2 treatment/month= Rs.2760 Stage- 3

Cost for step- 1 – Rs.1200 (Not necessary if given in step-1) Cost for step- 2 – Rs. 15 Cost for step -3 – Rs.25 Cost for step - 4 – Rs.300 Total cost for stage-3 treatment/day= Rs.1540 Total cost for stage-3 treatment/month= Rs.2700 Stage – 4: The patient should be referred to higher speciality centre. Approximate cost for investigation 1. Skin prick test – Rs.3500 2. Serum allergen-specific Ig E test - Rs.850 3. Full blood count – Rs.15 4. Thyroid antibody test – Rs.50 5. Thyroid profile- T3 & T4 –Rs. 200

TSH-Rs. 200 6. Skin biopsy – Rs.400 7. Motion test for ova cyst – Rs.15 8. Urine routine – Rs.50 Investigation in Siddha system: Neer kuri and Nei kuri,Malakuri and Manikkadai nool- Rs.50 Diet regimen: The following foods should be avoided 1. Salt, Pungent and Sour should be restricted 2. Millet, Maize, Bitter guard, Bingil, fish, dry fish, Egg, chicken, Kaarrarisi. 3. Artificial food colours 4. Additives, Alcohol, Narcotic drugs. 5. Using soaps and Detergents 6. Non- vegetarian foods 47

Prevention: 1. The patient is advised to take oil bath once in week 2, Purgation should be given once in 4 months 3. Vomiting should induced once in 6 months 4. Nasiyam should be given once in 45 days 5. Anjanam should be applied once in 3 days 6. Strictly avoid day sleep 48

KANN THINAYU (ALLERGIC CONJUCTIVITIS) Introduction In Siddha medicine the diseases were classified in to 4448, in which the eye diseases are 96 types. The Kann thinayu is one of them which is characterised by itching, irritation, redness of eye, burning sensation, watery discharge and blurred vision which can be correlated with allergic conjunctivitis of modern science. Definition: Conjunctivitis means inflammation of the conjunctiva. The conjunctiva is the

thin skin that covers the white part of the eyes and inside of the eyelids. Aetiology: Allergy means that the immune system overreacts to something to which it has become sensitive. Symptoms of increased immune activity include redness, wateriness and itching. These are part of the body's defense mechanism to things it sees as foreign and harmful. Causes include the following: Seasonal conjunctivitis due to pollens and moulds Seasonal conjunctivitis occurs at the same time each year. Most cases are due

to pollen and occur in the hay fever season. Grass pollens tend to cause symptoms in early summer, usually from April through to July in the UK. Tree pollens may cause symptoms as early as February or March or as late as September depending on when the tree species involved shed their pollen. Various other pollens and moulds may cause symptoms later in the summer. Perennial conjunctivitis This is a conjunctivitis that persists throughout the year. This is most

commonly due to an allergy to house dust mite. House dust mite is a tiny insect-like creature that lives in every home. It mainly lives in bedrooms and mattresses, as part of the dust. People with perennial conjunctivitis usually also have perennial allergic rhinitis which causes symptoms such as sneezing and a runny nose. Symptoms tend to be worse each morning when you first wake up. Allergies to animals Coming into contact with some animals can cause allergic conjunctivitis. This

is usually due to allergy to fur or hair. Giant papillary conjunctivitis This is uncommon. It is an inflammation of the conjunctiva lining the upper eyelid. It occurs in some people who have a small object on the eye - most commonly, a contact lens Causes for eye diseases mentioned in Siddha literature: Taken of heavy weight in head Sun exposure Not taken oil bath regularly Taken of bath in impure water Excessive use of narcotic drugs Anger Waking in barefoot 49

Clinical feature: The eyes are usually itchy and gritty The eyes water more than usual but do not become too gluey or sticky The skin on the inside of the eyelids looks red and sore The white of the eye look red or pink Burning sensation may occur, although the eyes are not usually painful and look The eyelids tend to swell Vision is not affected In severe causes the conjunctiva under the upper eye lids may swell lumpy Complication: Complication is rare but contact dermatoconjuctivitis and giant papillary

conjunctivitis occasionally causes inflammation and ulceration of cornea. Some permanent loss of vision may occur if there are untreated. Pathogenesis on the basis of Thirithosam: Deranged Pitham(Vitiated Pitham) by internal and external causative factor will join with Kapam and produce the disease in the skin Paraukal kaal of Vatham is also affected by vitiated Pitham and produce the diseases. Pirasaka pitham of Pitham and Avalampakam of Kapam are also affected.

Udal thathukkal affected by the Kaanakai are Saram, Senneer,and Oon. Investigation 1. Skin prick testing 2. Serum allergen-specific IgE testing 3. Full blood count. Sign and symptoms are staged from I to IV for treatment purpose Stage-1 The eyes are usually itchy and gritty The eyes water more than usual but do not become too gluey or sticky The skin on the inside of the eyelids looks red and sore The white of the eye look red or pink Stage-2 1. Symptoms of stage 1 +

2. Burning sensation may occur, although the eyes are not usually painful and look The eyelids tend to swell Stage-3 1. Symptoms of stage 1 and stage 2 + 2. In severe causes the conjunctiva under the upper eye lids may swell lumpy 3. Pain and purulent discharge due to secondary infection and contact Dermatoconjuctivitis Stage-4 (Referral criteria) 1. Severe stage of conjunctivitis and 50

2. Ulceration of cornea Treatment Step-1. Normalisation of the altered Uyir thathukkal Step-2. Internal medicine Step-3 External medicine Step-4 Special therapy Step-1.Normalization of altered Uyirthathukal The altered Uyirthathukal should be normalised by the following procedure. Pitham will be normalized by vomiting Kapam will be normalized by Nasiyam and Anjanam Vatham will be normalised by Purgation Step -2. Internal medicine Level-1 The level-1 contain the following form of medicine Chooranam Lekiyam

Nei Mathirai Level -2 The level-2 contain the following form of medicine Parpam Level- 3 The level-3 contain the following form of medicine Chenthuram Level- 4 The level-4 contain the following form of medicine 1. Mezhuku 2. Pathangam 3. Chunnam Step 3 External medicine Step-3 contain the following form of medicine 1. Thylam for oil bath 2. Anjanam 3. Pattikattal 4. Kalikkam(Eye drops) 5. Kann Kazhuval(Eye wash) Step4 Special therapy Pranayamam Meditation Treatment for different stage of diseases:

 Stage-1 of disease – chooses the suitable medicine from step- 1, step -2(level- 1), step- 3 and step-4  Stage-2 of disease – choose the suitable medicine from step- 2(level- 1 and level- 2), step -3 and step-4  Stage-3 of disease – choose the suitable medicine from step- 2(level- 1, level-3 or Level-4), step -3 and step-4 51

 Stage-4 of disease – referral criteria Approximate cost for different stage of treatment: Stage -1 Cost for step- 1 – Rs.1200 Cost for step- 2 – Rs.20 Cost for step -3 – Rs. 50 Cost for step - 4 – Rs.300 Total cost for stage-1 treatment/day= Rs.1570 Total cost for stage-1 treatment/month= Rs.3600 Stage-2 Cost for step- 1 – Rs.1200 (Not necessary if given in step-1) Cost for step- 2 – Rs. 25 Cost for step -3 – Rs.50 Cost for step - 4 – Rs.300 Total cost for stage-2 treatment/day= Rs.1575

Total cost for stage-2 treatment/month= Rs.3750 Stage- 3 Cost for step- 1 – Rs.1200 (Not necessary if given in step-1or step-2) Cost for step- 2 – Rs. 25 Cost for step -3 – Rs.50 Cost for step - 4 – Rs.300 Total cost for stage-3 treatment/day= Rs.1575 Total cost for stage-3 treatment/month= Rs.3750 Stage – 4 The patient should be referred to higher speciality centre Approximate cost for investigation: 1. Skin prick test – Rs.3500 2. Serum allergen-specific IgE test - Rs.100 3. Full blood count – Rs.15

Investigation in Siddha system: Neer kuri and nei kuri,malakuri and manikkadai nool- Rs.5 Diet regimen: The following foods should be avoided 1. Salt, Pungent and Sour should be restricted 2. Millet, Maize, Bitter guard , Brinjal, fish, dry fish, Egg, chicken, kaarrarisi. 3. Artificial food colors 4. Additives, Alcohol, Narcotic drugs. 5. Using soaps and Detergents 6. Non- vegetarian foods 52

Prevention: 1. The patient is advised to take oil bath once in week 2, Purgation should be given once in 4 months 3. Vomiting should induced once in 6 months 4. Nasiyam should be given once in 45 days 5. Anjanam should be applied once in 3 days 6. Strictly avoid day sleep 53

KULIR ERUMAL (ALLERGIC COUGH) Introduction In Siddha medicine the Saint Yugi munivar was classified the Kaba diseases in to 21 types. The Erumal is one of them which are further subdivided in to 12 types. The Kulir Erumal is one type which can be correlated with allergic cough of modern science. Definition: The altered Iyam in the body by cold atmosphere cause redness in nose and throat, watering from nose, chest congestion and cough , sneezing, wheezing,

difficulty in breathing, pain in neck ,face, ear, sweating and sputum with expectoration. Allergic Cough is a reflex caused by the stimulation of lining of the nose, throat, voice box or lungs and it is a normal defence mechanism .It is caused by abnormal sensitivity of our deference mechanism to normally harmless substances (allergens) such as dust, pollen and animal dander. Aetiology: 1. Allergic cough is due to immediate hypersensitivity reaction in the lining of

the nose, throat, voice box or lung .the antigen concerned in the seasonal form of the disorder are pollen from grasses, flowers, trees. 2, Allergen derived from house dust, fungal spores or animal dander. But similar symptoms can be caused by physical and chemical irritants-for example pungent odour or fumes, cold air, and dry atmospheres. 3. Allergic rhinitis, allergic dermatitis and allergic asthma Clinical feature: 1. Coughing is the most common symptom of allergic cough most likely caused by

Allergic rhinitis 2. Post nasal drip is a common symptom of allergic cough. It is caused by inflamed Sinuses. 3. Wheezing if the coughing is the result of allergic asthma, the cough accompanying with wheezing. 4. Other allergic symptoms such as sneezing, watery eyes, asthma, nasal congestion. In some cases hives and skin rashes may accompanied. 5. In some cases there is breathlessness and even cannot breathe may occur which is emergency one. Pathogenesis on the basis of Thirithosam

The Kabam is altered by various causes. Then the altered Kabam affects the throat, nose, lungs, ear and head and also stimulate the Uthanan Vayu then produce the diseases 54

Sign and symptoms are staged from I to IV for treatment purpose Stage 1 1. Cough 2. Post nasal drip 3. Sneezing, watery eyes, nasal congestion Stage 2 1. Symptoms of stage 1 + 2. The cough accompanying with wheezing. 4. Other allergic symptoms like hives and skin rashes may accompanied Stage 3 1. Symptoms of stage 1 and stage2 + 2. Cough with purulent sputum 3. Dysphasia 4. Depression 5. Long lasting persistent cough 6. Tiredness Stage 4 1. Symptoms of stage 3 + 2. Difficulty in breathing Line of Treatment

Step-1. Normalisation of the altered Uyir Thathukkal Step-2. Internal medicine Step-3 External medicine Step-4 Special therapy Step-1.Normalization of altered Uyirthathukal The altered Uyirthathukal should be normalised by the following procedure. Pitham will be normalized by vomiting Kapam will be normalized by Nasiyam and Anjanam Vatham will be normalised by Purgation Step -2. Internal medicine Level-1 The level-1 contain the following form of medicine Chooranam Lekiyam Nei 55

Mathirai Kasayam Theeneer Level- 2 The level-2 contain the following form of medicine Parpam Level -3 The level-3 contain the following form of medicine Chenthuram Level- 4 The level-4 contain the following form of medicine 1. Mezhuku 2. Pathangam 3. Chunnam Step- 3 External medicine Step-3 contain the following form of medicine 1. Thylam for oil bath 2. Patru(paste) 3. Pugai (Fumigation) 4. Vethu (Therapeutic inhalation) 5. Naasigaparanam (Nasal snuffing) Step-4 Special therapy Pranayamam Meditation

Treatment for different stage of diseases: 1. Stage-1 of disease – chooses the suitable medicine from step- 1, step -2(level- 1), step- 3 and step-4 2. Stage-2 of disease – choose the suitable medicine from step- 2(level- 1 and level- 2), step -3 and step-4 3. Stage-3 of disease – choose the suitable medicine from step- 2(level- 1, level-3 or Level-4), step -3 and step-4 4. Stage-4 of disease – referral criteria Approximate cost for different stage of treatment: Stage -1 Cost for step- 1 – Rs.1200

Cost for step -3 – Rs.2050 Cost for step - 4 – Rs.300 Total cost for stage-1 treatment/day= Rs.3590 Total cost for stage-1 treatment/month= Rs.64200 Stage-2 Cost for step- 1 – Rs.1200 (Not necessary if given in step-1) Cost for step- 2 – Rs. 47 Cost for step -3 – Rs.2050 Cost for step - 4 – Rs.300 Total cost for stage-2 treatment/day= Rs. Rs.3597 Total cost for stage-2 treatment/month= Rs.64410 Stage- 3 Cost for step- 1 – Rs.1200 (Not necessary if given in step-1) Cost for step- 2 – Rs. 45

Cost for step -3 – Rs.2050 Cost for step - 4 – Rs.300 Total cost for stage-3 treatment/day= Rs.3595 Total cost for stage-3 treatment/month= Rs.64350 Stage – 4 The patient should be referred to higher speciality centre Approximate cost for investigation 1. Skin prick test – Rs.3500 2. Serum allergen-specific IgE test - Rs.100 3. Full blood count – Rs.15 Investigation in Siddha system: Neer kuri and nei kuri,malakuri and manikkadai nool- Rs.50 Pathiyam(Diet regimen) Add

Rice or kanji – hand pounded rice, double boiled rice,rice kanji,pepper soup. Tender vegetables –athi(ficus racemosa),avarai(dolichos lablab),vazhai(musa paradisica) , kathari(solanum melangena),murungai(moringa oleifera ) sundai(solanum torvum),manathkali(physalis minima) Greens-karisali (Eclipta prostate), aru keerai (Amaranthus tristis), Siru keerai(Amaranthus campestris), Poonnaangani alternanthera sessilis), thoothuvalai (Solanum trilobatum), vallarai (Centella asiatica), Musumusukkai (Mukia

maderaspatana), Murungai (Moringa oleifera), Manali keerai (Gisekia pharanaeceoides) 57

Dairy product Cow‘s butter milk and ghee Non-vegetarian diet: Varappu nandu(farm crap), Dry fishes (Thitukkai (Trygon seption), Ayirai meen (loach)), Velladu(Capra hircus), Muyal(Rabbit) Avoid Chilled food, soft drinks, ice cream Surai(Lagenaria sicerania), poosani (Cocurbita maxima), Peerku(luffa acutangula), Pudalai (Trichosanthesa cucumerina) Advice Smoking, alcoholic beverages. Kitchen should have proper chimney and be well ventilated

Avoidance of open burning, use of water to suppress dust and wearing mask at work Place in areas of dust generation are advised. Adequate calories and protein rich diet. Avoid allergic substances to particular person, Prevention: 1. The patient is advised to take oil bath once in week 2, Purgation should be given once in 4 months 3. Vomiting should induced once in 6 months 4. Nasiyam should be given once in 45 days 5. Anjanam should be applied once in 3 days 6. Strictly avoid day sleep 58

NEER MOOKKADAIPPU (ALLERGIC RHINITIS) Introduction: In Siddha medicine the diseases were classified in to 4448, in which the Mookkdaippu noi are 9 types, the Neer mookadaippu is one of them which is characterised by nasal congestion, itching, irritation, watery discharge in the nose mild fever, headache, tiredness, body pain and cloudiness of sight which can be correlated with allergic rhinitis of modern science. Definition; This is a disorder in which there are episode of nasal congestion, watery nasal

discharge and sneezing. It may be seasonal or perennial. It is duo to inflammatory reaction of nasal mucosa. Aetiology: Allergic rhinitis is due to immediate hypersensitivity reaction in the nasal mucosa. The antigens concerned in the seasonal form of the disorder are pollen from grasses, flowers, trees. Perennial allergic rhinitis may be a specific reaction to antigen derived from house dust, fungal spores or animal dander. But similar symptoms can be caused by

physical and chemical irritants-for example pungent odour or fumes including strong perfumes, cold air, and dry atmospheres. it is also cause vasomotor rhinitis. Clinical feature: 1. Nasal congestion 2. Sneezing 3. Runny nose 4. Post nasal drip 5. Watery itchy eyes, this may be allergic pinkish 6. Itchy ear, nose and throat 7. Mild fever Other symptoms that may take longer to appear include. Stuffy nose, Breathing through mouth Rubbing the nose Eyes become sensitive to light Feeling tired Not sleep well

A long lasting cough Pressure in the ear Discomfort or pain in the face Dark circle or patches under your eyes 59

Pathogenesis on the basis of Thirithosam: Deranged Pitham(Vitiated Pitham) by internal and external causative factor will join with Kapam and produce the disease in the nose Melnokku kal is affected Sign and symptoms are staged from I to IV for treatment purpose Stage-1 1. Nasal congestion 2. Sneezing 3. Runny nose 4. Post nasal drip 5. Watery itchy eyes, this may be allergic pinkish 6. Itchy ear, nose and throat 7. Mild fever Stage -2 1. Symptoms of stage 1 + 2. Stuffy nose, 3. Breathing through mouth

4. Rubbing the nose 4. Eyes become sensitive to light 5. Feeling tired 6. Not sleep well 7. A long lasting cough 8. Pressure in the ear 8. Discomfort or pain in the face Stage-3 1. Symptoms of stage 1 and stage 2 + 2. Purulent discharge from nose 3. Dysphasia 4. Gummy secretion from nose 5. Depression Stage- 4 1. Stage 3 + 2. Severe cough 3. Wheezing 4. Difficulty in breathing Treatment Step-1. Normalisation of the altered Uyir thathukkal Step -2. Internal medicine Step-3 External medicine

Step-4 Special therapy Step-1.Normalization of altered Uyirthathukal The altered uyirthathukal should be normalised by the following procedure. 60

Pitham will be normalized by vomiting Kapam will be normalized by Nasiyam and Anjanam Vatham will be normalised by Purgation Step2. Internal medicine Leve-l1 The level-1 contain the following form of medicine Chooranam Lekiyam Nei Mathirai Kasayam Theeneer Level- 2 The level-2 contain the following form of medicine Parpam Level- 3 The level-3 contain the following form of medicine Chenthuram Level- 4 The level-4 contain the following form of medicine 1. Mezhuku 2. Pathangam 3. Chunnam

Step -3 External medicines Step-3 contain the following form of medicine 1. Thylam for oil bath 2. Patru(Paste) 3. Pugai (Fumigation) 4. Vethu (Therapeutic inhalation) 5. Naasigaparanam (Nasal snuffing) Step4 Special therapy Pranayamam Meditation Treatment for different stage of diseases:  Stage-1 of disease – chooses the suitable medicine from step- 1, step -2(level-1), step- 3 and step-4  Stage-2 of disease – choose the suitable medicine from step- 2 (level- 1 and level- 2), step -3 and step-4

 Stage-3 of disease – choose the suitable medicine from step- 2(level- 1, level-3 or Level-4), step -3 and step-4  Stage-4 of disease – referral criteria 61

Approximate cost for different stage of treatment Stage -1 Cost for step- 1 – Rs.1200 Cost for step- 2 – Rs.40 Cost for step -3 – Rs.2050 Cost for step - 4 – Rs.300 Total cost for stage-1 treatment/day= Rs.3590 Total cost for stage-1 treatment/month= Rs.64200 Stage-2 Cost for step- 1 – Rs.1200 (Not necessary if given in step-1) Cost for step- 2 – Rs. 47 Cost for step -3 – Rs.2050 Cost for step - 4 – Rs.300 Total cost for stage-2 treatment/day= Rs. Rs.3597 Total cost for stage-2 treatment/month= Rs.64410

Stage- 3 Cost for step- 1 – Rs.1200 (Not necessary if given in step-1) Cost for step- 2 – Rs. 45 Cost for step -3 – Rs.2050 Cost for step - 4 – Rs.300 Total cost for stage-3 treatment/day= Rs.3595 Total cost for stage-3 treatment/month= Rs.64350 Stage – 4 The patient will be referred to higher speciality centre Approximate cost investigation 1. Skin prick test – Rs.3500 2. Serum allergen-specific IgE test - Rs.100 3. Full blood count – Rs.15 Investigation in Siddha system:

Neer kuri and Nei kuri,Malakuri and Manikkadai nool- Rs.50 Pathiyam(diet regimen) Add Rice or kanji – hand pounded rice, double boiled rice,rice kanji,pepper soup. Tender vegetables: Athi (Ficus racemosa), Avarai(Dolichos lablab), Vazhai(Musa paradisica), Kathari (Solanum melangena), Murungai(Moringa oleifera) Sundai (Solanum torvum), Manathkali(physalis minima) 62

Greens-karisali(Eclipta prostate), Aru keerai(Amaranthus tristis), Siru keerai (Amaranthus campestris), Poonnaangani Alternanthera sessilis), Thoothuvalai (Solanum trilobatum), Vallarai (Centella asiatica), Musumusukkai (Mukia maderaspatana), Murungai (Moringa oleifera), Manalikeerai (Gisekia pharanaeceoides) Dairy product- cow‘s butter milk and ghee Non-vegetarian diet- Varappu nandu (farm crap), Dry fishes - Thitukkai(Trygon seption), Ayirai meen (Loach)), Velladu(Capra hircus), Muyal(Rabbit) Avoid

Chilled food, soft drinks, ice cream Sura i(Lagenaria sicerania), Poosani(cocurbita maxima), Peerku (luffa acutangula), Pudalai (Trichosanthesa cucumerina) Advice  Avoid smoking, alcoholic beverages.  Kitchen should have proper chimney and be well ventilated  Avoidance of open burning, ues of water to suppress dust and wearing mask at work  Place in areas of dust generation are advised.  Adequate calories and protein rich diet.  Avoid allergic substances to particular person, Prevention:

1. The patient is advised to take oil bath once in week 2, Purgation should be given once in 4 months 3. Vomiting should induced once in 6 months 4. Nasiyam should be given once in 45 days 5. Anjanam should be applied once in 3 days 6. Strictly avoid day sleep 63

CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) I. Definition COPD is characterised by airflow obstruction that is not fully reversible. The airflow obstruction does not change markedly over several months and is usually progressive in the long term. COPD is predominantly caused by smoking. Other factors, particularly occupational exposures, may also contribute to the development of COPD. Exacerbations often occur, where there is a rapid and sustained worsening of symptoms beyond normal day-to-day variations.

II. Introduction The airflow obstruction is present because of a combination of airway and parenchymal damage. The damage is the result of chronic inflammation that differs from that seen in asthma and which is usually the result of tobacco smoke. Significant airflow obstruction may be present before the person is aware of it. COPD produces symptoms, disability and impaired quality of life which may respond to pharmacological and other therapies that have limited or no impact on the airflow

obstruction. COPD is now the preferred term for the conditions in patients with airflow obstruction who were previously diagnosed as having chronic bronchitis or emphysema. There is no cure for COPD. Current conventional treatment is aimed at relieving symptoms, preventing recurrent exacerbations, preserving optimal lung function and enhancing the quality of life. Smoking cessation is the only therapeutic intervention shown to reduce disease progression. Although the allopathic medicine

management of COPD has been improved since the 1990s, the progress is slow. Unsatisfactory treatment outcomes from conventional drugs, and adverse effects associated with several classes of drugs, such as steroids and theophylline, contribute substantially to the increasing popularity of alternative medicine and, in particular, Siddha medicine. III. Aetiology  Smoking - Smoking is by far the biggest risk factor for COPD. If you smoke,

stopping is the single most effective way to reduce your risk of developing the condition. If you already have COPD, stopping smoking can halt its progression and reduce your risk of dying from it.  Passive smoking - Exposure to other people‘s smoke, especially in childhood, increases your risk of COPD. You should avoid exposure to tobacco smoke as much as possible.  Fumes and dust - Exposure to certain types of dust and chemicals at work,

including grains, isocyanates, cadmium and coal has been linked to the development of COPD. Even in people who do not smoke. The risk of COPD is higher if you breathe in dust or fumes in the workplace, and you also smoke.  Air pollution - Some research suggests that air pollution may be an additional risk factor for COPD. However, at the moment it is not conclusive and research is continuing.  Cannabis smoking - There is growing evidence that regularly smoking

cannabis, both with and without tobacco, can cause symptoms typical of chronic bronchitis, breathlessness and lung function changes. This is similar to those seen in regular tobacco smokers. 64

IV. Clinical Description Damage to the lungs caused by smoking will gradually build up, so you may not notice the symptoms of COPD at first. However, they can get worse over time. COPD does not usually become noticeable until after the age of 35. See your GP if you have the following symptoms:  increasing breathlessness when exercising or moving around  a persistent cough with phlegm that never seems to go away  frequent chest infections, particularly in winter

If you have COPD, the airways of the lungs become inflamed and narrowed. As the air sacs get permanently damaged, it will become increasingly difficult to breathe in and out. The symptoms of COPD are often worse in the winter, and it is common to have two or more flare-ups a year. A flare-up is when your symptoms are particularly bad. VI. Pathogenesis on the basis of Thirithodam The vitiated 'Pranvayu' combines with deranged 'Kapam' in the lungs causing

obstruction in the 'moothu kuzhal'(Respiratory passage). Kabam increased from its stage and induce the uthanan. Hence respiratory passage and apparatus become edematous and obstruct the passage. This results in gasping and laboured breathing. This condition is known as 'COPD' VII. Clinical Management for different stages of disease condition  To suppress the increased vatham humour medicated Ennai kuliyal (oil bath) is the first choice of treatment

 To reduce the increased vatham humour the viresanam (purgation)  To reduce the vitiated kabam , herbal steam bath can be advised  The internal medicines can be administered in the form of chooranam , mathirai, kudineer, parpam, Chenduram and karppam  The external therapies like piranayamam to be advised.  Yogasanams such as Padmaasanam, Sugaasanam, Salabaasanam, Dhanuraasanam, Halasanam, Patchimothasanam, sarvangasanam, mayuraasanam, artha achaendhrasanam Stage-I

With or without cough/Sputum. FEV1 / FVC<70%,. FEV1/ > 80% predicted Advice on smoking cessation and reduction of exposures to other risk factors Purgation Internal medicines External medicines; Oleation Stage-II With or without symptoms (Dyspnea, cough, sputum) FEV1 / FVC < 70%. 50% < FEV1/ < 80% predicted Advice on smoking cessation and reduction of exposures to other risk factors Purgation Internal medicines External medicines; Oleation, Inhalational therapy 65

Stage-III FEV1 / FVC < 70% 30% < FEV1 / < 50% predicted With or without chronic symptoms, cough, sputum production. Internal medicines External medicines Oleation, Inhalational therapy Stage IV ( Referral) FEV1 / FVC <70% FEV1 / < 30% predicted, or presence of respiratory failure or right heart failure Patient should be referred to the COPD clinic Dos o Go for morning or evening walk, do yoga mainly 'Pranayama' o Keep rooms well ventilated. o Drink boiled water in plenty

o Avoidance from direct contact of cold air, allergens (house dust mite, pollen, animal fur) o Quantify the exercise tolerance o Reduced Mental status like disturbed sleep, emotion etc o Patient has to measure his peak flow (reason) at work and at home to confirm this o Prevent disease progression (smoking cessation) o Alleviate breathlessness and other respiratory symptoms o Improve exercise tolerance and daily activity o Reduce frequency and severity of exacerbations o Improve health status Don’t’s

o Cold and damp places. o Smoking, alcoholism, tobacco o Perfumes, Agarbatti. Mosquito repellents o Over exercise DIET PURPOSE: This diet is indicated for individuals with COPD for the purpose of minimizing fatigue while eating, decreasing excess carbon dioxide production and improving overall client outcome. 2000 – 2500 KCAL Diet for COPD FOOD GROUP Servings Serving Size Kcal Range Meat (lean), Poultry, Fish, Dry 6-7 ounces 1 oz. cooked meat or 330-385 kcal Beans, Eggs, & Nuts poultry; 1 egg; ¼ cup

cooked dry beans or tofu; 1 TB. peanut butter Grains Bread, Cereal, Rice, & 6-8 1 slice bread; ¾-1 cup 480- 640 kcal Pasta ( at least ½ of all grains servings ready-to-eat cereal; ½ should be whole grains) cup cooked cereal, rice or pasta 66

Vegetables (including dark 5-6 1 cup raw leafy 125-150 kcal green or deep yellow as a servings vegetables; ½ cup of source of vitamin A at least other vegetables (raw or every other day) cooked); ½- ¾ cup vegetable juice Fruits (at least 1 should be high 4-5 1 medium apple, 240-300 kcal in vitamin C) servings banana, orange, pear; ½ cup chopped, cooked or canned fruit; ½- ¾ cup fruit juice Milk, Yogurt, & Cheese (low- 3 servings 1 cup milk or yogurt; 1 270 kcal fat) ½ oz. natural cheese; 2

oz. processed cheese Fats & Oils 7 servings 1 tsp margarine, oil, 315 kcal butter, mayonnaise; 1 TB. regular salad dressing Total Calories 2000- 2500 kcal DIET PRINCIPLES: The diet is tailored to each individual‘s caloric needs, eating habits, treatment goals, and presence of other medical conditions. The following should be considered for individuals with COPD: Adequate calories provided in less volume (e.g. smaller more frequent feedings) if the individual is easily fatigued while eating,

sodium restriction for peripheral edema and adjustment of calories as needed to achieve desirable body weight (excess calories should be avoided). Diets with 40- 55% of calories from carbohydrate are usually tolerated. Protein and fat may be the preferred calorie source for individuals with hypercapnea (provided COPD is not associated with heart disease), since less CO2 is produced than with carbohydrate metabolism. Pulmonary formulas (high fat/low carbohydrate) are available for oral

or tube feeding. Potential side effects of a high fat/low carbohydrate diet (e.g. decreased gastric emptying, increased gastrointestinal side effects and potential problems related to decreased carbohydrate intake) need to be considered. Approximate Medical Expenses Stage I: For oilation bath - Rs.600.00 For purgation - Rs.400.00 For internal medicine - Rs.1250.00 For Yogam and Piranayamam - Rs. 500.00 For Investigation - Rs. 800.00 (Complete blood count, ECG, X- ray, Sputum AFB, Spirometry)

Total - Rs. 3550.00/month Stage II For oilation bath - Rs. 600.00 For purgation - Rs. 400.00 For internal medicine - Rs. 2500.00 For Yogam and Piranayamam - Rs. 500.00 For Investigation - Rs. 800.00 (Complete blood count, 67

ECG, X- ray, Sputum AFB, Spirometry) Total - Rs.4800.00/month Stage III For oilation bath - Rs.600.00 For internal medicine - Rs.4500.00 For Yogam and Piranayamam - Rs. 500.00 For Investigation - Rs. 800.00 (Complete blood count, ECG, X- ray, Sputum AFB, Spirometry) AFB, Spirometry) Total - Rs.6400.00/month 68

OCCUPATIONAL LUNG DISEASE INTRODUCTION ‗Occupational Lung Disease‘ is a lung disease associated with a person‘s occupation or job. Nowadays, continuous and prolonged exposure to certain pollutants, allergens and irritants in the working environment may be an important cause for the incidence of Occupational Lung Disease. This does not mean that only the coal miners are more prone to get this type of respiratory disease. For instance, working in a cement factory or garbage landfill sites may

make a person to expose to hazardous chemicals, dusts, and fibers that may lead to a lifetime lung problems if not properly diagnosed and treated. Simply Occupational lung diseases are a broad group of diseases caused by the inhalation of dusts, chemicals, or proteins. Siddha System of Medicine deals this Occupational Lung Disease as one of the cause for ―Erumal Noi‖. DEFINITION In Erumal Noi, Kabam accumulates and causes inflammation in the nose,

pharynx, trachea, lungs resulting in the production of phlegm in these structures. Cough (Erumal) is a protective mechanism to expel the phlegm from the above structures. ETIOLOGY The agents responsible for the incidence of Occupational Lung Disease are 1. Dust particles from wood, cereals, asbestos, silica, chalk, pesticides etc., 2. Fumes during welding, smelting and fumes from industrial furnaces 3. Smoke from burning organic materials 4. Gases like ammonia, chlorine, carbon monoxide, sulphur di oxide

5. Vapours from paints, lacquers, perfumes, sprays CLINICAL DESCRIPTION The common symptoms of Occupational Lung Disease are  coughing  shortness of breath  chest pain  chest tightness  abnormal breathing pattern The symptoms of occupational lung diseases may be similar to other medical conditions or problems. PATHOGENESIS (MUKKUTRAVERPADU)  The Kabam is vitiated affecting nose, pharynx, trachea, lungs because of prolonged exposure.

 The vitiated kabam is heated and stimulate the Uthana Vayu (type of Vatham) resulting in the occurrence of cough.  Depending upon the virulence of these affected humours, various symptoms like dyspnoea, abnormal breathing pattern are resulted. 69

CLINICAL MANAGEMENT FOR DIFFERENT STAGES OF DISEASE CONDITION: Purgation – to alleviate the vitiated Kabam. The purgative medicine may be in the form of Thylam, Mathirai, Kulambu etc as prescribed by the Physician. STAGE 1 Internal medicines In the initial stages, when the symptoms are mild, the following internal and external medications are prescribed according to the Physician‘s directions. The medicines may be a combination of Chooranam, Mathirai, Kudineer, Parpam,

Chenduram, Manappagu, Rasayanam, Nei, Legyam, Vadagam, Karuppu. These medicines are prescribed with the aim of regulating the vitiated kabam and to inhibit the abnormal Uthana Vayu activity. In addition to that, the medicines having the activity of Expectorant, Mucolytic, Immunomodulaotrs are prescribed. External medicines The medicines in the form of Mathirai, Pasai, Thylam, Pugai to relive the congestion in the respiratory tract are used.

Otradam with herbs having the activity of decongestant property are used. STAGE II Internal medicines When there is chronic cough with purulent expectoration, breathing difficulty, the medicines in the form of Chooranam, Mathirai, Parpam, Chenduram Karuppu, which are having the activity of Expectorant, Mucolytic, Anti allergic, Anti Tussive are prescribed. External medicines The medicines in the form of Mathirai, Pasai, Thylam, Pugai, Pattru to relive the congestion in the respiratory tract are used.

Otradam with herbs having the activity of decongestant property are used. Pranayamam is advised to practice to ease the breathing difficulty. STAGE III Internal medicines When there is chronic cough with wheezing, the medicines in the form of Chooranam, Mathirai, Parpam, Chenduram Karuppu, which are having the activity of Expectorant, Mucolytic, Anti allergic, Anti Tussive are prescribed. Special treatment combinations as prescribed in the Texts may be prescribed. External medicines

The medicines in the form of Mathirai, Pasai, Thylam, Pugai, Pattru to relive the congestion in the respiratory tract are used. Otradam with herbs having the activity of decongestant property are used. Pranayamam is advised to practice to ease the breathing difficulty. DIET REGIMEN  Have frequent, small meals rather than taking three large meals 70

 Morning – 6.00 AM – 1 cup of Milk – 120 ml with pepper, turmeric powders and palm sugar candy(Pang karkandu)  Breakfast – 8.00 AM - 4 Idlis (75 gms each)/4 Idiyappam(75 gms each)/1 cup of Rice Milk Porridge (250 gms) with Jeeragam, leaves of Solanum trilobatum(Thoothuvalai) and a small piece of galangal root.  Forenoon – 11.00 AM – 1 cup of soup 120 ml made of Crab (Nandu)/ Solanum trilobatum(Thoothuvalai), Solanum xanthocarpum(Kandankathiri),

Coleus amboinicus (Karpooravalli) etc with 1 or 2 gooseberries/2 or 3 pieces of oranges/apple  Lunch – 1.00 PM - 1 cup of Rice (250gms) with Tender vegetables like brinjal, drumstick, kidney beans etc, along with rasam made of Crab (Nandu), Solanum trilobatum(Thoothuvalai), Solanum xanthocarpum(Kandankathiri), Coleus amboinicus (Karpooravalli) etc,  Evening – 4.00 PM – 1 cup of Lemon juice/Orange Juice – 120 ml/1 cup of soup 120 ml made of Crab (Nandu)/ Solanum trilobatum(Thoothuvalai),

Solanum xanthocarpum(Kandankathiri), Coleus amboinicus (Karpooravalli) etc  Dinner – 7.00 PM – 4 Idiyappam(75 gms)/ 1 cup of Rice Milk Porridge (250 gms) with 5 – 10 gms of paste (Thuvaiyal) made of Solanum trilobatum(Thoothuvalai), Solanum xanthocarpum(Kandankathiri)  Night – 8.00 PM – 1 cup of Milk (120 ml) mixed with pepper, turmeric powders and palm sugar candy at bed time. DON’TS  Smoking  Alcoholic drinks.  Exposure to dust, allergens, chemicals, gases, vapours etc.

 Living in densely populated, polluted inhabitants  Taking citrus and tomato in the diet, hot, spicy and fatty foods, caffeinated and carbonated drinks, chocolate, mint.  Taking food or liquids for 2-3 hours before bedtime  Avoid bending forward at the waist.  Avoid wearing tight fitting clothing. DO’S  Use face mask in working or living environment  Do regular exercises daily.  Regular practice of Pranayamam, Yogam  Performing holy rituals like Homam, yagam periodically

 Living in a natural environment with green plantations, trees.  Elevate the head of the bed 6-8 inches, by placing blocks under the legs of the head of the bed. 71

APPROXIMATE COST FOR PROCEDURES, MEDICINES ETC DURING TREATMENT AND POST TREATMENT STAGE I Medicine - Rs.50 - 75/day - Rs.1500 - 2250/month External Medication - Rs. 500/sitting. Investigations (first visit) Blood routine - Rs.15 X-ray - Rs.50 STAGE II Admission charges (Non-refundable)- Rs.25/- at the time of admission. Hospitalization charges - Rs.35/- per day These charges are inclusive of routine basic investigations and routine procedures. Medicine + Food in IPD - Rs.90/day + Rs.100/day = Rs.190/day

External Medication - Rs. 500/sitting. STAGE III Admission charges (Non-refundabl - Rs.25/- at the time of admission. Hospitalization charges - Rs.35/- per day These charges are inclusive of routine basic investigations and routine procedures. Medicine + Food in IPD - Rs.120/day + Rs.100/day = Rs.220/day - Rs.7650/month External Medication - Rs. 500/sitting. 72

SANTHUVATHAM (ARTHRITIS) INTRODUCTION: Saint yougi the father of Siddha pathology paved the way for those who are engaged in literary and clinical research in Siddha system of medicine.Yougi‘s classification of the diseases is mainly based on humoral and regional pathology.Under the vatha disease classification he dealt with different types of neuro muscular skeletal disorders.One among them is joint related disorders designated as

santhuvatham (arthritis) by Yougi.In the chapter of vatha diseases the aetiology, pathology, types, symptomatology, diagnosis,line of treatment and prognosis are very well explained.He has enumerated nearly fifteen types of arthritic conditions in his poems. Since arthritic conditions need a long term medical management ,it is the time for Siddha system of medicine to explore the possibillity for patient friendly management i.e., cost effective, efficacious, easily available & applicable

medications.Siddars followed a unique protocol to treat vatha diseases: 1. Oleation –medicated oil bath, 2. Purgation-tablet/medicated oil/kulambu 3. Internal medication-in the form of kudiner (decotion), chooranam (powder), mathirai (tablet), legium(confection), manapagu (syrp), parpam ,chendhuram(calyx), mezhugu (confection)etc., ( from root, herb to metals) 4.a.External medications- Pattru(Poultice), Poochu(Application of oinment, oil,

herbal leaf juices etc.,), Ottradam(foementation), ennai kattu(Oil pooling). b.External therapies-Thokkanam(Oil massage), Varmam (a unique pressure technique applied over vital energy points (Pranan) and its travelling pathway in the body, Yogam (Meditation), Pranayamam (breathing tecniques) and Aasanam (Posture). The signs and symptoms of some of the arthritic conditions explained by yougi may well be correlated with that of modern science ,which are as follows: 1. THALATHAMBA VATHAM- GOUT

2. CEGANA VATHAM- CERVICAL SPONDYLOSIS 3. THANDAGA VATHAM- LUMBAR SPONDYLOSIS 4. SANTHU VATHAM- OSTEO ARTHRITIS 5. NARITHALAI VATHAM- SUPPURATIVE ARTHRITIS 6. MALAITHAKAMBA VATHAM- ENTROPATHIC ARTHRITIS THALATHAMBAVATHAM ( GOUT) DEFINITION: Thalam+Thambam+Vatham Thalam means sole Thambanam means contraction of all pores or passages Vatham means movement/action (ref TVS dic) 73

It is a kind of rheumatism due to excessive intake of mustard, salt and tamarind in the food and it is expressed by: o gradual increase of boring pain in the sole, o parched condition of the body, o fatigue, o hard breathing, o 5 Thrist. AETIOLOGY: As per Saint yougi, 1. Food: Food: excessive intake of mustard, salt and tamarind rich food, meat, seafood. Vegetables: Beans, peas, asperagus, lentils (purine rich vegetables) Greens: Spinach 2. Beverages: Toddy, sweetened drinks. 3. Genetic:

In born error causing under excretion of malam (metabolic waste products-uric acid like ) in urine 4. Seasonal variations (mid June to mid Dec) vitiates vatham. THIRIDHOSA CONCEPT (PATHOGENESIS) Excessive intake of nonvegetarian diet, diet rich in starch and proteins,alcohol abuse, consumption of sweetened drinks causes derangement of pitham humor (signs of inflammation) which in turn affects joints (site of kabam) as the result derangement

of kabam occurs (stiffness, rigidityof the joints, fluid collection in the joints etc.,) lastly, deranged pitham & kabam causes vitiation of vatham (pain and restricted movement of the joints ). CLINICAL DESCRIPTION: As per yougi, 1. Swelling&heaviness of the foot 2. pain in the affected joint of the foot. The nature of the pain is throbbing, crushing & excruciating. 3. The affected joint appears red,warm & tender. 4. Stiffness of the body 5. Dryness of the skin 6. Difficulty in breathing

STAGES: STAGE 1 : Yougi’s version:”ullankal kanakkavae kudainthu noenthu karuki kanum” Inflammation of the meta tarsophalangeal joint at the base of the big toe, Tender, hot, swollen, painful joint. STAGE 2: Yougi‘s version:‖Varutheiye vanakkam chattrilammal thaan Valithume maennokki varutham kannum‖ In addition to the signs and symptoms of stage 1, Involvement of other joints (heels,knees,wrist and fingers) causing difficulty in movement. STAGE 3: Yougi‘s version: ”Karuthiyea mikakanathu ullankallai”

”Charuthiyae chadam ularanthu maelmoochundaie Thaagama udampu ularandhu thalarnthu kannum” Hyperuricemia (uricacid level in blood >7 & 8.9mg/dl) Hard, painless deposits of uric acid crystals-tophi Extensive tophi leads to chroinc arthritis (due to bone erosion ) Recurrent attack of acute inflammatory arthritis. STAGE 4: Referral when the uric acid level in the blood goes above 9mg/dl Urate nephropathy Uricacid stone formation in the kidney. DO’S AND DON’T’S: DO’S: Food includes: Wheat & dairy products.

Tendor brinjal, tender drumstick, lalab bean. Drumstick leaves, sessile leaves, black night shade, climbing brinjal,curry leaf. Pomegranate, Apple, Dates, Palm, Country fig. DON’T’S:Avoid: Mustard,sesame oil,yellow pumpkin,country arrack,ground nut, coconut,mango,jack fruit,garlic,asofoetida,tobacco,bitter guard,sesbania leaves. Foods of astringent ,sour,salt taste & tamarind rich foods. Beans,peas,asperagus,lentils,spinach. Toddy, Sweetened drinks, Cool temperature. 75

DIETERY REGIMEN Morning (6 a.m) 100 ml of Chukku malli coffee (without milk)/ green tea/ 1 country egg with 10 ml gingelly oil/ 100 ml of butter milk with 100 mg Asafoedita powder. Break fast(9 a.m) 60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/300 gms of puttu/300 gms of Idiyappam. Prenoon(11 a.m) 200 ml of Ulanthan kanji Lunch(1 p.m) Boiled rice -400 gms Sambar (without kizhangugal)-150 ml Poriyal (Avarai pinju. Katthari pinju, ladies finger, Vazhai thandu)- 150 gms

Rasam( Garlic) - 100 ml Butter milk (Kariveppilai thallippu)- 100 ml Fruit salad -100gms Evening (4 p.m) Navathaniya kanji/veg.soup - 200 ml Dinner(8 p.m) 60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/ 300 gms of puttu/ 300 gms of Idiyappam/ 60 gms of dosai -5 Nos. COSTING OF THALATHAMBA VATHAM FORM OF MEDICINES COST LEVELS (Anti-vatha drugs) (30 days) Oleation- oil form Rs.500 Purgation- tablet/ Rs.400 L0 (One mezhugu/ennai/ day) kuzhambu Grand total Rs.900 L0 + Rs.900

Internal medicine: + Kudineer,choornam, Rs.1068.75 L1 tablet,legiyum,syrup External therapies: Patru Rs.500 Patti Rs.400 Investigations: Routine CBC Rs.90 RFT Rs.400 CRP Rs.30 76

X-RAY Rs.30 Grand total Rs.3419 LO+L1 Rs.900 +Rs.2519 + + parpam, Rs.71 L2 chendrum External therapies: Patru Rs.500 Patti Rs.400 Thuvalai Rs.600 Yogam Rs.500 Investigations: Routine CBC Rs.90 RFT Rs.400 CRP Rs.30 X-RAY Rs.30 Grand total Rs.6040 L0+L1+L2 Rs.900+Rs.2519+Rs.4429 +Nei +Rs.330 L3 External therapies: Patru Rs.500 Patti Rs.400 Thuvalai Rs.600 Yogam Rs.500 Investigations: Routine CBC Rs.90 RFT Rs.400 CRP Rs.30 X-RAY Rs.30 Grand total Rs.10628 77

CEGANAVATHAM(CERVICAL SPONDYLOSIS) DEFINITION: A type of the vatha disease caused by vitiation of vatham due to increased pitham, decreased kabam as a result of life style modifications (food and deeds) and seasonal changes which affects the joints and produces a typical scorpian bite like neuralgic pain in the region below the neck,upper and lower back.The pain radiates to both shoulders and upper limbs interfers with the movements. AETIOLOGY: As per yougi,

 Consumption of bitter,astringent,pungent foods /spicy food.  Eating previous day cooked food  General debility due to starvation  Intake of toddy  Controlling excessive thirst  lifing heavy weight  Irregular sleep pattern (day sleep)  Seasonal variations (mid June to mid Dec) vitiates vatham. THIRIDHOSA CONCEPT (PATHOGENESIS): Life style changes pertaining to food habits and deeds,seasonal changes influences increase of pitham humor causes inflammation and degenerative changes

in the site of kabam thathu i.e joints by deranging the kabam thathu i.e.,lowers kabam causes stiffness & rigidity in the joints which in turn results in vitiation of vatham,which causes restricted movement of the joint. CLINICAL DESCRIPTION: As per yougi, 1. Pain below the neck and above the loin region, 2. Radiating pain in the shoulder and upper limb, 3. Tingling sensation and numbness of the upper limb, 4. Scorpion sting like pain, 5. Burning sensation of the eyes, 6. Heaviness of the body,

7. Constipation, 8. Giddiness, 9. Mental depression. STAGES: STAGE 1: Pain below the neck and upper back, 78

Interfering little with routine work. STAGE 2:  Pain below the neck and upper back,radiating to the shoulders and upper limbs, the moderate pain interfers significantly with routine work.,  Tingling sensation and numbness of the upperlimbs,  Burning sensation of the eyes. STAGE 3:  Pain below the neck and upper back,radiating to the shoulders and upper limbs.  Scorpion sting like pain.The pain will be severe , disabling & unable to perform routine work.  constipation.  Heaviness of the body.

STAGE 4: Referral  Frequent attack of giddiness, severe neck pain & rigidity.  Not able to do his/her work and confined to bed.  Development of progressive disability(cervical myelopathic symptoms….). DO’S AND DON’T’S: DO’S: Food includes:  Tendor brinjal, tender drumstick, lalab bean.  Drumstick leaves, sessile leaves, black night shade, climbing brinjal, curry leaf.  Pomegranate, Apple, dates, palm, country fig.  Goat‘s meat, prawn, fish. DON’T’S: Avoid

 Mustard,sesame oil, yellow pumpkin, country arrack, ground nut, coconut, mango, jack fruit, garlic, asofoetida, tobacco, bitter guard, sesbania leaves.  Consumption of bitter,astringent, pungent foods /spicy food..  Eating previous day cooked food  General debility due to starvation  Intake of toddy  Controlling excessive thirst  Lifing heavy weight  Irregular sleep pattern (day sleep)  Seasonal variations (mid June to mid Dec) vitiates vatham. 79

Rasam( Garlic) - 100 ml Butter milk (Kariveppilai thallippu)- 100 ml Fruit salad -100gms Evening (4 p.m) Navathaniya kanji/veg.soup - 200 ml Dinner(8 p.m) 60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/ 300 gms of puttu/ 300 gms of Idiyappam/ 60 gms of dosai -5 Nos. COSTING OF CEGANAVATHAM FORM OF MEDICINES COST LEVELS (Anti-vatha drugs) (30 days) Oleation- oil form Rs.500 Purgation- tablet/ Rs.400 L0 (one day) mezhugu/ennai/kuzhambu Grand total Rs.900 L0 Rs.900 + +

L1 Internal medicine: Rs.537 Kudineer,choornam, tablet,legiyum,syrup External therapies: Thokkanam Rs.400 Varmam(1sitting) Rs.300 Yogam Rs.500 Investigations: Routine CBC Rs.90 Serum calcium Rs.25 Bone density Rs.400 CRP Rs.30 80

X-ray Rs.30 Grand total Rs.3212 LO+L1+ Rs.900+Rs.2312 parpam,Chendrum Rs.148 L2 External therapies: Varmam(7sittings) Rs.1750 Ennaikattu Rs.400 Thokkanam Rs.400 Poochu Rs.500 Pottanam Rs.700 Yogam Rs.500 Investigations: Routine CBC Rs.90 Serum calcium Rs.25 Bone density Rs.400 CRP Rs.30 CT-Scan(specific region) Rs.200 Grand total Rs.8355 L0+L1+L2 Rs.900+Rs.2312+Rs.5143 +Nei +Rs.611 External therapies: Varmam(21sittings) Rs.4500 Ennaikattu Rs.400 Thokkanam Rs.400 Poochu Rs.500 L3 Pottanam Rs.700

Yogam Rs.500 Investigations: Routine CBC Rs.90 Serum calcium Rs.25 Bone density Rs.400 CRP Rs.30 MRI(specific region) Rs.3000 Grand total Rs.19,511 81

SANTHU VATHAM (OSTEOARTHRITIS) DEFINITION Due to lifestyle modification and seasonal variations the joint is affected by increased pitham decreased kabham and vitiated vatham, which in turn produces pain and swelling, redness of the joint, lowgrade fever and crepitation leads to restricted movement. AEITIOLOGY  SEASONAL FACTORS As per Yugi Vaithiya Chinthamani the Vatha diseases are precipitated in the months from Aani to Karthigai (June to December).Hence the seasonal factors are

involved and facilitate the Vadha disease.In Mudhuvenil kalam (Aani,Aadi i.e Mid June,July, Mid August) the increased environmental heat increases the evaporation of water from the body which in turn reduces the Kabam and increases the Vatham thathu reasulting in the production of vali diseases OTHER FACTORS:- Vatha disease is caused due to the following factors: 1. Excesssive intake of tubers, 2. Excessive intake of chilled food 3. Wandering in chill air 4. Getting drenched in rain 5. Living in hill region

6. Excessive sexual Indulgence 7. Walking under the hot sun 8. Excessive intake of water and bitterguard. 9. Hereditary PATHOGENISIS ON THE BASIS OF THE TRITHOSHA Due to lifestyle modification (Food and deeds) and seasonal variations the increased pitham (Internal heat energy) affects the joints resulting in the reduction of kabham (Dryness of synovium) in turn causes loss of lubricants resulting in vitiation of vatham. That leads to lowgrade fever, pain, swelling, redness, crepitation and

restricted movement of the joint. CLINICAL DESCRIPTION Azhal keel vayu is characterized by swelling of joints assiociated with severe pain and lowgrade fever. Since it is not quickly responding to medicine the long term medical care is said to be essential. As pitha increases, Kabha (Synovial fluid) in the joints decrease and hence dryness occur. so during flexion of joint crepitation occurs. STAGES Stage 1 Pain, Swelling, tenderness of joints 82

Stage 2:  Pain, Swelling, tenderness of joints  Difficulty in walking  Joint Crepitation Stage 3:  Pain, Swelling, tenderness of joints  Difficulty in walking  Joint Crepitation  Effusion & Stiffness in the joints  Movement restriction Stage 4: Referral :  Severe pain in the joints, Movement restriction.  Not able to do his/her work and confined to bed.  Development of progressive disability. DO’S AND DON’T’S: DO’S:Food includes: *Tendor brinjal,tender drumstick,lalab bean.

*Drumstick leaves,sessile leaves,black night shade,climbing brinjal,curry leaf. *Pomegranate,Apple,dates,palm,country fig. *Goat‘s meat,prawn,fish. DON’T’S:Avoid: *Mustard,sesame oil,yellow pumpkin,country arrack,ground nut,coconut,mango,jack fruit,garlic,asofoetida,tobacco,bitter guard,sesbania leaves. * Consumption of bitter,astringent,pungent foods /spicy food.. *Eating previous day cooked food *starvation *Intake of toddy *Controlling excessive thirst *Irregular sleep pattern (day sleep)

*Seasonal variations (mid June to mid Dec) vitiates vatham. DIETERY REGIMEN Morning (6 a.m) 83

100 ml of Chukku malli coffee (without milk)/ green tea/ 1 country egg with 10 ml gingelly oil/ 100 ml of butter milk with 100 mg Asafoedita powder. Break fast(9 a.m) 60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/300 gms of puttu/300 gms of Idiyappam. Prenoon(11 a.m) 200 ml of Ulanthan kanji Lunch(1 p.m) Boiled rice -400 gms Sambar (without kizhangugal)-150 ml Poriyal (Avarai pinju. Katthari pinju, ladies finger, Vazhai thandu)- 150 gms Rasam( Garlic) - 100 ml

Butter milk (Kariveppilai thallippu)- 100 ml Fruit salad -100gms Evening (4 p.m) Navathaniya kanji/veg.soup - 200 ml Dinner(8 p.m) 60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/ 300 gms of puttu/ 300 gms of Idiyappam/ 60 gms of dosai -5 Nos. COSTING OF SANTHU VATHAM FORM OF MEDICINES COST LEVELS (Anti-vatha drugs) (30 days) Oleation- oil form Purgation- tablet/ Rs.500 L0 (one mezhugu/ennai/kuzhambu Rs.400 day) Grand total Rs.900 L0 + Rs.900 + Internal medicine: Rs.537

Kudineer,choornam, L1 tablet,legiyum,syrup External therapies: Thokkanam Rs.400 Varmam(1sitting) Rs.300 Yogam Rs.500 Investigations: Routine CBC Rs.90 Serum calcium Rs.25 Bone density Rs.400 CRP Rs.30 X-ray Rs.30 Grand total Rs.3212 LO+L1+ Rs.900+Rs.2312+ parpam,Chendrum Rs.148 External therapies: L2 Varmam(7sittings) Rs.1750 Ennaikattu Rs.400 Thokkanam Rs.400 Poochu Rs.500 Pottanam Rs.700 84

Yogam Rs.500 Investigations: Routine CBC Rs.90 Serum calcium Rs.25 Bone density Rs.400 CRP Rs.30 CT-Scan(specific region) Rs.200 Grand total Rs.8355 L0+L1+L2 Rs.900+Rs.2312+Rs.5143 +Nei +Rs.611 External therapies: L3 Varmam(21sittings) Rs.4500 Ennaikattu Rs.400 Thokkanam Rs.400 Poochu Rs.500 Pottanam Rs.700 Yogam Rs.500 Investigations: Routine CBC Rs.90 Serum calcium Rs.25 Bone density Rs.400 CRP Rs.30 MRI(specific region) Rs.3000 Grand total Rs.19,511 85

THANDAGAVATHAM (LUMBAR SPONDYLOSIS) DEFINITION: It denotes pain and stiffness in hip & pain radiating to the lower extremities associated with heaviness and numbness. The term Thandagam refers to vertebral column with the spinalcord. The term also implies stiffness of the whole body,which is rigid and stiff like a rod.This condition is caused by vitiated vaayu as a result of prolonged sitting in a particular posture as practised in the first stage of yogam. AETOILOGY:

 Prolonged sitting as practised in the first stage of yogam.  Consumption of bitter,astringent,pungent foods /spicy food.  Eating previous day cooked food  General debility due to starvation  Intake of toddy  Controlling excessive thirst  lifting heavy weight  Irregular sleep pattern (day sleep)  Seasonal variations (mid June to mid Dec) vitiates vatham.. THIRIDHOSHA CONCEPT (PATHOGENESIS): Tubers like potato,unriped banana,yogic posture,seasons, Consumption of

bitter,astringent,pungent foods /spicy food.,restricted movements causes vitiation of vatha which inturn affects the vertebral column and causes thandagavatham. CLINICAL DESCRIPTION:  Low back pain increased with activity,  Radiating pain from hip to both lower limbs,  Paraspinal muscle spasm and tenderness,stiffness or limitation of motion,  Painful spinal deformity with restricted movement. STAGES: STAGE 1: Low back pain followed by prolonged sitting or standing. STAGE 2:

Low back pain radiating to both lower limbs. Pain interfers a little with routines, STAGE 3: Low back pain radiating to both lower limbs. Difficulty in walking and sitting, 86

Pain intefers significantly with routine works. STAGE 4: REFERRAL Bladder incontinence, Bedridden. DO’S AND DON’T’S: DO’S:FOOD INCLUDE Tendor brinjal,tender drumstick,lalab bean. Drumstick leaves,sessile leaves,black night shade,climbing brinjal,curry leaf. Pomegranate,Apple,dates,palm,country fig. Goat‘s meat,prawn,fish. DON’T’S:AVOID Avoid weight lifting,forward bending, Prolonged sitting and standing, Mustard,sesame oil, yellow pumpkin, country arrack, ground nut,coconut,mango,

jack fruit, garlic, asofoetida, tobacco, bitter guard, sesbania leaves. Consumption of bitter,astringent,pungent foods /spicy food.. Eating previous day cooked food starvation Intake of toddy Excessive thirst lifting heavy weight Irregular sleep pattern (day sleep) Seasonal variations (mid June to mid Dec) vitiates vatham. DIETERY REGIMEN Morning (6 a.m) 100 ml of Chukku malli coffee (without milk)/ green tea/ 1 country egg with 10 ml gingelly oil/ 100 ml of butter milk with 100 mg Asafoedita powder.

Break fast(9 a.m) 60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/300 gms of puttu/300 gms of Idiyappam. Prenoon(11 a.m) 200 ml of Ulanthan kanji Lunch(1 p.m) Boiled rice -400 gms Sambar (without kizhangugal)-150 ml 87

Poriyal (Avarai pinju. Katthari pinju, ladies finger, Vazhai thandu)- 150 gms Rasam( Garlic) - 100 ml Butter milk (Kariveppilai thallippu)- 100 ml Fruit salad -100gms Evening (4 p.m) Navathaniya kanji/veg.soup - 200 ml Dinner(8 p.m) 60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/ 300 gms of puttu/ 300 gms of Idiyappam/ 60 gms of dosai -5 Nos. COSTING OF THANDAGA VATHAM FORM OF MEDICINES COST LEVELS (Anti-vatha drugs) (30 days) Oleation- oil form Rs.500

Purgation- tablet/ Rs.400 L0 (one mezhugu/ennai/kuzhambu day) Grand total Rs.900 L0 Rs.900 + + L1 Internal medicine: Rs.537 Kudineer,choornam, tablet,legiyum,syrup External therapies: Thokkanam Rs.400 Varmam(1sitting) Rs.300 Yogam Rs.500 Investigations: Routine CBC Rs.90 Serum calcium Rs.25 Bone density Rs.400 CRP Rs.30 X-ray Rs.30 Grand total Rs.3212 88

LO+L1+ Rs.900+Rs.2312+ L2 parpam,Chendrum Rs.148 External therapies: Varmam(7sittings) Rs.1750 Ennaikattu Rs.400 Thokkanam Rs.400 Poochu Rs.500 Pottanam Rs.700 Yogam Rs.500 Investigations: Routine CBC Rs.90 Serum calcium Rs.25 Bone density Rs.400 CRP Rs.30 CT-Scan(specific region) Rs.200 Grand total Rs.8355 L0+L1+L2 Rs.900+Rs.2312+Rs.5143 +Nei +Rs.611 External therapies: L3 Varmam(21sittings) Rs.4500 Ennaikattu Rs.400 Thokkanam Rs.400 Poochu Rs.500 Pottanam Rs.700 Yogam Rs.500 Investigations:

Routine CBC Rs.90 Serum calcium Rs.25 Bone density Rs.400 CRP Rs.30 MRI(specific region) Rs.3000 Grand total Rs.19,511 89

NARITHALAIVATHAM (SUPPURATIVE ARTHRITIS) DEFINITION: *Narithalai means knee cap [ref.TVS dict,vol IV,part II,page:1539] *It is an acute arthritis marked by inflammation of joints especially in knee and ankle,pain ,heat,redness and swelling due to infection. (The common causative organisms are gonococci, pneumococci, staphylococci, streptococci,H.influenzae and gram-negative).Accumulation of morbid fluid which are followed by over growth of articular cartilages with destruction of the cartilages

and progressive deformity by assuming the shape of a jackal‘s head and there by rendering the patient unable to walk. *The knee becomes unusally large makes the patient difficult to fold or stretch the leg. AETIOLOGY: *Consumption of tubers,bitter,astringent. *Eating previous day cooked food *General debility due to starvation *Intake of toddy *Controlling excessive thirst *Irregular sleep pattern (day sleep) *Seasonal variations (mid June to mid Dec) vitiates vatham.. *Excess lust.

THIRITHOSHA CONCEPT (PATHOGENESIS): Food and deeds leads to vitiation of vatham uniting with the pitham (blood ) produces the inflammation of knee joint (site of kabam). CLINICAL DESCRIPTION: *Knee joint swelling,redness,pain and joint effusion, *Difficulty to fold or stretch the leg, *The inflammed knee joint assumes the shape of a jackal‘s head. *Palpitation. STAGES: STAGE 1: *Redness, swelling, pain in the knee joint, *Able to walk to some extent (mono articular), STAGE 2:

*Redness, swelling, pain in the knee joint, *Difficulty to fold or stretch the leg, *Palpitation. 90

*Pain significantly interfers with the routine work. STAGE 3: *Redness,swelling,pain in the larger joint of lower extremities such as knee,hip and ankle,shoulder and sterno clavicular joints (poly articular). STAGE 4: REFERRAL *Severe poly articular infection. *Bed ridden condition. DO’S AND DON’T’S: DO’S:FOOD INCLUDES *Tendor brinjal,tender drumstick,lalab bean. *Drumstick leaves,sessile leaves,black night shade,climbing brinjal,curry leaf. *Pomegranate,Apple,dates,palm,country fig.

*Goat‘s meat,prawn,fish. DON’T’S:AVOID *Mustard,sesame oil,yellow pumpkin,country arrack,ground nut,coconut,mango,jack fruit,garlic,asofoetida,tobacco,bitter guard,sesbania leaves. * Consumption of tubers,bitter & astringent foods. *Eating previous day cooked food * starvation *Intake of toddy *Controlling excessive thirst *lifing heavy weight *Irregular sleep pattern (day sleep) *Seasonal variations (mid June to mid Dec) vitiates vatham. DIETERY REGIMEN Morning (6 a.m)

Fruit salad -100gms Evening (4 p.m) Navathaniya kanji/veg.soup - 200 ml Dinner(8 p.m) 60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/ 300 gms of puttu/ 300 gms of Idiyappam/ 60 gms of dosai -5 Nos. COSTING OF NARITHALAIVATHAM FORM OF MEDICINES COST LEVELS (Anti-vatha drugs) (30 DAYS) Oleation- oil form Rs. 400 Purgation- tablet/ Rs.500 L0 mezhugu/ennai/kuzhambu (one day) Grand total Rs.900 L0 + Rs.900+ Internal medicine: Rs.513 Kudineer,choornam, L1 tablet,legiyum,syrup

External therapies: Patru Rs.500 Thuvalai Rs.600 Yogam Rs.500 Investigations: Routine CBC Rs.90 LFT Rs.220 RFT Rs.400 Sputum conc.culture Rs.50 PUS AFB(Smear, culture) Rs.50 Pus culture for Gonococci Rs.50 Pus culture for anaerobic –bacteria Rs.50 Grand total Rs.3923 LO+L1+ Rs.900+Rs.3023+ parpam,Chendroom Rs.147 External therapies: L2 Patru Rs.500 Thuvalai Rs.600 Patti kattal Rs.400 Yogam Rs.500 Investigations: Routine CBC Rs.90 LFT Rs.220 RFT Rs.400 Sputum conc.culture Rs.50 PUS AFB(Smear, culture) Rs.50

Pus culture for Gonococci Rs.50 Pus culture for anaerobic –bacteria Rs.50 Grand total Rs.6980 92

L0+L1+L2+ Rs.900+Rs.3023+Rs.4857 mezhugu,nei Rs.740 External therapies: L3 Leech therapy Rs.1000 Blood letting Rs.600 Patru Rs.500 Thuvalai Rs.600 Patti kattal Rs.400 Yogam Rs.500 Investigations: Routine CBC Rs.90 LFT Rs.220 RFT Rs.400 Sputum conc.culture Rs.50 PUS AFB(Smear ,culture) Rs.50 Pus culture for Gonococci Rs.50 Pus culture for anaerobic –bacteria Rs.50 Grand total Rs.14,030 93

MALAITHAKAMBA VATHAM (ENTEROPATHIC ARTHROPATHY ) DEFINITION: Malaithal means imbalance (ref:volV pg.739,tvs dict ) Kambam means tremor (ref:vol II pg.1111,tvs dict ) Enteropathic arthritis may occur as axial arthritis,pheripheral arthritis or mixed.As axial arthritis, symptoms of back pain and stiffness like that of ankylosing spondylitis and may precede GI symptoms.As pheripheral arthritis there is typically a pattern of panciarticular ( 4 or fewer joints ),and asymmetric arthitis. AETIOLOGY:

*Consumption of tubers,bitter,astringent. *Eating previous day cooked food *General debility due to starvation *Intake of toddy *Controlling excessive thirst *Irregular sleep pattern (day sleep) *Seasonal variations (mid June to mid Dec) vitiates vatham.. THIRIDHOSHA CONCEPT (PATHOGENESIS): Food and deeds cause vitiation of vatham which inturn causes derangement of vayu of GI reflexes (uthanan),vayu of excretion (abanan ),vayu of digestion

(pranan),vayu of absorption ( samanan) and the vayu of axial and pheripheral movements (viyanan) affected resulting in malaithakamba vatham (enteropathic arthritis ). CLINICAL DESCRIPTION : *Swelling in tha wrist joint, *Severe body pain, *Tremor in the hands and legs, *Numbness and rigidity below the hip region, *Dry and fissure in the lip ( sign of dehydration ) *Passing foul smelling flatus. STAGES: STAGE 1: *Swelling in tha wrist joint, *Severe body pain. STAGE 2: *Swelling in tha wrist joint,

*Tremor in the hands and legs. STAGE 3: *Swelling in tha wrist joint, *Severe body pain, *Tremor in the hands and legs, *Numbness and rigidity below the hip region, *Dry and fissured lip ( sign of dehydration ) *Passing foul smelling flatus. STAGE 4 : REFFERAL * Worsening of GI symptoms. *Progression of axial and pheripheral arthritis. DO’S AND DON’T’S: DO’S:FOOD INCLUDES *Tendor brinjal,tender drumstick,lalab bean. *Drumstick leaves,sessile leaves,black night shade,hog weed,climbing brinjal,curry leaf.

*Pomegranate,Apple,dates,palm,country fig. *Goat‘s meat,prawn,fish. DON’T’S:AVOID *Mustard,sesame oil,yellow pumpkin,country arrack,ground nut,coconut,mango,jack fruit,garlic,asofoetida,tobacco,bitter guard,sesbania leaves. * Consumption of tubers,bitter & astringent foods. *Eating previous day cooked food * starvation *Intake of toddy *Controlling excessive thirst *lifting heavy weight *Irregular sleep pattern (day sleep) *Seasonal variations (mid June to mid Dec) vitiates vatham. DIETERY REGIMEN

Morning (6 a.m) 100 ml of Chukku malli coffee (without milk)/ green tea/ 1 country egg with 10 ml gingelly oil/ 100 ml of butter milk with 100 mg Asafoedita powder. Break fast(9 a.m) 60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/300 gms of puttu/300 gms of Idiyappam. 95

Prenoon(11 a.m) 200 ml of Ulanthan kanji Lunch(1 p.m) Boiled rice -400 gms Sambar (without kizhangugal)-150 ml Poriyal (Avarai pinju. Katthari pinju, ladies finger, Vazhai thandu)- 150 gms Rasam( Garlic) - 100 ml Butter milk (Kariveppilai thallippu)- 100 ml Fruit salad -100gms Evening (4 p.m) Navathaniya kanji/veg.soup - 200 ml Dinner(8 p.m) 60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/ 300 gms of puttu/ 300 gms of Idiyappam/ 60 gms of dosai -5 Nos.

COSTING OF MALAITHAGAMBAVATHAM FORM OF MEDICINES COST LEVELS (Anti-vatha drugs) (30 DAYS) Oleation- oil form Rs. 400 L0 (one Purgation- tablet/ Rs.500 day) mezhugu/ennai/kuzhambu Grand total Rs.900 L0 + Rs.900 Internal medicine: + Kudineer,choornam, Rs.420 L1 tablet,legiyum,syrup External therapies: Poochu Oinment Rs.500 Investigations: Rs.200 Routine CBC Rs.90 CRP Rs.30 LFT Rs.220 Fecal examination Rs.15 XRAY Rs.30 Grand total Rs.2405 LO+L1+ Rs.900+Rs.1225 Parpam,Chendroom External +Rs.139 therapies:

L2 Poochu Rs.500 Oinment Rs.200 Investigations: Routine CBC Rs.90 CRP Rs.30 LFT Rs.220 Fecal examination Rs.15 XRAY Rs.30 Grand total Rs.3349 96

L0+L1+L2+ Rs.900+Rs.1225+Rs.2744 mezhugu,nei Rs.466 External therapies: L3 Poochu Rs.500 Oinment Rs.200 Investigations: Routine CBC Rs.90 CRP Rs.30 LFT Rs.220 Fecal examination Rs.15 XRAY Rs.30 Grand total Rs.6420 97

VALIPPU NOI (CONVULSION) Synonyms: Eluppu Noi, Esivu Noi Introduction: In Siddha System of medicine, the diseases of human beings are classified into 4448 types on the basis of Mukkutram theory. In normal healthy condition, the three humours exist with the ratio of 1:1/2:1/4 respectively. According to Siddha theory the cause of any disease is mainly due to the alteration in the equilibrium of three humors ie. Vatham, Pitham and Kabam. In Yugi Vaithya Chinthamani, Yugi Munivar

classified Valippu Noi is one among them. Valippu noi is caused by abnormality of physical and mental status. It is a brain disorder in which a person has repeated seizures (convulsions) over time. Seizures are episodes of disturbed brain activity that cause changes in attention or behavior. Definition: The onset is sudden and the symptoms are upward movements of the eyeballs, muscle twitching, myoclonic spasm, throat blocking, tongue dryness and frothy

excretion of the saliva and incontinence of urine and faeces the symptoms appears mentally disturbed, speechless and perspiration are also seen in that time. Clinical Description:  Giddiness before convulsion starts, flaccidity of extremities  Fainting, tingling sensation in the distal part of the fingers or twitching of n the fingers, affective mental state, visual disturbances  Movement loss, twitching of eyelids, loss of speech, tenderness all over the

body, thirsty, over perspiration, dribbling of the saliva, insomnia Etiology: Sexual transmitted disease, walking long distance, anger, misbehaviour and worst character, including more sexual intercourse act, in appropriate to the climate and taking more chilled items. Pathogenesis (Mukkutra theory) Convulsion arise due to the nature of foods taken, abnormality and allergic reactions, which increases the Vali humour. the Vali increased and defects the Pitha

and Kaba humours and make them to accompany it. Abana Vayu and other Vayus also get defected from their own state and cause convulsion. Types: Simple Partial Seizures: Mano Vali STAGES  The onset of involuntary movement of the contra-lateral.  Followed abnormal movement of face  Synchronous with the movements of hands 98

 Changes in somatic sensation, equilibrium, altering in hearing, olfaction or higher cortical function  This type serve as a warning or aura Complex Partial Seizure: Muyalagan Vali  It begins with aura  Sudden behavioral arrest of event  The behavioral arrest is usually accompanied by automatism  They typically confused  Transition to full recovery of consciousness for seconds to hour Grandmal Epilepsy: Kakkai Vali  It begins without warnings

 Initial tonic contraction of muscles throughout the body  Respiration impaired  Bite of tongue  After 10-20 minutes tonic to clonic stage muscle relaxation starts  Unresponsiveness, muscular flaccidity, excessive salivation, subquently complaints of headache, fatigue and muscle ache occur. Status Epilepticus: Sura Vali  Discrete seizures  Merging seizures with waxing and waning amplitude and frequency of EEG  Continuous ictal activity

 Continuous ictal discharges punctuated by low voltage flat periods  Periodic epileptiform discharges on a flat background Treatment Line of Treatment  Purgation  Oleation  Internal medicine  External medicine External therapy  Varmam  Pugai  Ottradam Rejuvenative medicine Yogam 99

Karpam Approximate cost for the management (1 day ) Purgation Rs – 400 (One time) Oleation: Rs - 500 Internal Medicine: Rs - 18 External Medicine: Rs - 26 External Therapy: Rs- 1300 Rejuvenative medicine: Yogam Rs- 500 Grand Total: Rs. 2744 REFERRAL CRITERIA:  Uncontrollable symptoms,  Chronic illness since several years SUBJECT TO CHANGE: Choice of medicines, doses and duration may be altered to the condition of the patients and severity of the disease. ADVICE ON COMPLETION OF TREATMENT AND PREVENTION:

 Regular exercises  Karpa medicines  Pranayamam PATHIYAM(DIET) Tender Vegetables: ErumuraiVatiththa Kangh (double boiled rice), kaththari Pinchu (Solanum melongena),.Avarai Pinchu (dolichoslablab), Aththippinchu (ficus racemosa), Mudakkarran (Cardiospermum halicacabum) Greens: Mudakkarran Keerai (Cardio spermumhalicacabum), Ponnakaanik Keerai (Alternanthera sessilis), Thoothuvealai Keerai (Solanum trilobatum), Mookkirattai Keerai (Boerhaaviadiffusa), Vealai Keerai(Cleome viscosa). Dairy products:

Cow buttermilk Non Vegitariayan Diet: Vellattu Kari, Kaadai, Avoid (Aagap Porutgal)  Surai (Lagenariasiceraria), Poosunai(Luffa acutangula), Vellari (Cucumissativus), Pudalai (Trichosanthes cucumerina), Peerkku (Luffaacutangula), 100

 Kaaramani(Vignaunguiculata),Ulunthu(Vignamungo), Kollu(Macrotylomauniflorum), Kadugu(Brassiajuncea  Sour, astringent tastes  Sea foods except small prawn Other Advice:  Bed rest  Regular exercise and Yogasanas  Avoid chilled atmosphere, sleep on cold floor, live on high altitude Investigation: Blood chemistry Blood sugar Rs. 50 CBC (complete blood count) Rs. 15 Kidney function tests Rs. 400 Liver function tests Rs. 220 Lumbar puncture (spinal tap) Rs. 400 Tests for infectious diseases

Head CT or MRI scan often done to find the cause and location of the problem in the brain.- Rs. 3000 Total- Rs. 4085 101

AUTO-IMMUNE DISORDERS VENPULLI-VITILIGO DEFINITION: Vitiligo is defined as a common dermatological disorder charactarised by well-circumscribed, milky white cutaneous macules devoid of melanocytes. ETIOLOGY: Nutritional - Defects in copper, protein and vitamins in diet, digestive upsets like amoebiasis, helminthes, chronic diarrhea, dysentery etc. Endocrines - Association with thyrotoxicosis and diabetes. Trophoneurosis and autoimmune imbalance-emotional stress and strain.

Infections and toxic products- Enteric fever, ill-health, focal sepsis. Drugs andchemicals like quinines, guanafuracin, amylphenol, chlorthiazide, broadspectrum antibiotics, Betablaeteus and chloroquin. CLINICAL FEATURES: Circumscribed depigmented patches frequently seen in hands, wrists, knees and around the mouth, nose, eyes, nipples, umblicus, anus. Sharply defined depigmented patches surrounded by light brown hyperpigmentation. Spotty dark pigment seen within the depigmented patches.

Depigmented scalp hair, hair loss and burning sensation. MUKKUTRA VERUPAADU: “Vaathamalaathu Meni Kedaathu “-Theran The deranged vaatham is the predominent cause for the occurrence of venpulli. The deranged vaatham and pitham leads to the development of venpulli. STAGES OF VITILIGO 1. Active (V1)  New lesions developing  Lesions increasing in size  Border ill defined 2. Quiescent/Stable (V2)  No new lesions developing  Lesion stationary in size  Border hyperpigmented and well defined 3. Improving(V3)

 Lesions decreasing in size  No new lesions developing  Border defined and signs of spontaneous repigmentation. 102

LINE OF TREATMENT 1. Purgation 2. Oleation: 3. Internal medicine 4. Karpam marunthu 5. External medicine 6. External therapy 7. Yogam - Common to all Stages REFERAL CRITERIA: Referred to concerned department for further management. 1. Depigmented patches spreading all over the body. 2. Depigmentation of scalp hair. 3. Burn coloured skin patches. PATHIYAM (DIET) Adviced: Tender Vegetables:  KaththariPinchu(solanum melongena)  AvaraiPinchu(dolichos lablab)  Aththippinchu(ficusracemosa)

 Mullangi(Rhaphanus sativus)  Pahal(Memortica charantia)  Sambal poosani(Benincasa hispida)  Thoothuvealai(Solanum trilobatum), Greens:  Sirukeerai (Amaranthus tricolor)  PonnakaanikKeerai (Alternantherasessilis),  ThoothuvealaikKeerai (Solanum trilobatum),  Keerai thandu (Amaranthus gangeticus)  Agathi (Sesbania grantiflora) Pulses:  Thuvarai Fruits:  Maadhulai (Punica granatum),  Pappali (Carrica pappaya), 103

 Naaval (Syzygium cuminum),  Paereechu (Foenix dactilifera),  Aththi (Ficus racemosus),  Thirachai (Vitis vinifera),  Kichilli pazham (Citrus aurantium),  Nelli (phyllanthus emblica) Rice:  Hard pounded unpolished rice Non-vegetarian:  Maada pura (Dancing pegion),  Mani pura (Dotted pegion),  Ven pura (White dove),  Ullan (Common snipe),  Vellaadu (Capra hircus),  Ayirai meen (Loach) 2.Avoid  Sour, Pungent and Salty taste.  Mustard seeds  Verkadalai (Arachis hypogea),

 Kaaramani (Vigna ungiculata),  Pataani (Pisum sativum),  Mochai (Lablab purpureus) PREVENTION: 1. Daily intake of greens, Sprouted pasipayaru (Vigna radiata) Venthayam (Trigonella foenum) 2. Take inji karpam, Karisalai Karpam, Ponnakaani karpam 3. Advised pranayamam, Sooriya vanakkam daily. Advice after completion of treatment:: 1. Avoid alcoholic bevarages 2. Change of occupation is advised if it is the causative factor. ONE DAY DIET: Early morning: Chukkumalli coffee-150ml. Breakfast:

Idli -3 Pudhina,karuveppillai chutney -20gm Aththi pazham-5 Lunch: Karisalai/Ponnamkanni poriyal - 50gm Fresh vegetable salad -100gm Pomegranate juice 150 ml Naval pazham-5 Evening: Aellurandai –5 Black dates -5 Aval with milk -100gm Dinner: Chappathi -2 Chenna -100gm Dry grapes -15gm COSTING OF TREATMENT (for 1 day) STAGE-I Purgation- Rs.400 Oleation- Rs.500 Internal medicine- Rs.30 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL- Rs. 1460 STAGE II Purgation- Rs.400

Oleation- Rs.500 Internal medicine- Rs.60 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL - Rs. 1490 STAGE III Purgation- Rs.400 Oleation- Rs.500 Internal medicine- Rs.80 Karpam- Rs.10 105

External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL Rs.1510 INVESTIGATION: 1. Routine blood investigation- Rs.90 2. Liver function test- Rs.220 3. Renal function test- Rs.400 Thyroid profile test- 1. T3 - Rs.200 2. T4 - Rs.200 3. TSH - Rs.200 4. TPO - Rs.300 106

UTHIRAVAADHA SURONITHAM (RHEUMATOID ARTHRITIS) DEINITION Rheumatoid arthritis is a generalised disease affecting the connective tissues of the whole body with localized involvement of the musculo skeletal system. ETIOLOGY: Geographical: RA has a world-wide distribution and affects 0.5-3%of the population.it is a significant cause of disability and mortality and carries a high socio-economic cost. Age: RA presents from early childhood to late old age.The most common age of onset is between 30 and 50 years.

Gender: Women before the menopause are affected three times more often than men. Familial: The disease is familial but sporadic.In occasional families it affects several generations. It is estimated to account for 60% of disease susceptibility. HLA types; There is strong association between susceptibility to RA and certain haplotypes. HLA-DR4, which occur in 50-75% of patients. STAGE I UTHIRAVAATHA SURONITHAM:  Pain and swelling in all major joints and small joints.  Loss of appetite,depression,

 Deranged pitham and elevated vayu leads to this condition. STAGE II PAITHIYAVAATHA SURONITHAM:  Severe pain in all major and minor joints.  Genralized weakness of both upper and lower limbs,  small joints,cheek,forehead,fever,aneamia,depression. Clinical features: Rheumatoid arthritis is more common in women and occurs between 25 and 40 years of age. It is a chronic disease with periodic acute exacerbations and

remissions.Morning stiffness is a very characteristic of Rheumatoid arthritis. Involves small joints of the hands and feet and later on spreading to the proximal joints like the knee, hip, elbow and shoulder. 107

Mukkutra Verupadu (Pathogenesis): The combined derangement of Vali and Azhal leads to the development of Uthiravaadha suronitham- Rheumatoid arthritis LINE OF TREATMENT 1. Purgation 2. Oleation: 3. Internal medicine 4. Karpam marunthu 5. External medicine 6. External therapy DIETERY REGIMEN ADD: Tender vegetables:  Kathari(Solanum melangena),  Avarai(Dolicus lablab),  Pudalai(Trichosanthe cucumerina),  Vellari(Cucumis sativus),  Kovai(Coccina grandis),  Murungai(Moringa oleifera),

 Athai(Ficus racemosa),  Surai(Lagenaria sicerarie),  Sundai (Solanum torvum),  Mullangai (Rhaphanus sativus),  Karunai kizhangu (Colocasia antiquarum)  Pirandai(Cissus quadrangularis) Greens:  Musumusukai(Mukia maderaspatna),  Ponnaangaani(Alternanthera sessils),  Mookirattai (Boerhavia diffusa)  Sirukeerai(Amaranthus tricolor)  Manali keerai(Gisekia pharanaceoides)  Puliyaari (Oxalis corniculata) Pulses:  Ulunthu (Vigna mungo ) Diary products:  Cow‘s buttermilk. 108

Non-vegetarian diets  Velladu(Capra hircus)  Ayirai meen(Loach)  Udumbu(Monitar lizard)  Kaadai (Gallus sonne ralti)  Kowthaari(Indian patridge) AVOID  Tubers except Karunai (Colocasia antiquorum), Ma porutkal(Carohydrate rich diets),Vazhai(tender fruit of Musa paradisiacal), Verkadalai(Arachis hypogea), Karamani(Vigna ungiculata), Pattani(Pisum sativam), Mochchai(Lablab purpureus).  Astringent tastes.  Sea Sour, foods expect small prawn. Other advices:  Rest for involved joint.

 Activities that involve excessive use of joint should be identified and avoided.  Regular mild exercises and Yogasanam.  To avoid chill weather, sleeping in bare floor,high altitude. ONE DAY DIET: Early morning: Chukku malli coffee - 150ml Breakfast : Mudakkaruthan adai - 2(200gm) Pirandai thuvayal - 25 gm Lunch: Veg salad - 50gm Ponnamkanni poriyal - 50gm Apple juice - 150 ml Evening: Ellurandai - 5 Ragi dosai - 2 (200gm) Dinner: Chappathi - 2 Chenna - 50gm COSTING OF TREATMENT(for 1 day) STAGE-I 109

Purgation- Rs.400 Oleation- Rs.500 Internal medicine- Rs.60 Karpam- Rs.20 External medicine- Rs.10 External therapy Varmam- Rs.1750(7 sitting) Patru- Rs.500(for specific region) Pattikattal- Rs.400 Yogam- Rs.500 TOTAL – Rs.4140 STAGE II Purgation- Rs.400 Oleation- Rs.500 Internal medicine- Rs.100 Karpam- Rs.20 External medicine- Rs.20 External therapy Varmam- Rs.3000(for 14 sitting) Leech therapy- Rs.1000(for 1 sitting) Patru- Rs.500 Pattikattal- Rs.400 Yogam- Rs.500 TOTAL- Rs.6440 Blood investigation

Routine blood investigation -Rs.90 Liver function test - Rs.220 Renal function test - Rs.400 ASO titre - Rs.250 CRP - Rs.25 RA factor - Rs.50 Anti CCP - Rs.700 X-ray -Rs.30 110

PUZHUVETTU(ALOPECIA AREATA) DEFINITION Alopecia areata is an immunologically mediated disease characterized by circumscribed regions of acute hair loss without surface scale or erythema. ETIOLOGY: The exact cause is unknown.The consensus of opinion is that alopecia areata is the result of physical or emotional stress in a sensitive individual. Some workers blame auto-immune mechanism,as by chemicals,drugs and infections. CLINICAL FEATURES

Rapid shedding of hair shafts to form small, well circumscribed round or oval patches is the most common presentation of alopecia areata. The hairless scalp is usually asymptomatic and appears normal only rarely does the patient notice tingling sensation or slight degree of erythema. Patches of erythema are typhicaly 3-5 cm in diameter MUKKUTRA VERUPADU- PATHOGENESIS “Vaathamallathu Meni Kedathu” -Theran Deranged vaatham is the predominant cause for puzhuvettu.

Deranged vaatham and pitham leads to the development of the disease puzhuvettu. STAGE -I Rapid and complete loss of hair in one or more round or oval patches, usually on the scalp, bearded area, eye brows, eyelashes and less commonly on other hairy areas of the body. STAGE II Early in the coutse there may be sparing of gray hair and white hair are rarely affected sudden. Whitening of hair may represent widespread alopecia areata in a patient with salt and pepper hair. STAGE -III

In about 10% of cases of alopecia areata especially in long stanging cases with extreme involvement the nails develop uniform pits they may form transverse or longitudinal lines. LINE OF TREATMENT 1. Purgation 2. Oleation: 3. Internal medicine 4. Karpam marunthu 5. External medicine 6. External therapy 111

PATHIYAM(DIET) Tender Vegetables –  Avarai (Dolichos lablab),  Athi (Ficus racemosa)  Murungai (Moringa oleifera)  Vaazhaithandu (Musa paradisiaca),  Mullangi (Rhaphanus sativus) Greens:  Pannai keerai (Chemissoa albida),  Parattai keerai (Evolvulus emarginatus)  Mullangi keerai (Rhaphanus sativus)  Mudakaruthankeerai(Cadiospermum helicacabam) Dairy products - Cow’s buttermilk AVOID: o Avoid frequent intake of sour and hot tastes. o Solam (Sorghum vulgare) o Kambu (Pennisetum typhoidum)

o Varagu (Paspalum scrobiculatum) o Vazhaikaai(tender fruits of Musa paradisiaca), o Paharkaai(Momordica charantia) o Mango(Mangifera indica) o Sakarai valli kizhangu (Ipomoea batatus) o Seppakizhagu (Calacasia esculanta) o Vellari(Cucumis sativus) o Koththavarai( Cyamopsis tetragonoloba) o Kollu (Macrotyloma uniflorum) o Koyya(Psidum guajava) o Kathari(Solanum melongena) o Vaankozhi kari(Turkey) ONE DAY DIET: Early morning: Arugampul juice -100ml Break fast : Idli - 4 Pudhina chutney -50gm 112

Lunch: Fresh veg salad -50gm Karisalai poriyal -50gm Evening: Nellithennural -5 pieces Dinner: Chappathi -2 Chenna -50gm. COSTING OF TREATMENT(for 1 day) STAGE-I Purgation- Rs.400 Oleation- Rs.500 Internal medicine- Rs.30 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL- Rs. 1460 STAGE-II Purgation- Rs.400 Oleation- Rs.500 Internal medicine- Rs.30 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL- Rs. 1460 STAGE-III Purgation- Rs.400 Oleation- Rs.500

Internal medicine- Rs.30 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL- Rs. 1460 Blood investigation Routine blood investigation-Rs.90 113

SYSTEMIC LUPUS ERYTHYMATOSUS (SLE) DEFINITION SLE is a multisystem disorder, primarily affects skin, joint and vascular system. The age of onset is usually between 16 and 42 years occuring more frequently in females (F:M::8:1) ETIOLOGY: There is unequivocal evidence for the presence of nautoantibodies directed against nuclear DNA and other tissue antigens.these autoantibodies form as a result of genetically determined immune imbalance;as a result, B-cells readily synthesize

antibodies directed against tissue proteins altered by ultraviolet,viruses,drugs, and other unknown factors causing damage by formation of immune complex and cytotoxicity. CRITERIA FOR DIAGNOSIS: MALAR RASH: Fixed erythema, flat or raised, over the malar eminences, tending to space the nasolabial folds. DISCOID RASH ERYTHEMATOUS: Erythematous raised patches with adherent keratotic scaling and follicular plugging ;atrophic scarring may occur in older lesions. PHOTO SENSITIVITY:

Skin rash as a result of unusual reaction to sunlight, By patient history or physician observation. ORAL ULCERS: Oral or nasopharngeal ulceration, usually painless, observed by a physician. ARTHRITIS: Non erosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling or effusion. SEROSITIS: PLEURITIS: History of pleuritic pain or rub heared by a physician or evidence of pleural effusion. PERICARDITIS: Documented by ECG or evidence of pericardial effusion. RENAL DISORDER:

a. Persisitent proteinuria > 0.5 gm/ day b.cellular casts– may be red cells, heamoglobin, granular, tubular or mixed NEUROLOGICAL DISORDER: A. Seizure- Due to absence of offending drugs or known metabolic derangements E.g Uremia, ketoacidosis or electrolyte imbalance. B. Psycosis 114

HEMATOLOGIC DISORDER: a. Hemolytic aneamia b. Lecopenia <4000/ml c. Lymphopenia<1500 ml d. Thrombocytopenia <100000 ml IMMUNOLOGIC DISORDER: Anti-DNA –Antibody to native DNA Anti-SM- present of antibody to SM nuclear antigen ANTINUCLEAR ANTIBODY: An abnormal titer antinuclear antibody by immunofluorescence. CHIEF CUTANEOUS FEATURES:  Butterfly rash  Photo sensitivity  Raynaud‘s phenomenon  Non scarring alopecia short hairs in the frontal region are referred to as cupus hairs  Urticarial vasculitis

 Mouth ulceration  Bullous lesions  Chronic discoid lesion  Cutaneous vasculitis  Others-Vasculopathy, periungal telangiectasia, leg ulcers, erythema muiliforme, thrombophlebitis, peripheral gangrene. According to Siddha system,deranged Vaatham andPitham,combined with Kabham causes above condition. Saaram, senneer, mamisam, enbu –deranged in this condition. LINE OF TREATMENT 1. Purgation 2. Oleation: 3. Internal medicine 4. Karpam marunthu 5. External medicine 6. External therapy PATHIYAM (DIET)

Adviced: Tender Vegetables:  KaththariPinchu(solanum melongena)  AvaraiPinchu(dolichos lablab) 115

 Aththippinchu(ficusracemosa)  Mullangi(Rhaphanus sativus)  Pahal(Memortica charantia)  Sambal poosani(Benincasa hispida)  Thoothuvealai(Solanum trilobatum), Greens:  Sirukeerai (Amaranthus tricolor)  PonnakaanikKeerai (Alternantherasessilis),  ThoothuvealaikKeerai (Solanum trilobatum),  Keerai thandu (Amaranthus gangeticus)  Agathi (Sesbania grantiflora) Pulses:  Thuvarai Fruits: o Maadhulai (Punica granatum), o Pappali (Carrica pappaya), o Naaval (Syzygium cuminum),

o Paereechu (Foenix dactilifera), o Aththi (Ficus racemosus), o Thirachai (Vitis vinifera), o Kichilli pazham (Citrus aurantium), o Nelli (phyllanthus emblica) Rice:  Hard pounded unpolished rice Non-vegetarian:  Maada pura (Dancing pegion),  Mani pura (Dotted pegion),  Ven pura (White dove),  Ullan (Common snipe),  Vellaadu (Capra hircus),  Ayirai meen (Loach) 2.Avoid  Sour, Pungent and Salty taste.  Mustard seeds  Verkadalai (Arachis hypogea),  Kaaramani (Vigna ungiculata),

 Pataani (Pisum sativum),  Mochai (Lablab purpureus) PREVENTION: 1. Daily intake of greens, sprouted pasipayaru(Vigna radiata) Fruits. 116

2. Take inji karpam, Karisalai karpam, Ponnakaani karpam 3. Advised pranayamam, Sooriya Vanakkam daily. ONE DAY DIET Early morning: Arugampul juice -150ml Breakfast: Idli - 4 Mudakathan adai - 2 Pudhina chutney - 20gm Lunch: Ponnamkanni poriyal - 50gm Veg salad - 20gm Pirandai thuvayal - 20gm Apple juice - 150ml Evening: Ragi dosai -2 Aval with milk - 25gm Dinner: Chappathi - 2 Chenna - 20gm COST OF TREATMENT:(for one day) Purgation- Rs.400 Oleation- Rs.500 Internal medicine- Rs.60 Karpam- Rs.20

External medicine- Rs.10 External therapy Varmam- Rs.1750(7 sitting) Patru- Rs.500(for specific region) Pattikattal- Rs.400 Yogam- Rs.500 TOTAL - Rs.4140 Blood Investigation: Routine blood investigation- Rs.90 Renal function test- Rs.400 Liver function test- Rs.220 ECG- Rs.100 MRI Brain- Rs.3000 Anti-DNA- Rs.500 Anti-Sm- Rs.500 Igm- Rs.100 IgG- Rs.100 ANA- Rs.100 TOTAL - Rs.5010 117

ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD) INTRODUTION: In Siddha system, the physiology of normal body activities is dealt in 96 Tathuvaṅkal (Philosophy).Maṉam (Mind), Puthi (Wisdom, Decision making), Muṉaippu (Accomplishment) Cittam(Determination) are directly responsible for mental well being. Vatham,Pitham and Kabam are the three humours which are the basic constitution of human body. Vitiation Pitham would affect Maṉam and leads to Mental illness DEFINITION:

Attention deficit hyperactivity disorder (ADHD) is a condition in which a person has trouble paying attention and focusing on tasks, tends to act without thinking, and has trouble sitting still. Attention deficit hyperactivity disorder(ADHD) is a common condition that affects children and adolescents and can continue into adulthood for some. CAUSES: The exact cause of ADHD is not known, although researchers continue to study the brain for clues. They suspect that there are several factors that may

contribute to the condition, including:  Heredity  Chemical imbalance: Imbalance of brain chemicals (neurotransmitters)  Brain changes  Brain Injury CLINICAL DESCRIPTION: Types of ADHD  There are three different subtypes of ADHD, including:  Combined ADHD (the most common subtype), which involves symptoms of both inattentiveness and hyperactivity/impulsivity  Inattentive ADHD (previously known as ADD), which is marked by impaired attention and concentration

 Hyperactive-impulsive ADHD, which is marked by hyperactivity without inattentiveness ATTENTION : 1. Inability to sustain attention on tasks or activities 2. Easily distracted by irrelevant stimuli and frequently interrupting ongoing tasks . 3. Inability to sustain attention on tasks or activities 4. Difficulty finishing schoolwork 5. Frequent shifts from one uncompleted activity to another 6. Procrastination 7. Disorganized work habits

8. Forgetfulness in daily activities (for example, missing appointments, forgetting to bring lunch) 118

HYPERACTIVITY :  Fidget, squirming when seated  Getting up frequently to walk or run around  Running or climbing excessively  Having difficulty playing quietly or engaging in quiet leisure activities  Always being 'on the go'  Talking excessively IMPULSIVITY:  Be very impatient  Blurt out inappropriate comments,  Show their emotions without restraint.  Act without regard for consequences  Interrupt conversations or others' activities. ADULT ADHD:  Chronic lateness and forgetfulness  Anxiety

 Difficulty controlling anger  Impulsiveness  Substance abuse or addiction  Mood swings  Depression  Relationship problems TREATEMENT: NORMALISATION OF ALTERED UYIRTHAATHUKKAL IN CHILDREN: KUDINEER: CHOORANAM: NEI ILAGAM PARPAM Medicines which has calming effect over the nervous system may be prescribed. OLEATION Oil bath may be advised twice a week with any of the following medicated oil. DIET(PATHIYAM) TENDER VEGETABLES Kaththari Pinchu(solanum melongena) Avarai Pinchu(Dolichos lablab)

GREENS: Mudakkarran Keerai(Cardiospermumhalicacabum) Ponnakaani Keerai(Alternantherasessilis), Thoothuvealai Keerai(Solanumtrilobatum), Mookkirattai Keerai(Boerhaaviadiffusa), Vealaik Keerai(Cleome viscosa), PULSES: Thuvarai Paruppu(Gajanas gajan) Venthayam(Trigonella foenum graecum) DAIRY PRODUCTS: Cow‘s milk Buttermilk Curd Ghee YOGAM Pranayamam-naadi suthi pranayamam Savaasanam Breakfast: Sprouted Bengal gram boiled-150gm Idli -3 Pudhina,karuveppillai chutney -20gm Athi pazham-5 Lunch:

Karisalai/Ponnamkanni poriyal - 50gm Fresh vegetable salad -100gm Pomegranate juice 150 ml Naval pazham-5 Evening: Black dates -5 Aval with milk -100gm Dinner: Chappathi -2 Chenna -100gm Dry grapes -15gm TREATMENT COST (For 1 day) 120

Oleation- Rs.500 Internal medicine- Rs.30 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL- Rs. 1060 INVESTIGATION: 4. Routine blood investigation- Rs.90 5. Liver function test- Rs.220 6. Renal function test- Rs.400 121

ANXIETY NEUROSIS (MATHA NOI OR SERUKKU NOI) INTRODUCTION: Siddha system of medicine is an ancient, unique and codified indigenous system of medicine. This system was formulated and established by Siddhars who are the spiritual scientists of the ancient Tamil culture about more than several thousand years back. Siddha system of medicine classified the clinical variety of mental illness based on the symptomatology. DEFINITION: Neurosis is a class of functional mental disorders involving distress but

neither delusions nor hallucinations, whereby behavior is not outside socially acceptable norms. It is also known as psychoneurosis or neurotic disorder, and thus those suffering from it are said to be neurotic. ETIOLOGY:  Chemical imbalance  Family genetics  Predisposing factor  Consuming alcohol  Prohibited drugs  Person‘s thoughts, for instance  Inflexible conviction in thoughts and ideas. TYPES:  Panic disorder with or without Agoraphobia  Acute stress disorder  Post-traumatic stress disorder

 Social phobia  Specific phobias  Obsessive compulsive disorder  Generalized anxiety disorders  Anxiety due to medical causes  Substance induced anxiety disorders CLINICAL DESCRIPTION:  Excessive anxiety.  Fear.  Rapid heart rate.  Hyperventilation.  Muscle pain.  Abdominal pain.  Headache.  Numbness and tingling .  Low self esteem  Irritability  Obsessive thoughts  Obsessive behaviors  Dependency 122

 Perfectionism  Chest pain  Nausea  Shortness of breath  Heart palpitations  Increase in blood pressure SIDDHA TYPES -7  Vali Mathanoi  Azhal Mathanoi  Iyya Mathanoi  Mukkutra Mathanoi  Kuruthi Mathanoi  Nanju Mathanoi  Madha udarkedu Mathanoi. PATHOGENESIS ON THE BASIS OF THE THIRITHODAMS: The unifying factor in Siddha psychiatry is the importance laid on the imbalance of three humours, especially are predominance of Azhal humour over the

other two. In madha noi there is increased udal thathukkal. STAGE-1 Specific phobias and social anxiety disorders are the commonest amongst all these types. Excessive, persistent and irrational fear of certain things or situations is termed as phobia.  Excessive anxiety.  Fear.  Rapid heart rate.  Hyperventilation.  Muscle pain.  Abdominal pain.  Headache.  Numbness and tingling .  Low self esteem Clinical management for different stages of disease condition: Treatement: Stage I

Normalisation of Altered Uyirthaathukkal Vaanthi and Kazhicchal Marunthugal: To neutralize the pitham vomiting will be advised. Kudineer: Chooranam: Nei: Ilagam 123

STAGE-2 Post Traumatic Stress Disorders and Generalized Anxiety Disorders are next commonest. Generalized anxiety disorders:  Restlessness  Irritability  Difficulty in concentrating  Sleep disturbances (difficulty in falling asleep, frequent waking in the middle)  Easy fatigue Post Traumatic Stress Disorders: Sleep disturbances, depression, feeling detached or numb (de realization), easy startling are commonly experienced. Often there are feelings of loss of pleasure or

interest in previously enjoyable activities (anhedonia). Women appear to be at greater risk than men for developing PTSD after traumatic experiences.  Obsessive thoughts  Obsessive behaviors  Dependency  Perfectionism TREATEMENT: NORMALISATION OF ALTERED UYIRTHAATHUKKAL VAANTHI AND KAZHICCHAL MARUNTHUGAL: To neutralize the pitham vomiting will be advised Internal medicines Kudineer: Chooranam: Nei: Ilagam Parpam: Drugs which is indicated for pitham diseases may be advised STAGE III

 Panic disorder with or without Agoraphobia  Acute stress disorder  Social phobia  Obsessive compulsive disorder  Anxiety due to medical causes  Chest pain  Nausea  Shortness of breath 124

 Heart palpitations  Increase in blood pressure TREATEMENT: NORMALISATION OF ALTERED UYIRTHAATHUKKAL VAANTHI AND KAZHICCHAL MARUNTHUGAL: To neutralize the pitham vomiting will be advised Kudineer: Chooranam: Nei: Ilagam Parpam: Chenthooram: Drugs which is indicated for pitham diseases may be advised OLEATION: Oil bath may be advised twice a week with any of the following medicated oil. PATHIYAM(DIET) Tender vegetables: ErumuraiVatiththaKangh (double boiled rice) , kaththariPinchu (solanum melongena)

AvaraiPinchu (Dolichos lablab) Aththippinchu (Ficusracemosa) Greens: MudakkarranKeerai (Cardiospermumhalicacabum) PonnakaanikKeerai (Alternantherasessilis), ThoothuvealaikKeerai (Solanumtrilobatum), MookkirattaiKeerai (Boerhaaviadiffusa), VealaikKeerai (Cleome viscosa), Pulses: ThuvaraiParuppu Venthayam (Trigonella foenum graecum) Dairy products: Cow milk Buttermilk Curd Ghee 125

ONE DAY DIET: Early morning: Chukkumalli coffee-150ml. Breakfast: Sprouted Bengal gram boiled-150gm Idli -3 Pudhina,karuveppillai chutney -20gm Athi pazham-5 Lunch Karisalai/Ponnamkanni poriyal - 50gm Fresh vegetable salad -100gm Pomegranate juice 150 ml Naval pazham-5 Evening: Black dates -5 Aval with milk -100gm Dinner: Chappathi -2 Chenna -100gm Dry grapes -15gm COSTING OF TREATMENT (for 1 day) STAGE-I TREATMENT COST (FOR 1 DAY) Oleation- Rs.500 Internal medicine- Rs.30 Karpam- Rs.10

External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL- Rs. 1060 STAGE II Oleation- Rs.500 Internal medicine- Rs.60 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 126

Nalanguma- Rs.10 TOTAL - Rs. 1090 STAGE III Oleation- Rs.500 Internal medicine- Rs.80 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL Rs.1110 INVESTIGATION: 7. Routine blood investigation- Rs.90 8. Liver function test- Rs.220 9. Renal function test- Rs.400 127

AUTISM INTRODUCTION : According to the modern science, Autism is a complex developmental disability that typically appears during the first three years of life and affects a person‘s ability to communicate and interact with others. Autism is defined by a certain set of behaviors and is a ―spectrum disorder‖ that affects individuals differently and to varying degrees. DEFINITION : Autism is a disorder of neural development characterized by impaired social

interaction, verbal and non-verbal communication, and by restricted and repetitive behavior ETIOLOGY Familial inheritance Genetic Vulnerability Environmental Factors (e.g. heavy metals such as mercury) TYPES It is classified in to following types Autism or Autistic Disorder A collection of developmental disorders in which a child engages in repetitive behaviours and has trouble communicating and connecting with others. It's usually

diagnosed around age 2 or 3, although some signs show up earlier. The affected child become very excited when they saw new toys, new things. Symptoms can be mild to severe and it can be accessed through CARS evaluation criteria. CARS is diagnostic assessment that rates children on various criteria ranging from normal to severe ,and yields a composite score ranging from non-autistic, moderately autistic or severely autistic. The scale is used to observe and subjectively rate fifteen items.

 Relationship with people  Imitation  Emotional response  Body use  Object use  Adaptation to change  Visual response  Listening response  Taste-smell-touch response and use  Fear and nervousness  Non-verbal communication  Activity level  Level and consistency of intellectual response  General impressions Childhood Autism Rating Scale 128

Each of the fifteen criteria listed above is rated with a score of: 1-normal for chid age 2-mildly abnormal 3-moderately abnormal 4-severely abnormal Midpoint scores of 1.5,2.5 and 3.5 are also used. Score Value 15-30 -Non autistic 30-37 -Mildly-Moderately autistic 38-60 -Severely autistic Regressive Autistic Spectrum Disorder Like autism, except that a child appears to develop normally until 18 to 24 months, then starts to regress. It occurs in about 20 to 30 percent of children with

autism spectrum disorders. Pervasive Developmental Disorder -- Not Otherwise Specified A child has a few autistic traits but doesn't meet the full criteria for an autism diagnosis. Asperger's Syndrome A milder form of autism, usually diagnosed between ages 2 and 6, in which a child has good language skills and average to above-average intelligence but is socially awkward and engages in odd, repetitive behaviors. Childhood Disintegrative Disorder (CDD)

A very rare disorder in which normally developing children lose motor, language, social, and potty skills around ages 2 to 4. Rett Syndrome An extremely rare disorder, similar to CDD, which occurs only in girls. CLINICAL DESCRIPTION Children with autism generally have problems in three crucial areas of development — social interaction, language and behavior. Children who are autistic may have repetitive, stereotyped body movements such as rocking, pacing, or

hand flapping. They may have unusual responses to people, attachments to objects, resistance to change in their routines, or aggressive or self-injurious behavior. The persons with autism have additional medical conditions such as sleep disturbance, seizures and gastrointestinal (GI) distress MUKKUTRAVERPADU( PATHOGENESIS) Vitiated Vatha kutram along with affected Udhanan (upward movements in the body especially speech) causes this disease. LINE OF TREATMENT Purgation 129

To neutralise the vitiated vatham Autism is treated with following internal and external medication INTERNAL MEDICINE Chooranam Maathirai Vadagam Parpam Chendooram EXTERNAL MEDICINE VARMAM Certain varmam points the head and neck may be advised to get good prognosis along with medicines OIL BATH DO‘S  Let your child cope  Celebrate your child  Explain in advance  Give your family the heads-up  Designate a mellow room  Mimic an outing without leaving your home  Take the holiday spirit home DONT‘S

 Don't inadvertently teach a child to communicate with negative behavior  Don't ask a question if you're not sure the child knows the answer  Do avoid dependence on echoic or verbal prompting when appropriate  Do avoid "incorrect" responding  To avoid gluten and casein containing foods  Gluten found in wheat, barley and rye and  Casein found in milk and dairy products are removed from the  child's daily food intake.  Eat green leafy vegetables and fibre foods ONE DAY DIET: Early morning:

Chukkumalli coffee-150ml. Breakfast: Sprouted Bengal gram boiled-150gm Idli -3 Pudhina,karuveppillai chutney -20gm Athi pazham-5 Lunch: Karisalai/Ponnamkanni poriyal - 50gm Fresh vegetable salad -100gm Pomegranate juice 150 ml Naval pazham-5 130

Evening: Black dates -5 Aval with milk -100gm Dinner: Chappathi -2 Chenna -100gm Dry grapes -15gm COSTING OF TREATMENT (for 1 day) Oleation- Rs.500 Internal medicine- Rs.30 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL- Rs. 1060 INVESTIGATION:  Routine blood investigation- Rs.90  Liver function test- Rs.220  Renal function test- Rs.400 131

BRAMAI (ENDOGENOUS DEPRESSION) INTRODUCTION In siddha system the physiology of normal body activities is dealt in 96 Thathuvangal (Philosophy), Manam(Mind), Puthi (Wisdom, Desision making), Munaippu (Accomplishment), Citham (Determination) are directly responsible for mental well being. Vali, Azhal, Iyam are the three humours which are the basic constituents of the human body.Any derangement in vali or azhal or both would affect manam and leads to mental illness. DEFENITION:

Endogenous depression is characterized by feelings of guilt and worthlessness and anhedonia.Anhedonia is the inability to derive pleasure from ones pleasurable activities such as exercise, hobbies or sex. ETIOLOGY: There is no apparent reason.It is believed that this kind of depression is caused by some chemical imbalance in the body. Common causes are: 1. Genetics 2. An imbalance in the amount of neurotransmitters 3. A deficiency of certain nutrients (Vitamines like vitamine D and vitamine B12).

CLINICAL DESCRIPTION: Experience of anhedonia along with feelings of Hopelessness Helplessness Worthlessness Guilt Self hate Fatigue or lack of energy Irritability and difficulty concentrating Social isolation Insomnia or Hypersomnia(Excessive sleeping) Changes in appetite with corresponding weight gain or loss Suicidal thouts or behaviors Hallucinations Delusions TYPES OF BRAMAI 1. VathaBramai 2. PithaBramai 3. KabaBramai PATHOGENESIS ON THE BASIS OF THE THIRITHODAMS

The unifying factor in siddha psychiatry is the importance laid on the imbalance of three humours, especially are predominance of azhal humour over the other two. 132

TREATEMENT STAGE 1 Experience of anhedonia along with feelings of Hopelessness Helplessness Worthlessness Guilt Self hate NORMALISATION OF ALTERED UYIRTHATHUKKAL VAANTHI AND KALICHAL MARUNTHUKAL. KUDINEER(Decoction) To neutralize the vitiatiated pitham CHOORANAM(Powdered medicine) NEI(Medicinal Ghee) ILAGAM(Electuary) Drugs which neutralize the pitham and strengthens the nerves should be prescribed OLEATION: Oil bath may be advised twice a week STAGE 2  Fatigue or lack of energy

 Irritability and difficulty concentrating  Social isolation  Insomnia or Hypersomnia(Excessive sleeping)  Changes in appetite with corresponding weight gain or loss  Suicidal thoughts or behaviors NORMALISATION OF ALTERED UYIRTHATHUKKAL VAANTHI AND KALICHAL MARUNTHUKAL. KUDINEER To neutralize the vitiatiated pitham CHOORANAM NEI ILAGAM PARPAM CHENTHOORAM 133

Drugs which neutralize the pitham and strengthens the nerves should be prescribed OLEATION: Oil bath may be advised twice a week. STAGE 3 Hallucinations Delusions NORMALISATION OF ALTERED UYIRTHATHUKKAL VAANTHI AND KALICHAL MARUNTHUKAL KUDINEER To neutralize the vitiatiated pitham CHOORANAM NEI ILAGAM PARPAM CHENTHOORAM Drugs which neutralize the pitham and strengthens the nerves should be prescribed OLEATION: Oil bath may be advised twice a week PATHIYAM(DIET) Tender Vegitables

Irumuraivadithakangi(Double boiled rice) Katharipinchu(Solanummelongena) Avaraipinchu(Dolichos lablab) Athipinchu(Ficusracemosa) GREENS MudakkatranKeerai(Cardiospermumh elicacabum) PonnankaaniKeerai(Alternantherasessilis) ThuthuvaelaiKeerai(Solanum trilobatam) MookirattaiKeerai(Boeraavia difusa) VelaiKeerai(Cleome viscosa) PULSES Thuvaraiparuppu (Cajanus cajan) Venthayam(Trigonella foenumgraecum) DAIRY PRODUCTS 134

Cow milk Butter milk Curd Ghee ONE DAY DIET: Early morning: Chukkumalli coffee-150ml. Breakfast: Sprouted Bengal gram boiled-150gm Idli -3 Pudhina,karuveppillai chutney -20gm Athi pazham-5 Lunch: Karisalai/Ponnamkanni poriyal - 50gm Fresh vegetable salad -100gm Pomegranate juice 150 ml Naval pazham-5 Evening: Black dates -5 Aval with milk -100gm Dinner: Chappathi -2 Chenna -100gm Dry grapes -15gm COSTING OF TREATMENT (for 1st day) STAGE-I Purgation- Rs.400 From 2nd Day onwards Oleation- Rs.500

Internal medicine- Rs.60 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL - Rs. 1090 135

STAGE II FOR 1st Day Purgation- Rs.400 From 2nd Day onwards Oleation- Rs.500 Internal medicine- Rs.60 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL - Rs. 1090 STAGE III For 1st Day Purgation- Rs.400 From 2nd Day onwards Oleation- Rs.500 Internal medicine- Rs.60 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL - Rs. 1090 INVESTIGATION: 10. Routine blood investigation- Rs.90 11. Liver function test- Rs.220 12. Renal function test- Rs.400 136

NINAIVU KOLARU (MEMORY DISORDER) INTRODUCTION: It is one of the most important condition affecting both adult and old age persons characterized by defective memory. DEFINITION: Memory disorder is the result of damage to neuroanatomical structures that hinders the storage, retention and recollection of memories ETIOLOGY:  Damage to the brain (most commonly in the occipital or parietal lobes)  Head injury  Malnutrition  Mental stress  Lack of sleep  Psychological illness  Chronic alcoholism

CLINICAL DESCRIPTION: Patients with this condition are able to recall events from every day of their lives Agnosia Agnosia is the inability to recognize certain objects, persons or sounds Alzheimer's disease Alzheimer's disease (AD) is a progressive, degenerative and fatal brain disease, in which cell to cell connections in the brain are lost. Amnesia Amnesia is an abnormal mental state in which memory and learning are affected out of all proportion to other cognitive functions in an otherwise alert and

responsive patient. Brain injury Traumatic brain injury often occurs from damages to the brain caused by an outside force, and may lead to cases of amnesia depending on the severity of the injury Dementia Refer to a large class of disorders characterized by the progressive deterioration of thinking ability and memory as the brain becomes damaged. \ TREATMENT Neutralization of vitiated Kabam and Vaatham. CLINICAL MANEGMENT OF VARIOUS STAGES: STAGE1: Forgetfulness of recently learned information

 Proper selection of purgative medicine to purify the body and enhance the blood circulation to brain CHOORANAM (Medicinal powder) MAATHIRAI (Tablet) LEGIUM (Electuary) NEI(Medicinal Ghee) Preparation which improves the memory and neutralize the vitiated kabham and Vataham EXTERNAL: Oil bath to reduce the stress and anxiety, etc.., STAGEII: Forgetfulness of important dates and events PURGATIVE MEDICINE: MAATHIRAI: PARPAM: CHENTHURAM: EXTERNAL: Oil Bath STAGEIII: Asking same information repeatedly. KARPAM:

NEI: EXTERNAL: Oil Bath STAGEIV: Increased dependency on reminder notes or electronic device or family members for things they used to handle on their own. NEI PARPAM KARPAM NEI DIET ADVICE:  Green leafy vegetables  Spinach  sprouts  tender vegetables AVOID  Junk foods  chat items, snacks  tinned foods 138

 non vegetarian diet DO‘s  meditation  sun salutation  wakeup early in the morning  recollect the phrases  write and memorize in easy ways  oil bath  good sleep DON‘TS  stress  alcohol, smoking  daytime sleep  watching television for longer duration ONE DAY DIET: Early morning: Chukkumalli coffee-150ml. Breakfast: Sprouted Bengal gram boiled-150gm Idli -3 Pudhina,karuveppillai chutney -20gm Athi pazham-5 Lunch: Karisalai/Ponnamkanni poriyal - 50gm Fresh vegetable salad -100gm

Pomegranate juice 150 ml Naval pazham-5 Evening: Black dates -5 Aval with milk -100gm Dinner: Chappathi -2 Chenna -100gm Dry grapes -15gm COSTING OF TREATMENT (for 1st day) STAGE-I Purgation- Rs.400 From 2nd Day onwards Oleation- Rs.500 Internal medicine- Rs.60 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 139

Nalanguma- Rs.10 TOTAL - Rs. 1090 STAGE II FOR 1st Day Purgation- Rs.400 From 2nd Day onwards Oleation- Rs.500 Internal medicine- Rs.60 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL - Rs. 1090 STAGE III For 1st Day Purgation- Rs.400 From 2nd Day onwards Oleation- Rs.500 Internal medicine- Rs.60 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL - Rs. 1090 INVESTIGATION: 13. Routine blood investigation- Rs.90 14. Liver function test- Rs.220

LEARNING DISORDER (KATRAL KOLARUGAL) INTRODUCTION: Learning disability refers to significant learning problems in an academic area. Types of learning disabilities include reading disability (dyslexia), mathematics disability (dyscalculia) and writing disability (dysgraphia). A group of disorders manifested by significant difficulties in the acquisition and use of listening, speaking, reading, writing, reasoning or mathematical abilities. AETIOLOGY:

Learning disorder occurs in most of the persons due to defect in brain's ability to receive and process information.  Heredity – Learning disabilities often run in the family.  Problems during pregnancy and birth  Accidents after birth  Malnutrition  Toxic exposure CLINICAL DESCRIPTION: People with a learning disability have trouble in performing specific types of skills or completing tasks if left to figure things out by themselves or if taught in conventional ways. 2 Types

1- By stage of information processing Learning disabilities fall into broad categories based on the four stages of information processing used in learning: input, integration, storage, and output 2- By function impaired :Reading disability (dyslexia), Mathematics disability (dyscalculia) and writing disability (dysgraphia). CLINICAL MANEGMENT OF VARIOUS STAGES OF DIESEASED CONDITION: Difficulty in understanding the sentence told to them Difficulty in expressing their knowledge

Difficulty in performing certain tasks which is done in their day today life Poor concentration CHOORANAM MAATHIRAI LEGIUM KARPAM: NEI: PARPAM 141

CHENTHURAM Drugs which mainly acting on Kabha and Pitha thatukkal to improve the learning qualities especially nervine tonics should be advised EXTERNAL  (Oil Bath) DIET ADVICE:  Green leafy vegetables  Spinach  Sprouts  Tender vegetables AVOID  Junk foods  Chat items, snacks  Tinned foods  Non vegetarian diet DO’s  meditation  sun salutation  wakeup early in the morning  recollect the phrases  write and memorize in easy ways  oil bath  good sleep DON‘TS  stress  alcohol, smoking

 daytime sleep  watching television for longer duration ONE DAY DIET: Early morning: Chukkumalli coffee-150 ml. Breakfast: Sprouted Bengal gram boiled-150gm Idli -3 Pudhina,karuveppillai chutney -20gm Athi pazham -5 Lunch: Karisalai/Ponnamkanni poriyal – 50 gm Fresh vegetable salad -100 gm Pomegranate juice - 150 ml Naval pazham -5 142

Evening: Black dates -5 Aval with milk -100gm Dinner: Chappathi -2 Chenna -100 gm Dry grapes -15 gm COSTING OF TREATMENT (for 1st day) STAGE-I Purgation- Rs.400 From 2nd Day onwards Oleation- Rs.500 Internal medicine- Rs.60 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL - Rs. 1090 STAGE II FOR 1st Day Purgation- Rs.400 From 2nd Day onwards Oleation- Rs.500 Internal medicine- Rs.60 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL - Rs. 1090 STAGE III

For 1st Day Purgation- Rs.400 From 2nd Day onwards Oleation- Rs.500 Internal medicine- Rs.60 Karpam- Rs.10 External medicine- Rs.10 Yogam- Rs.500 Nalanguma- Rs.10 TOTAL - Rs. 1090 143

INVESTIGATION:  Routine blood investigation- Rs.90  Liver function test- Rs.220  Renal function test- Rs.400 144

NEURO MUSCULAR DISEASES VATHAKARNAGAM (ATAXIA) Siddha medicine is an Indian traditional system of medicine .According to Siddha, physical health of human body is maintained by the three basic vital forces i.e Uyir thathukkal (Humours) namely, Vaatham, Pitham, Kabam which are activated by the function of Panchabootham (Five basic elements). When the above said humours are affected by the life style modifications and food habits they become kutrams and

causing for diseases. In Yugi Vaithya Chinthamani, Yugi munivar classified the Vatha diseases as 80 types. Under the vatha disease classification he dealt with different types of neuro muscular disorders. The signs and symptoms of some of the neuro muscular diseases explained by yugi may be correlated with that of modern science ,which are as follows. 1) VATHAKARNAGAM (ATAXIA) 2) PRANALAYA VATHAM (MUSCULAR DYSTROPHY) 3) AAGUNI VATHAM (MYOPATHY) 4) NADUKKU VAATHAM (PARKINSONS DISEASE)

5) MOTOR NEURONE DISEASE TREATMENT GUIDELINES FOR VATHAKARNAGAM (ATAXIA) INTRODUCTION: Vatham, Pitham and kapham are the three humors which are the constituents of the human body. In Yugi as per the text the signs and symptoms of Vathakarnagam may be correlated with the ataxia in modern science. The great sage Yugi describes as Vathakarnagam consisting of Vatham getting increased in whole of the body, Poor coordination, unsteady walk and a tendency to stumble, Difficulty with fine motor tasks. DEFINITION:

Vathakarnagam describes a lack of muscle control during voluntary movements, such as walking or picking up objects. LINICAL DESCRIPTION: Stage: 1 Pain and constipation, sweating, Loss of appetite,Poor coordination, unsteady walk and a tendency to stumble, Difficulty with fine motor tasks, such as eating, writing or buttoning a shirt. Stage: 2 Uncoordinated movements of trunk and limb, clumsiness, difficulty in walking, visual disturbance, headache. Stage: 3

Change in speech, Involuntary back-and-forth eye movements (nystagmus), Difficulty swallowing. 145

ETIOLOGY: High intake of sour taste. Excessive intake of bitter, pungent, and astringent taste foods, tubers, cold foods, sleep during day time. Ataxia may be caused by genetics, viral infections, autoimmune disorders, or injury. In some cases, the cause is unknown. PATHOGENESIS ON THE BASIS OF THE THIRITHODAMS: Due to lifestyle modification, occupation, food and other habits lead to development of this disease by causing derangement of three humors. In

vathakarnagam Vitiated Vatham associated with increased Azal and kabam leads to difficulty in walking, Change in speech, Involuntary back-and-forth eye movements, Difficulty swallowing. LINE OF TREATMENT Purgation Oleation Internal medicine External medicine External therapy Thokkanam Varmam Rejuvenating therapy Yogam Karpam APPROXIMATE COST FOR THE MANAGEMENT STAGE 1: Purgation: RS. 400(Initial day) Oleation Rs. 34(per day) as per requirement Internal medicine Rs .9.5(per day)

External medicine: Rs.7(per day) Rejuvenative medicine: Rs.5(per day) STAGE: 2 Purgation: Rs.400(Initial day) Oleation Rs.34(per day) as per requirement Internal medicine Rs.6(per day) External medicine: Rs.12.5(per day) External therapy Rs.1100(per session) as per requirement Rejuvenative medicine: Rs.2(per day) 146

Yogam Rs.500(per session) as per requirement STAGE 3: Oleation Rs.34(per day) as per requirement Internal medicine Rs.18(per day) External medicine: R.26(per day) External therapy Rs.300(per session) as per requirement Rejuvenative medicine: Rs .12.5(per day) Yogam Rs.500(per session) as per requirement STAGE: 4 REFERRAL CRITERIA: Extreme rigidity and restricted movements Chronic illness since several years NOTE: Choice of medicines, doses and duration may be altered to the condition of the

patients and severity of the disease. INVESTIGATION: CBC- Rs.15/- Blood Sugar- Rs.50/- Total Cholestrol-Rs.25/- TGL-Rs.50/- RFT- Rs.400/- LFT- Rs.220/- MRI- Rs.3000/- Myoglobin-urine &blood-Rs.60 Electromyography (EMG) –Rs.750(CGHS) Nerve Conduction Test - Rs.750(CGHS) Lumbar Puncture – Rs.400 Muscle Biopsy- Rs.450(CGHS) DIETERY REGIMEN Morning (6 a.m) 100 ml of Chukku malli coffee (without milk)/ green tea Breakfast (9 a.m) 60 gms of Idlis – 5 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai

chatney/300 gms of puttu/300 gms of Idiyappam. Prenoon(11 a.m) 147

200 ml of Navathaniya kanji Lunch (1 p.m) Boiled rice - 400 gms Sambar (without kizhangugal) - 150 ml Poriyal (Avarai pinju. Katthari pinju, ladies finger, Vazhai thandu)- 150 gms Rasam( Pepper & Garlic) - 100 ml Butter milk (Kariveppilai thallippu)- 100 ml Veg salad -100gms Evening (4 p.m) 50 gms Mudakkatran Adai -1 No /veg.soup - 200 ml Dinner (8 p.m) 60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/ 300 gms of puttu/ 300 gms of Idiyappam/ 60 gms of ragi dosai -5 Nos.

DO’S: PATHIYAM (DIET): TENDER VEGETABLES: KaththariPinchu(Solanum melongena) AvaraiPinchu(Solichos lablab) Aththippinchu(Ficus racemosa) GREENS: MudakkarruthanKeerai(Cardiospermumhalicacabum) PonnakaanikKeerai(Alternantherasessilis) ThoothuvealaikKeerai(Solanumtrilobatum) MookkirattaiKeerai(Boerhaaviadiffusa) PULSES: ThuvaraiParuppu DAIRY PRODUCTS: Cow buttermilk NON VEGITARIAYAN DIET: Vellattu Kari,Kaadai. DON’T’S: AVOID (AAGAP PORUTGAL) Surai(Lagenariasiceraria Poosunai(Luffaacutangula)

Peerkku(Luffaacutangula), Kaaramani(Vignaunguiculata Ulunthu(Vignamungo) Sour, astringent tastes and Sea foods except small prawn 148

OTHER ADVICE: Bed rest Regular exercise and yogasanas Avoid chilled atmosphere, sleep on cold floor, and live on high altitude. ADVICE ON COMPLETION OF TREATMENT AND PREVENTION: Regular exercises Karpa medicines Pranayamam 149

NEURO MUSCULAR DIESEASES PRANALAYA VATHAM (MUSCULAR DYSTROPHY) INTRODUCTION: According to Siddha theory the root cause of any disease is alteration in the equilibrium of three humors ie. Vatham, Pitham and Kabam. In Yugi Vaithya Chinthamani, Yugi munivar classified the Vatha diseases as 80 types and ―PRANALAYA VATHAM‖ is one among them. In Yugi as per the text the signs and symptoms of Pranalaya vatham may be correlated with the muscular dystrophy in modern science. DEFINITION:

A group of progressive hereditary degenerative disease of skeletal muscle; Muscle disease that weakens the musculoskeletal system and hamper locomotion. Defect in muscle proteins death of muscle cells &tissues. ETIOLOGY: Excessive intake of bitter, pungent, and astringent taste foods, cold foods, sleep during day time, excessive weight, excess sexual intercourse are the causes for vatha diseases. Changes in structural elements of the muscle cell-mainly in its membrane-

altered messenger RNA generally inherited. Mutation of dystropin gene/nutritional defects (no genetic history) CLINICAL DESCRIPTION: STAGE: 1 Loss of appetite, flatulence, indigestion, Headache, Sleeplessness, Body ache, malaise, paleness of body, Difficulty in walking. STAGE: 2 Abdominal distension, constipation, Drooling, Poor balance, Drooping eyelids, Calf deformation, Difficulty in walking. STAGE: 3. Difficulty in speaking swallowing, nausea, drooling, and Muscle wasting,

limited range of movements, frequent falls, inability to walk. PATHOGENESIS ON THE BASIS OF THE THIRITHODAMS: Changes in lifestyle, occupation, food and other habits lead to development of this Disease by causing derangement of three humors. In pranayala vatham Vitiated Azal(protein loss) associated with increased kabam and vatham(muscle wasting) leads to difficulty in walking,drooling,frequent falls. LINE OF TREATMENT Purgation Oleation Internal medicine External medicine 150

External therapy Thokkanam Varmam Rejuvenative therapy Yogam Karpam APPROXIMATE COST FOR THE MANAGEMENT STAGE 1: Purgation: Rs.400(Initial day) Oleation Rs.34(per day) as per requirement Internal medicine Rs .12(per day) External medicine: Rs.7(per day) External therapy Rs.800(per session) as per requirement Rejuvenating medicine: Rs.5(per day) STAGE: 2 Purgation: Rs.400(Initial day) Oleation Rs.34(per day) as per requirement Internal medicine Rs.6.5(per day) External medicine: Rs.10.5(per day)

External theraphy Rs.300(per session) as per requirement Rejuvenating medicine: Rs.12.50(per day) YAGAM: Rs.500(per session) as per requirement STAGE 3: Oleation Rs.34(per day) ) as per requirement Internal medicine Rs.16(per day) External medicine: Rs.25.50(per day) External theraphy Rs.300(per session) as per requirement Rejuvenative medicine: Rs.5.5(per day) YAGAM: Rs.500(per session) as per requirement STAGE: 4 REFERRAL CRITERIA: Extreme rigidity and restricted movements

Chronic illness since several years NOTE: Choice of medicines, doses and duration may be altered to the condition of the patients and severity of the disease. 151

INVESTIGATION: CBC- Rs.15/- Blood Sugar- Rs.50/- TOTAL CHOLESTROL-Rs.25/- TGL-Rs.50/- RFT- Rs.400/- LFT- Rs.220/- THYROID FUNCTION TEST- Rs.400/- MRI- Rs.3000/- CT- Rs.750/- CHEST X-RAY –Rs.30/- ECG-Rs.50/- ECHO-Rs.1000/- MUSCLE BIOPSY-Rs.450/- CPK –RS.25/- NERVE-EMG-RS.750(CGHS) DIETERY REGIMEN Morning (6 a.m) 100 ml of Chukku malli coffee (without milk)/ green tea Break fast(9 a.m) 60 gms of Idlis – 5 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/300 gms of puttu/300 gms of Idiyappam.

Prenoon(11 a.m) 200 ml of Navathaniya kanji Lunch(1 p.m) Boiled rice - 400 gms Sambar (without kizhangugal) - 150 ml Poriyal (Avarai pinju. Katthari pinju, ladies finger, Vazhai thandu)- 150 gms Rasam( Pepper & Garlic) - 100 ml Butter milk (Kariveppilai thallippu)- 100 ml Veg salad -100gms Evening (4 p.m) 50 gms Mudakkatran Adai -1 No /veg.soup - 200 ml Dinner(8 p.m) 60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai

chatney/ 300 gms of puttu/ 300 gms of Idiyappam/ 60 gms of ragi dosai -5 Nos. DO’S: PATHIYAM (DIET): TENDER VEGETABLES: 152

ErumuraiVatiththaKanghi(double boiled rice) AvaraiPinchu(Dolichos lablab) Aththippinchu(Ficus racemosa) GREENS: MudakkarranKeerai(Cardiospermumhalicacabum) PonnakaanikKeerai(Alternantherasessilis) MookkirattaiKeerai(Boerhaaviadiffusa) PULSES: ThuvaraiParuppu DAIRY PRODUCTS: Cow buttermilk NON VEGITARIAYAN DIET: Vellattu Kari DON’T’S AVOID(AAGAP PORUTGAL) Surai(Lagenariasiceraria Poosunai(Luffaacutangula) Peerkku(Luffaacutangula), Kaaramani(Vignaunguiculata Kollu(Macrotylomauniflorum) Kadugu(Brassiajuncea)

Sour, astringent tastes Sea foods except small prawn OTHER ADVICE: Bed rest Excessive involve of joints should be avoided Regular exercise and yogasanas Avoid chilled atmosphere, sleep on cold floor, and live on high altitude ADVICE ON COMPLETION OF TREATMENT AND PREVENTION: Regular exercises Karpa medicines Pranayamam 153

AAGUNI VATHAM (MYOPATHY) SYNONYMS: Thasaivatham INTRODUCTION: In Yugi Vaithya Chinthamani, Yugi munivar classified the Vatha diseases as 80 types and ―AAGUNI VATHAM ‖ is one among them. In Yugi as per the text the signs and symptoms of Aaguni Vatham may be correlated with the muscular dystrophy in modern science. Aaguni Vatham is a general term referring to any disease of muscles. Myopathies can be acquired or inherited, and can occur at birth or later in life. DEFINITION:

Aaguni Vatham is a diseases of skeletal muscle which are not caused by nerve DisordeRs. These diseases cause the skeletal or voluntary muscles to become weak. ETIOLOGY: Excessive intake of bitter, pungent, and astringent taste foods, cold foods, sleep during day time, excessive weight, excess sexual intercouRse are the causes for vatha diseases. Congenital or inherited Idiopathic Metabolic Inflammatory Endocrine Drug-induced or toxic CLINICAL DESCRIPTION: STAGE: 1

Weakness in the muscles of the shouldeRs, upper arms, thighs, and pelvis (proximal muscles), Walking and climbing staiRs may be difficult, Fatigued doing very light physical activity, Difficulty in getting out of the bathtub, Shaving or combing the hair STAGE 2 Weakness in the distal muscles of the hands and feet may be involved, Muscle wasting, Weak grasp, Handwriting problems, Walking difficulties (e.g., flapping gait). STAGE: 3 Atrophy and hyporeflexia, Normal level of consciousness, Gottron papules in

dermatomyositis, elbows and knees. PATHOGENESIS ON THE BASIS OF THE THIRITHODAMS: Changes in lifestyle, occupation, food and other habits lead to development of this disease by causing derangement of three humoRs. In Aagunivatham Vitiated 154

vatham associated with increased pitham and kabam leads to, malaise, fatigue, difficulty in walking, Symmetric proximal muscle weakness. LINE OF TREATMENT Purgation Oleation Internal medicine External medicine External therapy Thokkanam Varmam Rejuvenative medicine Yogam Karpam APPROXIMATE COST FOR THE MANAGEMENT STAGE 1: Purgation: Rs.400(Initial day) Oleation Rs.34(per day) as per requirement Internal medicine Rs .10.50(per day) External medicine: Rs.8.50(per day)

External therapy: Rs.1000(per session) as per requirement Rejuvenative medicine: Rs.12(per day) STAGE: 2 Purgation: Rs.400(Initial day) Oleation Rs.34(per day) as per requirement Internal medicine Rs.12(per day) External medicine: Rs.11(per day) External therapy: Rs.1300(per session) as per requirement Rejuvenative medicine: Rs.2 (per day) YAGAM: Rs.500(per session) as per requirement STAGE 3: Oleation Rs.34(per day) as per requirement Internal medicine Rs.19(per day) External medicine: Rs.2.50(per day)

External therapy: Rs.300(per session) as per requirement Rejuvenative medicine: Rs .12.50(per day) YAGAM: Rs.500 (per session) as per requirement 155

STAGE: 4 REFERRAL CRITERIA: Extreme rigidity and restricted movements Chronic illness since several yeaRs NOTE: Choice of medicines, doses and duration may be altered to the condition of the patients and severity of the disease. INVESTIGATION: Blood Sugar- Rs.50/- Total Cholestrol-Rs.25/- TGL-Rs.50/- RFT- Rs.400/- LFT- Rs.220/- Thyroid Function Test- Rs.400/- MRI- Rs.3000/- CT- Rs.750/- CREATINE KINASE (CK) LEVELS WITH ISOENZYMES.-Rs.100/- CALCIUM,-Rs25/- MAGNESIUM-RS.25/- DIETERY REGIMEN Morning (6 a.m)

100 ml of Chukku malli coffee (without milk)/ green tea Break fast(9 a.m) 60 gms of Idlis – 5 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/300 gms of puttu/300 gms of Idiyappam. Prenoon(11 a.m) 200 ml of Navathaniya kanji Lunch(1 p.m) Boiled rice - 400 gms Sambar (without kizhangugal) - 150 ml Poriyal (Avarai pinju. Katthari pinju, ladies finger, Vazhai thandu)- 150 gms Rasam( Pepper & Garlic) - 100 ml Butter milk (Kariveppilai thallippu)- 100 ml Veg salad -100gms 156

Evening (4 p.m) 50 gms Mudakkatran Adai -1 No /veg.soup - 200 ml Dinner(8 p.m) 60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/ 300 gms of puttu/ 300 gms of Idiyappam/ 60 gms of ragi dosai -5 Nos. DO’S: PATHIYAM (DIET) TENDER VEGETABLES: KaththariPinchu(Solanum melongena) AvaraiPinchu(Dolichos lablab) Aththippinchu(Ficus racemosa) GREENS: MudakkarruthanKeerai(Cardiospermumhalicacabum) PonnakaanikKeerai(Alternantherasessilis) ThoothuvealaikKeerai(Solanumtrilobatum)

MookkirattaiKeerai(Boerhaaviadiffusa) VealaikKeerai(Cleome viscosa) PULSES: ThuvaraiParuppu DAIRY PRODUCTS: Cow buttermilk NON VEGITARIAYAN DIET: Vellattu Kari,Kaadai,Kouthaari,.Udumpu DON’T’S AVOID (AAGAP PORUTGAL) Surai(Lagenariasiceraria Poosunai(Luffaacutangula) Vellari(Cucumissativus) Pudalai(Trichosanthescucumerina) Peerkku(Luffaacutangula), Sour, astringent tastes. OTHER ADVICE: Bed rest 157

Excessive involve of joints should be avoided. Regular exercise and yogasanas. Avoid chilled atmosphere, sleep on cold floor and live on high altitude. ADVICE ON COMPLETION OF TREATMENT AND PREVENTION: Regular exercises Kalpa medicines Pranayama 158

NADUKKU VAATHAM (PARKINSONS DISEASE) INTRODUCTION: In Yugi Vaithya Chinthamani, Yugi munivar classified the Vatha diseases as 80 types and ―Nadukku Vaatham ‖ is one among them. In Yugi as per the text the signs and symptoms of Nadukku Vaatham may be correlated with the ataxia in modern science. Nadukku Vaatham is a progressive disorder of the nervous system that affects the movement. It develops gradually, sometimes starting with a barely noticeable tremor in just one hand. DEFINITION:

Nadukku Vaatham is a degenerative disorder of the central nervous system. In Nadukku Vaatham, certain nerve cells (neurons) in the brain gradually break down or die. The dopamine levels decrease, it causes abnormal brain activity. CLINICAL DESCRIPTION: STAGE – I Loss of appetite, pain, Tremors in one limb Changes in posture, locomotion, and facial expression. Small Handwriting Trouble sleeping Constipation STAGE: 2 Tremors on both sides of the body. Slowing of body movements

Early impairment of equilibrium when walking or standing Urinary incontinence & Constipation. STAGE: 3 Rigidity Bradykinesia Cachectic stage (general reduction in vitality and strength of body and mind). Inability to stand or walk Swallowing difficulties (dysphagia) Excessive production of saliva (drooling) Depression Anxiety Insomnia Mild cognitive impairment. 159

ETIOLOGY: High intake of sour taste, Excessive intake of bitter, pungent, and astringent taste foods, cold foods and sleep during day time. The cause of Nadukku Vaatham is unknown, but several factors appear to play a role, including, Environmental triggers. Exposure to certain toxins or environmental factors may increase the risk of later Nadukku Vaatham, but the risk is relatively small. PATHOGENESIS ON THE BASIS OF THE THIRITHODAMS:

Changes in lifestyle, occupation, food and other habits lead to development of this disease by causing derangement of three humours. In Nadukku vaathm Vitiated vaatham associated with increased kabam and Azhal leads to Tremor, slowness of movement, postural instability, Difficulty with walking and balance. TREATMENT: LINE OF TREATMENT Purgation Oleation Internal medicine External medicine External therapy Thokkanam Varamam therapy Rejuvenative medicine Yogam Karpam APPROXIMATE COST FOR THE MANAGEMENT

STAGE – I Purgation - Rs -400(Initial day) Oleation: Rs-34(per day) as per requirement Internal medicine: Rs-18.5(per day) External medicine: Rs-7(per day) External therapy: Thokkanam- Rs-800(per session) as per requirement Rejuvenative medicine: Yogam- Rs-500(per session) as per requirement Karpam- Rs-2(per day) STAGE – 2 Purgation Rs -400(Initial day) Oleation Rs-34(per day) as per requirement Internal medicine- Rs-32.5(per day) 160

External medicine- Rs-11(per day) Varmam: Rs-300(per session) as per requirement Thokkanam: Rs-800(per session) as per requirement Rejuvenative medicine- Rs-5(per day) Yogam: Rs.500 (per session) as per requirement STAGE – 3 Oleation Rs--34(per day) as per requirement Internal medicine- Rs-18.5(per day) External medicine- Rs-13(per day) Varmam- Rs-300 (per session) as per requirement Rejuvenative medicine- Rs-5.5(per day) STAGE: 4 REFERRAL CRITERIA: Extreme rigidity and restricted movements

Chronic illness since several years NOTE: Choice of medicines, doses and duration may be altered to the condition of the patients and severity of the disease. INVESTIGATION: CBC- Rs.15/- Blood Sugar- Rs.50/- Total Cholestrol-Rs.25/- TGL-Rs.50/- RFT- Rs.400/- LFT- Rs.220/- THYROID FUNCTION TEST- Rs.400/- MRI- Rs.3000/- CT- Rs.750/- PET SCAN- Rs.15000 DIETERY REGIMEN Morning (6 a.m) 100 ml of Chukku malli coffee (without milk)/ green tea Break fast(9 a.m)

60 gms of Idlis – 5 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/300 gms of puttu/300 gms of Idiyappam. Prenoon(11 a.m) 161

200 ml of Navathaniya kanji Lunch(1 p.m) Boiled rice - 400 gms Sambar (without kizhangugal) - 150 ml Poriyal (Avarai pinju. Katthari pinju, ladies finger, Vazhai thandu)- 150 gms Rasam( Pepper & Garlic) - 100 ml Butter milk (Kariveppilai thallippu)- 100 ml Veg salad -100gms Evening (4 p.m) 50 gms Mudakkatran Adai -1 No /veg.soup - 200 ml Dinner(8 p.m) 60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/ 300 gms of puttu/ 300 gms of Idiyappam/ 60 gms of ragi dosai -5 Nos. DO’S:

PATHIYAM (DIET): TENDER VEGETABLES: KaththariPinchu(solanum melongena) AvaraiPinchu(dolichos lablab) Aththippinchu(ficusracemosa) GREENS: MudakkarranKeerai(Cardiospermumhalicacabum) PonnakaanikKeerai(Alternantherasessilis), ThoothuvealaikKeerai(Solanumtrilobatum), PULSES: ThuvaraiParuppu DAIRY PRODUCTS: Cow buttermilk NON VEGITARIAYAN DIET: Vellattu Kari. DON’T’S: AVOID(AAGAP PORUTGAL) Surai(Lagenariasiceraria) Poosunai(Luffaacutangula), Vellari(Cucumissativus),

Pudalai(Trichosanthescucumerina),Peerkku(Luffaacutangula), Ulunthu(Vignamungo), Sour, astringent tastes 162

Sea foods except small prawn OTHER ADVICE: Bed rest Excessive involve of joints should be avoided Regular exercise and yogasanas Avoid chilled atmosphere,sleep on cold floor, live on high altitude ADVICE ON COMPLETION OF TREATMENT AND PREVENTION: Regular exercises Karpa medicines Pranayamam 163

MOTOR NEURONE DISEASE SYNONYMS: Amyotrophic lateral sclerosis (ALS) Motor neuron disease (MND) Lou Gehrig's disease INTRODUCTION: Siddha system of medicine is an ancient, unique and codified indigenous system of medicine. This system was formulated and established by Siddhars who are the spiritual scientists of the ancient Tamil culture about more than several thousand years back. CASE DEFINITION: ALS is a neuro degenerative disease with various causes. It is characterized by

rapidly progressive weakness due to muscle atrophy and muscle spasticity, difficulty in speaking (dysarthria), swallowing (dysphagia), and breathing (dyspnea). ALS is the most common of the five motor neuron diseases. ETIOLOGY: The causes of MND are unknown, but worldwide research includes studies on:  Viruses, toxins, genetic factors and immune factors  Nerve growth factors and chemicals that control nerve cells and allow them to communicate with each other  Growth, repair and ageing of motor neurons.

CLINICAL DESCRIPTION: STAGE: 1 Difficulties picking up or holding objects Weakness at the shoulder, making lifting the arm above the head Difficult tripping up over a foot because of weakness at the ankle or hip These symptoms are usually painless and may be accompanied by widespread twitching of the muscles (fasciculation) or muscle cramps STAGE: 2 Muscle weakness Muscle spasms Pain Difficulties speaking and swallowing Saliva problems Excessive yawning Changes to mental abilities STAGE: 3

Significant shortness of breath PATHOGENESIS ON THE BASIS OF THE THIRITHODAMS: Changes in lifestyle, occupation, food and other habits lead to development of this disease by causing derangement of three humors. In MND Vitiated vatham associated with increased pitham and kabam leads to, malaise, fatigue, difficulty in walking, muscle weakness, stiffness of affected muscle. LINE OF TREATMENT: Purgation Oleation Internal medicine External medicine External therapy Varamam Rejuvenating therapy Yogam Karpam

APPROXIMATE COST FOR THE MANAGEMENT (FOR ONE DAY) STAGE 1: Purgation: Rs. 400(Initial day) Oleation Rs.34 (per day) as per requirement Internal medicine Rs.13.5(per day) External medicine: Rs.7.5(per day) Rejuvenative medicine: Rs.5(per day) Yogam Rs.500(per session) as per requirement STAGE: 2 Purgation: Rs.400(Initial day) Oleation Rs.34(per day) as per requirement Internal medicine Rs.11.5(per day) External medicine: Rs.8.5(per day) External therapy Rs.300(per session) as per requirement

Rejuvenative medicine: R.6(per day) STAGE 3: Internal medicine Rs.42.5(per day) External medicine: Rs.26(per day) External therapy Rs.300(per session) as per requirement Rejuvenative medicine: Rs .12.5(per day) 165

STAGE: 4 REFERRAL CRITERIA: Extreme rigidity and restricted movements Chronic illness since several years. NOTE: Choice of medicines, doses and duration may be altered to the condition of the patients and severity of the disease. INVESTIGATION: CBC- Rs15/- Blood Sugar- Rs.50/- Total Cholestrol-Rs .25/- TGL-Rs.50/- RFT- Rs.400/- LFT- Rs.220/- MRI- Rs.3000/- Electromyography (EMG) –Rs.750(CGHS) Nerve Conduction Test –Rs.750(CGHS) Lumbar Puncture –Rs.400 Muscle Biopsy-Rs.450 (CGHS) DIETERY REGIMEN

Morning (6 a.m) 100 ml of Chukku malli coffee (without milk)/ green tea Break fast(9 a.m) 60 gms of Idlis – 5 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/300 gms of puttu/300 gms of Idiyappam. Prenoon(11 a.m) 200 ml of Navathaniya kanji Lunch(1 p.m) Boiled rice - 400 gms Sambar (without kizhangugal) - 150 ml Poriyal (Avarai pinju. Katthari pinju, ladies finger, Vazhai thandu)- 150 gms Rasam( Pepper & Garlic) - 100 ml Butter milk (Kariveppilai thallippu)- 100 ml Veg salad -100gms

Evening (4 p.m) 50 gms Mudakkatran Adai -1 No /veg.soup - 200 ml Dinner(8 p.m) 166

60 gms of Idlis – 3 Nos with 50 gms of Kothumalli, Karuveppillai,Pirandai chatney/ 300 gms of puttu/ 300 gms of Idiyappam/ 60 gms of ragi dosai -5 Nos. DO’S: PATHIYAM (DIET): TENDER VEGETABLES: KaththariPinchu(solanum melongena) AvaraiPinchu(dolichos lablab) Aththippinchu(ficusracemosa) GREENS: MudakkarranKeerai(Cardiospermumhalicacabum) PonnakaanikKeerai(Alternantherasessilis), ThoothuvealaikKeerai(Solanumtrilobatum), PULSES: ThuvaraiParuppu DAIRY PRODUCTS: Cow buttermilk NON VEGITARIAYAN DIET:

Vellattu Kari DON’T’S: AVOID(AAGAP PORUTGAL) Surai(Lagenariasiceraria) Poosunai(Luffaacutangula), Vellari(Cucumissativus), Pudalai(Trichosanthescucumerina),Peerkku(Luffaacutangula), Kaaramani(Vignaunguiculata), Ulunthu(Vignamungo), Kollu(Macrotylomauniflorum), Kadugu(Brassiajuncea) Sour, astringent tastes Sea foods except small prawn OTHER ADVICE: Bed rest Excessive involve of joints should be avoided Regular exercise and yogasanas Avoid chilled atmosphere,sleep on cold floor, live on high altitude 167

ADVICE ON COMPLETION OF TREATMENT AND PREVENTION: Regular exercises Karpa medicines Pranayamam 168

KALLADAIPPU (RENAL CALCULI) INTRODUCTION Urinary stones have plagued human‘s science the earlier records of civilization. A kidney stone is a hard mass developed from crystals that separate from urine and build up on the inner surfaces of the kidney. Urinary stone affects 10-12% of the population in industrialized countries. The average lifetime risk of stone formation has been reported in the range of 5-10%. A Predominance of men over

women can be observed with an incidence peak between the fourth and fifth decade of life. Recurrent stone formation is a common part of the medical care of patients with stone disease. Calcium containing stones, especially calcium oxalate dihydrate and basic calcium phosphate are the most commonly occurring ones to an extent of 75- 90% followed by magnesium ammonium phosphate (struuite) to an extent of 10- 15%, uric acid 3-10% and cystine 0.5-1% (4-6).

Renal calculi are formed by deposits of poly crystallin aggregates composed of varied amounts of crystalloid and organic matrix. They can vary in size and may be found anywhere in urinary tract from the kidney to the bladder. Urinary stones have affected for centuries . The clinical symptoms for kalladaipu may be correlated with that of renal calculi in modern science. It induces the symptoms like oliguria, urethral pain mimics

a pain caused by an insertion of hot iron in the urethra, sweating all over the body. Anuria, agonizing pain, blood stained calculus stagnated in urethra. Definition: According to the text of siddh maruthuvam (pothu) , There is a gradual or suddenly obstruction to the flow of urine, pain with burning sensation in the urethral tract, low back pain, renal angle pain and sand like crystal deposit in urine. ETIOLOGY: As per yugi vaithiya Chinthamani, 1. Intake of turbid water

2. Food contaminated with stones, bones, hair and sand. 3. Intake of deteriorated food stuff and starch substances. 4. Eating flatulence producing food while indigestion 5. Mukkunam deranged by internal factors such as sexual perversion, anger, robbery. CLINICAL DESCRIPTION: According to the text of siddha maruthuvam(pothu), 1. Gradual or sudden obstruction to flow of urine 2. Unbearable pain (agonizing pain) in the penis 3. Excruciating pain and swelling is experienced at the tip of penis if the

calculus attempt to expel 4. Colicky pain radiating from loin to groin, lower abdomen, urethra, genitalia. 5. Burning and scanty micturition. 169

SIDDHA TYPES: 1. Vaatha kalladaippu 2. Pitha kalladaippu 3. Slethuma kalladaippu 4. Thontha kalladaippu PATHOGENISIS ON THE BASIS OF THIRITHODAM: The imbalance in one‘s diet and fluid intake increases the azhal kutram. This raised azhal kutram dries up the body fluid and urine resulting in increased concentration of salts. This further affects the keezh nokkukaal When the keezh nokkukaal is affected the urine will be obstructed with in urinary tract. This favors

deposition of urinary salts to develop into calculi anywhere in the kidney orurinary tract. CLINICAL MANAGEMENT FOR DIFFERENT STAGES OF DISEASE CONDITION: STAGE-1 DIAGNOSIS 1. Loin to groin pain 2. Dysuria 3. Burning micturition 4. Oliguria 4. Stone size - microlith to 5mm without obstruction or with mild obstruction. Line of treatment for STAGE-1 1. Purgation 2. Oleation 3. Internal medicines 4. External medicine STAGE -2 DIAGNOSIS 1. Loin to groin pain 2. Dysuria 3. Burning micturition 4. Oliguria

5. Nausea &Vomiting 7. Stone size - Stone size - ≥5mm to ≤10 mm without obstruction or with mild obstruction Line of treatment for STAGE-1I 1. Purgation 170

2. Oleation 3. Internal Medicines 4. External Medicine STAGE-3 DIAGNOSIS 1. Loin to groin pain 2. Dysuria 3. Burning micturition 4. Oliguria 5. Nausea &Vomiting 5. Fever 6. Unbearable pain (agonizing pain) in the penis 7. Stone size - ≥10 mm to ≤ 20 mm without obstruction or with mild obstruction Line of treatment for STAGE-1II 1. Purgation 2. Oleation 3. Internal medicines 4. External medicine STAGE-4 Referral - Conditions 1. Acute renal colic 2. Severe nausea and vomiting 3. High grade fever 4. Chill

5. Oliguria /Anuria 6. Marked obstruction required immediate surgery 7. Stone size ≥ 10mm causing Marked hydrouretero nephrosis DIETARY ADVISES DO’S: 1. Water intake 3-5 lit/day 2. Barely Kanji - 30 gm barley/day 3. Tender Coconut - 1/day 4. Plantain stems juice- 50ml once in 3 days Vegetables: 1. Radish 2. Lab Lab 3. Cucumber 4. Carrot 5. Beetroot Fruits: 1. Pineapple 2. Banana 3. Papaya 4. Lemon 171

5. Pomegranate DIET RESTRICTIONS DONT’S: Vegetables 1. Cauliflower 2. Tomato 3. Spinach 4. Mushrooms 5. Cabbage 6. Dark Greens Fruits 1. Grapes 2. Cherry 3. Straw Berry 4. Black berry Other food 1. Ice-Cream 2. Chocolate 3. Tinned Cool drinks 4. Too much of salt &sugar 5. Non-vegetarian foods 6. Milk Products 7. Fast Food 8. Processed foods DIET - CHART Break fast: Horse gram decoction 30 ml Steamed foods like idly, Idiyappam 11.oo am- Tender coconut-1 Lunch: Boiled rice, Raddish saambar

Plantain stem poriyal Pomegranate -1 5.00PM- Plantain stem soup Dinner: Wheat germ Chappathi Peanut kuruma Parsley porridge -1 cup Banana-1 3-4 liters of water intake (including fruit juice) /day HABITS DONT’S: 172

1. Alcohol 2. Coffee/tea 3. Smoking 4. Betel chewing 4. Supplementary Calcium 5. Control of Voiding of urine 6. Inadequate sleep (Must sleep8 hours) Approximate Cost for procedures, medicines etc during treatment and post treatment maintenance for prolonged medication if required. Stage 1 Cost for procedures during treatment: 2,370/- 1. Lab investigations (before treatment): Rs. 1,185/- Blood clinical chemistry: Rs. 820 Urine clinical chemistry: Rs. 185 X-Ray :Rs. 30 USG-KUB : Rs. 200 CT : Rs. 750

2. Lab investigations (after 45 days ): Rs. 1,185/- Blood clinical chemistry: Rs. 820 Urine clinical chemistry: Rs. 185 X-Ray : Rs. 30 USG-KUB : Rs. 200 CT : Rs. 750 Cost for Medicines during treatment: Rs.2, 360/- 1. Purgation: Rs.400/day (Initial) 2. Oleation: Rs.1, 200 3. Internal medicine: Rs.550 4. External medicine: Rs.210 Approximate Cost for Stage 1 during treatment: Rs.4, 730/- Stage 2 Cost for procedures during treatment: 2,370/- 1. Lab investigations (before treatment): Rs. 1,185/-

Blood clinical chemistry: Rs. 820 Urine clinical chemistry: Rs. 185 X-Ray : Rs. 30 USG-KUB : Rs. 200 CT : Rs. 750 2. Lab investigations (after 45 days ): Rs. 1,185/- Blood clinical chemistry: Rs. 820 173

Urine clinical chemistry: Rs. 185 X-Ray : Rs. 30 USG-KUB : Rs. 200 CT : Rs. 750 Cost for Medicines during treatment: Rs.2, 600/- 1. Purgation: Rs.400/day 2. Oleation: Rs.1, 200 3. Internal medicine: Rs.790 4. External medicine: Rs.210 Approximate Cost for Stage 2 during treatment: Rs.4, 970/- Stage 3 Cost for procedures during treatment: 2,370/- 1. Lab investigations (before treatment): Rs. 1,185/- Blood clinical chemistry : Rs. 820 Urine clinical chemistry : Rs. 185 X-Ray : Rs. 30 USG-KUB : Rs. 200

CT : Rs. 750 2. Lab investigations (after 45 days ): Rs. 1,185/- Blood clinical chemistry: Rs. 820 Urine clinical chemistry: Rs. 185 X-Ray : Rs. 30 USG-KUB : Rs. 200 CT : Rs. 750 Cost for Medicines during treatment: Rs.2, 700/- 1. Purgation: Rs.400/day 2. Oleation: Rs.1, 200 3. Internal medicine: Rs.890 4. External medicine: Rs.210 Approximate Cost for Stage 3 during treatment: Rs.5, 070/- Approximate Cost for post treatment maintenance (procedures, medicines etc) for prolonged medication if required.

Cost for post treatment maintenance: Depends upon the stages (stage 3 to stage 2 or stage 2 to stage 1) of the disease the above said cost for each stage can be taken for account. 174

KARUPPAI NAARTHASAI KATTI (UTERINE FIBROIDS) INTRODUCTION: Uterine fibroids are very common non-cancerous (benign) growths that develop in the muscular wall of the uterus. They can range in size from very tiny (a quarter of an inch) to larger than a cantaloupe. Occasionally, they can cause the uterus to grow to the size of a five-month pregnancy. In most cases, there is more than one fibroid in the uterus. While fibroids do not always cause symptoms, their size and

location can lead to problems for some women, including pain and heavy bleeding. DEFINITION: Uterine fibroids are noncancerous growths of the uterus that often appear during childbearing years. AETIOLOGY The causes are still unclear, but probable causes can be:  Genetic changes.  Hormonal changes.  Role of polypeptide growth factors CLINICAL DESCRIPTION The prevalence of Fibroid is highest in between 35 to 40 years. These are more

common in nulliparous. Most of the cases are Asymptomatic but the below are some of the symptoms that could arise.  Menstrual abnormality: Menorrhagia , Metrorrhagia.  Dysmenorrhoea  Dyspareunia  Infertility  Pressure symptoms  Recurrent pregnancy loss (miscarriage, preterm labour).  Lower abdominal or pelvic pain  Abdominal enlargement SIDDHA TYPES There are 3 types 1. VAYITRU PASAI-SAVIN KEELULLA NAARTHASAIKATTIGAL (Subperitoneal fibromyomas)

 It grows from outer part of cervix and can reach until the peritoneum surrounding the uterine cavity.  It is otherwise noted as Pasai-savin keelula naarthasai kattigal (subserous fibromyoma) 2. THASAI IDAPPATTA NAAR THASAI KATTIGAL (Interstitial fibromyomas)  It grows from the wall of the uterus and the growth is restricted inside the wall itself.  The growth does not penetrate internal part of uterus or external part of uterus. 175

3. PASAI CHAVIN KEEL PADALATHU NAARTHASAI KATTIGAL (Submucous fibromyomas)  It grows from the wall of uterus and penetrates into the uterus. It can make the wall of the uterus a very thin layer Fibroid is the commonest benign tumour of uterus. Tumour site is important than size. A small submucous fibroid may produce more symptoms than a big subserous fibroid. STAGE I (Intramural fibroid) Mostly Asymptomatic- 75% Sometimes lower abdominal pain. Functional pain scale 1&2 Menorrhagia

STAGE II (Subserous fibroid) Lower abdominal pain. Functional pain scale 3 Abdominal enlargement Pressure symptoms – It produce constipation, dysuria. Dyspareunia STAGE III (Submucous fibroid) Functional pain scale 4 Menorrhagia, Metrorrhagia Sub fertility STAGE IV (Referral) Functional pain scale 5 Persistent menorrhagia leads to anaemia Recurrent pregnancy loss (miscarriage, preterm labour) Loss of libido Severe intraperitoneal haemorrhage Line of treatment  Purgation (Initial)  Oleation (Initial)

 Internal medicine (For one day)  Karpa marundhu (For one day)  External medicine (For one day)  Yogam (Per session) 176

INVESTIGATION Routine blood investigation (CBC+Bl.Sugar+Total cholesterol) Rs 90 Liver Function test Rs 220 Renal Function test Rs 400 TVS Colour Doppler Rs 300 MRI- More accurate than USG Rs 3000 Laparoscopy (If uterine size is less than 12 weeks) Rs 500 HSG (To detect submucous fibroid in unexplained infertility) Rs 200 APPROXIMATE COST FOR THE MANAGEMENT STAGE I Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 11 Karpa marunthu Rs 12 External medicine Rs 5 Yogam Rs 500 STAGE II Purgation Rs 400

Oleation Rs 500 Internal medicine Rs 14 Karpa marunthu Rs 36 External medicine Rs 9 Yogam Rs 500 STAGE III Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 123 Karpa marunthu Rs 24 External medicine Rs 10 Yogam Rs 500 DIETERY REGIMEN 177

ADD  Hand powdered rice  Kuruvai rice  Manisambha rice  Kalludai sambha rice  manakathai rices  Valuzhuvai arisi pittu(Celastrus paniculatus) Tender vegetables:  Athi(Ficus racemosus),  Kathari(Solanum melangena),  Avarai(Dolicus lablab),  Pudalai(Trichosanthe cucumerina),  Vellari(Cucumis sativus),  Kovai(Coccina grandis),  Murungai(Moringa oleifera),  Vaazhai poo (Moringa oleifera),  Surai(Lagenaria sicerarie),  Sundai (Solanum torvum),  Mullangai (Rhaphanus sativus),

 Karunai kizhangu (Colocasia antiquarum)  Pirandai(Cissus quadrangularis) Greens:  Musumusukai(Mukia maderaspatna),  Ponnaangaani(Alternanthera sessils),  Mulaikeerai (Amaranthus blitum)  Sirukeerai(Amaranthus tricolor)  Pasalai keerai(Portulaca quadrifida)  Pannai keerai (Celocia argentea)  Parattai keerai (Ipomea reniformus) Puliyaari (Oxalis corniculata)  Paruppu keerIai (Portulaca oleracea)  Keerai thandu (Amaranthu gangeticus) Fruits:  Aruneli(Phyllanthus acidus)  Mthulai(Punica granatum)

 Sev vaazhaipazham,Vel vaazhaipazham, Rasthaali,Malai vaazhaipazham(Fruit of Musa paradisiacal)  Naaval (Syzygium cumini)  Thratchai (Vitis vinifera)  Athi (Ficus racemosa) Pulses:  Ulunthu (Vigna mungo ) Dairy products:  Cow‘s milk and buttermilk. Non-vegetarian diets  Velladu(Capra hircus)  Ayirai meen(Loach)  Kaadai  Kowthaari AVOID 178

 Hot sour and salted foods  Sarkarai vallli kizhangu(Ipomoea batatud)  Seppakizhangu(Colacasia esculanta)  Kothavarai(Cyamopsis teragonoloba)  Kollu (Macrotyloma uniflorum) Do’s  Have a stress free life, comfortable sleep.  Maintain a well-balanced diet and nutrition diet.  Advise to do pranayama,soorya vanakkam Don’ts  Avoid - oral contraception pills  Avoid - constipation  Avoid - indigestion  Avoid - Hot sour and salted foods 179

SOOTHAGAVALI ( PRIMARY DYSMENORRHOEA) INTRODUCTION: Soothagavali is a medical condition of pain during menstruation that interferes with daily activities. Although it's normal for most women to have mild abdominal cramps on the first day or two of their period, about 10% of women experience severe pain. DEFINITION: It is painful menstruation of sufficient magnitude so as to incapacitate day-to- day activities. SIDDHA TYPES  Aga Soothagavali (Irugi surungalvali)  Pura Soothagavali (Sanchidha Soothagavali)

AGA SOOTHAGA VALI (IRUGI SURUNGALVALI)-PRIMARY DYSMENORRHOEA AETIOLOGY There is no identifiable pelvic pathology. The mechanism of initiation of uterine pain in this is difficult to establish. But the following are too often related.  Psychosomatic factor  Abnormal anatomical and functional aspect of uterus  Role of Vasopressin and prostaglandin CLINICAL DESCRIPTION  The Pain begins few hours before or just with the onset of menstruation.

Severity of pain lasts for few hours and may extends to 24 hours but seldom persist beyond 48 hrs.  The pain is spasmodic and confined to lower abdomen, may radiate to back and medical aspect of thighs.  Systemic discomfort like Nausea, vomiting, fatigue, diarrhoea and headache may be associated. It may be accompanied by vasomotor changes causing pallor, cold sweats and occasional fainting. MUKKUTRA VERUPADU (PATHOGENESIS) The deranged Vatham has become the predominant cause for the occurrence

of Soothagavali  The deranged Vatham has deranged the Azhal and Iyam FUNCTIONAL PAIN SCALE Score Activity profile 0 No pain 1 Tolerable and pain does not prevent any activities 2 Tolerable and pain prevents some activities 3 Intolerable and pain does not prevent use of telephone, TV viewing and reading 180

4 Intolerable and pain prevents use of telephone, TV viewing and reading 5 Intolerable and pain prevents verbal communication Depending upon the functional pain scale it has been classified into four stages STAGE I Pain is tolerable and the pain doesn‘t prevents any activities or prevent some activities. But it is associated with nausea. STAGE II Intolerable pain that doesn‘t prevent TV watching, mobile phone using, and newspaper reading. .It is associated with nausea, vomiting, head ache and diarrhoea.

STAGE III Intolerable pain that prevents TV watching, mobile phone using, and newspaper reading. It is associated with nausea, vomiting, head ache and diarrhoea. It may be associated with pallor, cold sweats. STAGE IV (Referral) Intolerable pain that prevents verbal communication. Severe vomiting Pallor, cold sweats and occasional fainting. Line of treatment  Purgation (Initial)  Oleation (Initial)  Internal medicine (For one day)  Karpa marundhu (For one day)  External medicine (For one day)

 Yogam (Per session) Line of treatment common for all stages INVESTIGATION Routine blood investigation (CBC+Bl.Sugar+Total cholesterol) Rs 90 Liver Function test Rs 220 Renal Function test Rs 400 Ultrasonogram Rs 200 Hormonal assays Rs 1250 APPROXIMATE COST FOR THE MANAGEMENT OF AGA SOOTHAGAVALI STAGE I Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 7 Karpa marunthu Rs 12 Yogam Rs 500 STAGE II Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 11 181

Karpa marunthu Rs 12 External medicine Rs 13 Yogam Rs 500 STAGE III Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 54 Karpa marunthu Rs 24 External medicine Rs 13 Yogam Rs 500 PURA SOOTHAGAVALI (SANCHIDHA SOOTHAGAVALI) – SECONDARY DYSMENORRHOEA ETIOLOGY There are symptoms of associated pelvic pathology. The pain may be related to increasing tension in pelvic tissues due to premenstrual pelvic congestion or increased vascularity in the pelvic organs.  Pelvic endometriosis  Adenomyosis

 Uterine Fibroid  Chronic pelvic infection CLINICAL DESCRIPTION  The pain appears 10 days prior to the period and relieves with the start of bleeding.  The pain is dull situated in the back and in front without any radiation  The onset and duration of the pain depends on the pathology producing the pain MUKKUTRA VERUPADU (PATHOGENESIS) The deranged Vatham has become the predominant cause for the occurrence of Soothagavali The deranged Vatham has deranged the Azhal and Iyam

PURA SOOTHAGAVALI (Secondary dysmenorrhoea) Secondary dysmenorrhoea due to fibroid: Fibroid is the commonest benign tumour of uterus. Tumour site is important than size. A small submucous fibroid may produce more symptoms than a big subserous fibroid. STAGE I (Intramural fibroid) Mostly Asymptomatic- 75% Sometimes lower abdominal pain. Functional pain scale 1&2 Menorrhagia STAGE II (Subserous fibroid) Lower abdominal pain. Functional pain scale 3 Abdominal enlargement

Dyspareunia STAGE III (Submucous fibroid) Functional pain scale 4 Menorrhagia, Metrorrhagia Sub fertility STAGE IV (Referral) Functional pain scale 5 Persistent menorrhagia leads to anaemia Recurrent pregnancy loss (miscarriage, preterm labour) Loss of libido Severe intraperitoneal haemorrhage Line of treatment  Purgation (Initial)  Oleation (Initial)  Internal medicine (For one day)  Karpa marundhu (For one day)  External medicine (For one day)  Yogam (Per session)

Line of treatment common for all stages INVESTIGATION Routine blood investigation (CBC+Bl.Sugar+Total cholesterol) Rs 90 Liver Function test Rs 220 Renal Function test Rs 400 TVS Colour Doppler Rs 300 MRI- More accurate than USG Rs 3000 Laparoscopy (If uterine size is less than 12 weeks) Rs 500 HSG (To detect submucous fibroid in unexplained infertility) Rs 200 APPROXIMATE COST FOR THE MANAGEMENT STAGE I Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 11 Karpa marunthu Rs 12 External medicine Rs 5

Yogam Rs 500 STAGE II Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 14 Karpa marunthu Rs 36 External medicine Rs 9 Yogam Rs 500 STAGE III Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 123 Karpa marunthu Rs 24 External medicine Rs 10 183

Yogam Rs 500 ADENOMYOSIS Adenomyosis is a condition where there is ingrowth of the endometrium directly into the myometrium. STAGE I Mild increased menstrual bleeding than normal bleeding Functional pain scale 1&2 STAGE II Moderate increased menstrual bleeding than normal bleeding Functional pain scale 3 STAGE III Excessive menstrual bleeding Dyspareunia and frequency of urination Functional pain scale 4 STAGE IV (Referral) Uncontrollable menstrual bleeding Functional pain scale 5 Loss of libido

INVESTIGATION Routine blood investigation (CBC+Bl.Sugar+Total cholesterol) Rs 90 Liver Function test Rs 220 Renal Function test Rs 400 TVS Colour Doppler Rs 300 MRI Rs 3000 Line of treatment  Purgation (Initial)  Oleation (Initial)  Internal medicine (For one day)  Karpa marundhu (For one day)  External medicine (For one day)  Yogam (Per session) Line of treatment common for all stages APPROXIMATE COST FOR THE MANAGEMENT STAGE I Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 16

Karpa marunthu Rs 4 External medicine Rs 10 Yogam Rs 500 STAGE II Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 24 Karpa marunthu Rs 10 External medicine Rs 9 Yogam Rs 500 STAGE III Purgation Rs 400 184

Oleation Rs 500 Internal medicine Rs 35 Karpa marunthu Rs 12 External medicine Rs 10 Yogam Rs 500 PELVIC INFLAMMATORY DISEASE: It is a spectrum of infection and inflammation of the upper genital tract organs typically involving the endometrium, fallopian tubes, ovaries, pelvic peritoneum and surrounding structures. STAGE I Bilateral lower abdominal pain and pelvic pain which is dull in nature Fever, lassitude, head ache Abnormal vaginal discharge which becomes purulent and or copious STAGE II

Bilateral lower abdominal pain and pelvic pain which is dull in nature Fever, lassitude, head ache Abnormal vaginal discharge which becomes purulent and or copious Irregular and excessive vaginal bleeding Nausea and vomiting STAGE III Irregular and excessive vaginal bleeding Nausea and vomiting Dyspareunia STAGE IV (Referral) Temp > 39º c or 40º c Uncontrollable vaginal discharge Excessive vaginal bleeding Loss of libido Functional pain scale 5 INVESTIGATION

Routine blood investigation (CBC+Bl.Sugar+Total cholesterol) Rs 90 Liver Function test Rs 220 Renal Function test Rs 400 Microbiological swabs (Endocervical, urinary, vaginal) Rs 75 Inflammatory markers – CRP Rs 25 Diagnostic Serological assays for syphilis Rs 100 Laparoscopy Rs 500 Line of treatment  Purgation (Initial)  Oleation (Initial)  Internal medicine (For one day)  Karpa marundhu (For one day)  External medicine (For one day)  Yogam (Per session) Line of treatment common for all stages

APPROXIMATE COST FOR THE MANAGEMENT STAGE I Purgation Rs 400 185

Oleation Rs 500 Internal medicine Rs 8 Karpa marunthu Rs 4 External medicine Rs 10 Yogam Rs 500 STAGE II Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 16 Karpa marunthu Rs 10 External medicine Rs 9 Yogam Rs 500 STAGE III Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 14 Karpa marunthu Rs 12 External medicine Rs 13 Yogam Rs 500 ENDOMETRIOSIS The presence of functioning endometrium in sites other than uterine mucosa is

called Endometriosis. Depth of penetration is more related to symptoms rather than spread. American Fertility Scoring system of endometriosis (revised) Endometriosis <1 cm 1-3 cm >3 cm m Superficial 1 2 4 u e n Deep 2 4 6 o t i r e P R Superficial 1 2 4 Deep 4 16 20 y r a L Superficial 1 2 4 v O Deep 4 16 20 Posterior Cul- Partial Complete de-sac 4 40 Obliteration Adhesions <1/3 1/3 – 2/3 >2/3 Enclosure Enclosure Enclosure R Filmy 1 2 4 Dense 4 8 16 y r a L Filmy 1 2 4 v O Dense 4 8 16 R Filmy 1 2 4

* If the fimbriated end of the fallopian tube is completely enclosed, change the point assignment to 16 Stage I -1 to 5, Stage II 6-15, Stage III 16-40, Stage IV > 40 STAGE I Scoring 1- 5 Lower abdominal pain Pelvic pain Low back pain Dysmenorrhoea – pain scale 1&2 STAGE II Scoring 6- 15 Lower abdominal pain Dysmenorrhoea – pain scale 3 Menstrual irregularity (Menorrhagia, Polymenorrhoea) STAGE III Scoring 16-40 Lower abdominal pain Dysmenorrhoea – pain scale 4

Menstrual irregularity (Menorrhagia, Polymenorrhoea) Dyspareunia STAGE IV (Referral) Scoring >40 Lower abdominal pain Dysmenorrhoea – pain scale 5 Menstrual irregularity (Menorrhagia, Polymenorrhoea) Dyspareunia Sub fertility. INVESTIGATION Routine blood investigation (CBC+Bl.Sugar+Total cholesterol) Rs 90 Liver Function test Rs 220 Renal Function test Rs 400 TVS Colour Doppler Rs 300 MRI Rs 3000 Laparoscopy Rs 500 CA-125 Rs 500 Hormonal Assay Rs 1250 APPROXIMATE COST FOR THE MANAGEMENT STAGE I

Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 19 Karpa marunthu Rs 10 External medicine Rs 5 Yogam Rs 500 STAGE II Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 19 187

Karpa marunthu Rs 24 External medicine Rs 9 Yogam Rs 500 STAGE III Purgation Rs 400 Oleation Rs 500 Internal medicine Rs 82 Karpa marunthu Rs 12 External medicine Rs 10 Yogam Rs 500 DIETERY REGIMEN ADD  Hand powdered rice  Kuruvai rice  Manisambha rice  Kalludai sambha rice  manakathai rices Tender vegetables:  Athi(Ficus racemosus),  Kathari(Solanum melangena),  Avarai(Dolicus lablab),  Pudalai(Trichosanthe cucumerina),  Vellari(Cucumis sativus),  Kovai(Coccina grandis),

 Murungai(Moringa oleifera),  Vaazhai poo (Moringa oleifera),  Surai(Lagenaria sicerarie),  Sundai (Solanum torvum),  Mullangai (Rhaphanus sativus),  Karunai kizhangu (Colocasia antiquarum)  Pirandai(Cissus quadrangularis) Greens:  Musumusukai(Mukia maderaspatna),  Ponnaangaani(Alternanthera sessils),  Mulaikeerai (Amaranthus blitum)  Sirukeerai(Amaranthus tricolor)  Pasalai keerai(Portulaca quadrifida)  Puliyaari (Oxalis corniculata)  Paruppu keerIai (Portulaca oleracea)

 Keerai thandu (Amaranthu gangeticus) Fruits:  Aruneli(Phyllanthus acidus)  Mathulai(Punica granatum)  Sev vaazhaipazham, Rasthaali,Malai vaazhaipazham(Fruit of Musa paradisiacal)  Naaval (Syzygium cumini) 188

 Thratchai (Vitis vinifera)  Athi (Ficus racemosa) Pulses:  Ulunthu (Vigna mungo ) Dairy products:  Cow‘s milk and buttermilk. Non-vegetarian diets  Velladu(Capra hircus)  Ayirai meen(Loach)  Kaadai  Kowthaari AVOID  Hot, sour and salted foods  Sarkarai vallli kizhangu(Ipomoea batatud)  Seppakizhangu(Colacasia esculanta)  Kothavarai(Cyamopsis teragonoloba)  Kollu (Macrotyloma uniflorum) Do’s  Take well balanced diet  Do pranayama  Do soorya vanakkam  Have stress free life

 Take comfortable sleep.  Take lots of vigno mungo in food to strengthen the pelvic muscles. Don’ts  Avoid - oral contraception pills  Avoid - constipation  Avoid - indigestion  Avoid - Hot sour and salted foods 189

KUDIVERI NOI (ALCOHOLISM) INTRODUCTION Of all addictions, it is the addiction to alcohol that remains most prevalent. Perhaps, it is because alcohol is the most commonly used drug due to its easy availability. The clinical entity “KUDIVERI NOI” can be correlated with the Alcoholism and its related adverse effects . Synonym: Mathathiyam, Mathuval varunoi  The prevalence of alcoholism in India varies from 7% to 75% in Gujarat and Arunachal Pradesh respectively( Vivek Benegal, 2005)

 Number of drinkers in India increased from 1 in 300 to 1 in 20 in past 20yrs.  Average age of alcohol consumption in India has fallen by 9 years from 28 to19 years (NIMHANS Study)  3rd major life threatening problem after cardiac diseases and cancer  It is responsible for 50% of all homicides 25% of all suicides 50 -75% of road side accidents  It reduces life expectancy by about 10 yrs & Male female ratio is 2:1 to 3:1. DEFINITION

As per Siddha science, is Confusion of mental status and disorientation of speech due to excessive intake of toddy ,arrack and wine. CLINICAL DESCRIPTION Increased urge for taking alcohol, loss of appetite, sleeplessness, burning sensation in epigastric region, altered bowel habits, tremors of the hands and mental depression. Alcohol intoxication can be classified into four stages characterized by behavioral manifestations which depend upon blood alcohol level I stage:

- Characterized by sense of well being, warmth, increase of self confidence and lack of self control. - An excitement of sexual desire is evident. - Improves digestion of food. II stage: - Attention and concentration impaired, learning and retention become faulty - Usually manifest with excitable, irritable and self depreciating features. - Sleepfulness. III stage: - Sleeplessness - The subjects may disclose secrets at this point - Quarrelsome tendency 190

IV stage: - This stage marked by a depression of most bodily functions. - Staggering gait with postural abnormalities - Finally stage of stupor or coma prevails, which is characterized by rapid pulse and breathing, cold body. - Sometimes fatal. MUKKUTRA VERUPADU( PATHOGENESIS)  The deranged Pitham is the predominant cause for the said condition.  The deranged Pitham combining with other humors leads to the development of corresponding symptoms. I stage : Azhal II stage : Azhal Vali

III & IV stage: Mukkutram.  Keezhnokku kaal gets affected leading to symptoms like Diarrhoea or Constipation, Maelnokku kaal gets affected leading to symptoms like Vomitting, Difficulty in breathing etc and affected Paravukaal leads to symptoms like tremors, perspiration etc. MEDICAL TREATMENT that incorporates de addiction of alcohol may generally consists of the following 1. Detoxification 2. Preventing the relapse 3. Repairing the damage STAGE I A. STEP FOR DETOXIFICATION:

Drug in form of Surasam which consists of the detoxifying ingredients like Jamoon juice, Honey, Ginger juice, Lemon juice etc B. DRUG FOR PREVENTING THE RELAPSE: Drugs like Sugarcane juice, Grape juice, Decoction of Hedyotis corymbosa (Linn.) Lann etc C. REPAIRING THE DAMAGE 1. KUDINEER – DECOCTION Containing hepatoprotective herbs like (Hedyotis corymbosa (Linn.) Lam, (Tinospora cordifolia.Miers) 2. Chooranam 3. Parpam C. External: Head bath with cold water. STAGE II A. STEP FOR DETOXIFICATION: 191

A. STEP FOR DETOXIFICATION: Drug in form of Surasam which consists of the detoxifying ingredients like Jamoon juice, Honey, Ginger juice, Lemon juice etc B. DRUG FOR PREVENTING THE RELAPSE: Sugarcane juice, Grape juice, Decoction of Hedyotis corymbosa (Linn.) Lann etc C. REPAIRING THE DAMAGE KUDINEER a. Dry ginger, Adathoda vasica, Andrographis panniculata, Neem bark, Coriander seeds etc MEDICATED GHEE Medicated ghee made from Quail meat, Pepper, Cumin seeds -5ml (twice a day) C. External:

Head bath with oils having refrigerant action such as Ulunthu thylam Etc. III STAGE A. STEP FOR DETOXIFICATION: Drug in form of Surasam which consists of the detoxifying ingredients like Jamoon juice, Honey, Ginger juice, Lemon juice etc B. DRUG FOR PREVENTING THE RELAPSE: Sugarcane juice, Grape juice, Decoction of Hedyotis corymbosa (Linn.) Lann etc C. REPAIRING THE DAMAGE Fresh juice like Ginger juice along with dry ginger powder, Long pepper powder etc can be prescribed 2. Mutton soup D. External:

Head bath with Sitramuti thylam or Arakku thylam or Chukku thylam followed by lukewarm water. IV STAGE: As patient may be in a collapsed state, treatment for delirium to be undertaken. Tablets Parpam/Chenduram Other medicines for Kudiveri noi: In addition internal medicines that treat deranged Azhal (Pitham) can be prescribed Medicated ghee Parpam 192

Kukkil vennai Powder Diet: Food substances that neutralizes the Azhal – Pitham has to be included Rice varieties: Manakkathai arisi Kuruvai arisi Kaararisi Tender vegetables: Solanum melongena.L Moringa oleifera.Lam Ficus racemosa.L. Luffa acutangula (Linn) Roxb. Trichosanthes cucumerina.Linn. Oxalis corniculata. Linn. Allium cepa. Vigna mungo. L Cajanus cajan . L Vigna radiate.L Trigonella foenum – graecum. L Coriandrum sativum. Foeniculum vulgare Milk Curd Butter milk Others

Thiamine rich foods (Quail meat, Asparagus, Sunflower seeds etc) Antioxidant rich foods like Carrots, Peppers, Gooseberry etc Protein rich foods like Egg white, Soybeans, Lentils etc EFA rich foods like Whole grain foods, Olive oils, Egg, Almonds, Dark green leafy vegetables like broccoli, spinach etc Multivitamin rich food like Orange juice, Banana, Honey, Pomegranate juice etc To avoid Caffeine items Spicy oily food Sweets like chocolate

In case of chronic liver disease the following line of treatment can be followed In order to balance the deranged Azhal . i. Emesis ii. Purgation Fresh leaf juice of plants like Acalypha indica along with rock salt can be prescribed to induce emesis as well as purgation. Internal medicines: Decoctions 193

Chooranam Parpam Chenduram Medicinated ghee Diet regimen: Easy digestible food like double boiled rice porridges, tender vegetables of Solanum melongena.L Moringa oleifera.Lam Ficus racemosa.L. Luffa acutangula (Linn) Roxb. Trichosanthes cucumerina.Linn. Oxalis corniculata. Linn. Allium cepa. Soup varieties Quail soup Crab soup - added with pepper, ginger, coriandrum etc to induce the appetite. Early morning (6.00am) 5 ml of Gingerjuice + 5 ml of honey. Breakfast (8.00am)

1 cup of Millet porridge/ Oat porridge/ Wheat porridge/ Idly 3 nos/Dosai 1 no Pre noon (11.00am) Cumin seeds added Lemon juice 1 cup/ Sugarcane juice 100ml Lunch(1.00pm) 1 cup of steamed rice / 1 cup of Kichidi (Clean rice cooked with green dhal) with Sambar/Rasam to use only palmolein/Sesame/Soyabean oil/Olive oil,1 cup boiled vegetables or 1 boiled egg white ,1 cup of skimmed butter milk Evening(4.00pm) 1 cup of pomegranate juice/ Orange juice/Amla juice/Fruit salad made of Papaya, Guava, Apple, Banana.

Malted Ragi/Wheat payasam Evening (6 pm) Veg: Vegetable soup (Tomato, Braccoli, Moringa leaves, Garlic) Non veg: Quail soup, Crab soup. Dinner (8.00pm) Slices of bread 2-4/ Cereal flakes with milk (Corn/Wheat/Rice)/ 2-3 chappathis with vegetable gravy. A cup of milk Yoga recommended: Surya Namaskaram Pranayamam – Meditation techniques. 194

Savasana Others Psychotherapy Behaviour therapy BUDGET I STAGE: Drug in form of Surasam which consists of the detoxifying ingredients like Jamoon juice, Honey, Ginger juice, Lemon juice etc\ - Rs.50/- Sugarcane juice, Cumin seeds - Rs.40/- Kudineer Containing hepatoprotective herbs like (Hedyotis corymbosa(Linn.) Lam), (Tinospora cordifolia.Miers) 2. Chooranam 3. Parpam - Rs.30/- I stage – Rs. 120/ day II stage: Drug in form of Surasam which consists of the detoxifying ingredients like

Jamoon juice, Honey, Ginger juice, Lemon juice etc- Rs.50/- Sugarcane juice, Cumin seeds - Rs.40/- KUDINEER a. Dry ginger, Adathoda vasica, Andrographis panniculata, Neem bark, Coriander seeds etc - Rs. 50/- MEDICATED GHEE Medicated ghee made from Quail meat, Nutmeg - Rs. 5/- II stage Total: Rs 145/day - III stage Fresh juice like Ginger juice along with dry ginger powder, Long pepper powder etc can be prescribed - Rs. 25/- Drug in form of Surasam which consists of the detoxifying ingredients like Jamoon

juice, Honey, Ginger juice, Lemon juice etc - Rs.50/- Sugarcane juice, Cumin seeds - Rs.40/- III stage: Rs. 115/- Chronic liver disease: If treated with a combination of chooranam, parpam, tablet, syrup, oil and medicated ghee. 195

App.rate: Rs.70/- External application Ulunthu thylam / 100ml– Rs. 26/- Arakku thylam / 100ml – Rs 113/- Thappalam technique : Rs. 500/- 1. ROUTINE INVESTIGATION BLOOD  Hb (gm/dl ) - Rs. 25  ESR(mm/hr)- Rs. 15  Blood glucose( mg/dl): ( Fasting)- : ( Post – prandial)- Rs.50 2. SPECIFIC INVESTGATIONS Liver Function Tests  Serum Alkaline phosphate (u/l)  SGOT (u/l  SGPT (u/l)  Serum total bilirubin (mg/dl)  Serum Direct bilirubin (mg/dl)  Serum Indirect bilirubin (mg/dl)  Serum Total Protein ( g/dl)

 Serum Albumin( g/dl)  Serum Globulin( g/dl) -Rs: 220/- Lipid Profile  Serum cholesterol(mg/dl)- - Rs. 25/-  HDL cholesterol(mg/dl)-  LDL cholesterol(mg/dl)-  VLDL cholesterol(mg/dl)-  Serum triglycerides (mg/dl) - Rs.50/- Renal Function Test  Urea  Creatinine  Uric acid - Rs. 400/- Urine  Urine sugar (F)&(PP) - Rs. 10/-  Albumin - Rs. 10/-  Deposits  BS BP  Urobilinogen -Rs.50/-  Ketone -Rs 50/- 1. USG ABDOMEN AND PELVIS Rs. 200/- 196

2. Liver biopsy Rs. 250/- OTHER MARKERS: Gammaglutamyl transferase Serum Carbohydrate deficient transferin. Routine: Rs. 1355/- Disease specific: Rs. 705/- 197

KALANJAGAPADAI (PSORIASIS) DEFINITION : It denotes well defined erythematous rounded plaques covered with silvery scales which have a tendency for the extensor surface and scalp. ETIOLOGY : Hereditary Respiratory diseases Psychosomatic disorders Shock Seasonal changes Before puberty After menopause CLIMICAL FEATURES : 1. Erythematous, sharply demarcated papules and rounded plaques, covered by silvery scales. 2. Coin shaped plaques predominantly in elbows, knees and scalp.

3. Swelling of terminal interphalangeal joints , onycolysis. 4. Thimble pitting and ridging of the nails 6. Droplet shaped , small and scaly lesions most commonly in children nails . 5. Red , shiny , symmetrical patches in natal cleft 6. Petechial haemorrhage on scratching . 7. In later stage : Scales present in knee and elbow. Thickening of the skin with fissuring in palms and soles. Peeling of copious scales all over the body Coin shaped lesion with sterile pustules. Lesions are circular or elongated.

Lesions occur in umblical, submammary and axillary folds in females with oozing 1/4th of the psoriatic patient will have pitting on nails 7% of patients will suffer from Psoriatic arthritis. Line of Treatment Step l  Kazhichal maruthuvam  meganatha thylum 8- 30 ml with milk (50) at early morning  Karudan kizhangu thylum – 16 ml. with milk (50) at early morning 198

 kalarchi thylum 8- 16 ml. with milk (50) at early morning Step ll;internal medicine Chooranam  Parangi pattai chooranam 1- 2gm twice a day with honey  Thiripala chooranam 1- 2gmtwice a day with honey  Sivanar vembu chooranam 1- 2gmtwice a day with milk  Seenthil chooranam 1- 2gmtwice a day with ghee  Thalisathi chooranam 1- 2gmtwice a day with honey  Tirikaduku chooranam 1- 2gmtwice a day with hot water  Karisalai chooranam 1- 2gmtwice a day with honey Nei  Brahmi nei 10 -15 ml at morning

 Senkottai nei 5-10 ml twice aday  Venpoosani nei 5-10 ml twice aday Ilagam; Mahavallathy Ilagam- 3g twice a day Vilvathy Ilagam 5- 10g twice a day Nellikai Ilagam 5-10g twice a day Thylum; Vetpalai thylum 5-10 drops twice a day with milk Rasayanam; Gandaga rasayanam -1.3 -2 g twice a day Parangi rasayanam 5g twice a day Maathirai; Maha vasantha kusumahara maathirai 1-2 twice a day Kusta kaja kuligai 1-2 twice a day Parpam; Muthuchippi Parpam 200- 400 mg twice a day with milk

Sangu Parpam 100-300 mg twice a day with ghee Palagarai parpam 65-130mgtwice a day with milk Gandaga Parpam 35 mgtwice a day with milk Muthu Parpam 30-60mg twice a day with ghee Pavala parpam100-200 mgtwice a day with milk Chendooram; Ayachendooram-60-130mg 199

Ayakantha chendooram-65-130mg Kalameganarayana chendooram-50-100mg Sivanar amirtham-100-200mg Gowri-130mg Parangipattai pathangam-100-200mg Rasaganthi mezhugu-500mg Nanthi mezhugu-100-500g Kanthaga mezhugu-260-390mg STEP;3 EXTERNAL MEDICATION Neer & Poochu Wash the lesions with thiripalakudineer or Arasampattai kudineer and apply any of the followingsuitable medicated oil. Arugan thylam Vetpalai thylam Pungan thylamkarappan thylam. OLEATION Kaiyaan thylam Nellikai thylam REFERRAL CRITERIA

Pitting and riding of the nail. Extreme rigidity and restricted movement of the joint. Lesion spread all over the body. PATHIYAM ADD Tender vegetables Greens Dairy products AVOID Avoid frequent intake of sour and hot taste Solam, Kambu, Varagu, Paharkaai, Mango, Vazhaikaai, Vellari, Kollu, Koyya, Kathari, Vaankozhi kari. Seppakizhangu ADVISE ON COMPLETION OF TREATMENT AND PREVENTION; Advised to follow Iyama/Niyamas. Do Pranayamam and sooriya vanakkam. 200

Avoid allergic foods mentioned under pathiyam Take karpa medicine Avoid tobacco and alcoholic beverages 201

STANDARD TREATMENT GUIDELINES ONCOLOGY Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 BILIARY CANCER 4 2 Breast Cancer 11 3 Chronic Cancer Pain Management Guidelines: 43 4 MALIGNANCIES OF GASTROESOPHAGEAL JUNCTION (Adenocarcinoma GEJunction) 68 5 Cancer cervix 77 6 CARCINOMA ESOPHAGUS 90 7 Esophageal cancer 99 8 Gall Bladder cancer 108 9 Lung cancer 114 10 PEDIATRIC SOLID TUMORS 124 11 Neuroblastoma 132 12 Wilms’ tumor 135 2

Group Head Coordinator of Development Team Dr Anil K. D’ Cruz Director and Chief Head and Neck Services, Tata Memorial Hospital, Mumbai 3

NAME OF CONDITION: BILIARY CANCER I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Bile duct cancer is a relatively uncommon cancer with annual incidence of 1- 2/100,000 in Western studies. Recent trends show increasing incidence probably due to better diagnostic techniques. Although biliary cancer can occur anywhere in the biliary tract, 40-60% of them involve the hilum. 90% of these tumors are well differentiated and mucin producing adenocarcinomas. The peak age for bile

duct cancer is in the seventh decade and more males are affected than females. Patients usually presented with progressive jaundice, itching and weight loss. b) Case definition: For both situations of care (mentioned below*) INCIDENCE OF THE CONDITION IN OUR COUNTRY Worldwide incidence of biliary cancer is about 0.01% - 0.2% in large autopsy series. However the Indian data is still awaited. Majority of the patients are elderly males over sixty years. II. DIFFERENTIAL DIAGNOSIS

Majority of the patients with a hilar stricture harbor malignancy. However an alternate diagnosis is possible in 10-15% of patients. The differential diagnoses should consider gall bladder carcinoma, Mirizzi’s syndrome and Idiopathic benign focal stenosis of the bile duct. III. PREVENTION AND COUNSELING Most of the cases occur sporadically and a clear cut etiological agent is not indicated in biliary tract malignancy. However, a high incidence is noted in patients with

congenital biliary cystic disease (15-20%). A diagnosis of such a condition should warrant surgical treatment, so as to prevent the development of biliary malignancy in future. However, the benefit of surgery done after 20 yrs of age is questionable. Stringent measures of radiation protection is to be offered to the workers in the nuclear energy sector, since radioisotopes used commercially like Thorium, Radon etc are thought to be associated with the development of cholangiocarcinoma. 4

IV. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA The early symptoms of cholangiocarcinoma are non specific. Anorexia weight loss and pruritus are most common. 90% of the patients come to attention with painless jaundice. Clinical examination reveals jaundice and may also find enlarged firm liver. Diagnostic criteria Abdominal ultrasound examination which reveals dilated intrahepatic biliary radicles

with a collapsed gall bladder and extrahepatic bile duct must be suspected to be a case of hilar obstruction unless proven otherwise. Possible differential diagnosis of gall bladder cancer or Mirizzi syndrome must be considered, and further evaluation must be carried out by a contrast enhanced CT scan or MRI, and the expertise of a tertiary care center taken at this stage. Diagnosis is based on radiological criteria and pathological confirmation is not

mandatory prior to surgery in resectable lesions. Histopathological proof can only be achieved by endoscopic brush cytology or EUS guided needle biopsy and is not recommended prior to resection when the lesion is deemed resectable. Histological confirmation is mandatory prior to chemotherapy or radiotherapy. Investigations: MDCT can give valuable information regarding the level of obstruction, vascular invasion, and presence of atrophy/hypertrophy complex of liver lobes.

MRCP is the investigation of choice for obtaining a cholangiogram. ERCP or PTC allows bile sampling for cytology, which is positive in about 30% of cases. Combined brush cytology and biopsy specimens increase yield to 40–70%. Negative cytology from brushings does not exclude malignancy. Treatment: Prior radiological evaluation of resectability and patient’s performance status determine the treatment. In Resectable hilar cholangiocarcinoma standard curative surgery entails

hemihepatectomy with caudate lobectomy and extrahepatic bile duct excision with regional lymphadenectomy. Aggressive resections with combined portal vein resection to achieve RO resection may be considered in selected cases. Preoperative Biliary drainage may salvage segments of hepatic parenchyma and reduce risk of postoperative liver failure. Portal vein embolization to increase the remnant liver volume in patients with post- resection volumes are less than 25%.

Role of adjuvant therapy after resection remains controversial; however chemotherapy or chemo radiation may be tried 5

Unresectable tumors require endoscopic or percutaneous biliary drainage or stenting. Surgical bilio-enteric bypass may be required. Palliative Gemcitabine based chemotherapy may be considered along with supportive care. Liver transplantation is indicated at selected centres, for patients with early stage cholangiocarcinoma and anatomically unresectable lesions, but this approach should not be offered outside the scope of clinical trials.

*Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis Cholangiocarcinoma is to be suspected in an elderly patient with symptoms of pruritus ,painless and progressive jaundice. b) Investigations: MDCT MRCP c) Treatment: Biliary drainage and supportive care with or without chemoradiotherapy for unresectable and metastatic disease. This condition is not however suitable for

treatment at a secondary hospital, and must be referred to a tertiary care center. Standard Operating procedure a. In Patient b. Out Patient c. Day Care d) Referral criteria: Biliary obstruction with undilated gall bladder or extrahepatic bile ducts must be regarded as hilar obstruction unless proven otherwise. These patients must be referred for evaluation and management to a tertiary care center. Patients requiring major liver resections resection or portal vein resection. 6

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical Diagnosis: Cholangiocarcinoma is to be suspected in an elderly patient with symptoms of pruritus ,painless and progressive jaundice. b) Investigations: MDCT, MRCP EUS, Endoscopic/Percutaneous cholangioscopy, c) Treatment: Hepatectomy with caudate lobectomy and excision of the extrahepatic Biliary tree with regional lymphadenectomy in resectable disease.

Extended resections with portal vein resection and reconstruction where portal vein in involved. Biliary drainage and supportive care with or without chemoradiotherapy for unresectable and metastatic disease. Standard Operating procedure a. In Patient b. Out Patient c. Day Care d) Referral criteria: Patients considered candidates for liver transplantation may be referred to transplant units. V. WHO DOES WHAT? and TIMELINES a. Doctor b. Nurse c. Technician 7

VI. FURTHER READING / REFERENCES 1. Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet 2005; 366: 1303–1314. 2. Neuhaus P, Jonas S, Settmacher U et al. Surgical management of proximal bile duct cancer: extended right lobe resection increases resectability and radicality. Langenbecks Arch Surg 2003; 388: 194–200. 3. Killeen RP, Harte S, Maguire D, Malone DE. Achievable outcomes in the management of proximal

cholangiocarcinoma: an update prepared using ‘evidence-based practice’ techniques. Abdom Imaging 2008; 33: 54–57. 4. de Groen PC, Gores GJ, LaRusso NF et al. Biliary tract cancers. N Engl J Med 1999; 341: 1368–1378. 5. Heimbach JK, Gores GJ, Haddock MG et al. Liver transplantation for unresectable perihilar cholangiocarcinoma. Semin Liver Dis 2004; 24: 201–207. 6. McMasters KM, Tuttle TM, Leach SD et al. Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma. Am J Surg 1997; 174: 605–609.

7. Laurent S, Monsaert E, Boterberg T et al. Feasibility of radiotherapy with concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma: a prospective dose finding phase I-II study. Ann Oncol 2009; 20: 1369–1374. 8. Schoppmeyer K, Miethe S, Wiedmann M et al. Radiochemotherapy followed by gemcitabine and capecitabine in extrahepatic bile duct cancer: a phase I/II trial. Am J Clin Oncol 2006; 29: 576–582.

9. Glimelius B, Hoffman K, Sjoden PO et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 1996; 7: 593–600. 10. Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 2007; 96: 896–902. 11. Valle JW, Wasan HS, Palmer DD et al. Gemcitabine with or without cisplatin in patients (pts) with advanced

or metastatic biliary tract cancer (ABC): results of a multicenter, randomized phase III trial (the UK ABC-02 trial). Proc Am Soc Clin Oncol 2009; 27: Abstr 4503. 12. Fuller CD, Dang ND, Wang SJ et al. Image-guided intensity-modulated radiotherapy (IG-IMRT) for biliary adenocarcinomas: initial clinical results. Radiother Oncol 2009; 92: 249–254. 13. Castaldo ET, Wright Pinson C. Liver transplantation for non-hepatocellular carcinoma malignancy. HPB (Oxford) 2007; 9: 98–103.

14. Ortner ME, Caca K, Berr F et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology 2003; 125: 1355–1363. 15. Zoepf T, Jakobs R, Arnold JC et al. Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy. Am J Gastroenterol 2005; 100: 2426–2430. 8

16. Japanese Society of Biliary Surgery. Classification of biliary tract carcinoma. Second English edition. Tokyo: Kanehara; 2004. 17. Takada T, Miyazaki M, Miyakawa S, Tsukada K, Nagino M, Kondo S, et al. Purpose, use, and preparation of clinical practice guidelines for the management of biliary tract and ampullary carcinomas. J Hepatobiliary Pancreat Surg 2008;15:2–6 18. Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BS J, et al. Staging, resectability, and

outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001;234: 507–17. 19. Nagino M, Kamiya J, Arai T, Nishio H, Ebata T, Nimura Y. “Anatomic” right hepatic trisectionectomy (extended right hepatectomy) with caudate lobectomy for hilar cholangiocarcinoma. Ann Surg 2006;243:28–32. 20. Makuuchi M, Thai BL, Takayasu K, Takayama T, Kosuge T, Gunvén P, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery

1990;107:521–7 21. Nagino M, Kamiya J, Nishio H, Ebata T, Arai T, Nimura Y. Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg 2006;243:364–72. 22. Kawasaki S, Imamura H, Kobayashi A, Noike T, Miwa S, Miyagawa S. Results of surgical resection for patients with hilar bile duct cancer: application of extended hepatectomy after biliary drainage and

hemihepatic portal vein embolization. Ann Surg 2003;238:84–92 23. Miyazaki M, Ito H, Nakagawa K, Ambiru S, Shimizu H, Okaya T, et al. Parenchyma-preserving hepatectomy in the surgical treatment of hilar cholangiocarcinoma. J Am Coll Surg 1999;189:575–83. 24. Nimura Y, Kamiya J, Kondo S, Nagino M, Uesaka K, Oda K, et al. Aggressive preoperative management and extended surgery for hilar cholangiocarcinoma: Nagoya experience. J Hepatobiliary Pancreat Surg 2000;7:155–62

25. Hemming AW, Kim RD, Mekeel KL, Fujita S, Reed AI, Foley DP, et al. Portal vein resection for hilar cholangiocarcinoma. Am Surg 2006;72:599–604. 9

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 2 10

NAME OF CONDITION: Breast Cancer I. WHEN TO SUSPECT/ RECOGNIZE? Introduction: Breast cancer is the commonest cancer among women worldwide. In recent years, breast cancer has emerged as the commonest female malignancy in the majority of Asian countries. In India, breast cancer incidence has overtaken cervical cancer incidence in most urban registries. (1) This is attributed to several factors including diet, lifestyle, lowered fertility with increasing age at first childbirth, obesity etc. Case definition:

For both situations of care (mentioned below*) Histopathologically or cytopathological diagnosis of invasive or non invasive cancer of tissue obtained from breast. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY According to Globocan 2008, with an estimated 1.38 million new breast cancer cases diagnosed each year, female breast cancer is the second most common cancer in the world and the most common cancer among women, accounting for 4,58,000 cancer

deaths per year. (2) In India, breast cancer incidence varies from urban (30 per 100,000 population per year) to rural (5 per 100000 population per year) areas. (1) III. DIFFERENTIAL DIAGNOSIS 11

Mammary dysplasia (fibrocystic condition of the breast), fibroadenoma, intraductal papilloma, lipoma, fat necrosis, cystosarcoma phylloides, breast abscess and others depending on the clinical context. IV. PREVENTION AND COUNSELING Factors Associated With Increased Risk of Breast Cancer 1. Hormone replacement therapy 2. Obesity 3. Lack of exercise 4. Later age at first child birth 5. Lack of Breast-feeding 6. Family history of breast and ovarian cancers

A lactational period of 6 months or more is associated with decreased risk of breast cancer. Similarly, having the first live birth after age 30 doubles the risk compared to having first live birth at age less than 25 years. (3) Gaining weight after menopause can increase a woman's risk. A recent study found that putting on 9.9 kg (22 lbs) after menopause increases the risk of developing breast cancer by 18%. (4) Hormone replacement therapy used by women

attaining menopause has also been associated with increased risk of breast cancer. (5) While the societal trend towards reduced fertility is clearly non-modifiable it is possible to educate young Indians about the appropriate age to initiate childbearing (perhaps best before the age of 30 years) and the importance of breast feeding, not only for the child but also the woman. Obesity is the other potentially modifiable risk factor that requires 12

multidimensional preventive attention with major health benefits that extend beyond cancer prevention. Societal and public health intervention in these areas has the potential to abrogate much of the increase in breast cancer incidence that has been observed in the West. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA A number of international guidelines exist in order to ensure uniformity and quality in the

delivery of care to patients with breast cancer. (6-9) The majority of guidelines have been developed in the context of evidence and clinical practice in the Western world. There is little representation from developing countries, if any, in the expert panels that formulate these guidelines. Clinical practice in developing countries, however, continues to be largely guided by these guidelines since they are based on high quality evidence with expert

appraisal. Many of these guidelines are not literally applicable to developing countries because of constraints on resources and/or expertise. *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a. Clinical Diagnosis: Pathology guidelines: • Histopathological diagnosis of breast cancer by a biopsy (prior to neaoadjuvant chemotherapy, if planned) or on the surgical specimen is a must. In the latter situation 13

in operable breast cancer, pre-operative establishment of diagnosis by fine needle aspiration is appropriate and acceptable. • The essential elements of a histopathological report include the subtype, grade, adequacy of margins, axillary nodal status and immunohistochemically determined ER, PgR and CerbB2 (HER2) Immunohistochemistry (IHC) facility not mandatory in all centres that treat breast cancer, but referral affiliation with a central laboratory for obtaining this information in

all patients is mandatory. The ASCO/CAP guidelines should be followed for reporting on breast cancer specimens. (10, 11) ER and PR are important for prognostication and hormonal therapy of breast cancer. HER2 is important for guiding the choice of systemic HER2 targeted therapy in primary breast cancer, if the latter is feasible. Knowledge of HER2 status also has some prognostic value and predictive capability for anthracycline benefit. [5, 6, 7, 12] b. Investigations: Radiology guidelines

All centres treating breast cancer should have facilities for plain chest radiograph and ultrasound scanning of the abdomen. However, such centres need not necessarily have facilities for breast imaging including mammography, breast sonography and other advanced imaging techniques. Mastectomy is an appropriate surgical modality in such centres. Standard staging in locally advanced breast cancer includes chest radiograph or 14

CT scan of chest, USG Abdomen or CECT abdomen, and bone scan. Metastatic workup is not required in clinically early stage breast cancer. c. Treatment: Surgical guidelines Modified radical mastectomy (MRM) with axillary clearance is an appropriate surgical option for all stages of operable breast cancer and those who become operable after neoadjuvant treatment. The long-term safety and quality of life gains with breast conserving surgery have been proven in high quality studies and this procedure should

be offered to patients who are eligible to receive it. Thus eligible and desirous patients should be referred to an appropriate higher centre for breast conservation. A modified radical mastectomy involves removal of the entire involved breast using an elliptical skin incision, including the skin overlying the tumor and the nipple-areola complex with the underlying pectoralis fascia, sparing both the pectoralis muscles, along

with the removal of at least levels I and II axillary lymph nodes. Level III axillary lymph nodes should always be excised in large tumors, node positive axilla and locally advanced breast cancers post neoadjuvant chemotherapy. 1. Surgery after Neoadjuvant chemotherapy (NACT) The standard surgery for patients with LABC after NACT is MRM. 2. Full axillary dissection is the standard of care 15

A full axillary clearance that includes level III lymph nodes be undertaken as a standard procedure in breast cancer surgery in developing countries. There is relative abundance of large, non-screen detected cancers and locally advanced breast cancers in these regions with high possibility of axillary nodal involvement. (13) It needs to be noted that extensive axillary procedures could lead to increased incidence of adverse effects like shoulder stiffness and arm edema. (14)

3. Depot hydroxyprogesterone prior to surgery for primary breast cancer The adoption of pre-operative injection depot hydroxyprogesterone as a standard of care in patients with operable breast cancer is not currently ready for routine practice. There is a recent large randomised trial and other reports suggesting a positive benefit in node positive and large tumours but replication these findings is needed. (15) Radiation therapy guidelines: 1. Use of post mastectomy radiation

Post Mastectomy radiation should be used in all patients with >5 cm pathological tumour size and/or 4 or more positive nodes in axilla. (16) 2. Use of radiation in patients with 1-3 positive axillary nodes after mastectomy Among post mastectomy patients with 1-3 positive nodes, patients with additional poor risk features (young age, vessel invasion, inadequate axillary lymph node dissection) should receive radiotherapy. A subgroup analysis from the Danish study that showed a

survival benefit in these (1-3 node positive) patients equivalent to those with more than 16

3 involved nodes involved and other studies which have tried to analyse specific risk factors in these patients. (17, 18) 3. Use of appropriate megavoltage machines for radiation therapy may be used. Linear accelerator or Cobalt60 (Co60) unit is a valid option for radiotherapy after mastectomy when such treatment is indicated. [19] 4. Use of axillary nodal radiation after surgery. There is no routine indication of using axillary nodal irradiation after adequate surgical

clearance. [20] Such radiation can be used in rare instances in patients with miscroscopic or gross residual cancer in the axilla after surgical dissection. Systemic Therapy in Breast Cancer The following suggestions are a framework of suggestions in order to ensure optimal delivery of care to the majority of breast cancer patients presenting to all levels of the healthcare system in India. The panel recognizes that departures from guidelines may be required in individual cases in response to the specifics.

I. Adjuvant chemotherapy Adjuvant chemotherapy has become an important component of breast cancer management in the last 30 years. Robust evidence for its use has been generated in successive reviews of individual patient data by the Early Breast Cancer Trialists Cooperative Group. [21] a. Chemotherapy after surgery may be omitted in the following group of patients who may not benefit from the use of adjuvant chemotherapy. Such patients 17

could receive adjuvant hormone therapy alone. Adjuvant chemotherapy should be considered in all other patients who have no contra-indications to its use. i. Low grade tumors with strong estrogen and progesterone receptor positivity, without lympho vascular space invasion which are ≤ 2cm and node negative in post menopausal women. [8] 1. Optimal Adjuvant chemotherapy Anthracycline based chemotherapy is the backbone of adjuvant chemotherapy[21]

• In node negative early breast cancer patients 6 cycles of anthracycline based chemotherapy should be used. • In those with positive lymph nodes or locally advanced breast cancer, anthracycline and taxane based chemotherapy given sequentially is preferred. [22, 23]. If taxane based chemotherapy is not feasible or contraindicated, 6 cycles of anthracycline based chemotherapy is an acceptable alternative • CMF chemotherapy may be considered as an acceptable alternative when

anthracycline based chemotherapy is not possible due to feasibility issues or contra- indications. • Ovarian ablation (surgical or radiation) may be considered in certain patients, in hormone receptor positive patients. 2. Chemotherapy for LABC Neoadjuvant chemotherapy is given with the primary aim of making inoperable tumors operable in locally advanced breast cancer 18

• The optimal number of chemotherapy cycles is usually 3 to 6 cycles of neoadjuvant chemotherapy. [24, 25] • Anthracycline and taxane based chemotherapy is preferred. [26, 27] Sandwich therapy (chemotherapy followed by surgery followed by more chemotherapy) is widely practiced and is appropriate. Anthracycline based chemotherapy alone may also be used when taxane based chemotherapy not possible or contraindicated. • In HER 2 positive patients trastuzumab may be added to chemotherapy in the

neoadjuvant setting, if feasible. [28, 29] Despite randomized evidence indicating its cardiac safety in the neoadjuvant setting, concomitant use of anthracyclines and trastuzumab is not widely practiced. Taxanes (paclitaxel or docetaxel) are the preferred concomitant partner for trastuzumab. • Neoadjuvant hormone therapy may be considered in post menopausal women with strong hormone receptor positivity. [30] Aromatase inhibitors are preferred over

tamoxifen in this setting. [31, 32] The optimal duration of treatment is not well defined but may vary from 4-8 months or until after best response. [33] II. Adjuvant Hormonal Therapy Adjuvant hormonal therapy significantly improves survival in both pre and post menopausal women expressing hormone receptors. [21] It should be given to all patients expressing any degree of estrogen and or progesterone receptor positivity. The optimal duration of hormone therapy is 5 years. [8] 19

• Premenopausal women should receive tamoxifen for 5 years.[8] Addition of ovarian suppression to tamoxifen till now not proven to be of additional benefit. • Post menopausal women aromatase inhibitors is preferred either for 5 years or as switch therapy with 2-3 years of tamoxifen. [34, 35] • Tamoxifen for 5 years in post menopausal women is an acceptable alternative to aromatase inhibitors. [21] III. Adjuvant Targeted Therapy

Adjuvant targeted therapy is currently recommended with trastuzumab in patients with HER2 positive disease either after completion of chemotherapy or starting with the taxane component of the chemotherapy regimen. This is based on the proven benefits of adjuvant trastuzumab in disease-free and overall survival. American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) guidelines suggest the criteria of >30%

intense and complete staining (IHC) or FISH amplification >2.2 for HER2 positivity. [11] The present standard is to give trastuzumab for 1 year. [36, 37] There is also some evidence for the benefit of shorter duration (9-12 weeks) of adjuvant trastuzumab therapy and this an acceptable alternative in view of its wider financial feasibility. [38] When not feasible , the use of chemotherapy (preferable anthracycline based) without traztuzumab is an acceptable

alternative in patients with HER 2 overexpressing tumours. Patients should be routinely screened for cardiac contraindications to trastuzumab before starting this therapy and the cardiac function should be routinely monitored every 3-4 months using echocardiography or MUGA scan during this treatment. 20

Follow-up of patients after primary treatment: 1. Need for follow-up after primary treatment. At present regular post-treatment follow up of all patients with primary breast cancer should be considered. It is however notable that there is lack of evidence from randomized trials supporting any particular follow-up sequence or protocol. [39, 40] 2. Use of investigative modalities during follow-up. An annual to biennial mammogram is the only routinely required investigation during

follow-up in patients who are asymptomatic and have normal physical examination. This is based on evidence from two randomized trials that failed to prove any benefit from more extensive investigations of asymptomatic patients during follow up care. [41, 42] Standard Operating procedure: Not applicable VII. Referral criteria: Patients should be referred to a higher center (or another center) in the following situations.

a) The facility of treatment is not available at the treating center – e.g. breast conservation, advanced radiation delivery techniques if necessary, diagnostic dilemmas etc. b) The waiting list of patients for a particular treatment or therapy is excessively long (please see the time frames stated in this document) *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available 21

a) Clinical Diagnosis: Pathology guidelines: 1. Histopathological diagnosis of breast cancer by a biopsy (prior to neaoadjuvant chemotherapy, if planned) or on the surgical specimen is a must. In the latter situation in operable breast cancer, pre-operative establishment of diagnosis by fine needle aspiration is appropriate and acceptable. 2. The essential elements of a histopathological report include the subtype, grade, adequacy of margins , axillary nodal status and immunohistochemically determined ER,

PgR and CerbB2 (HER2). Immunohistochemistry (IHC) facility for dtermination of ER, PR and HER2 should be available. Fluorescent in situ hybridization (FISH) for HER2 amplification should also be available at tertiary hospitals. The ASCO/CAP guidelines should be followed for reporting. [10, 11] ER and PR are important for prognostication and hormonal therapy of breast cancer. HER2 is important for guiding the choice of systemic HER2 targeted

therapy in primary breast cancer, if the latter is feasible. There is also some prognostic and predictive capability (for anthracycline benefit) of HER2 testing. [12] In cases with equivocal (2+) HER2 score on IHC, fluorescent in situ hybridization (FISH) should be done. [11] 3. Incorporation of multigene assays in clinical decision making: With the available evidence and lack of validation in prospective randomized trials versus conventional decision-making, routine incorporation of multigene assays like

Recurrence Score (RS, Oncotype DXTM) in clinical decision making including prognostication and prediction of chemotherapy benefit is not standard. [43] VIII. Investigations: Radiology guidelines These centers should have facilities for mammography, local breast sonography and other advanced imaging techniques (CT scan, radionuclide bone scan etc). Magnetic resonance imaging (MRI) of the breast and positron emission tomography (PET) scans

are being increasingly used in the management of breast cancers. While there may be specific clinical situations that justify the use of these techniques, their routine use in the management of breast cancer is not recommended due to lack of robust evidence of benefit. 1. Local imaging prior to surgery Routine use of mammography and/or breast ultrasound in the evaluation of cases with early stage operable breast cancer should be considered in order to facilitate surgical

decisions. Addition of diagnostic breast ultrasound to mammography increases the accuracy and diagnostic yield, especially in patients with dense breasts and asymmetric densities, in addition to providing image guidance for diagnostic procedures such as biopsies. [44] 2. Routine breast MRI prior to breast conserving surgery 23

Routine use of breast MRI prior to BCT is not recommended. Evidence from randomized trial evidence has revealed a lack of benefit from routine preoperative breast MRI and has also suggested a high rate of false positives with this technique. [45] 3. Staging for locally advanced breast cancer Standard staging in locally advanced breast cancer includes chest radiograph or CT scan of chest, ultrasound or CT scan of the abdomen and bone scan. Metastatic workup is not

routinely required in clinically early stage breast cancer. 4. PET-CT for routine staging in early and locally advanced breast cancer Routine use of PET or PET-CT scanning for pre- treatment staging assessment of patients with early or locally advanced breast cancer is not recommended. [46] b) Treatment: 1. Mastectomy with axillary clearance in breast cancer. Modified radical mastectomy (MRM) with axillary clearance is an appropriate surgical option

for all stages of operable breast cancer and those who become operable after neoadjuvant treatment. A modified radical mastectomy involves removal of the entire involved breast using an elliptical skin incision, including the skin overlying the tumor and the nipple-areola complex with the underlying pectoralis fascia, sparing both the pectoralis muscles, along with the removal of at least levels I and II axillary lymph nodes. Level III axillary lymph nodes

should always be excised in large tumors, node positive axilla and locally advanced breast cancers post neoadjuvant chemotherapy.' 24

2. Use of breast conservation therapy (BCT) in developing countries Breast conserving surgery should be considered for all eligible patients in developing countries. There is overwhelming evidence for the equivalent safety and efficacy of BCT compared to mastectomy in appropriately selected patients. [47, 48] Tumors in developing parts of the world are most often not screen detected, larger, and there is variable availability of expertise for undertaking breast conservation [49]. Such patients should be

referred from secondary to tertiary centers with available expertise and infrastructure for breast conservation .Communication of the axillary dissection with the breast cavity should be avoided as far as possible. Separate incisions prevent transfer of seroma fluid between the lumpectomy and axillary areas and improve the cosmetic outcome. [22] 3. Use of oncoplastic procedures Oncoplastic procedures should be performed only in specialized centres with multidisciplinary expertise in these techniques. [50]

4. Defining adequacy of margins in primary breast surgery Margins after BCT should be technically free. Guidelines have variously defined an adequate margin in breast conservation from 1mm to 10 mm or more. [51, 52] Interestingly, the rate of finding IDC in the revised specimens has been in the range of only 30-40%. [53] Although there are conflicting reports, it is evident that obtaining a clean negative margin is desirable. 5. Surgery after neoadjuvant chemotherapy (NACT) 25

The standard surgery for patients with LABC is MRM after NACT. [54] In selected patients, BCT can be considered. The initial location and extent of tumor should be marked using techniques like biopsy scar, clips, tattoos etc. in patients being planned for NACT. This facilitates ease of subsequent surgery and has a bearing on local control. [55, 56] It should be noted that breast conservation is a valid option in selected cases of

large or locally advanced breast cancer who achieve excellent response after NACT. [57, 58] Expert judgment should be applied during the use of this procedure in patients with large and locally advanced breast cancer. 6. Full axillary dissection as a routine standard of care A full axillary clearance that includes level III lymph nodes should be undertaken as a standard procedure in breast cancer surgery in developing countries. There is relative

abundance of large, non-screen detected cancers and locally advanced breast cancers in these regions with high possibility of axillary nodal involvement. [49] However, it needs to be noted that extensive axillary procedures could lead to increased incidence of adverse effects like shoulder stiffness and arm edema. [59] 7. Sentinel lymph node procedure and other axillary sampling in breast cancer patients Sentinel lymph node biopsy (SLNB) could be considered in carefully selected patients

with early breast cancer in clinically negative axilla in centres that have this expertise. [60, 61] SLNB is not routinely recommended in lieu of formal axillary dissection view of higher degree of nodal positivity in this country. However, centres who have standardized this procedure in their institutions with documented results and less than 5-10% false negative rates, may consider this option in highly selected patients with 26

early breast cancer. Anatomically defined sampling of lower level axillary lymph nodes could also be considered an alternative form of reduced axillary surgery in centres with this expertise and with the same caveats as for SLNB. [62, 63] 8. Depot hydroxyprogesterone prior to surgery for primary breast cancer The adoption of pre-operative injection depot hydroxyprogesterone as a standard of care in patients with operable breast cancer is not recommended. There is a recent large

randomised trial and other reports suggesting a benefit in node positive tumours but replication of these findings in other studies is needed for routine care recommendation. [15, 64, 65, 66] Radiation therapy guidelines: 1. Use of post mastectomy radiation Post Mastectomy radiation should be used in all patients with >5 cm pathological tumor size and/or 4 or more positive nodes in axilla. [16] 2. Use of radiation in patients with 1-3 positive axillary nodes after mastectomy

Among post mastectomy patients with 1-3 positive nodes, patients with additional poor risk features (young age, vessel invasion, inadequate axillary lymph node dissection) should receive radiotherapy. A subgroup analysis from the Danish study that showed a survival benefit in these (1-3 node positive) patients equivalent to those with more than 3 involved nodes involved and other studies which have tried to analyse specific risk factors in these patients. [17, 18] 27

3. Use of radiotherapy after breast conservation Radiotherapy to the entire breast should be given to all patients with breast conservation. Whole breast radiotherapy should be followed by boost to the tumour bed by any suitable technique available at the center. 4. Use of appropriate megavoltage machines for radiation therapy may be used. Linear accelerator or Cobalt60 (Co60) unit are valid options for radiotherapy after mastectomy when such treatment is indicated. (19)

5. Use of tumor bed boost after BCT. Tumour bed boost should be given to all patients after whole breast radiotherapy, based on randomized evidence that its use improves local failure rates. [67, 68] Since no boost technique has been shown to be better than others (69), any reasonable locally available technique could be used. A higher boost dose is unlikely to compensate for the deleterious effect of a positive margin. 6. Use of axillary nodal radiation after surgery.

Use of axillary nodal irradiation after adequate surgical clearance is not routinely recommended. [20] Such radiation can be used in rare instances in patients with microscopic or gross residual cancer in the axilla after surgery. 7. Use of accelerated partial breast radiation (APBI). APBI should be considered in a highly selected group of patients with low risk features (such as age > 65 years, pathological tumour size < 2cm, and negative axillary nodes)

which is consistent with the recent ASTRO guidelines. [70] There has been recent 28

interest in using brachytherapy as the sole modality of radiation to decrease the treatment time and toxicities without compromising control. [71, 72] Systemic Therapy Guidelines The following suggestions are a framework of suggestions in order to ensure optimal delivery of care to the majority of breast cancer patients presenting to all levels of the healthcare system in India. The panel recognizes that departures from guidelines may be required in individual cases in response to the specifics.

IV. Adjuvant chemotherapy Adjuvant chemotherapy has become an important component of breast cancer management in the last 30 years. Robust evidence for its use has been generated in successive reviews of individual patient data by the Early Breast Cancer Trialists Cooperative Group. [21] a. Chemotherapy after surgery may be omitted in the following group of patients who may not benefit from the use of adjuvant chemotherapy. Such patients

could receive adjuvant hormone therapy alone. Adjuvant chemotherapy should be considered in all other patients who have no contra-indications to its use. i. Low grade tumors with strong estrogen and progesterone receptor positivity, without lympho vascular space invasion which are ≤ 2cm and node negative in post menopausal women. [8] 3. Optimal Adjuvant chemotherapy 29

Anthracycline based chemotherapy is the backbone of adjuvant chemotherapy [21] • In node negative early breast cancer patients 6 cycles of anthracycline based chemotherapy should be used. • In those with positive lymph nodes or locally advanced breast cancer, anthracycline and taxane based chemotherapy given sequentially is preferred. [22, 23]. If taxane based chemotherapy is not feasible or contraindicated, 6 cycles of anthracycline based chemotherapy is an acceptable alternative

• CMF chemotherapy may be considered as an acceptable alternative when anthracycline based chemotherapy is not possible due to feasibility issues or contra- indications. • Ovarian ablation (surgical or radiation) may be considered in certain patients, in hormone receptor positive patients. 4. Chemotherapy for LABC Neoadjuvant chemotherapy is given with the primary aim of making inoperable tumors operable in locally advanced breast cancer

• The optimal number of chemotherapy cycles is usually 3 to 6 cycles of neoadjuvant chemotherapy. [24, 25] • Anthracycline and taxane based chemotherapy is preferred. [26, 27] Sandwich therapy (chemotherapy followed by surgery followed by more chemotherapy) is widely practiced and is appropriate. Anthracycline based chemotherapy alone may also be used when taxane based chemotherapy not possible or contraindicated. 30

• In HER 2 positive patients trastuzumab may be added to chemotherapy in the neoadjuvant setting, if feasible. [28, 29] Despite randomized evidence indicating its cardiac safety in the neoadjuvant setting, concomitant use of anthracyclines and trastuzumab is not widely practiced. Taxanes (paclitaxel or docetaxel) are the preferred concomitant partner for trastuzumab. • Neoadjuvant hormone therapy may be considered in post menopausal women with

strong hormone receptor positivity. [30] Aromatase inhibitors are preferred over tamoxifen in this setting. [31, 32] The optimal duration of treatment is not well defined but may vary from 4-8 months or until after best response. [33] V. Adjuvant Hormonal Therapy Adjuvant hormonal therapy significantly improves survival in both pre and post menopausal women expressing hormone receptors. [21] It should be given to all patients expressing any degree of estrogen and or progesterone receptor positivity. The

optimal duration of hormone therapy is 5 years. [8] • Premenopausal women should receive tamoxifen for 5 years.[8] Addition of ovarian suppression to tamoxifen till now not proven to be of additional benefit. • Post menopausal women aromatase inhibitors is preferred either for 5 years or as switch therapy with 2-3 years of tamoxifen. [34, 35] • Tamoxifen for 5 years in post menopausal women is an acceptable alternative to aromatase inhibitors. [21] VI. Adjuvant Targeted Therapy 31

alternative in patients with HER 2 overexpressing tumours. Patients should be routinely screened for cardiac contraindications to trastuzumab before starting this therapy and the cardiac function should be routinely monitored every 3-4 months using echocardiography or MUGA scan during this treatment. Follow-up of patients after primary treatment: 1. Need for follow-up after primary treatment. At present regular post-treatment follow up of all patients with primary breast cancer

should be considered. It is however notable that there is lack of evidence from randomized trials supporting any particular follow-up sequence or protocol. [39, 40] 2. Use of investigative modalities during follow-up. An annual to biennial mammogram is the only routinely required investigation during follow-up in patients who are asymptomatic and have normal physical examination. This 32

is based on evidence from two randomized trials that failed to prove any benefit from more extensive investigations of asymptomatic patients during follow up care. [41, 42] Standard Operating procedure: Not Applicable a. In Patient b. Out Patient c. Day Care c) Referral criteria: Patients should be referred to a higher center (or another center) in the following situations. 1. The facility of treatment is not available at the treating center – e.g. breast

conservation, advanced radiation delivery techniques if necessary, diagnostic dilemmas etc. 2. The waiting list of patients for a particular treatment or therapy is excessively long (please see the time frames stated in this document) 33

VI. WHO DOES WHAT? and TIMELINES a. Doctor Doctor is the team leader in the entire set up. In the context of breast cancers the doctors would include specialists from Medical Oncology, Radiation Oncology, Surgical Oncology, pathology , radiology and other allied specialities. A joint clinic (tumour board) for taking collective decisions regarding the patients should be preferred. Suggested timelines Surgery Date of registration to surgery: 3 weeks Date of Joint Clinic to surgery: one week Chemotherapy

Surgery to 1st cycle of chemo: 4 weeks 1st cycle to 6th cycle: 120 days 1st cycle to 8th cycle: 160 days Radiotherapy Surgery to1st fraction of radiotherapy 200 days b. Nurse: NA c. Technician: NA 34

VII. FURTHER READING / REFERENCES 1. Consolidated report of population based cancer registries 2001-2004.Indian Council of Medical Research 2. Breast cancer incidence and mortality worldwide in 2008 summary. http://globocan.iarc.fr/factsheets/cancers/breast.asp 3. Chapter 19 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. Robbins Basic Pathology. Philadelphia: Saunders. ISBN 1-4160-2973-7. 8th edition

4. Kawai M, Minami Y, Kuriyama S et al. Adiposity, adult weight change and breast cancer risk in postmenopausal Japanese women: the Miyagi Cohort Study. Br J Cancer. 2010; 26 (103):1443-7. 5. Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003 Aug 9;362(9382):419-27. 6. Carlson RW, Allred DC, Anderson BO et al. Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2009;7:122-92

7. Aebi S, Davidson T, Gruber G et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncol 2010; 21 (Supplement 5): v9–v14. 8. Goldhirsch A, Ingle JN, Gelber RD et al. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009. Annals of Oncol 2009;20: 1319–1329. 9. Harnett A, Smallwood J, Titshall V et al. Diagnosis and treatment of early breast cancer,

including locally advanced disease--summary of NICE guidance. BMJ 2009 25; 338: b438. 10. Hammond ME, Hayes DF, Dowsett M et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of Etrogen and Pogesterone Rceptors in Beast Cncer. J Clin Oncol. 2010;28 (16):2784-95 35

11. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25:118- 145 12. Pritchard KI, Shepherd LE, O’Malley FP et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 2006; 354: 2103–2111. 13. Sandhu DS, Sandhu S, Karwasra RK, Marwah S. Profile of breast cancer patients at a

tertiary care hospital in north India. Indian J Cancer 2010;47:16-22 14. Ewertz M, Jensen AB. Late effects of breast cancer treatment and potentials for rehabilitation.. Acta Oncol. 2011;50(2):187-93. 15. Badwe RA, Hawaldar RW, Parmar V et al. Single Injection Depot Progesterone Prior to Surgery and Survival in Women with Operable Breast Cancer: A Randomized Controlled Trial. Abstr. 72: San Antonio Breast Cancer Symposium, 2009

16. Khatcheressian JL, Wolff AC, Smith TJ et al. American Society of Clinical Oncology. American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol. 2006 Nov 1;24(31):5091-7. 17. Troung PT, Olivotto IA, Kader HA et al. Selecting breast cancer patients with T1-T2 tumors and one to three positive axillary nodes at high post mastectomy locoregional

recurrence risk for adjuvant radiotherapy. Int. J Radiat Oncol Biol Phys 2005;61:1337-47. 18. Overgaard M, Nielsen HM, Overgaard J. Is the benefit of postmastectomy radiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b&c randomized trials. Radiother Oncol 2007;82:247–253. 19. Sarin R, Dinshaw KA, Shrivastava SK et al. Therapeutic factors influencing the cosmetic

outcome and late complications in the conservative management of early breast cancer. Int J Radiat Oncol Biol Phys. 1993 ;27:285-92.. 20. Beese SN, Munshi A, Buddrukar A et al. Breast radiation therapy guideline implementation in low and middle income countries. Cancer(suppl) 2008;113;2305- 2312. 36

21. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Lancet 2005;365:1687-1717 22. Laurentiis ME, Cancello G, D’Agostino D et al. Taxane-Based Combinations As Adjuvant Chemotherapy of Early Breast Cancer: A Meta-Analysis of Randomized Trials J Clin Oncol 2008;26:44-53

23. Swain SM, Jeong JH, Geyer CE et al. Longer Therapy, Iatrogenic Amenorrhea, and Survival in Early Breast Cancer. N Engl J Med 2010;362:2053-65. 24. Steger GG, Galid A, Gnant M et al.Pathologic Complete Response With Six Compared With Three Cycles of Neoadjuvant Epirubicin Plus Docetaxel and Granulocyte Colony- Stimulating Factor in Operable Breast Cancer: Results of ABCSG-14. J Clin Oncol 2007; 25:2012-2018. 25. Minckwitz GV , Kümmel S , Vogel P.et al. Intensified Neoadjuvant Chemotherapy in Early-

Responding Breast Cancer: Phase III Randomized GeparTrio Study. J Natl CancerInst; 2008:100,541-551 26. Bear, H. D. et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project protocol B-27. J. Clin. Oncol.24, 2019–2027 (2006). 27. Cuppone F, Bria E, Carlini Pet al. Taxanes as Primary Chemotherapy for Early Breast

Cancer Meta-analysis of Randomized Trials. Cancer 2008;113:238–46 28. BuzdarAU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005;23:3676-85 29. Gianni L, Eiermann W, Semiglazov V et al. Neoadjuvant chemotherapy with trastuzumab

followed by adjuvant trastuzumab versus neoadjuvant chemotherapy 37

alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 2010; 375: 377–84. 30. Semiglazov VF, Semiglazov VV, Dashyan GA, et al. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer 2007;110:244–54. 31. Eiermann W, Paepke S, Appfelstaedt J, et al. Preoperative treatment of postmenopausal

breast cancer patients with letrozole: a randomised double-blind multicenter study. Ann Oncol 2001;12:1527–32. 32. Cataliotti L, Buzdar AU, Noguchi S. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor positive breast cancer.Cancer 2006; 106:2095–103 33. Dixon JM, Renshaw L, Macaskill EJ, et al. Increase in response rate by prolonged treatment with neoadjuvant letrozole. Breast Cancer Res Treat 2009 ;113(1):145–51.

34. Dowsett M, Cuzick J, Ingle J et al. Meta-Analysis of Breast Cancer Outcomes in Adjuvant Trials of Aromatase Inhibitors Versus Tamoxifen. J Clin Oncol 28:509-518 35. The BIG 1-98 Collaborative Group. Letrozole Therapy Alone or in Sequence with Tamoxifen in Women with Breast Cancer N Engl J Med 2009;361:766-76. 36. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al.Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer .N Engl J Med 2005;353:1659-72.

37. Romond EH, Perez EA, Bryant J et al. Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer .N Engl J Med 2005;353:1673-84 38. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, M et al. Adjuvant Docetaxel or Vinorelbine with or without Trastuzumab for Breast Cancer. N Engl J Med 2006;354:809-20. 39. Aebi S, Davidson T, Gruber G, Castiglione M;Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. ESMO Guidelines Working

Group. Ann Oncol. 2010 May;21 Suppl 5:v9-14. 40. Grunfeld E, Hodgson DC, Del Giudice ME, Moineddin R. Population-based longitudinal study of follow-up care for breast cancer survivors. J Oncol Pract. 2010 ;6:174-81. 38

41. Grunfeld E, Mant D, Yudkin P, Adewuyi-Dalton R, Cole D, Stewart J, Fitzpatrick R, Vessey M. Routine follow up of breast cancer in primary care: randomised trial. BMJ. 1996 Sep 14;313:665-9. 42. Palli D, Russo A, Saieva C, Ciatto S, Rosselli Del Turco M, Distante V, Pacini P. Intensive vs clinical follow-up after treatment of primary breast cancer: 10-year update of a randomized trial. National Research Council Project on Breast Cancer Follow-up. JAMA. 1999;5;281:1586

43. Simon RM, Paik S, Hayes DF. Use of Archived Specimens in Evaluation of Prognostic and Predictive Biomarkers. J Natl Cancer Inst 2009;101: 1446 – 1452 44. Kornecki A. Current status of breast ultrasound. Can Assoc Radiol J. 2011 Feb;62(1):31- 40. 45. Houssami N, Ciatto S, Macaskill P et al. Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. J Clin Oncol 2008;26; 3248-3258

46. National Comprehensive Cancer Network Guidelines, Version 2, 2011 accessed at http://www.nccn.org/professionals/physician_gls/f_guidelines.asp 47. Arriagada R, Lê MG, Rochard F et al. Conservative treatment versus mastectomy in early breast cancer: patterns of failure with 15 years of follow-up data. Institut Gustave- Roussy Breast Cancer Group. J Clin Oncol. 1996;14:1558-64 48. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial

comparing total mastectomy, lumpectomy, and lumpectomy plus radiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-1241. 49. Leong SP, Shen ZZ, Liu TJ et al. Is Breast Cancer the Same Disease in Asian and Western Countries? World J Surg. 2010;34:2308-24. 50. de Lorenzi F. Oncoplastic surgery: the evolution of breast cancer treatment. Breast J. 2010 Sep-Oct;16 Suppl 1:S20-1 51. Peterson ME, Schultz DJ, Reynolds C, et al. Outcomes in breast cancer patients relative to

margin status after treatment with breast-conserving surgery and radiation therapy: the University of Pennsylvania experience. Int J Radiat Oncol Biol Phys 1999;43: 1029-1035 39

52. Obedian E, Haffty BG. Negative margin status improves local control in conservatively managed breast cancer patients. Cancer J Sci Am 2000; 6:28-33 53. Skripenova S, Layfield LJ.Initial margin status for invasive ductal carcinoma of the breast and subsequent identification of carcinoma in reexcision specimens. Arch Pathol Lab Med. 2010 ;134:109-114 54. Parmar V, Krishnamurthy A, Hawaldar R.Breast conservation treatment in women with

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57. Chen AM, Meric-Bernstam F, Hunt KK, et al. Breast-conserving therapy after neoadjuvant chemotherapy: The M.D. Anderson Cancer Center experience. J Clin Oncol 2004;22:2303-2312. 58. Parmar V, Krishnamurthy A, Hawaldar R et al. Breast conservation treatment in women with locally advanced breast cancer - experience from a single centre. Int J Surg. 2006;4:106-14. 59. Dillon MF, Advani V, Masterson C et al. The value of level III clearance in patients with

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for brachytherapy for carcinoma of the breast. Oncology. 2001;15:195-207 41

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 2 42

Chronic Cancer Pain Management Guidelines: These guidelines are meant for management of patients with the following pain scenarios: 1) Patients reporting with moderate to severe pain prior to any cancer therapy 2) Patients with advanced disease (including residual or recurrent disease) 3) Patients requiring pain relief during the cancer therapy esp. during chemotherapy or radiotherapy 4) Patient at end of life 5) Pain in cancer survivors. ETIOPATHOLOGY OF PAIN

• Pain can be somatic or visceral or neuropathic in origin. It can either be caused by the disease itself or by cancer therapy or may be unrelated to cancer. • The pain assessment is largely multidimensional. • It includes o The physiological component (nociception); o The sensory component (i.e. the subject’s perception of nociception, such as pain location, intensity and quality). o The affective component (i.e. mood & anxiety response)

o Cognitive component (i.e. how the pain affects patients’ thought processes and how the patients view themselves), o Behavioral components (i.e. pain behaviors such as analgesic intake or activity level) are assessed during a comprehensive patient assessment. 43

I. Cancer Pain Assessment Protocol 1. Aim: To lay down guidelines for a. Comprehensive assessment of patients with cancer for all types of pain b. Appropriate treatment regimens based on the underlying mechanisms causing pain. 2. Scope of these guidelines a. Help clinicians assess and manage cancer pain effectively b. To minimize risk of side effects due to analgesics c. To standardize prescriptions and procedures d. To individualize treatment with the goal of maximizing function & quality of life

3. Assessment of Pain Who should assess patient’s pain? The patient himself/herself is the most reliable assessor of pain and should, where possible, be the prime assessor of his or her pain. The patient should be the prime assessor of his or her pain. (D)* Due to frailty, cognitive impairment or communication deficits not all patients are able to relate the story of their pain. Completion of pain scoring tools may not be possible. In these cases families or health professionals may act as a surrogate.

How should pain be assessed? Careful history taking and listening attentively to the patient will usually diagnose the type of pain and this in turn dictates the therapy. The severity of the pain will determine the step of the World Health Organization (WHO) ladder at which the therapeutic intervention will begin. Detailed history of pain a. Location of pain b. Number of pains c. Intensity of pain : based on patient’s self report using; i. 0-10 numerical rating scale or 44

ii. pictorial scale ( Faces Pain rating scale) e. Timing of pain: onset, duration, course, intermittent or persistent f. Characteristics of the pain (Pathophysiology): i. Nociceptive pain: injury to somatic & visceral structures with activation of nociceptors • Somatic: sharp, well localized, throbbing, aching, stabbing, pressure-like • Visceral: diffuse, aching, cramping ii. Neuropathic pain: injury to peripheral or central nervous system. Described as burning, sharp, shooting, and tingling.

g. Aggravating & relieving factors h. Interference with daily activities: general activity, sleep, mood, appetite i. Etiology of pain: Is the pain caused by; • Cancer • Cancer therapy: Radiation, chemotherapy, surgery or procedure related pain • Unrelated cause j. Analgesic drug history: Current/past pain medication i. What medications? • What dose, how often & how long? ii. What was the response? • Pain relief • Side effects • Reason for discontinuation

k. Presence of clinically significant psychological disorder , anxiety or depression l. Oncologic treatment: includes i. Chemotherapy : ongoing & prior ii. Radiation therapy iii. Surgery m. Medical history i. Presence of other illnesses/ co-morbidities ii. Pre-existing chronic pain n. Physical examination: Includes general condition, gait of patient, local findings like swelling and inflammation, altered sensation like allodynia, hyperalgesia. 45

o. Laboratory & imaging studies to evaluate disease progression: i. All available investigations should be reviewed. ii. In advance cases repeating investigations for new onset pain is not warranted iii. However in select cases if the pain presentation is out of proportion of the clinical scenario, relevant imaging should be asked for. p. Reassessment at subsequent follow ups Pain assessment tools Patients with cancer pain should have treatment outcomes monitored regularly

using numerical rating scales. (D)* Observational pain rating scales should be used in patients who are unable to use a self assessment scale. (C)* The endpoint of assessment is; i. To establish a “Pain Diagnosis”: which includes the etiology and pathophysiology of pain ii. To Individualize treatment Use valid pain assessment tools to evaluate, at regular intervals, both pain intensity and the effectiveness of the pain management plan; document these reassessments. (A)* Frequency of assessments

Continual reassessment of the patient is required to identify the effectiveness of pain management, to identify and treat adverse side effects. All patients should be reassessed after 5-7 days of first visit, when possible. Principles of the World Health Organization (WHO) CANCER PAIN RELIEF PROGRAM • The patient is started on the appropriate level of the 3 steps WHO ladder for the degree of pain, analgesics are prescribed. Step 1: Paracetamol and/or non-steroidal anti-inflammatory drugs (NSAIDs)

Step 2: Weak Opioids e.g. codeine, tramadol Step 3: Strong Opioids e.g. Morphine • Oral route of drug delivery is advocated. • A patient’s treatment should start at the step of the WHO analgesic ladder appropriate for the severity of the pain. Prescription of analgesics should always be adjusted as the pain severity alters. If the pain severity increases and is not controlled on a given step, move upwards to the next step of the analgesic ladder. Do not prescribe another analgesic of the same potency.

• All patients with moderate to severe cancer pain, regardless of aetiology, should receive a trial of opioid analgesia. • Chronic pain in patients with cancer is usually continuous and where this is so, therapeutic plasma levels of analgesics should be maintained by giving the drug at regular intervals according to its pharmacokinetic and pharmacodynamic profile not as PRN basis. • Appropriate analgesia for breakthrough pain must be prescribed. 46

Figure 1: World Health Organization analgesic ladder II. Guidelines for prescribing Non-opioid analgesics - Paracetamol , NSAIDs may be used at any stage of WHO ladder - Used synergistically and produce better pain relief. Paracetamol and / or NSAID should be used unless contraindicated (A) a) Paracetamol: Paracetamol works as a weak prostaglandin inhibitor. It achieves this by blocking the production of prostaglandins, thereby blocks pain message to the brain and at source of

pain, hence has different action from Aspirin and NSAIDs (non-steroidal anti-inflammatory drugs). Paracetamol can be used by patients for whom NSAIDs are contraindicated, including those with asthma or peptic ulcers. Because there are few interactions with other medications, paracetamol can be taken by people with sensitivity to aspirin. Standard safe dose is 1000mg four times a day or upto 4 gm/day in a normal healthy adult. b) NSAIDs:

Use any NSAID that the patient has found effective and tolerated well in the past, otherwise consider ibuprofen to the maximal dose. Ibuprofen, 400 mg four times a day (daily maximum = 3,200 mg) Note that the potential adverse effects of chemotherapy, such as hematologic, renal, hepatic, and cardiovascular toxicities, can be increased by the concomitant prescription of NSAIDS. Opioid analgesics are a safe and effective alternative analgesic to NSAIDs. i. Monitoring for NSAID toxicities:

- Baseline blood pressure, BUN, creatinine, liver function studies [alkaline phosphatase, LDH, SGOT, SGPT], CBC, and fecal occult blood - Repeat every 3 mths to ensure lack of toxicity 47

ii. NSAID and toxicities: Age > 60 y, compromised fluid status, multiple myeloma, diabetes, interstitial nephritis, papillary necrosis, and concomitant administration of other nephrotoxic drugs (including cyclosporine, cisplatin) and renally excreted chemotherapy iii. Treatment of toxicity : - If patient develops gastrointestinal upset, peptic ulcer , hemorrhage or vomiting, consider discontinuing NSAID or changing to selective COX-2 inhibitor. COX-2 inhibitors

are associated with lower incidence of GI adverse effects and do not inhibit platelet aggregation, however, they have not been demonstrated to have reduced renal adverse effects.Consider adding antacids, H2 receptor antagonists, omeprazole. - Discontinue NSAID if liver function studies increase 1.5 times the upper limit of normal. - If congestive heart failure or hypertension develops or worsens, history of cardiovascular disease, discontinue NSAID.

- Risk of bleeding may significantly increase in patients on anticoagulants, such as warfarin or heparin, if NSAIDs are given. III. Guidelines for prescribing opioids in Cancer Pain: 1. Intent: a. To lay down guidelines for b. the use of opioid analgesics in patients with cancer pain c. the use of rescue doses for breakthrough pain d. Conversion / rotation from one opioid to another opioid e. Conversion of oral to transdermal route f. the management of opioid induced side effects

2. Scope of these guidelines a. To standardize prescription of opioids across the service & hospital b. To prevent and actively manage opioid related side effects 3. General principles of opioid prescription (APPENDIX I) a. The WHO analgesic ladder should be followed while treating pain in patients with cancer b. Start treatment at the WHO analgesic ladder step appropriate to the severity of pain c. Oral route preferred. Other routes (S.C, I.V, Transdermal, buccal, transmucosal,

PR) can be used when indicated, if oral route cannot be used d. Intramuscular route not recommended as it is painful and unreliable e. Analgesia should be prescribed on a “regular” and not on an “as required” basis f. Appropriate analgesia should be prescribed for breakthrough pain 48

g. Mixed agonists-antagonists have limited usefulness in cancer pain and should not be prescribed in combination with opioid agonists. Could precipitate withdrawal in opioid dependent patients h. Reassure patients about the low probability of addiction to opioids & encourage to adhere to treatment regime 4. Principles of opioid maintenance therapy a. Extended release or long-acting preparations on a regular schedule to provide background analgesia once dose requirements are stable

b. Rescue doses (1/6th of the 24 hr dose of morphine) in the form of an immediate acting/ short acting opioid preparation should be prescribed for breakthrough pain or acute exacerbations related to activity c. The same opioid, if possible, should be used for breakthrough and “around-the- clock” dosing d. Increase the dose of the “around-the-clock” preparation if patient requires more than 3 breakthrough analgesic doses e. Dose increase, if necessary i. Immediate release preparation: after every 24 hours

ii. Controlled release or extended release preparations: after 48 hours f. Each dose increment can be set at 33-50% of the pre-existing dose and should be accompanied by a proportionate increase in the rescue dose. g. Transmucosal fentanyl should be used only in opioid tolerant patients and initiated with the lowest dose h. For patients who experience inadequate pain relief or unacceptable side effects : Consider Opioid rotation 5. Conversion from one opioid to another (Opioid rotation)

a. For patients with inadequate pain relief and/or intolerable side effects while on strong opioids: Consider switching to a different opioid b. Determine the amount of current opioid taken in last 24 hours that produced good pain relief c. Calculate the equianalgesic dose of the new opioid d. An equianalgesic table (APPENDIX II-IV)should be used when switching to ensure equivalency e. Safe to reduce the dose of the new opioid by 25% to 50% when switching, if pain relief was good

f. If previously pain relief was inadequate, may begin with 100% of equianalgesic dose or increase by 25% g. Assess regularly for efficacy & side effects. 6. Principles for prescription of Transdermal fentanyl a. Pain should be well controlled on a short acting opioid prior to starting a Transdermal fentanyl patch. b. Should be used only in opioid tolerant patients 49

c. Not recommended for unstable or poorly controlled pain d. Fever and use of warming devices (warming blankets etc) accelerate absorption from the patch, hence are contraindications for its use. e. Analgesic duration is usually 72 hours, but some patients require replacement every 48 hours 7. Conversion from morphine / codeine to transdermal fentanyl a. Select mcg/hr dose of transdermal fentanyl based on the last 24 hr dose of Morphine or codeine (APPENDIX III)

b. An “as- required” dose of immediate release/ short acting morphine should be prescribed and will be needed particularly during the first 8 to 24 hours c. The patch dose can be increased after 3 days based on the amount of daily ‘as- required” opioid needed. 8. Management of side effects a. Constipation i. Should prescribe a stimulant laxative – stool softener (Liquid paraffin + Na picosulphate) ii. Increase dose when increasing dose of opioids iii. Adequate fluid and dietary fiber intake

iv. Add another laxative, e.g.; lactulose 30-60 ml/day, if constipation persists v. Severe constipation: Sena compounds (Senasoft) initiate with 1hs. vi. Enema, if fecolith b. Nausea i. Prophylactic use of anti-emetics may be recommended in emesis prone patients ii. If nausea develops; 1. Rule out other causes (constipation, CNS pathology, Chemotherapy, radiation therapy, hypercalcemia) 2. Consider metoclopramide 10 mg PO every 6-8 hrs, or in refractory

cases, haloperidol 0.5-1 mg PO every 6-8 h may be added 3. If nausea present despite above, add an “around-the-clock” serotonin antagonist e.g.; ondansetron 8 mg PO TDS. c. Pruritis i. Assess for other causes (other medications) ii. Antihistamines to be used. Diphenhydramine (Benadryl ) 25-50 mg IV or PO every 6 hrs or promethazine (phenargan)12.5 -25mg PO every 6 hrs iii. If persisting despite above, consider continuous infusion of naloxone 0.25

mcg/kg/h and titrate up to 1 mcg/ kg/ hr without decreasing analgesic efficacy 50

d. Sedation i. Assess for other causes (CNS pathology, other medications, hypercalcemia, dehydration, sepsis, hypoxia) ii. Reduce dose of opioid iii. Consider rotation iv. Increase non-opioid analgesics where feasible v. CNS stimulants e.g.; Caffeine 100-200 mg PO every 6 hrs could be considered e. Respiratory depression i. Shallow breathing & unresponsiveness. Consider naloxone infusion. Dilute 1 ampoule (0.4 mg/ml) in 9 ml of normal saline to a total volume of

10 ml. Give 1-2 ml (0.04-0.08 mg) every 30-60 seconds until symptoms improve. ii. If no improvement, consider other causes for change in CNS status f. Delirium i. Assess for other causes (e.g.; hypercalcemia, CNS metastases, other psychoactive medications) ii. Reduce dose of opioid if feasible iii. Haloperidol 0.5-2 mg PO or IV every 4-6 hrs g. Cognitive impairment i. Stable doses of opioids (> 2 weeks) unlikely to interfere with psychomotor & cognitive function. ii. Monitor during initial titration

h. Usually tolerance develops for all side-effects with time, except constipation. If persists, consider opioid rotation or maximize non-opioid / neuraxial analgesics/ neuroablative procedures. 9. Co-morbidities a. Liver disease i. All opioids are metabolized in the liver i. Opioid clearance reduced, bioavailability and half-life increased ii. Risk of adverse effects because of higher-than-expected plasma concentrations iii. Metabolism of morphine not significantly altered

iv. Avoid use of Acetaminophen in these patients b. Renal disease i. Active metabolites of propoxyphene ( norpropoxyphene), morphine (morphine-6-glucuronide [M6G], morphine-3-glucuronide [M3G] and nor morphine) and codeine may accumulate 51

ii. High levels of M3G may cause hyperalgesia and myoclonus iii. Use opioids with caution 1. Reduced dose and / or 2. Reduce frequency of administration iv. Avoid using morphine and codeine in patients with renal failure v. Fentanyl, Alfentanil and Buprenorphine are the safest opioids in patients with chronic renal disease stage 4 or 5 (GFR <30 ml/min). Transdermal fentanyl is the opioid of choice c. Dysphagia, Intestinal obstruction: Transdermal Fentanyl patches are the

treatment of choice. Start with the lowest strength patch (12.5 mcg) in opioid naïve patients. If already have taken morphine or other oral opioid, then start appropriate dose of Transdermal fentanyl referring to the conversion chart (APPENDIX III) APPENDIX I: Basic pharmacology of opioids (available in India) Drug Onset of Time to Duration Bioavailability Peak plasma Half life pain peak of pain (range) level relief pain relief relief Codeine 30-60 45-60 4-6 hr 40%(12-84%) 1-2 hr 2.5-3.5 hr min min

Tramadol 30 min 180 min 4-6 hr 75% 2 hr 6 hr Morphine 20-30 60-90 3-6 hr 35% (15-64%) 15-60 min 1.5-4.5 hr min min APPENDIX II:Oral to parenteral opioid equivalences table OPIOID Dose (mg) equianalgesic to 10 IV to PO Duration Of mg Morphine FACTOR Action PARENTERAL ORAL DOSE DOSE Codeine 130 mg 200 mg 1.5 3-4 hr Morphine 10 mg 30 mg 3 3-4 hr Tramadol ---- 50-100 mg --- 3-7 hr APPENDIX III: Dose conversion table from other opioids to Transdermal fentanyl Transdermal Morphine Codeine Fentanyl

IV/Sub cut Oral IV/Sub cut Oral 25 mcg/h 20 mg/day 60 mg/day 130 mg/day 200 mg/day 50 mcg/h 40 mg/ day 120 mg/day 260 mg/day 400 mg/day 52

75 mcg/h 60 mg/day 180 mg/day 390 mg/ day 600 mg/ day 100 mcg/h 80 mg/ day 240 mg/day 520 mg/day 800 mg/day APPENDIX IV: Dose conversion ratios (While switching opioids) Current opioid (oral) New opioid (oral) How to calculate 24 hour dose Codeine Morphine Divide by 10 Tramadol Morphine Divide by 5 Reference: Control of pain in adults with cancer: Summary of SIGN guidelines. BMJ 2008, 337:1106-1110) IV. Guidelines for prescribing adjuvants:

What is an adjuvant? An adjuvant is a medication that is not primarily designed to control pain, but can be used for this purpose. They are a diverse group of drugs that includes antidepressants, anticonvulsants (antiseizure drugs), and others. a) Antidepressants The best studied adjuvant analgesics are the tricyclic antidepressants (TCAs), such as amitriptyline , and desipramine. These drugs have been shown to relieve pain

independent of their effects on depression; that is, patients who are not depressed may experience pain relief. Once the correct dose is found for the individual patient, favorable results are usually seen within a week; however, side effects, including weight gain, dry mouth, blurred vision and constipation, are possible. They are prescribed either alone or with anticonvulsant in patients with neuropathic pain b) Anticonvulsants

Drugs that are primarily used to treat epilepsy (seizures) have been used to treat nerve pain conditions. Many anticonvulsant drugs have been shown in clinical studies to be effective. The most common side effects associated with these drugs are mental clouding and sleepiness. Gabapentin or pregabalin are two agents which are used commonly. c) Alpha-2-Adrenergic Agonists Currently, there are two alpha-2-adrenergic agonists that have some evidence as pain relievers: tizanidine and clonidine

d) Local Anesthetics Intravenous infusion of a local anesthetic is a special technique that may be used by pain specialists. Mexilitine has shown to be effective in chronic nerve pain syndromes with 53

lancinating type of pain. Other oral local anesthetics are also used. Lignocaine transdermal patch 5% is used in post herpetic analgesia e) Steroids Corticosteroids can be used as an effective analgesic for treating some cancer pain syndromes. Used in pain due to raised intracranial tension, nerve compression, epidural spinal cord compression, pain due intestinal obstruction, plexopathies and complex regional pain syndrome (reflex sympathetic dystrophy). f) Other Adjuvants

- Baclofen as a muscle relaxant, is also used to treat nerve pain syndromes. - Drugs that block wide dynamic range neurons involved in the experience of pain, the N- methyl-D-aspartate (NMDA) receptor, may also be used as very useful analgesic in refractory neuropathic pain conditions. Examples: Ketamine (anesthetic), dextromethorphan (the cough suppressant, but at higher doses than those needed to block cough) - Bisphosphonates: is considered for use as part of the regime to treat pain in patients

with metastatic bone pain (B) V. Guidelines for the management of Neuropathic Pain 1. Aim: a. To lay down guidelines for the; b. Assessment of neuropathic pain in patients with cancer c. Appropriate treatment regimens based on the underlying mechanisms causing pain. 2. Scope of these guidelines a. Help clinicians to assess and manage neuropathic pain in cancer effectively. b. To minimize risk of side effects due to analgesics c. To standardize prescriptions and procedures

d. To individualize treatment with the goal of maximizing function & quality of life 3.1 What is neuropathic pain? e. Pain arising as a direct consequence of a lesion or a disease affecting the somatosensory system (Neuropathic Pain Working Group 2006) f. Common neuropathic syndromes in cancer g. Brachial plexus neuropathies h. Chemotherapy-induced neuropathy: Cisplatin, Oxaliplatin, Paclitaxel, Thalidomide, Vincristine, Vinblastine i. Cranial neuropathies, Post herpetic neuropathy

l. Phantom limb m. Post-mastectomy syndrome n. Post-thoracotomy syndrome How to diagnose neuropathic pain? In the pain clinic, assessment of a pain patient with suspected neuropathic pain aims at recognition of neuropathic pain, localizing the lesion, and diagnosing the causative disease or event. Nerve compression has been reported to be the most common cause of neuropathic pain in cancer patients (79%), followed by nerve injury (16%) and sympathetically mediated pain (5%).

• Description/ Characteristics of pain: i. Spontaneous (Stimulus independent): 1. burning 2. shooting 3. stabbing 4. Electric shock-like pain 5. Pin & needles 6. Dysaesthesias (abnormal and unpleasant sensations) 7. Paraesthesias (abnormal, but not unpleasant sensations) ii. Stimulus evoked pains (Elicited by mechanical, thermal or chemical stimulus): 1. Hyperalgesia (increased response to normally painful stimulus) 2. Mechanical allodynia (pain from non-painful stimuli)

3. Inability to tolerate cloth, air from fan or air conditioning vent touching the skin 4. Cold allodynia (pain evoked by cold stimulus) Pain assessment tools: • painDETECT questionnaire: this simple scoring system is available in English, Hindi, Marathi and other many Indian languages, can be completed by individual patients, helped by their relatives. A diagnosis of neuropathic pain can be made. A total of score points are estimated out of 35 points. < 12 : negative , 13-18: possible, > 19 : positive

neuropathic pain. Frequency of assessments Review regularly, at least once a week, to determine the effectiveness of treatment. If patient is in hospital, more often twice a week. 4 Management of neuropathic pain a) Initiate pharmacotherapy with only one drug at a time 55

b) Neuropathic pain can be treated by unconventional analgesics (adjuvants) which are primarily not analgesics e.g. antidepressants, anticonvulsants or combined with conventional medications such as opioids. c) Adjuvants analgesics e.g. tricyclic antidepressants (TCAs) and anticonvulsants are used as first line drugs. d) If pain relief is inadequate with one drug, TCA+ anticonvulsants (Gabapentin or pregabalin) may be used.

e) Selective serotonin reuptake inhibitors (SSRI) or selective nor epinephrine reuptake inhibitors (SNRI) may be added as 2nd line drugs e.g. duloxitine, lamotrigine. f) Aggressive side effects management is required to open the therapeutic window. g) Opioids may be added as third line drug if the combination fails to provide satisfactory relief. h) Capsaicin cream, lidocaine 5% patch or Inj ketamine may also be used to obtain optimum pain relief. The starting dose and any titration of each pharmacological

intervention should be properly planned in individual patient, taking into consideration the potential side-effects and interactions with other medication. i) Non-Opioids: NSAIDs and Paracetamol have a limited use in neuropathic pain. j) However patient may have associated nociceptive pain which may respond to the same. k) Interventional treatments for neuropathic pain should be offered to any patient whose pain is not adequately treated with first and second line drugs or for patients

with intolerable side-effects from medication l) Invasive treatments should usually be carried out as part of a multidisciplinary treatment plan References: Paice JA. Mechanisms and management of neuropathic pain in cancer. www.SupportiveOncology.net .2003. Vol 1 (2); 107-120 Management of neuropathic pain in cancer. EAPC Congress Glasgow 56

VI. Guidelines for management of bone metastasis pain: 1. INTRODUCTION a) Cancer-induced bone pain (CIBP) is one of the most common types of cancer pain, present in 28-45% of patients with bone metastasis. CIBP often results in hospice or hospital admission and is associated with reduced quality of life, increased psychological distress and decreased physical and social functioning. b) The degree and location of bone metastases do not necessarily correlate with the

severity of pain. Some patients have widespread bone metastases but minimal pain, whereas others have minimal bone metastases but severe pain. Apart from CIBP, the other complications of cancer-induced bone disease are hypercalcaemia, cytopaenias and risk of pathological fractures. c) CIBP does not exist as a single entity, but is instead a combination of background pain and breakthrough pain. d) Almost half of breakthrough pain episodes were rapid in onset (<5 min) and short in

duration (<15 min). Forty-four per cent of patients with breakthrough pain had pain that was unpredictable e) Up to 45% of patients with CIBP report poor pain control 2. DIAGNOSIS: A cancer patient requires a comprehensive evaluation to determine the etiology and site of the specific pain syndrome involved bone metastasis. i. Plain X-ray: Lytic, nodular or rounded, well-circumscribed sclerotic lesions are seen on a plain x-ray.

ii. CT-scan: Is extremely useful to confirm isolated lesions, assess the extent of soft tissue involvement and to differentiate between metastasis and degenerative changes. iii. Bone scan: Is a sensitive imaging tool to detect bone metastases early and still the optimum method for diagnosis. However, small deposits (less than 2 mm) may be missed. iv. MRI: Useful to image the spine, vertebral bodies, paraspinal area including the soft

tissue component and spinal cord compression. It can differentiate between benign and malignant vertebral collapse4. v. PET-Scan: Positron emission tomography uses radioactive F-fluorodeoxyglucose (FDG) as a tracer to highlight metabolically active cells. It is not specific for bone metastases and will also identify any area with increased metabolic rate and glucose turnover. The test is now used as an investigational tool for most cancers5. 57

vi. Biochemical markers: The biochemical markers currently available lack specificity and are of no value in the diagnosis of skeletal metastasis. They include: alkaline phosphatase, urinary hydroxyproline and urinary hydroxyproline: creatinine ratio. 3. TREATMENT a. The current treatment options for CIBP are wide-ranging and include external beam radiotherapy, opioid analgesia, non-steroidal anti-inflammatory drugs (NSAIDs) and bisphosphonates. In addition, local surgery and anaesthetic

techniques are used. However, each of these treatment options is accompanied by limitations in their use. b. Radiotherapy is the gold standard treatment of CIBP. Complete pain relief is only achieved in about 25% of patients, whereas 50% of patients will achieve 50% pain relief . c. NSAIDs, being anti-inflammatory drugs are important in the treatment of CIBP based on experience rather than strong evidence. d. Opioids are an effective therapy for background pain in CIBP. However, a normal

release morphine will probably be ineffective in patients with rapid-onset, short duration breakthrough pain due to its slow onset of action. e. Alternative routes of fast acting opioids are transnasal(butorphenol),transmucosal (fentanyl). f. Bisphosphonates are used to reduce skeletal morbidity from bone metastases and for analgesia in CIBP. g. Pain produced by bone metastases influences the nervous system peripherally and centrally. Spontaneous breakthrough pain which may occur at rest in bone

metastasis, may poorly respond to opioids. References: 1. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006;12(20 Pt 2): 6243se6249s. 2. Colvin L, Fallon M. Challenges in cancer pain management bone pain. Eur J Cancer 2008;44(8):1083e1090. 3. Urch C. The pathophysiology of cancer-induced bone pain: current understanding. Palliat Med 2004;18(4):267e274. 4. Michaelson MD, Smith MR. Bisphosphonates for treatment and prevention of bone

metastases. J Clin Oncol 2005;23(32):8219e8224. 5. Wong R, Wiffen PJ. Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database Syst Rev 2002;(2): CD002068. 58

VII. Guidelines for the management of Breakthrough Pain (BTP) in cancer 1. Aim: To lay down guidelines for a. Identification & assessment of breakthrough pain in cancer patients. b. Appropriate treatment regimens for the management of such pain c. To reduce the intensity, severity & impact of each bout of pain 2. Definition: A transitory exacerbation of pain experienced by the patient who has a relatively stable and adequately controlled baseline pain (Portenoy et al 2004). Prevalence of BTP is 20- 65%.

3. What are the types of BTP? a. Incident pain: precipitated by movement/coughing b. Spontaneous pain : occurs in absence of a specific trigger & at random Should be differentiated from end-of-dose pain which occurs, • just prior to the scheduled dose of analgesia, • Either due to an inadequate analgesic dose or too long an interval. • Gradual onset. 4. How to identify breakthrough pain? a. Rapid onset b. Severe intensity c. Variable duration (usually 30 minutes) 5. Assess

- All patients with cancer pain for presence of BTP (D) - Each episode of breakthrough pain for; a. Frequency b. Duration c. Pain intensity d. Precipitating factors e. Baseline pain treatments and their effectiveness f. Re-assess to determine; i. Efficacy & tolerability of treatment. ii. Change in nature of the pain 6. Management of BTP a. Optimize the round-the-clock analgesia by titrating opioids b. Should always prescribe rescue analgesia and teach the patient how to use it.

c. Opioids are the rescue medications of choice. Little evidence to support the use of non-opioid analgesics for breakthrough pain. 59

d. The opioid should be chosen based on its pharmacokinetic properties. If possible, rescue dose should be of the same opioid used for baseline pain (Mercadante et al 2002)2 but there are no compelling reasons for using the same opioid. e. European Association of Palliative Care (EAPC) recommendations are to start with 1/6th (17%) of the daily dose, and subsequent titration according to clinical effect.(Hanks et al 2001)3. f. The dose of opioid rescue medication should be determined by individual

titration(Zeppetella, 2006)4 (B) g. Incident pain: pre-emptive use of a short acting opioid, 30 minutes before the activity which precipitates pain. (Mc Carberg, 2007)5. h. Spontaneous pain: Oral transmucosal fentanyl citrate (OTFC) found to be an effective treatment for breakthrough pain by a recent Cochrane review. (Zeppetella, 2006)4 i. End-of-dose failure: alter the around-the-clock medication to increase the dose or shorten the dosing interval (McCarberg, 2007)5.

j. Transdermal fentanyl: duration of action- 72 hours. In some patients (3-43%), duration is between 48-72 hrs & may require breakthrough medications after 48 hrs. Replace the patch in these patients every 48 hrs rather than 72 hrs instead of increasing the dose of the patch. k. More than 4 episodes of breakthrough pain in a day: review the baseline pain management. (Coluzzi, 1998)6 APPENDIX V. Management of BTP OTFC titration (adapted from Zeppetella2005) Start dose at 200mcg - Patient consumes over 15 min

- Waits for a further 15 mins, if analgesia inadequate, consumes another OTFC of the same strength Did patient have adequate pain relief? Yes No Successful dose determined Increase dose to next strength 60

APPENDIXVI: Titration to obtain “correct dose” of oral morphine for breakthrough pain Start with 1/6th (17%) of the daily dose TITRATE Pain relieved but side effects Pain not relieved & side troublesome effects troublesome Pain not relieved & no side effects Titrate dose Try alternative downwards treatment Titrate dose upwards 61

APPENDIXVII: Breakthrough dose of oral morphine for background dose of transdermal fentanyl Background dose of transdermal Breakthrough dose of oral fentanyl (µg/hr) morphine (mg) 25 < 20 50 25-35 75 40-50 100 55-65 125 70-80 150 85-95 175 100-110 200 115-125 225 130-140 250 145-155 275 160-170 300 175-185 62

REFERENCES: 1. Portenoy R.K, Forbes K, Lussier D, Hanks G. (2004). Difficult pain problems: an integrated approach. In Doyle D, Hanks G, Cherny N, Calman K , ed.Oxford Textbook of Palliative Medicine (3rd edn). Oxford University Press, Oxford, 438-458 2. Mercadante S, Radbruch L, Caraceni A, et al. (2002). Episodic (breakthrough) pain. Consensus Conference of an Expert Working Group of the European Association for Palliative Care. Cancer, 94:832-839

3. Hanks G W, de Conno F, Cherny N, et al. (2001). Morphine and alternative opioids in cancer pain: the EAPC recommendations. British Journal of cancer, 84: 587-593. 4. Zeppetella G, Ribeiro MDC. Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database of Systematic Reviews 2006 5. McCarberg, B. The treatment of breakthrough pain. Pain Med 2007 8:S 8-12 6. Coluzzi PH. Cancer pain management: newer perspectives on opioids and episodic

pain. Am J Hosp Palliat Care. 1998 Jan-Feb;15(1):13-22 7. Zeppetella G (2005).Is the recommended titration schedule for OTFC too conservative?. European Journal of Palliative Care,12(Suppl):6-7. 63

VIII. Guidelines for interventional Pain management: Indications: a) Usually nerve blocks are indicated when even oral strong analgesics do not provide even 50% pain relief and there are intolerable side effects. b) can be relieved. Verify interventional technique which will provide sufficient benefit for the diagnosed pain syndrome. c) Pain likely to be relieved with nerve block (eg, pancreas/ upper abdomen with celiac plexus block, lower abdomen with superior hypogastric plexus block, intercostal nerve,

or peripheral nerve) Commonly used interventional procedures 1) Neurodestructive procedures for well-localized pain syndromes a) Head and neck: peripheral nerve block b) Upper extremity: brachial plexus neurolysis c) Thoracic wall: epidural neurolysis, intercostal neurolysis d) Upper abdominal pain (visceral): celiac plexus block, thoracic splanchnicectomy e) Midline pelvic pain: superior hypogastric plexus block f) Rectal pain: intrathecal neurolysis, midline myelotomy or superior hypogastric plexus

block, Ganglion Impar g) Unilateral pain syndromes: cordotomy h) Consider intrathecal L/S phenol block 2) Radiological interventions: Percutaneous vertebroplasty/kyphoplasty, Radiofrequency ablation for bone lesions 3) Neurostimulation procedures for cancer-related symptoms (ie, peripheral neuropathy) 4) Regional infusions (requires spinal intrathecal infusion pump) easy to internalize implanted pump; for infusions of opioids, local anesthetics, clonidine, and ziconotide Contraindications ;

Infection, coagulopathy, very short or lengthy life expectancy, distorted anatomy, patient unwillingness, medications that increase risk for bleeding,(eg, use of anti-angiogenesis agents such as bevacizumab) or technical expertise for performing interventions is not available. 64

IX. Guidelines for pain management at end of life: 1.Introduction a) Many patients at the end of life are unable to verbally report pain using standardized scales. In this situation, evaluate behavioral cues such as facial grimacing, guarding, or vocalizing. b) Rule out other potential causes of distress such as constipation, urinary distension, or emotional and spiritual distress c) Administration of opioids may be complicated by the inability to swallow.

Alternate routes of administration include buccal, sublingual, rectal, subcutaneous, or intravenous delivery. d) Doses may be decreased in some cases, as organ system failure leads to reduced excretion of the drug and or its metabolites, as well as other factors. e) Myoclonus may occur when higher doses of opioids are administered, particularly in the face of renal dysfunction. Reducing the opioid dose or rotating to another opioid can be effective, and adding benzodiazepines can be helpful. 2.Management:

a) their anxiety. b) chaplains, and nurses) c) Provide emotional support to the dying patient and his or her family members. d) e) f) or grandchildren) when communicating about death. g) counseling and support. 65

References: Sykes N, Thorns A. The use of opioids and sedatives at the end of life. Lancet Oncol 2003;4:312–8. X. Guidelines for pain management in cancer survivors: 1. INTRODUCTION: A large number of disease-free cancer survivors live with pain or neuropathies induced by treatment or by the cancer itself. Sometimes these conditions resolve over time, but irreversible damage to tissue and nerves can cause pain and neuropathy to progress and persist indefinitely.

Because health care professionals may not recognize these as delayed problems or know how to identify those at greatest risk, many of these conditions go undiagnosed and untreated. Most chronic pain syndromes and neuropathies experienced by disease-free survivors of cancer originate from o an injury to peripheral nerves from surgical trauma, o neurotoxicity of chemotherapeutic agents o radiation-induced damage to nerves Other sources of persistent or intermittent pain include:

i. myofascial pain dysfunction syndrome, which is characterized by trigger points in muscle or at the junction of muscle and fascia that refer pain to other areas of the body, and which is associated with breast, thorax, and head and neck surgery in cancer survivors. ii. fistula formation following pelvic surgery. iii. chronic inflammation, such as radiation-induced enteritis or proctitis. iv. osteoradionecrosis,a radiation-induced demineralization and vascularization of the bone.

v. Persistent nerve damage from tumor infiltration of nerves. 2. TREATMENT: Anticonvulsants, tricyclic antidepressants, and opioids can be effective for alleviating neuropathic pain. Novel pharmacologic agents such as neuroprotective compounds e.g amifostine,glutamine,and glutathione,and neurotrophic factors (such as nerve growth factor) can also be effective. Vitamin E has shown some promise in prophylaxis of 66

chemotherapy- induced peripheral neuropathy with cisplatin and paclitaxel. Less is known about nonpharmacologic and alternative therapies. References: Levy MH, Chwistek M, Mehta RS. Management of chronic pain in cancer survivors, Cancer J. 2008 Nov-Dec;14(6):401-9. 67

MALIGNANCIES OF GASTROESOPHAGEAL JUNCTION (Adenocarcinoma GEJunction) Col (Prof) Sanjay Kapoor VSM, HOD Oncology Command Hospital Lucknow CASE DEFINITION Tumors having their center 5-cm proximal or distal to the anatomic cardia are classified as malignancies of the GE junction.Histologicaly they can be adenocarcinoma or squamous Cell carcinomas.Squmaous cell Carcinomas are treated as carcinoma esophagus,hence all the further discussion will be restricted to Adenocarcinoma GE Junction

Incidence of adenocarcinoam GEJunction is on the rise and is emerging as a new disease. Carcinoma esophagus is now more common in the lower third and there is marked increase in the carcinomas of proximal stomach creating the new identity of Adenocarcinoma of GEJunction. There is a rise in the incidence of almost 10% per year, more the non endemic areas or European world. Unlike Squamous cell carcinoma,Adenocarcinoma GEJunction is found in the developed

countries and in patients of upper socio economic status and has a better prognosis than the SCC esophagus. It is associated with Obesity, High Body mass index, GERD and Barrets Esophagus. Barrets Esophagus –this defined as the presence of intestinal metaplasia (mucin producing goblet cells) in columnar cell lined epithelium that replaces the squamous epithelium of the distal esophagus.This specialized metaplasia confirmed on histopathology is mandatory for

diagnosis of barrets Esophagus which confers a 40-125 fold higher risk for developing adenocarcinoma GEJunction and is the singlemost important risk factor. Classification of Barrets Esophagus Siewart’s Classification Type I – Epicenter of tumour or more than 66% of the tumor mass located >1 cm above the anatomic GE junction Type II- Tumor epicenter located within 1-cm proximal and 2-cm distal to the GE junction Type III- Tumor epicenter or more than 66% of the tumor mass is located more than 2

cm below the anatomic GE junction Revised Seiwart’s classification of 2000 Type I adenocarcinoma, which may infiltrate the GE junction from above Type II adenocarcinoma, which arises from the GE junction Type III adenocarcinoma, or subcardial gastric carcinoma, which infiltrates up to the GE junction from below WHEN TO SUSPECT Presenting Symptoms 68

Most common presenting feature of adenocarcinoma GEJunction is dysphagia, initially to solids and then to liquids. Other symptoms that patient may present with are • Odynophagia • Dyspepsia • Loss of weight • Anorexia • Left supraclavicular node • Haematemesis • Vomiting Differential Diagnosis All elderly patients presenting with long standing dyspepsia and features of GERD or with anorexia, loss of weight and dysphagia,should be investigated for carcinoma esophagus Common differential diagnosis are • GERD

• Barrets Esophagus • Cercinoma Stomach • Carcinoma Esophagus • Achlasia cardia • Hiatus Hernia • Esophageal diverticulum or stricture Examination Besides the routine general and systemic examination, patient should be assessed for • General condition • Nutritional status • Pallor • Left supraclavicular node WORKUP FOR DIAGNOSIS AND STAGING Investigations- Following investigations are mandatory for assessing any suspected or diagnosed case of Carcinoma Esophagus • Upper GI Endoscopy –To see for

(cid:216) Presence of growth (cid:216) Site of growth (cid:216) Nature of growth (cid:216) Vertical and circumferential extent of growth (cid:216) Passage of scope beyond the growth 69

(cid:216) Status of stomach (cid:216) Presence of Barrets esophagus ( Naso gastric feeding tube to be placed if esophageal lumen found to be obstructed) • Endoscopic Biopsy- from representative site. Following to be assessed (cid:216) Histology (cid:216) Differentiation (cid:216) Presence of Barrets esophagus • CECT Chest and upper abdomen-To see for (cid:216) Vertical and Horizontal extent of diseases (cid:216) Adherence or infiltration of surrounding structures like trachea, main bronchus,

aorta and pericardium (cid:216) Para esophageal nodes (cid:216) Involvement of GE Junction and proximal stomach in the lower third esophageal and GEJunction cancers (cid:216) Liver metastasis (cid:216) Pericardial and plural effusion (cid:216) Ascitis (cid:216) Perigastric lymphnodes • FNAB of left supraclavicular node if present and left scalene pad of fat biopsy if nodularity felt • Hb, TLC, DLC, blood grouping • Biochemistry-LFT,RFT, Blood Sugar, Electrolytes and platelets • ECG • Ba Swallow-

Optinal Investigations Following Investigations are optional and may be done in tertiary care centres where facilities are available • Endoscopic Ultrasound • Endoscopic ultrasonographic FNAB of paraesophageal nodes • PET Scan • Her 2 Ney receptor study by FISH technique on biopsy specimen STAGING (AJCC 7th Ed 2010) • Tis High grade dysplasia (ca in situ) 70

• T1a Tumour invades lamina propria or muscularis mucosa • T1b Tumour invades submucosa • T2 Tumour invades muscularis propria • T3 Tumour invades adventitia • T4a Resectable tumour invading pleura, pericardium or diaphragm • T4b Unresectable tumour invading other adjacent structures, • Nx Regional lymph nodes cannot be assessed • N0 No regional lymph node metastasis • N1 Metastasis in 1-2 regional lymph nodes • N2 Metastasis in 3-6 lymph nodes • N3 Metastasis in seven or more regional lymph nodes

• M0 No Metastasis • M1 Distant Metastsis Group staging Stage T N M • 0 T1 N0 M0 • 1A T1 N0 MO(G1,2) • 1B T1 N0 M0(G3) • T2 N0 M0(G1,2) • IIA T2 N0 M0(G3) • IIB T3 N0 M0 • T1-2 N1 M0 • IIIA T1-2 N2 M0 • T3 N1 M0 • T4a N0 M0 71

• IIIB T3 N2 M0 • IIIC T4a N1-2 M0 • T4b any M0 • any N3 M0 • IV any any M1 TREATMENT Neoadjuvant Therapy-All patients with growths T2N0 and beyond should receive 4 # of Neoadjuvant Chemotherapy with two drug regime of any combination including platinum and taxane based drugs can be used too Surgery-Surgery remains the gold standard in treatment of carcinoma GEJunction Since Surgery involves thoracic surgery and post operative critical care, treatment of

GEJunctionmalignancies should be undertaken where facilities and expertise for thoracic surgery and critical care are available Contraindications to Resection-Surgical resection should not be considered in the following circumstances • T4b lesion • Left supra-clavicular node • Distant metastasis • Multi-station bulky nodal mass • Poor general condition • Co-morbid medical conditions making patient unfit for anesthesia Treatment Treatment of Barrets esophagus

Low grade and High grade dysplasia and Metaplasia can be observed, however Barrets esophagus needs active treatment and close follows. Barrets Esophagus can be treated with Proton Pump inhibiters, Treatment of H pylori infection, Cox Inhibiters. Surgery for GERD and Hiatus hernia prevent formation and progress of Barrets esophagus and in certain circumstances when the segment is large or persistent and progressing then surgical management with resection may have to be resorted to

Treatment of Adenocarcinoma GE Junction Preoparative laproscopy may be undertaken before the definitive surgery to assess operability Segmantal Resection-The involved Segment can be excised with a margin of 5 cms through a left thoraco abdominal incision,running along the left 7th rib,upto the umbilicus (Sweet-Garloch incision) Continuity is maintained with gastro esophagectomy and D2 nodal dissection is done 72

with the resection of the involved segment.This procedure can only be undertaken if the growth is below the diaphragmatic hiatus.Anastamosis can be done handsewn or stapled. Partial Esophagectomy (Ivor-Lewis Procedure) This procedure is performed for cancers of the GEJunction invoving the lower third of the esophagus with a right thoracotomy and upper midline laparotomy incision. The lower third of esophagus is excised with a margin of 5 cms and anastamosis done with the gastric tube is done

in the mediastinum.Mobolization of stomach,formation of gastric tube and nodal dissection remain the same as for segmental esophagectomy Total Esophagectomy with two field nodal dissection to avoid a mediastinal anastamosis,Total esophagectomt can be performed for GEJunction cancers involving the lower third oesophagus. This includes the removal of complete esophagus, removal of paraesophageal lymphnodes and D2 dissection of gastric lymphnodes, and using a stomach tube as conduit to restore continuity

with anastamosis with cervical esophagus in the left side of the neck. This can be done by following two procedures • Transthoracic Total Esophagetomy (TTE), which includes a right posterolateral thoracotomy for mobilization of esophagus and paraesophageal nodal dissection ,mobilization of stomach with D2 nodal dissection of gastric lymph nodes ,total esophagectomy, gastric mobilization and formation of gastric tube through a upper midline laparotomy incision and pulling up the gastric tube and anastamosing

with proximal esophagus in the left side of the neck.A minimum of 15 nodes should be dissected for adequate nodal dissection.Mobilisation of the esophagus can also be done by VATS( Video Assisted Thoracic Surgery) • Transhiatal Total esophagectomy(THE) -Is a two step procedure where the thoracotomy is excluded and the esophagus is mobilized blindly thorugh transehiatal route.Adequate paraesophageal nodal dissection is not possible through this procedure,however it avoids a thoracotomy.

Total Gastrectomy with excision of lower third esophagus-Siewert’s Type three carcinomas of GEJunction which extend into proximal stomach are treated with total gastrectomy and excision of lower esophagus through a thoraco abdominal incision.Nodal Diseection remains the same nad continuity is restored with esophagojejunostomy. Early Carcinoma of GEJunction-It is rare to find early cases of cancer GEJunction in india,however small T1 lesions can be treated by any of the following procedures

• Endoscopic mucosal resection • Endoscopic submucosal resection • Radiofrequency ablation • Photodynamic therapy • Cryotherapy 73

• Local excision Histopathological Examination-Opertaive specimen should be examined for the following • Histology • Grade • Margins • Depth of invasion • Involvement of extra esophageal tissue • Lymphovascular invasion • Number of nodes dissected • Number of nodes involved • Perinodal & Perineural infiltration • Her-2 Neu by FISH in metastatic disease Adjuvant therapy- R0 RESECTION • NO PREOP THERAPY (cid:216) T1,T2,N0 ,OBSERVE (cid:216) T3 /N+, CCRT • AFTER NACT (cid:216) T2NO, CHEMOTHERAPY

(cid:216) T3 /N+ CCRT R1/R2 RESECTION CCRT Management of Unresectable tumors or of patients with poor performance status Definitive CCRT-Concurrent Radiotherapy with 6000Gy of radiotherapy with either of the following combination of drugs. • Cisplatin and 5FU • Paclitaxel/Docetaxel with 5FU 74

Management of Metastatic disease- Metastatic disease is managed with single or two drug regime using chemotherapy platinum,taxanes and 5-FU or supportive care. TRANSTUZUMAB (Herceptine)can be used for HER2 neu + cases Paliative Care Obstruction • Endoscopic lumen restoration • Laser excision • Endoscopic lumen enhancement (cid:216) Expandable stents (cid:216) Wire guided balloon dilatation • Surgical placement of gastrostomy or jejunostomy tube • Palliative Chemotherapy BLEEDING • Endoscopic intervention

• EBRT PAIN • Local blocks • Painkilllers FOLLOWUP All patients of GEJunction to be followed regularly after completion of treatment, to look for • Anastamotic Stricture • Anastamotic recurrence • Local recurrence • Nodal recurrence • Distant Metastasis ( Liver and lung) Frequency of follow-up-Once in every three months for two years and then six monthly till five years post treatment, followed by annual review, lifelong Following Investigation sto be done at Review • Hb,TLC,DLC • LFT • X-ray chest

• UGI Scopy ,once in a year • CECT Chest( Optioanl,without any symptoms) Prevention • Avoid alcohol and High calori diet • Avoid obesity • Treat GERD • Tretament of Barrets esophagus FLOWCHART Tis ----------------------------------- Endoscopic Mucosal Resection/Ablation T1a------------------------------------Endoscopic Mucosal Resection/Ablation OR Surgery T1b---------------------------------- Surgery T2,3,4 N0,1,2,3-------------------Neoadjuvant Chemotherapy------------------- Surgery Choice of Surgery

GEJunction Tumours-Segmental Resection GEJunction cancers with Involvement of lower third esophagus ---Partial or total esophagectomy GEJunction cancers with involvement of proximal stomach-Total gastrectomy and segmental resection of GEJunction. Post Surgery------------R0 RESECTION • NO PREOP THERAPY § T1,T2,N0 ,OBSERVE § T3 /N+, CCRT • AFTER NACT § T2NO, CHEMOTHERAPY § T3 /N+ CCRT R1/R2 RESECTION---------- CCRT Poor Performance status-------------------------------------------------------Definitive CCRT

Metastatic Disease/recurrence--------------------------Chemotherapy or Supportive care REFERANCES NCCN Guidelines 2011 CANCER-Principles & practice of oncology-Devita (7th & 8th Edition) 76

Cancer cervix Introduction : Cervical cancer is major world health problem for the women. It is the third most common cancer worldwide (1,2) and is the most common cancer among women in India. Every year about 1,32,000 Indian women are diagnosed of cervical cancer and over 80,000 die of the disease (IARC estimates) (3). In recent years, molecular biology has firmly established a causal relationship between persistent infection with high risk human papilloma

virus (HPV) genotypes and cervical cancer. Other epidemiological risk factors are early age of onset of coitus, larger number of sexual partners , smoking, high parity,prolonged contraceptive use, sexually transmitted disease and chronic immunosuppression(4) Cervical cancer progresses slowly from preinvasive cervical intraepithelial neoplasia to invasive cancer. It is a preventable cancer and successfully treatable when diagnosed in early stages where reported survival is more than 90%(5)

It is important to render the optimal treatment to these women to achieve the best survival as well as the quality of life. Gynae Oncologist / Gynaecologist trained in Oncology for at least one year in prestigious cancer center should preferably treat these patients jointly with Radiation Oncologist & Medical Oncologist as the management includes complex surgeries and multimodality team approach. Considerations have been given to the available facility for investigations and the expertise

available for treating cervical cancer in developing these guidelines. When to suspect: Symptoms Precancerous condition & early stage cervical cancer have no symptoms. Following symptoms require proper evaluation for cervical cancer Increased vaginal discharge Contact Spotting / Bleeding Inter menstrual Bleeding Postmenopausal Vaginal Bleeding Pain Lower Abdomen & Backache Incidence of the cervical cancer in our country : 1, 32,000 Cases of cervical cancer are diagnosed every year.

Mortality : 80,000 cases die of cervical cancer every year.( IARC ) (3) 77

Differential diagnosis : Cervical Polyp, Endocervical / Endometrial polyp presenting at cervix., cervical Leiomyoma & Condyloma cervix Prevention & Counseling : Primary prevention : HPV Vaccination : Vaccination against HPV-16 and HPV-18 reduces incident and persistent infections with efficacy of 91.6% (95% CI, 64.5–98.0) and 100% (95% CI, 45–100), respectively.(6) Barrier protection and/or spermicidal gel during sexual intercourse and avoiding the following high risk epidemiological factors.(4)

Cigarette Smoking High Parity Long-term use of oral contraceptives (>5 Years) Secondary Prevention : Screening via Gynecologic Examinations and Cytologic Screening Precancerous condition have no symptoms and is discovered on routine screening tests & usually diagnosed on colposcopic directed biopsy examination.(7) Regular gynecologic examinations Cytologic test (Papanicolaou smear) HPV DNA Testing 78

In low resource settings the following alternative approaches of VIA & VILI can be implemented effectively where Pap Test is not feasible for the mass screening because of the lack of trained manpower, infrastructure, quality assurance & the cost involved (8) Visual Inspection of cervix with Acetic Acid (VIA) VILI ( Visual Inspection of cervix with Lugol’s Iodine) Secondary prevention : Treatment of the premalignant cervical lesions.

Estimates from population studies in the developed countries suggest that screening using the Pap Test may decrease cancer incidence and mortality by more than 80%.(9) V) Optimal Diagnostic Criteria, Investigations, Treatment & Referral criteria Situation 1 : At Secondary Hospital / Non- Metro situation : Optimal Standards of treatment in situations where technology and resources are limited. a) Diagnostic criteria : History

Physical Examination & gynaecological examination including Per Vaginal & Per Rectal Examination. Definitive Diagnosis : On histopathology of cervical growth/ lesion biopsy either punch / knife / Colposcopic Biopsy / Endocervical curettage / Diagnostic LEEP Cone biopsy ( indicated for diagnosis of microinvasive cervical cancer ) b) Investigations : Histopathology/ Pathologic review Blood : Hb%, CBC, KFT, LFT, Blood Sugar F & PP, HbsAg, HIV Imaging : X-ray Chest,

USG Whole abdomen & TVS ( For Measuring the tumor size) or CECT/ MRI Whole abdomen when facility exists / IVP (Clinically Parametrial involvement is suspected and the CT facility is not available ) 79

EUA,Cystoscopy / Sigmoidoscopy when parametrial / bladder / rectal involvement is suspected. Other Investigations if required based on comorbid conditions. c) Cancer Cervix is staged as per the FIGO Staging 2009(9) Carcinoma of the cervix uteri. Stage I : The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded) IA Invasive carcinoma which can be diagnosed only by microscopy, with deepest invasion ≤5 mm and largest extension ≥7 mm

IA1 Measured stromal invasion of ≤3.0 mm in depth and extension of ≤7.0 mm IA2 Measured stromal invasion of >3.0 mm and not >5.0 mm with an extension of not >7.0 mm IB Clinically visible lesions limited to the cervix uteri or pre-clinical cancers greater than stage IA ⁎ IB1 Clinically visible lesion ≤4.0 cm in greatest dimension IB2 Clinically visible lesion >4.0 cm in greatest dimension Stage II Cervical carcinoma invades beyond the uterus, but not to the pelvicwall or to the lower third of the vagina

IIA Without parametrial invasion IIA1 Clinically visible lesion ≤4.0 cm in greatest dimension IIA2 Clinically visible lesion >4 cm in greatest dimension IIB With obvious parametrial invasion Stage III The tumor extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or non-functioning kidney ⁎⁎ IIIA Tumor involves lower third of the vagina, with no extension to the pelvicwall IIIB Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney

Stage IV The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to Stage IV IVA Spread of the growth to adjacent organs IVB Spread to distant organs ⁎ All macroscopically visible lesions—even with superficial invasion—are allotted to stage IB carcinomas. Invasion is limited to a measured stromal invasion with amaximal depth of 5.00 mm and a horizontal extension of not

>7.00 mm. Depth of invasion should not be >5.00mmtaken from the base of the epithelium of the original tissue—superficial or glandular. The depth of invasion should always be reported in mm, even in those cases with “early (minimal) stromal invasion” (~1 mm). 80

The involvement of vascular/lymphatic spaces should not change the stage allotment. ⁎⁎ On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. All cases with hydronephrosis or non-functioning kidney are included,unless they are known to be due to another cause. d) Treatment : Is decided based on the FIGO staging of the cervical cancer . (As described with the situation 2) Standard Operative procedures : Inpatient :

Type I Hysterectomy with or without Salpingo oophorectomy Trachelectomy Type II / III Radical hysterectomy with or without Salpingo oophoprectomy & Pelvic lymphadenectomy Outpatient : Biopsy / ECC / Colposcopy / Diagnostic LEEP Cervix Day Care : EUA / Cone Biopsy ./ LEEP Cervix ( Loop Eletric excision procedure) & Cystoscopy/ Sigmoidoscopy. Referral Criteria : Diagnosed cases of cervical cancer should preferably be referred to Regional Cancer Centre /

Nearest Cancer centre / Hospital with facility of Radiation Therapy / Gynae Cancer Surgery Suspecious cases with diagnostic dilemma. Young patients with the diagnosis of early stage cervical cancer who opt for fertility preserving surgery. Situation 2: At superspaeciality Facility in Metro location where higher – end technology is available. a) Diagnostic criteria : are similar to that in Situation 1. History 81

Complete Physical examination, Gynaecological examination including Per Vaginal & Per Rectal Examination. Definitive Diagnosis : On histopathology of cervical growth biopsy / endocervical biopsy / Endocervical curettage / Cone Biopsy Cervix / Diagnostic LEEP Cervix b) Investigations Histopathology / Pathologic review Blood : Hb%, CBC, KFT, LFT, Blood Sugar F & PP, HbsAg, HIV Imaging : X-ray Chest, CECT/ PET CT (Optional )/ MRI EUA,Optional in stage IB2 and greater / doubtful parametrial involvement.

Cystoscopy /Sigmoidoscopy when bladder/ bowel involvement is suspected. Other investigations required for the co- morbid conditions. c) Cervical Cancer is staged as per the FIGO 2009 Criteria. Treatment PRIMARY TREATMENT DEPENDING ON THE CLINICAL STAGE of the disease. In early stage of the disease, stage IB & IIA similar cure rates are achieved with either primary surgery or radiation therapeutic treatment. The choice between the primary surgical or

radiotherapeutic treatment depends on the age of the patient, co- morbid conditions, facilities & expertise available.(10) Stage IA1 • Extrafascial hysterectomy or • Observe if patient desires fertility or if inoperable (11) (only if cone biopsy has negative margins & no LVSI) 82

or • Modified radical hysterectomy or trachelectomy + pelvic lymph node dissection if lymphovascular invasion Or ICRT when unfit for Surgery (12) Dose 10,000 – 12,500 cGy at vaginal surface Stage IA2 • Modified Radical hysterectomy (Type II ) +pelvic lymph node dissection +/- para aortic lymph node sampling (13) or • Brachytherapy +/- pelvic RT(total point A dose : 75-80 Gy) or • Radical trachelectomy + pelvic lymph node dissection +/- paraaortic lymph node sampling.(14) Stage IB1 & IIA1

• Radical hysterectomy + pelvic lymph node dissection +/- paraaortic lymph node sampling (category 1)(5) or • Pelvic RT + brachytherapy (total point A dose : 80-85Gy) or • Radical trahelectomy for tumors</= 2cm (Stage IB1)(14) +pelvic lymph node dissection +/- paraaortic lymph node sampling. Laproscopic Surgery: The role of minimal access surgery in management of cervical cancer is evolving at present. Presently, laparoscopic radical hysterectomy with pelvic lymphadenectomy

can be offered to patients with stage IB1 cervical cancer as an alternative to the open abdominal radical hysterectomy in suitable patients with a low BMI and no major co‐morbid conditions. For optimizing results of the procedure, it should be done only by surgeons trained in the application of advanced laparoscopic surgery to gynecological cancer management and in specialized cancer centres with a large volume gynecologic oncological Stage IB2 & Stage IIA2 Treatment options

• Pelvic RT + concurrent cisplatin containing chemotherapy + brachytherapy (total point A dose >/= 85Gy( category 1)(15,16) or • Radical Hysterectomy + pelvic lymph node dissection 83

+ paraaortic lymph node sampling ( category 2B) or • Pelvic RT + concurrent cisplatin containing chemotherapy + brachytherapy (total point A dose 75-80Gy) adjuvant hysterectomy (category 3)( 15) Histopathology Tumor size, type, Grade, Lymphovascular space involvement, involvement of vagina, microinvasion of the parametrium, Number of nodes dissected, Number of positive nodes. Involvement of the Endometrium/ tubes/ ovaries or any coexisting pathology ADJUVANT TREATMENT DEPENDING ON SURGICAL FINDINGS

➢ Negative Nodes 1. Pelvic RT if combination of high risk factors (category 1) (ie large primary tumor ,deep stromal invasion ,and/or lymphovascular space invasion)(17) 2. No above risk factors : Observe ➢ Positive Pelvic nodes and/or Positive surgical margin and /or Positive parametrium 1. Pelvic RT + concurrent cisplatin containing chemotherapy (category 1)(18) +/- vaginal brachytherapy. ➢ Paraaortic lymph node positive by surgical staging A. Chest CT / PET CT scan Negative

Paraaortic lymph node RT + concurrent cisplatin containing chemotherapy + Pelvic RT +/- brachytherapy. B. Chest CT / PET CT Scan Positive for distant metastases 1. Suspicious Areas Biopsy Negative • Paraaortic lymph node RT + concurrent cisplatin containing chemotherapy + Pelvic RT +/- brachytherapy 2. Suspicious Areas Biopsy Positive ▪ Systemic therapy +/- individualized RT. PRIMARY TREATMENT DEPENDING ON THE CLINICAL STAGE Stage IB2, Stage IIA2, Stage IIB, IIIA ,IIIB ,IVA 84

A. Radiological Imaging CT/ MRI / PET(19,20) A1. Negative Adenopathy : Pelvic RT + concurrent cisplatin containing chemotherapy + brachytherapy. A2. Positive Adenopathy : Consider needle Biopsy. B. Surgical staging : Extraperitoneal or laparoscopic lymph node dissection (category 2 B)(21) B1.Para aortic Nodes Negative : Pelvic RT + concurrent cisplatin containing chemotherapy (category 1)+ brachytherapy. B2. Para aortic nodes Positive : See node status.

Stage IB2, Stage IIA2, Stage IIB, IIIA ,IIIB ,IVA Node Status A. Pelvic lymph node positive & Paraaortic lymph node negative by surgical staging Pelvic RT + concurrent cisplatin containing chemotherapy (category 1)+ brachytherapy. B. Paraaortic lymph node positive by surgical staging B1. Further radiologic workup negative for distant metastases: Pelvic RT + paraaortic lymph node RT +concurrent cisplatin containing chemotherapy + brachytherapy.

B2. Further radiologic workup positive for distant metastases:Consider Biopsy of suspicious areas. If Biopsy Negative: Pelvic RT + paraaortic lymph node RT + concurrent cisplatin containing chemotherapy + brachytherapy. If Biopsy positive: Systemic therapy +/- Individualized RT. SURVEILLANCE • Interval H& P. • Cervical / vaginal cytology every 3-6 months for 2 yrs,then every 6 months for 3-5 yrs,then annually. • Chest X Ray anually (optional) 85

• CBC, BUN, creatinine every 6 months (optional) • PET CT scan as clinically indicated. • Recommended use of vaginal dilator after RT. • Patient education regarding symptoms. Standard Operating Procedure Inpatient : All major / radical surgical Procedures Type I Hysterectomy with or without bilateral salpingo oophorectomy Type II / Type III Radical Hysterectomy with or without salpingo oophorectomy with Pelvic Lymphadenectomy.

Radical hysterectomy (type III) and bilateral pelvic lymphadenectomy involves removal of entire uterus, upper third vagina, bilateral parametria, uterosacral, utero‐vesical ligaments and bilateral pelvic lymph nodes. Bilateral salpino‐oophrectomy is discretionary. Radical trachelectomy Para aortic Lymphadenectomy / Sampling Outpatient : Colposcopy Biopsy, ECC, Diagnostic LEEP Cervix. Day Care : EUA & Cystoscopy, Rectosigmoidoscopy,Cone Biopsy Referral Criteria :

On diagnosis of the cervical cancer on histopathology. Young women with early stage ca cx opting for the fertility preserving surgery the patient should be referred to the Gynae Oncology, Tertiary Cancer centre. Who does what? And Timelines Doctor : Specialist : Primarily should be seen by Gynae Oncologist / Gynaecologist trained in oncology for at least 1 year in prestigious cancer centre. Diagnosis Workup Clinical Staging Treatment plan in multidisciplinary tumor board

Primary surgery / Radiationtherapy / Concurrent chemo radiation therapy Average time from diagnosis to execution of the treatment should be 2-3 weeks. 86

Nurse : Counseling To Implement orders Onco nursing Doctor patient co-ordination Technician: Technical Inputs of respective field. Radiotherapy technician Operating theatre technician Further Readings / References: 1. Parkin DM , Bray F, Ferlay J,Pisani P . Global cancer statistics , 2002. CA Cancer J Clin 2005; 55: 74 – 7108. 2. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence , mortality and prevalance

across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006;24: 2137- 2150. 3. Cancer survival in developing countries. Sankaranarayanan R, Black RB, Parkin DM, Editors. Lyon: IARC Press; 1998 (IARC Scientific Publications No. 145). 4. Comparision of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix : collaborative reanalysis of individual data on 8,097 women with squamous cell

carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies.Int. J Cancer 2007;120:885-891. 5. Sarieni P. Lancet 1991;338:818-19. 6. Paavonen J, Naud P, Salmeron J,et al .Efficacy of human papillomavirus ( HPV) – 16/18 AS04- adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICA) : Final analysis of a double blind , randomized study in young women .Lancet 2009;374(9686) :301-314. 7 . Shankaraman R et al : Cancer Nov 15; 1998; 83 (10) : 2150-56.

8. Visual inspection of the uterine cervix after the application of acetic acid in the detection of 87

cervical carcinoma and its precursors. Sankaranarayana R, Wesley R, Somanathan T et al. Cancer 1998;83: 2150-56. 9. Sergio Pecorelli et al International Journal of Gynecology and Obstetrics 105 (2009) 103–104 10. Randomised study of radical surgery versus radiotherapy for stage Ib- IIa cervical cancer. Landoni F,Maneo A, Colombo A et al.Lancet 1997;350:535-40. 11. Microinvasive carcinoma of the cervix. Sevin BU ,Nadji M, Averette HE, Hilsenbeck S, Smith D, Lampe B.Cancer 1992;70:2121-8.

12. Radiotherapy alone for medically inoperable carcinoma of the cervix : stage IA & carcinoma in situ. Grigsby PW, Perez CA.Int J Radiat Oncol Biol Phys 1991;21:375-8. 13. Early invasive carcinoma of the cervix . Jones WB, Mercer GO, Lewis JL, Rubin SC, Hoskins WI.Gynecol oncol 1993;51: 26-32. 14. Diaz JP, Sonoda Y ,Leitao MM ,et al. Oncologic outcome of fertility – sparing radical trachelectomy versus radical hysterectomy for stage IB1 cervical carcinoma . Gynecol Oncol 2008;111:255- 260.

15. Keys HM,Bundy BN ,Stehman FB,et al .Cisplatin , radiation & adjuvant hysterectomy for bulky stage IB cervical carcinoma .N Engl J Med 1999;340:1154-1161. 16. Morris M, Eifel PJ ,Lu J ,et al. Pelvic radiation with concurrent chemotherapy compared with pelvic & paraaortic radiation for high risk cervical cancer . N Engl J Med 1999;340:1137-1143. 17. Sedlis A, Bundy BN ,Rotman MZ,et al .A randomized trial of pelvic radiation therapy versus

no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy : A Gynecologic oncology group Study.Gynecol Oncol 1999;73:177-183. 18. Peters WA, Liu PY ,Barrett RJ, et al. Concurrent chemotherapy & pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high risk early stage cancer of the cervix. J Clin Oncol 2000;18:1606-1613.

19. Park JY , Kim EN, Kim DY ,et al.Comparision of the validity of magnetic resonance imaging & positron emission tomography/ computed tomography in the preoperative evaluation of 88

patients with uterine corpus cancer. Gynecol Oncol 2008;108 :486-492. 20. Boughanim M , Leboulleuq S, Rey A,et al. Histologic results of paraaortic lymphadenectomy in patients treated for Stage IB2/II cervical cancer with negative [18F] fluorodeoxyglucose positron emission tomography scans in the paraaortic area.J Clin Oncol 2008;26:2558 – 2561. 21. Goff BA, Muntz HG,Paley PJ ,et al. Impact of surgical staging in women with locally advanced cervical cancer. Gynecol oncol 1999;74:436-442. 89

CARCINOMA ESOPHAGUS Col (Prof) Sanjay Kapoor VSM,HOD Oncology Command Hospital Lucknow CASE DEFINITION Carcinoma Esophagus is the commonest cancer in Asian belt along China, Kazhakistan (endemic zone) .It is associated with poor socioeconomic status, nutritional deficiencies, smoking, alcohol and tobacco intake and eating of pickled food. H Pylori infection, hiatus hernia and GERD are predisposing factors for carcinoma esophagus. In India it is most common in North East and

constitutes 3-10 % of all malignancies in various regions/States WHEN TO SUSPECT Presenting Symptoms Most common presenting feature of carcinoma esophagus is dysphagia, initially to solids and then to liquids. Other symptoms that patient may present with are • Odynophagia • Features of GERD • Dyspepsia • Loss of weight • Anorexia • Left supraclavicular node • Haematemesis • Vomiting Differential Diagnosis All elderly patients presenting with long standing dyspepsia and features of GERD or with

anorexia, loss of weight and dysphagia,should be investigated for carcinoma esophagus Common differential diagnosis are • GERD • Achlasia cardia • Hiatus Hernia • Esophageal diverticulum or stricture Examination Besides the routine general and systemic examination, patient should be assessed for • General condition • Nutritional status • Pallor • Left supraclavicular node WORKUP FOR DIAGNOSIS AND STAGING Investigations- 90

Following investigations are mandatory for assessing any suspected or diagnosed case of Carcinoma Esophagus • Upper GI Endoscopy –To see for (cid:216) Presence of growth (cid:216) Site of growth (cid:216) Nature of growth (cid:216) Vertical and circumferential extent of growth (cid:216) Passage of scope beyond the growth (cid:216) Status of stomach (cid:216) Presence of Barrets esophagus ( Naso gastric feeding tube to be placed if esophageal lumen found to be obstructed)

• Endoscopic Biopsy- from representative site. Following to be assessed (cid:216) Histology (cid:216) Differentiation (cid:216) Presence of Barrets • CECT Chest and upper abdomen-To see for (cid:216) Vertical and Horizontal extent of diseases (cid:216) Adherence or infiltration of surrounding structures like trachea, main bronchus, aorta and pericardium (cid:216) Para esophageal nodes (cid:216) Involvement of GE Junction and proximal stomach in the lower third esophageal and GEJunction cancers

(cid:216) Liver metastasis (cid:216) Pericardial and plural effusion (cid:216) Ascitis (cid:216) Perigastric lymphnodes • FNAB of left supraclavicular node if present and left scalene pad of fat biopsy if nodularity felt • Hb, TLC, DLC, blood grouping • Biochemistry-LFT,RFT, Blood Sugar, Electrolytes and platelets • ECG • Ba Swallow-for lower third and GE Junction tumors • Bronchoscopy for Upper and middle third carcinoma esophagus Optinal Investigations

Following Investigations are optional and may be done in tertiary care centres where facilities are available 91

• Endoscopic Ultrasound • Endoscopic ultrasonographic FNAB of paraesophageal nodes • PET Scan • Her 2 Ney receptor study by FISH technique on biopsy specimen STAGING (AJCC 7th Ed 2010) • Tis High grade dysplasia (ca in situ) • T1a Tumour invades lamina propria or muscularis mucosa • T1b Tumour invades submucosa • T2 Tumour invades muscularis propria • T3 Tumour invades adventitia • T4a Resectable tumour invading pleura, pericardium or diaphragm

• T4b Unresectable tumour invading other adjacent structures, such as aorta, vertebral body, trachea etc • Nx Regional lymph nodes cannot be assessed • N0 No regional lymph node metastasis • N1 Metastasis in 1-2 regional lymph nodes • N2 Metastasis in 3-6 lymph nodes • N3 Metastasis in seven or more regional lymph nodes • M0 No Metastasis • M1 Distant Metastsis Group staging Stage T N M • 0 T1 N0 M0 • 1A T1 N0 MO(G1,2) • 1B T1 N0 M0(G3) • T2 N0 M0(G1,2) • IIA T2 N0 M0(G3) 92

• IIB T3 N0 M0 • T1-2 N1 M0 • IIIA T1-2 N2 M0 • T3 N1 M0 • T4a N0 M0 • IIIB T3 N2 M0 • IIIC T4a N1-2 M0 • T4b any M0 • any N3 M0 • IV any any M1 Pathology Almost 95% cancers of the Esophagus are Squamous cell carcinomas (excluding GE Junctions carcinomas) and the remaining may be Adenocarcinoma, soft tissue sarcoma, GIST and benign soft tissue tumors TREATMENT Neoadjuvant Therapy-All patients with growths T2N0 and beyond should receive Neoadjuvant

Chemoradiation with 5000Gy of radiotherapy with weekly Cis/Carbo platin and 5 Fu.Chemotherapy with two drug regime of any combination including platinum and taxane based drugs can be used too Surgery-Surgery remains the gold standard in treatment of carcinoma esophagus Since Surgery involves thoracic surgery and post operative critical care, treatment of esophageal malignancies should be undertaken where facilities and expertise for thoracic surgery and critical care are available

Contraindications to Resection-Surgical resection should not be considered in the following circumstances • T4b lesion • Left supra-clavicular node • Distant metastasis • Multi-station bulky nodal mass • Poor general condition 93

• Co-morbid medical conditions making patient unfit for anaesthesia Carcinomas of the cervical esophagus should be treated with Concomitant Chemo and Radio Therapy (CCRT) Treatment of Squamous Cell carcinoma Esophagus Preoperative Laprotomy can be done to asses operability Total Esophagectomy with two field nodal dissection is the preferred surgery for carcinoma esophagus. This includes the removal of complete esophagus, removal of paraesophageal lymphnodes and

D2 dissection of gastric lymphnodes, and using a stomach tube as conduit to restore continuity with anastamosis in the left side of the neck. This can be done by following two procedures • Transthoracic Total Esophagetomy (TTE), which includes a right posterolateral thoracotomy for mobilization of esophagus and paraesophageal nodal dissection ,mobilization of stomach with D2 nodal dissection of gastric lymph nodes ,total esophagectomy, gastric mobilization and formation of gastric tube through

a upper midline laparotomy incision and pulling up the gastric tube and anastamosing with proximal esophagus in the left side of the neck.A minimum of 15 nodes should be dissected for adequate nodal dissection.Mobilisation of the esophagus can also be done by VATS( Video Assisted Thoracic Surgery) • Transhiatal Total esophagectomy(THE) -Is a two step procedure where the thoracotomy is excluded and the esophagus is mobilized blindly thorugh transehiatal route.Adequate

paraesophageal nodal dissection is not possible through this procedure,however it avoids a thoracotomy.Being a blind procedure Transhiatal Total esophagectomy should be undertakem,preferably only for cancers of the lower third esophagus. Partial Esophagectomy (Ivor-Lewis Procedure) This procedure is performed for cancers of the lower third esophagus with a right thoracotomy and upper midline laparotomy incision. The lower third of esophagus is excised with a margin of

5 cms and anastamosis done with the gastric tube is done in the mediastinum.Mobolization of stomach,formation of gastric tube and nodal dissection remain the same as for total esophagectomy Management of Carcinoma Esophagus in special situations Early Carcinoma esophagus-It is rare to find early cases of cancer esophagus in india,however small T1 lesion scan be treated by any of the following procedures • Endoscopic mucosal resection • Endoscopic submucosal resection • Radiofrequency ablation

• Cryotherapy • Local excision GE Junction Cancers-Squamous Cell carcinoma of GE Junction-should be treated as Carcinoma esophagus with partial or total esophagectomy Involvement of proximal Stomach-Squamous cell carcinomas of GEJunction or lower third esophagus rarely involve proximal stomach,but if they do then surgical produre will depend on the extent of involvement.If thre is minimal involvement and adequate margin can be obtained

and adequate length of the gastric tube can be formed then proximal gastrectomt can be performed with total esophagectomy. Histopathological Examination-Opertaive specimen should be examined for the following • Histology • Grade • Margins • Depth of invasion • Involvement of extra esophageal tissue • Lymphovascular invasion • Number of nodes dissected • Number of nodes involved • Perinodal & Perineural infiltration • Her-2 Neu by FISH in metastatic disease Adjuvant therapy-

R0 resection-Observe (Note 1. Cases where less than 15 nodes are dissected, can be treated as R1 Resection 2, nodal Status cannot be adequately assessed after THE or Partial esophagectomy) R1/R2 Resection-CCRT Management of Adenocarcinoma Esophagus- The Surgical management of adenocarcinoma Esophagus is same as that of Squamous cell carcinoma but Neoadjuvant and adjuvant therapy differs and is as follows Neoadjuvant therapy-All patients with growths T2N0 and beyond should receive four cycles of

chemotherapy with two drug regime of any combination including platinum and taxane based drugs 95

Adjuvant therapy R0 RESECTION • NO PREOP THERAPY (cid:216) T1,T2,N0 ,OBSERVE (cid:216) T3 /N+, CCRT • AFTER NACT (cid:216) T2NO, CHEMOTHERAPY (cid:216) T3 /N+ CCRT R1/R2 RESECTION CCRT Management of other malignancies of esophagus-Soft Tissue sarcomas and GIST of esophagus are to be treated with total esophagectomy without nodal dissection.Chemotherapy in these cases chemotherapy would be same as that for soft tissue sarcomas and GIST of the rest of GI Tract.Benign tumors can be managed with excision .

Management of Unresectable tumors or of patients with poor performance status Definitive CCRT-Concurrent Radiotherapy with 6000Gy of radiotherapy with either of the following combination of drugs. • Cisplatin and 5FU • Paclitaxel/Docetaxel with 5FU Management of Metastatic disease- Metastatic disease is managed with single or two drug regime using chemotherapy platinum,taxanes and 5-FU or supportive care. TRANSTUZUMAB (Herceptine)can be used for HER2 neu + cases Paliative Care Esophageal obstruction

• Endoscopic lumen restoration • Laser excision • Endoscopic lumen enhancement (cid:216) Expandable stents (cid:216) Wire guided balloon dilatation • Surgical placement of gastrostomy or jejunostomy tube • External Beam Radiotherapy • Palliative Chemotherapy BLEEDING • Endoscopic intervention 96

• EBRT PAIN • Local blocks • Painkilllers TRACHEO ESOPHAGEAL FISTULA • Stenting FOLLOWUP All patients of Carcinoma esophagus to be followed regularly after completion of treatment, to look for • Anastamotic Stricture • Anastamotic recurrence • Local recurrence • Nodal recurrence • Distant Metastasis ( Liver and lung) Frequency of follow-up-Once in every three months for two years and then six monthly till five years post treatment, followed by annual review, lifelong

Following Investigation sto be done at Review • Hb,TLC,DLC • LFT • X-ray chest • USG Abdomen • UGI Scopy ,once in a year • CECT Chest( Optioanl,without any symptoms) Prevention • Decrease use of tobacco,alcohol and stop smoking • Minimal or no use of poorly preserved,pickled and smoked food • Improve hygiene • Treat GERD FLOWCHART Squamous Cell Carcinoma & Adenocarcinoam Tis ----------------------------------- Endoscopic Mucosal Resection/Ablation

T1a------------------------------------Endoscopic Mucosal Resection/Ablation OR Esophagectomy T1b-----------------------------------Esophgectomy Squamous Cell T2,3,4 N0,1,2,3-------------------Neoadjuvant CCRT-------------------Esophagectomy Post esophagectomty------------------R0-------------Observe 97

R1/2-----------CCRT AdenoCarcinoma T2,3,4 N0,1,2,3-------------------Neoadjuvant Chemotherapy-------------------Esophagectomy Post esophagectomty------------ R0 RESECTION • NO PREOP THERAPY § T1,T2,N0 ,OBSERVE § T3 /N+, CCRT • AFTER NACT § T2NO, CHEMOTHERAPY § T3 /N+ CCRT R1/R2 RESECTION---------- CCRT Poor Performance status-------------------------------------------------------Definitive CCRT Metastatic Disease/recurrence--------------------------Chemotherapy or Supportive care REFERANCES

NCCN Guidelines 2011 CANCER-Principles & practice of oncology-Devita (7th & 8th Edition) 98

Esophageal cancer WHEN TO SUSPECT Presenting Symptoms Most common presenting feature of esophageal cancer is dysphagia, initially to solids and then to liquids. Other symptoms that patient may present with are • Odynophagia • Dyspepsia • Loss of weight • Anorexia • Left supraclavicular node • Haematemesis • Vomiting Investigations Diagnostic Investigations 1. Barium Swallow (optional) : This continues to be the first investigation in majority of patients

presenting with dysphagia. It gives information regarding the 1. Site 2. length of lesion 3. Morphology (Proliferative/Stricturous/ulcerative or combination) 4. Extra esophageal spread (axis deviation, sinuses and fistulation) 2. Esophagoscopy : Fiberoptic esophagoscopy is essential for biopsy/cytology. Staging Investigations 1. CT scan : Chest and upper abdomen 2. Endoscopic ultrasonography (EUS) 3. Fiberoptic bronchoscopy : for tumours located at and above the level of the carina

CT scan and EUS are complimentary for assessing the lateral extension of disease and lymph node status. EUS scores over CT scan in assessment of the depth of tumour invasion, particularly in early cancer, and status of regional lymph node. However, in stricturous lesions, EUS may not always be possible. CT scan is equally accurate in assessment of T3/T4 lesions; abdominal CT scan additionally can screen liver and coeliac lymph nodes. Bronchoscopy is an essential non

invasive investigation for assessing the tracheo-bronchial tree for early or frank invasion. It is recommended prior to surgery or radiation for upper and mid esophageal disease. 99

PET scan can effectively detect presence of disseminated disease. However, presently it is an investigational modality of investigation. Thoracoscopy and laparoscopy for staging has been investigated and reported increased rate of detecting positive lymph nodes than non invasive staging modalities (Level IIb). Routine Investigations for assessing fitness for treatment 1. Hemogram 2. Liver Function Test/Renal Function Test 3. Chest X-ray 4. Pulmonary Function Test 5. ECG Treatment Options

Two factors determine the treatment: 1. General condition or the Performance status 2. Stage 1. General condition or performance status is an important factor in determining the treatment of a patient with cancer oesophagus. Dysphagia, particularly if it is long standing and complete, leads to chronic dehydration and malnutrition. Such patients will not tolerate surgery, radiation or chemotherapy. Supportive care to optimise general condition should be the priority.

Subsequently, if performance status improves, definitive treatment can be contemplated depending on stage of the disease. 2. Stage : Patients with localized disease are ideally treated with surgery in the absence of medical contraindications. As per the staging, presence of abdominal or celiac lymph nodes is classified as disseminated disease. However prognosis of patients with abdominal or celiac lymph node metastasis is not the same as that with systemic distant metastasis. Hence, patients

with operable local disease should be offered surgery with appropriate lymphadenectomy. • The preferred treatment of carcinoma of the cervical oesophagus is radical radiotherapy or concomitant chemoradiotherapy Stage 0 (TisN0M0) Patients are rarely diagnosed in this stage. The treatment of choice is surgery. If the disease is localised (preferably T1a), Endoscopic mucosal resection (EMR) can be offered in centres with expertise provided the patient is reliable for followup. For more extensive disease,

esophagectomy is the treatment of choice. Stage I (T1N0M0) Surgery is the treatment of choice. Radiation therapy may be offered if the patient is medically unfit or not willing for surgery. 100

Stage II/III (T2N0M0, T3N0M0, T1N1M0, T2N1M0) Surgery for T2 and T3 lesions Surgery for T4 lesions with limited infiltration of pleura or pericardium which is amenable to complete resection Neo adjuvant chemotherapy/concomitant chemo-radiation for T3/T4 tumours which are bulky or of doubtful resectability. If there is complete or partial response to neo adjuvant therapy and tumour appears resectable patient should proceed for surgery; if the response is sub optimal

and disease appears non resectable, patient should either proceed for radiation or palliative therapy (see below). Investigational treatments 1. Chemoradiotherapy alone or chemoradiotherapy followed by surgery 2. Neo adjuvant Chemotherapy followed by surgery 3. Post operative radiation therapy Stage IVa (ant T, any N, M1a) Surgery (per primum or following neo adjuvant therapy): If the disease is operable in the absence of distant metastases. However, more than 50% of patients will have distant

metastases. Such patients will be candidates for palliative treatment. Principles of Surgery Surgical Approach 1. Esophago-gastrectomy through left thoraco-abdominal approach (Garlock procedure) : for adenocarcinoma of the cardio-esophageal junction. 2. Trans thoracic esophagectomy with intrathoracic anastomosis (Ivor Lewis procedure). 3. Trans thoracic total esophagectomy with cervical anastomosis. 4. Trans hiatal esophagectomy with cervical anastomosis.

Adenocarcinoma of the cardio-esophageal junction can be resected through a left thoracoabdominal approach. Surgery involves mobilization of the oesophagus upto the inferior pulmonary vein along with dissection of lower paraesophageal lymph nodes, standard mobilization of stomach along with D2 lymphadenectomy. Gastro-oesophageal anastomoses could be either mechanical (using stapler) or hand sewn. Adenocarcinoma of the distal portion of the oesophagus or cardio-esophageal junction

extending into the lower oesophagus where the proximal extent of the tumour is such that adequate margin is not possible through the left thoraco-abdominal approach should be treated by either trans thoracic or trans hiatal esophagectomy. Phase III trial comparing transhiatal esophagectomy to transthoracic esophagectomy and lymphadenectomy for adenocarcinoma of the oesophagus did not find difference in median overall and disease free survival between the

two procedures. However, there was a trend towards superior long term (5-year) survival, not reaching statistical significance, in favour of transthoracic esophagectomy (Level Ib). 101

Carcinoma of the lower, mid and upper esophagus (excluding cervical oesophagus) is managed either by transhiatal or trans thoracic esophagectomy and esophago-gastric anastomosis in the neck or thorax. There is no consensus as to the best or the ideal surgical approach. Transthoracic esophagectomy has the advantage of mobilization of the oesophagus under vision. Also, systematic mediastinal lymph node dissection can be performed. Trans hiatal

approach, according to proponents, is less morbid with fewer pulmonary complications. There are four published Phase three trials comparing the two approaches. Three of these had few patients and thus, meaningful conclusions cannot be drawn. The fourth and the latest trial has 220 patients, all adenocarcinoma restricted to the distal oesophagus or cardio-esophageal junction. There was no difference in the median overall survival; however, there was a trend

towards a survival benefit at five years with the trans thoracic approach (Level Ib). The published meta analysis of over 60 trials (both prospective and retrospective) comparing transhiatal to transthoracic esophagectomy did not find any difference in the overall survival (Level IIc). Till results of large randomized trials are available the preferred surgical approach will continue to be biased by surgeons’ choice. Extent of lymphadenectomy

Lymph node metastasis is one of the most important prognostic factors for carcinoma of the oesophagus. Since the oesophagus has extensive lymphatic network and most patients present with advanced disease, the majority of patients undergoing surgery have lymph node metastases. Three field lymph node dissection (lower cervical, mediastinal and abdominal) is reported to improve survival without increased procedure related morbidity and mortality

(Level IIa). However, most reported studies are small or have compared results with historical controls. The only one randomized trial of over 60 patients has reported higher, though not statistically significant, survival in patients undergoing three field lymph node dissections (Level Ib). Extensive lymph node dissection provides ‘accurate nodal staging’ resulting in stage migration and apparent ‘improvement in survival’. In absence of conclusive Level I evidence, the

advantage of three field lymph node dissection over the conventional limited lymph node dissection remains speculative. In fact, an adequately powered randomized trial could answer the question regarding the importance of lymph node dissection in management of carcinoma oesophagus and indirectly address the issue of transhiatal versus transthoracic approach. Definitive radiation and chemo-radiation therapy Two published (RTOG and ECOG) randomized trials have reported better overall survival with

concomitant chemo-radiation than radiation therapy alone. However, increasing the dose of radiation therapy (50.4 versus 64.8) in concomitant setting did not result in increased survival (Inter Group trial). Meta analysis of 13 trials combining radiation with chemotherapy published in the Cochrane library has reported an absolute reduction in the mortality and local recurrence rate of 7% and 12% respectively in favour of combination therapy. The combination treatment

is associated with increased life threatening toxicities (Level Ia). There are no trials comparing concomitant chemo-radiation with surgery alone. However two trials comparing surgery to radiation alone have reported better survival with surgery (Level Ib). Hence based on the available evidence, if a patient is to be treated with definitive radiation, it should be combined with chemotherapy, provided performance status is optimal. 102

Surgery as adjuvant to radiation, chemotherapy or combination of both Pre-operative radiotherapy A meta analysis as well as the five published randomized trials comparing preoperative radiation therapy to surgery alone have not shown benefit of pre operative radiation over surgery alone (Level Ia). Pre-operative concomitant chemo-radiation There are eleven major trials and three meta analysis comparing preoperative concomitant

chemoradiation to surgery alone. Meta analysis of pre operative chemoradiation and surgery to surgery alone has reported improved survival and reduced loco-regional recurrence (Level Ia). However, combination treatment is associated with trend towards increased treatment related morbidity and mortality. In the absence of results from a large trial and increased treatment related morbidity, neo adjuvant chemo-radiation should be considered as one of the options of treating localized disease.

Pre-operative chemotherapy There are nine major published trials of pre-operative chemotherapy in the management of carcinoma of the oesophagus. The two large trials have reported results which are divergent. The Intergroup trial of 440 patients reported by Kelsen et al observed no improvement in survival with pre operative combination of cisplatin and fluorouracil among patients with adenocarcinoma or epidermoid carcinoma of the oesophagus. The MRC trial of 802 patients

reported improved survival with two cycles of cisplatin and fluorouracil without additional serious events. The meta analysis of all trials put together concludes that preoperative chemotherapy plus surgery appears to offer a survival advantage at 3, 4, and 5 years, which reached significance only at 5 years compared to surgery alone for resectable thoracic esophageal cancer of any histologic type. The number needed to treat for one extra survivor at five years is eleven patients. (Level Ia).

Post-operative radiotherapy Three trials have compared surgery and post operative radiation to surgery alone. The Chinese trial of 495 patients observed improved 5-year survival in patients with positive lymph nodes and stage III disease receiving post operative radiation. However, the difference in the overall survival between the two groups was statistically not different. The meta analysis of all three trials also does not show benefit of post operative radiotherapy. Therefore, in the absence of

Level I evidence post operative radiotherapy is indicated only for patients with positive margin and residual disease. Post operative chemotherapy Phase III trials of surgery and post operative chemotherapy have not reported survival benefit over surgery alone. A Phase III study by Japanese Clinical Oncology Group (JCOG) reported better disease free survival at 5-year with post operative chemotherapy; however there was no

difference in the overall survival (Level Ia).In adenocarcinoma of the cardio oesophageal 103

junction (and stomach) two trials – the MAGIC trial evaluating perioperative chemotherapy with three cycles of ECF given pre as well as 3 cycles given postoperatively, and the MacDonald post operative chemo-radiotherapy trial – both showed improved overall survival (Level Ib). Thus in patients with adenocarcinoma of the cardia having good performance status, perioperative chemotherapy (3 preoperative cycles of ECF and 3 postoperative cycles of ECF) or post operative

chemo-radiation should be the standard of care. Principles of Radiation therapy Radical radiotherapy The inclusion criteria are : - All lesions (except stenotic) in upper / mid / lower esophagus - Lesion £ than 5 cm on barium swallow and esophagoscopy - Histologically proven esophageal carcinoma - Karnofsky Performance Status (KPS) of > 60% - Age £ 60 years. - Metastatic work - up negative (No palpable S/C nodes, Bronchoscopy & USG abdomen normal). • External beam radiotherapy (EBRT) alone

Dose : 60 - 64.8Gy / 33 - 36 fractions, with reducing fields Portal design : Extended field: esophageal lesion including the lymph drainage areas, with 5 cm margin on either side upto 39.6Gy / 22 fractions/ 4.5 weeks Reduced fields/ boost: Lesion with 2 - 3 cm. margins, with oblique portals, upto 60 - 64.8Gy / 33 - 36 fractions • External beam radiotherapy and brachytherapy When feasible, external Radiotherapy can be combined with Intraluminal radiotherapy (ILRT) as a boost.

Dose of EBRT : 50.4Gy / 28 fractions with reducing fields. ILRT Boost : 5 - 8Gy / 2-3 fractions high dose rate (HDR), one week apart or single fraction 20Gy low dose rate (LDR). Concomitant chemo-radiation regimen • 50Gy in 25 fractions over 5 weeks, plus cisplatin intravenously on the first day of weeks 1, 5, 8, and 11, and fluorouracil, 1g/m2 per day by continuous infusion on the first 4 days of weeks 1, 5, 8, and 11. (RTOG regimen) 104

• 60Gy in 6 to 61/2 weeks. Chemotherapy to be initiated within 24 hours after the commencement of radiation therapy. 5-FU to be delivered by continuous infusion for 96 hours starting on day 2 at the rate of 1000 mg per m2 over 24 hours. This regimen of 5- FU to be repeated once again beginning on day 28. Bolus injection of mitomycin C (10 mg per m2) to be administered on day 2 and not to be repeated. The dose of mitomycin C not to exceed 18 mg and the dose of 5-FU not to exceed 1800 mg over a 24-hour

period. (ECOG regimen). Principles of Chemotherapy Neoadjuvant chemotherapy protocols • Two 4-day cycles, 3 weeks apart, of cisplatin 80 mg/m(2) by infusion over 4 h plus fluorouracil 1000 mg/m(2) daily by continuous infusion for 4 days. (MRC protocol) • Cisplatin, at a dose of 100 mg per square meter of body-surface area, given as a rapid intravenous infusion after prehydration on day 1. Immediately thereafter, fluorouracil

administered at a dose of 1000 mg per square meter as a continuous infusion from day 1 through day 5 (120 hours) of each cycle. The cycle to be repeated beginning on days 29 and 58. Surgery performed two to four weeks after chemotherapy (Intergroup protocol). Palliative treatment If the general condition is good, 1. Relief of dysphagia by placement of esophageal stent alone, preferably self expanding metallic stent as these are easy to deploy.

2. Radiation therapy with intubation if associated with significant dysphagia 3. Intraluminal radiation therapy alone. 4. Endoscopic laser destruction of tumour or electrocoagulation. Palliative radiotherapy The intent of treatment is to achieve quick and good palliation in the form of relief of dysphagia and pain. The inclusion criteria are : - Lesions in upper / mid / lower esophagus - Lesion £ 10 cm long on barium swallow and esophagoscopy - Histologically proven esophageal carcinoma

- Karnofsky performance status (KPS) of £ 50% - Recurrent / metastatic disease. Dose : 3000cGy /10 fractions /2 weeks Portal : Esophageal lesion with 2-3 cm margin Evaluation and response assessment is done after 4 - 6 weeks and further external Radiotherapy or Brachytherapy boost may be delivered. 105

Reduced field / boost : 2000cGy/10# / 2 weeks, using oblique portals Palliative radiation can also be delivered in the form of ILRT alone or in combination with EBRT. The dose per fraction ranges from 5 - 8Gy, in 2- 3 fractions, one week apart. There is no difference in local control or survival between high dose rate brachytherapy compared with external beam radiation. (Level II) Investigational Treatment 1. Palliative chemotherapy with intubation if associated with significant dysphagia. Response

rates ranging from 30% to 50% and one year survival ranging from 0% to 5% is reported with platinum based combination chemotherapy. If the general condition is poor with limited life expectancy 1. Nasogastric tube placement for feeding if possible. 2. Supportive care. Treatment of esophageal fistula 1. Esophageal intubation with stent. 2. Oesophageal and tracheal/bronchial stent placement (double stenting) when possible if the fistula is large or if the tracheal lumen is compromised.

Treatment of Recurrent disease 1. Salvage surgery for localised resectable failures. 2. Palliative treatment or supportive care alone as described before. Management algorithm for esophageal cancer Workup 1. Barium swallow (optional) 2. Upper GI scopy with biopsy / cytology 3. CT scan chest and upper abdomen 4. Fiber optic bronchoscopy – for upper and middle third growths 5. Routine hematology, biochemistry 6. Pulmonary function tests – if surgery contemplated

a. Assess stage of disease – (i) Localized (ii) Disseminated b. Assess performance and nutritional status 106

Disseminated disease with good performance status • Stenting • Palliative chemotherapy Poor performance status and / or nutritional status • Stenting Recurrent disease Best supportive care • Stenting – to relieve obstruction • Enteral feeding through nasogastric tube or gastrostomy • Pain relief 107

NAME OF CONDITION; Gall Bladder cancer VIII. WHEN TO SUSPECT/ RECOGNIZE? c) Introduction: It is the most common biliary tract cancer and is the fifth leading gastrointestinal malignancy in the United States. It produces symptoms late in the course of the disease, disseminates rapidly from the primary site, and responds infrequently to nonsurgical therapy. The overall median survival for all patients is less than 6 months. The disease is up to five times more common in females. It is usually

associated with gallstones, although few patients with gallstones actually develop gallbladder cancer Case definition: For both situations of care (mentioned below*) IX. INCIDENCE OF THE CONDITION IN OUR COUNTRY The reported crude rate for gallbladder cancer in India is 1/100,000. The comparison of different population based cancer registries indicates that GB cancer varies in different regions. The reported incidence ranged from 10/1, 00, 000 in Delhi to 2- 3/1, 00, 0 00 in South India.

X. DIFFERENTIAL DIAGNOSIS Xanthogranulomatous cholecystitis is a relatively rare inflammatory condition of the gallbladder, requires to be differentiated from GB cancer. Characteristic findings on the CT scan are intramural hypodense nodules. CA 19-9 levels may be normal, and FDG-PET scan may be negative. Mid bile duct cholangiocarcinoma may simulate a GB cancer and can be differentiated by optimal cholangiography as can Mirizzi syndrome. XI. PREVENTION AND COUNSELING

There is no way to prevent gallbladder cancer, however its risk may be decreased by maintaining healthy weight, avoiding tobacco and having surgery for high risk conditions such as patients with large stones, porcelain gallbladder, polyps, anomalous pancreatobiliary ductal union, and those belonging to certain races such as Pima Indians. XII. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA 108

Patients with gallbladder cancer are often initially asymptomatic. Nonspecific symptoms of abdominal pain and weight loss may mimic the symptoms of benign gallbladder disease. Jaundice is an ominous sign in patients with gallbladder cancer and usually indicates advanced disease. A palpable gallbladder may be found on examination. Ultrasonography is usually the first investigation in suspected gallbladder disease. Findings suggestive of cancer include asymmetric wall thickening, discontinuous

mucosa, echogenic mucosa, submucosal echolucency, or mass lesion. Doppler examination may help to assess the blood flow through areas of mucosal abnormalities and also the patency of the regional vasculature (hepatic artery and portal vein CT scan is currently the gold standard in imaging of a suspected GB cancer and can show the mass lesion, extension, vascular involvement, nodal disease and metastasis. Magnetic resonance imaging has the advantage of no radiation plus the opportunity

to have a all information in one single investigation that provides cross-sectional images of the tumour, extension, nodal disease , cholangiography and angiography. Laparoscopic evaluation should be considered before proceeding to open resection as up to 55% may have peritoneal secondaries. Biopsy is not essential for tumours deemed resectable by imaging, however for unresectable disease planned for nonsurgical therapy histologic confirmation is mandatory. Treatment:

Radical re-resection (after a complete staging including laparoscopy demonstrating resectability) is recommended for patients with incidental gallbladder carcinoma stage T1b (tumour invades muscle layer) or greater. Patients with T1a tumours (tumour invades lamina propria) do not further benefit from re-resection if the gallbladder were removed intact and should be observed only. Incidentally detected tumours at surgery should be confirmed by frozen section

biopsy and full evaluation should be performed using intraoperative ultrasound. Surgery is converted to open resection with en-bloc hepatic resection and lymphadenectomy with or without bile duct resection. Surgical resection is the only potentially curative treatment for preoperatively diagnosed resectable cancer. Resection is an extended cholecystectomy which includes cholecystectomy, en=bloc hepatic resection and lymphadenectomy (porta

hepatis, gastrohepatic ligament, retroduodenal) with or without bile duct excision. Involvement of the interaortocaval node is considered as synonymous of disseminated disease, and if this lymph node is positive at frozen section, curative resection must be abandoned. Bile duct resection is considered for cystic duct lesions or invasion of the bile duct or for clearance of bulky nodes. It may also be indicated when the bile duct is itself involved by tumour. Surgery may also involve 109

removal of adjacent organs such as the duodenum, colon, stomach, and pancreas to achieve RO resection, as negative margins is the most important determinant of survival. Resectable advanced disease diagnosed at surgery may be considered for operative treatment. Biliary enteric bypass, however if diagnosed prior to surgery should be considered for endoscopic or percutaneous biliary drainage. Adjuvant and palliative chemotherapy has limited role and Gemcitabine based

chemotherapy and 5FU based chemo radiation can be considered in patients with god performance status. *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited IX. Clinical Diagnosis: Any elderly patient with right upper abdominal pain and weight loss should be evaluated for gallbladder cancer and the diagnosis confirmed by imaging. When a patient reports with gall stones (symptomatic or asymptomatic), care should be

taken in reviewing the clinical history and also the ultrasound examination. If there is asymmetric gall bladder wall thickening, or mass lesion, or jaundice, then the patient needs more extensive evaluation in a tertiary care center. Since the best opportunity for long term cure of patients is in R0 resection (complete resection with negative margins), preoperative definition of tumour extent is critical, and patients must be managed in a tertiary care center. X. Investigations: USG, CT,MRI

XI. Treatment: Cholecystectomy for early lesions. Chemoradiotherapy XII. Referral criteria: All patients for extended cholecystectomy should be referred to specialist centre. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available 110

d) Clinical Diagnosis: Any elderly patient with right upper abdominal pain and weight loss should be evaluated for gallbladder cancer and the diagnosis confirmed by imaging. e) Investigations: USG,CT MRI, IOUS, f) Treatment: Extended cholecystectomy Chemoradiotherapy. Standard Operating procedure a. In Patient b. Out Patient c. Day Care XIII. WHO DOES WHAT? and TIMELINES a. Doctor b. Nurse c. Technician XIV. FURTHER READING / REFERENCES

1. Lundberg O, Kristoffersson A. Open versus laparoscopic cholecystectomy for gallbladder carcinoma. J Hepatobiliary Pancreat Surg 2001;8:525–9.Goetze TO, Paolucci V. Benefits of reoperation of T2 and more advanced incidental gallbladder carcinoma: analysis of the German registry. Ann Surg 2008; 247: 104–108. 2. Goetze TO, Paolucci V. Immediate re-resection of T1 incidental gallbladder carcinomas: a survival analysis of the German Registry. Surg Endosc 2008; 22: 2462–2465.

3. Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 2007; 96: 896–902. Shimada H, Endo I, Togo S, Nakano A, Izumi T, Nakagawara G. The role of lymph node dissection in the treatment of gallbladder carcinoma. Cancer 1997;79:892–9. 4. Chijiiwa K, Kai M, Nagano M, Hiyoshi M, Ohuchida J, Kondo K. Outcome of radical surgery for stage IV gallbladder carcinoma. J Hepatobiliary Pancreat Surg 2007;14:345–50. 111

5. Agarwal AK, Mandal S, Singh S, Bhojwani R, Sakhuja P, Uppal R. Biliary obstruction in gall bladder cancer is not sine qua non of inoperability. Annals of Surgical Oncology 2007, 14(10):2831-7. 6. Sikora SS, Singh RK. Surgical strategies in patients with gallbladder cancer: nihilism to optimism. Journal [2006, 93(8):670-81] 7. Nishio H, Nagino M, Ebata T, Yokoyama Y, Igami T, Nimura Y. Aggressive surgery for stage IV gallbladder

carcinoma; what are the contraindications? J Hepatobiliary Pancreat Surg 2007; 14:351–7. akai T, Shirai Y, Yokoyama N, Nagakura S, Watanabe H, Hatakeyama K. Early gallbladder carcinoma does not warrant radical resection. Br J Surg 2001;88:675–8. 8. Ouchi K, Mikuni J, Kakugawa Y; Organizing Committee, The 30th Annual Congress of the Japanese Society of Biliary Surgery. Laparoscopic cholecystectomy for gallbladder carcinoma: results of a Japanese survey of

498 patients. J Hepatobiliary Pancreat Surg 2002;9:256–60 9. Kokudo N, Makuuchi M, Natori T, Sakamoto Y, Yamamoto J, Seki M, et al. Strategies for surgical treatment of gallbladder carcinoma based on information available before resection. Arch Surg 2003;138:741–50. 10. Suzuki S, Yokoi Y, Kurachi K, Inaba K, Ota S, Azuma M, et al. Appraisal of surgical treatment for pT2 gallbladder carcinomas. World J Surg 2004;28:160–5.

11. Shimizu Y, Ohtsuka M, Ito H, Kimura F, Shimizu H, Togawa A, et al. Should the extrahepatic bile duct be resected for locally advanced gallbladder cancer? Surgery 2004;136:1012–7. 12. Kondo S, Nimura Y, Hayakawa N, Kamiya J, Nagino M, Uesaka K. Extensive surgery for carcinoma of the gallbladder. Br J Surg 2002;89:179–84. 13. Takada T, Amano H, Yasuda H et al. Is postoperative adjuvant chemotherapy useful for gallbladder

carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 2002; 95: 1685–1695. 14. Glimelius B, Hoffman K, Sjoden PO et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 1996; 7: 593–600. RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and

consumables and equipment. Quantity to also be specified) Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT 112

Lung cancer Introduction Lung cancer is a major problem in both developed and developing countries in the world. It is the leading type of cancer (more than a million new cases; 12.8% of all cancers) and the leading cause of cancer mortality (921,000 deaths; 17.8% of all cancer deaths) worldwide. It is expected that lung cancer will remain a major health problem at least for the next 30-40 years, even if there is a reduction in incidence as a result of smoking cessation interventions. In India,

Untreated, it has a high mortality with 95% patients dying within one year. Lung cancer is broadly divided into two types – small cell and non-small cell. This general histologic classification reflects the clinical and biological behavior of these distinct tumor types. Small cell lung cancers (SCLC) grow rapidly, metastasize widely and are treated primarily with chemotherapy. Eighty percent of SCLC are metastatic on presentation. Non-small cell lung

cancers (NSCLC) are divided into squamous cell cancers, adenocarcinomas and large cell carcinomas. Nearly half of all NSCLC in developed countries (and one fourth of cases in India) are diagnosed in localized or locally advanced stage when they are treated by resection or combined modality treatment with or without surgery. Smoking is the single most important risk factor for all types of lung cancers. Attempts to reduce

lung cancer mortality should therefore primarily be focused on smoking cessation, which has the potential to be the single most important public health intervention to reduce cancer deaths. Management of NSCLC I. Patients with localized NSCLC (T1-3, N0-1) These include patients upto T3N1 NSCLC, i.e., all stage I, II and T3N1 stage IIIA. Workup includes 1. Chest X-ray 2. CT scan chest and upper abdomen 3. Fiber optic bronchoscopy

4. Cyto/histological diagnosis if possible – sputum cytology, bronchoalveolar lavage/brushings cytology, post bronchoscopy sputum cytology, CT guided biopsy 5. Arterial blood gas analysis 6. Pulmonary function test and diffusion coefficient of carbon monoxide (DLCO) 114

7. Ventilation-perfusion (V/Q) scan – if pulmonary function tests reveal borderline pulmonary reserve 8. Mediastinoscopy is indicated in patients with T3 and/or N1 tumors 9. Metastatic workup – PET-CT scan, MRI scan brain– indicated in patients with T3 and/or N1 tumors Note : A cyto/histological diagnosis is preferable but not mandatory prior to surgery. A complete metastatic workup is indicated in a) Patients with T3 and/or N1 tumors

b) Borderline operative patients (increased risk because of borderline PFT or intercurrent cardiac or other medical illnesses) with early stage disease c) Patients with symptoms or signs of distant metastases. Patients with T1-2, N0 NSCLC with no symptoms of metastatic disease do not require a routine metastatic workup. Surgery is the treatment of choice in patients with localized disease with no involvement of mediastinal lymph nodes. (Level III, Grade B) Preoperative Management 1. Smoking cessation

2. Bronchodilators 3. Intermittent Positive Pressure Breathing (IPPB) 4. Chest physiotherapy 5. Antibiotics – only if infection present Surgical resection – general principles • Lobectomy or pneumonectomy should be done depending on the extent of disease (provided the patient has adequate pulmonary reserve). One randomized trial (LCSG) and eight non-randomized trials have shown lower survivals with sublobar resections compared to lobectomy. (Level Ib, Grade A)

• Limited resection (segmentectomy, wedge resection) may be done only if pulmonary reserve is inadequate for lobectomy, provided otherwise medically fit for surgery. Reduced survival compared to lobectomy, but better results than radical radiotherapy alone. (Level III, Grade B) • N1 and N2 lymph nodal resection and mapping (sampling or systematic lymph node dissection) should be done. There is universal consensus that SMLND is a better staging

and prognosticator than mediastinal lymph nodal sampling. There is no consensus that SMLND improves survival in patients with NSCLC. Two randomized trials found no difference in survival between mediastinal lymph node sampling and systematic mediastinal lymph node dissection, whereas one randomized and one large 115

nonrandomized trial found superior survival with systematic mediastinal lymph node dissection. (Level Ib, Grade A) • Curative (radical) radiotherapy should be given if the patient is medically unfit for surgery. (Level III, Grade B) • Parenchyma preserving lung resection (sleeve resection, bronchoplasty) is preferred over pneumonectomy if anatomically appropriate and negative margins can be obtained. (Level III, Grade B) VATS lung resections

Preliminary data from VATS lung resections suggest similar 2-3 year survival outcomes to open surgery but long term outcomes are not yet available. However, most studies of VATS lung resections have had strict selection criteria whereas comparative open surgeries have been an unselected group. There is also no objective evidence regarding the advantages of VATS lung resections over open surgery. Postoperative care 1. Perioperative antibiotics 2. Optimal pain control 3. Early mobilization

4. Chest physiotherapy 5. Incentive spirometry 6. IPPB Adjuvant therapy • There is definite benefit with cisplatin-based adjuvant chemotherapy in completely resected NSCLC. Several recent large multicenter randomized controlled trials and a meta analysis showed a significant survival advantage with cisplatin-based postoperative chemotherapy in completely resected NSCLC. (Level Ia, Grade A) • There is no role of adjuvant radiotherapy in completely resected early stage NSCLC. The

PORT meta analysis showed higher mortality in patients treated with post operative radiotherapy compared to patients treated with surgery alone (Level Ia, Grade A) • Adjuvant radiotherapy may be considered in patients with residual disease after lung resection or positive margins. (Level III, Grade B) II. Patients with positive mediastinal lymph nodes (T1-3, N2) Workup includes 1. Chest X-ray 2. CT scan chest and upper abdomen 3. Fiber optic bronchoscopy

4. Cyto/histological diagnosis – sputum cytology, bronchoalveolar lavage/brushings cytology, post bronchoscopy sputum cytology, CT guided FNAC 5. Mediastinoscopy and biopsy 6. Metastatic workup – MRI scan brain, PET-CT scan. 116

A. Preoperatively diagnosed N2 disease • Patients with clinico radiological N2 disease should undergo mediastinoscopy for histological evidence of N2 disease. (Level Ib, Grade A) • Patients should undergo multimodality treatment protocols. • Patients are primarily treated with neoadjuvant chemotherapy followed by surgery. Four randomized trials have shown significantly improved survival with neoadjuvant chemotherapy compared to patients treated with surgery alone. (Level Ib, Grade A)

• Patients progressing on neoadjuvant chemotherapy should be treated with definitive chemoradiotherapy. (Level III, Grade B) • Patients who do not progress on NACT and who have resectable disease should be treated with surgery provided they have adequate pulmonary reserve. (Level III, Grade B) • Patients with inadequate pulmonary reserve to tolerate lung resection should be treated with definitive chemoradiotherapy. (Level III, Grade B) B. Surgically discovered N2 disease

• Patients with N2 disease detected on thoracotomy should undergo lung resection provided the tumor can be completely resected. (Level III, Grade B) • Systematic lymph node dissection should be done. (Level III, Grade B) • Adjuvant therapy should be considered. (Level III, Grade B) Adjuvant therapy • The role of adjuvant radiotherapy in completely resected N2 NSCLC is unclear. Subset analysis in the PORT meta analysis showed no difference in survival

• Adjuvant radiotherapy may be indicated in patients with residual disease after surgery or positive margins. (Level III, Grade B) III. Patients with locoregionally advanced disease (T4 and N3) • Treatment of patients with T4 and N3 NSCLC is predominantly non surgical. (Level III, Grade B) • Patients with good performance status should be treated with combination chemo radiotherapy. Evidence from a meta analysis and 12 randomized controlled trials show a

survival benefit with cisplatin-based chemotherapy and radical radiotherapy compared to radiotherapy alone. (Level Ia, Grade A) • Concurrent chemo radiotherapy is preferable to sequential chemo radiotherapy. (Level III, Grade B) • There is no difference between daily and weekly chemoradiotherapy regimens. (Level Ia, Grade A) 117

• Cisplatin based chemotherapy regimens are better than non-cisplatin based chemotherapy. (Level Ia, Grade A) • Patients who may not tolerate combination chemo radiotherapy should be treated with radiotherapy alone. (Level III, Grade B) • Patients with malignant pleural effusion should be treated with pleurodesis. Palliative chemotherapy should be given in patients with good performance status. (Level III, Grade B) • Highly selected patients with stage III B disease may benefit from surgery as part of

multimodality treatment protocols. (Level IV, Grade C) IV. Patients with metastatic disease • The aim of treatment is palliation and prolongation of survival.(Level Ia, Grade A)) • Patients with good performance score (ECOG 0, 1) should be treated with platinum- based combination chemotherapy.(Level Ia, Grade A) • Combination chemotherapy regimens are better than single agent chemotherapy (Level Ia, Grade A) • Cisplatin-combinations have a higher response rate and may improve overall survival

when combined with a third-generation agent, but have higher toxicities. The second agent should be a third generation chemotherapy agent like docetaxel, paclitaxel, gemcitabine, pemtrexed, vinorelbine and irinotecan. (Level Ia, Grade A)) • Patients with tumours that have EGFR-activating mutations should be treated with an oral tyrosine kinase inhibitor. If EGFR mutation status is negative or unknown, then cytotoxic chemotherapy should be used. (Level I, Grade A))

• In patients with non-squamous histology, Pemetrexed based combination chemotherapy can be considered (Level Ib, Grade A)I). • Bevacizumab can be added to carboplatin-paclitaxel chemotherapy in the first-line setting, except in patients with squamous histology, brain metastases, clinically significant hemoptysis, inadequate organ function, PS > 1, therapeutic anticoagulation, uncontrolled hypertension or clinically significant cardiovascular disease. Bevacizumab

can be continued until progression of disease. (Level Ib, Grade A)) • Bevacizumab can be dosed at 7.5 mg/kg or 15 mg/kg IV every 3 weeks.(Level Ib, Grade A)) • Cetuximab can be added to cisplatin-vinorelbine chemotherapy in the first-line setting, in patients with EGFR-positive tumour as measured by IHC. Cetuximab can be continued until progression of disease. (Level I, Grade A)) • Elderly patients (> 70 years) or patients with ECOG performance status 2 can be

considered for chemotherapy, either single agent or in selected patients, combination chemotherapy. These patients benefit from chemotherapy, although the degree of benefit is less than for PS 0 and 1 patients and toxic effects of chemotherapy are more. • Patients with poor performance score (ECOG 3 and 4) should be treated with best supportive care (BSC). (Level Ia, Grade A) 118

• In patients receiving first-line chemotherapy, 4 to 6 cycles of chemotherapy should be administered.(Level I, Grade A)) • Maintenance chemotherapy with either docetaxel, pemetrexed or oral tyrosine kinase inhibitor may prolong progression-free survival and can be considered after completing first-line chemotherapy.(Level I, Grade A)) • Painful bone metastases and metastases in weight-bearing bones should be treated with palliative radiotherapy.(Level Ia, Grade A)

• Bisphosphonates may reduce adverse bone events in patients with bone metastases. (Level Ia, Grade A) • Highly selected patients with solitary brain, adrenal and lung metastasis may benefit from resection of the metastasis along with lung resection. (Level IV, Grade C) • In patients who have progressed after first-line therapy, and who have adequate performance status, second line therapy may be considered including pemetrexed, docetaxel, erlotinib or gefitinib.(Level I, Grade A))

• Second-line therapy can be continued as tolerated until disease progression. • Patients who have progressed on second-line therapy may be considered for erlotinib therapy, if they have not received a prior oral tyrosine kinase inhibitor.(Level I, Grade A)) Management of malignant pleural effusion (unknown primary) Workup includes 1. Clinical examination – look for primary in breast, lungs, abdomen, pelvis; lymph node biopsy if enlarged (lymphoma) 2. Chest X-ray 3. Pleural fluid cytology

4. Tumor markers – CEA, CA-125 (females) and CEA, PSA (males) 5. Fiber optic bronchoscopy 6. Thoracoscopy – if pleural fluid cytology is negative  The best palliation for patients with malignant pleural effusion with complete lung expansion after chest tube drainage is pleurodesis.  Talc has better results in pleurodesis than bleomycin and tetracycline.  Patients with incomplete lung expansion after chest tube drainage may be treated with a pleuro peritoneal shunt or an indwelling pigtail catheter.

 Palliative chemotherapy may be offered to patients with good performance status Radiotherapy Protocols Radical Radiotherapy Indications – in early NSCLC – medically unfit for surgery or patient refusing surgery. 60-65 Gy / 33-36 fr / 6-7 weeks Phase I : 40 Gy / 20 fr across the mediastinum Phase II : 10 Gy / 6 fr / 2 cm margin (spinal cord shielding) Phase III : 10-15 Gy / 1 cm margin 119

Supraclavicular fossa is included as primary coverage in upper lobe tumors. Palliative Radiotherapy Indications – unresectable disease KPS > 60% 39Gy / 13 fr / 2.5 weeks Phase I : 30Gy / 10 fr / 2 weeks / maximum margin 2 cm Phase II : 9Gy / 3 fr / 3 days / spinal cord shielding KPS = 60% 10Gy / 1 fr / 1 day (or) 17Gy / 2 fr / 1 week (or) 20Gy / 5 fr / 1 week (No difference in IAEA pilot study) Supra clavicular fossa is not included in the field. Postoperative Radiotherapy

Indications – Positive margins and residual disease 50-54Gy / 25-27 fr / 5-6 weeks Phase I : 40Gy / 20 fr across the mediastinum Phase II : 10-14Gy / 5-7 fr / 2 cm margin (spinal cord shielding) Metastatic Disease Parenchymal Brain Metastases 30Gy / 10 fr / 2 weeks Low performance score – 20Gy / 5 fr / 1 week Spinal Cord Compression 30Gy / 10 fr / 2 weeks (or) 20Gy / 5 fr / 1 week (along with steroids and supportive care) Painful bone metastases Single fr : 6-8Gy / 1 fr

Multiple fr : 30Gy / 10 fr / 2 weeks (or) 20Gy / 5 fr / 1 week Rarely, hemibody irradiation may be used for multiple bone metastases Endobronchial Radiotherapy Indications – salvage treatment for recurrent / residual endobronchial lesion. 7.5Gy / fr X 2 fr 1.2 weeks apart 1 cm off axis. Superior Vena Cava Syndrome 20Gy / 5 fr / 1 week – assess the response 20Gy / 10 fr / 2 weeks with reduced fields (along with steroids and supportive care) 120

Small Cell Lung Cancer Small cell lung cancer (SCLC) represents a distinct entity that is biologically and clinically different from Non Small cell Lung cancer. It is an aggressive cancer with a rapid proliferation index thereby making it very chemosensitive. SCLC is staged according to the International Association for Study of Lung Cancer, into Limited stage disease (LD) and Extensive stage disease (ED). Limited stage disease (LD) is defined as disease restricted to one hemithorax, with or without

involvement of ipsilateral regional nodes including hilar, mediastinal and supraclavicular. It also includes involvement of contralateral mediastinal and supraclavicular nodes and an ipsilateral pleural effusion. Disease more extensive than described above is considered Extensive stage disease (ED). Management of LD SCLC Patients with LD SCLC are treated for potential cure with chemoradiotherapy. The standard treatment of LD SCLC is concurrent radiation therapy with cisplatin based chemotherapy. (Level

IIa, Grade B) Role of chemotherapy SCLC are known to be chemosensitive tumours and have shown good response rates with cisplatin based chemotherapy. Current standard chemotherapeutic protocol is to give 4-6 cycles of cisplatinum and etoposide based regimen. (Level IIa) However, even with this protocol- though response rates were as high as 70-80% (including 50% complete responses), most patients still die of tumour progression/recurrence.

Therefore, newer chemotherapeutic regimens with dose intensification were attempted. These showed very high toxicities with no documented significant increase in survival in all phase II-III studies. (Level Ib, Grade A) Role of Radiation therapy (RT) in LD SCLC In patients treated with chemotherapy alone, locoregional failure in the thorax occurs in upto 80% of patients with SCLC. RT was accepted as a part of combined modality approach as a result of 2 meta-analyses which

clearly showed an improvement in local control with subsequent improvement in overall survival (Level Ia, Grade A). Thoracic RT should be administered early, i.e during the 1st or 2nd cycle of chemotherapy at curative doses to achieve increase in the overall survival. (Level Ib, Grade A) 121

Role of Surgery Surgery plays a much less definitive role in SCLC as compared to NSCLC. The available data indicate that surgery can be useful in T1, T2 tumours without nodal involvement. For small lesions, surgery can also be considered as first line treatment followed by chemotherapy. (Level IV, Grade C) Role of Prophylactic Cranial Irradiation (PCI) The central nervous system is a frequent site for metastases in SCLC (about 50% of isolated metastases) which results in significant morbidity.

In a meta-analyses performed by the Collaborative Group, PCI showed an absolute increase of 5.4% in 3 year survivals with an increase of 8.8% in the disease free survival. (Level Ia, Grade A) However the role of PCI, regarding the timing, dose and fractionation, eligibility of patients and neurological toxicity remains unclear. In conclusion, the standard accepted treatment for LD SCLC of the lung is concurrent chemoradiation (platinum based) with emphasis on an early start of thoracic radiation. Surgery

has a small role to play in small peripherally located tumours. Management of Extensive stage SCLC Platinum based chemotherapy remains the mainstay of management of ED SCLC. Two meta-analyses have clearly indicated the superior role of cisplatinum based chemotherapy regimens as compared to other agents. (Level Ia, Grade A) Carboplatin can also be used as an alternative to cisplatin, with no difference in efficacy or toxicity. The usual course of management is to give 4 cycles of cisplatin/carboplatin with

etoposide. There is no evidence for the use of maintenance therapy in ED SCLC outside of a trial setting. (Level Ib, Grade A) Further, there is no evidence for the use of dose intensification or change of chemotherapeutic agent. Trials have shown no increase in survivals with the above measures. Management of refractory/relapsed ED SCLC Inspite of being very chemosensitive, the progression free survival in ED SCLC, after

chemotherapy, is only 4 months. Most patients will relapse and the prognosis of such patients is very poor. For patients relapsing after 3 months from completion of induction treatment the same protocol as induction can be repeated. For patients who relapse within 3 months of induction, or for refractory disease, 2nd line chemotherapy should be given. (Level IV, Grade C) Topotecan used as a single agent is at present the best option available. 122

(Level Ib, Grade A) Surgery plays no role in management of ED SCLC. In all cases of ED SCLC supportive care should include, radiation therapy for bony metastases and the management of paraneoplastic syndromes. In conclusion, as ED SCLC is a disease with a poor prognosis to begin with and complete treatment will increase survival only by 8-10 months, good patient selection is of utmost importance. Age and performance status form important patient selection criteria. In fit

PEDIATRIC SOLID TUMORS XV. WHEN TO SUSPECT/ RECOGNIZE? d) Introduction: Pediatric solid tumours are a very diverse group of diseases with differing biologies and behaviours and a substantial proportion consists of characteristic entities that are rarely seen in adults. e) Case definition: The International Classification of Childhood Cancer, Third Edition (ICCC-3) contains 12 main diagnostic groups: I. Leukemias, myeloproliferative diseases, and myelodysplastic diseases

II. Lymphomas and reticuloendothelial neoplasms III. CNS and miscellaneous intracranial and intraspinal neoplasms IV. Neuroblastoma and other peripheral nervous cell tumors V. Retinoblastoma VI. Renal tumors VII. Hepatic tumors VIII. Malignant bone tumors IX. Soft tissue and other extraosseous sarcomas X. Germ cell tumors, trophoblastic tumors and neoplasms of gonads XI. Other malignant epithelial neoplasms and malignant melanomas XII. Other and unspecified malignant neoplasms

All of the groups except retinoblastoma are split into subgroups, and the most heterogeneous subgroups are in turn split into divisions. The pediatric solid tumors comprise of group III to XII. Group III and VIII requiring specialized orthopedic and neuro-surgery and neuro-radiation expertise are considered separately. XVI. INCIDENCE OF THE CONDITION IN OUR COUNTRY The annual incidence of cancer in children under 15 years of age is between 38 and 124 per

million. There is no organized Paediatric solid tumours registry in India; hence, robust epidemiologic data is not available for the country. All currently quoted data is based on population-based cancer registries across India under the National Cancer Registry Program. XVII. DIFFERENTIAL DIAGNOSIS  Trauma  Infection  Benign tumor 124

XVIII. PREVENTION AND COUNSELING The occurrence and progression of paediatric solid tumours like most other tumors is influenced by a variety of genetic changes. The accumulation of changes varies between tumor types and the exact pattern varies even for a particular tumor type. Genetic counseling is the communication of information and advice about inherited conditions. A standard medical history and examination is required for the affected person and in addition

the family pedigree needs to be constructed. For certain tumor syndromes it might also be necessary to examine apparently normal parents and other relatives for minor features of the condition. Alternatively, if a specific mutation is identified in the proband, genetic testing for this mutation can subsequently be offered to the relatives where appropriate. Counseling needs to include all aspects of the condition and the depth of explanation should be

matched to the educational background of the couple. Parents may feel responsible for the condition of their child. These fears need to be aired and allayed. In inherited tumors and syndromes there is an additional need to minimize feelings of guilt and stigmatization. 125

XIX. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited g) Clinical Diagnosis: History & Clinical Examination Documentation of congenital anomalies, evident signs of clinical syndromes Assessment of Performance Status and Nutrition h) Investigations: i. Baseline investigations

Complete Haemogram Hemoglobin, RBC, WBC, Platelets, ESR, Coagulation Profile Routine Biochemistry FBS, RFT, LFT & LDH Serology HbsAg, HCV, HIV ii. Histological Examination: (Immunohistochemistry) Tissue diagnosis FNAC, Biopsies, Cytology, bone marrow studies iii. Diagnostic Imaging: Contemporary imaging modalities Radiology X-ray, USG, CT scan 126

i) Treatment: Standard Operating procedure b. In Patient • All sick pediatric solid tumor patients are admitted for supportive care and initiation of treatment as required. • Patients planned for elective surgery are admitted a day prior to the surgery with complete work-up and treatment plan. • Patients with fever are admitted for management of Febrile Neutropenia. Once their condition is stable they are discharged and followed up in the OPD. a. Out Patient

 Patients undergo complete clinical evaluation and are recommended investigations to confirm the diagnosis and complete staging.  Sick patients and those with Medical oncologic emergencies are admitted in the ward for emergency management.  Stable patients are followed up in the OPD till the diagnosis and staging workup is complete.  Treatment decisions are taken in the Multidisciplinary Joint clinics at diagnosis, at the time of

local therapy planning, at time of completion of treatment and if required anytime in between. b. Day Care • Treatment for all stable pediatric solid tumor patients is started in the OPD/Day care. Admission is limited to patients with uncontrolled co-morbid conditions or complications of the disease or treatment related complications. . • Patients with advanced/relapsed disease not amenable to treatment are considered for palliative care and referred for the same. j) Referral criteria:

• Patients requiring additional investigations or expert opinion to be referred to institutions with adequate infrastructure and expertise. 127

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available k) Clinical Diagnosis: History & Clinical Examination Documentation of congenital anomalies, evident signs of clinical syndromes Assessment of Performance Status and Nutrition l) Investigations: i. Baseline investigations Complete Haemogram Hemoglobin, RBC, WBC, Platelets, ESR, Coagulation Profile Routine Biochemistry FBS, RFT, LFT & LDH Serology HbsAg, HCV, HIV

ii. Histological Examination: (Immunohistochemistry) Tissue diagnosis FNAC, Biopsies, Cytology, bone marrow studies Molecular pathology EWS-FLI 1, EWS-WT1, SYT-SSX1, n-myc, PAX-3FKHR etc Tumor Markers AFP, BHCG, Urinary VMA, HVA iii. Diagnostic Imaging: Contemporary imaging modalities Radiology X-ray, USG, CT scan, MRI Nuclear imaging PET scan, Bone scan, MIBG scan 128

m) Treatment: Standard Operating procedure c. In Patient • All sick pediatric solid tumor patients are admitted for supportive care and initiation of treatment as required. • Patients planned for elective surgery are admitted a day prior to the surgery with complete work-up and treatment plan. • Patients with fever are admitted for management of Febrile Neutropenia. Once their condition is stable they are discharged and followed up in the OPD. a. Out Patient

local therapy planning, at time of completion of treatment and if required anytime in between. b. Day Care • Treatment for all stable pediatric solid tumor patients is started in the OPD/Day care. Admission is limited to patients with uncontrolled co-morbid conditions or complications of the disease or treatment related complications. . • Patients with advanced/relapsed disease not amenable to treatment are considered for palliative care and referred for the same. n) Referral criteria:

• Patients with logistic problems will receive referral letters for institutions with adequate infrastructure and expertise including the necessary protocols. • Patients with advanced incurable disease will be triaged and will undergo counseling by the DMG’s palliative care team. Appropriate instruction and arrangement will be provided for referral of these patients for supportive care to institutions at convenient distance from their hometowns. 129

XX. WHO DOES WHAT? and TIMELINES First visit- Assessment by clinician and prescription of related basic investigations 1 day First Review - Assessment by senior clinicians of DMG (Additional investigations for diagnosis and staging work up) 1 week Second Review – Multi-disciplinary Joint Clinic presentation and flow chart of treatment plan as per prevailing protocol based on risk stratification Initiation and Monitoring of treatment

Third review: Post induction chemotherapy response evaluation at 8-9 weeks and implementation of planned local therapy Fourth Review – Post local therapy Fifth Review- On completion of planned treatment Follow up as per DMG policy for 2 years Reevaluation and registration in the After Completion of Therapy (ACT) clinic if disease free 130

Follow up in ACT clinic annually to monitor growth and development, late effects and encourage survivorship programme – “UGAM” XXI. FURTHER READING / REFERENCES • Steliarova-Foucher E, Stiller C, Lacour B, et al. International classification of childhood cancer, third edition. Cancer 2005;103:1457–1467  Arora RS et al. Epidemiolgy of Childhood cancer in India. Indian J Cancer 2009;46:264-273  Hodgson SV, Maher ER, Eng C, Foulkes W. A practical guide to human cancer genetics.

Cambridge University Press, Cambridge (2006). RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) HUMAN RESOURCES INVESTIGATIONS DRUGS EQUIPMENT 1. Qualified Surgeon Haematological, NSAIDs, Opioids OT equipment, 2. Qualified Radiation Oncologist Biopsy, Antacids, Electrical 3. Qualified Pediatric Medical Histopathology, CT Antiemetics, cautery,

Oncologist Scan/MRI, Contrast medium Hormonic 4. Pathologist Molecular (IHC) Chemotherapeutics scalpel, 5. Radiologist analysis. ( Most commonly Intaoperative X- 6. Trained Nurses used drugs) ray unit, 7. General Physician Vincristine, Anesthesia 8. Palliative Care specialist Ifosphamide, trolley, 9. Anesthetist Doxorubicin, mechanical 10. Clinical Psychologist Cisplatin, ventilators, 11. Medical Social Worker Carboplatin, Suction Etoposide, apparatus, Cyclophosphamide, nebulizers, Co60

Actinomycin D, unit, Linear Bleomycin, Accelerator, Topotecan, 2D/3D Methotrexate, Simulators, Temozolamide, 13 Treatment cis-Retinoic acid, planning system, 5FU,Vinblastine 131

Neuroblastoma Neuroblastoma is the most common extra cranial solid tumor in children. It arises from neural crest cells which differentiate in cells of the sympathetic ganglia and adrenal medulla. It remains a complex medical challenge with spontaneous regression at one end to an unpredictable clinical course and dismal outcome at the other end of spectrum. Image defined risk factors (IDRF) for Neuroblastoma Site of primary tumor: Cervical, cervico-thoracic, thoracic, thoraco-abdominal, abdominal, and

pelvic. Local extent:  Crossing midline  Encasement of any major vessel at that site like carotid, vertebral, IJV, subclavian, mediastinal great vessels, abdominal aorta and its branches, IVC, iliacs.  Infiltration of adjacent critical areas like skull base, trachea, main bronchi, brachial plexus, pericardium, , costo-vertebral junction (especially between D9-D12), porta- hepatis, hepato-duodenal ligament, mesenteric root, sciatic notch, intra-spinal extension

(more than 1/3rd diameter of spinal canal involved on axial image or loss of perimedullary space or abnormal cord)  Infiltration of adjacent organs like heart, diaphragm, liver, kidney, spleen, pancreas, etc Presence of multifocal primary Collections in cavities like pleural or peritoneal Adenopathy: Enlarged local or distant nodes Metastatic disease: Bony lesions, Liver or lung lesions 132

Neuroblastoma risk Stratification  Risk stratification should be done at a tertiary centre before initiation of therapy.  In unresectable lesions generous core biopsy (image guided) should be performed for histopathology and molecular studies. Risk Age Stage MYCN status Low <547 days 1, 2A/B,4S NA > 547 days 1, 2A/B NA Intermediate <547 days 3, 4 NA > 547 days 3 NA High <547 days 1, 2, 3, 4, 4S Amp > 547 days 1,2,3 Amp > 547 days 4 Any 133

Management Algorithm Neuroblastoma Resectable Unresectable (No IDRF) (IDRF +) Upfront Intermediate High risk Surgery risk Intermediate Low risk High risk NACT Induction CT risk Adjuvant CT Consolidation Observe Surgery Surgery + RT theapy Adjuvant CT Consolidation HD CT + ABMT SD CT + RT + RT theapy 13 CRA 13 CRA HD CT + ABMT SD CT + RT 13 CRA 13 CRA HD CT = High Dose Chemotherapy SD CT = Standard Dose Chemotherapy ABMT = Autologous Bone Marrow Transplant 13 CRA = 13 Cis Retinoic Acid 134

Wilms’ tumor Wilms’ tumor predominantly affects children under 5 years of age, most commonly during the first 2 years of life. Contemporary treatment of Wilms’ tumor has led to an overall survival of over 85% and the emphasis is now shifting from successful treatment to reducing treatment- associated morbidity without loss of efficacy. Radiological report for Wilm’s Tumor Should be a contrast enhanced CT/MRI of abdomen Laterality: Right or Left or Bilateral disease Location: which pole Size Local extent:

 Is it Completely Intra-renal location or is Perinephric spread evident  Renal sinus infiltration.  Renal vein status  IVC status.  Renal artery : comment about the abdominal origin as well, comment on accessory arteries if any  Infiltration of liver, pancreas, bowel, GB, or abdominal wall Significant ascites, Peritoneal implants Adenopathy: Enlarged nodes Metastatic disease: Lung, liver, bone or extra-abdominal nodes 135

Synoptic Pathology report for renal tumour Gross Examination: Received a specimen of right / left radical nephrectomy / nephrectomy/ partial nephrectomy measuring -------X------X-------- cm. including perinephric fat. Hilum of the kidney shows ureter measuring --------cm along with arterial and venous stumps. On cutting open, the kidney measures ----------X--------X--------cm and shows a tumour measuring

--------X--------X-------- cm involving---------------------------------of the kidney. Cut surface of the tumour is solid / nodular solid / solid-cystic. Areas of necrosis and hemorrhage are------------------ -----. Tumour invades through the renal capsule and extends into perinephric fat grossly / does not invade the renal capsule. Tumour involves / does not involve the Gerotta’s ( renal )fascia. Renal sinus is----------------. Renal vein invasion is--------------------------------. Renal pelvis and ureter

are-----------------------------. Resection end of ureter is ------------------------------- Resection end of renal vein is -----------------------------. Hilum of the kidney reveals-----------------nodes. Foci of nephroblastomatosis are not indentified / identified . A slice of the tumour is cut in a grid fashion and submitted for histopathology examination. Please draw the tumour and indicate tumour grid in the above diagram Block identification: 136

I- II- III- IV- V- Microscopy: Right / Left radical nephrectomy / Nephrectomy / Partial nephrectomy , Post chemotherapy / History of neo-adjuvent chemotherapy unknown- Triphasic / Biphasic / blastemal predominant / teratoid Wilm’s tumour of ------------kidney. -------------------------------------------------------------------------------------------------------------------------------

------------------------------------------------------------------------------------------------------------------------------- ---------------------------------------------------------------------- Favourable histology ( FH ) / unfavourable histology (UH ) Anaplasia is absent. Focal / diffuse anaplasia is seen. Vascular invasion -------------------- Tumour does not invade the renal capsule / invades the renal capsule and is seen in perinephric fat.. Gerotta’s fascia is -----------------------------------

Renal sinus involvement is------------------------------------- Renal vein involvement is ---------------------------- Hilar lymph nodes---------------------------------------------------------------------------------- Foci of nephroblastomatosis are not seen / -----------------type of nephroblastomatosis is present. ------------------------------------------------------------------------------------------------- Resection margins of ureter, renal vein and renal artery are ---------------------------------

------------------------------------------------------------------------------------------------------------------------------- -------------------------------- Impression: Right / Left radical nephrectomy / Nephrectomy / Partial nephrectomy , Post chemotherapy / History of neo-adjuvent chemotherapy unknown.: Wilm’s tumour, ----------------histology, ---------------invading renal capsule / -------------------- invading Gerotta’s fascia, -- -------involving --------------lymph nodes. 137

Management Algorithm WILMS TUMOR Resectable Unresectable/Metastatic Upfront resection Upfront chemotherapy 4-6 weeks VAD Nephrectomy with RP lymph node sampling Stage 1 FH/UH & Stage 3 FH Stage 4 FH 2 FH 18 weeks VA 24 weeks VAD 24 weeks VAD + Local RT( as per local stage ) RT + RT/Surgery for Metastases 24 weeks VAD +Cy +Eto Stage 2-4 UH Local RT + RT/Surgery for Metastases V= Vincristin A= Actinomycin D D= Doxorubicin Cy = Cyclophosphamide Eto= Etoposide RP = Retroperitoneal RT= Radiotherapy

Diagnostic Algorithm and Standard Treatment Guidelines for Management of Common Ear Conditions Background Deafness is defined as the inability to use hearing as a primary channel for receiving speech, even with amplification. Hearing loss is hearing impairment of various degrees. It is estimated that there are approximately 63 million people in India suffering from hearing impairment. A significant proportion of cases of hearing loss are due to common ear

diseases, which if diagnosed early and managed properly can significantly reduce the burden of decreased hearing. Considering the burden of the problem and the burden of disability due to decreased hearing/deafness, there was a pressing need for developing guidelines for diagnosis and treatment of patients with ear diseases. We have developed, in consultation with some of the leading experts in the country, an Algorithm for diagnosing common ear conditions and Treatment Guidelines for managing

these conditions. The principal objective of this exercise is to aid in reducing the burden of preventable hearing loss in the country. These guidelines have been developed with the objective of helping physicians, general practitioners or pediatricians at the primary and secondary level, who are often the first interface with a majority of patients, in arriving at a diagnosis of common ear conditions and instituting proper management. Standard Treatment Guidelines

These guidelines are intended to cover the management of the common ear conditions which may lead to hearing impairment. Common ear conditions which may lead to hearing impairment. (Click on the links below to see the guidelines) 1. Ear Wax 2. External auditory canal infections 3. Otomycosis 4. Acute Suppurative Otitis Media - ASOM 5. Chronic Suppurative Otitis Media - CSOM (Safe type) 6. Chronic Suppurative Otitis Media - CSOM (Unsafe type) 7. Otitis Media with Effusion - OME

Apart from these common ear conditions leading to decreased hearing there are other causes of preventable hearing loss, like excessive use of ototoxic drugs and noise induced hearing loss. These are also important causes of hearing loss and should receive adequate consideration. Early screening for hearing loss and early rehabilitation is recommended to reduce the disability caused by hearing impairment. Ear Wax- Signs and Symptoms » Wax seen in the ear » Pain / decreased hearing / itching in ear Treatment

» In case of severe pain analgesic should be given » Wax softener ear drops, 3-5 drops three times a day for 4-5 days » Removal of the wax by gentle syringing (refer the patient if you are not familiar with the procedure of syringing) » If pain persists refer to an ENT specialist 1

Advice to the patient » Not to instill oil in the ear » Not to use ear buds or any sharp object for cleaning the ear External Ear Canal Infections Otitis externa, Furunculosis Signs and symptoms » Pain and heaviness in the ear » Tenderness and swelling of the ear canal and surrounding area » Decreased hearing Treatment » Topical ear drops (Steroid and antibiotic combination) » 10% Ichthammol glycerine packing (to be changed or removed after 24 hours) » Anti-inflammatory drugs

» Systemic antibiotics [Amoxycillin+Cloxacillin / Amoxycillin] » If no improvement is seen in 5-7 days, refer to an ENT specialist Advice to the patient » Not to scratch the ear with pointed objects » Keep the ear dry (prevent water from getting into the ear) Otomycosis- Signs and symptoms » Pain and heaviness in the ear » Itching in the ear » Decreased hearing » Whitish debris/ spores in the ear canal Treatment » Antifungal ear drops three drops three times a day » Topical cleaning

» Gentle syringing and dry mopping Acute Suppurative Otitis Media (ASOM)- Signs and symptoms: » Earache/fever/excessive » Crying/URI/decreased hearing/ear discharge » Congestion/bulging/perforation of the tympanic membrane Treatment 1. Antibiotic therapy » Amoxycillin: » For children: 40- 60 mg/kg in three divided doses for 10-14 days » For adults: 500mg three times a day for 7 days. OR » Co-trimoxazole or Erythromycin (if allergic to penicillin) OR » Co-amoxyclav/Cefaclor (in case of no-response for 48-72

hours with above drugs) 2. Anti-inflammatory drugs for three days/till symptoms subside 3. In case of discharge – Borospirit/Ciprofloxacin/Ofloxacin ear drops 2

Refer to an ENT specialist if- » Patient develops features like vomiting with headache/facial palsy/dizziness/mastoid tenderness » Symptoms worsen even after 48 hours of second line medical treatment Advice to the patient- » Keep the ear dry (prevent water from getting into the ear) » In case of discharge – dry mopping of the ear with a clean cotton wick. » Not to put any indigenous eardrops Chronic Suppurative Otitis Media CSOM (Safe Type) Signs and symptoms

» Mucopurulent ear discharge for 3 months or longer hearing impairment » Central perforation of the tympanic membrane Treatment » Dry mopping of the ear using a cotton wick (or gentle suction under vision) » Topical Borospirit/Ciprofloxacin/Ofloxacin with/without steroid ear drops » If fungal infection is suspected/seen – add topical anti-fungal agent (like Clotrimazole) » If acute symptoms like increased discharge/pain appear then add systemic antibiotics (as per ASOM treatment guidelines)

» After control of infection the patient should be referred to an ENT specialist for surgical management. Advice to the patient » Keep the ear dry (prevent water from getting into the ear) » Dry mopping of the ear with a clean cotton wick » Not to put any indigenous eardrops Chronic Suppurative Otitis Media with Cholesteatoma (Unsafe Type) Signs and symptoms: » Foul smelling ear discharge » Hearing impairment » On examination - retraction pocket or perforation of tympanic membrane with whitish

flakes (cholesteatoma). Granulations or a polyp may be present. Treatment: All patients with unsafe CSOM need urgent referral to an ENT specialist because without treatment, serious, even fatal complications may occur. The treatment is essentially surgical. Danger Signs for immediate referral: Severe headache Projectile vomiting Vertigo Neck rigidity Facial nerve paralysis Mastoid abscess 3

Otitis Media with Effusion (OME) Signs and symptoms » Decreased hearing/fullness » Sometimes ear-ache On examination - dull, retracted ear drum sometimes with air bubbles and a visible air-fluid level Treatment » Most cases in children follow a course of spontaneous resolution so a policy of wait and watch with monthly follow up for three months is recommended. » If features of ASOM develop manage as per ASOM treatment guidelines

» If the effusion does not resolve even after three months then referral is indicated Diagnostic Algorithm This diagnostic algorithm has been prepared keeping in mind the common presenting complaints of patients coming with ear infections. The common presenting symptoms are: pain in the ear, discharge from the ear, hearing loss and combinations of these complaints. We have made a simple algorithm which can be used by the health care provider to arrive at

a diagnosis on the basis of the history of patients. The next level of diagnosis is based on the examination of the ear. This is possible at centers where facilities of otoscopy using an otoscope are available. Accordingly the health care provider can either refer the patient to an ENT specialist for further detailed evaluation and management or if possible, can manage the patient as per the treatment guidelines. 4

STANDARD TREATMENT GUIDELINES Management of Osteoarthritis Knee January 2017 Ministry of Health & Family Welfare Government of India

Index SCOPE ..................................................................................................................................2 INTRODUCTION ...................................................................................................................3 NEED FOR A STG/ GUIDELINE PURPOSE ..............................................................................4 RECOMMENDATIONS ..........................................................................................................5

4.1. Diagnosis of Osteoarthritis Knee - ........................................................................................ 5 4.2 Role of imaging ...................................................................................................................... 6 4.3Treatment ............................................................................................................................ 10

FOLLOW UP AND REVIEW : ....................................................................................................... 15 ARTHROPLASTY : ....................................................................................................................... 16 4.7 Summary ............................................................................................................................. 19

How this guideline was developed ............................................................................................ 21 7. Research Needs ..................................................................................................................... 23 8. Annexure (Adopt/Adapt Table) ............................................................................................ 24

SCOPE : Approach to Management of Osteoarthritis of Knee SCOPE POPULATION : Groups Covered : Adults with suspected Osteoarthritis (OA) of Knee persistent joint pain that becomes worse with use predominantly in people age 45 years or older morning stiffness lasting no more than half an hour Pathology Primary OA Knee Secondary OA Post traumatic Healed sequelae of infection or inflammatory disease Groups Not Covered : Acute / subacute Infection : TB, Pyogenic septic arthritis, Fungal, Hansen Acute Trauma

Acute Inflammatory diseases : RA, AS, Psoriatic, seronegative arthrititidis, Spondyloarthropathy Crystal arthritis (gout or pseudo-gout) Hemophilic arthropathy Bone and soft tissue tumours Health Care Settings : Primary Health Care 2

Management : Pharmacology, Physiotherapy Secondary Management : Pharmacology, Physiotherapy, Occupational Therapy, Orthosis Tertiary Management : Pharmacology, Physiotherapy, Occupational Therapy, Orthosis, Surgery Management Issue not covered : Alternative therapies (Ayurvedic,Unani and Homeopathic medications) and Yoga, Tai Chi INTRODUCTION 1.1 Definitions- 1.2 Burden of disease- 3

Knee OA is one of the leading causes of global disability and the real burden of osteoarthritis (OA) has been underestimated. The global age-standardized prevalence of knee OA was reported as 3.8%, higher in females than males (Cross et al, 2010). The prevalence of OA knee in India in a report by ICMR in 2012 was 3.28% in Delhi ; 5.81% in Dibrugarh and 6.52% in Jodhpur (ICMR study, 2012). However a community based cross sectional study across five sites in India conducted in big city, small city, town,

and village was reported in 2016 to be as high as 28.7% (Pal et al, 2016). Morbidity and mortality – CDC has reported an annual average of 0.2 to 0.3 deaths per 100,000 population due to OA. OA deaths are likely highly underestimated. For example, gastrointestinal bleeding due to treatment with NSAIDs is not counted (Sacks et al, 2004). The hospitalization rate per 100,000 in the US, for total knee replacement increased by 217% from 1992 to 2011 from 203.6 to 6455.

OA of the knee is one of five leading causes of disability among non-institutionalized adults6. About 80% of patients with OA have some degree of movement limitation. About 25% cannot perform major activities of daily living (ADL's), 11% of adults with knee OA need help with personal care and 14% require help with routine needs and about 40% of adults with knee OA reported their health "poor" or "fair." 2. CURRENT PRACTICES IN INDIA Pharmacological modalities like analgesics, NSAID’s, topical applications,

supplementations like glucosamine along with physiotherapy including exercises, massage, TENS, thermotherapy and braces along with acupuncture and ayurvedic as well as homeopathic and other alternate therapies are widely used by different care givers. Surgical interventions besides intra-articular injections including arthroscopy, osteotomy, unicondylar and total knee replacements are commonly done by orthopaedic surgeons across the country specially in different cities. NEED FOR A STG/ GUIDELINE PURPOSE 4

Osteoarthritis of the knee, a common chronic problem makes the patients try out a wide variety of therapeutic modalities hopping from doctors to physiotherapists to alternative therapists for pain alleviation and sometimes to avoid surgery even in advanced osteoarthritis. This manuscript would be useful for the patients as well as the primary level and secondary level health care professionals, for diagnosing a case of osteoarthritis of the

knee followed by guidelines regarding the non operative management with special reference to prevent unnecessary prescriptions of glucosamine or chondroitin products while emphasizing on self management strategies such as weight loss, exercise, suitable footwear, braces, walking aids and thermotherapy as well as other physiotherapy modalities including electrotherapy and acupuncture. Role of pharmacological management including analgesics,

topical ointments and intrarticular injections of steroids and hyaluronan are also elaborated. For the tertiary level orthopaedic surgeons, this manual would be a useful guideline for controversial and confusing trends sometimes practiced differently by various surgeons. These guidelines include indications of osteotomy and arthroplasty and unicondylar replacement versus osteotomy with no role of arthroscopic lavage and debridement. Details

of arthroplasty including prognostic factors, intra-operative considerations of analgesia, nerve blocks, tourniquets, tranexemic acid, surgical drains as well as choice of implants, cement, bilateral replacement, navigation, patient specific instrumentation and post operative protocols of cryotherapy, CPM, rehabilitation and hospital stay guidelines would also be of interest to the orthopaedic and arthroplasty surgeons. RECOMMENDATIONS 4.1. Diagnosis of Osteoarthritis Knee -

4.1.1 Clinical features: symptoms and signs (Hasan and Shuckett, 2010) 5

Algorithm of approach to joint pain (Harrison, 19th Ed) Symptoms The main symptoms of OA include pain around the knee, stiffness, and altered joint function. Initially this tends to be worse with weight bearing and ambulation. Eventually this can progress to pain day and night once cartilage loss leads to bone-on-bone contact. In contrast to inflammatory arthritides such as rheumatoid arthritis, with their prolonged morning stiffness and worsened pain in the morning, OA tends to worsen as the day

progresses. The stiffness in OA is termed “inactivity stiffness” and contrasts with the prolonged “morning stiffness” of rheumatoid arthritis. Inactivity stiffness in osteoarthritic lower limb joints lasts about 5 to 10 minutes and occurs when the patient gets up and bears weight after prolonged immobility. Signs On physical examination, a small effusion with a fluid bulge sign can be present in OA of the knee. Larger effusions can occur but are less frequent than in the inflammatory arthropathies.

There may be cartilaginous crepitus or a crackling feeling on palpation of the knee with motion. Eventually there may be coarse bone-on-bone crepitus whereby the opposing bone ends, denuded of cartilage, seem to grate against one another. There is often a loss of range of motion of the involved knee,particularly with progression of OA. Loss of cartilage of the knee can lead to malalignment of the leg with a varus deformity or

bow-legged positioning of the leg being evident. This angulation of the knee applies to medial compartment OA of the knees. Less commonly, patients may present with a valgus or knock-knee deformity, indicative of more advanced disease in the lateral compartment of the knee. On occasion, and much less commonly, patients may present with isolated OA in the patellofemoral joint, which itself may be very symptomatic. 4.2 Role of imaging 4.2.1 X Rays :

Since the 1970s, the standard view for radiographic assessment of the tibiofemoral joint has been the extended-knee radiograph, which is a bilateral antero-posterior image acquired while the patient is weight-bearing,with both knees in full extension. 6

Fig 1 : Standing (weight bearing) AP view of both Knee The primary utility of radiography in the diagnosis of OA is for evaluation of joint space width (JSW). JSW and subsequent joint space narrowing (JSN) were originally assessed using manual techniques that required minimal additional equipment or processing software (Chondrometry, 1995; Ravaud et al,1996). However, these methods were time consuming and subjective and have since been largely abandoned in favour of automated assessment,

which provides quick and precise measurements of joint space width (JSW). In addition to improving reproducibility of semi-quantitative scoring or manual measurements, automated assessment has also sparked additional characterizations of joint space, including minimum JSW, mean JSW, joint space area, and location-specific JSW (Roemer et al, 2011). Several studies have shown minimum JSW to be most reproducible and most sensitive to OA- related changes (Conrozier et al, 2001 ; Vignon, 2004).

On plain X-ray of an osteoarthritic joint, in addition to joint space narrowing, there tends to be subchondral sclerosis or an appearance of whitening of the subchondral bone. Osteophytes, which reflect a regenerative process with formation of fibrocartilaginous extensions or hooks at the joint margins, are common. Interestingly, the presence of osteophytes in one compartment, such as the lateral compartment in a patient with medial

compartment OA, is not indicative of disease in that compartment. It is simply indicative of the body’s reparative response to the abnormal stresses and presence of disease in the medial compartment. Currently, the Kellgren-Lawrence (KL) grading scheme is the most widely used and accepted standard for diagnosis of radiographic OA (Kellgren and Lawrence,1957 ; Bauer et al,2006). 7

A KL grade of 0 indicates that no radiographic features of OA are present while a KL grade of 1 is defined as doubtful JSN and possible osteophytic lipping (Kellgren and Lawrence,1957). Radiographic OA receives a KL grade of 2, denoting the presence of definite osteophytes and possible joint space narrowing (JSN) on anteroposterior weight- bearing radiograph (Kellgren and Lawrence,1957). Further disease progression is graded as

KL 3, characterized by multiple osteophytes, definite JSN, sclerosis, possible bony deformity and KL grade 4, which is defined by large osteophytes, marked JSN, severe sclerosis and definitely bony deformity (Kellgren and Lawrence,1957). The KL grading scheme has been criticized for characterizing the progression of OA as a linear process and combining osteophyte and JSN measurements (Roemer et al, 2011). More recently, the

Osteoarthritis Research Society International atlas has developed OA classification scores that evaluate tibiofemoral JSN and osteophytes separately in each compartment (Altman, 1995 ; Altman and Gold, 2007). While radiography is useful for evaluation of JSW, a 2005 study by Amin et al. revealed that a significant number of symptomatic patients show cartilage loss on MRI even when JSN or disease progression is not visualized using radiography. In this study, radiographic

progression was 91% specific but only 23% sensitive for cartilage loss (Amin et al, 2005). In patients with suspected posterolateral OA with a mild valgus deformity, a 30 degree flexed standing posteroanterior (PA) view with the beam directed 15 degrees from cephalad to caudad may be valuable in showing the disease in the posterior aspect of the lateral compartment of the knee (Leach et al, 1970 ; Cibere, 2006). 8

Fig 2 : Standing PA view of both Knee in flexed position for posterolateral osteoarthritis of knee with a mild valgus deformity Fig 3 : Standing PA view of both Knee In early cases, a standard standing AP view may appear normal or indicate very mild OA, whereas the standing flexed PA view may show bone on bone contact. Patellofemoral OA of the knee cap is also a common finding, best diagnosed on a skyline X-ray view(Hasan and Shuckett, 2010). The Knutsson view is most convenient with the

patient in supine position lying comfortably on the X Ray table. Fig 4 : Different positions for skyline view of patella-femoral joint, of which Knutsson view is most convenient. . Fig 5 : Skyline view of patella-femoral joint X Ray is needed when considering surgery. 9

X Ray will identify radio-opaque loose bodies, a less frequent cause of locking. (Royal College of Radiologists Recommendations) 4.2.2 Indications of Ultrasound US is useful for anterior knee pain with suspected tendinopathy or associated bursitis. (Royal College of Radiologists Recommendations) 4.2.3 Indications of MRI MRI is useful for persistent undiagnosed pain of knee joint. MRI is the investigation of choice to identify meniscal tears and loose bodies.( Royal College of Radiologists Recommendations)

MRI has emerged as an excellent modality for detection of OA when the plain radiographs indicate no disease or mild disease, and the patient’s symptoms are out of keeping with the apparent severity of disease.MRI can detect large focal articular cartilage lesions that cannot be detected on plain films (Boegard et al, 1998) 4.3Treatment A. GENERAL CORE TREATMENT 10

A 1.Patient Information : Offer accurate verbal and written information to all people with osteoarthritis to enhance understanding of the condition and its management, and to counter misconceptions, such as that it inevitably progresses and cannot be treated. Ensure that information sharing is an ongoing, integral part of the management plan rather than a single event at time of presentation. A 2.Patient self-management interventions :

Agree individualised self-management strategies with the person with osteoarthritis. Ensure that positive behavioural changes, such as exercise, weight loss, use of suitable footwear and pacing, are appropriately targeted. A3.Thermotherapy : The use of local heat or cold should be considered as an adjunct to core treatments. A4. Exercise and manual therapy : Advise people with osteoarthritis to exercise as a core treatment. Advise people with

osteoarthritis to exercise as a core treatment irrespective of age, comorbidity, pain severity or disability. Exercise should include: 1. Local muscle strengthening : Exercise has been found to be beneficial but the clinician needs to make a judgement in each case on how to effectively ensure participation. This will depend upon the person's individual needs, circumstances and self-motivation, and the availability of local facilities.

2. Manipulation and stretching : It should be considered as an adjunct to core treatments. A 5. Weight loss : Offer interventions to achieve weight loss as a core treatment for people who are obese or overweight. A 6. Electrotherapy : Should consider the use of transcutaneous electrical nerve stimulation (TENS) as an adjunct to core treatments for pain relief. A7. Nutraceuticals : Do not offer glucosamine or chondroitin products for the management of osteoarthritis.

A 8. Acupuncture : Do not offer acupuncture for the management of osteoarthritis. A 9. Aids and Devices : 11

1. Footwear : Offer advice on appropriate footwear (including shock-absorbing properties) as part of core treatments for people with lower limb osteoarthritis. 2. Brace / Insole : People with osteoarthritis who have biomechanical joint pain or instability should be considered for assessment for bracing/joint supports/insoles as an adjunct to their core treatments. 3. Walking Aid : Assistive devices (for example, walking sticks and tap turners)

should be considered as adjuncts to core treatments for people with osteoarthritis who have specific problems with activities of daily living. If needed, seek expert advice in this context B. PHARMACOLOGICAL MANAGEMENT B1.Oral analgesics: Paracetamol for pain relief in addition to core treatments regular dosing may be required. Paracetamol and/or topical non-steroidal anti-inflammatory drugs (NSAIDs) should be considered ahead of oral NSAIDs, cyclo-oxygenase 2 (COX-2) inhibitors or opioids like tramadol.

Usual Adult Paracetamol Dose for Pain: General Dosing Guidelines: 325 to 650 mg every 4 to 6 hours or 1000 mg every 6 to 8 hours orally. Paracetamol 500mg tablets: Two 500 mg tablets orally every 4 to 6 hours Tramadol Dose : Drugs.com Immediate-Release: -Initial dose: 25 mg orally once a day; titrate in 25 mg increments every 3 days to reach a dose of 25 mg four times a day; thereafter increase by 50 mg as tolerated every 3 days to reach a dose of 50 mg four times a day

-Maintenance dose: After titration, 50 to 100 mg orally as needed for pain every 4 to 6 hours -Maximum dose: 400 mg per day Extended-Release: -Initial dose (tramadol-naive): 100 mg orally once a day; titrate upwards in 100 mg increments every 5 days as needed and as tolerated. -Maximum Dose: 300 mg orally per day . 12

If paracetamol or topical NSAIDs are insufficient for pain relief for people with osteoarthritis, then the addition of opioid analgesics should be considered. Risks and benefits should be considered, particularly in older people. B2.Topical treatments : Consider topical NSAIDs and/or paracetamol ahead of oral NSAIDs, COX-2 inhibitors or opioids. Topical capsaicin should be considered as an adjunct to core treatments for knee or hand osteoarthritis. Do not offer rubefacients for treating osteoarthritis.

B3. NSAIDs and highly selective COX-2 inhibitors : Although NSAIDs and COX-2 inhibitors may be regarded as a single drug class of 'NSAIDs', these recommendations use the two terms for clarity and because of the differences in side-effect profile. Where paracetamol or topical NSAIDs are ineffective for pain relief for people with osteoarthritis, then substitution with an oral NSAID/COX-2 inhibitor should be considered. Where paracetamol or topical NSAIDs provide insufficient pain relief for people with

osteoarthritis, then the addition of an oral NSAID/COX-2 inhibitor to paracetamol should be considered. Use oral NSAIDs/COX-2 inhibitors at the lowest effective dose for the shortest possible period of time. When offering treatment with an oral NSAID/COX-2 inhibitor, the first choice should be either a standard NSAID or a COX-2 inhibitor (other than etoricoxib 60 mg). In either case, co-prescribe with a proton pump inhibitor (PPI), choosing the one with the lowest acquisition cost.

All oral NSAIDs/COX-2 inhibitors have analgesic effects of a similar magnitude but vary in their potential gastrointestinal, liver and cardio-renal toxicity; therefore, when choosing the agent and dose, take into account individual patient risk factors, including age. When prescribing these drugs, consideration should be given to appropriate assessment and/or ongoing monitoring of these risk factors. If a person with osteoarthritis needs to take low-dose aspirin, healthcare professionals

should consider other analgesics like tramadol before substituting or adding an NSAID or COX-2 inhibitor (with a PPI) if pain relief is ineffective or insufficient. 13

B 4. Intra-articular injections : 1. Intra-articular corticosteroid injections : Intra-articular corticosteroid injections should be considered as an adjunct to core treatments for the relief of moderate to severe pain in people with osteoarthritis. 2. Intra-articular hyaluronan : Do not offer intra-articular hyaluronan injections for the management of osteoarthritis. C. SURGERY INDICATIONS AND REFERRALS : 1. Physicians from Primary and Secondary Health Care Centres while referring a

person with osteoarthritis for consideration of joint surgery should ensure that the person has been offered at least the core (non-surgical) treatment options (mentioned above). 2. Decisions for surgery should be based after discussions between patient representatives, referring clinicians and surgeons, rather than using scoring tools for prioritization. 3. Consider referral for joint surgery for people with knee osteoarthritis with : a. Knee Pain b. Knee stiffness with restricted knee movements

c. Impaired or reduced knee function d. Substantial impact on their quality of life and activities of daily living e. Refractory to non-surgical treatment. 4. Refer for consideration of joint surgery before there is prolonged and established functional limitation and severe pain. 5. Patient-specific factors (including age, sex, smoking, obesity and co-morbidities) should not be barriers to referral for joint surgery. 6. When discussing the possibility of joint surgery, check that the person has been

offered at least the core treatments for osteoarthritis and give them information about: a. the benefits and risks of surgery and the potential consequences of not having surgery 14

b. recovery and rehabilitation after surgery c. how having a prosthesis might affect them d. how care pathways are organised in their local area. FOLLOW UP AND REVIEW : Offer regular reviews to all people with symptomatic osteoarthritis. Agree the timing of the reviews with the person Reviews should include: a. monitoring the person's symptoms and the ongoing impact of the condition on their everyday activities and quality of life b. monitoring the long-term course of the condition

c. discussing the person's knowledge of the condition, any concerns they have, their personal preferences and their ability to access services d. reviewing the effectiveness and tolerability of all treatments e. support for self-management. Consider an annual review for any person with one or more of the following: a. troublesome joint pain b. more than one joint with symptoms c. more than one co-morbidity d. taking regular medication for their osteoarthritis. ARTHROSCOPY :

Do not refer for arthroscopic lavage and debridement as part of treatment for osteoarthritis. Indication for arthroscopy : If the person with knee osteoarthritis has a clear history of mechanical locking (as opposed to morning joint stiffness, 'giving way' or X-ray evidence of loose bodies). OSTEOTOMY : 15

(inputs from Dr.Mathew …) ARTHROPLASTY : Prognostic Factors : 1. BMI : Strong evidence supports that obese patients have less improvement in outcomes with total knee arthroplasty. 2. Diabetes : Moderate evidence supports that patients with diabetes are at higher risk for complications with total knee arthroplasty. 3. Pain : Moderate evidence supports that patients with select chronic pain conditions have less improvement in patient reported outcomes with TKA.

4. Anxiety : Limited evidence supports that patients with depression and/or anxiety symptoms have less improvement in patient reported outcomes with total knee arthroplasty. 5. Liver Function : Limited evidence supports that patients with cirrhosis or hepatitis C are at higher risk for complications with total knee arthroplasty. 6. Pre-op Physiotherapy : Limited evidence supports that supervised exercise before total knee arthroplasty (TKA) might improve pain and physical function after surgery.

7. Delayed surgery : Moderate evidence supports that an eight month delay to total knee arthroplasty (TKA) does not worsen outcomes. Intra-op Knee Arthroplasty Considerations : 1. Local anaesthesia : Strong evidence supports the use of peri-articular local anesthetic infiltration compared to placebo in total knee arthroplasty (TKA) to decrease pain and opioid use. 2. Nerve block : Strong evidence supports that peripheral nerve blockade for total

knee arthroplasty (TKA) decreases postoperative pain and opioid requirements. 3. Anaesthesia : Moderate evidence supports that neuraxial anesthesia could be used in total knee arthroplasty (TKA) to improve select perioperative outcomes and complication rates compared to general anesthesia. 16

4. Tourniquet and blood loss : Moderate evidence supports that the use of a tourniquet in total knee arthroplasty (TKA) decreases intraoperative blood loss. 5. Tourniquet and Pain : Strong evidence supports that tourniquet use in total knee arthroplasty (TKA) increases short term post-operative pain. Limited evidence supports that tourniquet use in total knee arthroplasty (TKA) decreases short term post-operative function. 6. Tranexemic Acid : Strong evidence supports that, in patients with no known

contraindications, treatment with tranexamic acid decreases postoperative blood loss and reduces the necessity of postoperative transfusions following total knee arthroplasty (TKA). 7. Bone Cement : Limited evidence does not support the routine use of antibiotics in the cement for primary total knee arthroplasty. 8. Implant Design : Strong evidence supports no difference in outcomes or complications between posterior stabilized and posterior cruciate retaining

arthroplasty designs. Strong evidence supports use of either all-polyethylene or modular tibial components in knee arthroplasty (KA) because of no difference in outcomes. Strong evidence supports no difference in pain or function with or without patellar resurfacing in total knee arthroplasty. Moderate evidence supports that patellar resurfacing in total knee arthroplasty (TKA) could decrease cumulative reoperations after 5 years when compared to no patellar resurfacing in total knee arthroplasty (TKA).

Strong evidence supports the use of tibial component fixation that is cemented or cementless in total knee arthroplasty due to similar functional outcomes and rates of complications and reoperations. Moderate evidence supports the use of either cemented femoral and tibial components or cementless femoral and tibial components in knee arthroplasty due to similar rates of complications and reoperations. Moderate evidence supports the use of either cementing all components or

hybrid fixation (cementless femur) in total knee arthroplasty due to similar functional outcomes and rates of complications and reoperations. 9. Cement : Limited evidence supports the use of either all cementless components or hybrid fixation (cementless femur) in total knee arthroplasty due to similar rates of complications and reoperations. 17

10. Bilateral Arthroplasty Indications : Limited evidence supports simultaneous bilateral total knee arthroplasty (TKA) for patients aged 70 or younger or ASA status 1-2, because there are no increased complications. 11. Unicondylar Knee : Moderate evidence supports that total knee arthroplasty (TKA) could be used to decrease revision surgery risk compared to unicompartmental knee arthroplasty (UKA) for medial compartment osteoarthritis.

Limited evidence supports that unicompartmental knee arthroplasty might be used to decrease the risk of deep vein thrombosis (DVT) and manipulation under anesthesia compared to total knee arthroplasty (TKA) for medial compartment osteoarthritis. 12. Unicondylar vs Osteotomy : Moderate evidence supports no difference between unicompartmental knee arthroplasty (UKA) or valgus-producing proximal tibial osteotomy in outcomes and complications in patients with medial compartment knee osteoarthritis.

13. Navigation : Strong evidence supports not using intraoperative navigation in total knee arthroplasty (TKA) because there is no difference in outcomes or complications. 14. Patient Specific : Strong evidence supports not using patient specific instrumentation compared to conventional instrumentation for total knee arthroplasty (TKA) because there is no difference in pain or functional outcomes. Moderate evidence supports not using patient specific instrumentation compared

to conventional instrumentation for total knee arthroplasty (TKA) because there is no difference in transfusions or complications. 15. Drains : Strong evidence supports not using a drain with total knee arthroplasty. Post op Knee Arthroplasty Considerations : 1. Cryotherapy : Moderate evidence supports that cryotherapy devices after knee arthroplasty (KA) do not improve outcomes. 2. CPM : Strong evidence supports that CPM after knee arthroplasty (KA) does not improve outcomes.

3. Hospital Stay : Strong evidence supports that rehabilitation started on the day of the total knee arthroplasty (TKA) reduces length of hospital stay. 18

4. Rehabilitation : Moderate evidence supports that rehabilitation started on day of total knee arthroplasty (TKA) compared to rehabilitation started on postop day 1 reduces pain and improves function. Moderate evidence supports that a supervised exercise program during the first two months after total knee arthroplasty (TKA) improves physical function. Limited evidence supports that a supervised exercise program during the first two months after total knee arthroplasty (TKA) decreases pain.

Limited evidence supports that selected patients might be referred to an intensive supervised exercise program during late stage post total knee arthroplasty (TKA) to improve physical function. 4.7 Summary General Core Treatment : Individualised self-management strategies with the person with osteoarthritis. Ensure that positive behavioural changes, such as exercise, weight loss, use of suitable footwear, braces, walking aids and pacing, are appropriately targeted.

DO’s : Weight loss, Thermotherapy, Electrotherapy (TENS), Physiotherapy (Exercises and manipulation and stretchings), Footwear, Braces, Walking Aids And Pacing Don’t’s : Nutraceuticals (glucosamine or chondroitin), Acupuncture Pharmacological Management : Consider topical NSAIDs and/or paracetamol ahead of oral NSAIDs, COX-2 inhibitors or opioids which should be given at the lowest dose for shortest period along with lowest cost PPI, taking into account individual patient risk factors.

DO’s : Topical capsaicin , Intra-articular corticosteroid injections Don’t’s : Rubefacients , Intra-articular hyaluronan Warning : Patient on low-dose aspirin, consider other analgesics before substituting or adding an NSAID or COX-2 inhibitor (with a PPI). Surgery: 19

Appropriate referral for surgery in patients having pain, stiffness and reduced function that have a substantial impact on their quality of life and are refractory to non-surgical treatment. Do’s : Age, sex, smoking, obesity and co-morbidities not barriers for surgery. Explain before surgery the benefits and risks of surgery and the potential consequences of not having surgery, recovery and rehabilitation after surgery. Osteotomy or unicondylar same outcome.

Don’t’s : No surgery to be done without initial core treatment. Arthroscopic lavage and debridement (unless mechanical locking of knee). Bilateral knee replacement above age 70 years or ASA status more than 2. Navigation and patient specific instrumentation has no difference in outcome. 20

How this guideline was developed Osteoarthritis Knee STG Subgroup established Background December 2014: A Task Force was constituted to guide the development of Standard Treatment Guidelines (STG) in India. The Task Force subsequently approved the draft STG development manual of India (Part 1) for development of adapted guidelines. In addition, it approved a list of 14 topics recommended by a subgroup of the task force appointed to

select prioritized topics for STG development. These 14 topics are from 10 clinical specialties for which the first set of STGs will be developed. Clinical Subgroup on Orthopaedics Disease Condition – Osteoarthritis Knee Coordinator Dr. Mathew Varghese – Senior Consultant and Head, St.Stephen’s Hospital, New Dehi Rapporteur Dr.Sumit Sural – Professor,Department of Orthopaedics, Maulana Azad Medical College, New Delhi Experts Dr Anil Dhal, Director Professor , MAMC, New Delhi Dr. N.V.Kamath

Dr.Sumit Sural, Professor, MAMC, New Delhi Dr.Suranjan Bhattacharya, Dept.of Rehabilitation, CMC, Vellore Dr.A.K.Adhikari, Chief Pharmacist, St.Stephen’s Hospital Dr.Kora, Dy.Nursing Superintendent, St.Stephen’s Hospital Physician Dr.Gurtu Private Practitioner Dr Shekhar Agarwal, Sant Parmanand Hospital,New Delhi 21

Dr.V.B.Bhasin, Sir Ganga Ram Hospital, New Delhi Primary Care Practitioners None of the members report any conflict of interest in the development of this guideline and have all signed their declarations. May 2015: NHSRC with technical support from NICE international carried out a training workshop to guide the STG group members and chairs on the methodology to follow in developing adapted STGs suitable for the Indian context. This workshop was conducted on

29th & 30th May, 2015 and two members (Dr.Anil Dhal, Dr.Kamat and Dr.Sumit Sural,) of the Osteoarthritis Knee STG team attended. A search for guidelines on osteoarthritis Knee was performed on the National Guideline Clearinghouse (NGC) along with extensive google search for other guidelines like Royal College of Surgeons guidelines, American Academy of Orthopaedic Surgeons (AAOS), Osteoarthritis Research Society International guidelines (OARSI) and Australian Orthopaedic Association guidelines.

Extensive web search was done for high level evidence literature pertaining to Osteoarthritis of the knee, helped by Dr.Hari Kishan P, Senior Resident Orthopaedics,MAMC. A systematic approach was followed to ensure high quality of the process The NICE (2008 and 2014) guidelines were the most comprehensive and appropriate among all the guidelines. The American Academy of Orthopaedic Surgeons (AAOS 2015) guidelines regarding surgical aspects were appropriate and hence the surgical guidelines of

the recommendations were selected from it. After evaluating all the existing guidelines the process of adopt / adapt was performed as given below: a) Adopted recommendation - this entailed transferring a recommendation verbatim to the new STG. b) b) Adapted a recommendation - This included adapting the recommendation to ensure local compatibility with India or adding precisions to the wording to clarify the recommendation or changing of wording to active phrasing in order to ensure

language consistency was maintained throughout the document. It was ensured while adapting a recommendation that the evidence underpinning the recommendation remained intact. 22

After going through the available guidelines, the group adopted the majority of existing guidelines and only two guidelines were adapted from NISE. For this process, the STG subgroup met initially twice at Maulana Azad Medical College and later 3 times at St.Stephen’s Hospital where each time a video-conferencing was set up to include Dr.Suranjan Bhattacharya. One of the meetings was attended by Dr.Nikhil from the Ministry of Health and Family Welfare. The draft was written by Dr.Sumit Sural and all

circulated on all experts on the e mail and subsequently the major recommendations were discussed point wise in the videoconferencing meetings. An internal peer review meeting was held on 7th January 2016 attended by Dr.Sumit Sural and the draft was appropriately amended and circulated again on e mail to all concerned experts for their final comments. 7. Research Needs a. Evidence of alternate therapies as comparative study for pain management. b. Future Recommendations : 23

8. Annexure (Adopt/Adapt Table) S.No STG India Adopted/ Recommendations Reasons for Recommendations in the Original Adaptation Adapted Guidelines A : General Core Treatment A1:Patient Information A2 :Self management A3-6 :Physiotherapy A7 – Supplements A8: Alternative therapy A9 :Orthotic devices A1 Offer accurate verbal Adopt Nice (2008) and written information Patient to all people with Information osteoarthritis to enhance understanding of the condition and its management, and to counter misconceptions,

such as that it inevitably progresses and cannot be treated. Ensure that information sharing is an ongoing, integral part of the management plan rather than a single event at time of presentation. A2 Agree individualised Adapt Nice (2008) Reason for self-management Adapting Patient self- Agree strategies with the (Dr.Suranjan management individualised person with Bhattacharya) interventions self-management osteoarthritis. Ensure strategies with the that positive behavioural 24

changes, such as person with exercise, weight loss, osteoarthritis. use of suitable footwear Ensure that are appropriately positive targeted. behavioural changes, such as exercise, weight loss, use of suitable footwear and pacing, are appropriately targeted. A3 The use of local heat or Adopt Nice (2008) cold should be Thermotherapy considered as an adjunct to core treatments A4 Advise people with osteoarthritis to exercise Exercise and as a core treatment manual therapy irrespective of age,

comorbidity, pain severity or disability. Exercise should include: A4.1 Exercise has been found Adapt Nice (2008) Reason for to be beneficial Adapting local muscle Exercise has been (Dr.Suranjan strengthening found to be Bhattacharya) beneficial but the clinician needs to make a judgement in each case on how to effectively ensure participation. This will depend upon the person's individual needs, 25

circumstances and self-motivation, and the availability of local facilities. A4.2 Nice (2008) Manipulation should be and stretching considered as an adjunct to core treatments, particularly for osteoarthritis of the hip. A 5 Offer interventions to Adopt Nice (2008) achieve weight loss as a Weight loss core treatment for people who are obese or overweight. A6 Should consider the use Adopt Nice (2008) of transcutaneous Electrotherapy electrical nerve stimulation (TENS) as an adjunct to core

treatments for pain relief. A7 Do not offer Adopt Nice (2014) glucosamine or Nutraceuticals chondroitin products for the management of osteoarthritis. A8 Do not offer Adopt Nice (2014) acupuncture for the Acupuncture management of osteoarthritis A9 26

Aids and devices A9.1 Offer advice on Adopt Nice (2008) appropriate footwear Footwear (including shock- absorbing properties) as part of core treatments for people with lower limb osteoarthritis. A9.2 People with Adopt Nice (2008) osteoarthritis who have Brace / Insole biomechanical joint pain or instability should be considered for assessment for bracing/joint supports/insoles as an adjunct to their core treatments. A9.3 Assistive devices (for Adopt Nice (2008) example, walking sticks Walking Aid

and tap turners) should be considered as adjuncts to core treatments for people with osteoarthritis who have specific problems with activities of daily living. If needed, seek expert advice in this context B PHARMACOLOGICAL MANAGEMENT B1 :Analgesics B2 :Topical 27

B3 : NSAID B4 : Intra-articular injections B1 Oral analgesics B1.1 Paracetamol for pain Adopt Nice (2008) relief in addition to core treatments regular dosing may be required. Paracetamol and/or topical non-steroidal anti-inflammatory drugs (NSAIDs) should be considered ahead of oral NSAIDs, cyclo- oxygenase 2 (COX-2) inhibitors or opioids B1.2 If paracetamol or topical Adopt Nice (2008) NSAIDs are insufficient for pain relief for people with osteoarthritis, then the addition of opioid analgesics should be

considered. Risks and benefits should be considered, particularly in older people. B2 Topical treatments B2.1 Consider topical Adopt Nice (2008) NSAIDs and/or 28

paracetamol ahead of oral NSAIDs, COX-2 inhibitors or opioids. B2.2 Topical capsaicin should Adopt Nice (2008) be considered as an adjunct to core treatments for knee or hand osteoarthritis B2.3 Do not offer Adopt Nice (2008) rubefacients for treating osteoarthritis. B3 Although NSAIDs and COX-2 inhibitors may NSAIDs and be regarded as a single highly selective drug class of 'NSAIDs', COX-2 these recommendations inhibitors use the two terms for clarity and because of the differences in side-

effect profile. B3.1 Where paracetamol or Adopt Nice (2008) topical NSAIDs are ineffective for pain relief for people with osteoarthritis, then substitution with an oral NSAID/COX-2 inhibitor should be considered. [2008] B3.2 Where paracetamol or Adopt Nice (2008) topical NSAIDs provide insufficient pain relief for people with osteoarthritis, then the 29

addition of an oral NSAID/COX-2 inhibitor to paracetamol should be considered. B3.3 Use oral NSAIDs/COX- Adopt Nice (2008) 2 inhibitors at the lowest effective dose for the shortest possible period of time B3.4 When offering treatment Adopt Nice (2008) with an oral NSAID/COX-2 inhibitor, the first choice should be either a standard NSAID or a COX-2 inhibitor (other than etoricoxib 60 mg). In either case, co- prescribe with a proton pump inhibitor (PPI), choosing the one with the lowest acquisition cost.

B3.5 All oral NSAIDs/COX-2 Adopt Nice (2008) inhibitors have analgesic effects of a similar magnitude but vary in their potential gastrointestinal, liver and cardio-renal toxicity; therefore, when choosing the agent and dose, take into account individual patient risk factors, including age. When prescribing these drugs, consideration should be given to 30

appropriate assessment and/or ongoing monitoring of these risk factors. B3.6 If a person with Adopt Nice (2008) osteoarthritis needs to take low-dose aspirin, healthcare professionals should consider other analgesics before substituting or adding an NSAID or COX-2 inhibitor (with a PPI) if pain relief is ineffective or insufficient. B4 Intra-articular injections B4.1 Intra-articular Adopt Nice (2008) corticosteroid injections Intra-articular should be considered as corticosteroid an adjunct to core

injections treatments for the relief of moderate to severe pain in people with osteoarthritis. B4.2 Do not offer intra- Adopt Nice (2014) articular hyaluronan Intra-articular injections for the hyaluronan management of osteoarthritis SURGERY C1 : Indications and Referrals 31

C2 : Follow up and Reviews C3: Arthroscopy C4 : Osteotomy C5 : Arthroplasty Clinicians with Adopt Nice (2008) responsibility for referring a person with osteoarthritis for consideration of joint surgery should ensure that the person has been offered at least the core (non-surgical) treatment options Base decisions on Adopt Nice (2008, referral thresholds on amended 2014) discussions between patient representatives, referring clinicians and surgeons, rather than using scoring tools for prioritisation.

Consider referral for Adopt Nice (2008, joint surgery for people amended 2014) with osteoarthritis who experience joint symptoms (pain, stiffness and reduced function) that have a substantial impact on their quality of life and are refractory to non- surgical treatment. Refer for consideration Adopt Nice (2008, of joint surgery before amended 2014) there is prolonged and 32

established functional limitation and severe pain. Patient-specific factors Adopt Nice (2008, (including age, sex, amended 2014) smoking, obesity and co- morbidities) should not be barriers to referral for joint surgery. When discussing the Adopt Nice (2014) possibility of joint surgery, check that the person has been offered at least the core treatments for osteoarthritis and give them information about: the benefits and risks of surgery and the potential consequences of not having surgery recovery and

rehabilitation after surgery how having a prosthesis might affect them how care pathways are organised in their local area. C2 Follow up and Review C2.1 Offer regular reviews to Adopt Nice (2014) all people with 33

symptomatic osteoarthritis. Agree the timing of the reviews with the person Reviews should include: monitoring the person's symptoms and the ongoing impact of the condition on their everyday activities and quality of life monitoring the long- term course of the condition discussing the person's knowledge of the condition, any concerns they have, their personal preferences and their ability to access services reviewing the effectiveness and tolerability of all treatments support for self- management.

C2.2 Consider an annual Adopt Nice (2014) review for any person with one or more of the following: troublesome joint pain more than one joint with symptoms more than one co- 34

morbidity taking regular medication for their osteoarthritis. C3 : Do not refer for Adopt Nice (2008, arthroscopic lavage and amended 2014) Arthroscopy debridement as part of treatment for osteoarthritis, unless the person has knee osteoarthritis with a clear history of mechanical locking (as opposed to morning joint stiffness, 'giving way' or X-ray evidence of loose bodies). C4: Osteotomy C5 :Arthroplasty Prognostic Factors : BMI Strong evidence Adopt AAOS (2015) supports that obese Strong Evidence

patients have less improvement in outcomes with total knee arthroplasty Diabetes Moderate evidence Adopt AAOS (2015) supports that patients Moderate with diabetes are at 35

higher risk for Evidence complications with total knee arthroplasty Pain Moderate evidence Adopt AAOS (2015) supports that patients Moderate with select chronic pain Evidence conditions have less improvement in patient reported outcomes with TKA. Anxiety Limited evidence Adopt AAOS (2015) supports that patients Limited Evidence with depression and/or anxiety symptoms have less improvement in patient reported outcomes with total knee arthroplasty Liver Function Limited evidence Adopt AAOS (2015)

supports that patients Limited Evidence with cirrhosis or hepatitis C are at higher risk for complications with total knee arthroplasty Pre-op Limited evidence Adopt AAOS (2015) Physiotherapy supports that supervised Limited Evidence exercise before total knee arthroplasty (TKA) might improve pain and physical function after surgery. Delayed surgery Moderate evidence Adopt AAOS (2015) supports that an eight Moderate month delay to total Evidence knee arthroplasty (TKA) does not worsen 36

outcomes. Intra-op Considerations Local Strong evidence Adopt AAOS (2015) anaesthesia supports the use of peri- Strong Evidence articular local anesthetic infiltration compared to placebo in total knee arthroplasty (TKA) to decrease pain and opioid use. Nerve block Strong evidence Adopt AAOS (2015) supports that peripheral Strong Evidence nerve blockade for total knee arthroplasty (TKA) decreases postoperative pain and opioid requirements. Anaesthesia Moderate evidence Adopt AAOS (2015)

supports that neuraxial Moderate anesthesia could be used Evidence in total knee arthroplasty (TKA) to improve select perioperative outcomes and complication rates compared to general anesthesia. Tourniquet and Moderate evidence Adopt AAOS (2015) blood loss supports that the use of a Moderate tourniquet in total knee Evidence arthroplasty (TKA) decreases intraoperative blood loss. Tourniquet and Strong evidence Adopt AAOS (2015) Pain supports that tourniquet Strong Evidence use in total knee

increases short term post-operative pain. Limited evidence Adopt AAOS (2015) supports that tourniquet Limited Evidence use in total knee arthroplasty (TKA) decreases short term post-operative function. Tranexemic Strong evidence Adopt AAOS (2015) Acid supports that, in patients Strong Evidence with no known contraindications, treatment with tranexamic acid decreases postoperative blood loss and reduces the necessity of postoperative transfusions following total knee arthroplasty (TKA).

Bone Cement Limited evidence does Adopt AAOS (2015) not support the routine Limited Evidence use of antibiotics in the cement for primary total knee arthroplasty Implant Design Strong evidence Adopt AAOS (2015) supports no difference in Strong Evidence outcomes or complications between posterior stabilized and posterior cruciate retaining arthroplasty designs. Strong evidence Adopt AAOS (2015) supports use of either Strong Evidence all-polyethylene or 38

modular tibial components in knee arthroplasty (KA) because of no difference in outcomes. Strong evidence Adopt AAOS (2015) supports no difference in Strong Evidence pain or function with or without patellar resurfacing in total knee arthroplasty. Moderate evidence Adopt AAOS (2015) supports that patellar Moderate resurfacing in total knee Evidence arthroplasty (TKA) could decrease cumulative reoperations after 5 years when compared to no patellar resurfacing in total knee arthroplasty (TKA).

Strong evidence Adopt AAOS (2015) supports the use of tibial Strong Evidence component fixation that is cemented or cementless in total knee arthroplasty due to similar functional outcomes and rates of complications and reoperations. Moderate evidence Adopt AAOS (2015) supports the use of either Moderate cemented femoral and Evidence tibial components or cementless femoral and tibial components in knee arthroplasty due to 39

similar rates of complications and reoperations. Moderate evidence Adopt AAOS (2015) supports the use of either Moderate cementing all Evidence components or hybrid fixation (cementless femur) in total knee arthroplasty due to similar functional outcomes and rates of complications and reoperations. Cement Limited evidence Adopt AAOS (2015) supports the use of either Limited Evidence all cementless components or hybrid fixation (cementless femur) in total knee arthroplasty due to similar rates of

complications and reoperations. Bilateral Limited evidence Adopt AAOS (2015) supports simultaneous Limited Evidence bilateral total knee arthroplasty (TKA) for patients aged 70 or younger or ASA status 1-2, because there are no increased complications. Unicondylar Moderate evidence Adopt AAOS (2015) supports that total knee Moderate arthroplasty (TKA) Evidence could be used to decrease revision surgery risk compared to 40

unicompartmental knee arthroplasty (UKA) for medial compartment osteoarthritis. Limited evidence Adopt AAOS (2015) supports that Limited Evidence unicompartmental knee arthroplasty might be used to decrease the risk of deep vein thrombosis (DVT) and manipulation under anesthesia compared to total knee arthroplasty (TKA) for medial compartment osteoarthritis. Unicondylar vs Moderate evidence Adopt AAOS (2015) Osteotomy supports no difference Moderate between Evidence unicompartmental knee

arthroplasty (UKA) or valgus-producing proximal tibial osteotomy in outcomes and complications in patients with medial compartment knee osteoarthritis. Navigation Strong evidence Adopt AAOS (2015) supports not using Strong Evidence intraoperative navigation in total knee arthroplasty (TKA) because there is no difference in outcomes or complications. Patient Specific Strong evidence Adopt AAOS (2015) supports not using 41

patient specific Strong Evidence instrumentation compared to conventional instrumentation for total knee arthroplasty (TKA) because there is no difference in pain or functional outcomes. Moderate evidence Adopt AAOS (2015) supports not using Moderate patient specific Evidence instrumentation compared to conventional instrumentation for total knee arthroplasty (TKA) because there is no difference in transfusions or complications. Drains Strong evidence Adopt AAOS (2015) supports not using a Strong Evidence

drain with total knee arthroplasty Post op Cryotherapy Moderate evidence Adopt AAOS (2015) supports that Moderate cryotherapy devices Evidence after knee arthroplasty (KA) do not improve outcomes. CPM Strong evidence Adopt AAOS (2015) supports that CPM after Strong Evidence knee arthroplasty (KA) does not improve 42

outcomes. Stay Strong evidence Adopt AAOS (2015) supports that Strong Evidence rehabilitation started on the day of the total knee arthroplasty (TKA) reduces length of hospital stay. Rehab Moderate evidence Adopt AAOS (2015) supports that Moderate rehabilitation started on Evidence day of total knee arthroplasty (TKA) compared to rehabilitation started on postop day 1 reduces pain and improves function. Moderate evidence Adopt AAOS (2015) supports that a Moderate supervised exercise Evidence

program during the first two months after total knee arthroplasty (TKA) improves physical function. Limited evidence Adopt AAOS (2015) supports that a Limited Evidence supervised exercise program during the first two months after total knee arthroplasty (TKA) decreases pain. Limited evidence Adopt AAOS (2015) supports that selected Limited Evidence patients might be referred to an intensive 43

supervised exercise program during late stage post total knee arthroplasty (TKA) to improve physical function. 44

References 1. Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, Bridgett L, Williams S, Guillemin F, Hill CL, Laslett LL, Jones, Cicuttini F, Osborne R, Vos , Buchbinder R, Woolf A, March L. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014 Jul;73(7):1323- 30. 2. http:// icmr.nic.in/final/S.J.H.%20Final%20Project%20Report%202012. 3. Chandra Prakash Pal, Pulkesh Singh, Sanjay Chaturvedi, Kaushal Kumar

Pruthi, and Ashok Vij. Epidemiology of knee osteoarthritis in India and related factor. Indian J Orthop. 2016 Sep; 50(5): 518–522. 4. Sacks JJ, Helmick CG, Langmaid G. Deaths from arthritis and other rheumatic conditions, United States, 1979–1998. J Rheumatol. 2004;31:1823-1828. 5. Arthritis and Related Conditions Chapter 4. http://www.boneandjointburden.org/2013-report/iv-arthritis/iv. Accessed 07-23- 2015. 6. Guccione AA, Felson DT, Anderson JJ, Anthony JM, Zhang Y, Wilson PW, Kelly-

Hayes M, Wolf PA, Kreger BE, Kannel WB. The effects of specific medical conditions on the functional limitations of elders in the Framingham Study. Am J Pub Health. 1994;84(3):351-358. 7. Leach RE, Gregg T, Siber FJ. Weight-bearing radiography in osteoarthritis of the knee. Radiology 1970;97: 265–8. 8. Chondrometry Lequesne M. Quantitative evaluation of joint space width and rate of joint space loss in osteoarthritis of the hip. Rev Rhum Engl Ed 1995;62: 155–8.

9. Ravaud P, Chastang C, Auleley GR, Giraudeau B, Royant V, Amor B, et al. Assessment of joint space width in patients with osteoarthritis of the knee: a comparison of 4 measuring instruments. J Rheumatol 1996;23:1749–55. 10. Roemer FW, Crema MD, Trattnig S, Guermazi A. Advances in imaging of osteoarthritis and cartilage. Radiology 2011;260:332–54. 11. Conrozier T, Lequesne M, Favret H, Taccoen A, Mazieres B, Dougados M, et al. Measurement of the radiological hip joint space width. An evaluation of various

methods of measurement. Osteoarthritis Cartilage 2001;9:281–6. 45

12. Vignon E. Radiographic issues in imaging the progression of hip and knee osteoarthritis. J Rheumatol Suppl 2004;70:36–44. 13. Bauer DC, Hunter DJ, Abramson SB, Attur M, Corr M, Felson D, et al. Classification of osteoarthritis biomarkers: a proposed approach. Osteoarthritis Cartilage.2006;14:723–7. 14. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis 1957 : 16:494-502. 15. Altman RD. Gold GE. Atlas of individual radiographic features in osteoarthritis,

revised. Osteoarthritis Cartilage 2007;15(Suppl A):A1–A56. 16. Altman RD, Hochberg M, Murphy Jr WA, Wolfe F, Lequesne M. Atlas of individual radiographic features in osteoarthritis. Osteoarthritis Cartilage 1995;3(Suppl A): 17. Amin S, LaValley MP, Guermazi A, Grigoryan M, Hunter DJ, Clancy M, et al. The relationship between cartilage loss on magnetic resonance imaging and radiographic progression in men and women with knee osteoarthritis. Arthritis Rheum 2005;52:3152–9.

18. Leach RE, Gregg T, Siber FJ. Weightbearing radiography in osteoarthritis of the knee. Radiology 1970;97:265-268. 19. Cibere J. Do we need radiographs to diagnose osteoarthritis? Best Pract Res Clin Rheumatol 2006;20:27-30. 20. Manal Hasan, Rhonda Shuckett. Clinical features and pathogenetic mechanisms of osteo -arthritis of the hip and kneewww.bcmj.org VOL. 52 NO. 8, October 2010 BC Medical Journal 399. 21. Boegard TL, Rudling O, Petersson IF, et al. Correlation between radiographically

diagnosed osteophytes and magnetic resonance detected cartilage defects in the patellofemoral joint. Ann Rheum Dis 1998;57:395-400. 9. List of Abbreviations OA : Osteoarthritis STG : Standard Treatment Guidelines NICE : National Institute of Health and Care Excellence, United Kingdom AAOS : American Association of Orthopaedic Surgeons / American Academy of Orthopaedic Surgeons OARSI : Osteoarthritis Research Society International guidelines AP View :Anterop-posterior view PA View : Postero-anterior view 46

JSN : Joint space narrowing JSW : Joint space width KL grading : Kellgren-Lawrence grading TKR : Total Knee Replacement TKA : Total Knee Arthroplasty UKA : Unicompartmental knee arthroplasty NSAID : Nonsteroidal anti-inflammatory drug COX 2 : Cyclooxygenase-2 (COX-2 Inhibitors – a type of NSAID) PPI : Proton Pump Inhibitors (Pantoprazole, Omeprazole, Rabreprazole) TENS : Transcutaneous electrical nerve stimulation (Type of electrotherapy) DVT : Deep Vein Thrombosis 47

STANDARD TREATMENT GUIDELINES MEDICINE (RESPIRATORY DISEASES) Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 ACUTE RESPIRATORY DISTRESS SYNDROME 4 2 BRONCHIAL ASTHMA 12 3 CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) 18 4 INTERSTITIAL LUNG DISEASE 32 5 LUNG ABSCESS 37 6 SLEEP DISORDERED BREATHING 50 7 PLEURAL DISEASES 69 8 COMMUNITY ACQUIRED PNEUMONIA (Bacterial) 78 9 PULMONARY HYPERTENSION 87 10 SARCOIDOSIS 94 11 RESPIRATORY FAILURE 101 2

Group Head Coordinator of Development Team Dr S.K. SHARMA AIIMS 3

ACUTE RESPIRATORY DISTRESS SYNDROME I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Acute respiratory distress syndrome (ARDS) is the most severe form of acute lung injury resulting in extensive bilateral pulmonary infiltrates, severe refractory arterial hypoxemia and stiff lungs. Of the numerous clinical conditions identified to cause ARDS, sepsis syndrome, polytrauma, obstetric complications, and surgery, among others appear to be the most common causes. The site of injury

may be focused on either the vascular endothelium (eg. sepsis) or the alveolar epithelium (eg. aspiration of gastric contents). Injury to the endothelium results in increased capillary permeability and the influx of protein-rich fluid into the alveolar space. Injury to the alveolar lining cells also leads to pulmonary edema. In tropical countries, malaria, leptospirosis, tuberculosis (including miliary), enteric fever, and dengue haemorrhagic fever, organophosporus and paraquat poisoning;

scorpion sting; inhalation of toxic fumes (e.g.chlorine); and heat stroke are important causes of ARDS. Other known risk factors are bacteremia, sepsis, trauma with or without pulmonary contusion, fractures, particularly multiple fractures and long bone fractures, burns, massive transfusion, pneumonia, aspiration, drowning, postperfusion injury after cardiopulmonary bypass and acute pancreatitis. b) Case definition (for both situations of care): Acute lung injury Acute onset PaO /FIO £ 300* 2 2

SpO /FIO £ 315* 2 2 Bilateral infiltrates on the chest radiograph PCWP £ 18 mm Hg, or no clinical evidence of left atrial hypertension Acute respiratory distress syndrome Acute onset PaO /FIO £ 200* 2 2 SpO /FIO £ 235 2 2 Bilateral infiltrates on the chest radiograph PCWP £ 18 mm Hg, or no clinical evidence of left atrial hypertension * Irrespective of level of positive end-expiratory pressure

PaO = partial pressure of oxygen in the patient’s arterial blood; FIO = fraction of inspired oxygen; SpO = pulse oximetric 2 2 2 measurement of oxygen saturation; PCWP = pulmonary capillary wedge pressure 4

The severity of hypoxemia is necessary to make the diagnosis of ARDS. The cardiogenic pulmonary edema must be excluded either by clinical criteria or by a pulmonary capillary wedge pressure (PCWP) lower than 18 mmHg in patients with a Swan-Ganz catheter in place. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY Global estimates suggest that ARDS occurs in 1.5 to 75 cases / 100,000 population. No systematic studies have been carried out till date to define the

incidence of ARDS in India and reliable epidemiological data are not available. III. DIFFERENTIAL DIAGNOSIS 1. Cardiogenic pulmonary oedema 2. Other considerations Pneumonia Diffuse alveolar haemorrhage Idiopathic acute eosinophilic pneumonia Cryptogenic organizing pneumonia Acute interstitial pneumonia (Hamman-Rich syndrome) Metastatic malignancy Near drowning Drug reaction Noncardiogenic pulmonary edema Acute hypersensitivity pneumonitis Transfusion-related acute lung injury (TRALI) Leukemic infiltration

Fat embolism syndrome IV. PREVENTION AND COUNSELING No form of therapy is known to prevent the occurrence of ARDS. 5

OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis Symptoms The onset of ARDS is acute. The acute, or exudative, phase is characterised by rapid onset of dyspnoea, dry cough, respiratory failure, disorientation and agitation that usually develop 24 to 72 hours after the inciting event. The patient may be febrile or hypothermic. Signs

Tachypnoea, tachycardia, cyanosis, crepitations and rhonchi may be present. Arterial hypoxaemia that is refractory to high concentrations of supplemental oxygen therapy is a hall mark of ARDS. Chest auscultation may reveal bilateral rales and rales may be absent despite diffuse involvement. In intubated and mechanically ventilated patient decreased breath sounds over one lung may indicate a pneumothorax or endotracheal tube down the opposite main bronchus.

Careful physical examination to look for potential causes of sepsis including signs of lung consolidation or findings consistent with an acute abdomen, sites of intravascular lines, surgical wounds, drain sites, and decubitus ulcers for evidence of infection are needed. The cardiogenic pulmonary edema should be differentiated from ARDS, by carefully looking for signs of congestive heart failure or intravascular volume overload, including jugular

venous distention, cardiac murmurs and gallops, hepatomegaly, and edema. 6

b) Investigations 1. Pulse oximetry: Pulse oximetry reveals SpO /FIO ratio less than or 2 2 equal to 235. Severe refractory hypoxaemia in spite of supplemental oxygen therapy is evident. 2. Chest radiograph: The radiographic changes become evident by about 12 hours after the clinical onset of respiratory failure. Initially, patchy, ill- defined opacities may become apparent throughout the lungs. 3. Echocardiography: Echocardiography is useful in differentiating ARDS from cardiogenic pulmonary oedema.

4. Arterial blood gas (ABG) analysis: ABG analysis usually reveals severe refractory hypoxemia, hypocapnia and alkalosis if the patient is breathing spontaneously. Hypercapnia usually does not occur unless chronic lung disease is co-existent. c) Treatment: Standard Operating procedure a. In Patient 1. General therapeutic measures 1. SpO monitoring by pulse oximetry 2 2. Ensure adequate circulation and blood pressure using volume infusion and/or vasopressors

3. Treatment of the aetiologcal cause of ARDS (e.g., appropriate antibiotic therapy for patients with sepsis syndrome) 2. Supplemental oxygen therapy Initially, spontaneous ventilation using a face mask with a high flow gas delivery system can be used to deliver a FIO of up to 0.5 to 0.6. 2 b. Out Patient Not applicable. ARDS is managed in an intensive care (ICU) unit setting d) Referral criteria: 1. Diagnosis not clear 7

2. Response to therapy not optimal. Hypoxaemia (SpO ≤ 90) persists in 2 spite of supplemental oxygen therapy 3. Haemodynamic instability *Situation 2: At Tertiary hospital where higher-end technology is available a) Clinical Diagnosis As in situation V.1 a) above b) Investigations 1. As in situation V.1b) above PLUS 2. Computed tomography of the chest: Early in the exudative phase, computed tomography (CT) of the chest reveals diffusely distributed non-uniform ground

glass opacification or consolidation which may not conform to the gravity distribution. Later in the exudative phase, the consolidation becomes more homogeneous and gravity dependent. In the proliferative and fibrotic stages, there is a decrease in the overall lung density and the appearance of an interstitial reticular pattern. CT also facilitates identification of underlying pulmonary causes of ARDS (e.g., pneumonia and lung abscess) and complications of ARDS, such as, pneumothorax, pneumomediastinum and

interstitial emphysema may also be evident. 3. Swan-Ganz catheterization: The pulmonary capillary wedge pressure (PCWP) is less than 18 mm Hg and the cardiac index is more than 2.1 L/min. 4. Bronchoscopic procedures: Bronchoscopic procedures are helpful to exclude infectious causes of ARDS. c) Treatment: Standard Operating procedure a. In Patient 1. As in situation V.1c)a.1 above PLUS 8

2. General therapeutic measures Haemodynamic stabilization. Pulmonary and systemic arterial lines are inserted for hemodynamic monitoring and rational fluid replacement therapy. Adequate circulation and blood pressure is ensured using volume infusion (crystalloids) and/or vasopressors, taking the CVP/PCWP as the guideline. The intravascular volume is maintained as low as possible while maintaining an adequate cardiac index, mean arterial pressure, at the same

time ensuring adequate organ perfusion. In anaemic patients, transfusion of packed red cells can help improving oxygenation. Adequate nutrition should be ensured through the use of enteral feeding. Efforts should also be directed to prevent gastrointestinal bleeding and pulmonary thromboembolism 3. Supplemental oxygen therapy 3.1 Spontaneous breathing using a face mask with a high flow gas delivery system can be used to deliver a FIO of up to 0.5 to 0.6. Continuous positive 2

airway pressure (CPAP) may be added to improve PaO without increasing 2 FIO . If a FIO of more than 0.6 and CPAP of more than 10 cm H O are 2 2 2 needed to achieve PaO of more than 60 mm Hg, tracheal intubation and 2 assisted mechanical ventilation are required. 4. Ventilatory support Aim of mechanical ventilation is to maintain gas exchange with minimal complications. Tidal volume should be set in the region of 6 ml/kg (“lung protective ventilation”) rather than the conventional 10 to 12 ml/kg and

the plateau pressure should be limited to 30 to 35 cm H O to prevent 2 alveolar overdistension. PEEP and FIO2 settings are set as per ARDSnet protocol. Other alternative approaches, such as, prone positioning of the patient, high frequency jet ventilation (HFJV), high frequency oscillatory ventilation (HFOV), and liquid ventilation among others can also been tried in selected patients. The relative merits of these alternative methods of mechanical

ventilation must be critically weighed against the potential side effects in every setting. 9

5. Corticosteroids and ARDS 5.1 It is now conclusively established that corticosteroids have no useful role before the onset of ARDS or early in its course. When patients with ARDS have severe disease, and, do not show signs of improvement 7 to 14 days after the onset of ARDS (late ARDS), a one to two week trial with corticosteroids (prednisolone 2-4 mg/kg/day or equivalent) can be tried. 6. ARDS in the tropics 6.1 Infectious causes such as pulmonary and miliary tuberculosis,

falciparum malaria, enteric fever, and leptospirosis are rare but treatable causes of ARDS. When recognized to be the aetiological cause of ARDS, appropriate specific treatment must be instituted for primary conditions. b. Out Patient Not applicable. ARDS is managed in an intensive care (ICU) unit setting V. WHO DOES WHAT? and TIMELINES a. Doctor Diagnosis and Management including counseling b. Nurse Implementation of orders, monitoring of patients and counseling c. Technician Investigations

Respiratory physiotherapist For administering supportive care to patients admitted in ICU VI. FURTHER READING / REFERENCES 1. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818-24. 2. Rice TW, Wheeler AP, Bernard GR, Hayden DL, Schoenfeld DA, Ware LB. for the

National Institutes of Health, National Heart, Lung, and Blood Institute ARDS Network. Comparison of the SpO2/FIO2 ratio and the PaO2/ FIO2 ratio in patients with acute lung injury or ARDS. Chest 2007;132:410-7. Epub 2007 Jun 15. 3. Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, et al. National Heart, Lung, and Blood Institute acute respiratory 10

distress syndrome (ARDS) clinical trials network. Comparison of two fluid management strategies in acute lung injury. N Engl J Med 2006;354: 2564-75. 4. Wheeler AP, Bernard GR, Thompson BT, Schoenfeld D, Wiedemann HP, deBoisblanc B, et al. National Heart, Lung, and Blood Institute acute respiratory distress syndrome (ARDS) clinical trials network. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006;354: 2213-24. RESOURCES REQUIRED FOR ONE PATIENT

Situat HUMAN INVESTIGATIONS DRUGS & EQUIPMENT ion RESOURCES CONSUMABLES 1 1. Physician with 1.Pulse oximetry 1. Oxygen 1.Oxygen cylinder training in 2.Chest X-ray 2. Antibiotics 2.Nasal prongs echocardiography 3.Echocardiography 3. Inhaled 3.MC mask 2. Nurse 4.ABG analysis bronchodilators 4.X-ray machine 3. Radiographer 5.Echocardiography machine 6.ABG analyzer 2 Above plus Above plus Above plus Above plus 1.Computed 1.Parenteral and oral 1.CT machine

1.Intensivist tomography including bronchodilators 2.Microbiology CT pulmonary (theophylline, laboratory service 2. ICU staff with angiography terbutaline) for infectious pulmonary training 2.Bronchoscopy 2.Parenteral and oral aetiology work-up steroids 3.ICU (hydrocortisone, 4. Noninvasive and 3. Respiratory prednisolone) invasive ventilators physiotherapists 3.Central venous 5. HFOV (high catheter frequency 4. Radiologist 4.Swanz Ganz oscillatory catheter ventilation) [if 5.Microbiologist available]

BRONCHIAL ASTHMA I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Asthma is a common clinical problem encountered at all levels of health care. Asthma can be defined as a chronic inflammatory disorder of the airways. Different terms such as allergic or asthmatic bronchitis, wheezy bronchitis, intrinsic and extrinsic asthma are frequently employed in clinical practice. Asthma commonly begins in childhood and early youth, but may also start later in life at any age. Contrary to common belief, children do not

necessarily ‘grow out of asthma’. Almost two third of the asthmatic children continue to have symptoms in puberty/adulthood. About 5-10% children with ‘mild’ asthma may go on to develop severe asthma later in life. b) Case definition (for both situations of care): Asthma is characterized by recurrent episodes of cough, wheezing, breathlessness, and chest tightness that are often reversible, either spontaneously or with treatment. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY

The prevalence rates are variable depending upon the definition and methodology employed. As per the results of the Indian Study on Epidemiology of Asthma, Respiratory symptoms and Chronic bronchitis (INSEARCH), the population prevalence in adults is about 2 percent or more. In children, the prevalence is likely to be higher, exceeding 5 percent. Both men and women are about equally affected. III. DIFFERENTIAL DIAGNOSIS Diagnosis of asthma is a two-step approach. The first important step is to suspect

the diagnosis while the second step involves exclusion of other diagnoses and laboratory assessment to confirm the diagnosis and assess the severity stage of asthma. Documentation of reversibility and/or variability of forced expiratory flow, 1st second (FEV1) or peak expiratory flow (PEF) is important to diagnose asthma and differentiate it from chronic obstructive pulmonary disease. 12

IV. PREVENTION AND COUNSELING Exact cause of asthma is not known. Both environmental and genetic factors are important. A family history of asthma or atopy (allergy), presence of other atopic manifestations (e.g. allergic rhinitis, skin allergies) and airway hyper- responsiveness predispose an individual to develop asthma. However, asthma can develop in the absence of a family history. Asthma attacks are generally triggered by one or more of exposures/ risk-factors. Most patients may have more than one

trigger. Besides complying with the therapy for treatment and control of asthma, the common triggers (as below) should be identified and avoided: Respiratory infections – usually viral Allergens (Indoor/Outdoor) Air pollution (Indoor/Outdoor) including smoke and fumes (biomass fuel) Tobacco smoke (both active and passive) Drugs – beta-blockers and non-steroidal anti-inflammatory drugs (NSAIDs) Food additives and preservatives- food is normally not a trigger unless it is

specifically proved to be so in an individual. Since asthma is a lifelong problem, it is crucial that the patient and the family are educated about the disease and its management for a normal and healthy life. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital: Optimal Standards of Treatment in Situations where technology and resources are limited Diagnosis e) The diagnosis is essentially based on history and physical findings of wheezing.

FEV /FVC ratio less than 70% and reversibility more than 12% and 200 ml 1 establishes the diagnosis.This should also be categorized in to mild, moderate and severe depending upon the symptoms and treatment requirement. 13

Mild Moderate Severe Symptoms disturbing sleep < once per week > once per week Daily Daytime symptoms < Daily Daily Daily Limitation of accustomed Some Severe Nil activities limitation limitation Use of rescue medication * <1 unit per day 1-2 units per day >2 units per day FEV or peak expiratory flow Normal 60-80% <60% 1 f) Treatment: Basically in asthma four components are important in management; i) diagnosis, assessment and monitoring of severity ii) education for partnership of patient and

doctor iii) identification and control of trigger factors and iv) pharmacologic management. All these components of care are possible even at a place where resources are limited. Therefore primarily management of asthma does not vary due to resource constraint or lack of technology. It is important to effectively manage asthma to help an individual to live a normal life, and avoid acute exacerbations as well as long-term complications. Currently

available important anti-asthma drugs can be classified as controllers (required for maintenance treatment) and relievers (required for quick relief, rescue drugs). Inhaled corticosteroids constitute the cornerstone of maintenance therapy. • Controllers (Prophylactic, Preventive, Maintenance) • Taken daily to keep asthma under control • Steroids, long-acting beta-2 agonists, sustained-release theophyllines, leukotriene receptor antagonists, and cromones • Relievers (Quick relief, Rescue)

• Rapid acting drugs that relieve bronchoconstriction • Short acting beta-2 agonists, anticholinergics, theophyllines, short-course oral steroids The recommendations for use of drugs vary depending upon the stage of asthma. Mild asthma can be further divided into intermittent (symptoms for less than two days per week) and persistent (symptoms for more than two days per week) categories, and treatment given accordingly. Low dose inhaled steroids are 14

recommended. Alternatively, oral theophyllines can be used. Moderate asthma is treated with medium dose ICS + long acting beta-agonists (LABA) and/or leukotriene antagonists (LTRA). Alternate choices are: - medium dose ICS + LTRA / theophylline. Severe asthma is managed with high-dose ICS and/or oral steroids at the lowest dose + LABA + theophylline + LTRA. Systemic corticosteroids on long-term basis must be avoided. A short-course of up

to two weeks (0.5 mg/kg/day) is, however, often valuable for managing acute severe asthma. In addition to daily controller therapy, reliever medications on as-needed basis may be taken in all stages. Asthma control requires frequent stepping up or down of therapy. Patients with intermittent or seasonal symptoms can be managed with only reliever medications taken on an as-needed basis. Management of acute severe asthma Hour 1: 4 doses of inhaled salbutamol ± ipratropium, 100 mg hydrocortisone

(IV) or oral prednisolone 60 mg, oxygen, adequate hydration Hour 2: 4 more doses of inhaled salbutamol with ipratropium, IV aminophylline, subcutaneous terbutaline/adrenaline 0.3-0.5 mg (0.01 mg/kg for children) for 3 doses Acute severe asthma not responding within 2 hours of treatment, or deteriorating: REFER IMMEDIATELY Expectorants and mucokinetic drugs do not have any significant role. General principles of pharmacotherapy in patients with bronchial asthma

• Inhaled drugs should preferably be given using metered dose inhaler with spacer • Education about proper inhalation technique is most essential for optimal results • Long-acting beta-agonists (LABA) should always be combined with ICS • Short-acting beta-agonists (SABA) should be used only as reliever medication • Methylxanthines can be used as an alternative to inhaled steroids only in mild disease, or in acute severe asthma when standard treatment is not effective

• Anticholinergic drugs provide additive effect to SABA aerosol during exacerbations Systemic glucocorticoids are important only in the treatment of mild to moderate 15

exacerbations of asthma. g) Referral criteria: • Diagnosis unclear or in doubt • Atypical signs or symptoms • Failure to respond to treatment over one month • Other conditions complicating asthma or its diagnosis, necessitating additional work-up • Severe persistent asthma • Life-threatening asthma (cyanosis, mental obtundation) • Patients requiring additional tests such allergy testing, induced sputum eosinophil, FeNO etc • Patients requiring special treatment such as immunotherapy.

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available d) Clinical Diagnosis: Same as in Situation 1 (a) e) Investigations: exhaled nitric oxide (FeNO), induced sputum eosinophils f) Treatment: Standard Operating procedure a. In Patient: ventilator care b. Out Patient: same c. Day Care: same VI. WHO DOES WHAT? and TIMELINES a. Doctor: diagnosis, assessment of severity and prescription of medicines

for the patient. Explaining action plan to deal with exacerbation. b. Nurse: Educating patients about inhaler techniques and controlling trigger factors. c. Technician: Proper spirometry and measurement of peak flow 16

VII. Further reading/ references 1. Global Initiative for Asthma (GINA). Global strategy for the diagnosis and management of asthma in children 5 years and younger. Bethesda (MD): Global Initiative for Asthma (GINA); 2009. 21 p. 2. Asher MI, Montefort S, Bjorksten B, Lai CKW, Strachan D, Weiland SK, Williams H and the ISAAC Phase Three Study Group. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis and eczema in childhood-ISAAC Phase Three. Lancet 2006; 368:733-43

RESOURCES REQUIRED FOR ONE PATIENT Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 4. Physician 1. Chest radiograph 1. Inhaled 1. Oxygen 5. Nurse 2. Pulmonary function bronchodilators cylinder 6. Pulmonary test (salbutamol, 2. Nebulizers function test 3. Arterial blood gases ipratropium) 3. Spirometer technician 2. Inhaled 4. Handheld 7. Radiographer steroids spirometer (budesonide, (PEFR meter) beclamethasone) 5. X-ray machine 3. ICS 6. ABG analyzer (fluticasone/budeson -ide)+ LABA

(formoterol/salmete- rol) 4. Parenteral and oral bronchodilators (theophylline, terbutaline) 5. Parenteral and oral steroids (hydrocortisone, prednisolone) 6. Parenteral and oral antibiotics preferably macrolides 2 Above plus Above plus Above plus Above plus 1. ICU staff with 1. FeNO 1. Higher generation 1. ICU set-up pulmonary training antibiotics 2. Noninvasive and invasive ventilators 3. FeNO analyzer 17

CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) I. WHEN TO SUSPECT/ RECOGNIZE? c) Introduction: COPD should be suspected in any person, particularly in middle life, with history of tobacco smoking and/or other risk factors, and presenting with: • Cough, more during morning hours • Frequent sputum production • Breathlessness, mainly on exertion On clinical examination features of hyperinflation, diminished vesicular breath sounds with prolonged expiration and rhonchi are found. d) Case definition:

For both situations of care (mentioned below*) COPD is a preventable and treatable disease condition characterised by airflow limitation, which is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases, primarily caused by tobacco smoking. Chronic cough and sputum production often precede the development of airflow limitation by many years. Although COPD affects

lung, it also produces significant systemic consequences. The diagnosis must be substantiated by quality spirometry showing post bronchodilator FEV /FVC < 0.7 and FEV < 80% of predicted. 1 1 II. INCIDENCE OF THE CONDITION IN OUR COUNTRY COPD is primarily a disease of the adults. The prevalence of COPD reported in different population based studies from India is highly variable (Table 1). The prevalence rates in male subjects of 2.12% to 9.4% in studies reported

from North are generally higher than 1.4% to 4.08% reported from South 18

India. The respective range for female subjects varies from 1.33% to 4.9% from North and from 2.55% to 2.7% from South India. For epidemiological assessment, the rounded-off median prevalence rates were assessed as 5 percent for male and 2.7 percent for female subjects of over 30 years of age. The disease is distinctly more common in males. The male to female ratio varies from 1.32:1 to 2.6:1 in different studies with a median ratio of

1.6:1.COPD results from chronic inhalational exposure to various smokes, noxious particles and gases. Table 1. Prevalence of COPD and its smoking association in various population studies from India. Smoker: Population COPD prevalence (%) Non-smoker Ratio Men Women M:F Ratio Wig (1964) Rural Delhi 3.36 2.54 1.3 2.0 Sikand (1966) Delhi 7.0 4.3 1.6 2.5 Viswanathan (1966) Patna 2.12 1.33 1.6 Bhattacharya (1975) Rural U.P 6.67 4.48 1.6 Radha (1977) New Delhi 8.1 4.6 1.8 1.8

Thiruvengadam (1977) Madras 1.9 1.2 1.6 10.2 Viswanathan (1977) Delhi Rural 4.7 3.5 1.3 9.6 Urban 8.0 4.3 1.9 4.0 Charan (1977) Rural Punjab 2.28 1.63 1.4 Malik (1986) N.India Rural 9.4 4.9 1.9 5.5 Urban 3.7 1.6 2.3 7.0 Jindal (1993) N.India Rural 6.2 3.9 1.6 Urban 4.2 1.6 2.6 9.6 Ray (1995) South India 4.08 2.55 1.6 1.6 III. DIFFERENTIAL DIAGNOSIS Chronic bronchial asthma, bronchiectasis, tuberculosis, obliterative bronchiolitis, congestive cardiac failure, dilated cardiomyopathy, diffuse panbronchiolitis.

Asthma is a major differential diagnosis. In some patients with chronic asthma, a clear distinction from COPD is not possible using current imaging and physiological testing techniques. The following features sometimes help in differentiating the two conditions. COPD Asthma • Onset in mid-life • Onset early in life (often childhood) • Symptoms slowly progressive • Symptoms vary from day-to-day • Dyspnea during exercise • Symptoms (especially cough) at • Usually irreversible airflow night/early morning

limitation • Allergic rhinitis or conjunctivitis • Long smoking history and/or atopic dermatitis also present • Family history of atopy or asthma • Predominantly reversible airflow limitation IV. PREVENTION AND COUNSELING a) Smoking cessation: Cessation of smoking is of fundamental importance to the successful management of all stages of COPD. b) Adequate measures to control environmental pollutants and provision of occupational hygiene in dusty working environment.

c) Vaccines: COPD patients are particularly susceptible to influenza infection, thus annual influenza vaccination is recommended for all. Currently available vaccine pneumococcal vaccines (PPSV23) has not been shown to be effective particularly in high-risk patients. Trials are underway with pneumococcal conjugate vaccine [PCV-13 (CAPITA trail)] and further recommendations should wait till the outcomes of the trial are available. d) Health education about COPD: It is not a curable disease rather it is a

preventable and treatable disease. e) Strict adherence to treatment i.e. use of inhaled bronchodilators, with or without other necessary pharmacologic treatment is essential. 20

f) Prompt recognition of features of an exacerbation is of paramount importance, therefore, patients should be educated about warning signs and symptoms. g) Lifestyle modification and treatment of extrapulmonary manifestations such as coronary artery disease, osteoporosis, sarcopenia and anxiety/depression, and co-morbidities like type2 diabetes mellitus and metabolic syndrome. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA

*Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited h) Clinical Diagnosis: Patients usually present with: • History of tobacco use. • Cough with or without sputum production. Cough is particularly worse in the morning and sputum production is a frequent complaint in the early stages of COPD. • Dyspnoea on exertion: progressive breathlessness in COPD is a

persistent symptom with waxing and waning but there is never any time when patients are entirely asymptomatic. Onset of breathlessness is insidious with progressive course, and often a significant amount of ventilatory capacity has been lost before the patient presents to the physician. • Many patients complain of intermittent wheezing. However, nocturnal wheezing is uncommon in COPD and suggests diagnosis of asthma or heart failure. On clinical examination: patients are frequently seen sitting leaning

forward with their arms resting on a stationary object. Some patients also develop pursed lip breathing. Percussion of chest is not very helpful in COPD (might reveal features of hyperinflation of lungs). Auscultation 21

reveals diminished vesicular breath sounds with or without crackles and wheeze. Measurement of FET (forced expiratory time) is a valuable bedside technique to detect and assess airflow obstruction. An FET <5 seconds suggests that severe airflow limitation does not exist, whereas FET > 6 seconds indicates considerable airflow limitation. Many a times patients get disoriented, somnolent, or may complain of headache, which indirectly suggests CO retention. Such a situation will require the 2

application of non-invasive ventilation (NIV), if possible at the treating centre. Peripheral edema, raised JVP, and hepatomegaly are signs indicative of pulmonary hypertension and right ventricular failure (chronic cor pulmonale). i) Investigations: • Spirometry is essential to firmly establish the diagnosis. Post bronchodilator FEV /FVC <0.7 and post bronchodilator FEV <80%, 1 1 50% or 30% predicted are used for purpose of spirometric classification of COPD according to GOLD. Stage FEV /FVC FVC 1

Mild COPD £0.7 ‡80% Moderate COPD £0.7 50% - 80% Severe COPD £0.7 30% - 50% Very severe COPD £0.7 <30% or <50% plus chronic respiratory failure or pulmonary hypertension • Blood tests like haematocrit, chest radiograph (postero-anterior and lateral views) may be helpful in resource-poor settings. • ECG and echocardiography (if available). • 6-minute walk test. 22

j) Treatment: The goals of COPD management include: 1. Relief of symptoms 2. Prevent disease progression 3. Improve exercise tolerance 4. Improve health status 5. Prevent and treat extrapulmonary manifestations 6. Prevent and treat complications 7. Prevent and treat exacerbations 8. Prevent or minimise side effects from treatment 9. Reduce mortality Standard Operating procedure a. In Patient Patients would present to the hospital in an exacerbation which is

defined as an event in the natural course of the disease characterised by a change in the patient’s baseline dyspnoea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular medication. Signs of severity of an exacerbation that would require hospitalisation include: use of accessory muscles of respiration, paradoxical chest wall movements, cyanosis, peripheral oedema, haemodynamic instability, and decreased mental alertness. A chest

X-ray would help in identifying alternative diagnoses that could mimic an exacerbation, while an ECG would aid in the diagnosis of right heart hypertrophy, arrhythmias and ischaemic episodes. Blood tests including haemogram, sugar and renal functions should be performed. Blood sample for ABG measurement should be drawn, if facility exists. Management of exacerbations: • Administer controlled oxygen therapy 23

• Repeated administration of bronchodilators (β2 agonists and anticholinergics). Increased doses may be required in some patients. • Add oral or intravenous glucocorticoids • Consider adding an i.v. methylxanthine, if needed • Consider antibiotics when signs of bacterial infection • Monitor fluid balance and nutrition b. Out Patient Stable COPD can be managed with therapy at each stage of COPD as follows: Mild COPD Moderate COPD Severe COPD Very Severe COPD

FEV1/FVC<0.7 FEV1/FVC<0.7 FEV1/FVC<0.7 FEV1/FVC<0.7 FEV1>= 80% 50%<FEV1<80% 30%<FEV1<50% FEV1<30% PREDICTED or PREDICTED FEV1<50% plus chronic respiratory failure Active reduction of risk factor(s): Influenza vaccination Add short acting bronchodilator(when needed) Add regular treatment with one or more long acting bronchodilator(when needed); add rehabilitation Add inhalational corticosteroids (ICS) if repeated exacerbations Refer the patients to the specialist Antibiotics:

Antibiotics may be initiated in patients with altered sputum characteristics (increased volume and increased purulence) and increased dyspnoea. The choice should be based on local bacteria resistance patterns. c) Referral criteria: 24

i. Marked increase in intensity of symptoms ii. Severe COPD iii. Appearance of cyanosis, edema iv. Signs of respiratory failure v. Significant co-morbidities vi. Recurrent exacerbations vii. New onset arrhythmias viii. Diagnostic uncertainty ix. Old age x. Failure to control exacerbation *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available g) Clinical Diagnosis: Same as in Situation 1 (a) h) Investigations: • Same as in Situation 1 (b)

• Assessment of pulmonary haemodynamics • CT-thorax and ventilation-perfusion scanning (especially for those being planned for lung surgery) • Polysomnographic studies (if indicated) • Cardiopulmonary exercise testing • DEXA scan for osteoporosis [bone mineral density (BMD) and sarcopenia [fat free mass index (FFMI)] • Psychiatric evaluation for anxiety/depression • Alpha-1 antitrypsin deficiency screening (for those who develop COPD at a younger age and those with a strong family history of COPD). 25

i) Treatment: Standard Operating procedure a. In Patient • Same as in Situation 1 (c) • Noninvasive ventilation using BiPAP • Mechanical (invasive) ventilation • Surgical options including bullectomy and LVRS Indications for mechanical ventilation: 1. Severe dyspnea, use of accessory muscles of respiration and paradoxical abdominal motion 2. Severe acidosis pH< 7.25, and/or hypercapnia PaCO > 2 60mmHg which does not respond to NIV 3. Somnolence, impaired mental status 4. Unable to tolerate NIV

5. Life-threatening hypoxemia 6. Respiratory rate > 35/min 7. Impending respiratory arrest Diagnosis and management of cor pulmonale The patient develops chronic cor pulmonale when there are alterations in the structure and function of the right ventricle caused by a primary disorder of the respiratory system. Invariably this would manifest as pulmonary hypertension on echocardiography. Symptoms would include tachypnoea and increase in exertional dyspnoea.

Patients with chronic cor pulmonale and right heart failure will present with distended neck veins with prominent ‘V-y’ pattern suggestive of tricuspid regurgitation, cyanosis, peripheral oedema, splitting of second heart sound with accentuation of pulmonary component, left parasternal heave, long systolic or pansystolic murmur with accentuation during inspiration in the lower left sterna border, occasionally presence of right ventricular third

heart sound, right upper quadrant abdominal discomfort and pulsatile hepatomegaly. 26

Medical therapy for chronic cor pulmonale is generally focused on treatment of the underlying pulmonary disease and improving oxygenation and right ventricular (RV) function by increasing RV contractility and decreasing pulmonary vasoconstriction. In general, in patients with COPD, long-term oxygen therapy is recommended when the PaO is less than 55 mm Hg or the O saturation is 2 2 less than 88%. However, in the presence of cor pulmonale or impaired

mental or cognitive function, long-term oxygen therapy can be considered even if the PaO is greater than 55 mm Hg or the O saturation is greater 2 2 than 88%. This must be documented in at least two consecutive ABGs done 3 weeks apart in stable state. Pharmacotherapy includes salt restriction, diuretics, calcium channel blockers (indicated only if cardiac catheterization facilities available and vasoreactivity can be demonstrated), prostacyclin analogues (epoprostenol,

treprostinil, and iloprost), endothelin-receptor antagonists (bosentan), PDE5 inhibitors (sildenafil and tadalafil). The algorithms for correction of hypoxia and long term oxygen therapy are given below. 27

Algorithm to correct hypoxaemia in an acutely ill COPD patient For conversion of kPa into mmHg: 1 mmHg=0.133 kPa 28

b. Out Patient • Same as in Situation 1 b) c) Referral criteria: Patients with very severe COPD who are not controlled even on maximal medical therapy and LTOT and who fulfill the selection criteria for lung transplantation should be referred to a specialist centre where expertise of lung transplantation is available. VI. Who does what? and timeliness a. Doctor: Diagnosis and management including counseling b. Nurse : Implementation of orders and monitoring of patients

c. Technician: Carrying out investigations VII. FURTHER READING / REFERENCES • Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive lung disease. NHLBI/WHO workshop report. Bethesda, National Heart, Lung and Blood Institute. Updated 2010; pp 1-92. • Jindal SK, Gupta D, Aggarwal AN. Guidelines for the management of COPD in India: a guide for physicians (2003). Indian J Chest Dis Allied Sci 2004; 46: 137-153. 30

RESOURCES REQUIRED FOR ONE PATIENT Situati HUMAN INVESTIGATIONS DRUGS & EQUIPMENT on RESOURCES CONSUMABLE S 1 8. Physician 4. Chest radiograph 7. Inhaled 7. Oxygen 9. Nurse 5. Hemogram bronchodilators cylinder/concentrator 10. Laboratory 6. Pulmonary function (salbutamol, 8. Nebulizers (both technician tests ipratropium, electric and 11. Pulmonary 7. ABG tiotropium) electronic) function test 8. Eletrocardiogram 8. ICS 9. Spirometer along with technician 9. 2D-ECHO (fluticasone/bude 6-MW facility

12. Radiographer -sonide)+ LABA 10. X-ray machine (formoterol/salm- 13. Physician trained 11. ABG analyzer eterol) in ECHO/ 12. EKG machine 9. Parenteral and cardiologist 13. Echocardiography oral machine bronchodilators (theophylline, terbutaline) 10. Parenteral and oral steroids (hydrocortisone, prednisolone) 11. Parenteral and oral antibiotics (Amoxycillin and clavulanate combination, cefadroxil, cefotaxime, Piperacillin and tazobactum combination) 2 Above plus Above plus Above plus Above plus

2. ICU staff with 1. CT Scan 2. Higher 1. CT machine pulmonary 2.Polysomnography generation 2. ICU set up training 3.DEXA scan antibiotics 3. Noninvasive and 3. Physiotherapist invasive ventilators 4. Sleep laboratory 4. Polysomnography technician machine 5. Thoracic surgeon 5. DEXA machine 6. Psychiatrist 6. Operation theatre 7. Cardiologist with trained staff 8. Radiologist 9. Anesthetist 31

INTERSTITIAL LUNG DISEASE I. WHEN TO SUSPECT/ RECOGNIZE? a. Introduction: Interstitial lung disease (ILD) is a heterogeneous group of disorders with a common clinico-radiological presentation, hence grouped together. These diseases are characterized by predominant involvement of lung ‘interstitium’ i.e. the space between alveolar basement membrane and pulmonary vascular endothelial membrane. As the disease progresses it encroaches alveolar spaces, terminal

bronchioles and perivascular spaces, thereby ILDs are referred to as diffuse parenchymal lung disease (DPLD). ILDs due to systemic diseases such as connective tissue diseases, sarcoidosis, hypersensitivity pneumonitis, drugs, pneumoconioses and other miscellaneous conditions are termed as secondary ILDs. The primary pulmonary involvement is generally the Idiopathic pulmonary fibrosis (IPF/fibrosing alveolitis) or usual interstitial pneumonitis. b. Case definition: For both situations of care:

ILD is suspected in patients with onset of respiratory symptoms of relatively acute/ sub-acute duration of weeks to months. The predominant symptoms consist of breathlessness and dry cough. Weakness and weight loss are usually present. Chest pain/ heaviness and haemoptysis can occur in a few conditions. Elicitation of occupational history is mandatory. The chest X-ray film shows distinctly reticular, reticulo-nodular or nodular opacities which are patchy /basilar or diffuse in

distribution. Chest X-ray can occasionally be normal. High resolution CT scan of the chest is usually characteristic. Investigations for the underlying disease are important to rule out a secondary cause especially in those with atypical HRCT findings. Pathological diagnosis with bronchoscopic/ thoracoscopic and other surgical modalities is required for confirmation in only a few cases. II. INCIDENCE OF THE CONDITION IN INDIA The exact incidence and prevalence of the disease is not known. The common

causes of ILD in India include IPF, connective tissue related ILD (systemic sclerosis and rheumatoid arthritis) and sarcoidosis. In general, at most secondary- 32

level hospitals, 1-3 cases per month and at super-specialty hospitals, 1-3 cases per week of idiopathic ILD are likely. III. DIFFERENTIAL DIAGNOSIS Many disorders can present with symptoms similar to that of ILD and interstitial opacities on chest radiograph. The following are the common disorders that should be ruled out before making a diagnosis of ILD: a) Tuberculosis b) Atypical pneumonias (Mycoplasma and legionella) c) Fungal pneumonias (Aspergillosis, crytococcosis) d) Chronic bronchitis

Exclusion of a secondary causes such as a connective tissue disease, hypersensitivity pneumonia, pneumoconiosis, drug-toxicity is important before making the diagnosis of primary idiopathic ILD (such as IPF). IV. PREVENTION AND COUNSELLING Occupational and environment related interstitial lung disease may benefit from avoidance or decrease in intensity and duration of exposure. High index of suspicion and early recognition of interstitial lung disease can be helpful as it can

prevent further deterioration of lung function by avoidance of exposure. Smoking cessation is another important caution which must be exercised. The following are the few diseases in which avoidance of exposure can be advocated if ILD is detected early. 1) Silicosis (occupations-miners, sandblasting, workers in abrasive industries, such as stone, clay, glass, cement manufacturing and granite quarrying) 2) Asbestosis(asbestos manufacturing, construction trade, mining, milling and pipefitters)

3) Coal worker’s pneumoconiosis 4) Chronic hypersensitivity pneumonitis (pigeon breeders, farm dust and grain husk containing thermophilic actinomyces) V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA While ILD can be suspected at any secondary-level hospital, the confirmation, exclusion of secondary causes and initiation of management lies essentially in the 33

domain of the specialty hospitals. Follow-up management afterwards can, however, continue at the secondary –level, referring hospital. Diagnosis: The diagnosis of ILD is based on the combination of clinical, radiographic, and histopathology criteria. a. Clinical: i. Progressive breathlessness and/ or dry cough, ii. Physical findings: basal end-inspiratory crackles- superficial, dry and velcro-like. Finger clubbing may be present in IPF.

b. Radiographic findings: A good quality postero-anterior chest radiograph should be initial investigation of choice followed by HRCT chest for confirmation of presence of ILD. i. Chest radiograph- presence of reticular, nodular or reticulonodular shadows, shrunken lung fields and obscuration of cardiac and diaphragmatic margins. ii. HRCT Chest- presence of reticular shadows (inter and intralobular septal thickening), patchy ground-glass opacities/consolidation (predominantly subpleural and peripheral) and

honeycombing (indicates end-stage ILD) c. Pulmonary function tests: i. Spirometry: A restrictive abnormality is classical of ILD with reduced total lung capacity (TLC), functional residual capacity, and residual volume. Forced expiratory volume in one second (FEV ) 1 and forced vital capacity (FVC) are reduced. FEV /FVC ratio is 1 normal or increased. However, mixed (restrictive- obstructive)/obstructive pattern can be seen in patients with lymphangioleiomyomatosis, sarcoidosis, hypersensitivity

pneumonitis due to involvement of small airways. ii. Diffusing capacity for carbon monoxide (DLCO): reduced in all patients with ILD except in alveolar hemorrhage syndromes in which it is increased. iii. Significant oxygen desaturation on exercise (>3-4%). iv. ECG and 2D ECHO for pulmonary hypertension/cor pulmonale. d. Histopathology: The histopathology is required only in the presence of an early disease when the differential diagnosis is important from a treatable condition.

The pattern varies according to the disease. Idiopathic pulmonary fibrosis is 34

characterized UIP pattern. Sarcoidosis, Wegener’s granulomatosis and Churg- Strauss syndrome are characterized by granulomatous inflammation. e. 6-minute walk test (6MWT): For baseline and follow-up Treatment: The management of the patients with ILD is difficult and unsatisfactory. Anti- inflammatory therapy with steroids, azathioprine or cyclophosphamide forms the main backbone of drug therapy. Interstitial lung diseases which respond well to

immunosuppresive therapy include proliferative phase of NSIP, desquamative IP, cryptogenic organizing pneumonia, alveolar hemorrhage syndromes and sarcoidosis. Antioxidant and anti-fibrotic drugs such as N-acetyl cysteine and pirfenidone have some role for the treatment of idiopathic pulmonary fibrosis. None of the drugs are likely to provide benefit in advanced disease when only symptomatic treatment, home oxygen therapy, treatment of pulmonary

hypertension, pulmonary rehabilitation and treatment of co-morbid diseases should be offered to improve quality of life and avoid unnecessary side-effects of the drugs. REFERRAL CRITERIA: All patients in whom an interstitial lung disease is suspected or patients in whom alternative diagnosis like infection cannot be ruled out should be referred to a specialty hospital to confirm a diagnosis, identify the cause and initiate appropriate therapy. VI. WHO DOES WHAT? a. Doctor

Evaluate the patients, order investigations, make a diagnosis, advise proper treatment and perform follow-up b. Nurse Carry out the Investigations suggested by the doctors and help in follow-up of patients c. Technical staff Perform relevant investigations as per the advice of the treating physician 35

RESOURCES REQUIRED FOR ONE PATIENT Situatio HUMAN INVESTIGATIONS DRUGS & EQUIPMENT n RESOURCES CONSUMABLES 1 14. Physician 10. Chest radiograph 12. Parenteral and oral 14. Oxygen 15. Nurse 11. Pulmonary steroids cylinder 16. Laboratory function tests (hydrocortisone, 15. Oxygen technician 12. ABG analysis prednisolone) concentrators 17. Pulmonary 13. 2D-ECHO 13. N-acetyl cysteine 16. Spirometer function test 14. Inhaled 17. Hand-held technician Spirometer bronchodilators 18. Radiographer 18. X-ray

15. Sildenafil, bosentan 19. Physician with machine training in 19. ABG analyzer echocardiography 20. ECHO / cardiologist machine 2 Above plus Above plus Above plus Above plus 10. ICU staff with 1. CT Scan 3. Immunosuppressant 1. ICU pulmonary 2. Bronchoscopic drugs (azathioprine, 2. Noninvasive training biopsy cyclophosphamide, and invasive 11. Radiologist (Transbronchial pirfenidone) ventilators 12. Pathologist lung biopsy) 3. CT scan 13. Physiotherapist machine 4. Bronchoscope along with required

LUNG ABSCESS VIII. WHEN TO SUSPECT/ RECOGNIZE? e) Introduction: Lung abscess is a common form of suppurative lung disease that is characterized by a localized necrosis of pulmonary parenchyma and circumscribed collection of pus in the lung that is usually greater than 2 cm in diameter. Many local causes and systemic diseases can result in lung abscess formation. Primary lung abscess is more common and develops as a result of necrosis of lung parenchyma due to

an existing disease process that is occurring there, such as, untreated aspiration pneumonia especially due to staphylococcal klebsiella and anaerobic organisms,, or lung cancer. A lung abscess can also develop secondary to preexisting conditions, such as, bronchial obstruction, spread from an extrapulmonary focus of infection, bronchiectasis, or immunocompromised state. Acute and chronic is based on duration; acute <6 weeks and chronic > 6 weeks f) Case definition: (For both situations of care)

Primary lung abscess i. A patient with an ongoing episode of pneumonia of 2 to 3 weeks duration, or, a history of pneumonia in the recent past presents with respiratory symptoms and signs consistent with a lung abscess, (such as, cough, sputum, that may be putrid and foul smelling, haemoptysis, pleuritic chest pain, shoulder pain, or heaviness in the chest) and systemic manifestations like fever, night sweats, anorexia, weight loss, and digital clubbing.

ii. Chest radiograph evidence of a cavity or cavities with a fluid level IX. INCIDENCE OF THE CONDITION IN OUR COUNTRY Globally, the incidence of lung abscess has declined by nearly 10-fold during the preceding few decades in comparison with the pre-antibiotic era. No definitive studies have been carried out till date to define the incidence of lung abscess from India and reliable epidemiological data are not available. 37

X. DIFFERENTIAL DIAGNOSIS 1. Non-infectious diseases • Embolism with infarction • Vasculitis • Pulmonary neoplasm • Pulmonary sequestration • Bullae or cysts with air fluid level 2. Infections • Infected bulla • Infected pulmonary infarct • Infected cyst • Bronchiectasis • Empyema with air fluid level XI. PREVENTION AND COUNSELING 1. Measures for preventing aspiration of secretions in unconscious patients 2. Smoking cessation, good orodental hygiene

3. Early recognition of lung infections and institution of appropriate antibiotics in adequate dosage for appropriate duration. XII. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital: Optimal Standards of Treatment in Situations where technology and resources are limited k) Clinical Diagnosis Symptoms 1. The clinical manifestations of lung abscess may become evident coincident with the initial presentation of pneumonia or other underlying

condition, or may develop later in the course of the illness. 38

2. Conditions predisposing the patient for aspiration and development of lung abscess, such as altered sensorium, depressed cough and gag reflex, diseases of the oral cavity, gastrointestinal disease, and neurological disease are usually present. 3. Patients with primary lung abscess often have an ongoing episode of pneumonia of 2-3 weeks duration, or, a history of pneumonia in the recent past. Presenting symptoms include fever, cough, sputum, that may be

putrid and foul smelling. Pleuritic chest pain, shoulder pain, heaviness in the chest is also usually evident. Patients may also complain of chills, night sweats, anorexia, haemoptysis, weight loss, and digital clubbing. In patients with a secondary lung abscess, the clinical manifestations can develop over 48 to 72 hours. 4. Patients with hepatopulmonary amoebiasis may manifest abdominal symptoms, such as, right hypochondrium pain, bowel symptoms, among others.

5. In patients with perforation of the liver abscess into the lung, cough and expectoration of odourless anchovy sauce sputum may be evident. Signs 1. Patients with an acute lung abscess appear sick and toxic. New and focal respiratory signsmay be evident on physical examination of the chest. Presence of physical signs depends on the proximity lung abscess from the chest wall. 2. Signs due to complications, such as, pleural effusion, empyema, sepsis syndrome may also be present. l) Investigations

1. Chest radiograph: A chest radiograph is essential to establish the diagnosis of lung abscess. Lung abscess appears as an irregularly shaped cavity with an air-fluid level. The lesion may be solitary (primary lung infection), or sometimes, multiple (metastatic infection). Rapid pulmonary 39

cavitation within a dense segmental consolidation; and a rapidly enlarging nodular lesion, with or without cavitation suggest anaerobic infection. 2. Ultrasonography of the chest: Peripherally located lung abscesses, especially those in contact with pleura are detectable on ultrasonography of the chest. m) Treatment: Standard Operating procedure a. In Patient 1. General therapeutic measures Adequate drainage of the lung abscess is facilitated by

encouraging the patient to cough and by chest physiotherapy and postural drainage. 2. Antibiotic treatment: clindamycin administered intravenously in a dosage of 600 mg, eight hourly, followed by 150 to 300 mg orally four times daily is considered to be the preferred treatment of choice for lung abscess. Other antibiotic options include intravenous penicillin plus metronidazole and amoxycillin-clavulanate plus metronidazole. Antibiotic treatment is administered till the pulmonary infiltrates

have resolved or until the residual lesion becomes small and stable; the duration of antibiotic treatment is usually for 6 to 8 weeks. 2. Supplemental oxygen therapy In patients with hypoxaemia, spontaneous ventilation using a face mask with a high flow gas delivery system can be used to deliver a FIO of up to 2 0.5 to 0.6. b. Out Patient Not applicable n) Referral criteria: 1. Patients not responding to antibiotic treatment. 2. Occurrence of complications of lung abscess, such as, metastatic brain

abscess, sepsis, empyema, broncho-pleural fistula, pleura-cutaneous fistula, 40

massive life-threatening haemoptysis, spontaneous rupture of the abscess into uninvolved lung segments, and failure to resolve. *Situation 2: At Tertiary hospital where higher-end technology is available j) Clinical Diagnosis As in situation V.1 a) above k) Investigations As in situation V.1b) above PLUS 1. Computed tomography: computed tomography (CT) of the chest helps in delineating the size and location of abscesses. It also facilitates identifying

associated empyema, and detecting other conditions such as pulmonary infarction, infected bulla, and raising the suspicion of a cavitating lung malignancy. In lung abscesses that fail to communicate with a bronchus, the characteristic air-fluid level within a cavity will not be seen and instead, a focal, ground-glass infiltrate with indistinct borders may be evident. 2. Establishing microbiological diagnosis: 1. Ascertaining the microbiology of anaerobic infection of the lower airways

requires a specimen devoid of contamination by the flora of the upper airways or quantitative cultures that can distinguish pathogenic bacteria from the normal flora. 2. Specimens obtained from blind, deep suctioning via an endotracheal tube; radiologically guided, percutaenous transthoracic aspirates, specimens obtained at thoracotomy, quantitative cultures of specimens obtained at fiberoptic bronchoscopy (FOB), either by bronchoalveolar lavage (BAL) or with

the protected double-lumen catheter with a protected sampling brush are subjected to microbiological examination. 3. If the abscess is associated with an empyema, then culture of the empyema fluid may help in isolating the aetiological organisms. 41

l) Treatment: Standard Operating procedure a. In Patient As in situation V.1c) a.1 above PLUS 1. Drainage procedures Drainage procedures are usually reserved for patients with lung abscess who fail to respond to antibiotic therapy Percutaneous catheter drainage (for peripherally located lung abscess) Video-assisted thoracoscopic surgery (VATS) 2. Surgery Surgery is indicated if airway obstruction (e.g., due to a tumour or a foreign body) limits drainage. The surgical procedures performed include

lobectomy, wedge resection or pneumonectomy. When associated empyema is present, adequate drainage with tube thoracostomy is required; in patients with multiloculated empyemas, open pleural drainage is indicated. b. Out Patient Not applicable. XIII. WHO DOES WHAT? and TIMELINES a. Doctor: Diagnosis and Management including counseling b. Nurse: Implementation of orders, monitoring of patients and counseling c. Technician: Investigations XIV. FURTHER READING / REFERENCES

1. Schiza S, Siafakas NM. Clinical presentation and management of empyema, lung abscess and pleural effusion. Curr Opin Pulm Med 2006;12:205-11. 2. Mansharamani NG, Koziel H. Chronic lung sepsis: lung abscess, bronchiectasis, and empyema. Curr Opin Pulm Med 2003;9:181-5. 42

3. Mohan A, Vijayalakshmi Devi B, Chandra A. Lung abscess. In: Behera D, editor. NCCP Textbook of respiratory medicine; New Delhi: Jaypee Brothers Medical Publishers; 2011.p.171-7. RESOURCES REQUIRED FOR ONE PATIENT Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 1. Physician 1.Chest X-ray 1. Oral and i.v. 1. X-ray machine 2.Nurse 2.Ultrasonography of antibiotics 2. USG machine 3.Radiographer chest 2. Streptokinase 3. Intercostal tubes 3. sputum smear and 4. Negative suction

culture machines 4. Blood culture and sensitivity 2 Above plus Above plus Above plus Above plus 1. Intensivist 1.CT chest 1.Catheters and tubes 1. CT machine 2.Interventional 2.Interventional for drainage 2.Facilities for Radiologist radiology procedures procedures conducting 3.Thoracic 3.Bronchoscopy 2.Disposables for use interventional Surgeon 4.Conventional and during interventional radiology 4.Nurse and molecular procedures/ VATS/ procedures

Technician for microbiological surgical intervention 3.Bronchoscope assisting with diagnostic methods and facilities for bronchsocopy 5.Fiberoptic performing 5.Nurse and bronchoscopy interventional Technician for pulmonology assisting with procedures interventional 4.Microbiology radiology laboratory service procedures with facilities for 6.Nursing staff conventional and trained in molecular assisting thoracic diagnostic testing surgery 5.Video-assisted 7.Respiratory thoracoscope

therapist 6.Thoracic surgery operating theatre; recovery room and ICU 43

LUNG CANCER I. WHEN TO SUSPECT/ RECOGNIZE? g) Introduction: Lung cancer is the commonest form of malignancy world over and is the most common cause of death. The disease is fatal if not treated early. Although, tremendous advances have taken place, the 5-year survival rate is still around 15%. Tobacco smoking is the most common cause of lung cancer and detection at the early stage is the key to successful treatment and prolonged survival. h) Case definition: (For both situations of care)

It is a malignant condition of the lung and the tumor usually arises from the bronchi although this can originate from the alveoli (bronchoalveolar cell carcinoma). Bronchogenic carcinoma is of 4 major sub types: squamous cell carcinoma, adenocarcinoma, large cell carcinoma and small cell carcinoma. The first three are known as non small cell lung cancer. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY Lung cancer is the commonest form of malignancy in our country. It has surpassed

the oropharyngeal carcinoma which used to be the commonest form. ICMR cancer registry, hospital based as well as community based, reveal it to be the commonest form of cancer in males and is amongst the top ten cancers in females. There is an increase in the incidence of lung cancer in recent years. The cancer atlas program also shows that the north eastern region of the country has the highest prevalence/incidence. It is estimated that every year nearly 58,000

new cases of lung cancer are diagnosed in the country. III. DIFFERENTIAL DIAGNOSIS • Tuberculosis • Pneumonia • Lung abscess • Lung cysts • Pleural effusion of any cause 44

IV. PREVENTION AND COUNSELING Tobacco smoking cessation is the most important preventive measure. People working in high risk occupations with exposure to asbestos, arsenic, pollution, mercury, lead, and other heavy metals and chemicals need to have regular chest X-ray done. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital: Optimal Standards of Treatment in Situations where technology and resources are limited o) Clinical Diagnosis Symptoms

Cough, expectoration, chest pain, haemoptysis, breathlessness, weight loss, anorexia, weakness, hoarseness of voice, dysphagia, superior vena cava (SVC) obstruction etc. Signs Clubbing, findings of collapse, mass lesion, haemorrhagic pleural effusion, hard lymph nodes and SVC obstruction are some of the common clinical findings. p) Investigations 1. Chest radiograph: A chest radiograph is the cornerstone to establish the diagnosis of lung cancer which may reveal findings like mass, collapse,

pleural effusion, or mediastinal lymph nodes. There may be consolidation particularly non-resolving. Bronchoalveolar cell carcinoma will have an alveolar pattern on chest radiograph. q) Treatment: Usually no treatment is possible at this level. The diagnosis need to be established first by other means as discussed below. However, the patients should be treated symptomatically with cough suppressants, pain relieving agents etc. Once the diagnosis and follow-up plan is made by a tertiary care 45

hospital, the patient can be looked after for palliative therapy like pain management, thoracocentesis, cough suppressants and oxygen therapy etc. r) Referral criteria: 1. Diagnosis not clear. 2. It is important that the doctor at this level should be able to suspect a diagnosis of lung cancer from the chest X-ray. It is common for these patients to be misdiagnosed as having tuberculosis and continue receiving anti-TB treatment and important time is lost

before a diagnosis is achieved. Even if this is missed, a patient of tuberculosis should respond to ATT within a period of 2 to 3 weeks, failing which the patient should be referred. *Situation 2: At Tertiary hospital where higher-end technology is available m) Clinical Diagnosis As above. n) Investigations 1. Above plus 2. CT scan of chest (abdomen and brain is done for staging) 3. Sputum cytology 4. Fine needle aspiration cytology and biopsy 5. Bronchoscopy 6. Very rarely thoracotomy

7. Mediastinoscopy (rarely done now) 8. Bone scan (only in symptomatic patients) 9. PET Scan (if available) o) Treatment: a. Out Patient It is important to get a histological diagnosis and staging of the disease. The performance status (ECOG and Karnofsky scale) is to be ascertained. The overall financial conditions of the patient are to be accessed. There are four treatment options: 1) Early stage (Stage I to III A ) - surgery 46

2) Stage III B and Stage IV -- chemotherapy 3) Radiotherapy is usually a localized form of therapy and can be given in localized disease as a specific therapy. Both chemotherapy and radiotherapy can be given as an adjuvant therapy to surgery or as neo adjuvant setting to downstage the disease so that the patient is operable. 4) Recently targeted therapy (molecular therapy) is available in certain types of lung cancers. 5) Palliative or supportive therapy like pleurodesis in massive and

repeated effusions, care of nutrition, pain alleviation, management of chemotherapy related toxicities like nausea and vomiting, diarrhea or constipation, hair loss etc. One also needs to look after the terminal care of the patient. Suggested chemotherapy regimens: A cisplatin based 2-drug combination therapy is recommended. a) cisplatin plus gemcitabine b) cisplatin plus docetaxel c) carboplatin plus paclitaxel d) cisplatin and paclitaxel e) cisplastin and irinotecan is a good and cheap combination therapy

and can be used in our country. Pemetrexed is a new anti-folate anti-metabolite useful in adenocarcinoma of the lung. It is to be given in combination with cisplatin. The above combinations is for non small cell lung cancer. For small cell lung cancer one can use cisplatin and irinotecan or etoposide. Molecular therapy: epidermal growth factor receptor (EGFR) inhibitors like gefitinib and erlotinib are useful drugs for treating adenocarcinoma of the

lung particularly in non-smoking and Southeast Asian female patients. Cetuximab is a monoclonal antibody also useful in these patients. Vascular endothelial growth factor receptor (VEGFR) inhibitors like bevacizumab are a new drug useful for non squamous cell type of non small cell lung cancer. 47

One should keep in mind that chemotherapeutic drugs are toxic and costly also. All the aspects should be explained to the patient as well as to the family before such a decision is taken. VI. WHO DOES WHAT? and TIMELINES a. Doctor: Usually the chest physician makes the diagnosis and the management should include a team of thoracic surgeon, medical oncologist and radiotherapist. However, a chest physician or an internist can handle such a case in delivering chemotherapy with proper training.

b. Nurse : Implementation of orders, monitoring of patients and counseling, management of side-effects. c. Technician: Investigations VII. FURTHER READING / REFERENCES 1) Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008.Int J Cancer. 2010;127:2893-917. 2) Rami-Porta R, Chansky K, Goldstraw P. Updated lung cancer staging system. Future Oncol. 2009;5:1545-53.

3) Goldstraw P, Ball D, Jett JR, Le Chevalier T, Lim E, Nicholson AG, Shepherd FA. Non-small-cell lung cancer. Lancet 2011;378(9804):1727-40. 4) Rami-Porta R, Bolejack V, Goldstraw P. The new tumor, node, and metastasis staging system. Semin Respir Crit Care Med. 2011 Feb;32(1):44-51. 5) Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for

advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-98. 6) Behera D. Text Book of Pulmonary Medicine. 2nd Edition, 2010. Jaypee brothers Medical Publishers (P) Ltd. India. 48

RESOURCES REQUIRED FOR ONE PATIENT Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 1. Physician 1. Chest radiograph 1. Cough 1. X-ray machine 2. Nurse 2. Hemogram and suppressant 2. Hematology and 3. Radiographer blood chemistry 2. Analgesics biochemistry laboratory 2 All above plus Above plus 1. Chemotherpay Above plus 1. ICU staff 1. Sputum cytology protocol 1. Pathology (Physician, 2. FNAC cytology (cisplatin, laboratory (with nurses) and biopsy gemcitabine, facilities for

2. Radiologist 3. Bronchoscopy docetaxel, special stains) 3. Pulmonologist 4. Arterial blood paclitaxel, 2. CT scan machine 4. Pathologist gases carboplatin) 3. ABG machine 5. Oncologist 5. CT scan 2. Surgery protocol 4. Fiberoptic 6. Thoracic 6. Bone scan 3. Molecular therapy bronchoscope surgeon 7. PET scan (if (gefitinib, 5. Infusion pumps erlotinib) 7. Anesthetist available) 6. PET scan 8. Nuclear 8. SPECT-CT to 4. Radiotherapy machine (if medicine detect bone available)

specialist metastases 7. Bone scan 9. Radiotherapist machine 10. Nurse and 8. Operation technician for theatre assisting with 9. Radiotherapy bronchsocopy machine 11. Nurse and 10. SPECT-CT technician for assisting with interventional radiology procedures 12. Nursing staff trained in assisting thoracic surgery 13. Respiratory therapist 49

SLEEP DISORDERED BREATHING I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: • Sleep disordered breathing (SDB) constitutes a spectrum of disorders of various severity with intermittent snoring as the mildest form at one end and obesity hypoventilation syndrome (OHS) , the most severe form at the other end of the spectrum. Heavy snoring and upper airway resistance syndrome (UARS); mild, moderate and severe sleep apnea lie in between these two extremes. Because of the uncertainty about what constitutes

sleep apnea, the term SDB is used to describe events that do not satisfy criteria as apneas and hypopneas according to the conventional criteria, but which carry some of the same consequences, like, snore-arousals or respiratory effort-related arousal (RERA) or flow limitations. • Apnea: cessation of airflow ‡10 seconds with or without respiratory effort • Hypopnea: recognizable, transient reduction, but not a complete cessation of breathing ‡10 seconds. A‡50% decrease in the amplitude of a

validated measure of breathing must be evident or a <50% amplitude reduction that is associated with either an oxygen desaturation of ‡3% or an arousal on electroencephalography (EEG) • Respiratory effort - related arousal (RERA): is an event characterized by increasing respiratory effort for ‡ 10 seconds leading to an arousal from sleep, but which does not full fill the criteria for hypopnea or apnea. • Apnea - Hypopnea Index (AHI): defined as the number of obstructive apneas and hypopneas per hour

• Respiratory Distress Index (RDI): is defined as the number of obstructive apneas, hypopneas, RERAs and flow limitations per hour averaged over the course of at least 2 hours of sleep as determined by nocturnal polysomnography (PSG). • The term apnea-hypopnea index (AHI) is most commonly used conventional criteria to diagnose and quantitate the severity of sleep apnea, however recently as per the guidelines of American Academy of Sleep Medicine

(AASM) the term respiratory disturbance index (RDI) is increasingly used to 50

diagnose and describe SDB which includes besides apneas, hypopneas other events such as RERAs, and flow limitations b) Case definition: Diagnostic Criteria for OSAS (1) A Excessive Daytime Sleepiness (EDS) not better explained by other causes B. Two or more of the following not better explained by other causes • Choking or gasping during sleep • Recurrent awakenings from sleep • Un-refreshing sleep • Daytime fatigue • Impaired concentration C. PSG showing AHI > 5 in adults and >1 in children

OSAS must fulfill A or B, plus criterion C • The newly revised International Classification of Sleep Disorders defines OSAS as when a patient has an RDI of five or more than five per hour of sleep with the appropriate clinical presentation such as excessive daytime sleepiness, un-refreshing sleep, fatigue, insomnia, mood disorders or other neuro-cognitive disturbances. The severity of SDB is assessed by the number of abnormal breathing events per hour of sleep, degree of

sleepiness and the degree of oxygen desaturation during sleep. Mild AHI or RDI > 5-15/hour Moderate AHI or RDI > 15-30/hour Severe AHI or RDI > 30/hour 51

Severity Grading of OSAS (criteria for children) (2) AHI or RDI /hour Adults Children Mild: > 5-15 2-4 Moderate: >15-30 5-9 Severe: > 30 > 10 II. INCIDENCE OF THE CONDITION IN OUR COUNTRY The prevalence of SDB varies from region to region. It has been found to be present in 4% of men and 2% of women. In India various studies have shown the prevalence of SDB of 2.6% to 4.9% in adult males and 1% to 3.6% in adult females. About 4.8% children and 10.3% of elderly population in India have SDB. No gender

difference in the prevalence of SDB has been observed in children and elderly subjects. The factors associated with the pathogenesis of SDB include anatomically small airway, obesity, and loss of upper airway motor tone during sleep and dysfunction of central respiratory control. The various risk factors are body habitus (especially percentage of predicted neck circumference), obesity, genetics, craniofacial morphology, chronic rhino-sinusitis with nasal obstruction, smoking and alcohol consumption.

III. DIFFERENTIAL DIAGNOSIS • Narcolepsy • insomnia • Sleep hygiene disorder • Depression • Drug effect • OHS • Habitual snorers • Restless leg syndrome IV. CLINICAL FEATURES 52

The night-time symptoms of SDB include: • Loud, disruptive snoring • Nocturnal pauses in breathing • Gasping or choking for air during sleep • Restless sleep • Nocturia The daytime symptoms of SDB include: • Feeling of excessive daytime sleepiness • Grogginess and morning headache • Memory or leaning problems • Not being able to concentrate at work • Depression and irritability • Sexual dysfunction • Dry throat upon awaking • Frequent nocturnal enuresis The symptoms seen in women include:

• Report typical symptoms less frequently • Under-report snoring and underestimate symptom severity as compared to men • Non-specific somatic complaints such as insomnia, fatigue, myalgias, and morning headache • Amenorrhea and dysmenorrhea • Depression, anxiety and social isolation • Women tend to be more obese than men for the same degree of severity PRESENTATION IN CHILDREN Nocturnal symptoms in children include • Snoring • Restless sleep • Mouth breathing • Struggle to breathe/ gasp for air

• Feels depressed, sad or irritable • Sleepy during the day o Feels fatigued or tired during daytime o Excess activity, short attention span o Learning difficulties o Falling school performance o Difficulty to concentrate and memory lapses o Enlarged tonsils and adenoids Consequences of SDB are as follows: Physiological l Cardiovascular – Metabolic syndrome, hypertension, cerebrovascular accidents, coronary artery disease l Alterations in inflammatory biomarkers Behavioral l Tiredness in the morning

l EDS in permissive situation l Increased risk of motor vehicle accidents l Losses of concentration and productivity l Epworth Sleepiness Score & psychomotor vigilance test are abnormal l Behavioral effects can be variable amongst patients l Behavioral measurement alone are insufficient Social effects l Principally related to snoring l Disrupts social harmony by disturbance of bed-partner and others in a home l Falling asleep at social gatherings l Subjective measures are commonly used l Bed-partner scoring

V. PREVENTION AND COUNSELING Risk factor reduction: • Weight reduction • Avoid alcohol and cigarette smoking • Treatment of nasal congestion 54

• Surgical treatment of tonsillar and adenoid hypertrophy • Good sleep hygiene • Awareness about sleep disorders • Diagnosis and timely treatment of hypothyroidism VI. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited s) Clinical Diagnosis: The diagnosis of SDB depends on properly taken history from the patient and

the bed-partner regarding the typical daytime and night-time symptoms. Co- morbid conditions like hypertension, diabetes and other metabolic and hormonal problems. Good physical examination taking into account body mass index (BMI), neck length, percentage of predicted neck circumference (PPNC), cranio-facial anomalies like micrognathia and retrognathia, and evaluation of the upper airway using clinical examination scores, eg. Friedman score, X-ray

cephalometry, CT scan, MRI, and videoendoscopy. For the localization of the site of the obstruction multi-channel pressure measurement has also been used with some success. The gold standard test for the diagnosis and severity assessment of SDB is clinical polysomnography (PSG); however, there are many practical considerations and clinical caveats in PSG interpretation in sleep related sleep disorders. History should include any history of sleep problem, sleep diary, medication

history, medical problems, work history-shift work, alcohol or drug use, periodic limb movement disorders, dream history and teeth grinding. Physical examination should include measurement of body mass index (BMI; kg/m2), neck circumference and waist/hip ratio, examination of nose, oral 55

cavity, oropharynx, bony structure of head and neck. Sleep endoscopy is rarely needed to confirm airway collapse. t) Investigations: • Thyroid function tests • Blood sugar (fasting and post-prandial) • Serum insulin (fasting and post-prandial) • HbA c 1 • Lipid profile • ECG and echocardiography • Pulmonary function testing (if overlap with chronic obstructive airway disease is suspected) • Arterial blood gases [if overlap with chronic obstructive airway

disease or obesity-hypoventilation syndrome (OHS) is suspected] • Polysomnography o Full-night diagnostic study o Split-night with CPAP titration o Home study o Multiple Sleep Latency Testing (MSLT) if narcolepsy is suspected Requirement for standard diagnostic nocturnal polysomnography (PSG) includes recording and analysis of the following parameters: EEG, (EOG), (EMG), oro-nasal airflow, chest wall effort, body position, snore microphone, ECG, and oxyhemoglobin saturation. The duration of a

diagnostic NPSG is at least 6 h with the exception of the diagnostic portion of a split-night study, which is at least 2 h in duration. The various levels (types) of PSG are as follows Type 1- gold standard, in-lab, attended PSG Type 2- Comprehensive portable monitoring, unattended Type 3- cardio-pulmonary sleep study or modified portable sleep apnea testing Type 2 and Type 3 are acceptable in attended setting for patients without co- morbidity when scored by a trained physician

Type 3 underestimates the severity of SDB Type 4- continuous single or dual bio-parameter recording -underestimates severity 56

Indications of polysomnography are as follows: • For the diagnosis of SRBD and CPAP titration • Symptomatic patients with negative portable studies. • Full night PSG is required for CPAP titration of documented case of SDB; RDI > 15/hour or RDI > 5 with EDS • Evaluation of narcolepsy, and parasomnias • Before and after the application of dental appliances to assess the therapeutic benefits • Before and after upper airway surgery for snoring and SDB • After significant (10%) weight gain or weight loss

• Patients with specific medical condition o Coronary artery disease o Congestive heart failure o History of stroke o Treatment of transient ischemic attack (TIA) o Significant tachy- or brady- arrhythmias Indications for split-night study include: • AHI > 40/hour of at least 2 hours of sleep. • AHI between 20 and 40 in the presence of repetitive lengthy obstructions and major de-saturations. • CPAP titration must be carried out for more than 3 hours.

• PSG documentation of abrogation of all events with CPAP. u) Treatment: Treatment decision is based on evaluation of the patient’s history, anatomy, disease severity, symptoms and presence of co-morbidities. The severity of disease depends on • Severity of symptoms • Apnea hypopnea index (AHI) • Degree of oxygen desaturation o Minimum O desaturation 2 o Sleep time spent below 90% oxygen saturation 57

• Effect on sleep architecture o Presence or absence of REM and Delta sleep • Respiratory distress index (RDI) o Includes arousals with apneas and hypopneas All modes of treatments should be discussed and these include behavioral treatments, use of oral appliances, positive airway pressure (PAP) therapy and surgical therapy while providing real information about success with each mode of treatment. The behavioral modifications • Can reduce or eliminate OSA without the need for medication, device use

or surgery. o Sleep hygiene counseling o Sleep position therapy o Lifestyle modification and weight reduction o Avoidance of sedatives and alcohol o Smoking cessation o Avoidance of large meals before bedtime Continuous positive airway pressure (CPAP) is the gold standard for treatment of OSAS. It acts as a pneumatic splint to keep airway patent. The benefits of CPAP include the following. • Minimally invasive and reversible • Reduction and/or reversal of OSA-related signs and symptoms

Like snoring, excessive daytime sleepiness, un-refreshing or fragmented sleep, cognitive impairment • Decrease risk of accidents • Increased productivity • Decrease long-term complications of OSA like hypertension, heart disease, stroke, and death Common adverse events of CPAP are as follows: Minor (30-50% of Patients) (cid:216) Inconvenience 58

(cid:216) Skin ulceration due to mask (cid:216) Poor mask fit (cid:216) Claustrophobia (cid:216) Various nasal problems (15-45%) Major (cid:216) Massive epistaxis (cid:216) Pneumocephalus – following recent surgery or trauma causing CSF leak. Guidelines for titration • Patient should be evaluated for awake respiratory failure, congestive cardiac failure, and marked nocturnal hypoxemia. • CPAP titration should ideally be done in the hospital under supervision of a trained technician.

• Patient should receive adequate PAP education, hands on demonstration, careful mask fitting and acclimatization • CPAP should be increased till all the obstructive events: apneas, hypopneas, RERAs, snoring and desaturation dissapear. • Recommended minimum pressure is 4 cm and maximum of 15 cm (<12 yrs) and 20 cm H O (> 12 yrs) 2 • CPAP pressure of 1 cm H O should be increased with an interval no shorter 2 than 5 min. • CPAP pressure should be increased by 1 cm H O 2

o 1 apnea (<12 yrs) or 2 apneas (> 12 yrs) o 1 hypopnea (<12 yrs) 3 hypopneas (> 12 yrs) o 3 RERAs (<12 yrs) 5 RERAs (> 12 yrs) • Use of BiPAP is recommended if CPAP titration pressure is > 15 cm H O 2 • Titration algorithm is same for split-night study Titration in patients with cardio respiratory failure • Requires close supervision by trained technician or physician while commencing CPAP. • Many patients might require endotracheal intubation or urgent tracheostomy.

• The patient may become confused or delirious due to deranged blood gases. 59

• In trained hands, judicious use of CPAP or BiPAP can control breathing disturbances. • Auto CPAP should not be used CPAP adherence • No clear field standard exist o Too few studies to define amount of adherence needed to treat common sequelae • Average patient uses CPAP about 5 hours per night • Most clinicians generally recommend CPAP use for more than 4-5 hours per night on ≥ 70% of all nights Predictors of CPAP adherence • Early use patterns predict long-term adherence

o Patients appear to establish their patterns of use by the first month (as early as 4 days) o Adherence at 1 month appears to predict adherence at 3 months o Since adherence is established by 3 months, alternative forms of therapy should be considered for non-adherent patients Factors affecting CPAP adherence Patient related factors: • Lesser severity of symptoms • Little or no perceived benefit from therapy • Failure to understand importance of or directions for CPAP use

• Use of prescription/non-prescription drugs or alcohol • Lack of social support • Other medical illnesses or fatigue • Physical limitations (i.e. vision, hearing, hand coordination) II. Therapy related factors: • Complexity of therapy/device use • Increased rate of adverse reactions that go unaddressed • Lack of efficacy • Expense of therapy • Chronic nature of illness 60

• Compliance decreases over time III. Clinician related factors • Poor relationship with patient • Lack of clinician follow-up • Expression of doubt concerning therapeutic potential or creating falsely elevated expectations • Poor communication skills • Failure to identify concomitant use of alcohol and sedatives by the patient Measures to improve CPAP adherence: Technological interventions: Auto-titrating CPAP • Pressure delivery is auto-adjusted during changing airway conditions overnight

Bi-level positive pressure (BiPAP) • Set inhalation pressure with a lower set exhalation pressure Flexible pressure delivery (C-Flex, EPR) • Slight reduction in pressure during early exhalation Heated humidification • Decreases nasal/oral dryness for comfort • Improves nasal resistance Pressure ramp feature • CPAP starts at lower pressure (2-4 cmH O) and gradually ramps up to 2 prescribed pressure over set time period (5-45 min) Behavioral interventions: • Patient education

• Systematic desensitization and sensory awareness (for claustrophobia) o Wearing device for progressively longer periods • Cognitive behavioral therapy/Motivational Enhancement Therapy Reducing side effects: PROBLEM SOLUTIONS Skin breakdown/irritation • Refit mask • Try nasal pillows Eye irritation • Refit mask • Saline eye drops 61

• Eye mask Mouth leaks • Chin strap • Switch masks Mask leaks/discomfort • Refit or switch masks Nasal congestion • Heated humidification • Nasal saline sprays • Nasal steroids ± decongestants ± antihistamines • Correct any anatomic obstruction Epistaxis • Heated humidifiers and saline Rhinorrhea • Heated humidifier, nasal saline ± antihistamines Aerophagia • Reduce CPAP pressure • Consider APAP, BiPAP Claustrophobia • Switch to nasal pillows • Desensitization Difficulty in exhalation • Ramp feature

• Consider switching to APAP, BiPAP, flexible PAP • Consider re-titration Treatment with oro-dental appliances: useful for mild to moderate cases of OSAS who are not tolerant/ willing to use CPAP treatment • Improve upper airway baseline dimensions o Pulling tongue forward – tongue retaining device o Moving mandible forward – nocturnal airway patient device (NAPA) • Effectiveness of oral appliances o Significantly reduce or completely eliminate snoring o Significantly reduce AHI

o Subjective improvement in daytime function but objective evidence of improvement in sleepiness lacking o Adverse events include excessive salivation, temporo-mandibular joint arthritis, and overall lower compliance (50%) 62

Patient selection for oro-dental appliances: • Factors associated with better response o Younger age o Lower BMI o Lower AHI o Good protrusive range o Presence of adequate healthy denture • However, some studies have demonstrated success even in patients with more severe OSA Surgical treatment for OSAS • Patient selection for surgery depends on o OSA severity o Individual patient anatomy o Patients option for surgery o Presence of co-morbidities • Procedures used for localization of the site of obstruction

o X-ray cephalometry, CT and MR imaging, video endoscopy under sedation and multi channel pressure measurements. • Points of discussion while considering surgical option o Patient’s expectations and preferences o Patient’s expectation regarding cure of their snoring, apnea and symptoms of tiredness. o Presence of co-morbidities o Type of surgery o Pain and complication rates o Expected consequences o Morbidities o Cost o Need for evaluation following surgical procedure and possible need

• Procedure on the upper airway, which may improve PAP use and compliance. o Adeno-tonsillectomy o Nasal surgery for hypertrophied turbinate, deviated nasal septum or nasal polyps. • Surgery that improves OSA without surgically altering the upper airway o Tracheostomy o Bariatric surgery • Surgery that directly alters the upper airway Tracheostomy o Done on a temporary basis in the pre/peri-operative period o Not done routinely because of its associated hygiene and social burden

o Typically reserved for morbidly obese patients who can’t tolerate PAP o Morbidly obese patients with OHS who require upper airway bypass and nocturnal ventilation o Patients who are unable to tolerate PAP with significant co-morbidity Bariatric surgery • Bariatric surgery has a potential to reduce body weight significantly as a significant number of OSA patients are obese. Indications • BMI > 40 • BMI > 35 with significant co-morbidities • Has the advantage of treating other co-morbidities associated

with obesity Surgery that alters the upper airway • Uvulopalatopharyngoplasty (UPPP) • Tongue advancement • Hyoid suspension • Maxilo-mandibular advancement (MMA) 64

ALGORITHM FOR TREATMENT OF OSA & TREATMENT GOALS Mild (AHI >5-15) No symptoms Behavioral modification Symptoms Behavioral modification l Consider oral appliance l Consider PAP l Consider surgical intervention Moderate (AHI >15-30) No symptoms Behavioral modification l Consider PAP l Consider oral appliance l Consider surgical intervention Symptoms Behavioral modification PAP Surgical intervention for PAP failures Consider oral appliance Severe (AHI>30) Symptoms or no symptoms

Behavioral modification (rarely sufficient alone) PAP Surgical intervention for PAP failures l Consider tracheostomy if other treatments fail and significant symptoms or co-morbidities exist l Co-morbidities should also be taken into account when discussing the strength of recommendations l Patients with BMI >35 and co-morbidities or BMI>40 should be considered for bariatric surgery l Interventions should typically be applied in the order listed. Proceed down the list until success is reached. 65

Follow up Follow-up after medical and surgical intervention is critical to ensure that the patient has benefited from the chosen treatment and to provide an opportunity to implement further recommendations in case partial treatment response. v) Referral criteria: Patient should be referred when following are present: • Severe OSAS/OHS having cardio-respiratory failure • Co-morbidities • Overlap syndrome (COPD or ILD with OSAS) • Poor compliance to CPAP treatment • Severe, intractable adverse events

• Refusal for CPAP therapy • Consideration for oro-dental appliances and surgery • Requiring advanced investigations like nasal endoscopy, CT or MRI etc • Patients with complex sleep apnea *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available p) Clinical Diagnosis: Same as mentioned in Situation 1 q) Investigations: Same as mentioned in Situation 1 Level I polysomnography Patients requiring advanced investigations like nasal endoscopy, CT or MRI etc

r) Treatment: Titration and treatment of patients with severe cardio-respiratory failure Treatment and counseling of patients with poor CPAP adherence Oro-dental appliances and surgical treatment Standard Operating procedure 66

As mentioned above VII. WHO DOES WHAT? and TIMELINES a. Doctor Diagnosis and Management including counseling b. Nurse Implementation of orders, monitoring of patients and counseling c. Technician Investigations VIII. FURTHER READING / REFERENCES 1. Kushida CA, Littner MR, Morgenthaler T, Alessi CA, Bailey D, Coleman J Jr, Friedman L, Hirshkowitz M, Kapen S, Kramer M, Lee-Chiong T, Loube DL, Owens J, Pancer JP, Wise M. Practice parameters for the indications for polysomnography and related

procedures: an update for 2005. Sleep. 2005 Apr;28(4):499-521 2. American Academy of Sleep Medicine. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The report of an American Academy of Sleep Medicine task force. Sleep 1999; 22: 667-8 67

RESOURCES REQUIRED FOR ONE PATIENT Situation HUMAN RESOURCES INVESTIGATIONS DRUGS & EQUIPMENT CONSUMABLES 1 1. Physician with 1. Pulmonary 1. Tongue 1. Polysomnography sleep medicine function test retaining machine training 2. Arterial blood gas devices 2. Pulmonary 2. Nurse 3. Thyroid function 2. Nocturnal function test 3. Radiographer test airway machine 4. Laboratory 4. Blood sugar patient 3. Pathology technician 5. Lipid profile device laboratory

5. Biochemist 6. Electrocardiogram 3. CPAP 4. Biochemistry 6. Sleep laboratory 7. Serum insulin machine laboratory technician 8. Echocardiography with 5. Echocardiography 7. Cardiologist/ 9. Polysomnography humidifier machine Physician with 6. ABG analyzer echocardiography 7. Body composition training analyser 2 Above plus Above plus As above Above plus 1. Radiologist 9. X-ray 1. CT scan machine 2. ENT Surgeon cephalometry 2. MRI machine 3. Anesthetist 10. Nasal/oral video 3. Nasal/oral video

4. Bariatric surgeon endoscopy endoscope 11. CT scan 4. Operation theatre 12. MRI scan 5. DEXA scan 68

PLEURAL DISEASES I. WHEN TO SUSPECT/ RECOGNIZE? i) Introduction: There are 4 types of pleural diseases: pleurisy, pleural effusion, pneumothorax and pleural mesothelioma. Pleural mesothelioma is a malignant condition of pleura related to asbestos exposure occurring rather infrequently in our country compared to other lung cancers and is beyond the purview of this review. j) Case definition: For both situations of care: 1. Pleurisy is defined as an acute inflammation of the pleura. The inflammation

can be primary or secondary due to spread from an adjacent structure. Primarily, viral infections of the pleura result in pleurisy. Secondarily, the pleura may be involved due to pneumonia or pulmonary infarction. The present review is restricted to ‘primary’ pleurisy. 2. Pleural effusion is defined as an excessive accumulation of fluid in the lungs. There are mainly two types of pleural effusions: transudative and exudative pleural effusion.

Fundamentally, transudative pleural effusions reflect a systemic pathology and exudative pleural effusions reflect a local pleural pathology. Generally, transudative effusions are usually bilateral, whereas exudative effusions are usually unilateral. The common causes of transudative pleural effusions are congestive heart failure and hypoalbuminemic states (cirrhosis, nephrotic syndrome). The common causes of exudative pleural effusions are tuberculosis,

malignancy and traumatic hemothorax. Uncommon causes include pancreatitis, connective tissue diseases, non-traumatic hemothorax (embolism, malignancy) and chylothorax (tumors, filariasis) 3. Pneumothorax is defined as air in the pleural cavity resulting in collapse of the whole lung or some part of the lung. It may be traumatic or spontaneous. Traumatic pneumothorax can result in a life-threatening condition due to tension pneumothorax. 69

Spontaneous pneumothorax may occur without any associated underlying lung pathology (primary) or may be associated with underlying lung pathology (secondary). The common secondary causes include tuberculosis and chronic obstructive airway disease. Smoking and marfanoid habitus are important risk factors. Secondary pneumothorax is a more critical condition as the underlying lung is already compromised. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY

No systematic robust epidemiological studies are available from India III. DIFFERENTIAL DIAGNOSIS 1. Pleurisy • Cardiac: post-myocardial injury syndrome (Dressler syndrome) • Renal: chronic renal failure 2. Pleural effusion • Amebic liver abscess • Lower lobe collapse • Mass lesion 3. Pneumothorax • Pulmonary embolism • Acute coronary syndrome • Large bulla IV. PREVENTION AND COUNSELING Optimal treatment of primary systemic illness. Abstinence from smoking, alcohol and other substance abuse.

V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital: Optimal Standards of Treatment in Situations where technology and resources are limited 70

w) Clinical Diagnosis Symptoms 1. Pleurisy: sharp pain in the lateral hemithorax characteristically increasing on inspiration and coughing. 2. Pleural effusion: may be asymptomatic or associated with dull aching pain on the affected site. Dyspnea, dry cough may also be present. Symptoms of underlying systemic pathology may be associated. 3. Pneumothorax: sudden onset excruciating pain associated with dyspnea especially in a smoker. Signs 1. Pleurisy: acute history of fever, pleural rub.

2. Pleural effusion: findings of primary systemic disease, local examination reveals decreased tactile fremitus, stony dull note on percussion and absent breath sounds on auscultation. 3. Pneumothorax: marfanoid habitus, local examination reveals decreased tactile fremitus, tympanitic note on percussion and absent breath sounds on auscultation. x) Investigations 1. Pleurisy: No specific investigation per se. Patients with pleurisy normally improve in 7-10 days. 2. Pleural effusion:

Chest X-ray (PA and lateral views of chest radiographs): 50 ml fluid can be appreciated on lateral chest radiograph as a meniscus in the posterior costophrenic angle. Lateral decubitus film helps in differentiating a loculated effusion from a free fluid effusion. Ultrasound: USG helps in confirming a pleural effusion as compared to pleural thickening, which many times cannot be appreciated on a chest radiograph. It is also useful in diagnosing loculated effusions, subpulmonic

and subdiaphragmtic pathology like an amebic liver abscess. Pleural fluid (PF) evaluation 71

Diagnostic thoracocentesis performed with/without US guidance is the investigation of choice to differentiate between a transudative and exudative pleural effusion. This differentiation is the sheet anchor of further management. Colour Pale yellow: transudative Turbid : exudative Frank pus : empyema Blood-like : traumatic tap, hemothorax Milky : chylothorax Biochemistry {Protein and lactate dehydrogenase (LDH)} Light’s criteria have a high (> 98%) sensitivity and specificity to

classify PF. There are 3 criteria as follows: a. PF protein/serum protein> 0.5 b. PF LDH/ serum LDH> 0.6 c. PF LDH> 2/3 upper limit serum LDH Exudative PF: any one of 3 criteria present Transudative: even if one of the 3 criteria are absent pH: normal PF pH is 7.64. Cell cytology for polymorphonuclear or lymphocytic predominance Malignant cytology (if available at secondary level) Bacteriology: Gram stain and culture sensitivity in addition to pH are very

important investigations to decide regarding the management in cases of parapneumonic effusion vis-à-vis empyema. Adenosine deaminase (ADA) levels (if available at the secondary level) Higher ADA levels with lymphocytosis point to a diagnosis of tubercular pleural effusion Hematocrit (Hct): PF hct > 50% blood Hct signifies hemothorax differentiating from a traumatic thoracocentesis 3. Pneumothorax Chest radiograph: collapsed lung at the hilum with absence of lung markings in the periphery.

Important to evaluate the contralateral lung radiographically-normal or abnormal for management. 72

y) Treatment: Standard Operating procedure a. In Patient 1. Pleurisy: symptomatic treatment with non-steroidal inflammatory drugs. If symptoms persist, evaluate for pleural effusion. 2. Pleural effusion Therapeutic thoracocentesis - symptomatic relief of dyspnea (Caveat: not more than 1 litre of pleural fluid should be removed to prevent post thoracocentesis shock and re-expansion pulmonary edema in one sitting) In a transudate, the primary cause has to be managed. Exudative effusions

Tuberculosis: as per Revised National Tuberculosis Control Program (RNTCP) guidelines It needs to be remembered that in cases of suspected empyema, establishing the diagnosis as early as possible after admission is the key. A delay in the institution of ICD even by a few more hours results in more fibrosis and loculations, which further complicate the long term management. At admission, the following criteria help in deciding the plan in these patients PF bacteriology PF pH Chest tube drainage

Culture and/or Gram stain - > 7.2 No Culture and/or Gram stain + < 7.2 Yes Frank pus < 7 Yes 3. Pneumothorax 3.1.Primary spontaneous: Small pneumothorax requires observation. Large pneumothorax requires simple aspiration. If lung does not expand then tube thoracostomy. Secondary spontaneous Tube thoracostomy 3.3.Traumatic 73

3.3.1. Depends on size- simple observation to thoracostomy 3.4.Tension Medical emergency Large bore needle in second intercostal space. If air gushes out, tube thoracostomy b. Out Patient Treatment of primary systemic illness z) Referral criteria: 1. Diagnosis not clear 2. Response to therapy not optimal 3. Recurrent pneumothorax 4. Persistent air leak 5. Unexpanded lung after 3 days of tube thoracostomy *Situation 2: At Tertiary hospital where higher-end technology is available s) Clinical Diagnosis

As in Situation V.1 a) above t) Investigations 10. Pleurisy: As in situation V.1b) above 11. Pleural effusion: As in situation V.1b)2. above PLUS CT scan to accurately define the anatomy of lung parenchyma (lung abscess) and pleura (empyema by the split pleura sign, loculated effusion, pleural masses) Special investigations PF triglyceride > 110 mg/dl for chylothorax PF antinuclear factor for systemic lupus erythematosus (SLE) [specific but not very sensitive] 74

PF Rheumatoid factor and anti-citrullinated protein antibody (anti-CCP) PF amylase for pancreatitis Pleural biopsy Medical thoracoscopy and video-assisted thoracoscopy (also has therapeutic potential) 12. Pneumothorax: as in situation V.1b)3. PLUS Computed tomography to assess for blebs and associated pulmonary disease u) Treatment: Standard Operating procedure a. In Patient 3. Pleurisy: As in situation V.1c)a.1 above 4. Pleural effusion: As in situation V.1c)a.2 above PLUS

Pleurodesis with doxycycline – recurrent malignant pleural effusion Chest tube instilled fibrinolytic therapy (streptokinase) - parapneumonic effusions VATS (thoracotomy, if VATS not available)- non-resolving empyema Pneumothorax as in V.1c)a.3 above PLUS VATS with pleurodesis/bleb resection b. Out Patient Treatment of primary systemic illness VI. WHO DOES WHAT? and TIMELINES a. Doctor: Diagnosis and Management including counseling b. Nurse: Implementation of orders, monitoring of patients and counseling

VII. FURTHER READING / REFERENCES 1. Light RW, MacGregor MI, Luchsinger PC, et al. Pleural effusions: The diagnostic separation of transudates and exudates. Ann Intern Med 1972;77:507-13 2. Colice GL, Curtis A, Deslauriers J, et al. Medical and surgical treatment of parapneumonic effusions: An evidence-based guideline [ACCP consensus statement]. Chest 2000;118:1158-71 5. Baumann, MH, Strange, C, Heffner, JE, et al. Management of spontaneous

pneumothorax: an American College of Chest Physicians Delphi consensus statement. Chest 2001;119:590-602 6. Seaton A. Diseases of the Pleura. In: Seaton A, Seaton D and Leitch AG (editors). Crofton and Douglas's Respiratory Diseases, Fifth Edition. Oxford, UK: Blackwell Science Ltd. 2008.p.1152-81 7. Seaton D. Pneumothorax. In: Seaton A, Seaton D and Leitch AG (editors). Crofton and Douglas's Respiratory Diseases, Fifth Edition. Oxford, UK: Blackwell Science Ltd. 2008.p.1182-211 76

RESOURCES REQUIRED FOR ONE PATIENT Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 8. Physician 10. Chest radiograph 3. Anti-tuberculosis 4. X-ray machine 9. Surgeon 11. Pleural fluid therapy (DOTS) 5. USG machine 10. Nurse examination 4. Intercostal tube 6. Cytopathology 11. Radiographer (total and and 12. Laboratory differential cell histopathology technician count, malignant laboratories cytology, Mtb 7. Microbiology smear and laboratory culture, PCR, service

fungal smear and 8. ABG analyzer culture, protein, 9. ECHO machine LDH, glucose, ADA) 12. USG chest and abdomen 13. Arterial blood gas analysis 14. Echocardiography 15. Blood biochemistry 2 Above plus Above plus Above plus Above plus 14. Radiologist 13. Malignant 11. Streptokinase 6. CT scan machine 15. Pathologist cytology 12. Doxycycline 7. Pleural biopsy 16. Thoracic 14. Pleural fluid needle surgeon triglyceride 8. Immunology 17. Anesthetist 15. Pleural fluid laboratory

18. Nursing staff antinuclear services trained in antibody, anti- 9. Video-assisted assisting CCP antibody thoracoscope thoracic surgery 16. Markers for 10. Thoracic surgery connective tissue operating diseases theatre; 17. Pleural Biopsy recovery room 18. Video-assisted and ICU thoracoscopy 19. CT Scan 77

COMMUNITY ACQUIRED PNEUMONIA (Bacterial) I. WHEN TO SUSPECT/ RECOGNIZE? k) Introduction: Pneumonia, an infection of the pulmonary parenchyma is a commonly encountered, potentially life-threatening condition in clinical practice. In light of the recent pandemics of multidrug-resistant bacterial infections world-over, pneumonia has been categorized as either community-acquired pneumonia (CAP) or health care-associated pneumonia (HCAP). The subcategories of HCAP include

hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). In spite of the availability of potent new antimicrobials, CAP is associated with considerable morbidity and mortality, particularly in elderly patients and those with significant co-morbid illnesses. l) Case definition: For both situations of care: 1. Symptoms and signs consistent with an acute lower respiratory tract infection (productive cough, rusty sputum, pleuritic chest pain, etc.);

presence of at least one systemic manifestations (either a symptom complex of sweating, fever, shivers, aches and pains and/or temperature of >38 oC or more). 2. New focal signs on physical examination of the chest. 3. New chest radiograph evidence of pneumonic consolidation which is at least segmental or present in more than one lobe and is not known to be previously present for which there is no other explanation. 4. Confirmation of aetiological diagnosis by blood culture/sputum culture

and/or molecular diagnostic methods. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY Estimates form the developed world suggests that CAP occurs in 8 to 15 per 1000 persons per year; the highest rates are at the extremes of age. No systematic studies have been carried out till date to define the incidence of CAP in India and reliable epidemiological data are lacking. III. DIFFERENTIAL DIAGNOSIS 78

1. Common • Pulmonary embolism/infarction • Pulmonary oedema • Bronchogenic carcinoma • Pulmonary tuberculosis • Bronchiectasis 2. Uncommon • Pulmonary eosinophilia/eosinophilic pneumonia • Cryptogenic organising pneumonia • Pulmonary alveolar haemorrhage • Foreign body • Congenital pulmonary abnormality (eg. lobar sequestration) • Radiation pneumonitis IV. PREVENTION AND COUNSELING 1. Persons hospitalized with CAP who smoke should be counseled regarding smoking cessation.

2. Respiratory hygiene measures, including the use of hand hygiene and masks or tissues for patients with cough, should be used in outpatient settings and casualty as a means to reduce the spread of respiratory infections V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital: Optimal Standards of Treatment in Situations where technology and resources are limited aa)Clinical Diagnosis Symptoms

The onset of CAP is acute. Patients present with symptoms suggestive of acute lower respiratory tract infection, cough, rusty sputum, pleuritic chest pain, and constitutional symptoms, such as, fevers, sweating, chills, rigors, body aches and pains; temperature of >38 oC or more. Signs 79

Patients with CAP look sick and toxic. New and focal signs of pneumonic consolidation (reduced movements and expansion, increased tactile vocal fremitus, dull note on percussion, tubular bronchial breathing, increased vocal resonance, aegophony and whispering petriloquy; pleural rub) are present on physical examination of the chest. Signs due to complications, such as, pleural effusion, empyema, sepsis syndrome may also be present. bb) Investigations

1. Chest radiograph: A chest radiograph is the cornerstone to establishing the diagnosis of CAP or an alternative diagnosis, and to assess the extent of the disease and the presence of complications such as pleural effusion, lung abscess etc. 2. In all admitted patients: 2. 1. Pulse oximetry: pulse oximtery is useful for assessment of gas- exchange status. 2.2. Sputum Gram’s stain, culture; smear examination for acid-fast bacilli; blood culture. 2.3. Full haemogram.

2.4. Serum biochemistry (blood urea, serum creatinine, liver function tests). 3. Arterial blood gas (ABG) analysis: ABG analysis is helpful in detecting acute respiratory failure that may complicate the course of CAP. 4. Assessment of severity: This is best assessed by CURB-65 scoring system [confusion, urea >7mmol/L, respiratory rate >30/min, blood pressure (systolic <90 mmHg or diastolic <60 mmHg), Age >65yrs] and guides admission to ICU and antibiotics administration. Pneumonia Severity

Index (PSI) a prognostic model to identify those with low risk of death. cc) Treatment: Standard Operating procedure a. In-Patient 1. General therapeutic measures 1. SpO monitoring by pulse oximetry. 2 2. Adequate circulation and blood pressure is ensured using volume infusion and/or vasopressors. 80

3. Decision to admit The decision to admit patients with one or more adverse factors (confusion, respiratory rate > 30/min; systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg; age more than 65 years) without severity factors (hypoxaemia, bilateral or multilobar involvement on chest radiograph) should be individualized. Patients with one or more severity factors listed above need hospitalization Admission into an ICU: for patients with septic shock requiring

vasopressors or with acute respiratory failure requiring intubation and mechanical ventilation, direct admission into ICU will be required. Admission to an ICU is also recommended for patients with 3 of the following minor criteria for severe CAP: respiratory rate >30 breaths/min; PaO /FIO ratio£ 250; multilobar infiltrates; confusion/ disorientation; 2 2 uraemia (blood urea nitrogen level >20 mg/dL); leukopenia (total leukocyte count, < 4000 cells/mm3), thrombocytopenia (platelet count

<100,000/mm3), hypothermia (core temperature <36oC); and hypotension requiring aggressive fluid resuscitation. 4. Antibiotic treatment of the aetiological cause of CAP In-patient antibiotic therapy 4.1.1 In-patients, non-ICU treatment When admitted, these patients are treated with intravenous beta- lactam plus macrolide (Table 1 ). Table 1 Choice of antibiotics for in-patient treatment of CAP Choice of drug Daily dosage Intravenous beta-lactam Macrolide First choice Cefotaxime 2 g q8h Azithromycin 500 mg qd

Second choice Ceftriaxone 1 g q12h Third choice Co-amoxyclav 1.2 g q8h Duration of antibiotic therapy is 7 to 10 days based on clinical response 81

A switch to oral therapy can be made at 48-72 hours as most patients with CAP will have an adequate clinical response within 3 days, which includes improvement in cough and dyspnoea, absence of fever, decreasing white blood cell count and functioning gastrointestinal tract with adequate oral intake. Patient may be discharged on the same day if medical and social factors are favorable. 4.5. Pleuritic pain should be relieved using drugs such as paracetamol. 2. Supplemental oxygen therapy

In patients with hypoxaemia, spontaneous ventilation using a face mask with a high flow gas delivery system can be used to deliver a FIO of up to 2 0.5 to 0.6. b. Out Patient Out-patient antibiotic therapy The choice of antibiotics for out-patient treatment of CAP is as follows. For previously healthy patients and those who have not used antimicrobials within the previous 3 months, treatment with oral macrolide (e.g., azihtromycin) is indicated. For patients with comorbidities such as chronic

heart, lung, liver or renal disease, diabetes mellitus, alcoholism, malignancies, asplenia, immunosuppressing conditions or use of immunosuppressing drugs, or use of antimicrobials within the previous 3 months, and patients in regions with a high rate (>25%) of infection with high-level [minimum inhibitory concentration (MIC) ‡16 mg/mL] macrolide- resistant Streptococcus pneumoniae, oral treatment with co- amoxyclav in combination with macrolide is recommended. dd) Referral criteria:

1. Patients presenting with two or more adverse factors (confusion, respiratory rate> 30/min; systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg; age more than 65 years) or one or more severity factor (hypoxaemia, bilateral or multilobar involvement on chest radiograph). 82

2. Diagnosis not clear. 3. Patients not responding to therapy *Situation 2: At Tertiary hospital where higher-end technology is available v) Clinical Diagnosis As in situation V.1 a) above w) Investigations As in situation V.1b) above PLUS 13.Two blood cultures (minimum 20 ml) 14. Sputum or other respiratory tract specimen for Gram stain, bacterial culture and sensitivity tests; molecular diagnostic methods (e.g., polymerase chain reaction for respiratory pathogens)

15. Pleural fluid, if present, for microscopy, culture and pneumococcal antigen detection. 16. Investigations for Legionella pneumonia: Urine for Legionella antigen Sputum or other respiratory tract specimens (for Legionella culture and direct immunofluorescence) (if available) 5. Investigations for atypical bacterial pathogens: 5.1 If available, sputum or other respiratory sample for PCR or direct immunofluorescence (or other antigen detection test) for Mycoplasma

pneumoniae, Chlamydia spp, Pneumocystis jirovecii (if at risk) 6. Imaging studies: ultrasonography of the chest is useful for detecting complications such as pleural effusion, empyema. In non-responders, computed tomography of the chest can help in detecting an underlying malignancy and complications, such as, lung abscess. 7. Bronchoscopic procedures: should selectively be used in individual patients for aetiological confirmation and ruling out an alternative diagnosis, such as, malignancy. x) Treatment:

Standard Operating procedure a. In Patient As in situation V.1c)a.1 above PLUS 83

1. General therapeutic measures Patients should be assessed for volume depletion and may require intravenous fluids. Prophylaxis of venous thromboembolism with low molecular weight heparin should be considered for all patients who are not fully mobile. Nutritional support should be given during prolonged illness. Airway clearance techniques should be considered if the patient has sputum and difficulty in expectoration or in the event of a pre-existing lung condition. 2 Antibiotic therapy

As described under V.4 above PLUS In-patients, ICU treatment • A beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus azithromycin are recommended. • For penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are recommended. • If Pseudomonas is a consideration, an antipseudomonal beta-lactam (e.g., piperacillin tazobactam, cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin (750 mg) are recommended. or

The above beta-lactam plus an aminoglycoside and azithromycin or The above beta-lactam plus an aminoglycoside and an antipseudomonal fluoroquinolone are recommended. • For penicillin-allergic patients, aztreonam may be substituted for above beta-lactam) • Prior to use of respiratory fluoroquinolones, active pulmonary tuberculosis should be excluded. • If community acquired methicillin-resistant Staphylococcus aureus is a consideration, vancomycin or linezolid can be added. 2. Supplemental oxygen therapy

All patients should receive appropriate oxygen therapy with monitoring of oxygen saturation and inspired oxygen concentration with the aim to maintain PaO at 60 2 mm Hg or above and SpO between 94%–98%. 2 84

High concentrations of oxygen can safely be given in patients who are not at risk of hypercapnic respiratory failure. Oxygen therapy in patients at risk of hypercapnic respiratory failure complicated by ventilatory failure should be guided by repeated ABG measurements. 3. Ventilatory support Patients with CAP who develop acute respiratory failure require mechanical ventilation for maintaining gas exchange with minimal complications. 4. Management of complications Parapneumonic effusion/empyema

Early thoracocentesis is indicated for all patients with a parapneumonic effusion. Patients found to have an empyema should have effective pleural fluid drainage and appropriate antibiotic therapy. Streptokinase may be instilled if loculation(s) present. Lung abscess This condition is described in detail in another chapter b. Out Patient Not applicable. VI. WHO DOES WHAT? and TIMELINES a. Doctor: diagnosis and management including counseling b. Nurse: implementation of orders, monitoring of patients and

counseling c. Technician: investigations VII. FURTHER READING / REFERENCES 1. Lim WS, Baudouin SV, George RC, Hill AT, Jamieson C, Le Jeune I, Macfarlane JT, Read RC, Roberts HJ, Levy ML, Wani M, Woodhead MA; Pneumonia Guidelines Committee of the BTS Standards of Care Committee. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax 2009;64 Suppl 3:iii1-55. 2. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et

al; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44 Suppl 2:S27-72. 85

3. Postgraduate Institute of Medical Education and Research Chandigarh: practice guidelines for management of community and hospital-acquired pneumonias - a consensus statement. Lung India 2006;23:115-20. RESOURCES REQUIRED FOR ONE PATIENT Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 1.Physician 1. Chest X-ray 1. Oral and i.v. 1. X-ray machine 2.Nurse 2. USG chest antibiotics 2. USG machine 3.Radiographer 3. Pulse oximetry 2. Streptokinase 3. Pulse oximeter

4. Laboratory 4. ABG 4. ABG machine technician 5. Serum biochemistry 5. Oxygen cylinders 6. Hemogram 6. Nebulizers 7. Sputum smear and 7. Microbiology culture laboratory services 8. Sputum for AFB 8. Hematology and 9. Blood culture biochemistry 10. HIV ELISA for high laboratory services risk group 2 Above plus Above plus Above plus Above plus 1.Intensivist 1.CT chest 1.Oxygen supply 1.CT machine 2.Bronchoscopy 2.Tubes and other 2.Bronchoscope 2. Nurse and disposables for and facilities for

technician for thoracocentesis (when bronchoscopy assisting with indicated) 3.Clinical pathology bronchsocopy laboratory service 4.Microbiology 3. Nursing staff service with trained in ICU care conventional, serological and molecular 4. Pathologist diagnostic facilities for aetiological diagnosis confirmation 5. ICU 6. Noninvasive and invasive ventilators 86

PULMONARY HYPERTENSION I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: The diagnosis of pulmonary hypertension requires strong clinical suspicion in practice. It is usually found secondary to various systemic causes, the list of which is long but the usual causes include the rheumatic heart disease, and diseases of the respiratory system, including the obstructive airway diseases and the diffuse parenchymal pulmonary diseases. Dilation and hypertrophy of the right ventricle

develops in response to diseases of the pulmonary vasculature and/or lung parenchyma, which is known as cor pulmonale. Pulmonary hypertension may also occur as primary idiopathic disease due to the mutation of certain genes, such as BMPR-2. b) Case definition: Secondary hospital: presence of a pulmonary artery systolic pressure more than 40 mmHg at rest, calculated by the tricuspid velocity jet by trans-thoracic echocardiography.

Super-speciality hospital: presence of a mean pulmonary artery pressure (PAP) of more than 25 mmHg at rest, pulmonary capillary wedge pressure < 15 mmHg, accompanied by increased pulmonary vascular resistance (PVR) (more than 160 dynes/s/cm5), by right heart catheterisation. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY No systematic studies till date to define the incidence of pulmonary hypertension in our country III. DIFFERENTIAL DIAGNOSIS 1. Pulmonary artery hypertension (PAH) Idiopathic Heritable

ALK1, endoglin (with or without hereditary haemorrhagic telangiectasia) a) Drugs: aminorex, fenfluramine, dexfenfluramine, cocaine, phenylpropanolamine, amphetamines, L- tryptophan, methamphetamines, chemotherapeutic agents, fluoxetine, pergolide, oral contraceptives, oestrogen b) Toxins: toxic rapeseed oil Associated with (APAH) Connective tissue diseases HIV infection Portal hypertension Congenital heart disease Chronic haemolytic anaemia: sickle cell anaemia Schistosomiasis

1* Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis 2. Pulmonary hypertension due to left heart disease Systolic dysfunction Diastolic dysfunction Valvular heart disease 3. Pulmonary hypertension due to lung diseases and/or hypoxia Chronic obstructive pulmonary disease (COPD) Diffuse parenchymal lung disease (DPLD) Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep related breathing disorders (SRBDs) Alveolar hypoventilation disorders

Chronic exposure to high altitude Developmental abnormalities 88

4. Chronic thrombo-embolic pulmonary hypertension 5. Pulmonary hypertension with unclear and/or multifactorial mechanisms Haematological disorders: myeloproliferative disorders, splenectomy. Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis Metabolic disorders: glycogen storage disease, Gaucher’s disease, thyroid disorders Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

IV. PREVENTION AND COUNSELING Early diagnosis by strong clinical suspicion in clinical settings, and appropriate treatment of the underlying cause. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited ee) Clinical Diagnosis: Patient presents with dyspnoea on exertion, fatigue, chest pain, palpitations,

syncope, and lower extremity oedema. Examination reveals raised jugular pressure, left parasternal lift, right ventricular S , accentuated P , early systolic 4 2 click, midsystolic ejection murmur or early diastolic murmur at pulmonary area (Graham Steell) ff) Investigations: To confirm pulmonary hypertension, and determining the underlying cause. • Electrocardiogram • Chest radiograph • Trans-thoracic 2-D Doppler echocardiography 89

• Pulmonary function test • Arterial blood gas analysis gg) Treatment: General measures • Avoid heavy physical exertion or isometric exercise • Sodium restricted diet (less than 2.5 g per day) • Annual immunization against influenza • Avoid pregnancy (female patients) • Anticoagulants : idiopathic/chronic thrombo-embolism • Diuretics • Long-term oxygen supplementation to maintain oxygen saturation > 90% Specific treatment • Treat the underlying cause of pulmonary hypertension

• Pulmonary hypertension-specific agents (cid:216) Sildenafil* *20 mg 24 hourly gradually increased upto 20 mg 8 hourly with careful blood pressure monitoring. The drug can be used in PAH secondary to connective tissue diseases, chronic pulmonary thromboembolism and idiopathic pulmonary artery hypertension. hh) Referral criteria: • Diagnosis not confirmed with echocardiography and patient requires right heart catheterisation • Underlying cause not clear, before labelling as idiopathic pulmonary artery

hypertension • Worsening clinical condition of the patient • Suspected thrombo-embolism *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available y) Clinical Diagnosis: Same as level 1 90

z) Investigations: Same as level 1, in addition • CT pulmonary angiography (CTPA) • Ventilation-perfusion scan • Multi-detector CT chest • Overnight supervised polysomnography • Connective tissue disease work up : ANA/RF/ANCA/ anticentromere antibodies • HIV ELISA, CD4 count, plasma viral load (screening for pulmonary hypertension not indicated routinely in ART clinics) • Functional tests : 6-minute-walk test, cardio-pulmonary exercise test • Right heart catheterization with acute vasodilator testing

aa) Treatment: Same as level 1, in addition • Pulmonary hypertension-specific agents (cid:216) Calcium channel blockers (only in patients with positive acute vasodilator test) (cid:216) Sildenafil* 20 mg 24 hourly gradually increased upto 20 mg 8 hourly with blood pressure monitoring (cid:216) Bosentan* 62.5 mg 12 hourly for 4 weeks, followed by 125 mg 12 hourly (monitor liver functions monthly) * These drug can be used in PAH secondary to connective tissue diseases,

chronic pulmonary thrombo-embolism and idiopathic pulmonary artery hypertension. 91

Surgical intervention • Pulmonary thrombo-endarterectomy for chronic thrombo-embolic pulmonary hypertension • Atrial septostomy • Lung and combined heart-lung transplantation (for refractory cases) VI. WHO DOES WHAT? and TIMELINES a. Doctor Screening, diagnosis, treatment and follow-up b. Nurse Investigations and follow-up c. Technician Investigations VII. FURTHER READING / REFERENCES 1. Badesch DB, Abman SH, Simonneau G, et al. Medical therapy for pulmonary artery

hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. 2007;131:1917–28. 2. Vallerie V. McLaughlin, Stephen L. Archer, David B. Badesch. ACCF/AHA Expert Consensus Document on Pulmonary Hypertension. J. Am. Coll. Cardiol.2009; 53; 1573- 1619. 3. Galie N, Manes A, Negro L, et al. A meta-analysis of randomized controlled trials in pulmonary artery hypertension. Eur Heart J. 2009;30:394–403. 4. Christopher J Ryerson, Shalini Nayar, John R Swiston, Don D Sin. Pharmacotherapy in

pulmonary artery hypertension: a systematic review and meta-analysis. Respiratory Research 2010, 11:12. 5. McLaughlin VV, McGoon MD. Pulmonary artery hypertension. Circulation. 2006;114:1417–31. 6. Simonneau G, Robbins I, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine S, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009; 54:S43–S54.

7. Guidelines for the diagnosis and treatment of pulmonary hypertension. The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). European Heart Journal (2009) 30, 2493–2537. doi:10.1093/eurheartj/ehp297 92

RESOURCES REQUIRED FOR ONE PATIENT Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 1.Physician 1.Electrocardiogram Sildenafil 1.X-ray machine 2.Nurse 2.Chest X-ray 2.ECG machine 3.Radiographer 3. Trans-thoracic 2-D 3.ECHO machine 4.Lab technician echo 4.Spirometer along 5.Physician with 4. Arterial blood gas with 6-MWT facility training in analysis 5.ABG analyzer echocardiography/ 5. Pulmonary function cardiologist test 2 Above plus Above plus Above plus

1.Contrast-enhanced 1.Sildenafil 1. USG with Doppler 1.Radiologist CT chest, High- 2.Calcium channel machine resolution CT chest blockers 2. CT machine 2. Physician with sleep for underlying 3.Bosentan 3.Sleep laboratory medicine training pulmonary 4.Rheumatology parenchymal disease, laboratory service with 3. Cardiologist CTPA (CT pulmonary facilities for connective angiography) tissue disorders work- 4. Cardiothoracic and 2.Ventilation- up vascular surgeon perfusion scan 5.Cardiopulmonary

3.Overnight exercise testing 5. Microbiologist polysomnography laboratory 4.Connective tissue 6.Cardiac 6. Nursing staff for OT, disease work up : catheterization catheterization ANA/RF/ANCA/ laboratory laboratory anticentromere antibodies 7. ICTC centre for HIV 7. Technician for sleep 5. HIV ELISA*, CD4 testing, facilities for laboratory count, plasma viral CD4 cell counts, load plasma viral load 8. Technician for 6. Functional tests : 6- estimation clinical laboratory minute-walk test,

services cardio-pulmonary 8. CTVS operating 9. Nuclear Medicine exercise test theatre, recovery room expert 7. Right heart and post-op facilities catheterization with acute vasodilator testing 93

SARCOIDOSIS I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Sarcoidosis is a systemic disorder of unknown origin characterized by granulomatous inflammation in a variety of organs, most commonly the lungs. It affects people of all racial and ethnic groups. Sarcoidosis cases are increasingly being reported from India since the second half of the last century. The accurate diagnosis of sarcoidosis and the ability to differentiate it from tuberculosis are

challenges to physicians especially in countries with high prevalence of tuberculosis. b) Case definition (for both situations of care): Patients with sarcoidosis may present to different specialties as sarcoidosis is a multiorgan disorder. The clinical feature may vary depending on the ethnicity, duration of illness, site and extent of organ involvement and activity of the granulomatous process. Lung manifestations are seen in almost all (> 90%)

patients. Predominant pulmonary symptoms (30-50%) include dry cough [Indian patients experience frequent exacerbation (especially dry cough and wheezing) with seasonal change], dyspnea and chest pain. Organs other than lungs, usually involved in sarcoidosis include skin (macules, papules, plaques, erythema nodosum and rarely lupus pernio), joints (arthralgias more common than arthritis), eye (anterior and posterior uveitis), liver and spleen

(granulomatous hepatitis, hepatic cirrhosis and portal hypertension), peripheral lymph nodes, parotid, salivary glands (commonly parotid, rarely lacrimal and submandibular glands), nervous system [cranial nerve palsies (facial nerve involvement being commonest), headache, ataxia, cognitive dysfunction, weakness and seizures), heart (conduction blocks, tachy- and brady- arrhythmias cardiomyopathy with or without congestive cardiac failure, and sudden death),

kidney (hypercalciuria more common than hypercalcemia, and renal failure) and. Sarcoidosis is an unusual cause of fever of unknown origin. Constitutional symptoms such as fever, night sweats, fatigue and weakness, anorexia and weight loss are found to be more common in Indian patients. Many asymptomatic patients (30-50%) are discovered when a chest radiograph is obtained for screening purposes. Tuberculin skin testing frequently reveals anergy. 94

II) Incidence of the condition in our country The true burden of sarcoidosis in India is not clearly known as systematically documented reliable epidemiological data are not available. In general, at a secondary level hospital, 1-2 cases per month and at a specialty hospital, 1-3 cases per week are likely to be seen. III) Differential Diagnosis from other granulomatous diseases (as below) 1. Diseases due to Infective agents a) Mycobacterial i.Tuberculosis ii.Atypical mycobacterial infection b) Fungal

i. Histoplasmosis ii. Coccidiodomycosis c) Bacterial i. Brucellosis ii. Chlamydia infection iii. Tularemia d) Parasitic i. Leishmaniasis ii.Toxoplasmosis 2. Diseases due to exposure of organic or inorganic agents a) Chronic hypersensitivity pneumonitis (Farmer’s lung) b) Pneumoconiosis (especially silco-tuberculosis) c) Talc d) Granulomatous diseases related to metals i. Titanium ii. Aluminium iii. Zirconium iv. Chronic beryllium disease e) Methotrexate pneumonitis 3. Neoplasia a) Lymphoma

b) Tumour-related granuloma 4. Autoimmune disorder a) Granulomatous vasculitis (Wegener’s) 95

b) Primary biliary cirrhosis c) Churg-Strauss syndrome IV) Prevention and counseling Sarcoidosis is considered as a benign disease with a tendency to wax and wane either spontaneously or in response to treatment. It has been reported that 60-70% of patients have spontaneous remission and 10-30% of patients have a chronic course. Permanent sequelae are observed in 10-20 % of patients. V) OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA

*Situation 1: At Secondary Hospital: Optimal Standards of Treatment in Situations where technology and resources are limited a) Diagnosis Secondary hospital 1. History (occupational and environmental exposure; symptoms) 2. Physical examination with emphasis on lung, skin, eye, liver, heart, nervous system and salivary glands 3. Peripheral blood counts (white blood cells, red blood cells, platelets) 4. Serum chemistry (calcium, liver enzymes, creatinine, blood urea nitrogen and angiotensin converting enzyme)

5. Urine analysis (routine and 24-hr urinary calcium) 6. Chest radiograph (postero-anterior view) 7. Abdominal ultrasound 8. Tuberculin skin test 9. Spirometry 10.Electrocardiogram (ECG) 11.Biopsy of superficial organs (e.g. skin, lymph nodes) A provisional diagnosis of sarcoidosis can be made based on clinic-radiographic findings with a negative tuberculin skin test result. Sarcoidosis is a possibility when chest radiograph shows bilateral hilar adenopathy in an asymptomatic

patient. In some cases, erythema nodosum and bilateral hilar adenopathy on chest radiographs with fever and arthritis (Lofgren syndrome) suggests sarcoidosis. The diagnosis can be established when clinic-radiographic findings are supported by histological evidence of non-caseating granulomatous inflammation in one or more of the involved organs; other causes of granulomas should be excluded. A diagnosis of sarcoidosis is reasonably certain without biopsy in patients who

present with Löfgren's syndrome. In all other cases, a biopsy specimen should be 96

obtained from the involved organ that is most easily accessed, such as the skin, peripheral lymph nodes, lacrimal glands, or conjunctiva. If diagnosis requires pulmonary tissue, transbronchial biopsy by means of bronchoscopy has a diagnostic yield of at least 85% when multiple lung segments are sampled. If biopsy of a deep organ is required, the patient may require referral to a specialty hospital. *Situation 2: At Tertiary hospital where higher-end technology is available

In addition to the investigations suggested under secondary hospital, the following investigations should be available at the super-specialty hospital. 1. Contrast enhanced and high resolution chest tomography. 2. 18F-fluorodeoxyglucose positron-emission tomography (18FDG PET-CT) may be useful in assessing the extent of organ involvement and in pinpointing the candidate organ(s) for diagnostic biopsy. 3. Pulmonary function tests [spirometry, lung volumes, carbon monoxide

diffusing capacity (DLCO), and 6-min walk test (6MWT) 4. Arterial blood gas analysis 5. Biopsy to obtain histological confirmation of non-caseating granulomas (with special stains and cultures to exclude tuberculosis, fungal diseases and malignancy) 6. Fibreoptic bronchoscopy including endobronchial and transbronchial lung biopsy and bronchoalveolar lavage to rule out infectious etiology 7. Ophthalmic evaluation with slit-lamp examination

8. Other tests depending on clinical presentation and suspicion of extrathoracic disease 9. Mediastinoscopy, video-assisted thoracoscopic surgery (VATS), open lung biopsy c) Treatment Secondary hospital Asymptomatic patients with normal lung function and patients with minimal, well tolerated symptoms, mild functional abnormalities and with chest X-ray stage 1 should be observed without treatment because of the potential for spontaneous

improvement. These patients require treatment only if symptom develops or lung function deteriorates. Patients with symptoms and with chest X-ray stages 2 to 4 can be treated with corticosteroids. Pulmonary sarcoidosis is treated with 97

prednisolone (30-40 mg/day, gradually tapered to 5-10 mg/day over 2-3 months; Indian patients don’t require higher dosages). Treatment should be continued for a minimum duration of 12 months. Patients with cough alone can be treated with inhaled corticosteroids. Topical steroids have also been found to be useful in some patients with skin sarcoidosis, nasal involvement, or uveitis. Hydroxychloroquine should be added in patients with cutaneous and joints

manifestations. Sarcoidosis patients with multi-organ involvement, requiring further investigations and alternate forms of treatment can be referred to a tertiary care super specialty hospital. Super-specialty hospital In addition to the treatment recommended for patients at secondary hospital, patients with severe ocular disease, neurosarcoidosis, cardiac sarcoidosis and malignant hypercalcaemia require treatment with oral corticosteroids as the first-

line treatment. Several patients (~25%) relapse after discontinuation of corticosteroid therapy and some with frequent relapses may require indefinite therapy. Patients with sarcoidosis requiring long-term corticosteroids therapy and those with comorbidities e.g. diabetes, hypertension and who suffer from major side- effects of steroids can be offered steroid-sparing alternative treatments. Relapses of sarcoidosis may also require alternate steroid sparing drugs. Prednisolone

requirement has been found to be considerably reduced in patients receiving methotrexate (5-15 mg weekly) for six months. Folic acid 1 mg/day may reduce toxicity of methotrexate. Other cytotoxic drugs for sarcoidosis are azathioprine (50-200 mg/day) and cyclophosphamide (50-150 mg/day). The antimalarial drugs chloroquine and hydroxychloroquine (200-400 mg/day for 6 months) have been found to be useful in lupus pernio, nasal sarcoidosis, disfiguring skin sarcoidosis

and hypercalcaemia. As hydroxychloroquine is found to be less toxic, it can be used for prolonged periods without retinal damage. Hydroxychloroquine has also been reported to be useful in chronic pulmonary sarcoidosis and also in neurosarcoidosis failed on corticosteroid treatment. Refractory sarcoidosis can be treated with infliximab intravenously 3-5 mg/kg (2wkly for 2 doses initially and later on 3-10mg/kg every 4-8 wkly VI) WHO DOES WHAT? and TIMELINES

b. Nurse Implementation of orders, monitoring of patients and counseling c. Technician Investigations VII) FURTHER READING / REFERENCES 1. Baughman RP, Culver DA, Judson MA. A concise review of pulmonary sarcoidosis. Am J Respir Crit Care Med 2011; 183: 573-81. 2. Gupta D, Sharma OP. Sarcoidosis. In: Textbook of Pulmonary and Critical Care Medicine. M/s Jaypee Publishers, N. Delhi 2011 pp.1188-1216. 3. Jindal SK, Gupta D, Aggarwal AN. Sarcoidosis in India: Practical issues and difficulties

in diagnosis and management. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19:176-84. 4. Hunninghake GW, Costabel U, Ando M, Baughman R, Cordier JF, du Bois R et al. ATS/ERS/WASOG Statement on Sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16:149-73. 5. Sharma SK, Mohan A. Sarcoidosis: Global scenario and Indian perspective. Indian J Med Res 2002; 116:221-47. 6. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007; 357:2153-65

7. Dempsey OJ, Paterson EW, Kerr KM, Denison AR. Sarcoidosis. BMJ 2009; 339:b3206 8. Holmes J, Lazarus A. Sarcoidosis: extrathoracic manifestations. Dis Mon 2009; 55: 675- 92. 9. Sharma SK, Soneja M, Sharma A, Sharma M, Hari S. Rare manifestations of sarcoidosis. Ind J Med Res 2012 (in press) 99

RESOURCES REQUIRED FOR ONE PATIENT Situation HUMAN RESOURCES INVESTIGATIONS DRUGS & EQUIPMENT CONSUMAB LES 1 1. Physician 1. Chest X-ray Oral 1.X-ray machine 2.Nurse 2. Hemogram, serum corticosteroi 2.Spirometer 3.Laboratory chemistry ds 3.EKG machine technician 3. Serum ACE levels 4. Clinical laboratory 4.Pulmonary function 4.Pulmonary function tests services including test technician 5.Electrocardiogram serum ACE levels 5.Radiographer 6. Tuberculin skin test Tuberculin 5. ABG analyzer

7. ABG analysis PPD, 6. ECHO machine 8. 2D-Echo syringes 2 As above plus Above plus Above plus Above plus 1.Interventional 1.Contrast-enhanced CT methotrexat 1.CT machine radiologist, chest and e, 2.Bronchoscope 2.Thoracic surgeon High-resolution CT chest for hydroxychl 3.Pathology service 3.Anaesthetist underlying pulmonary oroquine, for interpretation of 4.Pathologist parenchymal disease azathioprine histopathological 5.Nuclear medicine 2.Tissue biopsies , specimens

expert 3.Ophthalmic evaluation cyclophosp 4.Ophthalmic 6.Opthalmologist 4.PET-CT scan (if available) hamide, evaluation setup 7. Nursing staff trained 5.Mediastinoscopy, VATS infliximab including slit lamp in assisting thoracic examination surgery 5.Nucelar medicine facility for PET-CT (if available) 6.Mediastinoscope 7.Video-assisted thoracoscope 100

RESPIRATORY FAILURE I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: The respiratory system performs the vital function of gas exchange. Respiratory failure results when the respiratory system fails in one or both of its gas exchange functions of oxygenation and carbon dioxide elimination. Depending on the rapidity of development, respiratory failure can also be classified into (i) acute; (ii) acute on chronic; and (iii) chronic respiratory failure. Acute respiratory distress

syndrome (ARDS) is a special type of acute respiratory failure and has been dealt with in a separate chapter and will not be discussed in this chapter. b) Case definition: For both situations of care (mentioned below*) Based on the arterial blood gas (ABG) analysis, respiratory failure may be classified as (i) type I (hypoxaemic) respiratory failure; and (ii) type II (hypercapnic) respiratory failure. Type I respiratory failure is characterized by

arterial oxygen tension (PaO ) less than 60 mm Hg with a normal or low partial 2 pressure of arterial carbon dioxide (PaCO ). Type II respiratory failure is 2 characterized by arterial hypoxaemia (PaO less than 60 mm Hg) and a PaCO 2 2 greater than 50 mm Hg. Acute respiratory failure develops over minutes to hours; chronic respiratory failure develops over several days or longer. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY No systematic studies have been carried out till date to define the incidence of

acute or chronic respiratory failure in India and reliable epidemiological data are lacking. III. DIFFERENTIAL DIAGNOSIS Even though, several conditions (e.g., bilateral diaphragmatic paralysis, obstructive sleep apnoea) may mimic respiratory failure clinically, ABG analysis is essential for establishing a diagnosis of respiratory failure. 101

IV. PREVENTION AND COUNSELING 1. Optimal treatment of underlying diseases that can result in respiratory failure. 2. Abstinence from smoking, alcohol and other substance abuse drugs. 3. Early diagnosis by a high index of clinical suspicion in relevant clinical settings and institution of appropriate treatment of the underlying cause. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital: Optimal Standards of Treatment in

Situations where technology and resources are limited The following clinical scenarios raise the suspicion of respiratory failure. However, ABG analysis is eventually required to diagnose respiratory failure. a) Clinical Diagnosis Acute respiratory failure Symptoms Symptoms at presentation in patients with acute respiratory failure can be due to hypoxaemia, hypercapnia and the manifestations due to the aetiological cause. 1. Manifestations of hypoxaemia

Acute onset hypoxaemia results in dyspnoea, irritability, impaired intellectual function, altered sensorium, progressing convulsions, coma and death Cardiac arrhythmias may develop especially if there is dyselectrolytaemia or if the patient is also receiving diuretics or digitalis 2. Manifestations of hypercapnia Patient with rapidly developing hypercapnia often manifests irritability, confusion and somnolence. The skin may be warm and flushed Tachycardia may be present The peripheral pulse may be bounding

Increased cerebral blood flow and intracranial tension may manifest as papilloedema Asterixis, tremor, myoclonic jerks, and seizures may also develop 102

Coma may ensue 3. Manifestations due to aetiological cause Patients presenting with pneumonia may present with a history of a febrile illness, cough and sputum production. When acute respiratory failure develops in the setting of human immunodeficiency virus (HIV) infection, or organ transplantation, Pneumocystis pneumonia, bacterial and fungal pneumonias constitute important treatable causes of acute respiratory failure. 3.3. In persons with acquired immunodeficiency syndrome (AIDS),

paradoxical worsening of opportunistic infections, termed immune reconstitution inflammatory syndrome (IRIS) has been described shortly after the initiation of highly active antiretroviral therapy (HAART). A history of poisoning with substances such as organophosporus pesticides, sedatives, hypnotics, and other drugs with potential for causing respiratory depression may sometimes be evident. In the setting of sepsis syndrome, trauma, pancreatitis, onset of acute

respiratory failure may indicate development of ARDS (also known as non- cardiogenic pulmonary oedema) Signs 1. Physical examination of the respiratory system may reveal localising clues in patients with conditions such as pneumonia, pulmonary oedema, asthma, or chronic obstructive pulmonary disease (COPD). 2. Central cyanosis, tachycardia and peripheral vasodilatation may be evident. 3. Presence of pulsus alternans, evidence of left atrial hypertension in the

form of left parasternal heave, loud pulmonary component of the second heart sound, gallop rhythm, cardiac murmurs, clicks, rub, may point to cardiogenic pulmonary oedema as the cause of respiratory failure, while their absence may point to ARDS. 4. Areflexic flaccid quadriparesis in a febrile patient should arouse a suspicion of acute anterior poliomyelitis. 5. Ascending paralysis suggests a possibility of acute inflammatory demyelinating polyneuropathy (AIDP).

6. Trismus, muscle spasms suggest a possibility of tetanus. 7. Acute respiratory failure requiring mechanical ventilation due to myasthenic crisis may be the first manifestation of myasthenia gravis. 103

Chronic respiratory failure Symptoms Symptoms at presentation in patients with chronic respiratory failure can be due to hypoxaemia, hypercapnia and the manifestations due to the aetiological cause 1. Manifestations of chronic hypoxemia When it develops gradually, hypoxaemia is surprisingly well tolerated and dyspnoea on exertion may be the only complaint. Patients with chronic respiratory failure due to interstitial lung disease, pneumoconiosis, fibrosing alveolitis often complain of progressively

worsening dyspnoea. 2. Manifestations of chronic hypercapnia Headache on waking up in the morning may be a common complaint. Signs 1. The skin may be warm and flushed 2. Tachycardia may be present 3. Peripheral pulse may be bounding. 4. Increased cerebral blood flow and intracranial tension may manifest as papilloedema. 5. Asterixis, tremor, myoclonic jerks, and seizures may also develop. 6. Central cyanosis and signs of cor-pulmonale may also be evident.

7. Kyphoscoliosis, thoracic cage abnormalities, findings suggestive of underlying causes such as hypothyroidism, motor neuron disease or muscular dystrophy may be present. b) Investigations 1. Pulse oximetry: pulse oximetry helps in detecting arterial hypoxemia 2. Chest radiograph: chest radiograph can help in identifying cause of respiratory failure and ruling out other causes such as pneumothorax. 3. Echocardiography: useful in differentiating acute respiratory failure from cardiogenic pulmonary oedema.

4. ABG analysis: ABG analysis is necessary to confirm the diagnosis of respiratory failure 104

c) Treatment: Standard Operating procedure a. In Patient General therapeutic measures 1. SpO monitoring by pulse oximetry 2 2. Treatment of the aetiological cause of acute respiratory failure (e.g., antibiotics for bacterial pneumonia). 3. In acute exacerbation of COPD, nebulized beta-2 agonists, ipratropium and parenteral corticosteroid administration. Supplemental oxygen therapy Acute type I respiratory failure 1. Initially, spontaneous ventilation using a face mask with a high flow

gas delivery system can be used to deliver a FiO of up to 0.5 to 0.6. 2 2. Continuous positive airway pressure (CPAP) may be added to improve PaO without increasing FIO . 2 2 Acute type II respiratory failure 1. In patients with type II respiratory failure, high flow oxygen therapy can be detrimental. Controlled oxygen delivery can be administered through nasal prongs at 1 to 1.5 L/min or by a Venturi mask with the flow set to deliver 24% to 28% oxygen (the Venturi mask has the

advantage of delivering a predictable FiO , but the nasal prongs are better 2 tolerated by the patient). b. Out Patient Acute respiratory failure is managed in an intensive care (ICU) unit setting. d) Referral criteria: 1. Diagnosis not clear. Even though clinical manifestations of hypoxemia and hypercapnia may raise the suspicion of respiratory failure, ABG analysis is essential for diagnosing respiratory failure. Hence, patients with suspicion of respiratory failure should be referred

to a tertiary hospital where higher-end technology is available. 2. Hemodynamic instability 105

*Situation 2: At Tertiary care hospital where higher-end technology is available a) Clinical Diagnosis As in situation V.1 a) above b) Investigations 1. As in situation V.1b) above PLUS 2. Computed tomography of chest 3. Tests for pulmonary thromboembolism Doppler studies for deep vein thrombosis CT pulmonary angiography D-dimer estimation V/Q scanning 4. Diagnostic testing to establish the aetiological cause of respiratory failure c) Treatment: As in situation V.1 c) above PLUS 1. Respiratory stimulants

In patients with type II respiratory failure, hypercapnia and acidosis, who are awaiting initiation of non-invasive ventilation (NIV), when NIV is not available or is poorly tolerated respiratory stimulants such as doxapram (initial dosage 5 mg/min, reducing according to the response to 1 to 3 mg/min; maximum dosage 600 mg) for short periods (24 to 36 hours) can be tried. 2. Ventilatory support If the arterial hypoxemia does not get corrected with the measures

described above, ventilatory support may be required. Non-invasive ventilation NIV modalities such as continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) are used in the management of acute respiratory failure. NIV has been particularly found to be useful in the management of acute respiratory failure due to acute exacerbations 106

of COPD, decompensated congestive heart failure with mild to moderate degree of pulmonary oedema, Pneumocysits pneumonia and if severe co-morbid illnesses are present, among others. However, NIV should be considered as a therapeutic option only at centers equipped with facilities for tracheal intubation and mechanical ventilation. Excessive secretions and unconscious patient are contraindications for NIV. Mechanical ventilation When other measures fail to maintain adequate respiratory

effort, tracheal intubation and assisted mechanical ventilation will be required. The mode of ventilation should be individualised to suit the needs of the patient. Following the initiation, the ventilator settings should be adjusted based on the patient's underlying disease process, gas exchange, lung mechanics, and response to mechanical ventilation. Aims of assisted ventilation in patients with respiratory failure due to COPD and asthma include decreasing the load of the

respiratory muscles, ensuring adequate oxygenation, and minimizing the development of dynamic hyperinflation and its associated adverse consequences. Care must be exercised to avoid causing further hyperinflation, and the set level of external PEEP should always be less than the level of intrinsic PEEP. In patients with acute severe asthma, development of dynamic hyperinflation can be minimised by delivering the lowest possible minute ventilation in the least possible time.

3. Weaning from mechanical ventilation A patient who has stable underlying respiratory status, adequate oxygenation, intact respiratory drive, and stable cardiovascular status should be considered for weaning. c. Out Patient 1. Acute respiratory failure is managed in an intensive care (ICU) unit setting 107

2. Chronic respiratory failure can be managed in the out-patient setting, ideally, at a tertiary health care level; however, many patients are managed at secondary level health care also. Drug treatment Drugs, such as, including medroxyprogesterone, acetazolamide, protriptyline, and almitrine bismesylate can be used for the management of chronic ventilatory failure. Domiciliary oxygen therapy Patients with COPD and chronic respiratory failure must be encouraged

to ambulate. Controlled, low flow oxygen therapy (1 to 2 L/min) is administered for at least 15 hours a day. Compressed gas cylinders, liquid oxygen and oxygen concentrators have been used for domiciliary oxygen therapy. Delivery devices that have been used include nasal prongs, cannulae and face masks. Since long-term oxygen therapy (LTOT) is expensive, oxygen conserving devices such as reservoir oxygen delivery; electromechanical pulsing devices; and trans-tracheal catheter

delivery can be used. For the outdoor activities, very light weight battery operated portable oxygen concentrators can be used, but, these are 4-5 times more expensive than the usual concentrators. Alternatively, light- weight oxygen cylinders which can be refilled by the oxygen concentrators can be used. VI. WHO DOES WHAT? and TIMELINES a. Doctor. Diagnosis and management including counseling b. Nurse. Implementation of orders, monitoring of patients and counseling c. Technician Investigations

d. Respiratory physiotherapist For administering supportive care to patients admitted in ICU VII. FURTHER READING / REFERENCES 1. Zimmerman JL. Respiratory failure. Blood Purif 2002;20:235-8. 2. Plant PK, Elliott MW. Chronic obstructive pulmonary disease. 9: management of ventilatory failure in COPD. Thorax 2003;58:537-42. 3. Davidson AC. The pulmonary physician in critical care. 11: critical care management of respiratory failure resulting from COPD. Thorax 2002;57:1079- 84. 108

SOURCES REQUIRED FOR ONE PATIENT Situatio HUMAN INVESTIGATION DRUGS & EQUIPMENT n RESOURCES S CONSUMABLES 1 1. Physician 1. Pulse oximetry 1. Oxygen 1. Oxygen cylinder 2. Nurse 2. Chest X-ray 2. Oxygen concentrator 2. Inhaled 3. Radiographer 3. ABG analysis 3. Ventilator for NIV bronchodilators 4. Technicians for 4. Echocardiography 4. Mechanical (salbutamol, performing 5. Pulmonary function ventilator ipratropium) pulmonary testing 5. Nasal prongs function testing 3. ICS (fluticasone/ 6. MC mask

5. Physician with budesonide)+ LABA 7. X-ray machine training in (formoterol/salmeterol 8. Pulse oximeter echocardiography ) 9. Spirometer 4. Parenteral and oral 10. ABG machine bronchodilators 11. Echocardiography (theophylline, machine terbutaline) 5. Parenteral and oral steroids (hydrocortisone, prednisolone) 6. Parenteral and oral antibiotics 2 Above plus Above plus Above plus Above plus 1. ICU staff with 1. Computed 1. Respiratory stimulants 1. CT machine

pulmonary tomography 2. Higher antibiotics 2. USG with Doppler training including CT machine 2. Respiratory pulmonary 3. V/Q scanning physiotherapists angiography machine 3. Radiologist 2. Doppler studies 4. Clinical pathology 3. D-dimer estimation laboratory service 4. Nuclear medicine 4. V/Q scanning for D-dimer expert estimation 5. ICU set-up 6. Noninvasive and invasive ventilators 109

STANDARD TREATMENT GUIDELINES Management of Recurrent Spontaneous Abortion January 2017 Ministry of Health & Family Welfare Government of India 1

Index Scope .............................................................................................................................. 3 Background ..................................................................................................................... 4 Investigations for recurrent miscarriage ......................................................................... 6

Recommendations .......................................................................................................... 7 Management of Recurrent Spontaneous Abortion (RSA) ............................................... 8 Treatment before Pregnancy .......................................................................................... 8 Treatment during Pregnancy ........................................................................................ 11

Treatment of RSA Patients with Antiphospholipid Syndrome ...................................... 12 Treatment of women presenting with RSA associated with inherited thrombophilia . 14 Treatment of women with unexplained RSA ................................................................ 15 Summary ...................................................................................................................... 17 2

STG Recurrent Miscarriage Scope Definition Miscarriage is defined as a spontaneous loss of pregnancy before 20 weeks of gestation. Group to be covered Women with three or more first trimester and one or more second trimester miscarriage (RCOG Greentop). Early evaluation is considered if fetal cardiac activity was present, women >35 years with two or more abortions and the couple has had difficulty in conceiving. Group not covered Two or more losses with one or more live issues. Burden of the disease

In India, the prevalence of recurrent miscarriage is around 7.4%. Rationale Since the true prevalence of recurrent miscarriage is still unknown and the multimodality approach being used at different levels of care by health care workers, this guideline attempts to provide an evidence based platform to investigate and manage women with recurrent miscarriage. Financial constraints A number of investigations related to recurrent miscarriage are expensive, so financial

constraints do come-up while investigating couple. Target Users All levels of healthcare including the primary, secondary and tertiary levels. Main outcomes Live pregnancy. Key clinical issues Causes, investigations and treatment of couples with recurrent miscarriage (RM). 3

Collection of evidence Evidence based existing guidelines which reviewed were Greentop, American Society of Reproductive Medicine, National Clearing House and The Obstetrician and Gynaecologist. Criteria for referral At the primary level, a thorough history and examination have to be carried out and the patient has to be referred to the secondary care level for further management. If higher modalities of treatment like surgery is required, the patient should be referred to the tertiary care level.

Background Introduction Women with three or more first trimester and one or more second trimester miscarriage are the one who have to be evaluated for recurrent miscarriage (Greentop Guidelines). It affects 1% of fertile couples (Berry et al 1995). 1-2% of pregnancies miscarry before 24 weeks (RCOG). The mechanism of RM remains poorly understood. The cause remains elusive in 50% of cases even after thorough investigations (TOG). Causes of recurrent miscarriage 1) Epidemiological factors

• Advanced maternal age, number of previous miscarriages and advance paternal age are independent risk factors for RM. • The risk is highest if maternal age is >35 years and paternal age >40 years. • The risk of miscarriage increases after each pregnancy loss reaching almost 30% after two and 40% after three consecutive losses. • Maternal smoking, alcohol consumption (5 units or more per week throughout pregnancy or 3 or more per week in first trimester), caffeine consumption (3-5

cups per day, obesity, illicit drug use like cocaine (TOG)(ref) increase the risk. • The evidence of the effect of anaesthetic gases in theatre workers is conflicting (RCOG Ref12-13). 2) Acquired and inherited thrombophilias Acquired thrombophilias are antiphospholipid syndrome (APS), hyperhomocysteinemia and acquired protein C resistance (APCR). • Antiphospholipid antibody syndrome is the most important treatable cause of RM. • APL antibodies are present in 15% of RM in comparison to only 2% in women

• Inherited thrombophilias include Antithrombin-III, Protein C deficiency, Protein S deficiency (uncommon and strongly thrombogenic), Factor-V Leiden, Prothrombin gene mutation (20210A) (common and weekly thrombogenic). • The association between fetal loss and inherited thrombophilia depends on the type of thrombophilia and timing of fetal loss (Rey et al, Lancet 2003). 3) Genetic causes • Increased incidence of structural chromosomal anomalies to the tune of 2-5% is

seen in couples with RM. These are either balanced reciprocal or Robertsonian translocations (RCOG 35,38). All the four factors low maternal age at second miscarriage, history of three or more miscarriages, history of two or more miscarriages in brothers and sisters and history of two or more miscarriages in parents of either partner all increase the probability of carrier status (Franssen 2005). • In couples with RM, chromosomal abnormalities of embryo account for 30-57%

of further miscarriages (RCOG 39,40). 4) Anatomic factors a) Congenital uterine malformations • Reported prevalence of uterine anomalies in recurrent miscarriage population ranges between 1.8-37.6%. • Women with arcuate uteri have more second trimester miscarriage and those with septate uteri are more likely to miscarry in the first trimester (RCOG 45). b) Cervical incompetence: • Essentially a clinical diagnosis, with unknown true incidence, cervical

incompetence is a recognized cause of recurrent second trimester abortions. • The diagnosis is usually suggested by a second trimester miscarriage preceding a spontaneous rupture of membrane or painless cervical dilatation. 5) Endocrine factors • Current evidence indicate that treated thyroid dysfunction and controlled diabetes mellitus is not a risk factor for RM (RCOG 47,48) and the prevalence of diabetes mellitus and thyroid dysfunction is similar to general population (RCOG 49,50).

• Obesity is also associated with statistically significant increased risk of first trimester and recurrent miscarriage (Lashen 2004). • Hypersecretion of LH, luteal phase defect, increased free androgen index and hyperprolactinemia all have a role in recurrent miscarriage. • Increased free androgen index appears to be a prognostic factor for a subsequent miscarriage in women with RM (RCOG 55). 6) Immune factors • There is no clear evidence to support the hypothesis of human leucocyte antigen

incompatibility between couples, the absence of maternal leucocytotoxic antibodies or the absence of maternal blocking antibodies(RCOG). • A no more than modest association between cytokine polymorphism and recurrent miscarriage has been seen (RCOG 61). 5

• Mannan-binding lectin (MBL) is a C-type lectin that participates in the innate immune defence by activating complement. Low MBL levels are associated with RM and that low MBL is associated with significantly higher miscarriage rate in next pregnancy (20%) (Kilpatric et al 1995, Cruz et al 2002). However, most women with low MBL do not experience RM. 7) Infective factors • The role of infection in recurrent miscarriage is unclear. Bacterial vaginosis is

consistently associated with recurrent second trimester abortions and preterm delivery, but association with first trimester abortion is inconsistent. Investigations for recurrent miscarriage The women with recurrent miscarriage should be looked after by a trained and expert health professional within a dedicated recurrent miscarriage clinic. Clearly written patient leaflets are recommended to provide take home written information. 1) Antiphospholipid antibodies

• For diagnosis, a woman should have two positive tests at least 12 weeks apart of either lupus anticoagulant or anticardiolipin (aCL) IgG/IgM in moderate to high titres (>40 g/l). • Dilute Russell Viper Venous Test (drVVT) along with platelet neutralization procedure is a more sensitive and specific test than either activated prothrombin times test (aPTT) or kaolin clotting time (KCT). aCL antibodies are detected using ELISA (RCOG 31). 2) Inherited thrombophilias

• Women with any unexplained still birth and two or more second trimester losses should be offered screening (Lavignee LG. Hematologica 2005). • With only second trimester miscarriage women should be screened for inherited thrombophilias for inherited thrombophilias including Factor V Leiden, prothrombin gene mutation and protein S [D] (Meta-analysis by Rey et al). 3) Anatomic Factors a) Uterine factors • Suspected uterine anomalies may further require a confirmation with

hysteroscopy, laparoscopy or a 3D ultrasound [(cid:252)]. 3D ultrasound in particular has become an accurate, reproducible, non-invasive outpatient method for diagnosis (Saliim et al 2003). 6

• There is insufficient evidence to assess the effect of uterine septum resection in females with RM and uterine septum to further prevent miscarriage [C]. b) Cervical incompetence • There is currently no satisfactory objective test to clearly identify cervical weakness in non-pregnant state. 4) Endocrine factors • Role of estimation of serum progesterone, serum hCG, inhibin and actinin levels is yet to be established. Recommendations 1. Thorough history and Clinical examination is a must

2. Offer testing for APS with lupus anticoagulant (LAC) and anticardiolipin antibody (aCL) ideally before the next pregnancy (HR Wilson 2006 and NGC) to any woman with history of three or more pregnancy losses <10 weeks or one or more loss of a morphologically normal fetus >10 weeks or one or more premature birth <34 weeks due to severe preeclampsia or placental insufficiency. 3. Offer parental karyotype only when probability of carrier status is >2.2% (Franssen 2005).

4. Do not offer testing for human leucocyte antigen, maternal leucocytotoxic antibodies and maternal blocking antibodies. 5. Do not offer TORCH investigations. 6. Do not offer investigations for hyperhomocysteinemia outside a research protocol. 7. Offer screening for inherited thrombophilias only if other causes have been ruled out, with any unexplained still birth and two or more second trimester losses and if only second trimester miscarriages are present.

8. Offer cytogenetic analysis on products of conception of third and subsequent consecutive miscarriages. 9. Offer parental peripheral blood karyotyping of both partners in couples with RM where testing of products of conception reveal an unbalanced structural chromosomal translocations. 10. Consider pelvic ultrasound in all women with recurrent first trimester miscarriages and with one or more second trimester miscarriages to assess uterine anomalies. 7

Management of Recurrent Spontaneous Abortion (RSA) The etiology of RSM is multifactorial. Appropriate treatment continues to be a challenge, and there is need for larger well-planned double-blinded randomized controlled trials or standardized research protocols for the investigations and treatment of RSA to effectively resolve many of the problems which remain a source of dilemma for most treating physicians. The investigation and management of women with recurrent spontaneous

abortion should be done in a centre well equipped with readily available facilities for all ancillary investigations and well trained qualified personnel. The management of RSA depends on the causative factor, though in 75% of the cases the cause remains unexplained, thus only 25% of the women require treatment as per the cause. Management depends on the time of detection of these cases, before pregnancy and during pregnancy. Treatment before Pregnancy

1. Counseling the couple should be done regarding the investigations and the outcome of the investigations, the treatment plan to be followed, and the outcome of such treatment 2. Psychological support. Women with RSA are usually quite anxious and full of uncertainty about the outcome of their next pregnancy. A strong psychological support should be provided and should be dealt with tender loving care all through the period of consultation

3. Those couples with abnormal karyotypes detected during the screening period should be referred to a clinical geneticist, where available, for detailed counseling about the outcome of future pregnancies. 4. Surgery for detected anatomical disorders (congenital and acquired): Hysteroscopic resection of uterine septum preferably using cold scissors rather than cautery or bipolar cutting devices, resection of submucous fibroids, and 8

treatment of intrauterine adhesions presenting as Asherman syndrome can be undertaken before another pregnancy is embarked upon. Women who have multiple uterine fibroids with an uterine size more than 14 weeks’ size should be encouraged to secure appropriate treatment (including myomectomy) before embarking on another pregnancy. However, it should be noted that the exact role of a resection of the uterine septum is still unresolved since there are no published controlled randomized

trials of the benefits of surgical correction of uterine abnormalities on pregnancy outcome. Uncontrolled studies have indicated a positive effect on pregnancy outcome. Evidence • There is insufficient evidence to assess the effect of uterine septum resection in women with recurrent miscarriage and uterine septum to prevent further miscarriage (RCOG) • Almost 65% to 85% of patients with bicornuate or septate uteri have a successful pregnancy outcome after metroplasty. However, 59.5% of the

patients with such anomalies have a successful subsequent pregnancy without surgery, with a cumulative live birth rate of 78.0%. Further evidence is needed to recommend metroplasty surgery in these women (Evidence level II). • Correction of septate defects in particular may have beneficial effects (live birth rate 83.2%, range from 77.4%- to 90.9%) and should be considered in women with RPL. The primary limitation of existing data is the lack of randomized, controlled therapeutic trials ASRM)

• Because randomized trials in this area are lacking and difficult to conduct, the general consensus is that surgical correction of significant uterine cavity defects should be considered • The clinical management of pregnancy-loss patients with Asherman syndrome/intrauterine synechiae, uterine fibroids, and uterine polyps is also controversial, and there is no conclusive evidence that surgical treatment 9

reduces the risk of pregnancy loss. Minimally invasive surgeries are the better option for the treatment of structural defects.(RCOG) • There are no published randomised trials assessing the benefits of surgical correction of uterine abnormalities on pregnancy outcome. Open uterine surgery has never been assessed in prospective trials but is associated with postoperative infertility and carries a significant risk of uterine scar rupture during pregnancy. These complications are less likely to occur after

transcervical hysteroscopic resection of uterine septae; experience from case series appears promising However, before a clear judgement can be made, this procedure must be evaluated in a prospective controlled trial • In the event of irreparable anatomic uterine abnormalities and RPL, IVF with transfer of embryos to an appropriately selected gestational carrier also may be a clinical consideration(ASRM) Repair of cervical lacerations: Abdominal Cerclage

Surgical correction of traumatic cervical lacerations should be undertaken before further pregnancies are planned. Transabdominal cerclage can be offered as an alternative treatment for patients presenting with second-trimester miscarriage or early preterm labour who have had unsuccessful transvaginal cerclage because of a short or scarred cervix. A systematic review comparing abdominal with vaginal cerclage has indicated a lower risk of delivery before 24 weeks’ gestation

although the timing of performing transabdominal cerclage before or during pregnancy remains unresolved 5. Medical treatment: Endocrine disorders including thyroid dysfunction and diabetes mellitus should be well controlled before another pregnancy is planned. Patients presenting with PCOS should be appropriately managed with medical and surgical methods to achieve regular ovulation, and assisted reproductive technology may be indicated in some of these patients with PCOS. 10

Treatment during Pregnancy 1. Psychological support: Psychological support and tender loving care should be continued all through the pregnancy. The women should be encouraged for more frequent antenatal visits (usually 2 weekly appointments) and should be reassured and to be well supported 2. Treatment for the thyroid dysfunction and diabetes mellitus should be continued to ensure that these endocrine disorders are well controlled 3. Treatment of RSA Patients with Cervical Disorders: Cervical cerclage

Because of conflicting evidence, the management of women presenting with RSA, usually late in the first trimester, and with second-trimester miscarriages is really difficult for the treating physician who needs to decide on the definitive treatment for such patients. • A meta-analysis of 4 randomized controlled trials reported that prophylactic cerclage did not reduce the risk of miscarriage or preterm delivery in women at risk of such disorders because of cervical weakness.

• Another meta-analysis on women from 4 randomized controlled trials with a short cervix (<25 mm diagnosed by transvaginal ultrasound examinations) and a history of previous second-trimester miscarriage confirmed that cervical cerclage may reduce second-trimester miscarriages and the incidence of preterm delivery. It has been documented that cervical cerclage may be associated with some minor maternal morbidity. • Prophylactic cerclage can be applied in women who present with a history of

recurrent second-trimester abortions, a history of a typical single second-trimester abortion, or with ultrasound-indicated cervical weakness where a cervical length of 25 mm or less has been detected by transvaginal ultrasound. • In women with a less specific history, serial cervical ultrasonographic monitoring can be carried out in the index pregnancy and prophylactic cerclage can be performed in women with a short cervix (cervical length of <25 mm). 11

Evidence • Cervical cerclage is associated with potential hazards related to the surgery and the risk of stimulating uterine contractions and hence should be considered only in women who are likely to benefit (RCOG) • Women with a history of second-trimester miscarriage and suspected cervical weakness who have not undergone a history-indicated cerclage may be offered serial cervical sonographic surveillance. (RCOG) • In women with a singleton pregnancy and a history of one second-trimester

miscarriage attributable to cervical factors, an ultrasound-indicated cerclage should be offered if a cervical length of 25 mm or less is detected by transvaginal scan before 24 weeks of gestation. (RCOG) Treatment of RSA Patients with Antiphospholipid Syndrome APS, the most frequently diagnosed immunological cause of RSA and the only proven thrombophilia associated with an adverse pregnancy outcome, has also been identified as the most treatable cause of RSM. LDA & LMWH

• Low doses of acetylsalicylic acid and low molecular weight heparin (LMWH) are the best solution in women suffering from recurrent spontaneous miscarriage. This treatment combination of low dose aspirin and low molecular weight heparin reduces the miscarriage rate by 54%. • The efficacy of low molecular weight heparin plus aspirin remains unproven as LMWH data were based on only two trials. These trials were criticized as studies

were not blinded and the randomization procedure had been criticized in one of the trials and inclusion criteria were very different. • Third trial showed no significant difference in live birth rate with LMWH treatment versus aspirin or a combination of both versus aspirin in women with recurrent miscarriage. 12

• A meta-analysis showed the combination of unfractionated heparin and aspirin confers a significant benefit in live births (RCOG, ASRM). • A small trial showed comparable results with LMWH plus aspirin as an alternative to unfractionated heparin and aspirin in the management of recurrent miscarriage secondary to APS. • The consensus is combination of low molecular weight heparin and aspirin is superior to aspirin alone in achieving more live births. Therefore, it is

recommended treatment for recurrent miscarriages with antiphospholipid syndrome (Evidence level I). Evidence • Pregnant women with antiphospholipid syndrome should be considered for treatment with low-dose aspirin plus heparin to prevent further miscarriage (RCOG) • The combination of twice daily unfractionated heparin and low-dose aspirin appears to confer a significant benefit in pregnancies with aPLs and otherwise unexplained recurrent pregnancy loss; comparable efficacy of low molecular

weight heparin has not been established (ASRM,2012). Treatment with heparin and LDA should be commenced as soon as a pregnancy test is positive and continued all through pregnancy and into the puerperium with specific breaks. LDA should be stopped at 35 weeks’ gestation because of some adverse neonatal effects of LDA, and heparin should not be administered during labour and operative obstetric operations because of the risk of hemorrhage. Glucocorticoids :

Glucocorticoids should not be given in antiphospholipid antibodies syndrome without connective tissue disorder. Low-dose prednisone is given when lupus is present and with the advice of rheumatologist. Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody. Corticosteroids administered to women during pregnancy presenting with RSA associated with APS do not improve the live 13

birth rate compared with heparin and LDA, and such therapy should not be encouraged, especially as corticosteroids are associated with significant fetal and maternal morbidity. Evidence • Neither corticosteroids nor intravenous immunoglobulin therapy improve the live birth rate of women with recurrent miscarriage associated with antiphospholipid antibodies compared with other treatment modalities; their use may provoke significant maternal and fetal morbidity (RCOG)

• Administration of prednisone does not improve pregnancy rates and may be associated with an increased risk of gestational hypertension and gestational diabetes (ASRM) Treatment of women presenting with RSA associated with inherited thrombophilia • Role of anticoagulation therapy in the treatment of RSA with hereditary thrombophilia is debatable. Treatment of women presenting with RSA associated with inherited thrombophilia poses many challenges because there is no strong

evidence to support the treatment of these patients with aspirin and/or heparin. • Few studies suggested low molecular weight heparin therapy during pregnancy may improve the live birth rate of women with second-trimester miscarriage associated with inherited thrombophilia. However, there is currently no evidence supporting treatment, because observational research is hampered by poor methodology or inconsistent results. (RCOG,ASRM.. insufficient evidence) .

• Recent meta-analysis showed that the use of LMWH in women with inherited thrombophilia with recurrent pregnancy loss is not indicated. • Women with thrombophilia should be followed closely without routine prophylactic low molecular weight heparin other than for prevention of venous thromboembolism in limited circumstances (Evidence level I). 14

• Although some studies have indicated that heparin may improve live birth rates in women with inherited thrombophilia , a more recent has stated that there was no significant difference in the live birth rate in women with RSA and inherited thrombophilia who have been treated with a combination of aspirin and LMWH or aspirin alone. 4. Luteal support Role of Progesterone In spite of the fact that progesterone has been identified as being essential for the

implantation and maintenance of pregnancy, great controversy still exists about the role of progesterone supplementation in supporting early pregnancy and in the prevention and/or reduction of first-trimester miscarriages/recurrent early spontaneous first-trimester miscarriages. Treatment of women with unexplained RSA It should be recalled that in about 50–60% of patients presenting with RSA, in spite of comprehensive investigations, no etiological factor is identified, and these are classified

as unexplained or idiopathic RSM. Therapy for these cases of idiopathic RSA remains a great challenge and increases the state of dilemma which the treating physicians confront on a regular basis. Therapy for many of these patients is empirical, the treating physician faces a lot of pressure in deciding on whether to offer some other forms of controversial therapy to these patients. A psychological support and tender loving care should be part

of the treatment offered to these patients. Efforts should be made to find an appropriate therapy for patients with idiopathic RSA • Psychological support: should be offered tender loving care, psychological support as well as dedicated intensive monitoring and comprehensive care and they should be reassured that a successful future pregnancy could be in the range of 75%. Women should be reassured for a successful future pregnancy with supportive care.(Evidence level III) 15

• Aspirin 75 mg OD: Evidence is debatable. There is paucity of evidence to make any recommendation on aspirin for treating recurrent miscarriage in women without antiphospholipid syndrome. Few RCT suggested clear benefit of using aspirin for such women. Recent trial failed to support any role of Aspirin in unexplained recurrent miscarriage. Aspirin helps in improving uterine perfusion. Aspirin is useful in many undiagnosed implantation failure patients. However, in

the absence of strong evidence, routine use of Aspirin is not recommended (Evidence level II) • LMWH: Use of LMWH to prevent miscarriage is not recommended in the absence of antiphospholipid syndrome (Evidence level II). • The role of low molecular weight heparin and aspirin treatment specifically for the prevention of recurrent miscarriage remains controversial. Two recent randomized controlled trials reported that low molecular weight

heparin and aspirin treatment showed no improvement in the live birth rate among women with unexplained recurrent miscarriage Proper RCT should be done to test the efficacy of this treatment (RCOG) The combination of twice daily unfractionated heparin and low-dose aspirin appears to confer a significant benefit in pregnancies with otherwise unexplained recurrent pregnancy loss (ASRM). • Progesterone: Meta-analysis of 4 randomized trials and only 132 women in total

showed a statistically significant reduction in miscarriages. Further, the evidence is awaited before making recommendation on use of progesterone in explained miscarriage. (Evidence level III). • Human chorionic gonadotrophin (hCG): Recent Cochrane review failed to find quality evidence to support use of hCG for preventing miscarriage. A well- designed randomized controlled trial of adequate power and methodological quality is required. Therefore, the use of hCG is not recommended (Evidence level II.

• Steroids: The effect of prednisolone therapy for some women with recurrent miscarriage may be due to altered endometrial angiogenic growth factor 16

expression and reduced blood vessel maturation. The role is mostly limited to recurrent miscarriage with known connective tissue disorders. Rheumatologic advice should be taken with patients diagnosed having recurrent pregnancy loss and connective tissue disorder. The results from the Prednisolone Trial are awaited; it is a randomized controlled trial of prednisolone for women with idiopathic recurrent miscarriage and raised uNK cells in the endometrium. There

is no robust evidence to recommend steroid use for unexplained recurrent miscarriage (Evidence level III) • Immunoglobulins: IVIG administration for treatment of recurrent miscarriage is not justified outside the context of research as discussed earlier (Evidence level II) • Intravenous intralipid solution: No evidence of benefit with use of intralipid. Well controlled, large-scale, and confirmatory studies required before it can be recommended for routine use (Evidence level III)

Recent randomized controlled trials have indicated that interventions with the drugs stated above do not improve live birth rates in women with unexplained/idiopathic RSA. As clearly recommended, empirical treatment of patients with unexplained RSM with the drugs stated above should be resisted and discontinued, and restate that in spite of the challenges we face in finding suitable evidence-based therapy for our patients with RSA, we should resist offering empirical treatment. Summary

• The management of RSA is quite varied and challenging. • The use of LDA and heparin, an established treatment for APS, has been associated with a live birth rate of 54–74%. • The role of LDA and heparin therapy in congenital thrombophilia remains controversial. • Surgical treatment for uterine anatomical disorders requires further studies. • The management of unexplained or idiopathic RSA remains a clinical dilemma, and although psychological care has been associated with a favorable outcome, the 17

empirical use of LDA and heparin and/or intravenous immunoglobulin, should be discouraged because available results do not support this line of management. • There is a need for larger, randomized, double-blinded, multi-centred, placebo- controlled studies to establish an evidence-based basis for the aetiology, diagnosis and treatment of RSA, and the definition of RSA should be standardized in such studies. One of the major setbacks in the field of the management and research in RSA is the lack

of large, well-conducted, double-blinded, randomized, placebo-controlled and preferably multi-centred trials with well-defined objectives and dealing with patients with standardized definitions of RSA. Treatment RCOG (2012) ASRM(2012) ESHRE(2006) Aspirin plus Recommended Recommended Insufficient heparin therapy Evidence Level: 2+ Live birth rates with evidence for Abortion rate 74% vs without 42.9% antiphospholipid Decreased to 54% antibodies Aspirin plus Not recommended Recommended _ heparin therapy

in women with unexplained recurrent abortion Resection of Insufficient evidence Should be considered - uterine septum Supportive care Insufficient evidence Recommended Recommended for women with unexplained recurrent miscarriage 18

Other Treatment RCOG ASRM ESHRE Anticoaggulants for Insufficient - Insufficient evidence hereditary evidence thrombophilias Immunotherapy Not Recommended Not Recommended Insufficient evidence Progesterone Insufficient Insufficient -Insufficient supplementation evidence evidence evidence HCG Insufficient _ _ supplementation evidence Folic acid _ _ Insufficient evidence supplementation for hyperhomocytenemia Vitamin - - Not Recommended supplementation

Steroid treatment Not Recommended Not Recommended Not Recommended Cervical pessary Not Recommended - - Serial sonographic Not Recommended - - surveillance 19

National Guidelines for Diagnosis & Management of Viral Hepatitis 2018

National Guidelines for Diagnosis & Management of Viral Hepatitis

Preface Viral hepatitis is increasingly being recognized as a public health problem in India. While hepatitis A and E – that are water and foodborne infections – are often the cause for sporadic or outbreaks of hepatitis in India and recover completely with no clinical sequelae, hepatitis B and C can lead to chronic infection and thereafter sequelae like cirrhosis and hepatocellular carcinoma. Viral hepatitis is a leading cause of death in the world, which is comparable to that of HIV, tuberculosis

and malaria. Cirrhosis and hepatocellular carcinoma, which are the sequelae of chronic hepatitis B and C, accounted for more than 90% of all hepatitis B and C related deaths. Further, mortality from HBV- and HCV-associated cirrhosis and hepatocellular carcinoma is still increasing because of poor access to treatment. While prevention can reduce the rate of new infections, treatment eliminates existing infections; thus combining both prevention and treatment makes hepatitis B and C elimination

feasible long term goal. The Government of India has decided to launch the National Viral Hepatitis Control Program with provision of free diagnosis and treatment for viral hepatitis through the National Health Mission. Consequently, it is of utmost importance to have standard national guidelines that are robust, evidence based, and simple to be followed at the decentralized level. It should also enable the service providers to

decide on the assessment of patient, treatment options, managing special situation ( like co-infections), parameters for timely referrals and quality service delivery. The current guidelines are a outcome for the collective effort of the members of Technical Resource Group on hepatitis Treatment, constituted by the MoH & FW, and that had representations of clinicians and program managers from across the country, representing different sectors (government, private sector, academic institutes, community

members, development partners). The group has taken into considerations the latest available evidence, global guidelines (such as EASL, WHO etc) and adapted them to the Indian context taking relevant considerations from with the extensive experience of delivering services in the state of Punjab. I hope, these guidelines will offer the needed guidance for delivering quality treatment and services in a public health approach.

ACRONYMS AFP Alfa Feto Protein AIDS Acquired Immuno Deficiency Syndrome ALF Acute Liver Failure ALP Alkaline Phosphatase ALT Alanine amino transferase AntiHBc Antibody to Hepatitis B core antigen AntiHBe Antibody to Hepatitis B envelope antigen APRI AST to Platelet Ratio Index ART Anti-Retroviral Therapy ARVs Anti Retro Virals AST Aspartate aminotransferase CBC Complete Blood cell Count CD4 Cluster of Differentiation 4 CEMRI Contrast Enhanced Magnetic Resonance Imaging CHB Chronic Hepatitis B

CT Computed Tomography d4T Stavudine DAA Directly acting anti-viral DCV Daclatasvir ddI Didanosine DDIs Drug Drug Interactions DMLT Diploma in Medical Laboratory Technology DNA Deoxyribo Nucleic Acid DOEACC Department of Electronics and Accreditation of Computer Courses DPT Diptheria Pertussis Tetanus EASL European Association for Study of the Liver eGFR estimated Glomerular Filtration Rate EQA External Quality Assessment FEFO First Expiry First Out HAV Hepatitis A Virus HBIG Hepatitis B Immuno Globulin

HBV Hepatitis B Virus HBsAg Hepatitis B Surface Antigen HBeAg Hepatitis B envelope Antigen HCC Hepatocellular Carcinoma HCV Hepatitis C Virus HCVcAg Hepatitis C Virus core Antigen HDV Hepatitis D Virus HEV Hepatitis E Virus Hib Haemophilus influenzae type b HIV Human Immunodeficiency Virus HR Human Resource ICTC Integrated Counseling and Testing Centre ICU Intensive Care Unit IDSP Integrated Disease Surveillance Programme INR International normalized ratio

IP In Patient LDV Ledipasvir M&E Monitoring and Evaluation MLT Medical Laboratory Technology MO Medical Officer MRI Magnetic Resonance Imaging MTC Model Treatment Centres NACO National AIDS Control Organization NACP National AIDS Control Program NAs Nucleos(t)ide analogues NAT Nucleic Acid Testing NITs Non Invasive Tests NCDC National Centre for Disease Control NHM National Health Mission NSAID Non Steroidal Anti Inflammatory Drug NVHMU National Viral Hepatitis Management Unit NVP Nevirapine OP Out Patient

OST Opioid Substitution Therapy PIP Program Implementation Plan PCR Polymerase Chain Reaction PEG-IFN Pegylated Interferon PLHIV People Living with HIV PMU Program Management Unit PWID People Who Inject Drugs QC Quality Control RAS Resistance-Associated Substitution RBV Ribavarin RNA Ribo-nucleic acid SoE Statement of Expenditure SOF Sofosbuvir SOP Standard Operating Procedure SSO State Surveillance Officer SVHMU State Viral Hepatitis Management Unit SVR Sustained Virological Response

TAF Tenofovir Alafenamide Fumarate TB Tuberculosis TC Treatment Centre TDF Tenofovir Disoproxil Fumarate TG Transgender TPCT Tri Phasic Computerised Tomography UID Unique Identification ULN Upper limit of normal USG Ultra Sono Graphy VEL Velpatasvir WHO World Health Organization

SECTION 1: GUIDELINES FOR DIAGNOSIS AND MANAGEMENT OF VIRAL HEPATITIS 14 Introduction 15 Estimating the problem statement 15 Hepatitis A Infection 16 Clinical presentation 16 Laboratory Diagnosis 17 Management 18 Hepatitis B Infection 18 Clinical Presentation 18 Acute Hepatitis 18 Chronic Hepatitis 19 Assessment and Staging of HBV Chronic infection 22 Management 23 Whom To Treat 23 When To Stop Treatment 26 Monitoring 27 Special Situations 29 Pregnancy 29 Co-morbidities 30

Hepatitis C Infection 32 Clinical Course of Hepatitis C Infection 33 Laboratory Diagnosis 33 Whom To Test 34 Treatment of Viral Hepatitis C in Adults 34 Clinical Assessment before Initiating Treatment 35 Assessment of Degree of Fibrosis 35 Baseline and follow-up Investigations 35 Whom To Treat 36 What Regimen To Use 36 Side Effects of Drugs Used in Treatment 38 Drug Interactions with DAA 39 Special Situations and co-morbidities 39 Treatment of Patients with Decompensated Cirrhosis 39

Management of Treatment Experienced Patients 40 People who inject drugs 40 Persons with HIV/HCV Co-infection 41 Management of Cirrhotic Patients after HCV clearance in SVR 12 43 Persons with chronic kidney disease 43 Persons with HBV/HCV co-infection 43 Persons with TB/HCV co-infection 43 Women of child-bearing age 44 Hepatitis E 44 Clinical Presentation 44 Laboratory Diagnosis 44 Management of Viral Hepatitis E 44 Special Situations 45

SECTION 2: OPERATIONAL GUIDELINES TO ROLL OUT TREATMENT OF HEPATITIS C 48 Introduction 49 Organization of Services 49 Guidelines for the Organization of Services 49 Objectives and functions of the Treatment Sites 49 Selection criteria and steps for setting up a Treatment Site 50 Infrastructure 50 Human Resource 50 Training 55 Logistics 56 Financial management 56 Patient Flow at the Treatment Centers 57 Monitoring and Evaluation of the Treatment sites 59 Recording tools 60 Reporting tools 60

Annexure 1: Assessing severity of liver disease 62 Annexure 2: Algorithm for the Laboratory Diagnosis of Viral Hepatitis 64 Annexure -3: Drug interactions between DAA and some commonly prescribed medications. 65 Annexure 4: Feasibility Visit for Setting Hepatitis Treatment Center 66 Annexure 5: Patient Testing &Treatment Card 68 Annexure 6: Hepatitis C Treatment Register 69 Annexure 7a: DAA Stock register 70 Annexure 7b: Drug Dispensation Register 71 Annexure 8: Monthly reporting format 72

Annexure 9: Consent form 75 References 76 List of Contributors 78

1 SECTION GUIDELINES FOR DIAGNOSIS AND MANAGEMENT OF VIRAL HEPATITIS 14 National Guidelines for Diagnosis & Management of Viral Hepatitis

Introduction Viral hepatitis is recognized as a public health problem globally. Various etiological agents (Hepatitis A, B, C, D and E viruses) have been implicated that can lead to acute, chronic or sequel of chronic infection. While hepatitis A and E are often the cause for sporadic or outbreaks of hepatitis, hepatitis B and C can either clear spontaneously or can lead to chronic infection and there after sequelae like cirrhosis and hepatocellular carcinoma (HCC).

Viral hepatitis is increasingly being recognized as a public health problem in India. Hepatitis A Virus (HAV) and Hepatitis E Virus (HEV) are important causes of acute viral hepatitis and acute liver failure (ALF). Due to paucity of data, the exact burden of disease for the country is not established. However, available literature indicates a wide range and suggests that HAV is responsible for 10-30% of acute hepatitis and

5-15% of acute liver failure cases in India. It is further reported that HEV 10-40% of acute hepatitis and 15-45% of acute liver failure. Hepatitis B surface antigen (HBsAg) positivity in the general population ranges from 1.1% to 12.2%, with an average prevalence of 3-4%. Anti-Hepatitis C virus (HCV) antibody prevalence in the general population is estimated to be between 0.09-15%. It is estimated that there are 40 million people chronically infected with

Hepatitis B Virus (HBV) and based on some regional level studies, it is estimated that there are 6-12 million people with Hepatitis C in India. Chronic HBV infection accounts for 40-50% of HCC and 20-30% cases of cirrhosis in India. Chronic HCV infection accounts for 12-32% of hepatocellular carcinoma (HCC) and 12-20% of cirrhosis. Population based syndromic and health facility based surveillance of viral hepatitis is mandated under the Integrated Disease Surveillance Program (IDSP).

Recently, a meta-analysis of studies on hepatitis C prevalence was undertaken by SGPGI, Lucknow. The study documented the pooled prevalence of Hepatitis C amongst various sub populations. This meta-analysis concluded that based on the above studies, it can be estimated that India (current population = ~1.3 billion) has 5.2 to 13 million anti-HCV positive persons. The data on HCV viremia rates among anti-HCV

antibody positive persons were not available. Hence it is difficult to arrive at a conclusion on this. However, using data from elsewhere that 60%-70% of anti-HCV persons have HCV viremia, it can be estimated that India as ~3 million to ~9 million persons with active HCV infection. Estimating the problem statement There are a few estimates that are available from global publications. However, it is assumed that these estimates are likely to change, as data sets and evidence increase across India.

National Guidelines for Diagnosis & Management of Viral Hepatitis 15

Table 1: WHO Global Disease estimates 2016 viral hepatitis could be contributing to nearly 2.85% of all deaths in India: Hepatitis Numbers in thousands Total ( in thousands) a. Acute hepatitis A 5.0 b. Acute hepatitis B 43.3 78.7 c. Acute hepatitis C 1.1 d. Acute hepatitis E 29.2 Liver cancer Numbers in thousands Total ( in thousands) a. Liver cancer secondary 15.3 to hepatitis B 20.1 b. Liver cancer secondary 4.9 to hepatitis C Cirrhosis of the liver Numbers in thousands Total ( in thousands)

a. Cirrhosis due to hepatitis B 141.8 173.6 b. Cirrhosis due to hepatitis C 31.9 Estimated Total Deaths ( All causes) 9559.1 % of deaths attributed to viral hepatitis 2.85% Similarly, the Global Burden of diseases in 2016, suggests that the mortality attributable to viral hepatitis in India could be 1.18% of all deaths. The National Health Profile 2016 identified viral hepatitis to contribute to 3% of all deaths related to communicable diseases in India in 2015.

Acute viral hepatitis is a systemic infection affecting the liver predominantly. Almost all cases of acute viral hepatitis are caused by one of five viral agents: HAV, HBV, HCV, the HBV-associated delta agent or hepatitis D virus (HDV) and HEV. All these human hepatitis viruses are RNA viruses, except for hepatitis B, which is a DNA virus but replicates like a retrovirus. Although these agents can be distinguished by their molecular

and antigenic properties, all types of viral hepatitis produce clinically similar illnesses. These range from asymptomatic and inapparent to fulminant and fatal acute infections common to all types, on the one hand, and from subclinical persistent infections to rapidly progressive chronic liver disease with cirrhosis and even hepatocellular carcinoma, common to the blood borne types (HBV, HCV, and HDV), on the other. Hepatitis A Infection

HAV is a non-enveloped RNA virus belonging to the picornavirus family, with 4 genotypes belonging to one serotype. This agent is transmitted almost exclusively by the fecal-oral route. It is an outbreak prone disease with an incubation period of around 4 weeks. Person to person spread of HAV is enhanced by poor personal hygiene and overcrowding. Excretion in the stool occurs for only 7-14 days after the onset of the clinical illness and is

diagnostic of an acute HAV infection. No carrier state has been identified. Inactivated attenuated vaccine, which is safe, immunogenic and effective, is available. Clinical presentation The incubation period for HAV ranges from 15-45 days. The prodromal symptoms of acute viral hepatitis are systemic and quite variable. Constitutional symptoms of low grade fever, anorexia, nausea and vomiting, 16 National Guidelines for Diagnosis & Management of Viral Hepatitis

fatigue, malaise, arthralgias, myalgias, headache, photophobia, pharyngitis, cough and coryza may precede onset of jaundice by 1-2 weeks. Dark urine and clay colored stools may be noticed by the patient from 1-5 days before the onset of clinical jaundice. With the onset of clinical jaundice, the constitutional prodromal symptoms usually diminish. The liver becomes enlarged and tender and may be associated with right upper quadrant pain and discomfort.

During recovery phase the constitutional symptoms disappear, but usually some liver enlargement and abnormalities in liver biochemical tests are still evident. Laboratory Diagnosis HAV has an incubation period of ~4 weeks. Its replication is limited to the liver, but the virus is present in liver, bile, stools and blood during late incubation period and acute pre-icteric / pre-symptomatic phase of illness.

In acute hepatitis with clinical jaundice, the serum bilirubin levels are above 2.5mg/dL and serum alanine aminotransferase (ALT) is more than 10 times the upper limit of normal. Jaundice ALT IgG Anti-HAV IgM Anti-HAV Fecal HAV 0 4 8 12 16 20 Weeks after exposure Fig.1: Laboratory Markers of HAV Infection Source: Faud AS, Kasper DL, Braunveld E, Hauser SL, Longo DL, Jameson JL, Loscalzo J, Harrison’s Principles of Internal medicine, 19th Edition: http://www.accessmedicine.com

Detection of anti- HAV antibody in serum/plasma is important in diagnosis of infection, as HAV is present in blood transiently during the incubation period. IgM antibodies against HAV are generally detectable 5-10 days before onset of symptoms and can persist for up to 6 months. Anti-HAV IgM antibodies indicate acute infection. IgG antibodies against HAV becomes the predominant antibody during convalescence and remains detectable

indefinitely. Anti-HAV total antibodies (IgG and IgM) or specific IgG (but anti-HAV IgM negative) indicate immunity to hepatitis A either because of past infection or vaccination. National Guidelines for Diagnosis & Management of Viral Hepatitis 17

The serum aminotransferases, aspartate aminotransferase (AST) and ALT increase to a variable degree during prodromal phase of illness and precede the rise in bilirubin levels. Yellowish discoloration of sclera (jaundice) and skin is usually visible when serum bilirubin value is >2.5 mg/dL. Management There is no role for antiviral drugs in therapy for HAV infection. Virtually all previously healthy patients

with hepatitis A recover completely with no clinical sequelae. The case fatality is very-very low (~0.1%) but is increased in advanced age and in the presence of underlying debilitating diseases. Infection in the community is best prevented by improving social conditions especially overcrowding and poor sanitation. Hepatitis B Infection HBV, a double-stranded DNA virus, belongs to the family of hepadnaviruses. HBV infection is a global public

health problem. Perinatal transmission and occasionally horizontal transmission early in life are most common in high prevalence areas. Sexual contact and percutaneous transmission also contribute to the transmission of HBV. Clinical Presentation The spectrum of clinical manifestations of HBV infection varies in both acute and chronic disease. During the acute phase, manifestations range from subclinical or anicteric hepatitis to icteric hepatitis and, in some cases,

fulminant hepatitis. The incubation period for HBV varies from 30-180 days. In chronic phase, manifestations range from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and HCC. Extra-hepatic manifestations can also occur with both acute and chronic infection. Acute Hepatitis: Approximately 70 percent of patients with acute HBV infection have subclinical or anicteric hepatitis, while 30

percent develop icteric hepatitis. The disease may be more severe in patients co-infected with other hepatitis viruses or with underlying liver disease. Fulminant hepatitis B is unusual, occurring in approximately 0.1 to 0.5 percent of patients; it is believed to be due to massive immune-mediated lysis of infected hepatocytes. A serum sickness-like syndrome may develop during the prodromal period, followed by constitutional symptoms, anorexia, nausea, jaundice, and right upper

quadrant discomfort. The symptoms and jaundice generally disappear after one to three months, but some patients have prolonged fatigue even after normalization of serum aminotransferase concentrations. The complete eradication of HBV rarely occurs after recovery from acute HBV infection and that latent infection can maintain the T cell response for decades following clinical recovery, thereby keeping the virus under control.

The rate of progression from acute to chronic hepatitis B in immunocompetent persons is determined primarily by the age at infection. The rate is approximately 90 percent for a perinatally acquired infection, 20 to 50 percent for infections between the age of one and five years, and less than 5 percent for an adult-acquired infection. Treatment for acute HBV is mainly supportive. In addition, appropriate measures should be taken to prevent infection in exposed contacts.

18 National Guidelines for Diagnosis & Management of Viral Hepatitis

The decision to hospitalize patients should be taken on a case-to-case basis. Patients, who have a coagulopathy, are deeply jaundiced, or encephalopathy should generally be hospitalized. Hospitalization might also be considered in patients who are older, have significant comorbidities, cannot tolerate oral intake, or have poor social support systems. In acute cases, the patients who have fulminant hepatitis or hepatitis B with underlying cirrhosis should be considered for antiviral treatment.

Chronic Hepatitis: A history of acute hepatitis is elicited in only a small percentage of patients with chronic HBV infection. In low or intermediate prevalence areas, approximately 30 to 50 percent of patients with chronic HBV infection have a past history of acute hepatitis; such a history is lacking in the remaining patients in these areas and in the majority of patients in high prevalence areas (predominantly perinatal infection).

Many patients with chronic HBV are asymptomatic (unless they have decompensated cirrhosis or have extrahepatic manifestations), while others have nonspecific symptoms such as fatigue. Some patients experience exacerbations of the infection which may be asymptomatic, mimic acute hepatitis, or manifest as hepatic failure. Physical examination may be normal, or there may be stigmata of chronic liver disease. Jaundice, splenomegaly,

ascites, peripheral edema, upper gastrointestinal bleed and encephalopathy may be present in patients with decompensated cirrhosis. Laboratory tests may be normal, but most patients have a mild to moderate elevation in serum AST and ALT. During exacerbations, the serum ALT concentration may be as high as 50 times the upper limit of normal, and alfa-fetoprotein (AFP) concentrations as high as 1000 ng/mL may be seen. A progression

to cirrhosis is suspected when there is evidence of hypersplenism (decreased hemoglobin, white blood cell and/ or platelet counts) or impaired hepatic synthetic function (hypoalbuminemia and/or prolonged prothrombin time/ international normalized ratio (INR). Extrahepatic manifestations — Extrahepatic manifestations, which are thought to be mediated by circulating immune complexes, occur in 10 to 20 percent of patients with chronic HBV infection. As mentioned above,

acute hepatitis may be heralded by a serum sickness-like syndrome manifested as fever, skin rashes, arthralgia, and arthritis, which usually subsides with the onset of jaundice. The two major extrahepatic complications of chronic HBV are polyarteritis nodosa and glomerular disease. Natural Course and Phases of Chronic Hepatitis B Infection The natural course of chronic HBV infection is determined by the interplay between virus replication and the

host immune response. Other factors that may play a role in the progression of HBV-related liver disease include gender, alcohol consumption, and concomitant infection with other hepatitis virus(es). The outcome of chronic HBV infection depends upon the severity of liver disease at the time HBV replication is arrested. National Guidelines for Diagnosis & Management of Viral Hepatitis 19

Immune active Inactive Immune escape/ Phase Immune Tolerant (clearance) (immune control) Reactivation HBeAg HBeAg/Anti HBe Anti HBe Positive positive HBVDA HBV DNA cirrhosis 2x109IU/ml 2x104IU/ml HCC ALT Level ALT Liver histology Minimal minimal Active Hepatitis Minimal/ Inactive Active Hepatitis Inflammation inflammation AGE 20 35 60 35+ This phase seen in With increased immune HBeAg remains Progression from HBV transmission response HBV DNA level negative in HBeAg negative

at birth/1-2 years decreases. 70-85% with inactive phase to of life. low viral load HBeAg negative Liver enzymes fluctuate. <2 x 103 IU/mL hepatitis B with HBeAg +ve and with persistently mutation in core high viral load Active inflammation in normal liver or core promoter (107 IU/mL) but liver enzymes but region of HBV no elevation of ending in HBeAg hepatitis activity genome resulting transaminases and negative and may continue in in HBeAg negative minimal activity HBeAb +ve some but with continued

in liver as there is (HBeAg seroconversion) HBV replication and no immunological Fibrosis/ progression in liver response. Ongoing activity could cirrhosis noted in disease. progress those who had to fibrosis and liver progressed in cirrhosis immune active with HCC. phase Fig.2: Natural History of Chronic HBV Infection Modified from: Hepatitis B Virus Infection, Yun-Fan Liaw, Chia-Ming Chu, Lancet 2009; 373 : 582-92 20 National Guidelines for Diagnosis & Management of Viral Hepatitis

Replicative phase: Immune tolerance — In patients with a perinatally acquired HBV infection, the initial phase is characterized by high levels of HBV replication—the presence of hepatitis B e antigen (HBeAg) and high levels of HBV DNA in serum—but no evidence of active liver disease as manifested by lack of symptoms, normal serum ALT concentrations, and minimal changes on liver biopsy. The immune tolerance phase usually lasts 10 to 30 years, during which there is a very low rate of spontaneous

HBeAg clearance. Replicative phase: Immune clearance — The transition from the immune tolerance to the immune clearance phase occurs during the second and third decades in patients with perinatally acquired HBV infection. During the immune clearance phase, spontaneous HBeAg clearance increases to an annual rate of 10 to 20 percent. HBeAg seroconversion is frequently, but not always, accompanied by biochemical exacerbations (abrupt

increases in serum ALT). Exacerbations are believed to be due to a sudden increase in immune-mediated lysis of infected hepatocytes. They are often preceded by an increase in serum HBV DNA and a shift of HBcAg (hepatitis B core antigen) from nuclear to cytoplasmic sites within hepatocytes, suggesting that immune clearance may be triggered by an increase in viral load or a change in the presentation of viral antigens. How these changes occur is not known.

Most exacerbations are asymptomatic and are discovered during routine follow-up. However, some are accompanied by symptoms of acute hepatitis and may lead to the incorrect diagnosis of acute hepatitis B in patients who are not previously known to have chronic HBV infection. Exacerbations may be associated with an elevation in the IgM anti-HBc titer, which may lead to misdiagnosis of acute HBV infection and an increase

in the serum alpha-fetoprotein concentration, which may raise concerns about the diagnosis of HCC. Patients with severe exacerbations should be referred to specialized centers for liver transplantation and receive treatment with nucleos(t)ide analogues (NAs). Not all exacerbations lead to HBeAg sero-conversion and clearance of HBV DNA from the serum, a phenomenon termed abortive immune clearance. These patients may develop recurrent exacerbations with an intermittent

disappearance of serum HBV DNA with or without a transient loss of HBeAg. Such repeated episodes of hepatitis may increase the risk of developing cirrhosis and HCC. Low or non-replication phase/inactive carrier state — Patients in the low or non-replicating phase/inactive carrier state are HBeAg negative and anti-HBe positive. In some patients, HBV DNA is undetectable in serum by polymerase chain reaction assays, and liver disease is in remission as evidenced by normal serum ALT

concentrations and the resolution of necro-inflammation in liver biopsies. HBeAg-negative patients with a persistently normal serum ALT can still have significant histologic inflammation and/or fibrosis. Because of the fluctuating nature of chronic HBV infection, patients should not be categorized as inactive carriers unless there are at least three ALT levels and two to three HBV DNA levels over a 12-month period

of observation. Studies suggest that combined quantification of HBsAg level and HBV DNA at a single time point may help in differentiating inactive carrier phase versus HBeAg-negative chronic hepatitis. HBsAg <1000 international units/mL in an HBeAg-negative patient with serum HBV DNA <2000 international units/mL identifies the inactive carrier phase with a high diagnostic accuracy (94 percent). HBeAg-negative chronic hepatitis — Some patients continue to have moderate levels of HBV replication and

active liver disease (elevated serum ALT and chronic inflammation on liver biopsies), but remain HBeAg negative. Such patients are said to have HBeAg-negative chronic hepatitis. They have a residual wild-type virus or HBV variants that cannot produce HBeAg due to precore or core promoter genetic variations. Patients with HBeAg-negative chronic hepatitis are older and have more advanced liver disease. They also tend to have fluctuations in HBV DNA and ALT levels.

National Guidelines for Diagnosis & Management of Viral Hepatitis 21

Resolution of chronic HBV infection — Some patients with chronic HBV infection become HBsAg negative. The annual rate of delayed clearance of HBsAg has been estimated to be 0.5 to 2 percent in Western patients and much lower (0.1 to 0.8 percent) in Asian countries In most reports, patients who cleared HBsAg appeared to have a good prognosis. In the absence of other causes of liver injury, progression to cirrhosis and hepatic

decompensation after HBsAg clearance is rare. However, the risk of hepatocellular carcinoma remains, and surveillance should continue in those who have HCV or hepatitis D virus (HDV) co-infection, cirrhosis, or are older than 50 years at the time of HBsAg clearance. Laboratory Diagnosis Laboratory testing during the acute phase reveals elevations in the concentration of alanine and aspartate aminotransferase levels (ALT and AST); values up to 1000 to 2000 international units/L are typically seen during

the acute phase with ALT being higher than AST. The serum bilirubin concentration may be normal in patients with anicteric hepatitis. The prothrombin time is the best indicator of prognosis. In patients who recover, the normalization of serum aminotransferases usually occurs within one to four months. A persistent elevation of serum ALT for more than six months indicates a progression to chronic hepatitis. Assessment and Staging of HBV Chronic infection

Routine assessment of HBsAg-positive persons is needed to guide management and indicate the need for treatment. This generally includes assessment of: 1. Serological markers of HBV infection ; 2. Measurement of HBV DNA levels; and 3. Assessing severity of liver disease by a. Liver enzymes b. Non-invasive tests (NITs) such as aspartate aminotransferase (AST)-to-platelet ratio index (APRI), FIB-4, transient elastography (FibroScan). c. Liver biopsy, if available Serological markers of HBV infection

Chronic Hepatitis B (CHB) infection is defined as the persistence of HBsAg for more than 6 months. Previous HBV infection is characterized by the presence of antibodies (anti-HBs and anti-HBc). Immunity to HBV infection after vaccination is characterized by the presence of only anti-HBs. HBeAg: It also needs to be established whether the person is in the HBeAg-positive or HBeAg-negative phase of infection (please see the table above), though both require lifelong monitoring, as the condition may change

over time. In persons with CHB, a positive HBeAg result usually indicates the presence of active HBV replication and high infectivity. Spontaneous improvement may occur following HBeAg-positive sero-conversion (anti- HBe), with a decline in HBV replication, and normalization of ALT levels. This confers a good prognosis and does not require treatment. HBeAg can also be used to monitor treatment response, as HBeAg (anti-HBe) sero-

conversion in HBeAg-positive persons with a sustained undetectable HBV DNA viral load may be considered a potential stopping point of treatment. However, this is infrequent even with potent NAs therapy. Some HBeAg- negative persons have active HBV replication but are positive for anti-HBe and do not produce HBeAg due to the presence of HBV variants or pre-core mutants. 22 National Guidelines for Diagnosis & Management of Viral Hepatitis

Measurement of HBV DNA levels Plasma HBV DNA concentrations quantified by real-time polymerase chain reaction (PCR) correlate with disease progression and are used to differentiate active HBeAg-negative disease from inactive chronic infection, and for decisions to treat and subsequent monitoring. HBV DNA concentrations are also used for optimal monitoring of response to antiviral therapy, and a rise may indicate the emergence of resistant variants.

Plasma HBV DNA levels should be expressed in IU/mL to ensure comparability; values given as copies/mL can be converted to IU/mL by dividing by a factor of 5 to approximate the conversion used in the most commonly used assays (i.e. 10,000 copies/mL = 2000 IU/mL; 100,000 copies/mL = 20,000 IU/mL; 1 million copies/mL = 200,000 IU/mL). The same assay should be used in the same patient to evaluate the efficacy of antiviral therapy. Assessing severity of liver disease A full assessment should include

• Clinical evaluation for features of cirrhosis and evidence of decompensation, and • Measurement of serum bilirubin, albumin, ALT, AST, alkaline phosphatase (ALP), and prothrombin time; as well as full blood count, including platelet count. • Other routine investigations include ultrasonography and alpha-fetoprotein (AFP) measurement for periodic surveillance for HCC, and endoscopy for varices in persons with cirrhosis.

Please refer to Annexure 1 for details on assessing severity of liver disease ( fibrosis and cirrhosis) Please refer to Annexure 2 for the algorithm for laboratory diagnosis of Viral hepatitis Management Whom To Treat It is critical to evaluate the patient carefully as treatment of hepatitis B is life-long in most cases. The clinical spectrum and phases of the chronic hepatitis B pose difficulty in deciding on whom to treat. Table 2: Whom to treat and whom to monitor WHOM TO TREAT WHOM NOT TO TREAT

As a priority, all adults, adolescents Antiviral therapy is not recommended and can be deferred in and children with CHB and evidence of persons without evidence of cirrhosis, and with persistently compensated or decompensated cirrhosis normal ALT levels and low levels of HBV replication (HBV should be treated, regardless of ALT levels, DNA <2000 IU/mL), regardless of HBeAg status or age. HBeAg status or HBV DNA levels • Where HBV DNA testing is not available: Treatment

can be deferred in HBeAg-positive persons aged 30 years or less and persistently normal ALT levels. Treatment is recommended for adults with CHB Continued monitoring is necessary in all persons with who do not have evidence of cirrhosis, but are CHB, but in particular those who do not currently meet aged more than 30 years (in particular), and have the recommended criteria for whom to treat or not treat, persistently abnormal ALT levels and evidence to determine if antiviral therapy may be indicated in the

of high-level HBV replication (HBV DNA >20 future to prevent progressive liver disease. These include 000 IU/mL), regardless of HBeAg status. persons without cirrhosis aged 30 years or less, with HBV DNA levels >20 000 IU/mL but persistently normal ALT; National Guidelines for Diagnosis & Management of Viral Hepatitis 23

Non-Cirrhotic HBeAg positive Chronic HBV infected patient VIRAL HBV DNA HBV DNA HBV DNA LOAD < 2000 IU/mL < 2000-20,000 IU/mL > 20,000 IU/mL ALT Any Any ALT-2x ULN or N ALT>2x ULN • If elevated ALT, • If elevated ALT, exclude other exclude other • Observe for causes causes 3 months, if • Assess fibrosis • Assess fibrosis • Assess fibrosis no concerns noninvasively noninvasively noninvasively of hepatic Fibrosis • Monitor 3 monthly • Monitor 3 monthly • Monitor 3 monthly decompensation

• Individualize liver • Individualize liver • Individualize liver • Treat if no biopsy@ biopsy@ biopsy@ seroconversion • Treat if moderate to • Treat if moderate to • Treat if moderate to • Obtain histology severe inflammation severe inflammation severe inflammation or assess or significant or significant or significant fibrosis non- fibrosis.$ fibrosis. $ fibrosis. $ invasively. $ @Biopsy if non-invasive tests suggest evidence of significant fibrosis, ALT persistently elevated, Age>35 yr or family h/o

HCC or cirrhosis.$ • Moderate to severe inflammation on liver biopsy means either Hepatic activity index by Ishak activity score >3/18 or METAVIR activity score A2 or A3 • Significant fibrosis on liver biopsy means F >2 by METAVIR fibrosis score or Ishak fibrosis stage > 3 • Liver stiffness > 8 kPa (by Fibroscan) or APRI > 1.5 indicates significant fibrosis; Liver stiffness > 11 kPa (by Fibroscan) or APRI > 2.0 indicates cirrhosis

Fig.3: Treatment indications for non-cirrhotic HBeAg positive chronic HBV infected patients Non-Cirrhotic HBeAg negative Chronic HBV infected patient VIRAL HBV DNA < 2000 IU/mL HBV DNA > 2000 IU/mL LOAD ALT ALT > ULN ALT > ULN ALT-2x ULN or N ALT>2x ULN • If elevated ALT, • Assess fibrosis • Observe for 3 exclude other causes noninvasively months, if no • Assess fibrosis • Monitor ALT 3-6 concerns of hepatic • Assess fibrosis noninvasively monthly and DNA decompensation noninvasively

• Monitor 3 monthly 6-12 monthly • Treat if no Fibrosis • Individualize liver • Individualize liver • Individualize liver seroconversion biopsy@ biopsy@ biopsy@ • Obtain histology • Treat if moderate • Treat if moderate to • Treat if moderate or assess fibrosis to severe severe inflammation to severe non-invasively. $ inflammation or or significant inflammation or significant fibrosis.* fibrosis.$ significant fibrosis.$

@Biopsy if non-invasive tests suggest evidence of significant fibrosis, ALT persistently elevated, Age>35 yr or family h/o HCC or cirrhosis.$ • Moderate to severe inflammation on liver biopsy means either Hepatic activity index by Ishak activity score >3/18 or METAVIR activity score A2 or A3 • Significant fibrosis on liver biopsy means F >2 by METAVIR fibrosis score or Ishak fibrosis stage > 3

• Liver stiffness > 8 kPa (by Fibroscan) or APRI > 1.5 indicates significant fibrosis; Liver stiffness > 11 kPa (by Fibroscan) or APRI > 2.0 indicates cirrhosis Fig.4 :Treatment indications for non-cirrhotic HBeAg-negative chronic HBV-infected patients Reference: SK Sarin et al, Asian-Pacific clinical practice guidelines on the management of Hepatitis B: A 2015 update; Hepatol Int (2016) 10:1-98 24 National Guidelines for Diagnosis & Management of Viral Hepatitis

There are various antiviral agents recommended for treatment of CHB. The section below deals with these drugs and their dosages in adults and children. Table 3: Recommended drugs for the treatment of CHB and their doses in adults Drug Dose 1 Tenofovir disoproxil fumarate (TDF) 300 mg once daily 2 Entecavir ( adult with compensated liver disease and lamivudine naive) 0.5 mg once daily 3 Entecavir ( adult with decompensated liver disease) 1 mg once daily

4 Tenofovir alafenamide fumarate ( TAF) 25 mg once daily Table 4: Recommended drugs for the treatment of CHB and their doses in children Drug Dose Tenofovir (in children 12 300 mg once daily years of age and older, and weighing at least 35kg) Entecavir (in children 2 years Recommended once-daily dose of oral solution (mL) of age or older and weighing Body weight (kg) Treatment –naïve persons* at least 10kg. the oral solution 10 to 11 3 should be given to children with a body weight up to 30kg) >11 to 14 4

>14 to 17 5 >17 to 20 6 >20 to 23 7 >23 to 26 8 >26 to 30 9 >30 10 *Children with body weight more than 30 kg should receive 10mL (0.5mg) of oral solution or one 0.5 mg tablet once daily Selection of antiviral drug for CHB: • In all adults, adolescents and children aged 12 years or older in whom antiviral therapy is indicated, the NAs which have a high barrier to drug resistance (tenofovir or entecavir) are recommended.

• In woman of childbearing age Tenofovir may be preferred as the drug of choice in the eventuality of a pregnancy. Entecavir is not recommended in pregnancy. • Tenofovir is preferred in patients who have been exposed to lamivudine who have a potential for Entecavir resistance. • Entecavir is recommended in children aged 2–11 years. • Entecavir may be preferred over Tenofovir in: National Guidelines for Diagnosis & Management of Viral Hepatitis 25

Age > 60 years; bone disease due to chronic steroid use or use of other medications that worsen bone density, history of fragility fracture, osteoporosis; altered renal function with eGFR < 60 mL/min/1.73 m2 or albuminuria > 30 mg/ 24 hr or moderate dipstick proteinuria or Low phosphate (<2.5 mg/dL) or in patient on hemodialysis (Ref: EASL guidelines) • Tenofovir alafenamide fumarate ( TAF) is the drug of choice in patients with reduced renal function or

bone disease bone toxicities, where entecavir is contraindicated • Drugs with a low barrier to resistance (lamivudine, adefovir or telbivudine) are available but not recommended as they lead to drug resistance. • Despite the inconvenience of injections and side effects PegIFN may be considered in a sub group of non cirrhotics where a finite therapy might achieve a sustained response. Key points in counseling and preparing the patient prior to initiation of therapy

Preparing to start treatment: Patients should be counseled about the indications for treatment, including the likely benefits and side-effects, willingness to commit to long-term treatment, and need to attend for follow-up monitoring both on and off therapy; the importance of full adherence for treatment to be both effective and reduce the risk of drug resistance; and cost implications. Measurement of baseline renal function and assessment of baseline risk for renal dysfunction should be

considered in all persons prior to initiation of antiviral therapy When To Stop Treatment All persons with cirrhosis based on clinical evidence (or APRI score >2 in adults) require lifelong treatment with NAs, and should not discontinue antiviral therapy because of the risk of reactivation, which can also cause severe acute-on-chronic liver injury. The discontinuation of treatment of Hepatitis B is usually not recommended and should be done at specialized

centers under the guidance of the necessary expertise Decision to discontinue therapy requires careful consideration on the risk of virological relapse, decompensation and death on discontinuation versus the financial implication of continued cost of medications and monitoring. All patients with cirrhosis should not discontinue antiviral therapy because of the risk of reactivation which may potentially lead to decompensation and death. Discontinuation may be considered in patients without cirrhosis:

• With persistent HBsAg loss after one year of consolidation treatment (regardless of prior HBeAg status or availability of HBV DNA levels) • HBeAg loss and sero-conversion to Anti-HBe after completion of one year (preferably 3 years) of additional treatment with persistently normal ALT levels and undetectable HBVDNA levels. • Careful long term monitoring for reactivation with serial 3-6 monthly HBeAg, ALT and HBVDNA levels is

mandatory in those who have discontinued treatment for consideration of retreatment. Relapse may occur after stopping therapy with NAs. Retreatment is recommended if there are consistent signs of reactivation (HBsAg or HBeAg becomes positive, ALT levels increase, or HBV DNA becomes detectable again) 26 National Guidelines for Diagnosis & Management of Viral Hepatitis

Monitoring The disease is complex and has sequelae, resolution as well as drugs side effects. Hence, three types of monitoring is necessitated • Monitoring for disease progression and treatment response in persons with CHB prior to, during and post-treatment • Monitoring for tenofovir or entecavir side-effects • Monitoring for hepatocellular carcinoma Table 5: Monitoring : Parameters and frequency Interval 3 Months 6 Months 9 Months 12 Months (Months) HBeAg/Anti HBe √ √ √ √ √ √ √ √ √ √ √

HBVDNA √ √ √ √ √ √ √ √ √ √ √ ALT √ √ √ √ √ √ √ √ √ √ √ √ AST √ √ CBC (Platelet) √ √ √ APRI/FIB4/ √ √ √ Fibro Scan USG √ √ √ √ Serum Creatinine √ eGFR √ Phosphate √ Urine Protein: √ Creatinine Ratio Not on Treatment Treatment Discontinue Treatment Monitoring for those: Not on Treatment: Frequent monitoring with monthly ALT and 3 monthly HBeAg/Anti HBeAg and HBVDNA quantitative would be required in those with fluctuating ALT and HBV DNA 2000-20,000 IU/mL, who are as yet not on treatment.

In active chronic B with persistently normal ALT and HBV DNA <20,000IU/mL, may be monitored annually On Treatment: More frequent 3-6 monthly assessment is required initially in those with advanced liver disease in the first year. Discontinued Treatment: Careful long term monitoring for reactivation with serial 3-6 monthly HBeAg, ALT and HBVDNA levels is mandatory in those who have discontinued treatment for consideration of retreatment. National Guidelines for Diagnosis & Management of Viral Hepatitis 27

Monitoring for disease progression and treatment response in persons with CHB prior to, during and post-treatment It is recommended that the following be monitored at least annually: --ALT levels (and AST for APRI), HBsAg, HBeAg, and HBV DNA levels (where HBV DNA testing is available) --Non-invasive tests (APRI score, FIB-4 or FibroScan) to assess for the worsening of fibrosis/presence of cirrhosis, in those without cirrhosis at baseline

--If on treatment, adherence should be monitored regularly and at each visit. More frequent monitoring is needed • In persons who do not yet meet the criteria for antiviral therapy: More frequent monitoring for disease progression may be indicated in: persons who have intermittently abnormal ALT levels or HBV DNA levels that fluctuate between 2000 IU/mL and 20 000 IU/mL (where HBV DNA testing is available) and in HIV co-infected persons.

• In persons on treatment or following treatment discontinuation: More frequent on-treatment monitoring (at least every 3 months for the first year) is indicated in: persons with more advanced disease (compensated or decompensated cirrhosis); during the first year of treatment to assess treatment response and adherence; where treatment adherence is a concern; in HIV co-infected persons and in persons after discontinuation of treatment. Monitoring for tenofovir and entecavir toxicity

Measurement of baseline renal function and assessment of baseline risk for renal dysfunction should be considered in all persons prior to initiation of antiviral therapy. Renal function should be monitored annually in persons on long-term tenofovir or entecavir therapy, and growth monitored carefully in children. Measurement of baseline renal function includes: serum creatinine (Cr) levels, and calculation of creatinine

clearance (CrCl)/estimated glomerular filtration rate (eGFR) using the Cockcroft–Gault (CG) CG formula: eGFR = (140 – age) x (weight in kg) x 0.85 (if female) / (72xCr in mg/dL) Table 6: Recommended dosage of Tenofovir in adults with renal impairment CrCl (mL/min) Dose 30-49 300 mg every 48h 10-29 300 mg twice weekly (every 72-96 hours) <10 and not on Haemodialysis No recommendation On Haemodialysis 300 mg every7d Monitoring for hepatocellular carcinoma (HCC)

Routine surveillance for HCC with abdominal ultrasound and alpha-fetoprotein testing every six months is recommended for: • Persons with cirrhosis, regardless of age or other risk factors • Persons with a family history of HCC • Persons aged over 40 years (lower age may apply according to regional incidence of HCC), without clinical evidence of cirrhosis (or based on APRI score ≤2), and with HBV DNA level >2000 IU/mL (where HBV DNA testing is available).

28 National Guidelines for Diagnosis & Management of Viral Hepatitis

Special Situations Pregnancy Care of the pregnant woman All pregnant women with HBV should be evaluated for the need of treatment for hepatitis B and any associated liver disease, and given advice about prevention of transmission. Only a proportion of those with hepatitis B virus infection (pregnant or otherwise) need treatment. Hepatitis B in a pregnant woman is not a reason for considering termination of pregnancy. Similarly, the need for

caesarean delivery should be decided based on obstetric indications, and not on the presence of HBV infection. Administration of hepatitis B vaccine to pregnant women with HBV provides no benefit either to the mother or the baby. Care of the baby Immunoprophylaxis of hepatitis B virus infection The newborn baby should be administered a timely first dose (the ‘birth dose’) of hepatitis B vaccine (monovalent) as soon as possible after birth, ideally within 24 hours. Even within this time duration, the earlier

it can be administered, the better. If, for some reason, the birth dose is not administered within 24 hours, it should still be administered as soon as it is possible and not omitted. This dose is administered intramuscularly in the anterolateral thigh. This birth dose must be followed by timely administration of 3-doses of hepatitis B-containing vaccine [e.g. monovalent hepatitis B vaccine, tetravalent combination vaccine with DPT (DPT-

Hep B) or a pentavalent vaccine (DPT+Hep B+Hib)]. The hepatitis B vaccine birth dose followed by these three doses is the most effective method for prevention of mother-to-child transmission of hepatitis B. Hepatitis B immunoglobulin (HBIG) may provide some additional protection in situations where risk of transmission is particularly high – i.e. babies born to mothers with hepatitis B who also have detectable

detectable HBeAg and/or high viral load. However, additional benefit provided by it, over properly-administered hepatitis B vaccine (as described above) is small. Also, HBIG is costly and has limited availability. If a decision is taken to administer HBIG (0.5 ml or 100 international units, intramuscular), this should be done as soon after birth as possible (and within 12-24 hours) and in a limb other than the one in which hepatitis B vaccine has been administered.

Data on benefit and risks of administering anti-hepatitis B drugs to the pregnant women for prevention of mother-to-child transmission are unclear. Breast feeding A mother who has hepatitis B may breast feed her baby, unless there is an exuding injury or disease of the nipple or surrounding skin. The advantages of breast feeding far outweigh the risk, if any, of transmission of hepatitis B to a baby who has received hepatitis B vaccine. Timing of testing

If it is felt that the baby needs to be tested for hepatitis B, this should be done only after 1 year of age. Any positivity before this age is difficult to interpret and may resolve spontaneously over time. National Guidelines for Diagnosis & Management of Viral Hepatitis 29

Co-morbidities HIV and Hepatitis B Co-infection The natural history of both diseases is affected when a person is co-infected with both HIV and Hep B and this has implications on management of both diseases. Current evidence suggests that human immunodeficiency virus (HIV) infection has an adverse impact on HBV-related liver disease progression, with higher serum HBV DNA polymerase activity, lower rates of loss of serum hepatitis B e antigen, and increased risk of cirrhosis, liver-

related mortality, and hepatocellular carcinoma at lower CD4 T-cell counts. HBV infection is more likely to be chronic in those with HIV infection. In some cohorts, liver disease has emerged as a leading cause of death in HIV-infected persons co-infected with either hepatitis B or C, as mortality due to other HIV-related conditions has declined following the introduction of antiretroviral therapy (ART).

Similarly, the HBV infection also negatively impacts the progression of HIV infection leading to faster immune deterioration and higher mortality. Other studies have suggested that HBV is associated with a rapidly progressive course of HIV infection . A retrospective analysis indicated that the risk of death in 64 individuals co-infected with HIV and HBV was approximately two-fold higher than that in individuals with HIV mono

infection. Prospective observational cohort among those with primary HIV infection showed that HBV co- infection is an independent predictor of immunologic deterioration in such group of patients. In another large prospective multicentre cohort by Chun et al among 2352 (PLHIV) with sero-conversion window of less than 3 years, co-infected persons with Hepatitis B were associated with two times higher risk of AIDS/death, higher among HBV co-infected patients compared to HBV mono-infected patients

The HIV-Hepatitis co-infected persons show faster CD4 decline, slower CD4 recovery following ART, increased incidence of AIDS and non-AIDS events, increased rate of ARV toxicity and increased chances of Immune reconstitution hepatitis. In one of the large cohort studies of more than 5000 co-infected persons, the relative risk of liver related deaths was found to be 17 times higher than those with HBV mono-infected patients.

Other challenges among co-infected include cross-resistance between HIV and HBV drugs, increased liver injury, either due to direct hepatotoxicity or to ART-related immune-reconstitution hepatitis, with elevation of ALT; if ART does not cover both HIV and HBV infections adequately, fulminant hepatitis is an eventuality. Evaluation of HIV and HBV Co-infected Persons The risk of HBV infection may be higher in HIV-infected adults, and therefore all persons newly diagnosed with

HIV should be screened for HBsAg. Those found positive for HBsAg should be evaluated further following the guidelines for evaluation of those with HBV Infection. Besides routing clinical evaluation, one should look for sign of cirrhosis and hepatic decompensation like ascites and pedal oedema. The lab investigations, besides routine haemogram and biochemistry, should specifically include Liver Function Test (LFT), prothrombin time, AFP, ultrasound and upper gastrointestinal endoscopy. The virological

examination should include HBeAg, Anti-HBe antibody and HBV DNA quantitative (Real-Time PCR). Assessment of severity of fibrosis : The assessment of degree of fibrosis and cirrhosis is important. Please refer to Annexure 1 for details. 30 National Guidelines for Diagnosis & Management of Viral Hepatitis

Treatment of HIV and HBV Co-infected patients All HIV positive patients with HBV co-infection should start dual anti HIV & HBV therapy with tenofovir based ART regimen irrespective of CD4 count, HBV viral load or status of liver disease e.g., ALT level or fibrosis stage. In HBV and HIV co-infected adults and adolescents, tenofovir + lamivudine + efavirenz as a fixed-dose combination is recommended as the preferred option to initiate ART under the National AIDS Control Program.

This three drug combination includes the drugs with efficacy against hepatitis B. Stopping Tenofovir based ART should be avoided in HIV + HBV co-infection for concern of severe hepatitis flare and decompensated following HBV reactivation. This treatment strategy has achieved high rates of HBV DNA suppression (90%), HBeAg loss (46%) and HBsAg loss (12%) in HBeAg-positive patients after 5 years of treatment, without evidence of resistance, and reduced

progression to cirrhosis with no significant differences in response in those with or without HIV co-infection . To date, no viral resistance to tenofovir in vivo has been described, although resistant strains have been identified in vitro. Although the risk of developing cirrhosis is negligible in HBV-HIV-co-infected persons on long-term tenofovir combined with lamivudine therapy, the risk of HCC persists, but is low.

If ARVs need to be changed because of HIV drug resistance or some drug toxicity, then tenofovir and lamivudine should be continued together with the new ARV drugs unless TDF is specifically contraindicated due to its toxicity. Prevention of HBV infection The risk of HBV infection may be higher in HIV-infected adults, and therefore all persons newly diagnosed with HIV should be screened for HBsAg and immunized if HBsAg is negative. Those already infected with HBV

(HBsAg positive) do not benefit from HBV vaccine. PLHIV who have already suffered from HBV in the past and have developed protective titre of Anti-HBs antibody (>10 mIU/mL) also do not require HBV vaccine. Response to HBV vaccine is lower in persons with HIV or with a low CD4 count, and a meta-analysis has shown that a schedule of four double (40 μg) doses of the vaccine provides a higher protective anti-HBs titre than the regular three 20 μg dose schedule

Besides this, all infants born to HBV positive women need to be immunized within 24 hours of birth (Dose - 0) followed by 6, 10 & 14 weeks (dose – 10 µg IM) and HBIG – (0.5 ml or 100 international units, intramuscular), this should be done as soon after birth as possible (and within 12-24 hours) and in a limb other than the one in which hepatitis B vaccine has been administered. National Guidelines for Diagnosis & Management of Viral Hepatitis 31

HBsAg Positive CIRRHOSIS • Clinical criteriab • NITs (APRI score >2 in adults or FibroScan) AGEc >30 Years (in Particulary) ALTd,e Persistently abnormal HBV DNA > 20,000 IU/ ml INITIATE NA THERAPY AND MONITOR • Tenofovir or entecavir • Entecavir in children aged 2-11 years Fig. 5: Algorithm on the management of persons with chronic hepatitis B infectiona Modified from WHO guidelines 2015 32 National Guidelines for Diagnosis & Management of Viral Hepatitis TNEMTAERT ROF TNEMSSESSA Yes No AGE≤30 years

ALTd,e ALTd,e ALTd,e Intermittently Persistently Persistently abnormal normal normal HBV DNA HBV DNA HBV DNA 2000 - < 2000 IU/ml < 2000 IU/ml 20,000 IU/ml DEFER TREATMENT AND MONITOR NIT : non-invasive tests, ALT alanine aminotransferase, APRI aspartase aminotransferase-to-platelet ratio index a Defined as persistence of hepatitis B surface antigen (HBsAg) for six months or more. The algorithm does not capture all potential scenarios, but the main categories for treatment or monitoring. Recommendations

for settings without access to HBV DNA testing are provided in the relevant chapters. b Clinical features of decompensated cirrhosis: Portal hypertension (ascites, variceal haemorrhage and hepatic encephalopathy), coagulopathy, or liver insufficiency (jaundice). Other clinical features of advanced liver disease/ cirrhosis may include: hepatomegaly, splenomegaly, pruritus, fatigue, arthralgia, palmar erythema, and oedema. c The age cut-off of >30 years is not absolute, and some persons with CHB less

than 30 years may also meet criteria for antiviral treatment. d ALT levels fluctuate in persons with chronic hepatitis B and require longitudinal monitoring to determine the trend. Upper limits for normal ALT have been defined as below 30 U/L for men and 19 U/L for women, though local laboratory normal ranges should be applied. Persistently normal/abnormal may be defined as three ALT determinations below or above the upper

limit of normal, made at unspecified intervals during a 6–12–month period or predefined intervals during 12-month period. e Where HBV DNA testing is not available, treatment may be considered based on persistently abnormal ALT levels, but other common causes of persistently raised ALT levels such as impaired glucose tolerance, dyslipidaemia and fatty liver should be excluded. Hepatitis C Infection

Hepatitis C virus, which, before its identification was labeled "non-A, non-B hepatitis," is a linear, single-stranded enveloped RNA virus belonging to the flavivirus family.

Clinical Course of Hepatitis C Infection Hepatitis C infection is usually acquired through infected syringes and needles, and transfusion of infected blood. Sexual transmission of HCV occurs infrequently in heterosexual couples. It is reported to be more common in HIV-positive persons, particularly in MSM. The risk of transmission of HCV from a mother to her child occurs in 4–8% of births to women with HCV infection, and in 10.8–25% of births to women with HIV and HCV co-infection.

HCV causes both acute and chronic hepatitis. Acute hepatitis is often clinically mild and marked by fluctuating elevations of serum aminotransferase levels; >50% likelihood of chronicity, leading to cirrhosis in >20%. Chronic infection with HCV is usually clinically silent, and is only very rarely associated with life-threatening disease. Spontaneous clearance of acute HCV infection occurs within six months of infection in 15–45% of

infected individuals in the absence of treatment. Almost all the remaining 55–85% of persons will harbor HCV for the rest of their lives (if not treated) and are considered to have chronic HCV infection. Left untreated, chronic HCV infection can cause liver cirrhosis, liver failure and HCC. Of those with chronic HCV infection, the risk of cirrhosis of the liver is 15–30% within 20 years. The risk of HCC in persons with cirrhosis is approximately 2–4% per year. Laboratory Diagnosis

As illustrated in figure 6, following an initial eclipse phase of 1–2 weeks when no virological or serological markers of infection may be detected, the natural course of HCV infection is characterized by the appearance of HCV RNA, then HCV core p22 Ag in the absence of an antibody response for a further 6–10 weeks. During this serological window, it has been shown that free (i.e. not complexed with antibody) HCV core antigen (HCVcAg)

can be detected in a proportion of individuals. Following the development of the antibody response, HCVcAg becomes complexed with these antibodies specific for HCV. Anti-HCV HCV RNA HCV Ag 0 1 2 3 4 5 6 months 24 decades Fig.6: Approximate Time course of virological and immunological markers of HCV infection with (A) Self-resolving HCV infection, and (B) Chronic HCV infection Ref: WHO guidelines; Feb. 2017 National Guidelines for Diagnosis & Management of Viral Hepatitis 33 esahp espilcE

Sero-con Virus Waning B chronic Serological Window version clearance anti-HCV Seroreversion Serological Window Seroconversion/actual phase phase HCV RNA Anti-HCV HCV Ag 0 1 2 3 4 5 6 esahp espilcE A months 12 24 decades 12

The standard method of diagnosis is by detection of anti-HCV antibody. Third generation immunoassays, which incorporate proteins from the core, NS3, and NS5 regions, can detect anti-HCV antibodies usually within 6 - 8 weeks of infection, i.e., from the initial phase of elevation of aminotransferases. Both rapid diagnostic tests (RDTs) and Immunoassays are available, with comparable sensitivity and specificity. This test does not

differentiate between current and past infection. The test may also be false positive in some situations and the diagnosis of an individual patient should be confirmed by HCV RNA detection prior to considering treatment. Since anti-HCV antibodies from an infected mother may persist in children <18 months of age, HCV RNA detection is also used to diagnose HCV infection in this age group (after 2 months of age)

Window period. Assays designed solely to detect antibodies to HCV inevitably have a window period of infectivity in early infection, during which antibodies may be undetectable. HCV RNA is typically not used to determine exposure to HCV, in spite of its short window period (1–2 weeks after the onset of acute infection) primarily because of cost. There are some situations with occult HCV infection, i.e. HCV RNA detectable in the

absence of any serological markers (i.e. HCV seronegative), which may be due to underlying immunosuppression in, for example, HIV-infected populations. Screening for HCV infection is done using serological testing for antibodies to HCV. If positive, a Nucleic Acid Test (NAT) for HCV RNA is needed to confirm chronic HCV infection. It is important to consider the possibility of infection with other blood borne viruses in persons infected with HCV, and to offer screening for HBV and

HIV in addition to HCV. Screening for other infections, for example tuberculosis (TB), is also indicated in some groups at risk, such as people living with HIV, prisoners and People who inject drugs (PWID). The algorithm for the diagnosis of Hepatitis C infection is enclosed as Annexure 2 Whom To Test Diagnostic serologic testing for HCV will be available to all people who would access the testing sites. However,

the initial focus would remain on testing specific population groups that have been documented to have a higher positivity rates in different studies across India. These focus or priority populations for testing will include but not limited to: 1. People who inject drugs ( PWID) 2. Men who have sex with men 3. Female sex workers 4. People who received blood transfusion before routine testing for hepatitis C 5. People who need frequent blood transfusion, such as, thalessemic and dialysis patients

6. People living with HIV 7. Inmates of prisons and other closed settings Treatment of Viral Hepatitis C in Adults The spectrum of disease in persons infected with HCV extends from mild fibrosis to cirrhosis and HCC. Compensated cirrhosis may progress over time to decompensated cirrhosis associated with ascites, oesophageal and gastric varices, and eventually to liver failure, renal failure and sepsis, all of which are life-threatening. HCC

may also occur at a rate of 2–4% per year in persons with cirrhosis. The diagnosis of decompensated liver disease is based on both clinical examination and laboratory monitoring, and therefore a careful medical examination of patients must be made prior to commencing therapy. The stage of disease may be assessed by liver biopsy or by using a variety of non-invasive methods. Chronic HCV infection is the leading cause for end-stage liver disease (cirrhosis) and its complications including

development of ascites, variceal bleeding, severe infections, etc, HCC and liver-related deaths worldwide. There 34 National Guidelines for Diagnosis & Management of Viral Hepatitis

is substantial economic burden if HCV patients are not treated. HCV is a major cause of morbidity globally, with estimated 495,000 deaths; in India, HCV infection was estimated to be responsible for 37,000 deaths in the year 2015. The availability of highly effective DAAs has however changed the HCV treatment paradigm, leading to hope of elimination of this infection as a public health threat by the year 2030. In a recent study, this has been

demonstrated that the treatment with generic DAAs available in India will improve patient outcomes, provide a good value for money within 2 years, and be ultimately cost-saving. Therefore, HCV treatment should be a priority from a public health as well an economic perspective. Treating HCV-infected persons could prevent decompensated cirrhosis, HCC and liver-related mortalities. Treating all persons with HCV along with preventive measures will ultimately eliminate HCV infection from India.

Staging of HCV infection is important as it identifies patients with advanced disease, a group that requires enhanced monitoring and prioritization for treatment before the onset of decompensated cirrhosis. In many high-income countries, all persons with chronic HCV infection who do not have a contraindication for therapy are considered to be suitable for treatment (although many are not able to access treatment because of eligibility restrictions placed by third- party payers to reduce costs).

Clinical Assessment Before Initiating Treatment A number of clinical considerations are important for the management of persons with chronic HCV infection. Pre-treatment evaluation of the risk of adverse events should be based on the patients clinical details, concomitant medications, and knowledge of treatment regimen to be administered. A detailed history for alcohol consumption as well as any other medications that the patient might be taking

should be taken. An alcohol intake assessment should be done for all persons with HCV infection followed by the offer of a behavioral alcohol reduction intervention for persons with moderate-to-high alcohol intake. The risk of cirrhosis and HCC varies, depending upon certain patient characteristics or behaviors. For example, men, persons who consume excess alcohol, persons with HBV or HIV co-infection and immunosuppressed

individuals are all at higher risk of developing cirrhosis or HCC. Disease associated with HCV infection is not confined to the liver. Extrahepatic manifestations of HCV include cryoglobulinaemia, glomerulonephritis, thyroiditis and Sjogren syndrome, insulin resistance, type 2 diabetes, and skin disorders such as porphyria cutanea tarda and lichen planus. Persons with chronic HCV infection are more likely to develop cognitive

dysfunction, fatigue and depression. These outcomes may be associated with replication of the virus in the brain; however, the causal link between these manifestations and chronic HCV infection is not certain. Assessment of Degree of Fibrosis Assessing the degree of liver fibrosis is an important step in the clinical management of persons with HCV infection. Persons with cirrhosis are at increased risk of HCC and death due to liver failure. Furthermore, the

selection of treatment regimens can depend on the presence or absence of cirrhosis. Please refer to Annexure 1 for assessment of degree of fibrosis and cirrhosis Baseline and follow-up Investigations The directly acting antivirals are much better tolerated by patients, as they have fewer adverse events and thus less need for early discontinuation of therapy. However, there remains the need for laboratory monitoring in

patients with cirrhosis, those with significant comorbidities and those treated with ribavirin therapy. A summary monitoring schedule framework for the treatment of patients is shown in Table below. If blood parameters become abnormal on therapy, increased monitoring and dose adjustment may be required. Clinical judgement based on the patient’s clinical details such as presence of HIV co-infection, cirrhosis or renal impairment,

potential Drug –Drug Interactions and clinical well-being during treatment may necessitate more frequent monitoring National Guidelines for Diagnosis & Management of Viral Hepatitis 35

Table 7: Monitoring schedule framework for the treatment of patients Time Regimen: Only DAAs Regimen: DAAs and Ribavirin (non-cirrhotic usually) (cirrhotic usually) CBC, Adherence and HCV CBC, Adherence and HCV RNA S.Creatinine, LFT side effects RNA S.Creatinine , LFT side effects Baseline Yes Yes Yes Yes Week 1 Yes Yes Week 2 Yes Yes Week 4 Yes Yes Yes Yes Week 8 Yes Yes Week 12 Yes Yes Week 12 after Yes Yes Yes completion of treatment ( SVR-12)

CBC, complete blood counts; LFT, liver function tests; SVR, sustained viral response Whom To Treat Any individual diagnosed to have infection with hepatitis C virus (viremia +) needs treatment. The duration of treatment will depend on the several situations such as, cirrhosis versus non-cirrhosis, presence of decompensation (ascites, variceal bleeding, hepatic encephalopathy, or infection(s), treatment naïve versus treatment experienced (to peg IFN, DAAs, etc). What Regimen To Use

DAAs are the recommended first line treatment in India. The combination of the DAAs and the duration of treatment will depend on presence or absence of cirrhosis and on the genotype of the virus. The following algorithm will provide guidance on selection of regimen and the duration in treatment naïve hepatitis C patient . Person with confirmed HCV infection (detected HCV RNA) Undertake baseline investigations – APRI,FIB-4 and Elastography (if available) Patient does not Patient has Cirrhosis

have Cirrhosis (compensated, Child-Pugh A) Treat with SOF + Treat with SOF + DCV for 12 weeks VEL for 12 weeks Perform HCV RNA 12 weeks after completion of the treatment HCV RNA not detected HCV RNA detected Treatment completed Refer to higher center for further management SOF, sofosbuvir; DCV, daclatasvir; VEL, velpatasvir Fig. 7: Algorithm for guidance on selection of regimen and duration of treatment in hepatitis C naïve patient . 36 National Guidelines for Diagnosis & Management of Viral Hepatitis

Table 8: Regimens recommended Regime Category of patients Regime recommended Duration of type Treatment I Patient without cirrhosis(uncomplicated) Sofosbuvir(400mg) & Daclatasvir(60mg)* 84 days (12 wks) II Patient with cirrhosis- Sofosbuvir(400mg) + Velpatasvir(100mg) 84 days(12 wks) compensated (Child-Pugh A) III Patient with cirrhosis- decompensated Sofosbuvir(400mg) + Velpatasvir 84 days(12 wks) (Child-Pugh B and C)** (100mg) & Ribavirin(600-1200mg**) In Ribavirin intolerant patients - 168days ( 24 wks)

Sofosbuvir(400mg) + Velpatasvir(100mg) *dose adjustments in PLHIV, renal insufficiency, etc. ** Refer to the Model Treatment Center (MTC) Table 9: Dosage of recommended DAA Name of drug Dosage Sofosbuvir 400 mg once a day Daclatasvir 60mg once a day Sofosbuvir + Velpatasvir Sofosbuvir(400mg) + Velpatasvir (100mg) once a day Ribavirin 800-1200 mg (to be decided based on weight, hemoglobin level, renal function and presence of cirrhosis) Counseling Messages for Screening Test Results:

All patients should be provided information on the meaning of their test results by the attending clinicians/ trained health care workers/peer counselors: Providing Pre-test information: through media such as posters, brochures, websites and short video clips shown in waiting rooms. This would include information on viral hepatitis and the benefits of testing for hepatitis B or C; the meaning of a positive and negative test result; a brief description of prevention options; confidentiality

of the test result; the practical implications of a positive test result, including the when and where of treatment available. Post-test information/counseling for a non-reactive hepatitis C screening test: » Explain the meaning of the non-reactive antibody test, ensuring that the patient understands a negative antibody test does not protect him/her from future infection in the event of risk taking behaviors. » Discuss that if the patient was recently exposed (6 months), he/she may be in a window period and

recommend repeat screening in 6 months, and provide information on hepatitis C prevention, risk and harm reduction. » Encourage the patient to make healthy choices and to get vaccinated against hepatitis B, if appropriate. Post- test counseling and linkages to treatment services for a reactive hepatitis C screening test: » Explain the meaning of the reactive antibody test and counsel on the need for diagnostic testing

(hepatitis C RNA test) to confirm a diagnosis of chronic hepatitis and other tests for staging of liver disease. » Explain that the patient is most likely chronically infected and provide basic hepatitis C disease and treatment information. Make an active referral to the viral hepatitis treatment units. » Discuss the importance of minimizing risk behaviors to avoid transmitting hepatitis C infection to others, and encourage notification and screening of needle sharing and sexual partners.

» Encourage and offer HBV and HCV testing for family members, including children, and sexual partners. » Discuss healthy liver practices, including stopping or reducing alcohol intake and getting vaccinated against hepatitis A and B, if appropriate. National Guidelines for Diagnosis & Management of Viral Hepatitis 37

Adherence counseling by trained pharmacist: 1) Pill count: the total number of pills/doses dispensed and the total number of pills/doses returned at monthly visits for each drug for the entire treatment duration for all patients; 2) Patient self-reports: it helps to determine reasons for non-adherence Though the majority of patients can be initiated the treatment for hepatitis C, there are several situations in which it is recommended to refer the patient to a specialized center. These include:

a. Patients with decompensated cirrhosis b. Treatment experienced patients c. Patients on chemotherapy with deranged liver enzymes d. Patient with impaired renal function e. Patient with HCC f. Paediatric patients g. Thalassemic patients Side Effects of Drugs Used in Treatment New DAA regimens are well tolerated by patients. Certain regimens have been shown to be safe for use in patients with decompensated liver cirrhosis and those who have undergone liver transplantation. However,

close monitoring is required in these patients and it is recommended that such regimens be undertaken only in units with the expertise to manage these patients and treat complications if they arise. Daclatasvir: The common adverse reactions associated with this drug are fatigue, headache and nausea, seen in studies that have either used the drug in combination with sofosbuvir with or without ribavirin.

Sofosbuvir with or without ledipasvir: Both drugs have been well tolerated by patients. They are reasonably well accepted by patients, with low rates of discontinuation in clinical studies. Fatigue, headache, insomnia and nausea are the most common adverse events reported. Recent evidence has emerged of significant bradyarrhythmias associated with sofosbuvir in patients also taking amiodarone and therefore it is contraindicated in these patients.

Sofosbuvir with Velpatasvir: Both drugs have been well tolerated by patients. Headache, fatigue, anemia, nausea, insomnia, diarrhea, weakness, rash and depression are the most common adverse events reported, which are at as similar frequency to placebo-treated patients. Dose adjustment of ribavirin Anaemia is a common, predictable side-effect of ribavirin therapy and dose adjustment is often required. Patients whose haemoglobin level falls below 10 g/dL should have their ribavirin dose reduced from

800–1200 mg/day (depending on the patient’s weight and HCV genotype) to 600 mg/day. A patient whose haemoglobin level falls below 8.5 g/dL should discontinue ribavirin therapy. For patients with a history of stable cardiovascular disease, dose reduction of ribavirin is required if the haemoglobin decreases by ≥2 g/dL during any 4-week period. In addition, for these patients, if the haemoglobin remains <12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination therapy.

The dose of ribavirin in patients with renal failure must also be adjusted; patients with an eGFR <50 mL/ min/1.73 m2 should not be treated with ribavirin and those on haemodialysis must have the dose lowered to 200 mg per day or take it three times per week. Increased monitoring is required in this group. Among patients with decompensated cirrhosis, ribavirin dosing should either be weight-based or started at an initial dose of 600 mg and increased as tolerated.

38 National Guidelines for Diagnosis & Management of Viral Hepatitis

Drug Interactions with DAA The following tables provide common drug interactions of the commonly used DAA. Therapy with DAAs: contraindications/warnings There are few contraindications to treatment with DAAs. The cytochrome P450 (CYP)/P-glycoprotein (P-gp) inducing agents, such as carbamazepine and phenytoin, are contraindicated with all regimens. Simultaneous use lead to significantly reduced concentrations of DAAs, which may lead to virological failure.

Other concomitant medicine-related interactions are discussed in table ….. The University of Liverpool website, www.hep-druginteractions.org, is a good resource for checking for drug interactions with DAA. Sofosbuvir should be used with caution in patients with severe renal impairment (eGFR <30 ml/min/1.73 m2) at MTC . Table 10: Contraindications to therapy with Ribavirin Absolute Contraindication Relative Contraindication • Pregnancy or unwillingness • Abnormal haematological indices: to use contraception

» Hemoglobin <10 g/dL • Breastfeeding women » Neutrophil count <1.5x109/L • Severe concurrent medical disease, including severe infections » Platelet count <90x109/L • Poorly controlled cardiac failure • Serum creatinine >1.5 mg/dL • Chronic obstructive pulmonary disease • Haemoglobinopathies (sickle cell disease or thalassaemia) • Previous ribavirin hypersensitivity • Significant coronary artery disease • Co-administration of didanosine

Annexure-3 highlights drug interactions between DAA and some commonly prescribed medications. The University of Liverpool website, www.hep-druginteractions.org, is a good resource for checking for drug interactions with DAAs. Special Situations and co-morbidities Treatment of Patients with Decompensated Cirrhosis DAAs can cause severe complications when prescribed to persons with decompensated cirrhosis (presence of

ascites, jaundice, history of hepatic encephalopathy and variceal bleed or Child-Pugh score ≥7 [Class B and C], http://www.hepatitisc.uw.edu/page/clinical-calculators/ctp). Therefore, they should be used only in settings where specialized care for managing such cases is available. Therefore refer all these patients to a specialized center for further evaluation, HCV genotype estimation should be done in all patients. Following regimens would be used to treat these patients (Table 11).

Table 11: DAAs in the Treatment of Decompensated Cirrhosis * All Genotype Ribavirin tolerant Daily fixed-dose combination of SOF (400 mg) + VEL (100 mg) + weight-based RBV** x 12 weeks Ribavirin intolerant Daily fixed-dose combination of SOF (400 mg) + VEL (100 mg) x 24 weeks SOF: sofosbuvir; VEL: velpatasvir; RBV: ribavirin. * to be managed at model treatment center (MTC), **Ribavirin should be administered orally with food twice daily, with the dose determined according to body weight (1000

mg daily in patients with a body weight of <75 kg and 1200 mg daily in patients with a body weight ≥75 kg). Ribavirin should be started at lower dose (600 mg perday) then gradually increase to the máximum tolerated dose. National Guidelines for Diagnosis & Management of Viral Hepatitis 39

Management of Treatment Experienced Patients Refer all these patients to a specialized center for further evaluation, especially analysis for resistance associated substitutions (RAS), endoscopy, imaging (TPCT, CEMR, etc), etc. HCV genotype estimation should be done in all patients. These patients would be treated by regimens as shown in Table 12. Table 12: DAAs in the Management of Treatment Experienced Cirrhotic and Non-cirrhotic Patients. Treatment No cirrosis / Non-Genotype 3 Genotype 3

failure Compensated regimen cirrhosis Peg IFN+RBV No cirrhosis Daily fixed-dose combination Daily fixed-dose combination of SOF (400 mg) + VEL of SOF (400 mg) + VEL Or SOF+RBV (100 mg) x 12 weeks (100 mg) x 12 weeks Compensated cirrhosis Daily fixed-dose combination Daily fixed-dose combination of of SOF (400 mg) + VEL SOF (400 mg) + VEL (100 mg) + (100 mg) x 12 weeks weight-based ribavirin* x 12 weeks SOF+DCV/LDV No cirrhosis Daily fixed-dose combination Daily fixed-dose combination of

of SOF (400 mg) + VEL SOF (400 mg) + VEL (100 mg) + (100 mg) + weight-based weight-based ribavirin x 24 weeks ribavirin x 24 weeks Compensated cirrhosis Daily fixed-dose combination Daily fixed-dose combination of of SOF (400 mg) + VEL SOF (400 mg) + VEL (100 mg) + (100 mg) + weight-based weight-based ribavirin x 24 weeks ribavirin x 24 weeks SOF: sofosbuvir; RBV: ribavirin, VEL: velpatasvir. *Ribavirin should be administered orally with food twice daily, with the dose determined according to body weight

(1000 mg daily in patients with a body weight of <75 kg and 1200 mg daily in patients with a body weight ≥75 kg). Ribavirin should be started at lower dose (600 mg perday) then gradually increase to the maximum tolerated dose. Reference Gane EJ, Shiffman ML, Etzkorn K, Morelli G, Stedman CAM, Davis MN, Hinestrosa F, Dvory-Sobol H, Huang KC, Osinusi A, McNally J, Brainard DM, McHutchison JG, Thompson AJ, Sulkowski MS; GS-US-342-1553 Investigators. Sofosbuvir

velpatasvir with ribavirin for 24 weeks in hepatitis C virus patients previously treated with a direct-acting antiviral regimen. Hepatology. 2017 Oct;66(4):1083-1089. doi: 10.1002/hep.29256. Epub 2017 Aug 26. PubMed PMID: 28498551. People who inject drugs Globally, approximately 67% of PWID have evidence of anti-HCV antibodies. PWID are at increased risk of HCV-related disease and transmission, as well as for all-cause morbidity and mortality, and therefore require

specialized care and should be considered as a priority for HCV treatment. In reality, many PWID with HCV infection are unaware that they are infected and HCV treatment rates among them are very low. This is due to a number of reasons, including the criminalization of drug use, as well as discrimination and stigma in health care settings. When caring for PWID, the central tenets of respect and non-discrimination should be followed, and additional adherence and psychological support given as required.

Screening As a population with a high prevalence of HCV infection, all PWID should be offered screening for HCV as an integral component of a comprehensive package of harm reduction interventions. Repeated screening is required in individuals at ongoing risk of reinfection, and the possibility of reinfection after spontaneous clearance or successful treatment should also be considered. Those who have been previously infected should

be re-tested at least annually using HCV RNA testing, as the antibody remains positive after the first infection. HCV case-finding and treatment in specialist drug dependency services has also been shown to be cost-effective in high-income settings. The higher the treatment rates, the more cost-effective HCV case-finding becomes, as more of those identified will be treated, and a greater population impact would be seen. Screening for HBV and HIV is also recommended in PWID.

40 National Guidelines for Diagnosis & Management of Viral Hepatitis

Care Treatment of HCV in PWID requires integration of services, as other health care needs, including treatment for HIV and TB as well as drug and alcohol dependency, are often also present. Harm reduction strategies, including the provision of OST and sterile injection equipment, are required in order to prevent acquisition of HCV and other blood borne viruses such as HBV and HIV. At all times, avoidance of discrimination or stigmatization of PWID is essential. Care should be given only with

informed consent. Moreover, acceptability of services is a vital component of health care, and peer interventions may help with reducing injecting drug use and promoting safer injection practices. PWID are at risk of infection with HBV and should be vaccinated using the rapid vaccination regimen. Interventions in PWID offer important area of synergies with the National AIDS Control Programme (NACP) and the different intervention can be delivered using the targeted interventions.

Persons with HIV/HCV Co-infection Persons with HIV/HCV co-infection generally have more rapid progression of liver fibrosis, especially those with a CD4 cell count of <200 cells/mm3. Furthermore, even among patients in whom ART leads to successful control of HIV infection (i.e. undetectable HIV viral load), the risk of hepatic decompensation among co-infected patients is higher than among patients with HCV mono infection. For these reasons, all persons with HIV/HCV

co-infection should be considered for HCV treatment. Evaluation of HIV and HCV Co-infected persons The assessment of those with HCV/HIV includes clinical evaluation – history, physical examination for jaundice, hepato-splenomegaly, ascites, cirrhosis/decompensation and laboratory tests including LFT, prothrombin time, complete haemogram, AFP, etc. Other tests required are abdominal ultrasound, endoscopy, assessment of liver

fibrosis (APRI/FIB 4/fibro-Scan- please refer Annexure 1, and HCV RNA quantitative assay. Treatment of HIV and HCV Co-infection In the past, treatment of HIV and HCV co-infected persons with interferon and ribavirin combination therapy was difficult, as many patients had to discontinue treatment due to side-effects such as depression or weight loss as well as severe anaemia, thrombocytopenia and neutropenia. Furthermore, SVR rates in patients with

co-infection were lower than among HCV-mono infected patients. Outcomes of HCV therapy with DAAs in persons with HIV co-infection are comparable to those with HCV mono infection. Thus, DAA therapy has substantially simplified the treatment of persons with HIV and HCV co-infection. There are fewer Drug-Drug Interactions (DDIs) between DAAs and ARV medicines, and SVR rates with DAA- based therapy among persons with HIV co-infection are higher than 95%, even for those with prior HCV

treatment failure or advanced fibrosis. Therefore, there is no longer a need to consider HIV/HCV co-infected patients as a special, difficult-to treat patient population. The need to check for DDIs between HIV and HCV medications, however, needs to be emphasized. It is advisable to first initiate treatment for HIV and achieve HIV suppression before starting HCV treatment, although there are some circumstances where it may make sense to treat HCV infection first and then initiate

therapy for HIV. This could include persons with moderate-to-severe fibrosis at risk of rapid liver disease progression if the HIV infection is not associated with significant immunosuppression at the time of treatment. Also, in view of the short duration of HCV treatment, the risk of DDIs between HCV and HIV medicines and the increased risk of ART-related hepatotoxicity in the presence of HCV infection, treating HCV infection first can simplify subsequent ART depending on the regimen available locally.

National Guidelines for Diagnosis & Management of Viral Hepatitis 41

Potential harmful effects of ARV drugs include their hepatotoxic effects. Several studies have shown that hepatotoxicity as a result of ART may be worsened in the presence of concomitant HCV infection. However, the highest rates of hepatotoxicity have been observed with ARV drugs that are no longer commonly used or recommended, including stavudine (d4T), didanosine (ddI), nevirapine (NVP) or full-dose ritonavir (600 mg twice

a day) . For most HIV/HCV co-infected persons, including those with cirrhosis, the benefits of ART outweigh concerns regarding drug-induced liver injury. Raised liver enzymes may be the result of ART-induced drug toxicity and/ or opportunistic infections, making interpretation of liver enzyme elevations more problematic than for patients with HCV infection alone. ALT and AST should be monitored at 1 month after ART initiation

and then every 3–6 months. A significant elevation of AST/ALT should prompt careful evaluation for other causes of liver function impairment (e.g. alcoholic hepatitis, hepatobiliary disease), and may require short-term interruption of the ART regimen or specific drug suspected of causing the elevation. Daclatasvir is associated with significant drug interactions with many NNRTIs and PIs, and its concomitant

use requires caution, dose adjustments or consideration of alternative DAAs. The dose of daclatasvir will be 30 mg with ATV/r and 90 mg with EFV. Ledipasvir (LDV) and sofosbuvir have shown reduced potential for drug interactions with ARV drugs due to their use of different metabolic pathways. A complete list of drug-drug interactions is available at www.hep-druginteractions.org. Table 13: Drug Interactions Between Direct-Acting Antivirals and Antiretroviral Drugs

Selected Daclatasvir Sofosbuvir Ledipasvir/ Sofosbuvir/ HIV Drugs Sofosbuvir Velpatasvir 3TC √ √ √ √ ABC √ √ √ √ FTC √ √ √ √ TDF √ √ √ √ Monitor for TDF toxicity. Monitor for TDF toxicity. Unboosted ATV √ √ √ √ ATV/r or ATV/c √ √ √ ↓ DCV dose to √ If a PI/r or PI/c is If a PI/r or PI/c is 30 mg/day used with TDF, ↑ used with TDF, ↑ TDF concentrations TDF concentrations DRV/r or DRV/c √ √ are expected. If co- are expected. If co- LPV/r administration is administration is necessary, monitor necessary, monitor

√ √ for TDF-associated for TDF-associated toxicities.* toxicities.* EFV √ ↑ DCV dose to √ X √ 90 mg/day If used with TDF, monitor NVP √ for TDF toxicity. ↑ DCV dose to √ X 90 mg/day RAL √ √ √ √ ATV/r = atazanavir/ritonavir; ATV/c = atazanavir/cobicistat; DAA = direct-acting antiviral agents; DRV = darunavir; DRV/r = darunavir/ritonavir;; DTG = dolutegravir; DSV = dasabuvir; EFV = efavirenz; FTC = emtricitabine; LPV/r =

lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivir; RTV = ritonavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; *Consider alternative HCV or ART to avoid increases in TDF exposure. If co-administration is necessary, monitor patient for TDF-associated adverse reactions. Key to Symbols: √ = ARV agents that can be used concomitantly

X = ARV agents not recommended ( Ref: Guidelines for the Use of Anti-retroviral Agents in HIV-1-Infected Adults and Adolescents; Downloaded from https://aidsinfo.nih.gov/guidelines on 6/27/2018) 42 National Guidelines for Diagnosis & Management of Viral Hepatitis

Management of Cirrhotic Patients after HCV clearance in SVR 12 HCV infection can be considered cured in non-cirrhotic patients who have achieved a SVR 12 after 12 weeks of completing the treatment. Thus no follow-up is required. Patients with a history of excessive alcohol drinking, obesity, type 2 diabetes, hypertension etc should be periodically subjected to a thorough clinical assessment as needed. In patients with cirrhosis who have achieved cured (successful treatment), long-term post-SVR follow-up

studies have demonstrated that there is a persistence of risk of developing HCC, although it is significantly reduced compared to untreated patients or patients who did not achieve an SVR. Thus, HCC surveillance in these patients must be indefinite. These patients with liver cirrhosis who have achieved SVR should remain under surveillance for HCC every 6 months by ultrasound, and for oesophageal varices by endoscopy if varices were present at pre-treatment endoscopy.

There is increased risk of reinfection (1-8%) following successful HCV among patients at high risk, such as PWIDs or men who have sex with men, etc. Thus the risk of reinfection should be explained to the patient in order to positively modify risk behavior. Following SVR 12, the monitoring for HCV reinfection should be recommended in these patients with ongoing risk behavior. If reinfection is identified during post-SVR follow- up, then retreatment is indicated. Persons with chronic kidney disease

There is an unmet need for DAA treatment in patients with severe renal disease (eGFR <30 mL/min/1.73 m2) and those requiring haemodialysis. Sofosbuvir, which is used in many approved regimens, does not have the safety and efficacy data to support its use in these situations. Patients receiving ARV drugs in combination with tenofovir and sofosbuvir may require enhanced renal monitoring. Given the complex management needs for this group, these patients should be referred to higher and specialized

center for appropriate management. Persons with HBV/HCV co-infection It is important to check for the presence of HBV infection before starting HCV treatment. HBV and HCV co-infection may result in an accelerated disease course; HCV is considered to be the main driver of disease. Persons co-infected with HBV and HCV can be treated with antiviral therapy for HCV; SVR rates are likely to be similar to those in HCV-mono infected persons. During treatment and after HCV clearance, there is a risk of

reactivation of HBV, and this may require treatment with concurrent anti-HBV antiviral therapy. DDIs must be checked before initiating treatment. Persons with TB/HCV co-infection People at increased risk of infection with HCV are also often at increased risk of infection with TB. Therefore, screening for active TB should be part of the clinical evaluation of patients being considered for HCV treatment.

If the patient does not have any one of the following symptoms – current cough, fever, weight loss or night sweats – TB can be reasonably excluded; otherwise, the patient should undergo further investigations for TB or other diseases. Most of the DAAs interact with metabolic pathways in the liver, which increases and/or decreases the drug level of DAAs when co-administered with antimicrobial medicines such as rifabutin, rifampin and rifapentine.

Therefore, concurrent treatment of HCV infection and TB should be avoided. Active TB should generally be treated before commencing therapy for HCV. Furthermore, in persons with HCV infection being treated for TB, it is important to monitor liver function tests, as the risk of anti-mycobacterial -induced hepatotoxicity is National Guidelines for Diagnosis & Management of Viral Hepatitis 43

higher in patients with TB/HCV co-infection than in those with TB mono infection, although the risk of severe hepatotoxicity is rare. Concurrent treatment of HCV infection and multidrug-resistant TB is particularly complicated because of many DDIs between DAAs and second-line antimicrobials. There are limited data on the management of persons co- infected with HCV, HIV and TB, but such cases need sound clinical judgement in order to reduce the additive

side-effects, pill burden and DDIs. Baseline liver function tests for individuals with chronic liver disease are encouraged prior to initiating treatment for latent TB infection. For individuals with abnormal baseline test results, routine periodic laboratory testing should be carried out during the treatment of latent TB infection. Women of child-bearing age None of the DAAs have been evaluated among pregnant women. Thus, women with childbearing potential

should be counseled that they require effective contraception during treatment and for six months after completion of therapy. Safety of DAAs in pregnancy has not been established. Ribavirin is associated with fetal abnormalities. DAAs are thus contraindicated in pregnant women and those with child bearing potential unless effective contraception (i.e. two forms of contraception) can be guaranteed during treatment and, for women

taking ribavirin, for 6months after completing therapy. Pre-treatment pregnancy tests should be conducted prior to treatment initiation. Hepatitis E Hepatitis E virus (HEV) is a non-enveloped single stranded RNA virus belonging to Hepevirus. This agent is transmitted almost exclusively by the fecal oral route. It is an outbreak prone disease with an incubation period of around 2-10 weeks. Clinical Presentation

The illness usually begins after the incubation period of 14-70 days as an acute viral syndrome with mild fever, marked loss of appetite, aversion to food, upper abdominal discomfort ,nausea and/vomiting. Within a few days of onset of these non-specific symptoms jaundice can appear with the resolution of these non-specific symptoms. Jaundice usually persists for 1-6 weeks and then gradually resolves. In children, most HEV infections

occur without any symptom or as a mild illness without jaundice. In contrast, in adults, acute hepatitis E may have a prolonged cholestatic phase with significant itching. Acute liver failure may be seen in a small proportion (0.4-5%) which is higher in pregnant women normally within a week of onset of symptoms. Laboratory Diagnosis Cases of hepatitis E are not clinically distinguishable from other types of acute viral hepatitis. Diagnosis is

strongly suspected in appropriate epidemiologic settings e.g. occurrence of several cases in localities in known disease-endemic areas, in settings with risk of water contamination, if the disease is more severe in pregnant women and if hepatitis A has been excluded. Definitive diagnosis of hepatitis E infection is based on the detection of specific IgM antibodies to the virus in a person’s blood. In acute hepatitis with clinical jaundice, the serum bilirubin levels are above 2.5mg/dL and

serum ALT is more than 10 times the upper limit of normal. Management of Viral Hepatitis E There is no specific treatment capable of altering the course of acute hepatitis E. As the disease is usually self-limiting, hospitalization is generally not required. Hospitalization is required for people with fulminant hepatitis and symptomatic pregnant women. 44 National Guidelines for Diagnosis & Management of Viral Hepatitis

Immunosuppressed people with chronic hepatitis E benefit from specific treatment using ribavirin, an antiviral drug. In some specific situations, interferon has also been used successfully. Special Situations Certain population sub-groups are at a higher risk for severe disease following HEV infection. These include pregnant women, persons with pre-existing liver disease and persons with immunosuppression. During HEV

epidemics, fulminant hepatitis occurs with a disproportionately high rate among pregnant women. Overall case-fatality rates from hepatitis E have ranged from 0.1% to 4%; however, case-fatality rates among pregnant women are much higher, being 10%-25%. It is important to recognize patients with acute hepatitis E occurring in these special situations as sick patients who need hospitalization. Management of acute viral hepatitis during pregnancy

The patient is preferably managed in a hospital with ICU facilities and blood banking to provide adequate blood product support, in addition to Obstetric services. • Monitor blood pressure, exclude toxaemia of pregnancy. • Permit oral intake, maintain adequate hydration. • Monitor closely for development of signs of acute liver failure. Premature induction of labor has no proven role in preventing or treating ALF.

If spontaneous premature rupture of membranes or premature labor occur, one should: Give vitamin K (10 mg IV, repeat after 24 h), monitor fetal heart rate, arrange blood (may need if postpartum bleeding occurs). If the fetus is >34-36 weeks, consider induction of labour, otherwise manage conservatively. For premature rupture of membranes, give antibiotic prophylaxis. In case of intrauterine death, induction of labor (misoprostol or oxytocin) should be considered in a patient not

in acute liver failure. However, if the mother has acute liver failure, labour should not be induced. Oxytocin should be used after delivery, to prevent post-partum bleeding. If bleeding occurs, use oxytocin infusion; if needed, ergometrine or misoprostol can be used. Use blood transfusion, if necessary. For baby, assess for hypothermia and hypoglycaemia, and treat if present. Administer vitamin K, give normal vaccines and initiate breast feeding (if the mother can nurse).

Diagnosis and management of acute liver failure Acute liver failure: Definition Acute liver failure (ALF) is defined as a severe injury to a previously normal liver, presenting initially as jaundice, and then altered mental state (hepatic encephalopathy) within 4 weeks of the onset of jaundice. Hepatic encephalopathy manifests as mental changes, restlessness, reversal of sleep pattern, altered consciousness and/

or persistent vomiting. It is often associated with cerebral edema, which may manifest as slowed heart rate, high blood pressure and irregular respiration. Less commonly, coagulopathy may develop with bleeding from one or more body sites. ALF can be complicated by secondary bacterial infection (leading to sepsis), renal failure, multi-organ failure, and carries a high risk of death. National Guidelines for Diagnosis & Management of Viral Hepatitis 45

How to suspect The development of one or more of the following should lead to suspicion of impending acute liver failure, or of severe acute hepatitis: • Severe or persistent nausea and vomiting • Mental state changes: excessive sleepiness, irritability, agitation, disorientation, confusion, abnormal behaviour or decreased level of consciousness • Spontaneous bleeding (nasal, oral, vaginal, diarrhoea, vomiting) • Repeated episodes of hypoglycemia • Fever not possible to manage with tepid sponging

• Dehydration or inability to maintain oral hydration, or not passing urine Differential diagnosis In such patients, other diseases (e.g. severe malaria, dengue infection, leptospirosis, other less common systemic infections, sepsis, cholangitis, liver abscess, drug toxicity) may need to be excluded by clinical or laboratory evaluation. Management Patients with manifest or suspected ALF should be hospitalized. Hospitalization may also be considered in

persons with acute hepatitis who are at high risk of developing ALF (e.g. pregnant women with hepatitis E in the last trimester, or those with underlying chronic liver dysfunction). The patient is preferably managed in ICU or high dependency unit. Treatment should focus on: a. General care of seriously ill or unconscious patient, including i. Close observation and monitoring of vital signs, changes in sensorium and bleeding, urine output, etc

ii. Quiet surroundings; head of the bed elevated at ~30O with head in neutral position iii. Nil by mouth, maintenance of fluid and electrolyte balance by intravenous route, while avoiding over- hydration and hyponatremia (these can worsen cerebral edema) iv. Steps to prevent bed sores and corneal injury v. Monitoring of blood sugar, and prevention and treatment of hypoglycaemia b. Treatment of symptoms, including i. Fever: Sponging, paracetamol if needed ii. Vomiting: Domperidone

iii. Itching: Calamine lotion c. Patients with encephalopathy should receive lactulose (via nasogastric tube – thin tube, placed gently to avoid injury and bleeding) 30 ml 2-3 times per day initially, later adjusted to produce 2-3 soft stools daily (avoid diarrhea). Mannitol (0.5-1.0 g/Kg IV) may be considered in case of prominent cerebral edema, provided urine output is good. In such patients, transfer to a hospital with intensive care facilities may need consideration.

d. Vitamin K may be administered if coagulopathy is prominent (10 mg IV/d X 3 days) e. Prevention and treatment of complications 46 National Guidelines for Diagnosis & Management of Viral Hepatitis

i. Bacterial infections: consider prophylactic antibiotic, look for and treat early. ii. Stress ulcers/bleeding: H2 receptor antagonist or proton pump inhibitor iii. Bleeding: blood or fresh frozen plasma transfusion iv. Seizures: diazepam v. Shock: IV fluids vi. Hypoxia: Oxygen The following should be avoided or used with caution: a. Invasive procedures that carry the risk of bleeding b. Hepatotoxic drugs c. Drugs that increase the risk of bleeding (e.g. aspirin, NSAIDs) d. Sedative drugs

e. Corticosteroids Specific anti-viral agents have no role in management, except possibly in case of acute severe hepatitis B. Referral of a Patient with Acute Liver Failure to a Tertiary Care Center When to refer? • When the patient develops any degree of alteration in sensorium and INR is above 1.5 Where to refer? • Transfer the patient to a specialized intensive care with the skills to provide airway and ventilator management (tertiary care unit)

• Facility for liver transplantation is available (if patient is willing) How to transport the patient? • Transfer without delay along with a trained health care personnel • Detailed discussion between the transferring and receiving physicians/team is essential before the transfer • In the scenario of an evolving hepatic encephalopathy - intubate and sedate to ensure a controlled and safe transfer • Appropriate fluids should be available for ongoing volume resuscitation

• Patient should be maintained normoglycaemic • Vasopressors should be drawn-up and available. • Mannitol should be available for management of raised intracranial pressure during transit. National Guidelines for Diagnosis & Management of Viral Hepatitis 47

2 SECTION OPERATIONAL GUIDELINES* TO ROLL OUT TREATMENT OF HEPATITIS C (*Operational guidelines for roll out of treatment of hepatitis B will be disseminated subsequently) 48 National Guidelines for Diagnosis & Management of Viral Hepatitis

Introduction The Government of India has decided to launch the integrated initiative for Prevention and Control of Viral Hepatitis with provision of free treatment for hepatitis C through the National Health Mission. To roll out the treatment for hepatitis C with a public health approach, the present section has been developed for facilitating the operationalization of the treatment of Hepatitis C across the country and intends to address the operational aspects of the same. Organization of Services

The services will be delivered through designated treatment sites that are located within an existing public health facility, including tertiary care facilities followed by district hospitals. The extent of services will depend upon the availability of the expertise and resources in the selected sites. There will be 15 sites that will be identified as Model Treatment centers (MTC). These will also act as places for referral, capacity building and

mentoring for the other treatment centers (TC). Selection of the Model treatment Center sites will be done by the central unit for viral hepatitis, with concurrence of states being the implementing agency. Guidelines for the Organization of Services Objectives and functions of the Treatment Sites The management of hepatitis C has been simplified over the last few years since the introduction of Directly

Acting Antivirals. The main objective of the treatment site under the initiative is to enhance the access to treatment for hepatitis C. Model Treatment Centre (MTC) and Treatment Centre (TC): The treatment for hepatitis C will also involve management of patients that present with a range of clinical presentations, cirrhotic and non-cirrhotic, treatment naive or treatment experienced, special situations like renal impairment etc. Hence, to effectively

manage the patients with HCV infection, it is planned to have a tiered approach for service delivery. All the treatment centers will have the capacity to deliver the DAA in uncomplicated cases (and few other scenarios as per the national technical guidelines). They could be situated in public health care facilities like the medical colleges, district hospitals etc. However, the cases that need more specialized care will be referred to higher

centre that have the requisite capacity and experience to manage the complicated cases (e.g. decompensated cirrhosis, thalessemics with HCV infection, HCV infection in renal impairment etc.). These health care facilities with specialized services for diagnosis and management (like availability of Gastroenterologist/hepatologist, Doppler, CT scan, MRI scan etc.) are termed as Model Treatment center. Hence, the MTC will perform all the

functions of a treatment centre , will also receive in-referrals and also be the centers for training, mentoring and conducting operational research under the initiative. As the complications of chronic viral hepatitis are vast, the scope of initiative will be restricted to the use of directly acting antivirals in treatment of hepatitis C as per the prescribed regimens. Functions of the Model Treatment Center: 1. To ensure Screening/ Diagnosis in suspected cases of Hepatitis C Infection

2. Treatment & Management of Hepatitis C infection 3. In referrals for cases screened / diagnosed elsewhere, for the management of viral hepatitis 4. Management of complicated cases referred from other treatment centers. 5. Management of cases under special categories as per national guidelines( eg: thalassemics, patient with treatment failure etc. ) 6. Ensure compliance and completion of treatment National Guidelines for Diagnosis & Management of Viral Hepatitis 49

7. Training and mentoring of other treatment sites 8. Operational research Functions of the Treatment Center : 1. To ensure Screening/ Diagnosis in suspected cases of Hepatitis C Infection 2. Treatment and Management of uncomplicated Hepatitis C infection 3. In referrals for cases screened/diagnosed elsewhere, for the management of viral hepatitis. 4. Out referrals to MTC for clinical management of hepatitis as per national treatment guidelines. 5. Ensure compliance and completion of treatment

Selection criteria and steps for setting up a Treatment Site Each site will be selected by the state, based on the burden of disease according to available evidence in form of studies, outbreaks, case reports, blood bank data etc. Once the sites are identified and proposed, a joint team will visit the facility and assess its feasibility for delivery of services, adequacy of needed space and man power and

willingness of the institute to set up such center. The team that will undertake the feasibility visit should ideally comprise of the state and district officials of the initiative, central unit officials and other invited partners. The report of feasibility visit should be prepared, signed and kept with the state officials. The format for feasibility visit is attached as Annexure 4 Inclusion criteria for consideration as a potential treatment site include:

1. Established evidence of case load for Viral hepatitis C infection or its sequel 2. Evidence of high hepatitis burden in catchment area 3. Commitment and Willingness of the Institute to have a center and consequent agreement to follow the SOP and protocols under the initiative 4. Availability of required infrastructure 5. Availability of appropriate human resource for clinical and laboratory management, as well as other services routinely. Infrastructure

The institution will be responsible for providing essential infrastructure for setting up the center. The institution should identify adequate space from where the services can be delivered, preferably in vicinity of OPD services. It should be clearly displayed at several places in the hospital for the ease of access by the patients especially in the blood bank premises, STI clinics, HIV/ICTC centres etc. There should be services available

every day preferably, and have definite timings displayed boldly across the facility. It will be the responsibility of the institution to provide basic furniture like chairs, tables, cabinet/almirah etc., space for storage of drugs, and have necessary electrical and other fixtures. It has to be noted that no separate allocation will be made for infrastructure and state has to bear the costs if any. Human Resource

The services will be delivered through the existing health system and the institution will have to nominate a nodal officer who would be responsible for the day to day functioning of the centers. Ideally, this could be the Head of department of Internal Medicine/Gastroenterology/Hepatology (or a person deputed /nominated by HOD) in tertiary centers and the physician in district hospitals and elsewhere. The patients should be seen by

the attending physician from the system and the documentation of the patient data and management should be recorded in the formats that are made available under the program. To assist the delivery of services in a uniflow system and to ensure efficacy, the treatment centers will be provided the following staff under the program in a phased manner: 50 National Guidelines for Diagnosis & Management of Viral Hepatitis

Staffing provided by the program Table 14: Staff at the treatment sites. S No Model Treatment centers S No Treatment centers 1 Medical Officer – 1 1 Pharmacist -1 2 Pharmacist -1 2 Data Entry Operator – 1 3 Data Entry Operator – 1 3 Peer Support -1 4 Peer Support -1 Since the Model Treatment centers will also undertake additional tasks like training, mentoring, operational research and conducting review meetings with state and central unit, they will be provided one contractual

position of level of Medical Officer( MO). To facilitate the diagnosis and laboratory monitoring of treatment, the initiative will strengthen the laboratories to deliver services as per the national guidelines. The laboratories so established (preferably in the same institute as the treatment center) will have the following manpower that the program will provide in a phased manner, as per the level of facility. Table 15: Staff at the state laboratory. S No Manpower at State laboratories

1 Technical Officer – 1 2 Data Entry Operator – 1 3 Laboratory Technician – 1 Table 16: Staff at the district laboratory. S No Manpower at District laboratories 1 Laboratory technician -1 The staff should be recruited by the institution as per the norms and procedures followed for recruitment of contractual staff as per the guidelines of the National Health Mission (NHM). The remuneration for all these

staff shall be in accordance to the state NHM norms. There should be an in-built system of appraisal of such staff from time to time. Terms of Reference for various staff at Treatment site 1. Nodal Officer a. Overall responsibility of the functioning of the centre, reporting to state / central unit, participation in review meeting, coordinate and develop referral system and linkages with other departments of the hospital

b. Ensure that patient are not discriminated in the hospital and are not denied admission/ care. c. Ensure that all ethical practices including confidentiality are maintained. d. Ensure availability of adequate stock of quality drugs as per defined targets at all times e. Ensure reporting of any short expiry drug in a timely manner to allow timely relocation and avoid financial loss f. All administrative matters relating to the centre including sanctioning of leave of contractual staff, annual

performance appraisal of the staff etc. as per guidelines g. Ensure adherence to the highest standards of quality and excellence in patient care h. Review and monitor the functioning of the centre periodically and in depth and ensure submission of reports as required. i. Act as Focal point for interaction with central unit/ State program management officials etc. National Guidelines for Diagnosis & Management of Viral Hepatitis 51

2. Medical officer ( MO) of Model Treatment Center ( MTC) Qualification: The MO should be a Medical graduate (MBBS) with 5 years of experience in clinical care preferably related to infectious diseases. S/he must be registered in the concerned state Medical Council. A candidate with higher education will be preferred. Job Responsibilities a. S/he is the functional team leader of the centre under the overall guidance of the Nodal officer. The MO

has to supervise the administrative and medical functions of the centre on a day- to- day basis and provide leadership to staff to work as a cohesive team and deliver the services effectively b. S/he should examine the patients, advise required investigations, review the investigations and prescribe the treatment. c. Refer difficult/ complicated cases to the Nodal Officer or other specialist for further expert opinion and interventions including admission and inpatient care, if required

d. Monitor the consumption and availability of drugs, and alert the concerned authorities in case of impending shortage well in advance so as to enable adequate replenishment without disruption of services e. S/he must ensure that all records, registers, cards are updated on a daily basis and reports are sent to the concerned authorities on time. All reports should be checked by the MO before taking approval from the Nodal Officer for sending them to the concerned authorities

f. S/he has to ensure that the guidelines for running and maintaining the centre are abided by. g. Facilitate and coordinate trainings in the centre. h. Ensure that a daily due list is prepared for the patients expected to visit and a follow up action is taken to contact the defaulting patients. i. Any other duty assigned by Nodal Officer/ Initiative. 3. Pharmacist Qualification: The pharmacist should hold a Degree in Pharmacy from a recognized institute. If candidate with

degree is not available, diploma holder in pharmacy with 3 years of experience in health care institution can be considered. S/he must be registered in the concerned state pharmacy council. Job responsibilities of Pharmacist: a. S/he has to work under the guidance and supervision of nodal officer/MO b. Dispense drugs with proper counseling / interaction with patient c. Advise the patients and family about the importance of adherence during each visit

d. Counsel the patient on possible drug toxicities and report the same, if significant e. Do pill count and report any adverse effects of drugs Also, confirm the next visit date and inform the patient f. Maintenance of the drug stores g. Maintain and update drug stock and drug dispensing registers regularly every day. Inform the concerned medical and nodal officer in case of any discrepancy. Duly take signature of nodal officer every fortnightly in the stock register

h. Ensure that the centre has enough stock of drugs for at least 3 months and inform the concerned authority about any near expiry or excess stocks well in time for relocation to other sites and ensure FEFO protocol is followed i. Physical verification of the drugs under the supervision of the nodal officer and/or the MO j. Besides all the above, any other duty assigned by nodal officer. In case pharmacist is not available/on leave, the nodal officer in consultation with the head of institute will

make any alternative arrangement so that the functioning does not suffer and regular staff of the facility must also be integrated for service delivery. 52 National Guidelines for Diagnosis & Management of Viral Hepatitis

4. Data entry operator Qualification: The Data entry operator should be a graduate with Diploma in Computer Applications (from a recognized institute or university) or ‘O’ Level course from DOEACC. S/he has to undergo training under the initiative in monitoring and evaluation tools (M & E) of the programme aimed to build the capacity of the person in recording data, preparing and sending reports and maintaining records properly. Job responsibilities of Data Entry Operator:

1. S/he has to work under the guidance and supervision of MO and/or nodal officer 2. Ensure that all data recording and reporting is updated 3. Print and share all circulars/information sent by central unit/States to the Nodal Officer/MO and maintain a file for the important orders/communication 4. Maintain the attendance register for the centre staff and get it verified by the nodal officer everyday and by the Nodal Officer at the end of the month

5. Maintain the HR file including the bio-data of the staff, copies of certificates, appointment letters, contractual service agreement, performance appraisal report, training details, remuneration etc. 6. Prepare and send all the monthly reports prescribed by central unit after approval of Nodal Officer 7. Assist in analysis of data under the supervision of the Nodal Officer 8. Any other duty assigned by nodal officer. 5. Peer supporter

Qualification: The peer supporter should be a person preferably with or recovered from the disease (hepatitis B or hepatitis C) , with a minimum of intermediate (12th) level education. S/he must also have sound knowledge of the local language and working knowledge of English. Job responsibilities of peer supporter: a. S/he has to work under the guidance and supervision of nodal officer /MO b. Be the first interface with patient at centre c. Ensure entries in the visit register

d. Be a peer educator for patients at centre and provide psycho-social support to newly registered patients e. Provide assistance to patients enrolled at the centre, within the hospital (OP and IP) f. Discuss the importance of adherence to treatment and need of viral load at 12 weeks post treatment (SVR) with the patients , Keep track of drug adherence of patients , counseling them on the importance of regularity of visits and timely investigations

g. Follow up the patients and assist in patient retrieval, where necessary and as far as possible h. Any other duty related to the initiative assigned by nodal officer/MO Terms of Reference for various staff of the Laboratories Laboratory In-charge (State Lab) Designated Microbiologist of the Institution, or Pathologist in the absence of Microbiologist Job Responsibilities a. Supervises the work of Laboratory personnel b. Verification and signing of reports generated in the laboratory

c. Ensuring that all job responsibilities are adhered to by all the laboratory personnel d. Management of funds with relation to laboratory National Guidelines for Diagnosis & Management of Viral Hepatitis 53

e. Ensure participation in and review of EQA f. Ensure training and competence of all the laboratory personnel Technical officer (State Lab) Qualification: MSc Medical Microbiology with 1 year experience in clinical laboratory services. Candidates with PhD Medical Microbiology from recognized university with 3 months experience in clinical laboratory services will be preferred. Job Responsibilities a. Supervises the work of Laboratory technician under the guidance of the Laboratory In-charge.

b. Molecular testing where available c. Preparation of SOPs and work instructions. d. Verification of reports generated in testing laboratory e. Preparation of quality control (QC) samples f. Preparation & distribution of proficiency panels (PT) panels g. Inventory and financial document management in lab. h. Maintaining and monitoring timely calibration / verification of all devices and ensuring that all monitoring and measurements are done with devices having valid verification / calibration status.

i. Adherence to Biosafety guidelines. j. Maintenance of records and logs in laboratory. k. Disposition of nonconforming products in her area of operation. l. Help in the conduct of teaching and training programs. m. Participate in surveillance activities of programme, through NCDC n. Onsite field visit to district lab for mentoring and quality assurance. o. Reporting to laboratory In-charge p. Any other duty assigned by laboratory In-charge Laboratory Technician (State/District Laboratory):

Qualification: DMLT two year course or certificate in MLT for one year or B.Sc in MLT from recognized university. Job Responsibilities a. Collect / receive specimens in the laboratory. b. Assist in sample transportation to referral laboratory as and when required. c. Performs tests for hepatitis markers and preparation of reports. d. Storage and maintenance of serum samples as per guidance. e. Confirmation of reference samples from state medical college labs and compilation of reports.

f. Perform regular internal quality control testing ,EQA and their documentation g. To maintain essential records in the laboratory h. Inventory preparation for equipment and reagents. i. Indent for supplies to the Laboratory through Lab In charge and ensure sufficient stock of Laboratory consumables is available. j. Participate in trainings and workshops conducted. k. Assist in molecular testing of samples where required.

l. To maintain cleanliness in and safety and follow proper biomedical waste disposals. m. Any other work/ activity assigned from time to time. 54 National Guidelines for Diagnosis & Management of Viral Hepatitis

Data Entry Operator( State laboratory): Qualification: The Data Entry Operator should be a graduate with Diploma in Computer Applications (from a recognized institute or university) or ‘O’ Level course from DOEACC. S/he has to undergo training under the initiative in monitoring and evaluation tools (M & E) of the initiative aimed to build the capacity of the person in recording data, preparing and sending reports and maintaining records properly. Job responsibilities of Data Entry Operator:

1. S/he has to work under the guidance and supervision of nodal officer ( Microbiologist) 2. Ensure that all data recording and reporting is updated for all activities under the program, including surveillance of viral hepatitis, if the lab is also participating in the surveillance program for viral hepatitis 3. Print and share all circulars/information sent by central unit/States to the Nodal Officer and maintain a file for the important orders/communication

4. Maintain the attendance register for the program staff and get it verified by the nodal officer ( daily/ end of the month ) 5. Maintain the HR file including the bio-data of the staff, copies of certificates, appointment letters, contractual service agreement, performance appraisal report, training details, remuneration etc 6. Prepare and send all the monthly reports prescribed by central unit after approval of Nodal Officer 7. Assist in analysis of data under the supervision of the Nodal Officer

8. Any other duty assigned by nodal officer. Training Trainings are important for any new initiative as well as for building the capacity of the service delivery points for an effective implementation. To ensure standardized and uniform quality of service delivery, there will be capacity building of the different cadres of staff in the program, using standardized training modules and facilitator guides. The following table summarizes the proposed trainings. Table 17: Proposal for trainings.

Cadre of Health Number Responsible agency Remark care worker of days multi-specialty team 1 Institutional nodal person with head Sensitization about at Institute of institution and SVHMU program and its contents/approach Medical Officers 3 NVHMU for standardized manual; SVHMU Induction training for implementation and monitoring Medical Officers 2 NVHMU for standardized manual; SVHMU Refresher trainings for implementation and monitoring as deemed necessary Pharmacist 2 NVHMU for standardized manual; SVHMU

for implementation and monitoring Peer supporter 1 NVHMU for standardized manual; SVHMU for implementation and monitoring Lab technicians 3 NVHMU for standardized manual; SVHMU Also include EQA for implementation and monitoring Technical Officer labs 3 NVHMU for standardized manual; SVHMU Also include EQA for implementation and monitoring Data Entry Operator 2 NVHMU and SVHMU National Guidelines for Diagnosis & Management of Viral Hepatitis 55

Logistics The drugs provided for the treatment centers will be provided through the state as per the laid down procedures and as per the list of drugs indicated in the treatment algorithm in the technical guidelines for clinical management of hepatitis. It will be ensured that no stock out/expiry happens in any circumstance, once the center starts functioning. A provision of 10% buffer stock needs to be maintained all the time as per

the laid down procedure. These drugs should be kept under safe custody and proper storage conditions shall be maintained. The nodal person of the center should undertake physical verification of the stocks periodically and the stock registers should be regularly updated and duly signed by the pharmacist and nodal officer. Financial management The treatment center will be provided funds as per the pattern of assistance under the initiative through the

state management unit of the NHM. The institute must handle the funds allocated for the purpose it is meant for and generate a statement of expenditure (SOE) from time to time as per the policy and procedures laid down by the state. Table 18A and 18B below details the pattern of assistance: Table 18A:Pattern of assistance for Model Treatment Centers. Budget Head Number Total (Annual), Remarks in INR Nodal Officer 1 Regular cadre From Regular cadre Medical Officer 1 As per state NHM norms for each

Pharmacist 1 personnel. To be Data Entry operator 1 transferred from Peer support 1 SVHMU of NHM Total (HR) Grant-in-aid for Hepatitis A and 100,000 Hepatitis E case management Meeting/ Training 6 128,000 To be transferred from Contingency ( photocopy/internet/ SVHMU to MTC communication/ Resistance testing in selected cases/ Printing M & E tools/ Tablets for M & E 300,000 if needed) any other operational costs etc.) Table 18B:Pattern of assistance for Treatment Centers.

Budget head Number Total (Annual), Remarks in INR Human Resource Nodal Officer 1 Regular cadre From Regular cadre Pharmacist 1 As per state NHM norms for each personnel. Data Entry operator 1 To be transferred from Peer support 1 SVHMU of NHM Total (HR) Grant-in-aid for Hepatitis A and 100,000 Hepatitis E case management Meeting/ Training 6 24,000 To be transferred from Contingency ( photocopy, internet/ SVHMU to TC communication/ Resistance testing in selected cases/ Printing M & E 50,000

tools/ Tablets for M & E if needed) any other operational costs etc) 56 National Guidelines for Diagnosis & Management of Viral Hepatitis

Patient Flow at the Treatment Centers The following sections elaborate on the flow of patient at the treatment center and also can be used to guide the smooth functioning of the staff. There are two components: 1. Enrollment of the patient into care 2. Follow up visits of the patient Enrollment of the patient: The patients who present to the center could either have a definite diagnosis or might have suspected infection. In case the person is found to have hepatitis C infection by the anti-HCV test (from a

government facility), they should be confirmed with HCV RNA as per the diagnosis algorithm in the national guidelines. Every person who has a detectable HCV RNA is eligible to receive treatment after taking consent (annexure 9) Patient presents to the Treatment center Treatment naiive Treatment experienced Refer to Model Treatment Center. If already at MTC, to be managed case by case Patient is referred from other health care provider or Refer to Model Treatment Center. If already

presents due to suspicion/ perceived risk by self at MTC, to be managed case by case Get a anti HCV done, and if positive get a HCV viral load done Patient has a positive anti-HCV and a recent HCV Viral load that is detectable. Peer supporter enters the details in HCV Treatment register and makes the HCV Treatment card Doctor: Confirms the status, Examine the patient, Advises Baseline investigations and gives the necessary forms. Peer supporter guides the patient to laboratory

Lab technician: draws the blood, performs the tests/ ensures transport and ensures that the reports are generated and sent to the clinician at the treatment center. Keeps close coordination with the peer supporter and pharmacist. Ensures that test results are updated in records Doctor reviews the case with clinical assessment and investigation, evaluates for the presence or absence of cirrhosis (using non-invasive criteria), prescribes the medicines as per the guidelines and

send to pharmacist. In case of specific situations*, refers the patient to MTC Pharmacist dispenses the medicines as prescribed (28 days) and updates the drug stock and dispensing register, gives a follow up date, reinforces adherence to treatment. Does pill count in follow up Patient leaves the center with clear Data manager enters the data into the excel sheet instruction for follow up SVR done after completion of 12 weeks of treatment

* These specific situations are described in the treatment guidelines and include retreatment cases/ pregnant women/patients with decompensated cirrhosis, malignancy, renal insufficiency etc Fig.8: Patient Flow at the Treatment Centers National Guidelines for Diagnosis & Management of Viral Hepatitis 57

Every patient found anti HCV positive is registered in care for onward enrolment and has to be confirmed with a detectable HCV viral load for being eligible for treatment. Cases where anti-HCV is positive but no HCV viral RNA is detected do not have an active HCV infection and do not need treatment. Sequential entries for all the registration are to be maintained in the hepatitis C Treatment Register (Annexure 6).

Once confirmed, the testing and treatment card for the patient is made. It is made in two sets: one to be kept at the center and other given to the patient. The center should take an address proof (Aadhaar card as UID is mandatory) from the patient. The confidentiality of the information provided by the patient is to be protected at all cost. Any divulgence of such information will have penal implication as per law for

anyone responsible for such divulgence. The testing and treatment card will capture patient demographic information diagnosis and treatment details (Annexure 5). The sections on name and demographic details are filled by the peer supporter while enrolling. The section on the clinical parameters and the laboratory investigations are filled by the treating doctor. The service provider signs the card at the respective places mentioned. The data entry operator maintains the digitize format of the same.

The details are also entered at each visit as and when they are advised. The follow up entries help in monitoring the disease progress, counseling of the patient for regular treatment, review of adherence of the patient to therapy. The drugs will be dispensed for 28 days. However, the pharmacist should ensure that the patient is given a follow-up day after 25 days. This will ensure that the patient does not land in a situation

where s/he is out of drug stock. At every visit, the pharmacist should also count the remaining drugs (pill count) to have an idea if any doses have been missed. The patient should be instructed to bring the bottle of DAA with her/him at every visit so that the pharmacist can perform pill count, collect the old bottle and issue a new one. The complicated cases, as defined in the technical guidelines, should be referred to the MTC. At the MTC,

the drugs should be dispensed and once the patient is stable and the treating doctor is confident that the patient can be managed at the nearest treatment site, then the drug dispensation can be done at the nearest site. However, the patient should be referred back to MTC in case it is deemed necessary for appropriate management. The uncomplicated cases, as defined in the technical guidelines, should be initiated treatment at the

treatment center. Once the patient is stable and the treating doctor is confident that the patient can be managed at the nearest treatment site, then the drug dispensation can be done at the nearest site. However, the patient should be referred back in case it is deemed necessary for appropriate management. 58 National Guidelines for Diagnosis & Management of Viral Hepatitis

Table 19: Summary of the key actions to be undertaken for patient management and record maintenance and the responsible person. Visit Number Key activity ( but not limited to) Responsible person Ascertain Diagnosis of active Hepatitis Attending doctor C ( anti HCV as well as HCV RNA) Enter patient details in Hepatitis C Treatment Peer Supporter Register and demographic details in treatment card First visit and Take a detailed history and examination Attending Doctor baseline, after

Categorize presence/Absence of Cirrhosis Attending Doctor confirmation of and fill relevant section in Treatment card active hepatitis Select Regimen and start treatment Attending Doctor C infection Explain patient on adherence and follow up date Peer supporter and pharmacist Dispense prescribed medicines Pharmacist Get the baseline investigations done Doctor, Lab technician and furnish report to center Educate on adherence and regular follow up Doctor ,Peer supporter and pharmacist

Dispense prescribed medicines Pharmacist Check for any side effects Attending Doctor Follow up visit Get any investigations needed as per technical Attending Doctor guidelines, prescribe the medicines Update investigations in treatment card Lab technician, Doctor Counsel on Treatment completion and need for Doctor, peer supporter End of Treatment SVR after 12 weeks of completing treatment Recheck the contact details including phone Peer supporter Update the record from the register and Data entry operator

For all visits card to the excel based sheet Ideally, there should be no expiry at any center. However, in the event there is expiry of some medicines under the program, they should be discarded as per the hospital policy. The process should be documented with details on the quantity of drug, batch number and should be signed by three regular government employees including the nodal officer of the center. In case there is no institutional policy for discarding the medicines, from the

central and state unit for viral hepatitis under NHM must be sought through a written communication clearly mentioning the absence of such institutional policy. Justifications and reasons for the same must be recorded in writing and kept for review by supervising authorities Monitoring and Evaluation of the Treatment sites The treatment sites and the laboratory will be reviewed regularly by the nodal officers for the site level day to

day functioning. In addition, the district/state and National officials will also undertake supervisory site visits for supportive supervision and mentoring. The suggested frequency of the monitoring and mentoring visits are: Table 20: Frequency of visit to the treatment sites. Level Frequency of visit National Annual State Quarterly District Once monthly National Guidelines for Diagnosis & Management of Viral Hepatitis 59

During the visits, the officials should try and provide on spot trouble shooting wherever needed, should provide clarification, assess the HR availability and required infrastructure, check the completeness and quality of records and reports submitted and randomly check the drug stocks ( physical stocks vs the reported stocks) Additionally, review meetings will be conducted that will provide a platform for experience sharing and review the progress. Recording tools

The following recording tools are to be used under the program: 1. Site Feasibility Form: Annexure 4 2. Patient Treatment card : Annexure 5 a. to be maintained at center b. Patient Treatment card ( for the patient to retain) 3. Hepatitis C Treatment register: Annexure 6 4. Drug stock and dispensing register: Annexure 7a and 7b 5. Excel based tool for comprehensive record in the documents above. Reporting tools

There will be a monthly report that each laboratory and treatment center will have to collate and submit to the state and national officials. The reporting will be in a standard format that will be developed by NCDC and initially, it will be paper / excel based and later there will be plan to digitalize the same. The monthly reporting format is attached as Annexure 8 Information from the prescribed records and registers is compiled and used in filling up various monitoring

reports which are forwarded to State Surveillance Officer (SSO) and other officials at state (NHM) and central level at central unit. Monthly reports from centres should be forwarded by 5thof every month to SSO and other state level officers by email. The reports at the state level should be compiled into a state report, the facility level reports have to be checked and feedback should be provided to centers.

The responsibility of information collection, reporting, management and analysis rests at four levels: 1. The treatment sites for creation and maintenance of patient records and files, operational information and reporting to state and NCDC through monthly reports and special studies 2. State NHM, SSO and Program management unit for analysis and consolidation of information, quality control, assessments, supportive supervision and guidance, feedback and dissemination of information to

state-level stakeholders; for Programme Implementation Plans (PIPs) 3. Central unit for compilation of reports, analysis, evaluation and dissemination of information back to State NHM and to national and international stakeholders for advocacy and planning. Responsibility of reporting, flow of information and frequency of reporting is summarized below: 60 National Guidelines for Diagnosis & Management of Viral Hepatitis

Table 21: Flow of information and frequency of reporting. Level Reporting Person responsible Reporting to Frequency of Submission form for reporting Submission date by Facility Monthly Report Nodal Officer SVHMU for Monthly 5th of every (Treatment) of Center Hepatitis and SSO month State PMU Consolidated SSO / Program I/C Central unit Monthly 10th of every report of the state month Independent evaluation of the program will also be planned and organized by National Program Management

Unit. Key gaps identified during implementation of the program and innovative interventions would also be planned through operational research and will follow the established procedures under the guidance from the central unit. Table 22: Monitoring Indicators for the Hepatitis C initiative. S Indicator Baseline Target for Source of reporting/data No Year 1 / verification and level Input indicators 1 Number of Treatment sites 0 15 Reports from centers approved for Hepatitis C

2 Are National guidelines N/A Yes Program Documents; and SOPs developed? At NVHMU 3 Is there a standard Training N/A Yes Program Documents; curriculum developed? At NVHMU Process Indicators 4 % of Treatment sites 0 80% Report from treatment center with 100% manpower as mentioned in the program 5 Number of Persons receiving NA 100,000 Analysis report at central unit treatment for HCV in the country 6 Number of functional Treatment 0 15 Monthly Reports from sites in country who are managing Treatment site

Hepatitis C under the program Outcome indicators % of patients who achieved SVR 12 (Treatment completed) National Guidelines for Diagnosis & Management of Viral Hepatitis 61

Annexure 1: Assessing severity of liver disease A full assessment should include » Clinical evaluation for features of cirrhosis and evidence of decompensation, and » Measurement of serum bilirubin, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and prothrombin time; as well as full blood count, including platelet count. » Other routine investigations include ultrasonography and alpha-fetoprotein (AFP) measurement for

periodic surveillance for HCC, and endoscopy for varices in persons with cirrhosis. Liver enzymes: Aminotransferase levels may fluctuate with time, and single measurements of ALT and AST do not indicate disease stage. Usually, the ALT concentrations are higher than those of AST, but with disease progression to cirrhosis, the AST/ALT ratio may be reversed. Tests of liver synthetic function and/or portal

hypertension include serum albumin, bilirubin, platelet count and prothrombin time. A progressive decline in serum albumin concentrations, rise in bilirubin and prolongation of the prothrombin time are characteristically observed as decompensated cirrhosis develops. Liver biopsy: Liver biopsy has been used to ascertain the degree of necro-inflammation and fibrosis, and to help guide the decision to treat. There are several established methods of scoring histology and measuring activity

(necroinflammation) separately from stage (fibrosis). However, limitations of biopsy include sampling error, subjectivity in reporting, high costs, the risks of bleeding and pneumothorax, discomfort to the patient, and the need for training and infrastructure. The pathological features of CHB on liver biopsy depend upon the stage of the disease, host immune response and degree of virus replication. Table 23: Metavir staging for liver biopsy. Metavir Stage F0 F1 F2 F3 F4

Definition No Fibrosis Portal fibrosis Portal fibrosis Numerous septa Cirrhosis without septa with septa without cirrhosis Non-invasive tests (NITs): Though liver biopsy remains the gold standard, non-invasive methods for assessing the stage of liver disease are supplanting it due to the limited availability and accessibility to liver biopsy and have been validated in adults with CHB. Blood and serum markers for fibrosis, including APRI and FIB-4, or

transient elastography (FibroScan) performed to rule out advanced fibrosis. APRI (AST-to-platelet ratio index) and FIB 4 are recommended as the preferred non-invasive tests (NIT) to assess for the presence of cirrhosis (APRI score >2: FIB 4 >3.25 in adults). Transient elastography (e.g. FibroScan) may be the preferred NITs in settings where they are available and cost is not a major constraint. APRI and FIB-4 can be readily calculated by the following formulae

APRI = * (AST/ULN) x 100) / platelet count (109/L) FIB-4 = (age (yr) x AST (IU/L)) / (platelet count (109/L x [ALT (IU/L)1/2]) 62 National Guidelines for Diagnosis & Management of Viral Hepatitis

For APRI, ULN signifies the upper limit of normal for AST in the laboratory where these investigations were undertaken. For example, in a patient with an AST of 92 IU/L (where laboratory ULN for AST is 40 IU/L) and a platelet count of 80x109/L, the APRI would be: (92/40)x100/80 = 2.87. This value is >2 and is consistent with the presence of cirrhosis. The optimal cut-off values for different NITs that correlate with specific stages of liver fibrosis have been derived

and (in the case of APRI and FIB-4) also validated. APRI and FIB-4 use two cut-off points for diagnosing specific fibrosis stages, as the use of a single cut-off would result in suboptimal sensitivity and specificity. A high cut-off with high specificity (i.e. fewer false-positive results) is used to diagnose persons with fibrosis (i.e. greater than or equal to a particular stage [e.g. ≥F2]), and a low cut-off with high sensitivity (i.e. fewer false-negative results) to rule

out the presence of a particular stage of fibrosis. Some persons will fall in the indeterminate range of test results (i.e. their score will be between the low and the high cut-off) and will need future re-testing and evaluation. APRI APRI FIB-4 Transient elastography (low cut-off) (high cut-off) (FibroScan)* Cirrhosis 1.0 2.0 - >11–14 kPa (METAVIR F4) Significant fibrosis 0.5 1.5 1.45 (low) >7–8.5 kPa (METAVIR ≥F2) 3.25 (high)

*There are no validated exact cut-offs for specific stages of fibrosis with FibroScan. This table presents the range of the most commonly used cut-offs for F4 and ≥F2 stages of fibrosis in CHB. A mean cut-off of 12.5 kPa may be used to diagnose cirrhosis and guide treatment decisions, after taking into account key limitations. (Reference : Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection., WHO, 2015) Ascertaining the Degree of Cirrhosis

The degree of cirrhosis is important to be ascertained before the treatment is initiated. The Child–Pugh Score is a system for assessing the degree of liver disease, and classified patients as Class A, B, or C based on clinical and laboratory criteria. Those with Class C have the most severe liver disease. Some HCV regimens are contraindicated among persons with Child-Pugh Class B and C or decompensated cirrhosis. The following table depicts the Child Pugh Score: Table 24: The Child Pugh Score. Points 1 2 3

Encephalopathy None Minimal (grade 1 or 2) Advanced (grade 3 or 4) Ascites Absent Controlled Refractory Total bilirubin <34 (<2) 34–51 (2–3) >51 (>3) (μmol/L) (mg/dL) Albumin (g/dL) >3.5 2.8–3.5 <2.8 Prothrombin time <4 or <1.7 4–6 or 1.7–2.3 >6 or >2.3 (seconds) or PT-INR Child–Pugh Class A: 5-6 points Child–Pugh Class B: 7-9 points Child–Pugh Class C: 10-15 points National Guidelines for Diagnosis & Management of Viral Hepatitis 63

Annexure 2: Algorithm for the Laboratory Diagnosis of Viral Hepatitis Testing algorithm for Diagnosis of Viral Hepatitis in jaundiced patients Specimen: Serum/Plasma* HAV HEV HBV HCV IgM Anti IgM Anti IgM Anti HBsAg Anti HCV HBc HAV HEV Reactive Non-reactive Reactive Non-reactive Reactive Non-reactive Reactive Non-reactive Reactive Non-reactive Report : Report : Report : Report : If HbsAg is Reactive and lgM anti HBc is Non- Report: Report: HAV HAV HEV HEV reactive: HBV positive HCV Ab HCV Ab

Positive Negitive Positive Negitive Positive# Negative# If lgM Anti HBc is Reactive and HBsAg is Non- reactive: HBV positive If both Reactive: HBV positive If both Non-reactive: HBV negative * Serum samples to be used for serological and biochemical testing, to be aliquoted and stored at -200 C for retesting for quality purposes, dispute etc. #All HCV antibody (Ab) positive to be referred to treatment centre. Plasma samples to be collected and aliquoted

in 3 sterile cryo vials. One vial to be used for quantitative hepatitis C RNA estimation and two archived at -800 C for quality assurance Fig.9: Testing algorithm for Diagnosis of Viral Hepatitis in jaundiced patients Testing algorithm for Diagnosis of Viral Hepatitis in suspected patients (without jaundice) Specimen: Serum/Plasma* HBV HCV HBsAg Anti HCV Reactive Non-Reactive Reactive Non-Reactive Report: Report: Report: Report: HBV HBV HCV Ab HCV Ab Positive Negative Positive# Negative

* Serum samples to be used for serological and biochemical testing, to be aliquoted and stored at -200 C for retesting for quality purposes, dispute etc. #All HCV antibody (Ab) positive to be referred to treatment centre. Plasma samples to be collected and aliquoted in 3 sterile cryo vials. One vial to be used for quantitative hepatitis C RNA estimation and two archived at -800 C for quality assurance Fig.10: Testing algorithm for Diagnosis of Viral Hepatitis in suspected patients (without jaundice)

64 National Guidelines for Diagnosis & Management of Viral Hepatitis

Annexure -3: Drug interactions between DAA and some commonly prescribed medications Table 25: Drug interactions between DAA and some commonly prescribed medications. Sofosbuvir Daclatasvir Sofosbuvir/ Sofosbuvir/ Ledispavir Valpatasvir Immunosuppressants Azathioprine No interaction No interaction No interaction No interaction Cyclosporine No interaction No interaction No interaction No interaction Everolimus No interaction Potential interaction Potential interaction Potential interaction

Mycophenolate No interaction No interaction No interaction No interaction Sirolimus No interaction No interaction No interaction No interaction Tacrolimus No interaction No interaction No interaction No interaction Antiretrovirals Zidovudine No interaction No interaction No interaction No interaction Tenofovir No interaction No interaction Potential interaction Potential interaction Lamivudine No interaction No interaction No interaction No interaction

Efavirenz No interaction Potential interaction* Potential interaction Significant interaction Nevirapine No interaction Potential interaction No interaction Significant interaction Abacavir No interaction No interaction No interaction No interaction Protease inhibitors No interaction No interaction No interaction No interaction Lipid lowering drugs Statins No interaction Potential interaction Potential interaction Potential interaction

Fibrates No interaction No interaction Potential interaction Potential interaction Ezetimibe No interaction No interaction No interaction No interaction Cardiovascular drugs Amiodarone Significant interaction Significant interaction Significant interaction Significant interaction Digoxin No interaction Potential interaction Potential interaction Potential interaction Clopidogrel No interaction Potential interaction No interaction No interaction

Dabigatran No interaction Potential interaction Potential interaction Potential interaction Atenolol No interaction No interaction No interaction No interaction Propranolol No interaction No interaction No interaction No interaction Carvidolol Potential interaction Potential interaction Potential interaction Potential interaction Amlodipine No interaction Potential interaction Potential interaction Potential interaction

Diltiazem No interaction Potential interaction Potential interaction Potential interaction Nifedipine No interaction Potential interaction No interaction No interaction Enalapril No interaction No interaction No interaction No interaction National Guidelines for Diagnosis & Management of Viral Hepatitis 65

Annexure 4: Feasibility Visit for Setting Hepatitis Treatment Center Checklist for Feasibility of Hepatitis Treatment Center 1 Name of the town / District/ City: 2 Type of Hospital: ( Medical College/ District Hospital / Other tertiary care) 3 Name of the Medical Superintendent or IC of the institution 4 Names of the identified Nodal officer by Institute 5 Date of Feasibility Visit 6 Members of the Visiting Team a b c d 7 Complete postal address of the Hospital with Pin Code

8 Contact details of the Nodal person ( mobile and email ) BACKGROUND INFORMATION 1 Is the Institution willing to set up a center for hepatitis treatment Yes No 2 Is the In-charge keen on establishing services? Yes No a Willing to allocate necessary space Yes No b Willing to have nodal person for treatment and lab services Yes No c Integrate the functioning and follow the National guidelines Yes No and protocols , including recording and reporting 3 What is the annual OPD of the hospital

4 Is there super-speciality( Gastroenterology/ Hepatology) Yes No 5 How many cases of acute hepatitis are seen annually ( explore last years report) 6 How many cases of hepatitis B and C are seeking care ( explore previous reports) 7 Is there a blood bank in institute? What is sero-positivity for hepatitis Yes No B and hepatitis C in last three years ( record year wise) 8 If this is a district hospital, where are patients referred or usually go for complicated cases? 9 Do you have a HIV related service?

a ICTC Yes No b ART center Yes No c Opioid Substitution Center Yes No d Involvement with Prison Yes No 8 Is the institution implementing any other program under NHM? Please mention name(s) Yes No INFRASTRUCTURE 1 Location of the proposed centre ( is it in vicinity to OPD services) Yes No Is there an ICU Yes No 2 Number of rooms a Doctors Yes No b Pharmacist Yes No c Data Entry Operators Yes No d Drug Storage & Pharmacist Yes No e Lab Technician Yes No f Peer supporter Yes No

3 Is institution willing to provide necessary furniture ( chairs, tables, Almirah etc) Yes No 4 Will the center have access to internet Yes No 66 National Guidelines for Diagnosis & Management of Viral Hepatitis

HUMAN RESOURCES 1 Does the institution have the required capacity to manage chronic hepatitis Cases? Yes No a Gastroenterologist/Hepatologist Yes No c Physician ( Internal Medicine) Yes No d Pediatrician Yes No e Microbiologist Yes No f Pathologist Yes No g Obstetrician Yes No h Others (Mention) LABORATORY CAPACITY / INVESTIGATIONS FACILITY 1 Does the institute have a capacity to do HCV RNA Yes No 2 Does the Institution have facility to do HCV Screening Yes No test (immunoassay - please specify)

3 Are the following investigation routinely available Yes No a Complete Blood Count / Hemogram Yes No b Renal Function test Yes No c Liver Function Test (please ask for each test) Yes No d Blood Sugar Yes No e INR Yes No f Platelet count Yes No g Pregnancy Test Yes No h X Ray Yes No I Ultra Sound abdomen with Doppler Yes No J Fibroscan Yes No k CT scan l MRI m Endoscopy n Liver Biopsy Yes No o Others S No Key Issues Identified Follow-up Actions suggested FINAL RECOMMENDATION OF THE TEAM (Please tick)

Recommended to Select Site for Opening Hepatitis Treatment Site Not Recommended to Select Site for Opening Hepatitis Treatment Site Signature of the Feasibility Visit Team: 1…………………………………………… 2…………………………………………… 3…………………………………………… 4……………………………………………. National Guidelines for Diagnosis & Management of Viral Hepatitis 67

Annexure 5: Patient Testing & Treatment Card PATIENT TESTING & TREATMENT CARD Registration Details Hospital ID Number Patient ID under program Date of starting DAA : …./….…/………. Basic Demographic Information Name : …………………………………………………. Age : ……………………… Gender : M F TG Address Contact number Aadhaar Number Date of Anti-HCV testing Rapid ELISA Other Date of HCV Viral Load Result Previous Exposure to Hepatitis C Treatment Yes No If yes, details DAA Interferon Details

Is there Cirrhosis at Registration No Compensated Decompensated Criteria for evaluating cirrhosis ( At least one) …/..……/..… :Date Ultrasound Fibroscan .……………………… (LSM Value (in kPa …/..……/..… :Date ……Score …………… Platelet Count ..………AST …/..……/..… :Date APRI* ………ALT .…………… AST ..……… Age /..……/..… :Date FIB-4* ……Score ……………………… Platelet Count If Decompensated cirrhosis, select basis CP Score Variceal Bleed Ascites E ncephalopathy Regimen Prescribed Duration of Treatment 12 weeks 24 weeks

Patient not treated at this center but transferred to higher center Date …………………………..Place……………………… *mandatory. The center must do both APRI and FIB-4 scoring. 68 National Guidelines for Diagnosis & Management of Viral Hepatitis

Baseline and Follow Up Investigations S No Date Hemoglobin Platelet ALT AST S. S INR HCV Viral Other-1 (USGetc) of Count Bilirubin Albumin Load Visit 1 2 3 4 5 Follow Up Visits Visit Date Pills Left Any New Any other Any Next Signature Signature of Patient’s Number of Complaints or medications Remark Follow of Doctor Pharmacist Signature/ Visit side effects up date Thumb Impression 1 2 3 4 5 Treatment Outcomes Failure SVR Achieved (write ( Date) HCV RNA Relapse Lost to Follow up Death Other quantity)

Annexure 6: Hepatitis C Treatment Register 12 Follow up Date 1 2 3 4 5 6 7 8 9 10 11 13 14 15 16 17 and status (Months) S. No. National Guidelines for Diagnosis & Management of Viral Hepatitis 69 rebmuN noitartsigeR tneitaP fo emaN egA GT /F/M xeS sserdda s’tneitaP tcirtsiD rebmun tcatnoC reviG eraC / naidrauG tcatnoc dna eman yna fi ,rebmun yrotsih tnemtaert roirP gnitset VCH-ITNA fo etaD *gnitset ANR VCH fo etaD VCH tnemtaerT erP leveL ANR * detrats nemigeR III ,II ,I tnemtaert fo trats fo etaD

1 2 3 4 5 6 noitelpmoc fo etaD tnemtaerT fo 21 RVS fo etaD euD no enoD RVS RVS fo tluseR **yna fi ,skrameR Month: Year: 1 Y N 2 Y N 3 Y N *HCV RNA is done only if ANTI-HCV is positive. In case HCV RNA is not detectable, please put a line across the rest of the fields from 10-16 ** In the remarks, please mention the status of patient ( died, lost to follow up, stop treatment due to medical reasons, transferred out, referred to higher center). For any of these, also mention date.

Annexure 7a: DAA Stock register Important: Separate page to be maintained for each drug. Summary should be filled on the last day of the month. Name of the drug / Regimen __________________________________________ A B C D E F Stock Received Stock Date Opening transferred Stock Stock Balance Remarks Stock Quantity n u b m at b ch er E d x a p t i e ry Manu d fa a c te turing offi o c u ia t lly (co d n is s p u e m n p s t e i d o n) d e i x s p ca ir r e d d e / d stock Monthly summary:

Stock at the start of the month / Opening Stock (A): Reusable stock returned during the month (D): Stock received during the month (B): Stock dispensed (consumed) during the month (E): Stock transferred out officially during the month (C): Stock expired/discarded during the month (F) Stock at the end of the month (F) = (A+B) − (C+D+E): 70 National Guidelines for Diagnosis & Management of Viral Hepatitis

Annexure 7b: Drug Dispensation Register Patient Number of Tablets Dispensed Signature Patient SI. No. Patient Name Registration Number National Guidelines for Diagnosis & Management of Viral Hepatitis 71 1 nemigeR 2 nemigeR 3 nemigeR Important: Separate page to be maintained for each day. Date: ______/______/______ Total tablets Dispensed * Specify other drugs used. Signature of the pharmacist/drug dispenser: ___________________________________

Annexure 8: Monthly reporting format 1.Name of Centre 2. Code Number 3. Name of the District 4. Name of the State 5. Name of the Site Incharge 6. Report for the period month year 7. Number of Hepatitis C infected people seeking adult adult children total care at the treatment center (Registering in Care) male female <18 years 7.1 Cumulative number of persons registered in Hepatitis C care at the beginning of this month 7.2 Number of new persons registered in during this month

7.3 Cumulative number of persons registered at the end of this month = 7.1 + 7.2 adult adult children total 8. Initiation of Treatment male female <18years 8.1 Cumulative number of patients ever started on Treatment (Number at the beginning of this month) 8.2 Number of new patients started on Treatment during this month 8.3 Number of patients on Treatment "transferred in" during this month 8.4 Cumulative number of patients ever received Treatment (Number at the end of this month) = 8.1+ 8.2 + 8.3

9. Treatment status (at the end of the month) out adult adult children total of all patients ever started on treatment (8.4) male female <18years 9.1 Cumulative number of patients who have completed treatment 9.2 Cumulative number of patients who are currently taking treatment ( 9.2=9.1-( 9.3+9.4+9.5+9.7+9.8) 9.3 Cumulative number of patients who "transferred out" 9.4 The number of all patients whose treatment status in this month is “stopped treatment” due to medical reasons

9.5 Cumulative Number of patients who are lost to follow-up (LFU) 9.6 The number of patients who did not return to the (Defaulter) and missed their doses in this month 9.7 Total number of patients Referred to Higher center for further management 9.8 number of deaths reported 10. Sustained Virologic Response adult adult children total male female <14 years 10.1 Cumulative number of patients who are eligible for SVR ( i.e have completed 12 weeks after end of treatment)have completed

12 weeks treatment ( Out of 9.1) 10.2 Cumulative number of patients who have undergone SVR out of the eligible patient ( out of 10.1) 10.3 Cumulative number of undetectable HCV RNA ( out of 10.2) 72 National Guidelines for Diagnosis & Management of Viral Hepatitis

11. REGIMENS AT THE END OF THE MONTH Regimen a) Number of ADULTS b) Number of CHILDREN alive and on treatment alive and on treatment Others Total number of patients 12. DRUG STOCKS 12.1 Drug Stock Status (use separate sheet if required) Generic a) Opening b) Stock Add expiry d) Consumption e) Expiry f) stock g) Amt. h) Issues / Drug Name stock received date during the month during the on last reqst for Comments during month day 3 mo. month of the based on month existing stock Other

12.2 Was there a stock-out of DAA this month? Yes No Signature of Nodal Officer: Date: Addendum for Lost to Follow up S No Reason for lost to follow up Number of Patients Total* *Total should match 9.5 Addendum for Deaths S No Reason for Death Number of Patients 1 Liver related causes 2 Due to causes not related to liver disease Total* *Total should match 9.8 National Guidelines for Diagnosis & Management of Viral Hepatitis 73

Guidance on Monthly report: 1. Section 7 captures all the registrations at the treatment center. It will come from the hepatitis C Treatment Register. 2. Out of all the registrations, there will be a significant proportion that will have undetectable viral load and will not need treatment. The section 8 captures the details on those who were started treatment. This will also come from hepatitis C Treatment Register.

3. Section 9.3 to 9.8 will be taken from Remarks column of the hepatitis C Treatment Register 4. Section 11 will come from hepatitis C Treatment Register or from drug dispensing register 5. Section 12 will come from drug stocks register 74 National Guidelines for Diagnosis & Management of Viral Hepatitis

Annexure 9: Consent form INDIVIDUAL’S CONSENT FORM FOR TESTING AND MANAGEMENT OF VIRAL HEPATITIS I, ______________________________________________ (full name), daughter/son of _______________________ ____________________ (full name) age ________ resident of (address) ____________________________________ _____________________ have read/have been read over and explained (circle appropriate) the accompanying guidance and have understood the information provided to me related to the investigations and proposed

management required (if available) I understand that the purpose of these tests is to: • Establish my Viral Hepatitis status, • Evaluate the presence of liver disease which may be associated with Hepatitis infection. • I can allow the program to archive my specimen for further molecular testing related to viral hepatitis only in the interest of public health, provided that any information/data/detail relating to or emanating

from my molecular sample shall not be divulged to any third party under any circumstances. A breach of this condition shall automatically forfeit my consent and the program’s right to retain such information and shall further render them liable to penal action and compensation. I understand that if a diagnosis of Chronic Hepatitis B/C is confirmed, I will be offered treatment as per the provisions in the initiative. I give my consent to the proposed management offered by the initiative subject to

strict protection of my information. Patient Signature: _________________________________ DATE: ____________ Staff member name obtaining consent: ______________________________________ Staff signature: ___________________________________ DATE: ____________ National Guidelines for Diagnosis & Management of Viral Hepatitis 75

REFERENCES 1. Central Bureau of Health Intelligence, Ministry of Health and Family Welfare. National Health Profile. New Delhi : s.n., 2016. 2. Chun HM, Roediger MP, Hullsiek KH, et al. Hepatitis B Virus Coinfection Negatively Impacts HIV Outcomes in HIV Seroconverters. The Journal of Infectious Diseases. 2012;205(2):185-193. doi:10.1093/infdis/jir720. 3. Colin JF, Cazals-Hatem D, Loriot MA, et al. Influence of human immunodeficiency virus infection on

chronic hepatitis B in homosexual men. Hepatology 1999;29:1306-1310. 4. Colin JF, Cazals-Hatem D, Loriot MA, Martinot-Peignoux M, Pham BN, Auperin A, et al. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology. 1999;29(4):1306–10.133 5. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach – 2nd ed. WHO, 2016

6. Cost-effectiveness of Hepatitis C Treatment using generic direct-acting antivirals available in India. Aggarwal, R, et al., et al. s.l. : PLOS One, 2017, Vol. 12. e0176503. 7. Easterbrook P, Sands A, Harmanci H. Challenges and priorities in the management of HIV/HBV and HIV/HCV coinfection in resource-limited settings. Semin Liver Dis. 2012;32(2):147-57 8. Eskild A, Magnus P, Petersen G, Sohlberg C, Jensen F, Kittelsen P, Skaug K.Hepatitis B antibodies

in HIV-infected homosexual men are associated with more rapid progression to AIDS. AIDS. 92 Jun;6(6):571-4 9. Gane EJ, Shiffman ML, Etzkorn K, Morelli G, Stedman CAM, Davis MN, Hinestrosa F, Dvory-Sobol H, Huang KC, Osinusi A, McNally J, Brainard DM, McHutchison JG, Thompson AJ, Sulkowski MS; GS-US-342-1553 Investigators. Sofosbuvir velpatasvir with ribavirin for 24 weeks in hepatitis C virus patients previously treated with a direct-acting antiviral regimen. Hepatology. 2017 Oct;66(4):1083-

1089. doi: 10.1002/hep.29256. Epub 2017 Aug 26. PubMed PMID: 28498551. 10. Goel, Amit. Hepatitis C Virus Infection in India:A Systematic Review of Seroprevalence Data. Dept of gastroenterology,SGPGI, WHO India Country Office. 2017. 11. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. WHO 2015 12. Guidelines for the screening care and treatment of persons with chronic hepatitis C infection. Updated version, April 2016, WHO

13. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents; Downloaded from https://aidsinfo.nih.gov/guidelines on 6/27/2018 14. Harrison’s Principles of Internal Medicine, 19th edition 15. Hawkins C, Christian B, Ye J, Nagu T, Aris E, Chalamilla G, et al. Prevalence of hepatitis B co- infection and response to antiretroviral therapy among HIV-infected patients in Tanzania. AIDS. 2013;27(6):919–27.

16. Hoffmann CJ, Thio CL. Clinical implications of HIV and hepatitis B co-infection in Asia and Africa. Lancet Infect Dis. 2007;7(6):402–9. 76 National Guidelines for Diagnosis & Management of Viral Hepatitis

17. Ioannou GN, Bryson CL, Weiss NS, Miller R, Scott JD, Boyko EJ. The prevalence of cirrhosis and hepatocellular carcinoma in patients with human immunodeficiency infection. Hepatology. 2013;57:249-257. 18. Konopnicki D, Mocroft A, de Wit S, Antunes F, Ledergerber B, Katlama C, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS. 2005;19(6):593–601.

19. Mathews G, Bhagani S. The epidemiology and natural history of HIV/HBV and HCV co-infections. J HIV Ther. 2003;8:77–84. 20. Prevalence of Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D virus and Hepatitis E virus as causes of acute viral hepatitis in north India: A Hospital based study. Jain, Prakash P, et al., et al. 2013, Indian Journal of Medical Microbiology, Vol. 31, pp. 261-5.

21. Puoti M, Spinetti A, Ghezzi A, Donato F, Zaltron S, Putzolu V, et al. Mortality for liver disease in patients with HIV infection: a cohort study. J Acquir Immune Defic Syndr. 2000;24(3):211–17. 22. Standard Operating Procedure, Mukh Mantri Punjab Hepatitis C Relief Fund: http://pbhealth.gov.in/ mmphcrf.htm 23. Thio CL, Seaberg EC, Skolasky R Jr, et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet 2002;360:1921-1926.

24. Thio CL. Hepatitis B and human immunodeficiency virus co-infection. Hepatology. 2009;49(5 Suppl):S138–45. 25. Wandeler G, Gsponer T, Bihl F, Bernasconi E, Cavassini M, Kovari H, et al. Hepatitis B virus infection is associated with impaired immunological recovery during antiretroviral therapy in the Swiss HIV cohort study. J Infect Dis. 2013;208(9):1454–8. Gilson RJC, Hawkins AE, Beecham MR, et al. Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of

infection. AIDS. 1997;11:597–606. 26. Weber, Rainer & A Sabin, Caroline & Friis-Møller, Nina & Reiss, Peter & M El-Sadr, Wafaa & Kirk, Ole & Dabis, Francois & G Law, Matthew & Pradier, Christian & De Wit, Stephane & Akerlund, Börje & Calvo, Gonzalo & Monforte, Antonella & Rickenbach, Martin & Ledergerber, Bruno & N Phillips, Andrew & Lundgren, Jens. (2006). The D:A:D Study Group Liver-related deaths in persons infected

with the human immunodeficiency virus: the D:A:D study. Arch Intern Med 166: 1632-1641. Archives of internal medicine. 166. 1632-41. 10.1001/archinte.166.15.1632. 27. WHO Global Disease estimates 2016; WHO 2016 28. WHO guidelines on hepatitis B and C testing, WHO, Feb 2017 29. World Health Organization media centre. Hepatitis A fact sheet in world health organization media centre. [Online] 2016. http://www.who.int/mediacentre/.

30. Yanagimoto S, Yotsuyanagi H, Kikuchi Y, et al. Chronic hepatitis B in patients coinfected with human immunodeficiency virus in Japan: A retrospective multicenter analysis. J Infect Chemother 2012;18:883-890 National Guidelines for Diagnosis & Management of Viral Hepatitis 77

LIST OF CONTRIBUTORS Dr R. K. Dhiman - Gastroenterologist, PGIMER, Chandigarh Dr Rakesh Aggarwal - Gastroenterologist, SGPGI, Lucknow Dr C. E. Eapen - Hepatologist, CMC, Vellore Dr Samir R. Shah - Hepatologist, Global Hospital, Mumbai Dr Narayanasamy K - Hepatologist, MMC, Chennai Dr Praveen Malhotra - Gastroenterologist, PGIMS, Rohtak Dr Mamta Manglani - Paediatric hemato-oncologist, LTMMC & GH, Sion, Mumbai Dr Srijaya S - Gastroenterologist, GMC, Trivandrum Dr T. Jiten Singh - Physician, RIMS, Imphal

Dr Mohd. Shaukat - Advisor, Dte GHS, MoHFW, Delhi Mr Mehmood Pracha - Senior Advocate, Delhi Dr Sujeet Kumar Singh - Director, NCDC, Delhi Dr R. S. Gupta - DDG CST, NACO, Delhi Dr Sandhya Kabra - Additional Director, NCDC, Delhi Mr Sella Senthilm - Assistant Drug Controller, Office of DCG(I), Delhi Mr Abou Mere - Representative, Community Organisation Dr Aparajita Ravi Sondh - State Surveillance Officer, IDSP, Haryana Dr Nicole Seguy - CD team leader, WHO (India)

Dr Vimlesh Purohit - NPO (HIV & Hepatitis), WHO (India) Dr Rekha Jain – Consultant, Delhi Dr Partha Rakshit - Deputy Director, NCDC, Delhi Dr Hema Gogia - Deputy Assistant Director, NCDC, Delhi Dr Preeti Madan - EIS Officer Cohort 5, NCDC, Delhi 78 National Guidelines for Diagnosis & Management of Viral Hepatitis

80 National Guidelines for Diagnosis & Management of Viral Hepatitis

STANDARD TREATMENT GUIDELINES ENDOCRINOLOGY Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 DIABETES MELLITUS 6 2 HIRSUTISM 22 3 HYPOTHYROIDISM 27 4 OSTEOPOROSIS 28 5 POLYCYSTIC OVARIAN SYNDROME 32 6 THYROTOXICOSIS 39 7 OBESITY 41 2

Group Head Coordinator of Development Team Dr Sailesh Lodha Fortis Escorts Jaipur 3

Contributors- 1. Dr Anil Bhansali Head ,Department of Endocrinology PGI Chandigarh 2. Dr.Anil Kumar Singh Consulting Senior Endocrinologist Patna 3. Dr.K.D.Modi Consulting Senior Endocrinologist Hyderabad 4. Dr.Nikhil Tandon Professor,Department of Endocrinology AIIMS,New Delhi 5. Dr Pramod Gandhi Consulting senior Endocrinologist Nagpur 6. Dr Sailesh lodha Consulting senior Endocrinologist Jaipur Reviewers 1. Col M K Garg Head ,Department of Endocrinology R & R New Delhi 2. Professor M.S.Sheshadri

Head,Department of Endocrinology CMC Vellore 3. Dr.Rajesh Khadgawat Asso.Professor ,Department of Endocrinology AIIMS ,New Delhi 4. Dr Rakesh Sahay Professor ,Department of Endocrinology Osmania Medical college Hyderabad 5. Dr Rama Walia Asst Professor ,Department of Endocrinology PGI,Chandigrah 6. Dr Sanjay Bhadada Asso.Professor ,Department of Endocrinology 4

PGI ,Chandigarh 7.Dr Tushar Asso.Professor,Department of Endocrinology Seth GS Medical College Mumbai 8. Department of Endocrinology, AIIMS, New Delhi 9. Department of Endocrinology, I.P. Apollo Hospital, New Delhi 5

DIABETES MELLITUS Introduction Diabetes Mellitus (DM) is a global epidemic. Type -2 diabetes which forms almost 95 % of the total diabetes in India is largely a preventable disorder. India harbours more than 50 million diabetics. DM is associated with development of specific long-term organ damage (chronic complications) including retinopathy with potential blindness, nephropathy with a risk of progression to renal

failure requiring lifelong dialysis or renal transplantation, neuropathy with risk for foot ulcers, amputation, and Charcot joints and autonomic dysfunction such as sexual, bowel and bladder impairment. Patients with diabetes are at a particularly high risk for vascular complications like cardiovascular, cerebrovascular, and peripheral artery disease. A recent rise in the number of adolescent and young Type -2 diabetics in India is an alarming trend. This is largely due to lifestyle

factors.Recent Indian data suggest prevelence rates of 15 to 20 % in urban areas and about half of it in rural areas. DM poses a great threat to the health of our nation, it costs dearly the exchequer as the treatment of acute and chronic complications of diabetes are expensive. Beside this is the cost of day to day medication, tests, monitoring and loss of productive work due to illness. Hence it is important to recognise this disorder as early as possible. Attempt should be made to

detect hyperglycemia in prediabetes stage to prevent progression to diabetes. And finally the aim is to treat this disorder effectively to prevent the devastation of the chronic complications. Definition DM is a chronic metabolic disorder of carbohydrate, fat, and protein metabolism characterized by hyperglycaemia,resulting from defects of insulin secretion, insulin action, or a combination of both 1 . Type 1 diabetes is due to an absolute lack of endogenous pancreatic insulin production,

whereas in Type 2 diabetes, insulin resistance is the basic defect which is contributed by a combination of genetic predisposition, physical inactivity, and obesity. Classification Old terms like IDDM (insulin dependant DM), NIDDM (non insulin dependant DM)adult onset diabetes or juvenile diabetes have been abondoned. ADA classification of 1997 which was later accepted by WHO is the most widely accepted classification of DM . Classification of Diabetes Mellitus

1. Type 1 -(beta -cell destruction, usually leading to absolute insulin deficiency) A. Autoimmune B. Idiopathic 6

2. Type 2 -(may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with or without insulin resistance) 3. Other specific types (see Table ) Genetic defects of b-cell function -MODY 1 to 9, mitochondrial DNA. Genetic defects in insulin action Diseases of the exocrine pancreas (pancreatitis trauma, pancreatectomy, neoplasm cystic-fibrosis etc) Endocrinopathies (acromegaly, Cushing's syndrome, gucagonoma, pheochromocytoma, hyperthyroidism etc)

Drug- or chemical-induced Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes, e.g.: Down’s syndrome, Friedreich’s ataxia, Klinefelter’s syndrome, Wolfram’s syndrome 4. Gestational diabetes Characteristics of Diabetes In India Onset is about one decade earlier than the west Occurs at a lower BMI Central obesity is more common Type 1- less than 5% of the total diabetes Cardiovascular complications occur early PVD is less common than the west

Foot problems more common No structured treatment protocol Lack of trained manpower like diabetes educators,endocrinologists Cost of the treatment is a big hinderance Social and religious factors play an important role Diagnosis Any one of the following: Symptoms of diabetes + casual plasma glucose concentration > 200mg/dl (Casual - any time of the day without regard to time since last meal) Fasting plasma glucose > 126mg/dl (Fasting - no caloric intake for atleast 8 hours)

2 Hour plasma glucose during OGTT > 200mg/dl (OGTT according to WHO criteria) Note-HbA1c > 6.5% indicates diabetes, however it cannot be considered as a diagnostic tool in isolation. Impaired glucose metabolism Impaired Fasting Glucose (IFG): 7

FPG > 100 and 125 mg per dL Impaired Glucose Tolerance (IGT): 2hr PGPG > 140 and 199 mg per dL FPG > 100mg/dl and > 125mg/dl be classified as having IFG. Prevalence of diabetes is increasing rapidly in developing countries like India Occurs due to relative insulin deficiency in an individual with insulin resistance Usually asymptomatic and detected during evaluation for unrelated indications, but may present with hyperglycemic symptoms- Frequent urination, excessive thirst, excessive hunger

Weight loss, delayed healing of wounds, pain in calves, burning feet Tiredness, Itching -especially in genital area Tingling and numbness, blurring of vision, lethargy, somnolence, Sometimes the symptoms are due to complications of diabetes when patient presents to a clinician for the first time with a complication like erectile dysfunction. Type 1 DM: Absolute insulin deficiency due to autoimmune destruction of pancreatic beta cells.

Onset is mostly in childhood or in young adults before 35 years, about may rarely occur in elderly. Symptoms Abrupt onset of severe hyperglycemic symptoms. Sometimes the child may present with just weakness, lethargy, bedwetting. May present as diabetic ketoacidosis . MODY-Maturity onset diabetes of the young: Monogenic form of diabetes associated with mutation in a single gene Diagnostic Criteria • Aged less than 25 years at onset

• Autosomal dominant transmission of diabetes with three generations involved • Absence of ketosis at any time • Controllable without insulin at least in the early stages of the disease 8

• Clinical criteria are no longer acceptable and genetic analysis is needed to confirm the diagnosis. Clinical Features • Patients usually non-obese.Respond better to sulphonylureas in initial few years of diabetes. • Do not need insulin initially- later may become insulin-requiring (MODY 1, 3 and 5) • Isolated Mild fasting hyperglycemia- MODY 2- no treatment required • Diabetes with renal cysts/ renal agenesis RCAD (renal cysts and diabetes syndrome)- MODY 5 Fibrocalculous pancreatic diabetes-(FCPD):

Severe hyperglycemia in a lean patient from a tropical country like India with recurrent pain abdomen, evidence of chronic pancreatitis after excluding other causes of chronic pancreatitis like alcoholism ,should be considered for FCPD.Absence of ketosis and presence of pancreatic calculi is the characteristic feature. Latent Autoimmune Diabetes Of Adults (LADA): Type 1 Diabetes Which Presents Late GAD(Glutamic acid decarboxylase) autoantibody positive Age at onset > 35 years Lean patient

Insulin treatment required within one year of onset Many patients with Type 2 diabeteswho are lean, have no family history of diabetes and who require insulin early in the course of the disease actually have LADA Screening for Diabetes: Ethnically every Indian falls into a high risk category however it may not be feasible to screen everyone. The following population group need screening. Family history of diabetes Cardiovascular disease, Hypertension

Overweight or obesity, males with a waist >90cm females with a waist >80cm Sedentary lifestyle Patients who are on steroids Previously H/O IFG ,IGT Dyslipidemia History of gestational diabetes People who were born with a birth weight >9 pounds or LBW Polycystic ovary syndrome 9

If normal, repeat screening in 3 yrs for low risk subjects and every year for high risk subjects. If IGT or IFG repeat screening in 1 year. All pregnant ladies should be screened at -24-28 weeks if the risk is low, or at first ante natal visit if she belongs to a high risk group. Risk factors for GDM: Risk factors for GDM- Overweight or obesity Family history of diabetes mellitus History of IGT,IFG Poor obstetric history History of delivery of an infant with a birth weight >9 pounds

History of polycystic ovary syndrome Fasting plasma glucose concentration >90 mg/dL or 2-hour postprandial glucose >140 mg/dL Physical Examination : • Height, weight, BMI • Blood pressure measurement, including postural variation if indicated • Thyroid examination • Skin examination of insulin injection site and for acanthosis nigricans. • Xanthelesma Comprehensive foot examination • Inspection-see for redness or cracks or dryness of skin and shape of the foot

• Palpation of dorsalis pedis and posterior tibial pulses • Ankle and knee jerks • Proprioception, vibration and monofilament sensation • Dilated retinal examination • Dental examination Investigations at the time of diagnosis: 10

• Fasting and postprandial plasma glucose • HbA1c • Fasting lipid profile • AST/ALT • Urine complete exam, including assessment of microalbuminuria • Serum creatinine, and estimated GFR • TSH if there is dyslipidemia and in women >40 • ECG Markers of glycemic status • Plasma glucose • Whole blood glucose (glucose meters) • Urine glucose • Glycosylated hemoglobin (HbA1c) .HbA1c is an index of long term Glucose Control, performed on venous blood Test results are not affected by - Time of the day

- Meal intake - Exercise - Just administered diabetes drugs - Emotional stress - Patient cooperation In certain situations HbA1c can be falsely high(uremia,alcoholism etc) or low(blood loss iron defeciency anemia,pregnancy,hemoglobinopathies ,reduced RBC survival). eptide • It connects the A and B chain of insulin in the proinsulin molecule , • by-product of insulin biosynthesis • For every molecule of insulin in the blood, there is one molecule of C-Peptide. 11

• Very low levels: - Type 1 diabetes - Complete surgical removal of pancreas • Clinical utility of C-peptide measurement is very limited .Its measurement and interpretation of the results should be done by an Endocrinologist. Microalbuminuria • Test for presence of microalbuminuria annually in all Type 2 diabetics starting at diagnosis and Type 1 diabetic with DM more than 5 years Methods Measurement of the albumin to creatinine ratio in a random spot collection or 24 hour urine

collection for creatinine and albumin with simultaneous measurement of serum creatinine. Normoalbuminuria Microalbuminuria Macroalbumiuria Albumin/day <30 mg 30-300 >300 Albumin/creatinine <30 30-300 >300 ratio* Albumin excretion rate <20(mcg/min) 20-200 >200 * mcg of albumin/mg creatinine Albumin excretion rate (AER)- It is based on the albumin concentration ,the duration of the urine collection and the urine volume, and has the advantage of giving results which are independent of

the ingested fluid quantity.AER is the gold standard for the diagnosis of microalbuminuria. Foot examination- this should include examination of the shape of feet, bony prominences, calluses, deformities of the toes. Skin examination for texture ,color and loss of sweating, loss of hair. Nail examination for thickening, ingrowings, fungal infections. Inspection of interdigital webspaces for fungal infections and minor traumas Sensory examination of foot. Palpation of

dorsalis pedis and posterior tibial arteries. Joint movements for checking the power of the muscles (muscle wasting) and joint integrity. Vibration test (128Hz), nylon monofilament test, ankle brachial index, peripheral doppler may provide very important information. Continuous glucose monitoring(CGM) is indicated in pregnancy,brittle diabetes,insulin pump users.For Type -1 diabetics and elderly it can be used periodically to study hypoglycemia more closely. Monitoring

Glucose Frequency depends on the the kind of treatment and the severity of illness.It may be as low as twice a month to as high as 6-7 times in a day.# A1C Once in 3-4 months and six monthly if glycemic control is good Lipids Quarterly if uncontrolled, otherwiseOnce in 12 months* Creatinine Once* 12

Urine complete exam Once* Urine microalbumin Once in a year* ECG Once in a year* Fundoscopy Once in a year for all Type -2 diabetics from the time of diagnosis*.In Type -1 once every year from 4-5 years after diagnosis or at the age of 10 years.More frequent exams are needed in advanced retinopathy *Frequency of these tests can be more whereever indicated # monitoring should include fasting,preprandial and 2-hour postprandial and bed time glucose

levels .Occasionally between 2:00 -3:00AM glucose measurement is indicated to detect nocturnal hypoglycemia.Self monitoring of glucose by Glucose measuring devices at home is desirable for all diabetics.Patients on insulin need to monitor more frequently as compared to those on OADs. Nutrition therapy: Diet therapy has to be individualised based on the likes and dislikes, calorie requirement (overweight or underweight), lifestyle and comorbidities. Carbohydrates should form

50-65 % of the total calories, proteins should form 15-20% (like non diabetics) and fats -15-25%. Average Indian diets usually contain the desired fiber content (15-25 gm/1000 cal). The saturated fat consumption should be minimised to < 10% of the total calories. If the LDL is >100 than it should be further reduced to <7%.Trans fats should preferably be eliminated completely from the diet. Vegetable oils should be used interchangeably so that the desired omega 3:6 ratio is achieved

.No one kind of oil can be recommended. Coconut and palm oils should be avoided. There is no role of any additional multivitamins, trace elements ,antioxidants or any kind of neutraceuticals except Vit D. Consumption of fresh fruits ,salads and green vegetables should be encouraged which would supply all the multivitamins, trace elements, antioxidants. Absolute restriction of sucrose is not essential however it should be minimised. Restricted protein intake of 0.8 to 1.0

g/kg per day is required in patients who are in the earlier stages of chronic kidney disease and to g/kg per day in patients who are in the later stages of chronic kidney disease . Artificial sweeteners: Sucralose,Aspartame,Saccharin,Acesulfamec and a few others are non caloric sweeteners.Their consumption should be minimised .The scientific data favouring their safety is scanty hence they can be used in smaller quantities with a caution although the accepted

daily intake for Aspartame is 50 mg/kg/day and for Sucralose and saccharin is 5 mg/kg/day. Vaccination- Pneumococcal vaccine may be recommended for all diabetics. Life style interventions – The Diabetes Prevention Program found that people at risk of developing type 2 diabetes were able to cut their risk by 58% (it was 74% in subgroup of asians) with moderate physical activity (30 minutes a day) and weight loss (5 to 7% of body weight, or about 15 lb). For

people over age 60, the risk was cut by almost 71% .Adopting healthy lifestyle with increasing physical activity and weight reduction is key for achieving success in diabetes management. The effect of physical activity and other life style interventions on glucose and BP is comparable to pharmacological treatment. The goals of the life style interventions should be to achieve at least 5% reduction in body weight in obese. The individuals with high risk should be systematically

targeted with lifestyle interventions regardless of their glucose status. Regular daily physical activity of 45 minutes or more is recommended for all diabetics in general. Besides leisure time physical activity, other forms of activity like walking ,occupational or daily commuting on foot or 13

bicycle, household chores ,activity at work place is also helpful and should be encouraged. Later the intensity and duration of exercise can be increased according to one's general health and age. To begin with it could be just brisk walk. The aim is to raise and sustain the heart rate for 15-20 minutes to 60-85% of the maximal heart rate for that age. Maximal heart rate is 220 minus age. Exercise should be preceded by an additional 05 minute warmup and followed by a 05 minute cool

down. Thorough examination before starting physical activity is mandatory in view of associated comorbidities like CAD, proliferative retinopathy, autonomic neuropathy, arthritis, feet problems etc. Cessation of smoking, tobacco and moderating alcohol intake(only for those who are already taking alcohol, it cannot be recommended in any form for those who are not taking alcohol) should be reemphasised on every clinic visit.

Stress management: Relieving stress by adopting healthy lifestyle or by any other method including the traditional Indian methods is helpful. Oral drugs: Oral anti diabetic drugs (OADs) have no or very little role in Type -1 diabetes. They can be initiated at the time of detection of diabetes or after a trial of lifestyle measures for 6-8 weeks. Choice of an oral agent depend on many factors like duration of the diabetes, age and weight of

the patient, presence of other comorbidities ,lifestyle of the patient ,degree and type of hyperglycemia(fasting /postprandial)and susceptibility to hypoglycemia. Metformin(MF) and Sulphonylureas (SU) alone or in combination should form the base or the first line therapy in most of the OAD requiring diabetics.Sensitisers (like MF , Pioglitazone )and Alpha glucosidase inhibitors (AGI) are useful throughout the lifespan of a diabetic. Secretagogues like SU and Glinides are not

very useful in long duration of diabetes and progressively lose their efficacy as their action is dependant on residual beta cell mass which progressively decline in all Type -2 diabetics. Glinides are useful as monotherapy in elderly where a potent long acting SU is relatively contrindicated. DPP-4 inhibitors are not suitable for burnt out or long standing diabetes. As cost is often an issue for choosing an OAD ,DPP-4 inhibitors can be added if mono or dual therapy fails. At present they

cannot be recommended as first line therapy. Pioglitazone can be used as mono,dual or tripple therapy.Alpha glucosidase inhibitors are useful adjunct with any of the above mentioned drugs if postprandial hyperglycemia is the main target, though by themselves they are weaker drugs if used alone. Two OADs from a same group should not be used together. If HbA1c is mildly elevated (around 7%) monotherapy may be sufficient. For moderately elevated HbA1c (around 8%)dual

drug therapy as seperate or in fixed combination can be initiated. However MF or SU as monotherapy in higher doses may be sufficient even for these patients. For HbA1c of more than 9%, combination therapy is initiated or intensified as dual or tripple therapy or insulin can be added as single bed time dose if fasting hyperglycemia is the main target .Insulin as multiple doses(premixed or split mixed )can be added to the OADs. In some situations where other

measures fail, insulin can be used along with a combination of OADs and GLP-1 analogues. IGT- MF and Acarbose can be used to delay the onset of diabetes. Side effects of OADs Sulphonyureas: Hypoglycemia, nausea, constipation, pain abdomen, weight gain, hematological abnormalities, headache, skin disorders. Not very useful with higher doses of insulin,avoided in advanced renal failure. Glinides: Hypoglycemia,nausea,constipation,pain abdomen,diarrhoea. 14

Metformin: Pain abdomen, nausea, vomiting, diarrhoea, anorexia, weight loss, flatulence, B-12 defeciency. Contraindicated if serum creatinine is >1.4 in women and >1.5 in males, also contraindicated in CHF, advanced hepatic and respiratory failure.Avoided in periop period. Alpha glucosidase inhibitors- Flatulence, constipation, pain abdomen, diarrhoea, vomiting. Avoided in serious GI disorders. DPP-4 inhibitors- constipation, pain abdomen, diarrhoea, swelling ,headache, URI, arthralgia,

anorexia. Not very useful in long standing diabetes. Pioglitazone: fluid retension, anaemia, weight gain, sinusitis, worsening of retinopathy, Fractures in postmenopausal women. Contraindicated in CHF, fluid overload states and in advanced hepatorenal dysfunction. Recent data impicates it in bladder cancer. It has been banned in Germany. A great caution is required in patient selection for its use . Mechanism of action of OADs Insulin secretagogues Sulphonylureas,Glinides

Insulin sensitisers Pioglitazone,Metformin Drugs acting locally on gut Alpha glucosidase inhibitors Potentiating Incretin axis,glucagon DPP-4 Inhibitors suppression When HbA1c is high ,fasting glucose should be the target first and when Its relatively better or towards normal side the postprandial glucose should be targeted first to achieve better glycemic control. Insulin – Insulin is a potent anabolic hormone .The effects other than glucose lowering are

important in many clinical situations where anabolic activity is desired. Indications Type -1 DM, pregnancy, severe infections, severe catabolic states, OAD failure,acute stressful situations like acute coronary syndrome, stroke, acute renal or hepatic failure, periop period. Secondary diabetes, post transplant diabetes ,congestive heart failure are also indications for insulin usage. Insulin can be added to existing OADs for short durations (e.g. steroid use in a diabetic on OADs) or long durations.

Insulin preparations and their pharmakokinetics- Insulin Onset Peak Effective Duration Rapid-actingAnalogue Aspart ,Lispro 5-15 min 30-90 min <5 h Glulisine 5-15 min 30-90 min <4 h Short-acting Regular 30-60 min 2-3 h 5-8 h Intermediate 15

NPH 2-4 h 4-10 h 10-16 h Long-acting Glargine 2-4 h No peak 20-24 h Detemir 3-8 h No peak 5.7-23.2 h Premixed 75% insulin lispro protamine 5-15 min Two 10-16 h suspension/25% insulin 50% insulin lispro protamine 5-15 min Two 10-16 h suspension/50% insulin 70% insulin aspart protamine 5-15 min Two 10-16 h suspension/30% insulin 70% NPH/30% regular 30-60 min Two 10-16 h 75%NPH/25% regular 30-60 min Two 10-16 h 50%NPH/50% regular 30-60 min Two 10-16 h

Animal insulin is no longer preferred as more safe and cheap synthetic human insulin is easily available in abundance. Basal insulin therapy -if only fasting hyperglycaemia is the concern and patient is already on OADs then basal may be added to OADs. Shifting to rapid acting analogues or their premixed preparations are preferred in the following situations: • When good control is not possible with short acting or premixed human insulins, • Occurrence of frequent hypoglycemia,

• When lifestyle of the patient demands immediate intake of food after insulin injection • Renal or hepatic failure where more predicted and shorter action of insulin is desired. • Allergic reactions to human insulin. Insulin should be injected on anterior abdominal wall as the first preferred site,other sites can be thighs,buttocks and lastly the arms.Injecting repeatedly at one site can cause lipodystrophy and erratic insulin absorption.

Other injectable therapies-GLP-1 analogues- Currently available GLP-1 analogues Exenatide and Liraglutide are a good choice in an obese Type-2 diabetic. They can be used as an adjunct with any OAD except DPP-4 inhibitors for reducing both fasting and postprandial hyperglycemia. Hypoglycemia is uncommon if used alone. Nausea, vomiting, abdominal pain, distension, dyspepsia, diarhoea and headache are the common side effects. Usage should be avoided in

patients with associated severe GI disorders like pancreatitis. Exenatide is given twice daily subcutaneously before meals and Liraglutide once daily with disregard to the meals but almost at the same time daily. Weight loss is an advantage with these agents which make them a useful tool for obese diabetics. They are contraindicated in Type-1 DM and acute hyperglycemic 16

complications. Insulin pump: At present due to its prohibitive cost its usage is very limited. All patients who qualify for insulin pump therapy should be referred to a centre where expertise for a pump is available. Pump therapy requires a lot of motivation and time from both - the patient and the clinician. Indications • All Type -1 diabetics who are poorly controlled with basal-bolus therapy. • Pregnancy • Frequent hypoglycemia or hypoglycaemic unawareness

• Persistently elevated fasting glucose (Dawn phenomenon) • Multiple chronic complications with labile glucose requiring fine tuning of glycemic control • Management of labile diabetes after renal or hepatic transplant • In situations where insulin requirement is very high a trial of pump therapy can be given. Hypertesion in diabetics: Lifestyle measures form the cornerstone of hypertension management. Salt intake should be

restricted to less than 6 gm per day. Restriction of salt intake should however be individualised .Care has to observed in elderly and in people who sweat much particularly in summers. The target BP is 130/80 for all diabetics and 120/70 in established nephropathy (creatinine >1.5 or proteinuria >1 gm per day) .BP should be measured at each visit .Measuring postural variation in BP is useful in autonomic dysfunction. Therapy should be individualised based on the associated comorbidities

and side effects of drugs. Lifestyle measures and dietry adjustments are essential to attain the desired goals. ACE (Angiotensin Converting Enzyme )Inhibitors and ARBs (Angiotensin Receptor Blockers) can be used interchangeably as a first line antihypertensive agent in all diabetics. Second line agent could be calcium channel blockers or cardioselective betablockers. Diuretics and alpha blockers can also be used whereever needed. Glucose intolerence due to any of these agents is not clinically significant.

Diabetic dyslipidemia- Classically, DM induces elevation in triglyceride and LDL, and low HDL levels.It should be treated aggressively with a LDLc target of <100 mg/ dl without CAD and <70 mg/ dl with CAD.Goal for triglycerides is <150 mg/dl and for HDLc is > 45 mg/dl. Statins form the cornerstone of lipid lowering therapy.Statins are also useful if microvascular complications like nephropathy and retinopathy are present. Addition of fibrate or ezitimibe is

indicated when desired goals are not met.Triglycerides of >400 is an indication for the use of fibrate as a primary therapy. Combination of niacin can be useful if HDL is persistently low. Usually anti lipid therapy is lifelong and doses need adjustments based on periodic lipid profile. Dietary modifications and lifestyle measures can alone be sufficient sometimes. Statins can produce myalgias and rarely myopathy . Aspirin(ASA) usage in diabetes- Low dose(75-150mg) ASA prophylaxis should be given to all 17

diabetics over 50 years of age with one additional cardivascular risk factor. Watch for adverse events -GI bleed and hemorrhagic stroke . Management of diabetes in pregnancy- prepregnancy counseling for the desired goals for glucose and blood pressure,lifestyle measures ,nutrition.Shifting to insulin and withdrawl of ACE inhibitors and lipid lowering drugs is required in prepregnancy period.Folic acid 10 mg daily should be started to prevent neural tube defects. Screening for GDM

Glycemic targets in pregnancy- fasting- 95 mg/dl, 2hours post prandial-<120 and one hour <140. Diabetic Foot: Even a small ulcer should be given full attention .Neglecting small ulcers or trauma can finally become the reason for limb loss. Diabetic foot results predominantly due to neuropathy ,associated with infection and ischemia.X- ray of the foot may expose foreign body or gas and must be done .Shifting these patients to insulin

helps in better glycemic control and early healing. Infections of the foot are polymicrobial and require wide spectrum coverage. Limb and life threatening infections must be treated with parenteral antibiotics. Pus collection of any magnitude should be drained out and explored widely. Early surgery is always desired .Iodinated solutions , H2O2 and other strong antiseptics should be avoided for cleaning the wound as they prevent angiogenesis. Planter lesions will heal only with offloading the affected foot.

Referral to a higher center necrotising fascitis, any chronic non healing ulcer, lesion associated with systemic involvement, presence of significant ischemia charcot's joint, requirement of advanced imaging and customised footwear or orthotic support. Targets BMI 21-25 Fasting glucose 80-120 2 hours postprandial glucose 130-160 HbA1c 6.5-7.0 BP 140 / 80 Total Cholesterol <150 LDLc <100 Triglycerides <150 HDLc >40 for males, > 50 for females Hospitalised patient -periop period

Targets-Preprandial glucose- <110 2 hours Postprandial glucose-<180 Critically ill patients- 140-180 18

Most of these patients will be on insulin which preferably should be given as bolus -basal therapy i.e.3-4 boluses of short acting insulin and a bedtime dose of NPH or long acting insulin. Stable patients who are eating well can be managed with 2-3 time insulin (premixed or split mixed)In all hemodynamically compromised situations, acute myocardial infarction, stroke, high dose steroid therapy, immediate post op period of major cardiac surgery, severe sepsis, very high glucose levels

,patients on ventilator. IV infusion of short acting insulin with glucose monitoring every 1-2 hours is preferred. Basal insulin requirement must be assessed for all patients to prevent fasting and inter prandial glucose peaks. Patients who are nil by mouth may also need some basal insulin. Overlap between subcutaneous and IV insulin for 30-60 minutes should be done to prevent sudden hyperglycemia relapse when shifting from IV to subcutaneous insulin. Hypoglycemia: more common in following situations

Patients who are older, have renal or liver disease Have a long duration of diabetes, autonomic neuropathy, hypopituitarism Regularly miss meals, erratic meal pattern unusual exercise Take greater than the prescribed dose of their medication Concomitant medication – Levofloxacin*, beta blockers, * hyperglycemia is more common with Levofloxacin though rarely hypoglycemia can occur. Diabetes Education: Educating the patient for lifestyle modifications, hypoglycemia, insulin

therapy, foot care, benefits of quitting smoking and tobacco, reducing alcohol helps in achieving the targets of therapy. Sick day guidelines: The objective of these guidelines is to avoid hospitalisation during situations like acute diarrhoea, vomiting febrile illness. And if at all it is required the patient is able to prevent DKA or other diabetes related acute complications. All diabetics should be taught these simple

rules or a handout may be given mentioning- In any febrile illness or whenever there is poor intake of food and water due to any illness dehydration and ketosis must be avoided .Never omit your medication -insulin or OAD. Infact sometimes a higher dose is required when we are sick even when we are not eating. Blood glucose and urine ketones must be checked frequently -every 4-6 hourly. Type 1 diabetics may require monitoring 2-4 hourly. Try to eat small amounts of

carbohydrates every 2-4 hourly ,soft food or liquids are easier to take .!00-120ml of fluid every hour (carbohydrate free if glucose is >250 and with carbohydrates if glucose is less than 250. Fluids and carbohydrates are required to maintain hydration and calorie requirement and preventing hypoglycemia. Dehydration and worsening ketosis are ominous signs . Physician must be consulted if nausea or vomiting persists with ketosis .If blood glucose is persisting more than 300 on two

consecutive times .If breathing becomes rapid or laboured, fever >100 degree F persisting more than 24 hours, persisting diarrhoea or vomiting or pain abdomen. Inability to take fluids for more than 4 hours due to vomiting drowsiness or altered sensorium or anyother unexplained symptoms. Drug treatment adjustments during sickdays- stop metformin, and preferably other OADs except sulphonylureas, increase or decrease sulphonylureas according to the glucose readings. Addition of 19

short acting insulin may be required to OADs.In situations where patient is already on insulin, long acting or intermediate insulin should be continued in the same doses. Dose of short acting insulin can be adjusted by measuring sugars 4-6 hourly.Premixed insulins should be supplimented by short acting insulins usually 20-25 %extra or more dose of insulin is required in addition to the usual dose of insulin.However if vomiting or diarrhoea persists hypoglycemia can occur.

Prevention of diabetes: Identify the high risk population .Fasting glucose and OGTT should be used for identifying IFG and IGT.No drug is recommended for the prevention of diabetes.MF and Acarbose can be used in IGT and IFG.Lifestyle measures mentioned in section 2.3 should be persued for prevention of diabetes. Referral to a tertiary center /Endocrinologist: In the following situations a referral to a tertiary

center where endocrinologist is available should be done at least once or more in a year. Diabetes in a neonate or an infant, all Type -1 diabetics with polyendocrinopathy, Coeliac disease or with growth hormone defeciency. Diabetes with complications, brittle diabetes, pregnancy with diabetes, diabetes with endocrine tumors like pheochromocytoma, pituitary tumor, rare varieties of diabetes like diabetes with lipodystrophies or rare syndromes, requirement of CGM or insulin

pump. Diabetes after liver or renal transplant. In any other situation where glycemic control is not achieved despite of all efforts. Referral to a nephrologist: serum creatinine >1.5 ,proteinuria more than >1 gm/day,nephropathy in absence of retinopathy ,suspicion of a nondiabetic renal disease. Referral to a retinal surgeon: when early NPDR is progressing ,CSME,advanced retinopathy. Referral to a neurologist: severe neuropathic symptoms not responding to the standard treatment,

suspicion of non diabetic neuropathy, amyotrophy, stroke, mononeuropathy. Referral to a cardiologist: angina or its equivalent ,diabetic cardiomyopathy,peripheral vascular disease requiring further workup Who does what Doctor- history taking, physical examination, ordering investigations, prescrbing treatment. Nurse- patient education -like explaining the basics of diabetes and its complications, foot care, exercises, hypoglycemia, self monitoring of glucose, insulin injection devices and techniques.

Dietician- calorie calculation, explaining the concept of carbohydrate counting, food exchanges, glycemic index, modifications in diet during special situations like pregnancy, renal impairment. Technician- drawing blood ,doing ECG, installing CGMS, insulin pump installation and its management except the insulin dose calculation and its modifications . Biothesiometry and use of other gadgets for foot care. Suggested reading /references

1. Epidemiology of Type -2 Diabetes : Indian scenario.Indian Journal of medical research 2007: 125(3) 2. Joslin's Diabetes Mellitus,14th edition.Edited by C.Ronald kahn et al.Publisher -Lippincott Williams & Wilkins. 20

3. American Association of clinical Endocrinologists -medical guidelines for clinical practice for the management of Diabetes Mellitus 2007 4. Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus.Boyd E. et al.Diabetes care, 2007: 30, supplement 2 5. American Diabetes Association .Standards of medical care in diabetes. Diabetes care 2010; 33: suppliment. 6. The Diabetes Prevention Program Research Group. Reduction in the incidence of type 2

diabetes with lifestyle intervention or metformin. New Engl Med J. 2002;346:393-403. 21

HIRSUTISM I. WHEN TO SUSPECT /RECOGNISE a) Introduction: Hirsutism is the presence of excessive growth of terminal hair that appears in a male pattern in a woman. Though the presence of hirsutism may be a purely cosmetic and social concern to the affected woman, medically it can be indicative of conditions like Polycystic Ovarian Syndrome (PCOS), non classic Congenital Adrenal Hyperplasia (CAH) or virilizing tumours of the ovaries or adrenals.

Androgens are essential for the conversion of vellus (small, straight and fair) hairs into terminal (larger,thicker,coarser, curlier and darker) hairs. This conversion is dependent on the level of the circulating androgens, their metabolism locally at the pilo-sebaceous unit by the enzyme 5 alpha reductase into dihydrotestosterone, and the subsequent binding of the latter to its receptor. This local metabolism and androgen-receptor interaction is highly variable. As a result pilosebaceous

units vary in their sensitivity to androgen. Therefore, the degree of hirsutism may be very different between individuals with similar levels of circulating androgens. b) Case definition: Hirsutism is a clinical diagnosis. Hirsutism should be distinguished from hypertrichosis which is generalised excessive vellus hair growth in a non sexual pattern. Hypertrichosis is androgen- independent. Its origin is hereditary or secondary to systemic conditions and certain drugs.

Typically, hirsutism is defined clinically by judging the severity of hirsutism (graded subjectively from 1 to 4) in each of nine defined body areas. A total score of more than 8 out of a maximum of 36 is considered significant. This is the Ferriman-Gallwey hirsutism scoring system. Apart from its subjective nature and other drawbacks, the total score does not reflect the significance of higher degrees of hirsutism in one area alone (“focal hirsutism”) if the other areas are unaffected. Thus

focal hirsutism which is causing distress to a woman may not lead to a “significant” total FG score of 8. This has led to the concept of “patient-important hirsutism” – i.e. hirsutism that is significant for the individual seeking medical attention. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY: About 5 % of women in the west have hirsutism. Data for our country are lacking. It is encountered commonly in practice. III. ETIOLOGY: Polycystic ovary syndrome Idiopathic (hirsutism without hyperandrogenemia)

Late-onset or non-classic congenital adrenal hyperplasia Androgen-secreting tumours Ovarian tumours Adrenal tumours Cushing's syndrome Hyperprolactinaemia Acromegaly Thyroid dysfunction Iatrogenic Androgen therapy (testosterone, anabolic steroids) Danazol Androgenic progestins (levonorgestrel, norethindrone and norgestrel) 22

Glucocorticoids Polycystic ovaries, idiopathic hirsutism and drug-induced hirsutism constitute the largest proportion of cases. Hypertrichosis can occur in the following conditions or with some drugs as indicated below Porphyria Phenytoin Cyclosporine IV. COUNSELLING Patients have to be informed of treatment options and time frame of efficacy of various modalities – especially the delayed onset of pharmacologic therapy and that laser and intense pulsed light

(IPL) modalities are methods of long term hair reduction and not “permanent” removal. The need for continued therapy for sustained control should also be explained. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT AND REFERRAL CRITERIA: 1) Diagnosis: Hirsutism is a clinical diagnosis. The presence of excess terminal hairs in a male pattern has to be documented. The Ferriman Gallewey score of > 8 is helpful if the scoring is feasible. A baseline FG

score is also useful for assessing treatment response. Strict requirement of FG score >8 for diagnosing and treating hirsutism is not applicable. Some patients have already removed their hair or have been treated before their first medical encounter precluding any scoring attempt. One also has to bear in mind the situation of “focal hirsutism” and “patient-important hirsutism”. The Ferriman Gallwey Scoring System

Hirsutism is scored from 0 (none) to 4 (severe) in each of nine defined areas, and the total score added. 23

Clinical evaluation is also directed at discerning clues to specific etiologies. ----Drug use ----Androgen secreting neoplasm: Sudden onset, rapid course, progression, virilisation (clitoromegaly, temporal hair recession, muscularity, voice change) or abdominal/pelvic mass suggest the possibility of androgen secreting neoplasm. ----PCOS : Perimenarcheal onset of menstrual irregularity, infertility, acne, male-pattern alopecia, obesity, acanthosis nigricans.

---Non-classic CAH: history of consanguinity in parents, family history of infertility, hirsutism, menstrual irregularity or both ---Cushing’s syndrome: Hypertension, striae, easy bruising ---Hyperprolactinemia: Galactorrhoea ---Primary hypothyroidism: Goitre, other clinical features ---Acromegaly: Acral enlargement, coarse features, prognathism 2) Investigations: Patients with isolated, mild hirsutism need not have any tests done. Patients with the following need to be investigated:

Moderate or severe hirsutism, i.e. FG score >15 Hirsutism of any degree when it is sudden in onset and/or rapidly progressive progressing despite therapy associated with menstrual irregularity/infertility/obesity/acanthosis nigricans associated with features of virilization 1. Serum Testosterone: Serum testosterone should be checked early morning. In women who are having regular cycles it should be checked between days 4-10. In others, either a random sample or one obtained after

progesterone induced bleeding should be used. Testosterone levels in the upper normal range or mildly elevated (70 -150 ng/dl) is usual for PCOS. Serum testosterone values in the adult normal male ranges (200 – 1100 ng /dl) are seen in virilizing neoplasms. If serum total testosterone is normal in the situation where elevated levels are expected, serum albumin and SHBG should be checked in addition and the free androgen index calculated. Commercially available free testosterone assays may be unreliable.

2. Other tests are to be chosen according to the suspected etiology i) Ultrasound : PCOS, adrenal/ovarian neoplasm ii) Serum basal 17 hydroxy progesterone and if this is between 3 -10 ng/ml a Synacthen stimulation test : non classic CAH iii) Serum DHEAS : Adrenal neoplasm iv) Additional tests for hypothyroidism, hyperprolactinemia, acromegaly, Cushing ’s syndrome, when suspected c) Treatment : Treatment has to be prolonged and often continuous for control of hirsutism. When cosmetic

measures alone are insufficient treatment, it has to be complemented with (a) pharmacologic therapy, or (b) direct long term hair removal methods. The choice between pharmacological therapy and hair removal methods depends on patient preference, cost, and the area needed to be treated (wider areas require pharmacologic therapy). In those with hyperandrogenemia, pharmacologic therapy needs to be combined with hair removal methods to achieve better control of hirsutism. 1. Pharmacologic therapy :

Any chosen pharmacologic therapy needs to be given a trial of at least six month before 24

augmenting dosage, combining, or changing drugs. i) Oral contraceptives : OCPs containing progestin with less (norgestimate, desogestrel) or no (drospirenone) androgenic potential are better than those containing levonorgestrel. ii) Antiandrogens : Because of their teratogenic potential, antiandrogens should not be used alone in all those who can conceive and are not on effective contraception. Spironolactone is the most commonly used antiandrogen at 100-200 mg/day in divided doses.

Finasteride at 2.5 to 5 mg per day is less effective. It is a type 2 alpha reductase inhibitor and inhibits conversion of only one of the isoenzymes responsible for formation of dihydrotestosterone from testosterone. Flutamide (250-500 mg per day) is rarely used because of its hepatotoxic potential but can be used with periodic monitoring of LFT in severe refractory cases. Topical eflornithine cream is used for focal hirsutism (e.g. facial hirsutism). It inhibits ornitihine

decarboxylase which catalyses the rate limiting step for polyamine synthesis which is necessary for hair growth. It does not remove hair but reduces the growth and appearance of facial hair. 2. Hair removal/reduction methods : • Temporary Depilation - Removal of hair shaft from the skin surface e.g. shaving and chemical depilatory creams Epilation – Removal of hair shaft from above the bulb – waxing and plucking • “Permanent” methods of hair reduction

Electrolysis – destruction of hair follicles by insertion of a needle and use of electric current can be used for limited focal hairs as it is time consuming. The cost is less than photoepilation. Photoepilation (laser or intense pulsed light) is a costly modality, but can be used for treating relatively wider areas. The energy absorbed by the melanin destroys the hair follicles. There is a reduction of 30 % or more in the number of terminal hair after a given

setting. More than one sitting is therefore required. Vellus hair follicles remain and can exhibit conversion into terminal hairs when androgen excess is not taken care of. Standard Operating Procedure : 1. Confirm hirsutism. Distinguish from hypertrichosis. 2. Ascertain history of development and progression of hirsutism. 3. Check for other features of hyperandrogenism (acne, male-pattern alopecia), virilisation 4. Rule out exposure to androgens, and features of PCOS, Cushing’s syndrome, acromegaly,

5. Isolated mild hirsutism in women with normal cyclical menstruation, does not require further testing unless there is inadequate response to or progression despite empirical treatment. 6. Total testosterone should be checked in all others. Free testosterone index in case the latter is unexpectedly normal. 7. Other tests would depend on the endocrinopathy clinically suspected. 8. Treatment is offered to all women with patient-important hirsutism despite cosmetic measures.

9. Pharmacotherapy and electrolysis/photoepilation are the available options – choice for latter measures being made on patient preference, availability, affordability and extent of area affected. Pharmacotherapy often needs to be combined with hair reduction methods in women with hyperandrogenemia to achieve better and sustained control. 10. Pharmacotherapy is precluded in all those trying to or likely to conceive 11. OCPs alone are an option for most. Antiandrogens alone can be used only in those who

follow effective contraception. Antiandrogens and OCPs are therefore often used in combination. 12. Any pharmacotherapy should be given a trial of at least 6-9 months before modification. d) Referral criteria 1. When endocrinological conditions like acromegaly, Cushing’s syndrome, CAH are suspected 2. When facilities for photoepilation or electrolysis is not available. VI. FURTHER READING / REFERENCES Evaluation and treatment of hirsutism in premenopausal women. J Clin Endocrinol Metab : 93(4),1105-20, 2008

Rosenfeld RL. Clinical Practice. Hirsutism. N Eng J Med: 353, 2578-88, 2005 26

HYPOTHYROIDISM Hypothyroidism is the second most common endocrine disorder after diabetes and affects individuals of all ages from new born to elderly population. The prevalence of congenital hypothyroidism varies from 1 in 2500 to 1 in 3000 newborns and the prevalence of primary hypothyroidism in adults is around 5-40%. However, the incidence of subclinical thyroid dysfunctions is on rise possibly because of increasing awareness about the disease among masses

,easy and wide spread availability of thyroid hormone assays and possibly universal salt iodization programme. Screening is recommended for the following high risk groups: -All new born infants -Pregnant women -Strong family history of thyroid disorders/or autoimmune disorders -Having an autoimmune disease like T1DM -Patients with depression, dyslipidemia and infertility Primary hypothyroidism constitutes around 95% of the patients with hypothyroidism and in rest

5% it is due to secondary hypothyroidism and drugs. The majority of patients with hypothyroidism are due to Hashimoto’s thyroiditis and postablative therapies particularly 131I radioablation and thyroid surgery in patients with Graves’ disease. Hypothyroidism in few patients is related to thyroiditis and drugs like lithium and amiodarone. Iodine deficiency is a rare cause of hypothyroidism . The symptoms and signs include weakness (99%), dry coarse skin (76%), slow speech (34%),

periorbital puffiness (60%), constipation (40%) and others like pallor and cold skin(48%). Presence of goitre (40%) and delayed deep tendon reflexes (77%) are usual finding on examination. Diagnosis of primary hypothyroidism is easily established by low T4, low T3 and high TSH (≥10µU/ml). Serum T3 levels are usually normal as increased 5’ monodeiodinase activity and preferential secretion of T3 by the thyroid gland maintains it until the disease advances.

Subclinical hypothyroidism is diagnosed by normal T3 and T4 levels and serum TSH is above the reference range. Secondary hypothyroidism is characterized by low T3, T4 and low TSH which may be accompanied with other hormone deficiencies as well. Management Management of adult hypothyroidism requires treatment with L-thyroxine which is built-up gradually over a period of weeks from 25 µg and increasing to 100-125 µg daily. The tablet is to be

taken in the morning fasting state 45 min, prior to intake of food. The doses may be required to built up more gradual in elderly patients and patients with coronary artery disease. The concurrent administration of iron, calcium and antacids interfere with L-thyroxine absorption and therefore these medications should be administered 6-8h later after L-thyroxine administration. The L-thyroxine replacement is unambiguous in pregnant women with subclinical hypothyroidism

(SCH), while in other patient with SCH, presence of goitre, TMA positivity, high LDL-Ch or signs/symptoms related to hypothyroidism warrants L-thyroxine replacement. If there is no benefit in symptoms with L-thyroxine over a period of 3-6 months, then treatment can be withdrawn. Clinical improvement with therapy with L-thyroxine is marked by dieresis, weight loss, increase in heart rate, appetite and feeling of well being. However, change in voice and improvement in

myopathy may take a longer time to recover. Periodic monitoring of thyroid function is required to assess the adequacy of therapy. The target TSH to be maintained is between 0.5 to 2.5 µU/ml. Initially at 6 weeks and later once in 6 months estimating TSH is usually sufficient to assess the adequacy of replacement therapy. 27

OSTEOPOROSIS I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Osteoporosis is a skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis is a silent disease until it is complicated by fractures—fractures that can occur following minimal trauma. These fractures are common and place an enormous medical and

personal burden on aging individuals and a major economic toll on the nation. Osteoporosis can be prevented and can be diagnosed and treated before any fracture occurs. Importantly, even after the first fracture has occurred, there are effective treatments to decrease the risk of further fractures. b) Case definition: According to the World Health Organization (WHO) diagnostic classification, osteoporosis is defined by bone mineral density (BMD) at the hip, spine or forearm, that is less

than or equal to 2.5 standard deviations below the young normal mean reference population (1). The categories in WHO definition are: 1. Normal: BMD higher than 1 SD below the young adult mean 2. Osteopenia, or low bone mass: BMD between 1 and 2.5 SD below the young adult mean 3. Osteoporosis: BMD lower than 2.5 SD below the young adult mean 4. Established (or severe) osteoporosis: BMD lower than 2.5 SD below the young adult mean and the presence of one or more fragility fractures

Thus, osteoporosis is defined in practice by a surrogate marker (i.e., BMD), not a health outcome (fracture), even if other factors can influence the likelihood of fractures. The relationship between BMD and fractures is very similar to that between hypertension and stroke and stronger than that between serum cholesterol and coronary heart disease. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY Osteoporosis affects an enormous number of people, of both sexes and all races, and its

prevalence will increase as the population ages. It is estimated that with this 2.5 SD threshold, 30% of white women older than 50 years have osteoporosis (2), a fraction that is similar to the lifetime risk of fracture at the hip, spine, and forearm for a 50-year-old woman (3). By this definition, about 0.6% of young adult women have osteoporosis, and 16% have low bone mass. Though there is paucity of large population based data that define the prevalence of osteoporosis and fracture

from India, recent reviews estimate there are over 25 million people in India with osteoporosis, which is expected to reach about 36 million by 2013 (4, 5). Osteoporosis was attributed to widespread vitamin D deficiency and reduced dietary calcium intake. Vitamin D deficiency is very common in India. III. DIFFERENTIAL DIAGNOSIS Evaluation of a patient suspected of having osteoporosis includes an adequate history and physical

examination and assessment of the potential causes of secondary osteoporosis and diseases 28

mimicking osteoporosis like osteomalcia. Occasionally metastasis to spine can mimic osteoporotic fractures. Risk factors for secondary osteoporosis  Endocrine disorders - Hyperparathyroidism, hypogonadism, hyperthyroidism, diabetes mellitus, Cushing disease, prolactinoma, acromegaly, adrenal insufficiency  Gastrointestinal/nutritional conditions - Inflammatory bowel disease, celiac disease, malnutrition, gastric bypass surgery, chronic liver disease, anorexia nervosa, vitamin D or calcium deficiency

 Renal disease - Chronic kidney disease, idiopathic hypercalciuria  Rheumatologic diseases - Rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus • Hematologic disease – Multiple myeloma, thalassemia, haemophilia, systemic mastocytosis, lymphoma, leukemia, sickle cell disease,  Genetic disorders - Cystic fibrosis, osteogenesis imperfecta, homocystinuria, Ehlers-Danlos syndrome, Marfan syndrome, hemochromatosis, hypophosphatasia

 Others - Porphyria, sarcoid, immobilization, pregnancy/lactation, chronic obstructive pulmonary disease (COPD), parenteral nutrition, HIV/AIDS Medications known to cause or accelerate bone loss • Corticosteroids - Prednisone (≥ 5 mg/d for ≥ 3 mo)  Anticonvulsants - Phenytoin, barbiturates, carbamazepine (These agents are associated with treatment-induced vitamin D deficiency.)  Heparin (long-term)  Chemotherapeutic/transplant drugs - Cyclosporine, tacrolimus, platinum compounds,

cyclophosphamide, ifosfamide, methotrexate  Hormonal/endocrine therapies - Gonadotropin-releasing hormone (GnRH) agonists, luteinizing hormone-releasing hormone (LHRH) analogs, depomedroxyprogesterone, excessive thyroid supplementation  Lithium  Aromatase inhibitors - Exemestane, anastrozole IV. PREVENTION AND COUNSELING Several interventions to reduce fracture risk can be recommended to the general population.

These include an adequate intake of calcium and vitamin D, lifelong participation in regular weight- bearing and muscle-strengthening exercise, avoidance of tobacco use, identification and treatment of alcoholism, and treatment of other risk factors for fracture such as impaired vision. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA Target group: Postmenopausal women and men age 50 and older. • Counsel on the risk of osteoporosis and related fractures.

• Check for secondary causes. • Advise on adequate amounts of calcium (at least 1,200 mg per day) and vitamin D (1000-2,000 IU per day) including supplements if necessary for individuals age 50 and older. Serum vitamin D level of > 30 ng is required to prevent vitamin D deficiency • Recommend regular weight-bearing and muscle-strengthening exercise to reduce the risk of falls and fractures. • Advise avoidance of tobacco smoking and excessive alcohol intake.

• In women age 65 and older and men age 70 and older, recommend BMD testing. • In postmenopausal women and men age 50-69, recommend BMD testing when there is concern based on their risk factor profile. 29

• Recommend BMD testing to those who have had a fracture, to determine degree of disease severity. • Initiate treatment in those with hip or vertebral (clinical or morphometric) fractures. • Initiate therapy in those with BMD T-scores ≤ -2.5 at the femoral neck or spine by dual-energy x- ray absorptiometry (DXA), after appropriate evaluation. • Initiate treatment in postmenopausal women and men age 50 and older with low bone mass (T-

score between -1.0 and -2.5, osteopenia) at the femoral neck or spine and a 10-year hip fracture probability ≥ 3% or a 10-year major osteoporosis-related fracture probability ≥ 20% based on WHO absolute fracture risk model (FRAX®).FRAX tool computes the 10 year probability of hip fracture or a major osteoporotic fracture in a specific population.Till It is validated for Indian population data from other asian countries can be used.

• Current pharmacologic options for osteoporosis prevention and/or treatment are bisphosphonates (alendronate, ibandronate, risedronate and zoledronic acid), calcitonin, estrogens and/or hormone therapy, parathyroid hormone (teriparatide) and estrogen agonist/antagonist (raloxifene). Adequate vitamin D is also required for maintaining bone health. The daily requirement of vitamin D is 1000-2000 IU. Mega doses of vitamin D (sachets containing 60,000 IU

,Injection of cholicalceferol as 3.0 lacs or 6.0 lacs IU) is appropriate in most situations.Toxicity due to over dose of vitamin D is rare. • BMD testing performed in DXA centers using accepted quality assurance measures is appropriate for monitoring bone loss. For patients on pharmacotherapy, it is typically performed two years after initiating therapy and every two years thereafter; however, more frequent testing may be

warranted in certain clinical situations.Ideally DXA scan of three sites (hip, spine and forearm)should be done .Results of DXA should be interpreted with caution in situations like spondylosis,and other degenerative diseases of hip and spine .Other conditions like fluorosis,metallic implants in bone can also lead to falsely elevated DXA score.DXA will not differentiate between low calcium content in the bone being caused by osteoporosis (quantitative

abnormality)and osteomalacia which is a qualitative abnormality. *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited By definition, diagnosis of osteoporosis requires assessment of BMD by DXA. Formal diagnosis of osteoporosis thus can only be made in the centers where DXA is available. Monitoring of therapy for osteoporosis also requires serial analysis of BMD by DXA preferably by the same machine.

a) Clinical Diagnosis: Osteoporosis is to be suspected in situations like occurrence of fractures following trivial trauma and presence of risk factors for osteoporosis. b) Investigations: DXA is an essential modality for establishing the diagnosis and monitoring therapy for osteoporosis. X-ray of spine can show an osteoportic vertebral fracture. Biochemical parameters like serum calcium, phosphate, alkaline phosphatase are within normal range in

osteoporotic patients. Serum intact parathyroid level is also in the normal range. c) Treatment: Bisphosphonate or teriperatide along with adequate calcium and vitamin D supplementation can be instituted in all settings. Oral Bisphosphonates because of their efficacy,safety and ease of administration are the first line therapy for osteoporosis.GI toxicity with oral Bisphosphonates can be avoided with appropriate precautions.The cost of treatment with

teriperatide can be a constraint.Teripartide should be given under supervision of an endocrinologist.It is important to remember and recognise atrial fibrillation and osteonecrosis of jaw ,which are rare side effects of Zolidronic acid therapy. Standard Operating procedure: Orthopedic interventions can be required for management of 30

osteoporotic fractures. a. In Patient - NA b. Out Patient – Treatment can be instituted in outpatient settings. c. Day Care – Injection of zolidronate once every year d) Referral criteria: For DXA For biochemical and hormonal investigations *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available DXA facilities are usually available in speciality centers. Otherwise, the basic treatment remains the same. a) Clinical Diagnosis: same for situation 1

b) Investigations: do c) Treatment: do Standard Operating procedure: do a. In Patient b. Out Patient c. Day Care d) Referral criteria: NA VI. WHO DOES WHAT? a. Doctor: Endocrinologist, orthopedician or a physician who can assess the risk factors for osteoporosis and assess the need for ordering a DXA scan, interpret the BMD report and institute appropriate therapy. b. Nurse: Educate the patient about injecting teriperatide and administration of bisphosphonates

c. Technician: DXA technician, laboratory staff for biochemical and hormonal assay. VII. FURTHER READING / REFERENCES 1. World Health Organization: Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. World Health Organ Tech Rep Ser 1994. 2. Kanis JA, Melton III LJ, Christiansen C, et al: The diagnosis of osteoporosis. J Bone Miner Res 1994; 9:1137-1141. 3. Melton III LJ: How many women have osteoporosis now?. J Bone Miner Res 1995; 10:175-177

4. Handa, R., Management of osteoporosis: the Indian perspective. Clin. Calcium 2004, 14, 100– 105. 5. Malhotra, N., Mithal, A., Osteoporosis in Indians. Indian J. Med. Res. 2008, 127, 263–268. RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation HUMAN RESOURCES INVESTIGATIONS DRUGS & CONSUMABLE EQUIPMENT 1 2 31

POLYCYSTIC OVARIAN SYNDROME I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Polycystic Ovarian Syndrome (PCOS) is the commonest endocrine disorder of the reproductive age group females. Though the structural term “polycystic” is an integral part of its name, the presence of polycystic ovaries is not an essential component of the condition. In fact, PCOS is a functional disorder of the ovaries characterised by complete or incomplete triad of chronic oligo-/anovulation, hyperandrogenism and,

sonologically detectable “polycystic” ovaries. PCOS is known to have significant association with some very important medical conditions like metabolic syndrome, diabetes, cardiovascular disease, endometrial cancer and, obstructive sleep apnoea. The syndrome typically begins around menarche but may appear later in life especially in women who experience weight gain. PCOS is to be suspected in women with one or more of the following : Oligomenorrhoea/amennorhoea Subfertility/infertility

Hirsutism/acne/androgenic alopecia Incidental sonologic detection of “polycystic” ovaries b) Case definition: A universally accepted definition has been lacking. It is currently diagnosed by applying the diagnostic criteria proposed at the 2003 Rotterdam international consensus conference. As PCOS is a syndrome, it is defined by a combination of features rather than any one single manifestation. 32

It is also a diagnosis of exclusion. Other conditions which can mimic PCOS by causing menstrual irregularity and/or hyperandrogenism must be excluded. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY The prevalence in the west is between 5-7% and increasing with the trend of increasing obesity. The prevalence in our country is undetermined but is a common condition encountered in practice specially by endocrinologists, gynaecologists and dermatologists. III. DIFFERENTIAL DIAGNOSIS

Non classic congenital adrenal hyperplasia Cushing’s syndrome Primary hypothyroidism Hyperprolactinemia Acromegaly Virilising adrenal and ovarian tumour Drugs IV. PREVENTION AND COUNSELING The only mode of prevention is prevention of obesity. Women with PCOS need to be counseled about the condition itself along with its associations, specially metabolic and cardiovascular. A properly informed patient would be better equipped to choose

between different modalities of treatment, especially in case of hirsutism. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA 1) Clinical Diagnosis: The current definition of PCOS is the one that was evolved in 2003 at the Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop. According to this definition PCOS can be diagnosed if ANY two out of the three features mentioned below are present, and other 33

mimicking conditions (e.g. congenital adrenal hyperplasia, androgen-secreting tumours, Cushing's syndrome) have been excluded: 1. Oligo- and/or anovulation 2. Clinical and/or biochemical signs of hyperandrogenism 3. Polycystic ovaries It is a condition arising out of functional abnormalities of the ovaries and the documentation of polycystic ovaries is not an essential criterion. By the same token, the presence of polycystic ovaries alone does not suffice to make the diagnosis.

History and physical examination is important to determine the presence of features of the syndrome, their temporal profile, and relevant family history. Clinical clues to ascertain likelihood of other mimicking medical conditions are to be looked for. Similarly clinical evaluation should also focus on the possibilities of other known associations of PCOS. Clinical Features of PCOS : i) Oligo- and/or anovulation oligomenorrhoea (i.e.fewer than 9 menstruations in a year) amenorrhoea

dysfunctional uterine bleeding subfertilty /infertility. ii) Hyperandrogenism hirsutism acne male pattern alopecia Associations of PCOS:: i) Metabolic syndrome and insulin resistance obesity hypertension acanthosis nigricans ii) Sleep apnoea excessive snoring and daytime sleepiness Differential diagnosis of PCOS : i) Non-classic CAH: family history of infertility, hirsutism or both ii)Cushing’s syndrome: Hypertension, striae, easy bruising 34

iii) Hyperprolactinemia : Galactorrhoea iv) Primary hypothyroidism : Goitre, other clinical features v)Acromegaly : Acral enlargement, coarse features, prognathism vi) Virilising adrenal/or ovarian neoplasm : clitorimegaly, extreme hirsutism and male- pattern baldness, abdominal/pelvic mass vii) Drug history for exposure to androgens, anabolic steroids, valproic acid, cyclosporine 2) Investigations: To confirm diagnosis : i) Ultrasound of ovaries.

Regularly menstruating women should be scanned in the early follicular phase (cycle days 3-5). Oligo-/amenorrhoeic women should be scanned either at random or between days 3 and 5 after a progestin-induced withdrawal bleeding. Presence of 12 or more follicles, measuring 2-9 mm in diameter in either ovary, and/or increased ovarian volume (>10ml) is consistent with the diagnosis. Whenever feasible, transvaginal approach should be used specially in obese individuals. ii) Serum testosterone.

It should be measured in the morning preferably in the follicular phase. A level in the upper normal range or slightly elevated is generally seen in PCOS. A level in the range of normal adult males is suggestive of virilising disorders. If total testosterone is normal, a reliable free testosterone level if available should be asked for. For differential diagnosis : i) TSH TSH should be measured to rule out primary hypothyroidism. Hypothyroidism can cause

ovulatory dysfunction but not significant hyperandrogenism. Therefore the role of measuring TSH in women with significant hyperandrogenism is to rule out a chance co- existence of a common disorder responsible for ovarian dysfunction and subfertility. ii) Prolactin Prolactin levels should be measured in the fasting state in the morning to rule out hyperprolactinemia resulting from prolactionomas. Like hypothyroidism, hyperprolactinemia can cause ovulatory dysfunction but not significant

hyperandrogenism. Importantly, many patients with PCOS may have prolactin levels in the upper normal range or slightly elevated and, therefore, this should not be considered indicative of prolactinomas. iii) Gonadotropins and Estradiol 35

Measurement of FSH and LH levels is not required for diagnosis of PCOS These are useful for differential diagnosis in the group of females with oligo- or anovulation without features of hyperandrogenism, namely : a) Pre mature ovarian failure (high FSH/LH) b) Hypogonadotropic hypogonadism (normal/low FSH/LH and low estradiol). PCOS, in contrast, has normal FSH, with or without elevated LH, and normal estradiol iv) Serum 17-hydroxyprogesterone

This is to be measured in the follicular phase of menstrual cycle in the morning only in those in whom non-classic CAH is considered to be a possibility. v) Serum DHEAS In those whom virilising adrenal neoplasms need to be ruled out. vi) Tests for acromegaly and Cushing’s syndrome need to be done only in those with suspicious clinical features. Ancillary Studies to look for associations of PCOS : i) Oral Glucose Tolerance Test ii) Fasting Lipid Profile iii) Polysomnography

Only when there is a suspicion of sleep apnoea 3) Treatment: Treatment choice depends on the component of the condition which is desired to be addressed in a given clinical situation. Applicable to all : i) Weight loss in those overweight. All overweight/obese individuals with PCOS, weight reduction is recommended. A 5-7 % weight loss can help improve Insulin resistance and thereby improve ovulatory dysfunction, hyperandrogenism, metabolic abnormalities ii) Metformin 36

By reducing hepatic glucose output reduces insulin levels and can have a wide effect like weight loss. Effect of metformin is evident regardless of baseline body weight. Applicable to those with menstrual irregularity and desire to conceive: i) Metformin ii) ovulation induction with antiestrogens (clomiphene) or aromatase inhibitor (lerotrozole), or gonadotropins Metformin can be used in combination with other ovulation inducing agents.

Applicable to those needing treatment for menstrual irregularity alone : i) cyclical progesterone ii) OCPs Applicable to those needing treatment for hirsutism : i) Cosmetic measures (bleaching, waxing, shaving, chemical depilation) ii) Permanent hair reduction (electrolysis, photoepilation) iii) Pharmacologic therapy (not for those desiring/likely to conceive) OCPs iv) Antiandrogens (spironolactone) and 5 alpha reductase inhibitor (finasteride) OCPs are commonly combined with antiandrogens

Standard operating procedure 1. Consider PCOS in women with hirsutism and/or other cutaneous markers of hyperandrogenism, oligo- or amenorrhoea, subfertility. 1. Rule out pregnancy in amenorrhoeic women. 37

2. Check testosterone level 3. Pelvic sonography 4. Exclude other conditions mimicking PCOS to confirm diagnosis of PCOS. Choice of test would depend on the clinical situation. TSH and prolactin should be checked in all those with menstrual irregularity and/ or infertility. 5. Check for associated features of metabolic syndrome – including glucose intolerance and dyslipidemia. 6. Consider possibility of sleep apnoea 7. Insulin resistance reduction with weight loss (in those overweight) and metformin can

help ameliorate all features 8. For oligo- or amenorrhoea : cyclic OCPs or progestin alone 9. For hirsutism : cosmetic measures along with pharmacologic therapy and/or electrolysis/photoepilation 10. For infertility : metoformin and/or other ovulation induction measures 4) Referral criteria: i) When endocrinological conditions like acromegaly, Cushing’s syndrome, virilising conditions and non-classic CAH are suspected or diagnosed and appropriate endocrinologic and surgical services are not available.

ii) Infertile women needing ovulation induction with complex regimen if experience with the same is not available. iii) Assisted reproduction services. VI. FURTHER READING / REFERENCES Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome(PCOS). Human Reproduction Vol.19, No.1; 41-47, 2004 Ehrmann DS. Polycystic Ovary Syndrome. N Eng J Med 352 :1333-36, 2005 38

HYROTOXICOSIS Thyrotoxicosis refer to clinical syndrome of toxicosis associated with excess circulating thyroid hormones which may or may not be associated with increased gland activity while hyperthyroidism is associated with increased gland activity and increased levels of circulating thyroid hormones. Therefore, all patients with hyperthyroidism are thyrotoxic while vice versa is not true. The common cause of thyrotoxicosis include Graves’ disease, toxic multinodular goitre (MNG),

toxic adenoma and thyroidits. The symptoms associated with thyrotoxicosis include weight loss, despite increased appetite, palpitation, heat intolerance, fatigue, weakness, frequent motions and trembling. The signs include tachycardia, tremor, warm moist skin, goitre (96%), hyperreflexia eye signs and dermopathy®. Grades of goiter grading as per WHO classification include a) Grade 0: Thyroid neither palpable nor visible. b). Grade 1: Thyroid palpable but not visible with neck in

normal position c). Grade 2:Thyroid palpable and visible with neck in normal position The monosymptomatic manifestation of thyrotoxicosis include malabsorption syndrome, loan atrial fibrillation, attention deficiency disorder, tall stature & hypokalemic/hyperkalemic periodic paralysis. The diagnosis of hyperthyroidism is based on increased T3, T4 and suppressed TSH (<0.05 µU/ml) with clinically evident toxicosis. The usefulness of 99mTc scan is only in a situation when there is a

clinical suspicious of thyroiditis particularly when there is history of fever, neck pain, rapid weight loss and tender goitre. 99mTc scan is also useful in establishing a diagnosis of toxic adenoma. Estimation of TPO antibody is not required, however it is positive in significant titres in 70-80% of patients with Graves’ disease and its presence is a marker of autoimmune thyroid disease. Ultrasonography is useful for establishing a diagnosis of multinodular goitre as sometimes a single

large nodule is only present clinically. Treatment of thyrotoxicosis include drugs, (thionamides) 131radioablation after failure of drug treatment and rarely surgery if goitre is very large (III/IV). The drug treatment include the use of neomercazole (NMZ) in doses of 30-40 mg per day usually in a single daily dose preferably in the morning fasting state. The doses higher than this does not yield any additional benefit. However,

the NMZ should be administered in three divided doses if patient is severely toxic. Use of non iodized salt is currently recommended along with NMZ to avoid iodine as a fuel to hyperthyroid gland. The NMZ doses are gradually tapered once the patient becomes euthyroid that usually spans over 3 months and continued for 24 months usually in doses of 5mg as even this minimum dose possesses immunomodulatory action. There is no extra-benefit of extending the treatment

beyond 24 months in preventing the recurrence of disease. The disease is said to be in remission 39

when the patients remains euthyroid at least for a period of one year after stoppage of treatment. However, remission rate is around 40-50%, therefore majority of the patients required reintroduction of drug or ablative treatment. Management of associated thyroid orbitopathy include methyl prednisolone in low dose pulse therapy (4.5 gm over 8 weeks) and if failed to response addition of azathropine is recommended. Recently rituximab has been used for orbitopathy with success. 40

OBESITY Obesity is an increasingly important health problem worldwide including the developing countries. In India, obesity is emerging as an important health problem particularly in urban areas. Almost 30- 65% of adult urban Indians are either overweight or obese or have abdominal obesity. The rising prevalence overweight and obesity in India has a direct correlation with the increasing prevalence of obesity-related co-morbidities; hypertension, the metabolic syndrome, Dyslipidemia, Type 2

diabetes mellitus (T2DM), and cardiovascular disease (CVD). "obesitygenic" lifestyle of excess caloric intake and decreased physical activity, these same genes contribute to obesity and poor health. Obesity is commonly considered to be one of the most important preventable causes of premature death, second only to smoking. Therefore, this marked increase in obesity has enormous public health implications Definitions and measurement of overweight and obesity

Obesity is generally defined conceptually as the condition of excess body fat. However, There is no precise definition of excess. The degree of adiposity is a continuous trait not marked by any clear division into normal and abnormal. In addition, direct measurement of body fat is difficult. Thus, for practical purposes, obesity is often defined as excess body weight rather than as excess fat. In epidemiologic studies, for both children and adults, body mass index (BMI) is used to express the

degree of obesity. This index is calculated as the body weight (kg) divided by the stature ([height in Meter]2 squared) (wt/M2), BMI correlates well with body fat and is relatively unaffected by height. BMI = Weight in Kg (height in meter)2 Waist Circumference (WC) and Waist Hip Ratio (WHR) Cut-offs for Obesity Abdominal obesity is increasingly being recognized as an important cardiovascular risk factor. The cardiovascular risk associated with abdominal obesity can be attributed to excess abdominal

adipose tissue (visceral Fat), both intra-abdominal adipose tissue (IAT) and subcutaneous adipose tissue (SCAT). Common surrogate measures of abdominal obesity are Waist Circumference (WC) and Waist Hip Ratio (WHR). Waist circumference is a simple, easily obtainable anthropometric parameter, which can be assessed in the outpatient setting. Measurement of WHR is more difficult as accurate measurement of hip circumference may not always be possible since it requires difficult

task especially in women in India. Further, changes in WHR may not accurately reflect the extent of obesity or changes in weight. As with BMI, the relationship of central fat to risk factors for health varies among populations as well as within them. Current classifications of obesity are based on BMI and waist circumference. The one recommended by the World Health Organization and the NHLBI is shown in Table-1. BMI has a curvilinear relationship to risk. Several levels of risk can be

identified using the BMI. Table – 1. Definitions for adults Classification of Overweight & Obesity and risk of disease as Recommended by the WHO & NHLBI. Risk of disease with waist circumference Waist Circumference < 35 in (<88 cm)(women) >35 in (>88 cm) (women) Weight category BMI < 40 in (<102 cm) (men) > 40 in (>102 cm) (men) Underweight <18.5 41

Healthy weight 18.5-24.9 Overweight 25.0-29.9 Increased High Obesity class I 30.0-34.9 High Very high Obesity class II 35.0-39.9 Very high Very high Obesity class III 40 > Extremely high Extremely high Asian Indians exhibit unique features of obesity; excess body fat, abdominal adiposity, increased subcutaneous and intra-abdominal fat, and deposition of fat in ectopic sites (liver, muscle, etc.). Obesity is a major driver for the widely prevalent metabolic syndrome and type 2 diabetes mellitus

(T2DM). The proposed cut-offs for defining overweight and obesity by WHO are not appropriate for Asian Indians, and that Asian Indians are at risk of developing obesity related co-morbidities at lower levels of BMI and waist circumference (WC). The currently recommended cut-offs of WC (>102 cm in men and >88 cm in women) are also not be applicable to all the populations due to heterogeneity and different relationship with

cardiovascular risk. Asian Indians appear to have higher morbidity at lower cut-off for WC than do White Caucasians. • Methodology of WC Measurement: WC should be measured using non-stretchable flexible tape in horizontal position, just above the iliac crest, at the end of normal expiration, in the fasting state, with the subject standing erect and looking straight forward and observer sitting in front of the subject. • Both BMI and WC should be used together (with equal importance) for population- and

clinic-based risk stratification. For Japanese, a BMI of 23 or 24 kg/m2 has the same percent fat as that of a BMI of 25 in Caucasians or 28 to 29 in African-Americans. On the basis of these differences and the observations that the risk for diabetes and hypertension had doubled when the BMI was 25 kg/m2, a taskforce from the Asia-Oceania section of the International Association for the Study of Obesity has proposed an alternative table, where obesity is defined as a BMI >25 kg/m2 and high-risk waist

circumference at >90 cm for men and >80 cm for women. Hence it is also recommended for Asian Indian population. Classification of Obesity as Recommended by the Asia - Pacific Task force – Risk of co morbidities with waist circumference< 80 cm (women)> 80 cm (women) Weight categoryBMI< 90 cm (men)> 90 cm (men)Underweight <18.5LowAverageHealthy weight18.5-22.9AverageIncreasedOverweight> 23At Risk23 – 24.9IncreasedModerateObesity class I25 – 29.9ModerateSevereObesity class II> 30SevereVery Severe

Classification of Obesity as per fat distribution Obesity can also be classified based on the regional distribution of the fat Android (or abdominal or central, males) - Collection of fat mostly in the abdomen (above the waist) • Apple-shaped • Associated with insulin resistance and CAD Gyneoid (below the waist, females) - Collection of fat on hips and buttocks • Pear-shaped • Associated with mechanical problem Definitions of Obesity for children and adolescents In children with 2-19 years old 42

BMI : > 85th to 95th percentile for that age – Possible risk of overweight and should undergo further evaluation. BMI : > 95th percentile for that age – Overweight In the United States, the 2000 CDC BMI for age growth charts are recommended for screening of individuals who are overweight and those who are at risk for overweight. No BMI for age reference exist for children younger than 2 years. Nor are there any consistent recommendations for the definition of overweight in this age group. • Overweight

• BMI between 85th to 94th percentile for age and sex • Obese • BMI ≥95th percentile for age and sex -or- BMI ≥30 kg/m² • Severe obesity • ≥99th percentile (equivalent to BMI of 30-32 kg/m² for 10-12y.o. -or- ≥34 kg/m² for 14-16y.o.) • Weight for length is used in the under 2-yr age group For the evaluation of obesity in Indian children IAP growth charts are used. At present, IAP suggests to use WHO growth charts and Growth charts by Agrawal DK. IAP expect to come out

with its own new growth charts. Till the time IAP comes out with IAP Charts, it is suggested to use WHO growth charts, which can be accessed at http://www.who.int/childgrowth/standards/chart_catalogue/en/index.htmlHowever with secular trends growth charts often change & periodic revision of Growth charts done should be accepted. Obesity is associated with various organ System Dysfunction & they are Cardiovascular Hypertension, Coronary artery disease, Congestive heart failure, Cor pulmonale, Varicose veins,

Pulmonary embolism. Musculoskeletal Hyperuricemia and gout, Immobility-Osteoarthritis (knees and hips), Low back pain Psychologic Depression, low self-esteem, Body image disturbance, Social stigmatization Respiratory Dyspnea, Obstructive sleep apnea, Hypoventilation syndrome, Pickwickian syndrome, Asthma Gastrointestinal Gastroesophageal reflux disease (GERD), Nonalcoholic fatty liver disease (NAFLD), Cholelithiasis, Hernia, Colon cancer Genitourinary

Urinary stress incontinence, Obesity-related glomerulopathy, Hypogonadism (male), Breast and uterine cancer, Pregnancy complications Neurological Stroke, Idiopathic intracranial hypertension, Meralgia paresthetica Integument Striae (stretch marks), Stasis pigmentation of legs Lymphedema, Cellulitis, Intertrigo, carbuncles, Acanthosis nigricans, skin tags, Hirsutism in patients with PCOS. Endocrine Metabolic syndrome, Type 2 diabetes, Dyslipidemia, PCOS, Hyperandrogenemia, menstrual

disorders, Amenorrhea, infertility. There two ways by which endocrine system is affected in Obesity. 43

Endocrine Diseases associated Hormonal abnormalities due to Obesity with Obesity • Hypothyroidism • Û cortisol production • Cushing’s Syndrome • ÛInsulin resistance • Growth Hormone Deficiency • Ü SHBG in women • Hypogonadism • Ü progesterone levels in women • Polycystic Syndrome (PCOS) • Ü testosterone levels in men • Insulinoma • Ü growth hormone production • Traumatic Hypothalamic Obesity. • Monogenic Mutations

• Other Genetic Syndromes – Prader Willi Syndrome, Lawerence Moon Bield Syndrome, Bardett Bield Syndrome, Alstroms Syndrome, etc Note: Hypothyroidism is not the cause of significant obesity. Weight gain in hypothyroidism is due to fluid retention & is usually not more than 2-5 kg. Obesity and Obstructive Sleep Apnea Obesity is the most powerful risk factor for obstructive sleep apnea (OSA). Several pathophysiologic mechanisms relates obesity to the development of OSA These mechanisms

include anatomic and functional obstruction of the pharyngeal airway. Sleep deprivation, daytime somnolence and metabolic dysregulation may also contribute to obesity in the setting of OSA. Although history and physical examination may help predict OSA in obese individuals, polysomnography is the gold standard for making the diagnosis of OSA and assessing effects of therapy. Weight loss is an important strategy for treating OSA. However, the cornerstone of current

management is continuous positive airway pressure. Clinical Evaluation Basic evaluation in clinics is measurement of Height, Weight, BMI, Waist Circumference. Detection of acanthosis nigricans or skin tags should suggest significant insulin resistance. A number of physical features of an obese individual may help identify a specific cause for the individual's problem. Features of the hypothalamic syndrome, Cushing's syndrome, Polycystic

ovarian disease (Which is a common in younger women) should be looked for. Among the various genetic diseases that produce obesity, Prader-Willi is the most common. It includes hypotonia, mental retardation, and sexual immaturity, and can usually be recognized clinically. Bardet-Biedl syndrome, with its polydactyly and retinal disease, is distinctive. Obesity and red hair in a child might suggest a defect in the processing of POMe. Laboratory Evaluation

Common laboratory tests which should be done as a part of the obesity evaluation are - Plasma Glucose (Fasting & Post glucose or postprandial), Plasma Lipids, Thyroid Functions, serum uric acid, Liver function tests, Prostate-Specific Antigen in Males, Ultrasound of the Gall Bladder. Other tests like overnight dexamethasone suppression test, serum gonadotropins, etc may be done depending on the patients clinical profile. (Serum insulin has no role in the evaluation of obesity in

day today practice except in suspected cases of Insulinoma which is very rare.) Management of Obesity Obesity prevalence has increased markedly over the past few decades. The obesity pandemic has huge implications for public health and our society. There are many Health benefits of moderate weight loss (5-1 0% of present body weight) Reduction in Death - 20% overall, 30% diabetes-related & 40% cancer- related 44

deaths Blood pressure Reduction - 10 mmHg decrease Improvement in Lipids - 15 % decrease in cholesterol & improvement in other lipids Improvement in Glycemic control in patients with Diabetes. Hence weight loss program should be achieved by following principles • Lifestyle Modification – Diet control, Exercise, & Behavioural Modification. • Pharmacotherapy • Surgery Lifestyle Modification Principles of weight loss • Decrease total energy intake (TEl), Maintain a balanced deficit diet

• Increase physical activity (Adjust energy balance to prevent weight regain) appropriate for that age. • Behavior modification; • Maintenance program - monitoring and long term follow-up. While managing obesity we should remember certain facts that • Do not recommend Rapid weight loss (i.e. >5-10% weight loss in 6 months), it should be slow so that maintainance becomes easy. Rapid weight loss is associated with rebound weight gain which sometimes can be more than initial weight.

• We should have realistic expectations of 5-10% weight loss in 1 year. • Passive exercise, Heat or Vibration therapy, etc should not be recommended. Obesity management programs The therapies and degree of intensity of any weight loss program should be based on an assessment of the degree of adiposity (anthropometry) and the presence or absence of medical risk factors. Mild to moderate uncomplicated overweight and obesity may require advice with a specific eating and

physical activity program. Greater degrees of obesity and risk, or the presence of disease, require more intensive lifestyle interventions, the use of pharmacotherapy, or surgery & treatment of basic cause of Obesity if any. Any weight management program must provide a weight maintenance component. Regular and long-term follow-up visits and interventions are part of the management of Obesity. Diet intervention 45

Although energy (calorie) restriction produces good weight loss, some individuals may find this irksome and impossible to maintain. It is the total calorie intake which decides patients weight rather than the type of food. However for some patients, a low-fat eating plan may prove effective. Such plans may be maintained for several years. Greater losses may be obtained by additionally reducing energy intake. Men may also need to reduce energy intake by limiting their alcohol intake.

There is no long term difference between low calorie diet (LCD) & Very low calorie Diet (VLCD). Physical activity /exercise program Emphasis should be placed on increasing total daily activity to between 60 and 90 min each day. Although exercise and fitness are important, the initial emphasis should be on increasing the activities of daily living, in particular more walking. A formal written exercise prescription has been

shown to increase effectiveness in general practice. Giving patients the opportunity to use or purchase a pedometer and then setting the number of steps they need do in a day may prove an effective method of increasing activity. For patients with arthritis or other disabilities, hydrotherapy (exercising in water) may be a way of initiating movement and this type of activity can assist weight loss. Patient can do any type of exercise which is suitable for his/her age & associated comorbid condition.

Behavior modification This therapy is important and central to any weight loss program. There are many components to behavior modification, but one simple is the use of a food and exercise diary. This allows habit recognition and changes accordingly. All subjects, but most particularly those who are overweight or obese, under-report food intake and over report the activity they undertake. A diary provides an important starting point for discussion and suggests possible interventions. Additional behavioral

therapies include discussion about habits, change and alternative ways of approaching situations. Other techniques involve stress management, improving self-esteem and, occasionally, more spe- cific counseling or psychiatric intervention. Such a lifestyle program should involve a team of health professionals (dietitians, physiotherapists, nurses, psychologists). Good results and satisfaction are usually obtained by the involvement of

multidisciplinary teams. Some commercial groups use conventional therapy (e.g. Weight Watchers or programs used in some gyms), whereas others rely on alternative or natural therapies and still others use magic treatments that sound plausible but which really have neither have any scientific basis nor effectiveness. Examples of the magic type of therapy would be total-body wrapping, some herbal and bulking agents. Few have been tested rigorously and very are costly, but the very

existence of such program and therapies shows that many individuals desire to lose weight but need to be guided into the correct approach and provided with effective therapy. Maintenance program, Monitoring and longer term follow-up This is an essential part of any weight loss program but the most neglected part. Follow-up programe are essential and very effective. Patients involved in an obesity treatment program require the following monitoring of weight (ideally monthly, no greater than bimonthly);

monitoring of pulse rate and blood pressure; monitoring of obesity-related risks and diseases (e.g. dyslipidemia, type 2 diabetes). Drug therapy The decision to give pharmacotherapy for obesity is made from clinical judgment-based on the 46

requirement of the each individual patient in terms of potential benefits balanced against potential risks. BMI between 25 and 30 with comorbid conditions is the definite indication to start pharmacotherapy along with lifestyle intervention. The various drugs which have been used for obesity are : 1. Appetite suppressants a. Adrenergic agents (e.g. amphetamine, methamphetamine phenylpropanolamine, Phentermin) 2. Serotonergic agents (e.g. fenfluramine desfenfluramine, SSRIs like setoraline, fluoxetine)

3. Thermogenc agents - Ephedrine, caffeine 4. New ones a. Serotonin and Noradrenaline reuptake Inhibitor - Sibutramine; b. Intestinal Lipase inhibitors - Orlistat c. The CB blocker - Rimonabant, 1 Among all these drugs currently only Orlistat is approved drug for the medical management of obesity. All other drugs are either not approved or banned for their use in obesity. Orlistat is an intestinal lipase inhibitor. It irreversibly inhibits the action of gastric and pancreatic lipases which

are required to hydrolyse dietary fat before absorption. Unabsorbed triglycerides and cholesterol are excreted in faeces. It can cause Weight loss of 5-8.5 % at the end of 1 yr. Side effects include steatorrhoea, flatus, fecal incontinence and oily spotting. Absorption of fat soluble vitamins may be lowered with orlistat. Hence vitamin supplementation is recommended. The maximum effect of orlistat is achieved at a dose of 120 mg thrice daily with every fatty meal.

In patients with Fat restricted diet this drug is of no use. There is no good scientific evidence for the alternative therapies. Surgical Treatment of Obesity – Overview Gastrointestinal surgery is the most effective approach for inducing major weight loss in extremely obese patients. Bariatric surgery has evolved over the last half century as a treatment option for patients suffering from morbid obesity. It involves modification of the digestive system by either

decreasing the gastric volume (restrictive) or altering the path of the food bolus causing an element of malabsorption (Malabsorptive). These alterations effect appropriate changes in eating behavior and aid lifestyle modifications to help weight loss. Indications for Bariatric Surgery - • Patients with a BMI 40 kg/m2 or more without any comorbid condition. • Patients with a BMI of 35.0 to 39.9 kg/m2 (with comorbidiry) and one or more severe

medical complications of obesity (e.g., hypertension, heart failure, Type 2 Diabetes Mellitus, sleep apnea). • Additional eligibility criteria are the inability to maintain weight loss with conventional therapy, acceptable operative risks, The Surgical Options for Weight loss Surgery Restrictive Procedures • Laparoscopic adjustable gastric banding (LAGB) • Sleeve gastrectomy Combined Procedures • Roux-en-Y gastric bypass (RYGBP) Malabsorptive Procedures 47

• Bilio-pancreatic diversions (BPD) • Bilio-pancrearic diversion with duodenal switch (BPD-DS) Experimental Procedures  Duodeno-jejunal bypass  Ileal interposition  Implantable pulse generators Over the years, minimally invasive surgery has evolved from general laparoscopic surgery to advanced laparoscopic surgery. Given the advantage of laparoscopy with other general surgery procedures, it was a logical step to attempt these complex bariatric procedures using minimally

invasive approach. Laparoscopic BPD-DS has higher complication rate compared to gastric bypass or banding and a mortality rate as high as 5%. Bariatric Surgery Outcomes - Weight Loss Bariatric surgery is currently the most effective method to treat severe obesity. The amount of excess weight loss (EWL) varies according to procedure. Long term data is now emerging that shows maintenance of weight loss 5-15 years after modern bariatric procedures. This sustained

weight loss has a major impact on individual patient health and longevity. Approach to Obesity management Prevention: With Limited options of drug treatment prevention becomes an important step. Prevention should start from Childhood so that we can prevent future health hazards. Balanced diet & regular Aerobic physical activity is must for everyone & should be educated since childhood. References: • A Misra et al Consensus Statement for Diagnosis of Obesity, Abdominal Obesity and the Metabolic

Syndrome for Asian Indians and Recommendations for Physical Activity, Medical and Surgical Management. JAPI Vol. 57 • February 2009  Misra A, Khurana L. Obesity and the metabolic syndrome in developing countries. J Clin Endocrinol Metab 2008;93(11 Suppl 1):S9-30.  World Health Organization. Obesity: preventing and managing the global epidemic. Report of a WHO consultation presented at: the World Health Organization; June 3-5, 1997;Geneva, Switzerland. Publication WHO/NUT/NCD/98.1.

 NHLBI Expert Panel. The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Bethesda, MD: National Institutes of Health. NIH publication 00-4084. 2000.  R.F. Kushner, J.L. Roth / Endocrinol Metab Clin N Am 32 (2003) 9/5-933  National Heart Lung, and Blood Institute. Clinical guidelines on the identification evaluation, and treatment of overweight and obesity in adults. The evidence report. Ob Res 1998;6(Suppl 2):51 S-21 OS.

 American Association of Clinical Endocrinologists, American College of Endocrinology AACE/ACE position statement on the prevention, diagnosis and treatment of obesity (1998 revision). Endocr Pract 1998;4:299-350. Available at: http://www.aace.com/clin/guides/obesityguide.pdf. Accessed October 19, 2003.  WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet. 2004;363(9403):157-63. 48

 World Health Organization. Obesity: preventing and managing the global epidemic. Report of a WHO consultation presented at: the World Health Organization; June 3-5, 1997;Geneva, Switzerland. Publication WHO/NUT/NCD/98.1. • George A Bray, Claude Bouchard – Handbook of Obesity Clinical Applications third edition: Classification & evaluation of Overweight or Obese Patient. 2008: 1-28  Agarwal DK et al. Physical and sexual growth of affluent Indian children from 5 to 10 years

of age. Indian Pediatr 1992; 29: 1203-1282.  Agarwal DK and Agarwal KN. Physical growth in affluent Indian children (birth to 6years). Indian Pediatr 1994; 31: 377-413. 49

GUIDELINES FOR THE MANAGEMENT OF CARDIOVASCULAR DISEASES IN INDIA Part 1 Ministry of Health & Family Welfare Govt. of India, New Delhi 1

Contents S.No. Topic Page No. 1 CONGENITAL HEART DISEASE 5 2 ACUTE CORONARY SYNDROME/NON ST ELEVATION MI 13 3 ST ELEVATION MYOCARDIAL INFARCTION (STEMI) 32 2

The cardiovascular diseases are very important cause of morbidity and mortality in India. There is increase in incidence and prevalence of cardiovascular disease in this country. The healthcare burden of this menace is enormous. To fight this growing burden of cardiovascular epidemic government of India under the leadership of Dr. Jagdish Prasad, Director General, Health Services, constituted a special task group of experts for preparation of the guidelines of cardiovascular disease. The task group under

the leadership of Prof. (Dr.) Upendra Kaul, Executive Director & Dean of Cardiology (Fortis Group of Hospitals) prepared the initial guidelines for the following diseases 1. Congenital Heart Disease. 2. Acute coronary syndrome/Non ST elevation MI 3. ST elevation myocardial infarction (STEMI) GROUP MEMBERS Dr Satyavan Sharma, Professor and Head of Dr Krishna Kumar, Consultant in Pediatric Cardiology, Bombay Hospital Institute of Medical cardiology, Seven Hills Hospital, Seven Hills Health

Sciences, Interventional Cardiologist, Bombay City Hospital Dr Balram Bhargava, Prof of Cardiology Cardio Dr Tapan Ghose, Principal Consultant Fortis Thoracic Center, AIIMS Hospital, Vasant Kunj, New Delhi Dr Ajit Mullasari, Director Cardiology, Institute of Dr Parneesh Arora, Sr Consultant Fortis Cardiovascular Diseases (A Unit of Madras Medical Hospital, NOIDA Mission Prof Balram Airan, Head of CTVS, CT Centre, AIIMS Dr Thomas Alexander, Kovai Medical Centre and Hospital, Coimbatore

Prof C N Manjunath, Director and HOD, Cardiology Dr Radha Krishnan, Associate Director ,Sree Jaideva Institute of Cardiovascular Sciences and Department of Paediatric Cardiology and Research Congenital Heart Disease 3

Dr. Karthikeyan Ganesan Assistant Professor, All India Institute of Medical Sciences, New Delhi REVIEW OF STGs The draft guidelines were forwarded to many experts for critical review, suggestions and amendments. The following experts have reviewed these draft guidelines. The sub group would like to place on record their useful contribution and acknowledges their efforts. 1 Prof Soma Raju Chairman and Chief 2 Prof S C Manchanda Senior Consultant, Cardiologist, Sir Ganga Ram Hospital, New

1.0 INTRODUCTION This brief document will provide a broad outline for selected congenital heart diseases. It needs to be recognized that there are unlimited possibilities because of the enormous variety of congenital heart diseases. Therefore only a few common situations will be discussed here. Guidelines have been recently developed and published through consensus among all leading pediatric cardiologists in India and these references are listed below. They cover most common situations and provide a

ready reference. 1. Shrivatsava S, Saxena A, Iyer KS, Radhakrishnan S, Kumar RK, Maheswari S, Pediatric Cardiac Society of India Recommendations for Timing of Surgery/Catheter Intervention in Left-to- Right Shunts, Indian Heart J 2006; 58: 169-171. 2. Working group on management of congenital heart diseases in India, Consensus on Timing of Intervention for Common Congenital Heart Diseases. Ind Pediatr 2008;45:117-126. 3. Working group on management of congenital heart diseases in India, Drug Therapy of

Cardiac Diseases in Children, Ind Pediatr 2009;46:310-338. 4. Kumar RK, Sandoval J, Consensus Statements on Pulmonary Hypertension Associated with Congenital Heart Disease: Advanced pulmonary vascular disease: The Eisenmenger syndrome, Cardiol Young 2009; 19(E-Suppl. 1): 39-44. 5. Kumar RK, Shrivastava S, Pediatric Heart Care in India, Heart 2008;94;984-990. The following book is specially written for the Indian situation:

Kumar RK, Prabhu SS, Ahamed Z, IAP Specialty Textbook of Pediatric Cardiology, Jaypee brothers, New Delhi, India, 2008. The following three conditions will be covered here 1. Cyanotic congenital heart defects 2. Left to right shunts 3. Acute rheumatic fever 6

2.0 Cyanotic Heart Disease: 1. Introduction: Disease categories 2. Cyanotic Spells and their management 3. Timing of intervention for common lesions 2.1 Disease Categories: Cardiac conditions that result in cyanosis are extremely diverse. The management guidelines are unique to every lesion. Even within lesions there are numerous categories that require individualized attention. For example Tetralogy of Fallot has numerous anatomic variations that can seriously

influence how the condition is managed. Broad principles have been listed in published guidelines (reference 3). Common lesions in broad categories of cyanotic congenital heart disease (CCHD) that include conditions associated with reduced pulmonary blood flow, CCHD with increased pulmonary blood flow and CCHD associated with pulmonary hypertension are discussed in the published reference. 2.2 Cyanotic Spells: Since cyanotic spells are common to a variety of CCHD conditions associated with reduced

pulmonary blood flow, it will be discussed in greater detail here: Hyper cyanotic or Cyanotic spell is a pediatric emergency, which requires prompt recognition, and intervention to prevent disabling cerebro-vascular insults and to save lives. A cyanotic spell needs to be taken seriously not just because of the immediate threat but also because it indicates the need for early operation. How to recognize a spell? • Commonly seen below 2 years [peaks between 2 months to 6 months]

• Onset is usually spontaneous and unpredictable • Occurs more often in early morning, although can occur at anytime in the day. • Infant cries incessantly, are irritable and often inconsolable. • Tachypnea is prominent and a cardinal feature. Typically these infants have a pattern of • Deep and rapid breathing without significant subcostal recession. • Cyanosis deepens as the spell progresses. • Later gasping respiration and apnea ensues, which leads to limpness and ultimately • Anoxic seizures. 7

• Can last from minutes to hours. • Auscultation reveals softening or disappearance of pulmonary ejection murmur. • Occasional patient can have profound bradycardia. Cardiac lesions which produce spells • Tetralogy of Fallot. • TOF with Pulmonary atresia. • Tricuspid atresia and PS. • DORV with VSD and PS. • D-TGA or L-TGA with VSD and PS. • Single ventricle with PS. • Atrioventricular septal defect with PS. Management of spells

1. Check airway and start oxygen. If child is uncomfortable with mask or nasal cannula, deliver oxygen via tube whose end is held ½ - 1 inch away from nose. This corresponds to delivering 80% oxygen. 2. Knee - chest position. 3. Obtain a reliable intravenous access. 4. Sedate child with subcutaneous morphine 0.2 mg/kg/dose]or i/m ketamine [ 3-5 mg/kg/dose] if the access is not obtainable expeditiously. 5. Soda -bicarbonate 1- 2 ml/kg given as 1:1 dilution or can be diluted in 10 ml/kg of isolyte-P which

is given bolus as the initial resuscitating fluid. 6. Correct hypovolemia (10ml/kg fluid bolus of isolyte P or dextrose normal saline). 7. Keep the child warm. 8. Start beta -blockade. Beta blockade is fairly safe unless a specific contraindication like bronchial asthma or ventricular dysfunction exists. It should always be given with heart rate monitoring. Medications and dosages: • IV metoprolol 0.1 mg/kg, given slowly over 5 min. • Can repeat every 5-min for a maximum of 3 doses.

• Can be followed by infusion 1-2 mcg/kg/min • Monitor saturation, heart rates & BP • Aim to keep heart rate below 100/min. 8

Other options • I/v esmolol: 500mcg/kg over 1 min as loading dose, 50 mcg/kg/min for 4 minutes; if desaturation persists without a significant decrease in heart rate the loading dose will need to be repeated and the infusion rate can be increased in 50 mcg/kg/min increments until 300mcg/kg/min; this infusion should be maintained at the rate that produces the desired result. Esmolol is relatively expensive but has the advantage of being very short acting.

• I/v propranolol [0.1 mg/kg].If desaturation persists and there is still no significant trend towards improvement despite maximum beta blockage • Start vasopressor infusion. Methoxamine given i/v at dose of 0.1mg-0.2 mg/kg /dose or i/m (0.1- 0.4 mg/kg/dose). Phenylepherine: 5ug/kg as bolus and then 1-4 ug/kg/min as infusion. • If spells are persistent, consider paralyzing the child, elective intubation and ventilation and plan for surgery, which can be corrective or palliative [BT shunt]

• If convulsions occur- consider IV diazepam 0.2 mg/kg or IV midazolam 0.1-0.2 mg /kg/dose, as slow push. Appropriate and timely management of cyanotic spells can save lives and prevent CNS insults. After a Spell: • After a spell is successfully managed, a careful neurological examination is mandatory. In case of suspicion of neurologic insult during a spell, a CT scan is to be done to assess the presence and extent of cerebral infarcts.

• Initiate maximally tolerated beta-blockade (propranolol 0.5-1.5 mg/kg/dose 8hourly or 6 hourly). The dose can be titrated by the heart rate response. Beta blockade may help improve restiniled segmental analysis by 2D echo for complete diagnosis. • Plan towards early corrective or palliative operation (depending on the age and anatomy). • Correct anemia by packed cell transfusion. Hemoglobin levels < 12 gm/dl merit correction

through a blood transfusion in children with cyanotic spells; Continue therapeutic (if anemic) or prophylactic iron therapy (if not anemic). Preventing a Spell in a Child with a Cyanotic Congenital Heart Defect Parents of patients diagnosed to have a cyanotic congenital heart defect should be counseled if the possibility of occurrence of a spell is anticipated: • Explain to them the circumstances when a spell may occur. • Avoid dehydration. • Rapid control of temperature whenever fever occurs

Obtaining IV access in a cyanotic child can precipitate spells. Difficulty in obtaining access can potentially be avoided by sedating child with IM ketamine [3-5 mg/kg] and/or by using local anesthetic skin ointment before attempting for venous access or blood sampling. 2.3 Timing of Intervention in common cyanotic heart diseases: Broad guidelines have been published (reference 3). Numerous anatomic variations dictate specific

decisions for individual patients. Additionally the paucity and variable capabilities of centers capable of infant and newborn heart surgery in India will need to be recognized (reference 5). All these factors make decision making in individual patients quite complicated and highly individualized. 3.0 Left to right shunts: 1. Introduction: Timing and indications of surgical or catheter-based intervention 2. Medical management while awaiting surgery or intervention

The timing of surgical or trans-catheter intervention for left to right shunts is a critical decision and one of the most important tasks the pediatric cardiologist is asked to perform. Simply stated, the decision about when to intervene requires carefully balancing the results of the procedure with the natural history of the conditions. The extraordinary variety of conditions associated including unlimited combination of defects complicates the decision making process. Further, during the last

30 years there have been numerous advances in the field of pediatric cardiology and pediatric cardiac surgery. These advances have enabled improved results from operations and trans-catheter interventions and have allowed the procedures to be performed early. In addition, we now have information on the natural history of many congenital heart conditions. An increasing number of studies are being published on the long-term results of operations and interventions for congenital

heart disease. Because of the wealth of information available to us the decision about when to intervene in CHD" now involves careful consideration of a number of variables that influence natural history and procedural outcome. There are no simple rules for the numerous CHD conditions and the decision making process has to be individualized for every patient. Detailed guidelines for individual left to right shunts are provided in reference number 1 and 2.

These are fairly contemporary and represent a consensus of national experts. While awaiting surgery or catheter intervention, medications need to be administered. Specific guidelines have been developed for this purpose and are published (reference number 4) through a consensus of national experts. 10

4.0 ACUTE RHEUMATIC FEVER (RF) AND RHEUMATIC HEART DISEASE (RHD): In the past 4-5 decades there have been modest advances in our understanding of the disease process. There have been minor changes in the diagnostic criteria and management practices for RF have also largely remained unchanged for the last 20-30 years. However, there have been important changes in the epidemiology both in India and the rest of the world. There appears to have been a

sharp decline in RF and RHD in parts of India that have shown improving indices of human development. Physicians living in these parts of India need to be mindful of the prospect of over- diagnosis of RF. For most of India, however, the disease is still quite common and it is important to not miss the initial episode of RF because secondary penicillin prophylaxis still remains the most effective way of preventing RHD. The algorithm displayed in the next page summarizes the initial management of RF.

Consensus guidelines have been published (see reference below): Saxena A, Kumar RK, Gera RPK, Radhakrishnan S, Misra S, Ahamed ZA (writing committee members), Consensus guidelines on pediatric acute rheumatic fever and rheumatic heart disease, Indian Pediatrics, 2008;45:565-573. 11

CONSENSUS DOCUMENT FOR THE DIAGNOSIS AND TREATMENT OF NON-ST ELEVATION ACUTE CORONARY SYNDROME 13

1.0 INTRODUCTION AND SCOPE OF THE DOCUMENT : Acute Coronary syndrome (ACS) has evolved as a useful operational term to refer to clinical symptoms that are compatible with acute myocardial ischemia. Non-ST elevation (NSTE) ACS comprises unstable angina (UA) and NSTE myocardial infarction (NSTEMI). The aim of the treatment in ACS is to prevent myocardial necrosis, fatal or non-fatal myocardial infarction (MI), recurrent (1)

hospitalization and resultant morbidity and mortality. The CREATE registry data revealed that NSTE-ACS patients take a long time (median 420 minutes) to reach to the hospital in India. Surprisingly, the incidence of NSTE ACS patients was less in this registry in contrast to reports from the west where NSTE ACS is more frequent than STEMI. It is important to note that the mortality of (2) STEMI and NSTE ACS is comparable after 6 months . The adverse events in NSTE ACS continue over

days and weeks in contrast to STEMI where most events occur before or shortly after the presentation. A large number of detailed guidelines are available from American College of (3) (4) Cardiology (ACC) / American Heart Association (AHA) and European Society of Cardiology . An expert consensus document on the management of ischemic heart disease (IHD) in India is also (5) available . The current document evaluates and summarizes the currently available evidence on

the management of NSTE ACS to assist the Indian physicians in selecting the best management. 2.0 DIAGNOSIS OF NSTE ACS : All patients presenting to a health care provider with symptoms suggestive of ACS should be considered as high priority. For the purpose of this document, an arbitrary division is made to categorize the health care facilities available in India for care of ACS patients (table 1). In big cities

centers with varying degree of sophistication are usually available. On the other hand, in parts of India (especially rural) even the basic facilities are not available. Every health care centre should have a functioning ECG machine available 24 hours a day. Health workers at these centers should be trained to interpret the ECG so that treatment can be initiated without delay. Telemedicine (fax, e- mail, and internet) is advancing in our country and a networking between the centers can be of great value. 14

2.1 Definition of terms: The term, NSTE-ACS includes UA and NSTEMI. These two conditions are closely related whose pathogenesis and clinical manifestations are similar but of differing severity. The clinical presentation depends on the severity of stenosis and the degree of thrombosis. In patients where ischemia is severe, there can be myocardial damage with the release in troponin I (TnI), troponin T (TnT), or CK-MB and the condition is referred to as NSTEMI. If there is no evidence of enzyme

elevation, the condition is labeled as UA. It is important to remember that the appearance of biomarkers may be delayed by up to several hours after the onset of ischemic symptoms. The distinction between the terms UA or NSTEMI is retrospective. It is also common to describe patients as Trop T- ve NSTE ACS (UA) or Trop T +ve NSTE ACS (NSTEMI). 2.2 Clinical presentation of NSTE ACS: The clinical presentation of NSTE ACS encompasses a wide variety of symptoms. An accurate history

recording is very important. The important points in the history include nature of anginal symptoms, prior history of IHD, sex (male), older age and an increasing number of traditional risk factors. The (3) following clinical presentations are usually included in NSTE ACS . • Prolonged (> 20 min) anginal pain at rest. • New onset (de novo) severe angina (class III of the classification of Canadian Cardiovascular (6) Society (CCS) .

• Recent destabilization of previously stable angina with atleast CCS III angina characteristics (crescendo angina) or • Post MI angina. The typical clinical presentation of NSTE ACS is retrosternal pressure or heaviness (“angina”) radiating to the left arm, neck or jaw which may be intermittent (usually lasting several minutes) or persistent. These complaints may be accompanied by other symptoms such as diaphoresis, nausea,

abdominal pain, dyspnea, and syncope. There are several atypical symptoms and these include epigastric pain, recent onset indigestion, stabbing chest pain, chest pain with pleuritic symptoms, or increasing dyspnea. Atypical complaints are often observed in younger and older patients, in women, and in patients with diabetes. 15

2.3 Clinical assessment of NSTE ACS: Physical examination: The clinical examination is frequently normal. The presence of tachycardia, heart failure or haemodynamic instability must prompt the physician to expedite the diagnosis and treatment of patients. It is important to identify clinical circumstances that may precipitate or exacerbate NSTE- ACS, such as anaemia, infection, fever and metabolic or thyroid disorders. An

important goal of physical examination is to exclude non cardiac causes of chest pain and non- ischemic cardiac disorders (e.g. pulmonary embolism, aortic dissection, pericarditis, valvular heart disease) or extra cardiac causes. Electrocardiogram (ECG): The resting 12 lead ECG is the first diagnostic tool. It should be recorded as soon as possible and immediately interpreted by a qualified physician. The finding of persistent ST

elevation suggests STEMI which requires a different treatment. ECG recordings should be repeated at least at 6 and 24 h, and in the case of recurrence of chest pain/symptoms. ECG should be compared with any previously available recordings. In NSTE ACS, ECG may show ST segment deviation, T wave changes or may remain normal. It should be emphasized that a completely normal ECG does not exclude the possibility of NSTE ACS. In several

studies, around 5% patients with normal ECG who were discharged from the emergency department (7) were ultimately found to have acute MI or UA . ST segment shifts and T wave changes are the ECG indicators of unstable CAD. The number of leads showing ST depression and the magnitude of ST (8) depression are indicative of the extent and severity of ischemia and correlate with the prognosis . ST depression of > 2 mm carries a increased mortality risk. Inverted T waves, especially if marked

(greater than or equal to 2mm (0.2 MV) also indicate UA/ NSEMI). Q waves suggesting prior MI indicate a high livelihood of IHD. The utility of ECG becomes less if ECG is abnormal due to pre- existing intraventricular conduction defect or left ventricular hypertrophy (LVH).Ischemia in the left circumflex coronary artery territory is frequently missed in the common 12 lead ECG. It may be detected in lead V4-R, V3- R as well as in leads V7 – V9. These leads should be recorded if clinically indicated.

Biochemical markers : Several biomarkers have been investigated in recent years to be used for diagnosis and risk stratification. Cardiac troponin (CTn) is the biomarker of choice because it is the most sensitive and specific marker of myocardial injury/ necrosis available. Unfortunately, there is a lack of understanding of many of the analytical and clinical issues that govern the use of this 16

important biomarker. The diagnostic cut off for MI using cardiac troponins should be based on the th (9) 99 percentile of levels among healthy controls as recommended by the consensus committee . All laboratories need to validate their values. The diagnosis of NSTE- ACS should never be made only on the basis of cardiac biomarkers, the elevation should always be interpreted in the context of clinical presentation. Troponin levels usually increase after 3-4 hours. If the first blood sample for CTn is not

elevated, a second sample should be obtained after 6-9 h, and sometimes a third sample after 12-24 hours is required. Troponin level may remain elevated upto 2 weeks. Troponin elevation can occur in cardiac and non cardiac conditions including chronic renal failure. In NSTE ACS, elevated CTn values signal a higher acute risk and an adverse long term prognosis. The elevated troponin level is also useful for selecting appropriate treatment. Creatine Kinase MB is less sensitive and specific for the

diagnosis of NSTE ACS. However, it remains useful for the diagnosis of early infarct extension (reinfarction) and peri-procedural MI because of its short half-life. Many other biochemical markers like CRP, NT- Pro BNP, myoglobin are commercially available. At the present time, there use is not recommended for the diagnosis. Echocardiography: Echocardiography and Doppler examination should be done to assess the global

left ventricular function, any regional wall motion abnormality. Echocardiography also helps in excluding other causes of chest pain. 2.4 Risk Stratification at presentation: Many patients with NSTE- ACS require observation/hospitalization in an environment with continuous electrocardiographic monitoring and defibrillation capability. The risk stratification at presentation is useful, however, it is important to understand that patients who are stable initially,

NSTE ACS includes a heterogeneous group of patients with a highly variable prognosis. The risk (10) stratification is necessary for prognosis assessment and treatment. A simple TIMI risk score which takes into consideration clinical variable can be used (Table 2). The TIMI risk score is available at www.timi.org. A low TIMI score <3 usually indicates a low risk and a TIMI score > 3 indicates intermediate or high risk. In general, patients having multiple coronary risk factors, advanced age,

rest angina, clinical left ventricular (LV) dysfunction, prior history of percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABGS) indicate a high risk. Elevation of troponin or CK-MB indicates myocyte necrosis and a high risk. It is important to note that the TIMI risk score is just a guide and may not be reliable in young patients. There are other risk models based (11) (12) on PURSUIT trial and GRACE registry .

Data from western countries suggest that patients with acute chest pain might be better served by transport to an adequately equipped facility (category A) than by sending them to a less equipped facility (category B, C or D). It is well documented that early invasive therapy (early coronary angiography followed by appropriate revascularization) is preferable in high risk patients. These patients should preferably be admitted to category A hospitals or promptly transferred to such a

facility. If a high risk patient is initially admitted in Category B, C or D hospital, a decision for transportation should be taken. The decision is to be individualized depending on the clinical, social and economic considerations. 2.5 Differential diagnosis: A number of patients evaluated for suspected NSTE ACS are found not to have acute ischemia. This includes patients with non cardiac pain (e.g. pulmonary embolism, musculoskeletal or esophageal

discomfort) or cardiac pain not caused by myocardial ischemia (e.g. pericarditis). These patients should be evaluated as dictated by the individual presentation. 18

3.0 MANAGEMENT OF NSTE-ACS: Patients who are awaiting hospitalization are advised to chew non enteric coated aspirin (162 to 325 mg). They may receive sublingual nitrate or GTN spray for pain relief. Patients with definite or probable NSTE-ACS who are stable should be admitted to an impatient unit for bed rest with continuous rhythm monitoring and careful observation for recurrent ischemia. High risk patients, including those with continuing discomfort and/ or haemodynamic instability, should

be hospitalized in a coronary care unit (CCU) and observed for at least 24-48 hours without any major complications. 3.1 What not to do ? A. Fibrinolytic (thrombolytic) therapy using streptokinase, urokinase, tenecteplase or any other agent should not be used in patients with UA and NSTEMI. These agents can prove harmful. B. Glycoprotein IIb/IIIa agents like abciximab, tirofiban and eptifibatide are mostly useful in patients

undergoing percutaneous coronary interventions (PCI). The routine “upstream” use of the agents is not recommended. 3.2 Anti- ischemic and analgesic therapy: All patients must receive medication for relief of pain. Oxygen is useful for initial stabilization particularly in those with hypoxemia. Topical, oral or intravenous nitrates are recommended for pain relief. Intravenous nitroglycerin (NTG) is particularly helpful in those who are unresponsive to sublingual NTG, in hypertension and in

those with heart failure. Nitrates should be used with caution if systolic blood pressure is below 100 mm of Hg. 19

Morphine sulfate (1 to 5 mg intravenously), if available, is a good option for pain relief in patients whose symptoms are not relieved despite NTG or other anti ischemic therapy. The non steroidal anti inflammatory drugs (NSAIDs) and COX-2 inhibitors should not be administered for pain relief due to (13) increased risk of cardiovascular events . Oral beta blockers are useful for pain relief. The use of intravenous beta blockers should be avoided

particularly in haemodynamically unstable patients. Calcium channel blockers are of utility in vasospastic angina and in patients with contraindications to beta blockade. Other antianginal drugs like ivabradine, trimetazidine, ranolazine and nicorandil have limited role to play. 3.3 Antiplatelet agents: Platelet activation plays a key role in NSTE- ACS and antiplatelet therapy should be administered once the diagnosis is entertained. Aspirin (cyclo oxygenese inhibitor) should be administered to all

patients unless contraindicated. Initial dose of chewed non-enteric aspirin from 162 to 325 mg is recommended. The subsequent dose of aspirin can be 75 to 150mg daily on a long term basis. GI bleeding appears to increase with higher doses. Clopidogrel is recommended in all patients with an immediate dose of 300 mg followed by 75 mg daily. In patients considered for a PCI, a loading dose of 600 mg is advised to achieve more rapid

inhibition of platelet function. Clopidogrel should be maintained for 12 months unless there is an excessive risk of bleeding. A new antiplatelet agent, belonging to thienopyridine group of ADP receptor inhibitors has recently (14) been investigated in TRITON TIMI- 38 trial . Prasugrel reduces the platelet aggregation by irreversibly binding to P2Y12 receptors on the platelets. Prasugrel is a prodrug and has rapid onset of

action (1 hour). It is converted to active and inactive metabolites. The active metabolite has half life of about 7 hours. In patients undergoing PCI for ACS, the agent showed lower incidence of ischaemic events when compared to clopidogrel. It was particularly effective in diabetics (4.2% 20

absolute risk reduction for ACS). Bleeding incidence was similar (2.2% vs 2.3%). The agent is correctly recommended for the following patients (1) Patient presenting with STEMI (2) NSTEMI patient with diabetes mellitus or young male patients undergoing PCI (3) Patient with history of stent thrombosis (4) non responders to clopidogrel. This agent is contraindicated in patients with >75 years of age or in patient having history of TIA or any stroke. The loading dose is 60 mg orally. The maintenance

dose is 10 mg daily. In patient weighing <60 kg, the maintenance dose has to be reduced to 5 mg daily. (15) Another new drug, ticagrelor has been found to be superior as compared to clopidogrel in ACS . Ticagrelor is an oral, reversible, non thinopyridine P2Y12 antagonist. This is not a prodrug. This has a more rapid onset of action (30 min) and rapid off sent of action (4-72 hours). In ACS, Ticagrelor was associated with mortality reduction compared to clopidogrel (9.8% vs 11.7%, P=<0.001). However

nonfatal bleeding was higher (16.1% vs 14.6%, P=0.0084). The loading dose is 180 mg. Maintenance dose is 90 mg twice daily thereafter. All patients presenting with ACS/NSTEMI should receive aspiring plus any one of these three (Clopidogrel/Prasugrel/Ticagrelor) agents. The use of GP IIb / IIIa inhibitors has undergone a major change in the current era of high dose clopidogrel and newer anticoagulants. These agents are used either upstream beginning prior to

angiography or administered after angiography during the PCI. The upstream use of GP IIb/IIIa inhibitors have considerably reduced. Eptifibatide have not shown efficacy in reducing ischemic events in high risk NSTE-ACS patients when used upstream and maintained during the PCI procedure. In routine practice, these days patients are often taken to catheterization laboratory without prior (16) use of GP IIb / IIIa agent . Any of the three agents is used depending on the clinical and

angiographic characteristics. 3.4 Anticoagulants: (3,4) Anticoagulation is recommended for all patients in addition to antiplatelet agents . An increasing number of anticoagulants (previously referred to as antithrombins) are available and include unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux and bivalirudin. 21

The choice of anticoagulation depends on the risk of ischemic and bleeding events and choice of the initial management strategy (e.g. urgent invasive, early invasive or conservative). Enoxaparin (1mg/kg bw twice daily) is a preferred anticoagulant and is a good option in patients treated conservatively or by invasive strategy. Enoxaparin can be stopped within 24 h after an invasive strategy where as it should be administered up to hospital discharge (usually 3 to 5 days) in conservative strategy.

Fondaparinux is recommended on the basis of most favourable efficacy/ safety profile and the (17) recommended dose is 2.5 mg daily . This agent causes least bleeding complications. An additional UFH in standard dose of 50-100 U/kg bolus is necessary during PCI due to slightly high incidence of catheter thrombosis. Bivalirudin is currently recommended as an alternative anticoagulant for urgent and elective PCI in (18) moderate or high risk NSTE ACS . Bivalirudin reduces the risk of bleeding as compared with

UFH/LMWH plus GP IIb/IIIa inhibitor. 3.5 Statins & other drugs: Statins are recommended for all NSTE ACS patients, irrespective of cholesterol levels. Statin should be initiated early after admission, with the aim of achieving LDLC levels <70 mg/dL. Atorvastatin is usually the preferred agent. High dose (40-80 mg) is used for the initial period (1-2 months). Subsequent dosing is bsed on the target LDL (<70 mg/dL) level.

ACE inhibitors are indicated in patients with reduced LV systolic function in diabetes and all other patient of proven CAD. ARB are indicated in those patients who are intolerant to ACE inhibition. 22

4. CORONARY REVASCULARIZATION : Revascularization for NSTE ACS is performed to relieve angina, ongoing myocardial ischemia and to prevent progression to MI or death. The indications for revascularization and the preferred approach, PCI or CABGS depend on the extent and severity of the lesions, the patient’s condition (19) and co-morbidity . 4.1 Coronary angiography : An invasive strategy always starts with angiography. The indications for urgent and routine early angiography are shown in table 3 and 4.

Those patients who have no recurrence of chest pain, normal serial ECGs, no elevation of troponins and no heart failure are considered as low risk. In these patients, a stress test is advised prior to discharge. Coronary angiography is contemplated, if the stress test is positive. 4.2 Conservative and Invasive strategy : There is a controversy which remains as to the optimal timing between hospital admissions, initiation of medical therapy and invasive evaluation. There are large numbers of randomized

controlled trials (RCT) which have addressed this issue. The term invasive strategy refers to coronary angiography and subsequent revascularization within 2 to 24 hours of hospitalization. Conservative strategy (selective invasive) refers to initial medical stabilization followed by angiography and appropriate revascularization, usually within 72 hours or prior to hospital discharge. RCTS have shown that an early invasive strategy reduces ischemic end points mainly by reducing severe (20)

recurrent ischemia and the need for re-hospitalization and revascularization . This strategy (21) reduces cardiovascular death and MI at up to 5 years of follow-up . From the available data, following conclusions can be drawn. 23

1. High risk/unstable patients benefit most from the early revascularization therapy & these patients should be promptly treated in advanced centers. 2. A systematic approach of immediate angiography is not necessary in patients who are stabilized with a contemporary pharmacological approach. Likewise, immediate transfer of stabilized patients admitted in hospitals without onsite cardiac catheterization facilities is not mandatory, but should be

organized within 72 h. Figure 1 provides a flow chart for management of NSTE-ACS patients. 4.3 Percutaneous Coronary Intervention (PCI) and Coronary Artery Bypass Grafting (CABG) : The mode of revascularization is usually based on the severity and distribution of the CAD. The PCI is usually performed for the culprit lesion using drug eluting stents. Significant lesions in multiple vessels can be treated either in same sitting or in staged fashion as considered appropriate. CABG is

usually advised for complex CAD not amenable to PCI, left main with triple vessel disease, total occlusions and diffuse disease. It is important to consider the bleeding risk as these patients are on aggressive antiplatelet therapy. The benefits of CABG are greatest after several days of stabilization with medical treatment and stopping the antiplatelet agents. 5. LONG TERM MANAGEMENT: Patients with NSTE ACS after the initial phase carry a high risk of recurrence of ischemic events.

Therefore, active secondary prevention is an essential element of long term management. Life style alterations is very important. This is termed as therapeutic life style changes (TLC). Smoking cessation, weight reduction, blood pressure control, management of diabetes, lipid intervention, antiplatelet agents, beta blockers, ACE inhibitors (or ARB) remain extremely important interventions. Isotonic exercise like brisk walk, swimming, cycling, jogging for 30-45 minutes daily or at least 150

minutes weekly should be advised to all these patients. The exercise prescription (type, duration and intensity) should be individualized based on the clinical status of the patient. Lastly psychological (22) factors like anxiety and depression are to be identified and treated . 24

REFERENCES : 1. Xavier D, Pais P, Devereaux PJ, et al : Treatment and outcomes of acute coronary syndromes in India (CREATE) : a prospective analysis of registry data. Lancet 2008; 171 : 1435-42. 2. SavonittoS, Ardissino D, Granger CB, et al : Prognostic value of the admission electrocardiogram in acute coronary syndromes. JAMA 1999; 281: 707-713. 3. ACC/AHA 2007 Guidelines for the management of patients with unstable angina / non-ST

elevation myocardial infarction. Executive summary. J Am Coll Cardiol 2007 ; 50 : 652 – 726. 4. Guidelines for the diagnosis and treatment of non-ST segment elevation acute coronary syndromes. The task force for the diagnosis and treatment of non –ST segment elevation acute coronary syndromes of the European Society of cardiology. European Heart Journal 2007; 28 : 1598 – 1660. 5. API expert consensus document on management of ischemic heart disease JAPI 2006 ; 54 : 469 – 480.

6. Campeau L, Letter. Grading of angina pectoris. Circulation 1976 ; 54 : 522-523. 7. Rouan GW, Lee TH, Cook EF et al : Clinical characteristics and outcome of acute myocardial infarction in patients with initially normal or nonspecific electrocardiograms (a report from the multicenter chest pain study). Am J Cardiol 1989 : 64 : 1087 – 1092. 8. Holmvang L, Clemmensen P, Linadhi B et al : Quantitative analysis of the admission

electrocardiogram identifies patients with unstable coronary artery disease who benefit the most from early invasive treatment. J Am Coll Cardiol 2003 ; 41 : 905 – 915. 9. Thygesen K, Mair J, Katus H et al : Recommendations for the use of cardiac troponin measurement in acute cardiac care. European Heart Journal 2010; 31: 2197-2200. 10. Antan EM, Cohen M, Berink PJ et al : The TIMI risk score for unstable angina / non ST elevation MI : a method for prognostication and therapeutic decision making. JAMA 2000:

284: 835 – 842. 11. Boersma E, Pieper KS, Steyerberg EW et al : Predictors of outcome in patients with acute coronary syndrome without ST segment elevation. Results from an international trial of 9461 patients. The PURSUIT investigators. Circulation 2000 ; 101 : 2557 – 67. 12. Granger CB, Golberg RJ, Dabbous O et al : Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med 2003 ; 163 : 2345-53.

13. Gibson GH, Jaobsen S, Rasmussen JN et al : Risk of death or reinfarction associated with the use of selective cyclo-oxygenase – 2 inhibitors and nonselective nonsteroidal anti- inflammatory drugs after acute myocardial infarction. Circulation 2006; 113 : 2006-13. 14. Montalescort G, Wiviott SD, Braunwald E et al : Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial 25

infarction (TRITON-TIMI-38) : double blind, randomized controlled trial. Lancet 2009 ; 373 : 723-731. 15. Wallentin L, Becker RC, Budaj A et al : Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-57. 16. Bhatt DL, Roe MT, Peterson ED et al : Utilization of early invasive management strategies for high-risk patients with non ST-elevation acute coronary syndromes : results from the CRUSADE Quality improvement initiative. JAMA 2004; 292: 2096-2104.

17. Yusuf S, Mehta SR, Chrolaviclus S et al : Efficacy and safety of fondaparinux compared to enoxaparin in 20,078 patients with acute coronary syndromes without ST segment elevation. The OASIS (Organization to Assess strategies in Acute Ischemic Syndromes) – 5 investigators. N Engl J Med 2006 : 354 : 1464 – 1476. 18. Stone GW, McLaurin BT, Cux DA et al : Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355: 2203-2216.

19. Guidelines on myocardial revascularization. The task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardiothoracic Surgery (EACTS). European Heart Journal 2010 ; 31: 2501 – 2555. 20. Mehta SR, Cannon CP, Fox KA et al : Routine versus selective invasive strategies in patients with acute coronary syndromes : a collaborative meta-analysis of randomized trials. JAMA 2005; 293 : 2908 – 2917.

21. Fox KA, Clayton TC, Damman P et al : Long term outcome for routine versus selective invasive strategy in patients with non ST-elevation acute coronary syndrome. A meta analysis of individual patient data. J Am Coll Cardiol 2010; 55 : 2435 – 2445. 22. Joep P, Guy DB, Helmut G et al. The fifth joint task force of the European Society of Cardiology and other societies on Cardiovascular Disease Prevention in clinical practice

(constituted by representatives of nine socities and by invited experts). Europan Heart Journal (2012):33;1635-1701. 26

Table 1 : Type of hospitals / centers treating ACS patients in India. Category Facilities • A Advanced care with ICCU, catheterization laboratory, PCI and Coronary artery bypass graft (CABG) Surgery. • B ICCU with trained staff for thrombolysis, CPR, defibrillation, pacing etc. • C ICU with no specialized cardiac care • D No ICCU or ICU Abbreviations: ICCU = Intensive coronary care unit, ICU = Intensive care unit, CPR = Cardio- pulmonary resuscitation. Other as in text.

Table 2 : The TIMI risk score for NSTE-ACS. Characteristics Points Historical Age ≥ 65 1 ≥ 3 risk factors for CAD 1 Known CAD (Stenosis ≥ 50 %) 1 Aspirin use in past 7 days 1 Presentation Recent (£ 24 H) severe angina 1 ST – segment deviation ≥ 0.5 mm 1 › Cardiac markers 1 Risk Score = Total Points (0-7) Abbreviations : As in text 27

Table 3 : Indications for urgent coronary angiography and invasive strategy. • Refractory angina (e.g. evolving MI). • Recurrent angina despite intense antianginal treatment (associated with ST depression (£ 2 mm) or deep negative T waves. • Clinical symptoms of heart failure or haemodynamic instability (‘Shock’). • Life threatening arrhythmias (ventricular fibrillation or ventricular tachycardia). Table 4 : Indications for early coronary angiography : • Elevated troponin levels.

• Dynamic ST or T wave changes. • Diabetes mellitus, reduced renal function. • Depressed LVEF < 40%. • Early post MI angina. • PCI within 6 months. • Previous CABG. • Intermediate to high risk according to risk score. Abbreviations : as in text. 28

Figure 1 : Flow – chart for management of NSTE-ACS. Patient presenting with ASA / Clopidogrel / LMWH or Enoxaparin High risk Low risk Initially planned Initially planned Immediate angio planned: Early angio planned: Early non-invasive stress testing +ve -ve PCI PCI Angio Medical + GP IIb/IIIa + GP IIb/IIIa or Bivalirudin PCI or CABGS Abbreviation : as in text 29

CONSENSUS DOCUMENT FOR THE DIAGNOSIS AND TREATMENT OF ST ELEVATION ACUTE CORONARY SYNDROME 30

1.0 AIM AND SCOPE OF THESE RECOMMENDATIONS Recent documents have described the evidence-based diagnosis and management of acute ST 1-4 segment elevation myocardial infarction (STEMI) . While these are erudite and exhaustive, they are tailored to the situation in developed countries. Because of the substantially different ground reality in India, there is a need for modifications in the interpretation of the evidence and application of treatments to the Indian context.

This statement attempts to provide guidance to Indian physicians and healthcare providers at the grass-root level in making decisions for the optimal management of patients with STEMI. 2.0 DIAGNOSIS OF STEMI Early diagnosis is the key to early treatment of STEMI. A history of chest pain or discomfort lasting 10-20 minutes should raise the suspicion of acute STEMI in susceptible individuals (middle-aged male

patients, particularly if they have risk factors for coronary disease). It must be recognized that pain may be atypical in character or location. A 12-lead ECG must be performed as soon as possible. ECG should be interpreted within ten (10) minutes of arrival in health care centre. If the initial ECG is not suggestive of STEMI but the patient continues to have symptoms, repeat ECGs must be obtained (every 15 minutes, not after 12 hours or next day) and compared to the first ECG. While markers of

myocardial necrosis are useful in corroborating the diagnosis, it must be emphasized that they may not be elevated early after the onset of symptoms. In doubtful cases, echocardiography may be a useful adjunct in making the diagnosis, particularly among young patients without prior history of coronary disease. Equipment, personnel and training Every primary health center should have a functioning ECG machine available 24

hours a day. Health workers at these centers should be trained to recognize the cardinal features of STEMI so that treatment can be initiated without delay. It may not be necessary for all health centers to have access to facilities for cardiac biomarker testing. Use of qualitative test-strips in these centers may be expensive and may lead to diagnostic confusion, and their use should be discouraged.. 31

3.0 MANAGEMENT OF STEMI 3.1 Risk stratification The initial assessment should include the rapid identification of patients who may be at high risk of cardiogenic shock or death. The following characteristics have been most consistently associated 5-7 with adverse outcomes in patients with STEMI : i. Older age (age ≥75 years) ii. Higher Killip class (class III or IV) iii. Lower systolic blood pressure (<100 mm Hg) iv. Higher heart rate (>100/min) v. Anterior MI

The greater the number of risk factors, the higher is the risk. Therefore, after instituting initial treatment (which may include fibrinolytic therapy), such patients are best transferred to hospitals with coronary care units and catheterization laboratory facilities. 3.2 Initial treatment The first treatment that should be given is 325 mg of (preferably) non enteric-coated aspirin to be 8 chewed . All patients should receive aspirin. Clopidogrel should be administered at a loading dose of 9-10

300 to 600 mg to all patients . Patients undergoing primary PCI should receive a 600 mg loading 11 dose . All patients should receive medications to relieve pain. These may include opioid analgesics (morphine sulfate intravenously) where available. Sublingual or intravenous nitrates should be administered if systolic blood pressure is ≥120 mm Hg. If systolic BP is ≥ 100 mm Hg but less than 120 mm Hg, nitrates must be administered cautiously. Non steroidal anti-inflammatory drugs (NSAIDs, 12

3.3 Choice of reperfusion therapy 3.3.1 Fibrinolytic therapy vs. primary PCI Reperfusion therapy is the cornerstone of STEMI management and should be instituted in all 8-13 patients presenting within 12 hours of onset of symptoms . The most efficacious reperfusion therapy available is timely primary PCI, but it may not be the most effective in the Indian context, 14 given the relative paucity of PCI-capable centers . Moreover, since most of these centers are

located in urban areas, the distances involved in transporting patients from rural areas become prohibitive. Fibrinolytic therapy therefore remains the most practicable reperfusion strategy for India. The most recent data from India suggests that only about 8% of patients with STEMI receive 15 primary PCI . Nearly 60% of patients receive fibrinolysis with streptokinase as initial treatment. It should be emphasized that even among urban/semi-urban dwellers (only 17% of patients enrolled in

the CREATE registry were from rural areas), a third of patients did not receive any form of 15 reperfusion therapy. Patients presenting to PCI-capable centers should of course be treated with timely primary PCI if the door-to-balloon time is anticipated to be less than 90 minutes from the time of arrival at the 4 hospital . It should be recognized that door-to-balloon times may be greater than 2 hours even in PCI-capable centers during off-duty hours, weekends and holidays, and immediate fibrinolysis may

be the better option when delays are anticipated. Such hospitals should implement processes to minimize and monitor door-to-balloon times. Table 1 Indications for transfer of patients (after fibrinolytic therapy) to centers with CCUs and/or PCI capabilities 1. Patients in cardiogenic shock or those who are at high risk of developing cardiogenic shock†21 2. Failed fibrinolytic therapy 3. High-risk pa(cid:1)ents‡*22 33

3.3.2 Choice of fibrinolytic agent Traditionally, streptokinase has been the most commonly used fibrinolytic agent in India. However, streptokinase is not fibrin-specific, requires to be given as an infusion over one hour and may be associated with hypersensitivity reactions. Recently, there is some favorable evidence for the use of 16-17 tenecteplase in Indian settings . Tenecteplase has theadvantage of being fibrin-specific, can be

given as a bolus dose, and has a lower incidence of hypersensitivity reactions. TIMI 3 flow in the infarct related coronary artery may also occur more frequently with tenecteplase when compared to 18 streptokinase. Tenecteplase should be administered at a dose of 0.5 mg/kg body weight . Personnel and training Given that nearly a third of patients in urban India do not receive any reperfusion therapy, it may be worthwhile for the government to consider making tenecteplase available at primary health centers

as a policy decision. This would also entail adequate training of medical and paramedical personnel at these centers so that they can administer tenecteplase without delay. Studies conducted around the world have found that administration of bolus-dose fibrinolytic agents by paramedical personnel is safe. The government should commission studies to confirm the safety of such a practice in the Indian context before its widespread implementation. 3.3.3 The case for pre-hospital fibrinolysis

Due to lack of awareness, lack of ambulance services and the distances involved, most patients with 15 STEMI living in urban/semi-urban India reach hospital after a delay of 5 hours . This delay can be shortened by institution of systems to initiate pre-hospital evaluation and fibrinolysis. Pre-hospital fibrinolytic therapy has clearly shown to improve outcomes and has compared favorably with 19 primary PCI . 3.4 Transport of patients to centers with CCUs and/or PCI capability

Recent studies in Europe and North America have suggested that transport of patients to PCI- capable centers may be a better strategy than immediate fibrinolytic therapy. Such a strategy may however not be suitable for most parts of India because of the distances involved and the insurmountable logistics of transport. Nevertheless, it may be possible for small geographic units (urban or rural) to develop systems for the provision of efficient services for transporting patients to

designated PCI-capable centers. Recent data from India suggests that only 6% of patients with STEMI 15 travel to hospital by ambulance . 34

After administration of fibrinolytic therapy several situations may necessitate transfer of patients to centers with CCUs and/or PCI capabilities. These are listed in table 2 below. Table 2 Indications for transfer of patients (after fibrinolytic therapy) to centers with CCUs and/or PCI capabilities 1. Patients in cardiogenic shock or those who are at high risk of developing cardiogenic shock†21 2. Failed fibrinolytic therapy 3. High-risk pa(cid:1)ents‡*22

† Age >70 years, systolic blood pressure <120 mmHg, heart rate >110/min or <60/min, and increased time since onset of symptoms. ‡ Patients with ST elevation ≥2 mm in anterior leads or 1 mm in inferior leads who have at least one of the following high-risk factors: systolic blood pressure < 100 mm Hg,heart rate >100/min, Killip class IIor III, ST-segment depression of ≥2 mm inthe anterior leads, or ST- 22 segment elevation of ≥1 mm in right-sided lead V4 (V4R).

* PCI may then be performed as and when needed or as part of a pharmacoinvasive strategy 3.5 Adjunctive therapies 3.5.1 Antiplatelet treatment Aspirin and clopidogrel should be administered as discussed in section 3.2. Glycoprotein IIb/IIIa antagonists may be used in patients undergoing primary PCI although their role in patients pre- loaded with clopidogrel is unclear. These agents may be administered in the catheterization

laboratory, at the time of the procedure. There is no role of administering these agents within the 25 context of a strategy to bridge the time delay before primary PCI (facilitated PCI) . Abciximab, eptifibatide and tirofiban appear to be similarly effective and may be used depending upon local 3 preferences and availability . 35

3.5.2 Antithrombotic therapy Patients receiving fibrinolytic therapy Following treatment with both fibrin-specific and non fibrin-specific fibrinolytic agents, there is strong evidence for the use of antithrombotic agents for reducing reinfarction or recurrent 13,24 ischemia . Recent studies suggest that low molecular weight heparins (LMWH) may be better 24-26 than unfractionated heparin (UFH) for this purpose . The LMWHs enoxaparin or reviparin may

be administered for up to 8 days post-MI. Fondaparinux has recently been shown to reduce the occurrence of death or reinfarction while concomitantly reducing the risk of major bleeding, and 27 may therefore be considered among patients undergoing treatment with streptokinase . There is no role for bivalirudin among patients receiving fibrinolytic therapy. Patients undergoing primary PCI should receive periprocedural UFH or bivalirudin. Fondaparinux

(without added UFH) may increase the risk of catheter thrombosis. Patients not receiving any reperfusion therapy Fondaparinux may be the preferred agent among 29 patients who have not received any reperfusion therapy . 3.5.3 Beta adrenergic antagonists Oral beta-blockers should be administered in the first 24 hours to patients who do not have heart failure, a low output state, are not at increased risk of developing cardiogenic shock (see footnote in 21

table 2), or do not have other contraindications to beta-blocker therapy . Intravenous beta-blockers may be administered in the first 24 hours in the presence of hypertension or tachyarrhythmia, in the 2 absence of the above contraindications . 3.5.4 ACE inhibitors and ARBs ACE inhibitors improve survival in patients who have reduced left ventricular ejection fraction (LVEF 4 ≤ 40%) and those who are in heart failure following STEMI . Benefits are proportionately lower

among low risk patients. ACE inhibitors should be started in the first 24 hours after STEMI in the 30-31 absence of contraindications. ARBs may be used in patients who do not tolerate ACE inhibitors . 36

3.5.5 Other agents Routine use of intravenous or oral nitrates does not improve outcomes in patients with STEMI. Nitrates may be used for pain relief. There is no role for the routine use of calcium antagonists, intravenous magnesium, antiarrhythmic agents or glucose-insulin-potassium infusions, and may be 4 associated with adverse outcomes in some cases . High dose statins should be initiated as early as possible during hospital stay as part of secondary prevention measures. The dose of statin to be

used in Indian patients is not clear, but lowering LDL levels to ≤70mg/dL may be a useful target. 3.6 Management post-fibrinolytic therapy Several studies have suggested that routine angiography and PCI of the infarct related artery may 32-35 reduce the rates of re-occlusion or re-infarction . However, none of these studies have shown a reduction in mortality with this strategy. Because of the resource intensiveness of this strategy and

the absence of an effect on survival, this panel favors a more conservative approach consisting of revascularization guided by the results of risk stratification by early exercise stress testing. Angiography (and revascularization) should of course be performed in the event of spontaneous ischemia or the development of mechanical complications. After the acute phase of STEMI, therapeutic lifestyle changes (including smoking cessation, exercise

and dietary modification) and drugs for secondary prevention assume critical roles in improving outcomes in the medium and long-term. Patient counseling and education is the key to maintaining adherence to therapy in the long run. 37

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Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 2003;108:135-42. 27. Peters RJ, Joyner C, Bassand JP, et al. The role of fondaparinux as an adjunct to thrombolytic therapy in acute myocardial infarction: a subgroup analysis of the OASIS-6 trial. Eur Heart J 2008;29:324-31. 28. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218-30. Oldgren J, Wallentin L, Afzal R, et al.

29. Effects of fondaparinux in patients with ST-segment elevation acute myocardial infarction not receiving reperfusion treatment. Eur Heart J 2008;29:315-23. 30. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico. Lancet 1994;343:1115-22.

31. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial 39

infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. Lancet 1995;345:669-85. 32. Fernandez-Aviles F, Alonso JJ, Castro-Beiras A, et al. Routine invasive strategy within 24 hours of thrombolysis versus ischaemia-guided conservative approach for acute myocardial infarction with ST-segment elevation (GRACIA-1): a randomised controlled trial. Lancet 2004;364:1045- 33. Le May MR, Wells GA, Labinaz M, et al. Combined angioplasty and pharmacological

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STANDARD TREATMENT GUIDELINES Management of Dry Eye Disease in India Quick Reference Guide May 2016 Ministry of Health & Family Welfare Government of India

2 Contents 1. Introduction ………………………………………………………………………………………… 3 2. Case Definition ………………………………………………………………………………………. 4 3. Epidemiology of Dry eye Disease ………………………………………………………….. 4 4. Recommendations ………………………………………………………………………………… 4 Clinical Pathway 1 : Overview of Dry Eye Disease …………………………………. 5 Clinical Pathway 2: Prevention of Dry Eye Disease ………………………………… 6 4.1. Diagnosis of Dry eye disease ………………………………………………………………… 7

Table 1- Risk factors in Dry eye disease Clinical Pathway 3- Diagnostic classification of Dry eye Clinical Pathway 4- Sequence of Dry eye tests ……………………… 7 Clinical Pathway 3- Diagnostic Classification of Dry eye disease …………… 10 Clinical Pathway 4- Practical Sequence of Dry Eye tests ………………………. 11 Table 2- Classification of Dry eye by severity ………………………………………. 13 Clinical Pathway 5- Treatment Algorithm for Dry eye management ….. 14 4.2. Management of Dry Eye ……………………………………………………………………. 15

Clinical Pathway 6- Overview of Dry Eye Management ………………………. 15 Clinical Pathway 7- Treatment of dry eye based on severity …………….. 17 Clinical Pathway 8- Artificial Tear Substitutes in Dry eye disease management ……………………………………………………….. 19 4.3. Provider & Setting …………………………………………………………………………. 21 4.4. Counselling & Referral ………………………………………………………………………. 21 Clinical Pathway 9 Treatment & Referral based on level of care ……….. 21 4.5. Recommendations for Prevention of Dry eye disease ………………………. 22

3 1.Introduction The term dry eye syndrome or dry eye disease has been described as a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbances and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface (Dry Eye Work Shop –DEWS,2007). Dry eye represents a disturbance of the

lacrimal functional unit, an integrated system composed of the lacrimal glands, ocular surface (cornea, conjunctiva, eye lids and the meibomian glands) with the sensory and motor nerves that connect these structures. The overall function of the lacrimal functional unit is to preserve tear film integrity, ocular surface health, maintaining corneal transparency and surface stem cell population, thereby significantly influencing the

quality of images projected onto the retina. Decreased tear secretion, delayed tear clearance from the ocular surface and altered tear composition may compromise tear film stability, sometimes accompanied by ocular inflammation. Disturbances integral to the lacrimal functioning unit are considered to pay an important role in evolution of different forms of dry eye. 2. Disease Definition Dry Eye Syndrome or Dry Eye Disease refers to a group of disorders of the ocular tear film

attributed to reduced tear production or excessive tear evaporation, associated with ocular discomfort and /or visual symptoms with possible disease of the ocular surface 3. Epidemiology & Prevalence of Dry eye disease Epidemiological information on dry eye syndrome has been limited by lack of uniformity in its definition and the inability of any single diagnostic test or set of diagnostic tests to confirm or rule out the condition. Dry eye syndrome is a common condition that causes

varying degrees of discomfort and disability. While clinic-based studies confirm its frequency (17% of 2127 consecutive new outpatients were diagnosed with dry eye following comprehensive examination), such studies may not reflect the overall population . In a population-based sample of 2520 elderly (65 or older) residents of Salisbury, Maryland, USA, 14.6% were symptomatic, which was defined as reporting one or more dry eye symptoms often or all the time. The combination of being symptomatic

and having a low Schirmer test (≤5 mm with anesthesia) or a high rose bengal score (≥5) was seen in 3.5% of the residents. A population-based study of dry eye conducted in Melbourne, Australia, using different diagnostic criteria reported higher percentages of the 926 participants aged 40 to 97 who had a low Schirmer test (16.3% ≤8 mm)or a high rose bengal score (10.8% ≥ 4).There is no population-based study in relation to dry eye

disease in India. However, there are three published reports on prevalence of dry eye among hospital-based population from North and Eastern India and the prevalence varies between 18.4% and 40.8%. A study from higher altitudes reported a higher prevalence of 54%. Since these data are hospital based, they are likely to overestimate the prevalence of dry eye.

4 Section 4 - Recommendations 1. Diagnosis 2. Management 3. Provider & Setting 4. Counseling & Referral 5. Prevention Clinical Pathway 1

7 4.1 Diagnosis of Dry Eye Syndrome Table1- Risk Factors for Dry eye Disease High level of evidence Moderate level of evidence Low level of evidence • A ge • Medications- Tricyclic • Smoking • Female Sex antidepressants, • Hispanic ethnicity • Postmenopausal estrogen selective serotonin • Anti cholinergic drugs- t herapy reuptake inhibitors, anxiolytics & • Antihistamines diuretics, beta blockers. antipsychotics • Collagen vascular disease • Diabetes mellitus • Alcohol

• C orneal refractive surgery • HIV/HTLV1 infections • Menopause • Irradiation • Systemic chemotherapy • Botulinum toxin injection • Hematopoietic stem cell • Cataract surgery with a • Acne transplantation large incision • Gout • Vitamin A deficiency • Keratoplasty • Oral contraceptives • hepatitis C • Isotretinoin • Pregnancy • Androgen deficiency • Low air humidity • Sarcoidosis • Ovarian dysfunction (The definition and classification of dry eye disease: report of the Definition and Classification Sub

Committee of the International Dry Eye Workshop. Ocul Surf 2007; 5:75-92) 4.1.1. Identify characteristics of the causative factors, such as adverse environments, prolonged visual efforts, or ameliorating circumstances, which is helpful in diagnosing dry eye 4.1.2. Use supporting clinical observations and tests to confirm diagnosis of dry eye 4.1.3. Question about patient symptoms and signs, exacerbating conditions, duration of symptoms and ocular history to elicit helpful information

4.1.4. Pay particular attention to the skin, eyelids, adnexa, proptosis, cranial nerve functions, mouth, skeletal system and hands 4.1.5. On slit lamp biomicroscopy evaluation, focus on the tear film, eye lashes, anterior and posterior eyelid margins, puncta, conjunctiva and cornea. Pay particular attention to Meibomian gland dysfunction in evaluation of tear film.

8 4.1.6. Test for anti-thyroid and anti-thyroglobulin antibody in dry eye patients suspected of thyroid eye disease. 4.1.7. Order a B-Scan sonogram or other imaging study to assess extra ocular muscle thickness in patients with dry eye who have suspected thyroid eye disease 4.1.8. Recommend/ Perform conjunctival biopsy for dry eye patients who have significant chronic conjunctivitis with a nodular appearance or cicatrisation

Figure 1-Severe Blepharitis is a major risk factor for Dry eye disease ( See Recommendations 4.1.4 and 4.1.5)

9 Figure 2: Filamentary Keratitis in Recurrent Dry Eye Disease Figure 3 – Severe Dry eye with corneal scarring, vascularization and characteristic Conjunctival folds with significant reduction in tear film Clinical Pathway 3 Diagnostic Classification of Dry Eye Disease

10 Major etiological factors for dry eye disease Source: Lemp MA (chair). Definition and classification of dry eye disease: report of the definition and classification subcommittee of the International Dry Eye Work Shop (DEWS - 2007). Ocul Surf 2007; 5: 77 DRY EYE Aqueous Deficient Evaporative Sjogren`s syndrome Non- Sjogren’s Extrinsic Intrinsic syndrome Primary Secondary (RA, SLE, Decreased Lacrimal Reflex Contact lens Wegener`s Vitamin A Lacrimal Obstruction (Decreased Scleroderma deficiency

Production Afferent/ Etc) Medication Efferent) SJS, OCS Trachoma (Environmental) Medication Primary Secondary Post-Surgical Oil Deficient Lid related HSV/VZV Riley Day Congenital Idiopathic Alacrima (Age Blepharitis Obstructive Related)? (SJP,OCS Etc.) Blink Abnormality Infiltrative Surgical (Sarcoidosis, Radiation Structural Lymphoma, Induced GVHD, (Lid Aperture) HIV)

11 4.1.9. For patients with moderate to severe aqueous tear deficiency, establish the diagnosis by using one or more of the following tests: Tear break-up time test, ocular surface dye staining and Schirmer test 4.1.10. Perform these tests in this sequence because the Schirmer test can disrupt tear film stability and cause false positive ocular surface dye staining Clinical Pathway 4 Practical Sequence of Dry eye Tests

12 (The definition and classification of dry eye disease: report of the Definition and Classification Sub Committee of the International Dry Eye Workshop. Ocul Surf 2007; 5:75- 92) Figure 4 Schirmer’s Test to assess Tear film. Results less than 10 mm without anaesthesia considered abnormal. Consistently low Schirmer test readings are suggestive of aqueous tear deficiency Figure 5- Fluorescein Dye staining of cornea and Conjunctiva in mild to moderate Dry eye disease

13 4.1.11. Allow several minutes between the dye testing and the Schirmer test 4.1.12. Assess corneal sensation when trigeminal nerve dysfunction is suspected 4.1.13. Consider a laboratory and clinical evaluation for autoimmune disorders for patients with significant dry eye, other signs and symptoms of an autoimmune disorder or a family history of an autoimmune disorder 4.1.14. Consider testing for an underlying Sjogren Syndrome in patients with moderate

punctate staining of the cornea and /or conjunctiva as these patients will require a multi- disciplinary approach. 4.1.15. Evaluate aqueous tear production with the Schirmer test. It gives variable results and do not use as the sole criterion for diagnosing dry eye. Table 2-Classification of Dry Eye Severity 1 2 3 4 Discomfort Mild/ Episodic Moderate, Severe, frequent, Severe Occurs under episodic or or constant and/or environmental chronic with or withour stress disabling stress without stress and cosntant

Visual None or episodic Annoying and/or Annoying, Constant, Symptoms Mild fatigue limiting activity chronic/constant possibly episodic Limiting activity disabling Clinical Signs None to mild None to mild, Moderate to Conjunctival may or may not marked injection & have staining, conjunctival marked reduced tear staining, marked staining, meniscus, TBUT < central corneal severe 10 staining, punctate filamentary erosions, keratitis, scarirng, TBUT < 5, almost Schirmer score < immediate 5 TBUT, Schirmer

14 Based on 2007 International Dry Eye Workshop (DEWS) Report Behrens et al, Cornea 2008, International Task Force (ITF) Guidleines

15 Clinical Pathway 5 Treatment Algorithm for Dry Eye Syndrome Management Artificial Tears with preservative, 4 times a day Preservative Free Ointment Qhs With Patch During Sleep For Nocturnal Lagophthalmos Preservative free Tear Substitute Increase in frequency as needed Occlusive spectacles, side shields, Goggles, Vaporizer / Avoid heat, wind, 10% Acetylcystein in case of Excess mucus Topical Corticosteroids or Cyclosporine to treat inflammation Temporary Punctal Occlusion Autologous Serum Tears

16 4.2. Management of Dry Eye Clinical Pathway 6- Overview of Dry Eye Management

17 Treatment of Mild Dry Eye 4.2.1. Place patients who have suggestive symptoms without signs on trial treatments with artificial tears when other potential causes of ocular irritation have been eliminated 4.2.2. For patients with a clinical diagnosis of mild dry eye, address potentially exacerbating exogenous factors such as anti histamine or diuretic use, cigarette smoking and exposure to second hand smoke, and environmental factors such as air drafts and low humidity environments

4.2.3. Suggest measures such as lowering the computer screen to below eye level to decrease lid aperture, scheduling regular breaks, and increasing blink frequency to decrease the discomfort associated with computer and reading activities 4.2.4. Prescribe emulsions, gels and ointments to treat dry eye symptoms 4.2.5. Increase use of artificial tears as required, but recommend frequent tear instillation depending on the lifestyle or manual dexterity of the patient

4.2.6. Prefer Nonpreserved tear substitutes; however, you may recommend tears with preservatives for patients with mild dry eye and otherwise healthy ocular surface 4.2.7. Prescribe non preserved tears when tear substitutes are frequently and chronically used 4.2.8. Use Systemic Doxycycline in patients with evidence of Meibomian gland dysfunction 4.2.9. Correct eye lid abnormalities resulting from blepharitis 4.2.10. Correct eye lid abnormalities resulting from trichiasis

4.2.11. Correct eyelid abnormalities resulting from lid malposition

18 Clinical Pathway 7 TREATMENT RECOMMENDATIONS FOR DRY EYE SYNDROME BY DISEASE SEVERITY LEVEL (Adopted from AAO Preferred Practice Pattern 2013, Dry Eye Syndrome Clinical Pathway: TREATMENT RECOMMENDATIONS FOR DRY EYE SYNDROME BY DISEASE SEVERITY LEVEL (Adopted from AAO Preferred Practice Pattern 2013, Dry Eye Syndrome Reference: Pflugfelder. Management and Therapy Subcommittee of the International Dry Eye Workshop. Management and therapy of dry eye disease: report of the Management and

Therapy Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf 2007;5:174 • Education and environmental Moderate Dry Eye modifications • E limination of offending • In addition to above topical or systemic treatments: m edications • Anti-inflammatory agents • Aqueous enhancement u sing artificial tear (topical cyclosporine and • Systemic anti-inflammatory corticosteroids), agents substitutes, gels/ointments • Punctal plugs • Mucolytic agents • Eyelid therapy (warm

• Spectacle side shields • Autologous serum tears compresses and eyelid • Contact lenses scrubs) • Permanent punctal • Treatment of contributing occlusion ocular factors such as • Tarsorrhaphy b lepharitis or meibomianitis • Correction of eyelid a bnormalities Severe Dry Eye Mild Dry Eye Reference: Pflugfelder. Management and Therapy Subcommittee of the International Dry Eye Workshop. Management and therapy of dry eye disease: report of the Management

and Therapy Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf 2007;5:174

19 Treatment of Moderate Eye Disease 4.2.12. Use low dose topical corticosteroid therapy at infrequent intervals for short period of time ( i.e., several weeks) to suppress ocular inflammation 4.2.13. Monitor patients prescribed corticosteroids for dry eye for adverse effects such as increased intraocular pressure and cataract formation 4.2.14. Do not routinely recommend omega-3 fatty acid supplements for dry eye treatment since there is no evidence of their efficacy

4.2.15. Consider punctual occlusion for patients with aqueous tear deficiency when medical means of aqueous enhancement are ineffective or impractical 4.2.16. Punctal plugs are not routinely recommended for dry eye management in India owing to their relatively high cost. Punctal occlusion by thermal cauterization is preferred for patients with aqueous tear deficiency resistant to medical and conservative measures of treatment

4.2.17. Use non invasive therapies like Eye glass side shields and moisture chambers

20 Clinical Pathway 8- Artificial Tear Substitutes in Management of Dry Eye Disease • Low viscosity eye drops based on Polyvinyl Alcohol (PVA), Polyvinyl Mild Dry Eye Pyrrolidine (PVP) with Preservative Stage I • Frequency of application < 4 times daily • Low viscosity eye drops with PVA withour preservatives Moderate Dry • PVP without preservatives Eye • low viscosity cellulose derivatives Stage IIa • Hyaluronic Acid 0/1% • Osmoprotection • Higher viscosity cellulose derivatives without preservatives,

Moderately frequency of application >4 times daily Severe Dry Eye • Hydrogels (Carbomers), with preservative, frequency < 4 times Stage IIb daily • Hyaluronic Acid 0.3% Severe Dry Hydogels without preservatives Eye combined with unpreserved PVA, PVP Stage III Combined with Hyaluronic Acid 0.3%

21 Treatment of Severe Dry Eye 4.2.18. Hydroxy Propyl Cellulose eye drops, emulsions, gels are frequently used in moderate to severe dry eye. Punctal occlusion may be attempted in patients who are unable to use frequent artificial tears 4.2.19. Prescribe autologous serum drops to improve ocular irritation symptoms a well as conjunctival and corneal dye staining in patients with Sjogren syndrome and Graft versus host disease

4.2.20. Treat filamentary keratitis with debridement of the filaments or application of topical mucolytic agents, such as acetylcysteine 10 % four times a day 4.2.21. Perform debridement of filaments with a cotton-tip applicator, dry cellulose sponge, or a non -toothed forceps 4.2.22. Avoid treatment with contact lenses in patients with associated neurotrophic keratopathy 4.2.23. Perform thermal cautery if permanent punctal occlusion is to be accomplished.

4.2.24. Perform a stepwise punctal occlusion so that no more than one punctum is cauterized in each eye at a treatment session 4.2.25. Perform a limited tarsorraphy to decrease tear evaporation in patients with severe dry eye who have not responded to other therapies 4.2.26. Recommend Boston Scleral Contact lenses in treatment of severe dry eye

22 4.3. Provider & Setting 4.3.1. If you are a health care provider other than an ophthalmologist, refer patients with dry eye who have moderate or severe pain, lack of response to therapy, corneal infiltration or ulceration, or visual loss to an ophthalmologist 4.4. Counseling & Referral 4.4.1. Educate patients with dry eye about the chronic nature of the disease process and provide specific instructions for therapeutic regimens

4.4.2. Periodically reassess the patients’ compliance and understanding of the disease, the risks for associated structural changes and re inform the patient as necessary 4.4.3. Caution patients with pre-existing dry eye that kerato-refractive surgery, particularly LASIK may worsen their dry eye condition 4.4.4. Treat dry eye, when present, prior to considering kerato-refractive surgery 4.4.5. Refer patients with moderate to severe dry eye unresponsive to treatment or when

systemic disease is suspected to an ophthalmologist who is experienced in management of these entities 4.4.6. Refer patients with systemic immune dysfunction or those who require immunosuppressive therapy to an internist or rheumatologist Clinical Pathway 9- Treatment of Dry Eye Disease based on Level of Care

23 4.5 Recommendations for Prevention of Dry Eye Disease Suggest the following recommendations to those at risk of dry eye disease: 4.5.1 Avoid excessive movement and windy conditions 4.5.2. Avoid hot, dry environments since both heating and air conditioning can worsen dry eye disease 4.5.3. Use humidifier to keep the air moist. Adding moisture to the air reduces dry eye symptoms 4.5.4. Wear wrap around glasses to reduce effect of wind on ocular surface to reduce evaporative dry eye symptoms.

4.5.5. Recommend taking frequent breaks while reading, seeing television and using mobile phone or computer devices. 4.5.6. Position computer screen below eye level to reduce lid aperture and minimize tear evaporation 4.5.7. Recommend refraining from smoking and exposure to secondary smoke 4.5.8. Recommend use of hot compresses and eye massage 4.5.9. Recommend use of artificial tears and lubricating gels as soon as symptoms of dry eye disease appear

Standard Treatment Guidelines Snakebite June 2016 Directorate General of Health Services Ministry of Health and Family Welfare Government of India With Technical Support from National health Systems Resource Centre 1

Contents 1. THE NEED FOR STGs ................................................................................................................... 5 Snakebite is a neglected Tropical disease ....................................................................................... 5 Antivenoms are essential medicines .............................................................................................. 6

Determinants of snakebite incidence and severity of envenoming .............................................. 6 Existing variation in management of snakebite .............................................................................. 7 Classification of medically important species ............................................................................... 8 Sources of information on snakes .................................................................................................. 9

2. THE PURPOSE OF THE STG ............................................................................................................. 9 3. DECLARATION OF INTEREST ......................................................................................................... 10 4. THE FUNDING SOURCE ................................................................................................................. 10

5. THE SCHEDULED REVIEW ............................................................................................................. 10 6. SCOPE OF THE STG ....................................................................................................................... 10 7. LIST OF ALL RECOMMENDATIONS ................................................................................................ 11

8. METHODOLOGY .......................................................................................................................... 14 How the relevant guideline(s) were selected as source of recommendation ................................ 16 How recommendations were selected, adopted or adapted ........................................................ 18 9. STAGES OF MANAGEMENT .......................................................................................................... 26

10. FIRST AID TREATMENT GUIDELINES....................................................................................... 26 First aid: Bystanders/victim .......................................................................................................... 26 At the community or village level (Warrell 2010) ......................................................................... 27

At the PHC level ........................................................................................................................... 28 Important don’ts .......................................................................................................................... 29 Traditional methods to be discarded/ inappropriate methods ..................................................... 29

Tight Tourniquets ..................................................................................................................... 29 Pressure –immobilization ......................................................................................................... 31 Cutting and Suction .................................................................................................................. 32

Electrical Therapy and Cryotherapy .......................................................................................... 32 Traditional Remedies ............................................................................................................... 32 Role of Snake Stones and Scarification ..................................................................................... 33

11. TRANSPORT TO HOSPTIAL ..................................................................................................... 33 12. RECOMMENDATIONS ........................................................................................................... 34 Clinical features of snakebite ...................................................................................................... 34

Treatment in the dispensary or hospital ....................................................................................... 34 At a health care facility ................................................................................................................ 36 Asymptomatic (i.e., Non Venom Related Symptoms) .................................................................. 37

Dry Bite ........................................................................................................................................ 37 Symptomatic Patients .................................................................................................................. 37 Neuroparalytic (Progressive weakness; Elapid envenomation) ................................................. 37

Vasculotoxic (Haemotoxic or Bleeding) .................................................................................... 39 Locked-in syndrome (LIS) ......................................................................................................... 40 Life threatening complications ................................................................................................. 40 2

Systemic capillary leak syndrome ............................................................................................. 40 Painful Progressive Swelling (PPS) ............................................................................................ 41 Myotoxic .................................................................................................................................. 42

Occult Snakebite ...................................................................................................................... 42 Differential identification of type of snakebite based on the symptoms and signs .................... 43 CRITICAL ARRIVAL ........................................................................................................................ 44 Patient assessment: Non critical arrival and Critical patients after stabilization ........................... 46

Handling Tourniquets................................................................................................................... 47 Physical examination ................................................................................................................... 47 Examination of pregnant women ............................................................................................. 49

Diagnosis Phase: Investigations .................................................................................................... 49 20 Minute Whole Blood Clotting Test (20WBCT) ...................................................................... 49 Late-onset envenoming ............................................................................................................... 52

13. ANTI SNAKE VENOM (ASV) .................................................................................................... 52 Monovalent vs. Polyvalent ............................................................................................................... 53 ASV dosage forms ............................................................................................................................ 54

ASV administration ...................................................................................................................... 54 ASV Dosage .................................................................................................................................. 55 ASV dosage in victims requiring life saving surgery ...................................................................... 56

What can ASV Do and more importantly what can it NOT Do? ..................................................... 57 Swelling and ASV.......................................................................................................................... 58 Monitoring of Patients on ASV therapy ........................................................................................ 58

Victims who arrive late ................................................................................................................ 59 ASV and Pregnancy ...................................................................................................................... 59 ASV in Paediatric victims .............................................................................................................. 60

ASV in Repeat bites ...................................................................................................................... 60 ASV REPEAT DOSE ........................................................................................................................... 61 Adverse Anti Snake Venom Reactions .......................................................................................... 61

Mechanism of the Reaction ......................................................................................................... 62 Prediction of Adverse Reactions ................................................................................................... 62 Preventing Adverse Reactions ...................................................................................................... 63

Treatment of Adverse Reactions .................................................................................................. 64 Contraindications to antivenom & Prophylaxis of high risk patients ............................................. 65 Observation of the response to ASV ............................................................................................. 67 ASV in Recurrence of systemic envenoming ................................................................................. 68

14. NEUROTOXIC ENVENOMATION ............................................................................................. 69 Airway Support Items .................................................................................................................. 71 Bridging Devices........................................................................................................................... 72

The Ideal Solution ........................................................................................................................ 72 15. HAEMOTOXIC ENVENOMATION, BLOOD PRODUCTS AND RENAL IMPAIRMENT .................... 73 Persistent or Severe bleeding....................................................................................................... 74 Role of Anticoagulants ............................................................................................................. 74

Dangers of venipuncture in patients with haemostatic abnormalities ...................................... 74 Renal Failure ............................................................................................................................ 75 3

16. PAIN, WOUND MANAGEMENT AND THE SURGICAL ASPECTS OF SNAKEBITE ......................... 78 Pain and Wound Management .................................................................................................... 78 Antibiotics and Tetanus ............................................................................................................... 78 17. SNAKE VENOM OPHTHALMIA ............................................................................................... 79

Surgery and Snakebite ................................................................................................................. 79 Life Threatening Conditions Requiring Surgery ............................................................................. 80 Debridement of Necrotic Tissue ................................................................................................... 80

20.REHABILITATION ......................................................................................................................... 83 21. SNAKEBITE MANAGEMENT AT DIFFERENT LEVELS OF HEALTHCARE ...................................... 83 A. In basic or primary care facilities (PCF) ..................................................................................... 83 B. At a Primary health Care Center (PHC) ..................................................................................... 85

C. At the district hospital .............................................................................................................. 87 D. At the tertiary care or medical college ..................................................................................... 88 22.CONDITIONS AND EQUIPMENT ACCOMPANYING NEUROTOXIC REFERRAL ................................. 89 23.EQUIPPING A BASIC HOSPITAL FOR EFFECTIVE SNAKEBITE MANAGEMENT ................................. 89

Holding Quantities of ASV/ Stocks of ASV ........................................................................................ 90 24.SNAKEBITE PREVENTION & OCCUPATIONAL RISK ........................................................................ 91 25. PATIENT INFORMATION SHEET ............................................................................................. 91 ANNEXURE 1. SNAKE BITE EXAMINATION PERFORMA ..................................................................... 95

1. THE NEED FOR STGs Snakebite is an acute life threatening time limiting medical emergency (Kulkarni & Anees, 1994). It is a preventable public health hazard often faced by rural population in tropical and subtropical countries with heavy rainfall and humid climate (Warell DA 1992). The numbers of snakebite fatalities in India has long been controversial. There is a huge gap between the number of snakebite deaths reported from direct survey and official data. Only 7.23%

snakebite deaths were officially reported (Majumdar et al, 2014; Mohapatra et al, 2011). Earlier hospital based reports estimated about 1,300 to 50,000 annual deaths from snakebites per year in India. The registrar General of India’s Million Death Study 2001-2003 conducted to ascertain the cause of death based on interviews by medical personnel and social workers in over a million households in randomly selected locations around India. The Million Deaths Study reported 46,000

deaths by snakebite in India per year; non-fatal bites may be as high as 1.4 million per year (Mohapatra et al, 2011). This proportion represents about 45,900 annual snakebite deaths nationally or an annual age-standardized rate of 4.1/100,000, with higher rates in rural areas (5.4) and with the highest rate in the state of Andhra Pradesh (6.2). Annual snakebite deaths were greatest in the states of Uttar Pradesh (8,700), Andhra Pradesh (5,200), and Bihar (4,500). Other

Indian states with high incidence of snakebites cases are Tamil Nadu, West Bengal, Maharashtra and Kerala (Hati et al, 1992; Gaitonde et al, 2008). Because a large proportion of global totals of snakebites arise from India, global snakebite totals might also be underestimated. (Mohapatra et al, 2011). In a retrospective study conducted in one district of West Bengal only 22.19% of the snakebite victims attended the hospitals (Majumder et al, 2014). This is because even today most of the

victims initially approach traditional healers for treatment and many are not even registered in the hospital. Singh et al reported among the snakebite victims, about 60.76% received first aid at the site of incident, and 20.25% of them sought hospital care after consulting the traditional healers (ozhas, or mantrik and tandrik). Time lapsed for seeking hospital treatment was less than 4 h in 55.69% of the cases and more than 12 h in 7.59% of the cases. Most (41.79%) patients were

frightened, but no local or systemic symptoms had appeared when they reported the emergency (Singh A et al 2015). Although total number of bites may be more than 5-6 lakhs but only 30% are venomous bites. Snakebite is a neglected Tropical disease Though snakebite is a life threatening centuries old condition, it was included in the list of neglected tropical diseases by World Health Organization in the year 2009 (Warrell and WHO 2009; Bawaskar

HS, 2014). Since snakebite is an environmental, occupational and climatic hazard and mostly affect farmers, plantation workers, herdsmen, fishermen, snake restaurant workers and other food 5

producers, resulting in tens of thousands of deaths each year and chronic physical handicap in many cases (WHO, 2007; Williams, 2010; Warrell et al, 2013; Gutierrez et al 2013; Bawaskar 2014). Antivenoms are essential medicines The only specific antidotes to snake venoms are immunoglobulin antivenoms (Warrell, 2010) and are recognized as Essential medicines (19.2 Sera and immunolobulins WHO Essential Medicines List)

and should be included as Essential Medicines in the national and state Essential Medicines Lists Determinants of snakebite incidence and severity of envenoming The incidence of snakebites depends critically on the frequency of the contact between snakes and humans. Two seasonal peaks of snakebite incidence usually coincide with increases in agricultural activity or seasonal rains. Epidemic of snake bite may occur from heavy floods or water logging or

when the snakes’ habitat is invaded by a large workforce involved in road building. Bites may be inflicted in the home by peridomestic species such as Cobra which may live in roof spaces or under the floor and by Kraits which enter human dwellings at night in search of their prey and may bite people who move in their sleep. Most snake bites occur in rural areas, and more commonly among males than females except where the work force is predominantly female – tea and coffee picking and peaking at ages 15–29.

The risk of envenoming after bites by venomous snakes varies with the species but is on average only around 50%. Many bites are dry bites i.e., fangs though pierce the skin but no envenoming results due to either mechanical inefficiency of the venom apparatus striking at an angle or through clothing or voluntary retention of venom by the snake. Morbidity and mortality depends on the age and size of victim (children receive larger

envenomation relative to body size) as well as comorbid conditions such as elderly patients, anaemia, hypertension, diabetes mellitus and renal disease succumb more easily to snake venom (Alirol et al, 2010). In pregnant women, snakebite carries definite but unquantified risks to mother and foetus, mainly from bleeding and abortion (WHO 2015). Other factors affecting severity and outcome are listed in Table 1. Factors not contributing to outcome are size of the snake and time of

bite (day/night) (Warrell, 1999) Table 1. Factors contributing to severity and outcome in snakebite Factor Effect on outcome Exercise Exertion following snakebite has poor outcome due to enhanced systemic absorption of toxin 6

Factor Effect on outcome Individual Sensitivity of individual to venom (atopy or previous sensitization) modifies the sensitivity clinical picture Bite Bite number; depth of bite; dry bite; bite through clothes, shoes, or other characteristics protection; amount of venom injected; condition of fangs; fed / hungry snake and duration for which snake clings to the victim, all affect outcome Snake species Different species have different lethal dose, lethal period, and aggressiveness

Secondary Presence or absence of pathogenic organisms in the mouth of the snake infection Treatment Nature of first aid given and time elapsed before first dose of antivenom. Factors not contributing to outcome are size of the snake and time of bite (day/night). Do NOT ignore or dismiss bites by small snakes. They should be taken just as seriously as bites by large snakes of the same species (WHO, 2015). Venom of smaller, younger vipers may be richer in

some dangerous components such as those affecting hemostasis because of venom composition varies ontogenically with the snake’s age and size (Tun-Pe et al, 1995a). Existing variation in management of snakebite Currently, treatment quality is highly varied, ranging from good quality in some areas, to very poor quality treatment in others. Cobra bite leads to early death hence reported less in hospital statistics

as victim may not reach medical facility. The high fatality due to Krait bite is attributed to the non- availability of antisnake venom (ASV), delayed and inappropriate administration of ASV, lack of standard protocol for management and inexperienced doctors and non-availability of ventilator or bag and valve (Bawaskar et al, 2008). In India, there has always been a crisis of antivenom supply (Bawaskar et al, 2001) and non –availability of effective antivenom, poor potency, poor safety and

the absence of published preclinical or well-designed clinical trial data for Indian antivenoms are other concerns. On one hand there is shortage of ASV but on the other hand scarce ASV is being wasted due to excessive dosage of ASV in the absence of a Standard Treatment Guideline. Victims are not only misdiagnosed as - abdominal colic, and vomiting due to indigestion, appendicitis, stroke, head injury, ischemic heart disease, food poisoning, trismus, hysteria and Guillain-Barre´

syndrome but also subjected to unnecessary investigations including MRI scans of the brain and lumbar puncture thus causing undue delay in ASV therapy. Delayed administration of ASV or waiting until victim develops systemic manifestations i.e., a 6 h wait results in systemic envenoming and high fatality (Bawaskar et al, 2008). Moreover chance of snakebite death being missed are more than for deaths occurring from several

other causes. Thus recorded figures of snakebite deaths be regarded as under-estimates of the total fatality from this cause. Majority of the snakebites treatment has remained with the traditional, herbal or ayurvedic practitioners and thus majority of snakebite victims are not seen or recorded in the hospitals and dispensaries (Sharma et al 2004; Sharma et al 2005.). 7

The continuing inadequacies in the reporting of snakebite incidence, morbidity and mortality prompts the following recommendation (WHO 2015): Snakebite should be made a notifiable disease and death certification should use the specific International Classification of Disease Code 9 ICD code) T63.0 (Toxic effect of contact with venomous animals- snake venom and sea snake veno (ICD-10 version 2015 http:/apps.who.int/classifications/icd10/browse/2015/en#/T63.0) Classification of medically important species

The three major families of venomous snakes are the Elapidae, the Viperidae, and the Colubridae Hydrophiinae (Warrell, 2010). Elapidae (cobra, king cobra, krait, and coral snake): These snakes have heads that are of about the same width as their necks. The head is covered with large scales but lack loreal shields. Their pupils are round and they are oviparous. These snakes have grooved fangs that are short, fixed, and

covered by mucous membrane. Several species of cobra can spit their venom for one metre or more towards the eyes of perceived enemies. Venomous sea snakes have flattened paddle-like tails and their ventral scales are greatly reduced in size or lost. Viperidae (vipers): The head of a viper is triangular, wider than the neck, and has loreal shields. They have vertically elliptical pupils and are ovi-viviparous. Their fangs are long, movable, and

canalized like hypodermic needles. They are further subdivided into pit viper and pitless viper subfamilies. The Crotalinae (pit vipers) have a special sense organ, the pit organ, to detect their warm-blooded prey. This is situated between the nostril and the eye. Viperidae are relatively short, thick-bodied snakes with many small rough scales on the top (dorsum) of the head and characteristic patterns of coloured markings on the dorsal surface of the body. Hydrophiinae (sea snake):

Sea snakes are found in the vicinity of the seacoast. They have a small head and a flattened tail that helps them swim. Though venomous, they seldom bite. There are more than 2000 species of snakes in the world. About 300 species are found in India out of which 52 are venomous. and of these four “the Big Four”, namely common cobra (Naja naja), Russell’s viper (Dabiola russelii), saw-scaled viper (Echis carinatus) and common krait (Bungarus

caeruleus) are highly venomous and believed to be responsible for most of the venomous bites in 8

India (Warrell DA., 1999; Alirol et al, 2010). However, this assumption of great four, has led to non- identification of other venomous species which are going unnoticed and leading to deaths (Simpson 2007). But other species have now been proved important in particular areas, such as Naja oxian (North), N. Kaouthi (east), Hypnale hypnale (south-west coast and Western Ghats (Joseph et al, 2007), Echis carinatus sochureki (Rajasthan) (Kochar et al,2007) and Trimeresurus

(Craspedocephalus) malabaricus (Hassan District, Mysore). The recent discovery of the hump nosed pit viper, capable of causing life threatening symptoms has demonstrated this (Parikh 1996). This non-recognition has led the ASV manufacturers to produce antivenom only against these four species only (Simpson ID et al , 2007) Thus there is a need to abandon the old concept of “The Big Four” in order to determine all the medically significant species in India. Sources of information on snakes

There are many sources of information on the web on snakes inhabiting Indian continent, such as World Health Organization WHO Venomous snakes and antivenoms search interface : http://apps.who.int/bloodproducts/snakeantivenoms/database/snakeframeset.html: Indian Herpetological Society http://www.indianherps.org/ Clinical effects of envenoming by same species of snake are almost similar except a few regional variations. Kraits are active during night hours, often biting a person sleeping on floor bed.

Maximum Viper and Cobra bites occur during the day or early darkness, while watering the plantation or walking bare foot in grown grass or soybean crops. Snakes of Medical Significance Indian venomous snakes of medical significance have usually been regarded as only four species: Russell’s Viper, Saw Scaled Viper, Cobra and Krait. These species were believed to be causing all fatalities in India. However this concept has led to some serious problems:

1. ASV Manufacturers only produce antivenom against these species 2. The assumption that only ‘The ‘Big 4’ can cause serious symptoms and death has led to mis- identification of species. 3. Other deadly snakes may be going un-noticed and causing death and disability! The recent discovery of the Hump-nosed Pitviper as a species capable of causing life threatening symptoms has demonstrated this. In order to determine the actual list of medically significant species in India, the old concept of ‘The

Big Four’ is to be abandoned for a newer more flexible model that enables better classification of species. 2. THE PURPOSE OF THE STG 9

The guidelines are comprehensive covering first aid, transport to a health facility, initial assessment, diagnosis and management and are targeted at doctors, health officials (nurses, dispensers and community health workers) and first aid providers involved in dealing with snakebite victims. The guidelines aim to provide sufficient practical information to allow medically trained personnel to assess and treat patients with snakebites at different levels beginning with first aid, to management

at primary health care to tertiary care and referral centres. 3. DECLARATION OF INTEREST None 4. THE FUNDING SOURCE The development of the guidelines was supported from Ministry of Health & family Welfare through National Health System Resource Centre (NHSRC) in technical collaboration with National Institute of Heath and Care Excellence (NICE) International. 5. THE SCHEDULED REVIEW The review is scheduled after 2 years or earlier in case of any break through advance in therapy or

level of evidence for major recommendations 6. SCOPE OF THE STG The guidelines covers all clinical issues and aspects of management of snakebite including clinical features, community interventions measures (first aid, transport and referral criteria), snakebite diagnostic features, treatment with and with antisnake venom, snakebite complications and snakebite management in primary, community health care centres up to tertiary care. These

guidelines provide brief guidance about follow-up and rehabilitation of the snakebite victims. The guidelines also cover all populations and age groups including pregnant women. Though community education on snakebite is outside the terms of reference of this guideline but prevention of snakebite is an essential component of any community education programme it is covered as part of the patient education leaflet. These guidelines do not cover detailed management of complications of snakebite such as

hypotension, shock, dissemination intravascular coagulopathy, acute kidney injury, detailed ICU care as well as management of chronic complications of snakebite due to restrictions on the length of this document. 10

7. LIST OF ALL RECOMMENDATIONS 1. First aid and transport i. Quick transport to Hospital in an ambulance equipped with transport ventilator. Situational adaptation; Ambulance with Transport ventilators are ideal, but very rarely available in Rural India, Recommendation may DELAY transfer to Base Hospital. The patient must be quickly transported to a place where they can receive medical care (dispensary or hospital) as quickly, but as safely, passively and comfortably, as possible. Any movement especially

movement of the bitten limb, must be reduced to an absolute minimum to avoid increasing the systemic absorption of venom. Motorbike is a practical alternative especially in rural areas for rapid transport but third person must sit behind the patient to support on bike. ii. If ASV available must be administered in appropriate dose before shifting victim to higher centre. iii. Immobilization of the bitten limb with situational adaptation in case splint for

immobilization is not available use bandages or cloth to hold the splints (wooden stick), but do NOT block the blood supply or apply pressure. iv. Tight (arterial) Tourniquets should NOT be used for snakebite first aid as it may cause gangrenous limbs. Situational adaptation v. Pressure immobilization (Sutherland method) modified in case victim is expected to reach the hospital in more than 30 minutes but less than 3 hours crepe bandage may be applied by

qualified medical personnel only till the patient is shifted to the hospital. The bandage is wrapped over the bitten area as well as the entire limb with the limb placed in a splint. It should be capable of admitting a finger beneath it. If trained personnel is not present, Must not be tried) vi. Release of tight bands, bandages and ligatures: In case of venomous envenomation, tourniquet/light band, bandages/ligatures should be removed only after patient has reached

the hospital, medical staff and resuscitation facilities are available and antisnake venom has been started in the presence of the doctor by the bedside of the patient and keep Atropine Neostigmine injection ready. vii. If envenomation is confirmed on local examination and bite is non-venomous tourniquet, if any can be removed after establishing IV line. In case of multiple ligatures, all the ligatures can be released in Emergency Room with doctor on the bed side of the patient EXCEPT the

most proximal one; which should only be released after admission and all preparations for resuscitation facilities are available and antivenom treatment has been started. Expert consensus - viii. Avoid any interference with the bite wound (incision, rubbing, vigorous cleaning, massage, application of herbs or chemicals) ix. Electrical therapy has no role in snakebite first aid and cryotherapy may do more harm x. No role of black stones and scarification No role of Traditional Remedies

xi. No role of local ASV 2. Diagnosis of snake bite i. 20 WBCT Added Accepting that the 20WBCT may remain negative (clotting) in patients with evolving venom-induced DIC, the test should be repeated frequently and antivenom 11

treatment should not be delayed if there is other evidence of anti-haemostatic disturbances (e.g., spontaneous systemic bleeding distant from the bite site. Added- frequency of 20 WBCT specified. If clotted, the test should be carried out every 1 h from admission for three hours and then 6 hourly for 24 hours. In case test is non-clotting, repeat 6 hour after administration of loading dose of ASV ii. In case where the 20WBCT result is inconsistent with the patients’ clinical condition,

normal control blood is used for comparison. 3. Management of snakebite i. Resuscitation: Adapted as per American Heart Association Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care 2015: CABDE approach ii. Removal of tourniquet- If envenomation is confirmed on local examination and bite is non- venomous, tourniquet, if any can be removed after establishing IV line in the presence of the doctor. In case of multiple ligatures, all the ligatures can be released in Emergency Room

EXCEPT the most proximal one; which should only be released after admission and all preparations. iii. Antivenom treatment should not be delayed if there is other evidence of spontaneous systemic bleeding distant from the bite site. In case test is non-clotting, repeat 6 hour after administration of loading dose of ASV. In case of neurotoxic envenomation repeat clotting test after 6 hours. Expert Consensus in case with a history of Bite; known or unknown, if there

is spontaneous abnormal bleeding beyond 20 minutes from time of bite, ASV is to be started, do NOT wait for 20 WBCT report. iv. REPEAT dose of ASV should also be given if abnormal bleeding does not stop one hour after completion of 1st 10 vials. v. A trial of anticholinesterase (“AN test”) should be performed in every patient with neurotoxic envenoming, as it would be in any patient with suspected myasthenia gravis. However, this

should not delay antivenom treatment or endotracheal intubation. Patients must be observed closely as they may deteriorate while the trial of anticholinesterase is being carried out. vi. Added criteria for continuing or stopping Stop Atropine Neostigmine (AN) dosage schedule if: vii. Patient has complete recovery from neuroparalysis. Rarely patient can have recurrence, carefully watch patients for recurrence. viii. Patient shows side effects in the form of fasciculations or bradycardia.

ix. If there is no improvement after 3 doses. x. No response to 3 doses of AN test Adapted In case of no improvement after 3 doses of atropine neostigmine, indicating probable Krait bite. Krait affects pre-synaptic fibres where calcium ion acts as neurotransmitter. Give Inj. Calcium gluconate 10ml IV (in children 1-2 ml/kg (1:1 dilution) slowly over 5-10 min every 6 hourly and continue till neuroparalysis recovers which may last for 5-7 days.

4. Differential identification of type of snakebite based on the symptoms and signs Identification of the type of snake should not hold the treatment though to a large extent the manifestation of snakebite depends upon the species of snake. Take One smart phone photograph of the snake, dead or alive, if available, for confirmation by an expert. 5. Routine use of ASV to any patient claiming to have bitten by a snake should be strongly

discouraged as they expose patients who may not need treatment to the risks of antivenom reactions. Adopted and added the patient may have reaction to any horse serum preparation 12

like antirabies immunoglobin sensitizing patient to any future use of Horse serum product; they also waste valuable and scarce stocks of antivenom. 6. For vasculotoxic snakebite - Two regimens low dose infusion therapy and high dose intermittent bolus therapy can be used. Adopted Low dose infusion therapy is as effective as high dose intermittent bolus therapy and also saves scarce ASV doses. 7. ASV Therapy and maximum dose of ASV

i. Max dose of ASV for neuroparalytic snakebite – ASV 10 vials stat as infusion over 30 minutes followed by 2nd dose of 10 vials if no improvement within 1st hour. Repeat 2nd dose even after 2-3 hours; if relapse of signs of Neurotoxicity is noted; may be due to delayed absorption). Expert consensus. ii. In vasculatoxic envenomation - Envenomation by the Hump-nosed Pit viper does not respond to normal Indian polyvalent ASV and coagulopathy may continue for up to 3

weeks. If 30 vials of ASV have been administered reconsider whether continued administration of ASV is serving any purpose, particularly in the absence of proven systemic bleeding. If large doses have been administered and the coagulation abnormality persists, give fresh frozen plasma (FFP) or cryoprecipitate (fibrinogen, factor VIII), fresh whole blood, if FFP not available 8. Criteria for repeat dose of ASV- Persistence or recurrence of blood coagulability after 6 h or

of bleeding after 1-2 h and deteriorating neurotoxic or cardiovascular signs after 1-2 hours. 9. Dose in children and pregnancy Snakes inject the same dose of venom into children and adults. Children and pregnant women must therefore be given exactly the same dose of antivenom as adults. 10. Skin and conjunctival “hypersensitivity” tests should not be used. 11. Routine use of prophylactic adrenaline is recommended before ASV, except in known

hypertensive, and if patient presents with blood pressure more than 140/90 in adult victims or if evidence of suspicion of underlying cardiovascular disease. The adult dose of adrenaline (epinephrine) is 0.25 mg of 0.1% solution by subcutaneous injection (Children 0.005 mg/kg body weight of 0.1% solution). i. Use of histamine, anti-H1 and anti-H2 blockers, corticosteroids and the rate of intravenous infusion of antivenom between 10 and 120 minutes), do not affect the

incidence or severity of early antivenom reactions. ii. There is no absolute contraindication to antivenom treatment, but patients who have reacted to horse (equine) or sheep (ovine) serum in the past (for example, after treatment with equine anti-tetanus serum, equine anti-rabies serum or equine or ovine antivenom) and those with a strong history of atopic diseases (especially severe asthma) are at high risk of severe reactions and should therefore be given antivenom only if they

have signs of systemic envenoming. 12. Severe Hypersensitivity reaction to ASV For high risk patients i. In patients with history of hypersensitivity or exposure to animal serum such as equine ASV, tetanus-immune globulin or rabies-immune globulin in past, severe atopic conditions: ii. Give ASV only if they have signs of systemic envenoming. iii. Subcutaneous epinephrine (adrenaline) 0.25 mg of 0.1% solution to be given just before antivenom treatment is started 13

iv. Give Inj. Hydrocortisone 200 mg and Chlorpheniramine maleate 22.75 mg prior to the administration of ASV. 13. No Role of anticoagulants and coagulants in vasculotoxic envenomation 14. Criteria for fasciotomy in snake-bitten limbs i. Haemostatic abnormalities should be corrected (antivenom with or without clotting factors) ii. Clinical evidence of an intracompartmental syndrome iii. Intracompartmental pressure >40 mmHg (in adults)

iv. Early treatment with antivenom remains the best way of preventing irreversible muscle damage.In any case, fasciotomy should not be contemplated until haemostatic abnormalities have been corrected, otherwise the patient may bleed to death. Intra- compartmental pressure >40 mmHg of normal saline (in adults). This can be confirmed by vascular Doppler and rising CPK in thousands. Bedside Compartment pressure measurement procedure.

15. Management of snake bite patients at basic or Primary healthcare facilities Adapted – referral criteria added - referral to a higher centre depending on availability of ASV, ventilation facility, hemodialysis facility and infrastructure. 16. Equipping a Basic Hospital for Effective Snakebite Management 8. METHODOLOGY An Indian guideline on the management of snakebite has been evolved through intensive discussions and workgroups amongst 12 invited experts from India, plus a review and discussion of

relevant research publications and papers (list of experts enclosed). The invited experts comprised a select group of professionals drawn from the fields of clinical medicine, toxicology, & pharmacology. The participants came from a wide variety of leading institutions, States, representing different levels of healthcare in the public as well as private sector. Facilitator Dr. Sangeeta Sharma, Professor & Head, Department of Neuropsychopharmacology Institute of Human Behaviour and Allied Sciences, Delhi

Co-Facilitator Dr. Ashoo Grover Scientist , Indian Council for Medical Research , New Delhi Expert Dr. D. B. Kadam Professor & Head, Dept. of Medicine, B. J. Medical College, Pune Dr. Himmat Bawaskar, Bawaskar Hospital & Research Centre, Raigad, 14

Maharashtra Dr. Dayal Bandhu Majumdar Senior MO, National Medical College, Kolkata Dr. S. Ragunanthanan Professor & Head Poison Centre, Madras Medical College Dr. Arvind Mathur Professor , Jhodhpur Medical College Dr. Rakesh Lodha Additional Professor, Paediatrics, AIIMS, New Delhi Dr. Anurag Agrawal Assistant Professor, Paediatrics, MAMC, New Delhi Dr. J. N. Srivastava Advisor, Quality Improvement, NHSRC Physician Dr. Rajiv Kapil Consultant Physician, Lal Bahadur Shastri Hospital, Delhi

Private Practitioner Dr. Sadanand Raut Vighnahar Nursing Home, Narayangaon, Pune Paramedic Mrs. Sunita Bisht, /Nurse/Rehabilitation ICU Nurse, GTB Hospital Delhi Experts Primary Care Dr. Sanjay Bajaj, Practitioners SMO, State Health Services, Himachal Pradesh ASV Manufacturer Dr. M.V. Khadilkar Premium Laboratories, Pune Project Dr. Nikhil Prakash Manager/Quality Senior Consultant, Quality Improvement, NHSRC Professional

The guidelines have been reviewed by experts having ground experience of handling snakebite cases including those from Indian Society of Toxicology and manufacturer of the antisnake venom. 1. Dr Jeevan Kuruvilla, Gandhi Health Centre, Bardwah 2. Dr Omesh Bharti, Government of Himachal Pradesh 3. Dr DP Punde, Senior Physician, Punde Hospital, Nanded, Maharashtra 4. Dr Joseph K Joseph, President Toxicological Society of India, Kochi 5. Dr VK Himgire, Nanded

The guidelines have also been reviewed by Global Snakebite Initiative (GSI) group. The Global Snakebite Initiative is an internationally-active non-profit organisation, registered in Australia, and led by snakebite experts who are dedicated to improving access to good quality, robustly tested, safe, effective antivenoms in the world’s poorest communities. 15

How the relevant guideline(s) were selected as source of recommendation Much of snakebite treatment is not based on clinical trials as very few have been carried out by experts in the past. Although it is desirable to have good quality evidence from clinical trials in support of the recommendations made for the management of snakebite. Feasibility of conducting randomized controlled trials (RCT) to assess the comparative efficacy of various treatment options

in snakebite is limited. Yet at the same time there is an urgent need for recommendations on snakebite since waiting for a good quality evidence before publication of the guidelines would be neither helpful nor realistic as meanwhile snakebite victims would continue to die in absence of good effective first aid and guidelines on use of antisnake venom (i.e., indications, dosage etc). Moreover victim first reach the primary health centre, the medical officer who never treated

snakebite victims earlier is in-charge of the health facility, therefore, standard treatment guidelines and practical training of the doctors in providing first aid and early management of snakebite is urgently required. Search for existing guidelines on snakebite was conducted through Pub med and grey literature and the following guidelines for management of snakebite were identified: Available guidelines and Selected guidelines Rationale for selection of source articles in the literature for

adoption/adaptation of recommendations 1. A2 Snakebite • Recent guidelines Management in Asia & • Pertinent to Asian region Africa Guidelines • Developed based on syndromic produced by: Pakistan approach based on available Medical Research Evidence Council, Pakistan Medical Association; National Program for Family Planning and Primary Health Care and Indian Journal of Emergency Pediatrics, 2011. 2. Guidelines for the Pertinent to Asian region based on management of snake- available evidence

bites by Warrell, David A. World Health Organization 2010. 3. Guidelines for the clinical • Currency of the guidelines management of • Pertinent to Asian region based 16

snakebite in the South on available evidence East Asian Region, 2015 (Draft 4. A Module on the • Recent State specific guidelines “Management of Snake (West Bengal) Bite Cases” For Medical • Based on syndromic approach Officers. Developed By • Adopted/adapted to Indian PUBLIC Health Branch Of situation The Directorate Of Health Services & Institute Of Health & Family Welfare Kolkata. Department Of Health & Family Welfare. Government of West Bengal. 5. Handbook on Treatment Guidelines For Snake Bite

And Scorpion Sting 2008 - TNHSP Publication. Tamil Nadu Health Systems Project Health and Family Welfare Department, Government of Tamil Nadu, Chennai. 6. Surjit Singh and Gagandeep Singh. Snake Bite: Indian Guidelines and Protocol. Page 424- 428 7. Draft national snakebite • Draft guidelines developed by management Protocol. multidisciplinary expert group Dte General of Health • Pan India specific based on Services. Ministry of available evidence Health and family adopted/adapted to Indian

Welfare. Government of India 2009 developed situation with technical support form WHO Country Office, India. 8. Snakebite & Spider bite For management followed Clinical Management identification of snake approach Guidelines. Nsw Ministry Of Health 2014. Third 17

Edition 9. Syed Moied Ahmed, Mohib Ahmed, Abu Nadeem, Jyotsna Mahajan, Adarash Choudhary, and Jyotishka Pal. Emergency treatment of a snakebite: Pearls from literature J Emerg Trauma Shock. 2008 Jul-Dec; 1(2): 97– 105. doi: 10.4103/0974- 2700.43190. 10. High Dose versus low- dose antivenom in the treatment of poisonous snakebites: A systematic review. Rashmi Ranjan Das, Jhuma Sankar, Nishanth Dev. IJCCM 2015; 19: 340-349. How recommendations were selected, adopted or adapted

Recommendations given in draft national guidelines, Warrell 2010, WHO draft 2015 and A2 snakebite management in Asia and Africa guidelines are largely adopted following deliberations of the group of experts Diagnosis of the species of snake responsible for the bite is important for optimal clinical management which could be achieved by identifying dead snake or by inference from the “clinical syndrome” of envenoming. In the draft national guidelines (2009) the line of

treatment were largely decided on the basis of the identification of the snake (Elapid or Viperine). The expert group decided to develop guidelines largely focusing on the syndromic approach since catching of snake is not only dangerous but also may cause undue delay in approaching medical care besides identification of snake requires skills which may not be available at the lower levels of health care. Moreover, neither bite marks nor clinical manifestations may correlate with the

species of snake brought as evidence. Lastly there may be overlapping of the symptoms of envenomation. Symptoms and signs vary according to the species of snake responsible for the bite and the amount of venom injected. The Guideline Development Group recognises the limitations of syndromic approach though as more careful study of the clinical effects of snakebites shows that the range of activities of particular venom is very wide. For example some elapid venoms such as those of Asian

Cobra, can cause severe local envenoming formerly thought to be an effect only of viper venoms. 18

Also Russell’s viper venom cause paralytic signs suggesting elapid neurotoxicity and muscle pains and dark brown urine suggesting sea snake rhabdomyolysis. There may be a considerable over lap of clinical features on presentation still a “Syndromic approach” may still be useful, especially when the snake has not been identified. Management of snakebite Remarks First aid and transport Quick transport to Hospital in an WHO 2015 Adapted – situational adaptation

ambulance equipped with transport Ambulance with Transport ventilators are ventilator ideal, but very rarely available in Rural India, Recommendation may DELAY transfer to Base Hospital. The patient must be quickly transported to a place where they can receive medical care (dispensary or hospital) as quickly, but as safely, passively and comfortably, as possible. Any movement especially movement of the bitten limb, must be reduced to an absolute minimum to avoid increasing the systemic absorption of venom.

Motorbike is a practical alternative especially in rural areas for rapid transport but third person must sit behind the patient to support on bike. If ASV available must be administered in appropriate dose before shifting victim to higher centre. Immobilization of the bitten limb WHO 2015 Adapted – situational adaptation in case splint for immobilization is not available use bandages or cloth to hold the splints (wooden stick), but do NOT block the blood supply or apply pressure.

Tight (arterial) Tourniquets should NOT WHO 2015 Situational adaptation be used for snakebite first aid as it may Pressure immobilization (Sutherland cause gangrenous limbs. method) modified in case victim is expected to reach the hospital in more than 30 minutes but less than 3 hours crepe bandage may be applied by qualified medical personnel only till the patient is shifted to the hospital. The bandage is wrapped over the bitten area as well as the entire limb with the limb placed in a splint.

beneath it. If trained personnel is not present, Must not be tried) Release of tight bands, bandages and WHO 2015 Adapted. In case of venomous ligatures – ideally these should not be envenomation, tourniquet/light band, released until the patient is under bandages/ligatures should be removed only medical care in hospital, hospital staff after patient has reached the hospital, and resuscitation facilities are available medical staff and resuscitation facilities are

and antivenom treatment has been available and antisnake venom has been started. started in the presence of the doctor by the bedside of the patient and keep Atropine Neostigmine injection ready. Expert consensus - If envenomation is confirmed on local examination and bite is non-venomous tourniquet, if any can be removed after establishing IV line. In case of multiple ligatures, all the ligatures can be released in Emergency Room with doctor on the bed side of the patient EXCEPT the most

proximal one; which should only be released after admission and all preparations for resuscitation facilities are available and antivenom treatment has been started. Avoid any interference with the bite A2, Adopted wound (incision, rubbing, vigorous WHO 2015 cleaning, massage, application of herbs or chemicals) Electrical therapy has no role in snakebite first aid and Cryotherapy may do more harm No role of black stones and scarification No role of Traditional Remedies No role of local ASV WHO 2015 Adopted

Presentation and examination of snakebite victims Examination of Pregnant women WHO 2015 Adopted Signs and Symptoms of Snakebite A2, WHO Adapted – signs and symptoms have been Asymptomatic/non venom related 2015 arranged in order of appearance to guide symptoms of snake bite the treating doctors in diagnosis and monitoring of the patient. Diagnosis of snake bite 20 WBCT WHO 2015 Added- frequency of 20 WBCT specified. If 20

Accepting that the 20WBCT may clotted, the test should be carried out every remain negative (clotting) in patients 1 h from admission for three hours and then with evolving venom-induced DIC, the 6 hourly for 24 hours. In case test is non- test should be repeated frequently and clotting, repeat 6 hour after administration antivenom treatment should not be of loading dose of ASV delayed if there is other evidence of anti-haemostatic disturbances (e.g., spontaneous systemic bleeding distant

from the bite site. In case where the 20WBCT result is Adopted inconsistent with the patients’ clinical condition, normal control blood is used for comparison. Management of snakebite ABCDE approach WHO 2015 Adapted as per American Heart Association Airway Guidelines for cardiopulmonary Breathing (respiratory movements) resuscitation and emergency Circulation (arterial pulse) cardiovascular care 2015 Disability of the nervous system (level CABDE approach of consciousness) Circulation (arterial pulse)

Exposure and environmental control Airway (protect from cold etc.) Breathing (respiratory movements) Disability of the nervous system (level of consciousness) Exposure and environmental control (protect from cold etc.) In case of venomous envenomation, WHO 2015 Adapted - If envenomation is confirmed on tourniquet should be removed only local examination and bite is non- after completion of loading dose of venomous, tourniquet, if any can be

ASV in the presence of the doctor. removed after establishing IV line in the presence of the doctor. In case of multiple ligatures, all the ligatures can be released in Emergency Room EXCEPT the most proximal one; which should only be released after admission and all preparations. Antivenom treatment should not be Expert Consensus in case with a history of delayed if there is other evidence of Bite; known or unknown, if there is spontaneous systemic bleeding distant spontaneous abnormal bleeding beyond 20

from the bite site. In case test is non- minutes from time of bite, ASV is to be clotting, repeat 6 hour after started, do NOT wait for 20 WBCT report. administration of loading dose of ASV. REPEAT dose of ASV should also be given if In case of neurotoxic envenomation abnormal bleeding does not stop one hour repeat clotting test after 6 hours. after completion of 1st 10 vials. 21

A trial of anticholinesterase (“AN test”) WHO 2015 Adopted. Added criteria for continuing or should be performed in every patient stopping Stop Atropine Neostigmine (AN) with neurotoxic envenoming, as it dosage schedule if: would be in any patient with suspected 1. Patient has complete recovery from myasthenia gravis. However, this neuroparalysis. Rarely patient can have should not delay antivenom treatment recurrence, carefully watch patients for or endotracheal intubation. Patients recurrence.

must be observed closely as they may 2. Patient shows side effects in the form of deteriorate while the trial of fasciculations or bradycardia. anticholinesterase is being carried out. 3. If there is no improvement after 3 doses. No response to 3 doses of AN test Adapted In case of no improvement after 3 doses of atropine neostigmine, indicating probable Krait bite. Krait affects pre- synaptic fibres where calcium ion acts as neurotransmitter. Give Inj. Calcium gluconate 10ml IV (in children 1-2 ml/kg (1:1

dilution) slowly over 5-10 min every 6 hourly and continue till neuroparalysis recovers which may last for 5-7 days. Differential identification of type of WHO 2015 Identification of the type of snake should snakebite based on the symptoms and not hold the treatment though to a large signs extent the manifestation of snakebite depends upon the species of snake, unfortunately, • Catching of snake is not only dangerous • Undue delay in approaching medical care • Identification of snake requires skills

• Neither bite marks nor clinical manifestations may correlate with the species of snake brought as evidence. • Overlapping of the symptoms of envenomation. • Take One smart phone photograph of the snake, dead or alive, if available, for confirmation by an expert. Routine use of ASV to any patient WHO 2010 Adopted and added the patient may have claiming to have bitten by a snake reaction to any horse serum preparation should be strongly discouraged as they like antirabies immunoglobin sensitizing

expose patients who may not need patient to any future use of Horse serum treatment to the risks of antivenom product; they also waste valuable and reactions scarce stocks of antivenom. 22

For vasculotoxic snakebite - Two WHO 2015 Adapted. Low dose infusion therapy is as regimens low dose infusion therapy effective as high dose intermittent bolus and high dose intermittent bolus therapy and also saves scarce ASV doses. therapy can be used. ASV Therapy and maximum dose of WHO 2015 Expert consensus. Max dose of ASV for ASV neuroparalytic snakebite – ASV 10 vials stat Not specified in WHO SEARO 2015 as infusion over 30 minutes followed by 2nd

document. mentions “….Medical dose of 10 vials if no improvement within 1st personnel must usually rely in hour. Repeat 2nd dose even after 2-3 hours; manufacturers’ recommendations if relapse of signs of Neurotoxicity is noted; stated in the package insert. may be due to delayed absorption). In vasculatoxic envenomation - Envenomation by the Hump-nosed Pit viper does not respond to normal Indian polyvalent ASV and coagulopathy may continue for up to 3 weeks. If 30 vials of ASV

have been administered reconsider whether continued administration of ASV is serving any purpose, particularly in the absence of proven systemic bleeding. If large doses have been administered and the coagulation abnormality persists, give fresh frozen plasma (FFP) or cryoprecipitate (fibrinogen, factor VIII), fresh whole blood, if FFP not available Criteria for repeat dose of ASV WHO 2015 Adopted Persistence or recurrence of blood coagulability after 6 h or of bleeding after 1-2 h and deteriorating

neurotoxic or cardiovascular signs after 1-2 hours. Snakes inject the same dose of WHO 2015 Adopted venom into children and adults. Children must therefore be given exactly the same dose of antivenom as adults. Skin and conjunctival WHO 2010 & Adopted “hypersensitivity” tests should not 2015 be used. Routine use of prophylactic WHO 2015 Adopted adrenaline is recommended before 23

ASV, except in known hypertensive, and if patient presents with blood pressure more than 140/90 in adult victims or if evidence of suspicion of underlying cardiovascular disease. The adult dose of adrenaline (epinephrine) is 0.25 mg of 0.1% solution by subcutaneous injection (Children 0.005 mg/kg body weight of 0.1% solution). Use of histamine, anti-H1 and anti-H2 WHO 2015 Adopted blockers, corticosteroids and the rate of intravenous infusion of antivenom between 10 and 120 minutes), do not

affect the incidence or severity of early antivenom reactions. There is no absolute contraindication WHO 2015 Adapted Added history of reaction to to antivenom treatment, but patients treatment with equine anti-tetanus serum who have reacted to horse (equine) or and antirabies immunoglobin, equine anti- sheep (ovine) serum in the past (for rabies serum or equine or ovine antivenom) example, after treatment with equine anti-tetanus serum, equine anti-rabies serum or equine or ovine antivenom)

and those with a strong history of atopic diseases (especially severe asthma) are at high risk of severe reactions and should therefore be given antivenom only if they have signs of systemic envenoming. Severe Hypersensitivity reaction to Expert consensus - Desensitization ASV procedure only in case of severe For high risk patients anaphylaxis reaction with shock and In patients with history of generalised anasarca after injection of very

hypersensitivity or exposure to animal few ml of ASV usually less than 5 ml of serum such as equine ASV, tetanus- diluted ASV despite reaction occurring after immune globulin or rabies-immune prophylaxis of adrenaline. globulin in past, severe atopic Change the batch of ASV conditions: 1. Give ASV only if they have signs of systemic envenoming. 2. Subcutaneous epinephrine (adrenaline) 0.25 mg of 0.1% solution to be given just before antivenom treatment is started 24

3. Give Inj. Hydrocortisone 200 mg and Chlorpheniramine maleate 22.75 mg prior to the administration of ASV. No Role of anticoagulants and A2, WHO Adopted coagulants in vasculotoxic 2015 envenomation Minimize the risk of renal damage WHO 2015 Adopted from excreted myoglobin and/or haemoglobin Pain and wound management A2 and WHO Adopted 2015 Snake venom Ophthalmia A2 and WHO Adopted 2015 Criteria for fasciotomy in snake-bitten A2, WHO Adopted. There is little objective evidence

limbs (WHO) 2015 that the intracompartmental pressure due • Haemostatic abnormalities to snakebite in India, ever reaches the have been corrected prescribed limit for a fasciotomy. Very (antivenom with or without limited trial data has tended to confirm this. clotting factors) In a small case study in India, using a Stryker • Clinical evidence of an monitor, despite grossly swollen limbs, intracompartmental syndrome which matched the 6Ps, only one case from

• Intracompartmental pressure 12 achieved an intracompartmental >40 mmHg (in adults) pressure where fasciotomy would be Early treatment with antivenom considered. By the time coagulation was remains the best way of preventing restored in the victim, the irreversible muscle damage. intracompartmental pressure had reduced to normal levels. In any case, fasciotomy should not be WHO 2015 Adopted contemplated until haemostatic abnormalities have been corrected, otherwise the patient may bleed to death.

Intra-compartmental pressure >40 WHO 2015 Adopted. Bedside Compartment pressure mmHg of normal saline (in adults). measurement procedure given in case This can be confirmed by vascular Insert a 16 no. needle in the suspected Doppler and rising CPK in thousands. compartment at a depth of 1 cm and connect to a simple tubing irrigated with normal saline. Measure rise in the saline column in the tubing. A rise more than 40 cm of saline corresponds to 30mm Hg of lymphatic/ capillary pressure and is 25

suggestive of compartment pressure. This necessitates fasciotomy procedure. Management of snake bite patients at WHO 2015 Adapted – referral criteria added - referral basic or Primary healthcare facilities to a higher centre depending on availability of ASV, ventilation facility, hemodialysis facility and infrastructure. Equipping a Basic Hospital for Effective A2 Adopted Snakebite Management 9. STAGES OF MANAGEMENT The following steps or stages are often involved: Management of snakebite

• First aid treatment • Transport to hospital • Rapid clinical assessment and resuscitation • Investigations/laboratory tests • Clinical assessment and species diagnosis, if possible • Antivenom treatment • Observing the response to antivenom • Deciding whether further dose(s) of antivenom are needed • Supportive/ancillary treatment • Treatment of the bitten part • Follow-up • Rehabilitation 10. FIRST AID TREATMENT GUIDELINES First aid: Bystanders/victim

Snakebite first aid remains a critical part of snakebite management to enable them to reach the nearest medical facility in the best possible condition and yet a lack of clarity and attention to the evidence has resulted in little positive progress (Simpson, 2008). Much of the first aid currently carried out is ineffective and dangerous (Simpson, 2006). Historical and newer methods continue to hold sway when evidence has either rejected them or shown they have little merit. Untrained

personnel usually apply first aid in the immediate aftermath of snakebite. It is essential therefore that first aid advice is clear, simple to apply and provide the maximum benefit and least time delay The following methods are recommended keeping in view the available evidence and concluded that other methods are not appropriate for the conditions in India. 26

Principles of first-aid First-aid treatment is carried out immediately or very soon after the bite, before the patient reaches a dispensary or hospital. It can be performed by the snake-bite victim himself/herself or by anyone else who is present and able. Aims of first-aid • Attempt to retard systemic absorption of venom. • Preserve life and prevent complications before the patient can receive medical care • Control distressing or dangerous early symptoms of envenoming.

• Arrange the transport of the patient to a place where they can receive medical care. ABOVE ALL, AIM TO DO NO HARM! Provide first-aid measures, supportive measures immediately. Observe for signs of envenomation. Administer ASV therapy as soon as there is evidence of envenomation. At the community or village level (Warrell 2010) 1. Check history of snakebite and look for obvious evidence of a bite (fang puncture marks,

bleeding, swelling of the bitten part etc.). However, in krait bite no local marks may be seen. It can be noted by magnifying lens as a pin head bleeding spot with surrounding rash. 2. Reassure the patient as around 70% of all snakebites are from non-venomous species. Control anxiety as excitement will increase heart rate and lead to spread of venom. 3. Immobilize the limb in the same way as a fractured limb. Use bandages or cloth to hold the

splints (Any rigid object may be used as a splint. e.g. spade, piece of wood or tree branch, rolled up newspapers, ruler etc.), but do NOT block the blood supply or apply pressure. Splint should extend the entire length of the limb, immobilizing all of the joints of the limb. Ideally the patient should lie in the recovery position (prone, on the left side) with his/her airway protected to minimize the risk of aspiration of vomitus. 4. Nil by mouth till victim reaches a medical health facility. 27

5. Traditional remedies have NO PROVEN benefit in treating snakebite. 6. Shift the victim to the nearest health facility (PHC or hospital) immediately. 7. If ASV available must be administered in appropriate dose before shifting victim to higher centers. 8. The patient must be quickly transported to a place where they can receive medical care (dispensary or hospital) as quickly, but as safely, passively and comfortably, as possible. Any

movement especially movement of the bitten limb, must be reduced to an absolute minimum to avoid increasing the systemic absorption of venom. Ambulance with Transport ventilators are ideal, but very rarely available in Rural India, therefore, waiting for an ideal ambulance may DELAY transfer to a hospital. Motorbike is a practical alternative especially in rural areas for rapid transport but third person must sit behind the patient to support on bike.

Victim must not run or drive himself to reach a Health facility. Motorbike Ambulance may be a practical alternative for rural India where no other transport is available. 9. No time should be wasted in attempting to kill or capture the snake. This solely wastes time and can lead to other victims However, if the snake has already been killed, it should be taken with the patient to the dispensary or hospital for identification by the doctor.

However, do not handle the snake with your bare hands as even a severed head can bite! (WHO, A2) At the PHC level 1. Secure IV line in PHC itself and use normal saline to keep iv access open. Start fluids if patient is in shock. 2. If possible PHC medical officer can accompany with patient to know the progress and management and treat shock and cardiopulmonary resuscitation (CPR) on the way. 3. Inform the doctor of any symptoms such as progress of swelling, ptosis or new symptoms 28

that manifest on the way to hospital. 4. Remove shoes, rings, watches, jewellery and tight clothing from the bitten area as they can act as a tourniquet when swelling occurs. 5. Leave the blisters undisturbed. Important don’ts Do not attempt to kill or catch the snake as this may be dangerous. As far as the snake is concerned - do not attempt to kill it as this may be dangerous. If possible to take a picture of the snake safely for identification by an expert.

MOST TRADITIONAL FIRST AID METHODS SHOULD BE DISCOURAGED: Discard traditional first aid methods (black stones, scarification) and alternative l medical/herbal therapy as they have no role and do more harm than good by delaying treatment. Do not wash wound and interfere with the bite wound (incisions, suction, rubbing, tattooing, l vigorous cleaning, massage, application of herbs or chemicals, cryotherapy, cautery) as this may introduce infection, increase absorption of the venom and increase local bleeding.

Do NOT apply or inject antisnake venom (ASV) locally. l Traditional methods to be discarded/ inappropriate methods Traditional methods should be discouraged as THEY DO MORE HARM THAN GOOD! Tight Tourniquets Traditional tight (arterial) tourniquets made of rope, belt, string or cloth to be effective had to be applied around the upper part of the limb, so tightly that the peripheral pulse was occluded. Most of the debate about efficacy/practicability is explained by the fact that most tourniquets 29

are incorrectly tied around the lower part of the limb. Some authors have argued that this is because non-experts simply cannot apply a tourniquet effectively (Ismail, 1983). This method is extremely painful and very dangerous if the tourniquet was left on for too long (more than about 40 minutes), as the limb might be damaged by ischaemia. Finally, psychologically, victims with ligatures tend to believe the venom flow has been inhibited.

There is a further danger that this confidence in the power of the ligature will lead them to seek medical attention with less urgency. They have the following drawbacks and problems: • Risk of Ischemia and loss of the limb (Warrell, 1999). • Increased risk of necrosis with 4/5 of the medically significant snakes of India. (Fairly, 1929; Pugh et al, 1987; Warrell, 1995). • Risk on release of tourniquet: Increased risk of massive neurotoxic blockade when tourniquet is released (Watt et al , 1988).

• Haemostatic Risks: Risk of embolism if used in viper bites. Pro-coagulant enzymes will cause clotting in distal blood. In addition, the effect of the venom in causing vasodilation presents the danger of massive hypotension when the tourniquet is released. • They do not work! (Tun Pe,1987; Khin-Ohn Lwin, 1984). Venom was not slowed by the tourniquet in several experimental studies, as well as in field conditions. Often this is

because they are tied on the lower limb or are incorrectly tied (Amaral, 1998; Nishioka, 2000). • They give patients a false sense of security, which encourages them to delay their journey to hospital. • Most tourniquets tied by lay people are ineffective as they are tied on the wrong portion of the limb and tied too loosely (Norris et al 2005). • Tourniquets should not be applied if there is a danger of necrotic venom activity i.e. virtually all cobras and vipers (Sutherland et al, 1981).

Tight (arterial) Tourniquets should NOT be used for snakebite first aid as it may cause gangrenous limbs. If victim is expected to reach the hospital in more than 30 minutes but less than 3 hours crepe bandage may be applied by qualified medical personnel only till the patient is shifted to the hospital. The bandage is wrapped over the bitten area as well as the entire limb with the limb placed in a splint. It should be capable of

admitting a finger beneath it. If a trained personnel is not present do NOT try tourniquet) (Expert Group Consensus) 30

Pressure –immobilization The pressure-immobilization first aid technique was developed in the 1970's by Professor Struan Sutherland. Its purpose is to retard the movement of venom from the bite site into the circulation, thus "buying time" for the patient to reach medical care. Research with snake venom has shown that very little venom reaches the blood stream if firm pressure is applied over the bitten area and

the limb is immobilised (Howarth et al, 1994). Bandage is applied upwards from the lower portion of the bitten or stung limb. Even though a little venom may be squeezed upwards. This is acceptable if pressure immobilisation is done on site of snake bite within minutes. Keeping Indian scenario in view, patient reaches medical facility after at least one hour to many hours, this technique then will be hazardous as it may lead to massive absorption of venom. Hence it is

recommended to have immobilization from proximal to distal as shown in the photographs below Figure 2: Pressure immobilization (Sutherland method) From Sutherland et al 1979) In case of venomous envenomation, tourniquet/light band, bandages/ligatures should be removed only after patient has reached the hospital, medical staff and resuscitation facilities are available and antisnake venom has been started in the presence of the doctor by the bedside of the patient (Expert Consensus).

If envenomation is confirmed on local examination and bite is non-venomous tourniquet, if any can be removed after establishing IV line. In case of multiple ligature, all the ligatures can be released in Emergency Room with doctor on the bed side of the patient EXCEPT the most proximal one; which should only be released after admission and all preparations for resuscitation facilities are available 31

and antivenom treatment has been started (Watt et al., 1988; Expert Consensus). Cutting and Suction • Cutting the wound and the use of suction or suction devices remains controversial. • However, the large number of viper bites globally, with the anti-haemostatic effect of the venom, makes cutting the wound highly hazardous as well as increasing the probability of infection. • Cutting a victim with incoagulable blood increases the risk of severe bleeding as the clotting

mechanism is no longer effective and increases the risk of infection. No venom is removed by this method. • Suction devices increase the risk of tissue necrosis and also do not extract significant amount of venom from the wound. Hence suction devices are neither safe nor effective (Alberts et al, 2009; Hardy et al, 1992). Though suction devices are not usually used in India but lay people have strong belief on mouth suction, (as they are habituated to see in the cinemas) is strongly prohibited (Bush 2004).

• Washing the wound requires rubbing of the skin, which will inevitably involve massaging the tissue, thereby causing more venom to be absorbed. This should not be done as the action of washing increases the flow of venom into the system by stimulating the lymphatic system (Gray, 2003). Electrical Therapy and Cryotherapy Electric shock therapy for snakebite received a significant amount of press in the 1980’s. The theory

behind it stated that applying an electric current to the wound denatures the venom (Guderian et al, 1986; Davis et all 1992). Much of the support for this method came from letters to journals and not scientific papers (Bucknall, 1991; Kroegal et al, 1986). Cryotherapy involving the application of ice to the bite was proposed in 1950s. However, subsequently showed increased necrotic effect of venom, thus practice of cryotherapy may do more harm (Glass 1991).

Do not wash wound and interfere with the bite wound (incisions, suction, rubbing, tattooing, vigorous cleaning, massage, application of herbs or chemicals, cryotherapy, cautery) as this may introduce infection, increase absorption of the venom and increase local bleeding Electrical therapy has no role in snakebite first aid and Cryotherapy may do more harm. (WHO 2015 and A2 2011). Traditional Remedies Traditional remedies are usually concerned with curing snakebite in its totality. Traditional healers

and Ayurvedic medicine for example, offer a full treatment philosophy, which they believe ‘cures’ snakebite. 32

There is a key aspect to the mathematics of snakebite that must be understood to place traditional medicine in context. In the case of 100 snakebites, 70 are likely to result from a non-venomous species. The remaining 30 bites will result from a venomous species. However, approximately 50% of bites from venomous species result in a dry bite where no venom is injected. It is thus likely that in the case of 100 snakebites, 85 victims will have nothing wrong with them and not require any treatment.

This is the mathematics that shows how traditional treatments APPEAR to ‘cure’ snakebite. Once the traditional healer realises that the victim has been truly envenomed then the victim is eventually sent to hospital. It is worth remembering that the traditional healer has the least interest in treating an envenomed victim as victims that die under traditional treatment reduce confidence in the healer. One or two specific traditional treatments need examination.

Sometimes prior ingestion and local application of these traditional remedial materials may complicate the clinical picture of a bite case. Vomiting induced or skin rashes with some swelling by these materials may mimic envenomation. Role of Snake Stones and Scarification The use of Black Snake Stones to attempt to cure snakebite is common in some developing countries and might contribute to delay in sending the victim to the health facility. In Africa and

other countries scarification is a common traditional treatment for snakebite. Cuts are administered to ‘help’ remove the venom from the envenomed victim. In common with generalised cutting this activity is dangerous, as it will encourage bleeding and is ineffective. No role of black stones and scarification 11. TRANSPORT TO HOSPTIAL The patient must be transported to a place where they can receive medical care (dispensary or

hospital) as quickly, but as safely, passively and comfortably, as possible. Any movement especially movement of the bitten limb, must be reduced to an absolute minimum to avoid increasing the systemic absorption of venom (WHO 2015). Any muscular contraction will increase the spread of venom from the site of the bite. A stretcher, bicycle, motorbike, cart, horse, motor vehicle, train or boat whichever mode of transport is available, or if nothing is available the patient can be carried

(e.g. using the “fireman’s lift” method). If possible, patients should be placed in the recovery position, in case they vomit. Instructions while referring • Inform the need for referral to the patient and/caregiver (family member or the accompanying attendant). • Give prior intimation to the receiving centre using available communication facilities. • Arrange for an ambulance. Call Emergency helpline 102/108 etc. Transport in an ambulance 33

equipped with transport ventilator. If ventilator is not available tight-fitting face mask connected to an anaesthetic (Ambu) bag should be available. However, do not waste time to get an ideal ambulance. Motorbike may be a practical alternative in rural areas for rapid transport but third person must sit behind the patient to support on bike. • If ASV is not available at First contact centre transfer to the nearest health facility where ASV is available confirmed by telephone.

• Transfer to a higher health facility (Secondary Care Hospital or Tertiary Care Hospital) where mechanical ventilator and dialysis facilities are available for dialysis and ventilation, if required after completion of ASV infusion only. • During transfer, continue life-supporting measures and provide airway support with the help of an accompanying staff, if required. • Do not insert nasogastric tube routinely. It is indicated only if victim has obtunded mentation

and or gag reflex is poor. If this is not possible give head up position to victim during transport to avoid aspiration of gastric content • Send the referral note with details of treatment given clearly mentioning the clinical status at the time of referral. 12. RECOMMENDATIONS Clinical features of snakebite Some people who are bitten by snakes (or suspect or imagine that they have been bitten) may develop quite striking symptoms and signs, even when no venom has been injected. This results

from an understandable fear of the consequences of a real venomous bite. Anxious people may hyperventilate so that they develop pins-and-needles sensation in the extremities, spasm of their hands and feet, and dizziness. Others may develop vasovagal shock after the bite or suspected bite, with faintness and collapse with profound slowing of the heart. Others may become highly agitated and irrational and may manifest a wide range of misleading symptoms (Ahmed et al, 2008].

The clinical presentation of a snakebite victim varies with the age and size of the patient, the species of snake, the number and location of the bites, and the quantity and toxicity of the venom. Treatment in the dispensary or hospital Signs and symptoms of snakebite The signs and symptoms of snakebite follow the four main categories of envenoming i.e. progressive weakness, bleeding, myotoxic and painful progressive Swelling (Figure 1). The clinical

presentation of a snakebite victim varies with the age and size of the patient, the species of snake, the number and location of the bites, and the quantity and toxicity of the venom. Victims of snakebite may suffer any or all of the following (WHO 2015): 1. No physical effects other than the fang/tooth puncture due to bites by non-venomous 34

snakes, animals other than snakes (lizards, fish, rodent, spiders), dry bite by venomous snake. 2. Local envenoming confined to the bitten part of the body. These effects may be transient, resolving in hours or a few days; may persist for few weeks or debilitating, some time permanently due to local necrotic effects of venom and complicating infections. 3. Systemic envenoming involving organs and tissues distant from the bitten part of the body.

These effects may be transient, persistent, life threatening and debilitating, sometimes permanently. 4. Effects of anxiety prompted by frightening experience of being bitten (real or imagined) and by exaggerated beliefs about the potency and speed of action of snake venoms. The symptoms may mislead the treated personnel. 5. Effects of first-aid and other pre-hospital treatments that may cause misleading clinical features. 35

Suspected snake bite •Neuroparalytic Krait symptoms with Overt bite Occult bite no local signs History of bite No history of bite •Severe Nonvenomous (70%) / venomous (30%) abdominal pain, vomiting Asymptomatic Dry bite Symptomatic* 1. ASV Predominant symptom manifestation 2. AN*** 3. Ventilation Anxiety, palpitations, tachycardia, Paraesthesia Progressive painful Neuroparalytic Vasculotoxic Myotoxic Observe for swelling 24 hours Cobra •Russel’sviper Flat tailed Krait Sea snake Viper Saw Scale viper

•Muscle ache •Ptosis •Bleeding •Muscle swelling •Diplopia •Demonstrable •Local necrosis •Dysarthia coagulopathy (20WBCT •Involuntary •Ecchymosis •Dysphonia incoagulable) contractions of •Blistering •Shock muscles •Dyspnoea •Painful •Acute kidney injury •Compartment •Dysphagia swelling (not seen with Saw syndrome •Paralysis •Compartment scale viper) syndrome 1. ASV**¥ 1. ASV**¥ 1. ASV** 2. Supportive treatment 2. Supportive 2. AN*** 3. Dialysis treatment ASV# 3. Ventilation 4. Blood transfusion 3. Dialysis

* Even though present as predominant manifestation but there may be overlap of syndrome as well. # ASV indicated in rapidly developing swelling only. Purely localized swelling with or without bite marks is not an indication of ASV. ** For reaction to antisnake venom (ASV) Dose of Adrenaline 0.5 mg IM (in children 0.01 mg/kg) ¥ Specific ASV for sea snake and Pit viper bite is not available in India. However, available ASV may have some advantage by cross reaction.

*** ‘AN’ injection Atropine 0.6 mg followed by neostigmine(1.5mg) IV stat (In children Inj. Atropine 0.05 mg/kg followed by Inj. Neostigmine0.04 mg/kg IV.) Repeat neostigmine0.5 mg (in children 0.01mg/kg) with atropine every 30 minutes for 5 doses. Thereafter taper dose at 1 hour, 2 hour, 6 hours and 12 hour. Positive response is measured as 50% or more recovery of the ptosis in one hour. If no response after 3rddose stop AN injection. No AN injection in confirmed krait bite

• The snake specie shown above are indicative only. Russell’s viper envenoming in Tamil Nadu and some other areas commonly causes paralysis –the venom of this species varies considerably across its range in India. Figure 1. Four presenting clinical syndromes of snakebite i.e. progressive weakness (neuroparalytic/neurotoxic), bleeding (vasculotoxic/haemotoxic), myotoxic and painful progressive Swelling and its management. At a health care facility Diagnosis phase History and Symptoms

Examine the bite site and look for fang marks, or any signs of local envenomation. Fang mark or their patterns have no role to determine whether the biting species was venomous or non venomous or amount of venom injected, severity of systemic poisoning and nature of poisoning – Elapidae or viperidae venom etc. Some species like Krait may leave no bite marks. 36

See figure 1 for presenting clinical syndromes of venomous snakebite. Asymptomatic (i.e., Non Venom Related Symptoms) Many will appear to be asymptomatic as: 1. The bite is from a non venomous species (approximately 70% of snakebites are from non venomous species 2. The bite is from a venomous species but has not injected enough venom to cause symptoms or has injected none at all (dry bites) 3. The venom is of a sufficiently high level to cause symptoms but is now progressing

through the tissue without causing swelling to indicate its presence. The delayed appearance of symptoms and signs of snakebite is very common after krait envenoming The victim may be envenomed but no visible signs or immediately detectable symptoms are visible (The victim may have incoagulable blood or bleeding or renal failure may be underway but not visible) Patients many a times present with nonspecific symptoms related to anxiety. Common symptoms in these patients are:

• Palpitations, sweating, tremulousness, tachycardia, tachypnoea, elevated blood pressure, cold extremities and paraesthesia. These patients may have dilated pupils suggestive of sympathetic over activity. • Differentiate from symptoms and signs of envenomation listed below. • Redness, increased temperature, persistent bleeding and tenderness locally. However, local swelling can be present in these patients due to tight ligature Dry Bite

Bites by nonvenomous snakes are common and bites by venomous species are not always accompanied by the injection of venom (dry bites). The percentage of dry bites ranges from 10–80% for various venomous snakes. Some people who are bitten by snakes (or suspect or imagine that they have been bitten) or have doubts regarding bite may develop quite striking symptoms and signs, even when no venom has been injected due to understandable fear of the consequences of a

real venomous bite. Even in case of dry bite, symptoms due to anxiety and sympathetic over- activity (as above) may be present. As symptoms associated with panic or stress sometimes mimic early envenoming symptoms, clinicians may have difficulties in determining whether envenoming occurred or not. Symptomatic Patients Neuroparalytic (Progressive weakness; Elapid envenomation) Neuroparalytic snakebite patients present with typical symptoms within 30 min– 6 hours in case of

Cobra bite and 6 – 24 hours for Krait bite; however, ptosis in Krait bite have been recorded as late 37

as 36 hours after hospitalization. These symptoms and signs can be remembered as 5 Ds and 2 Ps. • 5 Ds – dyspnoea, dysphonia, dysarthria, diplopia, dysphagia • 2 Ps – ptosis, paralysis • In chronological order of appearance of symptoms – furrowing of forehead, Ptosis (drooping of eyelids) occurs first (Figure 3), followed by Diplopia (double vision), then Dysarthria (speech difficulty), then Dysphonia (pitch of voice becomes less) followed by Dyspnoea

(breathlessness) and Dysphagia (Inability to swallow) occurs. All these symptoms are related to 3rd, 4th, 6th and lower cranial nerve paralysis. Finally, paralysis of intercostal and skeletal muscles occurs in descending manner. • Other common signs are facial paralysis, inability to open mouth and protrude the tongue. Patients who have no control over the neck (“broken neck sign.”) are at immediate risk and require urgent airway intervention.. • Additional features like stridor, ataxia may also be seen.

• Associated hypertension and tachycardia may be present due to hypoxia. Figure 3. Ptosis with neuroparalytic snakebite To identify impending respiratory failure bedside lung function test in adults viz. 1. Single breath count – number of digits counted in one exhalation - >30 normal 2. Breath holding time – breath held in inspiration – normal > 45 sec 3. Ability to complete one sentence in one breath. Cry in a child whether loud or husky can help in identifying impending respiratory failure.

Bilateral dilated, poorly or a non-reacting pupil is not the sign of brain dead in elapid envenoming (Figure 3). Refer patients presenting with neuroparalytic symptoms immediately to a higher facility for intensive monitoring after giving Atropine Neostigmine (AN) injection (schedule of AN injection described below). 38

Vasculotoxic (Haemotoxic or Bleeding) General signs and symptoms of Viperine envenomation) Vasculotoxic bites are due to Viper species. They can have local manifestations as well as systemic manifestations. Local manifestations – these are more prominent in Russell’s viper bite followed by Saw scaled viper and least in Pit viper bite. Local manifestations are in form of: • Local swelling, bleeding, blistering, and necrosis.

• Pain at bite site and severe swelling leading to compartment syndrome. Pain on passive movement. Absence of peripheral pulses and hypoesthesia over the fuels of nerve passing through the compartment helps to diagnose compartment syndrome. • Tender enlargement of local draining lymph node. Systemic manifestations – • Visible systemic bleeding from the action of haemorrhagins (Figure 4) e.g. gingival bleeding, epistaxis, ecchymotic patches, hematemesis, hemoptysis, bleeding per rectum, subconjunctival

hemorrhages, haematuria, continuous bleeding from the bite site, bleeding from pre-existing conditions e.g. haemorrhoids, bleeding from freshly healed wounds. • Bleeding or ecchymosis at the injection site is a common finding in Viper bites. • The skin and mucous membranes may show evidence of petechiae, purpura ecchymoses, blebs and gangrene. • Swelling and local pain. • Acute abdominal tenderness may suggest gastro-intestinal or retro peritoneal bleeding.

• Lateralizing neurological symptoms such as asymmetrical pupils may be indicative of intra- cranial bleeding. • Consumption coagulopathy detectable by 20WBCT, develops as early as within 30 minutes from time of bite but may be delayed. Figure 4. Local and systemic Vasculotoxic (haemotoxic or Bleeding) manifestations of Viperine envenomation. 39

Locked-in syndrome (LIS) Locked-in syndrome (LIS) is defined as quadriplegia and anarthria with preserved consciousness. Patients retain vertical eye movement, facilitating non-verbal communication.In complete locked in syndrome (LIS) patient cannot communicate in any form. Central LIS is seen commonly due to lesions in the ventral pons (Smith and Delargy, 2005; Prakash et al, 2008; Poovazhagi, 2013). Peripheral causes of LIS are severe acute polyneuropathies, neuromuscular junction blockade due

to myasthenia gravis toxins and snakebite (Prakash et al, 2008). Knowing the peripheral causes are very important as one may make a wrong diagnosis of brain death and is treatable and complete recovery can be possible with timely intervention. Confirmatory tests like EEG, cerebral blood flow, nerve conduction velocities are recommended to avoid misdiagnosis of coma or brain death. Peripheral LIS usually occurs in Elapidae bites, especially Krait bite and hence increasing ones

suspicion rate is important as they can be referred to a centre with ventilator support. Life threatening complications • Acute Kidney Injury (AKI) e.g. declining or no urine output, deteriorating renal signs such as rising serum creatinine, urea or potassium. Some species e.g. Russell’s viper (Daboia sp) frequently cause acute Kidney Injury. Patient presents with bilateral renal angle tenderness, hematuria, hemoglobinuria, myoglobinuria followed by oliguria and anuria with AKI.

• Hypotension due to hypovolaemia or direct vasodilatation or direct cardiotoxicity aggravates acute kidney injury. • Parotid swelling, conjunctiva oedema, sub-conjunctival haemorrhage, renal failure, acute respiratory distress syndrome [leaking syndrome] and refractory shock. • Long term sequelae e.g. pituitary insufficiency with Russell’s viper (Daboia sp), Sheehan’s syndrome (Tun-Pe et al, 1987) or amenorrhea in females. Systemic capillary leak syndrome

Idiopathic systemic capillary leak syndrome (ISCLS) is a rare disorder characterized by episodes of severe hypotension, hypoalbuminemia, hemoconcentration without albuminuria. During "attacks" of ISCLS, profound derangement of the vascular endothelium results in leakage of plasma and proteins into the interstitial compartment. It is due to capillary hyper permeability with massive extravasation of plasma containing macro molecules smaller than 200KD.

Capillary leak syndrome is a sinister complication of Daboia russelii bite as it is beset with an excess of morbidity and mortality. It is seen in more commonly in males as compared to females. Manifestations like parotid swelling, conjunctival chemosis, myalgia, thirst & systemic hypotension 40

observed in patients of Daboia russelii bite indicate capillary leak syndrome. Hemoconcentration, increased HCT, leukocytosis, pleural effusion are early laboratory and radiological markers of capillary leak syndrome and should alert the clinician to seek urgent interventions in Daboia russelii bite. After the advent of capillary leak syndrome, meticulous monitoring of CPK and blood pressure control is necessary to avoid the inception of renal failure. Patients with capillary leak syndrome are likely to

have severe renal failure and complications related to it. Patients with capillary leak syndrome required higher dose of ASV compared to those without it. Early recognition and effective treatment like infusion of fresh frozen plasma and reduction of hemoconcentration may play a key role to reduce its gruesome mortality (Menon et al, 2015; Atkinson et al, 1977). A B C D Figure : A) 17 year old patient with viper bite at admission. B) & C) Same patient with

periorbital swelling, Conjunctival chemosis and icterus 24 hours later. D) Another patient with viper bite developing parotid swelling 24 hours later. Painful Progressive Swelling (PPS) Progressive painful swelling is indicative of local venom toxicity. It is prominent in Russell’s viper bite, Saw scaled viper bite and Cobra bite. This is associated with • Local necrosis which often has a rancid smell. Limb is swollen and the skin is taut and shiny.

Blistering with reddish black fluid at and around the bite site. Skip lesions around main lesion are also seen. (Figure 5). • Ecchymoses due to venom action destroying blood vessel wall. • Significant painful swelling potentially involving the whole limb and extending onto the trunk. • Compartment syndrome. • Regional tender enlarged lymphadenitis. 41

Figure 5. Snakebite marks and local swelling and necrosis Myotoxic This presentation is common in Sea snakebite. Patient presents with: • Muscle aches, muscle swelling, involuntary contractions of muscles, trismus. • Passage of dark brown urine. • Compartment syndrome, cardiac arrhythmias due to hyperkalaemia, acute kidney injury due to myoglobinuria, and subtle neuroparalytic signs. Occult Snakebite • Krait bite victims often present in the early morning with paralysis with no local signs. Krait has

nocturnal habitat and has small teeth. Hence bite marks usually cannot be identified even on close examination. • Typical presenting history is that the patient was healthy at night, in the morning gets up with severe epigastric/umbilical pain with vomiting persisting for 3 – 4 hours and followed by typical neuroparalytic symptoms within next 4- 6 hours. There is no history of snakebite. Vomiting, neurotoxicity and serum creatinine serve as useful signpost for clinical decision making, can help

the clinician assess prognosis of their patients more accurately and predict mortality among inpatients with snake bite (Kalantri et al, 2005). • Unexplained respiratory distress in children in the presence of ptosis or sudden onset of acute flaccid paralysis in a child (locked-in syndrome) are highly suspicious symptoms in endemic areas particularly of Krait bite envenomation. Sometimes patients may present with throat pain or chest pain also. 42

Early morning symptoms of acute pain abdomen with or without neuroparalysis can be mistaken for a acute appendicitis, acute abdomen, stroke, GB syndrome, myasthenia gravis and hysteria (Bawaskar, 2002). Krait bite envenoming is diagnosed by developing descending neuroparalysis while GB syndrome is by ascending paralysis. Strong clinical suspicion and careful examination can avoid not only costly and unnecessary investigations such as CT scan, MRI, nerve conduction

studies, CSF studies and many others but also help in avoiding undue delay in initiation of a specific treatment with ASV. Atropine neostigmine (AN) test helps to rule out myasthenia gravis. Differential identification of type of snakebite based on the symptoms and signs Though to a large extent the manifestation of snakebite depends upon the species of snake, unfortunately, in many cases the biting snake is not seen, and if it is, its description by the victim is

often misleading (Harris et al, 2010). Therefore identification of the type of snake should not hold the treatment. At times the bite mark might not be visible (e.g., in the case of Krait). The clinical manifestations of the patient may not correlate with the species of snake brought as evidence. Examine carefully the snake, if brought, and identified if possible. Discourage bringing the killed snake into the emergency department. Identification of the species even if killed should be carried

out carefully, since crotalids can envenomate even when dead. One smart phone photograph of the snake, dead or alive, if can be taken safely, for confirmation by an expert would also help in identifying the snake. If snake is not available for identification in such a situation showing specimens of snakes preserved in formalin in glass jars or pictures of snakes would help the patient or the witness to recognize the offending snake which facilitates the judgment of the clinician (Figure 6).

Inspection of local site of bite can also help to identify snake’s species. Local swelling, bleeding, blistering, necrosis suggests Cobra bite. Minimum local changes indicate Krait bite. Local bleeding suggests Nilgiri Russell’s viper. Pain in abdomen and hyper peristalsis indicates Krait bite. A more reliable method of identifying the offending snake is the detection of venom antigen through immunodiagnosis such as ELISA but this test is not available in India. 43

Figure 6. Snake identification by the patient ON PRESENTATION, PATIENTS CAN BE CRITICAL OR NON CRITICAL (FIGURE 1). Figure 1. Management of Snakebite Snakebite is a medical emergency, history, symptoms and signs must be obtained rapidly. CRITICAL ARRIVAL Rapid primary clinical assessment and resuscitation SIGNs and SYMPTOMs of an envenomation at some point in time, not necessarily current, which may be detected. They are NOT in themselves criteria for administering ASV (A2).

Rapid primary clinical assessment and resuscitation: CABDE approach Circulation (arterial pulse) Airway Breathing (respiratory movements) Disability of the nervous system (level of consciousness) Exposure and environmental control (protect from cold etc.) Airway patency, respiratory movements, arterial pulse and level of consciousness must be checked immediately. Patients should be intubated if possible or provided with airway support

and ventilated with a resuscitation bag. However, the Glasgow Coma Scale cannot be used to assess the level of consciousness of patients paralyzed by neurotoxic venoms (see below). Clinical situations in which snake-bite victims might require urgent resuscitation: 44

(a) Profound hypotension and shock resulting from direct cardiovascular effects of the venom or secondary effects, such as hypovolaemia, release of inflammatory vasoactive mediators, haemorrhagic shock or rarely primary anaphylaxis induced by the venom itself. (b) Terminal respiratory failure from progressive neurotoxic envenoming that has led to paralysis of the respiratory muscles. (c) Sudden deterioration or rapid development of severe systemic envenoming following the

release of a tight tourniquet or compression bandage (see Caution above). (e) Cardiac arrest precipitated by hyperkalaemia resulting from skeletal muscle breakdown (rhabdomyolysis) after bites by sea snakes, certain kraits and Russell’s vipers. If the patient arrives late: Late results of severe envenoming such as renal failure and septicaemia complicating local necrosis. If the victim underwent respiratory failure shortly before reaching the hospital, it is likely that a full

recovery will be possible. This factor should be communicated to staff responsible for mechanical ventilation of the patient. Often a key decision is whether to continue with mechanical ventilation with a patient who is nonresponsive for several hours on the ventilator. Patients with neurological envenomation may require many hours or days on a ventilator to achieve recovery (Kularatne 2002), particularly in the case of pre synaptic envenoming. The reality is that in many developing

countries ventilators are unavailable in most hospitals and even where present are in short supplies. There is thus a tendency to ventilate patients for a short period, achieve no response and then discontinue ventilation due to ‘sepsis’ or some other ‘cause’ of death. (A2) In the case of pre synaptic envenoming this is disastrous! It is vital that the physician who initially receives the patient fully investigates the timeline of respiratory arrest and informs ventilation

staff of the likely outcome. In reality, a patient that underwent respiratory arrest some distance from the hospital will not survive unless good airway support with a resuscitation bag and airway maintenance tools was provided in the interim period. Vasculotoxic patients presenting with bleeding from multiple orifices with hypotension, reduced urine output, obtunted mentation (drowsy, confused), cold extremities need urgent attention, ASV

and ICU care for volume replacement, pressor support, dialysis and infusion of blood and blood products (See following sections). Neuroparalytic patients presenting with respiratory paralysis, tachypnoea or bradypnoea or paradoxical respiration (Breathing movements in which the chest wall moves in on inspiration and out on expiration, in reverse of the normal movements.), obtunded mentation, and peripheral skeletal muscle paralysis need urgent ventilator management with endotracheal intubation,

ventilation bag or ventilator assistance along with ASV. Other patients can be evaluated to decide severity of their illness. The clinician must detect the evidence of envenoming early as it governs the decision of administering antivenom therapy, which in turn has a direct impact on the prognosis. These 45

observations and physical signs are based on local and systemic manifestations of envenoming. Since the manifestations of specific patterns of envenoming are snake specific, the identification of the offending snake would help the clinician to look for particular clinical signs and evidence. Properties of snake venom depend mainly on the species of the snake but geographical factors could further modify it. Thus it is prudent to look for features of envenoming as a whole with an open mind.

Patient assessment: Non critical arrival and Critical patients after stabilization Detailed clinical assessment and species diagnosis All patients will be kept under observation for a minimum of 24 hours. History • Ask questions as to what the victim was doing at the time of the bite. Some activities such as grass cutting or feeding stock animals in the evening can be suggestive of snakebite. A precise history of the circumstances of the bite and the progression of local and systemic symptoms and

signs is very important. The doctor can immediately see evidence that the patient has been bitten by a snake (e.g. fang marks) and the nature and extent of signs of local envenoming. • Bite marks are of no use in identifying if a species is venomous or not though in some countries bite marks have limited use in determining species (Nishioka et al, 1995; Norris, 1995). Many non venomous species leave just two fang-like marks e.g. Wolf Snakes. Some species like the

Krait may leave no bite mark at all. Many venomous species have more than two fangs, as they grow reserve fangs in case the main ones break off. • Determine the exact time of the bite. This can give indications as to the progression of any symptoms. If the patient has arrived at the hospital soon after the bite, there may be few symptoms and signs even though a large amount of venom may have been injected. If the

patient was bitten at night while asleep, a Krait was probably implicated; if in a paddy field, a cobra or Russell’s viper; if while tending fruit trees, a green pit viper; if while swimming or wading in water a cobra (fresh water) or sea snake (sea or estuary). • A common early symptom of systemic envenoming is vomiting. Patients who become defibrinogenated or thrombocytopenic may begin to bleed from old, partially-healed wounds as

well as bleeding persistently from the fang marks. The patient should be asked how much urine has been passed since the bite and whether it was of a normal colour. Patients who complain of sleepiness, drooping eyelids or blurred or double vision may have neurotoxic envenoming. An important early symptom of sea snake envenoming that may develop as soon as 30 minutes after the bite is generalized pain, tenderness and stiffness of muscles and trismus.

• Where possible identify the snake responsible. Snake colouration is a very unreliable means of determining species. Have the victim carefully bring the snake to hospital if it has been killed. If the snake has been killed and brought, its correct identification can be very helpful. If it is obviously a harmless species (or not a snake at all!), the patient can be quickly reassured and discharged from hospital. 46

• Determine if any traditional medicines have been used. Traditional treatments can cause problems, in addition to the time taken to administer them. For example, the ingestion of herbal or other products can generate symptoms that confuse the diagnosis. In some areas the ingestion of clarified butter or ‘ghee’ is a common remedy use to induce vomiting. The rationale is that venom is thus vomited from the body. The victim’s vomiting may be entirely unrelated to envenomation.

• Sometimes chilli is ingested to counteract the venom, which can result in abdominal pain in the victim. In areas where abdominal pain may be indicative of envenomation e.g. krait areas, this can mislead the doctor. • Obtain a brief medical history (e.g., date of last tetanus immunization, use of any medication, presence of any systemic disease, and history of allergy) Early clues that a patient has severe envenoming (WHO): • Rapid early extension of local swelling from the site of the bite. In

Cobra bite on finger, necrosis may start in few minutes. • Early tender enlargement of local lymph nodes, indicating spread of venom in the lymphatic system • Visible signs of neurological impairment such as ptosis, muscular weakness, respiratory distress or respiratory arrest. • Early spontaneous systemic bleeding especially bleeding from the gums, bite site, haematuria, haemoptysis, epistaxis or ecchymoses. • Unconsciousness either with or without respiratory arrest. • Passage of dark brown urine

• Snake identified as a very venomous one i.e., Cobra, Russell’s viper. Handling Tourniquets Care must be taken when removing tourniquets tied by the victim. Sudden removal can lead to a massive surge of venom leading to neurological paralysis, hypotension due to vasodilation etc. Before removal of the tourniquet, test for the presence of a pulse distal to the tourniquet. In case of venomous envenomation, tourniquet should be removed only after starting of loading

dose of ASV in the presence of the doctor (Expert Consensus). Be prepared to handle the complications such as sudden respiratory distress or hypotension. If the tourniquet has occluded the distal pulse, then a blood pressure cuff can be applied to reduce the pressure slowly. If envenomation is confirmed on local examination and bite is non-venomous, tourniquet, if any can be removed after establishing IV line in the presence of the doctor. In case of multiple ligature, all

the ligatures can be released in Emergency Room EXCEPT the most proximal one; which should only be released after admission and all preparations (Expert consensus) Physical examination 47

Careful assessment of the site of the bite and signs of local envenomation and examination of the patient should be carried out and recorded (Annexure 1). Monitor the patient closely and repeat all above, every 1-2 hourly. Check for and monitor the following: Pulse rate, respiratory rate, blood pressure and 20 minutes Whole Blood clotting test (20 WBCT) every hour for first 3 hours and every 4 hours for remaining 24 hours.

Check distal pulses and monitor if there is presence of gross swelling. The presence of a pulse does not rule out compartment syndrome. Pain on passive movement, pallor, pulseless limb, hypoaesthesia over the sensory nerve passing through the compartment are suggestive of compartment syndrome. Measure compartment pressure directly if there is concern that a compartment syndrome is developing. The diagnosis is established if the compartment pressure,

measured directly by inserting a 16 G IV cannula and connecting it with manometer, is raised above 40 cm water/saline. Direct measurement is necessary before resorting to fasciotomy since compartment syndrome is rare in snakebite victims and fasciotomy done without correction of hemostatic abnormality may cause the patient to bleed to death (Warrell 1999). Physical examination should start with careful assessment of the site of the bite and signs of local envenoming.

Examination of the bitten part: The extent of swelling, which is usually also the extent of tenderness to palpation (start proximally), should be recorded. Lymph nodes draining the limb should be palpated and overlying ecchymoses and lymphangitic lines noted. A bitten limb may be tensely oedematous, cold, immobile and with impalpable arterial pulses. These appearances may suggest intravascular thrombosis, which is exceptionally rare after snake-bite, or a compartmental

syndrome, which is uncommon. If possible, intracompartmental pressure should be measured and the blood flow and patency of arteries and veins assessed (e.g. by Doppler ultrasound). Early signs of necrosis may include blistering, demarcated darkening (easily confused with bruising) or paleness of the skin, loss of sensation and a smell of putrefaction (rotting flesh). General examination: Measure the blood pressure (sitting up and lying to detect a postural drop indicative of hypovolaemia) and heart rate.

Examine the skin and mucous membranes for evidence of petechiae, purpura, discoid haemorrhages, ecchymoses and, in the conjunctivae, for haemorrhages and chemosis. Thoroughly examine the gingival sulci, using a torch and tongue depressor, as these may show the earliest evidence of spontaneous systemic bleeding. Examine the nose for epistaxis. Abdominal tenderness may suggest gastrointestinal or retroperitoneal bleeding. Loin (low back) pain and tenderness

suggests acute renal ischaemia (Russell’s viper bites). Intracranial haemorrhage is suggested by lateralising neurological signs, asymmetrical pupils, convulsions or impaired consciousness (in the absence of respiratory or circulatory failure). 48

Examination of pregnant women Potential complications of envenoming in pregnancy include antepartum and postpartum haemorrhage indicated by vaginal bleeding, premature labour, abortion/stillbirth and foetal distress. Monitor uterine contractions and foetal heart rate. Foetal bradycardia, tachycardia or later deceleration after each uterine contraction indicate foetal distress. In case of vaginal bleeding or the need for imminent surgery correct antihaemostatic abnormalities after antivenom treatment

should be accelerated using blood products. Lactating women who have been bitten by snakes should be encouraged to continue breast feeding (WHO 2015). Diagnosis Phase: Investigations 20 Minute Whole Blood Clotting Test (20WBCT) It is considered as the most reliable test of coagulation and can be carried out, at the bedside without specialist training. It can also be carried out in the most basic settings. A few ml of fresh venous blood is placed in a NEW, CLEAN AND DRY GLASS vessel/tube to avoid

false positive tests (that Recycled glass vessels are not cleaned with detergents or other cleansing fluids) and left at ambient temperature for 20 minutes. The glass vessel should be left undisturbed for 20 minutes and then gently tilted, not shaken. Caution: If the vessel used for the test is not made of ordinary glass, or if it has been cleaned with detergent, its wall may not stimulate clotting of the blood sample (surface activation of factor XII – Hageman factor) and test will be invalid

In case where the 20WBCT result is inconsistent with the patients’ clinical condition, repeat the test in duplicate, including a “control” (blood from a healthy person such as a relative) (WHO 2015) Results Interpretation If the blood is solid i.e. has clotted the patient has passed the coagulation test and no ASV is required at this stage. 20 WBCT may remain negative (clotting) in patients with evolving venom – induced DIC, therefore, the patient is re-tested every hour for the first three hours and then 6

hourly for 24 hours until either test result is not clotted or clinical evidence of envenomation to ascertain if dose of ASV is indicated. Antivenom treatment should not be delayed if there is other evidence of spontaneous systemic bleeding distant from the bite site. In case test is non-clotting, repeat 6 hour after administration of loading dose of ASV. In case of neurotoxic envenomation repeat clotting test after 6 hours (Expert Consensus)

Other investigations that may assist in the management of snake bite at various levels of healthcare 49

At Primary health centre Peak flow meter in patients (adolescents and adults) presenting with neuroparalytic syndrome. If Peak flow meter is not available in PHC then assess respiratory function using bedside tests - single breath count, breath holding time and ability to complete one sentence in one health as described earlier. Urine examination for albumin and blood by dipstick. At District Hospital In addition to the above Prothrombin time Platelet count, Clot retraction time Liver function test (LFT)

Renal Function test (RFT) Serum Amylase Blood sugar ECG Abdominal ultrasound 2D Echo (if available) At Tertiary Health Care Centre In addition to the above In neuroparalytic envenomation • Arterial blood gases. Caution: Arterial puncture is contraindicated in patients with haemostatic abnormalities. • Pulmonary function tests • In Vasculotoxic venomation • For coagulopathy- BT, CT, PT, APTT, Platelet, Serum Fibrinogen, FDP D-Dimer assay, LDH, peripheral blood smear

• Hemolysis -Urine for myoglobin, Urine haemoglobin • For renal failure- Urine microscopy for RBC, casts, RFT, urinary proteins, creatinine ratio • Hepatic injury – LFTs including SGOT, SGPT, Alkalien phosphatase, serum proteins • Cardiotoxicity- CK-MB, 2D Echo, BNP • Myotoxic – CK, SGOT, Urine myoglobin, compartment pressure • Infection- Serum procalcitonin, culture (blood, urine, wound) and sensitivity Arterial blood gases and urine examination should be repeated at frequent intervals during the

acute phase to assess progressive systemic toxicity). Rationale and interpretation of the tests: i. Hemogram: The hemogram may show transient elevation of hemoglobin level due to hemoconcentration (because of the increased capillary leak) or may show anemia (due to 50

hemolysis, especially in viper bites). Presence of neutrophilic leucocytosis signifies systemic absorption of venom (Warrell DA. 1999). Thrombocytopenia may be a feature of viper envenomation. ii. Platelet count: This may be decreased in victims of envenoming by vipers. White blood cell count: An early neutrophil leucocytosis is evidence of systemic envenoming from any species. Blood film: Fragmented red cells (“helmet cell”, schistocytes) are seen when there is microangiopathic haemolysis.

Plasma/serum: May be pinkish or brownish if there is gross haemoglobinaemia or myoglobinaemia. iii. Serum creatinine: This is necessary to rule out acute kidney injury after viper and sea snakebite. iv. Serum creatine kinase (CK): Elevated levels of these markers suggests muscle damage (caution for renal damage) and raised amylase suggests pancreatic injury v. Prothrombin time (PT) and activated partial thromboplastin time (aPTT): Prolongation may be

present in viper bite (to be repeated 6 hourly, if abnormal). vi. Fibrinogen and fibrin degradation products (FDPs): Low fibrinogen with elevated FDP is present when venom interferes with the clotting mechanism. vii. Urine examination for Proteinuria/ RBC/ Haemoglobinuria/ Myoglobinuria: The colour of the urine (pink, red, brown, black) should be noted and the urine should be tested by dipsticks for blood or haemoglobin or myoglobin. Standard dipsticks do not distinguish blood, haemoglobin

and myoglobin. Haemoglobin and myoglobin can be separated by immunoassays but there is no easy or reliable test. Microscopy will confirm whether there are erythrocytes in the urine. viii. Electrocardiogram (ECG): Nonspecific ECG changes such as bradycardia and atrioventricular block with ST-T changes may be seen (Nayak et al, 1990) ix. Electroencephalogram (EEG): Recently, EEG changes have been noted in up to 96% of patients

bitten by snakes. These changes start within hours of the bite but are not associated with any features of encephalopathy. Sixty-two percent showed grade I changes, 31% cases manifested grade II changes (moderate to severe abnormality), and the remaining 4% showed severe abnormality (grade III). These abnormal EEG patterns were seen mainly in the temporal lobes (Ramachandran S et al, 1995). However, rarely needed for patient management.

x. Pulse oximetry for oxygen in patients with respiratory failure or shock. xi. Electrolyte determinations: These tests are necessary for patients with respiratory paralysis and systemic symptoms. xii. Arterial blood gases and pH may show evidence of respiratory failure (neurotoxic envenoming) and acidaemia (respiratory or metabolic acidosis). xiii. X-Ray/ CT/ Ultrasound (The use of X-Ray and ultrasound are of unproven benefit, apart from identification of bleeding in Viperine bites). 51

Feature Cobras Kraits Russell’s Viper Saw Hump Scaled Nosed Viper Viper Local Pain/ Tissue YES NO YES YES YES Damage Ptosis/ Neurological Signs YES YES YES! NO NO Haemostatic NO NO! YES YES YES abnormalities Renal Complications NO NO YES NO YES Response to Neostigmine YES NO? NO? NO NO Response to ASV YES YES YES YES NO Late-onset envenoming The patient should be kept under close observation for at least 24 hours. Many species, particularly

the Krait and the Hump-nosed pitviper are known for the length of time it can take for symptoms to manifest (Joseph et al 2003). Often this can take between 6 to 12 hours. Late onset envenoming is a well documented occurrence (Ho et al, 1986; Warrell et al, 1977; Reitz, 1989). In many cases of Common krait bites in West Bengal, bilateral ptosis appeared after 24- 36 h after admission for pain abdomen. This is also particularly pertinent at the start of the rainy season when snakes generally give birth to

their young. Juvenile snakes, 8-10 inches long, tend to bite the victim lower down on the foot in the hard tissue area, and thus any signs of envenomation can take much longer to appear. 13. ANTI SNAKE VENOM (ASV) If ASV is indicated i.e. signs and symptoms of envenomation with or without evidence of laboratory tests, administer FULL dose as soon as indicated. In a patient with a history of bite; known or unknown, if there is spontaneous abnormal bleeding beyond 20 minutes from time of

bite, start ASV, do NOT wait for 20 WBCT report. There are no absolute contraindications to ASV. Do not routinely administer ASV to any patient claiming to have bitten by a snake without signs and symptoms of envenoming as ASV exposes such patients to the risks of ASV reactions unnecessarily; besides wastage of valuable and scarce stocks of ASV. However, at the same time do not delay or withhold ASV on the grounds of anaphylactic

reaction to a deserving case. Do NOT give incomplete dose. Purely local swelling, even if accompanied by a bite mark from an apparently venomous snake, is not a ground for administering ASV. Swelling, a number of hours old is also not a ground for giving ASV. However, rapid development of swelling indicates bite with envenoming requiring ASV. 52

Inappropriate use of antivenom In some parts of the world, a small standard dose of antivenom is given to any patient claiming to have been bitten by a snake, irrespective of symptoms or signs of envenoming. Sometimes the local community are so frightened of snake-bite that they compel the doctor to give antivenom against medical advice to the patient with such a claim. Routine use of ASV to any patient claiming to have bitten by a snake should be strongly

discouraged as they expose patients who may not need treatment to the risks of antivenom reactions; The patient may have reaction to any horse serum preparation like Antirabies immunoglobin; they also waste valuable and scarce stocks of antivenom. Monovalent vs. Polyvalent Anti snake venom (ASV) in India is polyvalent i.e. it is effective against all the four common species; Russell’s viper (Daboia russelii), Common Cobra (Naja naja), Common Krait (Bungarus

caeruleus) and Saw Scaled viper (Echis carinatus). There are no currently available monovalent ASVs primarily because there are no objective means of identifying the snake species, in the absence of the dead snake. It would be impossible for the physician to determine which type of Monovalent ASV to employ in treating the patient. The call for monovalent ASVs because “they are cheaper” is another example of intuition being emphasised over evidence. ASV production economics are complex and in many of the

developing countries, which have a low cost of ASV, the use of monovalent ASVs may actually INCREASE the cost of the final product as batch, testing, distribution & storage costs for specific ASVs may be higher. It must be remembered that: The majority of victims do not bring the dead snake for identification Doctors are unreliable in making a correct identification even if the snake is brought ELISA testing kits would need to be provided. India should make an attempt to establish this test

will save maximum ASV and prevent ASV crisis A number of monovalent ASVs would need to be provided to many physicians which has planning, logistical & cost implications Producing a separate batch for each monovalent ASV may well increase the costs of production and testing versus polyvalent ASVs. Very few countries have ELISA testing despite it being referred to for nearly 30 years; the main example is Australia where it is used to identify biting species NOT level of envenomation (World

There are key problems with monovalent ASVs that are often overlooked: The clinical symptoms to administer the ASV must be clear and mutually exclusive. If two species cause the same symptom, monovalent ASVs are not useful. A good example of this is the case of China where both the Chinese cobra (Naja atra and the White-lipped pit viper (Cryptelytrops albolabris) produce significant local swelling. Local doctors have difficulty in determining whether to use SIBP Naja atra ASV or pit viper ASV.

If ELISA is to be developed: It is costly to develop the base product It must be rigorously tested to eliminate false positives and negatives It must be based on local snakes; the kits cannot be imported. If your country does not have it now, then it will be many years before it is reliably available. Enzyme Linked Immuno Sorbent Assay testing for snake species and level of envenomation ARE NOT YET AVAILABLE in India. There are known species such as the Hump-nosed pit viper (Hypnale

hypnale) where polyvalent ASV is known to be ineffective. In addition, there are regionally specific species such as Sochurek’s Saw Scaled Viper (Echis carinatus sochureki) in Rajasthan, where the effectiveness of polyvalent ASV may be questionable. Further work is being carried out with ASV producers to address this issue. ASV dosage forms ASV comes in two forms lyophilised powdered and liquid. Lyophilised ASV is simply liquid ASV

freeze-dried. There is NO evidence that clinically one form is better at neutralising venom than the other. They each have advantages or disadvantages that must be considered: Lyophilised Liquid Advantages Advantages Long Shelf Life (3-5 Years) Ready to use Requires no cold chain Disadvantages Disadvantages Speed of reconstitution of 30-60 minutes Short Shelf Life (2 years) Requires a cold chain Liquid ASV requires a reliable cold chain and refrigeration and has a 2 year shelf life. Lyophilised

ASV, in powder form, requires only to be kept cool. This is a useful feature in remote areas where power supply is inconsistent. ASV administration 54

ASV should be given only by the IV route, and should be given slowly, with the physician at the bed side during the initial period to intervene immediately at the first sign of any reaction. The rate of infusion can be increased gradually in the absence of a reaction until the full starting dose has been administered (over a period of ~1 hour). Epinephrine (adrenaline) should always be drawn up in readiness before ASV is administered.

ASV must NEVER be given by the IM route because of poor bioavailability by this route. Also do NOT inject the ASV locally at the bite site since it is not effective, is extremely painful and may increase intra-compartmental pressure. Take all aseptic precautions before starting ASV to prevent any pyrogenic reactions to ASV. ASV Dosage In the absence of definitive data on the level of envenomation, such as provided by ELISA testing

(Greenwood et al, 1974; Theakston et al, 1977; Ho et al, 1986), symptomology is not a useful guide to the level of envenomation. Any ASV regimen adopted is only a best estimate. What is important is that a single protocol is established and adhered to, in order to enable results to be reliably reviewed. This suggests that the total required dose will be between 10 vials to 25 vials as each vial neutralises 6mg of Russell’s Viper venom. Not all victims will require 10 vials as some may be injected with less

than 63mg. Not all victims will require 25 vials. However, starting with 10 vials ensures that there is sufficient neutralising power to neutralise the average amount of venom injected and during the next 12 hours to neutralise any remaining free flowing venom. If the biting snake is identified to be a Saw Scaled Viper, 5 vials may be given as a starting dose. Otherwise in all cases, starting dose remains 10 vials.

Detect remaining free flowing Viper venom by 20WBCT at 6 hours from completion of first dose of 10 vials of ASV, additional 2nd dose can be given after six hours from the 1st dose. There is no evidence that shows that low dose strategies (Paul et al, 2004; Srimannanarayana et al, 2004; Agrawal et al 2005) have any validity in India. These studies have serious methodological flaws: the randomization is not proper, the allocation sequence was not concealed, the evaluators were not

blinded to the outcome; there was no a priori sample size estimation, and the studies were underpowered to detect the principle outcome. The same problem relates to high dosage regimens (Wallace, 2004), often based on Harrison’s textbook of medicine, which was written specifically for U.S. snakes and not intended for use in the developing world. In an attempt to guide physicians, where possible, maximum dose levels have been provided. The

amount of snake venom, injected by the snake is not infinite; it will have an upper range. There is a tendency amongst physicians to believe that more ASV is better, and to continue using ASV past the 55

point where the amount of ASV given is in excess of the maximum amount of venom possible (Bhat 1974). This is both wasteful of resources and expensive. For neuroparalytic snakebite – ASV 10 vials stat as infusion over 30 minutes followed by 2nd dose of 10 vials after 1 hour if no improvement within 1st hour. For vasculotoxic snakebite - Two regimens low dose infusion therapy and high dose intermittent bolus therapy can be used. Low dose infusion therapy is as effective as high dose intermittent

bolus therapy and also saves scarce ASV doses (Adopted). Low Dose infusion therapy – 10 vials for Russell’s viper or 6 vials for Saw scaled viper as stat as infusion over 30 minutes followed by 2 vials every 6 hours as infusion in 100 ml of normal saline till clotting time normalizes or for 3 days whichever is earlier. Or High dose intermittent bolus therapy - 10 vials of polyvalent ASV stat over 30 minutes as infusion,

followed by 6 vials 6 hourly as bolus therapy till clotting time normalizes and/or local swelling subsides. No ASV for Sea snakebite, confirmed Green Pit snakebite even if with signs of envenomation as available ASV do not contain antibodies against them. The recommended dosage level has been based on published research that Russell’s Viper injects on average 63mg SD 7 mg of venom (Tun Pe, 1986). Logic suggests that initial dose should be

calculated to neutralise the average dose of venom injected. This ensures that the majority of victims should be covered by the initial dose and keeps the cost of ASV to acceptable levels. The range of venom injected is 5mg – 147 mg by a Russell’s viper. The total required dose range between 10 and 30 vials as each vial neutralizes 6 mg of Russell’s Viper venom. Depending on the patient condition, additional vials can be considered. ASV dosage in victims requiring life saving surgery

Initial Dosing Exceptions A major exception to the initial dosing guidelines is in the case of need for vital life saving surgery to resolve a serious complication of snakebite. For example, in the case of intracranial bleed, with a requirement for surgery to remove the clot, it is vital to restore coagulation. In such cases before surgery coagulation must be restored to avoid catastrophic bleeding and higher initial dose of ASV

(up to 30 vials) can be administered (A2). The initial dose is high therefore significant care needs to be taken to observe any adverse reactions due to the volume of protein being administered. 56

ASV in syringe 10 vials of AVS dissolved in 100 ml of distilled water and added to 400ml of normal saline Mention date and time of starting infusion Administer 10 vials of ASV in first hour. Maintain slow drip for 24 hours Figure 8. ASV infusion and dosage schedule Each vial of AVS be dissolved in 10 ml of distilled water and added to an infusion medium such as normal saline (i.e. 10 vials of AVS dissolved in 100 ml of distilled water and added to 400ml of normal saline). The volume of infusion is reduced

according to the body size and the state of hydration of the patient. In oliguric patients restrict fluids and use infusion pump to give full dose of ASV over 30 minutes. What can ASV Do and more importantly what can it NOT Do? It is vital to remember the capabilities and limitations of ASV if it is to be used effectively. ASV Can Bind to a venom molecule that it is effective against and neutralise that venom molecule rendering

it unable to bind to the target cell but only whilst the venom molecule is circulating in the blood or lymph and is unbound. ASV prevents the patient’s condition from worsening by neutralising venom that otherwise could have bound and completed its damaging effect on the victim. It does not reverse anything nor does it make the patient better. The latter is the result of the body’s normal functions, such as the liver replacing clotting factors, being able to return to normal by the elimination of the

circulating venom. ASV Cannot: 1) Reverse necrotic action of the venom on tissue 2) Reverse local swelling 3) Reverse renal failure 4) Reverse coagulopathy; the liver does this. 5) Reverse pre synaptic envenoming; the nerve damage is structural and large quantities of ASV are ineffective, the body must regenerate synaptic vesicles 57

6) Prevent local necrosis; the damage is done too quickly and the venom is in the tissue and therefore not reachable by the ASV (Gutierrez et al, 2007) 7) Prevent local swelling; the damage is done too quickly and the venom is in the tissue and therefore not reachable by the ASV (Gutierrez et al, 2007) Some of these points should be obvious and yet they are frequently given as reasons for administering ASV. Swelling and ASV

The most controversial aspect of ASV use is in the case of swelling. The role of ASV in the case of swelling centres on whether: 1. Swelling can be controlled or reduced by ASV 2. Swelling is a useful criteria for administering ASV Swelling: Control or Reduction? The proposed evidential support for ASV to be able to control swelling comes principally from the U.S.A. A number of studies purport to show that ASV has brought swelling under control (Heard et

al, 1999; Thorson et al, 2003; Lavonas et al, 2004). These studies are not robust however, as they link the causal of administering ASV with the outcome of halted swelling: envenoming is a dynamic process and the halting of the swelling may be due to the fact that the oedema-causing portion of the venom is exhausted. Persistent swelling in Viper bites needs no more ASV after the clotting defect is cured. Surgical intervention may be needed to treat prolonged swelling. Monitoring of Patients on ASV therapy

All patients should be watched carefully every 5 min for first 30 min, then at 15 min for 2 hours for manifestation of a reaction. At the earliest sign of an adverse reaction suspend temporarily. Maintain a strict intake output chart and note colour of urine to detect acute kidney injury early. How long after the bite can antivenom be expected to be effective? Antivenom treatment should be given as soon as it is indicated. It may reverse systemic

envenoming even when this has persisted for several days or, in the case of haemostatic abnormalities, for two or more weeks. It is, therefore, appropriate to give antivenom for as long as evidence of the coagulopathy persists. Whether antivenom can prevent local necrosis remains controversial, but there is some clinical evidence that, to be effective in this situation, it must be administered within the first few hours after the bite (Warrell et al., 1976; Tilbury 1982). 58

Test doses have been shown to have no predictive value in detecting anaphylactoid or late serum reactions and should not be used (Warrell et al, 1999). These reactions are not IgE mediated but Complement activated. They may also pre-sensitise the patient and thereby create greater risk. Skin or Conjunctival Test for ASV has been discarded in the WHO, 2010. A false negative Skin test may make the treating doctor reluctant to keep monitoring the patient for any adverse reaction to ASV.

Victims who arrive late Sometimes victims arrive late after the bite, often after several days, usually with acute kidney injury. Determine current venom activity such as bleeding in case of viperine envenomation. Perform 20WBCT and determine if any coagulopathy is present then administer ASV. If no coagulopathy is evident, treat kidney injury, if any. In patients with neuroparalytic envenomation (ptosis, respiratory failure etc.) 1. Continue respiratory support until recovery

2. Give 10 vials of ASV on arrival and if no improvement within one hour repeat 10 vials of ASV (No more than 20 vials of ASV). 3. No further ASV and Atropine Neostigmine (AN) infusion is required ONLY to reverse the Ptosis. Ptosis in Common Krait bite is due to presynaptic blockage, further ASV and Neostigmine dose beyond 3 doses cannot reverse it, since regeneration is a natural process and may take 4-5 days. Both ASV and AN injection should be stopped when the initial syndrome of pharyngeal muscle

palsy is over. ASV and Pregnancy There is little study data on snakebite during pregnancy, mainly due to the fact that much of the literature comes from developed countries where women working in rural areas whilst pregnant are rare. Snakebite during pregnancy is not common (Seneviratne et al, 2002; Sebe et al, 2005). It is unclear if snake venom or components or ASV cross the placenta (Seneviratne et al, 2002).

The common expectation that snakebite invariably leads to spontaneous abortion of the foetus is not supported by available data. In one study in Sri Lanka, only 30% of victims aborted (Seneviratne et al, 2002). In the case of an envenomed victim, ASV is required to neutralise the unbound venom in the normal way. Where ASV is given there is good maternal outcome (Seneviratne et al, 2002). The period of greatest risk appears to be during the first trimester and with cases of systemic

envenoming, particularly with systemic bleeding and coagulopathy (Seneviratne et al, 2002). This would indicate that wherever possible, patients in the first trimester, with systemic signs of envenomation particularly bleeding, should be referred to a gynaecologist for specialised review. In 59

cases of abortion this usually occurred within 7 days of the bite (Seneviratne et al, 2002). ASV dose in pregnancy Pregnant women are treated in exactly the same way as other victims. ASV should be given in the same dose and under the same criteria as standard victims. Refer the victim to a gynecologist for assessment of any impact on the foetus. ASV in Paediatric victims There is often confusion as to the starting dose for children, which concentrates on their body size. It

has been argued that children should receive less ASV due to their smaller body size or larger doses as their blood volume is less and therefore venom can spread faster. The answer to this question lies in clearly understanding the role of ASV. Its function is to neutralise unbound venom, injected by the venomous snake. Snakes do not vary the amount of venom injected into children or adults and therefore the dose of ASV for children is THE SAME as that for adults.

Snakes inject the same dose of venom into children and adults. Children must therefore be given exactly the same dose of antivenom as adults. Antivenom manufacturers, health institutions and medical research organizations should encourage and promote the proper clinical testing of antivenoms as with other therapeutic agents. This is the only reliable guide to the initial dose (and safety) of an antivenom. ASV dose in children

Children also are given exactly the same dose of ASV as adults as snakes inject the same amount of venom into children and adult. Infusion: liquid or reconstituted ASV is diluted in 5-10 ml/kg body weight of normal saline. However, reduce amount of fluid in running bottle to 200 ml to avoid fluid over load. ASV in Repeat bites It is rare for a patient to be bitten again, following a bite from a venomous species. Repeat bites,

however, do carry a slight increased risk of adverse reaction to the ASV, as it has been administered previously. However, some professions like Herpetologists and snake charmers are prone to repeated venomous snakebite). The dosage schedule for ASV in the event of a second bite is, however, unchanged. The same starting dose and repeat dose schedule as for a normal bite applies. If there is concern of an adverse 60

reaction due to a second administration of ASV, then a prophylactic regimen of adrenaline can be considered. Any reaction should be handled in the normal way. ASV REPEAT DOSE Repeat dose in vasculotoxic or haemotoxic envenomation Repeat clotting test every 6 hours until coagulation is restored. Administer ASV every 6 h until coagulation is restored. Envenomation by the Hump-nosed Pit viper does not respond to normal

Indian polyvalent ASV and coagulopathy may continue for up to 3 weeks. If 30 vials of ASV have been administered reconsider whether continued administration of ASV is serving any purpose, particularly in the absence of proven systemic bleeding. If large doses have been administered and the coagulation abnormality persists, give fresh frozen plasma (FFP) or cryoprecipitate (fibrinogen, factor VIII), fresh whole blood, if FFP or cryoprecipitate are not available.

Repeat dose: neuroparalytic or neurotoxic envenomation ASV 10 vials stat as infusion over 30 minutes followed by 2nd dose of 10 vials if no improvement within 1st hour. Repeat 2nd dose may be required even after 2-3 hours if relapse of signs of neurotoxicity are noted (may be due to delayed absorption). Maximum dose is 20 vials of ASV for neurotoxically envenomed patients. Adverse Anti Snake Venom Reactions The concept of adverse reactions to ASV has had a significant negative impact on snakebite

treatment far in excess of the actual risk. Reported levels of ASV reactions have been very high, the risk of fatal anaphylactoid reactions stressed; with the result that doctors have been reluctant to treat victims (World Health Organisation, 1981; Warrell, 1993; Warrell, 1999; Ariaratnam et al, 2001; Warrell, 2003; Isbister et al, 2006; World Health Organisation, 2007; Simpson, 2008; Deshmukh et al, 2014; Deshpande et al 2013). These reactions however, if managed correctly can

be easily treated in even the most basic medical facilities and moves for improvements in ASV quality need to be balanced with costs of so doing (Krifi et al, 1999). Early anaphylactic reactions occurs within 10–180 min of start of therapy and is characterized by itching, urticaria, dry cough, nausea and vomiting, abdominal colic, diarrhoea, tachycardia, and fever. Minority of these patients may develop severe life-threatening anaphylaxis characterized by

hypotension, bronchospasm, and angioedema (WHO 2015). Any new sign or symptom after starting the ASV in drip should be suspected as a reaction to ASV such as vomiting, hot or cold feeling; sudden dry cough, new pain abdomen, dyspnoea; fall of BP and shock, swelling of face, conjunctiva and protrusion of the tongue due to angiooedema. 61

Pyrogenic reactions usually develop 1–2 h after treatment. Symptoms include chills and rigors, fever, and hypotension. These reactions are caused by contamination of the ASV with pyrogens during the manufacturing process. Late (serum sickness–type) reactions develop 1–12 (mean 7) days after treatment. Clinical features include fever, nausea, vomiting, diarrhoea, itching, recurrent urticaria, arthralgia, myalgia, lymphadenopathy, immune complex nephritis and, rarely, encephalopathy. Patients who suffer

early reactions that are treated with antihistamines and corticosteroids are less likely to develop late reactions. (WHO 2015) Mechanism of the Reaction The specific mechanism responsible for generating adverse reactions is not clear. 1. Complement activation directly by the ASV proteins There is some evidence that ASV is able to activate complement in vitro (Sutherland, 1977; Leon et al, 2001; Leon et al, 2005) 2. Complement activation mediated by immune complexes Prediction of Adverse Reactions

A frequently used mechanism in response to ASV reactions is to try and predict them with the use of a ‘test dose’. An intra dermal test dose is administered to the victim, approximately 30 minutes is allowed to elapse and inspection is used to determine if any wheals are present indicating sensitivity. Skin tests are widely used in testing for Type I hypersensitivity allergic reactions. They indicate high

levels of IgE in the presence of a specific allergen. They are of no use in predicting ASV reactions for the following reasons: 1. They are non predictive – ASV reactions are complement activated and not mediated by IgG, they are also de novo reactions (Malasit et al, 1986; Gutierrez et al, 2007) 2. They waste time when the patient needs ASV 3. They may pre-sensitise the patient and make a severe reaction more likely when the major amount of ASV is administered.

Skin and conjunctival “hypersensitivity” tests will reveal IgE mediated Type I hypersensitivity to horse or sheep proteins. However, since the majority of early (anaphylactic) or late (serum sickness type) antivenom reactions result from direct complement activation rather than from IgE-mediated hypersensitivity, these tests are not predictive. Since they may delay treatment and can in themselves be sensitising, these tests should not be used. 62

Preventing Adverse Reactions The use of prophylactic drugs to prevent adverse reactions to ASV is common. Despite the fact that developed country ASVs are often regarded as superior products, reaction rates of 25% or higher are reported when using these ASVs (Isbister et al, 2006; Isbister et al, 2008). The prophylactic approach is based largely on two studies in Sri Lanka, which appeared to show that prophylactic doses of adrenaline or hydrocortisone and antihistamine prevented reactions

(Premawardenha et al, 1999; Gawarammana et al, 2004). No adverse reactions to the adrenaline were observed in this study. However, subsequent fatality (Dassanyake et al; 2002) raised concerns about intracranial bleeding (a known complication of systemic envenoming following bites by vipers, hypertension and arrhythmias, if adrenaline prophylaxis were to be used routinely especially in children, pregnant women and in patients with heart disease. Both these studies were

statistically underpowered, with one stopping half way through the study as the results at that stage were regarded as good! Other poorly constructed retrospective studies also appear to support the use of premedication to prevent reactions (Williams et al, 2007). Other studies have shown no benefit to prophylactic regimens (Isbister et al, 2008) Snake bite victims are anxious and have sympathetic overdrive in form of tachycardia hypertension

excessive sweating, tachypnoea. Routine administration of adrenaline before ASV will lead to augmentation of this symptoms as well as hypertension. In patients with coagulation disorder this will lead to intracerebral bleed. In Indian scenario routine adrenaline is contraindicated in known hypertensive, cardiac disease patients, and if patient presents with blood pressure more than 140/90 in adult victim. A study in Brazil indicated that antihistamine alone was not effective in preventing reaction (Wen-

Fan et al, 1999). Systematic analysis by Habib 2011 reported a substantial beneficial effect of adrenaline pre-medication, but a marginal benefit with the combination of pre-medications used against early adverse reactions could not be excluded. Future studies are recommended and they should explore possible synergism of broader combinations of drugs and effects of mode of antivenom administration in large randomized controlled trials. Meanwhile, highly purified antivenoms with less

risk of early anaphylaxis reaction should be made available in the rural tropics. Routine use of prophylactic adrenaline is recommended before ASV, except in known hypertensive, and if patient presents with blood pressure more than 140/90 in adult victims or if evidence of suspicion of underlying cardiovascular disease. The adult dose of adrenaline (epinephrine) is 0.25 mg of 0.1% solution by subcutaneous injection (Children 0.005 mg/kg body weight of 0.1% solution).

Use of histamine, anti-H1 and anti-H2 blockers, corticosteroids and the rate of intravenous infusion of antivenom between 10 and 120 minutes), do not affect the incidence or severity of early antivenom reactions. (WHO 2015; deSilva 2011; Habib 2011) All patients should be 63

watched carefully for two hours after the completion of antivenom administration and should be treated with epinephrine/adrenaline at the first sign of a reaction [level of evidence T]. WHO Treatment of Adverse Reactions ASV reactions are straightforward to manage if: 1. They are identified early 2. They are treated immediately 3. They are treated with the drug of choice 4. The correct mode of administration of the drug is used 5. Correct reassessment period is used Step 1: Identified Early

Many ASV reactions pass unnoticed as the doctor is not actively looking for them. Local experience with the ASV will almost certainly establish an average time to onset of the reaction. For example, with Indian ASVs the average onset time for reactions is 20 minutes (Kochar et al, 2007). This is a key period to examine the patient carefully, particularly across the trunk, as this is where reactions are first evident. A useful technique is to shine a torch across the trunk as this casts the urticaria in

shadow. Step 2: Treated Immediately At the first sign of a reaction, stop the ASV. The first signs include a single patch of urticaria or any itching. Often the patient will become restless just before these signs and symptoms manifest. Other symptoms are vomiting, hot or cold feeling; sudden dry cough, new pain abdomen, dyspnoea; fall of BP and shock, swelling of face, conjunctiva and protrusion of the tongue due to angio- oedema. Step 3: Drug of Choice

Administer Epinephrine (adrenaline) (1 in 1,000 solution, 0.5 mg (i.e. 0.5 ml) in adults intramuscular over deltoid or over thigh; In children 0.01 mg/kg body weight) for early anaphylactic and pyrogenic ASV reactions. Ideally 2 syringes should be drawn up ready if the ASV is known to cause frequent reactions. Administer Chlorpheniramine maleate (adult dose 10 mg, in children 0.2 mg/kg) intravenously. Step 4: Correct Mode of Administration

The critical factor in managing ASV reactions is speed! The longer the reaction persists, the longer 64

will be the period the victim is without ASV and the more venom will be permitted to bind to the target cells. Therefore speed of effect of adrenaline is critical. The mode of administration therefore is intramuscular (IM). The deltoid muscle is the best site (American Association of Allergy, Asthma, and Immunology, 2003; McClean-Tooke et al, 2003; Simons et al, 2001). The time for adrenaline to reach peak effect is 8 minutes via the IM route and 34 minutes via the

subcutaneous route (Simpson, 2007). Despite a preponderance of doctors who would use the subcutaneous route, IM is the first option (Simons et al, 2001; Simpson, 2008). In extremely rare, severe life threatening situations, 0.5mg of 1:10,000 adrenaline can be given IV. This carries a risk of cardiac arrhythmias however, and should only be used if IM adrenaline has been tried and the administration of IV adrenaline should be carried out in the presence of ventilatory equipment and ICU trained staff.

Step 5: Correct Reassessment Period Once the initial dose of adrenaline is given IM, the patient is closely monitored. Around 3 minutes, the patients pulse rate should begin to increase confirming the drug was correctly administered IM. At 8 minutes, the adrenaline will reach peak levels and at this stage 5-7 minutes are spent examining the patient for signs of improvement. If none are evident or the patient’s condition has

worsened, a second dose is administered IM. In very rare cases, a third dose may be necessary. (expert consensus). The majority of patients will respond to a single dose, the remainder will respond to the second dose. Using the IM route it is possible to administer 2 doses of adrenaline in the same time, as it would take a single dose of subcutaneous adrenaline to reach peak effect. After adrenaline, Promethazine HCl 25mg IM (children 0.5mg/kg/ day IV or Promethazine HCl can

be used at 0.3-0.5mg/kg IM, or Chlorpheniramine maleate 10mg (children 0.2 mg/kg by IV injection over a few minutes and f hydrocortisone 100mg (children 2mg/kg) IV but is unlikely to act for several hours. Corticosteroids do not reduce the risk of recurrence (biphasic anaphylaxis). (WHO 2015) Once the patient has recovered the ASV can be restarted slowly for 10-15 minutes keeping the patient under close observation. Then the normal drip rate should be resumed. (WHO 2015)

Late Serum sickness reactions can be easily treated with an oral steroid such as prednisolone, adults 5mg 6 hourly, paediatric dose 0.7mg/kg/day. Chlorpheniramine 2 mg 6 hourly orally (children 0.25 mg/kg/day in divided doses). Contraindications to antivenom & Prophylaxis of high risk patients 65

There is no absolute contraindication to antivenom treatment, but patients who have reacted to horse (equine) or sheep (ovine) serum in the past (for example, after treatment with equine anti- tetanus serum, equine anti-rabies serum or equine or ovine antivenom) and those with a strong history of atopic diseases (especially severe asthma) are at high risk of severe reactions and should therefore be given antivenom only if they have signs of systemic envenoming.

These high risk patients may be pre-treated with subcutaneous epinephrine (adrenaline) 0.25 mg of 0.1% solution just before antivenom treatment is started followed by an intravenous antihistamines (both anti-H , such as promethazine or chlorpheniramine; and anti-H , such as 1 2 cimetidine or ranitidine) and corticosteroid. In asthmatic patients, prophylactic use of an inhaled adrenergic β agonist such as salbutamol may prevent bronchospasm (de Silva et al, 2011). 2 For high risk patients

In patients with history of hypersensitivity or exposure to animal serum such as equine ASV, tetanus-immune globulin or rabies-immune globulin in past, severe atopic conditions: 14. Give ASV only if they have signs of systemic envenoming. 15. Subcutaneous epinephrine (adrenaline) 0.25 mg of 0.1% solution to be given just before antivenom treatment is started 16. Give Inj. Hydrocortisone 200 mg and Chlorpheniramine maleate 22.75 mg prior to the administration of ASV.

Treatment of Late (serum sickness–type) reactions Inj. Chlorpheniramine 2 mg in adults (In children 0.25 mg/kg/day) 6 hourly for 5 days. In patients who fail to respond within 24–48 h give a 5-day course of Prednisolone (5 mg 6 hourly in adults and 0.7 mg/kg/day in divided doses in children. Desensitization procedure only in case of severe anaphylaxis reaction to ASV • Desensitization protocol is needed rarely in patients who develop severe anaphylaxis with shock

and generalised anasarca after injection of very few ml of ASV usually less than 5 ml of diluted ASV. This protocol takes 3 - 4 hours and should be reserved for exclusively such patients. • Change the batch of ASV. Pre-medication: Administer Inj. Hydrocortisone 100 mg I.V. and Inj. Adrenaline 0.5 ml subcutaneously/ intramuscularly (± Promethazine) Table . Steps of dilution of ASV Steps Instructions Total Solution Dilution of Volume dilution 66

1. Dilute 1 ml of ASV in a vial with 10ml A 10 ml of normal saline 2. 1ml of solution A + 9 ml of 10 ml B 1: 10 saline 3. 1ml of solution B+ 9 ml of 10 ml C 1: 100 saline 4. 1ml of solution C + 9 ml of 10 ml D 1: 1000 saline 5. 1ml of solution D + 9 ml of 10 ml E 1: 10,000 saline After dilution and preparation of Solution E, Observation of the response to ASV If an adequate dose of appropriate antivenom has been administered, the following responses may be observed.

General: The patient feels better. Nausea, headache and generalised aches and pains may disappear very quickly. This may be partly attributable to a placebo effect. Spontaneous systemic bleeding (e.g. from the gums): This usually stops within 15-30 minutes. Blood coagulability (as measured by 20WBCT): This is usually restored in 3-9 hours. Bleeding from new and partly healed wounds usually stops much sooner than this.

In shocked patients: Blood pressure may increase within the first 30-60 minutes and arrhythmias such as sinus bradycardia may resolve. 67

Neurotoxic envenoming of the post-synaptic type (cobra bites) may begin to improve as early as 30 minutes after antivenom, but usually takes several hours. Envenoming with presynaptic toxins (kraits and sea snakes) will not respond in this way. Active haemolysis and rhabdomyolysis may cease within a few hours and the urine returns to its normal colour. Red colour urine may persist for several days in spite of adequate ASV treatment due to damage of Renal papillae, no further ASV can help).

ASV in Recurrence of systemic envenoming In patients envenomed by vipers, after an initial response to antivenom (cessation of bleeding, restoration of blood coagulability) signs of systemic envenoming may recur within 24-48 hours. This is attributable to: • Continuing absorption of venom from the “depot” at the site of the bite, perhaps assisted by improved blood supply following correction of shock, hypovolaemia etc, after elimination of

antivenom (range of elimination half-lives: IgG 45 hours; F(ab’) 80-100 hours; Fab 12-18 hours) 2 (Ho et al., 1986; Ho et al., 1990) • Redistribution of venom from the tissues into the vascular space, as the result of antivenom treatment (Rivière et al., 1997). • Recurrent neurotoxic envenoming after treatment of cobra bite has also been described. When coagulation has been restored no further ASV should be administered, unless a proven

recurrence of a coagulation abnormality is established. There is no need to give prophylactic ASV to prevent recurrence (Srimannarayana et al, 2004). Recurrence has been a mainly US phenomenon, due to the short half-life of Crofab ASV. Indian ASV is a F(ab) product and has a half-life of over 90 2 hours and therefore is not required in a prophylactic dose to prevent re-envenomation. Evidence suggests that ‘reversibility’ of pre synaptic neurotoxic envenoming is only possible in the

first few hours. After that the body recovers by using its own mechanisms. Large doses of ASV, over long periods, have no benefit in reversing envenomation. Confusion has arisen due to some medical textbooks suggesting that ‘massive doses’ of ASV can be administered, and that there need not necessarily be a clear-cut upper limit to ASV’ (Pillay, 2005). These texts are talking about snakes which inject massive amounts of venom, such as the King

Cobra or Australian Elapids. There is no justification for massive doses of 50+ vials in India (Agrawal et al, 2001), which usually result from the continued use of ASV whilst the victim is on a ventilator. No further doses of ASV are required; unless a proven recurrence of envenomation is established, additional vials to prevent recurrence is not necessary. 68

Facts to be remembered while administering ASV (Tamil Nadu) 1. ASV is available in a polyvalent form and marketed in liquid or lyophilised preparations in 10ml vial / ampoule. 2. Remember to use and maintain cold chain system for liquid form. Users are informed to ascertain whether the cold chain is maintained. 3. There is no dose adjustment for ASV administration for children. 4. Before administering ASV, health staff should read and check the status of vial or ampoule containing ASV.

5. Elicit history of prior exposure to ASV. If a patient had received ASV earlier and comes back with features of snake envenomation again, he / she has to be considered as a fresh case and treated accordingly. However, care should be taken while administering ASV, since he / she has been sensitised. 6. ASV treatment should be initiated with readiness with adequate agents for managing anaphylaxis or anaphylactoid reaction.

7. Anaphylactic or late serum sickness cannot be determined or prevented by test dose. Therefore, do not administer ASV test dose. 8. ASV neutralises the unbound venom, hence give it early. 9. ASV administration should not be delayed or denied on the grounds of anaphylactic reactions to a deserving case. 10. ASV is required only in those who show definite signs and symptoms of envenomation. 11. ASV can be administered slowly as IV infusion or high dose intermittent bolus in normal saline. No

local administration of ASV at the site of bite as it has been proven to be ineffective and painful, and raises the intra-compartmental pressure, particularly in the digits. 12. Give premedication with Epinephrine by SC route except in hypertensive and cardiovascular disease patients. 14. NEUROTOXIC ENVENOMATION Antivenom treatment alone cannot be relied upon to save the life of a patient with bulbar and respiratory paralysis.

Neostigmine is an anticholinesterase that prolongs the life of acetylcholine and can therefore reverse respiratory failure and neurotoxic symptoms. It is particularly effective for post synaptic neurotoxins such as those of the Cobra (Watt et al, 1986). There is some doubt over its usefulness against the pre-synaptic neurotoxin such as those of the Krait and the Russell ’s viper (Warrell et al, 1983; Theakston et al, 1990). However it is worth trying in these cases.

1. In all cases of neurotoxic envenomation the 'AN challenge Test' is administered, Do not give AN in case of confirmed krait bite. Atropine 0.6 mg followed by neostigmine (1.5mg) to be given IV stat and repeat dose of neostigmine 0.5 mg with atropine every 30 minutes for 5 doses (In children, Inj. Atropine 0.05 mg/kg followed by Inj. Neostigmine 0.04 mg/kg Intravenous and repeat dose 0.01 mg/kg every 69

30 minutes for 5 doses). A fixed dose combination of Neostigmine and glycopyrolate IV can also be used. Thereafter to be given as tapering dose at 1 hour, 2 hour, 6 hours and 12 hour. Majority of patients improve within first 5 doses. Observe the patient closely observed for 1 hour to determine if the neostigmine is effective. After 30 minutes, any improvement should be visible by an improvement in ptosis. Positive response to “AN” trial is measured as 50% or more recovery of the ptosis in one hour.

Stop Atropine neostigmine (AN) dosage schedule if: a) Patient has complete recovery from neuroparalysis. Rarely patient can have recurrence, carefully watch patients for recurrence. b) Patient shows side effects in the form of fasciculations or bradycardia. c) If there is no improvement after 3 doses. Improvement by atropine neostigmine indicates Cobra bite. A few Nilgiri Russell’s viper bites victims also improve with this regimen.

Give one dose of “AN” injection before transferring to the higher centre. Rapid deterioration of Cobra bite neurotoxic syndrome may kill the patient on the way to transfer. If there is no improvement after 3 doses of atropine neostigmine, this indicates probable Krait bite. Krait affects pre-synaptic fibres where calcium ion acts as neurotransmitter. Give Inj. Calcium gluconate 10ml IV (in children 1-2 ml/kg (1:1 dilution) slowly over 5-10 min every 6

hourly and continue till neuroparalysis recovers which may last for 5-7 days. A trial of anticholinesterase (“AN test”) should be performed in every patient with neurotoxic envenoming, as it would be in any patient with suspected myasthenia gravis. However, this should not delay antivenom treatment or endotracheal intubation. Patients must be observed closely as they may deteriorate while the trial of anticholinesterase is being carried out.

Some authors have suggested that it may be possible to treat patients with anticholinesterase drugs solely, in the case of elapid bites (Bomb et al, 1996). However this approach ignores the value of neutralising the free flowing venom before it can attach and require reversing. Anticholinesterase drugs being used, as a substitute for ASV should only be considered if no ASV is available (Bomb et al, 1996). The more venom that can be neutralised before it binds to target receptors reduces the

severity of the envenomation (A2) In case of Cobra bite, if the patient attends a small centre where indoor admission facility is not available; one dose of “AN” injection should be given before transferring to the next indoor centre. Rapid deterioration of Cobra bite neurotoxic syndrome may kill the patient on the way to transfer. This is applicable in emergency Ambulance service for Snakebite also. 70

Airway Support Items In the case of unconscious patients suffering from neurotoxic envenoming death may result from aspiration, airway obstruction or respiratory failure. In the vast majority of cases, if the patient’s breathing is maintained, they will survive. The critical period is usually the journey from the initial contact with medical care to the more advanced hospital with mechanical ventilation. A clear

airway must be maintained. Once there is loss of gag reflex and pooling of secretions in the pharynx, failure of the cough reflex or respiratory distress, a cuffed endotracheal tube or laryngeal mask airway (LMA) should be inserted. If this is impossible for any reason, a tracheostomy should be performed and a snugly-fitting or cuffed tracheostomy tube inserted. All the Medical Officers posted in the Rural Health centres must have training (induction training

after posting) on Endotracheal intubation. All the Ambulances and Rural Health Centres must have 2-3 LMA in stock). Training at Poison Control Centre at Madras Medical College could be a Model for each state. Although artificial ventilation was first suggested for neurotoxic envenoming 140 years ago, patients continue to die of asphyxiation because some doctors believe that antivenom alone is sufficient treatment (WHO 2015).

If treating the patient in a peripheral hospital with no access to mechanical ventilation, the patient’s inability to perform a neck lift will trigger referral to a better-equipped hospital. The patient, either conscious or unconscious will require airway support on the journey, as that is where respiratory failure is likely to occur. A number of options are available. In many primary care hospitals facilities are basic and airway support equipment is limited. Usually

the equipment consists of a resuscitation bag alone, which can be used to maintain a victim’s air supply in the short term. Family members or friends can be instructed in the use of this equipment should it become necessary on the journey. The important points to communicate are that the mask should be placed over both the nose and mouth in a rolling manner starting at the bridge of the nose. Preferably, bag-valve-mask ventilations are given using the “C-E” grips [thumb and index

finger of each hand forming a “C” over top of the mask and long, ring and little fingers forming an “E” under the jaw – pressing the mask onto the face]. The bag should be squeezed at a specific cadence of “squeeze – release – release.” This method ensures the victim receives a good quantity of air but also allows time for exhalation. However, in cases of neurotoxic envenomation, if respiratory failure occurs it will be due to flaccid

paralysis and there is a strong likelihood that the tongue will fall back and obstruct the airway. The effective functioning of a resuscitation bag in these circumstances will be highly limited. Nasopharyngeal airway (NPA) support is an excellent emergency measure in these situations (Bajaj et al, 2008). If available, NPAs should be inserted before transportation to the referral hospital, which will dramatically increase the probability of effective respiratory support during the journey. 71

It is possible however to improvise nasopharyngeal tubes (NT) from endotracheal tubes (ET), which are usually readily available or can be obtained easily. Two rubber or plastic size 6.5 ET tubes for females, size 7 for males or size 5 for either can be adapted to provide NT (Roberts et al, 2005). The tubes are cut to the distance between the nostril and the tragus, lubricated and inserted into the nostrils of a conscious or unconscious patient (Quraishi et al, 2008; Simpson and Jacobsen, 2009).

Cut to the correct length they will not trigger the gagging reflex and thus can be used when a patient is conscious (Simpson and Jacobsen, 2009). In the event that a patient cannot perform a neck lift and is to be transferred to a better-equipped hospital, the tubes can be inserted and the individuals accompanying the victim instructed to use the resuscitation bag if the victim stops breathing (Simpson and Jacobsen, 2009). Bridging Devices

An improved solution is the use of an airway-bridging device such as a laryngeal tube (LT) or laryngeal mask airway (LMA) (Simpson, 2007). These devices are not “definitive” airways (defined as a cuffed endotracheal tube positioned below the vocal cords), but provide excellent airway support. They are inserted blindly and give a very high percentage possibility of being inserted correctly (Bailey and Hett, 1994; Springer and Jahr, 1995; Pollack, 2001; Murphy, 2004; Murphy

and Schneider, 2004; Wiese et al, 2008). Use of such airways by accompanying laypersons has not been studied, but it is very possible that the lay provider can adequately ventilate the unconscious victim during transfer using a properly placed laryngeal tube. The creation of a better seal makes the use of an LT tube more preferable over rough journeys experienced when transporting snakebite victims in many developing countries (Ocker et al, 2002; Gaitini et al, 2008)

Use of the LMA requires greater skill in maintaining proper positioning, making it a less optimal choice for use by untrained individuals. The Ideal Solution The ideal solution is the ability to endotracheally intubate the victim and provide a definitive airway defined as placing a cuffed tube below the vocal chords (Akram et al, 2004). However, in primary care centres in many developing countries, the equipment is unavailable and doctor

confidence in performing intubation is not high (Simpson, 2007; Simpson and Jacobsen, 2009). The endpoint therapy will be a mechanical ventilator to provide long-term respiratory support. In presynaptic envenoming, the period of ventilation may be extensive whilst the body restores synaptic vesicles. However, in developing countries, where such facilities are limited, an improvised or bridging solution is necessary to ensure the victim survives the inevitable journey. Developed world derived

protocols advising endotracheal intubation or tracheostomy, once loss of the gag reflex or pooling 72

of secretions occurs is simply impractical in most developing world facilities (Warrell, 1999; Simpson and Jacobsen, 2009). 15. HAEMOTOXIC ENVENOMATION, BLOOD PRODUCTS AND RENAL IMPAIRMENT The presence of systemic bleeding with or without hypotension is a common feature of snakebite, particularly in the case of viperine bites. Hypotension, severe reductions in haemoglobin concentration, platelet reductions i.e. thrombocytopenia, or frank bleeding can increase the pressure to administer blood related

products. Hypotension due to action of the venom can have a number of causes in snakebite, ranging from loss of circulating volume due to haemorrhaging, vasodilation due to the action of the venom or direct venom effects on the heart. Test for hypovolaemia by examining the blood pressure lying down and sitting up, to establish a postural drop. In the majority of cases the timely use of ASV will stop systemic bleeding. However in some cases

the bleeding may continue to a point where further treatment should be considered. 1. Strict bed rest to avoid even minor trauma. 2. Screen for hematuria, hemoglobinuria, myoglobinuria by Dipstick method. Dipstick test is positive in all three presentations listed above. Centrifuged urine showing pink colour indicates hemoglobinuria, clear supernatant (RBCs settle down as deposit) indicates myoglobinuria. 3. Closely monitor urine output and maintain 1 ml/kg/h urine output.

4. Volume Replacement in snake bite: If the patient has intravascular volume depletion, indicated by supine or postural hypotension, or empty neck veins, proceed as follows: (1) Establish intravenous access. (2) Give fluid challenge: An adult patient can be given two litres of isotonic saline over one hour or until the jugular venous pressure/central venous pressure has risen to 8-10 cm above the sterna angle (with the patient propped up at 450). Observe the patient closely while this is being

done. The fluid challenge must be stopped immediately if pulmonary oedema develops. In cases where generalised capillary permeability has been established a vasoconstrictor such as dopamine can be used. Dosing is 2.5- 5µg/kg/minute. Treatment is by means of plasma expanders and raising the foot of the bed. There is no conclusive trial evidence to support a preference for colloids or crystalloids. In addition fresh

frozen plasma or factors present a possibility in order to boost volume and restore factors. In many areas, particularly in developing countries, the only available alternative will be fresh blood. 73

Persistent or Severe bleeding In the majority of cases the timely use of ASV will stop systemic bleeding. However in some cases the bleeding may continue to a point when further treatment should be considered. The major point to note is that clotting must have been re-established before additional measures are taken. Adding clotting factors, FFP, cryoprecipitate or whole blood in the presence of un-neutralised venom will increase the amount of degradation products with the accompanying risk to the renal

function (White, 2005). Role of Anticoagulants When there are signs of current bleeding such as bleeding from the gums, there is the intuitive thought that coagulants can play a role in inhibiting bleeding. For example, drugs such as Botropase, a coagulant, are sometimes used in response to visible bleeding. It is however, a compound derived from the venom of one of two South American pit vipers both of which cause

coagulation by activating the clotting cascade. It uses the same means to achieve coagulation as the snake concerned in the envenomation and should not be used in viper bites as it simply prolongs the coagulation abnormality by causing consumption coagulopathy in the same way. Other drugs such as heparin have been intuitively thought to be beneficial in snakebite induced coagulation and DIC and apparently supported but by very weak research (Paul et al, 2003; Paul et al, 2008).

However, like much of what is intuitively recommended in snakebite, heparin is contraindicated. Venom induced thrombin is resistant to Heparin, the effects of heparin on antithrombin III are negated due to the elimination of ATIII by the time heparin is administered and in itself heparin can cause bleeding. In the case of trial evidence, heparin has been shown to have no beneficial effect (Tin et al, 1992; White, 2005). Heparin is ineffective against venom-induced thrombin and may cause bleeding on its

own account. It should never be used in cases of snake-bite. Antifibrinolytic agents are not effective and should not be used in victims of snake-bite. Dangers of venipuncture in patients with haemostatic abnormalities In patients with incoagulable blood, any injection (subcutaneous, intramuscular) and, particularly venepuncture, carries a risk of persistent bleeding and haematoma formation. Repeated venipuncture can be avoided by using an indwelling cannula and three-way tap system.

When blood coagulability has been restored, the dead space should be filled with heparinised saline, but if this is not flushed out before blood sampling, misleading results will be obtained in clotting tests, including the 20WBCT. Arterial puncture is contraindicated in such patients. 74

In patients with coagulopathy, sites of venous access and placement of intravenous cannulae or catheters should be chosen where haemostasis by external pressure is most likely to be effective, e.g. the antecubital fossa. If possible, avoid jugular, subclavian and femoral vein puncture. A pressure pad must be applied at the site of any venipuncture. Longer Term Issues Russell’s Viper bites are known to cause acute pituitary adrenal insufficiency (Tun Pe et al, 1987 ;

Eapen et al 1976). This condition may contribute to shock. Follow-up checks on known Russell’s Viper victims need to ensure that no long term pituitary sequelae are evident. Renal Failure Renal failure is a common complication of species such as Russell's Viper. The contributory factors are intravascular haemolysis, DIC, direct nephrotoxicity and hypotension and rhabdomyolysis (Chugh et al, 1975; Shastry et al, 1977; Than-Than et al, 1989). The contributory factors are

intravascular haemolysis, DIC, direct nephrotoxicity and hypotension (Chugh et al, 1975) and rhabdomyolysis. Renal damage can develop very early in cases of Russell’s viper bite and even when the patient arrives at hospital soon after the bite, the damage may already have been done. Studies have shown that even when ASV is administered within 1-2 hours after the bite, it was incapable of preventing ARF (Myint-Lwin et al, 1985).

Declining renal parameters require referral to a specialist nephrologist with access to dialysis equipment. Peritoneal dialysis could be performed in secondary care centres. Haemodialysis is preferable in cases of hypotension or hyperkalaemia. Oliguric phase of renal failure Most, but not all, patients with acute renal failure are oliguric, defined as a urine output of less than 400 ml/day or less than 20 ml/hour. Conservative management may avoid the need for dialysis.

If the patient has intravascular volume depletion, indicated by supine or postural hypotension, or empty neck veins, proceed as follows: 1. Establish intravenous access. 2. Give fluid challenge: An adult patient can be given two litres of isotonic saline over one hour or until the jugular venous pressure/ central venous pressure has risen to 8-10 cm above the sternal angle (with the patient propped up at 45º). The patient must be closely observed

while this is being done. The fluid challenge must be stopped immediately if pulmonary oedema develops. If the urine output does not improve it is reasonable to try a furosamide and/ or mannitol challenge, but these are not of proven benefit. In a recent case in CNMC&H 75

where Creatinine was 4mg/dl; this challenge test worked successfully to avoid Dialysis in a 45 y old female bitten by Russell’s viper. In some patients it can be difficult to determine the height of the central venous pressure by clinical examination. Direct measurement of central venous (superior vena caval) pressure through a long catheter, preferably inserted at the antecubital fossa, can be helpful in this circumstance. The catheter is connected to a saline manometer, the 0 point of which must

be placed at the same level as the right atrium (that is, at the sternal angle when the patient is propped up at 45º). However, in someone who is obviously volume-depleted, resuscitation should start immediately, and not be delayed until a central venous line has been inserted. 3. Insert a urethral catheter with full sterile precautions 4. If the patient has oliguria or dipstick positive for blood give a trial of forced alkaline diuresis

(FAD) within first 24 hours of the bite to avoid pigment nephropathy leading to acute tubular necrosis (ATN). Delayed FAD has no role. Sequence of FAD in adults is as follows: a) Inj. Frusemide 40 mg IV stat b) Inj. Normal saline 500 ml + 20 ml of NaHCO over 20 minutes 3 c) Inj. Ringer’s lactate 500 ml + 20 ml of NaHCO over 20 minutes 3 d) Inj. 5% dextrose 500 ml + 10 ml of Potassium Chloride over 90 minutes e) Inj. Mannitol 150 ml over 20 min

Whole cycle completes in 2 h 30 min and urine output of 3 ml/min is expected. If patient responds to first cycle continue for 3 cycles. FAD converts oliguria into polyuria and avoid ATN and acute kidney injury needing dialysis in more than 75% patients. If there is no response to furosemide discontinue FAD and refer patient immediately to a higher center for dialysis. 5. Conservative management: If the urine output does not improve, despite these challenges

no further diuretics should be given and fluid intake should be restricted to a total of the previous day’s output plus “insensible losses” (500-1000 ml/day). If possible, the patient should be referred to a renal unit. The diet should be bland, high on calories (1700/day), low in protein (less than 40g/day), low in potassium (avoid fruit, fruit juices and potassium- containing drugs) and low in salt. Infections will cause tissue breakdown and increase urea

levels. They should be prevented or treated promptly with non-nephrotoxic antibiotics (i.e. avoid aminoglycosides such as gentamicin). 6. Biochemical monitoring: Serum potassium, urea, creatinine and, if possible, pH, bicarbonate, calcium and phosphate should be monitored frequently. If this is not possible the electrocardiogram (ECG) should be examined for evidence of hyperkalaemia, especially following bites by sea snakes, or Sri Lankan or South Indian Russell’s vipers, or if the patient is

passing dark brown urine, indicating rhabdomyolysis or intravascular haemolysis. 7. Detection and management of hyperkalaemia: ECG evidence of hyperkalaemia: tall peaked T waves, prolonged P-R interval, absent P waves, wide QRS complexes. Emergency treatments, which will control hyperkalaemia for 3-6 hours only, should be given if serum potassium >6.0 mmol/l A. Give 10 ml of 10% calcium gluconate intravenously over 2 minutes (with ECG 76

monitoring if possible) repeated up to three times B. Give 50 ml of 50% dextrose with 10 units of soluble insulin intravenously C. Sodium bicarbonate (40 ml of 8.4%) by slow intravenous infusion D. A β agonist aerosol by inhaler (e.g. salbutamol 5-10 mcg) may also be used. 2 8. Management of severe acidosis: If the patient is hypotensive and profoundly acidotic (deep sighing “Kussmaul” respirations, very low plasma bicarbonate concentration or very low pH -

<7.10), sodium bicarbonate should be given. Based on volume of distribution of bicarbonate which is 40% of body weight, bicarbonate deficit can be calculated. Usually 2-3 ampoules (40 ml of 8.4% sodium bicarbonate equivalent to 1 mmol/ml) in 5% dextrose water, or half of the calculated deficit can be replaced in 3-4 hours. Severe acidosis in snakebite is usually associated with acute renal failure. Volume expansion by sodium bicarbonate can cause fluid

overload. Therefore, if there is no clinical improvement dialysis is required. Intravenous bicarbonate may precipitate profound hypocalcaemia and fits, especially in patients with rhabdomyolysis. 9. Dialysis: Indications for dialysis • (a) Absolute value of Blood urea >130 mg/dl (27 mmol/L) (BUN 100 mg/dl), Sr. Creatinine > 4 mg/dl (500 μmol/L) OR evidence of hypercatabolism in the form of daily rise in blood urea 30 mg/dL (BUN > 15), Sr. Creatinine > 1 mg/dL, Sr. Potassium > 1 mEq/L and fall in

bicarbonate >2 mmol/L • Fluid overload leading to pulmonary oedema • Hyperkalaemia (>7 mmol/l (or hyperkalaemic ECG changes) • Unresponsive to conservative management. • Uremic complications – encephalopathy, pericarditis. nausea, vomiting, hiccups, fetor, drowsiness, confusion, coma, flapping tremor, muscle twitching, convulsions, pericardial friction rub, signs of fluid overload. Prevention of renal damage in patients with myoglobinuria or haemoglobinuria

To minimize the risk of renal damage from excreted myoglobin and/or haemoglobin (WHO 2015): Correct hypovolaemia (see above) and maintain saline diuresis (if possible) Correct severe acidosis with bicarbonate (see above) Give a single infusion of mannitol (200 ml of 20% solution over 20 minutes) (not of proven benefit) Diuretic phase of kidney injury This is as important and as life-threatening as the oliguric phase. Urine output increases to 5-10

litres/24 hours following the period of anuria. The patient may become polyuric and volume depleted so that salt and water must be carefully replaced. Hypokalaemia may develop, in which case a diet rich in potassium (fruit and fruit juices) is recommended. 77

Renal recovery phase The diuretic phase may last for months after Russell’s viper bite. In Myanmar and South India, hypopituitarism may complicate recovery of Russell’s viper bite victims. Corticosteroid, fluid and electrolyte replacement may be needed in these patients. Persisting renal dysfunction In Myanmar, persistent tubular degenerative changes were observed in Russell’s viper bite victims who showed continuing albuminuria, hypertension and nocturia for up to 11 months after the bite,

despite apparent recovery in renal function. In India, 20%-25% of patients referred to renal units with acute renal failure following Russell’s viper bite suffered oliguria for more than four weeks suggesting the possibility of bilateral renal cortical necrosis. This can be confirmed by renal biopsy or contrast enhanced CT scans of the kidneys. In Sri Lanka, some patients envenomed by hump-nosed pit vipers develop chronic kidney dysfunction requiring

dialysis or renal transplantation but these options are not open to impoverished rural people. Patients with patchy cortical necrosis show delayed and partial recovery of renal function but those with diffuse cortical necrosis require regular maintenance dialysis and eventual renal transplantation. 16. PAIN, WOUND MANAGEMENT AND THE SURGICAL ASPECTS OF SNAKEBITE Pain and Wound Management Snakebite is painful! The action of the spreading factor and tissue damaging toxins in the venom

can cause significant pain at the bite site and in the bitten limb. Pain relief is a vital but often overlooked aspect of snakebite management. The drug of choice is Paracetamol, Adult dose of 500-1000mg 4-6 hourly. Paediatric dose 10mg/kg every 4-6 hourly orally. If available, mild opiates such as Tramadol, 50 mg can be used orally for relief of severe pain. In cases of severe pain at a tertiary centre, Tramadol can be given IV. Aspirin should not be used due

to its adverse impact on haemostasis due to inhibition of platelet aggregation. Do not use non- steroidal anti-inflammatory drugs (NSAIDs) as they can cause bleeding. This can be particularly dangerous in a patient already having coagulopathy. Antibiotics and Tetanus There are many factors that contribute to potential infection in snakebite, including poor or dangerous first aid, oral snake flora and environmental factors (Ehui et al, 2007; Habib, 2003).

There has been considerable confusion concerning the role of antibiotics in snakebite management. Some texts have argued for routine prophylaxis with antibiotics, due to the bacterial content of the snakes mouth and saliva, others have argued against routine prophylaxis, reserving antibiotics for use only where local necrosis is present (Blaylock, 2001). 78

In cases where the victim has cut the wound or in cases of necrosis, antibiotic use is advised (Blaylock, 1999). Where wound infection is suspected give prophylactic broad-spectrum antimicrobial treatment for cellulitis after completion of first 10 vials of ASV) with following. 1. Inj. Amoxiciilin+ clavulanic acid 1.2 g IV thrice daily for first 7 days then switch to oral therapy Tab. Amoxiciilin+clavulanic acid 625 mg three times a day for further 3-7 days; In

children, the dose is 100 mg/Kg/day in three divided doses intravenously; for oral therapy, the dose is 50 mg/kg/day in three divided doses. 2. Inj. Metronidazole 400 mg IV infusion thrice daily for 7 days; in children- 30 mg/kg/day in 3-4 divided doses. Alternatively Inj Ceftriaxone 1 g IV twice daily (in children the dose is 100 mg/kg/day in two divided doses)for 7 days. Both Amoxiciilin+ clavulanic acid and Ceftriaxone are mainly excreted through

Kidney. Therefore, in case of acute kidney injury in Viper bites dose of both these antibiotics should be reduced and adjusted according to renal function. Tetanus booster doses, if not immunized already should be given although these can be delayed until coagulation is restored in cases with incoagulable blood. In many areas tetanus inoculation will not be thorough and tetanus toxoid should thus be given. 17. SNAKE VENOM OPHTHALMIA

Sometimes Naja Kouthia venom may spit into the eye of a careless snake handler while handling a Naja kouthia holding it close to the face. This venom is directed at the eyes and causes extreme pain and conjunctivitis. Management of venom ophthalmia 1. Urgent decontamination by copious irrigation with drinking water 2. Instill topical 0.5% adrenaline in the eye 3. Topical administration of local anaesthetics – Tetracaine or Proparacaine HCl. Exclude corneal

abrasions by fluorescein staining with a slit-lamp examination and application of prophylactic topical antibiotics Moxifloxacin eye drops 6 times a day 4. Prevent posterior synechiae, ciliary spasm and discomfort with topical cycloplegics 5. Antihistamines in case of allergic keratoconjunctivitis. Topical or intravenous antivenom and topical corticosteroids are contraindicated. Corneal injury should be managed by an Ophthalmologist only. Surgery and Snakebite

Surgical interventions are a contributory factor in resolving snakebite but must be used with caution. In developing countries surgical procedures can be carried out unnecessarily based on reliance on developed world approaches. Some interventions are necessary and should be deployed 79

when required such as life saving procedures and removal of necrotic tissue. Others such as fasciotomy should be used sparingly and under much defined conditions. Skin grafting and amputation of a necrotic digit may be required in some cases of snakebite. These cases should be referred to the surgeon after completion of antivenom treatment. Surgical interventions in these cases are in the general principles of surgery, not much related with Anti venom therapy. Life Threatening Conditions Requiring Surgery

A particularly serious consequence of snakebite is intra cranial bleeds. These frequently result in mortality and perhaps represent the worst of all complications. Key to survival is surgical intervention to remove the clot and thereby relieve pressure within the cranial cavity. Before surgery can take place coagulation must be restored rapidly and thus a very larger initial dose of ASV is given in excess of the normal dosage levels in order to ensure restoration of coagulation within a 6-hour period.

It is recognised that this large initial dose may be in excess of the required amount to achieve neutralisation of the venom. The critical point here is that coagulation must be definitively restored in the shortest period i.e. 6 hours, and thus the risk of exceeding the required amount is acceptable to ensure life saving surgery can take place. Debridement of Necrotic Tissue Local and extensive necrosis resulting from venom action may necessitate debridement of

necrotic tissue. The necrotic area should be kept clean and topical agents can be applied Anindhya et al, 2004). In most rural settings the victim will need referral to a facility that can perform surgery and is equipped with a surgeon. It is worth waiting 5-7 days before commencing a debridement of necrotic tissue in order that the line of demarcation between viable and non-viable tissue can be specified (Blaylock, 2005) 18. COMPARTMENT SYNDROME

The appearance of an immobile, tensely-swollen, cold and apparently pulseless snake-bitten limb may suggest to surgeons the possibility of increased intracompartmental pressure, especially if the digital pulp spaces or the anterior tibial compartment are involved. Swelling of envenomed muscle within such tight fascial compartments could result in an increase in tissue pressure above the venous pressure, resulting in ischaemia. However, the classical signs of an intracompartmental

pressure syndrome may be difficult to assess in snake-bite victims and many unnecessary, dangerous and debilitating fasciotomies are performed, especially where surgeons rather than 80

physicians have the primary responsibility for managing snake-bite cases. Clinical features of a compartmental syndrome Disproportionately severe pain. Weakness of intracompartmental muscles. Pain on passive stretching of intracompartmental muscles. Hypoaesthesia of areas of skin supplied by nerves running through the compartment. Obvious tenseness of the compartment on palpation. Compartment syndrome is a widely used concept in snakebite and is undoubtedly overused in many areas. The sight of the ‘6 Ps’:

• Pain on passive stretching • Pain out of proportion • Pulselessness • Pallor • Parasthesia • Paralysis 6 Ps with significant swelling in the limb, can lead to the conclusion that the intracompartmental pressure is above 40 mm of mercury and thus requires a fasciotomy. Detection of arterial pulses by palpation or doppler ultrasound probes, does not exclude intracompartmental ischaemia. The most reliable test is to measure intracompartmental pressure directly through a cannula introduced into

the compartment and connected to a pressure transducer or manometer. Avoid surgical intervention unless intracompartmental pressure is sufficiently high to cause blood vessels to collapse and lead to ischemia. Fasciotomy does not remove or reduce any envenomation. Criteria for fasciotomy in snake-bitten limbs (WHO) • Haemostatic abnormalities have been corrected (antivenom with or without clotting factors) • Clinical evidence of an intracompartmental syndrome

• Intracompartmental pressure >40 mmHg (in adults) Early treatment with antivenom remains the best way of preventing irreversible muscle damage. There is little objective evidence that the intracompartmental pressure due to snakebite in India, ever reaches the prescribed limit for a fasciotomy. Very limited trial data has tended to confirm this. In a small case study in India, using a Stryker monitor, despite grossly swollen limbs, which matched

the 6Ps, only one case from 12 achieved an intracompartmental pressure where fasciotomy would be considered. By the time coagulation was restored in the victim, the intracompartmental pressure 81

had reduced to normal levels. (A2) In any case, fasciotomy should not be contemplated until haemostatic abnormalities have been corrected, otherwise the patient may bleed to death (Fig. 66c). Not only in reversing coagulopathy, antivenom may also be helpful in reducing severe limb oedema (Rojnuckarin et al., 2006) [level of evidence T]. However, corticosteroids are not effective in ameliorating local effects of envenoming

and, since they carry the risk of side-effects, they should not be used (Reid et al., 1963; Nuchprayoon et al., 2008) [level of evidence T]. (WHO) The patient should be referred to a surgical specialist but it is worth the treating clinician ensuring that objective criteria are used to assess the actual intracompartmental pressure in the limb (A2). The limb can be raised in the initial stages to see if swelling is reduced. However, this is

controversial as there is no trial evidence to support its effectiveness. Persistent moderate swelling of the limb after viper bite can be successfully managed by systemic broad spectrum antibiotics and repeated Magnesium Sulphate compress (in the layers of wet bandage, changed 2-3 times a day) for 5-7 days. Figure 10. Compartment pressure measurement procedure. 19.DISCHARGE & FOLLOW-UP Discharge If no symptoms and signs develop after 24 hours the patient can be discharged. Keep the patient

under observation for 48 hours if ASV was infused. Follow-up A snakebite victim discharged from the hospital should continue to be followed up. At the time of 82

discharge patient should be advised to return to the emergency, if there is worsening of symptoms or signs such as evidence of bleeding, worsening of pain and swelling at the site of bite, difficulty in breathing, altered sensorium etc. The patients should also be explained about the signs and symptoms of serum sickness. (fever, joint pain, joint swelling) which may manifest after 5-10 days. 20.REHABILITATION

1. In patients with severe local envenoming, maintain limb in a functional position. For example, in the leg, equinus deformity of the ankle should be prevented by application of a back slab. 2. Start simple exercises while the patient is still in hospital for restoration of normal function in the bitten part. Conventional physiotherapy after discharge from hospital may accelerate functional recovery of the bitten limb. Give a time table of rehabilitation activities.

3. Functional effects of local envenoming range from persistent stiffness and induration to severe deformity, tissue loss, especially dermonecrosis, requiring skin grafting and gangrene requiring debridement and amputation. 21. SNAKEBITE MANAGEMENT AT DIFFERENT LEVELS OF HEALTHCARE A. In basic or primary care facilities (PCF) All levels of the health service can contribute to the management of patients with suspected snake-

bite. Since the treatment of severe envenoming is a medical emergency that may require a range of medical skills, equipment, antivenom and other medicines, referral should be to the highest level of care that is readily available. However, in the rural areas where snake-bites are most frequent, transfer to a hospital may not be feasible within the reasonable time frame of a few hours. In that case, a lower level of health facility services must cope with the emergency as suggested below.

“FIRST HOUR is the Golden hour in Snakebite management” should always be the Golden Rule in Snakebite Management. In whatever condition, after whatever hours of the actual bite a venomous bite patient arrives at a Health Facility, FIRST DOSE of ASV MUST be given at first contact health centre. A key objective of this protocol is to enable doctors in Primary Care Facilities (PCF) or Basic Care Facilities (BCF) to treat snakebite with confidence. These facilities are the backbone of medical care

in developing countries but are poorly equipped and with only one or a small number of doctors that staff them. Evidence suggests that even when equipped with anti snake venom, PCF/BCF doctors lack the confidence to treat snakebite due to the absence of a protocol tailored to their needs and outlining how they should proceed within their context and setting. The following summarizes a sequence of activities to be carried out in these settings for optimal response. 83

At the community or village level (WHO) 1. Check history of snake-bite and look for obvious evidence of a bite (fang puncture marks, swelling of the bitten part etc.). 2. Immobilize the patient as far as possible by laying him/her down in a relaxed but safe position (e.g. the recovery position), immobilize especially the bitten limb and give reassurance. 3. Arrange transport of the patient to medical care as quickly, safely and passively as possible by

vehicle, boat, bicycle, motorbike, stretcher etc. Ideally the patient should lie in the recovery position (prone, on the left side) with his/her airway protected to minimise the risk of shock and inhalation of vomit. 4. Victim must not run or drive himself to reach a Health facility. Motorbike Ambulance is a practical alternative for rural India but third person must support the patients Referral Criteria Referral Criteria: Vasculotoxic envenomation

1. If no ASV is available, transfer to a hospital (where ASV availability is confirmed over the phone). 2. If 20 WBCT is “not clotted” after loading dose of 10 vials of ASV as in case of Viper bite. 3. If patient is continuing to bleed even after full dose of ASV transfer to a tertiary care medical college or higher level of health facility. 4. Progressive septicaemia 5. Signs of kidney injury or abnormal kidney function test transfer to a tertiary care medical college or higher level of health facility.

Referral Criteria: Neurotoxic Envenomation 1. Progressive neuroparalysis - transfer with life support in ambulance for mechanical ventilation. Whilst it is entirely possible to maintain a neurotoxic victim by simply using a resuscitation bag, this should always be used as a last resort; the ideal means of support remains a mechanical ventilator (Battery operated Transport Ventilator) operated by qualified staff. 2. PHC and even many referral hospitals are not equipped with mechanical ventilators. The most

important factor, therefore, is when to refer a patient to a hospital with a ventilator. 3. The key criteria to determine whether respiratory failure, requiring mechanical ventilation is likely, is the ‘neck lift’ to elicit broken neck sign. Neurotoxic patients should be frequently checked on their ability to perform a neck lift. If they are able to carry out the action then treatment should continue until recovery in the PHC. Neck lift test is also useful for children

except very young children who may not be able to follow commands. Other tests which indicate descending paralysis are declining single breath count, pooling of saliva. 4. If the patient reaches the stage when patient cannot do neck lift immediately refer the patient to a hospital with a mechanical ventilator. 5. Maintain oxygen saturation using Pulse oximetry. Oxygen saturation <90% patient indicates requirement for ventilator support. 84

Figure 11. ‘‘Broken neck’’ sign observed in a 14-year-old girl bitten by a Russell’s viper in India. Envenoming by cobras, kraits and—in some areas—by Russell’s viper frequently leads to progressive descending paralysis. In this case, neuroparalysis persisted for five days despite antivenom treatment, but without progression toward respiratory failure.(Alirol E et al , 2010) Instructions while referring • Inform the need for referral to the patient and/caregiver (family member or the accompanying

attendant). • Give prior intimation to the receiving centre using available communication facilities. • Arrange for an ambulance. Call Emergency helpline 102/108 etc. Transport in an ambulance equipped with transport ventilator. If ventilator is not available tight-fitting face mask connected to an anaesthetic (Ambu) bag should be available. However, do not waste time to get an ideal ambulance. Motorbike is a practical alternative in rural areas for rapid transport but

third person must sit behind the patient to support on bike. • If ASV is not available at First contact centre transfer to the nearest health facility where ASV is available confirmed by telephone. • Transfer to a higher health facility (Secondary Care Hospital or Tertiary Care Hospital) where mechanical ventilator and dialysis facilities are available for dialysis and ventilation, if required after completion of ASV infusion only.

• During transfer, continue life-supporting measures, and provide airway support with the help of an accompanying staff, if required. • Insert nasogastric tube in case of severe neurotoxic envenomation • Send the referral note with details of treatment given clearly mentioning the clinical status at the time of referral. B. At a Primary health Care Center (PHC) Patient Arrival & Assessment 85

1. Assess circulation, airway and breathing and deal with any life threatening symptoms on presentation. 2. Establish large bore intravenous access and start normal saline slow infusion. 3. Before removal of the tourniquet/ligatures, test for the presence of a pulse distal to the tourniquet. If the pulse is absent ensure a doctor is present before removal or ligatures. 4. In case of clinically confirmed venomous bite, tourniquet should be removed only after

starting of loading dose of ASV and keep Atropine Neostigmine injection ready. In case of multiple ligatures, all the ligatures can be released in Emergency Room EXCEPT the most proximal one; which should only be released after admission and all preparations. 5. Carry out a simple medical assessment including history and simple physical examination – local swelling, painful tender and enlarged local lymph glands, persistent bleeding from the bite

wound, blood pressure, pulse rate, bleeding (gums, nose, vomit, stool or urine), level of consciousness, drooping eyelids (ptosis) and other signs of paralysis. The Glasgow Coma scale cannot be used to assess the level of consciousness of patients paralyzed by neurotoxic venoms. 6. The snake, if brought, should be carefully examined and identified, if possible. (One smart phone photograph of the snake, dead or alive, if available, should be taken for confirmation by an expert).

7. Clotting test ‘20WBCT’ in clean, new, dry, glass test tubes should be carried out to diagnose vasculotoxic envenomation. Report should be given as Clotted or Not Clotted. Never write Positive/negative. If clotted continue every 1 hour for the 1st 3 hours from the time of hospitalization and then 6 hourly for 24 hours. If a neurotoxic snakebite is confirmed, clotting test can be repeated after 6 hours. If not clotted administer antisnake venom (ASV).

8. Give analgesia by mouth if required: Paracetamol (acetaminophen) (adult dose 500 mg to 1 g maximum 4 g in 24 hours; children 10-15 mg/kg/dose (maximum 100mg/kg/day). Do NOT give aspirin or non-steroidal anti-inflammatory drugs which can cause bleeding and renal dysfunction. 9. Assess the need and feasibility of transporting the patient to a higher level of the health service (see A above). 10. If the necessary skills, equipment, antivenom and other drugs are available, give intravenous

fluid to correct hypovolaemic shock. These skills include ability to diagnose local and systemic envenoming, set up intravenous infusion or intravenous injection, identify the early signs of anaphylaxis. 11. If the patient fulfils criteria for antivenom treatment, give ASV. If no ASV is available, transfer to a health facility where ASV is available. 12. Adrenaline is made ready in two syringes of 0.5mg (1:1000) for IM administration if symptoms

of any adverse reaction appear. If symptoms do appear, ASV is temporarily suspended while the reaction is dealt with and then recommenced (for details see treatment of early ASV reactions). 13. If the patient has evidence of respiratory paralysis, give oxygen by mask or laryngeal mask airway (LMA), and intubate the patient and make arrangements for transfer to a higher facility accompanied by a Medical Officer carrying an Ambu bag, additional endotracheal tubes,

oxygen, facemasks and basic drugs for resuscitation. During the journey the endotracheal tube may slip into right bronchus leading to left lung collapse and right side pneumothorax may also occur. To prevent the tube being bitten, a mouth gag should be inserted. The tube may get obstructed due to secretions or kinking leading to cyanosis and resistance to Ambu-ventilation. 86

Then the tube should be pulled out immediately and Ambu- ventilation could be continued with a face mask. Administer Atropine and Neostigmine before transferring to a hospital as recommended above. No AN injection in confirmed Krait bite. 14. It is assumed that assisted ventilation other than by a tight-fitting face mask connected to an anaesthetic (Ambu) bag will not be possible at this level. 15. While admitted for observation, IV fluid with a slow plain drip of Normal saline should be

started, and a Tetanus Toxoid given after ruling out or correction of coagulopathy. 16. Patient should be placed under observation for 24 hours (even if the victim gives a history of a nonvenomous snakebite. The bite victim becomes so frightened and confused immediately after a bite, many a time gives false identification history). If no symptoms develop after 24 hours the patient can be discharged. 17. Discourage the use of ineffective and potentially harmful drugs such as corticosteroids,

antihistamines, and heparin. C. At the district hospital Proceed as in B above in addition to the followings: 1. If ASV indicated and had not been given already start without any delay, do not wait for any test report. 2. Carry out a more detailed clinical and laboratory assessment including biochemical and haematological measurements, ECG or radiography, as indicated to get a baseline data. 3. If the patient is bleeding severely irrespective of full dose of ASV or is already seriously anaemic

give transfusion of blood or fresh frozen plasma or transfer where facility is available. 4. Reassess analgesia (see B above) and, if required, consider giving Tramadol 50 mg orally. In case of severe pain administer Inj. Tramadol 50 mg IV. Avoid pethidine or morphine in neurotoxic envenomation. A deeply sedated patient may create confusion regarding level of neuro- paralysis. 5. Give tetanus toxoid booster (if not given already), to all snakebite victims provided coagulation is restored.

6. In case of cellulitis consider antibiotics, and consider surgical debridement of dead tissue. 7. If the patient has evidence of acute kidney injury (AKI), treat with dialysis. If this is not available, transfer to a specialized hospital. For details see Annexure. 87

8. If the patient has evidence of bulbar or respiratory paralysis, insert endotracheal tube with the help of the anesthesiologist if available or by a trained medical personnel or laryngeal mask airway (LMA). If there is evidence of respiratory failure, assist ventilation manually by anaesthetic bag or mechanical ventilator. 9. Initial dose of ASV is administered over 1 hour. The first blood drawn from the patient should be typed and cross-matched, as the effects of both venom and ASV can interfere

with later cross-matching. 10. Atropine neostigmine “AN” challenge test is administered using 0.6mg of atropine IV first followed by 1.5 mg of neostigmine IV (Schedule described above). Rarely, if patient require more than 2nd dose of AN test. Stop after 3rd dose if there is no response. In Krait bite practice of continuing Neostigmine drip till ptosis persists beyond 24 h is not beneficial. Pre-synaptic blockage by Krait venom does not respond to AN injection.

11. If after 2 hours from the end of the first dose of ASV, the patient’s symptoms have worsened i.e. paralysis has descended further, a second full dose of ASV is given over 1 hour. D. At the tertiary care or medical college Proceed as in B and C above in addition to the followings: 1. In the ICU, the standard protocol should be followed during assisted ventilation and the patient should be monitored for all parameters including level of consciousness.

Avoid drugs such as sedatives, morphine and neuromuscular blocking agents. Some patients go into a deep coma state but recover completely. Hence, diagnosis of brain death should not be considered. Recovery of respiratory muscles is reflected by improvement of neck flexors where flexing the neck against gravity indicates timing to wean off ventilation. Prophylactic antibiotics are unnecessary. 2. Multiple organ failure. Management is supportive, and prevention of organ damage in those at

risk are therefore crucial. Aggressive early resuscitation, adequate antivenom therapy, excision of devitalized tissue and treatment of infection are important. Prompt recognition of organ dysfunction and immediate intervention may reverse organ impairment and improve the outcome. 3. If the patient has evidence of acute kidney injury peritoneal or haemodialysis or haemofiltration. Indications for dialysis as described above. 4. More advanced surgical management of local necrosis (e.g. split skin grafting).

5. More advanced investigations including bacterial cultures and imaging (CT scans) as indicated. 6. CNS complication and intracranial bleeding to be managed according to the standard practice. Neurosurgical opinion may be requested according to intracranial pathology. However, haemostatic abnormalities must be corrected. 7. Coma, autonomic dysfunctions. Patient in deep coma recovers fully provided there is no hypoxic brain damage. Autonomic dysfunctions are transient and don’t need treatment. Sometimes

treatment might be harmful e.g. treating with antihypertensive drugs to lower the increased blood pressure due to sympathetic hyperactivity. 8. Uncommon complications such as hepatic dysfunction, pancreatitis, endocrine insufficiency and deep venous thrombosis should be managed according to the standard practice. 88

9. Implement rehabilitation by physiotherapists. 22.CONDITIONS AND EQUIPMENT ACCOMPANYING NEUROTOXIC REFERRAL The primary consideration is to be equipped to provide respiration support to the victim if respiratory failure develops before or during the journey to the institution with mechanical ventilation. The key priority is to transfer the patient with a facemask, resuscitation bag and a person, other than the driver of the vehicle, who is trained of how to use these devices. If respiration fails then

the victim must be given artificial respiration until arrival at the institution. Greater success can be achieved with two additional approaches, prior to despatch In the conscious patient, two Nasopharyngeal Tubes (NP) should be inserted before referral. These will enable effective resuscitation with the resuscitation bag by not allowing the tongue to fall back and block the airway, without triggering the gagging reflex. Improvised Nasopharyngeal tubes can

be made by cutting down size 5 endotracheal tubes to the required length i.e. from the tragus to the nostril. NP tubes should be prepared and kept with the snakebite kit in the Basic Medical Facility. This is preferable as the patient may well be unable to perform a neck lift but still remain conscious and breathing. The danger will be that respiratory failure will occur after the patient has left the BCF/PCF and before arriving at the eventual institution. In that case the patient will be pre-

prepared for the use of a resuscitation bag by the use of NP tubes. In the unconscious patient, a Laryngeal Mask Airway or preferably a Laryngeal Tube Airway should be inserted before referral, which will enable more effective ventilatory support to be provided with a resuscitation bag until the patient reaches an institution with the facility of mechanical ventilation. 23.EQUIPPING A BASIC HOSPITAL FOR EFFECTIVE SNAKEBITE MANAGEMENT Anti Snake Venom Choice of ASV

The type of ASV used will be determined by availability, cost and effectiveness of the cold chain. Lyophilised ASV, in powdered form has a shelf life of 5 years and requires merely to be kept out of direct sunlight. Liquid AV/ASV, which is easier to administer, has a shelf life of two years and requires refrigeration. Assumptions The assumption in this section is that this is a basic setting i.e. without laboratory analysis capability,

mechanical ventilator or renal dialysis capability. In such a situation the following basic principles 89

apply: 1. Victims with coagulopathy will require eventual transfer to a better-equipped hospital, due to the requirement to test for occult bleeding or renal failure. 2. Once the initial dose of ASV is given to a victim with coagulopathy, a six-hour window is available before ASV will require re-administration. 3. Neurotoxically envenomed patients can be treated entirely locally, if there is no evidence of respiratory failure and a need for long-term mechanical ventilation.

4. The trigger to indicate respiratory failure as being imminent is the failure of a patient to be able to perform a neck lift. 5. If the patient is unable to perform a neck lift, this will require transfer to a better-equipped hospital with a ventilator BUT will crucially require airway support for the journey as described in Section. Holding Quantities of ASV/ Stocks of ASV It is imperative that hospitals which cover areas where snakebite is a feature, maintain adequate

stocks of ASV. This should include locating institutions or vendors where ASV can be sourced quickly in the event of an upsurge in usage. Partly this problem can be eased by using the administration guidelines below. There remain a great number of occasions where ASV is used in non venomous bites because doctors have no clear guidelines and are not confident to wait for specific signs of envenomation. At the same time ASV stocks to be maintained well in advance of the peak seasons which has maximum demand.

Holding quantity can be established using the following equation: (xd X 1.2) t where: x =number of envenomings on average per month d = the maximum number of vials likely to be applied at the medical facility to a single patient i.e. 2 doses to a Neurotoxically envenomed patient t = length of time normally experienced for replenishment in months. Suppose we are dealing with a basic facility with two envenomings per month then x=2: the

maximum dose required per patient determines a key part of usage, so for example, if the maximum dose for a patient at a basic facility is 2 doses of 10 vials for a neurotoxic patient, d = 20. 1.2 represents the safety factor to ensure greater than minimal stock is available. The restocking time in months is represented by t. If the restocking period is 2 months for ASV to be replaced the equation would require 2 X 20 X 1.2 X 2 = 96 vials would be the ASV base stock amount. Other Support Drugs

The following drugs should be held, stocking assumptions for each anticipated bite in a given period are as follows: - Adrenaline 90

Adult dosage of 0.5mg of 1:1000 with a potential of three doses maximum per patient (i.e. stock of a minimum 10 vials) Hydrocortisone and Antihistamine Adult dosage of antihistamine and hydrocortisone: only one application per patient is normally required before referral (i.e. stock of 10 vials) Neostigmine and Atropine Adult dosage of 1.5mg for neostigmine and 0.6mg atropine for the test phase of treatment: ongoing

support if test shows positive response is 0.5mg neostigmine every 30 minutes. Victims who are responsive usually recover quite rapidly so assume a dosage requirement of 12 hours i.e. 24 x 0.5mg ampoules. Further atropine may also be required @ 1 ampoule of 0.6mg atropine for every 5-6 ampoules of 0.5mg neostigmine. Dose required per neurotoxic bite would be about 30 ampoules (0.5 mg) of neostigmine and five ampoules of atropine. Paracetamol: 500mg tablets IV fluids: Normal Saline

24.SNAKEBITE PREVENTION & OCCUPATIONAL RISK Snakebite prevention is an important activity and can make a contribution to reducing snakebite. It must be looked at with a degree of realism if it is to be successful. 25.PATIENT INFORMATION SHEET After snakebite occurs Do’s and Don’ts Do’s • Seek medical help right away. • Call ambulance and transfer patient to a medical health facility. Arrange transport of the patient to medical care as quickly, safely and passively as possible by vehicle ambulance (toll

free no. 102/108/etc.), boat, bicycle, motorbike, stretcher etc. • Keep the person calm. Reassure them that bites can be effectively treated in an emergency room. Restrict movement, and keep the affected area below heart level to reduce the flow of venom. • Remove any rings or constricting items, because the affected area may swell. • Create a loose splint (it should be capable of inserting one finger beneath) to help restrict movement of the area.

• Ideally the patient should lie in the recovery position (prone, on the left side) with his/her airway protected to minimize the risk of aspiration of vomitus. 91

• Monitor the person's vital signs -- temperature, pulse, rate of breathing, and blood pressure -- if possible. If there are signs of shock (such as paleness), lay the person flat, raise the feet about a foot, and cover the person with a blanket. Don’ts • Do NOT waste time in traditional first aid methods • Do NOT allow the person to become over-exerted. If necessary, carry the person to safety. • Do NOT apply a tourniquet. Do NOT block the blood supply or apply pressure.

• Do NOT apply cold compresses to snakebite. • Do NOT cut into snakebite with a knife or razor. • Do NOT try to suck out the venom by mouth or wash the wound. • Do NOT give the person stimulants or pain medications unless a doctor tells you to do so. • Do NOT give the person anything by mouth. • Do NOT raise the site of the bite above the level of the person's heart. • Do NOT attempt to kill or catch the snake as this may be dangerous. Bring in the dead snake

only if this can be done safely. Do NOT waste time hunting for the snake, and do NOT risk another bite if it is not easy to kill the snake. Be careful of the head when transporting it - a snake can actually bite for several hours after it is dead (from a reflex). Prevention of snakebites • Snakebite is invariably an accident. As it is an accident, it can be avoided in many cases. Some judicious, timely precautions are extremely important to avoid the risk of snake –

bites. People should be aware of such preventive measures. • Education: Know your local snakes, know the sort of places where they like to live and hide, at what times of year, at what times of day/night or in what kinds of weather they are most likely to be active. Learn when and where snakes may be found: • Snakes rest in cool, shaded areas during hot weather. • Snakes are predatory carnivores, but they are also preyed upon by other animals including

snakes. For their preying habits and survival tactics, they tend to be secretive. Snakes avoid confronting larger animals and humans. • Avoid snakes as far as possible, including snakes performing for snake charmers. • Do NOT put your hands or fingers or feet into holes or nest or places you cannot see or any hidden place, where snakes may live. • Most of the snakebites occur in the rainy season and after flood, because snakes are

compelled to come out from their living and hiding places. Be especially vigilant about snakebites during the rainy season and after flood, and take adequate precautions while walking on the roads and fields. • Mostly snakebite is encountered during ploughing, planting and harvesting. Leave snakes alone: • If you see a snake, do nothing; let it go and do NOT try to touch the snake. Keep a distance, it is better to run away. Snakes cannot attack when it is about 25 – 30 ft away. 92

• NEVER handle, threaten or attack a snake and never intentionally trap or corner a snake in an enclosed space. They do not attack man unless they are handled, threatened, trapped or cornered or their body parts are touched unintentionally (such as pressed down or crushed with the foot inadvertently). • Do NOT pick up a dead snake or that appears to be dead. Even dead snakes can deliver venom through their fangs. Even an accidental scratching from the fang of a snake's severed

head may inflict deadly venom. • Rattlesnakes shake the ends of their tails to make a rattle sound that warns that it feels threatened. If you hear a rattlesnake, move away quickly. Learn what venomous snakes look like • People of a locality should know what sort of snakes (both venomous and non – venomous) are existing there, the habits of those snakes, their living and hiding places, at what time of year and at what time of day or night they are most likely to be out and active.

• Snake charmers and snake handlers carry greater risk of snakebite. Avoid free hand handling of venomous snakes; adequate equipment must be used for handling. • Sea snakes may sometimes be caught in nets. Fishermen are advised not to touch those snakes. • Venomous snakes are born fully equipped with venom and fangs. Young snakes are more pugnacious and ready to defend themselves, so do not discount a snake going by its size. Dress to protect yourself:

• Wear shoes or boots and pants to protect your feet and legs. • Always check footwear before wearing them. • Identify major situational sources of bites; walk at night with sturdy footwear (preferably with high boots) and use a torch while walking outside the house. Outdoor • Avoid defecation in open field. If unavoidable carry torch or lamp. • Light your path: Use a flashlight or lamp when you walk outside at night or visit the latrine (outdoor) at night.

• Do NOT walk in areas where you cannot see the ground. • When walking, walk with a heavy step as snakes can detect vibration and will move away. • Carry a stick when grass cutting or picking fruit or vegetables or clearing the base of trees or collecting wood. Use the stick to move the grass or leaves first. Give the snake a chance to move away. If collecting grass or leaves that have previously been cut and placed in a pile, disturb the grass with the stick before picking the grass up.

• Keep checking the ground ahead while cutting crops like millet, which are often harvested at head height and concentration is fixed away from the ground. • Try to avoid sleeping on the ground. Use bamboo cot and scrupulous use of a mosquito net can prevent snakebites, scorpion stings, and mosquito bites alike. If you have to sleep on the ground use mosquito net that is well tucked in under the mattress or sleeping mat. 93

• During trekking, etc. through forests or mountains, stay on clearly marked tracks. Step on to rocks or logs rather than straight over them – snakes may be sunning themselves on the sides. The Garden or Compound • Clear heaps of rubbish, building materials and termite mounds. • Clear any bush or jungle. • Keep grass short or cleared. • Close rat holes, if any. Indoor • In the house: Do not keep livestock, especially chickens, in the house, as snakes may come to hunt them.

• Regularly check houses for snakes and, if possible, avoid those types of house construction that will provide snakes with hiding. • Store food in rat-proof containers. • Also keep animal feed and rubbish away from your house. They attract rats and snakes follow. • There is no chemical/onions which can effectively repel snakes. Bleaching powder or gammaxane may be spread which may to some extent prevent the entry of snake in the

house as they repel small creatures like rat and frog; snakes would not come following them. • Seal any rat hole in and around the houses. • Meticulously observe heaps of fire woods, cow dung cakes and similar materials at first and then handle. • Keep plants away from doors and windows. Snakes like cover and plants help them climb up and into windows. • Do NOT have tree branches touching the house. Keep grass short or clear the ground around

the house and clear low bushes in the vicinity so that snakes cannot hide close to the house. • Inspect mud made ovens or chulhas at first before cleaning. During construction of new house • Indoor toilets should be made compulsory at the time of issuing permission for new housing construction. 94

ANNEXURE 1. SNAKE BITE EXAMINATION PERFORMA Name …………………………………….. Age ……………………….. Sex M/F Address ……………………………………………………………………………………………………….. Date ……………….time of bite ………………..Activity at time of bite …………………… Sleeping on floor bed … Yes/No …. Cot …… Yes/No ……… Mosquito net Yes/No Snake Seen Yes/No Killed Yes/No Specimen photo in mobile Yes/No Identification of snake in photos specimen as ………………………….………………….. Confirmed specimen of snake ………………………………………….……………………………. Local site

Fangs marks ……………...Active bleeding from fangs Yes/No Blood clot Yes/No Time of development of edema …………………………………………….……………..………… Extension of edema …………………………………………….…………………………………………. Regional lymphangitis ……………………………………….…………….……………..……………. Pain in abdomen ……………………………………………Vomiting ……………..…………………. Blood pressure …………………………………. Pulse rate ………………………………… Active bleeding Gum/ from abrasions /any other site 20WBCT on arrival Clotted /Not clotted Time…………….…... Repeat 20WBCT Clotted /Not clotted Time…………….……

Repeat 20WBCT Clotted /Not clotted Time………….……… ASV administered ……………………. Dose given ……………vials Time………..….…..… Repeat 20WBCT after ASV Clotted /Not clotted Time………….…………………… Progress after ASV 20WBCT at 1h ………….2h…………..3h……………6h…………12h……….18h……..24h… Progress INR ……………………………………………....APTT ……………………..………………… Blood urea ………………………………Serum creatinine …………….………………….. Urine ………………………………………………………….. Haematuria /hemoglobinurea Haemogram …………………………………………Platelet count…………………………………

Blood transfusion, if any ……………………………………………………………………………… Fresh Frozen Plasma (FFP), if any ………………………………………………………………… 95

Dialysis, if any …………………………………………………………………………………………….. Compartment syndrome Present/Not present Neuroparalytic symptoms Bilatral Ptosis ……………………………………. Opthalmoplegia ………………………………… Bulbar palsy ………………………..……. Respiratory rate ………………../min sPO ……………% One minute count …………. 2 Muscle power on arrival Upper limb ……………………lower limb …………………….. Progress ………………………… Pelvic girdle …………………………………………………………………………………………………….. Reflexes Planter on arrival …………………….Progress ……………………………………….….

Voice on arrival ……………………………………………………………………………………………….. Distance between Inter teeth margin …………On arrival ………….. Progress ………… Protrude of tongue in relation to teeth margin …………On arrival ……….progress Pupil size …………. reacting to light…………… On arrival…………………………..... Progress after ASV total dose ……………….After Repeat dose ………………………….. Intubation time ………………..Ambu bag ventilation/ Mechanical ventilator Follow up Recovery time in days……………… Total ASV dose given……………………....

Blood transfusion given/not given FFP given/not given Dialysis days……….. Ventilations total days ……………… Disability………………………………. Hypoxic brain injury ………………….. Amputation of limb ……………………. Plastic surgery 96

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STANDARD TREATMENT GUIDELINES ON ACUTE SINUSITIS SECTION TABLE OF CONTENTS PAGE NO. Section 1 Introduction 1 1.1 Definition 1.2 Burden of disease 1.3 Morbidity and mortality Section 2 Current practices in India 2 Section 3 Need for a STG/ Guideline purpose 2 Section 4 Recommendations 4.1 Diagnosis 2-4 4.2 Role of imaging 4 4.3 Treatment 4-5 4.4 Ancillary therapy 5-6 4.5 Alternative diagnosis 6 4.6 When to refer to specialist 6-7 4.7 Summary 8 Section 5 Patient information sheet 9-11

Section 6 How this STG was developed 11-21 Section 7 Research needs 22 Section 8 Annexure 23-25 Section 7 References 26

STANDARD TREATMENT GUIDELINES ON ACUTE SINUSITIS 1. INTRODUCTION 1.1 Definitions- Acute sinusitis is an inflammation of the paranasal sinuses and the nasal cavity lasting no longer than 4 weeks characterized by purulent nasal discharge (anterior, posterior or both) accompanied by nasal obstruction, facial pain-pressure-fullness, or both. The term Acute sinusitis and Acute rhinosinusitis has been used interchangeably in

literature are same entity and hence in the rest of the guidelines term Acute sinusitis is used. 1.2 Burden of disease- Though acute sinusitis is a very common disease and a significant burden on the health services, data on prevalence of acute sinusitis in India could not be obtained by the clinical sub group when a systematic literature search using Pubmed and Google.Twelve percent of US population (nearly 1 in 8 adults) reported being diagnosed

with rhino sinusitis in the prior 12 months in a 2012 national health survey1. Approximately 0.5% of all upper respiratory tract infections are complicated by sinusitis; the incidence of acute sinusitis ranges from 15 to 40 episodes per 1000 patients per year, depending on the setting. It is much more common in adults than it is in children, whose sinuses are not fully developed. Acute sinusitis is the second most common infectious disease seen by General

Practitioners (GPs). Most acute sinusitis is caused by the same viruses that cause the common cold (ARI). It is self-limiting disease and most of them can be treated symptomatically. Treatment with antibiotics is required only on cases when the symptoms persist for more than 10 days indicating that there is superadded bacterial infection. 1.3 Morbidity and mortality – Exact incidence of acute sinusitis in India was not available when a literature search was

performed on Pubmed or Google scholar. Whatever data is available is from western population.Rhinosinusitis is an extremely common condition. Incidence rates among adults are higher for women than men (1.9-fold), and adults between 45 and 74 years are most commonly affected. 1

2. CURRENT PRACTICES IN INDIA It is common practice for most diagnoses of upper respiratory tract infection to receive prescription for antibiotics from primary care physicianwithout a diagnosis of sinusitis.All patients going to primary care physician receive prescriptions for antibiotics. This occurs despite the fact that natural history of disease is self limiting. Despite the high prevalence and economic impact of sinusitis, considerable practice variations existsacross and within

the multiple disciplines involved in managing the condition. Currently there are no standard treatment guidelines available for diagnosis and management of acute sinusitis in India. 3. NEED FOR A STG/ GUIDELINE PURPOSE There is widespread misuse of antibiotics by the general practitioners and primary care physicians to treat even simple upper respiratory tract infection. This indiscriminate use of the antibiotics has led to the development of drug resistance and is an economic burden to

the health services. Apart from this there is an additional expense from lost productivity, reduced job effectiveness, and impaired quality of life. All this can be avoided if we have standard treatment guidelines for acute sinusitis. In additionthere is anover of use of various other ancillary treatments like antihistaminics, steroids, pain killers, decongestants, vitamins, mucolytics, steam inhalations, saline douching and saline spray etc. The use of all

these ancillary treatment also placesa lot of financial burden on the patients and health services. Use of the all these ancillary treatments must be based on scientific evidence and a standard treatment guideline will streamline this. Developing a STG on acute sinusitis will help improve quality of care and decrease costs by accurate diagnosis of the condition, appropriate medical therapy, effective radiological imaging and appropriate subspecialist consultation. 4. RECOMMENDATIONS

4.1 Diagnosis of Acute Sinusitis-Up to 4 weeks of purulent nasal drainage (anterior, posterior, or both) accompanied by nasal obstruction, facial pain-pressure-fullness, or both. 4.1.1 Acute viral sinusitis (the common cold) is caused by,or presumed to be caused by viral infection. A clinician should diagnose acute viral sinusitis when symptoms or signs of acute rhinosinusitis are present less than 10 days and the symptoms are not worsening.

4.1.2 Acute bacterialrhinosinusitis(ABRS) is made on the basis of following any of the three clinical presentation criteria. 1. Onset with persistent symptoms or signs compatible with acute rhinosinusitis, lasting for more than 10 days without any evidence of clinical improvement 2

2. Onset with severe symptoms or signs of high fever (>39°C /102°F) and purulent nasal discharge or facial pain lasting for at least 3–4 consecutive days at the beginning of illness 3. Onset with worsening symptoms or signs characterized by the new onset of fever, headache, or increase in nasal discharge following a typical viral URI that lasted 5–6 days and were initially improving (‘‘double-sickening’’). 4. Rule out allergic rhinitis (AR) which is diagnosed when in addition to nasal

obstruction and discharge there is also itchy nose, excessive sneezing, red and watery eyes.* 4.1.3 Clinical features: symptoms and signs Diagnosis of Acute sinusitis is probable if 2 or more of these major symptoms are present or 1 major symptom along with 2 or more minor symptoms (RI 2004) Major Symptoms • Purulent anterior or posterior nasal discharge) • Nasal blockage/congestion/obstruction • Facial congestion/ fullness • Facial pain/pressure/fullness • Hyposmia/anosmia

• Fever (acute only) high grade more than 39 degree Celsius. Minor Symptoms • Headache • Ear pain/fullness/pressure • Halitosis • Dental pain • Cough • Fever • Fatigue Signs (may be seen but absence of these does not exclude Acute sinusitis)* expert group consensus • Hypo-nasal speech indicating nasal obstruction • Swelling, redness of the skin due to congestion of the capillaries (erythema) or abnormally large fluid volume (edema) localized over the involved cheek bone or periorbital area

• Palpable cheek tenderness or percussion tenderness of the upper teeth • Purulent drainage in the nose or posterior pharynx 3

• Signs of extra-sinus involvement (orbital or facial cellulitis, orbital protrusion, abnormalities of eye movement, neck stiffness indicating complications. 4.2Role of imaging 4.2.1 Do not use radiographic imaging for patients who have a diagnosis of acute sinusitis, unless a complication such as orbital and intracranial extension or alternative diagnosis is suspected. 4.2.2 If symptoms of sinusitis persist for more than three weeks despite antibiotics or recur

more than four times per year, a sinus CT scan should be performed while the patient is symptomatic to reassess diagnosis and determine need for referral (UM). 4.2.3 Plain sinus x-rays, are not at all recommended in management of sinusitis. 4.2.4 Indications of CT scan PNS • Severe headache associated with facial swelling or cranial nerve palsy or neck rigidity • Forward displacement or bulging of the eye (proptosis) • Visual disturbances 4.3Treatment

4.3.1 When should empiric antibiotic therapy be initiated? Initiate empiric antimicrobial therapy as soon as the clinical diagnosis of ABRS is established as defined in recommendation. 4.3.2 Choice of antibiotic for ABRS 1. Amoxicillin-clavulanate is recommended as empiric antimicrobial therapy for ABRS in adults. 2. The recommended duration of therapy for uncomplicated ABRS in adults is 5–7 days. 3. For partial but incomplete resolution after an initial course of antibiotics, extend the

duration of antibiotic therapy by an additional 7 to 10 days. Use of High-dose (2 g orally twice daily or 90 mg/kg/day orally twice daily) amoxicillin- clavulanate is recommended for patients with acute sinusitis (eg, evidence of systemic toxicity with fever of more than 39 degree C [102 degree F] or higher, and threat of suppurative complications, attendance at daycare, age <2 or >65 years, recent hospitalization, antibiotic use within the past month, or who are immunocompromised. 4

4.3.3Choice of antibiotic for ABRS in penicillin allergic patients Use of doxycycline (100mg every 12hr) or a respiratory fluoroquinolone (levofloxacin 500mg daily or moxifloxacin 400mg daily) is recommended as an alternative agent for empiric antimicrobial therapy in adults who are allergic to penicillin. 4.3.4 Treatment failure for ABRS 1 Reassess the patient after 7 days to confirm ABRS, exclude other causes of illness, and

detect complications if the patient fails to improve with the initial management option or worsens during the initial management. 2 If ABRS is confirmed in the patient initially managed with observation, the clinician should begin antibiotic therapy. 3 The second line antibiotics include high dose amoxicillin/clavulanate combination(2 g orally twice daily or 90 mg/kg/day orally twice daily), levofloxacin (500mg daily), and moxifloxacin (400mg daily) or the combination of clindamycin (300 mg 12 hr) plus a

third-generation oral cephalosporin {cefixime(200 mg 12 hr) or cefpodoxime(200 mg 12 hr) }. 4 Worsening is defined as progression of presenting signs or symptoms of ABRS or onset of new signs or symptoms. Failure to improve is lack of reduction in presenting signs or symptoms of ABRS by 7 days after diagnosis, which would not apply if the patient had persistent, yet gradually improving, symptoms. 5 ABRS may take up to 7 days to improve, persistence or minor worsening prior to 7 days

does not necessarily indicate treatment failure, and complete cure (absence of all signs and symptoms) may take 14 days or longer. 4.4 Ancillary therapy 4.4.1 Decongestants (topical- Oxymetazoline and Xylometazoline) Use of topical decongestants is recommended in case of severe nasal obstruction for short duration. (Maximum of 5 days). These should be used with precautions in patients with hypertension. 4.4.2 Analgesics Nonsteroidal anti-inflammatory drugs like paracetamol 500 mg tab tds/sosor

diclofenac sodium 50 mg tab tds/sos, are recommended for pain relief associated with acute sinusistis. 4.4.3 Antihistamines Routine administration of antihistamines are not recommended in patients of sinusitis. 4.4.4 Intra nasal corticosteroid spray 5

Though INCSs are not essential for treatment of ABRS they are recommended as an adjunct to antibiotics in the empiric treatment of ABRS for 10 days. Fluticasone ormometasone intra nasal sprays are recommended twice daily. 4.4.5 Steam inhalation Steam inhalation is recommended by the expert group twice a day for 5-7 days. 4.4.6 Nasal spray and douching with physiologic/hypertonic saline Intranasal saline irrigations with either physiologic or hypertonic saline are

recommended as an adjunctive treatment in adults with ABRS. 4.5 Alternative Diagnoses • Allergic rhinitis • Headache, migraine or tension • Nasal drying (sicca patients) • Gastroesophageal reflux • Atrophic rhinitis • Temperomandibular joint pain, dental pain • Atypical facial pain 4.6 When to refer to ENT specialist? Any symptoms orsigns suggestive of complications Refer to an ENT specialist if any of the following indications are present: (IDSA 2012 guidelines)

1. Severe infection (high persistent fever with temperature >39 degree C [>102 degree F] 2. Orbital edema, severe headache, visual disturbance, altered mental status, meningeal signs) 3. Recalcitrant infection with failure to respond to extended courses of antimicrobial therapy 4. Immunocompromised host 5. Multiple medical problems that might compromise response to treatment (eg, hepatic or renal impairment, hypersensitivity to antimicrobial agents, organ transplant) 6. Unusual or resistant pathogens

7. Fungal sinusitis or granulomatous disease 8. Nosocomial infection. 9. Anatomic defects causing obstruction and requiring surgical intervention 6

10. Multiple recurrent episodes of acute bacterial rhinosinusitis (ABRS) (3–4 episodes per year) suggesting chronic sinusitis 11. Chronic rhinosinusitis (with or without polyps or asthma) with recurrent ABRS exacerbations. 7

4.7 Summary ABRS (4.1.2): Purulent nasal discharge, nasal obstruction, facial pain/fullness: a) Persistent & not improving ≥ 10 days b) Severe ≥ 3-4 days, or c) Worsening / double sickening Initiate first line antibiotic therapy (4.3.2) Amoxicillin+ clavulanate Improvement after 3-5 No improvement / worsening after days 3-5days Complete 5-7 days of antimicrobial therapy Reassess diagnosis Broaden coverage or switch Complications (4.5) to different antimicrobial (4.6): class (4.3.4): • Referr

• High dose al to amoxicillin+clavul special anate ist • Levofloxacin • CT Improvement after 3-5 • MoxifloxaNcoi nim provement / worseninsgc aanft er days 3-5days Complete 5-7 days of antimicrobial • Refer to specialist therapy • CT/MRI: suppurative complications/noninfec tious causes • Sinus/meatal culture for pathogen-specific therapy 8

5. Patient Information Sheet 5.1 Diagnosis of Acute Sinusitis Question 1. What are sinuses? Answer 1. Sinuses are hollow spaces in the bones around the nose that connect to the nose through small, narrow channels. The sinuses stay healthy when the channels are open, which allows air from the nose to enter the sinuses and mucus made in the sinuses to drain into the nose. Question 2. What is sinusitis? Answer2. Sinusitis, also called Acute sinusitis or rhinosinusitis, affects about 1 in 8

adults annually and generally occurs when viruses or bacteria infect the sinuses (often during a cold) and begin to multiply. Part of the body’s reaction to the infection causes the sinus lining to swell, blocking the channels that drain the sinuses. This causes mucus and pus to fill up the nose and sinus cavities. Question 3. How can I tell if I have acute sinusitis? Answer 3. You have acute sinusitis when there has been up to 4 weeks of cloudy or

colored (not clear) drainage from the nose plus one or both of the following: (a) a stuffy, congested, or blocked nose or (b) pain, pressure or fullness in the face, head, or around the eyes. Question 4. How can I tell if my sinusitis is caused by viruses or bacteria? Answer 4. Acute viral sinusitis is likely if you have been sick less than 10 days and are not getting worse. Acute bacterial sinusitis is likely when you do not improve at

all within 10 days of getting sick or when you get worse within 10 days after beginning to get better. Question 5 Why is it important to tell if my sinusitis is caused by bacteria? Answer 5. Because sinusitis is treated differently based on cause: acute viral sinusitis does not benefit from antibiotics, but some patients with acute bacterial sinusitis may get better faster with an antibiotic. 5.2 Treating Acute Bacterial Rhinosinusitis (ABRS) Question 1. How long will it take before I feel better? 9

Answer 1. Most patients with ABRS feel better within 7 days, and by 15 days, about 90% are cured or improved. Question 2. Is there anything I can do for symptomatic relief? Answer 2. There are several ways to relieve sinusitis symptoms that should be discussed with your doctor to decide which are best for you: 1. Acetaminophen or ibuprofen can relieve pain and fever. 2. Saline irrigations, or washing out the nose with salt water, can relieve symptoms and remove mucus that is hard to blow out. 3.

Nasal steroid sprays can reduce symptoms after 15 days of use, but the benefit is small (about 14 people must use them to get 1 person better), and side effects include headache, nasal itching, and nosebleeds. Decongestants may help you breathe easier and can be taken as a nasal spray (for no more than 3 days in a row to avoid worsening congestion) or by mouth. Question 3. Is there anything I should not do? Answer 3. Antihistamines and oral steroid medicines should not be used routinely

because they have side effects and do not relieve symptoms. If I have ABRS, do I have to take an antibiotic? No, both watchful waiting and antibiotic therapy are proven ways to treat ABRS. Most people get better naturally, and antibiotics only slightly increase symptom relief (about 10 to 15 people must use antibiotics to get 1 more person better after 7-15 days). Question 4.Is there any downside to using antibiotic? Answer 4. Antibiotics have side effects that include rash, upset stomach, nausea,

vomiting, allergic reactions, and causing resistant germs. Question 5.What is “watchful waiting” for ABRS? Answer 5. Watchful waiting means delaying antibiotic treatment of ABRS for up to 7 days after diagnosis to see if you get better on your own. Question 6.How is watchful waiting done? Your doctor can give you an antibiotic prescription, but you should only fill the prescription and take the antibiotic if you do not get better after 7 days or if you get

worse at any time. If you do use the antibiotic, contact your doctor’s office and let them know. Question 7.If I use an antibiotic, for how many days should I take it? 10

Answer 7. Antibiotics are usually given for 10 days to treat ABRS, but shorter courses may be equally effective. Ask your doctor about a 5- to 7-day course of antibiotics since side effects are less common. 6. How this guideline was developed 1) Acute sinusitis STG Subgroup established Background December 2014: A Task Force was constituted to guide the development of Standard Treatment Guidelines (STG) in India. The Task Force subsequently

approved the draft STG development manual of India (Part 1) for development of adapted guidelines. In addition, it approved a list of 14 topics recommended by a subgroup of the task force appointed to select prioritized topics for STG development. These 14 topics are from 10 clinical specialties for which the first set of STGs will be developed. The topic of Acute sinusitis was included in this first list and was the dealt with by the ENT clinical subgroup. Clinical Subgroup on ENT

Disease Condition – Sinusitis in Adults Coordinator Dr. A. K. Agrawal – Director Professor MAMC, New Dehi None Rapporteur DrAvani Jain, Senior resident, MAMC, New Delhi of the Experts Dr Sunil Kumar Dhanda, Professor and Head, LHMC, New memb Delhi ers Dr Ravi Meher, Professor , MAMC, New Delhi report Physician any Private Practitioner Dr Sanjay Sachdeva, Chairman ENT, Max Hospital, Saket, confli New Delhi Primary Care Dr V K Monga, Leading private practitioner ct of Practitioners interes

t in the development of this guideline and have all signed their declarations. May 2015: NHSRC with technical support from NICE international carried out a training workshop to guide the STG group members and chairs on the methodology to follow in developing adapted STGs suitable for the Indian context. This workshop was conducted on 29th & 30th May, 2015 and two members (Ravi Meher and Sunil Dhanda) of the ENT STG team attended. 2) Scope of the STG 11

The task group decided to concentrate on the Acute sinusitis and exclude chronic sinusitis altogether since the aetiology, diagnosis of chronic sinusitis is different and may involve surgical treatment. The task group excluded the children because they have very small, underdeveloped sinuses and acute sinusitis in children is rarely seen in general practice. The scope of the STG on acute sinusitis was initially drafted by the three experts i.e. Dr A K

Agarwal, Dr Sunil Kumar and Dr Ravi Meher. It was subsequently reviewed and approved by the STG sub group in the first meeting held on 12 Oct 2015 from 2.00 pm to 4.30 pm in Dr A K Agarwal chamber at MAMC. In the meeting it was decided that the scope will include the clinical diagnosis, the indication and choice of antibiotics, when to get radiological investigations and when to refer to an ENT specialist. There was a consensus on

developing these guidelines for the general practitioners who are the first contact with the patients of sinusitis in India. Also there was intent to give clear cut guidelines for use and choice of antibiotics for treating acute sinusitis. 3) Search & select guidelines A search for guidelines on Acute sinusitis was performed on the National Guideline Clearinghouse (NGC) website and following three guidelines were retrieved. 1. IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in

Children and Adults. 2. Clinical Practice Guideline (Update): Adult Sinusitis by American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015. 3. Acute Rhinosinusitis in Adults by University of Michigan. Following are the web links to the above guidelines • https://www.idsociety.org/uploadedFiles/IDSA/Guidelines- Patient_Care/PDF_Library/IDSA%20Clinical%20Practice%20Guideline%20for%20 Acute%20Bacterial%20Rhinosinusitis%20in%20Children%20and%20Adults.pdf

• http://www.med.umich.edu/1info/FHP/practiceguides/Rhino/rhino.pdf • http://oto.sagepub.com/content/152/4/598.full.pdf+html Overview The STG on Acute Sinusitis was developed by a team of experts and relevant stakeholders. 4) Compare & shift guidelines After going through the available guidelines, the group selected all the above three guidelines as source guidelines. Since all the three guidelines are from the National Guideline Clearinghouse, we did not need perform the AGREE instrument to check

their quality. The selected three guidelines were subsequently approved as source guidelines by the STG sub group on acute sinusitis. 12

The First Face - to - face Meeting - The STG sub group on acute sinusitis met on 12 Oct 2015 from 2.00 pm to 4.30 pm in DrA K Agarwal chamber at MAMC, New Delhi. All the members of the STG sub group declared that they do not have any conflict of interest/ financial interest in the development of the STG. DrAvani Jain was introduced to all the members of the group as Rapporteur. 1. The group discussed the various guidelines in detail and found that the IDSA

Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adult is the most comprehensive guideline available and majority of the recommendations may be adopted as such. 2. Also there was discussion on finding some good Indian studies on acute sinusitis which can identify the common organism causing sinusitis in India and also the antibiotic sensitivity pattern. 3. Dr Agarwal stressed the need of including the Transillumination test as one

of the diagnostic criteria of acute sinusitis. There was no consensus on the issue among the members and hence further literature search on Transillumination test was advised by Dr Agarwal. 4. The rough draft of the STG on acute sinusitis to be mailed to all the members before the next meeting. 5) Search & select recommendations IDSA guidelines were the most comprehensive and appropriate among all the guidelines and hence majority of the recommendations were selected from it. The STG subgroup

met again on 1st Dec at 2.00 pm in Maulana Azad Medical College in which all the major recommendations in the rough draft were discussed point wise. The third meeting was held on 27th Jan 2016 again at the same venue. All the recommendations were discussed at length and modifications suggested by Dr Abhaand the NICE team were incorporated in the STG. • Dr Agarwal stressed the need of including the Transillumination test. The issue of

dark room and availability of a strong light source to perform the test was deliberated. It was decided that since the test is a simple one and has high predictive value it should be included in the guidelines and must be done if the facility of performing it are present. • Regarding ancillary treatment there was a general consensus that the local nasal decongestants should be recommended only in cases of severe nasal obstruction

though the guidelines does not approve its use in acute sinusitis. This is because it does provide symptomatic improvement in case of nasal obstruction to the patient though it might not alter the natural course of the disease. It was also discussed that the nasal decongestant must not be given for more than 5 days and should be used with precautions in case of hypertensive patients. 13

• Similarly the INCSs have been recommended as an adjunct to the treatment of acute sinusitis as they have good anti-inflammatory effects but they are not essential part of the treatment as addition of INCSs therapy will increase the cost of the treatment. They must be always given in case there is an associated history of suggestive of allergic rhinitis. There is an anticipated barrier to the diagnosis of Acute Sinusitis is the differentiation of

VRS from ABRS in a busy clinical setting. This is facilitated by the clear, unambiguous criteria for diagnosing ABRS on the history and time course of illness, without invasive tests or imaging studies. Patient education may also help address this barrier, as mentioned in patient information sheet. When diagnosed with VRS, patients may pressurize clinicians for prescribing antibiotics, in addition to symptomatic therapy. This

can be overcome by educational handout of patient information. Some clinicians might object to amoxicillin with clavulanate as first-line therapy for ABRS, based on assumptions that newer, more expensive alternatives “must be” more effective. Most favourable clinical outcomes for non severe ABRS, however, result from natural history, not antibiotics, and randomized controlled trials of comparative efficacy do not support superiority of any single agent for initial empiric therapy. Education about the use of

antibiotics, their efficacy and possibility of drug resistance may help in dispelling these myths. 6) Adopt/ adapt recommendations MoHFW guideline Adopted/ Original Remarks Adapted Guideline Definitions Acute sinusitis is an Adapted UMHS Addition of the inflammation of the paranasal guidelines 2011 symptoms sinuses and the nasal cavity characterized by lasting no longer than 4 weeks purulent nasal characterized by purulent nasal discharge (anterior, discharge (anterior, posterior posterior or both)

or both) accompanied by nasal accompanied by obstruction, facial pain- nasal obstruction, pressure-fullness, or both. facial pain-pressure- fullness, or both. Diagnosis of Acute sinusitis Acute Sinusitis- Up to 4 weeks Adopted IDSA 2012 of purulent nasal drainage guidelines (anterior, posterior, or both) 14

accompanied by nasal obstruction, facial pain-pressure- fullness, or both. Acute viral sinusitis Acute viral sinusitis or the Adopted AAO 2015 common cold is caused by virus and symptoms or signs of acute rhinosinusitis are present less than 10 days and the symptoms are not worsening. Acute bacterial rhinosinusitis(ABRS) Diagnosis of ABRS is made on Adopted IDSA 2012 the basis of following criteria. guidelines • Onset with persistent symptoms or signs compatible with acute rhinosinusitis, lasting for

more than 10 days without any evidence of clinical improvement • Onset with severe symptoms or signs of high fever (>39°C /102°F) and purulent nasal discharge or facial pain lasting for at least 3–4 consecutive days at the beginning of illness • Onset with worsening symptoms or signs characterized by the new onset of fever, headache, or increase in nasal discharge following a typical viral URI that lasted 5–6 days and were initially improving (‘‘double-sickening’’).

Rule out allergic rhinitis (AR) New Expert group Important to rule our which is diagnosed when in recommendat consensus allergic rhinitis as it addition to nasal obstruction and ion may have similar discharge there is also itchy presentation. nose, sneezing, red and watery 15

eyes. Clinical features: symptoms and signs Diagnosis of ARS is probable if Adopted IDSA 2012 2 or more of these major guidelines symptoms are present or 1 major symptom along with 2 or more minor symptoms. Signs (may be seen but Adapted Expert group absence of these does not consensus exclude Acute sinusitis) • Hypo-nasal speech indicating nasal obstruction • Swelling, redness of the skin due to congestion of the capillaries (erythema) or abnormally large fluid volume (edema) localized

over the involved cheek bone or periorbital area • Palpable cheek tenderness or percussion tenderness of the upper teeth • Purulent drainage in the nose or posterior pharynx • Signs of extra-sinus involvement (orbital or facial cellulitis, orbital protrusion, abnormalities of eye movement, neck stiffness indicating complications. When should empiric antibiotic therapy be initiated? We recommend that empiric Adopted IDSA 2012 antimicrobial therapy be guidelines initiated as soon as the clinical

diagnosis of ABRS is established as defined in recommendation.+ Choice of antibiotic for ABRS Amoxicillin-clavulanate rather Adopted IDSA 2012 than amoxicillin alone is guidelines recommended as empiric antimicrobial therapy for ABRS in adults. Duration of therapy 16

The recommended duration of Adopted IDSA 2012 therapy for uncomplicated guidelines ABRS in adults is 5–7 days. For partial but incomplete Adopted IDSA 2012 resolution after an initial guidelines course of antibiotics, extend the duration of antibiotic therapy by an additional 7 to 10 days. Use of High-dose (2 g orally Adopted IDSA 2012 twice daily or 90 mg/kg/day guidelines orally twice daily) amoxicillin- clavulanate is recommended patients with ABRS, those with severe infection (eg, evidence

of systemic toxicity with fever of more than 39 degree C [102 degree F] or higher, and threat of suppurative complications, attendance at day care, age <2 or >65 years, recent hospitalization, antibiotic use within the past month, or who are immunocompromised. Choice of antibiotic for ABRS in penicillin allergic patients Use of doxycycline (100mg Adopted IDSA 2012 12hr) or a respiratory guidelines fluoroquinolone (levofloxacin 500mg daily or moxifloxacin 400mg daily) is recommended

as an alternative agent for empiric antimicrobial therapy in adults who are allergic to penicillin. Treatment failure for ABRS 1 Reassess the patient after 7 Adopted AAO 2015 days to confirm ABRS, guidelines exclude other causes of illness, and detect complications if the patient fails to improve with the initial management option 17

or worsens during the initial management. 2 If ABRS is confirmed in the patient initially managed with observation, the clinician should begin antibiotic therapy. 3 The second line antibiotics include high dose amoxicillin/clavulanate combination (2 g orally twice daily or 90 mg/kg/day orally twice daily), levofloxacin (500mg daily), and moxifloxacin (400mg daily) or the combination of clindamycin plus a third- generation oral cephalosporin (cefixime or cefpodoxime). 4 Worsening is defined as

progression of presenting signs or symptoms of ABRS or onset of new signs or symptoms. Failure to improve is lack of reduction in presenting signs or symptoms of ABRS by 7 days after diagnosis, which would not apply if the patient had persistent, yet gradually improving, symptoms. 5 ABRS may take up to 7 days to improve, persistence or minor worsening prior to 7 days does not necessarily indicate treatment failure, and complete cure (absence of all signs and symptoms) may take 14 days or longer.

Role of imaging Clinicians should not obtain Adopted AAO 2015 18

radiographic imaging for guidelines patients who meet diagnostic criteria for acute rhinosinusitis, unless a complication or alternative diagnosis is suspected. Indications of Imaging If symptoms of rhinosinusitis Adapted UMHS guidelines Reframing of the persist for more than three 2011 sentence weeks despite antibiotics or recur more than four times per year, a sinus CT scan should be performed. Plain sinus x-rays Plain sinus x-rays, are not at all Adapted UMHS guidelines Reframing of the

recommended in management 2011 sentence of sinusitis. Decongestants (topical- Oxymetazoline and Xylometazoline) Use of topical decongestants is Adapted AAO 2015 recommended in case of severe guidelines and nasal obstruction for short Expert group duration. (Maximum of 5 consensus days). These should be used with precautions in patients with hypertension. Analgesics Nonsteroidal anti- Adapted AAO 2015 inflammatory drugs like guidelines paracetamol 500 mg tab tds/sos or diclofenac sodium 50 mg

tab tds/sos, are recommended for pain relief associated with acute sinusistis Antihistamines Routine administration of Adapted AAO-HNS 2015 antihistamines are not guidelines recommended in patients of sinusitis. Intra nasal corticosteroid spray(INCS) Though INCSs are not Adapted UMHS guidelines These are not essential for treatment of 2011 essential for ABRS they are recommended treatment of as an adjunct to antibiotics in ABRS until there 19

the empiric treatment of ABRS is an element of for 10 days. Fluticasone allergic rhinitis ormometasone intra nasal also sprays are recommended twice daily. Steam inhalation Steam inhalation is New Expert group recommended by the expert recommendation consensus group twice a day for 5-7 days. Nasal spray and douching with physiologic/hypertonic saline Intranasal saline irrigations Adopted IDSA 2012 with either physiologic or guidelines hypertonic saline are recommended as an adjunctive

treatment in adults with ABRS When to refer to ENT specialist? Refer to an ENT specialist if Adapted IDSA 2012 any of the following guidelines indications are present: 1. Severe infection (high persistent fever with temperature >39 degree C [>102 degree F] 2. Orbital edema, severe headache, visual disturbance, altered mental status, meningeal signs) 3. Recalcitrant infection with failure to respond to extended courses of antimicrobial therapy 4. Immunocompromised host 5. Multiple medical problems that might

compromise response to treatment (eg, hepatic or renal impairment, hypersensitivity to 20

antimicrobial agents, organ transplant) 6. Unusual or resistant pathogens 7. Fungal sinusitis or granulomatous disease 8. Nosocomial infection. 9. Anatomic defects causing obstruction and requiring surgical intervention 10. Multiple recurrent episodes of acute bacterial rhinosinusitis (ABRS) (3–4 episodes per year) suggesting chronic sinusitis 11. Chronic rhinosinusitis (with or without polyps or asthma) with recurrent ABRS exacerbations.

Recommendations selected from various source guidelines are considered adaptations of existing guidelines and should maintain the standards (evidence) used in the original guideline. A systematic approach was followed to ensure high quality of the process. The STG clinical sub group was required to make a series of judgments on the new STG recommendations. There was clear documentation of the deliberations and the reasons for

each recommendation being adapted in the process in order to maintain quality assurance. This led to several options: a) Adopted recommendation - this entailed transferring a recommendation verbatim to the new STG. b) Adapted a recommendation - This included adapting the recommendation to ensure local compatibility with India or adding precisions to the wording to clarify the recommendation or changing of wording to active phrasing in order to ensure language consistency was

maintained throughout the document. It was ensured while adapting a recommendation that the evidence underpinning the recommendation remained intact. 7) Writing the STG: All the recommendations (adopted/ adapted) were compiled and implementation tools were developed. Dr AbhaMehndiratta and her colleague Dr Laura Downey from NICE group helped in giving important feedback on the rough draft we sent on mail. The suggestions were well taken by all the group members and were incorporated in the final draft. 21

7. Research needs There are still knowledge gaps in existing practice patterns and the quality of supporting literature. We present these gaps below to highlight areas for future research and investigation. • Determine incidence and disease burden of ABRS in India • Determine organisms commonly responsible for ABRS in India • Clinical differentiation of bacterial from viral acute rhinosinusitis • Determine whether 7- or 10-day symptom duration is more likely to be associated with ABRS.

• Assess the validity of diagnosing ABRS before 10 days based on persistent fever plus concurrent purulent nasal discharge. • Conduct randomized controlled trials (RCTs) to determine the efficacy of an “observation option”fornonsevere ABRS, by randomizing patients to immediate vs delayed antibiotics and assessing clinical outcomes. • Perform RCTs of antibiotics vs placebo using strict diagnostic criteria and stratify by clinical severity (ie, mild, moderate, or severe).

• Perform RCTs to assess the comparative efficacy of different antibiotics for initial management of uncomplicated ABRS. • Assess the benefits of various symptomatic therapies for ABRS in properly conducted RCTs. • Determine optimum salinity, pH, and regimen for administering nasal saline irrigation. • Determine whether there is a difference in efficacy between isotonic and hypertonic concentrations for intranasal saline irrigations.

• Devise strategies or treatment regiments to avoid the rebound effect of topical nasal decongestants. • Conduct RCTs to determine the efficacy of adjuvant therapy (nasal steroids, antihistamines, decongestants) in combination with antibiotics. 8. Annexure 1. How to do saline irrigations? The expert group recommends using boiled and cooled water for irrigation. One table spoon of salt (around 9 gm.) can be added to a liter of water for making irrigation solution. There

are commercial preparations also available of normal and hypertonic saline which may be used. Nasal saline irrigations can be done using a neti pot or commercially available squeeze bottle. The saline irrigation is done by inserting the neti pot or the nozzle of the squeeze bottle in one of the nostril and allowing the flow of saline from one nostril and 22

comes our via the opposite nostril while patient keeps saying ‘K’ ‘K’ ‘K’ ‘K’. This helps in closing the nasopahyrynx by soft palate and thus prevent any risk of saline going into the oropharynx and airway. It is recommended by the group to be done for twice a day for 5-7 days. 2. Role of CT scan CT scans provide much better definition than a plain sinus x-ray hence plain sinus x-rays, are not at all recommended in management of sinusitis. In general, more advanced imaging

modalities such as CT or MRI should be reserved for recurrent or complicated cases or when suppurative complications such as orbital or intracranial extension are suspected. In general, CT is considered the gold standard for assessing bony and anatomical changes associated with acute or chronic sinusitis, whereas MRI is useful to further delineate the extent of soft tissue abnormalities and inflammation. CT is also necessary for surgical planning and for intraoperative image guided surgical navigation.

CT findings that correlate with ABRS are • Sinus opacification • Air fluid levels (> minimal) • Marked mucosal thickening • Polyps Refer the patient to ENT specialist when following on CT findings are present • Unilateral disease • Sinus expansion • Bony erosion 3. Empiric antibiotic therapy • Benefits: Prompt antimicrobial therapy for patients more likely to have acute bacterial rather than viral rhinosinusitis should shorten the duration of illness,

provide earlier symptom relief, restore quality of life, and prevent recurrent infection or suppurative complications. • Harms: Prompt antimicrobial therapy may result in overuse of antibiotics, enhanced cost, and risk of adverse effects in those patients who do have true bacterial infection but mild disease. However, the patient selection criteria specified in recommendation make this possibility less likely. • A systematic review of 12 randomized controlled trials with radiologically

confirmed ABRS found no difference in clinical success for antibiotics given for 3 to 23

7 days vs a 6- to 10-day course of therapy. Adverse events are more common with antibiotic therapy with 10 days of therapy compared to shorter courses. An average event rate of 15% to 40% is observed, with the most frequent complaints being nausea, vomiting, diarrhea, abdominal pain, headache, skin rash, photosensitivity, and vaginal moniliasis. Adverse events rarely are of sufficient severity to cause a change in therapy. Conversely, the incidence of adverse events is lower when

antibiotics are given for 5 days instead of 10 so short courses should be considered for patients with less severe illness. • For partial but incomplete resolution after an initial course of antibiotics, extend the duration of antibiotic therapy by an additional 7 to 10 days for a total of 3 weeks of antibiotics. • Benefit: Clinical outcomes that are comparable to broader spectrum antibiotics for initial therapy; potential reduced bacterial resistance by using a narrow-spectrum

antibiotic as first-line therapy; cost-effectiveness of amoxicillin vs other antibiotic choices. The addition of clavulanate to amoxicillin substantially improves the coverage for both ampicillin-resistant H. influenzae and M. catarrhalis in ABRS. • Risks/ Harms: Potential increased gastrointestinal adverse effects with amoxicillin- clavulanate compared with other antibiotics and adverse effects from penicillin allergy. Treatment failures

• If the patient does not have the symptom cluster of purulent nasal drainage accompanied by nasal obstruction, facial pain-pressure fullness, or both but instead has individual symptoms, alternate diagnoses should be explored. Migraines, tension headaches, cluster headaches, and temporomandibular joint disorder are common causes of facial pain that can be mistaken for ABRS. Similarly, nasal discharge or congestion can arise from common noninfectious causes that include allergic rhinitis,

vasomotor rhinitis, deviated nasal septum, and nasal valve collapse. Imaging studies are not indicated for uncomplicated ABRS but may be appropriate to “rule out” ABRS (eg, a misdiagnosis) if the patient does not respond to therapy. Patients with a reconfirmed diagnosis of ABRS who fail treatment, especially those with a worsening pattern of illness, should be examined for complications that include orbital or intracranial spread of infection. Suggestive findings on physical

examination include proptosis, visual changes, severe headache, abnormal extraocular movements, changes in mental status, and periorbital inflammation, edema, or erythema. Acute frontal sinusitis typically causes severe headache localized to the forehead over the orbits, with tenderness produced by pressure on the floor of the frontal sinus. Sphenoidal sinusitis typically causes a dull ache in the back of head, specifically over the occiput with radiation to the frontal and retro-

orbital regions. Culture of nasal secretions may help guide subsequent antibiotic 24

therapy and is best performed by direct sinus aspiration rather than by nasopharyngeal swab. Endoscopically guided cultures of the middle meatus are an alternative in adults. 4. Intranasal corticosteroids • Benefits: The beneficial effect of INCSs could be attributed to their anti- inflammatory properties, which may reduce mucosal swelling and promote drainage. • Risks/Harms. Short-term risks of INCSs are minimal but may include susceptibility

to oral candidiasis. Routine administration of INCSs will clearly increase the cost of treating ABRS. However, in patients with concurrent allergic rhinitis, INCS should be routinely administered. 5. Steam inhalation • Steam inhalation moistens the mucosa and improves ciliary action thereby improving the drainage and providing symptomatic relief. Inhaled steam may soften secretions and provide symptomatic relief, but again, little objective evidence exists regarding their use.

6. Intranasal saline irrigations • Intranasal saline irrigations with either physiologic or hypertonic saline are recommended as an adjunctive treatment in adults with ABRS (IDSA). It has been postulated that saline irrigation improves nasal symptoms by enhancing mucociliary function, decreasing mucosal edema, mechanically clearing inspissated mucus, and decreasing inflammatory mediators. Several studies evaluated the role of hypertonic

vs physiologic saline on nasal airway patency and mucociliary clearance in patients with symptomatic rhinosinusitis. Both saline preparations significantly improved mucociliary clearance compared with pretreatment values; however, only physiologic saline significantly improved nasal airway patency. In other studies, as compared with isotonic saline, hypertonic saline may have a superior anti- inflammatory effect and better ability to thin mucous and transiently improve mucociliary clearance.

• Benefits: Nasal saline irrigation, alone or in conjunction with other adjunctive measures, may improve quality of life, decrease symptoms, and decrease medication use for ABRS, particularly in patients with frequent sinusitis. • Risks/harms: Nasal burning, irritation, and nausea were the most frequently reported adverse effects from intranasal saline irrigation (7%–32% in various studies). In addition, saline irrigants should be prepared from sterile or bottled water in light of

recent reports of primary amebic encephalitis from contaminated tap water used for saline nasal irrigation. 25

References 1. https://www.idsociety.org/uploadedFiles/IDSA/Guidelines- Patient_Care/PDF_Library/IDSA%20Clinical%20Practice%20Guideline%20for %20Acute%20Bacterial%20Rhinosinusitis%20in%20Children%20and%20Adult s.pdf 2. http://www.med.umich.edu/1info/FHP/practiceguides/Rhino/rhino.pdf 3. http://oto.sagepub.com/content/152/1_suppl/S1.full.pdf+html 4. http://oto.sagepub.com/content/152/4/598.full.pdf+html 5. Blackwell DL, Lucas JW, Clarke TC. Summary health statistics for U.S. adults:

national health interview survey, 2012. Vital Health Stat. 2014; 10:1-171. 6. http://www.entnet.org/sites/default/files/uploads/PracticeManagement/Resources /_files/adult-sinusitis-patient-info-diagnosis-of-sinusitis.pdf 7. http://www.entnet.org/sites/default/files/uploads/PracticeManagement/Resources /_files/adult-sinusitis-patient-info-treating-acute-bacterial-rhinosinusitis.pdf 26

STANDARD TREATMENT GUIDELINES OTORHINOLARYNGOLOGY (ENT) Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 ALLERGIC RHINITIS 4 2 DEVIATED NASAL SEPTUM (DNS) 6 3 EPISTAXIS 9 4 BRANCHIAL CYST 12 5 BRANCHIAL FISTULA 14 6 MOUTH ULCERS 16 7 ACUTE PAROTITIS 17 8 SUBMANDIBULAR SIALADENITIS 19 9 THYROGLOSSAL DUCT CYST AND FISTULA 21 10 ACUTE LARYNGOTRACHEO BRONCHITIS 23 11 ADENOIDITIS 25 12 CHRONIC LARYNGITIS 26 13 BENIGN LESIONS OF LARYNX 28 14 DEEP NECK SPACE INFECTION 29 15 FOREIGN BODY IN AERODIGESTIVE TRACT 31 16 GOITRE 33 17 LARYNGOPHARYNGEAL REFLUX (LPR) 35

18 CARCINOMA ORAL CAVITY 37 19 CARCINOMA HYPOPHARYNX 44 20 CARCINOMA LARYNX 51 21 CERVICAL LYMPHADENOPATHY 64 22 PERITONSILLAR ABSCESS (QUINSY) 68 2

Group Head Coordinator of Development Team Dr J M Hans Ex-HOD Dept. of Otorhinolaryngology Dr.RML Hospital New Delhi 3

ALLERGIC RHINITIS WHEN TO SUSPECT/ RECOGNIZE A. Definition: Allergic rhinitis is allergic inflammation of nasal airways. B. Introduction: When a foreign protein (allergen) is inhaled by a previously sensitized individual, a reaction between the allergen and the antibodies takes place on the nasal mucosa. This inflammatory reaction presents as itching in the nose, sneezing and nose block. C. Allergic rhinitis may be seasonal or perrineal. Allergic rhinitis is found to co exist with

Bronchial asthma, nasal polyps, sinusitis, adenoid hypertrophy, Eustachian tube dysfunction and otitis media. INCIDENCE IN OUR COUNTRY D. No exact data are available in our country. DIFFERENTIAL DIAGNOSIS E. The diagnosis is clinical. The differential diagnosis would include 1. Vasomotor rhinitis 2. Hormonal rhinitis in pregnancy, hypothyroidism etc 3. Nasal block due to deviated nasal septum 4. Immotile cilia syndrome 5. Specific rhinitis caused by granulomatous diseases like wegener’s and sarcoidosis.

PREVENTION AND COUNSELLING F. Allergic rhinitis can be prevented by environmental control measures and allergen avoidance by reducing outdoor exposure during pollen season. For indoor allergens prevention would include: 1. Covering mattresses with impermeable covers 2. Washing of bed linen every two weeks in hot water 3. Avoidance of exposure to pets OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA AT SECONDARY HOSPITAL/ NON METRO SITUATION 4

G. CLINICAL DIAGNOSIS: the diagnosis is essentially based on history. The basic evaluation should include: 1. Complete ENT examination 2. Nasal examination for condition of nasal mucosa and polyps if any. 3. Evaluation of respiratory system to exclude asthma H. INVESTIGATIONS: 1. complete blood count, 2. Absolute eosinophil count. 3. X Ray of paranasal sinuses. 4. Other investigations based on associated conditions I. TREATMENT: 1. OUT PATIENT: 1. Nasal decongestants: avil, cetrizine, fexofenadine etc

2. Nasal Steroid sprays: Fluticasone, Mometasone, Budesonide etc 3. Oral steroids: for refractory cases and those with asthma. 2. DAY CARE: nil 3. INPATIENT: 1. Surgical procedures like septoplasty, adenoidectomy with or without grommet insertion, polypectomy may be required. 2. Manangement of comorbities. J. REFERRAL CRITERIA: 1. Extensive nasal polyposis 2. Associated complications not manageable in the centre. AT TERTIARY HOSPITAL/ METRO SITUATION

K. CLINICAL DIAGNOSIS: nasal examination is complemented with nasal endoscopy under local anaesthesia. L. INVESTIGATIONS: 1. Allergy skin testing 2. IgE estimation if available 3. CT Scan of paranasal sinuses M. TREATMENT: Additional measures which may be required are 1. OUT PATIENT: antihistamines, nasal steroid sprays, leukotrienne antagonists and oral steroids. 2. DAY CARE/ INPATIENT: 1. Septoplasty 2. Endoscopic sinus surgery 3. management of comorbidiites. N. REFERRAL CRITERIA:

DEVIATED NASAL SEPTUM (DNS) WHEN TO SUSPECT/ RECOGNIZE O. Definition: Deviated Nasal Septum is deflection of nasal septum from midline. P. Introduction: Deviated Nasal Septum (DNS) may be caused by birth trauma, trauma to face during life or due to asymmetric growth of cartilages and bones of nose. They may present with nose block, recurrent nasal discharge, infections of nose and sinuses, bleeding from nose or headaches. In gross DNS, there may be a concomitant deviation of external nose also.

INCIDENCE IN OUR COUNTRY Q. Very few people have absolutely straight nasal septum. Most minor DNS are not symptomatic and do not require treatment. Only symptomatic DNS need be mentioned to the patient and treated. DIFFERENTIAL DIAGNOSIS R. The differential diagnosis includes: 1. Acute or chronic Rhinosinusitis 2. Nasal Allergy 3. Large Adenoid mass in children 4. Foreign Body/ Rhinolith in children 5. Nasal Polyps 6. Growths/ Tumors of nose PREVENTION AND COUNSELLING

S. DNS cannot be prevented. Minor deviations do not require treatment. Symptomatic DNS can be corrected by surgery through the nostrils under Local or General Anaesthesia. Surgery is usually done after the age of 16 years when the facial growth is complete. Surgery in younger patients may be undertaken if grossly symptomatic and not amenable to medical management for nasal obstruction. T. In septoplasty, the deviated portion of the nasal septum is removed. The nose is packed for

1 -2 days to prevent bleeding. Patient is discharged after removal of packs. The nose takes 1 -2 weeks to heal completely. 6

OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA AT SECONDARY HOSPITAL/ NON METRO SITUATION U. CLINICAL DIAGNOSIS: The diagnosis of DNS is made on: 1. History of facial trauma if any 2. Complaints of nasal obstruction, discharge, bleeding or headache 3. Complete ENT examination 4. Nasal examination including anterior rhinoscopy and Cold Spatula Test. 5. Evaluation of extent and site of trauma to face if any V. INVESTIGATIONS: 1. complete blood count, 2. bleeding and clotting time.

3. X Ray of paranasal sinuses 4. X Ray of nasal bones in trauma. 5. Other investigations based on general clinical condition W. TREATMENT: 1. OUT PATIENT: Associated conditions causing nasal obstruction can be treated medically as out patient with: 1. Antihistaminics oral or nasal sprays 2. Monteleukast 3. Steroid nasal sprays 4. Antibiotics for nasal and sinus infections 2. DAY CARE: 1. Removal of foreign body or rhinolith from nose. 2. Anterior nasal packing for bleeding from nose.

3. Septoplasty surgery may be performed as day care if adequate facility for post op care is available at home. 3. INPATIENT: 1. Septoplasty. 2. Manangement of comorbities. X. REFERRAL CRITERIA: 1. External deformity requiring rhinoplasty 2. Nasal Polyps requiring endoscopic sinus surgery 3. Bleeding not controlled with anterior and posterior nasal packing. 4. Midface fractures would require a maxillofacial consultation. 5. Other co morbidities requiring appropriate cross consultations.

AT TERTIARY HOSPITAL/ METRO SITUATION Y. CLINICAL DIAGNOSIS: The evaluation should include: 1. Review of general evaluation of clinical condition 2. Complete ENT examination 7

3. Nasal Endoscopic examination under Local/ General Anaesthesia to identify deviation of septum, sinusitis, polyps, site of bleeding or any growths in nose. 4. Evaluation of extent and site of trauma to face if any Z. INVESTIGATIONS: 1. complete blood count, 2. bleeding and clotting time. 3. Prothrombin Time/ PTTK/ INR 4. CT Scan of nose and paranasal sinuses AA. TREATMENT: Additional measures which may be required are 1. OUT PATIENT/ DAY CARE: Endoscopic electro cautery of bleeding point 2. INPATIENT:

1. Rhinoplasty for external deviation of nose 2. Endoscopic sinus surgery 3. Maxillofacial reduction of fracture and wire and plate fixation. 4. Biopsy and / or excision of tumor if any 5. Management of comorbidiites. BB. REFERRAL CRITERIA: 1. In adequate facilities for any of the above. 8

EPISTAXIS WHEN TO SUSPECT/ RECOGNIZE CC. Definition: Epistaxis is bleeding from nose. Blood may flow anteriorly or go posteriorly. It may be clotted or flow from nose . DD. Introduction: Nose bleeds are common as nose is rich in blood supply and is prominent on the face. Most epistaxis are minor and are managed at home. Only a small percentage comes for medical attention. INCIDENCE IN OUR COUNTRY EE. No exact data are available in our country. DIFFERENTIAL DIAGNOSIS

FF. The diagnosis is clinical. Hence it has no differential diagnosis. The various common causes of epistaxis may be local or systemic. GG. Local causes 1. Low humidity: as in dry climate in summers and winters 2. Infection- Rhinitis, sinusitis 3. Trauma: Injury to nose by direct trauma or by nose picking. 4. Surgery: Septoplasty or endoscopic sinus surgery HH. Systemic causes: 1. Hypertension 2. Blood thinning drugs like aspirin, clopidogrel, warfarin

3. Benign growths like Angiofibroma and Rhinosporidiosis 4. Cancers like Sinonasal cancers and Carcinoma of nasopharynx PREVENTION AND COUNSELLING II. Epistaxis can be prevented by keeping the nasal mucosa moist in dry climates by douching with water, applying creams and nasal sprays JJ. Most epistaxis are mild and can be dealt effectively at home. The soft parts of nose are pinched tightly for 10-20 minutes. The head is bent forward and kept above the level of

heart. Any blood flowing in to throat should be spit into a bowl. Ice can be applied locally. After the epsitaxis is controlled, patient is advised not to blow nose, keep the nasal mucosa moist and blood pressure under control. 9

OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA AT SECONDARY HOSPITAL/ NON METRO SITUATION KK. CLINICAL DIAGNOSIS: When the epistaxis is not controlled with local pressure for over 20 min, expert medical care is required. The basic evaluation should include: 1. Pulse, BP monitoring, 2. General evaluation of clinical condition 3. Complete ENT examination 4. Nasal examination to identify cause and site of bleeding. 5. Evaluation of extent and site of trauma to face if any

LL. INVESTIGATIONS: 1. complete blood count, 2. bleeding and clotting time. 3. X Ray of paranasal sinuses and nasal bones in trauma. 4. Other investigations based on general clinical condition MM. TREATMENT: 1. OUT PATIENT: General condition of the patient is stabilized. 2. DAY CARE: 1. If the site of bleeding is identified, chemical or electro cautery is done to stop the bleeding. 2. If not, then anterior nasal packing is done with ribbon gauze soaked in

liquid paraffin and antibiotic solution, gelfoam or hemostatic sponge. The packs are kept in place for two to three days. 3. INPATIENT: 1. It the bleeding still continues, a posterior nasal packing with gauze or Foley’s catheter may be done. 2. Manangement of comorbities. NN. REFERRAL CRITERIA: 1. Massive blood loss 2. Bleeding not controlled with anterior and posterior nasal packing. 3. Midface fractures would require a maxillofacial consultation.

4. Other co morbidities requiring appropriate cross consultations. AT TERTIARY HOSPITAL/ METRO SITUATION OO. CLINICAL DIAGNOSIS: When the epistaxis is not controlled with anterior and posterior nasal packing, the evaluation should include: 1. Review of general evaluation of clinical condition 2. Complete ENT examination 3. Nasal Endoscopic examination under Local/ General Anaesthesia to identify cause and site of bleeding. 4. Evaluation of extent and site of trauma to face if any 10

PP. INVESTIGATIONS: 1. complete blood count, 2. bleeding and clotting time. 3. Prothrombin Time/ PTTK/ INR 4. Contrast enhanced CT Scan of paranasal sinuses 5. MR Angiography 6. Digital substraction angiography (DSA) of carotid and vertebral artery system QQ. TREATMENT: Additional measures which may be required are 1. OUT PATIENT/ DAY CARE: Endoscopic electro cautery 2. INPATIENT: 1. Septoplasty 2. Maxillofacial reduction of fracture and wire and plate fixation. 3. External carotid artery ligation

4. DSA embolisation of bleeding vessel 5. Biopsy and / or excision of tumor if any 6. Management of comorbidiites. RR. REFERRAL CRITERIA: 1. In adequate facilities for any of the above. 11

BRANCHIAL CYST Introduction: Branchial cleft cysts are congenital epithelial cysts, which arise on the lateral part of the neck from a failure of obliteration of the second branchial cleft in embryonic development. Phylogenetically, the branchial apparatus is related to gill slits. (Branchia is Greek for gills). Definition: At the fourth week of embryonic life, the development of 4 branchial (or pharyngeal) clefts results in 5 ridges known as the branchial (or pharyngeal) arches, which

contribute to the formation of various structures of the head, the neck, and the thorax. The second arch grows caudally and, ultimately, covers the third and fourth arches. The buried clefts become ectoderm-lined cavities, which normally involutes around week 7 of development. If a portion of the cleft fails to involute completely, the entrapped remnant forms an epithelium-lined cyst with or without a sinus tract to the overlying skin.

Incidence in India: Unknown. Branchial cleft cysts are the most common congenital cause of a neck mass. An estimated 2-3% of cases are bilateral. A tendency exists for cases to cluster in families. Differential diagnosis: 1. Lymphadenopathy (reactive, neoplastic, lymphoma, metastasis) 2. Vascular neoplasms and malformations 3. Capillary hemangioma 4. Carotid body tumor 5. Lymphatic malformation (cystic hygroma) 6. Ectopic thyroid tissue 7. Ectopic salivary tissue Prevention and Counseling: NA

Optimal Diagnostic Criteria, Investigations, Treatment & Referral Criteria Clinical Diagnosis: Diagnosis is usually made clinically. Many branchial cleft cysts are asymptomatic. Depending on the size and the anatomical extension of the mass, local symptoms, such as neck swelling, dysphagia, dysphonia, dyspnea, and stridor may occur. A branchial cyst commonly presents as a solitary, painless mass in the neck of a child or a

young adult. A history of intermittent swelling and tenderness of the lesion during upper 12

respiratory tract infection may exist. Discharge may be reported if the lesion is associated with a sinus tract. Branchial cysts are smooth, non-tender, fluctuant, translucent masses, which occur along the lower one third of the antero-medial border of the sternocleidomastoid muscle between the muscle and the overlying skin. Secondary branchial cleft cyst lesion: The lesion may be tender if secondarily inflamed or

infected. When associated with a sinus tract, mucoid or purulent discharge onto the skin or into the pharynx may be present. Investigations: 1. Fine-needle aspiration may be helpful to distinguish branchial cleft cysts from malignant neck masses. Fine-needle aspiration and culture may help guide antibiotic therapy for infected cysts. 2. A sinogram may be obtained. If a sinus tract exists, radio-opaque dye can be injected to delineate the course and to examine the size of the cyst.

3. Ultrasonography helps to delineate the cystic nature of these lesions. 4. A contrast-enhanced CT scan shows a cystic and enhancing mass in the neck. It may aid preoperative planning and identify compromise of local structures. 5. MRI allows for finer resolution during preoperative planning. The wall may be enhancing on gadolinium scans. Treatment: Surgical excision is definitive treatment for branchial cleft cysts. A series of

horizontal incisions, known as a stair step or stepladder incision, is made to fully dissect out the occasionally tortuous path of the branchial cleft cysts Standard Operating Procedure: As in patient surgery should be performed Referral Criteria: depends upon competency of operating surgeon and available resources. 13

BRANCHIAL FISTULA Introduction: Branchial fistulas are uncommon anomalies of embryonic development of branchial apparatus. Second branchial arch and pouch anomalies are common anomalies of branchial apparatus. Definition: During embryonic development, the second arch grows caudally; envelop the third, fourth and sixth arches and form the cervical sinus by fusing with the skin caudal to these arches. The edges of cervical sinus fuse and the ectoderm within the fused tube disappears.

Persistence of ectoderm gives rise to branchial cyst. The branchial fistula results from the breakdown of the endoderm, usually in the second pouch. A persistent fistula of the second branchial cleft and pouch pass from the external opening in the mid or lower neck in the line of the anterior border of the sternocleidomastoid muscle, deep to platysma along the carotid sheath, then pass medially deep between the internal and external carotid arteries after crossing over the glossopharyngeal nerve and

hypoglossal nerve. Finally, it opens internally in the tonsillar fossa usually on the anterior face of the upper half of the posterior pillar of the fauces or in the intratonsillar cleft. Most of the times it is a simple sinus opening that extend up the neck for a variable distance. Complete branchial fistula with internal opening into tonsillar region is rare. Incidence in India: Unknown. Although branchial fistulas may occur in any age group,

commonly patients present to clinician in first and second decades of life. Differential diagnosis: sinus from an infected lymph node Prevention and Counseling: NA Optimal Diagnostic Criteria, Investigations, Treatment & Referral Criteria Clinical Diagnosis: 1. History - Diagnosis is usually made clinically. Patient complains of mucopurulent discharge from an opening in lower lateral part of neck. 2. Examination – A small punctum in the skin at the junction of upper two third and

lower one third of anterior border of sternocleidomastoid muscle. Investigations: The tract of fistula can be diagnosed by a dye test or fistulogram and sometimes negative preoperative test might become positive under general anaesthesia because of muscle 14

relaxation. Occasionally the fistula tract may be blocked by thick secretions or granulation tissue. Treatment: Surgical excision Standard Operating Procedure: As in patient surgery should be performed Referral Criteria: depends upon competency of operating surgeon and available resources. 15

MOUTH ULCERS Mouth ulcers are sores or open lesions in the mouth. Causes, incidence, and risk factors Mouth ulcers are caused by many disorders. These include: SS. Canker sores TT. Gingivostomatitis UU. Herpes simplex VV. Leukoplakia WW. Oral cancer XX. Oral lichen planus YY. Oral thrush The skin lesion of histoplasmosis may also appear as a mouth ulcer. Canker sores are more common in young adults than in children or older adults. Symptoms 1. Open sores in the mouth 2. Pain or discomfort in the mouth

The appearance and exact location of lesions varies with the specific disorder. Signs and tests A health care provider or dentist usually diagnoses the type of mouth ulcer, based on its appearance and location. Blood tests or a biopsy of the ulcer may be needed to confirm the cause. Treatment The goal of treatment is to relieve symptoms. The cause, if known, should be treated. Gentle, thorough oral hygiene may relieve some of the symptoms. Topical (rubbed on) antihistamines,

antacids, corticosteroids, or other soothing preparations may be recommended for applying directly to the ulcer. Avoid hot or spicy foods, which often increase the pain of mouth ulcers. 16

ACUTE PAROTITIS Parotitis is an inflammation of one or both parotid glands, the major salivary glands located on either side of the face, in humans. The parotid gland is the salivary gland most commonly affected by inflammation. CAUSES : Infectious parotitis Acute bacterial parotitis: Parotitis as Extrapulmonary Tuberculosis: Acute viral parotitis (mumps): HIV parotitis: Autoimmune causes These are also collectively known as chronic punctate parotitis or chronic autoimmune parotitis. Sjögren's syndrome:

Mikulicz disease: Lymphoepithelial lesion of Godwin: Blockage Blockage of the main parotid duct, or one of its branches, is often a primary cause of acute parotitis, with further inflammation secondary to bacterial superinfection. The blockage may be from a salivary stone, a mucous plug, or, more rarely, by a tumor, usually benign. Chronic nonspecific parotitis: Recurrent parotitis of childhood Sialadenosis (sialosis): Sarcoidosis: Pneumoparotitis: 17

Symptoms ZZ. Abnormal tastes, foul tastes AAA. Decreased ability to open the mouth BBB. Dry mouth CCC. Fever DDD. Mouth or facial pain, especially when eating EEE. Redness over the side of the face or the upper neck FFF. Swelling of the face (particularly in front of the ears, below the jaw, or on the floor of the mouth) Signs and tests An examination by the health care provider or dentist shows enlarged salivary glands. Pus may

drain into the mouth. The gland may be painful, particularly with bacterial infections. Viral infections such as mumps may cause painless swelling of the glands. A CT scan or ultrasound may be done if the doctor suspects an abscess. Treatment In some cases, no treatment is necessary. If there is pus or a fever, or if the infection is known or thought to be bacterial, antibiotics may be prescribed. Antibiotics are not effective against viral infections.

If there is an abscess, surgical drainage or aspiration may be done. Good oral hygiene, with thorough tooth brushing and flossing at least twice per day, may aid healing and help prevent an infection from spreading. If you are a smoker, stop smoking as it helps in recovery. Warm salt water rinses (1/2 teaspoon of salt in one cup of water) may be soothing and keep the mouth moist. Drink lots of water and use sugar-free lemon drops to increase the flow of saliva and reduce

SUBMANDIBULAR SIALADENITIS INTRODUCTION: The submandibular gland, along with the parotid and sublingual glands, comprise the major salivary glands. The minor salivary glands are scattered along the upper aerodigestive tract, including the lips, mucosa of the oral cavity, pharynx, and hard palate. The submandibular gland is the second largest (approximate weight, 10 g) of the major salivary glands (the parotid gland is the largest). Anatomically, it is situated in the submandibular triangle of the neck.

DEFINITION: Sialadenitis of the submandibular gland is a relatively commonly encountered yet infrequently discussed topic. Causes range from simple infection to autoimmune etiologies. Causes GGG. Acute sialadenitis HHH. Chronic sialadenitis III. Sialolithiasis JJJ. Autoimmune sialadenitis KKK. Sialadenosis Differential Diagnoses The differential diagnosis of submandibular sialadenitis and sialadenosis includes the following: 1. Infectious (acute) cause - Bacterial or viral disease

2. Inflammatory cause - Sialolithiasis, radiation-induced disease 3. Autoimmune cause - Sjögren disease, lupus 4. Granulomatous cause - Tuberculosis, tularemia, sarcoidosis, catscratch disease, actinomycosis 5. Drug-related cause - Thiourea 6. Neoplastic (benign) cause - Pleomorphic/monomorphic adenoma, oncocytoma, ductal papilloma, hemangioma, foreign body, ranula, lymphoepithelial cyst 7. Neoplastic (malignant) cause - Adenoid cystic carcinoma, mucoepidermoid carcinoma,

adenocarcinoma, undifferentiated carcinoma, malignant oncocytoma, squamous cell carcinoma 8. Endocrine cause - Hypothyroidism, diabetes mellitus 9. Metabolic cause - Vitamin deficiency, cirrhosis, obesity, bulimia, malabsorption INVESTIGATIONS 1. Ultrasonography 2. Sialography 3. Computed tomography scanning 4. Magnetic resonance imaging 5. Fine-needle aspiration and biopsy TREATMENT : One management scheme is as follows: 1. Acute sialadenitis 19

1. Medical management - Hydration, antibiotics (oral versus parenteral), warm compresses and massage, sialogogues 2. Surgical management - Consideration of incision and drainage versus excision of the gland in cases refractory to antibiotics, incision and drainage with abscess formation, gland excision in cases of recurrent acute sialadenitis 2. Salivary calculi 1. Medical management - Hydration, compression and massage, antibiotics for the infected gland

2. Surgical management - Duct cannulation with stone removal, gland excision in recurrent cases 20

THYROGLOSSAL DUCT CYST AND FISTULA Introduction: Thyroglossal duct cyst is a rare but occasional cause of a benign midline neck mass. Definition: The cyst is usually located at the midline of the neck. Thyroglossal duct cysts result from the dilatation of a remnant tract at the site where the primitive thyroid descended from its origin at the base of the tongue to its permanent location, low in the neck. Failure of

subsequent closure and obliteration of this tract predisposes to thyroglossal cyst formation. It most often occurs before age 20, but may be found in the older population as well. It is more common in males. The thyroglossal duct cyst may rupture spontaneously and present as a draining sinus, which has been erroneously called a thyroglossal fistula, although communication with foramen caecum (true fistula) is extremely rare. Incidence in India: Unknown Differential diagnosis: Dermoid Cyst Lipoma Lymph Node

Minor Salivary Gland Tumour Sebaceous Cyst Hypertrophied Pyramidal Lobe Prevention and Counseling: NA Optimal Diagnostic Criteria, Investigations, Treatment & Referral Criteria Clinical Diagnosis: Diagnosis is usually made clinically. Thyroglossal duct cysts most often present with a palpable asymptomatic midline neck mass at or below the level of the hyoid bone. The neck mass moves with swallowing and on protrusion of tongue. Some patients will

have neck or throat pain, or dysphagia (difficulty in swallowing). Investigations: 1. Fine needle aspiration cytology 2. Ultrasound,thyroid function tests to ensure nomal thyroid gland 3. Radionuclide scanning if normal thyroid not located 21

Treatment: Excision (Sistrunks operation). The intimate association of the tract with hyoid bone mandates simultaneous removal of the central portion of the hyoid bone to ensure complete removal of the tract. Standard Operating Procedure: As In patient the surgery should be performed Referral Criteria: depends upon competency of operating surgeon and available resources 22

ACUTE LARYNGOTRACHEO BRONCHITIS Introduction: Acute laryngotracheo bronchitis or Croup is most of the times a viral infection caused by parainfluenza type 1 and 2 virus in children between 6months to 3years of age. Secondary bacterial infection by gram positive cocci may occur. Definition: It is an inflammatory condition of the larynx, trachea and bronchi. Differetial diagnosis: It has to be differentiated from acute epiglottitis. Acute epiglottitisAcutelaryngotracheobronchitis

H.influenza type b Parainfluenza type 1 and 2 2-7years of age 3months to 3years Supra glottis involved subglottic area No prodromal symptoms prodromal symptoms present Sudden onset slow onset High grade fever low grade or no fever Cough absent present barking seal like cough Stridor present present Odynophagia present absent Thumb sign on lateral view steeple sign- anteroposterior view 23

Clinical diagnosis: Hoarseness of voice, croupy cough, fever, inspiratory stridor, suprasternal, intercostal recession. Steeple sign on anteroposterior radiograph of neck. Examination of larynx is avoided, it may precipitate complete obstruction. Investigations: Complete blood count,serum electrolytes, radiograph of neck and chest. Treatment: Intravenous antibiotics, humidification, parenteral fluids, streroids to relieve oedema, racemic

adrenaline via respirator, intubation/tracheostomy if respiratory obstruction increases despite of medical management. Tracheostomy if intubation is required beyond 72hours. 24

ADENOIDITIS Introduction: The nasopharyngeal tonsils, commonly called “adenoids” are situated at the junction of roof and posterior wall of the nasopharynx. Adenoid tissue is present at birth, shows physiological enlargement upto the age of six years, and then tends to atrophy at puberty and almost completely disappears by the age of 20. Definition: Adenoiditis is the infection of the adenoids. Enlarged and infected adenoids may cause nasal

obstruction, mouth breathing, nasal discharge, sinusitis, epistaxis, change of voice, Eustachian tube blockage leading to conductive hearing loss, recurrent attacks of acute otitis media, serous otitis media, typical facial appearance known as adenoid facies, pulmonary hypertension in long standing cases. Differential Diagnosis: 1. congenital 2. infection- bacterial, viral 3.allergy 4. malignancy- adenoid cystic carcinoma 5.nasopharyngealangiofibroma 6.causes of nasal obstruction Clinical Diagnosis:

History, general examination, local examination with posterior rhinoscopy mirror, flexible or rigid nasopharyngoscope, lateral radiograph nasopharynx. Investigations: Complete blood count, blood grouping, prothombin time, bleeding time, clotting time,serum electrolytes, renal and liver function tests,xray chest and nasopharynx, electrocardiogram. Treatment: When symptoms are not marked breathing exercises, decongestant nasal drops and antihistaminics. When symptoms are marked adenoidectomy is done.

Adenoidectomy is the standard operating procedure. Done under general anesthesia with oral intubation. Boyle davis mouth gag is inserted, adenoids palpated digitally and removed with the help of adenoid curette with and without guard. Hemostasis is achieved by packing the area for sometime. 25

CHRONIC LARYNGITIS LLL. Chronic Laryngitis Without Hyperplasia It is a diffuse inflammatory condition symmetrically involving the whole larynx, i.e. true cords, ventricular bands, and root of the epiglottis. Aetiology 1. It may follow incompletely resolved acute simple laryngitis or its recurrent attacks. 2. Presence of chronic infection in paranasal sinuses, teeth and tonsils . 3. Occupatonal factors, e.g. exposure to dust and fumes such as in miners, strokers, gold or

iron smiths and workers in chemical industries. 4. Smoking and alcohol. 5. Persistent trauma of cough as in chronic lung disease. 6. Vocal abuse. Clinical Features 1. Hoarseness. This is the commonest complaint. 2. Constant hawking. There is dryness and intermittent tickling in the throat and patient is complited to clear the throat repeatedly. 3. Discomfort in the throat. 4. Cough. It is dry and irritating. Treatment

1. Eliminate infection of upper or lower respiratory tract. Infection in the sinuses, tonsils, teeth or chronic chest infection should be treated. 2. Avoidance of irritating factors, e.g.smoking, alcohol or polluted environment. 3. Voice rest and speech therapy.Voice rest has to be prolonged for weeks or months. 4. Steam inhalations.They help to loosen secretions and give relief. 5. Expectorants.They help to loosen viscid secretions and give relief from hawking. MMM. Chronic Hypertrophic laryngitis

It may be either a diffuse and symmetrical process or a localised one, the latter appearing like a tumour of the larynx. Aetiology Same as discussed under chronic laryngitis without Hyperplasia. Pathology Pathological changes starts in the glottis region and later may extend to ventricular bands base of epiglottis and even subglottis . Initially there is hyperaemia ,oedema and cellular infiltration in the submucosa. The

mucous glands suffer hypertrophy at first but later undergo atrophy with diminished secretion and dryness of larynx. Clinical features 26

This disease mostly affects males (8:1) in the age group of 30-50 years. Hoarseness ,constant desire to clear the throat, dry cough and discomfort in throat when the voice has been used for an extended period of time, are the commom presenting symptoms. Examination: On examination, changes are often diffuse and symmetrical. 1. Laryngeal mucosa, in general, is dusky red and thickened. 2. Vocal cords appear red and swollen.

3. Ventricular bands appear red and swollen and may be mistaken for prolapsed or eversion of the ventricle. 4. Mobility of cords gets impaired due to oedema and infiltration, and later due to muscular atrophy or arthritis of the cricoarytenoid joint. Treatment Conservative: Same as for chronic laryngitis without hyperplasia. Surgical: Stripping of vocal cords, removing the hyperplastic and oedematous mucosa, may be done in selected cases.Damage to underlying vocal ligament should be carefully avoided. One

BENIGN LESIONS OF LARYNX TYPES NNN. Solid lesions 1. Vocal nodule 2. Vocal polyp 3. Reinke’s oedema 4. Contact ulcer 5. Intubation granuloma 6. Leukoplakia or keratosis OOO. Cystic lesions Vocal cord nodule Vocal cord nodule is a mass of tissue that grows on the vocal folds (vocal cords). Typically this mass will appear on the junction of the anterior and middle two-thirds of the vocal fold, where contact is most forceful. Vocal cord polyp

A polyp is usually a red or reddish lesion that has a sharp margin and is clearly different from surrounding tissue. It can be either broad-based or narrow-necked. It may be smooth and round, or it may have lobes. Some polyps that have been present for a long time can take on odd shapes. There is a lot of variability in size. Polyps may occur singly or in pairs, one on each vocal fold directly opposite one another. Almost always, they occur at the midpoint of the vocal fold. Reinke's edema

Reinke's edema, also known as polypoid degeneration, is the swelling of the vocal folds due to fluid collection (edema). Granuloma A granuloma is a benign growth that results from irritation or trauma. It is usually found at the back of the vocal fold, over a part of cartilage called the vocal process which lies just underneath the membrane covering the larynx. Contact Ulcer Contact granuloma, also known as a contact ulcer, is a condition where an ulcer is found in the

vocal fold. The most common cause of the condition is sustained periods of increased pressure on the vocal folds, and is commonly seen in people who use their voice excessively. Gastroesophageal reflux disease is also thought to be a contributing factor in the development of contact ulcers. Treatment : 5. Voice rest, 6. To remove the source of the irritant (e.g. smoking cessation, vocal rest, etc.). 7. Microlaryngoscopic surgery 28

DEEP NECK SPACE INFECTION INTRODUCTION Deep neck space infections most commonly arise from a septic focus of the mandibular teeth, tonsils, parotid gland, deep cervical lymph nodes, middle ear, or sinuses. These deep cervical space infections have become relatively uncommon in the postantibiotic era. Consequently, many clinicians are unfamiliar with these conditions. In addition, with widespread use of antibiotics and/or profound immunosuppression, the classic manifestations of these infections,

such as high fever, systemic toxicity, and local signs of erythema, edema, and fluctuance, may be absent. Deep neck space infections often have a rapid onset and can progress to life-threatening complications. Thus, clinicians must be aware of such infections and should not underestimate their potential extent or severity. SPACES: Submandibular space Parapharyngeal space Retropharyngeal space Prevertebral space Peritonsillar space Parotid space

Potential routes of spread — The deep cervical fascial spaces are normally bound together by loose connective tissue and intercommunicate to varied degrees. A thorough understanding of the potential anatomic routes of infection not only provides valuable information on the nature and extent of infection but also suggests the optimal surgical approach for effective drainage. CLINICAL FEATURES A. Peritonsillar, parotid, parapharyngeal, and submandibular abscesses are generally

associated with sore throat and trismus (the inability to open the jaw). Trismus indicates 29

pressure or infection of the muscles of mastication (the masseter and the pterygoids) or involvement of the motor branch of the trigeminal nerve. Findings on physical examination include swelling of the face and neck, erythema, and purulent oral discharge. There may be pooling of saliva in the mouth and asymmetry of the oropharynx. Lymphadenopathy is usually present. B. Dysphagia and odynophagia are secondary to inflammation of the cricoarytenoid joints.

C. Dysphonia and hoarseness are late findings in neck infections and may indicate involvement of the tenth cranial nerve D. Unilateral tongue paresis indicates involvement of the twelfth cranial nerve. E. Stridor and dyspnea signify airway obstruction and may be manifestations of local pressure or spread of infection to the mediastinum. INVESTIGATION IMAGING Computed tomography (CT) is the imaging modality of choice for the diagnosis of deep neck

space infections . CT allows the critical evaluation of soft tissues and especially bone from a single exposure. In addition, the axial imaging format of CT is particularly well suited to the head and neck. Because CT can localize a process and define its extent, particularly extension into the mediastinum or the cranial vault, it is also an invaluable tool for planning and guiding aspiration for culture or open drainage.

Magnetic resonance imaging (MRI) is useful for assessing the extent of soft tissue involvement and for delineating vascular complications. However, MRI takes significantly longer than CT to obtain good quality images, which may cause discomfort or claustrophobia. In addition, individuals with certain implanted devices cannot undergo MRI. Plain radiography is of limited utility for the evaluation of deep neck space infections; it is sometimes helpful for detecting retropharyngeal swelling or epiglottitis

TREATMENT — Appropriate antibiotics in conjunction with surgical drainage of loculated infection are essential for a successful outcome of deep neck space infections 30

FOREIGN BODY IN AERODIGESTIVE TRACT Introduction: Foreign body aspirated into air passage can lodge in the larynx, trachea or bronchi. Children below 4 years are more often affected. Non irritating foreign bodies like plastic, glass or metalls may remain symptomless for a long time. Irritating foreign bodies(vegetative) like peanuts, beans, seeds, etc gives a diffuse violent reaction leading to congestion and oedema of tracheobronchial mucosa-vegetal bronchitis Symptoms:

Choking, gaging, wheezing: lasts for short time. Foreign body can be cuffed out or it may lodgein arynx or tracheobronchial tree. Symptomless interval Later symptoms depend on site of its lodgement: →Laryngeal: Large foreign body complete can lead to sudden death Partial: pain, harseness, croupy cough,aphonia, dyspnoea, wheezing and hemopptysis. →Traheal: loose- palpatory thud, audible slap →Bronchial:Right>le(cid:1). Can lead to atelectasis or check valve Diagnosis: Xray Fluoroscopy CT scan Bronchograms

D/D Acute laryngotraheo bronchitis Acute Simple laryngitis Laryngismus Striduluz Management: Antibiotics 31

Steroids Laryngeal Foreign Body: In complete obstruction Pound on back, turn patient upside down, follow Heimlichs Manoeuvre(stand behind the person¸and place your arms around his lower chest and give four abdominal thrusts) If this fails: Cricothyrotomy or emergency tracheostomy Once acute respiratory emergency is over: Direct laryngoscopy/ laryngofissure Tracheal/Bronchial Foreign bodies: →Conven(cid:1)onal rigid Bronchoscope →Rigid Bronchoscope with telescopic aid →Bronchoscopy with C arm fluroscopy

→Dormia Basket/ Fogarthy Balloon →Thoracotomy and bronchotomy for peripheral foregn bodies →Flexible Fibre op(cid:1)c bronchosopy 32

GOITRE A goiter or goitre (Latin gutteria, struma), is a swelling in the thyroid gland which can lead to a swelling of the neck or larynx (voice box). Goitre rarely occurs when the thyroid gland is functioning properly. Worldwide, over 90% cases of goitre are caused by iodine deficiency. Classification : They can be classified in several ways by morphology, appearance, cause and other characteristics. PPP. Non-Toxic: 1. Simple (struma diffuse) 2. Multinodular (struma nodosa)

3. Uninodular (struma uninodosa) QQQ. Toxic: 1. Diffuse (Graves) 2. Toxic multinodular 3. Toxic nodule RRR. Special: 1. Cancer 2. Thyroiditides 3. Inflammatory SSS. Various causes: 1. Chronic infection 2. Actinomycosis 3. Amyloidosis Other type of classification: 1. Class I - palpation struma - in normal posture of the head, it cannot be seen; it is only found by palpation. 2. Class II - the struma is palpative and can be easily seen.

3. Class III - the struma is very large and is retrosternal; pressure results in compression marks. Causes : Worldwide, the most common cause for goiter is iodine deficiency. Selenium deficiency is also considered a contributing factor. In countries that use iodized salt, Hashimoto's thyroiditis is the most common cause. Further causes include 1. thyroid autonomy 2. autoimmune conditions of the thyroid (Hashimoto thyroiditis, Morbus Basedow)

3. medications and substances such as lithium, antithyroid agents, thyocyanate 4. inflammations (thyroiditis) 5. cysts 33

6. benign and malignant neoplasms 7. pituitary problems 8. acromegaly 9. thyroid hormone insenstitvity 10. sarcoidosis, amyloidosis 11. hydatiform mole Signs and symptoms : Goiter associated with hypothyroidism or hyperthyroidism may present with symptoms of the underlying disorder although the symptoms are often unspecific and hard to diagnose. Goiter not associated with hormonal abnormalities will not cause any symptoms aside from the

presence of anterior neck mass. However, for particularly large masses, compression of the local structures may result in difficulty in breathing or swallowing. In those presenting with these symptoms, malignancy must be considered. Toxic goiters will present with symptoms of thyrotoxicosis such as palpitations, hyperactivity, weight loss despite increased appetite, and heat intolerance. Treatment : Goiter caused by suspected iodine deficiency is very frequently treated by a combination of

levothyroxine and iodine supplementation depending on thyroid hormone levels. Treatment may not be necessary if the goiter is small. Goiter may be related to hyper- and hypothyroidism (especially Graves' disease) and may be reversed by treatment. Graves' disease can be corrected with antithyroid drugs (such as propylthiouracil and methimazole), thyroidectomy (surgical removal of the thyroid gland), and iodine-131 (131I - a radioactive

isotope of iodine that is absorbed by the thyroid gland and destroys it). Hypothyroidism may raise the risk of goiter because it usually increases the production of TRH and TSH. Levothyroxine, used to treat hypothyroidism, can also be used in euthyroid patients for the treatment of goitre. Levothyroxine suppressive therapy decreases the production of TRH and TSH and may reduce goiter, thyroid nodules, and thyroid cancer. Blood tests are needed to

ensure that TSH is still in range and the patient has not become subclinically hyperthyroid. If TSH levels are not carefully monitored and allowed to remain far below the lower limits of normal (below 0.1 mIU/L or IU/mL), there is epidemiologic evidence that levothyroxine may increase the risk of osteoporosis and both hip and spinal fractures.[4] (Such low levels are therefore not intentionally produced for long periods, except occasionally in the treatment of TSH-dependent thyroid cancers.)

Thyroidectomy with 131I may be necessary in euthyroid goitrous patients who do not respond to levothyroxine treatment, especially if the patients have difficulty breathing or swallowing. 131I, with or without the pre-injection of synthetic TSH, can relieve obstruction and reduce the size of the goitre by thirty to sixty-five percent. Depending on how large the goitre is and how much of the thyroid gland must be removed or destroyed, thyroidectomy and/or 131I treatment may

destroy enough thyroid tissue as to produce hypothyroidism, requiring life-long treatment with thyroid hormone pills. 34

LARYNGOPHARYNGEAL REFLUX (LPR) INTRODUCTION ; Laryngopharyngeal reflux (LPR), also extraesophageal reflux disease (EERD) refers to retrograde flow of gastric contents to the upper aero-digestive tract, which causes a variety of symptoms, such as cough, hoarseness, and asthma, among others. Although heartburn is a primary symptom among people with gastroesophageal reflux disease (GERD), heartburn is present in fewer than 50% of the patients with LPR. Other terms used to

describe this condition include atypical reflux, and supraesophageal (or supra-esophageal) reflux. Signs and symptoms : Extraesophageal symptoms are the result of exposure of the upper aerodigestive tract to the gastric juice. This causes a variety of symptoms, including hoarseness, postnasal drip, sore throat, difficulty swallowing, indigestion, wheezing, chronic cough, globus pharyngis and chronic throat-clearing. Diagnosis :

As there are multiple potential etiologies for the respiratory and laryngeal symptoms, establishing LPR as the cause based on symptoms alone is unreliable. Further laryngoscopic findings such as erythema, edema, laryngeal granulomas, and interarytenoid hypertrophy have been used to establish the diagnosis; but these findings are very nonspecific, and have been described in the majority of asymptomatic subjects undergoing laryngoscopy. Response to acid-

suppression therapy has been suggested as a diagnostic tool for confirming diagnosis of LPR, but studies have shown that the response to empirical trials of such therapy (as with proton- pump inhibitors) in these patients is often disappointing. Treatment : Management of symptoms for patients within this subgroup of the GERD spectrum is difficult. Several studies have emphasized the importance of measuring proximal esophageal, or, ideally,

pharyngeal acid exposure in patients with clinical symptoms of LPR, to document reflux as the cause of the symptoms. Once these patients are identified, Nissen fundoplication should be offered to the patients in the early phase of disease, as medical treatments often don’t provide any benefit, and a delay in referring patients for surgical treatment is associated with poor outcome ACUTE PHARYNGITIS INTRODUCTION : It is acute inflammation of pharynx. AETIOLOGY: 35

VIRAL: TTT. Rhinovirus UUU. Influenza VVV. Parainfluenza WWW. Measles XXX. Chickenpox YYY. Harpes simplex BACTERIAL 1. Streptococcus 2. Diphtheria 3. Gonococcus FUNGAL 1. Candida albicans CLINICAL FEATURES 1. Mild phyaryngitis : Discomfort in throat ,malaise,low grade fever 2. Moderate tosevere : Pain in throat ,malaise,dysphagia,headache,high fever,phyaryng show erythema,exudates,enlargement of tonsils and lymphoid follicles on the posterior phyryngeal wall

3. Very severe : Oedema of soft palate and uvula with enlargement of cervical nodes DIAGNOSIS 1. Culture of throat swab is helpful in the diagnosis of bacterial pharyngitis.Itcan detect 90% of group A Streptococci.Diphtheria is cultured of special media.Swab from a suspected case of gonococcal phyaryngitis should be cultured immediately without delay. TREATMENT 1. General measures : Bed rest ,plenty of fluids,warm saline gargles or pharyngeal irrigations and analgesics form the mainstay of treatment.

2. Specific treatment : 3. Streptococcal pharyngitis treated with penicillin G 4. Dipthera is treated with penicillin and arythromycin 5. Gonococcal treated with tetracyclin 6. Fungal pharyngitis : Nystatin is the drug of choice THE VIRAL INFECTION CAUSING PHARYNGITIS Herpangina : It is caused by group A coxsackie virus and mostly affects children. Characteristic features include fever,sore throat and vesicular eruption on the soft palate and pillars. Vesicles are small and surrounded by a zone of erythema.

Infectious mononucleosis : It is caused by Epstein-Barr virus.It affects older children and young adults, and is characterised by fever ,sore throat, exudative pharyngitis,Lymphadenopathy, splenomegaly and hepatitis. Cytomegalovirus : It most affects immunosuppressed transplant patients.Clinically,it mimics infectious mononucieosis but heterophil antibody test is negative. Measles and chickenpox : Measles is characterised by the appearance of Koplik’s spots on the buccal

mucosa opposite the molar teeth.The spots appear 3-4 days before the appearance of rash. 36

CARCINOMA ORAL CAVITY Introduction- Tumours of lips and oral cavity often present a significant problem to the surgeon with regards to early diagnosis and staging, access for resection and reconstruction of both soft tissues and bone. Tumour of lips are now included within the UICC classification for oral cavity tumours. Surgical Anatomy- Anatomic Sites and Subsites for Lip and Oral Cavity- Lip External upper lip (vermilion border) External lower lip (vermilion border) Commissure Oral Cavity Buccal mucosa

Mucosa of upper and lower lips Cheek mucosa Retromolar areas Bucco-alveolar sulci, upper and lower (vestibule of mouth) Upper alveolus and gingiva (upper gum) Lower alveolus and gingiva (lower gum) Hard palate 37

Tongue Dorsal surface and lateral borders anterior to circumvallate papillae (anterior two thirds) Inferior (ventral) surface Floor of mouth Epidemiology- The lip is the most common site of cancer in the mouth. It is most common in white people and approximately 93% of the tumour present in the lower lip and the male to female ratio 80:1. The most common tumour is squamous cell carcinoma. In case of oral cavity cancer an estimated 387500 new cases are diagnosed annually

worldwide. It constitutes 30-40% of head and neck cancer in India and the country ranks among the top few in the world in the incidence of these cancers. Buccal mucosa is a common subsite in Indian population, probably aided by the chewing habit that is prevalent in this country. In India, buccal mucosa cancer is the most common cancer in men and third most common cancer 38

in women. The oral cancers assume importance in the cancer control programme of the country because of its impact on the overall health of the population as well as potential as a target for early detection and prevention Predisposing Factors-  Smoking tobacco is a potential risk factor for oral cancer. An interaction occurs between redox-active metals in saliva and the low reactive free radicals in cigarette smoke. The incidence of oral cavity cancers in persons who smoke is approximately 6 times that of

those who do not. It causes sequential histological changes in oral mucosa. Over a prolonged period of exposure, these changes eventually lead to neoplastic transformation.  Alcohol consumption- alcohol beverages may contain carcinogens or pro-carcinogens including nitrosamine and urethane contaminants and ethanol. Ethanol is metabolized by alcohol dehydrogenage and to some extent by cytochrome p450 to acetaldehyde, which may be carcinogenic. The combined effect of alcohol and cigarette is synergistic.

The risk for a person who smokes and drink is 15 that of an individual who neither habit.  Betel nut chewing- it cause damage to buccal mucosa.  Dental caries  Hot spicy food  Chronic glossitis  Malnutrition  Poor oral hygiene Precancerous Conditions- Oral cancer can occur as denovo or on existing pre-malignant conditions. These include- 1. Leucoplakia- this is a clinical term without a definitive histological definition.

Leukoplakia is a white mucosal based keratotic plaque that cannot be wiped free from the underlying tissue. It is defined as white patch in oral mucosa that cannot be characterized clinically or pathologically as any other disease. Most frequent 39

sites are the buccal mucosa and the commissures. Leukoplakia with epithelial dysplasia (20%) is found to have greater chance of malignant transformation. Only 6% of lesion eventually progressed to SSC. A biopsy is indicated if the lesion is suspicious. 2. Erythroleukaplakia- the associated risk for malignant transformation is greater than leukoplakia. 3. Submucosal fibrosis- most frequently encountered in individuals who chew betel nut, or

poor oral hygiene, or periodontitis. The risk of developing oral carcinoma is 7.6% over a 10 year period. 4. Lichen planus- it also been associated with the development of oral carcinoma. Symptoms of Oral Cancer-  White or red patches in your mouth  A mouth sore that won't heal  Bleeding in mouth  Loose teeth  Problems or pain with swallowing  A lump in neck  An earache Differential Diagnosis- 1. Chronic non-healing ulcer in oral cavity- characteristic findings in favor of malignant ulcer are-

• Seen in elderly • Usually seen at margin and ant 2/3 of tongue • Single or multiple • Raised, rolled out and everted edge • Floor covered with necrotic debries and looks dirty gray • Discharge is offensive • Painless initially but painful later wit Otalgia due to involvement of lingual nerve • Associated with lymph node enlargement and it is hard in consistency 2. Pre-malignant conditions like leukoplakia and erytholeukoplakia 40

TNM Staging- T1: Tumor 2 cm or less in greatest dimension T2: Tumor more than 2 cm but not more than 4 cm in greatest dimension T3: Tumor more than 4 cm in greatest dimension T4a: Moderately advanced local disease. Lip: Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face, ie, chin or nose Oral cavity: Tumor invades adjacent structures only (eg, through cortical bone [mandible, maxilla], into deep [extrinsic] muscle of tongue [genioglossus,

hyoglossus, palatoglossus, and styloglossus], maxillary sinus, skin of face) T4b: Very advanced local disease. Tumor invades masticator space, pterygoid plates, or skull base, and/or encases internal carotid artery Prognostic Markers- Various features of the cancer allow to prognosticate the outcome of the treatment.  Pathological involvement of cervical node  T-stage  Tumour thickness- chance of nodal metastasis is maximum with tumour thickness >5mm.

 Surgical margins- the chance of treatment failure is high when the margin of resection is closed (<5mm) or involve. Evaluation- 1. History & Examination - Almost 90% of the cancers are of squamous cell variety. Buccal mucosa is the most common site affected in India. The sump area or ‘coffin corner’ at the posterior tongue/ floor of the mouth is a common site for cancer but may be missed by cursory 41

inspection. So, a through history and physical examination is very important for its early detection. 2. Biopsy can be taken at OPD if lesion is large otherwise it can be taken under GA. 3. Endoscopies can be carried out to rule out other synchronous malignancy. 4. Chest imaging, CT/MRI if indicated. 5. Preanesthesia studies. 6. Dental evaluation. Treatment protocol- 1. For T1–2, N0 disease a) Excision of primary (preferred) ± unilateral or bilateral selective neck dissection.

- If it is associated with No adverse features like (extracapsular nodal spread, positive margins, pT3 or pT4 primary, N2 or N3 nodal disease, nodal disease in levels IV or V, perineural invasion, vascular embolism) then only follow up is required. - If it is associated with one positive node without adverse feature RT can be given optional. If it is associated Adverse features then planned for Re-excision or Chemo/RT and follow up.

b) An alternative to surgery - External-beam RT ± brachytherapy 70 Gy to primary 50 Gy to neck at risk. - If pt came with No residual disease then follow up is required. - If pt landed with Residual disease then Salvage surgery can be better choice. 2. For T3, N0 disease Excision of primary and reconstruction as indicated and unilateral or bilateral selective neck dissection is the treatment of choice. - If it is associated with No adverse features like (extracapsular nodal spread, positive

margins, pT3 or pT4 primary, N2 or N3 nodal disease, nodal disease in levels IV or V, perineural invasion, vascular embolism) RT can be given optional. 42

- If it is associated adverse features then planned for Re-excision or Chemo/RT and follow up. 3. T4a, Any N; T1-3, N1-3 disease Surgery is treatment of choice. a) For N0, N1, N2a-b, N3 Excision of primary, ipsilateral comprehensive neck dissection ± contralateral selective neck dissection (reconstruction as indicated) can be considered. b) For N2c (bilateral) disease Excision of primary and bilateral comprehensive neck dissection (reconstruction as indicated) can be planned.

- In both cases if there are No adverse features RTc (optional) can be given and then follow up. - If it is associated Adverse features (extracapsular nodal spread, positive margins, pT3 or pT4 primary, N2 or N3 nodal disease, nodal disease in levels IV or V, perineural invasion, vascular embolism) then planned for Re-excision or Chemo/RT and follow up. Treatment Protocol for Pre-Malignant Lesion- 1. Full history and examination. 2. Biopsy a) Biopsy negative- Discharge

b) Leukoplakia and other pre-malignant lesion- Excision biopsy, Laser etc- Follow up in H & N clinic c) Other pathology like Lichen planus, candidiasis- Oral medication d) Biopsy positive- EUA and imaging- Definitive treatment Preventive Measures-  Don't smoke. Don't drink more than 1 or 2 alcoholic drinks, if any, a day  Sick immediate attention to doctor in chronic non-healing ulcer mouth  Maintain adequate oral/dental hygiene. 43

CARCINOMA HYPOPHARYNX Introduction- Hypopharynx is a highly important anatomical site as physiologically it is a component upper aero-digestive tract and it also represents a common conduit for both respiration and deglutition. Hence, any tumor or treatment of tumors in this area will produce disturbances in swallowing and inevitable aspiration. Tumors arising in this area often present in advanced state and so, key to cure lies in early and accurate diagnosis and prompt treatment.

Surgical Anatomy- It is triangular space extending from the level of hyoid bone above to the lower border of cricoid cartilage below. The hypopharynx consists of three regions- pyriform sinus on each side, the posterior pharyngeal wall, and the post cricoid region. Pyriform sinus (PFS)- It represents channels formed on either side of the larynx. It is bounded by pharyngoepiglottic fold superiorly, the apex inferiorly, thyroid cartilage laterally and hypopharyngeal surface of AE fold medially.

Posterior pharyngeal wall- It extends form floor of ventricle superiorly to inferior border of cricoids cartilage inferiorly and from one apex of PFS to the other. Post-cricoid region- It extends from at the level of arytenoids cartilage and connecting folds to inferior border of cricoids cartilage. The hypopharynx is lined throughout by squamous epithelium. The pyriform sinus has rich lymphatic supply. In general, the lymphatic in this area drain in deep cervical lymph node at

level IV but inferior part of PFS and post cricoid area also drain in paratracheal lymph node in level VI and posterior pharyngeal wall drain in retropharyngeal area. Almost all carcinoma of hypopharynx are SSC carcinoma in type. PFS comprise maximum of around 50% of total, postcricoid tumors make up around 40% and posterior pharyngeal wall make up remaining around 10%. 44

Tumors of PFS can be divided into those which primarily involve the lateral wall or the medial wall. Those arising from medial wall are more extensive and involve AE fold and paraglottic space and can therefore fix the hemilarynx on that side. Occasionally it can involve postcricoid area where vocal cord fixation can occur if cricoarytenoid joint is involved. As PFS is rich in lymphatic supply, 70-75% patients of pyriform fossa tumor have palpable neck

mass at presentation which usually involve level II-IV deep cervical node and 5% have bilateral node at presentation. Epidemiology- Age specific incidence of pharyngeal cancer show an increase risk of developing disease with increasing age for both men and women. Postcricoid tumors remain the only SSC of head and neck that is more common in women. The overall incidence of tumor in UK is approximately 1-3 per 100000. Etiological Factors-

Alcohol and tobacco remain the two principal carcinogen implicated in the tumors of the upper aerodigestive tract, to include the hypopharynx and they are synergistic to each other. A major dietary risk factor (iron deficiency) in relation to postcricoid carcinoma has been described particularly in patients with Plummer-Vinson syndrome. This syndrome is associated with anemia, glossitis, esophageal web, koilonychias and achlorhydria. Some also have a history of radiation to the neck. Symptomatology-

• Dysphagia • Pain • Hoarseness • Neck mass • Hemoptysis • Weight loss 45

The clinical picture caused by a large tumor is often unmistakable, but in the early stages the symptoms may be indefinite. Whilst the feeling of lump in the throat, which is worse on swallowing saliva is rarely of serious significance (e.g globus pharyngicus) or persistent soreness, should always be treated with extreme suspicion, especially in elderly patients who smoke and drink. Persistent pharyngeal pain is nearly always a sinister symptom and if

associated with malignancy it reflects deep invasion in larynx and pharyngeal structures. It is often associated with referred pain to ipsilateral ear. Differential Diagnosis- 1. Globus pharyngicus- It usually presents in young women as a sensation of a lump in throat in midline between hyoid and suprasternal notch but more commonly at cricoid level. It is intermittent and typically occurring between meals, when swallowing saliva, in the evening or during stress and, although uncomfortable but

never painful. 2. Pharyngeal oesophageal motility disorder- in patients with throat symptoms who have no abnormality found on examination and investigation and diagnosis can be confirmed by barium video fluoroscopic swallow examination. 3. Benign tumors like Leiomyomas common in hypopharynx and upper oesophagus. 4. Lipomas and fibrolipomas occur occasionally. TNM CLASSIFICATION- T1 Tumor size ≤ 2 cm and limited to one sub-site T2 Tumor size > 2 but ≤ 4 cm or more than one sub-site

T3 Tumor size > 4 cm or hemilarynx fixation T4a Tumor invades Thyroid / cricoid cartilage, hyoid bone, thyroid gland esophagus, central compartment soft tissue T4b Prevertebral fascia, mediastinal structures, Internal carotid artery Work up- 46

History and physical examination, Biopsy ,HPV testing suggested, Chest imaging, CT with contrast or MRI or PETCT and CT with contrast of primary and neck, Dental evaluation, including panorex as indicated, Speech & swallowing evaluation as indicated, Examination under anesthesia with endoscopy and Pre-anesthesia studies. Examination - All patients presenting with a throat complaint or a mass in the neck requires a full head and neck and general examination. Patients can be examined in OPD using

either indirect laryngoscopy, a rigid Hopkin’s endoscope or FOL passed through the nose. Particular attention should be paid to obvious swelling or ulceration and also to the presence of pooling of saliva in pyriform fossa (Chevalier Jackson’s sign) and oedema of arytenoids. Presence or absence of laryngeal crepitus should be look for. Absence of crepitus means any postcricoid or posterior pharyngeal wall involvement. It is important to carry out any imaging studies prior to endoscopy and biopsy if possible

since FNAC; endoscopic and open biopsy can all create artifactual features on both CT and MRI. Specific Uses of Imaging-  To assess the extent of primary tumour, its relation to larynx, and any extension into pre and paraglottic space  To exclude a second primary or distant metastases  Involvement of cartilage  To assess the neck Barium swallows extremely useful investigation in tumour involving postcricoid and cervical oesophagus. Treatment Protocol-

1. T1, N0, selected T2, N0 (not requiring total laryngectomy) disease - a) Definitive RT can be considered - If Primary site: complete response then only follow up is required. 47

- If pt presented with Primary site: residual tumor then Salvage surgery + neck dissection as indicated. b) Alternatively Surgery: Partial laryngopharyngectomy (open or endoscopic) + Ipsilateral or bilateral selective neck dissection is the treatment of choice. - If there are no adverse features like extracapsular nodal spread, positive margins, pT3 or pT4 primary, N2 or N3 nodal disease, Perineural invasion, vascular embolism only follows up is required. - With Adverse features Chemo/RT can be consider.

2. T1, N+; T2-3, any N (if total laryngectomy required) disease – a) Induction chemotherapy x 2 cycles and follow-up. - If Primary site: Complete response then Definitive RT can be considered. - If patient presents with residual tumor in neck then Neck dissection can be done. - If primary site: Partial response then planned for Induction Chemotherapy 3rd cycle and follow up. - If primary site: CR then Definitive RT can be considered. - Primary site: PR then Chemo/RT and follow up

- If CR: only observation required. - If Primary site: < PR then planned for Surgery. - If pt is having no adverse features RT can be considered. - With any adverse features Chemo/RT can be given. b) An alternative to induction chemotherapy - surgery Laryngopharyngectomy + selective (N0) or comprehensive (N+) neck dissection, including level VI can be consider. - Patient with no adverse features only follow-up required - With adverse features Chemo/RT and follow up required. 48

c) Third option is CCRT. - If Primary site: complete response but with Residual tumor in neck then Neck dissection can be consider. - In case of complete response of neck then Post-treatment evaluation (minimum 12 wks) with PET, Contrast-enhanced CT or MRI and physical exam is required. - If inv are negative only observation is required. And if inv are positive then Neck dissection is considered. - If patient presented with Primary site: residual tumor then Salvage surgery + neck dissection as indicated.

3. For T4a, any N disease – a) Surgery + comprehensive neck dissection (preferred) is treatment of choice followed by RT or Chemo/RT. b) Or alternatively Induction chemotherapy x 3 cycles and follow-up. - If patient presented with Primary site: CR or PR and stable disease in neck then consider Chemo/RT. - If Primary site: complete response but Residual tumor in neck then Neck dissection can be consider. - If patient presented with Primary site: residual tumor after chemo/RT then

Salvage surgery + neck dissection as indicated. - If pt presented with Primary site: < PR or progression in neck after NACT then Salvage surgery + neck dissection as indicated. c) Third option is CCRT. - If patient presented with Primary site: complete response but Residual Tumor in neck then Neck dissection can be considered. - If pt presented with Primary site: residual tumor Salvage surgery + neck dissection is indicated. 49

Prognostic Factors- • Tumour sizes ( less or more than 5 cm) • Tumour site (PFS and posterior pharyngeal wall tumours do best ) • Vocal cord paralysis • Presence or absence of lymph node metastases • Size and number of node involve • Presence or absence of distant metastases • Presence of Perineural spread 5 year survival rates in the Liverpool series- • PFS- 31% • Postcricoid- 29% • Posterior pharyngeal wall- 20% Prevention And Counseling- Abstinence of alcohol and cessation of smoking is first and

CARCINOMA LARYNX Introduction- Larynx is not only important for respiratory function but also for deglutition and phonation. Carcinoma of larynx along with carcinoma of oral cavity is the most common malignancies in head and neck malignancy. It often present early when a high cure rate can be achieved. Treatment remains controversial but early cancer may treat with either surgery or radiotherapy, depending on size, site of tumor and patient and doctor preference. Advanced

disease treated with radical surgery and post op radiotherapy. Surgical Anatomy- The larynx can be embryological, clinically and anatomically divided into Supraglottis, glottis and subglottis. Supraglottis- the Supraglottis subsites include-  Epiglottis- including tip, lingual and laryngeal surfaces  AE fold  Arytenoids  Ventricles  False cords The inferior boundary of Supraglottis as defined by the AJCC is the horizontal plane

passing through the apex of the ventricle. The anatomic division is located at the arcuate line, which marks the change from respiratory epithelium to squamous variety. Glottis- It includes  True vocal cords  Anterior commissures  Posterior commissures According to AJCC the inferior border of glottis is the horizontal plane 1 cm inferior to level of the upper surface of the vocal cord. 51

Spread of Tumour- Laryngeal cancer may spread from its original site to other parts of the larynx by direct mucosal and sub mucosal extension, by lymphatic and vascular permeation, by perineural spread or by direct invasion of adjacent structures. These “pathways of spread” have traditionally been the basis of conservation surgical procedures. Barriers of Tumour Extension- • Ventricular fold • Conus elasticus • Anterior commissure • Perichondrium Preferred Pathways for Tumour Extension-

 Epiglottis fenestrations  Anterior commissure ligament  Pre/Paraglottic space  Cricothyroid/ thyrohyoid membrane Supraglottis- Supraglottis tumours have a propensity for bilateral spread and also a high propensity for lymph node metastases. Midline tumors may metastasize bilaterally. Glottic tumours- The anterior commissure ligament (Broyle’s ligament) has been traditionally believed to be resistant to tumour spread. However, once involved, it facilitates subglottic and supraglottic

spread along the anterior midline as its fibers extends longitudinally. Lateral extension to paraglottic space has traditionally been assessed by clinical sign of limitation/fixation of vocal fold movement. Currently imaging should be used to supplement this assessment. 52

Subglottis- Early extralaryngeal extension through cricothyroid membrane and circumferential involvement usual. Epidemiology- 1.5 % of all cancers. Glottic: Supraglottic = 3:1. Incidence in UK 4 per 100000. In India its incidence is 10 per 100000. Peak age of incidence 55-65 years of age with male: female= 3-4:1. Risk Factors-  Geographic  Social class V  Urban  Smoking  Alcohol  Radiation Etiology- Until the complex molecular interactions of all associated etiologic agents for any cancer

can be understood, these interactions are best thought of as associations. Thinking of intrinsic (eg, genetic) factors and/or extrinsic (eg, smoking) factors as causes is too simple. To most people, a cause implies a condition that is both necessary and sufficient to produce a pre specified result. Laryngeal carcinomas have multiple associations. The foremost risk factor for the development of laryngeal cancer is tobacco use. The risk

of developing laryngeal cancer with tobacco increases with use and decreases after cessation. When associated with the intake of alcohol, a strong synergistic effect is created. However, whether or not alcohol alone is an independent risk factor is still unclear. All the potential risk factors for laryngeal cancer that have been studied are as follows: 53

 Tobacco use  Excessive ethanol use  Male sex  Infection with human papilloma virus  Increasing age  Diets low in green leafy vegetables  Diets rich in salt preserved meats and dietary fats  Metal/plastic workers  Exposure to paint  Exposure to diesel and gasoline fumes  Exposure to asbestos  Exposure to radiation  Laryngopharyngeal reflux Pathophysiology- The larynx is an essential organ that is responsible for the following vital functions:  Maintaining an open air way  Vocalizing

 Protecting the lungs from more direct exposure to noxious fumes and gases of unsuitable temperatures  Protecting the lungs from aspiration of solids and liquids  Allowing leverage, by closing the glottis during a Valsalva maneuver, to increase upper- body strength and to ease solid-waste removal Malignant tumors of the larynx affect laryngeal physiology depending on tumor location and size. Supraglottic tumors usually cause upper airway obstruction. Conversely, glottic tumors

affect initially voice quality. In addition, malignant tumors of the larynx affect swallowing physiology. The mechanism of swallowing is altered when tumors invade and alter the physiology of the swallowing muscles. This is expressed as difficulty swallowing and aspiration. 54

Liquids and solid food gain access into the trachea. Pathophysiology of malignant tumors of the larynx is at the molecular and histologic level. Histologic progression occurs from normal laryngeal mucosa to dysplastic mucosa to carcinoma in situ to invasive carcinoma. This progression is a multi-step process of accumulated genetic events that lead to the development of larynx tumors. Presentation- Given the functions of the larynx mentioned above, one can easily imagine the

consequences of a carcinoma destroying and/or obstructing the laryngeal structures and their mechanisms (eg, vocal-cord movement). Symptoms vary with the structures involved by malignancy and its accompanying inflammatory reaction. Although the particular tumor, the site, and the patient's constitution play key roles in any given individual, laryngeal cancers as a whole can cause any of the following findings, alone or in combination: 1. Glottis- a) Hoarseness b) Sore throat

c) localized pain( cartilage invasion) d) Dyspnea e) Otalgia (involvement of deep structure) 2. Supraglottis- a) Odynophagia b) Sore throat c) Weight loss d) Aspiration e) Tone breath f) Otalgia g) Neck mass (either tumour itself or lymph node) h) Lymph node metastases in Supraglottic tumour- 55

• T1- 0% • T2- 15% • T3- 20% • T4- 30% 3. Subglottis- a) Dyspnoea b) Hemoptysis Differential Diagnosis- 1. Chronic laryngitis- present with hoarseness of voice and mimic early glottic cancer specially in older people or should be differentiated from squamous intraepithelial neoplasia like, Keratosis (keratin formation by superficial layer only), parakeratosis (nucleus retained abnormalities in superficial layer), dysplasia (nuclear variation,

mitosis, loss of normal epithelial layering), carcinoma in situ (cells of malignant cytology but confined superficial to basement membrane). 2. Benign tumour papillomas- it constitutes 85% of all benign tumour larynx and can be multiple (Juvenile papilloma) or single (adult papilloma). The causative organism Human papilloma virus type 6 and 11. Malignant changes may occur in a juvenile papilloma but usually only if the patient has been irradiated. Evaluation-

1. History - As in all clinical evaluations, the history is the first step in gathering the facts. Assess or inquire about the following: • Weight loss • Fatigue • Pain • Difficulty breathing or swallowing • Vocal changes noted by the patient and his or her family • Ear pain • Coughing up blood or solid material 2. Physical examination- • General condition • Nutritional status • Full head and neck examination which includes inspection and palpation of the oral

cavity and oropharynx to rule out second primary tumors or other lesions, as well as evaluation of dentition. 56

• Flexible laryngoscope - to evaluate the function and anatomy of the entire larynx. Evaluation of vocal cord motility and the location and extension of the tumor are crucial to stage the patient accurately. • Palpation of the neck looking for enlarged lymph nodes • Evaluation of the cranial nerves should also be included in the physical examination. Imaging Studies- It is important to carry out any imaging studies prior to endoscopy and biopsy if possible

since FNAC; endoscopic and open biopsy can all create artefactual features on both CT and MRI. Specific Uses of Imaging- • To assess the extent of primary tumour, its relation to larynx, and any extension into pre and para glottic space • To exclude a second primary or distant metastases • Involvement of cartilage • To assess the neck Tissue Biopsy- DL scopy and biopsy and panendoscopy TNM Staging (Glottic carcinoma) T1 - limited to VC, normal mobility (May inv ant/post com.) T1a - one vocal cord

T1b - both VC T2 - extends to Supraglottis and/or glottis, impaired VC mobility T3 - limited to larynx with hemilarynx fixation, paraglottic space/minor thyroid cart erosion (inner cortex) 57

T4a - invades through thyroid cartilage, /extralarngeal tissues,(trachea, soft tissues, muscles of tongue, strap muscles, thyroid gland &esophagus, l T4b - Prevertebral fascia, mediastinal structures, ICA. Treatment protocol- (glottic carcinoma) 1. For carcinoma in situ a) Endoscopic removal (stripping/laser) b) RT and follow up. 2. For Most T1-2, N0 (total laryngectomy not required) a) RT b) Partial laryngectomy is the treatment of choice.

3. For most T3; N0-1 Resectable tumors requiring total laryngectomy a) CCRT - if Primary site: Complete response (N0 at initial staging) then only follow up is required. - If Primary site: Complete response (N+ at initial staging) with residual tumor in neck then Neck dissection can be considered. - If Primary site: residual tumor is there then Salvage surgery + neck dissection is indicated. b) Second option is Surgery. In case of No disease Laryngectomy with ipsilateral

thyroidectomy unilateral or bilateral selective neck dissection (reconstruction as indicated) and follow up. And in case of N1 disease Laryngectomy with ipsilateral thyroidectomy, ipsilateral comprehensive neck dissection ± contralateral selective neck dissection (reconstruction as indicated). - If pt presented with No adverse features like extracapsular nodal spread, positive margins, pT4 primary, N2 or N3 nodal disease, perineural invasion, vascular embolism only follow up required. 58

- Adverse features chemo/RT can be consider. 4. For most T3, N2-3 disease a) CCRT can be tired. - If Primary site: complete response but with Residual tumor in neck then Neck dissection can be consider. - In case of complete response of neck then Post-treatment evaluation (minimum 12 wks) with PET, Contrast-enhanced CT or MRI and Physical exam is required. If inv are negative only observation is required. And inv are Positive then Neck dissection is considered.

- If pt presented with Primary site: residual Tumor then Salvage surgery + neck dissection as indicated. b) Second option is Surgery- Laryngectomy with ipsilateral thyroidectomy, ipsilateral or bilateral comprehensive neck dissection (reconstruction as indicated). - If pt presented with No adverse features like extracapsular nodal spread, positive margins, pT4 primary, N2 or N3 nodal disease, perineural invasion, vascular embolism only follow up required. - With Adverse features chemo/RT can be consider.

c) Third option is Induction chemotherapy x 3 cycles and follows the same principle of management. 5. For most T3, N2-3; Selected T4a a) NACT 3 cycle and follow up. - If pt presented with Primary site: CR or PR and stable disease in neck then Chemo/RT can be consider. - If Primary site: complete response but with Residual tumor in neck then Neck dissection is done. - If pt presented with Primary site: residual tumor then Salvage surgery + neck dissection as indicated. 59

- In case of Primary site: < PR or progression in neck then Salvage surgery + neck dissection as indicated. 6. For T4a, Any N disease a) Surgery is the only treatment. - For N0 disease Laryngectomy with ipsilateral thyroidectomy unilateral or bilateral selective neck dissection (reconstruction as indicated). - For N1disease Laryngectomy with ipsilateral thyroidectomy, ipsilateral comprehensive neck dissection ± contralateral selective neck dissection (reconstruction as indicated).

- For N3 disease Laryngectomy with ipsilateral thyroidectomy, ipsilateral or bilateral comprehensive neck dissection (reconstruction as indicated) followed by Chemo/RT. TNM Classification- (Supraglottis) T1 - one subsite, normal vocal cord mobility T2 - more than one adjacent subsite of supraglottis/ region outside supraglottis (mucosa of BOT, vallecula, PF med wall) without larynx fixation T3 - limited to larynx with hemilarynx fixation/ invades postcricoid, pre-epiglottic

area, paraglottic space/minor thyroid cart erosion (inner cortex) T4a - invades thyroid cartilage / extra-laryngeal tissues, (trachea, soft tissues, muscles of tongue, strap muscles, thyroid gland &esophagus, l T4b - pre-vertebral fascia, mediastinal structures, ICA. Treatment protocol- (Supraglottic Larynx) 1. For Most T1-2, N0 disease not requiring total laryngectomy a) Endoscopic resection ± selective neck dissection 60

b) Open partial supraglottic laryngectomy ± selective neck dissection c) Definitive RT . d) if pt presented with One positive node without other adverse features then Consider RT. if pt presented with adverse features: positive margins then Further surgery or RT or Consider chemo/RT. if pt presented with Adverse features: extracapsular nodal spread then consider Chemo/RT and follow up. 2. For T3, N0 T4a, N0 requiring total laryngectomy

a) Low-volume base-of tongue involvement not penetrating through cartilage planned for CCRT. - If pt presented with Primary site: Complete response then only follow up required. - If pt presented with Primary site: residual tumor then Salvage surgery + neck dissection as indicated. b) Second option is Laryngectomy, ipsilateral thyroidectomy with ipsilateral or bilateral selective neck dissection. - If pt presented with N0 or one positive node without adverse features then RT optional.

- If pt presented with Adverse features then consider Chemo/RT. c) Third option is RT if patient not candidate for concurrent chemo/RT and follow up.\ 3. For T4, N0 High volume invasion of base of tongue, penetration through cartilage a) Laryngectomy, ipsilateral thyroidectomy with ipsilateral or bilateral selective neck dissection can be considered followed by Chemo/RT. 4. For Node positive disease T1-2, N+ and selected T3-4a, N0-1disease a) CCRT can be tired.

- If Primary site: complete response but with Residual tumor in neck then Neck dissection can be consider. 61

- In case of complete response of neck then Post-treatment evaluation (minimum 12 wks) with PET, Contrast-enhanced CT or MRI and Physical exam is required. If inv are negative only observation is required. And inv are Positive then Neck dissection is considered. b) Second option is Partial supraglottic laryngectomy and comprehensive neck dissection(s). - if there is No adverse features only Observation required. With Adverse features give Chemo/RT.

5. For Most T3, N2-N3 1disease requiring total laryngectomy a) CCRT can be tired. - If Primary site: complete response but with Residual tumor in neck then Neck dissection can be consider. - In case of complete response of neck then Post-treatment evaluation (minimum 12 wks) with PET, Contrast-enhanced CT or MRI and Physical exam is required. If inv are negative only observation is required. And inv are Positive then Neck dissection is considered.

- If Primary site: residual tumor then Salvage surgery + neck dissection as indicated. b) Second option is Laryngectomy, ipsilateral thyroidectomy with comprehensive neck dissection. If no adverse features consider RT. With Adverse Features give Chemo/RT. c) Third option Most T3, N2-3 disease NACT 3 cycle and follow up. - If pt presented with Primary site: CR or PR and stable disease in neck then Chemo/RT can be consider. - If Primary site: complete response but with Residual tumor in neck then Neck

dissection is done. - If pt presented with Primary site: residual tumor then Salvage surgery + neck dissection as indicated. 62

- In case of Primary site: < PR or progression in neck then Salvage surgery + neck dissection as indicated. 6. For T4a, N2-N3 Cartilage destruction Skin involvement Massive invasion of base of tongue then Laryngectomy, ipsilateral thyroidectomy with ipsilateral or bilateral neck dissection followed by Chemo/RT can be considered. Preventive Measures  Don't smoke. Don't drink more than 1 or 2 alcoholic drinks, if any, a day.  Avoid exposure to known toxins.

 Seek attention of doctor in case of change of voice and any other throat problem. 63

CERVICAL LYMPHADENOPATHY Introduction- Lymphadenopathy is an abnormal increase in size and/ or altered consistency of lymph nodes. It is a clinical manifestation of regional or systemic disease and serves as an excellent clue to the underlying disease. Cervical lymphadenopathy (C.L.) is a fairly common clinical presentation. Surgical anatomy and classification - Cervical lymph nodes are lymph nodes found in the neck. There are approximately 300 lymph nodes in the neck

Cervical lymph nodes are classifieds into 7 groups. They are- • Level I: Submental and submandibular nodes o Level Ia: Submental triangle o Level Ib: Submandibular triangle • Level II: Upper jugular nodes • Level III: Middle jugular nodes • Level IV: Lower jugular nodes • Level V: Posterior triangle group • Level VI: Pre-tracheal, pre-laryngeal and post-tracheal • Level VII: Mediastinal 64

Incidence - Age < 30 - 79% benign; 15% lymphomatous; 6% carcinomas - Age > 50 - 40% benign; 16% lymphomatous; 44% carcinomas - 0.6 annual incidence of generalized lymphadenopathy Differential diagnosis- Common infectious causes of lymphadenopathy 1. Adenovirus 2. CMV 3. Enterovirus 4. EBV 5. Varicella 6. Herpes simplex 7. Staphlococcus infection 8. Group A hemolytic Streptococcus 9. Tularemia 10. Brucellocis 11. Tuberculosis 12. Atypical mycobacteria 13. Klebsilla 14. AIDS 15. Bubonic plague 16. Anthrax

Common non-infectious causes of lymphadenopathy 1. Hodgkin's disease 2. Lymphomas 3. Leukemia 4. Metastatic disease 5. Histiocytosis 6. SLE and JRA 7. Kawasaki Disease 8. Sarcoidosis Symptoms and signs- 1. Neck Swelling Lymph node character 65

i) Stone hard: typical of cancer usually metastatic ii) Firm rubbery: can suggest lymphoma iii) Soft: infection or inflammation iv) Matting: tubercular 2. Pain- (i) Painful lymph node present in acute inflammatory condition. (ii) Painless lymph node mainly present in granulomatous or malignant conditions 3. Size - Rapid increase in size could be due to malignancy. Evaluation 1. Laboratory studies a) CBC count, including a careful evaluation of the peripheral blood smear. An

erythrocyte sedimentation rate is nonspecific but may be helpful. b) Evaluation of hepatic and renal function and a urine analysis are useful to identify underlying systemic disorders that may be associated with lymphadenopathy. c) Additional studies, such as lactate dehydrogenase (LDH), uric acid, calcium, and phosphate, may be indicated if malignancy is suspected. Skin testing for tuberculosis is usually indicated. d) In evaluating specific regional adenopathy, lymph node aspirate for culture may

be important if lymphadenitis is clinically suspected. e) Titers for specific microorganisms may be indicated, particularly if generalized adenopathy is present. These may include Epstein-Barr virus, cytomegalovirus (CMV), Toxoplasma species, and human immunodeficiency virus (HIV). 2. Imaging studies a) Chest radiography is usually the primary screening imaging study. Additional imaging studies are usually based on abnormal chest radiograph findings. Chest

radiography is often helpful in elucidating mediastinal adenopathy and underlying diseases affecting the lungs, including tuberculosis, coccidioidomycosis, lymphomas. b) CT scan and MRI especially helpful in case of metastatic disease to know the extent of involvement. 66

c) Nuclear medicine scanning is helpful in the evaluation of lymphomas. d) Ultrasonography may be helpful in evaluating the changes in the lymph nodes and in evaluating the extent of lymph node involvement in patients with lymphadenopathy. 3. Fine Needle aspiration Cytology 4. Lymph Node Biopsy / Excisional Biopsy Management 1. Treatment with antibiotics (covering the bacterial pathogens frequently implicated in lymphadenitis) followed by re-evaluation in 2-4 weeks is reasonable if clinical findings

suggest lymphadenitis. Benign reactive adenopathy may be safely observed for months. Infectious lymph adenopathy usually requires treatment with appropriate antibiotics. 2. Granulomatous condition requires address of general condition, and treatment with steroids and immunoglobins depending on conditions. 3. In cases of malignant conditions, patient can be managed on different modality of treatment viz chemotherapy, radiotherapy or surgery depending on type and stage of malignancy. 67

PERITONSILLAR ABSCESS (QUINSY) Introduction: Peritonsillar abscess is a common infection of Head & Neck region. Although not generally considered as a deep neck space infection physicians must be aware of the typical clinical presentation & diagnostic strategies in order to quickly diagnose & appropriately treat these patients to prevent complications. Case Definition: PTA is a collection of pus between the fibrous capsule of the tonsil usually at

the upper pole & the superior constrictor muscles of pharynx. Incidence in our Country: 0.9/10000/yr (Age Range- 3-91 yrs) Differential Diagnosis 1. Infectious - Peritonsillar Cellulitis Parapharyngeal abscess Dental - Upper 3rd molar abscess Co-existing Infectious Mononucleosis 2. Inflammatory-Kawasaki disease 3. Vascular-Post traumatic Internal Carotid Artery Aneurysm 4. Benign lesions-Benign Lympho-epithelial Cysts 5. Neoplastic –Large tonsil tumours with extra tonsillar spread (eg. Squamous cell

carcinoma); Tonsillar lymphoma; Rhabdomyosarcoma 6. Peritonsillar space tumours-Minor Salivary gland tumours 7. Anterior Pillar Mucosal tumours-Squamous cell carcinoma Prevention and Counselling 1. Do not smoke. 2. Maintain good oral hygiene 3. Promptly treat oral infections. 4. If recurrent tonsillitis, tonsillectomy can be considered. 5. Always finish the course of antibiotics given in prescription even if you feel better within few days of starting the course. Optimal Diagnostic Criteria & Investigations

*Situation 1: At Secondary Hospital / Non Metro situation: Optimal standards of treatment in situations where technology & resources are limited 1. Clinical diagnosis- a) History (i) Progressive, usually unilateral sore throat over 3-4 days. (ii) Odynophagia (iii) Dysphagia for solids then liquids (iv) Ipsilateral otalgia (v) Headache, body ache (vi) Fever,chills& rigors b) General Examination (i) Muffled & thick speech (hot potato voice / plummy voice) (ii) Foul breath (iii) Vitals – Fever; tachycardia

c) Local Examination (i) Limited mouth opening (Trismus) (ii) Torticollis (iii) Oral cavity- Dental caries (iv) Oropharynx- Soft Palate-Congested ,Bulging Anterior Tonsillar Pillar- Congested, Edematous Tonsil-Edematous (May not appear enlarged as it gets buried in edematous pillars Uvula-Edematous, pushed to opposite side. 2. Investigations a) Complete Blood counts b) Serum electrolytes c) Needle aspiration of pus (i) Culture (ii)Sensitivity 69

d) Imaging (i) Orthopantogram (ii) X- Ray Neck AP view – Distortion of soft tissue Lateral view- Rule out other differential diagnosis Treatment & Referral Criteria Standard Operating Procedure 1. Needle Aspiration - Infiltration of 2% Lignocaine with Adrenaline (1: 100,000) given. - Using Needle 16-18 gauge & 10 ml syringe aspirate from the area which is most fluctuant. - Aspirate at superior pole initially because it is the most common area where

abscess is present; then middle 1/3rd followed by lower 1/3rd if pus is not returned from superior pole. - Needle guard is used to prevent accidental injury to Internal Carotid Artery due to tip of needle migrating too far posteriorly. Only 0.5 cm of needle needs to be exposed. - If needle guard is unavailable a curved clamp can be used to expose a small portion of needle before inserting it into area of aspiration. 2. Incision & Drainage

- Local infiltration of 2 percent Lignocaine with Adrenaline ( 1: 100,000) given. - Using No.11 blade scalpel / Quinsy knife a large peritonsillar abscess is incised. - It allows free flow of pus as the abscess cavity decompresses. - To prevent risk of aspiration, allow patient to hold Yankauer catheter tip & do suction of pus. 3. Abscess /Hot Tonsillectomy 4. Interval Tonsillectomy 5. In-Patient Care a) Airway- Tracheostomy may be essential in case of compromised airway b) Breathing

c) Circulation- IV Fluids d) Antibiotics- IV until acceptable swallowing is feasible. 70

e) Antibiotic of choice- - Penicillin G Benzathine (Adult- 600mg iv q 6 hr for 12-24 hr Paediatric- 12,500- 25000 U/kg iv q 6hr) - Erythromycin (Adult- 15-20 mg /kg/day PO /iv divided q6h; Not more than 4 g/day; Paediatric- 30-50mg/kg/day PO/iv divided q6h) f) Analgesics- Paracetamol - 500 mg TDS; Pethidine g) Hydrogen peroxide/ Saline mouth wash h) Single dose iv Steroid 5. Out Patient Care a) Analgesics b) Antibiotics c) Hydrogen peroxide gargles

*Situation 2: At superspeciality Facility in Metro Location Where Higher End Technology Is Available 1. Clinical Diagnosis - same 2. Investigations a) Complete blood count b) Serum Electrolytes c) Monospot /Heterophile Antibody Test for Infectious Mononucleosis d) Needle Aspiration of Pus - Culture & Sensitivity e) Blood Culture - If Septicemia. f) Imaging (i) Orthopantogram (ii) X- ray Neck - AP view; Lateral view (iii) CT-Scan Neck with Contrast Indications for CT Scan - Failure of I&D

Findings in CT Scan - Hypodense fluid collection with rim enhancement in tonsil. - Foreign body (fish/chicken bone) as an inciting factor. g) USG - Intraoral or Transcutaneous h) MRI Angiography 3. Treatment - same Further reading / references 1. Scott- Brown` S Otorhinolaryngology , Head And Neck Surgery 7th Edition 2. Otorhinolaryngology- PL Dhingra 3. eMedicine 72

National Guidelines on PPrreevveennttiioonn,, MMaannaaggeemmeenntt aanndd CCoonnttrrooll ooff RReepprroodduuccttiivvee TTrraacctt IInnffeeccttiioonnss aanndd SSeexxuuaallllyy TTrraannssmmiitttteedd IInnffeeccttiioonnss Department of AIDS Control Ministry of Health and Family Welfare Government of India July 2014 Maternal Health Division STI/RTI Division

CONTENTS Preface..............................................................i Foreword ...........................................................iii Acknowledgements ...................................................v List of Abbreviations..................................................vii List of Figures........................................................xi List of Tables.........................................................xi

List of Flowcharts ....................................................xii 1. Introduction and Overview of STI/RTI .....................................1 2. Syndromic Case Management ...........................................5 3. STI/RTI among Special Populations ......................................45 A. Pregnant Women................................................46 B. Children and Adolescents .........................................49

C. Sex Workers, MSM, TS & TG, PWID..................................51 4. Management of Sexual Violence ........................................55 5. Elimination of Parent-to-Child Transmission of Syphilis.......................65 6. STI Surveillance......................................................79 7. Education & Counselling in STI Programme................................83 8. Brief Introduction to STI/RTI ..............................................87

ANNEXURES A1. Laboratory Tests for STI/RTI .............................................106 A2. Syphilis Screening using Rapid Point of Care Tests (POC).......................115 A3. Disinfection and Standard Precautions.....................................118 A4. Treatment Failure, Recurrence, Relapse & Persistence of STI/RTI ................128 A5. List of Drugs .........................................................132

A6. Cross Referral Linkages between DSRC and Other Facilities.....................133 A7. Integration of STI/RTI Prevention and Management in RMNCH+A Programme .....134 A8. Condom and Its Proper Usage Technique...................................138 A9. List of Regional STI Training, Research & Referral Laboratories ..................142 A10. Technical Resource Group on Sexually Transmitted Infection Services............145

A11. List of Sub-committee Members for Revising National Guidelines on STI/RTI ......147 A12. List of Peer Reviewers..................................................148

LIST OF ABBREVIATIONS AIDS Acquired Immuno- Deficiency Syndrome ANC Ante Natal Clinic ARD Ano-rectal Discharge ARSH Adolescent Reproductive and Sexual Health ART Antiretroviral Therapy ARV Antiretroviral ASHA Accredited Social Health Activist BV Bacterial Vaginosis CA Condyloma Acuminata CD Cervical Discharge CHC Community Health Centre CMV Cytomegalovirus CSF Cerebrospinal Fluid CV Candida Vaginitis DAC Department of AIDS Control DAPCU District AIDS Prevention and Control Unit

DFA Direct Fluorescent Antibody DGI Disseminated Gonococcal Infection DMC Designated Microscopy Centre DOT Directly Observed Therapy DPM District Programme Manager DSRC Designated STI/RTI Clinics EC Emergency Contraception ELISA Enzyme Linked Immuno Sorbent Assay e-PTCT Elimination of Parent to Child Transmission (of syphilis) EQAS External Quality Assurance System FC Female Condom FIDU Female Injecting Drug user vii

FP/FW Family Planning/Family Welfare FSW Female Sex Worker FTA-ABS Fluorescent Treponemal Antibody Absorption Assay GASP Gonorrhoea Antimicrobial Surveillance Programme GI Granuloma Inguinale GUD – NH Genital Ulcer Disease Non-Herpetic GUD – H Genital Ulcer Disease Herpetic GV Granuloma Venereum HBIG Hepatitis B Immuno Globulin HBsAg Hepatitis B Surface Antigen HBV Hepatitis B Virus HCP Health Care Provider HIV Human Immunodeficiency Virus HPF High Power Field HPV Human Papilloma Virus HRG High Risk Group

HSS HIV Sentinel Surveillance HSV-1 Herpes Simplex Virus Type 1 HSV-2 Herpes Simplex Virus Type 2 IB Inguinal Bubo ICTC Integrated Counselling and Testing Centre ICMR Indian Council of Medical Research IgM Immunoglobulin M IPHS Indian Public Health Standards IUD Intra Uterine Device KOH Potassium Hydroxide LAP Lower Abdominal Pain LGV Lympho Granuloma Venereum LHV Lady Health Visitor viii

LT Laboratory Technician MARP Most At Risk Population MC Molluscum Contagiosum MCV Molluscum Contagiosum Virus MDG Millennium Development Goal MH Maternal Health MHA-TP Micro Haemagglutination Assay for Treponema pallidum MIF Micro Immuno Fluorescence MO Medical Officer MOHFW Ministry of Health and Family Welfare MPHW Multi-Purpose Health Worker MSM Men who have Sex with Men MTCT Mother to Child Transmission NACO National AIDS Control Organisation NACP IV National AIDS Control Programme Phase IV

NGO Non-Governmental Organization NGU Non Gonococcal Urethritis NHM National Health Mission NIRRH National Institute of Research in Reproductive Health ObGyn Obstetrics and Gynaecology OIF Oil Immersion Field PCR Polymerase Chain Reaction pH Power of Hydrogen (a figure expressing the acidity or alkalinity) PHC Primary Health Centre PID Pelvic Inflammatory Disease PLHIV People Living with HIV POC Point of Care Test PPTCT Prevention of Parent to Child Transmission (of HIV) PSS Painful Scrotal Swelling ix

PSU Public Sector Undertaking PWID People Who Inject Drugs RMNCH+A Reproductive Maternal, Neonatal, Child Health and Adolescent Programme RNTCP Revised National Tuberculosis Control Programme RPR Rapid Plasma Reagin RSTRRL Regional STI Training, Research and Reference Laboratory RVVC Recurrent Vulvo Vaginal Candidiasis SACS State AIDS Control Society SSTRL State STI Training and Reference Laboratory STI/RTI Sexually Transmitted Infections/ Reproductive Tract Infections TI Targeted Interventions

TPHA Treponema pallidum Haemagglutination Assay TPPA Treponema pallidum Particle Agglutination Assay TS/TG Transsexual/Transgender TSU Technical Support Unit TV Trichomonas vaginalis UD Urethral Discharge VD Vaginal Discharge VDRL Venereal Disease Research Laboratory VIA Visual Inspection with Acetic Acid VILI Visual Inspection with Lugol’s iodine VVC Vulvo Vaginal Candidiasis WHO World Health Organization x

LIST OF FIGURES Figure 2.a : Anogenital warts .............................................39 Figure 2.b : Molluscum contagiosum .......................................42 Figure 2.c : Genital scabies...............................................43 Figure A1.a : Potassium hydroxide preparation of vaginal fluid showing ...........109 budding yeast and mycelia Figure A1.b : “Clue cells” in vaginal wet mount (400X)..........................109

Figure A1.c : Trichomonas vaginalis in a wet mount of vaginal ...................109 discharge (400X) Figure A1.d : Gram stained vaginal smear showing a normal flora ................ 111 of lactobacilli (1000X) Figure A1.e : Gram stained vaginal smear with typical..........................111 “clue cell” (1000X) Figure A1.f : Gram stained vaginal smear showing large Gram ...................111 negative rods (Mobilincus mulieris) (1000X)

Figure A1.g : Gram stain smear: Gram negative diplococci of ....................112 Neisseria gonorrhoeae Figure A1.h : Test serum is mixed with antigen and the card is................... 114 placed on appropriate rotator Figure A1.i : Reading RPR results for 10 undiluted sera showing..................114 reactive and non-reactive samples. Figure A2.a : Strip test with interpretation of results .......................... 115 Figure A3.a : Hand washing procedures.....................................119

Figure A6.a : Linkages between DSRC/ General OPD and other facilities............133 Figure A8.a : How to use a male condom....................................139 Figure A8.b : How to use a female condom ..................................140 LIST OF TABLES Table 2.1 : Symptoms of STI/RTI ...........................................9 Table 2.2 : Medical, obstetric and menstrual history ...........................9 Table 3.1 : Interactions between STI/RTI and pregnancy .......................46

Table 3.2 : Screening for vaginal infections..................................48 Table 4.1 : Post-exposure prophylaxis of STI for adults and older children .........60 and adolescents weighing more than 45 kg xi

Table 4.2 : Post-exposure prophylaxis of STI in children........................61 Table 5.1 : Estimated proportion and number of adverse outcomes ..............68 in untreated pregnancies affected by syphilis, India, 2010-11 (based on WHO tool for estimation) Table 5.2 : e-PTCT of syphilis: monitoring indicators...........................75 Table A1.1 : Clinical criteria for Bacterial vaginosis (BV) ........................107

Table A1.2 : Wet mount microscopy examination of vaginal discharge ............108 Table A1.3 : Gram stain microscopy of vaginal smears .........................110 Table A1.4 : Procedure of RPR test ........................................112 Table A1.5 : Interpreting serological test results for syphilis.....................114 Table A3.1 : Management of health care waste ..............................121 Table A3.2 : Hypochlorite solution of 0.5%, 1% and 2% available chlorine..........126

Table A3.3 : Common disinfectants used for environmental cleaning in ...........126 health centres Table A7.1 : Contraceptives for Clients with STI, HIV and AIDS...................135 LIST OF FLOWCHARTS Flowchart 2.1 : Management of Vaginal Discharge syndrome ......................16 Flowchart 2.2 : Management of Cervical Discharge syndrome .....................19 Flowchart 2.3 : Management of Urethral Discharge/Burning Micturition in Males......21

Flowchart 2.4 : Management of Genital Ulcer Disease Non-Herpetic syndrome........24 Flowchart 2.5 : Management of Genital Ulcer Disease Herpetic syndrome............27 Flowchart 2.6 : Management of Painful Scrotal Swelling in Males...................30 Flowchart 2.7 : Management of Inguinal Bubo .................................32 Flowchart 2.8 : Management of Lower Abdominal Pain in Females .................34 Flowchart 2.9 : Management of Oral & Anal STI ................................37

Flowchart 3.1 : Management of STI during routine visit by Female Sex workers........53 Flowchart 3.2 : Management of STI during routine visit by MSM, TS/TG..............54 Flowchart 4.1 : Algorithm for management of Sexual Violence.....................63 Flowchart A : Initial syphilis screening......................................116 Flowchart B : Repeat syphilis screening (every 6 months).......................117 xii

National AIDS Control Organisation 1. Introduction and Overview of STI/RTI Sexually Transmitted Infections (STI) and Reproductive Tract Infections (RTI) have a major impact on sexual and reproductive health. As per the World Health Organization (WHO), globally 499 million new episodes of curable sexually transmitted infections (syphilis, gonorrhoea, chlamydia and trichomoniasis) occur yearly (2008 estimates); a significant

proportion of these infections occurring in developing countries. Sexually transmitted infections are an important cause of infertility in men and women. In pregnant women with untreated early syphilis, 21% of pregnancies result in stillbirth and 9% in neonatal death. Drug resistance, especially for gonorrhoea, is a major threat to STI control globally. Some STI can increase the risk of HIV acquisition and transmission by three-fold or more.

Of the more than 30 identified pathogens known to be transmitted sexually, syphilis, gonorrhoea, chlamydia, trichomoniasis, human immunodeficiency virus (HIV), human papilloma virus (HPV), herpes simplex virus (HSV), and hepatitis B virus (HBV) have been linked to the greatest incidence of illness. Sexually Transmitted Infections/Reproductive Tract Infections (STI/RTI) are an important public health problem in India. A community based STI/RTI prevalence study conducted during

2002-03 by the Indian Council of Medical Research (ICMR) has shown that 6% of the adult population in India has one or more STI/RTI. This amounts to occurrence of about 30-35 million episodes of STI/RTI every year in the country. Controlling STI/RTI helps to decrease HIV infection rates and provides a window of opportunity for counselling on HIV prevention and improving sexual and reproductive health. Currently, the available data from the STI/RTI control and prevention programme suggests a

significant decline of bacterial STI (syphilis, gonorrhoea). Chancroid is almost on the verge of disappearance. On the other hand, viral STI (herpes, genital warts, hepatitis B) are showing an increasing trend. There is a significant burden of lower RTI (trichomoniasis, bacterial vaginosis and candidiasis) among women with no evidence to suggest a decline in their prevalence, thus affecting the quality of their reproductive health.

National and State health policies and Indian Public Health Standards (IPHS) are prescribed to achieve and maintain quality of care to the community through the public healthcare delivery system and to achieve programmatic goals. The STI/RTI management services are a key programme strategy for prevention of HIV. The syndromic case management of STI/RTI is adopted as a universal strategy, is applicable at all levels of the health care system (Primary,

Secondary and Tertiary care) and ensures access to a package of standardized STI/RTI 2

National AIDS Control Organisation management services both for the general population with an emphasis on pregnant and non- pregnant women, children and adolescents and high risk behaviour groups. The guidelines presented in this document are designed for health care providers working at all levels of the public health care delivery system, public sector undertakings and private sector to enable them to diagnose and treat common STI/RTI following the syndromic approach. These

guidelines should be regarded as a source of technical guidance for programme implementation and will not replace standard text books. These guidelines also cater to the needs of Programme Managers and health care providers working in the Reproductive Maternal, Neonatal, Child Health and Adolescents Programme (RMNCH+A) and the STI/RTI Control and Prevention Programme under the Department of AIDS Control (DAC). The RMNCH+A Programme will find the guidelines useful in implementing

effective syndromic case management services through the network of PHCs/CHCs/Mobile Medical Units/and Rural Hospitals. Similarly STI/RTI Programme Managers at State AIDS Control Societies (SACS) and Technical Support Units entrusted with the responsibility of implementing STI/RTI services to both general and high risk groups through targeted interventions (TIs) will find the guidelines useful in ensuring access to quality STI/RTI management services.

The guidelines also provides guidance to service providers to address STI/RTI among high risk groups such as Male and Female Sex Workers (M/FSW), Men who have Sex with Men (MSM), Transsexuals and Trans genders (TS/TG), and People who Inject Drugs (PWID). The guideline details comprehensive STI/RTI syndromic case management supported by photographs of common STI/RTI to provide a visual impression; syndromic management flowcharts including partner management; management of STI/RTI syndromes among

pregnant women; standardized drug regimens; and Directly Observed Treatment strategies to enhance compliance wherever possible. Each syndromic flow chart includes specific instructions that should be followed. The guidelines describe details of procedures of minimal laboratory tests which can be conducted with basic equipment and minimal skills at various levels of health facilities. These laboratory tests enhance the sensitivity and specificity of syndromic case diagnosis and reduce

over diagnosis and over treatment. But under no circumstances should treatment be withheld for want of test results, as it may cause further secondary cases in the community. A brief note on newer STI diagnostics such as ‘rapid point of care’ tests for syphilis is also included. In addition, the document also provides information on syndrome specific counselling and client-centred STI/HIV prevention counselling. Interactive counselling can be used effectively by 3

National AIDS Control Organisation all health care providers, counsellors, and other clinical staff for educating the patients on preventing future infection and combating current infection. The Designated STI/RTI Clinic (DSRC) comprises both STI and Gynaecology clinic and should have cross referral linkages with Integrated Counselling & Testing Centres (ICTC), Prevention of Parent to Child Transmission (PPTCT) centres, Anti retroviral Therapy (ART) centres, Blood

Banks, Adolescent Reproductive and Sexual Health (ARSH) clinics, FP/FW clinics, other speciality clinics and general laboratory, Targeted Intervention projects, and Care and Support Centres including PLHIV networks. This ensures enhanced coverage and better utilization of DSRC (STI/RTI) services. Further, DSRC should also have referral linkages with State STI Training and Reference Laboratories (SSTRL) and Regional STI Training, Research and Reference Laboratories

(RSTRRL) for managing cases of suspected treatment failure and persistent infections. The National AIDS Control Programme IV (NACP IV) acknowledges the need for engaging with both organized Public Sector and Private Sector in provision of STI/RTI services. It is important that treatment facilities in both public and private sectors are linked to targeted interventions projects which will enhance the access to and coverage of quality STI/RTI service delivery to

general population and high risk behaviour groups. The Department of AIDS Control already has formalized MoUs, with organized Public Sectors (such as Coal and Shipping) and private health care sectors. The health services of these organizations and individual providers in private practice are highly encouraged to use and adhere to the National STI/RTI guidelines. This will help to standardize and scale up the STI/RTI management services. Universal adherence to

standardized drug regimens helps to reduce emergence of drug resistance. The health care providers are directed to follow and adhere to the recommended syndromic treatment regimens. However, alternative regimens can be considered in instances of significant drug allergy or other contraindications to the recommended regimens as specifically mentioned under each condition. The choices for therapy are prioritized based on efficacy, convenience, and cost.

Currently the programme is generating aetiological STI data from Regional STI Training, Research and Reference Laboratories. It is envisaged to scale up aetiological screening by establishing additional Regional and State STI Training and Reference Laboratories. These centres will act as STI laboratory based surveillance sites. The data generated from these STI surveillance sites will be useful to identify the emergence of STI hotspots, drug resistance,

evidence based planning and will enable the programme to take appropriate mid course corrections, if needed. 4

National AIDS Control Organisation 2. Syndromic Case Management A syndrome is defined as a group of common symptoms and signs caused by more than one organism. An STI/RTI syndrome is a combination of symptoms and signs typically associated with sexually transmitted microorganisms, e.g. Genital ulcer disease syndrome, which may be due to syphilis, chancroid, herpes simplex, etc. The aim of STI/RTI syndromic case management is to identify the syndrome correctly and

manage them accordingly. While clinical diagnosis is based on identifying the specific causative agent, syndromic diagnosis leads to immediate treatment for all of the most important possible causative agents. This is important because mixed infections occur frequently in STI/RTI. Besides, syndromic management of STI/RTI can effectively treat cases in settings with limited or no laboratory facilities. This means syndromic treatment can quickly render the patient non-infectious.

Objectives of STI/RTI Syndromic Management 1 Enhance access to STI/RTI control and prevention services to all; especially for pregnant and non-pregnant women, adolescents and high risk group population who are constrained to seek services and face several access related barriers. 2 Focus on prevention, with special reference to counselling, partner management, condom demonstration and provision; follow -up and management of side effects.

3 Emphasis mostly on single dose regimens and directly observed therapy (DOT) for better treatment adherence and outcomes. 4 Reinforce Behaviour change communication - inter personal communication leading to improved knowledge on causation, transmission and prevention of STI/RTI. 5 Ensure good linkages with Obstetrics & Gynaecology, Ante Natal Clinic, and cross referral linkages with Integrated Counselling and Testing Centres, Prevention of Parent to Child

Transmission Centres, ART centres, Blood Banks, ARSH clinic, Designated Microscopy centres (RNTCP), Community Support Centres including PLHIV networks and Targeted Intervention projects. Ensure linkages also with Regional and State STI Training and Reference Laboratories especially for managing suspected treatment failure and persistent cases. 6

National AIDS Control Organisation 6 Screen all attendees of designated STI/RTI clinic and ANC clinic for syphilis and HIV preferably through single window and single prick testing. 7. Ensure non-judgemental STI/RTI control and prevention service provision for high risk groups such as Male & Female Sex Workers, Men who have Sex with Men, Transsexuals/Transgenders and People who Inject Drugs (PWID). 8. Offer interactive counselling to clients by all health care providers, counsellors, and other

clinical staff. Client-centred STI/RTI/HIV counselling can increase the likelihood that the patient undertakes or enhances risk-reduction practices. Essential Steps of STI/RTI Syndromic Case Management The essential steps of STI/RTI syndromic case management include: 1. History taking 2. Clinical examination: genital/oral and ano-rectal apart from general examination 3. Appropriate syndromic diagnosis as per syndromic flow charts 4. Minimal laboratory tests, wherever available.

5. Early and effective treatment, preferably single dose and directly observed. 6. Promotion and provision of condoms. 7. Counselling for behaviour change and risk reduction 8. Referral for syphilis screening and HIV counselling and testing 9. Partner/s notification and management. 10. Follow-up as per schedule. 11. Documentation of case details and laboratory results 1. History taking History must be taken in a language, which the client understands well. Clients are often

reluctant to talk about their condition due to shyness or fear of stigma. Individuals may come to 37

National AIDS Control Organisation the clinic with other non specific complaints or requesting a check-up, assuming that the health care provider will notice any thing abnormal that needs treatment. Therefore, health care workers should maintain a high index of suspicion about the possibility of STI/RTI. Hence health care providers should ensure privacy, confidentiality, be empathetic, understanding, non- judgmental and culturally sensitive while eliciting history.

Start the conversation by welcoming your client, taking them into confidence and encouraging him/ her to talk about their complaints. If a couple comes together, each of them needs to be interviewed and examined separately. Clients seeking services from ARSH clinics, antenatal care, abortion, infertility and family planning/welfare services should be viewed as opportunities to provide general information about STI/RTI and should be asked about STI/RTI symptoms and referred for services as per the need.

Patients with problems relating to the genital area tend to be guarded and evasive while giving a history. • Ask an open-ended question, such as “What brought you to hospital?” to initiate a dialogue. • Phrase your questions in a way such that the opportunity for the patient to mislead you is minimized. For example, “When did you last have sex with someone?” is preferable to “Did you have sex with someone?” • Once the subject is broached and patient is comfortable, closed-ended questions

(calling for “yes” or “no” answers) can be helpful in eliciting brief answers, for example, “Do you have pain?” • In order to make an accurate diagnosis it is often necessary to ask more questions during the examination. • Do not show annoyance if the patient’s history has obvious discrepancies or keeps changing. Presenting symptoms and signs Obtain a detailed history of the presenting symptom/s. Enquire about the presence of other

symptoms that are common, such as discharge from the urethra in a patient with genital ulcers, or recurring genital ulcers in a patient presenting with urethral discharge. 8

National AIDS Control Organisation Table 2.1: Symptoms of STI/RTI FEMALES MALES Dysuria, frequency of urination Dysuria, frequency of urination Vaginal discharge Urethral discharge Genital ulceration Genital ulceration Abnormal growth or mass in genital area Abnormal growth or mass in genital area Lower abdominal pain Acute scrotal swelling, pain Inguinal lymphadenopathy Inguinal lymphadenopathy Vulval itching Genital itching, Balanitis Dyspareunia Dyspareunia Perianal pain Perianal pain

Anal discharge Anal discharge Pharyngitis Pharyngitis Medical, obstetric and menstrual history History of other illnesses, medication (current and past) and allergies to medication should be noted. Table 2.2: Medical, obstetric and menstrual history MEDICAL HISTORY MENSTRUAL HISTORY OBSTETRIC HISTORY Other illness such as Diabetes mellitus Date of last menstrual period Missed or overdue period Medications - current and past Regular/irregular periods Contraception

Drug allergies Pain during periods Mode of delivery Past History of catheterization Excessive bleeding Number of pregnancies and outcomes Post-coital bleeding Sibling status Past History of termination of pregnancy Behavioural risk assessment If the patient is to receive proper education and counselling, these must be preceded by behaviour risk assessment. Make sure that the patient is aware that the history will be kept strictly confidential. Inquire about the following risk factors:

• Marital status: married, living together, single, separated, widowed. • Occupation: sex workers (male and female), seamen, workers in the hospitality industry, transport workers, migrant workers, etc. 9

National AIDS Control Organisation • Travel: Frequent traveller (holidays, business or employment). • Unprotected casual sexual encounters (other than with regular partner). • Previous history of STI. • History of injections or blood transfusions. • Substance use: alcohol, drugs (e.g. heroin). • Tattooing. • Partner with symptoms suggestive of STI. • Multiple sexual partners. Sexual history A sexual history must be taken from all patients before examining them and managing their

sexual health problems. All individuals should be asked about the following: • Sex of the partner. • Type of exposure (oral, vaginal, anal). • Use of condoms with any type of partner. • Relationship to partner/s (spouse, regular non-spouse, casual). • Problems or symptoms in the partner/s. • Date of last sexual intercourse. • Number of partners in the past three months. 2. Clinical examination This is an important step to arrive at a probable syndromic diagnosis and avoids making an

incorrect diagnosis based on the patient’s history alone. Inform the patient that you will do a genital examination and obtain the patient’s permission to do so. Ensure privacy during the examination. Always have a female attendant when examining a female patient (particularly if the HCP is a male). Genital examination includes a bimanual and speculum examination of the genital tract for all female patients, and rectal examination (including proctoscopy, if indicated and available) for

National AIDS Control Organisation In addition to genital examination, an oral examination (to look for oral STI ) and an adequate and appropriate general examination is also required. 3. Minimal laboratory tests If laboratory facilities are available, use appropriate, available tests to confirm a probable syndromic diagnosis. In particular, the Rapid Plasma Reagin (RPR)/rapid treponemal test, Gram stain and wet mount can assist in the diagnosis. If HIV testing facilities are available, offer HIV

counselling and testing or refer the patient for this. Do not delay or with hold treatment because laboratory investigations are incomplete or the results of the tests are not available. 4. Appropriate syndromic diagnosis Correct syndromic diagnosis: On the basis of the history, clinical examination and laboratory investigations (if available) that have been carried out, the following actions must be taken. • Use the appropriate syndromic flowchart for managing the patient.

• Be particularly careful when confronted with a patient with lower abdominal pain (in women) and scrotal swelling (in men). • Be certain that you are not dealing with a surgical emergency. Arrange for early follow up if uncertain. (Please see the flow charts specific to the syndrome) 5. Early and effective treatment Treat the patient as per national STI treatment guidelines. While treatment will be curative in most instances, only palliative therapy is possible in the case of viral STI.

When prescribing medication, educate patients on the following: • Compliance — educate the patient on the importance of taking the treatment as prescribed. The full course of treatment should be taken even if the patient feels better after a few doses. • Side effects — patients may stop therapy due to adverse effects unless they have been previously informed of possible adverse effects.A dvise the patient to come back if these effects are intolerable. 11

National AIDS Control Organisation • Treatment failure — re-evaluate for possible non-compliance or re-infection.If neither seems likely, then refer to a higher centre providing adequate laboratory support. 6. Promotion and provision of condoms • Prevention of STI and HIV - Explain to the patient the association between STI and HIV, and that the same risk behaviours can lead to acquisition and/or transmission of both these conditions. Educate the patient on the methods of risk reduction through safer sex

practices including abstinence and regular use of condom during sexual intercourse with any partner. • Condom use - Discuss the use of condoms for risk reduction.P rovide free condoms if feasible and available.D emonstrate on a penis model the correct way of using a condom and develop the patient's skills in correct use.D esensitize the patient about condoms, especially if he or she is a regular risk-taker who should be consistently using condoms. 7. Counselling for behaviour change and risk reduction

Counselling is an interactive confidential process where a health care provider helps a patient to reflect on issues associated with STI/RTI and to explore possible lines of action. Counselling is more time-consuming than providing information, and also requires more empathy and understanding from health care workers. In a counselling session, the following issues should be addressed: a) Inform the partner (s) or spouse about the diagnosis of STI/RTI options: either the

patient or the HCP informs the partner(s) or spouse. b) Assess the patient's risk for HIV and assist the patient in making a decision to undergo HIV testing. c) Help the patient to learn about, and come to terms with, worrisome complications of STI/RTI, such as infertility and congenital syphilis. d) Educate the patient on his/her present STI/RTI and how it was acquired. Inform the patient that bacterial STI are curable, viral STI recur, and the effects of not taking

treatment properly. Patients with recurrent genital herpes and recurrent vulvo- vaginitis are usually very distressed and need repeated counselling sessions. 12

National AIDS Control Organisation e) Inform the patient on how to deal with an incurable STI, such as herpes genitalis or genital warts, which may be transmitted to the partner (s) or spouse. f) Educate the patient on how to prevent future infections, including strategies for discussing and introducing condom use with the partner (s) or spouse. g) Tell the patient about confidentiality, disclosure and the risk of violence or stigmatizing

reactions from the spouse, partner (s), family or friends and ways to overcome these. h) Enable patients to take control of their own lives and understand their responsibilities for disease prevention. 8. Referral for syphilis screening and HIV counselling and testing All the patients attending the DSRCs should be referred for syphilis screening and HIV testing after proper counselling and clarifying the patient’s curiosity, questions and doubts. 9. Partner notification and management

While maintaining confidentiality, the patients who have been put on treatment for STI/RTI must be encouraged to bring in their sexual partners for screening and management of STI as per the syndromic management guidelines. Note: Routine partner treatment is not required for asymptomatic partners of patients with GUD herpetic and for female patients with vaginal discharge especially when HCP suspects candida or bacterial vaginosis. 10. Clinical follow up

Appropriate clinical follow up is a part of comprehensive case management of STI/RTI. The follow up schedules are prescribed for each syndrome in the respective flow charts. Patients should be advised to return if their symptoms get worse or persist after the prescribed period of therapy. 11. Recording & reporting of cases Record each individual patient attending the clinic in records and registers as mentioned in the operational guidelines. Once a month the data is compiled and reported in the monthly SIMS

format. The records and registers should be kept in a safe place to ensure confidentiality of patient related information. 13

)sitinigaV( emordnys egrahcsiD lanigaV fo tnemeganaM :1.2 trahcwolF sitinigaV fo smsinagrO evitasuaC )VT( silanigav sanomohcirT • snacibla adidnaC • dna amsalpaerU ,amsalpocyM ,silanigav allerendraG gnidulcni smsinagro elpitluM • seboreana detavitlucnu dna suoiditsaf rehto sisainomohcirt ni egrahcsid lanigav yhtorF noitanimaxE sitinigav neewteb etaitnereffid ot noitanimaxe muluceps reP • .siticivrec dna yrotsiH fo sesuac suoirav eht fo snoitatneserp lacinilc cissalc ehT ,ytitnauq( egrahcsid fo epyt dna

erutaN • :elbahsiugnitsid eb ton yam tub ,gniwollof eht edulcni sitinigav )ycnetsisnoc dna ,ruoloc ,llems egrahcsid yhtorf hsineerg - sisainomohcirT o gnihcti latineG • egrahcsid etihw ydruc - sisaididnaC o ksir ssessA desaercni ,eniru gnissap elihw gninruB • ycneuqerf egrahcsid tnerehda – sisonigav lairetcaB o eneigyh latineg rooP • ro lavluv eht no gnillews ,reclu ynA • egrahcsid lacipyta htiw tneserp yam snoitcefni dexiM o s/retnuocne lauxes detcetorpnU • noiger laniugni civlep launamib yb dewollof

noitanimaxe mulucepS • srentrap lauxes elpitluM • srentrap lauxes ni stnialpmoc latineG • esaesid yrotammalfni civlep tuo elur ot noitanimaxe srentrap lauxes ni egnahc tneceR • ehcakcab woL • ,tnatiseh si tneilc ro elbissop ton si noitanimaxe muluceps fI :etoN .siticivrec dna sitinigav rof htob taert eht ni stnialpmoc ralimis fo yrotsiH • ycnangerp tuo elur ot yrotsih laurtsneM • tsap National AIDS Control Organisation 16

tnemtaerT )elbaliava fi( snoitagitsevnI yrotarobaL )adidnaC+VB+VT( sitinigaV sanomohcirT rof egrahcsid eht fo ypocsorcim tnuom teW • silanigav RO esod elgnis ,yllaro mg 2 elozadinceS .baT • snacibla adidnaC rof noitaraperp HOK %01 • RO syad 5 rof yliad eciwt ,yllaro gm 005 elozadiniT .baT lairetcab ni nees sllec eulc rof raems lanigav fo niats marG • .syad 7 rof yliad eciwt ,gm 004 elozadinorteM .baT sisonigav lacol RO esod elgnis yllaro gm 051 elozanoculF baT htiw sisaididnac rof taerT • silihpys rof

tset RPR • ecno yrassep lanigav gm 005 elozamirtolC gnitset dna gnillesnuoc VIH rof CTCI ot refeR • :etoN si redivorp fi ro htob rof taert rehtegot tneserp era siticivrec dna sitinigav fI • .siticivrec dna sitinigav htob rof taert neht noitanimaxe muluceps od ot elbanu gnihcuod diova ot tneilc tcurtsnI • eb dluohs dna srotcaf gnicneulfni eb osla yam VIH ,setebaid ,ycnangerP • snoitcefni tnerrucer ni deredisnoc elozadinortem gnirud stneitap yb dediova eb dluohs lohocla fo noitpmusnoC • .tnemtaert

fo noitelpmoc retfa sruoh 84 tsael ta rof dna ypareht nemow tnangerp fo tnemeganaM tuo elur ot enod eb dluohs noitanimaxe muluceps reP tnemeganam rentrap rof senilediug cificeps emordnyS fo erutpur erutamerp ,noitroba ekil snoitacilpmoc ycnangerp senarbmem :adidnaC dna VB ot eud sitinigaV roF )adidnaC+VB+VT( sitinigav rof tnemtaerT deriuqer toN • maerc/yrassep lanigav elozamirtolC htiw tnemtaert lacoL • tnemtaert laitini retfa tnemevorpmi on fi ylno rentrap tnerruc taerT • .sisaididnac rof ylno slocotorp

evoba gnisu rentrap dna tneilc taert ,citamotpmys si rentrap fI • .ycnangerp ni detacidniartnoc si elozanoculF larO • :noitcefni sanomohcirT roF .VT/VB rof syad 7 rof dib gm 004 elozadinorteM baT • locotorp evoba eht htiw syad 03 tsal eht ni srentrap lauxes lla taerT • ylefas eb nac elozadinorteM taht nwohs sah ecnedivE :etoN tnemtaert fo esruoc eht gnirud ecnenitsba lauxes esivdA • .ycnangerp fo retsemirt tsrif eht ni desu National AIDS Control Organisation 17

National AIDS Control Organisation 18 segassem gnillesnuoc yeK pu wolloF gnidrager )s(rentrap xes dna tneilc lesnuoc dna etacudE • ,syad 7 retfA gnikat fo ecnatropmi dna secitcarp xes refas ,ITR/ITS eruc citamotpmys tnemucod oT • .tnemtaert etelpmoc .silihpys dna VIH rof enod stset fo stluser tnemucod oT • dna tcerroc rieht tuoba etacude ,smodnoc edivorP • .esu tnetsisnoc fo kcal ot eud si ti rehtehw ssessa tsisrep sngis/smotpmys fI • dna noitcefni-er ro eruliaf tnemtaert ro ecnailpmoc tnemtaert .syad 7

retfa tisiv nruter eludehcS • .larrefer tpmorp esivda gnisopsiderp taht dednemmocer si tI .ecnerrucer fo evitacidni si shtnom 2 nihtiw smotpmys fo ecnerruceR :sisaididnac lanigav-ovluV .detanimile ro decuder eb gnihcuod lanigav ro snoitaraperp lanigav citoibitna/citpesitna dna scitoibitna fo esu eht sa hcus srotcaf .secnerrucer gnitneverp ni lufesu ton si elozanoculF ro nitatsyN laro htiw sucof latcer a fo tnemtaert suoenatlumiS ,sutillem setebaid dellortnocnu edulcni sisaididnac lanigav-ovluv tnerrucer rof

dnim ni tpek eb ot srotcaf gniylrednu rehtO .esu dioretsocitroc dna noisserppusonummi fo feiler ro tnemtaert rof gnihcuod fo esu eht troppus atad on dna ,espaler rof ksir eht esaercni thgim gnihcuoD :sisonigav lairetcaB yb detceffa ton si espaler fo doohilekil eht dna ypareht ot esnopser s’namow a taht etacidni slairt lacinilc fo stluser ehT .smotpmys .dednemmocer ton si srentrap lauxes fo tnemtaert enituor ,eroferehT .)s(rentrap lauxes reh fo tnemtaert

)siticivreC( emordnys egrahcsiD lacivreC fo tnemeganaM :2.2 trahcwolF siticivreC fo smsinagrO evitasuaC eaeohrronog airessieN • sitamohcart aidymalhC • smsinagro rehtO • silanigav sanomohcirT o suriv xelpmis sepreH o suriv amollipap namuH o ypocsoploc no egrahcsid lacivreC noitanimaxE na fo nialpmoc nemow emos tub ,citamotpmysa si yltneuqerf siticivreC • retfa .g.e( gnideelb lanigav laurtsnemretni dna egrahcsid lanigav lamronba .)esruocretni lauxes :siticivrec eziretcarahc sngis citsongaid rojam owT • eht

ni elbisiv etaduxe lacivrecodne tnelurupocum ro tnelurup a o ylnommoc( nemiceps baws lacivrecodne na no ro lanac lacivrecodne yrotsiH )siticivrec ro siticivrec tnelurupocum sa ot derrefer ,ytitnauq( egrahcsid fo epyt dna erutaN • a fo egassap eltneg yb decudni ylisae gnideelb lacivrecodne deniatsus o )ycnetsisnoc dna ,ruoloc ,llems .so lacivrec eht hguorht baws nottoc gnihcti latineG • .tneserp eb thgim sngis htob ro rehtiE desaercni ,eniru gnissap elihw gninruB • ksir ssessA .siticivrec dna sitinigav

neewteb etaitnereffid ot noitanimaxe muluceps reP • ycneuqerf s/retnuocne lauxes detcetorpnU • :siticivrec fo citsiretcarahc era serutaef gniwollof ehT ro lavluv eht no gnillews ro/dna reclu ynA • xivrec suotamehtyre o srentrap lauxes elpitluM • noiger laniugni egrahcsid lacivrec tnelurupocum o srentrap lauxes ni egnahc tneceR • ehcakcab woL • .esaesid yrotammalfni civlep tuo elur ot noitanimaxe civlep launamiB • eht ni stnialpmoc ralimis fo yrotsiH • ycnangerp tuo elur ot yrotsih laurtsneM • tsap htob

taert ,tnatiseh si tneilc ro elbissop ton si noitanimaxe muluceps fI :etoN lauxes eht ni smotpmys ro smelborP • .siticivrec dna sitinigav rof eht ni egrahcsid larhteru fo yrotsiH • )s(rentrap )s(rentrap elam National AIDS Control Organisation 19

)elbaliava fi( snoitagitsevnI yrotarobaL )aeohrronog dna aidymalhc( noitcefni lacivrec rof tnemtaerT silanigav sanomohcirT rof egrahcsid eht fo ypocsorcim tnuom teW • esod elgnis ,yllaro gm 004 emixifeC .baT • sah tset siht hguohT .iccoconog tceted ot raems lacivrecodne fo niats marG • SULP .cificeps ylhgih si ti ,ytivitisnes wol 1 nihtiw srucco gnitimov fI .doof erofeb ruoh 1 ,mg 1 nicymorhtizA .baT • cipocsorcim no dleif rewop-hgih rep CBW 01>( aeohrrocuel fo gnidnif A • taeper dna citeme-itna evig ,ruoh

dna laidymalhc htiw detaicossa neeb sah )diulf lanigav fo noitanimaxe :etoN ,sitinigav yrotammalfni fo ecnesba eht nI .xivrec eht fo noitcefni laccoconog a htiw noitammalfni lacivrec fo rotacidni evitisnes a eb thgim aeohrrocuel si redivorp fi ro htob rof taert rehtegot tneserp era siticivrec dna sitinigav fI • ton si ti ,evitisnes ylhgih si tset siht elihW .eulav evitciderp evitagen hgih dna sitinigav htob rof taert neht noitanimaxe muluceps od ot elbanu .tnemtaert revo ot dael yllaitnetop nac dna cificeps

.siticivrec .silihpys rof tset RPR • .gnihcuod diova ot tneilc tcurtsnI • .gnitset dna gnillesnuoc VIH rof CTCI ot refeR • gnirud stneitap yb dediova eb dluohs lohocla fo noitpmusnoC • fo noitelpmoc retfa sruoh 84 tsael ta rof dna ypareht elozadinortem .ertnec rehgih ot refer snoitagitsevni rehtruf roF • .tnemtaert nemow tnangerp fo tnemeganaM tnemeganam rentrap rof senilediug cificeps emordnyS .nemow tnangerp-non ni sa emaS tsal eht ni srentrap lauxes lla taert :noitcefni sanomohcirT dna siticivreC roF •

locotorp evoba eht htiw syad 03 tnemtaert fo esruoc eht gnirud ecnenitsba lauxes esivdA • pu wolloF ,syad neves retfA segassem gnillesnuoc yeK eruc citamotpmys tnemucod oT • refas ,ITR/ITS gnidrager )s(rentrap lauxes dna tneilc lesnuoc dna etacudE • .tnemtaert etelpmoc gnikat fo ecnatropmi dna secitcarp xes .silihpys dna VIH rof enod stset fo stluser tnemucod oT • .snoitadnemmocer emordnys rep sa )s(rentrap taerT • tnemtaert fo kcal ot eud si ti rehtehw ssessa tsisrep sngis/smotpmys fI • .larrefer tpmorp

esivda dna noitcefni-er ro eruliaf tnemtaert ro ecnailpmoc .tnemtaert fo esruoc eht gnirud ecnenitsba lauxes esivdA • tnerrucer dna tnetsisrep ot dael yam dna nommoc era sespaler :etoN .esu tnetsisnoc dna tcerroc rieht tuoba etacude ,smodnoc edivorP • .rotcaf yek a sa detubirtta si muilatineg .M .siticivrec .syad 7 retfa tisiv nruter eludehcS • National AIDS Control Organisation 20

selaM ni noitirutciM gninruB/egrahcsiD larhterU fo tnemeganaM :3.2 trahcwolF smsinagrO evitasuaC eaeohrronog airessieN • sitamohcart aidymalhC • silanigav sanomohcirT • amsalpocyM ekil smsinagro rehtO • ciretne ,suriv xelpmis sepreH ,muilatineg surivoneda dna airetcab sutaem demalfni :sitirhteru laccoconoG egrahcsid tnelurup htiw ksir ssessA yrotsiH noitanimaxE xes detcetorpnu tnecer o/H • ksir hgih gnidulcni erusopxe lauxeS • sutaem larhteru eht fo gnillews dna ssendeR • sti ni seussi rehto ro egakaerb

modnoC • eht ni xes latineg-oro ekil secitcarp egasu egrahcsid larhteru fo ecneserP • shtnom 2 suoiverp srentrap lauxes elpitluM • eht egassam yltneg neht ,nees ton si egrahcsid larhteru fI • egrahcsid larhterU • sutaem eht sdrawot sinep eht fo trap lartnev eht morf arhteru srentrap lauxes ni egnahc tneceR • eniru gnissap elihw gninrub ro niaP • diocum ro wolley-hsineerg ymaerc ,kciht rof kool dna fo evitseggus smotpmys htiw rentraP • egrahcsid noitaniru fo ycneuqerf desaercnI • tsap tnecer ni ITS

)elbaliava fi( snoitagitsevnI yrotarobaL tnemtaerT -marg etartsnomed ot raems larhteru eht fo noitanimaxe niats marG • dluohs egrahcsid larhteru rof tnemtaert eht ,nommoc si noitcefni laud sA aeohrronog fo esac ni iccocolpid ralullecartni evitagen .snoitcefni laidymalhc dna aeohrronog ,htob rof revoc yletauqeda larhteru eht ni )X0001( dleif noisremmi lio rep slihportuen 5 naht eroM • )DU( egrahcsid larhteru detacilpmocnu rof nemiger dednemmoceR fo tnemides eht ni dleif rewop hgih rep slihportuen 01 naht

erom ro raems emordnys sitirhteru laccoconog-non fo esac ni eniru diov tsrif eht eht ot detimil si esaesid eht taht etacidni snoitcefni detacilpmocnU silihpys rof tset RPR • .)sititcorp dna sitirhteru roiretna( noiger latinegona .gnitset dna gnillesnuoc VIH rof CTCI ot refeR • esod elgnis ,yllaro gm 004 emixifeC .baT • SULP RO noisivrepus rednu esod elgnis yllaro mg 1 nicymorhtizA .baT • syad 7 rof yad a eciwt gm 001 enilcycyxoD .paC ypareht fo trats fo syad 7 retfa nruter ot tneilc eht esivdA • dluohs

VIH htiw detcefni era osla dna emordnys DU evah ohw stneitaP • .evitagen VIH era ohw esoht sa nemiger tnemtaert emas eht eviecer )syad 7 retfa stsisrep airusyd ylno ro egrahcsid( tsisrep smotpmys nehW • srentrap tnangerp fo tnemeganaM eb dluohs yeht ,)s(rentrap dna tneilc xedni eht ni tnemtaert etauqeda retfa .silanigav sanomohcirT rof detaert eb dluohs egrahcsid larhteru htiw stneilc elam fo srentrap tnangerP • dna noitanimaxe lanigav rep sa llew sa muluceps rep gniod yb denimaxe )silanigav .T rof taert

ot( esod elgnis ,yllaro mg 2 elozadinceS .baT o .detaert eb dluohs ot tneitap eht refer ,tsisrep smotpmys fi ,tnemtaert evoba eht retfa nevE • ni evitceffe dna efas era noitcefni laccoconog revoc ot sniropsolahpeC • .ertnec rehgih ycnangerp RO esod elgnis ,yllaro gm 004 emixifeC .baT o noitcejni ralucsumartni yb gm 052 enoxairtfeC .jnI SULP tnemeganam rentrap rof senilediug cificeps emordnyS RO yllaro tats mg 1 nicymorhtizA .baT o tcatnoc lauxes tsal esohw emordnys DU htiw stneitap fo srentrap lauxes llA •

sisongaid ro smotpmys fo tesno erofeb syad 06 nihtiw saw tneitap eht htiw RO syad 7 rof yad a semit ruof yllaro gm 005 nicymorhtyrE .baT DU rof detaert dna detaulave eb dluohs tneitap eht ni noitcefni fo revoc ot syad 7 rof yad a semit eerht ,yllaro gm 005 nillicixomA paC .emordnys noitcefni laidymalhc yrotsih dna ycnangerp tuo gnilur retfa senil emas no srentrap elamef taerT • era enilcycyxod dna ,)nicaxolforpic ,nicaxolfo ekil( senoloniuQ :etoN .seigrella fo .nemow tnangerp ni detacidniartnoc . tnemtaert

fo esruoc eht gnirud ecnenitsba lauxes esivdA • National AIDS Control Organisation 22

segassem gnillesnuoc yeK pu wolloF refas ,ITR/ITS gnidrager )s(rentrap lauxes dna tneilc lesnuoc dna etacudE • syad neves retfA tnemtaert etelpmoc gnikat fo ecnatropmi dna secitcarp xes eruc citamotpmys tnemucod oT • snoitadnemmocer emordnys rep sa )s(rentrap taerT • silihpys dna VIH rof enod stset fo stluser tnemucod oT • tnemtaert fo esruoc eht gnirud ecnenitsba lauxes esivdA • taert elbissop fi ,noitcefni sanomohcirT ot eud si ti rehtehw ssessa ,tsisrep sngis/smotpmys fI • .esu tnetsisnoc dna tcerroc

rieht tuoba etacude ,smodnoc edivorP • yllaro mg 2 elozadinceS .baT htiw .syad 7 retfa tisiv nruter eludehcS • dna noitcefni-er ro eruliaf tnemtaert ot eud si ti rehtehw ssessa tsisrep sngis/smotpmys fI • .larrefer tpmorp esivda sitirhterU tnetsisreP dna tnerruceR .ypareht laiborcimitna fo noitaitini eht erofeb tneserp eb dluohs sitirhteru fo sngis evitcejbO • .detartsnomed neeb ton sah slaiborcimitna fo noitarud eht gnidnetxe fo eulav eht ,sitirhteru fo sngis evitcejbo tuohtiw tnemtaert retfa smotpmys

tnetsisrep evah ohw snosrep nI :etoN na ot desopxe-er erew yeht fi ro nemiger tnemtaert eht htiw ylpmoc ton did yeht fi nemiger laitini eht htiw detaerter eb nac sitirhteru tnerrucer ro tnetsisrep evah ohw snosreP • .rentrap lauxes detaertnu .muilatineg .M ro mucitylaeru .U tnatsiser-enilcycyxod dna silanigav .T yb desuac eb thgim syad 7 rof yliad eciwt gm 001 fo tnemtaert enilcycyxod retfa sitirhteru tnetsisreP • .stset citsongaid eht fo stluser eht gnitiawa elihw dednemmocer si nemiger gniwollof eht

,dedulcxe eb nac erusopxe-er dna nemiger laitini eht htiw tnailpmoc fI • snemigeR dednemmoceR RO esod elgnis a ni yllaro mg 2 elozadinorteM • esod elgnis a ni yllaro mg 2 elozadiniT SULP )edosipe laitini rof desu ton fi( esod elgnis a ni yllaro mg 1 nicymorhtizA • :etoN + yllaro mg 2 elozadinorteM + MI gm 052 enoxairtfeC edulcni thgim tnemeganam ,esac siht nI .emixifeC morf eruliaf tnemtaert ot eud eb osla yam egrahcsid larhteru tnetsisreP • .yrotarobaL ecnerefeR ITS tseraen eht ta gnirotinom ecnatsiser

laiborcimitna dna erutluc aeohrronog .N rof etatilicaf dna esivdA .yllaro mg 2 nicymorhtizA .doirep htnom-6 a nihtiw shtnom 3 naht erom rof niap civlep ecneirepxe ohw nem rof deredisnoc eb dluohs tsigoloru a ot larrefeR • .tnemtaert fo noitelpmoc retfa sruoh 84 tsael ta rof dna ypareht elozadinortem gnirud stneitap yb dediova eb dluohs lohocla fo noitpmusnoC • National AIDS Control Organisation 23

emordnys citepreH-noN esaesiD reclU latineG fo tnemeganaM :4.2 trahcwolF diorcnahC elaniugni amolunarG silihpy S smsinagrO evitasuaC )silihpyS( mudillap amenoperT • )diorcnahC( iyercud sulihpomeaH • )elaniugni amolunarG( sitamolunarg alleisbelK • )muerenev amolunargohpmyL( sitamohcart aidymalhC • National AIDS Control Organisation 24

noitanimaxE ksir ssessA yrotsiH elpitlum ro elgnis -reclu latineg fo ecneserP • s/retnuocne lauxes detcetorpnU • reclu latineG • :scitsiretcarahc reclU • srentrap lauxes elpitluM • noiger latineg eht ni noitasnes gninruB • silihpyS - sedon hpmyl mrif htiw reclu sselniaP o srentrap lauxes ni egnahc tneceR • hgih gnidulcni rentrap rehtie fo erusopxe lauxeS • xes latineg-oro ekil secitcarp ksir - sedon hpmyl laniugni tuohtiw reclu sselniaP o elaniugni amolunarG degralne ,lufniap htiw reclu elinep sselniap

tneisnarT o VGL – sedon hpmyl laniugni tnemtaerT htiw detaicossa dna elpitlum yllausu sreclu lufniaP o diorcnahc dna silihpys rof taert ,nees si reclu ylno dna nees ton era selcisev fI • diorcnahC -obub lufniap sesod dedivid owt ni esod tset retfa esod elgnis MI UI noillim 4.2 nillicinep enihtazneB .jnI o )silihpys rof( )ydaer yart ycnegreme htiw( SULP )elbaliava fi( snoitagitsevnI yrotarobaL 7 rof yad a semit ruof gm 005 nicymorhtyrE /esod elgnis yllaro mg 1 nicymorhtizA .baT o diorcnahc rof niats marG •

RO syad sisonavonod rof niats namhsieL • )diorcnahc rof( syad 3 rof yad a eciwt ,yllaro gm 005 nicaxolforpiC .baT silihpys rof tset RPR • :nillicinep ot tnarelotni ro cigrella slaudividni nI • gnitset dna gnillesnuoc VIH rof CTCI ot refeR • RO syad 51 rof yliad eciwt ,yllaro gm 001 enilcycyxoD .paC o ertnec rehgih ot refer snoitagitsevni rehtruf roF • .silihpys ylrae taert ot esod elgnis a sa mg 2 nicymorhtizA .baT :etoN silihpys gnitaert rof eciohc fo gurd eht si nillicinep enihtazneB .jnI • .ecnatsiser

gurd poleved yam ti sa nicymorhtiza gnisu ni desicrexe eb dluohs noituaC • .ypareht fo shtnom eerht retfa detseter dna pu dewollof eb dluohs stneitaP • .)MSM( nem htiw xes evah ohw nem gnoma desu eb ton dluohs nicymorhtizA • sepreh-non dna sepreh rof taert neht sisongaid lacinilc eht tuoba tbuod ni si redivorp fI • .rehtegot )diorcnahc dna silihpys( National AIDS Control Organisation 25

nemow tnangerp fo tnemeganaM tnemeganam rentrap rof senilediug cificeps emordnyS era sedimanoflus ,enilcycyxod ,)nicaxolforpic ,nicaxolfo ekil( senoloniuQ • emas htiw diorcnahc dna silihpys rof detaert eb dluohs srentraP • .nemow tnangerp ni detacidniartnoc .nemiger deredisnoc eb dluohs noitulid yna ni RPR rof evitisop tset ohw nemow tnangerP • roirp shtnom 3 tsal ni tneilc htiw tcatnoc ni era ohw srentrap lla taerT • tnemtaert etauqeda sselnu silihpys rof tnemtaert dedivorp eb dluohs dna detcefni .reclu

fo tesno eht ot evah sertit ydobitna cigolores laitneuqes dna sdrocer lacidem eht ni detnemucod si eht llit ro tnemtaert fo esruoc eht gnirud ecnenitsba lauxes esivdA • .denilced .laeh snoisel yart ycnegreme htiw( esod tset retfa MI UI noillim 4.2 nillicinep enihtazneB .jnI )ydaer nicymorhtyre htiw detaert eb dluohs nillicinep ot cigrella era ohw nemow tnangerP • pu wolloF .yreviled retfa silihpys rof detaert eb dluohs etanoen eht dna ,syad neves retfA • syad 51 rof yad a semit ruof yllaro gm 005

nicymorhtyrE .baT eruc citamotpmys tnemucod oT o gurd fo esuaceb ycnangerp ni detacidniartnoc si etalotse nicymorhtyrE :etoN etaniccus lyhte nicymorhtyre ro esab nicymorhtyrE ylnO .yticixototapeh detaler silihpys dna VIH rof enod stset fo stluser tnemucod oT o .ycnangerp ni desu eb dluohs fo kcal ot eud si ti rehtehw ssessa tsisrep sngis/smotpmys fI o dna noitcefni-er ro eruliaf tnemtaert ro ecnailpmoc tnemtaert .larrefer tpmorp esivda silihpys rof detaert slaudividni fo pu wolloF • shtnom 42 dna 21 ,6

,3 ta pu dewollof eb dluohs slaudividnI o .tnemtaert gniwollof segassem gnillesnuoc yeK ,noitanimaxe lacinilc tcudnoc ,tisiv pu wollof hcae gniruD o xes refas ,ITR/ITS gnidrager )s(rentrap lauxes dna tneilc lesnuoc dna etacudE • .)LRDV/RPR( stset lamenopert-non evitatitnauq dna ,evitatilauq tnemtaert etelpmoc gnikat fo ecnatropmi dna secitcarp ecnedive lacigolores si ereht fi nekatrednu eb dluohs tnemtaerteR o snoitadnemmocer emordnys rep sa )s(rentrap taerT • .espaler ro noitcefni-er fo tnemtaert fo esruoc

eht gnirud ecnenitsba lauxes esivdA • eb dluohs tset pu wollof ,elbarapmoc era stluser taht erusne oT o )LRDV/RPR( tset lamenopert-non emas eht gnisu yb demrofrep esu tnetsisnoc dna tcerroc rieht tuoba etacude ,smodnoc edivorP • .yllaitini desu saw taht .syad 7 retfa tisiv nruter eludehcS • National AIDS Control Organisation 26

National AIDS Control Organisation 27 emordnys citepreH esaesiD reclU latineG fo tnemeganaM :5.2 trahcwolF msinagrO evitasuaC )sepreh latineg( suriv xelpmis sepreH • silatineg sepreH etaduxe htiw sreclu laicifrepus elpitluM yrotsiH selcisev/reclu latineG • noiger latineg eht ni noitasnes gninruB • )elbaliava fi( snoitagitsevnI yrotarobaL noitanimaxE rentrap rehtie fo erusopxe lauxeS • silihpys rof tset RPR • selcisev fo ecneserP • xes latineg-oro ekil secitcarp gnidulcni sllec tnaig detaelcunitlum rof

raems kcnazT • latineg elpitlum fo ecneserP • ralimis fo yrotsih ro snoisel tnerruceR • gnitset dna gnillesnuoc VIH rof CTCI ot refeR • reclu/snoisore tsap eht ni snoisel

senilediug cificeps emordnyS tnemtaerT tnemeganam rentrap rof sepreh rof taert tneserp era sreclu lufniap elpitlum ro selcisev fI • rof tnemtaert rentrap oN • syad 7 rof yad a semit eerht gm 004 rivolcycA .baT :)sedosipe tsrif( sedosipe yramirP nI • fo ecnesba eht ni( sepreh .syad 7 rof yad a semit eerht ,yllaro gm 004 rivolcycA .baT :secnerruceR roF • )snoisel /edosipe evitca tnemtaert ot gnidnopser ton fi ,ertnec rehgih ot refer snoitagitsevni rehtruf roF • ecnenitsba lauxes esivdA • fo esruoc eht gnirud

diorcnahc dna silihpys ,sepreh rof taert neht sisongaid lacinilc eht tuoba tbuod ni si redivorp fI snoisel eht llit ro tnemtaert .rehtegot .laeh 004 rivolcycA .baT( ypareht evisserppus VSH redisnoc ,s/reclu fo sedosipe tnerrucer fo yrotsih fI :etoN eb yam ypareht evisserppuS .raey rep secnedicni 6 naht erom era ereht fi )yad a eciwt gm ohw stneitaP .dessessaer si ecnerrucer fo ycneuqerf eht dna raey a fo mumixam a retfa deunitnocsid .tnemtaert no detratser eb yam ecnerrucer fo setar hgih ylbatpeccanu evah

ot eunitnoc rivolcyca tnacifingis yllacinilc fo ecnegreme eht ht iw detaicossa neeb ton sah ypareht evisserppuS .stneitap tnetepmoconummi gnoma ecnatsiser nemow tnangerp fo tnemeganaM .snoisel citepreh rof ylluferac denimaxe dna sepreh latineg fo yrotsih deksa eb dluohs nemow tnangerp llA • .yllanigav reviled nac emordorp sti ro sepreh latineg fo sngis ro smotpmys tuohtiw nemoW • .sepreh latanoen tneverp ot noitces naeraseac yb dereviled eb dluohs ruobal fo tesno eht ta snoisel citepreh latineg htiw nemoW •

.sepreh tnerrucer ro sepreh latineg edosipe tsrif htiw nemow tnangerp ot yllaro deretsinimda eb yam rivolcycA • .ycnangerp fo skeew ruof tsal eht gnirud yad a semit eerht gm 004 rivolcycA .baT deretsinimda eb dluohs nemow tnangerP • sselnu silihpys rof tnemtaert dedivorp eb dluohs dna detcefni deredisnoc eb dluohs noitulid yna ni RPR rof evitisop tset ohw nemow tnangerP • .denilced evah sertit ydobitna cigolores laitneuqes dna sdrocer lacidem eht ni detnemucod si tnemtaert etauqeda )ydaer yart ycnegreme

htiw( esod tset retfa MI UI noillim 4.2 nillicinep enihtazneB .jnI o retfa silihpys rof detaert eb dluohs etanoen eht dna nicymorhtyre htiw detaert eb dluohs nillicinep ot cigrella era ohw nemow tnangerP o .yreviled syad 51 rof yad a semit ruof yllaro gm 005 nicymorhtyrE .baT ro esab nicymorhtyrE ylnO .yticixototapeh detaler gurd fo esuaceb ycnangerp ni detacidniartnoc si etalotse nicymorhtyrE :etoN era sedimanoflus ,enilcycyxod ,)nicaxolforpic ,nicaxolfo ekil( senoloniuQ .ycnangerp ni desu eb

dluohs etaniccus lyhte nicymorhtyre .nemow tnangerp ni detacidniartnoc National AIDS Control Organisation 28

segassem gnillesnuoc yeK pu wolloF gnidrager )s(rentrap lauxes dna tneilc lesnuoc dna etacudE • ,syad neves retfA • etelpmoc gnikat fo ecnatropmi dna secitcarp xes refas ,ITR/ITS eruc citamotpmys tnemucod oT o .tnemtaert silihpys dna VIH rof enod stset fo stluser tnemucod oT o .snoitadnemmocer emordnys rep sa )s(rentrap taerT • fo kcal ot eud si ti rehtehw ssessa tsisrep sngis/smotpmys fI o .tnemtaert fo esruoc eht gnirud ecnenitsba lauxes esivdA • dna ecnerrucer ro eruliaf tnemtaert ro ecnailpmoc

tnemtaert tnetsisnoc dna tcerroc rieht tuoba etacude ,smodnoc edivorP • .larrefer tpmorp esivda .esu silihpys rof detaert slaudividni fo pu wolloF • .syad 7 retfa tisiv nruter eludehcS • shtnom 42 dna 21 ,6 ,3 ta pu dewollof eb dluohs slaudividnI o .tnemtaert gniwollof ,noitanimaxe lacinilc tcudnoc ,tisiv pu wollof hcae gniruD o .)LRDV/RPR( stset lamenopert-non evitatitnauq dna ,evitatilauq ecnedive lacigolores si ereht fi nekatrednu eb dluohs tnemtaerteR o .espaler ro noitcefni-er fo eb dluohs tset pu

wollof ,elbarapmoc era stluser taht erusne oT o )LRDV/RPR( tset lamenopert-non emas eht gnisu yb demrofrep .yllaitini desu saw taht National AIDS Control Organisation 29

selaM ni emordnys gnillewS latorcS lufniaP fo tnemeganaM :6.2 trahcwolF smsinagrO evitasuaC eaeohrronog airessieN • sitamohcart aidymalhC • yb yltneuqerfni desuac eb osla nac gnillews latorcS • .noitcefni suriv spmum ,sanomoduesp ,smrofiloc ,sisairalif ,sisolucrebut sa hcus sesuac suoitcefni ITS noN o .noisrot dna ,amotameah tuohtiw ro htiw amuart sa hcus sesuac suoitcefni-noN o gnillews latorcS noitanimaxE gnillews latorcS • lacol desiar dna niks gniylrevo eht fo amedeo dna ssendeR • yrotsiH erutarepmet

ksir ssessA mutorcs ni niap dna gnillewS • snerefed sav dna simydidipe eht fo ssenredneT • s/retnuocne lauxes detcetorpnU • eniru gnissap elihw gninrub ro niaP • fi - sedon hpmyl laniugni/reclu latineg/egrahcsid larhteru detaicossA • trahcwolf evitcepser eht ot refer tneserp srentrap lauxes elpitluM • egrahcsid larhterU • elecordyh tuo elur ot tset noitanimulli-snart A • srentrap lauxes ni egnahc tneceR • revef ,esialam ekil smotpmys cimetsyS • tnemtaerT dna aeohrronog ,htob rof revoc yletauqeda dluohs

nemiger tnemtaert eht ,nommoc si noitcefni laud sA .snoitcefni laidymalhc )elbaliava fi( snoitagitsevnI yrotarobaL emordnys )SSP( gnillews latorcs lufniap rof nemiger dednemmoceR ot raems larhteru eht fo noitanimaxe niats marG • esod elgnis ,yllaro gm 004 emixifeC .baT • iccocolpid ralullecartni evitagen-marg etartsnomed aeohrronog fo esac ni SULP dleif noisremmi lio rep slihportuen 5 naht eroM • noisivrepus rednu esod elgnis yllaro mg 1 nicymorhtizA .baT • 01 naht erom ro raems larhteru eht ni )X0001(

ypareht fo trats fo syad 7 retfa nruter ot tneilc eht esivdA • fo tnemides eht ni dleif rewop hgih rep slihportuen sa nemiger tnemtaert emas eht eviecer dluohs evitisop VIH era ohw emordnyS SSP evah ohw stneitaP • laccoconog-non fo esac ni eniru diov tsrif eht .evitagen VIH era ohw esoht .sitirhteru )sciseglana dna egadnab-T htiw noitavele latorcs ,tser deb( niap ecuder ot ypareht evitroppuS • silihpys rof tset RPR • gnisuac ,tluser yam seussit ralucitset fo gnirracs dna egamad ,nevig ton si ypareht

evitceffe dna kciuq fI :etoN .gnitset dna gnillesnuoc VIH rof CTCI ot refeR • ytilitref bus National AIDS Control Organisation 30

National AIDS Control Organisation 31 srentrap tnangerp fo tnemeganaM rentrap rof senilediug cificeps emordnyS a gniod yb denimaxe eb dluohs emordnys SSP htiw stneilc elam fo srentrap tnangerP • tnemeganam .detaert eb dluohs dna noitanimaxe lanigav rep sa llew sa muluceps rep ,emordnys SSP htiw stneitap fo srentrap lauxes llA • ycnangerp ni evitceffe dna efas era noitcefni laccoconog revoc ot sniropsolahpeC • saw tneitap eht htiw tcatnoc lauxes tsal esohw RO esod elgnis ,yllaro gm 004 emixifeC .baT ro

smotpmys fo tesno erofeb syad 06 nihtiw eb dluohs ,tneitap eht ni noitcefni fo sisongaid noitcejni ralucsumartni yb gm 052 enoxairtfeC .jnI .detaert dna detaulave SULP gnilur retfa senil emas eht no srentrap elamef taerT • RO syad 7 rof yad a semit ruof yllaro gm 005 nicymorhtyrE .baT • seigrella fo yrotsih dna ycnangerp tuo RO syad 7 rof yad a semit eerht ,yllaro gm 005 nillicixomA .paC fo esruoc eht gnirud ecnenitsba lauxes esivdA • noitcefni laidymalhc revoc ot esod elgnis a ni yllaro mg 1 nicymorhtizA

.baT tnemtaert pu wolloF ,syad neves retfa pu wollof ot desivda si tneitaP • segassem gnillesnuoc yeK eruc citamotpmys tnemucod oT o secitcarp xes refas ,ITR/ITS gnidrager )s(rentrap lauxes dna tneilc lesnuoc dna etacudE • ,VIH rof enod stset fo stluser tnemucod oT o .tnemtaert etelpmoc gnikat fo ecnatropmi dna silihpys .snoitadnemmocer emordnys rep sa )s(rentrap taerT • eud si ti rehtehw ssessa tsisrep sngis/smotpmys fI • tpmorp esivdA .noitcefni-er ro eruliaf tnemtaert ot tnemtaert fo esruoc eht gnirud

ecnenitsba lauxes esivdA • detacilpmoc ecnis ertnec rehgih ot larrefer .esu tnetsisnoc dna tcerroc rieht tuoba etacude ,smodnoc edivorP • regnol dna laretnerap sdeen noitcefni laccoconog .syad 7 retfa tisiv nruter eludehcS • .tnemtaert fo noitarud

obuB laniugnI fo tnemeganaM :7.2 trahcwolF smsinagrO evitasuaC )VGL( muerenev amolunargohpmyl fo tnega evitasuac ,3L ,2L ,1L sravores sitamohcart aidymalhC • obub laniugnI diorcnahC fo tnega evitasuac iiercud sulihpomeaH • noitanimaxE yrotsiH eb yam hcihw niorg eht ni sedon hpmyl fo tnemegralne dezilacoL • eb yam hcihw noiger laniugni ni gnillewS • tnautculf dna rednet lufniap gnillews eht revo niks fo noitammalfnI • reclu latineg fo yrotsih gnidecerP • ksir ssessA sesunis elpitlum fo ecneserP • rentrap

rehtie fo erusopxe lauxeS • s/retnuocne lauxes detcetorpnU • sbmil rewol dna slatineg fo amedeO • xes latineg-oro ekil secitcarp gnidulcni evitcepser ot refer - egrahcsid larhteru ro reclu latineg fo ecneserP • srentrap lauxes elpitluM • .cte trahcwolf srentrap lauxes ni egnahc tneceR • revef ,esialam ekil smotpmys cimetsyS • National AIDS Control Organisation 32

sisongaid laitnereffiD tnemtaerT sisairalif ,amredoluforcS /sitinedahpmyl sisolucrebuT • syad 12 rof yliad eciwt yllaro gm 001 enilcycyxoD .paC • suna ,skcottub ,slatineg ,aera cibup fo niks fo noitcefni etuca ynA • SULP gnillews laniugni esuac osla nac sbmil rewol dna RO yllaro mg 1 nicymorhtizA .baT • rof ertnec rehgih ot refer detcepsus si sisolucrebut ro ycnangilam fI • diorcnahc revoc ot syad 3 rof yad a eciwt ,yllaro gm 005 nicaxolforpiC .baT .yspoib :etoN )elbaliava fi( snoitagitsevnI yrotarobaL fi

neve ,ertnec htlaeh yramirp eht ta deniard dna desicni eb reven dluohs obub A • sdnuorg lacinilc no si sisongaiD • a fI .yticinorhc dna noitamrof alutsif a fo ksir hgih a si ereht sa ,tnautculf si ti silihpys rof tset RPR • .etaripsa syawla tnautculf semoceb obub gnitset dna gnillesnuoc VIH rof CTCI ot refeR • mrof eht ni noitnevretni lacigrus ,selamef ni amedeo lavluv htiw sesac ereves nI • rehgih a ot derrefer eb dluohs yeht hcihw rof deriuqer eb yam ymotcevluv fo .ertnec srentrap tnangerp fo tnemeganaM

,enilcycyxod ,)nicaxolforpic ,nicaxolfo ekil( senoloniuQ • tnemeganam rentrap rof senilediug cificeps emordnyS .nemow tnangerp ni detacidniartnoc era sedimanoflus shtnom 3 tsal ni tneilc htiw tcatnoc ni era ohw srentrap lla taerT • eht htiw detaert eb dluohs nemow gnitatcal dna tnangerP • diorcnahc dna VGL rof detaert eb dluohs srentraP • .nemiger nicymorhtyrE VGL revoc ot syad 12 rof yliad eciwt ,yllaro gm 001 enilcycyxoD .paC o syad 12 rof yliad semit 4 ,yllaro gm 005 ,esab nicymorhtyrE .baT SULP ylno

etaniccus lyhte nicymorhtyrE ro esab nicymorhtyrE :etoN .nevig eb dluohs diorcnahc revoc ot esod elgnis yllaro mg 1 nicymorhtizA .baT o segassem gnillesnuoc yeK ,ITR/ITS gnidrager )s(rentrap lauxes dna tneilc lesnuoc dna etacudE • tnemtaert etelpmoc gnikat fo ecnatropmi dna secitcarp xes refas snoitadnemmocer emordnys rep sa )s(rentrap taerT • pu wolloF tnemtaert fo esruoc eht gnirud ecnenitsba lauxes esivdA • syad 12 dna 41 ,7 retfA .esu tnetsisnoc dna tcerroc rieht tuoba etacude ,smodnoc edivorP • eruc

citamotpmys tnemucod oT • syad 12 dna 41 ,7 retfa tisiv nruter eludehcS • silihpys dna VIH rof enod stset fo stluser tnemucod oT • National AIDS Control Organisation 33

National AIDS Control Organisation 34 emordnys niaP lanimodbA rewoL fo tnemeganaM :8.2 trahcwolF smsinagrO evitasuaC eaeohrronog airessieN • sitamohcart aidymalhC • )iccoc evitisop marg ,ps sedioretcaB( airetcab ciboreana ,allerendraG ,amsalpocyM • eht fo sredrosid yrotammalfni fo murtceps a fo sesirpmoc emordnys )PAL( niap lanimodba rewoL nairavo-obut ,sitigniplas ,sitirtemodne fo noitanibmoc yna gnidulcni ,tcart latineg elamef reppu .sitinotirep civlep dna ,ssecsba esaesid yrotammalfni civleP noitanimaxE

ksir ssessA yrotsiH ,eslup ,erutarepmet :noitanimaxe lareneG • s/retnuocne lauxes detcetorpnU • niap lanimodba rewoL • erusserp doolb srentrap lauxes elpitluM • reveF • lacivrec/lanigav :noitanimaxe muluceps reP • srentrap lauxes ni egnahc tneceR • egrahcsid lanigaV • sreclu ro noitsegnoc ,egrahcsid secitcarp ehcuod lanigaV • gnideelb lanigav ralugerri ,yvaeh ekil seitiralugerri laurtsneM • rewol :noitanimaxe lanimodba reP • gnidraug ro ssenrednet lanimodba aeohrronemsyD • :noitanimaxe civleP • ainuerapsyD

• ssenrednet laxenda/eniretu o sumsenet ,airusyD • ssenrednet tnemevom lacivrec o ehcakcab woL • ni enod eb dluohs tset ycnangerp eniru A :etoN )DUI ( eciveD eniretuartnI ekil esu evitpecartnoC • tuo elur ot DIP gnivah fo detcepsus nemow lla :etoN .ycnangerp cipotce neewteb DIP/PAL fo snoitatsefinam lacinilc eht ni secnereffiD • neeb ton evah nemow evitagen VIH dna nemow detcefni VIH .detaeniled llew ot denifnoc yliramirp si esu DUI htiw detaicossa DIP rof ksir ehT • .retfaereht nommocnu si dna noitresni

)elbaliava fi( snoitagitsevnI yrotarobaL noitanimaxe raems teW • aeohrronog rof niats marG • RSE dna tnuoc doolb etelpmoC • sllec sup rof ypocsorcim enirU • silihpys rof tset RPR • gnitset dna gnillesnuoc VIH rof CTCI ot refeR • rehgih ot refer snoitagitsevni rehtruf roF • ertnec sisongaid laitnereffiD ycnangerp cipotcE • tsyc nairavo detsiwT • ruomut nairavO • siticidneppA • sisolucrebut lanimodbA • National AIDS Control Organisation 35 sisongaiD ksir ta nemow rehto dna nemow gnuoy evitca yllauxes

ni detaitini eb dluohs tnemtaert ciripmE .esicerpmi si sisongaid lacinilc eht revewoH .sgnidnif lacinilc no desab si yllausU • muminim gniwollof eht fo erom ro eno fi dna ,deifitnedi eb nac DIP/PAL naht rehto ssenlli eht rof esuac on fi ,niap lanimodba rewol ro civlep gnicneirepxe era yeht fi ITS rof :noitanimaxe civlep no tneserp era airetirc ssenrednet noitom lacivreC o ssenrednet eniretU o ssenrednet laxendA o :sisongaid eht fo yticificeps eht ecnahne ot desu eb nac airetirc lanoitidda gniwollof

eht fo erom ro enO • )C°3.83>( F°101> erutarepmet larO o egrahcsid tnelurup-ocum lanigav ro lacivrec lamronbA o )ytilibairf lacivrec ro ,setaduxe lacivrec ,snoiterces lanigav ni setycocuel fo ecnanimoderp( noitammalfni tcart latineg rewol fo sngis fo ecneserP o diulf lanigav fo ypocsorcim enilas no CBW fo srebmun tnadnuba fo ecneserP o etar noitatnemides etycorhtyre detavelE o nietorp evitcaer-C detavelE o .sitamohcart .C ro eaeohrronog .N htiw noitcefni lacivrec fo noitatnemucod yrotarobaL o tnemtaerT

.nevig eb nac tnemtaert tneitap-tuo ,)ssecsba nairavo-obut fo ecnesba eht ni( DIP etaredom ro dlim nI • .seboreana dna sitamohcart .C ,eaeohrronog .N revoc ot deriuqer si yparehT TATS yllaro gm 004 emixifeC .baT o SULP )noitcefni ciboreana taert ot( syad 41 rof yliad eciwt ,yllaro gm 004 elozadinorteM .baT o SULP )noitcefni laidymalhc taert ot( syad 41 rof yad a eciwt ,yllaro gm 001 ,enilycyxoD .paC o syad 5-3 rof yad a semit eerht ,yllaro gm 004 neforpubI .baT o sitirtsag tneverp ot yliad eciwt , yllaro

gm 051 eniditinaR .baT o sruoh 84 - 42 fo revoc citoibitna rednu ,tneserp fi ,ecived eniretu artni evomeR • lacivrec ni noitcuder ,ssenrednet lanimodba ni noitcuder ,revef fo ecnesba .e.i( tnemevorpmi on fI .syad 3 rof evresbO • .tnemtaert tneitapni rof refer ,nesrow smotpmys fi ro )ssenrednet eniretu dna laxenda ,tnemevom :etoN neve dna syad 3 nihtiw tnemtaert ot dnopser ton seod ehs fi latipsoh eht ot tneilc eht refeR .noitidnoc suoires a eb nac DIP • .snesrow noitidnoc reh fi reilrae retfa sruoh 84 tsael

ta rof dna ypareht elozadinortem gnirud stneitap yb dediova eb dluohs lohocla fo noitpmusnoC • .tnemtaert fo noitelpmoc

National AIDS Control Organisation 36 nemow tnangerp fo tnemeganaM tnemeganam rentrap rof senilediug cificeps emordnyS tnangerp yna ,ycnangerp ni erar si DIP hguohT • lauxes dah yeht fi detaert dna denimaxe eb dluohs DIP/PAL htiw nemow fo srentrap lauxes elaM • derrefer eb dluohs DIP evah ot detcepsus namow .smotpmys fo tesno s’tneitap eht gnidecerp syad 06 eht gnirud tneitap eht htiw tcatnoc ytidibrom lanretam rof ksir hgih eht fo esuaceb( litnu dna detelpmoc si ypareht litnu esruocretni lauxes morf

niatsba ot detcurtsni eb dluohs stneitaP • ro tcirtsiD( ertnec rehgih a ot )yreviled mreterp dna .smotpmys evah regnol on srentrap lauxes rieht dna yeht detaert dna noitazilatipsoh rof )latipsoh gnihcaet )aidymalhc dna aeohrronog( egrahcsid larhteru rof srentrap elam taerT • ni efas eb dluow hcihw nemiger laretnerap a htiw .ycnangerp esu tnetsisnoc dna tcerroc no etacude ,smodnoc edivorP • .ycnangerp ni detacidniartnoc si enilcycyxoD • ealeuqes dna detaertnu tfel fi snoitacilpmoc eht tuoba mrofnI • pu

wolloF ecnailpmoc erusne ot syad 41 dna 7 ,3 retfa tisiv nruter eludehcS • segassem gnillesnuoc yeK eruc citamotpmys tnemucod oT o )s(rentrap lauxes dna tneilc lesnuoc dna etacudE • .silihpys dna VIH rof enod stset fo stluser tnemucod oT o dna secitcarp lauxes refas ,ITR/ITS gnidrager .tnemtaert etelpmoc gnikat fo ecnatropmi tcerid ni noitcuder ,ecnecsevrefed .g.e( tnemevorpmi lacinilc laitnatsbus etartsnomed dluohs stneitaP • )ssenrednet noitom lacivrec dna ,laxenda ,eniretu ni noitcuder ,ssenrednet

lanimodba dnuober ro emordnys rep sa )s(rentrap taerT • .41 dna 7 yad no spu-wollof tneuqesbus htiw ypareht fo noitaitini retfa syad 3 nihtiw .snoitadnemmocer citsongaid lanoitidda ,noitazilatipsoh eriuqer yllausu doirep siht nihtiw evorpmi ton od ohw stneitaP • fo esruoc eht gnirud ecnenitsba lauxes esivdA • .noitnevretni lacigrus dna ,stset .tnemtaert eruliaf tnemtaert ro ecnailpmoc tnemtaert fo kcal ot eud si ti rehtehw ssessa ,tsisrep sngis/smotpmys fI • dna tcerroc rieht tuoba etacude ,smodnoc edivorP

• .larrefer tpmorp esivda dna noitcefni-er ro .esu tnetsisnoc nehw deredisnoc ylsuoires eb dluohs DIP etuca htiw stneilc fo noitazilatipsoH niatrecnu si sisongaid ehT • dedulcxe eb tonnac ycnangerp cipotce ro siticidneppa .g.e seicnegreme lacigruS • detcepsus si ssecsba civlep A • sisab tneitaptuo na no tnemeganam sedulcerp ssenlli ereveS • tnangerp si namow ehT • nemiger tneitaptuo na etarelot ro wollof ot elbanu si tneilc ehT • .ypareht tneitaptuo ot dnopser ot deliaf sah tneilc ehT •

ITS lanA & larO fo tnemeganaM :9.2 trahcwolF smsinagrO evitasuaC eaeohrronog airessieN • sitamohcart aidymalhC • )silihpys( mudillap amenoperT • )diorcnahc( iyercud sulihpomeaH • )elaniugni amolunarg( sitamolunarg alleisbelK • )sepreh latineg( xelpmis sepreH • sreclu lana & larO :silihpys yradnoceS suriv amollipap namuH • noitanimaxE ,ssender ,noitareclu larO • fi( snoitagitsevnI yrotarobaL ,noitammalfni laegnyrahp )elbaliava cte htworg ksir ssessA yrotsiH fo noitanimaxe niats marG • – sreclu latcerona ro

latineG • evitagen marg rof baws latcer elpitlum ro elgnis dna lana ,laro detcetorpnU • eros ,xes laro detcetorpnU • esac ni iccocolpid ralullecartni s/retnuocne lauxes latineg taorht selcisev fo ecneserP • .aeohrronog fo srentrap lauxes elpitluM • lana htiw xes lana detcetorpnU • sup latceR • silihpys rof RPR • lauxes ni egnahc tneceR • latcer ,sumsenet ro egrahcsid emordnys ITS rehto ynA • ,aeohrraid ,niap dna gnideelb VIH rof CTCI ot refeR • srentrap lanimodba ,loots ni doolb gnitset dna gnillesnuoc

latcer rof ypocsotcorp oD( gnitaolb ,aesuan ,gnipmarc )elbaliava fi noitanimaxe National AIDS Control Organisation 37

National AIDS Control Organisation 38 ,sloots ni doolb ,aeohrraiD nees sreclu latcerona ro latineG xes laro detcetorpnu fo yrotsih htiw sitignyrahP ,aesuan ,gnipmarc lanimodba RO RO fo yrotsih htiw gnitaolb nees selciseV yrotsih htiw gnitaolb ,sumsenet ,egrahcsid lanA xes lana detcetorpnu xes lana detcetorpnu fo RO RO snoitpure ralucisev tnerrucer fo yrotsiH fo yrotsih htiw gnitaolb ro sup latceR xes lana detcetorpnu egrahcsid larhteru rof trahcwolf wolloF ylgnidrocca taert dna emordnys SULP reclu latineg

rof trahcwolf wolloF egrahcsid larhteru rof trahcwolf wolloF dedeen sa senicidem laeohrraid-itnA ylgnidrocca taert dna emordnys ylgnidrocca taert dna emordnys srentrap tnangerp fo tnemeganaM tnemeganam rentrap rof senilediug cificeps emordnyS ,enilcycyxod ,)nicaxolforpic ,nicaxolfo ekil( senoloniuQ • 3 tsal ni tneilc htiw tcatnoc ni era ohw srentrap lla taerT • .nemow tnangerp ni detacidniartnoc era sedimanoflus .shtnom eht htiw detaert eb dluohs nemow gnitatcal dna tnangerP • emordnys gnidnopserroc

rof detaert eb dluohs srentraP • .nemiger nicymorhtyrE .esac xedni ni desongaid sa segassem gnillesnuoc yeK pu wolloF gnidrager )s(rentrap lauxes dna tneilc lesnuoc dna etacudE • cimordnys evitcepser rep sa eb dluohs locotorp pu wolloF gnikat fo ecnatropmi dna secitcarp xes refas ,ITR/ITS snoitadnemmocer tnemtaert etelpmoc eruc citamotpmys tnemucod oT • snoitadnemmocer emordnys rep sa )s(rentrap taerT • silihpys dna VIH rof enod stset fo stluser tnemucod oT • tnemtaert fo esruoc eht gnirud ecnenitsba lauxes

esivdA • dna tcerroc rieht tuoba etacude ,smodnoc edivorP • .esu tnetsisnoc .syad 7 retfa tisiv nruter eludehcS •

NNaattiioonnaall AAIIDDSS CCoonnttrrooll OOrrggaanniissaattiioonn 2.10 Management of Other STI A. Anogenital warts Causative Organism: Human Papilloma Virus (HPV) Clinical features: Single or multiple soft, painless, pink in colour, “cauliflower” like growths which appear around the anus, vulvo-vaginal area, penis, urethra, and perineum. Warts could appear in other forms such as papules which may be keratinized. Diagnosis: Clinical diagnosis. Perivulvar warts Penile warts Perianal warts

Figure 2.a: Anogenital warts Differential diagnosis • Condyloma lata of syphilis • Molluscum contagiosum Treatment: Recommended regimens: Penile and Perianal warts (a) Chemical cauterization • 20% Podophyllin in compound tincture of benzoin applied to the warts, while carefully protecting the surrounding area with Vaseline, to be washed off after 3 hours. It should not be used on extensive areas per session. • Treatment should be repeated weekly till the lesions resolve completely.

National AIDS Control Organisation • Podofilox (podophyllotoxin) 0.5% solution or gel twice daily for 3 days, followed by 4 days of no treatment; the cycle repeated up to 4 times. Not more than 0.5 ml of Podofilox should be applied per day. • Imiquimod 5% cream applied with a finger at bed time, to be washed in the morning with soap and water. It should be applied three times a week up to 12 to 16 weeks. (b) Physical cauterization

• Cryotherapy with liquid nitrogen, solid carbon dioxide or cryoprobe, if available. Repeat application at 1~2weeks interval. Cryotherapy is preferred by many consultants. It is non- toxic, does not result in scarring if done properly and does not require any anaesthesia. • Electrocautery • Surgical excision Vaginal warts • Podophyllin 10~25%, using vaginal speculum. • Trichloroacetic acid (TCA), 50~75%, using vaginal speculum. Cervical warts • Podophyllin is contra-indicated.

• Biopsy of warts to rule out malignant change. • Cryo-cauterization is the treatment of choice. • Cervical cytology should be periodically done in the sexual partner(s) of men with genital warts. Note: Podophyllin and Podofilox are contra-indicated in pregnancy. Treatment should be given under medical supervision. Clients should be warned against self-medication. For other areas as penile shaft, scrotum, vulval skinand pubic areas

• Trichloroacetic acid, cryotherapy or electro/radiofrequency cauterization may be used. 40

National AIDS Control Organisation Urethral meatal warts • 5-fluorouracil, applied weekly for 3 weeks, may eradicate urethral lesions. The cream must be worked down into the urethra, avoiding exposure of the drug to the scrotal skin. A scrotal support or zinc oxide cream applied over the scrotal skin may be useful. Key counselling messages to all patients diagnosed with HPV infection: • Genital HPV infection is very common.

• Many types of HPV are passed on through genital contact, most often during vaginal and anal sexual contact. HPV can also be spread by oral sexual contact. • In most cases, HPV infection clears spontaneously, nevertheless, some infections do progress to genital warts, pre-cancers, and cancers. • The types of HPV that cause genital warts are different from the types that can cause anogenital cancers. • Within an ongoing sexual relationship, both partners are usually infected at the time one

person is diagnosed with HPV infection, even though signs of infection might not be apparent. • Treatments are available for the conditions caused by HPV (e.g. genital warts), but not for the virus itself. • HPV does not affect a woman’s fertility or ability to carry a pregnancy to term. • Tests for HPV are now available to help providers screen for cervical cancer in certain women. • HPV vaccines are available, which offer protection against the HPV types that cause cervical cancer and genital warts.

• Genital warts are not life threatening. If left untreated, genital warts might go away, stay the same, or grow in size or number. Except in very rare and unusual cases, genital warts will not turn into cancer. • It is difficult to determine how or when a person became infected with HPV; genital warts can be transmitted to others even when no visible signs of warts are present, and even after warts are treated. 41

National AIDS Control Organisation • It is not known how long a person remains contagious after warts are treated. • Genital warts commonly recur after treatment, especially in the first 3 months. • Women should get regular Pap tests as recommended, regardless of vaccination or genital wart history. Women with genital warts do not need to get Pap tests more often than recommended. • HPV testing is unnecessary in sexual partners of persons with genital warts.

• If one sex partner has genital warts, both sex partners benefit from getting screened for other STI. • Persons with genital warts should refrain from sexual activity until the warts are gone or removed. • Correct and consistent male condom use can lower the chances of giving or getting genital warts, but such use is not fully protective because HPV can infect areas that are not covered by a condom. B. Molluscum contagiosum Causative Organism: Pox virus

Clinical features: Multiple, smooth, glistening, globular papules of varying size from a pinhead to a split pea can appear anywhere on the body. Sexually transmitted lesions on or around genitals can be seen. The lesions are not painful except when secondary infection sets in. Figure 2.b: Molluscum contagiosum When the lesions are squeezed, a cheesy material comes out. Diagnosis: Diagnosis is based on the above clinical features. Treatment

• Individual lesions usually regress without treatment in 9-12 months. • Each lesion should be thoroughly opened with a fine needle or scalpel. The contents should be exposed and the inner wall touched with 25% phenol solution or 30% trichloroacetic acid. 42

National AIDS Control Organisation C. Ectoparasitic infections A) Pediculosis pubis Causative Organism: Lice - Phthirus pubis Clinical features: There may be small red papules with a tiny central clot caused by lice irritation. General or local urticaria with skin thickening may or may not be present. Eczema and impetigo may be present. Treatment: Recommended regimen: • Permethrin 1% crème rinse applied to affected areas and washed off after 10 minutes. Special instructions

• Retreatment is indicated after 7 days if lice are found or eggs observed at the hair-skin junction. • Clothing or bed linen that may have been contaminated by the client should be washed and well dried or dry cleaned. • Sexual partner must also be treated along the same lines. B) Scabies Causative Organism: Mite - Sarcoptes Scabiei. Clinical features: Severe pruritis (itching) is experienced by the client, which becomes worse at night. Other members of family also affected (apart from sexual

transmission to the partner, other members may get infected through contact with infected clothes, linen or Figure 2.c: Genital scabies towels). Complications • Eczematization with or without secondary infection • Urticaria 43

National AIDS Control Organisation • Glomerulonephritis • Contact dermatitis to anti scabetic drug Diagnosis: The burrow is the diagnostic sign. It can be seen as a slightly elevated grayish dotted line in the skin, best seen in the soft part of the skin. Treatment: Recommended regimens: • Permethrin cream (5%) applied to all areas of the body from the neck down and washed off after 8 - 14 hours. • Benzyl benzoate 25% lotion, to be applied all over the body, below the neck, after a bath, for

two consecutive nights. Client should bathe in the morning, and have a change of clothing. Bed linen should be disinfected. Special instructions • Clothing or bed linen that have been used by the client should be thoroughly washed and well dried. • Sexual partner must also be treated along the same lines at the same time. 44

National AIDS Control Organisation 3. STI/RTI among Special Populations A. Pregnant Women STI/RTI are among the most important causes of maternal morbidity and perinatal morbidity and mortality. The consequences of STI/RTI can be severe and life-threatening, such as pelvic inflammatory disease (PID), ectopic pregnancy and adverse pregnancy outcomes including abortion, stillbirth, pre term birth and congenital infections (due to syphilis, HSV, hepatitis B virus and HIV). STI/RTI in pregnancy

The interactions between STI and pregnancy include the effects of pregnancy on STI and of the STI on pregnancy. The latter is more important because STI may affect pregnancy outcomes. Table 3.1: Interactions between STI/RTI and pregnancy STI /RTI Effect of STI on pregnancy and neonate Effect of pregnancy on STI Gonorrhoea Prematurity Disseminated gonococcal Premature rupture of membranes infection is reported to be more common Chlamydia Chorioamnionitis Postpartum sepsis Conjunctivitis in the newborn

Syphilis Abortion No effect Prematurity Intrauterine growth retardation Stillbirth Congenital syphilis Chancroid No adverse effects of chancroid on pregnancy Ulcers will increase in size outcomes have been reported and become more vascular Herpes simplex Abortion Longer duration of symptoms virus (HSV) Intrauterine growth retardation Primary infection more severe Premature delivery Dissemination may occur Congenital HSV Neonatal herpes

Human papilloma Laryngeal papillomatosis (rare) Increase in size and number virus (genital warts) of warts Trichomoniasis Premature rupture of membranes No effect Pre-term labour Low birth weight 46

National AIDS Control Organisation STI /RTI Effect of STI on pregnancy and neonate Effect of pregnancy on STI Candidiasis Virtually none Increased frequency and severity of infection Bacterial vaginosis Premature rupture of membranes No effect Chorioamnionitis Premature delivery Low birth weight Puerperal sepsis Antenatal clinic visits provide opportunities for preventing and detecting STI/RTI. Therefore, women should be encouraged to attend antenatal clinics early in pregnancy.

Since most STI/RTI are asymptomatic in women, screening facilitates the identification of STI/RTI in pregnant women. HCPs should facilitate the screening of pregnant women considered to be at high risk for STI, since early detection and appropriate treatment of STI prevents mother-to-child transmission of infection during pregnancy and delivery. Screening for syphilis • An estimated two thirds of pregnancies among women with early untreated syphilis end in

abortion, stillbirth or neonatal infection. Hence all pregnant women should be routinely screened for syphilis with RPR or rapid treponemal tests at the first antenatal visit or as early as possible. • Re-testing in the third trimester is also recommended, if feasible, to detect infection acquired during pregnancy, particularly among women at high risk. • Any woman who delivers a stillborn infant after 20 weeks of gestation should be tested for

syphilis. No infant should leave the hospital without the maternal serologic status having been determined at least once during pregnancy. • As biological false-positive RPR tests may occur during pregnancy, positive results should be confirmed with specific treponemal tests such as the Treponema pallidum haem agglutination (TPHA) or fluorescent treponemal antibody absorption (FTA-ABS) test. • All mothers with syphilis should be treated appropriately according to the stage of syphilis.

Attempts should be made to complete treatment before 36 weeks of gestation. 47

National AIDS Control Organisation Screening for vaginal infections Table 3.2: Screening for vaginal infections When to screen Minimal Lab Tests Recommended approach Asymptomatic pregnant Gram-stained microscopic Usually most HCP prefer not to women with a history of examination of a vaginal treat in the first trimester of spontaneous abortion or smear pregnancy, treatment may be pre term delivery should given in cases where early

be screened for bacterial Wet mount of vaginal fluid treatment has the best chance vaginosis (BV) and in a drop of normal saline of preventing adverse trichomoniasis pregnancy outcomes Pregnant women with symptomatic vaginal discharge in the second or third trimester should be treated (without screening) for BV, trichomoniasis and yeast infection. Note: Fluconazole is not recommended for use in pregnancy. Management of STI/RTI in pregnancy

The management of STI/RTI in pregnant women is the same as for non-pregnant women: (cid:216)Offer recommended therapy (certain drugs are contraindicated in pregnancy). (cid:216)Educate and counsel the patient. (cid:216)Encourage partner referral and management. (cid:216)Follow up the patient. (cid:216)Assess the baby as soon as possible after delivery for any effect of maternal STI/RTI. The details of treatment for each syndrome is given under the respective syndromic management flow chart.

It is important to educate the couple regarding prevention of STI/RTI during the course of pregnancy, as STI/RTI acquired during pregnancy may lead to adverse pregnancy outcomes. Inadequate maternal treatment is likely to transmit infection from mother to child if delivery occurs within 30 days of therapy, if clinical signs of infection are present at delivery in a new born, or if the maternal antibody titre at delivery is fourfold higher than the pre-treatment titre

National AIDS Control Organisation Note: Women treated for syphilis during the second half of pregnancy are at risk for premature labour and/or foetal distress if the treatment precipitates the Jarisch-Herxheimer reaction. These women should be advised to seek obstetric attention after treatment if they notice any fever, contractions, or decrease in foetal movements. Stillbirth is a rare complication of treatment, but concern for this complication should not delay necessary treatment. All patients

who have syphilis should be offered testing for HIV infection. B. Children and Adolescents STI/RTI in children can be acquired through three different ways: i transplacental (occurring in utero) or intrapartum transmission (during labour and delivery) e.g. syphilis, HIV, cytomegalo virus (CMV) and human papilloma virus infection (HPV) ii post-natal transmission (during breast feeding, accidental and through sexual abuse)

iii due to sexual abuse or unsafe sexual practices among sexually active adolescents. The common sexual abuse encountered by girls is genital contact, masturbation, vaginal, oral or anal intercourse, while boys are subjected to fellatio or anal intercourse. Adolescents and youth in the age group of 10-24 years contribute to about 30% of our population. The data from various Indian studies reveal that adolescents indulge in premarital

sex more frequently and at an early age. The physiological risk of increased susceptibility to infections among adolescent girls is due to the presence of greater cervical ectopy which makes the cervix more susceptible to gonorrhoea, chlamydia and HPV. Adolescents face enhanced vulnerability to unwanted pregnancy and STI including HIV. Many interrelated and complex factors that put adolescents at risk of STI include poor education, unemployment and poverty.

Urbanization tends to disrupt family relationships, social networks and traditional values while generating more opportunity for sexual encounters. Lack of information about sexual health, as well as STI prevention, symptoms and treatment also put both male and female adolescents at risk of STI. Even when adolescents have accurate knowledge about STI, some incorrectly perceive their risk as low either due to familiarity with a sexual partner or as relationship

matures or simply because they are passing through a stage of life in which risk taking is particularly attractive especially under the strong influence of their peers, migration and displacement, multiple and concurrent sexual partnership, lack of access to effective and affordable STI services. Therefore there is an urgent need for improving the accessibility of adolescents to preventive and curative services including information and counselling. 49

National AIDS Control Organisation Under RMNCH+A programme, Adolescent Reproductive and Sexual Health (ARSH) services are expected to offer a core package of promotive, preventive, curative, counselling, referral and outreach services through public health care facilities to adolescents. Clinical presentation of STI/RTI in children and adolescents The presenting symptoms of STI/RTI among adolescents are very peculiar as very often they

present with symptoms other than those of the infection. Therefore risk assessment plays a crucial role. The increasing tendency of homosexual behaviour as reported by some studies must also be kept in mind and anogenital lesions must be looked for. Girls • In general, endogenous vaginitis rather than an STI/RTI is the main cause of vaginal discharge among adolescent females. • Approximately 85% of gonococcal infection in females will be asymptomatic. However,

there may be vulval itching, minor discharge, urethritis or proctitis. In prepubescent girls, a purulent vulvo vaginitis may occur. • Similarly, Chlamydia trachomatis infection is asymptomatic in the majority of cases. Symptoms that may occur in the adolescents are inter menstrual bleeding, post-coital bleeding and an increase in vaginal secretions. • Candida albicans is uncommon in adolescents prior to puberty. If present, the adolescent

may have a discharge, vulval itching, dyspareunia, perianal soreness or a fissuring at the introitus. Attacks of candida vulvitis may be cyclical in nature and correspond to menstruation. • Bacterial vaginosis does not produce vulvitis and the adolescent will not complain of itching or soreness. • The signs of acquired syphilis in children present with small chancres or mucocutaneous moist lesions either on the vulva or anus. Presentation of syphilis is the same in adolescents and adults. Boys

• Gonorrhoea among boys presents as proctitis, urethral discharge, asymptomatic pyuria, penile oedema, epididymitis and testicular swelling. Disseminated gonorrhoea presents with multiple systemic manifestations. • Chlamydia presents as non-specific urethritis. 50

National AIDS Control Organisation C. Sex Workers, MSM, TS & TG, PWID In some groups of population with high risk practices such as sex workers, men who have sex with men, transsexuals & trans genders, and people who inject drugs, the prevalence of STI and HIV is higher than the general population. These sub groups of population are also called as ‘Key Population’ or ‘Core Group’ or ‘Most at Risk Population (MARP)’. Clinical Management of STI/RTI

High rates of STI/RTI have been observed in commercial sex settings where condom use rates are variable and access to effective STI/RTI treatment services are limited. Effective prevention and treatment of STI/RTI among these core groups requires attention to both symptomatic and asymptomatic infections and have the following two components: • Treatment of Symptomatic Infections: As per the national syndromic case management guidelines. • Screening and Treatment of Asymptomatic Infections

o Regular medical check-ups should be conducted at least once in every three months where the HCP takes history, and carries out a clinical examination including internal examination to detect presence of infection/s. o Presumptive treatment for asymptomatic gonococcal and chlamydial infections. This should be administered only to sex workers, MSM, TS/TG and female injecting drug users (FIDU) during their first clinic visit and should be repeated ONLY if there is no

regular check-up for six months consecutively. o Biannual serologic screening for syphilis of sex workers, MSM, TS/TG and PWID. Female sex workers and MSM, TS&TG should be encouraged to attend the STI clinic for periodic routine health checkups. During the visit, the clinic staff should take a detailed history and perform an examination. Regular medical check-up should include examination of oropharynx, ano-rectum and genital examination including proctoscopy for all those who have history of

receptive anal intercourse. The rationale for presumptively treating sex workers who are asymptomatic is that they are frequently exposed to STI. The presumptive treatment of asymptomatic STI treatment among sex workers will be stopped, when there is: 51

National AIDS Control Organisation • Evidence of low prevalence of gonococcal and chlamydial infections (10% and below); • High condom use among sex workers (>70%); and • More than 80% of sex workers have access to STI/RTI services Sex workers should be counselled at every opportunity (in the clinic and in the community) on the importance of using condoms. Peer educators, outreach workers and clinic staff should reinforce the following messages to sex workers visiting the clinic:

• The only reliable way to protect oneself from HIV and STI/RTI is to use condoms consistently and correctly • Presumptive treatment is not a vaccine and will not cure all STI/RTI. Hence, it is very important to educate them on regular medical check-up and biannual syphilis screening apart from seeking care if they have any symptoms suggestive of STI/RTI. Outreach staff should also remind sex workers about their clinic appointments and help them keep their appointments.

It is also important to cater for STI management needs of MSM, TS/TG population groups. Emergence of anal and oral STI is a cause for concern. Service providers should be sensitive to the needs of the MSM, TS/TG population groups and be empathetic and non- judgemental while providing services. Please refer the following flowcharts on management of STI among female sex workers and MSM, TS/TG during routine clinic visits. 52

National AIDS Control Organisation Flowchart 3.1: Management of STI during routine visit by Female Sex Workers Clinic visit by sex worker First visit to clinic or due for Yes Treat for gonorrhoea presumptive and chalamydia treatment? Take history Unprotected sexa Yes Give treatment according with partner to partner's symptoms with STIs? Look for signs Genital or Yes Treat according of STI on exam anorectal ulcers? to the genital ulcer flowchart Examine Client (external genital, Treat

speculum, Bimanual Lower Yes according to and bimanual abdominal or the lower examination) cervical motion abdominal pain tenderness? flow chart Draw blood and send to referral laboratory for syphilis test Mucopurulent Yes Treat for discharge or gonorrhoea and every 6 red cervix? chlamydia months Treat according Visible vaginal Yes to vaginal discharge? discharge flowchartb a. Without condom or condom failure b. All currently active sex workers have positive risk assessment and should be

National AIDS Control Organisation Flowchart 3.2: Management of STI during routine visit by MSM & TS/TG Clinic visit by client First visit to clinic or Yes Treat for gonorrhoea due for presumptive and chlamydia treatment? Take history Unprotected sexa Yes Give treatment according with partner with to partner's symptoms STI? Pharyngitis with Yes Treat for gonorrhoea and history of chlamydia unprotected oral sex? Anal discharge or Yes Treat for gonorrhoea and tenesmus? chlamydia

Diarrhea, blood in Treat for gonorrhoea and stools, abdominal Yes chlamydia cramps, nausea, +anti-diarrheal medicines as bloating? needed Examine Client (oral, external Treat according anogenital, Look for signs Genital or Yes to the genital digital rectal, of STI on exam anorectal ulcers? ulcer flowchart proctoscope)b Treat for Yes Draw blood Rectal pus? gonorrhoea and and send to chlamydia referral laboratory for syphilis test Treat according every6 months Urethral Yes to the urethral discharge? discharge

flowchart a. Without condom or condom failure b. If asymptomatic, conduct digital rectal and proctoscope exam only if acceptable. 54

National AIDS Control Organisation 4. Management of Sexual Violence The World Health Organisation (WHO) defines Sexual Violence as "any sexual act, attempt to obtain a sexual act, unwanted sexual comments/ advances and acts to traffic, or other wise directed against a person's sexuality, using coercion, threats of harm, or physical force, by any person regardless of relationship to the victim in any setting, including but not limited to home

and work." Sexual assault, a form of sexual violence, is a term often used synonymously with rape. However, sexual assault could include anything from touching another person's body in a sexual way without the person's consent to forced sexual intercourse, including oral and anal sexual acts, child molestation, fondling and attempted rape. Forms of Sexual Violence include: • Coerced/forced sex in marriage or live in relationships or dating relationships. • Rape by strangers.

• Systematic rape during armed conflict, sexual slavery. • Unwanted sexual advances or sexual harassment. • Sexual abuse of children. • Sexual abuse of people with mental and physical disabilities. • Forced prostitution and trafficking for the purpose of sexual exploitation. • Child and forced marriage. • Denial of the right to use contraception or to adopt other measures to protect against STIs. • Forced abortion and forced sterilization. • Female genital cutting. • Inspections for virginity.

• Forced exposure to pornography. • Forcibly disrobing and parading naked any person. The Criminal Law Amendment Act (CLA) 2013 has expanded the definition of rape to include all forms of sexual violence-penetrative (oral, anal, vaginal) including by objects/weapons/fingers and non-penetrative (touching, fondling, stalking, etc.) and recognised right to treatment for all survivors/victims/victims of sexual violence by the public and private health care facilities.

Failure to treat is now an offence under the law. The law further disallows any reference to past 56

National AIDS Control Organisation sexual practices of the survivor. Health professionals need to respond comprehensively to the needs of survivors. The components of a comprehensive response include*: • Providing necessary medical support to the survivor of sexual violence. • Establishing a uniform method of examination and evidence collection by following the recommended protocols. • Informed consent for examination, evidence collection and informing the police.

• First contact for psychological support and validation. • Maintaining a clear and fool-proof chain of custody of medical evidence collected. • Referring to appropriate agencies for further assistance (e.g. legal support services, shelter services, etc.) Section 164 (A) of the Criminal Procedure Code lays out the following legal obligations of the health worker in cases of sexual violence: • Examination of a case of rape shall be conducted by a registered medical practitioner

(RMP) employed in a hospital run by the government or a local authority and in the absence of such a practitioner, by any other RMP. • Examination to be conducted without delay and a reasoned report to be prepared by the RMP. • Record consent obtained specifically for this examination. • Exact time of start and close of examination to be recorded. • RMP to forward report without delay to Investigating Officer (IO), and in turn IO to Magistrate.

Health professionals play a dual role in responding to the survivors of sexual assault. The first is to provide the required medical treatment and psychological support. The second is to assist survivors in their medico-legal proceedings by collecting evidence and ensuring good quality documentation. Often, because the victims feel uncomfortable talking about sexual violence, they may come to the clinic with other nonspecific complaints or request a check-up, assuming

*For further details, please refer “Guidelines & Protocols: Medico-legal care for survivors/ victims of sexual violence”. Available at http://mohfw.nic.in/showfile.php?lid=2737, accessed 15th June 2014. 57

National AIDS Control Organisation that the healthcare provider will notice anything abnormal that needs treatment. Therefore, healthcare workers should maintain a high index of suspicion and ask about any experience of sexual violence or abuse. A model format of management of sexual violence is given at the end of this chapter for reference and includes the various components of a comprehensive health care response to

sexual violence and must be carried out in all cases. Examinations should be conducted by an experienced clinician in a way that minimizes further trauma to the survivor. Trichomoniasis, BV, gonorrhoea, and chlamydial infection are the most frequently diagnosed infections among women who have been sexually assaulted. Post assault examination presents an important opportunity to identify or prevent STI. Chlamydial and gonococcal infections in

women are of particular concern because of the possibility of ascending infection. In addition, HBV infection can be prevented by post exposure administration of hepatitis B vaccine and immunoglobulin. Female survivors of reproductive age should be evaluated for pregnancy, if necessary. A comprehensive response to the survivor of sexual violence should include the following services: a. Initial resuscitation/ first aid

b.Informed consent: Consent should be taken for the following purposes: examination, sample collection for clinical and forensic examination, treatment and police intimation. Doctors shall inform the person being examined about the nature and purpose of examination and in case of child to the child's parent/guardian/ or a person in whom the child reposes trust. c. Detailed history taking including: • Menstrual history. If the survivor is menstruating at the time of examination then a second

examination is required on a later date in order to record the injuries clearly. • Details of prior vaccination especially with regard to tetanus and hepatitis B, in order to ascertain if prophylaxis is required. • Sexual violence history- present and previous episode(s) • Relevant medical history in relation to STIs (gonorrhoea, HIV, HBV etc.). If there is vaginal discharge, record its type, i.e., texture, colour, odour, etc. 58

National AIDS Control Organisation • Relevant surgical history in relation to treatment of fissures/injuries/scars of ano-genital area should be noted. d.Medical examination: Should include a general physical examination, examination of injuries, and local examination of genital parts/other orifices as per the recommended protocol. It is important to remember that presence of injuries is only observed in one third cases of

forced sexual intercourse. Absence of injuries does not mean the survivor has consented to sexual activity. As per the law, if resistance was not offered that does not mean the person has consented. e.Age estimation (physical/dental/radiological) – if requested by the investigating agency. f. Evidence collection as per the protocol: If a survivor reports within 96 hours (4 days) of the assault, all evidence including swabs must be collected, based on the nature of assault that

has occurred. The likelihood of finding evidence after 72 hours (3 days) is greatly reduced; however it is better to collect evidence up to 96 hours in case the survivor may be unsure of the number of hours lapsed since the assault. Evidence on the outside of the body and on materials such as clothing can be collected even after 96 hours. g.Documentation, packing, sealing and handing over the collected evidence: After the

examination the medical practitioner should document the report, formulate opinion, sign the report and handover the report and sealed samples to police under due acknowledgment. h.Treatment of injuries: Clean lacerations with antiseptic or soap and water. If the survivor is already immunized with Tetanus Toxoid or if no injuries, TT not required. If there are injuries and survivor is not immunized, administer 0.5 ml TT IM. If lacerations require repair and

suturing, which is often the case in minor girls, refer to the nearest centre offering surgical treatment. i. Testing/prophylaxis for STIs, HIV, Hepatitis B and Pregnancy: If facilities permit, swabs must be collected from various sites for wet mount examination or culture of a number of causative organisms. Blood should be collected for VDRL/RPR, HIV and HbsAg tests. Urine may be tested to rule out pregnancy. The wet mount should be examined for evidence of T. vaginalis,

BV and candidiasis and culture of a vaginal-swab specimen for T. vaginalis infection. Note: It is important to obtain informed consent for any examination, treatment or referral in a case of a victim of sexual assault. 59

National AIDS Control Organisation Compliance with follow-up visits is poor among survivors of sexual assault. As a result, the following routine preventive therapy after a sexual assault should be encouraged: (a)Prevention of unwanted pregnancy: Emergency Contraception (EC) to prevent unwanted pregnancy should be given within 72 hrs of unprotected sexual intercourse. The preferred choice of treatment is 2 tablets of Levonorgestrel 750 mg, within 72 hours. If vomiting

occurs, repeat within 3 hours (or 2 tablets COCs Mala D - 2 tablets stat repeated 12 hours within 72 hours). Although emergency contraception is most efficacious if given within the first 72 hours, it can be given for up to 5 days after the assault. Pregnancy assessment must be done on follow up and the survivor must be advised to get tested for pregnancy in case she misses her next period. (b)Post-exposure prophylaxis of STI: STI prophylaxis should be started as early as possible,

although the doses should be spread out (and taken with food) to reduce side-effects such as nausea. Table 4.1: Post-exposure prophylaxis of STI for adults and older children and adolescents weighing more than 45 kg For protection against Drug Gonorrhoea Tab. Azithromycin 1 gm orally, single dose under supervision Chlamydia PLUS Tab. Cefixime 400 mg orally single dose Trichomonas Tab. Metronidazole 2 gm single dose Bacterial Vaginosis OR Tab. Tinidazole 2 gm single dose

Post-exposure prophylaxis of STI in children: The identification of sexually transmissible agents in children beyond the neonatal period suggests sexual abuse. The significance of the identification of a sexually transmitted agent in such children as evidence of possible child sexual abuse varies by pathogen. Post-natally acquired gonorrhoea, syphilis, and non-transfusion, non-perinatally acquired HIV is usually diagnostic of sexual abuse(cid:63).

Sexual abuse should be suspected when genital herpes is diagnosed. (cid:63)The general rule that sexually transmissible infections beyond the neonatal period are evidence of sexual abuse has exceptions. For example, rectal or genital infection with C. trachomatis among young children might be the result of perinatally acquired infection and has, in some cases, persisted for as long as 2–3 years. Genital warts have been

diagnosed in children who have been sexually abused, but also in children who have no other evidence of sexual abuse. BV has been diagnosed in children who have been abused, but its presence alone does not prove sexual abuse. In addition, most HBV infections in children result from household exposure to persons who have chronic HBV infection. 60

National AIDS Control Organisation Examinations of children for sexual assault or abuse should be conducted in a manner designed to minimize pain and trauma to the child. The scheduling of an examination should depend on the history of assault or abuse. During the initial examination and 2-week follow-up examination (if indicated), the following should be performed: • Visual inspection of the genital, peri-anal, and oral areas for genital discharge, odour,

bleeding, irritation, warts, and ulcerative lesions. The clinical manifestations of some STI are different in children than in adults. • Specimen collection for N. gonorrhoeae culture from the pharynx and anus in boys and girls, the vagina in girls, and the urethra in boys. • Cultures for C. trachomatis from specimens collected from the anus in both boys and girls and from the vagina in girls. Culture and wet mount of a vaginal swab specimen for T. vaginalis infection and BV.

• Collection of serum samples to be evaluated immediately, preserved for subsequent analysis, and used as a baseline for comparison with follow-up serologic tests. Sera should be tested immediately for antibodies to sexually transmitted agents like T. pallidum, HIV, and HBV. Follow-up examination: • In circumstances in which transmission of syphilis, HIV, or hepatitis B is a concern but baseline tests are negative, it is recommended to conduct follow-up examinations at

approximately 6 weeks, 3 months, and 6 months after the last suspected sexual exposure to allow time for antibodies to infectious agents to develop. In addition, results of HBs Ag testing must be interpreted carefully, because HBV can also be transmitted non-sexually. Table 4.2: Post-exposure prophylaxis of STI in children For protection against Drug Gonorrhoea Cefixime 8 mg/kg of body weight as a single dose OR Ceftriaxone 125 mg by intramuscular injection

Chlamydia Erythromycin 12.5 mg/kg body weight orally 4 times a day for 14 days OR Azithromycin 20 mg/kg body weight orally once a day for 3 days Trichomonas Metronidazole 5 mg/kg body weight orally 3 times a day for 7 days 61

National AIDS Control Organisation (c) Post-exposure prophylaxis of HIV: Refer to district hospital and follow DAC guidelines for the same. (d) Post-exposure prophylaxis against Hepatitis B is recommended if the sexual assault survivor has not been vaccinated earlier. Draw a sample of blood for HBsAg and administer 0.06 ml/kg HB immune globulin immediately (anytime up to 72 hours after the sexual act). In addition, administer the first dose of the hepatitis B vaccine at the time of

the initial examination. Follow-up doses of vaccine should be administered 1–2 and 4–6 months after the first dose. If vaccine is not available, refer to the centre where Hepatitis B vaccination facilities are available. (e) Follow-up services: It is essential to explain the importance of follow-up appointments and services during the first visit itself. Sexual assault survivors should be clearly told whom to contact if they have other questions or subsequent physical or emotional

problems related to the incident. Follow-up examinations provide an opportunity to: • detect new infections acquired during or after the assault, • complete hepatitis B vaccination, if indicated, • complete counselling and treatment for other STI, and • monitor side effects and adherence to post exposure prophylactic medication, if prescribed. j. Psychological support (both at time of crisis and long-term): Psychosocial management

includes counselling and supportive services, which should be available onsite or by referral. Women or children who have been sexually abused may need shelter and legal protection. Adolescents in particular may need crisis support, as they may not be able or willing to disclose the assault to parents or caretakers. An evaluation of the sexual assault survivor’s personal safety should be made by a protective services agency or shelter, if available, and arrangements made for protection if needed. 62

National AIDS Control Organisation Flowchart 4.1: Algorithm for management of Sexual Violence Consent First Aid Age Estimation Physical Dental History Radiological Hand-over to Police Dry Examination Pack Treatment of Injuries Seal Evidence STI test and Collection prophylaxis HIV test and prophylaxis Emergency Treatment Documentation Contraception UPT (if applicable) Counselling Information and Discharge Follow-up Referral to other services 63

National AIDS Control Organisation 5. Elimination of Parent-to-Child Transmission of Syphilis Progress towards “Elimination of Parent to Child Transmission of Syphilis” is one of the new strategies launched by the STI/RTI control and prevention programme under the Department of AIDS Control (DAC) in collaboration with the Reproductive Maternal Newborn Child Health and Adolescent (RMNCH+A) programme of the National Health Mission.

Maternal syphilis leads to serious adverse outcomes of pregnancy in more than 50% of cases such as still birth, spontaneous abortion, low birth weight babies and birth of congenital syphilitic neonates who are at an increased risk of perinatal death. Detection and treatment of syphilis has been identified as being one of the most efficient and cost effective interventions to prevent congenital syphilis and improve child health. Thus, the strategy towards elimination of

parent-to-child transmission of syphilis will contribute to the achievement of Millennium Development Goals (MDG) 4 (reduce child mortality), 5 (improve maternal health) and 6 (combat HIV/AIDS, malaria and other diseases). To prevent congenital syphilis, increased awareness is needed at all levels among policy-makers, public health officials, health-care providers, communities, and pregnant women, regarding the extent and seriousness of syphilitic outcomes. Elimination of parent to child transmission (e-

PTCT) of syphilis is a feasible strategy for India, primarily because of very low prevalence of the infection and consequently of transmission. Goal & Objectives Goal: To eliminate “Parent-to-Child” Transmission of Syphilis by 2017. Target: To reduce the incidence of congenital syphilis to less than 0.3 cases per 1000 live births by 2017. Objectives: 1. To ensure universal registration of pregnant women at first ANC visit in first trimester;

2. To ensure screening of pregnant women for syphilis at least once during the pregnancy; 3. To identify and provide prompt treatment to all sero-reactive pregnant women; Readers are advised to refer the full text of the subject at www.naco.gov.in under STI component. 66

National AIDS Control Organisation 4. To ensure treatment of all infants born to sero-reactive women; 5. To reach partners of sero-reactive pregnant women, promotion of condom use, education and counselling on risk reduction and safer sex practices to prevent infection/re-infection; 6. To monitor core indicators of e-PTCT. The programmatic targets to achieve the e-PTCT goal are: 1. ANC coverage (pregnant women having at least one ANC visit) of = 95%;

2. Coverage of syphilis testing of ANC attendees of = 95%; 3. Treatment of syphilis-seropositive ANC attendees of = 95%; 4. Confirmation, treatment and follow-up of 100% of suspected cases of congenital syphilis. As the potential for parent to child transmission of syphilis remains high as long as syphilis is prevalent among High Risk Group populations, screening and treatment of syphilis among these groups also requires an emphasis on sustaining the gains achieved. Burden of Congenital Syphilis

Global Scenario As per the WHO global estimates for 2008, there were 1,360,485 (range 1,160,195-1,560,776) pregnant women with probable active syphilis infections, and of these women, 1,085,637 (79.8%) attended ANC.C onsidering the current screening and treatment scenario, it is estimated that globally there were 520,905 adverse outcomes associated with syphilis in pregnancy, which included 212,327 stillbirths or early foetal deaths, 91,764 neonatal deaths,

65,267 pre term or low birth weight infants, and 151,547 infected newborns. Indian Scenario In India, there is a paucity of data on adverse outcomes due to untreated syphilis in pregnancy and congenital syphilis. The average sero-prevalence of syphilis among ANC women during the 2010-11 round of HIV Sentinel Surveillance was 0.38%. Arunachal Pradesh (2.86%) showed the highest prevalence of syphilis among ANC women, followed by West Bengal (1.91%), Rajasthan

(1.17%), Tripura (0.6%), West Bengal (0.6%) and the rest of the states had prevalence of less than 0.5%. 67

National AIDS Control Organisation WHO estimates the burden of maternal syphilis and its adverse outcomes, including congenital syphilis, using sero-reactivity of syphilis as per HSS 2010-11. Of the estimated 29,681,000 pregnancies in India during 2010-11, using these data sources, the estimated burden of syphilis among pregnant women in India is 102,806 (range 98,640-107,276). With the assumption that 52% of pregnant women infected with syphilis would experience some adverse event (including

birth of newborn with congenital syphilis), the estimated number of adverse outcomes due to syphilis among pregnant women in India for year 2010-11, is given in Table 5.1. Table 5.1: Estimated proportion and number of adverse outcomes in untreated pregnancies affected by syphilis, India, 2010-11 (based on WHO tool for estimation) Outcome Estimated % of adverse Estimated number of outcomes in untreated adverse outcomes in India pregnancies affected for year 2010-11 by syphilis

Early foetal loss/ stillbirth 21% 21,248 Neonatal death 9% 9,111 Prematurity or low birth weight 6% 6,093 Clinical evidence of syphilis in newborn 16% 16,144 Any adverse outcome 52% 52,595 Impact of Maternal Syphilis on Pregnancy Outcomes Although pregnant women can transmit the infection to their foetus as early as nine weeks of gestation, transmission usually takes place between 16-28 weeks of pregnancy. The likelihood

of transmission is directly related to the stage of maternal syphilis during pregnancy, or the stage of pregnancy when infection is acquired. In early maternal syphilis, the maternal–foetal transmission rate can be as high as 80%, whereas in late syphilis infectivity decreases. The course of maternal infection does not seem to be altered by pregnancy. Pregnant women who are at a higher risk for developing STI and found negative in the first screening should be

screened again later in the pregnancy or at delivery. Note: Pregnant women at high risk for developing STI are those with current or past history of STI, repeated abortions, stillbirth, past history of delivery of premature baby and neonatal death; women with more than one sexual partner; sex worker and injecting drug users. 68

National AIDS Control Organisation Signs and symptoms of Congenital Syphilis Congenital syphilis may be asymptomatic, especially in the first weeks of life, in about 50% of cases. Usually, symptoms appear in the first months but the clinical manifestations may be delayed until the second year of life. The most frequent clinical signs of congenital syphilis at birth are hepato-splenomegaly (33%–100%), bone changes seen on X-ray (75%–100%), blistering skin rash especially on palms

and soles (40%), fever (16%), low birth weight (10%–40%), bleeding (10%), swelling of the joints, abnormal facies, snuffles, oedema, abdominal distension, pallor, respiratory distress and pseudo paralysis. Screening Tests for Syphilis Following infection with syphilis, blood tests can take 10–45 days to become reactive, depending on the type of the test. The health care provider should ensure that every pregnant woman is tested for syphilis at least once during the antenatal period.

A number of serological tests are available for screening of syphilis. A non-treponemal screening test (such as RPR or VDRL test) is done to detect reaginic antibody. Treponemal test is done as a confirmatory test for syphilis infection. A reactive serum with non-treponemal test is retested with treponemal test to confirm syphilis infection. New rapid treponemal tests (Point of Care Test) Rapid, simple treponemal tests called Point of care tests (POC) are used for screening syphilis

infection especially for those who are hard to reach and where even basic laboratory facilities are not available. They are suitable to screen pregnant women and high risk groups. Examples of POC tests are immuno chromatography strip (ICS) test. Advantages • Do not need equipment or special storage conditions and require minimal training. • Are now available and can be used on-site including in peripheral and hard to reach areas. • Have sensitivities ranging from 85%–98%, which is higher than that of RPR.

• Have comparable specificity to RPR ranging from of 92%–98%. 69

National AIDS Control Organisation • Although these tests are more expensive than the VDRL and RPR tests, they are more cost- effective because they enable reaching out to a larger population with little effort; hence more pregnant women can be tested and treated in a timely manner, thus preventing cases of congenital syphilis. Disadvantage • Low sensitivity in low-titre syphilis (e.g. RPR titre<1:8). All pregnant women found sero-reactive for syphilis should be encouraged to undergo testing

for HIV as well, because the risk factors for HIV and syphilis are the same. Spouses of reactive pregnant women should be motivated to receive testing and treatment for syphilis and HIV. Diagnosis of congenital syphilis Suspected case of congenital syphilis: “A still or live born baby of syphilis sero-reactive mother” Confirmed case of congenital syphilis: “A stillbirth, live-birth, or child aged <2 years with microbiological evidence of syphilis infection.

Microbiological evidence includes anyone of the following: • Demonstration of T. pallidum by dark field microscopy OR • Fluorescent antibody detection of T. pallidum specific IgM in the umbilical cord or placenta, or nasal discharge or skin lesion material. OR A child within first 2 years of life with clinical evidence* of syphilis and reactive syphilis serology irrespective of the mother’s serology *At least 2 of the following: Swelling of joints, snuffles, bullous skin lesions, hepato

splenomegaly, jaundice, anaemia, radiological changes in the long bones". Management of Maternal Syphilis • All pregnant women who test reactive for syphilis (POC test or RPR/VDRL) should be treated to avoid any case of congenital syphilis, although it may result in some over 70

National AIDS Control Organisation treatment because of false-positive results. The risk of over treatment, i.e. treatment of women with false-positive results, does exist but is outweighed by the benefits of expanded screening coverage. • Pregnant mother may be provided with treatment at any titre, i.e. even at lower titre, as the benefit of treatment outweighs the drawbacks by reducing maternal morbidity and preventing transmission of the infection to the foetus.

• Treatment should be provided early in pregnancy, preferably during the first trimester but definitely before the third trimester. • A simple rule is to treat as soon as the test for syphilis is found to be reactive. The earlier the result of the test is available and treatment started, the better it is. • Pregnant women should be retested during the third trimester where indicated and closer to delivery in order to detect re-infection.

• Partners of sero-reactive women should also be treated in order to prevent re-infection. • Patients and partners should be educated and counselled. o Risk reduction counselling and condom provision enables modification of risk behaviour and is important for preventing re-infection. o Sero-reactive women should be educated and counselled on how to prevent transmission to foetus and re-infection, including the use of condoms and the need to get their partners and newborn babies screened and treated.

Treatment of maternal syphilis depends on the stage of the infection: i. In early stage syphilis (<2 years duration), a single intramuscular injection of 2.4 million IU benzathine penicillin is sufficient. Allergy to penicillin should be excluded before giving the full dose. ii. In the late stage (>2 years), weekly intramuscular injections of 2.4 million IU benzathine penicillin are required for three weeks. Whatever the stage of infection, even a single dose of penicillin will prevent infection in the

foetus. Adequate treatment with penicillin will end infectivity within 24–48 hours. The RPR/VDRL titre is expected to decrease by fourfold in six months after treatment. The rate of sero-reversion depends on the pre-treatment titre and the stage of the disease. 71

National AIDS Control Organisation Alternative regimens for penicillin allergic pregnant patients Regimen 1: a. Early stage syphilis: Erythromycin, 500 mg orally, 4 times daily for 15 days b. Late stage of syphilis: Erythromycin, 500 mg orally, 4 times daily for 30 days OR Regimen 2: Azithromycin 2 gm orally as a single dose. Note: • For the treatment of syphilis during pregnancy, no proven alternates to penicillin exist.

• Alternative to penicillin should be considered for pregnant women who have a history of penicillin allergy. • Erythromycin estolate is contraindicated because of drug-related hepatotoxicity. Only Erythromycin base or Erythromycin ethyl succinate should be used. Follow up of pregnant woman treated for syphilis and her partner • Following treatment, quantitative non-treponemal serological tests should be performed again at late pregnancy and re-treatment should be undertaken if there is serological

evidence of re-infection or relapse. • Pregnant woman should be followed up at 3, 6, 12 and 24 months after delivery and during every follow up visit, clinical examination, qualitative and quantitative non-treponemal test (RPR) should be performed. Her partner also followed similarly. • To ensure that results are comparable, follow up test should be performed by using the same non-treponemal test (RPR/ VDRL) that was used initially. Management of Congenital Syphilis Regimen 1 (Prophylactic Treatment)

All asymptomatic babies who have no serological evidence of syphilis and are born to mothers who were adequately treated for maternal syphilis with penicillin during the current pregnancy 72

National AIDS Control Organisation prior to 4 weeks of delivery according to guidelines should be treated with a single dose of prophylactic penicillin: benzathine penicillin G 50,000 units/kg given as a single intra muscular injection. Regimen 2 (Curative Treatment) This should be given to: 1. All symptomatic babies 2. All asymptomatic babies For newborns i. Born to mothers who were treated with penicillin < 4 weeks before delivery,

ii. Born to mothers who were treated with non-penicillin regimens (erythromycin or azithromycin) during pregnancy iii. Born to mothers whose treatment status is unknown or undocumented For infants: i. Whose RPR/ VDRL titre is 4 fold higher than that of the mother at delivery ii. With a reactive syphilis IgM antibody test iii. Born to mothers who did not complete the recommended course of penicillin during pregnancy iv. Born to mothers whose non-treponemal titre had not dropped four fold

Intravenous treatment regimen: Aqueous crystalline penicillin G 100,000-150,000 million units/kg/day intravenously. It could be given as 50,000 units /kg /dose IV every 12 hours during the first 7 days of life and thereafter every 8 hours for 3 days to complete a total of 10 days of treatment. OR Intramuscular treatment regimen: Benzathine penicillin G or procaine penicillin 50,000 units/kg body weight intramuscularly daily for 10 days. 73

National AIDS Control Organisation Hospitalization of the infant should be considered in order to ensure the full course of treatment. If more than one day of treatment is missed, the entire course of treatment should be restarted. Follow up: With appropriate treatment of symptomatic infants, clinical features such as hepato- splenomegaly, jaundice and bone changes on X-ray usually resolve within three months of birth,

and serological markers such as IgM disappear within six months. Therefore, infants should be followed up at 3, 6, 12 and 24 months. During each follow up visit, a clinical examination, qualitative and quantitative non treponemal test (RPR/VDRL) should be performed. To ensure that results are comparable, follow up test should be performed by using the same non treponemal test (RPR/ VDRL) that was used initially. Treatment outcomes of syphilis treatment

Treatment outcomes may either be treatment success, treatment failure, re-infection or relapse of syphilis. • Treatment Success: Treatment success is determined by a fourfold decrease in RPR or VDRL titre by 6-12 months (for early and late syphilis) or 12-24 months (for latent syphilis) of treatment. • Treatment failure: Patients whose titres do not decrease appropriately probably either experienced treatment failure or were re-infected.

• Any patient with apparent treatment failure should be referred to a higher centre for further evaluation and management • If at any time symptoms develop or non-treponemal test titres increase fourfold, the patient should be referred to a higher centre for further evaluation and management. • All HIV-infected patients treated for syphilis should be evaluated clinically and serologically at 3, 6, 9, 12, and 24 months (at 6, 12, 18, and 24 months for latent syphilis) to rule out treatment failure.

Some patients retain reactive (low-titre) non-treponemal test results even after successful treatment for syphilis. In these "sero fast" individuals, reinfection with syphilis is indicated by a rise in test titre by at least fourfold. 74

National AIDS Control Organisation Recommended treatment for treatment failure and relapse cases: These patients should be retreated with weekly injections of benzathine penicillin G 2.4 million IU given intramuscularly for 3 weeks. Surveillance, Monitoring & Evaluation of e-PTCT of Syphilis The e-PTCT of syphilis strategy envisages a focused monitoring and evaluation system with specific indicators to monitor the progress of programmatic goals across states. Surveillance for e-PTCT of Syphilis

1. Prevalence of sero-syphilis among pregnant women: The Department of AIDS Control and RMNCH+A will monitor on a monthly basis the number of pregnant women accessing ANC services and the numbers subjected for syphilis screening and treated from all health facilities. This data will be collected by the programme passively every month from all health facilities. 2. Incidence of congenital syphilis in newborns: The Department of AIDS Control and

RMNCH+A will monitor the incidence of congenital syphilis among the newborns as per the standardized surveillance definition from all facilities once a year. The data for both of these indicators will be collected by strengthening the existing recording and reporting systems. The following indicators will be used to monitor e-PTCT of syphilis: Table 5.2: e-PTCT of Syphilis: Monitoring Indicators Indicator Numerator Denominator Method of Periodicity measurement Programme Indicators

Percentage of No. of pregnant Estimated RCH register and Monthly pregnant women women visiting number of Mother and visiting ANC clinic at ANC at least once pregnant women Child Tracking least once System (MCTS) Percentage of ANC No. of ANC women Number of ANC National Monthly attendees reactive for found reactive for attendees screened programme data syphilis syphilis for syphilis at least for ANC once (HMIS/MCTS and SIMS) Percentage of women No. of ANC women Number of ANC National Monthly

reactive for syphilis screened for attendees at first programme data during first visit testing syphilis at first visit visit for ANC (HMIS/MCTS and SIMS) 75

National AIDS Control Organisation Indicator Numerator Denominator Method of Periodicity measurement Programme Indicators Percentage syphilis Number of ANC Number of ANC National Monthly seroreactive ANC attendees attendees reactive programme attendees who seroreactive for for syphilis data for ANC received treatment syphilis who (HMIS/MCTS received treatment and SIMS) Percentage of syphilis Number of Syphilis Number of ANC National Monthly

seroreactive ANC seroreactive ANC attendees reactive programme data attendees whose attendees whose for syphilis for ANC partners were partners were (HMIS/MCTS and appropriately treated appropriately SIMS) treated Status of Syphilis test Number of Total number of National Monthly kits antenatal clinics antenatal clinics programme reporting stock out providing screening data for ANC of syphilis test kits for pregnant women (HMIS and for last 6 months SIMS)

Status of drugs Number of Total number of National Monthly recommended by antenatal clinics antenatal clinics programme programme for reporting stock out providing screening data for ANC treatment of Syphilis of benzathine for pregnant women (HMIS and penicillin in last 6 SIMS) months Number of suspected No. of reported Total number of live RCH register/ Monthly cases of congenital suspected cases of births and stillbirths MCTS syphilis congenital syphilis among syphilis (as per case seroreactive

definition) mothers Treatment of infants Number of infants Number of babies RCH register/ Monthly born to syphilis sero born to syphilis born to syphilis MCTS reactive mothers seroreactive seroreactive mothers who mothers received treatment Impact Indicators Incidence of No. of reported Total number of Line-listing Annual confirmed cases of confirmed cases of live births and available at ICTC congenital syphilis congenital syphilis stillbirths among and Regional and (as per case syphilis State STI Training

National AIDS Control Organisation Indicator Numerator Denominator Method of Periodicity measurement Stillbirth rate Number of Total number of RCH register/ Monthly pregnant women pregnant women MCTS who had still births registered with ANC Percentage of Number of syphilis Total number of RCH register/ Monthly stillbirths attributable seroreactive pregnant women MCTS to syphilis pregnant women registered with who had still births ANC *Details available in the Implementation Plan for e-PTCT Further reading:

1. Towards Elimination of Parent to Child Transmission of Syphilis: National Strategy for India 2. Implementation Plan: Elimination of Parent to Child Transmission of Syphilis In India 77

National AIDS Control Organisation 6. STI Surveillance STI Surveillance is the systematic collection, collation, analysis and interpretation of STI data with prompt dissemination to those who need to know, for relevant action to be taken. A well- functioning STI/RTI surveillance system provides information for planning, implementation, monitoring and evaluation of STI/RTI control and prevention programme. Objectives of STI/RTI Surveillance

• To measure the magnitude of STI/RTI and their distribution across time, place and persons; • To monitor trends of STI /RTI over years; • To guide STI/RTI programme planning, management; • To generate evidence based information for advocacy to formulate appropriate policy; • To provide data to monitor and evaluate the impact of interventions; • To help define needed resources for prevention and control of STI/RTI; • To determine aetiologies of common STI/RTI syndromes and anti-microbial susceptibilities

[including anti-microbial resistance studies of gonococci as part of Gonococcal Antimicrobial Surveillance Programme (GASP)] in order to improve patient care. Components of STI surveillance in India A. Passive Syndromic case reporting: The 1131 Designated STI/RTI Clinics and 1873 TI NGOs spread all over India submit monthly reports on syndromes diagnosed and treated among the general and key populations. B. STI/RTI aetiological reporting: The seven regional STI Training, Research and Reference

Laboratories submit quarterly reports on the aetiologies of common STI/RTI syndromes apart from reports on biannual Syphilis EQAS and GASP activities from the patients or the samples received from linked DSRCs and TI NGOs. C. HIV sentinel surveillance: Prevalence of sero-syphilis is also reported as part of annual HIV sentinel surveillance covering different sub populations as per the HSS protocol. The reporting units adhere to standardized Syndromic case definitions as defined in STI/RTI

operational guidelines enabling comparability over time and across regions. 80

National AIDS Control Organisation Similarly the aetiologic case definitions as defined in STI diagnostics standard operating procedures manual are followed by the Regional STI Training, Research and Reference laboratories for reporting. The STI/RTI surveillance data is unlinked and kept confidential following the principle of medical confidentiality that prevents unauthorized disclosure of personal identifying information of

patients and ensures the protection of human rights. In order to interpret data meaningfully and compare across time and place, uniform case definitions and standardized reporting forms and consistent reporting procedures are followed. Every year the surveillance data is analysed and shared with all SACS in the annual report apart from providing regular feedback to the states for timely action. Data from STI surveillance can also be used as an early warning sign of risky sexual

behaviours for HIV infection. Acute and treatable STI are markers of high risk behaviours such as Urethral discharge/ Genital ulcer disease syndromes and high titre syphilis. The prevalence of these STI suggest early warning of the emergence of HIV among MSM, FSW, ANC attendees; Populations and geographic areas in need of focussed HIV prevention programmes. Scale up plan of STI surveillance As the aetiological data from the existing seven Regional STI Training, Research and Reference

Laboratories is not representative of the country, it is proposed to establish 3 additional Regional and 45 State STI Training and Reference Laboratories covering all regions, States and Union Territories of India. These centres have already been identified as additional sentinel sites to report aetiological data (the list is annexed). The Apex Regional STI Training, Research and Reference Laboratory at Safdarjung hospital, New Delhi will closely monitor the quality of

laboratory testing procedures at these centres to ensure accurate data under the STI surveillance programme. SACS will ensure effective linkages between these STI aetiological reporting surveillance centres with public health facilities, private health sector and TI NGOs providing services to core and bridge group populations. Further Reading: 1. Operational Guidelines for Regional STI Training, Research and Reference Laboratories.

2. Operational Manual for State STI Training and Reference Laboratories at www.naco.gov.in 81

National AIDS Control Organisation 7. Education & Counselling in STI Programme Effective communication of information on prevention, especially on behaviour change, linked with effective treatment is key to the control of STI/RTI. Prevention information and condoms are to be provided at all levels of the health care system. Effective communication can be done in the following ways: Interpersonal communication: The face-to-face process of giving and receiving information

between two or more people. This involves both verbal and nonverbal communication. • Verbal communication: The way we talk with clients, the words we use, and their meanings. • Non verbal communication: The way we behave with clients, including actions, behaviours, gestures and facial expressions. Counselling: Face-to-face, personal, confidential communication in which one person helps another to make decisions and then to act on them. Good counselling has two major elements:

mutual trust between client and provider and the giving and receiving of relevant, accurate and complete information that enables the client to make a decision. It requires conversational and listening skills. Client counselling on STI/RTI: During the counselling session, provider should talk about causation, transmission, recommended treatment, adherence to treatment, prevention, risk reduction, behaviour change, condom demonstration and provision and partner referral.

Patient educatory information brochures in easy to read local language with illustrations to reinforce messages should be made available at STI/RTI service providing facilities. The five “P”s approach –can be used to elicit key information relating to five aspects –Partners; Prevention of pregnancy, Protection from STI/RTI, unsafe sexual Practices, and Past history of STI/RTI. Goals of client education and counselling

• Primary prevention or preventing infection in uninfected clients. This is the most effective strategy to reduce the spread of STI/RTI and can be easily integrated in all health care settings. • Secondary prevention, which prevents further transmission of that infection in the community and prevents complications and reinfection in the client. 84

National AIDS Control Organisation What the client needs to know Prevention of STI/RTI • Risk reduction • Safer sex practices. • Using condoms, correctly and consistently. Dual protection from STI and HIV and Pregnancy. Condom negotiation skills • Limiting the number of sex partners • Alternatives to penetrative sex Information about STI/RTI • How they are spread between people • Consequences of STI/RTI • Links between STI/RTI and HIV • STI/RTI symptoms-what to look for and what the symptoms mean

STI/RTI treatment • How to take medications • Signs that call for a return visit to the clinic • Follow up schedule • Importance of partner referral and treatment • Motivating male partners to come forward to seek services In STI/RTI service delivery settings, the following is recommended • HIV testing should be recommended for all DSRC clients after pre-test counselling and informed consent. As per the National AIDS Prevention and Control Policy, all HIV tests are

voluntary, based on the client's consent, accompanied by counselling and confidentiality of the test results. Ensure and assure confidentiality. The clients should be referred to the nearest ICTC and ensured that they have reached the ICTC. 85

• All STI attendees should be screened for syphilis. Both Syphilis and HIV test can be done at ICTC. • PLHIV with STI may need prolonged treatment and are to be followed up regularly for a longer duration. • Practice DOTS-STI. Administer the single dose STI drugs in the clinic setting to ensure complete adherence to the regimen. Educate the client against usage of self/ peer and over the counter medication. 86

National AIDS Control Organisation 8. Brief Introduction to STI/RTI 1. Genital /Oro-anal Ulcer Diseases: Syphilis, Chancroid, Herpes, GI and LGV 2. Genital/Anal Discharges & Oro Pharyngeal infections: Gonorrhoea, Chlamydia, CV, BV, TV 3. Painful Scrotal swelling: Gonorrhoea, Chlamydia 4. Lower Abdominal Pain: Gonorrhoea, Chlamydia, gram negative microbes 5. Inguinal Bubo: LGV, Chancroid 6. Genital /Oro-anal Growths: Warts 7. Other STI: Pediculosis Pubis, Scabies, Molluscum contagiosum, Hepatitis B

8.1 Syphilis Syphilis is a systemic disease caused by Treponema pallidum. On the basis of clinical findings; the disease has been divided into a series of overlapping stages, which are used to help guide treatment and follow-up. • Primary infection– ulcer or chancre at the infection site. • Secondary infection - manifestations that include, but are not limited to, skin rash, muco- cutaneous lesions, and lymphadenopathy.

• Tertiary infection - cardiac or gummatous lesions/Neurologic infection e.g. cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, loss of vibration sense, and auditory or ophthalmic abnormalities, which might occur through the natural history of untreated infection. • Latent infections - those lacking clinical manifestations are detected by serologic testing. Treatment for both late latent syphilis and tertiary syphilis might require a longer duration of therapy.

Diagnosis: Dark-field examination and tests to detect T. pallidum in lesion exudate or tissue are the definitive methods for diagnosing early syphilis. A presumptive diagnosis of syphilis is possible with the use of two types of serologic tests: (i) non-treponemal tests [e.g. Venereal 88

National AIDS Control Organisation Disease Research Laboratory (VDRL) and RPR] and (ii) treponemal tests [e.g. fluorescent treponemal antibody absorption (FTA-ABS) tests, T. pallidum particle agglutination (TPPA) assay, chemiluminescence immunoassays, etc]. False-positive non-treponemal test results can be associated with various medical conditions unrelated to syphilis, including autoimmune conditions, older age, and injecting-drug use;

therefore, persons with a reactive non-treponemal test should receive a treponemal test to confirm the diagnosis of syphilis. Non-treponemal test antibody titres may correlate with disease activity, and results should be reported quantitatively. A fourfold change in titre, equivalent to a change of two dilutions (e.g. from 1:16 to 1:4 or from 1:8 to 1:32), is considered necessary to demonstrate a clinically significant difference between two non-treponemal test results that were obtained using the

same serologic test. Non-treponemal test titres usually decline after treatment and might become non reactive with time; however, in some persons, non-treponemal antibodies can persist for a long period of time — a response referred to as the “serofast reaction.” Most patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of treatment or disease activity. However, 15%–25% of patients treated

during the primary stage revert to being serologically nonreactive after 2–3 years. Treponemal test antibody titres should not be used to assess treatment response. For most HIV-infected persons, serologic tests are accurate and reliable for the diagnosis of syphilis and for following a patient’s response to treatment. However, atypical syphilis serologic test results (i.e., unusually high, unusually low, or fluctuating titres) can occur in HIV-infected persons.

The VDRL in cerebrospinal fluid (CSF-VDRL), which is highly specific but insensitive, is the standard serologic test for CSF. The laboratory diagnosis of neurosyphilis usually depends on various combinations of reactive serologic test results, CSF cell count or protein, and a reactive CSF-VDRL with or without clinical manifestations. Management of Sex Partners: Persons who were exposed within the 90 days preceding the

diagnosis of primary, secondary, or early latent syphilis in a sexual partner might be infected even if sero-negative; therefore, such persons should be treated presumptively. Follow-Up: Clinical and serologic evaluation should be performed as per the GUD-NH flow chart. Patients who have signs or symptoms that persist or recur or who have a sustained fourfold increase in non-treponemal test titre (i.e., compared with the maximum or baseline

titre at the time of treatment) probably failed treatment or were re-infected. These patients should be retreated and re-evaluated for HIV infection. 89

National AIDS Control Organisation Penicillin Allergy Azithromycin as a single 2 gm oral dose is effective for treating early syphilis. However, T. pallidum chromosomal mutations associated with azithromycin resistance and treatment failures have been documented. As such, the use of azithromycin should be used with caution only when treatment with penicillin or doxycycline is not feasible. Azithromycin should not be

used in MSM. Please refer Chapter 5 for alternative regimens for penicillin allergic pregnant patients. Close follow-up of persons receiving any alternative therapies is essential. Persons with a penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin. Management of Persons Who Have a History of Penicillin Allergy No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis,

or syphilis in pregnant women. Penicillin also is recommended for use, whenever possible, in HIV infected patients. Because anaphylactic reactions to penicillin can be fatal, every effort should be made to avoid administering penicillin to penicillin-allergic patients, unless they undergo acute desensitization to eliminate anaphylactic sensitivity. The review of literature suggests that anaphylactic reactions to Benzathine penicillin are extremely rare events and in

fact there are hardly any cases published in literature. Nevertheless every facility which is administering penicillin should have the basic anaphylaxis management protocol in place. Penicillin skin testing with benzyl penicilloyl poly-L-lysine (the major determinant) and penicillin G can identify an estimated 90%–97% of the currently allergic patients. Patients who have positive test results should be desensitized. As these are not available in India, most of the

providers practice skin testing with the benzathine penicillin only. Syphilis among HIV Infected Persons Although they are uncommon, unusual serologic responses have been observed among HIV infected persons who have syphilis. Neurosyphilis should be considered in the differential diagnosis of neurologic disease in HIV infected persons. HIV infected persons should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy.

CSF examination and retreatment also should be strongly considered for persons whose non- treponemal test titres do not decrease fourfold within 6–12 months of therapy. If CSF examination is normal, treatment with benzathine penicillin G administered as 2.4 million units IM each at weekly intervals for 3 weeks is recommended. 90

National AIDS Control Organisation 8.2 Chancroid Causative organism: Haemophilus ducreyi, a gram negative bacilli. The combination of a painful genital ulcer and tender suppurative inguinal adenopathy is suggestive of chancroid. The diagnosis of chancroid can be made by (i) demonstrating the organism in the Gram stain by taking the smears from the surface of the ulcer, and (ii) culture. Note: • Men who are uncircumcised and patients with HIV infection do not respond as well to

treatment as persons who are circumcised or HIV negative. If the initial syphilis and HIV test results were negative, repeat screening for syphilis and HIV infection 3 months after the diagnosis of GUD-NH. • The time required for complete healing depends on the size of the ulcer; large ulcers might require >2 weeks. • Clinical resolution of fluctuant lymphadenopathy is slower than that of ulcers and might require needle aspiration or incision and drainage, despite otherwise successful therapy.

• HIV infected patients who have chancroid should be monitored closely as they are more likely to experience treatment failure and to have ulcers that heal more slowly. HIV infected patients might require repeated or longer courses of therapy than those recommended for HIV negative patients. • Different morphological forms of chancroid have been described. One variety known as transient chancroid manifests with inguinal bubo without genital ulceration. 8.3 Genital HSV Infections

Genital herpes is a chronic, life-long viral infection. Both HSV-1 and HSV-2 have been identified as causing genital herpes. Most cases of recurrent genital herpes are caused by HSV-2. Majority of genital herpes infections are transmitted by persons unaware that they have the infection or who are asymptomatic when transmission occurs. Cell culture and PCR are the preferred tests for diagnosing HSV. Failure to detect HSV by culture

or PCR does not indicate an absence of HSV infection, because viral shedding is intermittent. 91

National AIDS Control Organisation Both type-specific and non-type-specific antibodies to HSV develop during the first several weeks after infection and persist indefinitely. Accurate type-specific HSV serologic assays are based on the HSV-specific glycoprotein G2 (HSV-2) and glycoprotein G1 (HSV-1). IgM testing for HSV is not useful, because the IgM tests are not type-specific and might be positive during recurrent episodes of herpes. Screening for HSV-1 and HSV-2 in the general population is not

indicated. Counselling regarding the natural history of genital herpes, sexual and peri-natal transmission, and methods to reduce transmission is integral to clinical management. Topical therapy with antiviral drugs offers minimal clinical benefit, and its use is discouraged. Suppressive Therapy for Recurrent Genital Herpes: Suppressive therapy reduces the frequency of genital herpes recurrences by 70%–80% in patients who have frequent recurrences.

Suppressive antiviral therapy also is likely to reduce transmission when used by persons who have multiple partners (including MSM) and by those who are HSV-2 seropositive without a history of genital herpes and in discordant, heterosexual couples in whom the source partner has a history of genital HSV-2 infection. The individuals should also be counselled for consistent condom use and avoidance of sexual activity during recurrences. Note:

• Sexual transmission of HSV can occur during asymptomatic periods. Asymptomatic viral shedding is more frequent during the first 12 months after acquiring HSV-2. • Infected persons should be informed that male latex condoms, when used consistently and correctly, might reduce the risk of transmission of genital herpes. • Sexual partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of the asymptomatic partners of

persons with genital herpes is recommended to determine whether such partners are already HSV seropositive or whether risk for acquiring HSV exists. • The risk for neonatal HSV infection should be explained to all persons, including men. Pregnant women and women of childbearing age who have genital herpes should inform their providers who care for them during pregnancy and those who will care for their newborn infant about their infection.

• Symptomatic sexual partners should be evaluated and treated in the same manner as patients who have genital lesions. 92

National AIDS Control Organisation • Immuno-compromised patients can have prolonged or severe episodes of genital, perianal, or oral herpes. HSV shedding is increased in HIV infected persons. Clinical manifestations of genital herpes might worsen during immune reconstitution after initiation of anti retroviral therapy. • Suppressive or episodic therapy with oral antiviral agents is effective in decreasing the clinical manifestations of HSV among HIV positive persons.

• All acyclovir-resistant strains are resistant to valacyclovir, and the majority are resistant to famciclovir. Foscarnet 40 mg/kg IV every 8 hours until clinical resolution is attained, is frequently effective for treatment of acyclovir-resistant genital herpes. Intravenous cidofovir 5 mg/kg once weekly might also be effective. Imiquimod is a topical alternative and should be applied to the lesions once daily for 5 consecutive days. 8.4 Granuloma Inguinale (Donovanosis)

Causative organism: Klebsiella granulomatis, an intracellular gram-negative bacterium. Clinically, the disease is commonly characterized by painless, slowly progressive ulcerative lesions on the genitals or perineum without regional lymphadenopathy; subcutaneous granulomas (pseudo-buboes) might also occur. The lesions are highly vascular (i.e. beefy red appearance) and bleed easily on contact. The clinical presentation also can include hypertrophic, necrotic, or sclerotic variants. The

lesions also can develop secondary bacterial infection and can coexist with other sexually transmitted pathogens. The causative organism is difficult to culture, and diagnosis requires visualization of dark- staining Donovan bodies on tissue crush preparation or biopsy. Note: • Pregnant and lactating women should be treated with the erythromycin regimen, and consideration should be given to the addition of a parenteral aminoglycoside (e.g. gentamicin).

• Persons with both granuloma inguinale and HIV infection should receive the same regimens as those who are HIV negative; however, the addition of a parenteral aminoglycoside (e.g. gentamicin) can also be considered. 93

National AIDS Control Organisation 8.5 Lymphogranuloma Venereum Causative organism: Chlamydia trachomatis serovars L1, L2, or L3. The most common feature is tender inguinal and/or femoral lymphadenopathy that is typically unilateral. A self-limited genital ulcer or papule sometimes occurs at the site of inoculation. However, by the time patients seek care, the lesions have often disappeared. Rectal exposure in women or MSM can result in proctocolitis, including mucoid and/or

haemorrhagic rectal discharge, anal pain, constipation, fever, and/or tenesmus. Genital and colorectal LGV lesions can also develop secondary bacterial infection or can be co- infected with other sexually and non-sexually transmitted pathogens. Genital and lymph node specimens (i.e. lesion swab or bubo aspirate) can be tested for C. trachomatis by culture, direct immunofluorescence, or nucleic acid detection. Buboes might require aspiration through intact skin or incision and drainage to prevent the

formation of inguinal/femoral ulcerations. 8.6 Urethritis Urethritis, as characterized by urethral inflammation, can result from infectious and non- infectious conditions. N. gonorrhoeae and C. trachomatis are clinically important infectious causes of urethritis. Non- gonoccocal urethritis (NGU), which is diagnosed when examination findings or microscopy indicate inflammation without gonococci, is caused by C. trachomatis in 15%–40% of cases. M.

genitalium, which appears to be sexually transmitted, is associated with both symptoms of urethritis and urethral inflammation and accounts for 15%–25% of NGU. T. vaginalis, HSV, enteric bacteria and adeno virus also can cause NGU. Note: • Symptoms alone, without documentation of signs or laboratory evidence of urethral inflammation, are not a sufficient basis for retreatment. • Recurrent and Persistent Urethritis- Objective signs of urethritis should be present before

National AIDS Control Organisation 8.7 Cervicitis Causative organisms: C. trachomatis, N. gonorrhoeae, T. vaginalis and genital herpes (especially primary HSV-2 infection). Cervicitis frequently is asymptomatic, but some women complain of an abnormal vaginal discharge and intermenstrual vaginal bleeding (e.g. after sexual intercourse). Two major diagnostic signs characterize cervicitis: (i) a purulent or mucopurulent endocervical

exudate visible in the endocervical canal or on an endocervical swab specimen (commonly referred to as mucopurulent cervicitis or cervicitis); and (ii) sustained endocervical bleeding easily induced by gentle passage of a cotton swab through the cervical os. Either or both signs might be present. Gram stain of endocervical fluid is specific for the diagnosis of gonococcal cervical infection; however it is not a sensitive indicator, because it is observed in only 50% of women with this infection.

8.8 Gonorrhoea Causative organism: Neisseria gonorrhoeae. Because of its high specificity (>99%) and sensitivity (>95%), a Gram stain of a male urethral specimen that demonstrates polymorphonuclear leucocytes with intracellular Gram-negative diplococci can be considered diagnostic for infection with N. gonorrhoeae in symptomatic men. Gram stain of endocervical specimens, pharyngeal, or rectal specimens are not sufficient to detect infection. Note:

• Suspected Cephalosporin Treatment Failure or Resistance: Conduct culture and susceptibility testing of relevant clinical specimens at State reference centres or at Regional STI Training Research & Reference Laboratories. If compliance is in doubt then retreat and ensure partner treatment. • Disseminated Gonococcal Infection (DGI): frequently results in petechial or pustular acral skin lesions, asymmetrical arthralgia, tenosynovitis, or septic arthritis. The infection is

complicated occasionally by perihepatitis and rarely by endocarditis or meningitis. Hospitalization is recommended for therapy. 95

National AIDS Control Organisation • Ophthalmia Neonatorum caused by N. gonorrhoeae: Gonococcal infection among infants usually is caused by exposure to infected cervical exudate at birth. It is usually an acute illness that manifests 2–5 days after birth and in some cases upto 21 days. The most severe manifestations of N. gonorrhoeae infection in newborns are ophthalmia neonatorum and sepsis, which can include arthritis and meningitis. Less severe

manifestations include rhinitis, vaginitis, urethritis, and reinfection at sites of foetal monitoring. Infants who have gonococcal ophthalmia should be hospitalized and evaluated for signs of disseminated infection (e.g. sepsis, arthritis, and meningitis). 8.9 Chlamydial Infections Causative organism: Chlamydia trachomatis Asymptomatic infection is common among both men and women. C. trachomatis urogenital infection in women can be diagnosed by testing urine or by collecting

swab specimens from the endo-cervix or vagina. Diagnosis of urethral infection in men can be made by testing a urethral swab or urine specimen. Rectal C. trachomatis infections can be diagnosed by testing a rectal swab specimen. Direct fluorescent antibody technique (DFA), ELISA to detect antigen and for antibody detection Micro immuno-fluorescence (MIF) and ELISA tests are available apart from cultures. Chlamydial Infections among Infants: C. trachomatis infection of neonates results from

perinatal exposure to the mother’s infected cervix. A chlamydial aetiology should be considered for all infants aged =30 days who have conjunctivitis, especially if the mother has a history of untreated chlamydia infection. 8.10 B ac terial Vaginosis BV is a polymicrobial clinical syndrome resulting from replacement of the normal hydrogen peroxide producing Lactobacillus sp. in the vagina with high concentrations of anaerobic

bacteria (e.g., Prevotella sp. and Mobiluncus sp.), G. vaginalis, Ureaplasma, Mycoplasma, and numerous fastidious or uncultivated anaerobes. Women with BV are at increased risk for the acquisition of some STI (e.g. HIV, N. gonorrhoeae, C. trachomatis, and HSV-2), complications after gynaecologic surgery, complications of pregnancy, and recurrence of BV. Treatment of male sexual partners has not been beneficial in preventing the recurrence of BV. 96

National AIDS Control Organisation BV can be diagnosed by the use of clinical criteria or Gram stain. Note: • Routine treatment of sex partners is not recommended. • Treatment is recommended for all pregnant women with symptoms. • BV appears to recur with higher frequency in HIV positive women. Patients who have BV and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. 8.11 Trichomoniasis Causative organism: Trichomonas vaginalis (protozoa)

Diagnosis of vaginal trichomoniasis is usually performed by microscopy of vaginal secretions. Note: • Because of the high rate of reinfection among patients in whom trichomoniasis was diagnosed (17% were reinfected within 3 months in one study), re screening for T. vaginalis at 3 months following initial infection can be considered for sexually active women with trichomoniasis. • Sexual partners of patients with T. vaginalis should be treated. Patients should be

instructed to abstain from sex until they and their sexual partners are cured. • T. vaginalis infection in HIV infected women might enhance HIV transmission by increasing genital shedding of the virus; and treatment for T. vaginalis has been shown to reduce HIV shedding. For sexually active women who are HIV positive, screening for trichomoniasis at entry into care with subsequent screening performed at least annually is recommended. Re

screening 3 months after completion of therapy should be considered among HIV-positive women with trichomoniasis. 8.12 Vulvovaginal Candidiasis Causative organism: Candida albicans, occasionally other Candida sp. or yeasts. The diagnosis can be made in a woman who has signs and symptoms of vaginitis when either (i) a wet preparation (saline, 10% KOH) or Gram stain of vaginal discharge demonstrates yeasts, hyphae, or pseudohyphae; or (ii) a culture or other test yields a yeast species. 97

National AIDS Control Organisation Note: • Identifying Candida by culture in the absence of symptoms or signs is not an indication for treatment. • VVC is not usually acquired through sexual intercourse; no data supports the treatment of sexual partners. • Recurrent Vulvo-vaginal Candidiasis (RVVC): usually defined as four or more episodes of symptomatic VVC in 1 year. Vaginal cultures should be obtained from patients with RVVC to confirm the clinical diagnosis.

• Therapy for VVC in HIV infected women should not differ from that for sero-negative women. 8.13 Lower abdominal pain (Pelvic Inflammatory Disease) This syndrome comprises a spectrum of inflammatory disorders of the upper female genital tract, including any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis. N. gonorrhoeae and C. trachomatis are implicated in many cases; however, microorganisms that comprise the vaginal flora (e.g., anaerobes, G. vaginalis, Haemophilus

influenzae, enteric Gram-negative rods, and Streptococcus agalactiae) also have been associated. Diagnosis usually is based on clinical findings in sexually active young women at risk for STI if they are experiencing pelvic or lower abdominal pain, if no cause for the illness other than LAP/PID can be identified, and if one or more of the following minimum criteria are present on pelvic examination: • cervical motion tenderness OR • uterine tenderness OR • adnexal tenderness

In addition to one of the three minimum criteria, one or more of the following additional criteria can be used to enhance the specificity of the minimum criteria and support the diagnosis: 98

National AIDS Control Organisation • Abnormal cervical or vaginal mucopurulent discharge • Oral temperature >101° F (>38.3° C) • Presence of signs of lower genital tract inflammation (predominance of leucocytes in vaginal secretions, cervical exudates, or cervical friability) • Elevated erythrocyte sedimentation rate • Elevated C-reactive protein • Laboratory documentation of cervical infection with N. gonorrhoeae or C. trachomatis Note:

• Patients should demonstrate substantial clinical improvement within 3 days after initiation of therapy. • Patients who do not improve within this period usually require hospitalization, additional diagnostic tests, and surgical intervention. • Because of the high risk for maternal morbidity and pre term delivery, pregnant women who have suspected LAP/PID should be hospitalized and treated with parenteral antibiotics.

• The risk for PID associated with Intrauterine Device (IUD) use is primarily confined to the first 3 weeks after insertion and is uncommon thereafter. 8.14 Epididymo-orchitis Painful scrotal swelling is a clinical syndrome consisting of pain, swelling, and inflammation of the epididymis and testis that lasts <6 weeks. Most frequently caused by C. trachomatis or N. gonorrhoeae or by sexually transmitted enteric organisms (e.g. Escherichia coli and Pseudomonas sp.)

Men who have acute epididymitis typically have unilateral testicular pain and tenderness; hydrocele and palpable swelling of the epididymis usually are present. The spermatic cord is usually tender and swollen. 99

National AIDS Control Organisation 8.15 Human Papillomavirus (HPV) Infection Asymptomatic genital HPV infection is common. Diagnosis of genital warts is usually clinical, made by visual inspection. Genital warts can be confirmed by biopsy. Non-oncogenic, or low-risk HPV types (e.g. HPV types 6 and 11), are the cause of genital warts and recurrent respiratory papillomatosis. HPV types 16 and 18 are the cause of cervical cancers.

These HPV types are also associated with other anogenital cancers in men and women, including penile, vulvar, vaginal, and anal cancer, as well as a subset of oropharyngeal cancers. Two types of vaccine are available for prevention of HPV infections: bivalent vaccine containing HPV types 16 and 18 and a quadrivalent vaccine containing HPV types 6, 11, 16, and 18. Both vaccines offer protection against the HPV types that cause 70% of cervical cancers (i.e. types 16

and 18), and the quadrivalent HPV vaccine also protects against the types that cause 90% of genital warts (i.e. types 6 and 11). Both HPV vaccines are administered as a 3-dose series of IM injections over a 6-month period, with the second and third doses given 1–2 months and 6 months respectively after the first dose. Ideally, the same vaccine product should be used for the entire 3-dose series. Women who have received HPV vaccine should continue routine cervical cancer screening

because 30% of cervical cancers are caused by HPV types other than 16 or 18. Note: • Imiquimod, podophyllin, and podofilox should not be used during pregnancy. • Caesarean delivery should not be performed solely to prevent transmission of HPV infection to the newborn. • Persons who are HIV infected are more likely to develop genital warts than persons who are not HIV infected; moreover, lesions are more recalcitrant to treatment due to depressed cell-mediated immunity.

Cervical Cancer Screening for Women who attend DSRCs or have a history of STI • Cervical cytology (i.e. Pap test or VILI test) is an effective, low-cost screening test for preventing invasive cervical cancer. If the results of the Pap test are abnormal, follow-up care should be provided. 100

National AIDS Control Organisation • These tests should not be considered a screening test for STI. • If a woman is menstruating, a conventional cytology Pap test should be postponed, and the woman should be advised to have a Pap test at the earliest opportunity. • The presence of a mucopurulent discharge should not delay the Pap test. The test can be performed after careful removal of the discharge with a saline-soaked cotton swab.

• Women who have had a total hysterectomy do not require a routine Pap test unless the hysterectomy was performed because of cervical cancer or its precursor lesions. • Pregnant women should be screened at the same frequency as non-pregnant women. A swab and an Ayre’s spatula can be used for obtaining Pap tests in pregnant women, but cyto brushes are not recommended. • HIV positive women should be provided cervical cytology screening twice (every 6

months) within the first year after initial HIV diagnosis and, if both tests are normal, annual screening can be resumed thereafter. 8.16 Other Sexually Transmitted Infections Pediculosis Pubis The Pthirus pubis (the crab louse), also known as the pubic louse, is an insect that is an obligate ectoparasite of humans. It is typically found in the pubic hair, but may also live on other areas with coarse hair, including the eyelashes.

Persons who have pediculosis pubis (i.e. pubic lice) usually seek medical attention because of pruritus or because they notice lice or nits on their pubic hair. Pediculosis pubis is usually transmitted by sexual contact. Note: • Bedding and clothing should be decontaminated or removed from body contact for at least 72 hours. Fumigation of living areas is not necessary. • Patients with pediculosis pubis should be evaluated for other STI.

• Patients should be evaluated after 1 week if symptoms persist. Retreatment might be necessary if lice are found or if eggs are observed at the hair-skin junction. 101

National AIDS Control Organisation • Sexual partners that have had sexual contact with the patient within the previous month should be treated. • Pregnant and lactating women should be treated with either permethrin or pyrethrins with piperonyl butoxide; lindane and ivermectin are contraindicated in pregnancy and lactation. • Patients who have pediculosis pubis and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. Genital Scabies

Scabies is a contagious skin infection caused by the mite Sarcoptes scabiei. The mite is tiny and usually not directly visible. This parasite burrows under the host's skin, causing intense allergic itching. The disease most often transmitted by direct skin-to-skin contact, with higher risk with prolonged contact. Initial infections require four to six weeks to become symptomatic. Re- infection, however, may manifest symptoms within as few as 24 hours. Because the symptoms

are allergic, their delay in onset is often mirrored by a significant delay in relief after the parasites have been eradicated. Crusted scabies (Norwegian scabies), is a more severe form of the infection often seen in persons with immuno-suppression, debilitation, or malnourishment. Scabies in adults frequently is sexually acquired. Genital scabies manifest with red-brown pruritic nodules primarily on the lower trunk, scrotum, and thighs as well as burrows on penis.

The nodular form represents a delayed hypersensitivity reaction to the scabies mite. Note: • Bedding and clothing should be decontaminated or removed from body contact for at least 72 hours. • Fumigation of living areas is unnecessary. Molluscum Contagiosum Molluscum contagiosum (MC) is a viral infection of the skin. It is caused by a DNA pox virus called the molluscum contagiosum virus (MCV). MCV infects only humans. The virus commonly

spreads through skin-to-skin contact. This includes sexual contact or touching or scratching the bumps and then touching uninfected skin. Handling objects that have the virus on them (fomites), such as a towel, clothing or toys can also result in infection. The virus can spread from one part of the body to another or to other people. This common viral disease has a higher incidence in children (especially children aged one to ten years), sexually active adults, and 102

National AIDS Control Organisation those who are immuno deficient. MC can affect any area of the skin but is most common on the trunk of the body, arms, groin, and legs. MC is a self-limited infection and the lesions tend to routinely disappear without treatment. MC remains contagious until all the lesions are gone. MC is characterized by small pearly papules with a central depression whose core may be expressed, producing a white cheesy material. The lesions average 2 to 5 mm in size and are

usually painless, but may become inflamed, red, and swollen. Patients with HIV infection and other immuno compromising conditions can develop “giant” lesions (=15 mm in diameter), larger numbers of lesions, and lesions that are more resistant to standard therapy. Diagnosis is generally made clinically based on the appearance of the lesion. Hepatitis B Virus Infection Hepatitis B is caused by infection with the hepatitis B virus (HBV).Th e incubation period from

the time of exposure to onset of symptoms is 6 weeks to 6 months. Transmission:H epatitis B viruses (HBV), which predominantly transmit through the parenteral route.H BV is efficiently transmitted by percutaneous or mucous membrane exposure to blood or body fluids that contain blood. The primary risk factors associated with infection among adolescents and adults are unprotected sex with an infected partner, unprotected sex with more than one partner, MSM,

history of other STI, and illegal injection-drug use. Transmission through unsafe sexual intercourse and transmission from mothers to infants is well-established. Infections also occur as a result of iatrogenic exposures (transfusion/ transplantation/dialysis of infected blood/ blood products or organs/tissues), and use of contaminated injections/equipment. Treatment No specific therapy is available for persons with acute hepatitis B;tr eatment is supportive.

Persons with chronic HBV infection should be referred for evaluation to a physician experienced in the management of Chronic Liver Disease. Prevention and control:Pr evention and control can be achieved through safe and effective HBV vaccines. Two products have been approved for hepatitis B prevention: hepatitis B immune globulin (HBIG) and hepatitis B vaccine. HBIG provides temporary (i.e., 3-6 months) protection from HBV 103

National AIDS Control Organisation infection and is typically used as PEP either as an adjunct to hepatitis B vaccination in previously unvaccinated persons or alone in persons who have not responded to vaccination. The recommended dose of HBIG is 0.06 mL/kg. Pre-exposure Vaccination Hepatitis B vaccination is recommended for all unvaccinated adolescents, all unvaccinated adults at risk for HBV infection, and all adults seeking protection from HBV infection. Post-exposure Prophylaxis

Both passive-active PEP (the administration of HBIG and hepatitis B vaccine at separate sites) and active PEP (the administration of hepatitis B vaccination alone) have been demonstrated to be highly effective in preventing transmission after exposure to HBV. Exposure to HBsAg-Positive Source Unvaccinated persons or persons known not to have responded to a complete hepatitis B vaccine series should receive both HBIG and hepatitis vaccine as soon as possible (preferably = 24 hours)

Exposure to Source with Unknown HBsAg Status Unvaccinated persons who have a discrete, identifiable exposure to blood or body fluids containing blood from a source with unknown HBsAg status should receive the hepatitis B vaccine series, with the first dose initiated as soon as possible after exposure (preferably within 24 hours) and the series completed by using the age-appropriate dose and schedule. Pregnancy All HBsAg-positive pregnant women should be reported to higher centres .

National Centre for Disease Control under DGHS, MOHFW, Government of India, initiated surveillance for hepatitis. 104

National AIDS Control Organisation A1. Laboratory Tests for STI/RTI A1. Laboratory Tests for STI/RTI1 Laboratory tests improve the diagnostic sensitivity and specificity of STI/RTI syndromes, and particularly in women, help to differentiate serious infections (e.g. cervicitis) from milder but more common infections (e.g. vaginitis). The tests also help in detection of infections in asymptomatic individuals. Laboratory testing is even more important in pregnant women to

prevent the adverse consequences of syphilis, gonococcal and chlamydial infection in newborns. Laboratory diagnosis of STI/RTI includes three major equally important steps, i.e. collection of specimen, its transport and use of a sensitive and specific test. Laboratory procedures should include microscopic examination of fresh and stained specimens. The minimal laboratory tests recommended under the programme are: 1. RPR test for syphilis testing (qualitative and quantitative) for STI/RTI attendees and ANC

attendees. 2. Wet-mount slide preparations for microscopic examination: a. Normal saline slide preparation for detection of motile trichomonads. b. KOH slide preparation for detection of Candida spores and pseudohyphae, and "Whiff test" for detection of amines indicative of bacterial vaginosis (Whiff test to be performed by the examining clinician). 3. Determination of pH level of vaginal secretions (to be performed by the examining clinician).

4. Gram stain of cervical/rectal specimen for white blood cell (WBC) and gram-negative intracellular diplococci. 5. Gram stain of slides prepared from vaginal smears to diagnose bacterial vaginosis. 1Please refer Laboratory Manual for Diagnosis of Sexually Transmitted and Reproductive Tract Infections, February 2014. 106

National AIDS Control Organisation Vaginal pH The pH of vaginal fluid should be measured using pH paper of appropriate range (3.8 to 6.0). The vaginal fluid sample is collected with a swab from the lateral and posterior fornices of the vagina and the swab is then touched directly on to the paper strip. Alternatively, the pH paper can be touched to the tip of the speculum after it has been withdrawn from the vagina.

Care must be taken not to use any jelly (e.g. KY jelly) or disinfectant (e.g. savlon) before doing the pH test. Contact with cervical mucus must be avoided since it has a higher pH. The normal vaginal pH is 4.0. In BV, the pH is generally elevated to more than 4.5. The vaginal pH test has the highest sensitivity (true negative) of the four characteristics used for identification of BV (Refer Table A1.1), but the lowest specificity (true positive). An elevated pH is also observed if the vaginal

fluid is contaminated with menstrual blood, cervical mucus or semen, and in women with a T. vaginalis infection. In simple words it means that if the pH test is negative the result can be taken as it is but if it is positive one has to rule out other factors contaminating the sample such as menstrual blood, cervical mucus, semen or presence of T. vaginalis infection. BV can be diagnosed using simple clinical criteria with or with out the aid of a microscope as shown in the table below:

Table A1.1: Clinical criteria for Bacterial Vaginosis (BV) Collect specimen Note colour and consistency of discharge. Take a specimen of discharge from the sidewalls or deep in the vagina where discharge pools (or use discharge remaining on speculum). Touch pH paper to discharge on swab or speculum and note pH Prepare slide • Place specimen on a glass slide. Add a drop of 10% potassium hydroxide (KOH) and note for any fishy smell. • Make a wet smear with 0.9% normal saline, cover with cover slip

National AIDS Control Organisation What to look for The diagnosis of BV is based on the presence of at least 3 of the 4 following characteristics a. Homogeneous white-grey discharge that sticks to the vaginal walls b. Vaginal fluid pH>4.5 c. Release of fishy amine odour from the vaginal fluid when mixed with 10% potassium hydroxide (positive whiff test)· d. “Clue cells” visible on microscopy on wet preparation Important Look for evidence of other vaginal or cervical infections as multiple

infections are common. Wet mount microscopy Wet mount microscopy is the direct microscopic examination of vaginal discharge for the diagnosis of trichomoniasis, candidiasis and BV. Table A1.2: Wet mount microscopy examination of vaginal discharge Collect specimen Take a specimen of discharge with a spatula from the sidewalls or deep in the vagina where the discharge accumulates. Prepare slide Mix specimen with 1 or 2 drops of saline on a glass slide and cover with a cover slip.

What to look for • Examine at 100X magnification and look for typical jerky movement of motile trichomonads (ovoid, globular, pear shaped flagellated protozoan). • Examine at 400X magnification to look for yeast cells (round to ovoid cells with typical budding) and trichomonads. • To make identification of yeast cells easier in wet mount slides, mix the vaginal swab in another drop of saline and add a drop of 10% potassium hydroxide to dissolve other cells and note any fishy odour.

• Presence of clue cells (squamous epithelial cells covered with many small coccobacillary organisms). Wet mount shows stippled granular cells without clearly defined edges because of the large numbers of adherent bacteria present and an apparent disintegration of the cells. (The adhering bacteria are predominantly G.vaginalis, sometimes mixed with anaerobes). Important Look for evidence of other vaginal or cervical infections as multiple infections are common. 108

National AIDS Control Organisation Fig A1.a: Potassium hydroxide preparation of vaginal Fig A1.b: “Clue cells” in vaginal wet mount (400X) fluid showing budding yeast and mycelia Fig A1.c: Trichomonas vaginalis in a wet mount of vaginal discharge (400X) Whiff test Women with BV often complain of a foul vaginal smell. This odour is due to the release of amines, produced by decarboxylation of the aminoacids lysine and arginine by an aerobic

bacteria. When potassium hydroxide is added to the vaginal fluid, these amines immediately become volatile, producing the typical fishy odour. Place a drop of vaginal fluid on a glass slide and add a drop of 10% potassium hydroxide. Hold the slide close to nose to detect the amine odour. After a positive reaction, upon standing, the specimen will quickly become odourless because the amines will be rapidly and completely volatilized. 109

National AIDS Control Organisation Gram stain microscopy A gram stain of a vaginal smear has a higher specificity for the detection of clue cells than a wet mount preparation. Moreover, a Gram stain allows good evaluation of the vaginal bacterial flora. Normal vaginal fluid contains predominantly Lactobacillus species and exceedingly low numbers of streptococci and coryneform bacteria. In BV, lactobacilli are replaced by a mixed

flora of anaerobic bacterial morphotypes and G.vaginalis. However, gram stain microscopy has a very low sensitivity for detecting gonorrhoea among women; culture remains the method of choice. For men, gram stain microscopy of urethral discharge smear will show gram-negative intracellular diplococci in case of gonorrhoea. In case of non-gonococcal urethritis more than 5 neutrophils per oil immersion field (1000X) in the urethral smear or more than10 neutrophils

per high powerfield in the sediment of the first void urine are observed. Table A1.3: Gram stain microscopy of vaginal smears Collect specimen A Gram stain slide can be prepared at the same time as the wet mount by rolling the spatula/swab on a separate slide. 1) Heat fix. Prepare slide 2) Stain with crystal violet (60 seconds) and rinse. 3) Stain with iodine (60seconds) and rinse. 4) Decolourise with acetone-ethanol for few seconds (until the liquid runs clear).

5) Stain with safranin (60 seconds) and rinse. 6) Gently blot dry and examine under oil immersion (1000X) and count each type of organism. What to look for • Lactobacilli only: Normal. • Mixed flora, mainly lactobacilli with a few short rods (coccobacilli): Considered normal. • Presence of clue cells; mixed flora, mainly Gardnerella and anaerobic bacteria with a few lactobacilli: Diagnose as BV. • Presence of clue cells, mixed flora of Gram-positive, Gram-negative

and Gram-variable rods; no lactobacilli: Diagnose as BV. Important Look for evidence of other vaginal or cervical infections as multiple infections are common. 110

National AIDS Control Organisation Fig A1.d: Gram stained vaginal smearshowing a normal Fig A1.e: Gram stained vaginal smear with typical flora of lactobacilli (1000X) “clue cell” (1000X) Fig A1.f: Gram stained vaginal smear showing large Gram-negative rods (Mobilincus mulieris) (1000X) Use of gram stain for diagnosis of cervical infection 1. The Gram stain method in female does not provide conclusive evidence of the presence of

Gonococcal infection. Presence of gram-negative diplococci indicates infection but their absence does not rule out infection. 2. The costs associated with the method, including the cost of maintaining microscopes, outweigh the benefits in terms of improved quality of care. 111

National AIDS Control Organisation Fig A1.g: Gram stain smear: Gram-negative diplococci of Neisseria gonorrhoeae Rapid Plasma Reagin (RPR) test for Syphilis screening The programme recommends the use of a non-treponemal test – Rapid Plasma Reagin (RPR) test for routine screening for syphilis. Table A1.4: Procedure of RPR test o Inform about the procedure of the test to be conducted. o Seek consent. o Use a sterile needle and syringe. Draw 5ml of blood from a vein. Put in a plain test tube.

o Let the test tube stand for 20 minutes to allow serum to separate (or centrifuge for 3–5 minutes at 2000–3000 rpm). In the separated sample, serum will be on top. o Use a sampling pipette to transfer the serum. Take care not to include any red blood cells from the lower part of the separated sample. 112

National AIDS Control Organisation o Hold the pipette vertically over a test card circle. Squeeze it to allow one drop (50µl) of serum to fall onto a circle. Spread the drop to fill the circle using a toothpick or other clean spreader. Important: Several samples may be done on one test card. Be careful not to contaminate the remaining test circles. Use new tip and spreader for each sample. Carefully label each sample with a Client name or number.

o Attach dispensing needle to a syringe. Shake antigen. *Draw up enough antigen for the number of tests done (one drop per test). o Holding the syringe vertically, allow exactly one drop of antigen to fall onto each test sample. Do not stir. o Rotate the test card smoothly on the palm of the hand for 8 minutes (or rotate on a mechanical rotator). *Make sure antigen was refrigerated (not frozen) and has not expired. Interpreting results

After 8 minutes rotation, inspect the card in good light. Turn or tilt the card to see whether there is clumping (reactive result). Test cards include negative and positive control circles for comparison. Report as follows : 1. Non-reactive (no clumping or only slight roughness): Negative for syphilis 2. Reactive (highly visible clumping): Positive for syphilis 3. Weakly reactive (minimal clumping): Positive for syphilis Note: Weakly reactive can also be more finely granulated and difficult to see than the

National AIDS Control Organisation Fig A1.h: Test serum is mixed with antigen and the Fig A1.i: Reading RPR results for 10 undiluted sera card is placed on appropriate rotator showing reactive and non-reactive samples. The presence of small to large flocculated clumps indicates reactivity, whereas no clumping or a very slight roughness indicates non-reactivity Correlation and confirmation of test results • Syphilis tests detect antibodies, which are evidence of current or past infection.

• Non-treponemal tests such as RPR test detect almost all cases of early syphilis, but false positives are possible. RPR can be performed without a microscope. • Treponemal tests, such as Treponema pallidum haemagglutination test (TPHA), Fluorescent Treponema antibody absorption test (FTA-ABS), if available, can be used to confirm non-treponemal test results. • Quantitative RPR titres can help evaluate the response to treatment. The following table can be used to interpret syphilis test results.

Table A1.5: Interpreting serological test results for syphilis RPR RPR titre TPHA Active infection + >1:8 + Latent syphilis + Often <1:4 + False positive + Usually <1:4 - Successful treatment +or- 2 titres decrease (e.g. from 1:16 to 1:4) + Note: where additional tests are not available, all clients with reactive RPR should be treated. 114

National AIDS Control Organisation A2. Syphilis Screening using Rapid Point of Care Tests (POC) Syphilis testing Laboratory diagnosis traditionally follows initial screening of serum by a non-treponemal test (VDRL/RPR) confirmed by a specific treponemal test (TPHA/FTA-ABS). However, operational requirements for RPR/VDRL testing are not available at most primary care sites (available at only 2.9% PHCs and 24% CHCs in India2). Delay in obtaining test results through

referrals to offsite laboratories can delay or result in missed opportunities for treatment. Very often patients may not return for follow-up particularly if they are asymptomatic. Rapid point of care syphilis testing • Developed with an aim to integrate rapid, simple and technologically appropriate syphilis testing at venues with limited resources. • Six test kits validated by WHO o Sensitivity 84.5%, and o Specificity 97.7% by serum specimens. (Recommended for further field trials using whole blood).

• Rapid POC kits can be stored at 40C-300C for up to a year; the test does not require other equipment, or electricity, and can be performed by a trained para-medic. Immuno-chromatographic strip test performance using whole blood Put a drop of blood in the well of the test kit, wait for 8-10 minutes or as recommended by the manufacture of the kit and read the test result as given in figure A2.a. Fig A2.a: Strip test with interpretation of results Negative: Only one line below C (control line)

Positive: Lines below C (control) and T (test line) Indeterminate: No lines below C or T 2NIRRH. Rapid Assessment Survey, 2005-2006. 115

National AIDS Control Organisation Suggested guidelines for syphilis screening and treatment using point of care tests • Since it is a specific treponemal test, it cannot distinguish between a new infection and a prior infection which has been successfully treated. • However, all individuals testing positive at first clinic visit with POC tests should be treated. • Referral systems with the nearest Designated STI/RTI clinic or local laboratories need to be

set up for RPR testing for prognostic purposes and subsequent testing of POC positive individuals. Flowchart A: Initial Syphilis Screening (-) Repeat syphilis screening TPHA Strip Test after 6 months (follow flowchart A) (+) Treat for Syphilis* Come back after RPR Qualitative / Quantitative test Non reactive 6 months for repeat Encourage partner for RPR screening RPR testing RPR (follow flowchart B) Reactive RPR Decreasing / Repeat RPR quantitative (titers) Low** Come back after 3

after 3 months months for repeat RPR screening titers Not falling or rising (follow flowchart B) titers** Evaluate for: •neurologic involvement •compliance with previous treatment •reinfection (partner treatment) *Syphilis treatment -History of genital ulcer, maculo-papular rash or in early latent syphilis (within 1 year) : treat with Benzathine PCN 2.4 M unit, 1 dose - If documentation of previous negative serology is not available or unknown stage or late latent syphilis :

treat with Benz athine PCN 2.4 M units IM, 3 doses at weekly interval **Expect two dilution lower titer at 6 months. If initial titers was low (<1:8), it may be serofast and not decrease overtime. 116

National AIDS Control Organisation Flowchart B: Repeat Syphilis Screening (every 6 months) History of No Do TPHA strip test as TPHA strip first syphilis screening test (follow flowchart A) Yes Previous TPHA Previous TPHA Strip test (+) Strip test (-) Do TPHA strip test as first syphillis screening (follow flowchart A) Do RPR screening Decreasing / Low ** Come back after 6 months Repeat RPR qualitative for repeat RPR screening and quantitative test Titers (follow flowchart B) Not falling or rising titers**

Evaluate for • neurologic involvement • compliance to previous treatment • re-infection (partner treatment) • Repeat RPR after 3 months **Expect two dilution lower titer at 6 months. If initial titers was low (<1:8), it may be serofast and not decrease overtime 117

National AIDS Control Organisation A3. Disinfection and Standard Precautions Standard precautions require that healthcare workers assume that the blood and body substances of all patients are potential sources of infection, regardless of the diagnosis or presumed infectious status. Additional (transmission-based) precautions are needed for diseases transmitted by air, droplets and contact. A number of infections can be spread from the patient to the healthcare provider or to other

patients if basic precautions are not followed. Hepatitis B and C viruses and HIV are easily transmitted by reuse of contaminated sharps. Because most infections are often asymptomatic; it is not possible to know which patients have an infection. For this reason, standard precautions should be followed by all the healthcare workers. Standard Precautions Standard precautions include the following: 1. Hand washing and antisepsis (hand hygiene)

2. Use of personal protective equipment when handling blood, body substances, excretions and secretions 3. Appropriate handling of patient equipment and soiled linen 4. Prevention of needle-stick/sharp injuries 5. Management of healthcare waste 1. Hand washing and antisepsis (hand hygiene) Hand washing breaks the chain of infection transmission and reduces person-to-person transmission. It is the most important way to kill germs on the skin. Hands should be washed

even more thoroughly and for a longer time in the following situations: • Before and after helping someone give birth • Before and after touching a wound or broken skin • Before and after giving an injection, or cutting or piercing a body part • After touching blood, urine, stool, mucus, or fluid from the vagina 118

National AIDS Control Organisation • After removing gloves • Between contact with different patients Hands must be washed for a minimum of 10 - 15 seconds, count to 30 as you scrub your hands all over with the soapy lather. Use soap or other disinfectant to remove dirt and germs. Use a brush or soft stick to clean under the nails, then rinse, using running water. Do not reuse the same water. Immersion of hands in bowls of antiseptics is not recommended. Common towels must

not be used as they facilitate transmission of infection. If there is no clean dry towel, it is best to air-dry the hands. Fig A3.a: Hand washing procedures Procedure 1 Procedure 2 Procedure 3 Wet hands and wrists. Right palm over left, Palm to palm, Apply soap. left over right. fingers Interlaced Procedure 4 Procedure 5 Procedure 6 Back fingers to opposing Rotational rubbing of right Rotational rubbing backwards fingers interlocked. thumb clasped in left palm and forwards with tops of

and vice versa. fingers and thumb of right hand in left and vice versa Note: Repeat procedures 1-6 until the hands are clean. Rinse hands and pat dry. Source: World Health Organization. Regional Office for Western Pacific. Interim guidelines for national SARS preparedness. Manila: WHO, 2003, Page 45 119

National AIDS Control Organisation (cid:216)Hand washing is the simplest and most cost-effective way of preventing transmission of infection. (cid:216)Hands must be washed for a minimum of 10-15 seconds with soap or other disinfectant. (cid:216)Common towels must not be used as they facilitate transmission of infection. 2.Use of personal protective equipment when handling blood, body substances, excretions and secretions

Using personal protective equipment offers protection by helping to prevent microorganisms from: • Contamination of hands, eyes, clothing, hair; • Being transmitted to other patients and staff. Personal protective equipment includes: • Gloves • Masks • Aprons • Gowns • Caps/hair covers Gloves • Use gloves (clean, non-sterile) or a piece of plastic for handling dirty bandages, clothes, blood, vomit or stool. • Disposable gloves should not be reused.

• Gloves must be changed not only between contacts with different patients but between tasks/procedures on the same patient to prevent cross-contamination between different body sites. 120

National AIDS Control Organisation Personal protective equipment must be used effectively, correctly and at all times whenever contact with patient's blood, body fluids, excretions and secretions may occur. 3.Appropriate handling of patient equipment and soiled linen Ensure that all reusable equipment is cleaned and reprocessed appropriately before being used on another patient. Keep bedding and clothing lean. This helps in keeping sick people comfortable and helps in

preventing skin problems. Handle clothing and/or sheets carefully, which are stained with blood, urine, stool or other body fluids. Separate from other laundry for washing. Dry laundry thoroughly in the sun if possible or iron after drying. 4.Prevention of needle-stick/sharp injuries All the used disposable syringes and needles, scalpel blades and other sharp items should be placed in a puncture resistant container having a proper lid. These containers must be located

close to the procedure area. Never recap or bend needles. 5. Management of health-care waste Daily collection of waste must be encouraged and storage of uncollected, long stored waste or waste within the premises must be avoided. There are four main components of a waste disposal plan: Segregation, Disinfection, Proper storage and transportation, and Safe disposal. I. Segregation is separating waste by type at the place where it is generated/at source. Always

segregate waste into infectious and non-infectious waste at the source of generation. The bio- medical waste should be segregated into containers/bags at the point of its generation into colour coded containers/bags as per the following guidelines: Table A3.1: Colour coding and type of container for disposal of biomedical waste Colour coding Type of container to be used Type of waste Yellow Non-chlorinated plastic bag • Anatomical waste- human & animal • Discarded medicines and cytotoxic drugs

• Soiled waste (items contaminated with blood and body fluids) 121

National AIDS Control Organisation Colour coding Type of container tobe used Type of waste Red Non-chlorinated plastic bag/ • Laboratory waste (wastes from puncture proof container for clinical samples, pathology, sharps biochemistry, haematology, blood bank, etc) • Waste sharps (needles, syringes, scalpels, blades, glass, etc, that may cause puncture and cuts. This includes both used and unused sharps) • Infectious solid waste (Waste generated from disposable items other than the waste sharps such as

tubings, catheters, intravenous sets etc) Blue Non-chlorinated plastic bag / Chemical waste (chemicals used in container production of biologicals, chemicals used in disinfection, as insecticides, etc) Black Non-chlorinated plastic bag Municipal waste Source: Bio Medical Waste (Management and Handling) Rules, 2011 Never mix infectious and non-infectious waste at the source of generation or during the collection, storage, transportation or final disposal of waste.

II. Disinfection: Disinfection of waste at source can be carried out either by chemical treatment, autoclaving, or microwaving. Chemical treatment should be carried out using at least 1% hypochlorite solution or any other equivalent chemical reagent to ensure disinfection. While autoclaving, the autoclave should be dedicated for the purposes of disinfecting and treating biomedical waste. Medical waste should not be considered properly treated unless the

indicators indicate that the prescribed time, temperature and pressure were reached during the autoclave process. If these are not reached for any reason, then the entire load of medical waste should be autoclaved again. Microwave treatment should not be used for cytotoxic, hazardous or radioactive wastes, body parts, and large metal items. 122

National AIDS Control Organisation III. Proper storage and transportation: • Always collect the waste in covered bins. • Fill the bin up to the three-quarter level. • Clean the bin regularly with soap and water. • Never overfill bins. • Never mix infectious and non-infectious waste in the same bin. • Never store waste beyond 48 hours. While carrying or transporting waste from the source of generation to the site of final disposal,

always carry it in closed containers. Use dedicated waste collection bins for transporting waste. Never transport waste in open containers or bags as it may spill and cause spread of infections. Never transport waste with sterile equipment. IV. Safe disposal: Always remember to disinfect and shred the waste before its final disposal. Remember the following while disposing waste: • Anatomical waste should be disposed of by incineration or deep burial3 in a secured area.

There should be no chemical pre-treatment before incineration. Chlorinated plastics/ bags should not be incinerated. • All sharps including cut needles should be decontaminated and then put in a puncture- proof box before disposal. Once this container is 3/4 filled, it should be buried or incinerated. • Syringes are to be cut (with hub cutters) and chemically disinfected at the source of generation before they are finally disposed of in the sharps pit located at the health

facility. Chemical disinfection should be ensured using 1% hypochlorite solution or any other equivalent chemical reagent. Recent guidelines recommend mutilation/ shredding prior to disposal in order to prevent unauthorised reuse. 3Disposal of biomedical waste by deep burial is prohibited in towns and cities, and permitted only in rural areas where there is no access to common bio-medical waste treatment facility, with prior approval from

the prescribed authority. The deep burial facility should be located as per provisions and guidelines issued by Central Pollution Control Board. 123

National AIDS Control Organisation • Infectious solid waste (Waste generated from disposable items other than the waste sharps such as tubings, catheters, intravenous sets etc): Disinfection by chemical treatment/ autoclaving/ microwaving followed by mutilation or shredding and after treatment final disposal through registered or authorized recyclers. • Liquid medical waste (LMW) should be poured down a sink/drain/ flushable toilet or

buried in a pit. Rinse sink/drain/ toilet with water after pouring LMW. Pour disinfectant solution in used sink/drain/ toilet at end of each day. Decontaminate LMW container with 0.5% bleaching solution for 10 minutes before final washing. • Discarded medicines and Cytotoxic drugs (wastes comprising of outdated, contaminated and discarded medicines) should be disposed in secured landfill or by incineration. • Chemical waste that is potentially toxic or poisonous, including cleaning products,

disinfectants etc. should be thrown in toilets/drains after appropriate chemical treatment. Solids should be disposed in secured landfills. • Never throw infectious waste into general waste without any pre-treatment and shredding. Disinfection of Instruments Disinfect or sterilize equipment and instruments. Instruments must first be washed and then disinfected if they are to be used to: • Cut or pierce skin, • Give an injection, • Cut the cord during childbirth,

• Examine the vagina, especially during or after childbirth, a miscarriage, or an induced abortion, • Perform any trans-cervical procedure. These procedures include the following: • Decontamination makes inanimate objects safer to handle before cleaning and involves soaking soiled items in 0.5% chlorine solution for 10 minutes and wiping soiled surfaces 124

National AIDS Control Organisation such as examination tables with a 0.5% chlorine solution. Soaking instruments in bleach solution will help protect against acquiring infection while cleaning them. • Cleaning: After instruments and other reusable items have been decontaminated, they need to be cleaned to remove visible dirt and debris, including blood and body fluids. Cleaning is the most effective way to reduce the number of microorganisms on soiled

instruments and equipment. All instruments should be washed with soapy water and a brush until each one looks very clean, and thereafter rinse with clean water. Care should be taken not to cut or injure oneself on sharp edges or points. Gloves should be worn while washing instruments; if possible, heavy gloves should be used. • Sterilization destroys all microorganisms, including bacterial endospores, which are present on instruments or equipment. Instruments, surgical gloves, and other items that

come in contact with the blood stream or other sterile tissue should be sterilized. Sterilization can be achieved using an autoclave, dry heat, or a chemical. • High-Level Disinfection (HLD) destroys all microorganisms except some bacterial endospores on instruments or objects. It is the only acceptable alternative to sterilization and can be achieved by boiling, steaming, or soaking items in a chemical solution. The instruments should be steamed or boiled for 20 minutes. To steam them, a pot with a

lid is needed. The water does not need to cover the instruments, but enough water should be used to ensure steam coming out of the sides of the lid for 20 minutes. Do not overload with instruments. No instruments should protrude above the rim of the pot. To boil them, it is not necessary to fill the whole pot with water. But make sure the water covers all the instruments in the pot for the entire time. Put a lid on the pot. For both steaming and

boiling, start timing 20 minutes after the water with the instruments comes to a full boil. Do not add any new instrument to the pot once counting has started. The following table shows how to make a disinfection solution of 0.5%, 1% and 2% available chlorine. 125

National AIDS Control Organisation Table A 3.2: Hypochlorite solution of 0.5%, 1% and 2% available chlorine Product Chlorine How to dilute How to dilute How to dilute available to 0.5% to 1% to 2% Sodium 3.5% 1 part bleach to 1 part bleach to 1 part bleach to hypochlorite- 6 parts water 2.5 parts water 0.7 parts water liquid bleach Sodium 5% 1 part bleach to 1 part bleach to 1 part bleach to hypochlorite 9 parts water 4 parts water 1.5 parts water liquid NaDCC 60% 8.5 grams to 1 17 grams to 1 34 grams to 1

(sodium litre water litre water litre water dichlor- oisocyanurate) powder NaDCC (1.5g/ 60% 6 tablets to 1 11 tablets to 1 23 tablets to 1 tablet) - tablets litre water litre water litre water Chloramine- 25% 20 grams to 1 40 grams to 1 80 grams to 1 powder litre water litre water litre water Note: Bleach solution becomes unstable rapidly, hence it needs to be freshly prepared daily or changed on becoming dirty/turbid. Chlorine bleach can be corrosive. Protect metal instruments

by thoroughly rinsing them with water after soaking for 10 minutes. Cleaning of the Health Facility Patient care areas must be cleaned by wet mopping. Only dry sweeping is not recommended. Any areas visibly contaminated with blood or body fluids should be cleaned immediately with detergent and water. Table A3.3: Common disinfectants used for environmental cleaning in health centres Disinfectants Recommended use Precautions Sodium hypochlorite Disinfections of • Should be used in well-

1% In-use dilution, material contaminated ventilated areas 5% solution to with blood and body • Protective clothing required diluted 1:5 in clean fluids while handling and using water undiluted solutions • Do not mix with strong acids to avoid release of chlorine gas • Corrosive to metals 126

National AIDS Control Organisation Disinfectants Recommended use Precautions Bleaching powder Toilets / bathrooms-if Same as above 7g/litre with 70% liquid bleach is not available chlorine available, this may be (Table shows used dilutions for bleach) Alcohol (70%) Smooth metal surfaces, • Flammable, toxic, to be used Isopropyl, ethyl tabletops and other in well-ventilated area, alcohol, methylated surfaces on which avoid inhalation spirit bleach cannot be used • Kept away from heat source,

electrical equipment, flames, hot surfaces • Allow it to dry completely, particularly when using diathermy as it can cause diathermy burns Note: A neutral detergent and warm water solution should be used for all routine and general cleaning. When a disinfectant is required for surface cleaning, e.g. after spillage or contamination with blood or body fluids, the manufacturer’s recommendation for use and occupational health and safety instruction should be followed. 127

National AIDS Control Organisation A4. Treatment Failure, Recurrence, Relapse & Persistence of STI/RTI Treatment failure: If progression of disease continues following initiation of an effective regimen or if no clinical improvement occurs following the effective regimen. Relapse: Reappearance of the same symptoms/signs within the estimated period of their disappearance following an effective treatment regimen, as per its natural history, and if the

patient denies further sexual contact during the post-treatment period. Recurrence: A return of the symptoms, after a symptom free interval, as a phenomenon of the natural history of the disease. Recurrence may be due to relapse or due to reinfection. Persistence: Persistent infections are characterized as those in which the infectious agent is not cleared but remains in specific cells of infected individuals. Persistent infections may involve

stages of both silent and productive infection without rapidly killing or even producing excessive damage of the host cells. Suspected Treatment Failure • The health care provider should explore the following from the suspected case to ascertain the cause for treatment failure: o Where the medications prescribed and how many tablets were taken? (review to see whether DOT-STI followed) o Were the medicines shared with anyone, or was the medication stopped after the patient felt some improvement?

• Review the prescription (if available) to verify whether treatment given is in accordance to the national treatment guidelines. • Consider the possibility of drug resistance if cases of treatment failure are showing an increasing trend. Note: However, what may first appear to be clinical treatment failure may actually be due to circumstances other than antibiotic resistance, most commonly reinfection following successful

treatment. Failure to comply with treatment, especially where multi-dose treatments are employed; inadequate dosing; use of low-quality antimicrobials; or cases where only an unsatisfactory clinical history is available are other examples of sources of possible confusion in defining the presence of a “true” treatment failure, i.e. one that is due to antimicrobial resistance. 128

National AIDS Control Organisation Suspected Reinfection / Relapse / Recurrence / Persistence The HCP should explore the following from the suspected case to ascertain the cause for reinfection/relapse/recurrence/persistence: • Did your partner(s) get treated? • Did you use condoms or abstain from sex after starting treatment? • Did you have sex without condom after treatment? • Did you have complete disappearance of symptoms after treatment?

• Have you got similar lesions in the past; if yes, how many times and how frequently did they occur? Note: Recurrence of RTI is common with endogenous vaginal infections, especially when underlying reasons (such as douching, usage of vaginal drying agents, diabetes mellitus, usage of hormonal contraceptives, chronic malnutrition, anaemia) are not addressed. Management of treatment failure and relapse / persistent infections Treatment failure

All cases of treatment failures should be referred to the health facility where a concerned specialist is available. After receiving the individual patient, the specialist should review the case records, and after ruling out errors in diagnosis and management, advise necessary laboratory testing. Laboratory testing can be done either by transporting samples collected as per the national STI diagnostics manual SOP or if willing, patient can be referred to the state or regional

STI Training and Reference Laboratories after explaining to the patient and providing a proper covering letter. List of state and regional STI laboratories are annexed. Reinfection/relapse/ persistence • Consider retreatment with the same antibiotics. • Refer to higher health facility where concerned specialist is available especially if symptoms persist. 129

National AIDS Control Organisation Criteria for treatment failure/ recurrence/persistence for individual STI/RTI Primary and Secondary Syphilis • Patients who have signs or symptoms that persist or recur or who have a sustained fourfold increase in non-treponemal test titre (i.e. compared with the maximum or baseline titre at the time of treatment) probably failed treatment or were reinfected. These patients should be retreated and re-evaluated for HIV infection.

• HIV infected persons should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy. • For retreatment, weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks are recommended. • T. pallidum chromosomal mutations associated with azithromycin resistance and treat- ment failures have been documented. As such, the use of azithromycin should be used with caution only when treatment with penicillin or doxycycline is not feasible.

Azithromycin should not be used in MSM or general population. Close follow-up of persons receiving any alternative therapies is essential. Gonorrhoea • Most infections result from reinfection rather than treatment failure, indicating a need for improved patient education and referral of sex partners. • Clinicians should advise patients with gonorrhoea to be retested 3 months after treatment. Gonorrhoea treatment failure should be suspected if:

• Symptoms remain for more than 7 days after initial antibiotic treatment with Kit 1 regimen (Cefixime 400 mg + Azithromycin 1 gm) • The patient remains positive for one of the following tests for N. gonorrhoeae: 1. Presence of intracellular Gram-negative diplococci on microscopy taken at least 72 hours after completion of treatment; OR 130

National AIDS Control Organisation 2. Isolation of N. gonorrhoeae by culture taken at least 72 hours after completion of treatment; AND 3. Denies sexual contact during the post-treatment follow-up period. Persistent urethritis: Depending on the original site of infection, symptoms may include: • Persistent urethral discharge, dysuria, and/or pyuria (positive leucocyte esterase on urine dipstick) • Persistent pharyngitis or odynophagia

• Persistent rectal discharge, pain, bleeding, pruritis, tenesmus, or painful defecation. • Persistent vaginal discharge, dysuria, or post-coital spotting. Note: If decreased susceptibility to Cefixime or Ceftriaxone is suspected, it is important to refer the patient to either the state or regional STI laboratory where facilities are available to culture (N. gonorrhoeae) and perform antimicrobial susceptibility testing. Concerned SACS should

facilitate the sample transfer or patient referral to the nearest functional centre. Recommendation for Performing Tests-of-Cure Tests-of-cure after treatment (i.e. repeat testing 3–4 weeks after completing therapy) are recommended only for the following groups: • Pregnant women, • Cases where an antibiotic other than a recommended or alternate regimen was used, • Cases of suspected treatment failure. 131

National AIDS Control Organisation A5. List of Drugs (A) Essential STI/RTI Drugs (C) Essential General Medicines 1. Tab. Cefixime 200 mg or 400 mg. 1. Tab. Ranitidine 150 mg. 2. Tab. Azithromycin 500 mg or 1 g. 2. Tab. Metoclopramide 3. Tab. Acyclovir 200 mg or 400 3. Tab. Ibuprofen 400 mg. mg. 4. Tab. Paracetamol 500 mg. 4. Cap. Doxycycline 100 mg. 5. Inj. Adrenaline (epinephrine) 5. Benzyl benzoate 25% lotion. 1:1000 dilution 6. Tab. Erythromycin 250 mg or 6. Antihistramines for injection and

500 mg. oral administration (e.g. Diphenhydramine and 7. Tab. Metronidazole 400 mg. Chlorpheniramine) 8. Podophyllin tincture 20%. 7. Inj. Hydrocortisone 9. Cap. Amoxicillin 500 mg. 10.Tab. Secnidazole 1 g or 2 g. 11.Inj. Benzathine Penicillin 2.4 MU. 12.Inj. Distilled water ampoules/glass phials 10 ml. 13. Tab/Cap. fluconazole 150 mg. (B) List of Additional STI/RTI Drugs 1 Clotrimazole 500 mg vaginal pessary 2. Tab. Tinidazole 500 mg. 3. Gamma benzene hexachloride 1% lotion or cream

4. Tab. Ciprofloxacin 500 mg. 5. Trichloroacetic acid 30% 6. Vaseline or white petrolatum jelly 7. Applicators (wooden) 132

National AIDS Control Organisation A6. Cross Referral Linkages between DSRC and Other Facilities Patients with suspected STI/RTI may primarily attend either (A) Skin & STI clinic or (B) Gynaecology clinic or (C) General OPD clinic. These service delivery points are expected to have cross referral linkages with other providers, facilities both within the hospital as well as those which are located beyond the hospital such as Targeted Intervention NGOs (TI NGO). The

counsellor at DSRC plays a crucial role in these linkages. Counsellor at DSRC and DSRC in-charges should ensure minimal loss of referees; this can be achieved by effective counselling, by accompanied referral, by usage of line list to track the referred patients and by communicating with other facilities. All HIV positive clients detected at ICTC out of DSRC referrals are to be linked with ART centres and the pre-ART registration number

should be documented on the patient wise card without compromising their confidentiality. This is the responsibility of counsellor at DSRC and ICTC. No additional signs or symbols should be used on patient wise cards to identify the HIV status. The DSRC in-charge should ensure that counsellors adhere to the guidelines. The records are to be reviewed periodically by the District HIV/AIDS Nodal Officer or DPM wherever the DAPCU is present.

Through effective referral linkages, it is expected that each DSRC should receive a minimum of 14 clients a day. The STI focal persons at SACS/TSU and Mentors should actively monitor these linkages during their field visits and address any gaps. Similarly the District RCH Officer should monitor the linkages at sub-district level health facilities, and address any gaps. Fig A6.a: Linkages between DSRC/ General OPD and other facilities ICTC/PPTCT TI Projects ANC clinic Blood Bank ART centre DSRC

(Gynaecolo gy + PLHIV Networks STI clinics) or Male & and CCC Regional/ State Female General OPDs Reference Laboratories General Laboratory Family Planning/ Designated ARSH clinic Post -Partum Microscopy clinics Centres 133

National AIDS Control Organisation A7. Integration of STI/RTI Prevention and Management in RMNCH+A Programme There is increasing recognition of integration of STI/RTI prevention interventions in larger Reproductive Health Programmes. An attempt has been made to organise key reproductive health interventions which would support STI/RTI and HIV prevention. Promoting awareness, counselling and behaviour change Essential steps in the prevention of STI/RTI transmission are promoting a community norm of

STI/RTI prevention and educating people about STI/RTI and how to protect themselves. It is important that counselling sessions in reproductive health settings include discussions on STI/RTI as a consequence of risky sexual behaviour. Ignorance amongst providers is widespread and women themselves are often powerless to assess their STI/RTI risk, even with the best of counselling. Promotion of condoms as a method of dual protection

Condoms are being made easily available through ASHAs, community-based distribution programmes, social marketing and health institutions and other settings. Distributing condoms freely in settings where there are people at high risk of transmitting infection (such as in STI clinics, trucker halt points, red light areas, migrant workers' sites) could be an important intervention. Counselling for contraceptive choices STI/RTI risk-assessment is a principal aspect of contraceptive choice. Intra Uterine Devices

(IUDs) are not recommended for women who are at appreciably increased risk of STI/RTI, because IUD use among such women increases their risk of pelvic inflammatory disease. However, experience shows that the incidence of pelvic inflammatory disease is quite low when women are screened for their history and IUDs are inserted with aseptic technique. Higher STI risk in a population makes condom use more attractive because it offers "triple

protection" against STI, HIV and pregnancy. However, in typical use, condoms are not as effective in preventing pregnancy as are many other contraceptive methods. This dilemma has led to increased interest in promoting dual method use—i.e. the use of condoms along with other, more effective contraceptive methods. 134

National AIDS Control Organisation Linkage between contraceptive choices and STI/RTI People with STIs, HIV, AIDS, or on antiretroviral (ARV) therapy can start and continue to use most contraceptive methods safely. In general, contraceptives and ARV medications do not interfere with each other. There are a few limitations, however. See the table below. Table A7.1:Contraceptives for Clients with STIs, HIV and AIDS Method Has STI Has HIV or AIDS On Antiretroviral (ARV) Therapy

Intrauterine Do not insert an IUD in A woman with HIV Do not insert an device (copper- a woman who is at can have an IUD IUD if client is not bearing or very high individual inserted. clinically well. hormonal IUDs) risk for gonorrhoea and chlamydia, or who A woman with AIDS currently has should not have an gonorrhoea, chlamydia, purulent IUD inserted unless cervicitis, or PID. she is clinically well on ARV therapy. (A current IUD user who becomes infected (A woman who with gonorrhoea or develops AIDS while

chlamydia or develops using an IUD can PID can safely continue using an IUD safely continue using during and after the IUD.) treatment.) Female If client has Women who are infected with HIV, have gonorrhoea, sterilization AIDS, or are on antiretroviral therapy can chlamydia, purulent safely undergo female sterilization. cervicitis, or PID, delay Special arrangements are needed to sterilization until the perform female sterilization on a woman condition is treated

and cured. with AIDS. Delay the procedure if she is currently ill with AIDS-related illness. 135

National AIDS Control Organisation Method Has STIs Has HIV or AIDS On Antiretroviral (ARV) Therapy Vasectomy If client has scrotal Men who are infected with HIV, have skin infection, active AIDS, or are on antiretroviral therapy can STI, swollen, tender tip safely undergo vasectomy. Special of penis, sperm ducts, arrangements are needed to perform or testicles, delay vasectomy on a man with AIDS. Delay the sterilization until the condition is treated procedure if he is currently ill with AIDS-

and cured. related illness. Spermicides Can safely use Should not use Should not use (including when spermicides. spermicides if at high spermicides. used with risk of HIV, infected diaphragm or with HIV, or has AIDS. cervical cap) Combined oral Can safely use Can safely use A woman can use combined hormonal combined hormonal contraceptives, combined methods. methods. combined hormonal injectables, methods while combined taking ARVs patch, unless her combined ring treatment includes ritonavir.

Progestin-only Can safely use Can safely use A woman can use progestin-only pills. progestin-only pills. pills progestin-only pills while taking ARVs unless her treatment includes ritonavir. Progestin-only No special considerations. Can safely use progestin-only injectables or implants. injectables and implants 136

National AIDS Control Organisation Addressing Young People Family planning and maternal and child health programmes are increasingly rising to the challenge of reaching young adults and adolescents—an especially important group for STI and HIV prevention. A range of programmes such as ARSH interventions both in instructional and outreach settings should include information on STI prevention, use of condoms and management. Special attention should be given to reach out to adolescent boys. Innovative

interventions for adolescents can support this kind of behaviour change, including efforts at education, empowerment and delay of sexual intercourse. Antenatal Testing, Counselling and Treatment Antenatal screening and treatment for syphilis appear to be highly cost-effective: both screening and treatment are reasonably inexpensive, while morbidity and mortality from untreated syphilis in pregnant woman with varied adverse outcomes including birth of a

congenital syphilitic infant are high. Interestingly, identifying and treating male partners may be feasible in the antenatal context, perhaps because fathers will have a strong concern about preventing infection in their offspring. Advocacy and Policy The National Health Mission has strong policy and advocacy components. Large numbers of civil society organisations are deeply engaged with implementation at different levels. FP and MH

programmes have many links with nongovernmental organizations and other potential advocates who can help form a constituency to act effectively against STI and HIV. Current barrier methods are still unpopular with many people, and women have little that they can use directly to protect themselves. Also, simple, quick inexpensive diagnostic tests for various STI would overcome some of the deficiencies of the treatment approach.

To sum up, there is no single magic bullet to control HIV or STI. The dynamics of STI transmission support a three-pronged prevention strategy aimed at high transmitters, men and the general population. While ultimate success will require support from a number of other segments of the health community and from broader society, family planning and related health efforts can contribute, especially by building onto ongoing prevention activities. 137

National AIDS Control Organisation A8. Condom and Its Proper Usage Technique Condom is one of the barrier methods of contraception. Condoms are made of either natural rubber latex or polyurethane, which cannot be penetrated by sperm, STI microbes or by HIV. Condom offers dual protection, helps in avoiding unwanted pregnancies and gives protection against STI including HIV. Therefore promotion of the use of condoms and ready accessibility of

condoms is important for the control of STI and HIV. Management of STI includes counselling on preventive measures and use of condoms. All health facilities providing STI services must always have in stock the essential drugs and condoms. Condom education and provision is an integral part of STI syndromic case management General Instructions for Condom Use Remember: • The condom does not include spermicide. • Latex condoms cannot be used by persons with latex sensitivity or allergy, and are not

compatible with oil-based lubricants or medications. • Oil based lubricants can be used for condoms made from polyurethane. • Use a new condom each time you have sex. • Use a condom only once. • For best results, store condoms in a cool, dry place. Do not use a condom if: • The package is broken. • The condom is brittle or dried out. • The colour is uneven or has changed. • The condom is unusually sticky, old or damaged. Male Condom

Most male condoms are made of natural rubber latex, while some are made of polyurethane. Male condoms are of two types: Non lubricated and lubricated. 138

National AIDS Control Organisation Fig A8.a: How to use a male condom Step 1: Open Package • Use a new condom each time you have sex. • Check that it has not expired and that the packaging has no holes by pressing the pack between your fingers. • Push condom to one side of package to allow room to tear open other side. • Remove condom carefully. • DO NOT use finger nails, teeth or sharp objects to open package or remove condom. Step 2: Put it on • Squeeze closed top end of condom to make sure no air is

inside (can make it break). • Place condom over top of erect penis. • With other hand, unroll condom gently down the full length of the penis (one hand still squeezing top end). Step 3: During sex • Make sure condom stays in place. • If it comes off, withdraw the penis and put on a new condom before intercourse continues. • Once sperm has been released into the condom (ejaculation), withdraw the erect penis and HOLD the condom in place on penis. Step 4: Dispose off condom

• Remove condom ONLY when penis is fully withdrawn. • Keep both penis and condom clear from contact with your partner's body. • Knot the end of the used condom. • Place in tissue or bag before throwing it in dustbin • DO NOT flush condoms down the toilet. It will block the system. 139

National AIDS Control Organisation Female Condom Female condoms are made of polyurethane. One advantage of it over the male condom is that its size and shape enables it to cover a wider surface area including some of the external genitalia, thus it may offer additional protection against infections that can be transmitted by contact with skin normally not covered by a male condom. Fig A8.b: How to use a female condom Before Intercourse Step 1: Open Package

• Remove the female condom from the package, and rub it between two fingers to be sure the lubricant is evenly spread inside the sheath. If you need more lubrication, squeeze two drops of the extra lubricant included in the package into the condom sheath. Step 2: Put it in • The closed end of the female condom will go inside your vagina. Squeeze the inner ring between your thumb and middle finger. Step 3:Assure right position • Insert the ring into your vagina. Using your index finger,

push the sheath all the way into your vagina as far as it will go. It is in the right place when you cannot feel it. Do not worry, it can't go too far. Note: The lubrication on the female condom will make it slippery, so take your time to insert it. Step 4: During sex • The ring at the open end of the female condom should stay outside your vagina and rest against your labia (the outer lip of the vagina). Be sure the condom is not twisted. • Once you begin to engage in intercourse, you may have to

guide the penis into the female condom. If you do not, be aware that the penis could enter the vagina outside of the condom's sheath. If this happens, you will not be protected. 140

National AIDS Control Organisation After Intercourse Step 5: Disposal of condom • You can safely remove the female condom at any time after intercourse. If you are lying down, remove the condom before you stand to avoid spillage. • Place in tissue or bag before throwing it in dustbin. • DO NOT flush condoms down the toilet. It will block the system. • Do not reuse it. Note: During intercourse remember to remove and insert a new female condom if the condom

rips or tears during insertion or use, the outer ring is pushed inside, the penis enters outside the pouch, the condom bunches inside the vagina, or you have sex again. 141

National AIDS Control Organisation A9. List of Regional STI Training, Research & Referral Laboratories Sr. Name of the RSTRRL State Name of the linked State STI no Training & Reference Laboratory (Dept. of Microbiology) 1 Safdarjung Hospital, Uttar Pradesh Chhatrapati Shahuji Maharaj Medical Delhi University (CSMMU), Lucknow Institute of Medical Sciences (IMS) BHU, Varanasi JN Medical College, AMU, Aligarh Punjab Government Medical College, Amritsar Delhi University College of Medical Sciences, Delhi

2 Post Graduate Uttarakhand Himalayan Institute of Medical Sciences, Institute of Medical HIHT, Dehradun Education and Research Himachal Dr RP Government Medical College, PGIMER, Chandigarh Pradesh Tanda Kangra District 3 Maulana Azad Haryana Pt. BD Sharma Post Graduate Institute Medical College, of Medical Sciences, Rohtak New Delhi J&K Government Medical College, Jammu Telangana Kakatiya Government Medical College, 4 Osmania Medical Warangal College, Hyderabad.

Andhra Pradesh Sri Venkateswara Medical College (SVMC), Tirupati Andhra Medical College, Vishakhapatnam Guntur Medical College, Guntur Karnataka Bangalore Medical College & Research Institute, Bangalore Karnataka Institute of Medical Sciences (KIMS), Hubli Andaman & Nicobar Islands 142

National AIDS Control Organisation Sr. Name of the RSTRRL State Name of the linked State STI no Training & Reference Laboratory (Dept. of Microbiology) 5 Government Medical Goa Goa Medical College & Hospital, College, Nagpur, Bambolim Maharashtra Chhattisgarh Pt. JN Memorial Medical College, Raipur MP Gandhi Medical College, Bhopal Mahatma Gandhi Memorial Medical College, Indore 6 Topiwala National Maharashtra B J Medical College, Pune Medical College & BY

Nair Hospital, Mumbai, Government Medical College, Aurangabad Maharashtra 7 Medical College Gujarat Government Medical College & New Baroda & Sir Sayajirao Civil Hospital, Surat General Hospital, B J Medical College, Ahmedabad Vadodara, Gujarat Rajasthan RN Tagore Medical College, Udaipur Sawai Man Singh (SMS) Medical College, Jaipur Diu & Daman Dadra & Nagar Haveli 8 Institute of Tamil Nadu Tirunelveli Medical College (TVMC), Venereology, Tirunelveli Chennai, TN Madurai Medical College & Rajaji

Hospital, Madurai Coimbatore Medical College, Coimbatore Kilpauk Medical College, Chennai Kerala Trivandrum Medical College, Thiruvananthapuram Pondicherry PGIMER, Pondicherry Lakshadweep 143

Sr. Name of the RSTRRL State Name of the linked State STI no Training & Reference Laboratory (Dept. of Microbiology) 9 Institute of Serology, West Bengal RG Kar Medical College& Hospital, Kolkata, WB Kolkata North Bengal Medical College, Siliguri, Darjeeling Jharkhand Rajendra Institute of Medical Sciences (RIMS), Ranchi Bihar Patna Medical College, Patna SK Medical College, Muzaffarpur Orissa Shri Ram Chandra Bhanj Medical College (RCB), Cuttack 10 Government Medical Arunachal General Hospital, Naharlagun

College, Guwahati, Pradesh Assam Assam Silchar Medical College, Silchar Manipur Regional Institute of Medical Sciences (RIMS), Imphal Meghalaya North Eastern Indira Gandhi Regional Institute of Health & Medical Sciences (NEIGRIHMS), Shillong Mizoram Civil Hospital, Aizwal Nagaland Naga Hospital Authority, Kohima (NHAK) Sikkim Sikkim Manipal Institute of Medical Sciences (SMIMS) & STNM Hospital, Gangtok Tripura Agartala Government Medical College, Agartala 144

National AIDS Control Organisation A10.Technical Resource Group on Sexually Transmitted Infection Services Name & Designation Organisation 1 Dr. N. Usman, Ex-Director, Institute of Chairperson and STI Expert Venereology and Professor & HoD, DVL, Tagore Medical College, Chennai 2 Dr. Dinesh Baswal, Deputy MoHFW representative Commissioner, MH, MoHFW 3 Dr. Vipin Sharma, Research officer Dept of AYUSH 4 Dr. Arun Risbud, Scientist F, Microbiology, ICMR representative National AIDS Research Institute, Pune

5 Dr. Sanjay Chauhan, Scientist F, NIRRH, ICMR representative Mumbai 6 Dr.Razia Pendse, STI Specialist, HIV WHO representative Division, WHO SEARO 7 Dr. Rajesh Mehta, National Programme WHO representative Officer, Adolescent Reproductive and Sexual Health, WHO, New Delhi 8 Dr. Vanita Gupta, Project Director, SACS Representative Chandigarh SACS 9 Dr.Lalita Umraskar, Deputy Director STI, SACS Representative Goa SACS 10 Dr. Raman Gangakhedkar, Scientist E, Microbiology Expert NARI, Pune

11 Dr. Seema Sood, Additional Professor of Microbiology Expert Microbiology, AIIMS, New Delhi 12 Dr. Sanjay Zodpey, Professor of Public Public Health Expert and Health, Public Health Foundation of IPHA representative India 13 Dr. Shashi Kant, Professor of Community Public Health Expert and Medicine, AIIMS, New Delhi IAPSM representative 14 Dr. Somesh Gupta, Associate STI Expert and IADVL Professor DVL, AIIMS, New Delhi representative 145

National AIDS Control Organisation Name & Designation Organisation 15 Dr. Yogesh Marfatia, Editor-in-Chief IJSTD STI Expert and IASSTD & AIDS and Professor & HoD DVL, GMC, representative Baroda 16 Dr. Hema Divakar, Chairperson HIV/AIDS Obstetrics and Gynaecology Committee, FOGSI expert, FOGSI representative 17 Dr. Rekha Dawar, Professor and Head of Obstetrics and Gynaecology Department of ObGyn, Grant Medical expert College and JJ hospital, Mumbai 18 Dr. Sushena Reza Paul, Director, NGO representative

ASHODAYA, Mysore 19 Dr. Sunil D. Khaparde, Deputy Director NACO STI Division General, NACO 146

National AIDS Control Organisation A11.List of Sub-committee Members for Revising National Guidelines on STI/RTI Name Designation 1 Dr. N. Usman Chairman STI-TRG. Ex-Director IOV, MMC, Chennai 2 Dr.Himanshu Bhushan Deputy Commissioner, MH Division, MOHFW 3 Dr. S.D. Khaparde DDG (STI), NACO 4 Dr. Sanjay Chauhan Scientist F, National Institute of Research in Reproductive Health, Mumbai 5 Dr. Raman Gangakhedkar Scientist E, National AIDS Research Institute, Pune

6 Dr. V.K. Sharma Professor and HOD, Department of Dermatology, AIIMS 7 Dr. (Prof.) H.K.Kar Prof & HOD, DVL, RML Hospital, New Delhi 8 Dr. P. Vasant Kumar Prof & HOD, ObGyn, NRI Medical College & General Hospital, Chinakakani- 522503. Guntur Dist, Andhra Pradesh 9 Dr. Elangovan Prof, DVL, IOV, MMC, Chennai 10 Dr. Sameer Kumta BMGF Avahan Programme 11 Dr. J.V.D.S. Prasad DD STI, APSACS 12 Dr. Anup Amin AD(STI), GSACS 13 Dr. Dinesh Aggarwal NPO, UNFPA

14 Dr. Latha I/c STI Clinic, GH Manapparai, Trichy District, Tamil Nadu 15 Dr. Vishwajit Bharadwaj STI Expert, Wardha 16 Prof. Dr. Madulekha Prof & HOD, NIHFW, New Delhi Bhattacharya 17 Dr. Shobini Rajan Assistant Director General DAC, MOHFW, New Delhi 18 Dr. T.L.N. Prasad Technical Expert, DAC, NTSU, MOHFW, New Delhi 19 Dr. Aman Kumar Singh Technical Expert, DAC, NTSU, MOHFW, New Delhi 20 Dr. Anil Kumar Bhola Programme Officer, DAC, MOHFW, New Delhi 147

National AIDS Control Organisation A12. List of Peer Reviewers Name Designation 1 Dr. Muralidhar Formerly Deputy Director(STD), KSAPS 2 Dr. Teodora Wi MO RH Division, WHO HQ, Geneva 3 Dr. Yogesh Marfatia Editor, IASSTD & AIDS, Prof & HOD, Dept of DVL, GMC, Baroda 4 Dr. Vittal Mogasale Research Scientist (PER Unit Manager),Policy and Economic Research Unit, International Vaccine Institute, SNU Research Park, San 4-8 Nakseongdae dong, Gwanak-gu, Seoul 151-919, Kore

5 Dr. Abeyewickreme Iyanthi Formerly HIV-STI Advisor, SEARO, WHO 6 Dr. Kabir Sardana Associate Professor of DVL, MAMC, LNJP Hospital, Delhi 7 Prof. Dr Vasuki Abi Prof &HOD DVL, Chengalpattu Medical College, Tamil Nadu 8 Dr.Parimi Prabhakar Director, Regional Office, India HIV/AIDS Alliance, Sarovar Center, 5-9-22 Secretariat Road, Hyderabad 500063, AP 9 Prof. Dr. Bhushan Kumar Former Prof & HOD DVL, PGIMER, Chandigarh 10 Dr. Joginder Kataria Specialist DVL, Regional STI Training, Reference &

Research Laboratory, Safdarjung Hospital, Delhi 11 Dr. Vijay K Garg Director, Prof & HOD DVL, MAMC, LNJP Hospital, Delhi 12 Dr. Nitin Walia Prof & HOD DVL, Shadara Medical College, UP 13 Dr. Bitra George Country Director, FHI 360, Delhi 14 Dr. Seetharam Anjaneyulu Editor, Journal of NTRUHS, Vijayawada, AP 15 Dr. Anjana Das Director, STI Capacity Building, FHI 360, New Delhi 16 Dr. Anupam Khungar Pathni Consultant, FHI 360 148

STANDARD TREATMENT GUIDELINES OBSTETRICS & GYNAECOLOGY Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 LEIOMYOMA UTERUS/FIBROMYOMA/FIBROID UTERUS 5 2 ANTE PARTUM HAEMORRHAGE 13 3 ABRUPTIO PLACENTA 18 4 CARDIAC DISEASE IN PREGNANCY 28 5 DYSFUNCTIONAL UTERINE BLEEDING 41 6 ECTOPIC PREGNANCY 48 7 ANEMIA IN PREGNANCY 55 8 DIABETES AND PREGNANCY 67 9 CARCINOMA CERVIX 74 10 ADNEXAL MASS 79 11 CAESAREAN SECTION 84 12 HYPERTENSION IN PREGNANCY/PREECLAMPSIA 87 13 ECLAMPSIA 92 14 PELVIC ORGAN PROLAPSE 96 2

Development Team Group Head Coordinater Dr Ashley J D'cruz Narayana Hrudyalya Hospital. Bangalore Dr. Garima Arora Gandhi & Dr. Lavanya.R Department of Obstetrics and Gynaecology Narayana Hrudyalya Hospital. Bangalore Dr. Sharath Damodhar ( HOD, Dept. of Haemotology), Narayana Hrudayalaya Karnataka, Dr.Basavaraju Narasimhaiah, DGO, Tumkur Government Hospital, Karnataka, 3

Reviewed By Dr. Sudha Prasad Director Professor Department of Obstetrics and Gynaecology MAMC & LN Hospital, New Delhi Dr. Pushpa Singh Head, Department of Obst. & Gynaecology PGIMER and Dr. RML Hospital New Delhi Dr Abha Singh Dir. Prof &HOD Obst& Gynae , LHMC& SSKHospital, New Delhi Dr. Aruna Batra, Head of the Department Department of Obstactric and Gynecology, Safdarjung Hospital, New Delhi. 4

LEIOMYOMA UTERUS/FIBROMYOMA/FIBROID UTERUS I.INTRODUCTION AND CASE DEFINITION: Leiomyoma of uterus also called as fibromyoma or fibroid uterus is a benign tumor of uterus, essentially composed of smooth muscle tissue and a variable amount of fibrous connective tissue. It is the most common tumor of uterus , and is found in 20% of women in reproductive age group. 1 Leiomyomas are the reason behind one-third of all hospital admissions to gynecology services

and one of the commonest indications for hysterectomy. 2 Fibroid Uterus is more common among older nulliparous and obese women, particularly the ones with family history of this disease. Based on the location of tumor in the uterus, various types of myoma are-subserous, intramural and submucous fibroids. II.INCIDENCE OF FIBROID IN INDIA Nearly 20-30% women in reproductive age group have fibroid uterus. At any given time, nearly 15-25 million Indian women have fibroid uterus. III. DIFFERENTIAL DIAGNOSIS

• Adenomyosis • Bicornuate uterus • Ovarian tumor • Retroperitoneal connective tissue tumor • Calcified tuberous pyosalpinx Complications: • Torsion of pedunculated subserous fibroid • Infection of submucous myoma • Ascites may be caused rarely by pedunculated subserous fibroid • Intraperitoneal hemorrhage from rupture of a large vein on the surface of myoma (rare) • Malignant change in 0.2% of uterine fibroids • Degeneration (Hyaline/Cystic/Fatty/Red degeneration) 5

• Pregnancy complications like spontaneous abortion, preterm delivery, abruption- placentae • Labor complications: Inertia, Dystocia, PPH Pelvic pathologies commonly co-existent with fibroid uterus • Endometrial hyperplasia and endometrial polyps • Endometriosis • Anovulation and dysfunctional uterine bleeding • Pelvic inflammatory disease • Tubal pregnancy IV. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA

Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a). Clinical diagnosis: History • Most leiomyomas are asymptomatic and are diagnosed incidentally • Bleeding-Menorrhagia, Meno-metrorrhagia -Continuous/irregular bleeding and blood-tinged discharge per vaginum may occur in cases of surface ulceration of submucosal fibroid polyp. • Pressure symptoms-Pelvic discomfort or feeling of heaviness in pelvis

-Acute urinary retention -Urgency or frequency of micturition -Rarely dyspepsia or constipation • Pain –Dysmenorrhoea -Lower abdominal and pelvic pain: Not a common symptom but may occur in cases of fibroid polyp/ torsion of pedicle of subserous pedunculated fibroid/ degeneration of fibroid/ sarcomatous change in fibroid • Infertility 6

• Pregnancy complications-Increase in size with red degeneration, abortions, preterm labor, malpresentations • Labor complications-Inertia, Dystocia, PPH Examination • General physical examination-Pallor may be present in cases of anemia due to menorrhagia. • Abdominal examination may reveal a firm, non-tender, rounded/lobulated mass with side to side mobility and which is dull to percuss. (Only in cases of huge fibroids) • P/S exam- Submucosal fibroid polyp may be seen coming out of the cervix into the

vagina .with ulceration of surface of mass,seen as white discharge or bleeding. • P/V-Bimanual pelvic examination reveals an enlarged irregular firm uterus, but it may be symmetrically enlarged in cases of intramural and submucous fibroid. Subserous fibroid may be felt attached to the uterus or it may be felt as irregularity on one side or as an adnexal mass in case it is pedunculated or broad ligament fibroid. Submucosal fibroid

polyp may be seen/ felt coming out of the cervix into the vagina.D/D with inversion ut b) Investigations • CBC • Blood grouping and Rh • Urine routine and microscopy • Ultrasonography • Pap smear • Endometrial biopsy when diagnosis is in doubt c) Treatment Treatment modality should be individualized to each patient after considering patient’s age, severity of symptoms, need for fertility preservation, presence of other gynecological diseases and any other co-morbidity.

• Small Leiomyomas discovered incidentally and not associated with any complications usually do not require any treatment. Performing hysterectomy for an asymptomatic fibroid for the sole purpose of alleviating the concern that it may be malignant is not warranted. Such patients should be explained, reassured and called for examination at periodic intervals. 7

Asymptomatic fibroid may warrant treatment in following situations: • The size of fibroid uterus is more than 12-14 weeks pregnant uterus • Rapidly growing fibroid • Evidence of hydroureter / hydronephrosis resulting because of compression of ureters by the tumor. • Subserous pedunculated fibroids are liable to undergo torsion of pedicle and hence may be treated even if asymptomatic. • General measures: Correction of anemia with hematinics (iron & folic acid). Severe

anemics with ongoing blood loss may require packed cell transfusion. Reducing blood loss during periods. • Medical management: This should be tailored to suit the needs of the woman. However, the costs & side effects of different drugs may limit their long term use. Gonadotropin- releasing hormone agonists may be given pre-operatively in order to reduce blood loss and operating time prior to hysterectomy, myomectomy or myolysis. Indications of GnRH agonists administration:

A) Preoperatively to shrink fibroids and to reduce menstrual related anemia B) Short term alternative to surgery in perimenopausal females. C) Tab / Inj)tranexamic acid may reduce menorrhagia associated with fibroids D) Tab danazol has been associated with reduction in volume of fibroid by 20 -25%. Although long term response to danazol is poor ,it may offer an advantage in reducing menorrhagia Disadvantages of giving GnRH agonists E) High cost F) Side effects like hot flashes & vaginal dryness

G) Risk of development of osteoporosis if given for more than 6 months. H) Higher risk of recurrence of fibroids after myomectomy if GnRH analogues have been given pre-operatively. Some other drugs that can be employed along with their indications & side effects are enlisted below: 8

Treatment Indications & Potential unwanted outcomes experienced by some women (Common: 1 in 100 chance; less common: 1 in 1000 chance; rare: 1 in 10,000 chance; very rare: 1 in 100,000 chance) Levonorgestrel- Small fibroids not distorting the uterine cavity releasing intrauterine Common: irregular bleeding that may last for over 6 months; hormone- system related problems such as breast tenderness, acne or headaches, which, if present, are generally minor and transient Less common: amenorrhoea

Rare: uterine perforation at the time of insertion Tranexamic acid Menorrhagia Less common: indigestion; diarrhoea; headaches Non-steroidal anti- Menorrhagia & dysmenorrhea inflammatory drugs Common: indigestion; diarrhoea Rare: worsening of asthma in sensitive individuals; peptic ulcers with possible bleeding and peritonitis Oral progestogen Size reduction (norethisterone) Common: weight gain; bloating; breast tenderness; headaches; acne (but all are usually minor and transient) Rare: depression

Injected progestogen Size reduction Common: weight gain; irregular bleeding; amenorrhoea; premenstrual-like syndrome (including bloating, fluid retention, breast tenderness) Less common: small loss of bone mineral density, largely recovered when treatment discontinued Though many gynaecologists are using danazol & mifepristone to reduce the size of the fibroids with good results, there is no definite consensus on their use & further trials are necessary to clearly define their roles. • Surgical treatment

-Hysterectomy is the surgical removal of uterus which may be done abdominally/ vaginally or laparoscopically based on the size of uterus, mobility and descent of uterus, patient’s desire and presence of other gynecological diseases and other co-morbidities. In women who don’t wish to preserve uterus/ fertility, hysterectomy is a definitive treatment. Disadvantages of hysterectomy are the surgical and anaesthetic risks involved in the same. 9

-Myomectomy is the surgical removal of myomas while uterus is being preserved. This may be done abdominally/ vaginally/laparoscopically or hysteroscopically, depending on the site and size of myomas. The merit of myomectomy lies in preservation of fertility but the disadvantage is risk of recurrence of fibroids, which may require a repeat surgery. Myomectomy is usually preferred in patients less than 40 years of age, who wish to preserve their menstrual and

reproductive functions. Vaginal myomectomy is suitable for patients with submucous pedunculated fibroid projecting into vagina. d). Referral criteria • Patients desirous of fertility & have fibroids that distort the uterine cavity where no other factors have been identified can be managed by laparoscopic / hysteroscopic myomectomy & should be referred to a super specialty hospital, in case facilities for the same are not available in situation1.

• Pregnant women may require additional fetal surveillance when the placenta is implanted over or in close proximity to a fibroid. • In case laparoscopic hysterectomy is planned and adequate facilities / equipment / skilled laparoscopic surgeon / anaesthetist are not available, patient should be referred to a super specialty hospital in a metro location. • Patients suitable for uterine artery embolization procedure/myolysis • Presence of co-morbidities like cardiac diseases, pulmonary diseases etc.

• HRT may be given if indicated in postmenopausal women. Although it causes myoma growth in postmenopausal women, it does not appear to cause clinical symptoms. Postmenopausal bleeding and pain in women with fibroid should be investigated in the same way as in women without fibroids. Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical diagnosis- Same as situation1 b) Investigations -CBC -Blood grouping -Urine routine and microscopy

- Ultrasonography (Transabdominal & transvaginal) -Sonohysterography /Hysteroscopy - Pap smear 10

- Endometrial biopsy where indicated. -Magnetic resonance imaging (if needed) c) Treatment Treatment modality should be individualized to each patient after considering patient’s age, severity of symptoms, need for fertility preservation, presence of other gynecological diseases and any other co-morbidity. Management of asymptomatic fibroids, general measures and medical management as already mentioned in situation1. • Surgical treatment options are as already mentioned in situation1.Laparoscopic

hysterectomy or laparoscopic myomectomy can be offered in case where patient does not have any cardiac or respiratory disorders which contradict the same. Very large tumors may limit the suitability of the case for laparoscopic management. Subserous pedunculated fibroids are usually good candidates for laparoscopic myomectomy. Hysteroscopic myomectomy can be done for symptomatic submucosal fibroids. -Laparoscopic Myolysis or myoma coagulation is usually done with Nd:YAG lasers or

bipolar needles. This results in necrosis and shrinkage of myoma. It may be combined with endometrial ablation to reduce bleeding. Women may be candidates for myolysis if they have fewer than four myomas of ≤ 5 cm or if their largest myoma measures less than 10 cm in diameter.Laproscopic myolysis may present an alternative to myomectomy or hysterectomy for selected women with symptomatic intramural or subserous fibroids who wish to preserve their uterus but do not desire future fertility( sogc level II b )

• Non-surgical treatment: -Uterine artery embolization is an interventional radiologic procedure to occlude uterine arteries and hence relieves menorrhagia in more than 90% of patients. In this procedure, a micro-catheter is introduced into the uterine artery via femoral approach and usually polyvinyl alcohol foam particles are used to occlude uterine arteries. This results in infarction of myomas. It has the advantage of being a minimally invasive procedure, avoids surgery and entails a

shorter duration of hospital stay. Its role in preservation of fertility is yet undetermined pending long term studies. The disadvantage is risk of symptom recurrence in nearly 17% cases. Magnetic-resonance-guided focused ultrasound surgery: Magnetic-resonance-guided focused ultrasound surgery (MRgFUS) is a non-invasive thermo-ablative technique that uses focused high-energy ultrasound to ablate fibroid tissue. As in conventional diagnostic ultrasound, the ultrasound waves pass through the

anterior abdominal wall. Significant heating only occurs where the waves converge at the focus. Magnetic resonance guidance provides continuous imaging of the fibroid and other vital structures such as bowel, bladder and sacral nerves. Significant improvement in quality-of-life parameters has been reported in women undergoing MRgFUS. Given considerable symptoms at enrolment and a large decrease 11

in mean symptom levels, this appears to be a clinically significant result. The volume reduction after treatment is small compared with the mean levels seen after both myomectomy and uterine artery embolization (UAE). MRgFUS appears to be a safe intervention for uterine fibroids. Furthermore, women who have treatment with MRgFUS do not appear to develop symptoms similar to the postembolization syndrome symptoms associated with UAE.

However, the true place of MRgFUS is yet to be established in comparison with the other available treatment modalities by way of randomized controlled clinical trials3. References 1. Pratap Kumar, Narenda Malhotra. Jeffcoate’s Principles of gynecology. 7th ed. Jaypee publishing; 2008 2. Rock, John A.; Jones, Howard W. III. Te Linde’s Operative Gynecology. 10th ed. Lippincott Williams & Wilkins (LWW); 2008 3. Best Practice & Research Clinical Obstetrics and Gynaecology Vol. 22, No. 4, pp. 735– 747, 2008

4. SOGC Clinical Practice Guidelines;2003 5. NICE Clinical Guidelines44;2007 12

ANTE PARTUM HAEMORRHAGE Definition: APH is defined as bleeding from or into the genital tract occurring from 24th week of pregnancy and prior to the birth of the baby. Why it occurs? The causes of APH include placenta previa,abruption placenta,local causes and unexplained causes. Local causes comprise vasa previa and cervical or vaginal causes. Commonly it is due to: - Placenta previa - Abruptio placenta It may also be due to: - Exaggerated show, - Trauma to cervix or vagina - Cervical ectropion,

- Carcinoma of cervix or polyps - Vasa previa How to diagnose Placenta Previa? Definition: The term placenta previa refers to a placenta that overlies or is proximate to the internal os of the cervix. The placenta normally implants in the upper uterine segment. In placenta previa, the placenta either totally or partially lies within the lower uterine segment. Incidence: 1 in 300 pregnancies Maternal morbidity and mortality is high if it is not treated properly.

Perinatal morbidity and mortality also are primarily related to the complications of placenta previa, because the hemorrhage is maternal. Predisposing factors: o Advancing maternal age o Multiparty 13

o Multifetal gestations o Prior caesarean delivery o Prior placenta previa Differential Diagnosis: Abruptio placentae, other probable causes. Optimal Diagnostic Criteria, investigations, treatment and referral criteria: Situation 1: At Secondary Hospital/ Non-Metro situation: (Optimal Standards of Treatment in Situations where technology and resources are limited)- a) Clinical Diagnosis: It is on the basis of history, physical examination and investigations.

 History: Nature of bleeding: Painless, recurrent, bright red. Initial bleeding may not be profuse enough to cause death; but it is a warning sign and requires close monitoring or refer the patient to higher centre.  On physical examination: Patient might be in shock – Abdominal examination: Height of uterus proportionate to gestational age, presenting part may be felt high up (not engaged). – Malpresentations, malpositions usually present.

– Uterine contraction may or may not be present. Some degree of uterine irritability is present in about 20% of the cases. – Fetal heart sound may or may not be present, depending upon theamount of blood loss. If you suspect placenta previa, do not perform a vaginal examination without preparation. Per vaginal examination should be done in theatre but without any anesthesia with all preparations of immediate cesarean section. b) Investigations:  Blood investigations (Full blood count, blood group and type)

 Ultrasound examination: Rules out types of placenta previa; fetal anomalies, fetal parameters, presentation and position.  Transabdominal ultrasonography (TAS): - It should be with partially full bladder. - It is a simple, precise, and safe method to visualize the placenta. - TAS has an accuracy of 93-98%. - Four types of placenta praevia according to abdominal sonography Type I- Dips in to lower segment Type II - Reaches lower border of uterus up to cervical os but not covering completely.

Type III- covers the internal os Type IV - Covers the internal os, even on full dilatation of the cervix. At 18 weeks, 5-10% of placentas are low lying. Most ‘migrate’ with development of the lower uterine segment. - False-positive results can occur secondary to focal uterine contractions or bladder distention.  Transvaginal ultrasonography (TVS): Recent studies have shown that the transvaginal method is safer and more accurate than the transabdominal method. Transvaginal ultrasonography is

also considered more accurate than transabdominal ultrasonography. – Skilled person should only do. – The os–placental edge distance on TVS after 35 weeks’ gestation is valuable in planning route of delivery. When the placental edge lies > 20 mm away from the internal cervical os, women can be offered a trial of labour with a high expectation of success. A distance of 20 to 0 mm away from the os is associated with a higher CS rate, although vaginal delivery is still possible depending on the

clinical circumstances. – In general, any degree of overlap (> 0 mm) after 35 weeks is an indication for Caesarean section as the route of delivery c) Treatment : • Assess the blood loss • Resuscitate: 15

§ Monitor BP § Start IV Line § Restore blood volume by infusing normal saline § Explain the need of blood transfusion § Arrangements made to shift to higher centres. d) Referral criteria: Shift to hospitals where blood bank, neonatal and emergency cesarean section facilities are available. Situation 2: (At Super Specialty Facility in Metro location where higher-end technology is available) a) Clinical diagnosis: Diagnosis reached by history, physical examination and sonographic examination

After initial assessment further investigations need to be performed to ascertain cause , degree of bleeding, plan the on-going care and to decide mode and time of delivery. b) Investigations: As above. § Blood investigations (Full blood count, blood group and type) § Ultrasound examination : Best investigative tool to diagnose placenta previa. Rule out all Four types of placenta previa: o Type I- Dips in to lower segment o Type II - Reaches lower border of uterus up to cervical os but not covering

completely. o Type III- covers the internal os o Type IV - Covers the internal os, even on full dilatation of the cervix. – At 18 weeks, 5-10% of placentae are low lying. Most ‘migrate’ with 16

development of the lower uterine segment. - MRI: MRI has been suggested as a safe and alternate method and may be useful in determining the presences of placenta accreta/increta/percreta. c) Treatment: § NO VAGINAL EXAMINATION § Resuscitate: § Monitor BP § Assess the amount of bleeding. § Start IV line § Restore blood volume by blood products The definitive treatment depends upon the duration of pregnancy, fetal and maternal status and extent of hemorrhage:

§ Type I and Type II anterior - vaginal delivery can be expected. Trial of vaginal delivery can be given and caesarean is done if patient bleeds § Type II -b, III & IV - Elective/emergency caesarean section has to be done at the earliest. 17

Fig. Flow chart showing management of Placenta previa In every case of placenta previa , be careful for postpartum haemorrhage. ABRUPTIO PLACENTA Definition: Abruptio placenta is the detachment of a normally located placenta from the uterus before the fetus is delivered. It is an obstetric emergency. Types: It can be classified as- § Revealed (separation of placenta with blood visible outside) § Concealed (blood collects behind the separated placenta. Not visible outside) § Mixed, (common type). 18

According to Sher clinical grading for placental separation 1. Grade 1: (Herald bleed) diagnosed retrospectively 1. Less than 100cc -150cc of uterine bleeding 2. Uterus non-tender 3. No Fetal Distress 2. Grade 2 ; Classical features of abruption 1. Uterus tender 2. Fetal Distress 3. Concealed hemorrhage 3. Grade 3 1. Fetal death 2. Maternal shock 3. Extensive concealed hemorrhage 4. Coagulopathy Incidence : 1-2% Perinatal mortality rate associated with placental abruption is high. Causes: unknown .

But following are risk factors: o Increased age and parity o Preeclampsia/ Chronic hypertension o Preterm ruptured membranes o Multifetal gestation o Hydramnios o Cigarette smoking o Thrombophilias o Prior abruption o Uterine leiomyoma o External trauma (Sudden jerk or assault over abdomen) 19

o Anaemia o Short cord. Complications: Complications include the following: o Maternal blood loss leading to shock, disseminated intravascular coagulation [DIC], mult-iorgan failure. o Fetal distress or death o IUGR if chronic and mild. o In Rh negative mothers, chances of feto-maternal transfusion and Rh sensitization. o Prematurity Optimal diagnostic criteria, investigations, treatment & referral criteria for Abruptio placentae are following: Situation 1:

At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited. a) Clinical Diagnosis: Placental Abruption is a clinical diagnosis. Severity of symptoms and signs depends on degree of separation and blood loss. Symptoms: § Vaginal Bleeding § Uterine tenderness § frequent uterine contractions Signs: 20

§ Vital signs suggestive of cardiovascular compromise 1. Tachycardia 2. Orthostatic changes in blood pressure and pulse § Abdominal examination: 1. Uterus may be larger than gestational age 2. Uterine hyper tonicity 3. Fetal demise(depending upon the severity) § Hemorrhagic shock disseminated intravascular coagulation. Diagnosis is made by clinical picture and confirmed by ultrasonography. b) Investigations: § Full blood count § Blood grouping and typing, cross match § Coagulogram for DIC screening

§ Fetal heart monitoring § Trans-abdominal ultrasonography done for evaluation of fetal presentation, size, fetal well-being and placental localization and separation. c) Treatment: 1. Bed rest for mild symptoms 2. Prompt delivery for severe symptoms with aggressive supportive measures. Prompt delivery is usually indicated if any of the following is present(grade 2 or 3 abruption) 21

a) Maternal hemodynamic instability b) Non-reassuring fetal heart rate pattern on cardiotocography c) Near-term pregnancy 3. Resuscitation: 1. Start IV Line with normal saline and refer to higher centre. 2. Blood transfusion: Explain the need of blood replacement and send the relatives blood donation. 3. Vaginal delivery may be tried if patient is in advanced labour and baby is either not compromised or IUD. 4. Definite management: Stable patient (Grade I) management : § Hospitalization

§ Bed rest if the pregnancy is not near term and if mother and fetus are stable. Patient is followed up if: i. Bleeding does not threaten the life of the mother or fetus. ii. The fetal heart rate pattern is reassuring. iii. The pregnancy is not near term. iv. No Coagulopathy v. Optimal urinary output This approach ensures close monitoring of mother and , if needed, rapidly treated. Corticosteroids should be considered (to accelerate fetal lung maturity) if gestational age is <

34 wk. Injection Betamethasone 12 mg. IM 12hrs.apart total of two injections. 22

If bleeding resolves and maternal and fetal status remains stable, ambulation may be allowed. Patient may be discharged from hospital if pregnancy is not term. Patients are followed up in ante natal clinic. If bleeding continues or if status deteriorates, prompt delivery is indicated. Per vaginal examination is done in operation theatre and if findings are favourable, artificial rupture of membrane is done to augment the labor with syntocinon. If per vaginal findings

are not favourable, caesarean section may be done. Complications and shift to grade 2 or 3 abruption can happen any time so patient should be referred to higher center for monitoring. d) Complications: Maternal complications i. Hypovolemic shock ii. Renal Cortical necrosis iii. Coagulopathy iv. Amniotic fluid embolism v. Maternal Death vi. Uteroplacental apoplexy (Couvelaire uterus) \ vii. Bleeding into myometrium results in hypotonic wall viii. Risk of post partum hemorrhage Fetal complications

• Intrauterine growth retardation • Still birth e) REFERRAL CRITERIA : Shift to hospital where blood bank, neonatal and emergency cesarean section facilities and facility to treat multi organ failure and DIC are available. 23

Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available: a) Clinical Diagnosis: Detailed history, physical examination and investigations, will be done to confirm the diagnosis. b) Investigations: Blood count, Blood grouping and typing, cross match, Coagulogram for DIC screen. c) Ultrasound: Evaluation of fetal presentation, size, fetal well-being and placental localization and separation. d) Treatment: § Admit § History & examinations

§ Assess blood loss .It is always more than revealed. § Treatment for placental abruption varies depending on gestational age and the status of the mother and fetus. § Begin continuous external fetal monitoring for both the fetal heart rate and contractions. § Obtain intravenous access using 2 large-bore intravenous lines. § Institute crystalloid fluid resuscitation for the patient. § Type and cross match blood. § Begin a transfusion if the patient is hemodynamically unstable after fluid resuscitation.

§ Correct coagulopathy, if present. § Administer Rh immune globulin if the patient is Rh-negative. Management of coagulopathy Indicators for prompt delivery: a. Fetal distress (Non-reassuring fetal heart rate pattern). b. Maternal hemodynamic instability. c. DIC 24

d. Labor e. Term Vaginal delivery is acceptable as early as possible (generally preferred with DIC). § If bleeding is heavy (revealed or concealed) deliver as soon as possible. § Patient has to be delivered within 8 hours by Artificial rupture of membrane and Oxytocin 2.5units (not more than 5 units) in 500 cc of Dextrose. § If cervix is fully dilated deliver by forceps or vaccum extractor. § If vaginal delivery is not imminent or fetus is alive deliver by cesarean section.

§ All precautions for the prophylaxis of third stage of labor. In every case of abruptio placentae, be prepared for postpartum haemorrhage. FURTHER READING / REFERENCES. 1. Williams Obstetrics : 23rd edition 2. Practical guide to High Risk Pregnancy and Delivary by Fernando arias 3. RCOG Greentop guideline No: 27 RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs, and consumables

and equipment. Quantity to also be specified) Situation Human Investigations Drugs and Equipment resources consumables 25

1 Obstetrician CBC Gloves x 10 pairs Stethoscope Physician RBS Drapes for BP apparatus Anaesthetist Urine r/e, c/s delivery/Caesarean Pulse oximeter Paediatrician Blood Gp Rh Suture materials USG machine Nurses x 2 TSH Foleys catheter ECG monitors OT technician Serology Urobag Xray Lab technician VDRL CVP line Lab equipment House APTT,PT,INR Arterial line Labour room keeping USG IV canula Labour couch ECHO Drip sets Delivery/Caesarean ECG IV Fluids tray X Ray TED Stockings Vacuum apparatus Boyles apparatus

OT table Light source Oxygen Suction Baby warmer 2 Obstetrician CBC Gloves x 15 pairs Stethoscope Interventional RBS Drapes for BP apparaus - Cardiologist Urine r/e, c/s delivery/Caesarean Pulse oximeter Paediatric - Blood Gp Rh Suture materials USG machine Cardiologist TSH Foleys catheter ECG, Xray Cardiac - Serology Urobag Lab equipment Anaesthetist VDRL CVP line Labour room Neonatologist APTT,PT,INR Arterial line Labour couch Intensive care USG Venflons Delivery tray

Nurses x 5 ECHO Drip sets Caesarean tray OT technician ECG IVFluids Vacuum apparatus 26

Lab technician X Ray Epidural Boyles apparatus Porters Cardiac anaesthesia kit OT table House catheterization General Light source keeping ABG studies anaesthesia kit Oxygen Suction ICU bed Syringe pumps Baby warmer 27

CARDIAC DISEASE IN PREGNANCY 1. WHEN TO SUSPECT / RECOGNISE? The physiological adaptations of normal pregnancy can induce symptoms and alter clinical findings that may confound the diagnosis of heart disease. Heart disease should be suspected or diagnosed at booking for antenatal women. Heart disease may be suspected when a pregnant lady presents with symptoms of progressive dyspnea or orthopnea, nocturnal cough, hemoptysis, syncope or chest pain.

When there are clinical findings like cyanosis, clubbing, distended neck veins, systolic murmur of grade 3/6 or greater, diastolic murmur, cardiomegaly, persistent arrhythmias, persistent split second sound, or pulmonary hypertension. i. Introduction: The incidence of heart disease in pregnancy is 1% and it is the third leading cause of death in women of reproductive age group. Risk of maternal mortality ranges from 0 to 50% depending on the cardiac condition. ii. Case definition:

Rheumatic Heart Disease (RHD) remains an important cause of heart disease especially in developing countries like India. A large number of women undergoing valve replacement surgeries on oral anticoagulants warrant specialized care during pregnancy and childbirth. With advances in paediatric cardiac surgery more women with congenital heart disease (CHD) are now surviving and reaching child bearing age. Ischemic heart disease is also

on the rise as a result of increase prevalence of obesity, hypertension and diabetes in young adults and delayed child bearing. Maternal mortality is higher in conditions that restrict an increase in pulmonary blood flow especially pulmonary hypertension and mitral stenosis. The situation is at its worst 28

in Eisenmengers syndrome, where there is refractory hypoxaemia when the mortality is 25 to 50 %. Other cardiac complications associated with pregnancy include infective endocarditis, cardiac arrhythmias, development of cardiomyopathy. Fetal outcome in pregnancies complicated by maternal RHD is usually good although there is an increased incidence of growth restriction and preterm birth. The effects of maternal anticoagulant therapy with warfarin could lead to abortions,

stillbirths in 7%, warfarin embryopathy in 8%of live born infants. Warfarin exposure in the 2nd and 3rd trimesters could lead to disharmonic growth of organs due to hemorrhage in the fetus and deformation from scarring leading to corpus callosum agenesis, Dandy Walker malformation, cerebellar midline atrophy, optic atrophy and blindness, microphthalmia, mental retardation and developmental delay. Anticoagulation may be indicated in certain cardiac conditions such as mechanical heart

valves, atrial fibrillation and pulmonary hypertension. Fetal growth restriction and preterm birth are more common in pregnancies complicated by CHD with restricted maternal cardiac output, especially poor in cyanotic varieties when the fetal wastage rates may be as high as 40%. The etiology of CHD is multifactorial and incidence is 0.8 %. Incidence of CHD in the offsprings of parents with CHD ranges from 5 -10%. However, risk may be as high as 50% as in Marfan’s syndrome.

iii. INCIDENCE OF THE CONDITION IN OUR COUNTRY Nearly 1 % of all pregnant women have cardiac disease iv. PREVENTION AND COUNSELING Women may be aware of their cardiac condition before falling pregnant. An assessment of the patient’s clinical status and ventricular function are necessary to best predict the outcome of pregnancy. In more than 50% of women it is first diagnosed during pregnancy. A Cardiologist should be involved in initial assessment and followup. In some women,

life threatening cardiac abnormalities can be reversed by corrective surgery and subsequent pregnancy is less dangerous. 29

Women with conditions like pulmonary hypertension, severe left sided obstructive lesions, dilated aortopathy(>4cm) and severe systemic ventricular dysfunction should be counseled for early termination of pregnancy to avoid maternal mortality. Concurrent medical problems like infections, anaemia should be aggressively treated. Pneumococcal and influenza vaccines are recommended to avoid respiratory infections precipitating cardiac failure. Cigarette smoking and illicit drug abuses are prohibited to

prevent cardiorespiratory side effects and infective endocarditis. Women with cardiac disease should be counseled regarding the risk of maternal death, possible reduction in maternal life expectancy, fetal issues, need for timely switch over of anticoagulant therapy, need for frequent hospital attendance and possible admission, intense feto-maternal monitoring during labour. v. DIFFERENTIAL DIAGNOSIS a) Normal physiological changes of pregnancy b) Anaemia

vi. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA . Situation 1: At Secondary Hospital/Non-Metro situation: Optimal Standards of treatment in situations where technology and resources are limited a. Clinical Diagnosis: A clinical suspicion or recognition of cardiac disease based on history, clinical symptoms and signs as explained above is made b. Investigations: 30

Basic work up like complete blood counts, urine routine, blood grouping Rh typing, serology,VDRL, APTT, PT INR, scans for dating, aneuploidy screening qnd foetal anomalies. Nonivasive studies like electrocardiography, echocardiography and chest radiography with abdominal shielding can be conducted during pregnancy to support the diagnosis. . c. Treatment: Clinical Classification Schemes commonly used are that of NYHA and ACOG These classification systems are useful to clinicians to evaluate the functional

capacity and to aid in counseling the woman regarding advisability of conception or continuation of pregnancy. New York Heart Association (NYHA) Classification Scheme: • Class 1 Uncompromised. No limitation of physical activity. • Class II Slightly compromised. Slight limitation of physical activity. • Class III Markedly compromised. Marked limitation of physical activity. • ClassIV Severely compromised. Inability to perform any physical activity without discomfort

Risk of Maternal mortality Caused by Various Types of Heart Disease (ACOG1992a): Cardiac disorder Mortality % Group 1 - Minimal Risk 0-1 • Atrial septal defect • Ventricular septal defect 31

• Patent ductus arteriosus • Pulmonic or tricuspid disease • Corrected Tetrology of Fallot • Bioprosthetic Valve • Mitral stenosis (NYHA Classes 1and II) Group 2- Moderate Risk 5-15 2A: • Mitral stenosis (NYHA Classes III and IV) • Aortic stenosis • Aortic coarctation without valvar involvement • Uncorrected Fallot tetrology • Previous myocardial infarction • Marfans syndrome, normal aorta 2B: • Mitral stenosis with atrial fibrillation • Artificial valve Group 3- Major risk 25-50% • Pulmonary hypertension

• Aortic coarctation with valvar involvement • Marfan syndrome with aortic involvement The management in most instances is by a multidisciplinary team involving: • Obstetrician • Physician /Cardiologist • Anaesthetist • Paediatrician 32

Most women with functional Class 1 and 2 go through pregnancy without morbidity. However, special attention should be directed toward both prevention and early recognition of heart failure. Indicators being cough, progressive edema, tachycardia, haemoptysis and basal rales. Empirical therapy with diuretics and beta-blockers could be hazardous, so opinion of cardiologist /physician should be taken. Labour and Delivery: Vaginal delivery is recommended unless there is an obstetric indication for caesarean

section. Await spontaneous onset of labour. Avoid induction of labour to minimize risk of intervention thereby haemorrhage and infections. However, despite the increased risks of hemorrhage, infection and large fluid shifts, there are a few conditions in which labor is ill-advised and cesarean delivery is recommended: • Dilated aortic root ( >4cm) or aortic aneurysm • Acute severe congestive heart failure • A history of recent myocardial infarction • Severe symptomatic aortic stenosis

• Warfarin administration within 2 weeks of delivery • Need for emergency valve replacement immediately after delivery Careful fluid balance should be monitored. Avoid supine position. A semi recumbent position with lateral tilt preferred. Monitor vitals - pulse, respiration, BP, Oxygen saturation and intake output. Epidural analgesia by a skilled senior anaesthetist considering its hypotensive effect. Cut short 2nd stage of labour with outlet forceps or vacuum extractor to reduce maternal effort.

Infective endocarditis prophylaxis is recommended preferably 30-60 minutes before the procedure. Either Ampicillin 2g or Ceftriaxone 1g is given iv ( ±1g vancomycin if Enterococcus infection is a concern) 600mg Clindamycin iv is recommended in cases of Penicillin allergy. Avoid methyl ergometrine which causes intense vasoconstriction, hypertension and heart failure. Instead use syntocinon for delivery of placenta. Close monitoring of cardiac patient should continue after delivery because early

postpartum period is often a time of acute de-compensation. d. Referral Criteria: 33

All patients with moderate and major risk of maternal mortality should be referred to a higher centre for following facilities:- a) Super specialists in cardiology and anesthesia with in-depth understanding of each cardiac condition are available. b) facilities should be available for obstetric care with intensive monitoring of mother and fetus under the supervision of a high risk pregnancy specialist(Obstetrician) c) Neonatologist with a well equipped NICU is available.

d) Referral may be necessary for fetal echocardiography to plan neonatal care in advance. Situation 2: At superspeciality Facility in Metro location where higher –end technology is available a. Clinical diagnosis A clinical suspicion or recognition of cardiac disease based on history, clinical symptoms and signs as explained above is made. b.Investigations Basic work up as in any pregnancy like complete blood counts, urine routine, blood

grouping Rhtyping, VDRL, serology, APTT, PT, INR, ultrasound for dating, aneuploidy screening, anomaly scan. Fetal echocardiography when indicated depending upon the risk of transmission. Nonivasive studies like electrocardiography, echocardiography and chest radiography with abdominal shielding can be conducted during pregnancy to support the diagnosis. 34

If indicated, cardiac catheterization can be performed with limited x-ray fluoroscopy by an interventional cardiologist. . c. Treatment Clinical Classification Schemes commonly used are that of NYHA and ACOG. These classification systems are useful to clinicians to evaluate the functional capacity and to aid in counseling the woman regarding advisability of conception or continuation of pregnancy. The management in most instances is by a multidisciplinary team involving: • Obstetrician • Cardiologist

• Cardiac Anaesthetist • Neonatologist • Intensivists Antenatal period Severe mitral stenosis is associated with a higher risk of pulmonary edema. Both beta blockers and balloon mitral valvotomy are safe in pregnancy. Pulmonary edema should be treated in the usual way with oxygen and diuretics. Women with prosthetic heart valves on oral anticoagulants will need replacement with heparin in early pregnancy between 6 to 12 weeks, to prevent embryopathy.

Again warfarin should be discontinued and replaced with heparin at 35-36 weeks to allow clearance of warfarin from the circulation. Heparin is discontinued 4-6hrs before delivery and regional anesthesia to minimize risks of obstetric hemorrhage and spinal hematoma. Intravenous heparin is restarted 6 hrs after vaginal delivery and 24 hours after a caesarean section. Warfarin is usually started the night after delivery provided there are no bleeding complications and heparin is continued until 35

an INR of 2 or more is achieved. In an emergency situation VitK or fresh frozen plasma can be used to reverse warfarin anticoagulation and protamine sulfate for heparin anticoagulation. Labor and Delivery Vaginal delivery is recommended unless there is an obstetric indication for cesarean section. 1. Await spontaneous onset of labor and induction of labor should be very judiciously attempted to minimize risk of intervention thereby hemorrhage and infections.

2. Careful fluid balance with central venous pressure monitoring may be necessary to manage conditions like mitral stenosis and aortic stenosis optimally. Such monitoring is rarely indicated in women who have remained in functional class1& 2 3. Avoid supine position. A semi recumbent position with lateral tilt is preferred. 4. Monitor vitals - pulse, respiration, BP, Oxygen saturation and intake output. 5. Epidural analgesia is administered by cardiac anaesthetist judiciously based on

the cardiac hemodynamics, as it causes hypotension. 6. Cut short 2nd stage of labor with outlet forceps or vacuum extractor to reduce maternal effort. 7. Infective endocarditis prophylaxis to be given with broad spectrum antibiotics. 8. Avoid methyl ergometrine which causes intense vasoconstriction, hypertension and heart failure. Instead use syntocinon for delivery of placenta. Epidural anesthesia is preferred by most clinicians. Hypotension can be very

hazardous with pulmonary hypertension or aortic stenosis , when narcotic conduction analgesia or general anesthesia may be preferable. Peripartum Cardiomyopathy Risk factors include multiparity, multiple pregnancy, hypertension, increased age. 36

Diagnostic criteria a) Development of cardiac failure in the last month of pregnancy or within 5 months after delivery. b) Absence of an identifiable cause for the cardiac failure. c) Absence of recognizable heart disease prior to the last month of pregnancy d) LV systolic dysfunction shown on echo as ejection fraction <45%, and LV end – diastolic dimension >2.7cm/sqm Recommended treatment a) Fluid and salt restriction, treatment of hypertension, routine exercise postpartum if stable.

b) Drugs like digoxin, beta blockers, diuretics, vasodilators may be used. c) In selected patients’ aldosterone antagonists, inotropes, anticoagulation, implantable defibrillators, biventricular pacing, cardiac transplantation may be the last resort. Prognosis and recurrence depends on the normalization of left ventricular size within 6 months of delivery. d.Referral Criteria Even in a metro situation a multidisciplinary specialist team with skill and facilities

may not always be available under one roof. In such instances referral may be required to an optimal setup under one roof for best feto-maternal outcome. FURTHER READING / REFERENCES 37

• Williams Obstetrics 23nd edition 2008 • Obstetrics and gynaecology Clinics Update on Medical disorders in Pregnancy, volume 37, No 2, June 2010 • American College of Obstetricians and Gynaecologists -Cardiac disease in pregnancy. Technical Bulletin No 168, June 1992a 38

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs, and consumables and equipment. Quantity to also be specified) Situation Human Investigations Drugs and Equipment resources consumables 1 Obstetrician CBC Gloves x 10 pairs Stethoscope Physician RBS Drapes for BP appar Anesthetist Urine r/e, c/s delivery/Caesarean Pulse oximeter Pediatrician Blood Group Rh Suture materials USG machine

Nurses x 2 typing Foleys catheter ECG monitors Ot technician TSH Urobag X ray Lab technician Serology CVP line Lab equipment House keeping VDRL Arterial line Labour room APTT,PT,INR Venflons Labour couch USG Drip sets Delivery/Cesarean ECHO IV Fluids tray ECG TED Stockings Vacuum X Ray apparatus Boyles apparatus OT table Light source Oxygen Suction Baby warmer 2 Obstetrician CBC Gloves x 15 pairs Stethoscope Interventional - RBS Drapes for BP appar 39

Cardiologist Urine r/e, c/s delivery/Caesarean Pulse oximeter Pediatric - Blood Gp Rh Suture materials USG machine Cardiologist TSH Foleys catheter ECG,Xray Cardiac - Serology Urobag Lab equipment Anaesthetist VDRL CVP line Cath lab Neonatologist APTT,PT,INR Arterial line Labour room Intensivist USG Venflons Labour couch Nurses x 5 ECHO Drip sets Delivery tray Ot technician ECG IVFluids Caesarean tray Lab technician X Ray Epidural Vacuum appar Porters Cardiac anaesthesia kit Boyles appar

House keeping catheterization General OT table ABG studies anaesthesia kit Light source Oxygen Suction ICU bed Syringe pumps Baby warmer 40

DYSFUNCTIONAL UTERINE BLEEDING INTRODUCTION DUB affects 22 to 30% of women and accounts for 12% of gynaecological referrals. DUB is not one condition of one etiology – it is a group of disorders characterized by dysfunction of any part of the reproductive system – uterus, ovary, pituitary, hypothalamus, higher centers. In clinical practice, the diagnosis of DUB is usually made by exclusion of organic disease of the genital tract or systemic organic disease. DEFINITION

It is defined as abnormal uterine bleeding without any clinically detectable organic pathology. How to make diagnosis? History: 1. H/o Abnormal Uterine Bleeding: a) Excessive menses-duration of menstrual flow > 7 days or menstrual blood loss > 80 ml b) Frequent menses-duration of menstrual cycle < 21 days c) Irregular / acyclical uterine bleeding. 2. H/o Symptoms Suggestive Of: a) Pregnancy b) Dysmenorrhoea/ dyspareunia/ infertility may suggest endometriosis and PID, fibroids, adenomyosis

d) Symptoms suggestive of hypothyroidism, bleeding disorders, other systemic illness e) Ingestion of drugs, like antiplatelet drugs (aspirin, clopedrogel) Examination: 1. A general examination for signs of anemia, thyroid disease or bleeding disorders. 2. Abdominal examination for masses. 3. All women with abnormal genital tract bleeding must have a speculum examination to visualize the cervix, vagina and exclude any local cause. 4. Per vaginal examination – look for uterine enlargement

(fibroids), tenderness/fixity (PID, endometriosis), any adnexal mass. INCIDENCE: 1. Pubertal or adolescent DUB – usually women less than 20 yrs, incidence – 4% 2. Reproductive DUB – seen in women from 20 to 40 yrs, incidence – 57% 3. Perimenopausal DUB – women aged above 40 yrs, incidence – 39% 4. Postmenopausal DUB – incidence around 10% DIFFERENTIAL DIAGNOSIS: 1. Pregnancy related bleeding a) Abortions b) Ectopic pregnancy c) Guestational trophoblastic disease 2. Fibroid uterus 3. Endometrial cancer

5. PID, Endometriosis. 6. Endometrial TB 7. PCOS SITUATION 1: DIAGNOSTIC CRITERIA, INVESTIGATION, TREATMENT & REFERRAL CRITERIA DIAGNOSIS: Clinical diagnosis is made by history and examination as explained above. Final diagnosis is only made after investigations. INVESTIGATIONS: a) Urine pregnancy test b) Complete blood count c) Platelet count, BT, CT, PT, PTT especially in puberty menorrhagia not responding to treatment d) Thyroid profile e) LFT & RFT only in strongly suspected cases

f) USG – TAS/TVS: Ultrasound is the first-line diagnostic tool for identifying structural abnormalities. g) Pap smear h) Sonohysterography i) Endometrial biopsy – by Novac curette, By Pipelle aspirator • Women with irregular menstrual bleeding should be investigated for endometrial polyps and/or submucous fibroids. • Clinicians should perform endometrial sampling based on the methods available to them. An office endometrial biopsy should be obtained if possible in all

women presenting with abnormal uterine bleeding over 40 years of age or 43

weighing more than or equal to 90 kg to exclude endometrial cancer or atypical hyperplasia, treatment failure or ineffective medical treatment • D & C- mandatory in perimenopausal age group (>40 years) and is contraindicated in unmarried girls, puberty menorrhagia. j) Hysteroscopy – with hysteroscopic guided biopsy sensitivity is 98%. Hysteroscopy should be used as a diagnostic tool only when ultrasound results are inconclusive, for example, to determine the exact location of a fibroid or the

exact nature of the abnormality. [A] Hysteroscopically-directed biopsy is indicated for women with persistent erratic menstrual bleeding, failed medical therapy or transvaginal saline sonography suggestive of focal intrauterine pathology such as polyps or myomas. k) Laparoscopy – to exclude unsuspected pelvic pathology such as endometriosis, PID/Ovarian tumor. The indication is urgent is associated with pelvic pain. l) Saline infusion sonography should not be used as a first-line diagnostic tool.

m) Magnetic resonance imaging (MRI) should not be used as a first-line diagnostic tool. TREATMENT: General 1. Assurance and sympathetic handling of physiological or emotional problems 2. Normal routine activities 3. Correction of anemia by diet, haematinic and even by blood transfusion 4. Clinically evident systemic/endocrine abnormalities should be investigated and treated accordingly Medical Management: Non hormonal methods:

1. Anti fibrinolytic agents – oral/IV tranexemic acid – 500 mg-1gm twice or thrice daily till severe bleeding. Effective in ovulatory DUB, iatrogenic menorrhagia secondary to insertion of IUCD, Von Wilibrand’s disease 44

2. Prostaglandin synthetase inhibitors (NSAIDS) – Mefenamic acid – 250 mg – 500 mg – twice or thrice daily, effective in ovular DUB 3. Ethamsylate – 250 – 500 mg TDS oral/IV 4. Anti tubercular treatment when disease is confirmed Hormonal Method: To stop acute episodes of bleeding and to regulate the cycles 1. Progestins a. Tab nonethisterone 20 – 30 mg/day in divided doses. It arrests bleeding in 24 – 48 hrs; later dose is tapered and continued in cyclical fashion from

5th day of withdrawal flow in subsequent cycles for 3 to 4 cycles. b. Similarly Medroxy progesterone acetate (MPA) can also be used. 2. Cyclical therapy: In ovular bleeding: 1. OCP is given from 5th to 25th day of cycle for 3 consecutive cycles. In ovular bleeding where patients wants pregnancy or in case of irregular shedding or ripening dydrogesterone 10 mg per day from 16th to 25th day. In anovular bleeding: a) MPA 10mg 5th to 25th day, NE 5mg 5th day to 25th day for 3 consecutive cycles

b. DMPA – 150 mg I.m every three months useful in maintenance therapy in woman who have difficulty with or cannot take OCPs. c. Ormeloxifene (Sevista) – 2 tab of 60 mg/week that is on Sunday and Wednesday for 12 weeks, 1 tab of 60 mg on following Sunday or Wednesday for 12 weeks d. Levonorgestrol – Releasing IUD(Mirena) 45

Surgical Management Hysterectomy – TAH/vaginal hysterectomy/laparoscopic hysterectomy. Hysterectomy should not be used as a first-line treatment solely for HMB. Hysterectomy should be considered only when: • Other treatment options have failed, are contraindicated or are declined by the woman • There is a wish for amenorrhoea • The woman (who has been fully informed) requests it • The woman no longer wishes to retain her uterus and fertility REFERRAL CRITERIA

a) Puberty menorrhagia where bleeding disorders are suspected and further investigation are to be done. b) Young women who want to preserve the uterus and facilities for endometrial destruction and ablation are not available. c) Associated comorbid medical conditions in which surgery is required. SITUATION 2 DIAGNOSTIC CRITERIA, INVESTIGATION AND TREATMENT DIAGNOSIS: As in situation 1 INVESTIGATIONS: In addition to investigations as in situation 1, certain specific tests like Specific tests for

bleeding disorders :Testing for coagulation disorders (for example, von Willebrand disease) should be considered in women who have had HMB since menarche and have personal or family history suggesting a coagulation disorder. [NICE GUIDELINE 2007] TREATMENT: 1. Along with the general and medical treatment as mentioned in situation 1. 2. conservative surgeries: 46

like Endometrial destruction or ablation – hysteroscopic and non hysteroscopic methods are available (TCRE, uterine thermal balloon ablation, radio frequency induced endometrial ablation, etc.) 3. Pre-requisite for undergoing these procedures: a) To exclude atypical endometrium b) CIN, Ca cervix, Ca endometrium has to be ruled out c) Not expecting 100% amenorrhea d) Uterus size less than 12 weeks e) No pelvic inflammatory disease f) Completed family

g) If necessary patient should be ready to undergo hysterectomy h) Ready for regular follow up i) Surgically fit j) Patient should know that its not effective contraception 4. Associated co morbid medical conditions in which surgery is required: (Hysterectomy). 47

Ectopic Pregnancy Introduction When implantation of the embryo occurs outside the uterine cavity is called ectopic pregnancy. Common site of implantation is in the fallopian tube. The risk of death from an undiagnosed ectopic pregnancy is greater than that of an induced abortion or delivery. Therefore slogan is “If you think ectopic then only you can diagnose ectopic”. Earlier the diagnosis, better is the prognosis with conservation of the reproductive capacity. Chances of a subsequent successful

pregnancy are reduced in these women. Risk factors for ectopic pregnancy • PID • Endometriosis • IUCD use • Progesterone only contraceptive pill use • Pregnancy after tubal ligation, tubal surgery • ovulation induction and assisted reproduction techniques, I Case definition: For both situations of care (mentioned below) Implantation of the embryo anywhere else other than the endometrial lining of the uterine cavity is an ectopic pregnancy. II. Incidence of the condition in our country:

1 to 3% of all pregnancies. III. Differential diagnosis: Very early intrauterine pregnancy Heterotopic pregnancy 48

IV Optimal diagnostic criteria, investigations, treatment and referral criteria Situation1. At Secondary Hospital/ Non Metro situation: Optimal Standards of treatment in Situations where technology and resources are limited. a) Clinical Diagnosis: Presentation could be diverse depends on whether rupture has occurred. The reproductive age group woman may present with amenorrhoea, bleeding pv, pain abdomen, sometimes with shock due to rupture. b) Investigations: 1. A urine pregnancy test should be positive

2. Ultrasound –abdominal/ vaginal- thickened echogenic endometrium, absent intrauterine gestational sac, sometimes a pseudosac, fluid in the culde sac, occasionally haematosalpinx, adnexal mass or a tubal ring representing the gestational sac. 3. Culdocentesis if ultrasound facility is not available 4. Blood grouping crossmatching and reservation 5. Histopathological examination of the operative specimen to confirm diagnosis. c) Treatment:

The standard aim of care is to control the bleeding and remove the ectopic pregnancy. Start an IV line, arrange for blood transfusion, rush patient to the operating room. General anaesthesia, IV antibiotic prophylaxis given and catherised. Abdomen entered through a transverse suprapubic inscision. The affected tube is brought out and salpingectomy is performed. Strict haemostatsis secured. Peritoneal cavity cleared of blood and blood products. Mops and instruments counted and abdomen closed in layers.

Blood transfused depending on the amount of loss and post op hemoglobin. 49

Inj Anti D immunoglobulin given if the lady is Rh negative and husband Rh positive Patient should be advised to report immediately in future pregnancies 50

d) Referral Criteria: When an unruptured ectopic pregnancy is diagnosed and facilities are lacking for timely monitoring of serum beta hcg titres and medical management. When patient is stable and facilities or skill to offer laparoscopic surgery are not available When heterotopic pregnancy is diagnosed and patient is desirous of continuing with the intrauterine conception. After a life saving laparotomy, for need of blood transfusion. Situation2.:

At Superspeciality Facility in Metro location where higher end technology is available. a) Clinical diagnosis: Similar to situation 1 b) Investigations: As in situation 1. Special investigations: 1. Serum Beta hCG titres need estimation serially to facilitate expectant management or medical manangement with Methotrexate. When Methotrexate is used: 1. Complete blood count 2. Liver function test 3. Renal function test c) Treatment: When ruptured ectopic is diagnosed laparotomy may be done as in situation 1.

When laparoscopy is chosen- Salpingostomy or salpingectomy is peformed. Expectant management : Proportion of all ectopics will not progress to tubal rupture, but will regress spontaneously and be slowly absorbed. Level of hCG must fall and the woman becomes clinically well. 51

it is an option for clinically stable asymptomatic women with an ultrasound diagnosis of ectopic pregnancy and a decreasing serum hCG, initially less than serum 1000 iu/l.(ref rcog greentop) Women managed expectantly should be followed twice weekly with serial hCG measurements and weekly by transvaginal examinations to ensure a rapidly decreasing hCG level (ideally less than 50% of its initial level within seven days) and a reduction in the size of adnexal

mass by seven days. Thereafter, weekly hCG and transvaginal ultrasound examinations are advised until serum hCG levels are less than 20 iu/l . On hcg monitoring if the level increases or plateaues ,active medical management is resorted to. Medical management with Methotrexate –. (rcog greentop) The most widely used medical treatment at present is intramuscular methotrexate given as a single dose calculated from patient body surface area. Dose:

A single dose of 1mg/kg body weight or 50mg/square metre body surface area of methotrexate given intramuscularly in addition to leukovorum (folic acid antagonist) 0.1mg/kg IM. Methotrexate should not exceed 4 doses. There is 70-95% efficiency in the treated cases. It takes 4-6 weeks for the complete resolution of ectopic pregnancy with methotrexate. Methotrexate is also useful in the management of persistent ectopic which is a complication of conservative surgical treatment and incomplete removal of

trophoblastic tissue. Serum hCG levels are checked on days four and seven and a further dose is given if hCG levels have failed to fall by more than 15% between day four and day seven. Large uncontrolled studies have reported that about 14% of women will require more than one dose of methotrexate and less than 10% of women treated with this regimen will require surgical intervention. Can be considered for women with confirmed or high suspicion for ectopic pregnancy

who are hemodynamically stable with no evidence of rupture. Absolute contraindications are breast feeding, immunodeficiency, alcoholism, blood dyscrasias, active pulmonary disease ,peptic ulcer disease,hepatic renal or hematologic disorder. Gestation sac larger than 3.5 cm and embryonic cardiac motion are relative contraindications 52

Medical management with Methotrexate- d. Referral criteria: 1. Patients with comorbidities requiring multidisciplinary input. 2. When skilled manpower and facilities are not available. 3. When it is a heterotopic pregnancy usually a consequence of assisted reproductive techniques, referral to an ART center for further care is necessary. V. Further reading and references: RCOG guidelines Williams Obstetrics Te Linde’s operative gynecology Novaks text book for gynecology

VI. Resources required for one patient/procedure Situation Human Investigations Drugs and Equipment resources consumables 1. Gynecologist Blood tests Boyles Anesthetist OT Nurses 2 Laparotomy set 2. Gynecologist Blood tests Methotrexate Boyles Assistant HCG OT doctor quantitative Laparotomy set Anaesthetist Laproscopy set Nurses x 3 Laboratory Sonologist Ultrasound Technicians x2 machine House keeping Blood bank officer 53

ANEMIA IN PREGNANCY Anemia is defined as a decrease in the oxygen carrying capacity of the blood due to decrease in amount of RBCs or haemoglobin or both. I. WHEN TO SUSPECT/ RECOGNIZE?  WHO - Hemoglobin -11gm/dl or less -Mild 8-11 gm/dl -Moderate 5-7 gm/dl -Severe below 5 gm/dl  ICMR categories -Mild 10-10.9 gm/dl -Moderate 7-10 gm/dl -Severe below 7gm/dl -Very severe(decompensated) below 4gm/dl  RBC<3.2million  PCV<33% Introduction:

Anemia is a major problem in women of child bearing age in developing countries with effects that may be deleterious to mothers and fetuses. Over one third of the world’s population suffers from anemia, mostly iron deficiency anemia. India continues to be one of the countries with very high prevalence. National Family Health Survey (NFHS-3) reveals the prevalence of anemia to be 70-80% in children, 70% in pregnant women and 24% in adult men. Prevalence of anemia in India is nearly two thirds of the pregnant

women because of low bioavailability diet, defective absorption & chronic blood loss due to hook worm infestation & malaria and rapidly successive multiple pregnancies. Iron deficiency anemia is responsible for 95% of the anemias during pregnancy. 55

In India, anemia is directly or indirectly responsible for 40 percent of maternal deaths due to haemorrhage, cardiac failure ,infection & preeclampsia . India contributes to about 80 per cent of the maternal deaths due to anemia in South Asia. There is 8 to 10-fold increase in MMR when the Hb falls below 5 g/dl. Maternal anemia is associated with increased perinatal morbidity & mortality rates consequent to IUGR, preterm births, low iron stores and cognitive & affective dysfunction in the infant.

India was the first developing country to take up a National Programme to prevent anemia among pregnant women and children. The National Anemia Prophylaxis Programme of iron and folic acid distribution to all pregnant women in India through the primary health care system was evolved and implemented from 1972. In order to tackle this public health problem, a multi- pronged 12 x 12 initiative has also been launched in the country. The initiative is targeted at all

adolescents across the country with the aim for achieving hemoglobin level of 12 gm% by the age of 12 years by 2012. NCIDENCE OF THE CONDITION IN OUR COUNTRY  Incidence- About one third of the global population(over 2 billion) are anemic  CDC-Up to 56% of all women in India are anemic (Hb < 11 g/dl)  NNMB, DLHS and ICMR surveys showed that over 70 percent of pregnant women are anemic The World Health Organization (WHO) estimates that 42% of all women, and 65-75% of

pregnant women in our country are anemic. In India, the second National Family Health Survey in 1998–1999 (NFHS-II) showed that 54% of rural women of childbearing age were anemic compared with 46% of women in urban areas. Kerala has only a 23% prevalence of anemia compared with 62% in many northeastern states of India. III. DIFFERENTIAL DIAGNOSIS  Nutritional  Hemorrhagic  Hemoglobinopathies  Bone marrow disorder  HIV  Drug induced  Tuberculosis  Inherited disorders 56

 Anemia caused by inflammation, malignancy, chronic diseases & autoimmune disorders IV. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA Complete medical history and Physical examination is very important. *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: Symptoms: 1. Weakness 2. Easy fatiguability 3. Lassitude 4. Dizziness or vertigo especially when standing

5. Headache 6. Irritability 7. Indigestion, loss of appetite 8. Breathlessness 9. Palpitations 10. Generalized swelling 11. Symptoms due to cause of anemia like yellowing of skin & mucous membranes, bleeding from rectum etc. Signs: 1. Pallor 2. Icterus 3. Glossitis, stomatitis 4. Koilonychia 5. Tachycardia, systolic murmurs, bounding pulse 6. Fine crepitations at lung bases 57

7. Splenomegaly 8. Hepatomegaly 9. Edema b)Investigations: l Hb% l PCV l Peripheral smear for immature cells, type of anemia and MP. l Urine routine and microscopy, Urine C/S if required l Stool for Routine and microscopy l USG abdomen c) Treatment: Although there are several different forms of anemia, this health profile will only address the three most common: iron-deficiency anemia, vitamin B12 anemia and folic acid deficiency. Non-drug treatment  Awareness/ Education

 Improvement of dietary habits-diet rich in Vit C, protein and iron, cooking in iron utensils, avoiding tea & coffee intake with meals & overcooking  Food Fortification  Social services such as improvement of sanitation & personal hygiene for eradication of helminthiasis  Annual screening for those with risk factors  Routine screening for anaemia & providing iron supplementation for adolescent girls from school days

Iron rich foods: Pulses, cereals, jaggery, Beet root, Green leafy vegetables, nuts, meat, liver, poultry, Egg, fish, legumes, dry beans, and dry fruits viz: dates, figs, apricots etc . Drug treatment: Prophylaxis WHO recommendation  60mg elemental iron and 0.25mg folic acid daily 58

 To be given for 6 months in countries with prevalence <40% & additional 3 months postpartum where the prevalence >40% Government of India recommendation  100mg elemental iron and 0.5mg folic acid daily  To be given in the second half of pregnancy and lactation for atleast 100 days Ferrous sulphate is least expensive and best absorbed form of iron. It also allows more elemental iron absorbed per gram administered. If for some reason, this is not tolerated, then

ferrous gluconate & fumarate are the next choice for iron therapy. Treatment of Iron deficiency has included:  Oral iron  Parenteral iron  Blood transfusion  Oral Iron - First line therapy - 200mg FeSo4 (60mg elemental iron)2- 3 times daily in conjunction with folic acid. - If patient is non-compliant to oral therapy or if there is gastritis, then reduce doses & give it after meals or change over to ascorbic acid/ carbonyl iron or parenteral therapy.

- Diagnostic reevaluation if there is no significant clinical or haematological improvement within 3 weeks.  Parenteral Therapy: Indications: - Hb less than 7g/dl and pregnancy >30 weeks - Malabsorption Syndrome - Incapacitating side effects with oral iron Preparations: - Iron sucrose - Iron dextran 59

- Iron sorbitol citrate Total iron deficit (mg) = Amount of iron deficit + amount of iron to replenish stores Amount of iron deficit (mg) = (Hb target- Hb initial)gm/dl x Body wt (Kg) × 2.2 + Stores Or ( 100-Hb initial)% x Body wt (Pounds) x 0.3 + Stores where Stores (mg) = 50% of deficit or approx 1000mg Iron Sucrose Complex is considered to show a significant improvement of Hb and iron stores in pregnant women. The target Hb may be taken as 11gm% for the Indian population according to WHO guidelines.

 Deworming necessary : - Albendazole 400 mg single dose - Mebendazole 500 mg single dose or 100 mg twice daily for 3 days - Levamisole 2.5 mg/kg single dose, best if a second dose is repeated on next 2 consecutive days - Pyrantel 10 mg/kg single dose, best if dose is repeated on next 2 consecutive days - To prevent recurrence, patients should be advised to use footwear, improve sanitation, and personal hygiene.  Malaria prophylaxis in endemic area to be treated.

Treatment of Folic Acid/ Vitamin B12 deficiency  Tab. Folic acid 5 mg daily Prophylactic - all woman of reproductive age should be given 400mcg of folic acid daily. Preventive daily or intermittent iron or iron+folic acid supplementation taken by women during pregnancy reduces anaemia in mothers. There is evidence that taking iron or iron and 60

folic acid daily or intermittently has a similar effect in reducing anaemia at term and improving haemoglobin concentrations in the mother.  Vitamin B12 deficiency: Oral preparation of Vitamin B12 (not very effective) In Moderate cases- 1000mcg of Parenteral Cynocobalamine every month In Severe cases 1000mcg/day for 1 week, following by weekly for 1 month d)Referral criteria:  Hb less than 5 gm% in all trimesters, less than 7gm% if >36weeks  Cases not responding to treatment

 Associated with medical disorders eg:leukaemias/ other obstetric complications  Haemolysis or evidence of bone marrow suppression  Other types of anemia(Sickle cell anemia, Thalasemia)  Level II USG to rule out fetal complication/ compromise by CVS/ Amniocentesis .  If any of the below suspected, as the below are common in pregnancy: - Maternal risks during Antenatal period: Poor weight gain, preeclampsia, eclampsia, placenta previa, accidental haemorrhage, premature rupture of membranes, pre

term labour, cardiac failure etc. - Maternal risks during Intranatal period: Dysfunctional labour, accidental hemorrhage, shock, anesthesia risk, cardiac failure, if signs of respiratory distress - Maternal risks during Postnatal period: Postnatal sepsis, sub involution, embolism, PPH (primary, secondary). Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available A) Clinical Diagnosis: Same as situation 1 B)Investigations:  Same as situation 1, in addition

 Red cell indices  LFT, RFT, LDH  Coombs Test  Iron studies - serum iron - serum iron binding capacity - serum ferritin  Hb electrophoresis  Bone marrow aspiration/ Biopsy C)Treatment: Same as situation 1  Confirm iron deficiency anaemia  Treatment of IDA includes :  Oral iron,  Parenteral iron,  Recombinant erythropoietin and  Blood transfusion  Inj. Iron Dextran (50 mg / ml elemental iron) 2 cc IM on alternate day after test dose x 10 injections by Z technique.  Blood Transfusion

Packed cells to be transfused. Indications - Hb < 7 gm/dl & POG > 36 weeks - Hb < 6 gm/dl & POG < 36 weeks - CHF due to anaemia(exchange transfusion) - Replenish blood loss due to APH/PPH - Not responding to oral & parenteral therapy  Diagnosis & management of sickle cell disease, Haemoglobinopathies, Pancytopenia in cases not responsive to iron.  Manage congestive cardiac failure/ PIH / Placenta Previa if associated/ where indicated. Megaloblastic Anemia  VitB 12 or Folic Acid Supplementation

Oxygen and other measures to deal with heart failure and PPH to be kept ready.  To cut short second stage by Outlet forceps/vacuum delivery of fetus.  To routinely employ active management of third stage of labour.  LSCS only for Obstetric Indications . POSTPARTUM MANAGEMENT:  Iron should be continued till the patient restores her normal clinical & haematological state & for an additional 3 months for store replenishment.  Dietary advice

 Effective method of contraception as per WHO guidelines & should not conceive for atleast 2 years giving time for iron stores to recover.  Sterilization is preferred if the family is complete. 63

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs, and consumables and equipment. Quantity to also be specified) Situation Human Investigations Drugs and Equipment resources consumables 1. Obstetrician Hb% Gloves x 10 pairs Stethoscope Drapes for BP apparatus At Secondary Physician PCV delivery/Caesarean Pulse oximeter Suture materials USG machine Hospital/ Pathologist RBC Foleys catheter ECG monitors

Non-Metro Urobag Lab equipment situation Lab technician Peripheral smear Venflons Labour room, CTG Drip sets Labour couch Optimal House keeping Urine routine and IVFluids Delivery/Caesarean Standards of microscopy Antiseptics, tray Compatible Vacuum apparatus Treatment in Stool for Routine blood/packed cells Boyles appar Situations and OT table where Microscopy Light source Oxygen technology Suction and Baby warmer resources are limited 64

2. Obstetrician CBC Gloves x 15 pairs Stethoscope Pathologist Peripheral blood Drapes for BP apparatus At Super Anaesthetist smear delivery/Caesarean Pulse oximeter Neonatologist Reticulocyte Suture materials USG machine Specialty Intensivist count Foleys catheter ECG Facility in Nurses x 5 Urine routine Urobag Lab equipment Metro OT technician and microscopy CVP line Automated cell counter Lab technician Stool for Arterial line Biochemistry analyser location Porters Routine and Venflons Labour room, CTG

where House keeping Microscopy Drip sets Labour couch higher-end IVFluids Delivery tray Iron studies Epidural anaesthesia Caesarean tray technology is LFT,RFT,LDH kit Vacuum apparatus available Coombs Test General anaesthesia Boyles apparatus kit OT table Hb Drugs to manage Light source electrophoresis cardiac failure , PPH Oxygen Suction Bone marrow ICU bed aspiration/ Syringe pumps Biopsy Baby warmer Guidelines developed by - Dr. Lavanya.R ( Dept. of OBG, Narayana Hrudayalaya) Karnataka,

- Dr. Sharath Damodhar( HOD, Dept. of Haemotology, Narayana Hrudayalaya) Karnataka, - Dr.Basavaraju Narasimhaiah, DGO, Tumkur Government Hospital, Karnataka, V. FURTHER READING / REFERENCES  Cochrane Database of Systematic Reviews 2007  Medscape J Med. 2008; 10(12): 283.  DeMayer EM, Tegman A. Prevalence of anaemia in the World.World Health Organ Qlty 1998; 38 : 302-16.  WHO. 2004. Micronutrient deficiency: Battling iron deficiency anaemia: the challenge.

Available from: http://www.who.int/nut/ida.htm, accessed on April 24, 2008. 65

 Ezzati M, Lopus AD, Dogers A, Vander HS, Murray C. Selected major risk factors and global and regional burden of disease. Lancet 2002; 360 : 1347-60.  IIPS National Family Health Survey 1998-99 (NFHS-2): Available from: http://www.nfhsindia.org/india2.html;accessed on September 24, 2008.  IIPS. National Family Health Survey 2005-06 (NFHS-3): Available from: http://mohfw.nic.in/nfhsfactsheet.htmb accessed on September 24, 2008.

 DLHS on RCH. Nutritional status of children and prevalence of anaemia among children, adolescent grils and pregnant women 2002-2004. Available from: http://www.rchindia.org/nr_india.htm 2006, accessed on September 24, 2008.  Toteja GS, Singh P. Micronutrient profile of Indian population.New Delhi: Indian Council of Medical Research; 2004.  National Nutrition Monitoring Bureau (NNMB). 2002.NNMB Micronutrient survey. Hyderabad: National Institute of Nutrition.

 Maternal Mortality in India 1997-2003, Registrar General of India. Available from: http://www.censusindia.net/, accessed on December 15, 2008.  Breymann C. Iron deficiency and anemia in pregnancy: Modern aspects of diagnosis and therapy. Blood Cells Mol Dis 2002; 29: 506-16.  Practical guide to High Risk Pregnancy and Delivery; Fernando Arias, 2nd edition; chap-3, pg245-262.  Williams Obstetrics, Eds Cunningham FG, Gant NF, Leveno KJ et al. 22nd Edn. 2005. 66

DIABETES AND PREGNANCY 1. WHEN TO SUSPECT OR RECOGNIZE? a) Introduction: The prevalence of pre existing diabetes in pregnancy is increasing in parallel with the rise in the rates of obesity. Diabetes in pregnancy is associated with risks to the woman & to the developing fetus. Miscarriage, preeclampsia and preterm labor are more common in women with preexisting diabetes. In addition, diabetic retinopathy can worsen rapidly during pregnancy.Stillbirth,congenital malformations,

macrosomia, birthinjury, perinatal mortality & postnatal adaption problems such as hypoglycaemia are more common in babies born to women with pre existing diabetes. Outcomes of diabetic pregnancies have improved for the mother and the newborn due to understanding of the disease process, improved education, and new treatment modalities delivered in a team approach. Nausea and vomiting of pregnancy and associated insulin resistance can make glycaemic control a

challenge. Care of women with preexisting diabetes demands careful monitoring in the preconception, prenatal, and postpartum periods. Controversies still exist in screening, management, & treatment of gestational diabetes. b) Case definition: For both situations of care (mentioned below) Pre gestational diabetes: Women who present with keto acidosis or random plasma glucose levels greater than 200mg/dl plus classical signs and symptoms such as polyphagia, polyuria or

polydipsia are labeled as pregestational diabetes. American Diabetes Association (2004) also recommends that pregnant women with fasting glucose levels of 126mg/dl or greater be considered to have overt diabetes. Gestational diabetes mellitus: Current practice is a 2 step testing, screening and diagnosis. Universal screening is recommended in India as Asians are a high risk group for diabetes. • O’Sullivan 50 g glucose, 1 hour screening test cutoff ranges from 130mg/dl to 140 mg/dl.

 The next step, diagnostic 3 hour 100gm GTT has atleast 2 different algorithms for diagnosis of GDM. Diagnostic parameters for the 3 hour, 100g GTT NDDGC CCC time mg/dl mg/dl FBS 105 95 67

1hr 190 180 2hr 165 155 3hr 145 140 NDDGC-National diabetes data group criteria CCC -Carpenter Coustan Criteria  Recently, a single step 75 gm oral glucose tolerance test is also being used wherein a 2 hr plasma glucose level is measured after random administration of oral glucose.A plasma value > 140 mg% is diagnostic of GDM.It serves both as a screening &a diagnostic test. However, further studies are required before it is put to routine use in India. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY:

%of mothers III. DIFFERENTIAL DIAGNOSIS: Glycosuria of pregnancy IV. PRECONCEPTIONAL CARE: Preconception Counselling All women of reproductive age with preexisting diabetes should be advised about the potential benefits of prepregnancy planning. They should be offered education on the role of diet, appropriate body weight, and exercise. The American Diabetes Association has defined optimal preconceptional glucose control using insulin to include self-

monitored preprandial glucose levels of 70 to 100 mg/dL and postprandial values _ 140 mg/dL and _ 120 mg/dL at 1 and 2 hours, respectively. A reasonable target for HbA1c in prepregnancy counseling is to aim for 6%. An improvement in HbA1C levels can also be achieved by switching to short acting modern analogue and by enrolling the prepregnant subject into education programs that teach enhanced carbohydrate counting. Women with diabetes whose HbA1c is above 10% should be strongly advised

to avoid pregnancy. In prepregnancy counseling the current drug regime should also be reviewed. Some hypoglycemic drugs and the newer long acting insulin analogues have not been evaluated for safety in pregnancy and they should be replaced. Antihypertensives particularly ACE inhibitors and angiotensin receptor antagonists should be discontinued prior to pregnancy. Finally, folate, 400 µg/d, is given periconceptionally and during early pregnancy to decrease the risk of neural-tube

defects. When pregnancy occurs without any prepregnancy counseling , then an urgent assessment of all the previous factors should be undertaken as soon as possible at the antenatal clinic. Retinal & renal assessments are mandatory in all cases. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT AND REFERRAL CRITERIA 68

Situation1: At Secondary Hospital/Non-Metro situation:Optimal standards of situation where technology and resources are limited a) Clinical diagnosis:As described in case definition. Women with risk factors for GDM should be carefully screened like the obese, prior GDM, prior macrosomic infant, elderly mothers, multiple pregnancy, south east Asians, Hispanics, African Americans, polycystic ovarian syndrome, family history of diabetes.

Such women at very high risk may benefit from early screening in the first trimester. If early screening is normal, screening is repeated at 24 to 26 weeks. b) Investigations: • Close monitoring of blood glucose, baseline& interval glycosylated haemoglobin levels andurine sugar & ketones are helpful throughout pregnancy.Target blood glucose values are fasting 95mg%, 1 hour 140mg% & 2 hour 120mg%. • If a patient is controlled on diet, blood sugar monitoring with capillary blood

glucose levels 4 times a day (FBS and PPBS thrice) are enough. • Patients on pharmaceutical therapy- in addition need preprandial & 3 am values. • Other investigations required specially include ultrasound for dating, aneuploidy screening , anomaly scanning, growth profile monitoring for fetal weight, AFI and biophysical profile is necessary in poorly controlled diabetics. • Non stress test by 32 to 34 weeks. Lack of USG and NST facilities warrant referral to higher centers. c) Treatment:

Diet and exercise are instituted first. For many patients with GDM ,oral hypoglycemic or insulin therapy may be avoided altogether with no increase in adverse perinatal outcomes on diet alone. For women of normal weight, the American Diabetes Association recommends a caloric intake of 30 to 35 kcal/kg, taken as three meals and three snacks daily. For underweight women, this is increased to 40 kcal/kg/d. For those more than 120 percent above ideal weight, it is decreased to 24 kcal/kg/d. An ideal

dietary composition is 55 percent carbohydrate, 20 percent protein, and 25 percent fat with less than 10 percent as saturated fat. Generally a diet containing with CHO restriction to 45-60% preferably complex high fiber carbohydrates sources of known low Glycemic Index, lean proteins including oily fish, and a balance of polyunsaturated and monounsaturated fats is recommended. Women with a high BMI might be advised to restrict calorie intake with expert dietetic advice and consider suitable enhanced

mild or moderate exercise during the pregnancy. 1 to 2 miles walk at least 3 times a week is recommended. 69

Pharmacotherapy with insulin is instituted when diet and exercise therapy fail as evidenced by an abnormality in more than half the self monitored glucose values or an abnormal value in those women tested weekly. Recommended initial dose of Insulin is, 0.7-0.8 U/kg body wt in the 1st trimester 1.0 U/kg body wt in the 2nd trimester 1.2U/kg body wt in the 3rd trimester Dose is adjusted according to the response of hyperglycaemia to initial therapy.

Of the calculated daily dose, 2/3rds is given before breakfast, divided as 2/3rd NPH insulin and 1/3rd regular insulin, and the remaining 1/3rd of the daily dose is given as 1/2 regular insulin before dinner and 1/2 NPH insulin at bed time. Self-monitoring of capillary glucose levels using a glucometer is recommended because this involves the woman in her own care. The goals of glucose control recommended during pregnancy are Fasting _≤95 mg/dL, Premeal _≤100 mg/dL,1-hr postprandial ≤140

mg/dL, 2-hr postprandial _≤120 mg/dL and 0200–0600 _≤60mg/dL. Antenatal care- twice weekly visits required. Well controlled diabetics can deliver at 40 weeks Poorly controlled non compliant patients on pharmacotherapy need antenatal testing for monitoring macrosomia or growth restriction and timely planning of delivery when fetus is optimally mature with lung maturity. Women with pregestational diabetes with nephropathy, retinopathy may worsen and warrant earlier delivery. Preeclampsia, and IUGR may set in.

Good glycaemic control during pregnancy can avoid ketosis and sepsis. Diabetic ketoacidosis should be suspected when a pregnant diabetic mother presents with blood sugar more than 200mg/dl, vomiting and dehydration with low serum bicarbonate and presence of acetone as it could lead to fetal loss if not intensively managed in conjunction with a physician. Preterm labor in diabetics can be managed with antenatal steroids &tocolysis.However,women with insulin treated diabetes who are receiving steroids for

fetal lung maturation should be closely monitored andreceive additional insulin according to protocol.Also, betamimeticdrugs should not be used for tocolysis in such women. Labor and delivery- Women with pregestational diabetes and GDM requiring pharmacotherapy are best managed with IV fluids(100-150ml/hr),insulin drips and hourly glucose monitoring protocols to maintain blood glucose values at around 70

100mg% during active labor. Women with very mild GDM may not require insulin therapy but should have blood glucose assessment during labor. It is important to considerably reduce or delete the dose of long-acting insulin given on the day of delivery. Regular insulin should be used to meet most or all of the insulin needs of the mother at this time, because insulin requirements typically drop markedly after delivery. During labor and after delivery, the woman should be adequately

hydrated intravenously and given glucose in sufficient amounts to maintain normoglycemia. Capillary or plasma glucose levels should be checked frequently, and regular insulin should be administered accordingly. It is not unusual for a woman to require virtually no insulin for the first 24 hours or so postpartum and then for insulin requirements to fluctuate markedly during the next few days. Infection must be promptly detected and treated.

When estimated fetal weight is above 4.5 kg, elective caesarean is planned to avoid shoulder dystocia and birth trauma. In those where the EFW ranges between 4 to 4.5 kg, other obstetric factors should be considered in decision making for caesarean section.Uncontrolled diabetes & presence of end organ disease are other indications of caesarean section. Preparedness for the management of neonatal problems is a must. Post partum management-A 75 g GTT should be performed at 6 to 12 weeks

postpartum and other intervals thereafter for GDM mothers. Subsequently, testing can be done annually or triannually(ADA recommendation). Contraceptive advice needs to be given as per WHO recommendations. Referral criteria: • When careful monitoring facilities are not available. • For expert opinion regarding anomalies and paediatric surgery and for fetal echocardiography. • When there are comorbidities warranting multidisciplinary input especially in

pregestational diabetics and poorly controlled gestational diabetics. • When there is need for intensive neonatal care unit to manage problems in the newborn. Situation 2: At Superspeciality Facility in Metro location where higher end technology is available. a) Clinical diagnosis: As described in situation1. 71

b) Investigations: As described in situation I.Fetal echocardiography & periodic doppler studiesif growth retardation present. c) Treatment: As described in situation 1. A multidisciplinary team is involved early in care and planned delivery is carried out in the presence of anomalies to facilitate optimal care in a tertiary center with good nicu and paediatricsurgeons.An endocrinologist is necessary for the management of DKA.

d) Referral Criteria: Even in a metro situation not all centers will be equipped with the multiple specialists, skilled hands and facilities. The decision to refer to a better facility should be taken if it warrants to give the best care to the mother and the newborn. Summary of antenatal care for women withdiabetes* Visit Measures Preconceptional/ -Offer information, advice and support in relation to 1st visit establishing glycaemic control& effects of diabetes on pregnancy.

-Review medications for diabetes and its complications. -Folic acid supplementation. -Take a clinical history to ascertain the extent of diabetes-related complications. -Offer retinal and renal assessment if these have not been undertaken in the previous 12 months. 5-6 weeks -Confirm viability of pregnancy and gestational age. -Establish glycaemic control 16 weeks Offer retinal assessment at 16–20 weeks to women with pre-existing diabetes who showed signs of

diabetic retinopathy at the first antenatal visit. 22-24 weeks Offer four-chamber view of the fetal heart and outflow tracts plus scans that would be offered at 18–20 weeks as part of routine antenatal care. 28 weeks -Offer ultrasound monitoring of fetal growth and amniotic fluid volume. -Offer retinal assessment to women with pre-existing diabetes who showed no diabetic retinopathy at their first antenatal clinic visit. 72

32 weeks Offer ultrasound monitoring of fetal growth and amniotic fluid volume. 36 weeks -Offer ultrasound monitoring of fetal growth and amniotic fluid volume. -Offer information and advice about: i. timing, mode and management of birth ii. analgesia and anaesthesia iii. changes to hypoglycaemic therapy during and after birth iv. management of the baby after birth v. initiation of breastfeeding and the effect of breastfeeding on glycaemic control vi. contraception and follow-up.

38 weeks Offer induction of labour, or caesarean section if indicated, and start regular tests of fetal well-being for women with diabetes who are awaiting spontaneous labour. 39 weeks Offer tests of fetal well-being. 40 weeks Termination of pregnancy in diet controlled diabetics. *All women with diabetes should also receive routine antenatal care. V.FURTHER READING AND REFERENCES: Williams Obstetrics Obstetrics and Gynaecology clinics of North America, June 2010, Vol 37, No 2

NICE clinical guideline 63: March 2008 Current Progress in Obstetrics &Gynaecology, 2012, Vol 1 73

CARCINOMA CERVIX Introduction and Case definition: Carcinoma cervix is the cancer affecting the cervix, which is the lowermost part of the uterus. Cancer of cervix is a leading cause of mortality worldwide and especially in developing countries Worldwide cancer cervix is the second most common cancer among women, next only to breast cancer. But among Indian women, cancer cervix is the commonest cancer. Invasive cancer of

cervix is considered to be a preventable cancer as it is associated with a long pre-invasive state, which is detectable and treatable to a large extent. Various risk factors for carcinoma cervix are young age at first intercourse, multiple sexual partners, cigarette smoking, high parity and low socio-economic status. Human papillomavirus infection has been postulated to be the etiological factor for inducing dysplasia in the cervical epithelium. About 85% to 90% of cervical

cancers are squamous cell carcinomas, and the rest 10–15% are adenocarcinomas. Incidence in India: Based on the data of the population based cancer registries, the estimated number of new cancers during 2007 in India was 90,708.1 As per the same data, the age adjusted incidence rate of cervical cancer in India per 100,000 persons varies from 12.3 – 25.4 in various parts of the country.2 Prevention: Detection of pre-malignant lesions by Pap smear testing and HPV-DNA testing followed by

appropriate management of the detected lesions forms the mainstay of prevention of occurrence of invasive cervical cancer. Differential diagnosis -Fibroid polyp (especially when infected/ulcerated) -Tuberculosis of cervix -Cervical erosion Optimal Diagnostic Criteria, Investigations, Treatment & Referral Criteria Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited A .Clinical Diagnosis: History:

-Asymptomatic in early stages -Vaginal bleeding (postcoital/irregular/postmenopausal) -Foul smelling, blood stained vaginal discharge -Loss of weight/ appetite -Difficulty in micturition (advanced stages) Examination: -Malnourished, emaciated appearance (advanced stages) -Supraclavicular/groin lymphadenopathy (advanced stages) -Per speculum examination: Ulcero-proliferative friable growth on cervix with or without vaginal involvement. Cervix may bleed on touch. 74

Per vaginal examination: Expanded firm/friable irregular cervix Recto-vaginal examination: Nodularity of parametria (parametrial extension of disease) B .Investigations: -CBC -Blood grouping -Cervical biopsy on out-patient basis at the time of speculum examination for confirmation of diagnosis where obvious growth is visualized -In cases where no obvious lesion is found on the cervix at the time of visual examination, apply 3% acetic acid on cervix and take biopsy from dense white areas, if seen.

-Colposcope guided biopsy to be done in cases where there is abnormality detected on Pap’s smear and no obvious lesion on cervix. If facility of colposcopy is not available due to lack of equipment or expertise, patient should be referred to a centre with these facilities are available. -Endocervical curettage if there is suspicion of endocervical cancer. -Cone biopsy may be done if required, but only after colposcopy. -USG -Contrast CT scan if required. C.Treatment:

-Treatment of local infection with Tab. Ciprofloxacin 500mg BD X 5days & Tab. Metronidazole 400 mg TDS X 5days. -Oral iron and other nutritional supplements for malnourished and anemic patients. D.Referral criteria: All patients with carcinoma cervix should be referred to multi-specialty hospital that is adequately resourced and equipped with facilities for oncological surgeries, radiotherapy, chemotherapy and blood transfusion.

(* If a gynae-onco-surgeon is available along with anesthetist and blood bank facility, surgery for carcinoma cervix stage Ia & Ib1 may be done in situation1. In such situations, if need for post- operative radiotherapy arises, patient should be referred to situation 2 along with all records including surgical records) Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available A. Clinical Diagnosis: Same as situation 1 B. Investigations: -CBC -Blood grouping

-Cervical biopsy on out-patient basis at the time of speculum examination for confirmation of diagnosis where obvious growth is visualized. -Colposcopic examination and guided biopsy: in cases with abnormal Pap test results and no obvious lesion on the cervix. -Endocervical curettage during colposcopy to rule out endocervical carcinoma -Cervical conization in indicated cases. When carcinoma cervix is confirmed, further investigations required are: 75

-KFT -LFT -Urine analysis -Chest X-Ray -IVP -Other investigations: Ultrasonography, MRI or contrast CT scan Abdomen if MRI is not possibleand pelvis may be useful in select cases for planning therapy. - Cystoscopy / Barium enema / sigmoidoscopy- ifif imaging doesn’t rule out involvementC. Treatment: Treatment modality depends on the stage of disease, age of the patient, patient’s desire, need for preservation of ovarian function, presence of co-morbidities, associated

gynecological conditions requiring surgery and availability of facilities and expertise. Various modalities available are: -Surgery: For stages I & II a -Radiotherapy: For all stages -Chemo-radiation: For patients with high-risk cervical carcinoma after radical hysterectomy and in patients with locally advanced cervical carcinoma. Surgery (cid:216) Advantages: -Conservation of ovaries -Surgical injuries to bladder/ bowel are easier to treat compared to chronic bladder and

bowel problems resulting from radiation induced fibrosis and decreased vascularity. (cid:216) Disadvantages: -Not curative in advanced stages of carcinoma cervix -Requires expertise Surgical management depends on the stage, depth of invasion and lymph-vascular space invasion. Types of hysterectomies for carcinoma cervix: Type II: Also called as modified radical/ Wertheim’s hysterectomy. Medial half of cardinal and uterosacral ligaments are removed.

Type III: Also called as radical/ Meig’s hysterectomy. Most of the utersacral and cardinal ligaments along with upper third of vagina are removed. Type IV: Extended radical hysterectomy. The periureteral tissue, superior vesical artery and up to three-fourths of vagina are also removed. Type V: Portions of distal ureters and bladder are also resected. These days, type IV & type V hysterectomies are mostly not performed as patients with advanced malignancy are usually given radiotherapy.

Complications of radical hysterectomy: (cid:216) Acute complications: - Blood loss - Uretero-vaginal fistula (1% to 2%) - Vesico-vaginal fistula (1%) - Pulmonary embolus (1% to 2%) - Small bowel obstruction (1%) - Febrile morbidity (25 to 50%) (cid:216) Sub acute complications: 76

- Bladder dysfunction - Lypmhocyst formation (<5%) (cid:216) Chronic complications: - Hypotonic bladder - Ureteral strictures - Recurrent cancer - Lymphocyst formation Radiotherapy: (cid:216) Advantages: -Can be given in all the stages -Cure rates equivalent to surgery in early stages -Avoids surgical and anesthetic complications (cid:216) Disadvantages: -Induces radiation fibrosis of bowel and bladder in 6%-8% -May result in intestinal and urinary strictures (1.4%-5.3%)

-Induces vaginal fibrosis and stenosis -Premature menopause due to the affects of radiotherapy on ovaries. Clinical staging (FIGO) and stage-wise treatment recommendations Stage I: Carcinoma confined to cervix Stage Ia: Preclinical carcinomas of cervix, diagnosed only on microscopy Stage Ia1: ≤3 mm invasion and <7mm width horizontally No lymph-vascular space invasion -Conization/ Type I hysterectomy With lymph-vascular space invasion-Type I or II hysterectomy with (?) pelvic lymph node dissection

Stage Ia2: >3-5mm invasion- Type II hysterectomy with pelvic lymphadenectomy Stage Ib : >5mm invasion-Type III hysterectomy with pelvic lymphadenectomy and para-aortic lymph node evaluation. Stage II: Carcinoma extending beyond the cervix but not up to lateral pelvic wall. The carcinoma involves the vagina, but not the lower one-third. Stage IIa: No obvious parametrial involvement- Type III hysterectomy with pelvic lymphadenectomy and para-aortic lymph node evaluation.

Concurrent chemo-radiation therapy may be offered as an alternative to radical surgery for stages Ib and IIa, especially when the lesion size is more than 4cm, as this has been shown to be associated with improved survival rates. Indications of post-operative radiotherapy: -Positive surgical margins -Positive lymph nodes Stages IIb to IVb: Concurrent Chemo-radiation (Cisplatin based chemotherapy) is the main stay of treatment. Palliative treatment may be offered in advanced stage carcinoma cervix.

Stage III: Carcinoma extending up to the lateral pelvic wall. Carcinoma involves the lower one-third of vagina. Hydronephrosis or non-functioning kidney. Stage IIIa: No extension to the pelvic wall Stage IIIb: Extension up to the pelvic wall and/or hydronephrosis or non-functioning kidney. Stage IV Carcinoma extended beyond the true pelvis or involved mucosa of the bladder or rectum. Stage IVa: Spread of the growth to adjacent organs Stage IV b: Spread to distal organs

Recurrent Cervical cancer: For patients, who were primarily treated with surgery, should be considered for radiotherapy and vice-versa. Fertility sparing surgery; Women requesting fertility conservation should be offered radical trachelectomy and pelvic lymph node dissection providing the tumour diameter is less than 2 cm and no lymphatic vascular space invasion is present. Women with FIGO stage 1A2 and microscopic 1B1 may also be offered cold knife conisation or

large loop excision of transformation zone combined with pelvic LN dissection. Laproscopic vaginal radical hysterectomy shd not beoffered to patientswith tumour diameter greater than 2 cm Treatment during pregnancy; For pregnant patients diagnosed with cervicalcancer before 16 weeks of gestation immediate treatment is recommended For pregnant pt with disease of stage FIGO1A1,1A2,1B after 16 weeks of pregnancy may be delayed to allow fetal maturity

D. Referral criteria: In case of carcinoma cervix stage IIb or higher, it may be required to refer the patient to a cancer centre having facility for radiotherapy, as the same may not be available in all super-specialty hospitals. References: 1. National Cancer Registry Programme (NCRP, ICMR). Time trends in cancer incidence rates: 1982-2005. Bangalore: NCRP; 2009. 2. A. Nandakumar, T. Ramnath & Meesha Chaturvedi. The magnitude of cancer cervix in

India.National Cancer Registry Programme (ICMR), Bangalore, India. Indian J Med Res 130, September 2009, pp 219-221 Suggested Reading: 1. Novak’s Gynaecology. Ed Berek JS. Fourteenth edition. 2006 2. Te Linde’s Operative Gynaecology. Eds Rock J A, Jones III H W. Ninth edition 2003 78

ADNEXAL MASS Introduction The finding of an adnexal mass is a common clinical problem seen in women of all ages and presents a diagnostic and therapeutic challenge. Some of these are diagnosed incidentally during pelvic examination/radiographic imaging modalities. Primary goal of management is differentiation of gynecological from non- gynecological, and benign from malignant masses. Evaluation and Diagnosis Adnexal mass may represent structures in the uterine adnexa (ovary, fallopian tube, broad

ligament) or masses rising from bowel, urinary system and retroperitonium. Differential diagnosis is aided by taking into account • History and Examination - The woman’s age (high risk of malignany in premenarchal and postmenopausal) - Family history of breast and ovarian malignancy - Personal or family history of TB - Menstrual and obstetric history • Imaging studies • Serum Markers • Aspiration of unilocular cyst Clinical Diagnosis & Investigations (Common to both situations 1 and 2)

Symptoms: Many cases may be asymptomatic or may present with any of the following: - Abdominal pain, pelvic pain, dyspareunia - Menstrual irregularities, menorrhagia, dyspareunia, postcoital bleeding - Abdominal swelling (sometimes it is the first symptom), discomfort, bloating - Acute pain, vomiting and low grade fever (torsion, rupture & ectopic) - Pressure symptoms – retention of urine, frequency of micturition - Dyspnoea, Palpitation (very large tumours)

- GIT symptoms – indigestion, loss of weight, loss of appetite - Urinary symptoms – change in voiding habits, dysuria, hematuria Signs: - General physical – pallor, icterus, acne, hirsutism, lymphadenopathy - Breast & Systemic examination - Per abdomen Any visceromegaly, distended veins, ascites should be noted along with assessment of the abdominal mass: size, shape, surface (irregular, nodular), mobility, tenderness, and accessibility of lower limit. In case of adnexal mass its lower limit cannot

be defined (except in small cyst with long pedicle). - Per-vaginum: Uterus felt separately from mass in fornices, which may be unilateral or bilateral, may displace the uterus, movement of mass not transmitted to cervix; there may be nodules in the POD in malignancy/ tuberculosis/ endometriosis. Presence of a tense and tender adnexal mass, in a patient presenting as acute abdomen suggests adnexal torsion, whereas unilateral tender mass with cervical excitation pain raises the

suspicion of ectopic pregnancy, and bilateral tenderness suggests PID. 79

- Per Rectal examination to evaluate the rectal mucosa & uterosacral ligaments which may show thickening or nodularity in endometriosis & ovarian malignancy. Differential Diagnosis: • Gynecological - Functional ovarian cyst: Follicular cyst, Corpus luteum cyst - Inflammatory mass: Tuboovarian abscess, Hydrosalpinx - Others: Ectopic pregnancy, endometrioma, parovarian cyst, degenerated/pedunculated leiomyomata, mullerian anomaly

- Benign ovarian Tumors: Serous cystadenoma, Mucinous cystadenoma Mature teratoma, - Malignant ovarian: Germ cell tumor, Sex-cord or stromal tumor, Epithelial carcinoma • Nongynecological - Benign: Diverticular abscess, Appendiceal abscess or mucocele, Ureteral/bladder diverticulum, Pelvic kidney, Paratubal cysts - Malignant: Gastrointestinal cancers, Retroperitoneal sarcomas, Metastases Investigations: • Hb, PCV, CBC & ESR; RFT, LFT • Urine pregnancy test • X-ray Chest, abdomen

• USG – abdomen & pelvis to study the characteristics of the mass such as volume, wall thickness, septal structure, echogenicity, papillary excrescences, free fluid in abdomen. • Barium meal, enema, IVP (selected cases) • Upper GI endoscopy, colonoscopy (selected cases) • Tumour markers – CA125 - epithilial ovarian tumour, cutoff 35 U/ml CEA - GI tract tumour βHCG - Chrio carcinoma Inhibin - Granulosa cell tumour LDH – Dysgerminoma CA 19-9- Mucinous ovarian neoplasms

Alpha feto proteins- Endodermal Sinus Tumors • Risk of Malignancy Index (RMI screens for suspected ovarian cancer RMI = CA-125 X USG Points X Menopausal status. Cut off level: 200 - Menopausal status (Premenopausal – score 1, Postmenopausal – score 3) - Ultrasound Points: Score 0=0 point, Score 1=1 point & score 2-5 =3 points. (1 point each for multilocular nature, solid areas, bilaterality metastasis, ascites,) • Ascitic fluid cytology, FNAC of solid tumor has a questionable role

Situation 1: At Secondary Hospital / Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited REFERRAL OR CONSULTATION WITH A GYNECOLOGIC ONCOLOGIST • Elevated CA-125 >200U/mL in <50 years/ premenopausal women >35U/mL in > 50 years/ Postmenopausal women • Ascites • Evidence of abdominal or distant metastases 80

• Family history of breast or ovarian cancer in a first-degree relative • Nodular or fixed pelvic mass (>50 years/ postmenopausal) * Situation 2: At Super Specialty Facility in Metro location where higher- end technology is available Investigations • Color Doppler if available may be used to study low resistance ovarian arterial flow; however, it does not significantly improve diagnostic accuracy. • CT, MRI, PET may be done to evaluate the mass TREATMENT

Treatment depends on the diagnosis made after investigations. Patients with suspected malignancy should be referred to a higher center where facility for frozen section and services of a Gynecologic Oncologist and Medical Oncologist are available. mass: Hydrosalphinx - usually asymptomatic. No intervention required. Abscess – pus is drained, antibiotics. Tuberculosis should be ruled out in our country. Ectopic pregnancy: Medical or surgical management as indicated (detailed in ectopic pregnancy chapter)

Endometrioma: Usually do not resolve with observation and require Surgery – Small: Electrocoagulation/ laser vaporization – Big: Removal with removal of cyst wall to prevent recurrence Parovarian Cyst: No intervention is necessary, unless large or risk for torsion or uncertain diagnosis Mullerian Anomaly: Bicornuate uterus, uterus didelphys or bicornuate uterus with a communicating or non-communicating rudimentary uterine horn, can be identified by MRI &

best surgical plan, as removal of accessory horn or metroplasty can be decided Adnexal Torsion In premenopausal patients on direct visualization if the ovary appears potentially viable, ovarian conservation can be done following de-torsion; whereas in patients with a non-viable ovary, suspected malignancy, or postmenopausal patients one should do salpingo-oophorectomy. Ovarian cyst Treatment of an adnexal mass is determined by age of pt & reproductive needs, morphology of

lesion on USG/ CT/ MRI, presence of risk factors (postmenopausal, family history of ovarian/breast cancer, BRCA-1, 2 carriers, presence of ascites/ lymphadenopathy). (a) Conservative Management: Simple cyst in premenopausal woman: 81

(cid:151) 2/3rd of these regress over 2-3 menstrual cycles. Therefore a ‘Wait and See’ policy is recommended for 8-10 wks. OCPs can be given for 3 cycles; however, there is no proven benefit. Aspiration of simple cyst not useful as it reoccurs in 75% within 1 yr. (cid:151) When one is almost certain regarding the benign nature of the cyst, a yearly follow up is required, until resolved, for a simple cyst of 5-7 cm in low risk patients & 2-7 cm in high

risk patients; A cyst of >7cm needs further evaluation with MRI /Surgery (b) Surgical Management is recommended for the following: ◦ A cyst with significant pain and other features suggestive of rupture/torsion ◦ Any ovarian mass >10cm ◦ Ovarian cystic structure >7cm without regression for 6-8wks ◦ Any solid ovarian lesion ◦ Papillary excrescences in wall ◦ Palpable adnexal mass in postmenopausal patients ◦ Presence of ascites Surgery for Benign ovarian cyst

• Ovarian cystectomy or Oophorectomy if the cyst cannot be removed separately from ovaries. Benign ovarian mass can be removed laparoscopically if: - Surgical expertise skills appropriate for performing cystectomy or adnexectomy - Prompt and accurate frozen section services - Personnel and facilities available for timely surgical staging Surgery where Malignancy is suspected - Staging laparotomy has to be performed followed by histopathology and appropriate referrals for chemotherapy.

• Staging Laparotomy for Ovarian Cancer - Abdominopelvic exploration and taking Peritoneal washings from pelvis, bilateral paracolic gutters, and infradiaphragmatic areas - If desirous of fertility: Unilateral salpingo-oophorectomy Biopsy of the contralateral ovary if it appears suspicious - If postmenopausal or does not desire fertility: Bilateral salpingo-oophorectomy with total hysterectomy along with Pelvic node and Paraaortic lymph node dissection, infracolic omentectomy and

Peritoneal biopsies from cul-de-sac, vesical peritoneum, bilateral pelvic sidewalls and paracolic gutter and any additional suspicious areas Special Situations: 1. Mass with borderline histology In post menopausal woman – TAH with BSO If fertility to be preserved – cystectomy 2. Young women – Germ cell tumours Do unilateral adnexectomy and staging Radical surgery after finishing childbirth 3. Adnexal masses in pregnancy: mostly cystic, resolve There is a risk of torsion and rupture 82

Caesarean Section I. Incidence in our country: 10 to 50% depending on the level of care- whether a primary or tertiary referral center. II. Introduction and case definition: Caesarean section is a form of childbirth in which a surgical incision is made through a mother’s abdomen and uterus to deliver one or more babies. The commonest uterine incision is the lower segment incision. It may be done electively or as an emergency procedure. Optimal Investigations & Procedure (Common to both situations 1 and 2)

Clinical Diagnosis: Common indications recognizable during the antenatal period that may require cesarean section are malpresentations, antepartum haemorrhage, previous caesarean section or surgery on the uterus, bad obstetric history, IUGR, induction of labour for pre eclampsia, gestational diabetes, postdatism, premature rupture of membranes, fetal macrosomia, and cephalopelvic disproportion. Intrapartum indications include fetal distress, dysfunctional/ prolonged labour,

malpresentations, obstructed labour and cord prolapse. Pre-operative Investigations: § Hb%, BT, CT, urine routine, blood grouping, cross matching and reservation of blood § Ultrasound for presentation, placental position, biophysical profile. Timing of Caesarean Section: § Elective LSCS should be done preferably after 39 weeks to decrease neonatal morbidity. § Emergency LSCS should be done within 30 minutes of decision if there is immediate threat to life of women or foetus.

§ Emergency cesarean may be done up to 75 minutes when there is maternal or foetal compromise which is not life threatening. Treatment: IV line and Oxygen inhalation, Regional or general anaesthesia Pre-operative: § Informed Consent § Prepare abdomen, perineum and back § IV line to be established and bladder catherisation § Parenteral H2 blocker and antiemetic § IV antibiotic to be given before skin incision (Avoid co-amoxyclav) 84

Operative details: § Abdominal incision could be transverse suprapubic or vertical. § The uterine incision is usually transverse in the lower segment, midline vertical (Classical) may be indicated occasionally if lower segment is unapproachable due to dense adhesions. § Baby is extracted, cord clamped, cut and baby handed over to the paediatrician. Cord blood should be collected in Rh isoimmuniation cases. Placenta with entire membranes

removed by controlled cord traction. Oxytocics administered to contract the uterus and prevent post patum haemorrhage. Uterus sutured with absorbable sutures to secure haemostasis in two layers. No need of suturing the peritoneum. Uterus should not be exteriorised routinely. Surgical mops and instrument count to be checked. Abdominal wall closed in layers. Post operative: § Vitals, urine output, and bleeding are monitored, § IV fluids, antibiotics and pain medication given,

§ DVT prophylaxis advised if indicated, § Oral feeds encouraged with return of bowel sounds after 8 hours. § Early breast feeding and ambulation encouraged. Situation 1: At Secondary Hospital/ Non-metro situation: Optimal Standards of treatment in situations where technology and resources are limited. Cases warranting immediate delivery to save the life of baby or mother should be dealt with. In situations where skilled manpower and technology is not available, woman may to be referred

to higher institution. Situation 2: At super-specialty facility in metro location where higher end technology is available. Referral criteria: Situations warranting neonatal intensive care management facilities, need for blood and blood component therapy, special anaesthesia services like epidural analgesia; For the management of post operative complications of caesarean section like sepsis, secondary haemorhage, wound dehiscence, acute renal failure etc where multidisciplinary input is

warranted need to be tackled at super-specialty level. Additional Investigations that may be required: § Ultrasound Doppler studies in IUGR § Electronic fetal monitoring in labour § TSH, LFT, RFT, Coagulation profile tailored to the needs of the patient. Further Reading/ References: § RCOG Guidelines § Williams text book of Obstetrics 85

Resources required for one patient/procedure Situation Human resources Investigations Drugs and Equipment consumables 1 Obstetrician Written parenteral H2 Boyles Anaesthetist above blocker OT table with lateral tilt of Nurse antiemetic 15 degree or wedge Floor nurse IV antibiotic Light House keeping oxytocin Section tray Suction apparatus Baby Warmer electrocautery 2 Senior obstetrician Other Drugs as per Boyles Junior doctor individual patient Ot table Consultant Anesthetist Light Nurses x2 Section tray

floor Nurse Suction apparatus OT technician Baby Warmer Senior Hematologist Electrocautery Experienced Critical care bed pediatrician . . 86

Hypertension in pregnancy/Preeclampsia WHEN TO SUSPECT OR RECOGNIZE Definition: -when high blood pressure is noted during pregnancy, it may be one of the following: § Gestational Hypertension: new onset BP elevation of systolic >140mmHg/ diastolic >90mmHg on 2 occasions 6 hrs apart after 20 wks gestation in a previously normotensive woman § Preeclampsia - gestational hypertension and persistent proteinuria ≥ 1+ on dipstick urine analysis or >300mg/24 hours occurring >20 weeks pregnancy in a previously

normotensive, non proteinuric woman. Oedema is not a defining sign of PE. § Eclampsia - Generalized convulsions occurring after the 20th week of pregnancy in a patient with underlying pre-ecclampsia Incidence: 2-8% A higher incidence is seen in women with age > 40, nulliparity, family or prior pregnancy h/o PIH, past h/o diabetes mellitus, chronic hypertension, renal disease, antiphospholipid syndrome, and present pregnancy with multifetal gestation and vesicular mole. Complications

If not recognized and managed appropriately, preeclampsia can result in complications such as eclampsia, hypertensive encephalopathy, pulmonary edema, liver haematoma/rupture, renal failure, ARDS, HELLP syndrome, disseminated intravascular coagulation, cortical blindness. Prediction In situation 1 Roll over test at 28 -30 wks: increased blood pressure of 20mmHg when patient rolls over from lateral to supine position means a positive test. The test has a high negative

predictive value although the positive predictive value is low. In situation 2 If the facility for colour doppler is available it can be performed at 24-26 weeks: Persistence of diastolic notching in uterine artery after second trimester can be predictive of preeclampsia. Prevention 87

Low dose Aspirin (50-100mg/d) may reduce the risk of PE by 15%. It can be started in high risk at 20 weeks and has to be stopped at 34 weeks gestation. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: Optimal Standards in Situations where technology and resources are limited PHC The patient should be transferred to higher centre as soon as a diagnosis of preeclampsia is made. However, if the patient presents with eclampsia/impending

eclampsia, she should be started on MgSO4 and anti hypertensive (described later) and transferred after stabilizing. Non-Metro situations Patient should be hospitalized and evaluated in detail to assess the severity of disease, gestational age, maternal and fetal well being: History: Present illness - symptoms of impending eclampsia Past- diabetes mellitus, chronic hypertension, renal disease, antiphospholipid syndrome Family - hypertension, diabetes mellitus

Obstetric - h/o PE in previous pregnancy, preterm birth, IUGR, stillbirth or neonatal death Examination: Complete general physical and systemic examination should be carried out including record of maternal weight, BMI, pulse, B.P in all four limbs, and testing of limb reflexes (presence of hyper-reflexia indicates impending eclampsia). Obstetric Examination: Assess for presentation, fetal heart rate, estimated fetal weight, IUGR and

accidental hemorrhage in severe cases. Per-vaginal examination may be done if patient is complaining of pain abdomen, or if termination of pregnancy is decided. Investigations: § CBC, hematocrit, platelets, P/S for haemolysis § Serum uric Acid, creatinine, blood urea § S. Bilirubin, SGOT, SGPT, LDH § Urine R/E, M/E, C&S* § Total urinary protein excretion on 24-hr specimen* 88

§ Fundoscopy Diagnosis of severe preeclampsia is made if any of the following is present: • SBP > 160 or DBP 110 mm Hg on 2 occasions six hours apart • Proteinuria > 2+ or > 5 gms/ 24 hours • Oliguria (urine output< 400 ml/24 hours) • Sign and Symptoms of impending eclampsia (Nausea, vomiting, persistent headache, epigastric pain, visual disturbances) • Placental abruption, IUGR • Platelets< 100,000 /cubic mm • Micro angiopathic hemolysis (increased LDH) • Elevated liver enzymes (SGOT > 70 IU/ L)

• Serum Creatinine> 1.2 mg % unless previously elevated Referral Criteria - All cases of severe PE and threatened eclampsia should be referred to situation 2 following the initial management and stabilization, as the clinical course of these patients is unpredictable and may necessitate maternal and fetal intensive care and monitoring. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available Hospitalization:

Mild – Hospitalization is advised although complete bed rest is not advisable. Severe- Immediate hospitalization is recommended if BP ≥ 160/100 or alarm signs. Maternal Assessment: • Blood pressure measurement: At least 4 times a day, more often in severe cases • Urine quantification (24 hour protein ) on admission, repeat not required • Blood tests: Monitor kidney function, electrolytes, full blood count, transaminases, bilirubin twice a week in mild preeclapsia and thrice a week in severe preeclampsia

Fetal Assessment: The following tests should be carried out at diagnosis: • Cardiotocography • Ultrasound for fetal growth and amniotic fluid volume assessment • Umbilical artery doppler velocimetry. If the results of all fetal monitoring are normal, cardiotocography need not be repeated more than weekly unless if there is deterioration in maternal condition, vaginal 89

bleeding, abdominal pain, or reduced fetal movement. Repeat ultrasound for fetal growth, amniotic fluid volume assessment or umbilical artery doppler velocimetry is also not required more than every 2 weeks. Diet should be adequate in proteins; salt restriction is not advised in Preeclampsia. Antihypertensive Therapy: It can be initiated if DBP >100mmHg. Lower threshold may be considered if disease has arisen before 28 wks. Aim is to keep DBP between 80–100 mmHg, and SBP less than

150 mmHg. In mild PE, it reduces the occurrence of severe hypertension, but there is no benefit in terms of maternal & fetal outcome. In severe hypertension therapy is mandatory to reduce the risk of CVA. • Tab. Methydopa -250- 500 mg 3-4 times /day. • Tab. Labetalol-100-200 mg 2-3 /day.. • Labetalol: IV regimen: 20 mg stat. If DBP>110 after 20 min, give 40mg; ↑ to 80 mg & then 80 mg to a total of 220mg. If no response, discuss with senior physicians and anaesthetists.

• Use of ACE inhibitors is contraindicated in pregnant woman • Nitroglycerine (NTG) drip may be useful in hypertensive crisis: Dose - 50mg in 500ml 5%dextrose, start at 10ml/h, ↑ by 5ml every 10-15‘ till SBP ≈ 140mmHg Anticonvulsants Consider giving intravenous magnesium sulphate to women with severe pre-eclampsia who are in a critical care setting if birth is planned within 24 hours. Termination of Pregnancy: Mild to moderate PE: Terminate at 34+0 to 36+6 weeks depending on maternal and

fetal condition, risk factors and availability of neonatal intensive care. Severe PE: Terminate at 34 weeks. Induction before 34 weeks may be indicated if: • severe hypertension develops refractory to treatment • maternal or fetal indications of worsening condition Corticosteroid for Lung Maturity Two doses of betamethasone 12 mg IM 24 hours apart are recommended between 24- 36 weeks. Intrapartum care In women with severe pre-eclampsia

• Accurate recording of fluid balance (including delivery and postpartum blood loss, Intake/output chart) and Maintenance crystalloid infusion - 85 ml/hour, or urinary 90

output in preceding hour plus 30 ml. Diuretics and CVP monitoring may be required if pulmonary oedema is suspected. • Measure blood pressure, hourly in women with mild or moderate hypertension and continually in women with severe hypertension. Continue use of antihypertensive treatment during labour. • Do not routinely limit the duration of the second stage of labour in women with stable mild or moderate hypertension or if blood pressure is controlled within target

ranges in women with severe hypertension. Operative birth is recommended in the second stage of labour if severe hypertension has not responded to initial treatment • Use of Methergine is contraindicated for active management of 3rd stage. Ceasarean Section is indicated for severe IUGR/ primi remote from term with unfavorable cervix, for fetal distress or other obstetric indications. Thrombo prophylaxis to be considered in severe PIH. Analgesia & Anesthesia Issues:

• GA Risks: - Aspiration, laryngeal edema, difficult intubation, pulmonary edema/ arrythmias precipitated by pressor response to intubation, neuro-muscular blockade effect of mag sulf. • Continuous lumbar epidural preferred method of pain relief as well as for cesarean section provided there is no coagulopathy and platelet count is > 50,000/cu mm. • Need adequate pre-hydration of 1000 cc, Level should be advanced slowly to avoid low BP Postpartum Care

Women with PE who did not require anti-hypertensives: Measure BP at least four times a day while the woman is an inpatient, at least once between day 3 and day 5 after birth, and on alternate days thereafter until normal. Ask about severe headache and epigastric pain each time blood pressure is measured. Start antihypertensive treatment if blood pressure is ≥ 150/100 mmHg. Women with PE who took antihypertensive treatment: Measure BP at least four times

a day while the woman is an inpatient and every 1–2 days for up to 2 weeks after transfer to community care. Continue antenatal antihypertensive treatment, and reduce it if BP falls below 130/80 mmHg. If a woman has taken methyldopa to treat pre- eclampsia, stop within 2 days of birth, measure platelet count, transaminases and serum creatinine 48–72 hours after birth. Discharge the women when there are no symptoms of pre-eclampsia, BP is ≤

149/99 mmHg, with or without treatment, and blood test results are stable or improving. 91

All women who have had pre-eclampsia should have a medical review 6–8 weeks after birth to detect those women who still need antihypertensive treatment. Women who continue to have proteinuria (≥1+) a further review is required after 3 months to assess kidney function. Specific investigations like aPLa, LAC and thrombophilia screen may be needed. Eclampsia Generalized convulsions occurring after the 20th week of pregnancy with underlying pre-eclampsia Incidence

Antepartum 40%, Intrapartum 20%, Postpartum 40%. Although seizures may occur as long as 3 weeks postpartum, majority of cases (98%) occur on the first day. All cases of eclampsia are best managed at situation 2 or 3. If a woman with eclampsia is seen at situation 1, she should be stabilized with Magsulph and antihypertensives and transferred to higher centre only when stable and with full life support system, to limit maternal and fetal morbidity.

Immediate care is needed with airway support, adequate oxygenation, anticonvulsant therapy, and BP control. Delivery of neonate is the only definitive treatment, with Intensive postpartum care. General Measures: • Do not leave patient alone • Call for help and inform consultants - obstetrician & anesthetist on call • Prevent maternal injury: Place in semi-prone position, guardrails on the bed, padded tongue blade b/w teeth. • Airway: Maintain patency, start oxygen inhalation, suction of mouth secretions.

• Breathing: Assess, Ventilate as required. • Circulation: Left lateral tilt, If pulse, BP absent, initiate CPR, call ICU • After the seizure has ended, a 16- to 18-gauge IV line should be obtained for drawing specimens for laboratory studies and administering fluids • Attach ECG, automatic BP monitors, pulse oximeter • Indwelling Urinary catheter - Fluid input / output chart Treatment and prophylaxis of seizures: Magnesium sulphate is the anticonvulsant drug of choice. After ABC:

• Loading Dose: 4 g IV over 10-15 minutes Prepared by adding 8 ml of 50% MgSO4 solution to 12 ml of N Saline/ 20 ml of 20% solution • Maintainance Dose: 92

MgSO4 (50% solution) + 1ml Lidocaine 2% given IM every 4 hrs into alternate buttock • Monitor the following parameters before giving a repeat dose - respiratory rate > 16 breaths/minute - urine output > 25 ml/hour, and - patellar reflexes are present • Remember to subtract volume infused from total maintenance infusion volume (85 ml/hour) • A higher maintenance dose may be required initially to prevent recurrent seizures - consultant must make this decision

• If seizure continues, or if seizures recur, give a second bolus of magnesium sulphate: 2-4 g depending on weight of patient, over 5-10 minutes (2 g if < 70 kg and 4 g if > 70 kg) • If seizures continue despite a further bolus of Mg sulphate, Diazepam (10 mg IV) or thiopentone (50 mg IV) can be given. Intubation may become necessary in such women. Further seizures to be managed by IPPV & muscle relaxation. Magnesium Toxicity: • If urine output < 100 ml in 4 hours withhold Magsulph and review overall

management with attention to fluid balance and blood loss • Absent patellar reflexes: Stop MgSO4 infusion until reflexes return • Respiratory depression: Stop MgSO4 infusion, Give oxygen via facemask and place in recovery position and Monitor closely • Respiratory arrest: Stop MgSO4 infusion, Give Calcium gluconate (10 ml slow IV), Intubate and ventilate. • Cardiac arrest: Commence CPR, Stop MgSO4 infusion, Give IV Calcium gluconate*, Intubate and ventilate; If antenatal, immediate delivery

Other Anticonvulsant Drugs • Phenytoin - 20 mg/kg diluted in 100ml saline infused at maximum rate of 50 mg/min IV over 15-20mts followed by 100mg IV 8 hrly. It may cause hypotension, arrythmias, local phlebitis, and requires ECG monitoring • Diazepam - 10 mg IV at a rate of 1mg/min. It can cause maternal sedation, fetal respiratory depression, hypotonia and ↓ beat-to-beat fetal heart variability Treatment of Hypertension : 93

• Reduction of severe hypertension is mandatory to reduce the risk of CVA & further seizures. • Insufficient evidence to recommend one antihypertensive in preference to another and so the choice of which drug to use should depend on personal preference and availability. • Labetalol (20mg IV ↑ to 40 and 80mg every 20’ to max. 220mg) It may precipitate fetal distress, thereby necessitates continuous fetal heart rate monitoring. • NTG drip (5µg/m iv infusion, ↑to max 100µg/m) Fluid therapy:

• Close monitoring of fluid intake and urine output is mandatory. Fluid therapy should be limited to maintenance crystalloid (85ml/h or urine output in preceding hour plus 30ml) to avoid tissue overload, pulmonary edema & ARDS. Colloids remain in vascular tree and unless used carefully can cause circulatory overload. Antibiotics: Inj. Ampiciliin 500 mg x 6hrly IV to prevent infection Associated Complications: HELLP syndrome (3%), Disseminated intravascular coagulation (3%), renal failure (4%), ARDS (3%)

Differential Diagnosis - • Cerebral tumors, Cerebral venous thrombosis, Intracranial hemorrhage • Drug overdoses, Electrolyte imbalance • Epilepsy, head trauma, Stroke (ischemic/ non-ischemic) Monitoring: • Record BP every 10 minutes. Reduce DBP to 90-100 mm Hg with antihypertensive medication • Auscultate lungs for aspiration after convulsion ended • Monitor the neurologic status, urine output, respirations, and fetal status Laboratory workup:

• CBC, RFT, LFT, Electrolytes, Glucose, PLT, Coagulation profile • Urinalysis for proteinuria • Blood gases & Invasive PCWP monitoring may be necessary for accurate fluid management in patients with pulmonary edema or anuria • USG abdomen may be used to rule out abruptio placentae • CT scan/ MRI if focal neurological deficits or prolonged coma 94

Delivery : • The definitive treatment of eclampsia is delivery. • Attempts to prolong pregnancy in order to improve fetal maturity are unlikely to be of value. • However, it is inappropriate to deliver an unstable mother even if there is fetal distress. • Once seizures are controlled, severe hypertension treated, and hypoxia corrected, delivery can be expedited. • Vaginal delivery should be considered but caesarean section is likely to be

required in primigravidae remote from term with an unfavourable cervix/ deteriorating maternal or fetal condition • After delivery, high dependency care should be continued for a minimum of 24 hours. During Post partum period : • Mag sulf for 24 hrs after delivery or after last fit whichever is later • Continue Vital monitoring, antihypertensives, antibiotics • Counsel about next pregnancy Can it be prevented? Vigilant ANC & a well-timed delivery may prevent eclampsia, and Magnesium is

routinely given to women with severe PE in the expectation that it prevents progression to eclampsia, but fits which occur without warning may be impossible to prevent. 95

PELVIC ORGAN PROLAPSE INTRODUCTION Genital prolapse is a common gynecological operative problem. It can occur at any age, but is more common in multipara as a result of injury to pelvic floor muscles and fascia during childbirth and age related estrogen deficiency in postmenopausal women. In young age and nulliparous women it may be related to collagen deficiency or congenital elongation of cervix. DEFINITION: Pelvic organ prolapse is the downward displacement of one of the pelvic organs from its

normal location. All forms of prolapse are described in relation to the vagina: Anterior compartment prolapse • Cystocele: involves proximal 2/3rd of anterior vaginal wall with descent of bladder • Urethrocele: involves distal 1/3rd of anterior vaginal wall with descent of the urethra Posterior compartment prolapse • Rectocele: involves proximal 2/3rd of posterior vaginal wall with descent of rectum • Perineal Descent: Defect in perineal body Central compartment/Apical Prolapse

• Uterine prolapse: descent of the uterus and the vagina along with it • Vault prolapse: descent of the vaginal apex • Enterocele: herniation of small bowel loops along with descent of pouch of douglas WHEN TO SUSPECT/RECOGNISE: The following history should arouse a suspicion of pelvic organ prolapse: § Vaginal bulge/ Protrusion - Reducible//irreducible § Pelvic discomfort: - weakness perineal region/ dragging- bearing down sensation - low back ache relieved by lying down § urinary symptoms:

- Stress incontinence - Frequency/ urgency/ nocturia - urinary retention/ incomplete voiding § Defecation problems 96

- Difficulty in emptying rectum, tenesmus, splinting - Incomplete evacuation of the faeces - Fecal Incontinence § Sexual Function/ dyspareunia § Vaginal discharge - leucorrhoea, blood stained discharge Systemic symptoms of precipitating diseases such as chronic bronchitis, asthma, constipation, abdominal mass, ascites etc. should be asked for. EXAMINATION OF THE PATIENT General Physical examination • BMI • Gait • Spine examination to rule out neurological and anatomical defect Abdominal examination

• mass per abdomen/free fluid, organomegaly, hernial sites Neurological examination (S2-4) • Bulbocavernous / anal wink reflex Local examination Patient should be asked to hold urine to demonstrate SUI, and examination can be made in dorsal lithotomy/standing position depending upon the prolapse severity • Perineum: scar/s, introital laxity • Prolapsed part: location, ulceration, growth, pigmentation, keratinization, • Rugosities, sulci Per-speculum (P/S) Examination

• Ask the patient to strain and visualise the entire prolapse • Note the type and degree of prolapse in all segments (anterior, posterior, central) • In anterior segment prolpase, differentiate if it is paravaginal/ central • Check for cervical changes - elongation and hypertrophy of cervix, atrophy - decubitus ulcer - keratinisation - discharge – colour/blood stained • Measure the size of introitus and utero-cervical length Per-vaginum (P/V) Examination

• The prolapsed part is reduced and bimanual examination performed • Uterus size , mobility any other palpable mass is noted 97

• Tone of levator ani and Integrity of perineal body is noted • Occult SUI observed if any Rectovaginal examination • Help differentiate between enterocele and rectocele DIFFERENTIAL DIAGNOSIS - Local mass/ cysts arising from vagina, Gartner’s cyst - Fibroid polyp - Chronic inversion of uterus SITUATION 1 (Non-metro with limited resources) DIAGNOSIS - Diagnosis is clinical, confirmed by P/S, P/V, and rectovaginal examination. INVESTIGATIONS Routine Investigations 1. CBC, blood grouping and RH typing

2. FBS, PPBS 3. Blood urea, serum creatinine 4. ECG, chest X-ray 5. Urine- R/M and C/S Special Investigations 1. USG of abdomen and pelvis to rule out associated pelvic pathology and renal problems due to pressure effect on ureter 2. Papanicolou smear 3. Endometrial aspiration and ECC (if abnormal uterine bleeding) 4. Cervical or ulcer biopsy is done when malignancy is suspected 5. IVP – where kinking of ureter is suspected in long standing cases and residual volume of urine is more than 100 ml

TREATMENT APPROACH 1. Non-surgical Management a. Physiotherapy b. Vaginal Pessaries 2. Surgical PHYSIOTHERAPY - Useful in minor degrees of uterovaginal prolapse - During 6 months following delivery 98

• PFMT (Pelvic Floor Muscle Training) - Kegel’s exercise – Patient is taught to voluntarily contract the levator ani muscle and external anal sphincters and hold for 5 seconds each, 15-20 times per session, three sessions a day. • Vaginal cones of successively increasing weights 20 to 100 gms can be used to hold inside for 15 minutess. PESSARY TREATMENT It is non-surgical and palliative and can be used in following situations: • Patients awaiting surgery/ to help healing of decubitus ulcer

• Associated medical disorders contraindicating surgery • Refusal of surgery • Pregnancy Types of pessary: depending on availability one can use • Support pessaries (Ring, Hodge) • Space occupying type (Donut, Gelhorn) SURGERY Indications of Surgery • Stage I & II prolapse, if symptomatic e.g., – Small cystocele with significant SUI – Constant dragging sensation due to cervical descent – Small rectocele with definite pocket on P/R and splinting is required by the patient to defecate

• Stage III/ IV prolapse even if asymptomatic – As risk of generally obstructive voiding leading to post void residual urine and recurrent UTI – Ureteral kinking and dilatation may lead to impaired renal function Pre Operative Preparation 1. Vaginal tampoons to reduce the prolapse and replace the organ back. It helps to prevent kinking of ureter and congestion of organs and increase the blood flow. 2. Estrogens (oral/local) if atrophic vagina 3. Correction of anemia if present 4. Treatment of UTI if present

5. Treat diabetes and hypertension if present 6. Treat other systemic infection if present 7. Enema (bowel evacuation night before surgery) 8. Prophylactic antibiotics 99

Factors determining the choice of surgery Type of operation selected depend upon • Age • Life style • Which symptoms and related pelvic floor disorders are most bothersome for her • Patients desire to preserve menstrual and reproductive function • Her desire to have sexual function • Her preferred route of surgical access • Degree, type, and components of prolapse • Co-existing adnexal/ uterine pathology eg. TO mass, myomas, ovarian tumors • Coexisting medical and surgical conditions

• Previous history of pelvic surgery Surgical Options Anterior Compartment Defect: - Anterior colporraphy - Para vaginal repair Posterior Compartment Defect: - Posterior colporraphy and colpoperineorraphy - Site-specific repair of posterior vaginal wall defects Central Compartment Defect: Choice of operations in this defect is varied: Vaginal - Fothergill’s repair and Shirodker’s modification of Fothergill - Posterior culdoplasty and vault suspension with or without vaginal hysterectomy

- Sacrospinous fixation with or without vaginal hysterectomy - Colpocleisis if patient does not desire coital function Abdominal - Abdominal sling operations (Shirodker, Purandre) - Abdominal Colposacropexy with or without Hysterectomy REFERRAL CRITERIA Patients with following high risk factors should be referred to higher centers: 1. Previous history of pelvic surgery 2. Presence of urinary or fecal incontinence 3. Presence of urethral hypermobility 4. Presence of pelvic floor neuropathy

SITUATUON 2 (Metro situations where advance technology is available) DIAGNOSIS Diagnosis of POP can be made as in situation 1. However, a Pelvic Organ Prolapse Quantification (POPQ) system can be used to quantify prolapse to have a uniform internationally used terminology. This system quantifies prolapsed based on the topographic position of six defined vaginal points: 2 anterior, 2 apical & 2 posterior with measurements of Genital Hiatus (GH), Perineal Body (PB), and

Total Vaginal Length (TVL). It is a useful tool to enhance communication among clinicians/ researchers, to follow objectively changes in an individual patient over time, and to assess the success and durability of various surgical and non-surgical treatments. Pelvic Organ Prolapse Quantification (POPQ) Aa – on anterior vaginal wall, 3cm proximal to the external urethral meatus Ba - most distal part of the anterior vaginal wall C - most distal part of the cervix or vaginal vault

D - the posterior fornix, if the cervix is present. Ap - on posterior vaginal wall Aa Ba C 3cm proximal to the hymen Bp - most distal part of the Gh Pb Tvl posterior vaginal wall Ap Bp D INVESTIGATION Tertiary centres can use imaging procedures like cystourethrography, perineal ultrasound, MRI studies, pelvic neuro-muscle physiology testing with concentric needle/ 101

single fibre electromyography, if available, for identification of discrete fascial defects to plan appropriate surgical strategy. TREATMENT Tertiary centers can use • Laparoscopic approach for - vaginal vault suspension - paravaginal repairs • Mesh augmented prolapsed repair in following situations: - Nonexistent or suboptimal autologous tissue - Need to augment weak or absent endopelvic tissue - Connective tissue disorder - Unavoidable stress on the repair (eg, chronic lifting, chronic obstructive

pulmonary disease, chronic straining to defecate, obesity) - Need to bridge a space such as sacral colpopexy - Concern about vaginal length or caliber - Denervated pelvic floor - Recurrent prolapse 102

STANDARD TREATMENT GUIDELINES Management of Management of common Respiratory Infections in Children in India July 2016 Ministry of Health & Family Welfare Government of India 1

1. INTRODUCTION ............................................................................................................................... 3 2. Key Recommendations .................................................................................................................... 5 Assessment and Treatment of Sick Young infant (age < 2 months): ...................................................... 5

Assessment and Treatment of Children between 2months -5years .................................................... 10 MANAGEMENT OF PNEUMONIA WITH COOMORBIDITIES ..................................................................... 20 PNEUMONIA IN A CHILD WITH SEVERE ACUTE MALNUTRITION ......................................................... 20 PNEUMONIA IN A CHILD WITH HIV .................................................................................................... 21

ANNEXURE 1: SUPPORTIVE THERAPY FOR PNEUMONIA......................................................................... 22 ANNEXURE 2: MANAGING COMPLICATION OF PNEUMONIA .................................................................. 26 ANNEXURE 3: MANAGEMENT OF A CHILD WITH WHEEZE ...................................................................... 28 ANNEXURE 3: ACUTE UPPER RESPIRATORY TRACT INFECTION: .............................................................. 38

ANNEXURE 4: Dosages of drugs used for ARI: ........................................................................................ 42 2

1. INTRODUCTION Acute respiratory infections (ARI) encompass viral and bacterial infections of the respiratory tract. NFHS 3 data suggests that as many as 6% children under age five years in India showed symptoms of ARI at some time in the two weeks preceding the survey. While upper respiratory infections areoften self limiting, lower respiratory infections, in particular, pneumonias, pose life threatening situation. Most

pneumonia deaths are caused by bacteria. Pneumonias are the number one cause of under 5 child mortality, responsible for nearly 400 000 deaths in India annually. These deaths can be prevented by appropriate treatment with antibiotics. Pneumonia can be distinguished from other respiratory tract infections by the use of simple clinical signs such as respiratory rate and lower chest indrawing. Children with acute cough but who do not have any

sign of pneumonia usually would commonly have viral upper respiratory infection and should not receive antibiotics. This is important as unnecessary exposure can lead to increase in antimicrobial resistance in the community. The objectives of this guideline are: • Promote recognition of cases of pneumonia among children with suggestive symptoms like cough, and/or difficult breathing, • Recognize the severity of illness and need for referral,

• Institute appropriate treatment of ARI using standard treatment protocol at community and facility level. EFFECTIVE CASE MANAGEMENT OF ARI Effective case management includes: 3

Appropriate use Early recognition( of antibiotics of cases of /Prompt referral Pneumonia) of severe cases Recognition of Appropriate use cases that do not of have pneumonia bronchodilators( (and do NOT in children with require wheeze) antibiotics) • Early recognition of cases of pneumonia, • Appropriate use of antibiotics against the major causes of bacterial pneumonia, prompt referral of cases of severe pneumonia and providing pre-referral treatment,

• Providing good supportive care including appropriate and effective use of oxygen in health facilities to treat hypoxia which is usually in the causal pathway of pneumonia related death, • Appropriate use of bronchodilators in children with wheeze at health facility and identification of pneumonia mimickers for their rational therapy, • Recognition of cases that do not have pneumonia and do NOT require antibiotics but may benefit from supportive treatment. 4

2. Key Recommendations Assessment and Treatment of Sick Young infant (age < 2 months): i. At Community Level: The ANM should follow the following five steps for diagnosing and treating sepsis in young infants: The Flow Chart (on nextpage) outlines the five steps in detail. Any young infant brought to ANM is assessed for presence of signs described in assessment. If one or more signs are present the infant is classified as PSBI. ANM will counsel the mother regarding referral of

such a baby using free referral under JSSK and will start the pre referral dose of Injection Gentamicin and Syp Amoxicillin described in the Table XX based on the weight of the infant. 5

Summary of antibiotic treatment for sepsis in a young infant Young infant’s weight Amount of Gentamicin to Amount of Amoxicillin to be given intramuscularly as begiven per-orally as Syrup Injection (contains 80 mg in (contains 125mg / 5 ml) 2 ml vial) Less than 1.5 Kg To be referred to higher facility Above 1.5 kg – upto 2.0 Kg 0.2 ml 2 ml Above 2.0 kg – upto 3.0 Kg 0.3 ml 2.5 ml Above 3.0 kg - upto 4.0 Kg 0.4 ml 3 ml Above 4.0 kg - upto 5.0 Kg 0.5 ml 4 ml Route of administration intramuscular oral

Dosage 5 mg/kg/dose * 25 mg/kg/dose** Once a day Twice a day *Precaution: If the treatment is to be continued same vial can be reused for the entire course of 7days, provided itis stored properly and its contents do not change color or have turbidity. In case of any doubt it is better to use a new vial **The ANM will instruct the mother how to reconstitute the syrup if it is in powder form This table will help the ANM in giving the correct doses of both the syrup and injectable. She has to

weigh the infant before starting the treatment. Similarly ASHA can also weigh the infant and start Syp Amoxicillin in case she classifies the infant as a case of fast breathing. Steps to be taken by the ANM before and during referral to health facility 1. Warm the young infant by skin to skin contact with mother/care giver if temperature less than 35.5 (or feels cold to touch)while arranging referral and during transport. 2. Treat to prevent low blood sugar using Health Workers module of IMNCI

• If the child is able to breastfeed: Ask the mother to breastfeed the child. • If the child is not able to breastfeed but is able to swallow: Give 20-50 ml (10 ml/kg) expressed breast milk or locallyappropriate animal milk (with added sugar) before departure. If neither of these is available, give 20-50 ml (10 ml/kg) sugar water. • To make sugar water: Dissolve 4 level teaspoons of sugar (20 grams) in a 200-ml cup of clean water 7

ii. At the Facility Level: Assessment and Treatment of Sick Young Infants (0-2 months of age) for evidence of Pneumonia with/without sepsis/meningitis (Serious bacterial infection) at a Healthcare Facility: Pneumonia is classified as severe and very severe disease in young infants because of higher risk of hypoxia,apnea and death. Table 6: Clinical classification of sick young infants aged 0 to 2 months Clinical category Essential feature Possible serious bacterial infection – Convulsions or

(pneumonia, septicemia or meningitis ) Fast breathing (Respiratory rate > 60 per minute) or Severe chest indrawing or Nasal flaring or Grunting or Not able to feed Bulging fontanelle or Lethargy or unconsciousness or Less than normal movement or Axillary temperature≥ 37.5°C or more ortemperature <35.5°C) POINTS TO REMEMBER WHILE ASSESSING YOUNG INFANTS § As cough may be absent, respiratory rate should be measured in all neonates thought to be ill

by the mother or those who have acute feeding problems. Cough is not an essential criterion for screening for pneumonia in this age group. § The normal resting respiratory rate is higher and more variable than in the older infant, therefore, the threshold for the diagnosis of pneumonia is 60 breaths per minute or more. § In the young infant the respiratory rate should be measured for a full minute since they may have periods of apnea or irregular breathing normally. If the respiratory rate is fast, the rate

should be counted for a second time; the fast breathing is significant only if second count is also >60 bpm. The respiratory rate should be counted when the baby is calm and not crying or feeding. § When normal young infants are observed carefully, they often have mild chest indrawing because their chest wall is soft. However, severe chest indrawing, which is very deep and easy to see, is a sign of severe pneumonia. In case of doubt, the infant should be observed in 8

different position, lying flat in the mother’s lap or on a bed. Chest indrawing is significant if it is

is present all the time, in all positions and not only when the child is crying or upset but also when calm and peaceful. § It is important to consider the possibility of co-existing meningitis in sick young infants as the drug therapy (choice and duration of antibiotic) will be different for meningitis. Meningitis is suspected in the presence of bulging fontanelle, seizures or staring spells or altered sensorium.CSF examination should be done in such situations to confirm the diagnosis of meningitis.

Fig 4 : Management of Severe Pneumonia in children aged ≤ 2 months Severe Pneumonia in a young infant (≤ 2 months) No suspicion of meningitis Meningitis suspected • Admit 3rd generation • Maintain nutrition & hydration cephalosporins(Cefotaxime or • O inhalation Ceftriaxone) + gentamicin for 2-3 weeks 2 • Inj. Ampicillin + Gentamicin • Monitor for worsening Assess at 48 hours Improvement No improvement/same/ worsening • Feeding well • No chest indrawing • No Hypoxia SaO2>92%

Inj 3rd generation Cephalosporin (Cefotaxime or Complete 7-10 days of antibiotics Ceftriaxone) ± Gentamicin for 10-14 days and discharge NOTE A blood culture and an X-ray chest should be obtained if feasible. Any findings suggestive of meningitis indicate the need for a cerebrospinal fluid examination. Blood sugar and calcium estimation may be required if convulsions occur. Decisions regarding choice of antibiotics can

be made even when facilities for culture are not available particularly for babies born at home (Table 7). Hospital born babies may have infections with organisms peculiar to that 9 setting and blood cultures are then more useful.

Table 7: Antibiotic therapy for pneumonia/sepsis in infants <2months Antibiotic Each Dose Frequency Route Duration (mg/kg/dose) < 7 days age > 7 days age (Days) Inj. Ampicillin* 50 12 hrly 8 hrly IV, IM 7-10 And Inj. 5 24 hrly 24 hrly IV, IM 7-10 Gentamicin or Inj. Amikacin 15 24 hrly 24 hrly IV, IM 7-10 *If concomitant meningitis is suspected the drugs should be given IV and Inj cefotaxime 50 mg IV 8 hourly is used instead of Ampicillin. The total duration of therapy in meningitis is 2-3 weeks.

In case of suspected staphylococcal infection Injection Cloxacillin 50mg/kg 8hrly is to be added to the regime. Assessment and Treatment of Children between 2months -5years i. At Community Level: • For all sick children, thecommunity health worker should first check for general danger signs given in box below. Presence of any one of the general danger signs mandates quick assessment, pre-referral treatment and urgent referral to a hospital. GENERAL DANGER SIGNS a) Convulsions, b) Not able to feed /drink,

c) Lethargic/unconscious, d) Vomiting everything In addition in children with cough or difficult breathing, the respiratory rate is counted and patient assessed for presence of lower chest indrawing. • Respiratory rate should always be counted for full 1 minute when the baby is calm and not feeding. A respiratory rate of over 50 breaths per min in children between 2mo-1 year and over 40 breaths per minute in children 1-5 years of age is called as fast

breathing and this simple clinical sign is used by the health worker to identify likely cases of pneumonia in the community. • Presence of lower chest wall indrawing (LCI) - which is a definite inward movement of the lower chest wall on breathing in- identifies cases with severe disease in whom lung 10

now is getting stiffer. It is important to point out that the definition of chest indrawing does not include intercostal or supraclavicular retractions. • Pulse oxymetry is an important tool to identify children with co-existent hypoxia (SpO 2 <92%) and should be used wherever the facilities exist with the worker. • Children with history of recurrent wheezing (respiratory distress) can be identified by the health worker and should be given an initial trial with bronchodialtors before

starting antibiotics for rapid breathing. The worker should either give a single oral or equivalent inhaled doses of salbutamol (to be detailed depending on what formulation is available- mdi neb etc) and look for response over next 1 hour. In case of a good response with respiratory rate coming down and indrawing disappearing, the child may be treated with bronchodilator alone and not given any antibiotics; else the bronchodilator (salbutamol) is added to the antibiotic regimen.

• The community health workers based on the assessment for danger signs, respiratory rate and chest indrawing and SpO (where pulse oxymetry is possible) will classify these 2 children into action oriented categories as given in Table2 below. • Children aged 2–59 months require immediate referral if they have signs of severe pneumonia (central cyanosis, stridor at rest inability to drink or breastfeed, convulsions, lethargy, or unconsciousness or SpO of <92% (where facilities exist). 2

Table 2. Child (2 months to 59 months of age) with cough and or difficulty in breathingA: Presenting to a Health worker (ASHA, ANM) Signs Classify as Management • General danger signs (inability to Severe Refer to health care facility after giving first dose breastfeed or drink, lethargy or pneumonia of amoxicillin for assessment by doctor. reduced level of consciousness, If seen by ASHA, get assessment by ANM* convulsions) • • Fast breathing: Pneumonia * Give cotrimoxazole for 5 days and assess

Respiratory rates regularly o 2-11 months >50/min o 12-59 months >40/min • Chest Indrawing • No signs of severe pneumonia No signs of severe pneumonia or No pneumonia • Soothe the throat and relieve cough with safe pneumonia remedy). • Advise the mother when to return. • Follow up after 5 days if not improving, If coughing for more than 14 days refer to doctor for further investigation a Children with audible wheeze and/or history of wheezing in the past should be given a trial of bronchodilator

and those who show goos response may not need to be treated as pneumonia. * In case the family is not willing for referral, the ANM should administer oral amoxicillin with daily monitoring while preparing/ convincing the family for referral Please note: 11 • The mother is advised to continue feeding the child during the illness. Breast feeding may be continued.

Table 3. RECOMMENDED HOME MADE COUGH REMEDIES 1. Sugar, Ginger, Lemon juice, Basil/ tulsi leaves - Make hot drink* 2. Sugar, Ginger, Lemon juice, Mint - Make hot drink* 3. Saunf, Elaichi, Ginger, Sugar - Tea* *Let it cool until it is lukewarm before giving to the child Follow up care The mother should also be advised on how to give drugs at home and to look for signs of worsening illness like inability to feed, breathing harder and faster, and / or child getting sicker than before. If any

of these signs appear she should report immediately, or else, she should return after 2 days for follow up.At followup, the worker should check whether the child is improving (Cough is better) or worsening (Appearance of fast breathing, LCI or any sign of Very severe pneumonia) . Any child showing signs of worsening on follow-up should be referred immediately to a health facility. In case the child is found to have audible wheeze, oral salbutamol may be given before referral. ii. At Facility Level: 12

INITIAL ASSESSMENT: (cid:216) At the health facility it is important to make the distinction between pneumonia and other ALRIs and other clinical confounders. This requires a relevant history and appropriate examination including auscultation, to check for wheeze and complications of pneumonia. (cid:216) First of all an initial quick assessment is done to identify the children at immediate risk of death. Every child should be assessed for his airway, breathing and circulation and

appropriately treated, if needed even before more detailed assessment. Oxygen should be given depending on severity of distress at admission. The patient should be assessed for general danger signs (history of convulsions, presence of lethargy/altered sensorium, inability to feed and vomiting everything). (cid:216) A detailed examination including: Respiratory rate- Respiratory rate should always be counted for full 1 minute when the baby is calm and not feeding.

Chest indrawing - This is defined as definite inward movement of lower chest wall on breathing in. This should be looked for when the child is not feeding or crying. Stridor – It is a harsh inspiratory sound which may be accompanied with supra-sternal recession. Signs of severe respiratory distress – head nodding, grunting, irregular breathing, diaphoresis, cyanosis, apnoea, SpO < 92% etc. 2 Complete assessment includes complete examination to rule out other causes of respiratory

distress and associated infections (e.g. diarrhoea, meningitis, measles, or malaria). Congestive heart failure can mimic the signs of pneumonia and the two problems can also co-exist. Chest auscultation for signs of pneumonia including: o decreased breath sounds o bronchial breath sounds o crackles o abnormal vocal resonance (decreased over a pleural effusion, increased over consolidation) o pleural rub o Wheeze, can sometimes be associated with pneumonia in small children. It may even be

(cid:216) Presence of severe malnutrition: If on examination the child’s weight for height is less than -3SD or has bilateral pedal oedema or visible severe wasting or MUAC <11.5cm, thepatient is treated as a case of severe acute malnutrition as per standard protocols. Such children if treated only for their respiratory problem will continue to be at high risk of death. The underlying severe malnutrition also needs to be addressed appropriately. CLASSIFICATION:

(cid:216) It is recommended that a trial of rapid-acting bronchodilator is given to children with current wheeze and fast breathing before treating as pneumonia. This protocol will identify children with recurrent wheeze and curtail the unwarranted usage of antibiotics. Infants with first episode of wheeze, who usually have viral bronchiolitis, also do not need antibiotics though the response to initial bronchodilators may not be consistently seen in such a case. The treatment of

children with wheeze thus needs to be based on the clinical evaluation of the patient as well as response to inhaled bronchodilators as per initialalgorithm (Fig. 1). (cid:216) Among those finally now diagnosed as pneumonia, the physician should assess the severity of illness using the clinical signs of respiratory distress and hypoxia, as well as need for hospitalization as given in the Tables 4 and 5. Children with severe acute malnutrition may need

different management and have been detailed separately later. Table 4 - Indications for hospitalization in a child with Pneumonia 1. All children diagnosed as pneumonia with age < 2 months(PSBI) 2. Age > 2 months with • Non-response or worsening on domicilliary therapy • Convulsions • Inability to drink/feed • Grunting/ head nodding • lethargy/altered sensorium • Oxygen saturaion < 92% • Cyanosis • Severe Acute Malnutrition 14 Cough and / or Difficult breathing

Table 5. Child (2 months to 59 months of age) with cough and or difficulty in breathing: Presenting to a facility (doctor)* 15

Signs Classify as Management • General danger signs (inability to Severe Admit immediately breastfeed or drink, lethargy or pneumonia Administer intravenous Ampicillin (or reduced level of consciousness, Penicillin) Plus Gentamicin convulsions) Give oxygen if saturation < 92%. • Chest indrawing with oxygen Manage airway, as appropriate. saturation <92% or SpO facilities not 2 available • Fast breathing: Pneumonia • Home treatment Respiratory rates • Give Amoxycillin for 5 days

o 2-11 months >50/min • Soothe the throat and relieve cough o 12-59 months >40/min with a safe remedy And/or • Treat high fever if present • Chest indrawing (SpO 2 > 92%) • Treat wheeze if present And • Assess regularly No signs of severe pneumonia No signs of severe pneumonia or No Soothe the throat andrelieve cough with pneumonia pneumonia saferemedy). Advise the mother whento return. Follow up after 5 days ifnot improving. If coughing for more than14 days refer to doctor for further investigation

* If the child has wheezing, Give 3 doses of inhaled salbutamol and reassess If there is no improvement in symptoms: classify as Severe pneumonia OR pneumonia MANAGEMENT: OPD BASED TREATMENT OF NON-SEVERE PNEUMONIA IN CHILDREN 2MO-5 YRS OF AGE SEEN IN A HEALTH FACILITY (cid:216) If the child has only fast breathing and / or lower with chest indrawing without danger signs, having oxygen saturation >92% in room air and is able to feed, he can be treated at home with

antibiotics (Fig.2).The patients with wheeze should be assessed for fast breathing after a trial of rapidly acting bronchodilator as per initial algorithm (Fig. 1). Many patients with history of recurrent wheeze may have signs suggestive of pneumonia on presentation which may resolve partially or completely after a trial of bronchodilator. (cid:216) The antibiotic of choice is amoxicillin (25mg/kg twice daily or 15 mg/kg per dose thrice daily for

5 days).While under the CCM co-trimoxazole is recommended for treating non-severe pneumonia by an ASHA worker but for children diagnosed by a physician at a facility level the preferred drug is oral amoxicillin. This is recommended due to the presence of high resistance to Co-trimoxazole. (cid:216) Earlier children with lower chest indrawing were considered to have severe disease. More recently studies have documented that pneumonia with chest indrawing without hypoxia/ 16

danger signs and are able to feed can be managed on ambulatory basis with oral amoxicillin (Lodha R, Kabra SK, Pandey RM. Antibiotics for community-acquired pneumonia in children. Cochrane Database Syst Rev. 2013 Jun 4;6:CD004874.) Therefore children with chest indrawing without danger signs, having oxygen saturation >92% in room air and are able to feed, are now classified as pneumonia (non-severe) and are to be managed on ambulatory basis with oral amoxicillin for 5 days. Follow up care

The mother should be advised on how to give drugs at home and how to look for signs of worsening illness like inability to feed, breathing becomingharderand/ or child getting sicker than before. The patient is followed up after 2 days to check for signs of improvement and to review treatment as per algorithm detailed in Fig. 2. The treatment is continued for 5 days if the patient improves. If patient worsens and shows

signs of deterioration, he should be admitted, re-evaluated and treated as severe pneumonia. If the patient is same, and was taking his / her drugs appropriately, the same treatment is continued for 24 more hours. Should these be for severe pneumonia sent home too? The patient should also be checked again for wheeze and in case of auscultable wheeze or history of recurrent wheeze, the patient is treated with oral bronchodilator (Tab ?Syp? Salbutamol) in

addition. If there is still no improvement over next 24 hrs (i.e. after 72 hours of therapy), a change to second line drugs is recommended. All children whose cough has been persisting for over 2 weeks should be investigated for TB. FACILITY BASED TREATMENT OF SEVERE PNEUMONIA IN CHILDREN 2MO-5 YRS OF AGE Severe Pneumonia Pneumonia in a child with atleast: • Central cyanosis • Severe respiratory distress ( RR >70/min, head nodding, grunting, severe chest indrawing, SpO2 <92%)

• Inability to breastfeed/drink due to respiratory distress Such children are usually very hypoxic and need urgent treatment and oxygen therapy. They often • Convulsions cannot take orally and therefore need to be given intravenous fluids and parenteral antibiotics. The • Lethargy/unconsciousness initial treatment of choice is injection ampicillin and gentamicin in such cases (Fig 3) and treatment is given for a total course of 10 days. 17

These children need a very close monitoring for distress and oxygen saturation as they are at higher risk of complications. All children with hypoxia (suspected on clinical signs or pulse oximetry SpO2 <92%) should be given oxygen. The clinical signs are per se a poor predictor of hypoxemia and therefore using a pulse oximeter is always preferable. While Hypoxia is one of the major causes for high mortality in

pneumonia, oxygen is otherwise a precious source and therefore the use of oxygen therapy as dictated by SpO will ensure least wastage and directed therapy to the mostneedy cases. 2 It is important to have high index of suspicion for staphylococcal infection, particularly in cases with severe disease, as the initial choice of antibiotic does not adequately cover this albeit less common but more severeinfection. Staphylococcal pneumonia is suspected if any child with pneumonia has:

• Rapid progression of the disease, or • Pneumatocoele, or Pneumothorax, or Effusion on chest X-ray, or • Large skin boils or abscess or infected scabies or • Post- Measles pneumonia, which is not responding within 48 hours to the initial therapy. To cover for staphylococcal infection, Injection Cloxacillin should be added to the initial regime. Once the child improves, continue Cloxacillin orally 4 times a day for a total course of 3 weeks at least.

Children with complicated pneumonia (e.g. Empyema) need longer therapy for 4-6 weeks. Fig 3: Facility based treatment of Severe Pneumonia in a child of 2 months – 5 years age 18

• Admit • Check oxygen saturation – if<90%, give supplementation Oxygen to achieve SpO 2 at 90% or above. • IV Fluids • Get a chest skiagram* • IV Ampicillin + Gentamicin** • Treat wheeze, if present Monitor at least every 2-3hrsor frequently for any worsening • Increase in RR • Increase in distress • Fall in SpO2 / failure to improve SpO with incremental 2 oxygen Worse at any stage Reassess at 48 hrs Improved No improvement Complete IV antibiotics for 10 days

• Rule out air leak or empyema, if present treat appropriately • Give Injectable Third generation cephalosporin (Cefotaxime or ceftriaxone) + Cloxacillin for 7-10 days. • If Staphylococcal infection is confirmed or very likely then total treatment is given for 4-6 weeks • Consider Ventilatory Support if oxygenation not maintained *Chest X-ray should be done for all cases of very severe pneumonia to look for empyema, pneumothorax and other complications after stabilization

**Suspecting Staphylococcus infection: Add Cloxacillin to the regimen. 19

MANAGEMENT OF PNEUMONIA WITH COOMORBIDITIES PNEUMONIA IN A CHILD WITH SEVERE ACUTE MALNUTRITION Pneumonia is not only more common but is also more likely to be fatal in children with severe acute malnutrition. Besides it may be caused by wider range of bacteria including gram negative bacteria. Clinical presentation is less specific and may overlap with sepsis. • The child should be admitted in view of severe acute malnutrition and be treated as severe

pneumonia even though they may not have chest indrawing or signs of severe respiratory distress. Children with severe PEM sometimes can have pneumonia without fast breathing though will have other signs of respiratory distress like accessory muscle use and nasal flaring. A chest radiograph should be obtained, wherever possible. • Inj Ampicillin and Gentamicin is the antibiotic of choice as it gives an extended cover for gram

negative infections which are seen more often in cases with SAM. Theantibiotics are to be given for 7-10 days. Inj Cloxacillin should be added whenever there is suspicion of staphylococcal infection (see above). • Management of severe acute malnutrition i.e. maintaining temperature, prevention and treatment of hypoglycemia and appropriate feeding is essential additional treatment needed for favourable outcome. • Pulmonary tuberculosis and HIV should be diagnostic consideration if the patient does not show

PNEUMONIA IN A CHILD WITH HIV Incidence of pneumonia, including bacterial pneumonia, is much higher for HIV-infected children than for HIV-uninfected children. The common causes of bacterial pneumonia are similar but the range of bacterial pathogens is wider. Opportunistic infections such as P. jiroveci and cytomegalovirus are also seen and are associated with poor outcome. Pulmonary tuberculosis is common among HIV-infected

infants and children presenting as severe pneumonia in tuberculosis-endemic regions and it may even present as an acute pneumonia.Mixed infections and treatment failure are common.Case-fatality rates are reported to be 3–8 times higher than in HIV-uninfected children. Table 8: WHO recommendation for management of pneumonia in HIV-infected children Nonsevere pneumonia Severe pneumonia Oral amoxicillinfor 7 days Admit to hospital: • Avoid trimethoprim- • Intravenous (i.v.) ampicillin/penicillin

sulphamethoxazole in those taking it as and gentamicin prophylaxis • Treat P.jirovecii with i.v. co-trimoxazole • Regular follow-up to monitor progress and corticosteroids • Give oxygen if hypoxia • If not improving within 72 h change to second line antibiotic: ceftriaxone 21

ANNEXURE 1: SUPPORTIVE THERAPY FOR PNEUMONIA 1. OXYGEN THERAPY Who to give - Hypoxemia is reported in upto 59% of children hospitalized with pneumonia. Children with hypoxemia are at 4 times increased risk of death as compared to those without hypoxia. The clinical signs suggestive of severe hypoxemia - central cyanosis, and severe respiratory distress (inability to breastfeed, nasal flaring, head nodding, severe chest indrawing, grunting and lethargy) indicate that

child should be given oxygen immediately on admission and most of these will require high flow rates to start with. The clinical signs are useful but have variable sensitivity and specificity and do not accurately identify all hypoxaemic children. Children with severe pneumonia do not have signs of severe respiratory distress but a significant proportion of these too may have hypoxemia. The clinical examination of all hospitalized children with pneumonia should therefore be supplemented with the

measurement of SaO2 by pulse oximetry. At sea level SaO2 of less than 90% is suggestive of hypoxemia and need for oxygenation in infants and children(see box). Give oxygen to children with • Central cyanosis or • Severe respiratory distress - Resp rate >70/min - Inability to feed - Head nodding - Grunting - Nasal flaring - Lethargy • Oxygen saturation <90% OXYGEN DELIVERY: Various devices can be used to deliver oxygen. Whatever be the device chosen, oxygen should be given

to a child in the most non-threatening manner as anxiety and crying increases oxygen consumption and possibly respiratory distress. If a child is upset by one method of oxygen support, attempt should be made to deliver the oxygen by an alternative technique. It is important to have the proper flow meters to control oxygen flow rates and to use rates appropriate to the device selected and patient’s condition. DEVICES FOR OXYGEN DELIVERY:

Nasal catheter : A 8 FG catheter should be inserted to a depth equal to distance between the side of nostril to the inner margin of eyebrow. The catheter should be kept clear of mucus. In case nasogastric 22

tube is required for feeding, it should be inserted through same nostril as the oxygen catheter and the other nostril should be kept clear of all obstructions including mucous. Nasal prongs:It consists of two short soft prongs that arise from oxygen supply tubing and are designed to lie just within the nostrils. After placement inside the nostrils, these should be secured with a piece of tape on the cheeks near the nose. Nasal prongs are preferred over nasal catheter for delivering oxygen

to young infants and children with severe croup or pertussis as catheters can provoke paroxysms of coughing.Face Mask: It is a plastic mask connected to an oxygen source, fitting over the patient’s nose and mouth with side-to-side perforations that allow room air entrance when placed over the infant’s face. Usually high flow rates are needed (flow rates 5-6 litres/min) to avoid risk of carbon dioxide accumulation. It interferes with feeding and many infants refuse to keep the mask on. However, this is

a good device to achieve oxygenation in severely distressed and in emergency situations when high flow oxygen is required. Oxygen hood or Head box: It is a clear plastic or acrylic box placed surrounding the infant’s head. It needs high flow rates (8-10 L/min) to prevent re-breathing of carbon dioxide. With its usage Infants’ mobility and feedings get limited. Unlike nasal cannula, it does not have increased risk of gastric

distension or airway obstruction, but it is a rather wasteful manner of oxygen delivery and should not be used routinely in the wards. Wafting or blow by method - Children may not tolerate any of the above methods and get agitated by catheters or face mask. In such case oxygen can be administered by non-contact methods - giving high flow oxygen (8litre/min) through face mask or oxygen tubing kept aimed at the airway but held a little

away from the face of the child. This method should be used initially for a short period and replaced with any other method of delivery discussed above as soon as the patient can tolerate it. This method can also be used as an alternative for patients on oxygen therapy as a short term measure of oxygen therapy during feeding or dressing. Flow rate of oxygen- A flow meter should be used with oxygen delivery system to give a flow rate as below, when using nasal catheters/prongs.

Young infants upto 2 minutes 0.5 -1 litre per minute 2 months -5 years 1-2 litres per minute Monitoring a child on oxygen therapy:The infant or child on oxygen should be monitored closely to identify and correct any problem in delivery of oxygen and for signs of improvement. Check list for the patient on oxygen therapy: (cid:216) The position of prongs or catheter is checked to ensure that they are in place and are not blocked by mucus. (cid:216) Oxygen flow rate and connections are appropriate. 23

(cid:216) Heart rate, respiratory rate and signs of respiratory distress are not increasing, suggesting a need for increasing FiO and other measures as discussed before for worsening cases. 2 (cid:216) Oxygen saturation by pulse oximeter aiming to maintain it above 90%. Duration of oxygen therapy: Oxygen should be given continuously until the child is able to maintain a SaO >90% in room air. When the child is improving the oxygen flow rate is gradually reduced over a 2

period of hours as long as the patient tolerates it. Once the patient is stable on very low flow rates (0.5- 1lt/min) with no or minimal distress, the child is taken off oxygen for a few minutes. If the SaO remains 2 above 90%, oxygen can be discontinued. The saturation is checked again 1/2 hour later, and 3 hourly thereafter on the first day off-oxygen to ensure the child remains stable. Where pulse oximetry is not

available, the duration of oxygen therapy is guided by clinical signs, but these are less reliable. 2. TREATMENT OF FEVER If the child has fever give antipyretic such as paracetamol 15 mg/kg as and when required. Avoid nimuselide in infants and ibuprofen in children with wheeze. 3. SYMPTOMATIC TREATMENT OF COUGH Cough is a protective reflex and should not be suppressed in children with ALRI. There is no role of cough suppressants, mucolytic agents and cough expectorants in ALRI. The parents should be

counselled regarding the adverse effects of these agents in children. 4. FLUIDS A child with pneumonia who is sick enough to receive oxygen is generally not fit to receive oral or nasogastric feeding. Such patients require intravenous fluids. These children usually have one or more of the following: (cid:216) Cyanosis (cid:216) Restlessness (cid:216) Severe lower chest indrawing (cid:216) Grunting (cid:216) Shock and dehydration (cid:216) Poor acceptance of oral fluids

If there are indications for use of maintenance IV fluids, amounts given below in Table 9 are used: Table 9.Maintenance fluid requirement ml/day Body weight Fluid ml/day Upto 10 kg 100 ml/kg/ day 11-19 kg 1000ml + 50ml /kg for each kg bw in excess of 10kg./ day 24

Avoid giving IV fluids if the child is not in severe respiratory distress. Intravenous fluids should not be used merely to maintain the patency of IV catheter for administering antibiotics. Fluid administration in cases of pneumonia should be carefully monitored to prevent over-hydration caused by the syndrome of inappropriate antidiuretic hormone secretion. If there are no signs of dehydration and no other indications for IV use, frequent breast feeding provides

adequate fluid to exclusively breast fed infants < 6 months. Infants > 6 months accept breast feeds even when they are ill and it should be given more frequently during sickness. Non- breast fed infants should be given undiluted animal milk (approx 4 ml/kg/hour) and provided access to water as and when demanded. If the child cannot take orally, give IV maintenance fluids containing 5% dextrose with sodium (30 mmol/L and potassium (20 mmol/L). 5. FEEDING DURING PNEUMONIA Infants < 6 months

(cid:216) Breast milk is accepted, even by anorexic children. It should be given with greater than usual frequency. (cid:216) If the baby is unable to suck breast milk but is otherwise stable, breast milk should be expressed and given to infants who are too weak to suck by cup and spoon or by intragastric tube. Children > 6 months (cid:216) Breast feeding is continued in breast fed infants. In children with pneumonia, not requiring

oxygen, small calorie dense feeds (dalia, kheer, milk with bread, khichri or rice and dal) should be given every 2-3 hours. (cid:216) The child should be encouraged to feed. (cid:216) If the child is on oxygen, avoid feeding. Initiate oral or nasogastric feeding as soon as oxygen is not required. (cid:216) After recovery from pneumonia offer an additional feed at least for the next two weeks to ensure catch up growth.

(cid:216) Extra emphasis should be given to feeding in children with measles pneumonia, whooping cough and in those with malnutrition. Counsel the mother about appropriate feeding depending upon age of the child. 25

ANNEXURE 2: MANAGING COMPLICATION OF PNEUMONIA 1. PLEURAL EFFUSION AND EMPYEMA A child with pneumonia should be suspected to have pleural effusion or empyema if any one of the following is present. • Pain in chest during breathing • On examination, the chest is dull to percussion • Breath sounds are reduced or absent over the affected area. • A pleural rub may be heard at an early stage before the effusion is fully developed. • Fever persists despite antibiotic therapy.

A chest X-ray shows fluid on one or both sides of the chest. Diagnostic pleural tap is a must to make a diagnosis. Frank pus (thick or thin) is aspirated in cases of Empyema. The aspirate should always be sent for Gram’s staining and culture, Cytology, and for aspirate’s Sugar, LDH and protein levels. Treating Empyema a. Chest drainage: Management of fluid in the pleural cavity depends on the character of the fluid

obtained. If there is pus in the pleural cavity then a chest thoracotomy drain is must, unless the collection is very small. In case the disease is bilateral and significant, both sides may need drainage. b. Antibiotic therapy: Staphylococcus aureus is a common causative organism of empyema. Give Cloxacillin and Gentamicin as anti-staphylococcal drugs. Usually intravenous antibiotic therapy shall be needed for 7-10 days. Unlike pneumonia the fever comes down a little later by 5-7 days. When the child

improves, continue with cloxacillin orally, 4 times a day. Continue treatment for a total of 4-6 weeks. In case of a younger child (under 2 years) and/ or in the absence of staphylococcal stigmata (as described above) Penicillin or Ampicillin may be added to this regime to cover for pneumococcus and H. Influenza which are the other important causes for empyema. c: Supportive therapy: Every child should receive oxygen and other supportive therapy as needed

(nutritional support, and antipyretics/analgesic if required) d: Failure to improve: If fever and other signs of illness continue beyond 5-7 days, despite adequate chest drainage and antimicrobial therapy, assess for reasons for non response like phlebitis, metastatic 26

pus lesion elsewhere in the body, resistant bacteria or less commonly tuberculosis. The antibiotics may then be revised to Inj Co-Amoxyclavulanic Acid or as per the sensitivity of the pus isolate. TUBERCULOSIS : Consider the possibility of tuberculosis in a child with pneumonia if: • Child has unremitting fever and cough for more than 2 weeks and cause of fever cannot be found • Contact with a pulmonary TB case. • Lack of response of respiratory symptoms and signs to broad-spectrum antibiotics.

• Weight loss or failure to thrive. The diagnosis of tuberculosis in young children remains very problematic. Children can not usually bring out sputum and gastric aspirates are often negative with TB. Still, it is important to obtain early morning gastric aspirates, or sputum or pleural fluid for ZN (Ziehl-Neelsen) staining and examination for acid-fast bacilli, and, for culture. Radiological investigations may be useful, if tuberculosis is suspected. In addition

a positive skin test is a useful pointer. Mantoux test can however be negative in military TB, severe malnutrition, or recent measles; It is important to distinguish tuberculosis from other causes of pneumonia. 27

ANNEXURE 3: MANAGEMENT OF A CHILD WITH WHEEZE Wheezing occurs when the flow of air from lung is obstructed due to narrowing of small airways. Infection or an allergic response can cause narrowing of small airways. Due to the small size of their airways, small children are more prone to wheezing. The common causes of wheezing are: • Bronchiolitis • Asthma (recurrent episodes) • Acute respiratory infections such as pneumonia/ bronchitis • Inhaled foreign body

A childwith broncho- constriction can have audible or auscultable wheeze and signs of increased work of breathing such as fast breathing, chest indrawing. The expiratory phase of respiration is prolonged and a high pitched musical sound (wheeze) may be heard during expiration. The management of a child with acute wheezing associated with respiratory distress with or without past history of recurrent attacks of wheezing is detailed in Fig.7. 28

Fig 7: Algorithm for management of a child with acute wheezing associated with respiratory distress or past history of recurrent attacks of wheezing. Children with wheezing and respiratory distress Salbutamol by nebulizer or Metered dose inhaler Reassess after 30 minutes of the last dose Respiratory distress persists Respiratory distress improves • Admit in hospital Children with history of Children with first recurrent wheeze episode of wheezing • Recurrent wheezer– Treat as asthma

o Give rapid acting bronchodilator i.e. salbutamol by nebulizer or metered dose inhaler frequently. Add steroids Oral salbutamol at home for 5 days Oral salbutamol and manage as per asthma at home for Assess / Send for review for likely guidelines (Fig 8) long term treatment for asthma. 5 days • First Episode In a younger child (>2 yrs)– Consider Bronchiolitis and treat accordingly • Others Treat as pneumonia with wheeze – adding Antibiotic and appropriate treatment for pneumonia as asthma and

B ronchiolitis are less likely First episode of wheezing but no respiratory distress These children can be treated at home with oral bronchodilator and supportive care only. Children with wheezing and respiratory distress or those with recurrent wheezing It is important to assess the response to a rapidly acting bronchodilator (salbutamol metered dose inhaler or nebulizer) repeated at 15-20 minutes as described in Table 10. Subcutaneous epinephrine can 29

be used as a substitute, if it is not possible to give salbutamol by metered dose inhaler or nebulizer, but the latter is safer. Table 10: Doses of rapid acting bronchodilators (BD) Nebulized Salbutamol (5 mg/ml) 0.5 ml Salbutamol of nebulising solution (5mg/ml) plus 2.5 ml normal saline, nebulised over 10-15 minutes. Initial therapy is of 3 such doses in 1st hour. Salbutamol by MDI with spacer 2-4 puffs, 1 puff given every 3-5 minutes. (This makes it equivalent to 1 dose of nebulised

salbutamol). Three such courses are given in initial 1 hour Subcutaneous Epinephrine (adrenaline) 1:1000 0.01 ml per kg body weight; may be repeated dilution (1 mg/ml=0.1% solution) after 20 minutes, 3doses in 1st hour The subsequent dosage of BD depends on the diagnosis, severity and response. While more frequent doses may be needed and acceptable for children with asthma, children wheezing due to bronchitis or viral infections (WALRI) may not benefit from increased or frequent doses if the

initial response is not very good. The response to bronchodilator treatment is assessed 30 minutes after the last administration to decide whether the child needs inpatient care. Few children may respond within 10-15 minutes of initial therapy only to relapse again, hence there is a need for reassessment after 30 minutes of the last dose. If the child responds well, he can be treated at home with oral salbutamol.If the respiratory distress persists, further treatment is done as shown in algorithm (Fig. 7).

How to give Salbutamol by metered dose inhaler Salbutamol by metered dose inhaler is as efficient as by a nebulizer. Infants and young children lack the coordination to use a metered dose inhaler by themselves. Metered dose inhalers with a spacer device can be used for such children. Spacer devices are available commercially (250-750 ml volume) or can be made by modifying locally available containers (750-1000 ml).

(cid:216) Younger children, who are unable to use a mouthpiece, should be given inhaled salbutamol with a spacer device using a mask or with a homemade spacer with an opening that covers the child’s nose and mouth. The metered dose inhaler is attached to the opposite end of the spacer device and one puff is actuated at one time. The patient is asked to breathe for 3-5 breaths. Then the next puff is repeated similarly as needed. 30

Salbutamol by nebulizer Liquid salbutamol can be nebulized by means of a oxygen source or an electric air compressor. The gas flow should be at least 6-9 liters per minute. A continuous flow of oxygen wastes a large amount of oxygen. (cid:216) The top of the nebulizing chamber is unscrewed and 0.5 ml of the salbutamol respiratory solution and 2.5 ml of normal saline are filled in it. (cid:216) Anoxygen tubing is attached to the bottom of the nebulizer and the other end is hooked to an

electric air compressor or oxygen source. (cid:216) The nebulising chamber outlet at top is attached either to a mask or T-piece. (cid:216) For infants and young children who cannot cooperate, aerosol mask is preferred. It is not necessary for the mask to be tightly sealed to the child’s face. Older children can inhale through mouth using the T-piece. (cid:216) The child should be treated until the liquid in the nebulizer has been nearly used up. This usually takes 10-15 minutes.

(cid:216) The mask is washed with non-residue soap (such as dish washing detergent) prior to reuse. Similarly the tubing and nebulising chamber should also be washed daily.Boiling or autoclaving will destroy the tubing. Sterilization can be done by immersing in 2% Glutraldehyde solution (e.g. Cidex(r)) for 4 hours BRONCHIOLITIS Bronchiolitis, is a very common respiratory disease which like pneumonia presents as FB and LCI but is

caused by a number of seasonal viruses, particularly respiratory syncytial virus (RSV). Infants with acute bronchiolitis may present with a wide range of clinical symptoms and severity, from mild distress to impending respiratory failure. Characteristic clinical features of bronchiolitis include, • Age less than 2 years • Preceding upper respiratory illness and/or rhinorrhea, typically this coryza lasts 2-3 days

• Presenting with breathing difficulties, cough, poor feeding, and irritability, in the very young, apnoea. • High fever is uncommon. • Usually follows exposure to others with viral respiratory infection • signs of respiratory illness which may include the following common ARI symptoms: o fast breathing, chest indrawing,wheeze and/or crepitations on auscultation 31

o shortness of breath, nasal flaring,low O saturation 2 • Chest examination reveals signs of over inflation and the liver and spleen may be pushed down into the abdomen. Management: • The patients having severe / very severe disease as signified by presence of LCI and other signs of severe respiratory distress need to be admitted. Most of these have hypoxia and should be given oxygen, particularly if the SpO is below 90%. 2

• Nebulised epinephrine (2 ml of inj. Epinephrine 1:1000 solution in 2 ml of normal saline) may decrease distress or improve oxygenation. The dose can be repeated 4 hourly for 1-2 days depending on the response.If no response, repeat dose should not be given. • In case of severe disease, particularly if the child has personal or family history of atopy, beta 2 agonists like Salbutamol by nebulised route can be given. However, as the response to

bronchodilators in bronchiolitis is not predictable continued or more frequent usage should be done, only if there is a clinical response after 15-30 minutes of inhalation with initial doses (c.f. asthma). • Routine antibiotics have no role but may be used in young infants or in a really sick looking infant as the distinction from Pneumonia may be difficult. The risk of secondary infection is low andprophylactic antibiotics do not prevent it. Supportive care and monitoring should be done as for pneumonia.

ASTHMA Asthma is a chronic inflammatory condition of the airways associated with variable airflow obstruction that is often reversible. It is characterized by recurrent episodes of wheezing, cough, and difficulty in breathing, which respond to treatment with bronchodilators and anti-inflammatory drugs. Any child with more than 3 episodes of wheezing is likely to have asthma particularly in the presence of personal or family history of atopy. Treatment of acute asthma

Mainstay of drug therapy is bronchodilators and steroids. The types of drug used, their doses are largely governed by the severity of the attack (Fig 8). a. Mild attack – (Alert child with no signs of severe respiratory distress) 32

• Rapid-acting bronchodilators: - Nebulised Salbutamol 3 doses at 20 min interval. OR - Salbutamol by metered dose inhaler (MDI) with spacer: Give 4-5 puffs, spacing out each at 2-3 min interval. This becomes equivalent to a single nebulized dose. Repeat 4-5 puff course as before every 20 min, three times, in this hour. OR - Injection Adrenaline (0.01 ml of 1:1000 solution per kg per dose) subcutaneously every 20 min three times. • The child is reassessed after 1 hour:

- In case the respiratory distress resolves completely, and there are occasional or no rhonchi on auscultation, this is considered as a good response. The patient should be kept under observation for the next 4 hrs to see that the response is sustained. If the child continues to stay well and does not have fast breathing, the mother can be advised on home care with inhaled or oral salbutamol. - If the response is partial, but the child is stable and able to take orally, oral steroids

(Prednisone 1-2 mg/kg/day in 2-3 divided doses) should be started. The child is kept under observation for the next 4 hours to look for any deterioration. Such patients can then be sent home on oral steroids and oral/inhaled salbutamol. - Patients with deterioration are treated as moderate to severe attack. b. Moderate to severe attack (Presence of severe respiratory distress or cyanosis) • The patient should be admitted - Free flow oxygen should be given to keep saturations ≥ 90%

- Rapid-acting bronchodilators should be given - Nebulised Salbutamol 3 doses at 20 min interval; OR - Salbutamol by MDI with spacer: 4-5 puffs are given, spacing out each at 2-3 min interval. This becomes equivalent to a single nebulized dose. A repeat 4-5 puff course can be given as before every 20 min- three times, in first hour. OR - Injection Adrenaline subcutaneously every 20 min three times. This is preferred when there is very severe wheeze as in a silent chest. 33

- First dose of steroids (oral Prednisolone 1mg/kg) should be given promptly, if not started so far. • Continuous monitoring of the sensorium, respiratory rate, oxygenation, chest finding is very important in this potentially life-threatening situation. The patient is reassessed after every 20-30 min initially and every 1-2 hrs once the patient starts responding. Nebulized beta agonists and systemic steroids are the

mainstay of treatment and other drugs are added if only the response is poor or ill sustained. • If on reassessment, the response is partial or poor: - inhaled Salbutamol is continued as before for another hour. - Inhaled Ipratropium bromide can be added, where available. This can be mixed with Salbutamol nebulized solution and 3 initial doses are given at 20 min interval. - Systemic steroids should be continued.

• If the child starts improving or is stable, Salbutamol inhalations are continued at 1 or 2 or 4 hourly interval depending upon the time for which the response to initial treatment is sustained. Ipratropium bromide should however be continued only at 8 hourly intervals. Once good response is seen, Ipratropium inhalation is stopped and then gradually the interval between Salbutamol inhalations is increased till it’s being given every 6 hrs or so. At this stage discharge can be planned.

• In case of poor or no response after initial treatment with Salbutamol and Ipratropium: - 0.05-0.1ml/ kg body weight of 50% Magnesium Sulphate (taken with a 1ml syringe) is added to about 30-50 ml of normal saline and the solution is then given as intravenous infusion over 30 min or so. - Frequent Reassessment every 30 min to 1 hr is done. • if the response is still not good; Injection Aminophylline in a loading dose (5-6 mg/kg up to a

maximum of 300 mg) followed by maintenance infusion in a dose of 5 mg/kg every 6 hrs should be added. • Monitoring is continued intensively. Transfer may be planned to a higher facility continuing the current level of treatment in case of any deterioration or if no response is seen in next 4-6 hours. • Whenever patient shows good response and response is sustained for 4-6 hours, medications can be decreased. 34

Fig 8:Management algorithm for treating acute asthma in a hospital Initial Assessment and grade severity of attack History, Physical examination MILD ATTACK MODERATE TO SEVERE ATTACK Initial Treatment Initial Treatment • Salbutamol inhalation 2.5 mg/dose (5 mg/ml solution), by • Salbutamol inhalation 2.5 mg/dose (5 mg/ml solution), by nebuliser every 20 minutes x 3 nebuliser every 20 minutes x 3 or or • Salbutamol inhalation by MDI-Spacer 4 puffs (100mcg/puff)

• Salbutamol inhalation by MDI-Spacer 4 puffs at 2-3 min interval. This course is repeated every 20 minutes (100mcg/puff) at 2-3 min interval. This course is repeated x3 every 20 minutes x3 or or • Inj Adrenaline 0.01 ml/kg (maximum of 0.3 ml) of 1:1000 solution subcutaneous every 20 minutes x 3 Good Response Incomplete or poor response: Reassess every 30-60 :Home Treatment • Add Steroids min • Observe for 4 hrs Good Response • Continue Salnutamol 4-6 • Continue inhaled or at any stage

hly orally or inhalation oral salbutamol Repeat Initial treatment • Discharge if improvement 6hly as bReassessss Follow the gh/Difficult breath Yes principle of “Last in – First out” Home Treatment • halation (may mix or alternate • Omit with salbutamol) • Continue inhaled • Oxygen aminophylline or oral Reassess every 30- infusion in 12- 24 hours, if used salbutamol 6hly 60 min • Short course • Omit ipratropium steroids for 3-5 • Continue bronchodilator 1-2 inhalation in

hly and Ipratropium 8hly; next 12-24 hrs Continue steroids • Reduce the • Give one dose of Mag. Sulph, salbutomal /aminophylline inhalation to 4-6 hourly Reassess every 30-60 min • Give one dose of Mag. Sulph, /aminophylline choosing what was not used in the previous step Or 35

The “last in-first out” principle is used to withdraw medications. Aminophylline infusion is usually stopped in 24 hours followed by Ipratropium inhalation in next 24 hours. Then the frequency of Salbutamol inhalation should be decreased to about 4-6 hourly. (The details of the asthma medication are given at the end as Annexure). Antibiotics Antibiotics should not be given routinely for acute asthma. Antimicrobial treatment is indicated,

however, when there is persistent fever and other signs of pneumonia such as bronchial breathing. Mere presence of crackles is not an evidence of pneumonia and does not warrant antibiotics. Supportive care The child is given daily maintenance fluids appropriate for his / her age. Provision of adequate feeding for the child is encouraged as soon as food can be taken. Monitoring of the child A hospitalized child should be assessed by a nurse every 3 hrs even when improving, or every 6 hrs when

stable and by a doctor at least twice a day. Respiratory rate and signs of impending respiratory failure are monitored. Oxygen therapy should also be checked periodically. Discharge planning The patient is considered for discharge when: • Is able to take medication orally, • does not need oxygen therapy, and • is on 4-6 hrly salbutamol inhalations. Follow-up care for asthma Asthma is a chronic and recurrent condition. A long-term treatment plan should be made based on the frequency and severity of symptoms.

Any child with persistent symptoms or frequent episodes (>1 / month) or symptoms of cough and breathlessness following exercise should be assessed for the need for long-term preventive therapy with inhaled corticosteroids. Standard Asthma management guidelines for children should be used for further assessment and management of these cases. MANAGEMENT OF A CHILD WITH STRIDOR Stridor is a harsh noise during inspiration, which is due to narrowing of the air passage in the

oropharynx, subglottis or trachea. Stridor is most often caused by viral croup which is due to parainfluenzae virus, measles and RSV. Bacterial infections of epiglottis (epiglottitis due to H. influenzae B), trachea (bacterial tracheitis) and larynx (e.g Diphtheria) are far less common. The other less common causes of stridor are - foreign body, polyps, and retropharyngeal abscess. The child with stridor should 36

be assessed for fever, hoarseness of voice, barking cough , any history of difficulty in feeding or history of choking episode. The patient is examined for signs of obstructed breathing and respiratory distress. A child who has stridor when calm should be urgently referred to a hospital for management. VIRAL CROUP Croup is a common childhood disease marked by sudden onset of a distinctive barky cough that is usually accompanied by stridor, hoarse voice, and respiratory distress resulting from upper-airway

obstruction. It predominantly affects young children (6mo- 3 years) and the symptoms are usually worse during the night or early hours of the morning. It is usually preceded by non-specific upper respiratory tract symptoms before development of the barky cough and difficult breathing. Para influenza virus (type 1 and 3) is the most common causative agent. Mild croup is characterized by hoarse voice, harsh barking cough and stridor only when the child gets

upset. There is no chest indrawing at rest. SpO is more than 90% in room air. 2 Treatment of Mild croup • Can be managed at home. • Admission needed if croup is associated with measles • Oral Corticosteroids–(single dose of dexamethasone or equivalent) can be given if patient is brought/referred tohospital. Severe croup It is a serious condition, which can be fatal and is characterized by stridor in a calm child andlower chest

indrawing. Fast breathing may or may not be present. Child is assessed for signs of airway obstruction – severe chest indrawing, agitation, and cyanosis. Oxygen should generally be administered, without causing the child to be agitated, via an oxygen tube with the opening held within a few centimetres of the nose and mouth (blow-by oxygen or wafting method, see above). It is important to maintain a patent airway in such children. Even slight agitation in such severely

compromised children can lead to a complete obstruction.Antibiotics are not routinely indicated in croup(Table 11). Table 11: Treatment of moderate - severe croup • Admission to hospital is needed • Airway should be maintained • Steroid – Single dose dexamethasone (0.6 mg/kg) or oral prednisolone (1-2 mg/kg) should be given • Epinephrine (adrenaline) – Mixing 2 ml of inj. Epinephrine 1:1000 solution (in 2 ml of normal saline and given by nebulised route). May need few to several doses every 4 hours

• Oxygen should be given by blow by method or any other method tolerated by the patient Intubation or Tracheostomy may be needed in children with incipient complete obstruction. 37

ANNEXURE 3: ACUTE UPPER RESPIRATORY TRACT INFECTION: Upper respiratory infections such as cough and cold or rhinitis, pharyngitis /tonsillitis, sinusitis are common causes of morbidity in children. These are mostly caused by viruses and are self-limiting conditions. Important bacterial infections of upper respiratory tract include streptococcal sore throat and diphtheria. Common cold- This is the most common infection of infants and children. The patient presents with

nasal discharge or nasal congestion with low to moderate degree of fever. There may be history of similar illness in siblings or parents. Etiological agents of common cold include rhinovirus, corona virus, and influenza virus. Viral infection of the nasal mucosa results in vasodilatation and increased vascular permeability, which in turn cause nasal obstruction and rhinorrhoea - the main clinical symptoms of the

common cold. It is usually a self-limiting illness of short duration, and is occasionally accompanied by a bacterial complication. Most common bacterial complication is acute otitis media, which occurs in about 20% of children with viral upper respiratory infections. Other complications include sinusitis and pneumonia. Treatment No specific treatment is required. However, the mother is counselled to bring the child immediately if

she notices fast breathing or difficulty in feeding or if child becomes sicker. The following measures can be taken by the mother of any child with cough or cold. • Saline nose drops can be tried for relief of nasal congestion when it interferes with feeding. • Paracetamol can be used for reduction of high fever when this distresses the child and for relief of pain. • Safe remedies for cold /sore throat: Cough syrups or antihistaminics or decongestants are not recommended to be given. Safe,

soothing remedies are useful for both a cough and sore throat. Remedies which are safe, culturally acceptable and available at home should be given. Common safe remedies for cough and sore throat include ginger, honey, tulsi or herbal tea. These can be given to infants age > 6 months. For younger infants breast milk is the best remedy. It is important to educate the mother that a child’s cough performs a useful function in clearing

secretions from the airway and is not an illness in itself, which must be treated. OTC Cough or cold remedies contain atropine, codeine, alcohol or high doses of antihistamines which may sedate the child sufficiently to interfere with feeding and the child’s ability to clear secretions from the lungs. 38

PHARYNGITIS Pharyngitis or sore throat is common in the community, and occurs throughout the world, especially during childhood.Most cases are due to viruses. Viral pharyngitis: Thereis redness of pharynx along with other upper respiratory tract symptomssuch as nasal obstruction or discharge. However in contrast to streptococcal sore throat, pus points or membrane is not seen. Cervical lymph nodes are generally not enlarged or tender Streptococcal sore throat:

It is primarily a disease of school children but in crowded populations often affects preschool children as well. Untreated streptococcal sore throat can lead to rheumatic fever and acute post streptococcal glomerulonephrirtis and therefore, appropriate case management is important to-reduce the complications like rheumatic fever. Commonly presents with • Fever (high grade) • Sore throat • Severe pain on swallowing,and On examination, patients have

• Tonsillopharyngeal erythema, with or without exudates, and • Tender, enlarged anterior cervical lymph nodes. • Absence of cough, coryza, and conjunctivitis. (the presence of these point towards viral sore throat) The signs and symptoms of viral and bacterial sore throat overlap and it is often difficult to distinguish the two. WHO suggests a clinical decision rule for children under 5 years of age; acute streptococcal

pharyngitis should be suspected and presumptively treated when pharyngeal exudate plus enlarged, tender cervical lymph nodes are found in children with symptoms of sore throat. Those with exudates plus enlarged tender cervical lymph nodes are treated as likely streptococcal pharyngitis with antibiotics. This rule has high specificity (94.0%), but low sensitivity (16%). Considering that streptococcal sore throat is not common in preschool children, the current guidelines recommend the

WHO suggested clinical decision rule. In appropriate level health facilities, the clinical diagnosis can be supplemented by throat swab culture. Streptococcal sore throat is treated with 10 days course of Oral penicillin V or amoxicillin (50mg/kg/day). Shorter duration of treatment have been found to be as effective but are currently not recommended in countries with high rates of Rheumatic fever. 39

DIPHTHERIA: Diphtheria is an acute infectious disease caused by Corynebacterium diphtheria which mostly occurs in unimmunized or partially immunized children. The usual presentation is fever, toxaemia and sore throat. Throat examination shows a greyish white patch on tonsils and /or pharynx which bleeds when the membrane is removed.Cervical lymph nodes are enlarged leading to bull neck appearance. The diagnosis is confirmed by staining the throat swab with Albert stain which reveals club shaped organisms

which have a ‘Chinese letter pattern’. Treatment: • The patient should be admitted and isolated from other patients. • Diphtheria antitoxin 40.000units is given i.m. or i.v. • Crystalline penicillin is given to eradicate the bacteria (100,000 IU/kg q 6hrly for 10- 14 days). • Good supportive care is required to maintain nutrition and airway. • Monitoring for complications especially myocarditis and neuropathy should be done. EAR INFECTIONS:

Ear infections rarely cause death. However, they cause significant morbidity. Ear infections are the main cause of deafness in developing countries.Acute otitis media (AOM) is caused by S. pneumoniae, non- typable H. influenzae and M. catarrhalis. When a child has an acute ear infection, pus collects behind the tympanic membrane in the middle ear and causes pain and often fever. The fever and pain subsides

if there is perforation, but the child suffers from conductive hearing loss. These infections may extend and spread to the head and neck structures and to the brain. Acute Otitis Media (AOM) usually present with a history of rapid onset of signs and symptoms such as pain in ear, irritability (especially in infants), otorrhea, and/or fever. These findings other than otorrhea, are nonspecific and frequently overlap those of an uncomplicated viral upper respiratory

infection.Middle ear infection is suggested by presence of ear discharge or fullness or bulging of the tympanic membrane on otoscopy. Pain is prominent in acute phase but subsides if there is perforation of tympanic membrane. The diagnosis of acute otitis media can be made on otoscopy in hospitals. In the field situation, the assessment of a child with ear problem can be based on clinical examination without use of otoscopy. It takes into account the following three key features: • Ear pain

• Ear discharge and duration of discharge. • Swelling and tenderness of mastoid which indicates mastoiditis 40

Treatment: • Oral amoxicillin should be given for 5 days. • Fever and pain usually subsideswith Paracetamol • The ear should be dried by wicking with clean cloth if there is pus draining from the ear. Chronic otitismedia:An ear discharge that has been present for 2 weeks or more is treated as a chronic ear infection and is usually caused by Pseudomonas sp.and Staph. aureus. Topical quinolone ear drops should be instilled after wicking the ear dry. Systemic antibiotics are not required for chronic ear

infection. There is no role of antihistaminics or decongestants in treatment of acute /chronic ear infections Mastoiditis : Children with mastoiditis need specialized care and should be admitted in a hospital which has ENT specialist.Mastoiditis may be complicated by meningitis or brain abscess and such patients should be assessed and treated for these complications. 41

ANNEXURE 4: Dosages of drugs used for ARI: Dose according to body weight (kg) Dosage Form 3-<6 kg 6-<10 10-<15 15-<20 Aminophylline Loading dose: 250 mg/10 ml vial 1 ml 1.5 ml 2.5 ml 3.5 ml For asthma IV: 5-6 mg/kg (max. 300 mg) slowly over 20-60 minutes Maintenance dose: 1 ml 1.5 ml 2.5 ml 3.5 ml IV: 5 mg/kg up to Calculat every 6 hours OR by e EXACT continuous infusion dose 0.9 mg/kg/hour Amoxicillin 25 mg/kg two times a 250 mg tablet ½ 1 1 ½ 2 day For pneumonia Syrup (containing 125 mg/5

Or 15mg/kg/dose ml) thrice a day 5 ml 10 ml 15 ml - Ampicillin IM/IV: 50 mg/kg every Vial of 500 mg mixed with 1 ml 2 ml 3 ml 5 ml 6 hours 2.1 ml sterile water to give 500 mg/2.5 ml Cefotaxime IM/IV:50 mg/kg every Vial of 500 mg mixed with 2 0.8 ml 1.5 ml 2.5 ml 3.5 ml 6 hours ml sterile water OR vial of 1 g mixed with 4 ml sterile water OR vial of 2 g mixed with 8 ml sterile water Ceftriaxone IM/IV:50 mg/kg 2 ml 4 ml 6 ml 9 ml every 12 hours (max single dose 4 g) OR IM/IV:100 mg/kg once daily

4 ml 8 ml 12 ml 18 ml Cloxacillin IV:25-50 mg/kg every Vial of 500 mg mixed with 8 2-(4) ml 4-(8) ml 6-(12) 8-(16) 6 hours ml sterile water to give 500 ml ml mg/10 mls Vial of 250 mg mixed with IM 1.3 ml sterile water to give 1.8 (3.6) 2.5 (5) 0.6 42

250 mg/1.5 ml (1.2) ml 1 (2) ml ml 4 mg trimethoprim Oral: paediatric tablet (20 1 2 3 3 /kg and 20 mg mg TMP +100 mg SMX) Cotrimoxazole* sulfamethoxazole/kg (trimethoprim- two times per day sulfamethoxazo ie, TMP-SMX) Oral: Syrup (40 mg TMP+200 mg SMX per 5 ml) 2 ml 3.5 6 ml 8.5 ml Note: For interstitial pneumonia in children with HIV give 8 mg/kg TMP and 40 mg SMX/kg 3 times a day for 3 weeks. Dexamethasone Oral: 0.6 mg/kg 0.5 mg tablets 0.5 ml 0.9 ml 1.4 ml 2 ml single dose For several viral IM:5 mg/ml

croup Epinephrine 0.01 ml/kg (up to a (adrenaline) For maximum of 0.3 ml) wheeze of 1:10000 solution (or 0.1 ml/kg of 1:10000 solution) given subcutaneously with a 1 ml syringe A trial of 2 ml of 1:10000 nebulized solution 0.01 ml/kg of 1:1000 solution or 0.1 ml/kg of 1:10000 solution given subcutaneously with a 1 ml syringe For severe viral croup - 2 ml 2 ml 2 ml Erythromycin Oral: 12.5 mg/kg 4 250 mg tablet ¼ ½ 1 1 (estolate) times for 3 days 43

Gentamicin 7.5 mg/kg once per IM/IV: vial containing 20 mg 2.25- 4.5-6.75 7.5-10.5 - day (2 ml at 10 mg/ml) undiluted 3.75 ml ml ml IM/IV: vial containing 80 mg 2.25- 4.5-6.75 7.5-10.5 (2 ml at 40 mg/ml) mixed 3.75 ml ml ml - with 6 ml sterile water IM/IV: vial containing 80 mg (2 ml at 40 mg/ml) undiluted 0.5-0.9 1.1-1.7 1.9-2.6 ml ml ml 2.8-3.5 ml Benzylpenicillin IV: 50000 units/kg e Vial of 600 mg mixed with 2 ml 3.75 ml 6 ml 8.5 ml (penicillin G) very 6 hours 9.6 ml sterile water to give

1000000 units/10 ml General dosage Vial of 600 mg (1000000 units) Mixed with 1.6 ml sterile water to give 1,000,000 IM units/2 ml 0.4 ml 0.75 ml 1.2 ml 1.7 ml Salbutamol Oral: 1 mg per dose Syrup: 2 mg/5 ml 2.5 ml 2.5 ml 5 ml 5 ml <1 yr 2 mg per dose 1-4 yrs Tablets:2 mg ½ ½ 1 1 Acute episode 6-8 hrly Tablets: 4mg ¼ ¼ ½ ½ Inhaler with spacer: 2 doses contains 200 μg Metered dose inhaler containing 200 doses 5 mg/ml solution 2.5 mg in 2.5 ml single dose units Nebulizer: 2.5 mg/dose 44

National Leprosy Eradication Programme (NLEP) Training Manual for Medical Officer Central Leprosy Division, Directorate General of Health Services Nirman Bhawan, New Delhi

Table of contents National Leprosy Eradication Program (NLEP) Training manual for Medical Officer (MO) – CHC/PHC Sl. No. Topic Page Nos. Foreword Preface 1. Introduction: National Leprosy Eradication Programme 5 2. Epidemiology 6 3. Pathogenesis of Leprosy 8 4. Diagnosis of Leprosy 9 5. Grouping/Classification 15 6. Management of Leprosy 16 7. Leprosy Reaction 19 8. Relapse 22 9. Disability and Its Management 22 10. Ulcer Care 25 11. Supervision & Monitoring 26 12. I.E.C 28 Annexures

Annexure 1: Role of Medical Officer at PHC 30 Annexure 2: Training Curriculum 31 Annexure 3: Simplified Information System (SIS) Formats 32 Annexure 4: DPMR Formats 37 Glossary 42 Training Manual for Medical Officer 2

Dr. Jagdish Prasad Hkkjr ljdkj M.S.M.Ch. FIACS LokLF; ,oa ifjokj dY;k.k ea=kky; Director General of Health Services LokLF; lsok egkfuns'kky; fuekZ.k Hkou] ubZ fnYyh & 110 108 lR;eso t;rs GOVERNMENT OF INDIA MINISTRY OF HEALTH & FAMILY WELFARE DIRECTORATE GENERAL OF HEALTH SERVICES NIRMAN BHAWAN, NEW DELHI-110 108 Tel.: 23061063, 23061438 (O), 23061924 (F) E-mail: dghs@nic.in fnukad@ Dated: 14 Mar 2013 FOREWORD The National Leprosy Eradication Programme (NLEP) was started in the year 1983 with

the objective of achieving eradication of the disease from the country. Elimination has been achieved against this dreaded disease in 2005 when the leprosy recorded cases load had come down to less than 1 case for 10,000 Population at National level. Although the country has achieved elimination of leprosy as a public health problem, yet new case detection has remained about to 1.3 lacks annually. These newly detected cases have to

be provided quality leprosy services through the General Health Care system so that they are diagnosed and treated early with MDT. Medical officer at PHC/CHC is the key person to treat leprosy. Availability of this training manual should help in standardizing the training given to the Medical Officers, who in turn have to provide service to the persons affected by leprosy and also to teach the Health Workers under them. I am sure the manual prepared by experts & central leprosy division will be used by

the Medical Personnel working in the General Health Care system and make practical use of the same. I would like to acknowledge, all experts who helped in bringing out the training manual. Dr. Jagdish Prasad

LokLF; lsok egkfuns'kky; MkW- lh- ,e- vxzoky ¼LokLF; ,oa ifjokj dY;k.k ea=kky;½ DR. C.M. AGRAWAL Hkkjr ljdkj mi egkfuns(cid:39)kd ¼dq"B½ fuekZ.k Hkou] ubZ fnYyh & 110 108 Deputy Director General (Leprosy) DIRECTORATE GENERAL OF HEALTH SERVICES lR;eso t;rs (Ministry of Health & Family Welfare) Government of India Nirman Bhawan, New Delhi-110 108 Tel.: 91-11-2306 2653, Fax: 91-11-2306 1801 E-mail: ddgl@nb.nic.in 14 Mach, 2013 ................................ PREFACE

Medical officers working at Community Health Centre (CHC)/ Primary Health Center (PHC)/ Dispensary play a key role in diagnosis & treatment of Leprosy. They should be well versed with the basics of Lepsory, Multi Drug Therapy (MDT), Disability Prevention & Medical Rehabilitation (DPMR), Supervision & Monitoring and other components of National Leprosy Eradication Programme (NLEP). This training manual will help in building

their capacity in the above aspects. It is expected that after 3 days training, the medical officers will: be able to demonstrate the correct method of examination of skin (cid:108) lesions/peripheral nerves and counseling skills; correctly diagnose the disease; (cid:108) be able to describe how to manage reactions/neuritis (cid:108) be able to identify difficult to manage complications and refer them (cid:108) correctly list out the problems and possible remedial measures (cid:108)

be able to describe the methods of monitoring and supervision of the program. (cid:108) To achieve these learning objectives, medical officers have to concentrate on developing clinical and managerial skills required to manage a case of Leprosy. I presume that Medical Officers understand that skills development needs continued practice. Minimum essential contents have been included in this manual and more will be required to read before

and practice after the 3 days training. I hope this manual will be useful in capacity building of medical officers in management of Leprosy. I would like to thank International Federation of Anti Leprosy of Associations (ILEP) and the core group, for developing and revising the Medical Officers manual and for supporting its pringing (Dr. C. M. Agrawal) jk"Vªh; xzkeh.k LokLF; fe'ku Let's Fight Leprosy & Make Leprosy a History Website: www.nlep.nic.in

1 Introduction National Leprosy Eradication Programme The National Leprosy Control Program was launched by the Govt. of India in 1955. Multi Drug Therapy came into wide use from 1982 and the National Leprosy Eradication Program was introduced in 1983. Since then, remarkable progress has been achieved in reducing the disease burden. The National Leprosy Eradication Programme is 100% centrally sponsored scheme. MDT is supplied free of cost by WHO. Following are the programme components –

(i) Decentralized integrated leprosy services through General Health Care System. (ii) Training in leprosy to all General Health Services functionaries. (iii) Intensified Information, Education & Communication (IEC). (iv) Renewed emphasis on Prevention of Disability and Medical Rehabilitation and (v) Monitoring and supervision. Results (Objectives) to be achieved during 12th plan period i.e. 2012-2017 are as follow- • Improved early case detection • Improved case management • Stigma reduced

• Development of leprosy expertise sustained • Research supported evidence based programme practices • Monitoring supervision and evaluation system improved • Increased participation of persons affected by leprosy in society • Programme management ensured Training Manual for Medical Officer 5

2 Epidemiology Definition Epidemiology is the study of distribution and determinants of the disease (Leprosy) in a specified population (i.e., population covered by the health centre) and to apply this knowledge for the control of that disease. Leprosy in India: India contributes to more than 50% of new cases detected globally every year. India achieved goal of leprosy elimination in December 2005. 32 states/UTs achieved

elimination. 3 States / UTs viz. Bihar, Chhattisgarh and Dadra & Nagar Haveli has remained with PR between 1 and 2.3 per 10,000 population. A total of 1.27 lakh new cases were detected during the year 2011-12, which gives ANCDR of 10.35 per 100,000 population. A total of 0.83 lakh cases are on record as on 1st April 2012 given the Prevalence Rate (PR) of 0.68 per 10,000 Pop. On a new leprosy cases detected during 2011-12 indicates the

proportion of MB (49.0), Female (37.0), Child (19.7), and visible deformity (3.0). Total of 3865 persons with Gr. II disability detected in the new leprosy cases during 2011-12 which gives the Gr. II disability rate of 3.14 per million pop. In addition 4817 Gr. I cases were recorded which is 3.78% of the new cases during the year. A total of 12305 new child cases were recorded which gives the child case rate of 1.0 per 100000 pop. Distribution of cases in different Indian states 2011-12

16. others, 4% 1. Andhra Pradesh, 6% 15. Delhi, 2% 2. Assam, 1% 14. West Bengal, 12% 3. Bihar, 11% 4. Chhattisgarh, 5% 13. Uttar Pradesh, 17% 5. Gujarat, 6% 6. Jharkhand, 2% 7. Karnataka, 3% 12. Tamil Nadu, 4% 11. Rajasthan, 1% 8. Madhya Pradesh, 6% 10. Orissa, 5% 9. Maharashtra, 15% Determinants of Leprosy Agent: Leprosy is caused by Mycobacterium leprae intracellular, obligatory parasite. It is a slow growing bacillus and one Leprosy bacillus takes 12–14 days to divide in to two. It is an

acid-fast bacillus and is stained red by a dye called carbol fuschin. Training Manual Source of infection: Untreated Leprosy affected person (Human beings) is the only known for source for M leprae. Medical Officer 6

Portal of exit: The major sites from which bacilli escape from the body of an infectious patient is respiratory tract especially nose. Only small proportion of those suffering from Leprosy can transmit infection. Transmission of infection: Leprosy is transmitted from untreated Leprosy affected person to a susceptible person through droplets, mainly via the respiratory tract. Portal of entry: Respiratory route appears to be the most probable route of entry for the bacilli.

Incubation period: Incubation period (Duration from time of entry of the organism in the body to appearance of first clinical sign and symptom) for Leprosy is variable from few weeks to even 20 years. The average incubation period for the disease is said to be 5–7 years. Host factors Age: Leprosy can occur at any age but is usually seen in people between 20–30 years of age. Increased proportion of affected children in the population indicates the presence

of active transmission of the disease in the community. As the disease burden declines, it is seen more in older age groups. Gender: Disease occurs in both the genders. However, males are affected more as compared to females Immunity: Occurrence of the disease depends on susceptibility/immunological status of an individual. Socio-Economic Factors: Leprosy is a disease generally associated with poverty and related factors like overcrowding. However, it may affect persons of any socioeconomic group.

Factors influencing susceptibility • Age: Children are more susceptible than adults. • Individual immunity : May be determined by certain genetic factors which influence the susceptibility of an individual • Climate: Leprosy is prevalent in tropical and subtropical climates. Training Manual for Medical Officer 7

3 Pathogenesis of Leprosy Onset of leprosy is insidious. It affects nerves, skin and eyes it may also effect mucosa (mouth, nose pharynx), testis, kidney, voluntary/smooth muscles, reticulo-endothelial system and vascular endothelium. Bacilli enter the body usually through respiratory system. It has low pathogencity, only a small proportion of infected people develop signs of the disease. Though infected, majority of the population do not develop the disease. After entering the body, bacilli

migrate towards the neural tissue and enter Schwann cells. Bacteria can also be found in macrophages, muscles cells and endothelial cells of blood vessels. After entering Schwann cells or macrophages; fate of the bacterium depends on the resistance of the infected individual towards the infection organism. Bacilli start multiplying slowly (about 12-14 days for one bacterium to divide into two) within the cells, get liberated from the destroyed cells and enter other unaffected cells. Till this

state person remains free from signs and symptoms of leprosy. As the bacilli multiply, bacterial load increases in the body and infection is recognized by the immunological system. Lymphocytes and histocytes (macrophages) invade the infected tissue. At this stage clinical manifestation may appear as involvement of nerves with impairment of sensation and /or skin patch. If it is not diagnosed and treated in the early stages, further progress of the disease is determined by the strength of the

patient’s immune response. Specific and effective cell mediated immunity (CMI) provides protection to a person against leprosy. When specific CMI is effective in elimination / controlling the infection in the body, lesions heal spontaneously or it produces pauci bacillary (PB) type of leprosy. If CMI is deficient; the disease spreads uncontrolled and produces multi bacillary (MB) leprosy with multiple system involvement. Sometimes, the immune

response is abruptly altered, either following treatment (MDT) or due to improvement of immunological status, which results in the inflammation of skin or / nerves and even other tissues, called as leprosy reaction. Pathogenesis: M. Leprae Enters Transient Bacillemia Schwann cells, cooler places (Cutaneous nerves & Peripheral nerves trunks of limbs and face Strong Immunological Response Weak Immunlogical Response M. Leprae multiply in Schwann cells or Nerves only: Pure Neural Leprosy

Escape to skin: Skin lesions appear Engulfed Histiocytes - wandering Lesions may heal spontaneously Macrophages Training Manual Affect other organs in the body for Medical Officer 8

4 Diagnosis of Leprosy • A case of leprosy is diagnosed by eliciting cardinal signs of leprosy through systematic clinical (and wherever required bacteriological) examination. • At least one of the following cardinal (unique & very important) signs must be present to diagnose leprosy. a) Hypopigmented or reddish skin lesion(s) with definite sensory deficit b) Involvement of the peripheral nerves, as demonstrated by definite thickening with loss of sensation and weakness of the corresponding

muscles of the hands, feet or eyes, c) Demonstration of M leprae in the lesions. The first two cardinal signs can be identified by clinical examination alone while the third can be identified by examination of the slit skin smear. • A person with cardinal signs of leprosy and yet to complete full course of MDT may be called as “case of leprosy”. Differential Diagnosis There are many skin diseases and neurological condition which mimic leprosy. To

differentiate, cardinal signs of leprosy should be kept in mind. Any skin patch since birth, Milky white (de pigmented) or itchy is less likely to be leprosy. The common skin diseases under differential diagnosis may be psoriasis, secondary syphilis, vitiligo, birth marks, PKDL, lupus vulgaris etc. In cases of plantar ulcer or deformed hand or feet, nerve examination should be conducted to rule out other conditions. Clinical Examination

Clinical examination includes careful interview of patient to get detailed history and examination of skin and nerves. A. Case History: The leprosy history should elicit the following: • Name, sex, age (year of birth), address, occupation etc. • Presenting complaints and their duration (A patch of a few days or that which is present since birth or an itchy patch is unlikely to be leprosy) • History of recurrence (a recurrent lesion which “comes and goes” will not be due to leprosy)

• Any deformity, the time of its onset, and nature of its progress; • Treatment history - treatment taken, what drugs for how long. • Any other associated illness (jaundice, cough, swelling of the feet at present or in the recent past) • Any other person in the family or close contacts having similar disease or had the disease and was treated Training Manual for Medical Officer 9

B. Skin examination: Remember the cardinal sign: Hypo-pigmented or reddish skin lesion(s) with definite sensory deficit. • Choose a place where good light is available • As far as possible, choose a place where there is privacy • Always examine the whole skin from head to toe as much as possible. • Use the same order of examination always so that you do not forget to examine any part of the body. The following features must be noted when examining a patch on the skin Site: This is useful for follow-up.

Number: The number of lesions indicates the severity of the disease. This is useful for grouping and follow-up. Color: May be hypo- pigmented (lighter in color than the rest of the skin), or erythematous (red). Lesions of leprosy are never de- pigmented. Erythematous color can be used to identify disease activity or a reaction state. (Active lesions or those in reaction are often red). Sensory deficit: This is useful for diagnosis. Loss of sensation is a cardinal sign of leprosy.

Tenderness on gentle tapping: This is seen in reaction states. Presence of infiltration: This term refers to skin, which is thickened, shiny and erythematous. All three features must be present in the same area. Diffuse infiltration may be the only early presenting sign in severe forms of leprosy. Nodules may be found in the skin in severe forms of leprosy. Training Manual for Medical Officer 10

Testing the sensation over skin It is very important to pick up the skill of eliciting sensory loss in skin patch. • You will need a light ballpoint pen (with plastic body) without cap. • Explain to the person what you are going to do and demonstrate it. • Touch the skin with the tip of pen lightly, ask the individual to point to the spot touched with his index finger. • Repeat this procedure a few times until the patient is familiar and comfortable with the procedure.

• Now ask the patient to close his eyes and repeat the procedure (first on the normal skin then over the affected area). • While testing lesions over inaccessible areas (back, buttocks) the patient may be asked to count on each touch. Remember: • Do not use other “instruments” like pin, cotton wool, feather, etc. • When testing for sensation, touch the skin lightly with the pen. Do not stroke. • The pen should be perpendicular to the surface of the skin.

• Do not keep asking the patient whether he feels the touch. You may get misleading results. • Proceed from the normal skin to the patch. • Give only one stimulus at a time. • Vary the pace of testing. C Nerve examination: Remember the cardinal sign: "Involvement of the peripheral nerves, as demonstrated by definite thickening with a loss of sensation with or without weakness of the corresponding muscles of the hands, feet or eyes. "

Examination of nerves in all the patients is very important for diagnosis, grouping and for prevention of deformity. This involves two aspects: • palpation of the nerves for thickening, tenderness and consistency and assessment of nerve function - sensory and motor Palpation of Nerves a) The patient should be properly positioned. The examiner should also be positioned correctly. b) Locate the nerve correctly c) Observe the patient’s face while palpating the nerve to elicit tenderness.

d) Palpate gently with the pulp of the two fingers, not the tips of fingers, Training Manual e) Always palpate across the course of the nerve. for f) Feel along the nerve as far as possible in both directions. Medical Officer 11

The peripheral nerves most commonly affected in leprosy are Ulnar, Lateral Popliteal and Posterior Tibial nerve. Ulnar nerve Other nerves, which may be affected are – Lateral popliteal nerve Facial, Trigeminal, Median and Radial. Posterior Tibial nerve Ulnar nerve • Site: In the groove above and behind medial epicondyle of the elbow. • Position of patient: Both the patient and examiner facing each other. • To examine right ulnar nerve, ask the patient to flex the elbow joint slightly.

Hold the right wrist with your left hand. • With the right hand feel for the medial epicondyle. • Pass behind the elbow and feel the ulnar nerve in the groove. • Gently palpate with pulp of 2 fingers (index & middle) and feel across the nerve, constantly watching facial expression for signs of tenderness. • Trace the nerve proximally as far as to ascertain the length of the swelling. Lateral popliteal nerve • Site: back of the knee, behind the head of fibula.

• Position of patient: Patient standing with knees slightly flexed (not total) and examiner squatting. • Identify the head of fibula on the lateral aspect of knee in line with lower end of patella. • Pass backwards and feel the nerve just behind the fibular head. • Gently palpate with pulp of 2 fingers (index & middle) and feel across the nerve, constantly watching facial expression for signs of tenderness. • The palpable course of the nerve is very short. Posterior tibial nerve?

• Site: Below and behind the medial malleolus • Position of Patient: to rest the ankle on thigh • Identify the medial malleolus. Locate the nerve just below and behind medial malleolus (approximately at the midpoint between medial malleolus and heel) • Palpate with the pulp of finger and feel across the nerve constantly watching facial expression for signs of tenderness. • The palpable course of the nerve is very short. Training Manual for Medical Officer 12

Assessment of Nerves Function Voluntary Muscle Testing (VMT) • Voluntary muscle testing is done by first checking the range of movement to see whether movement is normal, reduced or absent due to paralysis. If movement is normal, a test for resistance is then done. Press gently in the opposite direction while asking the patient to maintain position, resisting pressure as strongly as possible. Then gradually press more firmly and judge whether resistance is normal, reduced or absent. The grading of the

result can be done as follows: (cid:111)S (Strong) = Able to perform the movement against full resistance (cid:111)W (Weak) = Able to perform the movement but not against full resistance (cid:111)P (Paralysed) = Not able to perform the movement at all. VMT for Facial Nerve: • Ask the patient to close his eyes and keep them lightly closed as if in sleep. • If there is no gap, ask him to close the eye tightly and try to pull the lower lid down

and see whether the patient is able to keep his eyes closed against resistance. Able to keep his eye closed Grade ‘S’ against resistance A gap visible between the Grade ‘P’ upper and lower eyelids Not able to keep his eye closed Grade ‘W’ VMT for Ulnar Nerve: • Ask the patient to push his little finger out in the same plane as palm. To test for weakness, push the little finger towards the hand while the patient tries to hold it in the test position. The pressure should be applied at the base of little

finger. Grade the muscle power as ‘S’, ‘W’ or ‘P’. VMT for Median Nerve: • Ask the patient to hold his thumb at right angle to the palm. To test for weakness, push the thumb towards index finger while the patient tries to hold it in the test position. The pressure should be applied at the base of thumb. Grade Training Manual the muscle power as ‘S’, ‘W’, or ‘P’. for Medical Officer 13

VMT for Radial Nerve: • Ask the patient to make a fist and then dorsiflex the wrist. To test for weakness, press the hand downwards as shown in the diagram while the patient tries to hold it in the test position. Grade the muscle power as ‘S’, ‘W’, or ‘P’. VMT for Lateral Popliteal Nerve: • Lift the foot off the ground and support at calf region. Then ask the patient to dorsiflex his foot fully. To test for weakness, push the foot downwards while the patient tries to hold it in

the test position. Grade the muscle power as S’, ‘W’, or ‘P’ as described above. Sensory test (S.T.)- Method of sensory test over the skin supplied by nerve is same as that for testing a patch. Given below are the suggested spots for testing sensation over the palms and soles. Points for ST in sole Points for ST in palm Efforts are made to ensure that persons with disability do not worsen. For example a person with anaesthesia in the foot should not develop ulcers. Patients should be helped

to manage their disabilities by self-care practice. Training Manual for Medical Officer 14

5 Grouping/Classification Grouping or classification of leprosy cases After making a diagnosis of leprosy, one should group the patient based on certain characteristics. This is important because it helps in selecting the correct combination of drugs for a given patient. Criteria for grouping Characteristic PB (Pauci Bacillary) MB (Multi Bacillary) 1 Skin lesions 1 - 5 lesions 6 and above 2 Peripheral nerve No nerve / only one More than one nerve nerve involvement

3 Skin smear Negative at all sites Positive at any site Grading Of Disabilities Hands & Feet • Grade 0: No anaesthesia, over palm/sole no visible deformity or damage • Grade 1 : Anaesthesia present, over palm/sole but no visible deformity or damage • Grade 2 : Visible deformity or damage present Eyes • Grade 0 : No eye problem due to leprosy; no evidence of visual loss • Grade 2: Severe visual impairment (vision worse than 6/60; inability

to count fingers at six meters), lagophthalmos, iridocylitis and corneal opacities. EHF score: It is some of the individual disability guide for each eye, hand and feet. EHF score can range for 0 to 12. Training Manual for Medical Officer 15

6 Management of Leprosy The treatment of leprosy is in the form of Multi Drug Therapy (MDT) which is the combination of two or three of the following drugs: a) Cap. Rifampicin b) Tab. Dapsone c) Cap. Clofazimine i. MDT kills the bacilli (M. leprae) in the body and thus stops the progression of the disease and prevents further complications. ii. As the M. leprae are killed, the patient becomes non-infectious and thus the spread of infection in the body is reduced. Moreover, spread of infection to

other persons is also reduced. iii. Using a combination of two or three drugs instead of one drug alone will ensure effective cure and there are no chances of development of resistance to the drugs. • Based on the grouping, the patients can be given any one of the standard MDT regimens mentioned below. In children, the dose may be adjusted suitably. • When the patient has completed the required number of doses (monthly pulses) of standard MDT regimens, s/he is released from Treatment - RFT.

MDT regimen (Adult) The appropriate dose for children under 10 years of age can be decided on the basis of body weight. Drugs used Dosage Frequency of Criteria for (adult) Administration RFT MB Rifampicin 600 mg Once monthly Completion leprosy Dapsone 100 mg Daily of 12 Clofazimine 300 mg Once monthly monthly Clofazimine 50 mg Daily pulses PB Rifampicin 600 mg Once monthly Completion leprosy Dapsone 100 mg Daily of 6 monthly pulses MDT regimen (Child - 10-14 years of age)

MB Rifampicin 450 mg Once monthly Completion leprosy Dapsone 50 mg Daily Once of 12 Clofazimine 150 mg monthly monthly Clofazimine 50 mg Every other day pulses PB Rifampicin 450 mg Once monthly Completion leprosy Dapsone 50 mg Daily of 6 monthly pulses The appropriate dose for children under 10 years of age can be decided on the basis of body weight. Training Manual • Rifampicin: 10 mg per kilogram for • Clofazimine: 6 mg per kilogram monthly and 1 mg per kilogram per body Medical Officer weight daily

Regarding fitness of patient for MDT, before starting treatment one must look for the following: a) Jaundice : If the patient is jaundiced, you will have to wait until jaundice subsides. b) Anaemia: If the patient is anaemic, treat the anaemia also simultaneously. c) Tuberculosis: If the patient is taking Rifampicin, ensure that he continues to take Rifampicin in the dose required for the treatment of tuberculosis along with other drugs required for the treatment of leprosy.

d) Allergy to sulpha drugs: If the patient is known to be allergic to sulpha drugs, Dapsone should be avoided. Clofazimine may be used instead. To ensure the regularity of treatment • Adequate counseling at the start of treatment will encourage the patient to be regular and complete the required number of doses of MDT. • Patients who are absent should be contacted immediately to identify the reasons and take corrective actions. • Flexibility in MDT delivery accompanied MDT (more than one pulse dose at

a time) may be adapted whenever it is essential. • The explanation a patient receives at the beginning of treatment is very important. It helps the patient to be regular and to complete the treatment in time. • Patients who have completed treatment before and return with extension of old lesions and/or appearance of new lesions could be relapse or the reaction. They should be referred to district nucleus or specialized centre. • All patients who fail to collect drugs should be contacted immediately and

effort should be made to ensure that the patient resumes treatment. Whenever a PB patient has missed more than three months of treatment or MB patient more than 6 months of treatment they should be declared as defaulter. They should re-examined after retrieval on regimen accordingly. • Patients migrating to another place in the middle of treatment could be given all the remaining doses of MDT with proper counseling. The patient is made RFT in the register at the expected month of completion of treatment.

• Treatment register (LF 02) and drug stock register (LF 03) are maintained at the health facility by pharmacist or any other identified person. The MO of the health facility should ensure that the treatment cards and registers are updated regularly. • At least 3 months drug stock should be maintained at the district whereas at the health facility level 2 months buffer should be available. PHCs with no case in the last 3 months need not keep any stock.

• District leprosy office should estimate the amount of drugs of all categories required for the whole year taking into consideration the stock in hand (with expiry date) and number of new cases expected. • Each health facility will prepare and submit monthly progress report (LF 04) to the block level PHC which will compile the reports and send the Training Manual consolidated report to DLO. for Medical Officer 17

Side Effects of Anti-Leprosy Drugs: Dapsone Training Manual for Medical Officer 18

7 Leprosy Reaction It is acute inflammatory response occurring in the course of the disease. It can occur at any time before, during or after treatment. It must be promptly diagnosed and treated to prevent any disability. Patients with the following characteristics are more likely to develop leprosy reactions: • Multiple lesions • Lesions close to the peripheral nerve • Lesions on the face • Postpartum period These patients should be monitored more frequently for early detection of reaction and

its prompt management. There are two principal types of Lepra reactions. Type 1 and Type 2. • Type 1 Lepra Reaction also known as Reversal Reaction may occur both in PB and MB leprosy. • Type 2 reaction is also known as Erythema Nodosum Leprosum (ENL) and occurs only in MB leprosy. Skin or nerves or both may be affected in reaction. Features Type 1 (Reversal reaction) Type 2 (ENL reaction) Skin Existing lesions suddenly Red, painful, tender, subcuta- become red, swollen, warm, neous nodules (ENL) appear

and tender. New lesions may commonly on face, arms and appear. Lesions when subsiding legs. They appear in groups may show scales on the surface and subside within a few days even without treatment Nerves Nerves close to the skin may Nerves may be affected but not become enlarged, tender and as common or severe as in painful (neuritis) with loss of Type1 nerve function Other organs Rarely affected Other organs like eye, joints, bones, testes, kidney may be affected

General Not common Fever, joint pains, fatigue symptoms Training Manual for Medical Officer 19

Managing a patient with Lepra Reaction Type 1 Lepra Reaction: The patient will need Corticosteroids in addition to rest and analgesics. The drug of choice is Prednisolone. The usual course begins with 40-60 mg daily in single dose preferably in the morning (up to a maximum of 1mg/kg of body weight), and the reaction is generally controlled within a few days. The dose is then gradually reduced fortnightly and eventually stopped. Proper precaution should be taken in patients with

diabetes, peptic ulcer, hypertension, etc. Necessary precautions for administering steroid should be taken. Schedule for Prednisolone therapy for an adult patient in type 1 reaction: 40 mg once a day for the first 2 weeks, then 30 mg once a day for weeks 3 and 4 20 mg once a day for week 5 and 6 15 mg once a day for weeks 7 and 8 10 mg once a day for weeks 9 and 10, and 5 mg once a day for weeks 11 and 12 In case of neuritis, (involvement of peripheral nerve) the period of treatment may be

prolonged according to the response. From 20 mg onwards the dose for each period would be for 4 weeks. Response to steroid therapy is generally seen within two weeks. Review the progress every two weeks. If there is no response the same dose may be continued for further two weeks. If there is good response, the dose may be tapered according to the schedule. It is also important to provide rest to the affected nerve, if involved, until symptoms

clear, by applying a padded splint or any suitable alternative material to immobilise the joints near the affected nerve. The aim is to maintain the limb in the resting position to reduce pain and swelling and prevent worsening of the nerve damage. In case of reaction not responding to treatment after 4 weeks with prednisolone or at any time showing signs of worsening the patient should be referred to the nearest referral centre. Training Manual for Medical Officer 20

Type 2 Lepra reaction (ENL): Type 2 reaction Treatment Mild: few nodules, mild fever Analgesics Severe: severe pain over Steroid - Prednisolone whole course not nodules, tendency for ulceration, exceeding 2 to 3 weeks (same dose as for Type 1 high fever, involvement of reaction but faster tapering) internal organs Neuritis Prednisolone regimen as for neuritis in Type 1 reaction Clofazimine is also effective for Type 2 reaction but is less potent than corticosteroids

and often takes 4-6 weeks to develop its full effects, so it should never be started as the sole agent for the treatment of recurrent Type 2 reaction. However, clofazimine may be extremely useful for reducing or withdrawing corticosteroids in patients who have become dependent on them. The dose required in such cases is 300 mg daily (maximum of 1 month), which may be given in three divided daily doses to minimize the gastro

intestinal side effects. It is tapered gradually to 100 mg daily. The total duration of clofazimine therapy should not exceed 12 months. Response will be seen after 2 - 4 weeks after starting the drug. Often, type 2 reaction may recur due to precipitating causes like infection, stress or helminthic infestation. Lepra reaction may subside faster or less likely to recur if precipitating factor is treated. • If a patient develops lepra reaction during treatment, do not stop MDT (complete the course of MDT).

• Leprosy reactions, which occur after completion of treatment, should also be managed as mentioned above. MDT should not be started again for such cases. Indications for referral include: • Failure to respond after 4 weeks of steroid treatment • Eye involvement • Other systemic involvement • Recurrent lepra reactions Training Manual for Medical Officer 21

8 Relapse Relapse is defined as the re-occurrence of the disease at any time after the completion of a full course of treatment. Relapse is indicated by the appearance of new skin lesions and, in the case of an MB relapse, by evidence on a skin smear of an increase in BI of two or more units. It is difficult to be certain that a relapse has occurred, as new lesions may appear in leprosy reactions PB relapses are difficult to differentiate from reversal reactions. If there are signs of

recent nerve damage, a reaction is very likely. The most useful distinguishing feature is the time that has passed since the person was treated: if it is less than three years a reaction is most likely, while if it is more than three years, a relapse becomes more likely. A reaction may be treated with steroids, while a relapse will not be greatly affected by a course of steroids, so using steroids as a 'therapeutic trial' can help clarify the diagnosis.

A relapsed case is treated with MDT regimen-PB or MB as per grouping after relasped Incidence of relapse after MDT is very negligible. 9 Disability and its Management Disabilities in leprosy are mainly due to damage to peripheral nerves. Nerve damage can occur as part of lepra reaction with signs of acute inflammation. It can also occur during the course of the disease without any obvious signs and symptoms of inflammation. Early detection and treatment of leprosy and early detection and treatment of nerve

dysfunction would prevent the occurrence of disability. Damage to the nerves results in impairment of sensory, motor and autonomic functions, leading to anaesthesia, paralysis of muscles in eyes and extremities, loss of sweating and fissures/cracks/ulcers over extremities. These disabilities can worsen because of neglect by the patient. Process of deformity in the hands and feet: Nerve damage Loss of sweat Loss of sensation Loss of motor function Crack Injury/pressure Weakness, paralysis Training Manual

Disabilities in relation to peripheral nerves that are damaged Site Nerve Feature Hand Ulnar Clawing of 4th and 5th finger nerve Loss of sensation and sweat over the little finger an the inner half of ring finger Median Inability to move the thumb away (abduction) and touch the tips nerve of other fingers (opposition). Loss of sensation over the thumb, index, middle and outer half of ring finger Ulnar & Clawing of all five fingers median Loss of sensation and sweat over the whole palm

Radial Wrist drop that is inability to nerve extend at wrist joint Foot Lateral Foot drop. Loss of sensation Popliteal over the lower leg and Nerve dorsum of the foot Posterior Claw toes. loss of sensation tibial & sweat over the sole of nerve the foot Face Facial Inability to close the nerve eye (lagophthalmos) Trigeminal Loss of sensation nerve over cornea Training Manual for Medical Officer 23

Process of changes in the eyes: Lagophthalmos Corneal anaesthesia Exposure keratitis- Corneal ulcer Disability can be prevented by: a. Detecting leprosy patients as early as possible (early diagnosis of leprosy before disabilities and deformities are set in) and treating them with MDT. b. Adequate counseling at the start and during treatment covering the following point for high risk patients. c. Possible signs and symptoms of reaction, and the need to report

immediately in case of nerve pain, loss of sensation, weakness, tingling/paraesthesia in the hand, face and foot. d. Detecting loss of nerve functions early (early diagnosis of lepra reaction / Neuritis). e. Check muscle strength and sensation (VMT and ST) i.e. assessment of nerve functions among patients at high risk regularly to detect complications early. f. Managing early loss of nerve function appropriately. If the patient has recent nerve function loss, he should be given a course of steroids.

10 Ulcer Care Management of complicated ulcers: All wounds are the result of tissue stress. Common causes of ulcer include: • Sudden injury (e.g. sharp objects that cut or pierce through the skin like thorns or broken glass or burns) • Repetitive pressure, friction or shear forces (e.g. foot ulcers from walking or hand ulcers from using unprotected hand tools) • Dryness of skin leading to cracks & fissures • Secondary infection in macerated skin of web space with candidiasis can lead to deep abscess

• Rarely rat bite can also produce an ulcer on toes, mainly after using vegetable oil on feet. There are a few major principles that should be remembered when planning ulcer management. If these principles are followed, simple ulcers will heal without any medication: • Rest • Good wound environment • Hygiene • Protection Rest: Almost all wounds will heal if they are rested. Almost all wounds will get worse if they are not rested. Regardless of the cause of injury, the first line in treatment of wounds is

to remove the cause of tissue stress and then to allow the injured part to rest so that damaged tissue can repair itself. So long as the person with a wound is healthy, damaged tissue will repair itself. Rest doesn’t necessarily mean that the patient must stay in bed (although for foot ulcers this is often the best option). If the person is unable to rest it may still be possible to rest the injured body part by splinting, crutches and standard MCR footwear used in leprosy.

Complications to be referred for management • Severe side effects of MDT drugs • Lepra reaction not responding to steroids even after 4 weeks • Suspected relapse • Eye complications • Severe ENL with involvement of internal organs • Infected chronic ulcers in foot. • Patients with disability eligible and willing for Reconstructive Surgery Training Manual for Medical Officer 25

11 Supervision & Monitoring Supervision - It is a way of ensuring support and guidance to the staff to enable them to perform their job effectively and efficiently. For this the person who supervises should be competent and should know the job responsibilities of the staff working under him. The supervisor should be able to identify and rectify problems interfering in the implementation of various activities by the subordinate staff. This is done by observing

the functioning of staff, through reviews during field visits using checklists, during monthly meeting and review of reports. Monitoring - The strategy of National Leprosy Eradication Programme is early case detection, prompt treatment with MDT and prevention of disability among patients. Data is continuously collected on all these activities and consolidated into a monthly progress report. Certain indicators are generated out of these reports and are used in

assessing the progress. This process helps in knowing whether the activities being carried out by the programme are proceeding according to the plan and take immediate corrective action in case of deficiencies / deviation. All cases detected are brought under treatment. Treatment compliance should be at least 95%. Timely discharge of cases should take place and records should be properly maintained. It is also important to

review the integration status through a set of indicators). It is essential to know the impact of the program (evaluation) through the use of indicators. (For additional details refer to SIS guidelines) Indicators - An indicator is a calculation, which is used to measure progress in implementation of various activities. It can help in assessing how well the leprosy control programme is functioning. For example, one can assess whether all cases are

detected without any delay; cases detected are promptly brought under treatment and discharged after adequate therapy. Caculation and analysis of indicators may be done as per government guidelines. Records Keeping - Records And Reports Under NLEP (Primary level) (cid:67)Patient card LF – 01 (cid:67)PHC treatment record LF – 02 (cid:67)Leprosy drug stock record LF – 03 (cid:67)NLEP monthly reporting form MLF – 04 (cid:67)Disability Register Form - P. I

(cid:67)Assessment of Disability and Nerve Function Form - P. II (cid:67)Referral Slip Form - P. III (cid:67)Prednisolone Card Form - P. IV Training Manual for Medical Officer 26

INDICATORS I II III IV V VI Indicator Numerator Denominator Source of data Use 1 Prevalence No. of patients Corrected Treatment Assess impact of the registered at given census register programme Assess point of time population Census operational efficiency 2 New Case No. of new cases Mid year Treatment Assess impact of Detection rate registered in a year population register census the programme 3 Proportion of No. of child cases Total no. of new Treatment Assess impact of

child cases among new cases cases registered register the programme among new cases registered in a year during the year 4 Proportion of No. of new cases Total no. of new Treatment Efficiency in case disabled among registered during the cases detected register detection (extent of new cases year with grade II during the year delay) disability. 5 Proportion of No. of new MB Total no. of new Treatment Assess impact of the MB cases among cases registered cases detected register programme

new cases during the year during the year 6 Treatment No. of MB cases No. of MB cases Treatment Reflects operational completion rate completing treat- started treatment register efficiency in case - MB ment among MB 2 years holding cases started treat- previously ment 2 years previously 7 Treatment No. of PB cases No. of PB cases Treatment Reflects operational completion completing treat- started treatment register efficiency in case rate - PB ment among PB 1 year holding cases started treat- previously

ment 1 year previously 8 Proportion of No. of health Total no. of Screening of a Reflects competence health facilities facilities providing health facilities sample of new in diagnosis of providing correct correct diagnosis cases detected in leprosy diagnosis in in 95% of cases the health facilities by the district 95% of cases nucleus 9 Proportion of No. of health Total no. of Screening of a Reflects competence health facilities facilities doing health facilities sample of new in classification of

providing correct correct cases detected in leprosy classification in classification the health facilities in 95% of cases by the district 95% of leprosy nucleus patients 10 Proportion of No. of health Total no. of Screening of Efficiency in health facilities facilities health facility records at maintaining maintaining SIS maintaining SIS by district health records. records correctly. records correctly. nucleus 11 Proportion of No. of health Total no. of Verification of Efficiency in

health facilities facilities having health records and drug stock having 1 month 1 month stock facilities drug stock by management stock of MDT of MDT district nucleus for each category of patients under treatment 12 Proportion of Number of health Total no. of Screening of Involvement of health sub- sub-centres functional records at PHC staff in case centres referring referring health sub- health facility finding suspects suspects in a year. centres by district nucleus

13 Proportion of Number of health Total no. of Screening of Involvement of health sub- sub-centres functional records at PHC staff in patient centres providing providing health sub- health sub- management follow-up follow-up centres with centre by treatment. patients on district nucleus treatment. treatment Training Manual 14 Proportion of Number of health Total no. of Reports Efficient for health facilities facilities preparing health available management of Medical Officer

preparing correct correct MPR in facilities at district information MPR and time 27 sending in time.

12 I. E. C Role of Medical Officer in IEC & Counseling It is well known that problems like delay in reporting by untreated cases, hiding the disease, poor drug compliance, irregular self care practices and discriminations are due to lack of awareness and stigma attached with leprosy. It is essential to make the people aware about early signs & symptoms of leprosy, free availability of full course of effective & safe treatment, disabilities are preventable and discrimination is unjustified. Medical

officers should be aware about facts about leprosy, standard messages to be disseminated, language & media to be used for spreading messages and frequency of disseminating messages. Interpersonal communication with persons affected, influential persons, village health sanitation committee and decision makers at all levels in the form of advocacy, address, counseling, training and focused group discussion will be helpful in reducing stigma. Demonstration of rational behavior, no distances, no

isolation is a strong force to change the behavior. Setting examples will reduce discriminations. M.O. need to guide health workers in organizing rallies, film shows or campaigns along with using mass media during anti leprosy day and other occasions builds attitudes in communities. Developing team of local volunteers in tribal and difficult to reach areas for increasing awareness & changing attitudes may prove a sustainable tool. Standard messages for different target persons may be –

1. Leprosy is a disease, not the curse of God. 2. Leprosy is completely curable if treated in time. 3. Full course of treatment is available free of cost in all government hospitals and health centers 4. Disabilities/Deformities due to leprosy are not inevitable and can be corrected by reconstructive surgery, self-care and simple exercises. 5. Leprosy do not spread by touch, nor it is hereditary. Counseling of persons affected, family members and community around is often

required to treat patients and remove discrimination. The objective of counseling is to encourage the needy person to realize about the existence of the problem and think analyzes and find the cause and reason behind it. Further it is hoped that the needy person himself would act and do something to solve the problem. This act of doing something to solve the problem is his/her own decision; however, it may incorporate the

guidance given by the counselor. In counseling decision to act or not to act should solely be taken by the needy person. And under any circumstance it should not be enforced. Advocacy with decision makers at all level also helps in rationale policy & practices and laws in favor of national program and to restore the lost functions & social status of affected persons IEC – Components • Information - knowledge based on scientific facts and figures.

• Education - Process of bringing out ability of a person/community through Training Manual learning for • Communication Process of transmission of information, ideas, attitudes, or Medical Officer emotion from one person (or group) to another (or others) primarily 28 through symbolic messages.

Purpose of communication is to transmit right information and develop mutual understanding. Aim: Change in behaviour including • Affecting Cognitive – Knowledge • Affective -Behaviour & Attitude • Psycomotor – skills/ practices IEC Plan • Assess Needs and knowledge levels • Define Tools and Methods • Include NRHM IEC Plan • Implement IEC activities • Evaluate Knowledge levels and behaviour change IEC -Features of a good message • Content: Should be Clear short, specific and need based

• Appeal: Must lead to/ ask for an action • Relationships: Express relationship among health care system and community (including persons affected by leprosy) • Emotions: Convey pleasing emotions, concern, care and motivation IEC - Key Messages • Leprosy is Curable • The disease is caused by leprosy germs and can be cured with medicines (MDT) that are available free of charge in all the health facilities. • Early signs & symptoms of leprosy

• Leprosy usually starts as a patch with loss of sensation or as numbness and tingling in hands &/ feet. Consult health worker on occurrence of any of these. • Disabilities can be prevented • Early detection with appropriate treatment helps prevent disability due to leprosy. • No place for segregation • Accept persons affected by leprosy in society • Treat the potential with compassion and empathy. Discrimination of patients is inhuman. IEC- Generic Information

• Deformities and disabilities are unfortunate remnant conditions of leprosy, which can be avoided if treated early. • Treated persons even with residual disability do not spread bacteria. • People do not contract leprosy by dressing ulcers and attending to leprosy patients. • Continued self- care by patients themselves improves their physical impairments and social life. • Some deformities can be corrected by operations to restore appearance and Training Manual function. for

• Treated person affected by leprosy can lead a normal life and become Medical Officer economically independent. 29

Annexure 1 ROLE OF MEDICAL OFFICER Clinical: • Examine suspects reported/referred, confirm the diagnosis and register them as PB or MB. • Prepare case card and start MDT • Diagnose and manage the complications of Leprosy. • Treat cases with ulcers and refer complicated ulcer • Diagnose leprosy reactions type 1 & 2, neuritis and quite nerve paralysis. Treat them with - Prednisolone regime or refer them if not manageable • Screen and refer willing cases for reconstructive surgery

• Ensure timely RFT after completion of MDT • EHF scoring at the time of diagnosis and RFT • Counsel the cases with specific problem • Ensure provision of MCR/protective footwear for needy persons • Ensure follow-up of cases referred back from referral center • Ensure adequate self-care training is given to all patients with grade 1 & 2 disabilities Managerial: • plan, implement and monitor activities • Supervise the performance of health workers responsible for NLEP

• Ensure proper recording (LF1, LF2, LF3, DPMR) and reporting (MLF4, 5 & SOE) as per guidelines • Ensure availability of two patient-months BCP, Prednisolone and other supportive drugs • Ensure implementation of IEC/BCC activities as per approved plan • Coordinate with local bodies/CBOs for welfare of affected people • Organize and participate in monthly review meetings • Monitor implementation of NLEP activities every months to improve early case detection ,

treatment completion, logistics and recording-reporting. Operational: • Attention is to be paid for early case detection and avoid any delay in starting treatment adopting possible modalities of case detection as per region/population. • Facilitate timely payment to ASHA for case detection and treatment completion • Supervised pulse therapy of MDT should be practiced. Extend facility of accompanied MDT to genuine cases. • Answer the question asked by patient or his relative. Training Manual for

2 eruxennA MULUCIRRUC GNINIART skrameR lairetaM dohtem gnihcaeT stnetnoC .xorppA evitcejbo gninraeL noisseS /cipoT deriuqer noitarud ,tniop rewoP erutcel evitcaretnI ?ysorpel si tahW ruoh 1 -tnega( ygoloimedipe ebircseD fo noitcudortnI stuodnaH ?timsnart ti seod woH dna )tnemnorivne-tsoh PELN dna ysorpel senilediug PELN ,stnenopmoC emmargorP PELN fo stnenopmoc ,stneitap ysorpeL esac eviL lanidrac ,tcepsus ot smotpmyS & sngiS sruoh 2 gniticile etartsnomeD ,sisongaiD ,PCB ,tniop rewop noitartsnomed ,emiger

TDM ,gnipuorg BM/BP ,sngis sngis lanidrac TDM ,noitacifissalc stuodnah ,ecnailpmoc retteb rof gnilesnuoC ,TFR a rof esruoc TDM ebircserP TDM fo stceffe edis esac nevig ,sesac noitcaeR noitartsnomed esaC evren etiuq ,snoitcaeR fo sepyT sruoh 2 epyt dna 1 epyt etaitnereffiD snoitcaeR ysorpeL stuodnah & tPP noitartsnomed-er dna ,sitiruen etuca ,sisylarap ebircserp dna snoitcaer 2 eeniart yb larrefer ,emiger enolosinderp etartsnomeD tnemtaert etairporppa tnemssessa noitcnuf evren dna steehs esicrexE erutcel

evitcaretnI ,ytilibasid gnipoleved fo ksir ta sesaC ruoh 1 ,snoitidnoc ksir etaremunE dna tnemssessA stuodnah dna raewtoof ,serocs FHE ,gnidarg OHW etaluclac dna ytilibasid gnidarg fo tnemeganam spmac DIOP ,secived evitsissa esac nevig a fo erocs FHE ytilibasid gnisserd ,sesac reclU ,noitartsnomed esaC fo tnemtaert ,snoitidnoc evitareclu-erP sruoh 2 dna erac reclu etartsnomeD fleS & eraC reclU slairetam yalp elor detacilpmoc fo larrefer ,sreclu elpmis erac fles rof lliks gnilesnuoc eraC erac fles ,sreclu

stuodnaH erutcel evitcaretnI rof larrefer ,yregrus rof snoitacidnI ruoh 1 airetirc ytilibigile etaremunE tnemtaert lacigruS yregrus fo pu-wollof ,yregrus tnemtaert lacigrus rof ysorpel fo & steehs esicrexE esicrexE ,sdrocer gnitadpu ,ysorpel ni stamrof SIS ruoh 1 PELN etaluclac ,RPM eraperP dna gnidroceR stuodnah dna noitaraperp ,srotacidni PELN atad nevig htiw srotacidni level CHP ta gnitroper stroper fo noissimbus stuodnaH erutcel evitcaretnI srekrow htlaeh fo gniniart boj-nO ruoh 1 rof tsilkcehc

a eraperP dna noisivrepuS sgniteem weiver ylhtnom ,AHSA & eht esylana ,noisivrepus ta PELN fo gnirotinom srotacidni level CHP stuodnaH erutcel evitcaretnI ,sgniteem puorg ,gnillesnuoC ruoh 1 gniteem puorg etatilicaF noitacudE ,noitamrofnI fo noitanimessid dna ycacovda noitacinummoC dna ,CPI/aidem hguorht segassem ruoivaheB & )CEI( semmargorp htlaeh loohcs egnahC )CCB( noitacinummoC & steehs esicrexE esicrexE ,sgurd evitroppus ,TDM ruoh 1 tnedni kcehC rehto dna sgurD stuodnah gnisserd ,raewtoof ,enolosinderp

Annexure 3.1 (L.F. 01) NATIONAL LEPROSY ERADICATION PROGRAMME (NELP) PATIENT CARD Sub centre PHC Block/CHC Districts State Registration Number: SC ST Others Name Age Female Male Address Classification PB MB New Case Other Type (Specify) Visible Deformity Yes No Remarks Date of First Dose AFTER ENTERING ABOVE INFORMATION IN THE PHC TREATMENT RECORD, THIS PATIENT CARD IS TO BE TRANSFERRED TO SUB CENTER FOR DELIVERY OF SUBSEQUENT DOSES Signature of Medical Officer Date of subsequent doses:

2 3 4 5 6 PB 7 8 9 10 11 12 (Final) Date of discharge End Status RFT Others (specify) this card is to be maintained at sub cenre. after every dose, update the PHC treatment record. after achieving end status, the MPW should sign this card and retain at sub centre Signature of Sub centre MPW FOR FUTURE REFERENE Guidelines to fill-up this card Registration Number Running number for the fiscal year at PHC level Classification PB- 1 to 5 patches and/or 1 nerve affected

MB – 6 and more patches and/or 2 or more nerve affected New Case A leprosy patient who has not taken MDT drugs anywhere earlier Other Type Includes Immigrant, Relapse, Referral or Restart of treatment End Status RFT – Released From Treatment OTHERS – DEFAULTER (Case of PB or MB consecutively absent for a period of 3/6 months from the last dose)/ DIED/MIGRATED/ UNKNOWN Training Manual for *In Urban situation, this same card I to be used. However, appropriate Health Unit, Area and Region may

Medical Officer be Indicated in the place of Sub center/PHC/Block 32

Training Manual for Medical Officer 33 )20 .F.L( 2.3 eruxennA DROCER TNEMTAERT CHP – )PELN( EMMARGORP NOITACIDARE YSORPEL LANOITAN CHC /CHP kcolB CHP raeY lacsiF etatS TCIRTSID skrameR etaD etaD elbisiV /BP /CS xeS egA sserddA emaN /weN buS geR fo sesoD tneuqesbuS fo etaD tsrif fo .rofeD BM TS F/M srehtO ertneC .oN TFR esod N/Y 21 11 01 9 8 7 6 5 4 3 2 BP )lanif(

Training Manual for Medical Officer 34 )30 .F.L( 3.3 eruxennA DROCER KCOTS GURD TDM YSORPEL – PELN _____________ : yrogetac yficepS – ])C(BP /)A(BP /)C(BM /)A(BM[ TDM fo yrogetac hcae rof egap etarapes esU )etatS ot pu level tsehgih txen htiw gnola eman htiw level yficeps esaelP – slevel etatS/tcirtsiD/CHP ta desu eb ot tamrof emaS( CHC /CHP kcolB CHP raeY lacsiF etatS TCIRTSID erutidnepxE tpieceR noitcasnarT skrameR ecnalaB yripxE hctaB oT ediV ytitnauQ yripxE .oN hctaB ediV morF .ytitnauQ etaD dnaH nI

Annexure 3.4 (M.L.F. 04, Page 1) NLEP MONTHLY REPORTING FORM PHC Block District State Reporting Month Year PB 1. No. of balance new cases at the beginning of the month MB TOTAL 2. No. of New Leprosy Cases detected in the reporting month During reporting month PB MB TOTAL Adult Child Total 3. Among new leprosy cases detected during the reporting Female month, number of Grade-I Deformity Grade-II SC ST 4. Number of New leprosy cases deleted during the month RFT - Otherwise deleted Total

5 Number of New leprosy cases under treatment at the end of the month (1+2-4) 6. Number of “other cases” recorded and put under treatment (i) Relapsed (ii) Reentered for treatment (iii) Referred (iv) Reclassified (v) From other states Total 7. No. of ‘other cases’ deleted from treatment RFT Otherwise deleted Total 8 No. of other cases under treatment at the end of reporting month 9. Leprosy Drug Stock at the end of the reporting month (if required use extra sheets) :

Blister Pack Quantity Expiry Date Total stock No. of patients Patient month under treatment BCP MB (A) MB (C) PB (A) PB (C) Training Manual for Medical Officer 35

Annexure 3.4 (M.L.F. 04, Page 2) NLEP – MONTHLY PROGRESS REPORT (Form PHC/CHC/Block PHC to District) PHC/BLOCK PHC/CHC Month S No. DPMR activity During the Cumulative total month From April till date 1 No. of Reaction cases recorded 2 No. of Reaction cases managed at CHC- at District Hospital- 3 No. of suspected relapse cases referred by PHC 4 No. of Relapse cases, confirmed at district hospital 5 No. of patients provided with foot-wear 6 No. of patients provided with self care kit

7 No. of patients referred for RCS to tertiary units 8 No. of patients-RCS done 9 No. of ulcer case managed 10 No. of ulcer case referred to secondary level 11 No. of cases developed new disability 12 No. of cases provided Gr-I MCR footwear 13 No. of cases referred for Gr-II MCR footwear 14 No. of cases referred for skin smear examination for AFB to secondary level 15 No. of cases found AFB +ve 16 No. of cases attended DPMR clinic 17 No. of ASHA /HW trained 18 No. of new cases referred /confirmed by ASHA

Training Manual for Medical Officer 37 1.4 eruxennA RETSIGER YTILIBASID )IP - mroF( tamroF RPMD etatS tcirtsiD CHC /CHP ytilibasid fo etiS ytilibasiD esaC weN /BM /TU /weN /egalliV sserddA /egA eht fo emaN .oN .lS II /I-.rG / )CN( BP esac dlO CHP /ertnec-buS xeS tneitap /esac TU tooF dnaH eyE TFR II.rG I.rG II.rG I .rG II-rG 0-rG 41 31 21 11 01 9 8 7 6 5 4 3 2 1 /dedivorp secivreS larrefeR retfa depoleved ytilibasiD weN etad htiw yradnoces ot refeR dedivorP secivreS RMP / noitcaeR sitirueN FHE /elpmiS

reclU skrameR /pu nekat pu wolloF enolosinderp fo gnitrats /I-epyT detacilpmoC tooF dnaH )II-rG(-eyE ton noitcaeR eyE detacilpmoC SCR rehtO reclU erac fleS /dioretS DII-epyT /I-rG( /I-rG( ot gnidnopser reclU yna fi gnisserD ecitcarp /esod )II-rG )II-rG diorets noitarud 03 92 82 72 62 52 42 32 22 12 02 91 81 71 61 51

Annexure 4.2 Page 1 (Form - PII) Disability Assessment form for primary level ASSESSMENT OF DISABILITY & NERVE FUNCTION Name Village Date of Registration S/O,W/O, D/O Sub-centre Date of RFT Age/Sex MDT No. Referred by Occupation MB/PB Date of assessment RIGHT LEFT Date Vision (0, 2) Light closure lid gap in mm Blink present/ Absent Little Finger Out Thumb up Wrist Extension . Foot up Disability Grade Hands Disability Grade Feet Disability Grade Eyes On Date Max. (WHO) Disability Grade EHF Score

Signature of Assessor Muscle power: S=Strong, W=Weak, P=Paralysed Score of vision: 0=Normal, 2= Blurred vision, unable to count finger, lagophthalomos, Corneal anaesthesia, ulcer, opacity EHF= maximum score=12 (2 for each eye, 2 for each hand, 2 for each foot) WHO Grading 0, I, II (This card should be filled up at time of registration and repeated after 3 months ( Once in 2 weeks in case of neuritis / reaction) Training Manual for Medical Officer 38

Annexure 4.2 Page 2 SENSORY ASSESSMENT DATE/ Palm Solo Comments ASSESSOR RIGHT LEFT RIGHT LEFT Key: (Put these mark/icon on the site where lesion is seen) (cid:51) Sensation Present within 3 cms Contracture Scan/Callus X Anaesthesia Wound Shortening Level ^ Clawing Crack Primary Level Care Training Manual for Medical Officer 39

Annexure 4.3 (Form - PIII) REFERRAL SLIP (To be used by ASHA/HW/MO PHC/MOCHC) PHC District Date Name of the person to be referred: SL. No in referral register Age and Sex : Address : Clinical finding: Reason / indication for referring: Referred to: Referred by: (Designation & place/ Signature) Action taken at referral centres: Instructions for follow up: Referred back by (Dr. Designation & place ) Signature & date: Training Manual for Medical Officer 40

Annexure 4.4 (Form - PIV) PREDNISOLONE CARD (This card should be kept with the patient) Instruction NATIONAL LEPROSY ERADICATION PROGRAMME • Take Prednisolone tablets as single dose PREDNISOLONE – CARD daily with milk / food but never on empty stomach Name of the Patient .......................................... • Restrict salt intake till on Prednisolone • Inform soon if you notice black stool Reg.No./MDT No. ............................................. (malena), pain upper abdomen or vomiting

Type ............................. MB / PB ............................ • Inform immediately if discharge in planter ulcer, any focus of infection, Date / Due Date off RFT ................................... persisting cough, mild fever or any deterioration Indication for Prednisolone therapy : • Don't stop Prednisolone before completion of regimen, even if there is .......................................................................... improvement or deterioration.

• Report for review / check up and next Date of starting Prednisolone .......................... dosage, every fortnight Signature of MO / Supervisor Page 4 Page 1 PREDNISOLONE RECORD Other drugs issued ......................................... Dosage Date of Next Sign. ....................................................................... Issue due date 40mg x 2 wk. .......................................................................

....................................................................... 30mg x 2 wk. 20mg x 2 wk. Progress / Remarks ........................................ Do (if required) ....................................................................... 15mg x 2 wk. ....................................................................... Do (if required) ....................................................................... 10mg x 2 wk. .......................................................................

Do (if required) Signature of MO ............................................. 5mg x 2 wk. Name ............................................................ Training Manual for Do (if required) Place .............................................................. Medical Officer 41 Page 2 Page 3

GLOSSARY Abduction - Movement away from anatomical central line of body Anesthesia - Loss of sensation Cardinal sign - Essential / unique sign Clawing - Deformity of hand where there is hyperextension of joints between fingers and palm and flexion of joints of the fingers CMHO - Chief Medical & Health Officer - Authority for all health aspects in a district Deformity - Abnormal appearance, disfigurement Disability- A difficulty in carrying out certain activities considered normal for a human being. A

disability results from impairment. Activity limitation and restricted participation is included under disability. DLO - District Leprosy Officer DLS -District Leprosy Society Endemic - Continuous presence of disease ENL - Erythema Nodosum Leprosum - Type 2 lepra reaction characterised by nodules in the skin Erythematous - Red in colour Exfoliative dermatitis - Condition characterized by universal erythema and scaling. Very often seen as drug reaction (e.g. Dapsone)

Exposure keratitis – Damage to cornea due to constant exposer. Foot drop - Inability to flex foot at ankle due to paralysis GHC - General Health Care Haemolytic anaemia - Anaemia produced by destruction of red blood cells (can be caused by Dapsone). Hepatitis - Inflammation of liver Ichthyosis - Condition where the skin is dry and scaly like that of a fish Incubation Period - Time interval between entry of organism and onset of symptoms

Jaundice - Condition characterized by yellowness of skin, Mucous, membranes and white of eyes Lagophthalmos - Inability to close the eye due to paralysis of eye lid Leprosy Reaction - Acute inflammatory manifestations in skin and/or nerves in leprosy MB - Multi Bacillary (more than 5 skin lesion or more than 1 nerve trunk involvement or bacteriologically positive) MCR - Micro Cellular Rubber for making footwear MDT - Multi Drug Therapy MPR - Monthly Progress Report NCDR - New Case Detection Rate

Nephritis - Inflammation of the kidney Training Manual Neuritis - Inflammation of nerve for NLEP - National Leprosy Eradication Programme Medical Officer 42

Nodule - Swelling in the skin Edema - A local or generalized condition in which the body tissues contain an excess amount of fluid Opposition - Bringing together pulp of thumb with pulp of other fingers Palpate - To ‘palpate’ is to examine by touch PB - Pauci Bacillary. Cases with less bacilli (upto 5 skin lesions or upto 1 nerve trunk involvement) PHC - Primary Health Centre Plantar - Referring to the sole of the foot Prevalence - Number of cases per 10000 population

Relapse - Re-occurrence of disease after cure RFT - Release From Treatment (the end of treatment) Scaling - Visible shedding of surface layer of skin in the form of scales. SLO - State Leprosy Officer ST - Sensory Testing Ulcer - Discontinuity of the skin or mucous membrane VMT - Voluntary Muscle Testing Wrist drop - Inability to extend wrist due to paralysis of muscles supplied by Radial nerve Training Manual for Medical Officer 43

Self-care Hands & Feet • Inspect the hands/ feet daily for hot, tender spots • Soak the hands/feet for about half an hour in water. • Scraping hard skin (if fissures/ cracks present) using any stone without sharp edges. • Apply vesatine or cooking oil when hands/ feet are wet. • Protect hands against heat & friction. • Walk slowly with short steps. Use footwear for anaesthetic feet. • Clean the wound with soap & water. Dress with clean cloth. • Consult medical officer if ulcer is foul smelling

• Oil massage and passive movements to keep the joints mobile Eyes • Check eyes daily using mirror. • Wear protective devices • Put moistening eye drop • Red / painful eye, consult doctor

ELIMINATION OF LYMPHATIC FILARIASIS LYMPHATIC FILARIASIS What is lymphatic filariasis (LF)? • Lymphatic filariasis (LF) is a GUIDELINES FOR DRUG parasitic disease, commonly DISTRIBUTORS known as elephantiasis. • It is caused by thread like worms known as filarial parasite. • The adult worms (male and female) settle in lymph nodes and the female worm gives birth to millions of young ones known as microfilariae (mf). Microfilaria in the blood of man Directorate of National Vector Borne

Disease Control Programme, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India • Generally no symptoms are seen Vector Control Research Centre, initially, but the lymphatic system is (Indian Council of Medical damaged. Research) Puducherry OUR RESOLVE: FREEDOM FROM FILARIASIS • With no symptoms initially, the persons with mf are not recognized and they continue to transmit the parasite to the community.

• The persons infected with the parasite Why should every one take DEC and may experience frequent acute albendazole tablets during Mass attacks of adenolymphangitis when Drug Administration (MDA)? they may have symptoms of fever, pain and redness in the affected body • People living in filaria endemic parts. areas, who look healthy, may be • After 6 to 8 years of infection, clinical carrying mf in their blood without symptoms such as swollen legs or any recognizable symptoms at the

enlarged lymph nodes/lymph vessels initial stage. or hydrocele may appear • Finding the infected persons at this • These chronic manifestations become stage and giving them alone irreversible as the lymphatic system treatment is tedious. has already been damaged. • Both DEC and albendazole are safe and even non-infected can How is LF transmitted? take the drugs. • DEC kills mf and albendazole • Filarial parasite species in India lives normally clears intestinal worms

only in man. The adult worm which is an added benefit. When produces microfilaria which circulates both the drugs are given to-gether, in the peripheral blood system of the it has effect on adult worm and infected people. When the mosquito therefore the parasites will be feeds on the infected person, it destroyed preventing the infected ingests the microfilaria. person from developing disease • When every individual in the community takes drugs under MDA, microfilaria will be cleared

and not present in the blood for the mosquitoes to transmit. • MDA repeated annually over 5-6 years may interrupt transmission. This eventually leading to future • The ingested microfilaria grows and generation being free of this within 12 days it reaches a stage infection when it can infect another human being. Who should take the drugs? • When the mosquito with infective stage larva bites another person, the • Everybody in the community, parasite enters and reaches the except pregnant women, children

lymphatic system. below two years of age and persons who are very sick from How to prevent infection? other illness. • Administration of single dose of When should people take DEC antifilarial drugs to the entire tablets? community (mass drug administration), yearly once for 5-6 • DEC tablets should be taken once years. in a year on the identified day of • Diethylcarbamazine (DEC) and MDA (National Filaria Day). albendazole are the drugs used for mass drug administration • The tablets should be taken after

• Protection from mosquito bites food. If the tablets are taken on 2

empty stomach, it may cause should list who should get the drugs stomach discomfort. and then mobilize their participation. Training will be provided to all the drug How many tablets should one distributors by the Medical Officer of the consume? PHC and VHN on MDA 15 days prior to the day of MDA. • The dose for different age groups is indicated below: Pre MDA activities: DEC Enumeration and motivation of the Age Albenda No of community by making at least two visits (in zole (400 Dose Tablets years) mg)

(100 mg) First visit: (Household enumeration) <2 Nil Nil Nil 2-5 100 1 tablet 1 tablet • Visit every house in your assigned mg area with in 15 days prior to the 6-14 200 2 tablets 1 tablet day of MDA mg • Identify yourself as an active 15 & 300 3 tablets 1 tablet member of the community and above mg display your Identity card Are there any side effects of drugs? • DEC and albendazole are safe drugs, which are in use for the last 50 years around the world. • People, who look healthy but have

parasite in their blood, may experience some side (therapeutic) effects due to the killing of parasites following drug consumption • One or combination of the following • Enquire about the details of the side effects may be experienced by a household and record: small proportion of population o Village name especially microfilaria carriers: o Street name o House number o Fever o Name, age and gender of o Headache the every member in the o Body ache household o Vomiting • Inform the family members about

o Dizziness the MDA programme and clarify o Rash and itching occasionally their doubts • These side effects are self limiting, usually disappear or subside within a Second visit: (Interpersonal contact) day without any medication. • Make house to house visit What should Drug Distributors do? • Meet all the available members • Explain to them: The ultimate goal of the drug distributor is o The problem due to LF in the to administer drugs to the assigned area and socio-economic

o Methods of prevention of LF • Approach every individual in the o Importance of MDA household o Possible side effects • Select the correct dose of DEC o Health and economic benefit of based on the age of the person MDA • Co-administer DEC with o Date and time of drug albendazole distribution • Ensure that the individual is o Ensure that all family members consuming the drugs in your are available at the time of MDA presence (supervised administration) • Record the absentees and their time of availability

• Advise to approach the Sub- centre/PHC if any inconvenience is faced Mopping-up: • Make daily visits to your assigned area for two days following MDA to cover the absentees o Request them to eat and be • If any case with side effects are ready for drug consumption come across, provide them with • Identify suitable time for contacting symptomatic treatment and delivering drug • If any case requires hospital • Distribute IEC materials admission, report to the VHN/rapid response team MDA activities:

• Consolidate your record on the number of people covered daily Checklist of items to be carried: Data consolidation and reporting; o Identity card o Sufficient number of tablets • Consolidate the data on : including paracetomol For a population of 250 o The total population o Eligible population Approximately 700 tablets of DEC o Number of people (100 mg) administered with drugs 275 tablets of albendazole o Number of people reported IEC materials with side effects o Type of side effects

o IEC materials such as hand encountered bills/bit notices o No. of people required o Family register – updated hospitalization o Flash cards on elephantiasis to o Number of tablets received explain to the community and distributed • Return the family register along Drug administration: with drugs in balance to the VHN • Visit the house at the agreed time • Identify all the eligible individuals for administering drugs 4

Tips for improving coverage & drug • Also inform that the mass drug compliance during MDA administration with DEC and albendazole alone will not cure the • Ensure that messages on the date of chronic complications such as MDA are displayed through lymphoedema and hydrocele. posters/banners in your area and • If there are patients in the family, premises of public places. they should be advised to • The local community leaders should approach the health care facilities

be informed and involved in MDA. in your locality • Explain to people about filariasis and • Hydrocele can be surgically how it spread and clear their doubts. operated in the Government • Inform people about the disabilities Hospitals free of charge. Enlist the caused by LF and its impact on hydrocele cases and motivate economic productivity and income. them to avail the factiities. • Educate people about its risk and • Identify and involve individuals in

social stigma especially in case of the village who will campaign for girls/women. MDA. Provide them with adequate • Inform people about the importance of IEC materials. prevention through consuming DEC and albendazole tablets on the day of OUR VISION : FUTURE GENERATION MDA . FREE FROM FILARIASIS • Inform people that they may not know that they are infected from this disease and if they do not take DEC tablets, the manifestations may appear later in the form of swelling of legs/ enlargement of lymph

nodes/lymph vessels or hydrocele. • Explain that once swelling appears, it is difficult or impossible to reverse. It may remain as a permanent disability causing social stigma, hampering the daily activities, quality of life and also be a financial burden. • If the whole community takes DEC tablets once a year for 5-6 years, the microfilariae in the infected persons HELP TO KEEP THIS SMILE ALIVE will be killed and the disease progression will be halted. The spread of filariasis will be stopped as

mosquitoes cannot pick up the infection and we can make the next generation free from filariasis. • Explain also that unless everybody takes the drug, the disease will continue to spread. • Killing of microfilariae by the drugs may cause some the side effects among a small proportion of people • Tablets should not be taken on empty stomach. 5

id2262435 pdfMachine by Broadgun Software - a great PDF writer! - a great PDF creator! - http://www.pdfmachine.com http://www.broadgun.com GUIDELINES CLINICAL MANAGEMENT OF ACUTE ENCEPHALITIS SYNDROME INCLUDING JAPANESE ENCEPHALITIS GOVERNMENT OF INDIA Directorate of National Vector Borne Disease Control Programme 22, Shamnath Marg, Delhi-110054 Directorate General of Health Services, Ministry of Health & Family Welfare AUGUST 2009

PREFACE Following outbreak of Japanese Encephalitis (JE) in Gorakhpur and Basti divisions in Eastern Uttar Pradesh during 2005, directorate National Vector borne Disease Control Programme developed surveillance guidelines and issued the same to all JE endemic states with the advice that JE be commonly reported under Acute Encephalitis Syndrome and after getting the confirmation from the Sentinel sites, a line list of JE cases be drawn and sent along with the prescribed formats.

AES including JE is reported mainly from Assam, Bihar, Karnataka, Tamil Nadu and Uttar Pradesh which contributes approximately 80% of cases and deaths respectively with a case fatality rate ranging from 20 to 25%. Specific anti-viral drug for AES including Japanese Encephalitis is not available till date and cases are managed symptomatically. In the wake of repeated outbreaks witnessed in the past, Directorate of NVBDCP has already

taken steps to strengthen the system of disease surveillance. JE surveillance which is a component of AES surveillance has been instituted with the establishment of sero- surveillance network. Vaccination for prevention of JE is being undertaken under Universal Immunization Programme. Prompt and effective case management needs more improved inputs viz service from health care providers (medical and paramedical), laboratory facilities for diagnosis of

JE cases and sufficient availability of drugs and equipment in treatment centres. Infrastructure of clinical management with Standard Operating Procedure / guidelines for management of cases should be available at District/CHS/PHC level. Experience gained from recent outbreaks has shown that due to lack of common understanding at all levels of health care delivery system there was confusion about management of cases and their timely referral.

These guidelines have therefore been prepared by the Directorate of NVBDCP for management of AES that includes Japanese Encephalitis cases as well. They are intended to guide the management of acutely ill children, especially those with fever, or loss of consciousness, convulsions, or other symptoms suggesting meningitis or encephalitis. They clearly outline issues like education of village level worker community for early referral of

suspects and care at the time of transportation which contributes immensely in reducing CFR. The main cause of high mortality is transporting patient over long distances without proper medical care in the hope of getting best treatment in the tertiary care hospital. Lack of First Aid during this long and time consuming transport is damaging the brain to an irreversible way. Medicare must be provided at the nearest hospital at the earliest1. A broad framework for management of patients with encephalitis

has been laid down with the aim to improve clinical practices which have a bearing on patient outcome and recovery. It is sincerely hoped that this document will guide clinicians at all levels to strengthen JE case management. The revised guidelines on case management of AES have been prepared in consultation with Dr. P.Nagabhushana Rao, international expert on the management of AES and Dr. V.K. Gupta, Prof. & HOD, Deptt. Of Pediatrics, RML Hospital along with expert

clinicians drawn from different health care institutions in the country. (G.P.S. DHILLON) Director i

Index Chapter Contents Page No. Chapter 1 Introduction 1-3 Chapter 2 Diagnosis of Japanese Encephalitis 4-6 Chapter 3 Management of Acute Encephalitis Syndrome (AES) Including Japanese Encephalitis 7-20 Annexure A AES case Investigation Form 21 Annexure B JE Laboratory Request and Report Form 22 Chapter 4 Clinical Differentiation of JE from Other Viral/Bacterial/ Parasitic Infections 23-24 Chapter 5 Equipments of Drugs at Various Levels 25-26 List of Contributors 27 ii

Chapter 1 1. INTRODUCTION Acute Encephalitis Syndrome (AES) including Japanese Encephalitis (JE) is a group of clinically similar neurologic manifestation caused by several different viruses, bacteria, fungus, parasites, spirochetes, chemical/ toxins etc. There is seasonal and geographical variation in the causative organism. The outbreak of JE usually coincides with the monsoon and post monsoon period when the density of mosquitoes increases while

encephalitis due to other viruses specially entero-viruses occurs throughout the year as it is a water borne disease. The encephalitis by Arbovirus of North America includes the newly introduced West Nile Encephalitis (WNE). The case fatality and morbidity is very high among various viral encephalitis specially in JE or entero-virus encephalitis in various parts of India. For surveillance purposes, all the cases of Acute Encephalitis Cases to be reported

under the heading of (cid:147)acute encephalitis(cid:148). In the WHO(cid:146)s guidelines for JE surveillance, syndromic surveillance for JE is recommended. This means that all cases of Acute Encephalitis Syndrome (AES) should be reported. Laboratory confirmation of suspected cases can be done where feasible. The following case definition should be used for reporting of suspected AES cases in endemic areas: 1.1 Case definition of Acute Encephalitis Syndrome (AES)

Clinically, a case of AES is defined as a person of any age, at any time of year with the acute onset of fever and a change in mental status (including symptoms such as confusion, disorientation, come, or inability to talk) AND/OR new onset of seizures (excluding simple febrile seizures). Other early clinical findings may include an increase in irritability, somnolence or abnormal behaviour greater than that seen with usual febrile illness. 1.2 Case classification

A case that meets the clinical case definition for AES i.e. suspected case should be classified in one of the following four ways (see Figure 1): a) Laboratory-confirmed JE: A suspected case that has been laboratory-confirmed as JE. b) Probable JE: A suspected case that occurs in close geographic and temporal relationship to laboratory-confirmed case of JE, in the context of an outbreak. c) (cid:147)Acute encephalitis syndrome(cid:148) (due to agent other than JE): A suspected case in

which diagnostic testing is performed and an etiological agent other than JE virus is identified. d) (cid:147)Acute encephalitis syndrome(cid:148) (due to unknown agent ) A suspected case in which no diagnostic testing is performed or in which testing was performed but no etiological agent was identified or in which the test results were indeterminate. 1

FIGURE 1 : FINAL CLASSIFICATION SCHEME FOR AES CASES Other Acute Encephalitis with Diagnostic +ve specific diagnosis tests IgM-ve -ve AES-unknown Adequate blood/ CSF specimen Igm +ve Lab confirmed JE Suspected AES (incl. JE) Geographic / temporal Link to a lab confirmed Probable JE JE outbreak No adequate blood/ CSF specimen No geographic / Temporal AES Unknown Link to a lab confirmed JE While the above classifications are useful for clearer definitions of AES cases, for practical

purposes, the two key definitions to be used are (cid:147)Suspected JE Cases(cid:148) for those that meet the criteria for AES, and (cid:147)confirmed JE cases(cid:148) for those AES cases which have laboratory confirmation for JE. Japanese Encephalitis (JE) is a mosquito borne zoonotic viral disease is one of the causes under AES. The virus is maintained in animals and birds. Pigs and birds, particularly the birds belonging to Family Ardeidae (e.g. cattle egrets, pond herons, etc.)

are the natural hosts. Pigs and wild birds are reservoir of infection and are often called as (cid:147)amplifier hosts(cid:148) in the transmission cycle, while man and horse are (cid:145)dead end(cid:146) hosts. Similarly other virus, fungus, parasite, spirochetes, toxin etc may cause similar illness. The disease affects the central nervous system and can cause severe complications, seizures and even death. The case fatality rate of this disease is very high and those

who survive may suffer with various degrees of neurological sequelae. Children suffer the highest attack rates because of lack of cumulative immunity due to natural infection. Meningitis, caused by bacteria, can be treated as soon as possible with antibiotics. Encephalitis, usually caused by a virus, cannot be treated with antibiotics. However, good clinical management is important to reduce the risk of disability or death from the disease. 2

Clinical involvement of the Central Nervous System (CNS) is an unusual manifestation of human viral infection. The spectrum of brain involvement and the outcome of the disease are dependent on the specific pathogen, the immunological state of the host and a range of environmental factors. Although specific therapy is limited to only several viral agents, correct diagnosis, and supportive and symptomatic treatment (when no specific therapy is available) are mandatory to ensure the best prognosis.

These guidelines have been prepared by the Directorate of NVBDCP for management of AES including Japanese Encephalitis cases in consultation with national experts. The list of the contributors may be seen at Annexure 5. The guidelines are intended to guide the management of acutely ill children, especially those with fever, a change in consciousness, convulsions, or other symptoms suggesting meningitis or encephalitis. 3

Chapter 2 2. DIAGNOSIS OF JAPANESE ENCEPHALITIS Objectives 1. Learn the case definition and common sign and symptoms and management especially at the peripheral level. 2.1 Clinical Manifestations Following an incubation period, in case of viral encephalitis including JE a prodrome of fever, headache, nausea, diarrhoea, vomiting, and myalgia occurs lasting for few days (1-5 days) followed by irritability, altered behaviour, convulsions and coma.

The progression of disease is rapid. Signs of raised intra cranial tension are commonly present in acute stage of illness. The patient may develop difficulty of speech and other neurological deficits like ocular palsies, hemiplegia, quadriplegia and extrapyramidal signs in the form of dystonia, choreoathetosis and coarse tremors. All the cases of Acute CNS involvement are reported in the syndrome of acute encephalitis i.e. all cases of Acute Encephalitis Syndrome (AES) should be

reported as they have similar clinical manifestations. Their case management usually follows a common protocol along with situation specific treatment. Diagnosis of JE will depend on laboratory investigations. The case definitions and case classification in the programme are given in the following paragraphs. 2.2 Case Definition of Suspected case: - Acute onset of fever, not more than 5-7 days duration. - Change in mental status with/ without  New onset of seizures (excluding febrile seizures)

 (Other early clinical findings (cid:150) may include irritability, somnolence or abnormal behavior greater than that seen with usual febrile illness) Important  In an epidemic situation fever with altered sensorium persisting for more than two hours with a focal seizure or paralysis of any part of body, is encephalitis.  Presence of rash on body excludes Japanese Encephalitis.  AES with symmetrical signs and fever is likely to be cerebral Malaria. 4

2.3 Case Classification: Laboratory-Confirmed case : A suspected case with any one of the following markers:  Presence of lgM antibody in serum and/ or CSF to a specific virus including JE/Entero Virus or others  Four fold difference in lgG antibody titre in paired sera  Virus isolation from brain tissue  Antigen detection by immunofluroscence  Nucleic acid detection by PCR In the sentinel surveillance network, AES/JE will be diagnosed by lgM Capture ELISA, and

virus isolation will be done in National Reference Laboratory. Probable Cases Suspected case in close geographic and temporal relationship to a laboratory-confirmed case of AES/JE in an outbreak Acute Encephalitis Syndrome due to other agent A suspected case in which diagnostic testing is performed and an etiological agent other than AES/JE is identified Acute Encephalitis Syndrome due to unknown agent A suspected case in which no diagnostic testing is performed / no etiological agent is

identified / test results are indeterminate Etiology/ causes of AES AES JE Non JE Viral Parasitic (Malaria) Single Stranded RNA Virus of Flaviv iridae family Protozoal (Amoebic) (Mosquito is vector) Arbovirus WNE Siprochetal (Syphilis) (Arthopod is vector) (West Nile Encephalitis in North America) VEE ( Venezuelan Horses) Trypanosomiases Not found in INDIA Tick Borne Encephalitis & others Acute TBM Dawson Bacterial Entero Viral Encephalitis Coxsackie A&B Fungal (Cryptococcal) Polio Non-polio Echo Toxin

Others Chemicals (No fever) Toxoplasmosis Unknown Cause Dengue Herpes Varicella 5

EC includes only 2 diseases. JE and Epidemic Brain Attack (EBA)/ Non JE, AES. Diagnosis: EBA can be easily differentiated from JE with the help of the following Table. 2.4 Differentiation of Japanese Encephalitis and Epidemic Brain Attacks/ NON-JE, AES. Japanese Encephalitis Epidemic Brain Attack (EBA) or Non JE/ AES Relation to onset About 6 weeks after Starts within 3 days after the onset of of Rains onset of rains rains Pain in abdomen No in 50% Diarrhea No in 50%

CSF lymphocytic pleocytosis normal except for increased tension CT scan Thalami hypodense Infarct in Middle cerebral artery territory MRI scan Thalami hyperintense Infarct in Middle cerebral artery territory. 6

Chapter 3 3. MANAGEMENT OF ACUTE ENCEPHALITIS SYNDROME (AES) INCLUDING JAPANESE ENCEPHALITIS Objectives 1. Learn the clinical management of AES. 2. Know the danger signs for referral. 3.1 Danger Sign & Line of Treatment Management of Acute Encephalitis Syndrome including Japanese Encephalitis is essentially symptomatic. To reduce severe morbidity and mortality, it is important to identify early warning signs and refer patents to health facility and educate the health

workers about the first line if management at the grassroots level. Chart 1 depicts what is to be done for a patient at the community level. Chart : Management of AES including Japanese Encephalitis At Community Level (PHC) Treatment Danger Sign Fever with any one of the following: Fever (cid:150) Tap water vigrous  Lethargy sponging  Unconsciousness (cid:150) Paracetamol  Convulsions  May be associated with other findings eg. Convulsions Paralysis, rash, hepatosplenomegaly (cid:150) Anti Convulsants

Secretion (cid:150) Suction REFERRAL TO NEAREST FIRST REFERRAL Nil Orally UNIT (FRU) Position of patient prone/Semi- prone with head on one side oxygen if p ossible. Further Danger Sign  Shock/ Hypotension/ Low BP/ Feeble Thready pulse  Need of Ventilator (cid:150) Poor respiratory efforts, cyanosis not managed by oxygen TREATMENT - I/V line (cid:150) I/V fluids - Correction of Blood Sugar - Suction (cid:150) Oxygen - I/V anti convulsant if convulsions are not controlled Refer to Tertiary Hospital

- Use of ambubag if necessary - Catheterization - Use of Mannitol - Inj. Paracetamol - Input/ output charting - Pulse, respiratory rate, temperature and B.P. monitoring 7

3.2 MANAGEMENT OF CASES OF AES INCLUDING JE Treatment at the health facility, it is important to exclude other causes of CNS affliction like meningitis or cerebral malaria which require specific treatment. Treatment will depend on the condition in which patient is received in the health facility. Since patients are likely to arrive with high grade fever and change in mental status or convulsions proceed with the assessment of patency of airway.

The treatment at PHC/ CHC District level or at tertiary care hospitals remains the same. Depending upon the needs of care and availability of facilities available at the centre/ hospital the patients to be transferred to the nearest higher centre for further management. It should be ensured before transferring the case, all the available treatment is provided to the patient. Only needy patients where such facilities are not

available, to be transported. The time consumed in transportation itself is a major cause of high mortality rate. In all endemic areas, all the facilities including training can be arranged before hand except Ventilatory Support. All Centres should be equipped with ambu beg and oxygen in addition to other medicines and I/V cannula. The treatment of the patients may require, as follow:- 1.) Management of Airways and Breathing. 2.) Management of Circulation. 3.) Control of Convulsion and Intracranial pressure

4.) Control of Temperature 5.) Fluid and Electrolytes and Calories/ Nutrition 6.) General management 7.) Specific treatment of any for treatable cause 8.) Investigations, Samples Collection & Transportation 9.) Reporting of a case 10.) Rehabilitation. 8

3.2.1 MANAGEMENT OF AIRWAY AND BREATHING Clear Airways Give Oxygen if needed Assessment  No oral feed of Airway and  Nurse in semi Breathing prone and prone position Clear secretions from Obstructed breathing / mouth Severe respiratory distress  Wiping oral cavity  Suction of mouth turning head on one side  Give Oxygen  Ventilate with Bag and Mask / Endo Tracheal Tube if breathing is laboured.  Refer the case to tertiary care centre for Ventilatory support if need. Fig 1. Position of the Patient

 Turn the patient on the prone side to reduce risk of aspiration.  Keep the neck slightly extended and stabilize by placing cheek on one hand.  Bend one leg to stabilize the body position. 9

Indications of Ventilatory Support 1. Detoriating General Condition 2. Very Shallow Respiration/ Severe Respiratory Distress/ Heart Sound are Feeble 3. Capillary Refilling time/ colour of Patient Not Improved 4. Dusky Colour of body/ Cyanosis 5. Needs continuous Bag and Mask (Ambu) respiration 6. ABG Parameters 10

3.2.2 MANAGEMENT OF CIRCULATION Establish IV line. Look for sign and symptoms of shock  Capillary refill > 3 secs (pediatric patient)  Cold extremities  Weak and rapid pulse Assess pediatric No dehydration  Symptomatic patient for dehydration management  Look for signs of referral  2/3rd of maintenance fluid by Intravenous route. Grade dehydration as  Severe dehydration: some/ severe dehydration IV fluid Ringer lactate/ Normal Saline as per WHO guidelines  Some dehydration

IV fluid (cid:150) Ringer Lactate/ Normal saline Shock present IV fluid Reassess Ringer Lactate 20 ml/kg/ hr (Repeat if shock Persists) Ringer Lactate (cid:150) 20 ml/kg, if shock Improvement: Continue improves, child is euvolmic, give maintenance IV fluid maintenance fluid, No improvement : Refer Shock Persists (cid:150) Inotrope Dopamine drip to higher centre in maintenance fluid 5 mcg/kg/ minute then again increase Dopamine upto 20mcg/kg/minute and similarly Dobutamine start with 5mcg/kg/minute &

increase upto 20 mcg/kg/minute (Till BP stabilizes) NB : These are broad guidelines; ultimate decision regarding management will depend upon the attending physician. 11

3.2.3 MANAGEMENT OF CONVULSIONS & I.C.T. Give anti convulsants if there was a history of convulsions and not given earlier, or convulsions are present. Number one to three are first drug of choice, if convulsions are not controlled. Anti Convulsants Sl. Name of Drugs Closes Available Route of Indication Limitation/ Side No. as Administration Effects 1. Phenobarbitone 20-40mg/kg 200mg per I/V Slowly after Convulsion in infants Good drug controlling

(Gardinal/Luminal) As loading ml. ampule dilution in can be used in all seizure & long term dose normal saline age groups use. 2. Phenytoin 15-20mg/kg 100mg/ I/V Slowly after Convulsion in all age Good drug for control of (Eptoin/Dilantin) 2ml amp. dilution in all groups seizure & as normal saline maintenance 3. Sod. Valporate 20-40 mg/kg I/V Oral Syrup can be All age group Syrup given as per -do- rectal 4. Diazepam 0.1-0.3mg/kg I/V or P/R  I/V slowly Uncontrolled May cause respiratory

 Syrup Convulsions arrest in newborns & Suppository infants. Short acting P\R 5. Lorazepam 0.05-0.1mg/kg I\V I/V Slowly Uncontrolled Tachy cardea, oral, Convulsion depression Confusion Safe in infants blurred vision 6. Midazolam 0.2mg/kg 1mg/5kg S/C, intra nasal Uncontrolled Short acting safe in injections convulsion in infants 7. Inj. Paraldehyde 11% 0.1-0.2mcg/kg deep gluteal can be replaced after ‰-hrs. Maintenance Dose - Phenobarbitone 3-8mg/kg/day I/V or oral - Phenytoin 5-8 mg/kg/day I/V or oral

- Sodium Valproate 40-60mg/kg/day Oral MANAGEMENT OF INCREASED INTRACRANIAL PRESSURE(Tension) (Only after correction of Dehydration) 1. Mannitol 20% I/V (cid:150) 5 ml/kg in ‰ hrs as 1 st dose than 2.5 ml/kg at 6 hrs. intervals upto 48 hours (8 doses). 2. Injection Lasix I/V (cid:150) 1 mg /kg upto 40 mg can be given. 3. Glycerol solution:- Oral (cid:150) 0.5 ml/kg mix with fruit juice can be given by nasogastric tube (cid:150) 3 times a day

4. Steroids (cid:150) are not indicated in viral encephalitis including JE. 12

3.2.4 CONTROL OF TEMPERATURE If No Rigors:- a) Tap Water Sponging: Not only on forehead, palms or soles, whole body to be wet with water and fan(ceiling/table/manual) is on. Cold sponging is harmful. b) If temperature is too high (cid:150) Cold Sponges may be kept on head, axilla and groins. c) Injection Paracetamol: 5mg/kg, deep intra muscular at either lateral side of thigh or upper outer Quadrant of hip. If injection is not available give Paracetamol 10-

15mg/kg maximum upto 600 mg by Nasogastric tube. Paracetamol Suppository are also available which may be used. Other antipyretic medicines e.g. nemusulide/ brufen/ meftal/ aspirin etc are not advisable, specially in children. If chills or Rigors present : - Don(cid:146)t cover patients - Don(cid:146)t do water sponging - Use Paracetamol injection, syrup, through nasogastric tube or Paracetamol suppository as advised above. 13

3.2.5 MANAGEMENT OF FLUID ELECTROLYTES AND CALORIES/NUTRITION (A) Assessment of Dehydration and Management 1. Dehydration Dehydration is classified into No/ Some/ Severe Dehydration. Since it is difficult to assess dehydration in a patient of encephalitis as the patient is lethargic and unable to drink,. therefore, skin turgor takes precedence over other signs. An objective way of classification would be as follows: (i) Some Dehydration:  Irritability  Thirsty  Sunken Eyes  Less Tears  Dry Mouth

 Skin Turgor Delay (ii) Severe Dehydration:  Floppiness  Drowsiness/ Lethargy  Unconscious  Inability to Drink (iii) Signs of shock  Oliguria/ anuria  Rapid and thready pulse  Capillary filling time > 3secs  Low Blood Pressure Management of Dehydration: (a) Some Dehydration:  IV fluid Ringer lactate/ N saline 100m/kg to be given over 8 hrs.  Where the facility for IV fluids is not available administer ORS 75m/kg in 4 hrs through nasogasrtic tube

 Reassess: if there is improvement continue with maintenance IV fluid/if no improvement is detected, switch to plan for severe dehydration (b) Severe Dehydration  IV fluid Ringer lactate 100ml/kg is given as per the table below Table 1: Rate of Fluid (Ringer 30ml/kg 70ml/kg Lactate) < 1yr 2 hrs 4 hrs >1yr 1 hrs 5 hrs  Reassess: If there is improvement switch to maintenance/ if no improvement is detected or deterioration is observed infuse IV fluid more rapidly. 14

2. Maintenance Maintenance fluid is administered at the following rate Table 2: Weight Fluid Volume 1 (cid:150) 10 10 ml / kg 11 (cid:150) 20 1000 ml + 50cc/kg over & above 10 kg 21 (cid:150) 40 1500 ml+20cc/kg over & above 10 kg (B) Calories/ Nutrition During CNS infections and convulsion and hyperphyrexia state, calories specially glucose required is increased and it should be given in form of 10% Dextrose or even 25% Dextrose may be given on arrival of the patient. A total dose of 200 mg/kg may be

given. All I/V fluids with Dextrose should be continued till patient is stabilized, convulsions are controlled, no vomiting and distention of abdomen, at this time, intra gastric feeding may added and slowly I/V fluids are replaced by total nasogastric feeding. 15

3.2.6 GENERAL MANAGEMENT 1. Suction : Frequent suction either by mucous sucker, or suction machine to be done on an unconscious patient, so secretion may not collect in mouth to avoid aspiration and maintenance the patency of airways. 2. Nasogastric Aspiration : Nil orally, place a Nasogastric/ Ryles tube into stomach and do a frequent suction to avoid any vomiting and aspiration. It will also help in decompensation of stomach and decrease intra abdominal pressure. It will help in respiration.

3. Care of Eye, Bowel Bladder & Back :  Eyes to be covered by wet gauge  An antibiotic Eye ointment may be applied twice a day or liquid paraffin may be put in eyes to avoid drying of Cornea.  If child does not pass stool, put a glycerine enema.  Bed should be well maintained, don(cid:146)t allow to form any bed sore. Spirit & powder may be applied on back and on all pressure points.  Frequent changing of patient(cid:146)s position.  Catheterize the patient to avoid soiling of beds.

 Physiotherapy once patient is stabilized  Other General Nursing Care  Treat Secondary infections (cid:150) by appropriate antibiotics  Treat underlying other pathology (cid:150) e .g. anemia, malnutrition, etc. 16

3.2.7 TREATMENT OF SPECIFIC CAUSE IF ANY 1. Herpes - Acyclovir (cid:150) 10 mg/kg/dose, slowly over a period of one hour (cid:150) 8 hourly X 21 days. 2. Zoster Varicella - Acyclovir (cid:150) 10mg/kg/dose, 1/2hrs slowly, over a period of 1 hour (cid:150) 8 hourly X 2-3 weeks. 3. Malaria - I/V Quinine (cid:150) 20 mg/kg in 5% Dextrose slowly over a period of 1hr then 10mg/kg 8 hourly. Monitor Blood Sugar and Blood Pressure. 4. Meningitis (Pyogonic) -

Start with inj. Ampicillin 400 mg kg 6 hourly upto 12gm/day + Inj. Ceftrioxone 100-150mg/kg as stat dose than in two dived doses 12 hourly + Steroid Change antibiotics according to C/S report and response. 5. TBM - Anti Tubercular Drugs (1NH, PZA, Rcin + Ethambutol + Steroids) 6. Toxoplasmosis - Pyrimethamine 2mg/kg/24 hours in two divided doses X 2 days than 1mg/kg/ on alternate day. 7. Amoebiasis - Metronidazole (cid:150) 10mg/kg I/V slowly 8 hourly X 10-14 days.

8. Fungal Infection - Inj. Amphotericin (cid:150) B 5mg/kg/24 hours or Fluconazole (cid:150) oral 200-400mg/kg for 3-6 months. 9. Neurocysticercosis - Albendazole oral 10/mg/kg(upto 400 mg)/day X 2 weeks. 17

3.2.8 INVESTIGATIONS, SAMPLE COLLECTION & TRANSPORTATION A. Investigations i. Complete blood counts ii. Peripheral blood smear-Malarial parasite iii. Blood glucose, Electrolytes iv. CSF and Blood for serology by lgM ELISA/ virus isolation, CSF is preferred since by the time patient presents with CNS manifestations the level of viremia in blood has decreased and there is cross reaction with other flaviviruses. v. Other test if necessary (cid:150) LFT/KFT/Blood Culture/X-ray/Ultra-

sound/CT/MRI/ECHO/ any specific test (cid:150) Enzyme/ECG/EEG/Suspected Etiology Virus isolation should be done only in Apex Reference Laboratories and only for selected cases by investigating team. B. Specimen Collection Blood(serum) and CSF specimen are to be collected. Blood specimen should be collected within 4 days after onset of illness for isolation of virus and at least 5 days after onset of illness for detection if 1g M antibodies. A second convalescent sample

should be collected 10-14 days after the first sample. Following precautions need to be taken when samples are collected: 1) Blood/Serum i) Equipment required  5ml vacutainer tube(non-heparinized) with 23g needle/5ml syringe with needle  5ml blood collection tube if syringe and needle are used for blood collection  Disposable gloves and face mask  Tourniquet  Sterlized swabs  Sterile serum storage vial  Specimen labels, marker pen  Band aid  Zip lock plastic bags  Lab request form

 Cold box(vaccine carrier) with ice pack  First- aid kit ii) Collection procedure  Collect 5ml blood in a sterile tube labelled with patient identification and date of collection.  Keep at room temperature till clot retracts from serum.  Blood can be stored at 4-8o celsius for 24hrs before serum is separated, do not freeze whole blood. 18

 Transport whole clotted blood specimen to laboratory on ice if it can reach lab in 24 hrs/centrifuge at 1000rpm for 10mins to separate the serum or if centrifuge is not available carefully remove serum with a pipette and transfer serum to a sterile vial and store at 4-8o C. C. Transportation  Specimen should be transported to laboratory as soon as possible, do not wait for collection of additional specimen.  Put specimen in zip pouch/plastic bag with absorbent material(cotton/tissue)

 Use vaccine carrier/thermos flask for transport. In vaccine carrier use frozen packs along the sides and place specimen in the centre. Transport as in reverse cold chain.  Place lab request form in a plastic bag and tape to inside of carrier  Inform the lab about the time and manner of transportation  Transport the serum on wet ice within 48hrs or it can be stored at 4-8o C for 7 days.  If a delay is anticipated sera should be frozen at - 20o C and transported on

frozen ice packs. Repeated freezing and thawing should be avoided as it affects the stability of IgM. Lumbar Puncture & CSF Examination All attempts should be made to collect CSF specimens for confirmation of diagnosis. i) Collection  Lumbar puncture is the most commonly used means of collecting specimen  Patient is positioned on his side with knees curled up to his abdomen, occasionally it is performed with the patient sitting or bent forward.

 Skin is scrubbed and local anesthetic is injected over lower spine. Spinal needle is inserted usually between L3 and L4 vertebrae.  Once the needle is in supra-archnoid space pressure can be measured and fluid is collected. Usually 2-3 ml of fluid is collected in a sterile screw capped bottle.  After sample is collected, the needle is removed and area is cleaned.  Patient is advised to lie flat for 6-8 hrs.  Perform physical examination of CSF, indicate the findings on the laboratory

requisition form and transport to the laboratory as soon as possible. Store at 4 C if delay in processing is anticipated. ii) Storage and Transportation  Store at 4 C as soon as possible after collection and dispatch at the earliest on wet ice in vaccine carrier/thermo flask.  Hands carry the specimen to laboratory preferably due to urgency.  For PCR transport specimen on dry ice.  A designated person should be responsible for storage, packing and transportation as per national guidelines. 19

3.2.9 REHABILITATION  Physiotherapy/ PMR  Advice of Pediatric Neurologist  Correction to fix deformity (cid:150) by Orthopaedic Surgeon  Child Psychologist advice  Various prosthesis  Artificial appliances 3.2.10 REPORTING OF A CASE It is very important to report all the suspected cases of AES or JE to the appropriate health authorities to prevent further spread of disease. It should be reported promptly in enclosed proforma (Annexure A & B). The details should be filled in clear

and neat writing and all the information in the proforma should be provided. 20

Annexure A ACUTE ENCEPHALITIC SYNDROME/ SUSPECTED JE CASE INVESTIGATION FORM EPID Number: AES-________-________-________-________ AESF-4 Reporting Information Date Case Reported: ________/________/________ Notified by : ___________________________ Date Case Investigated: ________/________/________ Investigated by: ___________________________ Patient Information Patient(cid:146)s Name: ________________________________ Sex: _____ Date of Birth : ______/______/_________ Age: years__________ months________

Father(cid:146)s Name:_________________________________ Religion: Muslim / Hindu / Other Address: Landmark: Village / Mohalla: _______________________________ Block / Urban Area: _____________________________ District : ______________________________________ State: ________________ Setting: Urban/ Rural Travel History over past Two Weeks from Onset of First Symptoms Dates of visit Date from : Date to : Address Block District and State Immunization History

JE immunization: Yes / No / Partial / Unknown Date of last JE immunization: ______/______/______ Signs and Symptoms Date of onset of first symptoms:_____/_____/_____ Headache: Yes / No / Unknown Change in mental Status: Yes / No / Unknown Paralysis: Yes / No / Unknown Fever: Yes / No / Unknown Unconsciousness: Yes / No / Unknown Seizure: Yes / No / Unknown Neck rigidity: Yes / No / Unknown Sample collection, tracking and results Date Date Sent Date Condition* Laboratory Result (Circle) Collection Result

CSF Positive Negative Not-tested Unknown Serum 1 Positive Negative Not-tested Unknown Serum 2 Positive Negative Not-tested Unknown Diagnosis and final classification Final Classification: Laboratory confirmed JE / Probable JE / AES unknown / AES other agent Clinical Diagnosis: ___________________________________________ Discharge Status Status at discharge: Alive / Dead / Unknown Date of discharge: ________/________/________ If alive, status of recovery: Recovered completely / Recovered with disability

If died, date of death: _____/_____/_____ *Condition is adequate if specimen is transported in reverse cold chain (Name & Signature) Designation 21

Annexure B JAPANESE ENCEPHALITIS LABORATORY REQUEST AND REPORT FORM AESF-5 Patient Number: Date: / / Patient name: Age: Name of parent of guardian: Province: District: Town/Village: Name of health facility: Number of doses of Japanese Encephalitis Vaccine: Date of last dose: / / Date of onset of illness: Name & address of treating doctors: Clinical Features: SPECIMENT SPECIMEN ID DATE OF COLLECTION DATE OF SHIPMENT TYPE / / / / (1) / / / / (2) / / / / (3)

Name of person to whom laboratory results should be sent: Address: Telephone Number: Fax Number: E-mail: For use by the receiving laboratory: Name of laboratory: Name of person receiving the specimen: Specimen condition*: SPECIMEN DATE DATE RESULT TEST TYPE TEST RESULT Date result to Remarks TYPE RECEIVED IN program/ sender LAB / / / / / / / / / / / / / / / / / / * Sample is good if: If sample is bad specify ? There is no leakage Add in the following information:

? Of adequate quantity Fever at onset: Y N Duration: ? Brought in cold chain Seizures: Y N ? Documentation is complete Altered level of consciousness: Y N Neck rigidity: Y N Any other information: _________________ Source : WHO Draft document operational guidelines (Name & Signature) Designation 22

Chapter-4 4. CLINICAL DIFFERENTIATION OF JE FROM OTHER VIRAL/BACTERIAL/ PARASITIC INFECTIONS JE primarily involves the gray matter of many parts of the Central Nervous System. Differentiation of Encephalitis and Encephalopathy and making a probable etiological diagnosis of Japanese Encephalitis and Epidemic Brain Attack in rural areas, (where facilities are minimum but expectations are maximum), on clinical grounds is extremely important to manage the encephalitis case not only as an individual but also

for the community since the management of JE and EBA call for immediate reporting to the Health Authorities for a wider coordinated intervention by many different departments to contain the epidemic. Epidemics of Viral Encephalitis demand a clinical diagnosis about the causative Virus for controlling the epidemic at the earliest and for asking for the specific test. Simple clinical observations help in assessing the depth of coma, planning

emergency measures necessary to save the child, limit disability, prognosticate and to initiate epidemic control measures. This must be followed by neurological examination for any localizing signs and to plan for the urgent investigations for a final diagnosis. Exclusion of treatable conditions like Cerebral malaria, Epidemic Brain Attack, Meningoencephalitis, Herpes simplex virus encephalitis, Varicella / Zoster encephalitis,

Metabolic causes of encephalopathy, Tuberculous Meningitis is extremely important since they require prompt additional specific treatment. The therapy for JE / Epidemic Brain Attack is primarily conservative and supportive since there is no specific treatment for both Japanese Encephalitis and Epidemic Brain Attack, and both have a high case fatality rate, if prompt medical and nursing care is not provided. Analysis of fatal cases of JE / Epidemic Brain Attack revealed that IGNORANCE

is killing more children than the pathogen per se. Only 1 death out of every 35 deaths is directly due to JEV and all others are preventable with prompt and early management bringing down the USUALLY REPORTED case fatality rate of JE from 35-50% to less than 1%. Similar degree of lowering of morbidity is also possible. Same is the case with Epidemic Brain Attack also. The prognosis of JE depends on the extent of involvement at primary

presentation, timely management and autoimmune mechanisms of this disease. 4.1 Japanese Encephalitis Case Definition: Suspected case for referral to Hospital:- i. Fever ii. Altered Sensorium Viral Encephalitis Syndromic Surveillance: Suspected JE Primary Criteria: i. Epidemic season ii. Acute Fever iii. Altered Sensorium lasting > 6 hours iv. No rash1 23

v. No evidence of any other encephalitis Supportive Criteria i. Focal Neurologic S/S ii. Endemic areas iii. JE Season iv. CSF consistent with Viral Encephalitis v. Normal metabolic Profile Probable JE (cid:149) Encephalitis syndrome (cid:149) CSF consistent with Viral Encephalitis (cid:149) Elevated IgM antibody (cid:149) Stable antibody Confirmed Case: (cid:149) Suspected case plus (cid:149) Any one or more of the following (cid:150) JE IgM in CSF

(cid:150) Or 4 fold or greater rise of antibody titers in paired sera (acute / convalescent) (cid:150) Or detection of virus, antigen or genome in tissue, blood or other body fluids. 4.2 Management in Tertiary Level Hospitals 1. Hypoxia is alleviated by intubation, positive pressure ventilation, and ensuring an arterial Pao of 65 mm Hg or better. 2 2. Hypotension is treated in a stepwise fashion by first volume infusion with isotonic

fluids to normovolemia, next vasopressors and finally treatment is directed at reducing ICP in an effort to maintain CPP greater than 50. 3. Brainstem involvement may necessitate intubation & mechanical ventilation. 4. Cardiac arrest requires resuscitation measures. 5. SIADH (Syndrome of Inappropriate Anti Diuretic Hormone) is treated with Hypertonic saline. 4.3 Doctor(cid:146)s Responsibility during Epidemics 1. Data Questionnaire filling Data Questionnaire Form For Epidemic Encephalitides Name: Age: Sex:

Full Address: 2. Duration of S/S less than 4 days Fever: Y / N Loss of Consciousness / Abnormal behavior: Y/N Abdominal Pain: Y/N Diarrhea: Y/N Rash: Y / N Focal / Asymmetrical Symptoms/Signs: Y / N 24

Chapter-5 5. EQUIPMENTS AND DRUGS AT VARIOUS LEVELS 5.1.1 Essential equipment at the PHC level: 1. Air way Sizes (cid:147)0(cid:148) and (cid:147)1(cid:148), 2. Mucus sucker, 3. Rubber feeding tube of various sizes 4. 5 ml & 2 ml Syringes with needles 5. Thermometer, 6. Adhesive tape 7. Enema set 8. Oxygen 5.1.2 Essential Drugs at the PHC level: 1. Syrup / Injection Paracetamol, 2. Diazepam rectal solution/ Syp. Diazepam/ Inj. Diazepam/Diazepam Suppository. 3. Suspension Valproate, 4. Glucose powder

5.2.1 Essential equipment at the CHC level Hospital: a. Air way Sizes (cid:147)0(cid:148) and (cid:147)1(cid:148), b. Mucus Sucker, c. Rubber feeding tube size 14, d. 5 ml Syringe, e. Thermometer, f. Adhesive tape, g. IV cannula, 22 to 24 , h. Ambu Bag, i. Foley's Catheters of various sizes j. Lumbar Puncture sets k. Provision for Cerebrospinal fluid analysis. l. Enema set 5.2.2 Essential Drugs at the CHC level Hospital: 1. Syrup Paracetamol, 2. Rectal solution or Syrup Diazepam, 3. Suspension Valproate,

4. Syrup Chloral hydrate, 5. Inj Diazepam, 6. Inj Phenytoin, 7. IV fluids N/2, N/5 with 5 % Dextrose, 10% Dextrose, Hypertonic saline, 8. Normal saline, 9. Inj Dexamethasone, 10. Inj Mannitol 20 %, 11. Inj Frusemide, 12. Oral Glycerol 13. Inj Dopamine 14. Inj Phenobarbitone. 15. Vitamins 16. Syrup / Tab Haloperidol 17. Syrup Chloral Hydrate 18. Inj Paraldehyde 19. Inj. Ampicillin 20. Inj. Chloramphenicol. 21. Inj Ceftriaxone. 26

LIST OF THE EXPERTS WHO IMMENSELY CONTRIBUTED IN DEVELOPING THE GUIDELINES ON AES INCLUDING JE 1. Dr. P. Nagabhushna Rao, Ex- Prof. & HOD, Department of Pediatircs, Nelofer Hospital Hyderabad, Andhra Pradesh. 2. Dr. V.K. Gupta, Professor & Head of Deptt. Pediatrics, PGIMER and Associated Dr. Ram Manohar Lohia Hospital, New Delhi. 3. Dr. K.P. Kushwaha, Professor & Head of Deptt. Pediatrics, BRD Medical College, Gorakhpur, Uttar Pradesh.

4. Dr. M.S. Prasad, Professor & Head of Deptt. Pediatrics, VMM. College and Associated Safdarjung Hospital, New Delhi. 5. Dr. Brijesh Kumar, Sr. Pediatrician, Distt. Hospital, Gorakhpur, Uttar Pradesh. 6. Dr. D.K.Patgiri, Prof. Pediatrics, Assam Medical College, Dibrugarh, Assam. 7. Dr. K.S. Anand, Professor & Head of Deptt. Neurology, PGIMER and Associated Dr. RML Hospital, New Delhi. 8. Dr. G.P.S.Dhillon, Director, Dte. of NVBDCP, Delhi. 9. Dr. V.K.Raina, Joint Director, Dte. of NVBDCP, Delhi. 27

slikav National Leprosy Eradication Program Disability Prevention & Medical Rehabilitation Guidelines for Primary, Secondary and Tertiary Level Care Central Leprosy Division Directorate General of Health Services, Ministry of Health & Family Welfare, July 2012 Printed by Novartis Comprehensive Leprosy Care Association, Government of India Mumbai, India as a Scientific Service to Medical & Paramedical Personnel. Nirman Bhavan, New Delhi

Mahatma Gandhi nursing Parchure Shashtri, the great Sanskrit scholar who suffered from leprosy

National Leprosy Eradication Program Disability Prevention & Medical Rehabilitation Guidelines for Primary, Secondary and Tertiary Level Care Central Leprosy Division Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India Nirman Bhavan, New Delhi

Contents Clinical Aspects 11 DPMR Aspects 24 Implementation of DPMR services at Primary level 45 Implementation of DPMR Services at Secondary Level 63 Implementation of DPMR Services at Tertiary Level 77 Annexures of forms 92

Novartis has been in the forefront of the fight against leprosy and has a long-term commitment to leprosy treatment and control that goes back 25 years. Since 2000, Novartis has donated more than 48 million multi-drug therapy blister packs through the World Health Organisation, helping cure over 5 million leprosy patients all over the world. India, with the highest case load, is the largest beneficiary. Leprosy continues to attract stigma due to the ensuing disability that follows delayed treatment

and Novartis has been advocating the cause of these patients through several initiatives in India and elsewhere. India is home to nearly half a million disabled persons afflicted with leprosy. For over two decades now, the Novartis Comprehensive Leprosy Care Association had been actively involved in developing innovative, affordable and sustainable solutions for the problems that affect persons suffering from leprosy. Among these are specially prefabricated splints, self-care kits and

grip-aids that play a contributory role in restoring independence. Reconstructive surgery plays a major role in reinstating the dignity of people impacted by leprosy and minimizing the stigma. Reaching disability prevention and medical rehabilitation to those in need calls for defining the roles and responsibilities of people at all levels of healthcare. The publication of this book on Disability Prevention and Medical Rehabilitation Guidelines is an attempt towards this.

We at Novartis feel humbled that Dr Atul Shah, Director, Novartis Comprehensive Leprosy Care Association, was selected as member of the Committee responsible for revising the guidelines. I would like to thank the Government of India on behalf of all of us at Novartis, the Novartis Foundation for Sustainable Development and the Novartis Comprehensive Leprosy Care Association for recognizing our role in the fight against leprosy and for giving us the opportunity

to publish these guidelines as our contribution in the efforts to eradicate leprosy through the National Leprosy Eradication Program (NLEP). It will always be our endeavor to work jointly with the Government to remove the social stigma associated with this disease. All good wishes Ranjit Shahani June 2012

Introduction NLEP Mile-stones 1952 National Leprosy Eradication Programme (NLEP) is implemented with Dr. Wardekar’s SET pattern for major objectives of reducing the disease burden, preventing disabilities and Survey Education and Treatment to improve awareness about leprosy in the country through general health 1955 care system. National Leprosy Control Program launched Multi Drug Therapy is still considered as most potent drug regimen to reduce

the burden of leprosy by interrupting transmission of disease and curing all 1981 MDT (multidrug therapy) registered cases of leprosy and making them released from treatment within recommended by World Health shortest possible time. India has achieved the milestone of leprosy elimination Organisation as cure since Dec. 2005 with wider use of MDT. But still a considerable numbers 1983 of new cases are being detected every year with disability and deformity. National Leprosy Eradication

There also exists large number of cases who have completed the full course Program launched of MDT but have got different types of deformities and disability due to 1991 consequences of permanent nerve damage. Amongst the leprosy cured there World Health Assembly adopts are some of them though presently do not have any deformity but may resolution to eliminate leprosy by develop same due to negligence in taking care of their anesthetics eye, hand the year 2000. Elimination was

or feet. As now the vertical program has been integrated into general health defined by WHO as prevalence of less than 1 per 10,000 population care system, it has become the responsibility of general health care system not only to ensure early case detection and provide regular MDT but also 1993 carry out all the activities required to prevent disability and provide medical World Bank assisted the NLEP rehabilitative services to patients who require those. 2004 Leprosy integrated with GHS

Presently the leprosy services like diagnosis & multi drug therapy, drug (general Health Service) procurement and simplified information system have been well established in 2005 general health care system starting from sub center to district HQ hospitals Leprosy ‘elimination’ achieved at and tertiary health care institutions. The disability prevention and medical the National level in India rehabilitation services are comprehensive care to be provided to all old and 2006

new disability cases of leprosy so that they will not worsen their condition. DPMR introduced as a It is estimated that around one million leprosy patients with disabilities component of NLEP exist in the country. There will be an average of 2000 to 3000 cured leprosy 2007 patients with disabilities living in a district. To institute care for individual Disability Prevention & Medical leprosy patients with disabilities, it is essential to identify each patient having Rehabilitation Guidelines for

disability / deformity due to leprosy and motivate them to avail services primary, secondary and tertiary level distributed by NLEP at nearest CHC. Block CHC will be identified as first referral center for provision of DPMR services. 2011 Guidelines on DPMR for It is felt that prevention of deformities and disabilities need to be given higher NLEP revised emphasis during the 12th Five Year Plan period (2012-2017). Operational Guidelines National Leprosy for DPMR Eradication Program 9

New Goal by WHO The DPMR activities are planned to be carried out in a three-tier system i.e. the Primary level care (First level), Secondary level care (Second level) To decrease the rate of disabilities and the Tertiary level care institutions (Third level). The Primary level care in new cases among 10 lacs are going to be started from village or community level to Community population by 35% with compare to the base line of 2010. Health Center (CHC) level in rural areas, Sub-Divisional Hospitals and

Urban Leprosy Centers /dispensaries in the urban areas. DPMR OPD/ clinic New Indicator will be established at CHC and sub-divisional hospitals by trained leprosy paramedical worker under the guidance of MO in charge. OPD/clinic will To decrease the visible disabilities function daily during the normal OPD timing within the premises of health to less than 1 per 10,000,00 population in the community by institution. Secondary level care centers include district hospitals and district

2020. nucleus team. At some places secondary level care is available in the NGO supported leprosy units. The tertiary level refers to few centers of excellence where complicated cases can be referred from primary or secondary level. Besides, tertiary care for management of deformities is available at medical colleges and RCS centers recognized by Government of India. It is important to remember that the important factor for continuing stigma

is the deformities. It is not necessary that disability means patient has visible deformity for example inability to feel hot and cold due to anesthesia is a disability without any visible deformity. In the same way medical fraternity believes any therapy whether medical or surgical which is able to prevent the occurrence of disability or recovery in sensation or motor power is termed as ‘Disability prevention’. However, general health services in broad

definition of POD, also includes measures to prevent the worsening of existing disability or deformity and prevention of secondary impairments like joint contractures in claw hand or ulcer occurring in an anesthetic foot. Thus, offering MCR (microcellular footwear) is considered a modality for disability prevention. Care at all levels needs to look at not only healing of the ulcer but also prevent recurrence. These operational guidelines which follow are expected to guide different

health personnel, community level functionaries, people affected with leprosy (PAL) and also tertiary care institutions to play their role in disability prevention, correction and care for all leprosy affected persons. National Leprosy Operational Guidelines 10 Eradication Program for DPMR

are generally multi-bacillary with positive skin smears. They represent what is called as the ‘leprosy of consequence’ as they transmit the disease before adequate treatment is initiated. In such cases slit skin smear examination will Doubtful leprosy case help in confirmation of diagnosis. On the other hand some of the cases of leprosy manifest with thickening or enlargement of peripheral nerves with Clinical examination sensory or motor impairment along the course of affected nerves. Careful

Elicit cardinal signs of leprosy sensory motor testing in the area supplied by the thickened nerve will help in confirmation of the diagnosis. Sometimes, electrophysiological studies or Skin smears nerve biopsy may be indicated to rule out other causes. If patch - skin biopsy from the patch In cases presenting with planter ulcer, anaesthesia without any other evidence of leprosy must be examined carefully with detailed history and investigations Nerve conduction velocity

for spinal lesions like meningomyelocoele in childhood or spina bifida etc. If nerve thickening - Similarly, in cases presenting with deformities without nerve thickening or nerve biopsy from the not definite sensory loss, differential diagnosis will need to be carried out radial cutaneous or sural nerve with other conditions like trauma, other type of palsy etc. in mind. Definite and ask for nerve staining result, electron microscopy and PCR

confirmation of leprosy may need Nerve Conduction Study, skin or nerve biopsy and PCR technique to detect leprosy infection in certain difficult to Aspiration cytology of nodules diagnose cases. and lymph glands if any Sometimes hypo-pigmented lesions on face and no enlarged nerves (indeterminate leprosy) especially in children with no definite loss of sensation are referred for confirmation; such cases may be kept under

observation and treated with antifungal ointment or vitamin deficiencies Some Differential Diagnosis meanwhile. However, if there are suspicious signs such as nodules or swelling on the face or earlobes, redness or infiltration in the patch, it is Vitiligo important to do a skin smear to confirm the diagnosis of leprosy. The positive Tinea Versicolor Pityriasis Alba report will establish the diagnosis while a negative report in the absence of Nutritional dyschromia

other cardinal signs would rule out leprosy. Enlargement of cutaneous nerves Herpes Zoster like great auricular nerve, supraorabital or supratrochlear nerves may also Lupus Vulgaris help clinician to diagnose leprosy in patient having facial lesion. When in Granuloma annulare doubt, histopathological examination of lesion will help in establishing Psoriasis alternative diagnosis. Post-Kalaazar Dermal Leishmaniasis Neurofibromatosis Operational Guidelines National Leprosy for DPMR Eradication Program 11

the patient identification (ID) number at the bottom of the slide. This number  Gloves must be on the request form. Collection of smear Clean the skin at the smear sites with a cotton wad drenched in alcohol or spirit. Allow it to dry. Light the spirit burner. Put a new blade on the scalpel handle. If you put the scalpel down, make sure the blade does not touch anything. Pinch the skin firmly between your thumb and forefinger; maintain pressure to press out the blood.

Make an incision in the skin about 5 mm long and 2 mm deep. Keep on pinching to make sure the cut remains bloodless. If bleeding, wipe the blood with cotton wad. Turn the scalpel 90 degrees and hold it at a right angle to the cut. Scrape inside the cut once or twice with the side of the scalpel, to collect tissue fluid and pulp. There should be no blood in the specimen, as this may interfere with staining and reading. Stop pinching the skin and

absorb any bleeding with a wad of cotton. Seal the cut site with Tr. Benzoin Spread the material scraped from the incision onto the slide, on the same side as the ID number. Spread it evenly with the flat of the scalpel, making a circle 8 mm in diameter. Rub the scalpel with a cotton wad drenched in alcohol. Pass the blade through the flame of the spirit burner for 3 to 4 seconds. Let it cool without touching anything. Repeat the steps above for the second

site. Spread this smear next to, but not touching, the first one. Discard the scalpel blade safely. Thank the patient. National Leprosy Operational Guidelines 12 Eradication Program for DPMR

Fixation of smear on slide Let the slide dry for 15 minutes at room temperature, but not in direct sunlight. Fix the smears by passing the slide, with the smears upwards, slowly through the flame of a spirit burner, 3 times. Do not overheat. The slide should not be too hot to touch. Put the slide in a slide box & send to the laboratory with the skin smear request form. Step 2: Staining the smear (Ziel-Neilson Technique) Filter the 1% carbol fuchsin solution through ordinary filter paper. Cover

the whole slide with 1% carbol fuchsin solution. Heat the slide gently by holding a burning spirit lamp underneath it until vapour begins to rise from Bacteriological Index (BI) the carbol fuchsin. Repeat this 3 times during a period of 5 minutes. Make 0, No bacilli seen in 100 fields sure the stain does not boil. If the stain dries, add some more reagent and 1+, 1 to 10 bacilli in 100 fields heat again. Wash gently under a running tap. Rinse until the run-off water

is colourless, although the smears will remain dark red. Register the slide in 2+, 1 to 10 bacilli in 10 fields the lab register. 3+, 1 to 10 bacilli, in each field Put the slide on the staining rack with the smeared side upwards. Up to 4+, 10 to 100 bacilli, in each field 10 slides can be stained together. Make sure that the slides do not touch 5+, 100 to 1000 bacilli, in each one another. field 6+,>1000 bacilli, in each field Decolorising:

Cover the smear with 1% acid-alcohol for 10 seconds. An alternative method is to cover with 5% sulphuric acid for 10 minutes. Rinse gently with water. Counter-Staining: Cover with 0.2% methylene blue for 1 minute. Rinse with water, and let the slide dry in the drying rack in an inclined position, with the smeared side downwards. The slide is now ready to be read. Step 3: Microscopic Examination Look for the presence of acid-fast bacilli under oil immersion lens. They

appear as fine red rods against a blue background. They can be straight or curved, and the red colour can be uniformly distributed (solid bacilli) or unevenly distributed (fragmented and granulated bacilli). Clumps of bacilli are called globi. Solid bacilli may suggest the presence of viable organisms and may be seen in new, untreated cases or in relapse cases. After examining the first field, move to the next field. Examine approximately 100 fields per smear. Operational Guidelines National Leprosy

Note on reading the skin smears You need a microscope with a 10x eye piece and 10x and 100x objectives. Start the examination using the 10x objective. If acid-fast bacilli are seen, quantify them according to the following scale for the Bacteriological Index (BI). Calculate the BI for each smear separately. The bacilli may be in the following forms solids, globi, fragmented & granular. Write the result of Microscopic Examination both smears in the lab register. Give the result in the referral slips. Report

Procedure the BI for both smears on the slide. For smear positive patients, the average  Put the slide under the BI will be taken as the BI for that patient. microscope with the smears upwards and the ID number Rinse the slide in xylene. Do not wipe it. Store the slide in a slide box for to the left. future quality control. Slides that are not kept for quality control should  Focus the image using the be destroyed, or disinfected, boiled and washed for re-use in routine 10x objective.

examinations (of stool or urine, for example). Slides should not be re-used  Put a drop of immersion oil for other skin smears or for sputum examinations. on the smear.  Switch to the 100x objective Histopathology of skin or nerve biopsy to touch the immersion oil (if necessary, move the Some cases may need investigations to confirm the diagnosis of leprosy coarse adjustment screw to or confirmation of relapse. Punch (5 mm) biopsy or incision biopsy for make sure that oil immersion

histopathological examination may help in reaching the conclusion if analyzed lens touches the oil). along with clinical criteria. Specimen is taken from just inside the edge of  Open the diaphragm the lesion / cutaneous branch of peripheral nerve under suspected lesion and completely and raise the processed. condenser to its highest position. The common nerve for biopsy includes the index branch of radial cutaneous

 Focus precisely with the fine nerve and sural nerve unless any other superficial sensory nerve is affected. adjustment screw. It is examined under microscope after proper staining with Fite Faracco stain. Presence of lepra bacilli in or around the nerve is diagnostic, but only granuloma or infiltration without support of clinical signs may mislead. It is probably advisable to give preference to the clinical presentation over the histological picture if the two are at variance, a situation that is not

uncommon. Fine Needle Aspiration Cytology (FNAC) from the lymph glands is usually helpful if patient is in suspected lepra reaction type 2. Radiological examinations X-rays are helpful in diagnosing osteoporosis, fractures of small bones, absorption of bones, sequestra. Ultrasonography of nerve trunks or internal organs e.g. testes, reticulo-endothelial organs may help in judging the diagnosis and prognosis of complicated cases. National Leprosy Operational Guidelines 14 Eradication Program for DPMR

Treatment The standard adult treatment regimen for MB leprosy is: Rifampicin..................600 mg once a month Clofazimine................300 mg once a month, and 50 mg daily Dapsone.....................100 mg daily Duration : 12 months (12 blister packs) The standard adult treatment regimen for PB leprosy is: Rifampicin..................600 mg once a month Dapsone.....................100 mg daily Duration : 6 months (6 blister packs) The standard child (ages 10 - 14) treatment regimen for

MB leprosy is: Rifampicin..................450 mg once a month Clofazimine................150 mg once a month, and 50 mg every other day Dapsone.....................50 mg daily Duration : 12 months (12 blister packs) The standard child (ages 10 - 14) treatment regimen for PB leprosy is: Rifampicin..................450 mg once a month Dapsone.....................50 mg daily Duration : six months (six blister packs) The appropriate dose for children under 10 years of age can be decided on

the basis of body weight. [Rifampicin: 10 mg per kilogram body weight, clofazimine: 1 mg per kilogram per body weight daily and 6 mg per kilogram monthly, dapsone: 2 mg per kilogram body weight daily. The standard child blister pack may be broken up so that the appropriate dose is given to children under 10 years of age. Clofazimine can be spaced out as required.] Rarely, it may be considered advisable to treat a patient with a high bacillary

index (BI) for more than 12 months. This decision may only be taken by specialists at referral unit after careful consideration of the clinical and bacteriological evidence. Operational Guidelines National Leprosy for DPMR Eradication Program 15

Treatment of complicated cases Treatment Type of Leprosy Paucibacillary Multibacillary Number of 1-5 / 1 >5 / >1 lesions / nerve trunk affected Bl according to Negative Positive the Ridley scale Regimen Daily: Dapsone 100 mg Daily: Dapsone 100 mg Once monthly supervised: Once monthly Rifampicin 600 mg supervised: Rifampicin 600 mg Clofazimine Lamprene 300 mg Duration of 6 blister packs 12 blister packs treatment Adverse reactions to MDT

MDT is remarkably safe and serious adverse effects are very rare. Generally the following problems are seen with MDT. Minor problems Drug Management Red urine Rifampicin Reassurance Brown discoloration of the Clofazimine Counseling skin Gastro-intestinal upset All three Give drugs with food Anaemia Dapsone Give iron and folic acid More serious problems Drug Management Itchy skin, rash, Steven Dapsone Jhonson Syndrome Dapsone or Stop the drugs and Allergy, urticaria Rifampicin consider alternative regimen

Jaundice Rifampicin Shock, purpura, renal failure Rifampicin National Leprosy Operational Guidelines 16 Eradication Program for DPMR

Dapsone poisoning Case should be hospitalized, gastric lavage is done and oxygen is started. Vital functions are assessed, if there is need 1% Methylene blue is given in doses of 2 mg per kg body weight. Activated Charcoal 25 mg 8 hrly is given orally. Ascorbic acid 500 mg hrly may be added. Detailed clinical assessment is required frequently. Laboratory aids maybe asked to assess Hepato-renal functions. Side effects of steroid therapy Common side effect of steroid is “moon face” (secondary Cushingoid

Syndrome) which disappear with decreasing/stopping steroids. Gastric ulcer, secondary infections, fungal infections, osteoporosis, secondary cataract or any other complication of Prednisolone therapy should be managed without delay. Internal medical conditions Chronic untreated leprosy (fortunately no longer seen) and chronic ENL reactions (still a serious complication in a small proportion of patients) may lead to internal medical complications. Such patients need referral to the appropriate specialists.

Psycho-social problems Psycho-social problems are related to widely-held beliefs and prejudices concerning leprosy and its underlying causes, not just to the problem of disability. People with leprosy often develop self-stigma, low self-esteem and depression, as a result of rejection and hostility of family and community members. Such negative attitudes are found also among staff in the health services, including doctors. These need to be addressed with counseling.

People with psycho-social problems may also need to be referred for counseling or other help. Operational Guidelines National Leprosy for DPMR Eradication Program 17

Reactions in Leprosy There are two types of reactions – Reversal Reaction (or Type 1) and Erythema Nodosum Leprosum (ENL or Type 2). Both the types of reactions can occur before the start of treatment, during treatment, or after the treatment has been completed. Both types can be divided into mild or severe. If the peripheral nerves or eyes are affected the reaction is to be considered severe. Lepra reactions are usually diagnosed by clinical examination only; however

few patients may require further investigations. Inflammatory changes in skin lesions or appearance of new lesions, patches or nodules with acute onset, draw the attention of the patient to report. Some cases develop signs of nerve damage (neuritis) without the obvious changes in skin lesions. Occasionally some cases may develop silent neuritis or quiet nerve paralysis which needs to be managed with care and follow up with proper sensory motor records. Differentiating features of two types of reactions

Distinguishing between the two types of reactions is usually not difficult. In reversal reaction, the leprosy skin lesion themselves become inflamed, red and swollen whereas, in an ENL reaction, crops of subcutaneous tender nodules, usually symmetrical (about 1 - 2 cm across) appear under the skin of the limbs or trunk, while the original leprosy skin patches remain as they were. ENL reactions cause a general feeling of fever and malaise, while reversal

reactions cause less systemic upset. The common differentiating features are given in the table below. Type 1 (Reversal Reaction) Type II (ENL) 1. Delayed hypersensitivity 1. Antigen antibody reaction 2. Occurs in both PB and MB type of cases (Borderline 2. Seen in MB cases only (BL & LL type) group) i.e. in unstable types like BT.BB.BL. 3. Skin lesions suddenly become reddish, swollen, 3. Red, painful, tender, sub cutaneous nodules (deep) ENL may

warm, painful, and tender. New lesions may appear. appear commonly on face, arms, legs, bilateral symmetrically. They appear in groups and subside within few days even without treatment (Evanescent skin nodules). Nodules are better felt than seen and these are recurrent (episodic) 4. Nerves close to skin may be enlarged, tender and 4. Nerves may be affected but not as common or severe as in painful (neuritis) with loss of nerve function (loss of Type 1 sensation and muscle weakness) and may appear

suddenly or rapidly. 5. Other organs - Not affected 5. Other organs like eyes, testis, and kidneys may be affected 6. General symptoms - Not common 6. Fever, joints pain, red eyes with watering National Leprosy Operational Guidelines 18 Eradication Program for DPMR

Severe reversal reactions should be treated with a course of steroids, usually lasting 3 – 6 months. There are a number of important side-effects associated with steroids, so a careful assessment must be made of any patient who requires them. Signs of an ENL reaction If any of the following signs is found, the reaction should be treated as severe:  Pain or tenderness in one or more nerves, with or without loss of nerve function  Ulceration of ENL nodules

Treatment of ENL It includes Prednisolone, bed rest, and rest to the affected nerves by splint and analgesics. For neuritis, treatment with Prednisolone should be prolonged to four weeks from 20 mg onwards. Prednisolone is given in the Prednisolone tablets given should be entered in the ‘Prednisolone Card’. following regime Tapering of Prednisolone may be done according to its response. Its intake  Start tablet prednisolone on empty stomach and salt restricted diet during its course should be insisted

(dose at 1mg / kg body upon to minimise the side effects. Any adverse effect or complication such as wt / day) is given as a malena, gastric ulcer, secondary infection in ulcer or lungs, fungal infection single morning dose after in body folds should be detected & treated as early as possible. breakfast (consider giving tab ranitidine 150 mg along Added Clofazimine for Type 2 reactions may be extremely useful for reducing with prednisolone).

or withdrawing corticosteroids in patients who have become dependent  After the reaction / on them; though it is less potent than steroids and often takes 4-6 weeks inflammation is controlled, to develop its full effect. Total duration of Clofazimine therapy should not prednisolone is tapered by 10 mg, fortnightly till the exceed 12 months. dose of 20 mg / day. Cases of lepra reaction, where Prednisolone is contraindicated or ineffective  Thereafter prednisolone

may be put on alternative drugs such as Thalidomide. It is an effective is tapered by 5 mg / day, drug in the treatment of severe ENL in leprosy. It has serious teratogenic fortnightly till withdrawal. risks. The risks of teratogenic effects must be balanced against the benefits Clofazimine is given in the of Thalidomide in treating severe, disabling and potential life threatening following regime ENL. Thalidomide should be considered for the treatment of severe ENL

 One capsule (100 mg) reaction at tertiary level only when the use of steroids is contraindicated or 3 times a day x 4 or more non-effective. Each patient selected for thalidomide therapy should give an weeks (depending on the informed consent after explanation of all the risks and benefits. Thalidomide response) then is started at 200 mg twice daily or 100 mg four times daily and ENL is usually  One capsule (100 mg) controlled within 72 hours and the dose can then gradually be tapered off.

2 times a day x next Maintenance dose of 50-100 mg daily may be required for prolonged period 4 - 12 weeks, followed by in some cases. Thalidomide must be administered under the strictest possible  One capsule (100 mg) once supervision. a day x next 4 - 12 weeks or more If a patient develops lepra reaction during the treatment, do not stop MDT (rather complete the course of MDT). Lepra reactions, which occur after completion of treatment, should also be managed as mentioned earlier. MDT

should not be restarted for such cases. National Leprosy Operational Guidelines 20 Eradication Program for DPMR

Steroid therapy – precautions There are many side effects of steroids. Advice everyone receiving steroids that the drugs may have side effects, and advise them to report any unusual symptoms to their health worker as soon as possible, so that further complications can be prevented. Follow-up after treatment with steroids People who have been given a course of steroids for reaction or nerve damage should be followed up closely because of the risk or recurrence. Each person

must understand that a reaction or new nerve damage may recur. They must know to recognize the early signs of nerve damage and be aware of how important it is to return promptly to the clinic for treatment. These signs include pain or tingling sensations, further loss of feeling or loss of muscle strength and inability to close the eye. People still on MDT should have their nerve function checked monthly by the health worker when they come to collect their treatment. Any deterioration

should be noted and the person referred. People who have already completed MDT by the time they come to the end of a course of steroids should be asked to come back three months and six months after the end of the course for review and nerve function assessment. People who still have lagophthalmos (weakness of eyelids) after completion of treatment with steroids should be considered for reconstructive surgery. Groups requiring special precautions when prescribing steroids

The following groups of people require special precautions when steroids are required. One must not give steroids to people with tuberculosis, diabetes, deep ulcers, osteomyelitis, corneal ulcer or other serious conditions without starting treatment for the underlying condition. Pregnant women All pregnant women should be treated at referral level, so as to minimize the steroid dose they are given and thus avoid harmful effects, such as growth

retardation, on the foetus. If steroids are given in the third trimester, this may cause adrenal suppression in the newborn infant; ideally, such infants should be monitored in a referral centre for a few days after birth. The doses of Prednisolone prescribed during pregnancy may be: In both PB and MB cases, start at 30 mg daily instead of 40 mg and limit the course to ten weeks rather than the normal twelve. In MB cases, starting at 30 mg daily but lasting for twenty weeks.

Operational Guidelines National Leprosy for DPMR Eradication Program 21

Children To minimize the effects of steroids on their growth, children can be given a course similar to that for pregnant women, but the starting dose of Prednisolone should not exceed 1 mg per kilogram of body weight per day. If it can be arranged, giving children steroids on alternate days may reduce the effect on their growth. A suitable regimen for PB cases would be 30 mg of Prednisolone daily for two weeks, then 30 mg on alternate days for two

weeks, with a gradually reducing dose over the total course of ten weeks. For MB cases, one should double the duration of each stage of the course. Tuberculosis If you suspect that a person has tuberculosis, the diagnosis must be confirmed and treatment started before giving steroids. A sputum specimen should be examined for acid-fast bacilli. If tuberculosis is diagnosed, Steroids can be stared as soon as effective anti-TB treatment is begun; always follow the

national guidelines for the diagnosis and treatment of tuberculosis. Diabetes People who show symptoms that suggest diabetes or whose urine tests positive for glucose should be referred to confirm whether the diagnosis is correct and, if it is, for management of the condition. Steroids may increase the diabetic’s requirement for insulin. A person taking steroids may also develop diabetes for the first time; this possibility must be considered when people develop typical symptoms of

diabetes during treatment with steroids – these symptoms include excessive thirst, increased urination and fluid intake. If sugar is found in the urine, serial blood sugar examinations must be made, firstly to establish the diagnosis and then to monitor the response to treatment. Insulin may be required in the first instance, but the condition usually resolves itself when steroids are stopped. National Leprosy Operational Guidelines 22 Eradication Program for DPMR

Relapse Relapse is defined as the re-occurrence of the disease at any time after the completion of a full course of treatment. MDT is a very effective treatment for leprosy. If a full course of treatment has been taken properly, relapse is generally rare. Relapse is indicated by the appearance of new skin lesions and, in the case of an MB relapse, by evidence on a skin smear of an increase in BI of 2 or more units. Fortunately, the use of a combination of drugs has

prevented the development of drug resistance in leprosy, so relapse cases can be treated effectively with the same drug regimen – MDT. It is difficult to be certain that a relapse has occurred, as new lesions may appear in leprosy reactions also. A reaction may be treated with steroids, while a relapse will not be greatly affected by a course of steroids, so using steroids as a ‘therapeutic trial’ can clarify the diagnosis. Various criteria may help in distinguishing a relapse from a reaction:

Criteria Relapse Reaction Time since completion of Usually more than Usually less than treatment 3 years 3 years Progression of signs and Slow Fast symptoms Site of skin lesions In new places Over old patches Pain, tenderness or swelling No Yes - skin & nerves Damage Occurs slowly Sudden onset General condition Not affected Operational Guidelines National Leprosy for DPMR Eradication Program 23

DPMR ASPECTS Nomenclature and Management of Nerve Impairment definitions A patient may present with complaints such as loss of sensations or dryness Anaesthesia / hypoaesthesia or weakness in the limbs. He may also present with thickening of the nerve It is the complete or partial trunk without any symptom/sign or acute neuritis i.e. painful, tender and impairment of sensation over thickened one or more nerves or chronic neuritis where pain and tenderness the skin to touch, pain and

temperature. is less prominent but damage to the nerve gradually increases to complete nerve destruction i.e. complete paralysis for more than one year (fibrosed Impairment nerve, “cord like” on palpation). It is the loss or abnormality of anatomical or physiological Examination of important nerves of the face and the neck structure or function. Commonly affected nerves in the face are Trigeminal nerve and Facial Deformity

Deformity is the visible alteration nerve. Besides these, thickening of greater auricular nerve, supra-orbital and in the form, shape or appearance supra-trochlear nerve can also be noted. of the body due to impairment produced by the disease process. Trigeminal nerve Disability Sensory part of the trigeminal nerve supplies the conjunctiva and cornea and It is any restriction or lack of part of the facial skin. Most important effect of involvement of the trigeminal

ability (resulting from impairment) nerve is reduced or loss of sensation of cornea and affects blinking of the to perform an activity considered eye. Hence, irregular/infrequent/absent blinking indicates involvement of normal for a human being. trigeminal nerve. Handicap Handicap is the disadvantage for Supraorbital and supratrochlear nerves a given individual resulting from Supraorbital and supratrochlear nerves are cutaneous branches of the an impairment or disability that

trigeminal nerve that may become visibly thickened and can be palpated by limits or prevents fulfillment of a passing the finger along the upper border of the orbit. role that is normal depending on the patient’s age and sex as well Facial nerve as relevant social and cultural factors. Facial nerve is purely a motor nerve and supplies various muscles of De-habilitation the face including orbicularis oculi. There is no sensation loss due to its

It is the progressive loss of social involvement. Paralysis of facial nerve in leprosy is of lower motor neuron status and isolation from the type affecting the muscles of half of the face on the same side with loss of society. creases and expressions. Face becomes flat and angle of mouth is pulled Destitution towards the normal side. Weakness/paralysis of orbicularis oculi is important It is the final stage of social because it affects the closure of the eyelid. Inability to close the eye is called

isolation without food or shelter. ‘Lagophthalmos’ and has grave consequences leading to blindness. Greater Auricular nerve National Leprosy Operational Guidelines 24 Eradication Program for DPMR

The nerve innervates skin of angle of the mandible and parotid area and can become visibly enlarged. It is visible on the side of the neck, below the ear, crossing the upper third of the sternomastoid muscle, lying parallel to the external jugular vein. To palpate the nerve ask the person to turn head to opposite side so as to tighten the sternomastoid muscle. Nerve is seen crossing the upper third of the muscle lying parallel to the external jugular vein. Examination of nerves of the upper limb

While examining the peripheral nerves look for the autonomic function of the nerve, dryness, crack, callosities, atrophy of muscles, deformities and any other secondary impairments like blisters or burns and ulcers. Ulnar nerve Ulnar nerve in leprosy is affected at the elbow and can be palpated in the olecranon groove, just above and behind medial epicondyle of the elbow. Its affection causes sensory loss on palmar aspect of little finger and medial

half of ring finger. The motor loss causes atrophy of hypothenar eminence, weakness in little finger in bringing it out or bent finger which is called clawing. It can also be tested by asking the person to move the little finger sideways or out i.e. away from the other fingers in the same plane as palm and noting the resistance against your finger. Long duration paralysis causes typical claw hand deformity, characterised by hyperextension at the metacarpophalangeal joint and flexion at the proximal

interphalangeal joint. Median nerve Median nerve is affected at wrist as it passes in the carpet tunnel under the flexor retinaculum of the hand and is palpable (with experience) proximal to the wrist, deep and medial to Palmaris longus tendon, when the wrist joint is semi flexed. Its affection cause loss of sensations on the palmar aspect of lateral three and a half fingers i.e. thumb, index, middle finger and lateral half of ring finger and corresponding part of the palm. The motor paralysis

cause flattening of the thenar eminence and also clawing of index and middle finger and/or Ape thumb deformity in which thumb lie in the plane of the palm and cannot be abducted. Paralysis of the median nerve is usually associated with that of the ulnar nerve resulting in complete claw hand. Radial nerve Operational Guidelines National Leprosy for DPMR Eradication Program 25

Radial nerve has two parts. The main nerve in the arm supplies the muscles at the back of the forearm and superficial cutaneous branch of radial nerve supplies the small part of the skin on the back of the hand. Superficial nerve is commonly affected in leprosy. Main trunk is only occasionally affected and is palpable in the oblique groove posterior to the insertion of deltoid muscle in the arm. Damage to the main nerve trunk causes disability because muscle balance of

all the joints of the hand i.e. wrist, fingers and thumbs, is disturbed. Sensory loss in the area of supply of radial nerve does not indicate involvement of main nerve trunk. Radial cutaneous nerve branches out early from the main nerve. Hence, thickening of this branch may not be associated with muscle weakness. Thickened radial cutaneus nerve can be seen or palpated occasionally at the lateral part of the wrist / back of the hand.

Radial nerve trunk supplies the muscle in the back of the forearm that extends Sites of nerve involvement the wrist, fingers and thumb. Person is unable to use the hand or extend the wrist, fingers and thumb. The high radial paralysis cause wrist drop deformity. It can be easily tested by asking patient to extend the wrist against resistance which he cannot do, followed by testing for the finger and thumb extension. Nerves of the lower limb

Most commonly affected nerves in the lower limb in leprosy are lateral popliteal nerve which is a branch of common peroneal nerve and the posterior tibial nerve which is a branch of the tibial nerve. Lateral popliteal nerve The lateral popliteal nerve (a branch of common peroneal nerve) gets affected at the knee, precisely behind the neck of the fibula on the lateral aspect of the leg. During early stages of involvement, patient may complain that big toe

gets in way while walking, and may find running difficult, due to weakness of big toe. Later, it may cause foot drop deformity in which foot is unable to dorsiflex the ankle. Its sensory supply extends on the dorsum to 1st web space. This fact is taken advantage in the surgical aspect for designing the neurovascular island pedicle flap to resurface the ulcers in the 1st metatarsal National Leprosy Operational Guidelines 26 Eradication Program for DPMR

region. Voluntary Muscle Test (VMT) for each nerve to detect nerve damage at early stage is tabulated as below- Facial nerve Ask patient to close eyes lightly, as during sleep, & check for lid gap. A gap of + 1 mm may be normal. Record the gap in millimeters on the form. To test for early weakness, ask the patient to close the eyes tightly and try to separate the eyelid with your thumb and index finger. Do not use excessive force! Ulnar nerve Ask patient to abduct the little finger & apply

resistance at the base of the little finger (“little finger out”). Record the strength. Median nerve Ask patient to hold the hand flat in a horizontal position and abduct the thumb (point upwards at 90 degrees “thumb up”). Resistance is applied at the head of the 1st Metacarpal towards the index finger. Wrist should be slightly extended. Radial nerve Ask patient to extend the wrist (“wrist up”). Apply assistance on the dorsum of hand. Lateral popliteal Ask patient to lift the foot (“foot up”). Apply

nerve assistance on the dorsum of foot. Posterior Tibial nerve Posterior tibial nerve is palpable at a site just below and behind the medial malleolus, approximately at the midpoint between medial malleolus and heel. This nerve supplies the skin of the entire sole. Posterior tibial nerve involvement does not experience any noticeable disability in the early stages. Later it produces claw toes and plantar anaesthesia, a major cause of

secondary disabilities like anesthetic foot with plantar ulcers. Nerve supplies the small muscles of the foot and there may not be any noticeable disability due to involvement of this nerve. However, spreading of toes can be tested. The test to detect early muscle weakness The muscle power of both hands and feet are categorized as: Steroids, whether taken by mouth S = Strong, W = Weak and P = Paralysed or locally applied, may make the

Cases with Grade – 0 disability who are at risk of developing disability are eye conditions worse. Therefore, those who have thickened nerves, positive skin smear, impairment of vision, never use steroids unless early nerve damage, skin lesions over / near trunk, puberty, pregnancy, on prescribed by a medical doctor. hormonal therapy. The findings of the examination are first noted in the Disability Assessment Form (form P-II) by PMW separately for right and left eyes, hands and feet.

Thereafter each eye, each hand and each foot is given its own grade. Operational Guidelines National Leprosy for DPMR Eradication Program 27

Eye involvement People who have corneal damage or iritis (denoted by red eye, pain or photophobia) should be referred for specialist diagnosis and management at a centre properly equipped for eye care. Corneal ulcers and keratitis are inflammatory conditions of the cornea. They are often caused by exposure, as a result of the person being unable to close the eye properly: there is pain, redness and often some loss of vision. The treatment usually consists of local

antibiotics, sometimes with a pad to keep the eye closed. Iritis, uveitis, iridocyclitis and scleritis are all types of inflammation inside the eye and they can all occur as part of a Type 2 reaction. These conditions cause pain, redness, photophobia and loss of vision, although the symptoms are not always severe. The treatment includes atropine eye ointment to prevent adhesion. Lagophthalmos The muscles which close the eye can become weak or paralyzed, if the facial

nerve is damaged in a leprosy reaction. The result is that the eye cannot close properly. There may be watering of the eye. Sometimes there is loss of sensation in the cornea (the clear part at the front of the eye) also, which leads to loss of normal blinking. In the early stages, lagophthalmos can be treated like any other case of neuritis, with steroids. When the condition is permanent, surgery to the eyelids may help to prevent corneal damage. Regular blinking and complete closure

of the eyes at night keep the cornea healthy. In lagophthalmos, the cornea is at risk of damage which makes it less and less transparent. Blindness is a common end result. When there is such inability that on closure of the eyelid cornea remains exposed, it is considered as severe lagophthalmos threatening further damage and needs to be treated on urgent basis. Patient is taught forced closure in mild case and closure by pulling the lateral angle of the

eyelid skin in severe cases. All people who are unable to close their eyes, or who do not blink should wear glasses. National Leprosy Operational Guidelines 28 Eradication Program for DPMR

Mild Lagophthalmos: When asked to close eyes lightly the person has a slight gap (< 6 mm) between the eye lids. In such cases ask the person to try and close their eyes with force. If the face muscles are still strong enough, the person will be able to close the gap. They should keep the eye forced closed while counting to 10. They should do this exercise as often as possible every day. Severe Lagophthalmos: When asked to close eyes lightly the person has a large gap (> 6 mm) or sign

of exposure Keratitis between the eye lids. In such cases, ask the person to try and close their eyes with force. Sometimes the face muscles are too weak to force the eyes closed. If the person still has a gap between the eye lids, they will need to do passive exercises to prevent the deformity from worsening and help keep the eye as healthy as possible. When eyes cannot be closed fully, the person should place their fingers at the outer corner of the eye and

gently pull outwards until the eye closes. This exercise should be done to a count of 10 as often as possible through the day. All people who are unable to close their eyes, or who do not blink should wear glasses. People who don’t blink should develop the “think blink” habit. They should be encouraged to force themselves to blink whenever they see a common object, such as a tree, a cow or a motorcycle. If they carry out the exercise of “think and blink” for long enough, the action will become a habit.

Visual acuity Check how well people can see by using a Snellen chart or by asking the person to count fingers at six meters distance. If there is recent visual loss in one or both eyes, so that the person cannot count fingers at six meters (visual acuity of < 6/60), they should be referred to an eye clinic. Cataracts are the most common cause of significant vision loss in the community and this is especially true in older people. People who have had leprosy can have

their cataracts operated on in exactly the same was as those who have not had leprosy, with an intraocular lens implant. Operational Guidelines National Leprosy for DPMR Eradication Program 29

Red eye A much less common complication of leprosy is inflammation inside the eye itself. The main signs of inflammation are pain and redness of the eye. Conjunctivitis and corneal exposure cause redness of the eye: they can be treated in a general clinic with antibiotic eye ointment and an eye pad. However, if the redness persists after a few days of treatment the person should be referred to an eye clinic. Red eye during type 2 reaction / ENL

indicates Iridocyclitis which needs referral to eye specialist. An eye that is persistently red may have exposure which needs surgical treatment or there may be inflammation inside the eye which requires special treatment beyond the scope of this book. Corneal anaesthesia When the cornea does not have sensation it is at risk of damage from objects like sand, insects or eyelashes. These can cause ulcers on the cornea. If the cornea (the clear front of the eye) has a white spot on it and the eye is red, a

corneal ulcer should be suspected. In such cases the person should be referred to a specialist immediately. Corneal ulceration is an emergency. If it is not treated very quickly the person may become blind. National Leprosy Operational Guidelines 30 Eradication Program for DPMR

Assessment & Grading of Disability Assessment of sensory function of nerve trunk Test the sensory loss in the area supplied by the affected nerve. To detect the sensory loss, use a ball pen and test the sensation at four points in the hand as well as in the foot. Impairment or absence of sensation at any of the point needs testing of the sensation at more points in that area to identify the exact extent of sensory loss. Assessment of the motor function of nerve (VMT)

Check the active range of movement of joints. If the voluntary movement of the joint is reduced or absent, it means that the muscle is either weak or paralysed. If movement is normal, test the strength of movement of the muscle by applying pressure gently in the opposite direction of the movement and gradually increase the pressure while asking the person to maintain the position. Judge whether resistance applied by the person is strong (normal),

of contractures of weak/paralysed muscle. Operational Guidelines National Leprosy for DPMR Eradication Program 31

Grading of disability Disability must be assessed, graded and recorded at the time of first examination and periodically at subsequent visits. Risk status of the affected person changes with the disability status of the person. Examination of WHO Disability Sensory Testing (ST) Voluntary Muscle Testing (VMT) Parts Grades Hands 0 Sensation present Muscle power normal (S) 1 Sensation absent Muscle power normal (S) 2 Sensation absent Muscle power weak or paralyzed (W/P) Feet

0 Sensation present Muscle power normal (S) 1 Sensation absent Muscle power normal (S) 2 Sensation absent Muscle power weak or paralyzed (W/P) Eye Vision Lid Gap Blinking 0 Normal No lid gap Present 2 Can not count fingers Gap between Absent at 6 meters eyelids present/red eye/corneal ulcer or opacity World Health Organisation advocates simple disability grading assessment in to grade 0, 1 and 2, where grade 0 is no disability, grade 1 is anesthesia

over palm and sole and deformity/visible disability is grade 2. While this may give an indication to the status on detection it does not measure the worsening or improvement by disability prevention and medical rehabilitation program longitudinally. Therefore, EHF score is used to grade the disability of the individual organ separately and to give an overall disability grade to the person as outlined below. EHF score is the sum of the individual disability grades. EHF score i.e. sum

of all the individual disability grades for two eyes, two hands and two feet (0-12) is recorded at each visit. The EHF score is more sensitive to change over time than the disability grade itself. An increase in the score, whether of an individual organ or the overall score would indicate some new or additional disability. National Leprosy Operational Guidelines 32 Eradication Program for DPMR

Management of deformities Paralytic deformities for tendon transfer surgery Pre and post-operative physiotherapy is essential for a successful outcome Prevention of disability (POD) of tendon transfer surgery and needs to be arranged. The conditions which It is the common term used to require tendon transfer surgery are claw hand due to paralysis of ulnar, describe various measures offered median or both nerves, foot drop due to paralysis of lateral popliteal nerve, to any leprosy disabled individual

to prevent primary or secondary claw toes due to the paralysis of posterior tibial nerve, lagophthalmos due to disability. paralysis of facial nerve and the wrist drop due to paralysis of radial nerve. Prevention of Worsening of Facial deformities for cosmetic / plastic surgery disability Madarosis: The loss of lateral parts of eye brows is due to lepromatous Some leprosy programmes use this infiltrate destroying the hair follicles. Free graft from scalp or a temporal term to emphasize that measures

artery island flap usually gives satisfactory result offered are in effect to prevent the worsening of the disability in a Sagging face / Mega lobule: This is due to rapid disappearance of the person who has already developed lepromatous infiltrate following treatment with chemotherapy and disability. destruction of elastic and collagen fibres in the dermis. The defect produces an appearance of premature ageing. Pre auricular or naso-labial face-lift is Deformity care Program /

indicated in selected cases. Disability Care Program These are colloquial terms often Nasal deformity: These are due to the invasion and destruction of the nasal used as synonyms and in general tissues by M. leprae. Depressed nose is mainly due to the destruction of include activities related to the nasal septum. The septal perforation is caused by non-specific infection caring of the leprosy disabled destroying the cartilage. Nasal deformities are the most prominent stigma persons. Programmes are aimed

of leprosy cases, the nasal mucosa is replaced by scar tissue which pulls the at prevention, correction and care of various disabilities in leprosy nose inwards. In a saddle nose defect, if the tip of the nose is in the normal affected person. In the holistic position, a bone or cartilage graft would be the operation of choice. In approach it also includes socio- advanced cases, a post–nasal inlay graft over a stent mould is to be preferred. economic rehabilitation of the

In rare cases, with total destruction of nose, a forehead rhinoplasty is the leprosy disabled persons. method of repair. Medical Rehabilitation Other deformities It is abroad term involving any Gynaecomastia or enlargement of male breast: This causes a lot of treatment whether medical or surgical aimed at providing embarrassment to the patient. In lepromatous leprosy, destruction of relief from signs and symptoms seminiferous tubules of the testis by lepromatous granuloma results in

of leprosy. In holistic approach hormonal imbalance producing gynaecomastia. It may follow testicular it also includes socio-economic atrophy resulting from the orchitis of type 2 reaction. This deformity can rehabilitation. be corrected by a modified Webster’s technique. Operational Guidelines National Leprosy for DPMR Eradication Program 33

Recurrent wounds of hands and feet Common causes of wounds include injury due to sharp objects that cut or pierce through the skin like thorns or broken glass, repetitive pressure, friction or shearing forces (e.g. foot ulcers from walking or hand ulcers from using unprotected hand tools), burns etc. The abscess develops following infection and need to be drained surgically. The deep infection may lead to osteomyelitis. Such patients may have sequestra (pieces of dead bone) in

the hand or foot which require removal. An X-ray of the affected part can help confirm the diagnosis. Sometimes in severe cases of recurrent wounds, amputation is the only solution, however this should only be considered as a last resort. Management of wounds in brief Probe the wound gently to search pus collection. Drain the pus, and flush the wound cavity with saline solution. Pack the wound with paraffin gauze and bandage it. Ask patient to elevate the part to facilitate healing and start

systemic antibiotics. Change the dressings daily and decide regarding surgical debridement after 3 days when inflammation has reduced, pus discharge is controlled, dead and avascular tissues are removed and wound is clear. Pack wound with gauze soaked in antiseptic solution. Dressings are continued on alternate day. Plaster cast may be considered after two weeks. Proper counseling of patient is required for better compliance and coordination. Complicated ulcers & Osteomyelitis

If an ulcer is found to be broken down in tissue only in the dermis and epidermis, it is termed a “simple ulcer”. If any ulcer is infected it is no longer simple ulcer. If the breakdown of tissue goes deeper than the dermis and other body parts are affected (i.e. tendons, tendon sheaths, bones and joints) the wound is termed a “complicated ulcer”. When the tissue around bones (periosteum) becomes infected the condition can lead to inflammation of bones (osteomyelitis).

National Leprosy Operational Guidelines 34 Eradication Program for DPMR

Osteomyelitis is very difficult to treat and can cause chronic, non-healing lesions in bones. Without enough nutrients the infected bone dies and the small pieces of dead bone break away. These loose pieces of dead bone, called sequestra, will cause irritation in the wound which will not heal until the sequestra are removed or fall out. If the normal process of granulation is continuously interrupted by the irritation of sequestra the wound responds by

producing hypergranulation tissue. Hyper granulation will be seen as masses of bright red tissue that bulge out of an ulcer. Wherever hyper granulation is seen it indicates that there is something irritating the wound and should be taken as a sign that further investigation is necessary. People with deep or dirty ulcers or osteomyelitis should be referred for septic surgery and antibiotics. You should suspect osteomyelitis if the person’s

hand or foot is warmer than normal, with or without swelling. Any person with a wound discharging pus should be referred for surgical advice and debridement (removal of dead and infected tissue) before taking steroids, or osteomyelitis may develop. Starting steroids before such treatment may lead to a worsening of the sepsis and more permanent damage, including the need for amputation. All wounds are the result of tissue stress. Common causes of ulcer include:

ulcer management. If these principles are followed, simple ulcers will heal without any medication: These principles are rest, good wound environment, hygiene and protection. Operational Guidelines National Leprosy for DPMR Eradication Program 35

Rest: Almost all wounds will heal if they are rested. Regardless of the cause of injury, the first line in treatment of wounds is to remove the cause of tissue stress and then to allow the injured part to rest so that damaged tissue can repair itself. So long as the person with a wound is healthy, damaged tissue will repair itself. Rest doesn’t necessarily mean that the patient must stay in bed (although for foot ulcers this is often the best option). If the person is

unable to rest it may still be possible to rest the injured body part by splints. Splinting Walking with crutches (or even with a walking stick)- It will rest foot ulcers. Whatever the circumstances, the injured part should not be allowed to perform normal functions whilst the tissue is still being repaired. The best option is for the person to spend as much time as possible, lying down with his foot raised above the level of his heart (bed rest). However, this

is very rarely possible amongst people who must struggle to feed themselves and their families, so other options should be explored. It is also very important to find out whether the person is able to change his activities so that he doesn’t need to walk so much: for example, can he temporarily swap work with another person? Other transport options should also be considered: for example, riding a bicycle. Management in brief 1. Examination of general condition of a case and local wound area.

Probe the wound gently to search pus collection. drain the pus, if any. 2. Flush the wound cavity by saline solution. 3. Pack the wound with gauze and bandage it. 4. Elevate the part to facilitate healing. 5. Start systemic antibiotics. 6. Change the dressings daily and check for any further pus collection. National Leprosy Operational Guidelines 36 Eradication Program for DPMR

7. Surgical debridement after 3 days when inflammation is reduced, pus discharge is controlled and wound is clear. All the dead tissues and avascular tissues are removed. Wound space is packed with gauze soaked in Savlon solution. Dressing on alternate day after checking any more collection of pus, to be done. 8. Plaster cast with off-loading device may be considered after two weeks when wound is totally clear, healing has started and no signs of inflammation are there.

9. Wide spread use of antiseptics and topical antibiotics are to be avoided. 10. Oral preparation of zinc, vitamin C and vitamin A may be supplemented. 11. Proper counseling of patient is required for better compliance and coordination. Treating the ulcer is a great opportunity to reduce fear & stigma through demonstrating ulcer care without any discrimination. Family members are also encouraged to learn and practice the dressing of ulcer and nursing care of patient.

Salvage procedures of the limbs such as arthrodesis of the subtalar or ankle joints This is done for fixed equines deformities of the foot or totally paralysed feet with a flail ankle or forefoot deformities. These procedures are followed by immobilisation for long duration followed by specialised foot wear. Operational Guidelines National Leprosy for DPMR Eradication Program 37

Criteria for referral of cases for RCS The general criteria have been grouped into three categories: social and motivational, physical and the leprosy treatment criteria. The patients and the health worker both must be involved in the decision of referral for surgery. Social and motivational criteria All patients who would be benefited occupationally, economically or socially are considered suitable for reconstructive surgery. The employed technique of

surgery must have the potential to make a difference to patient’s acceptance in the family, improve the socioeconomic situation and be reintegrated as ergonomically independent member of the society. Patients must be well motivated and should have demonstrated that they are responsible for their own health and follow instructions on treatment and care of their eyes, hands, and feet before surgery. Patients who are not well motivated in self-care are not likely to be willing to participate in essential

pre and postoperative physiotherapy. Physical criteria The best age for referral for tendon transfer is between 15-45 years, but patients younger than 15 years or older than 45 years may be operated depending upon the particular circumstance. The muscle paralysis should be present for at least one year and preferably not longer than 3 years. There may exceptional cases where there has been muscle paralysis for longer than 3 years and the individual has kept the

joints supple through passive exercises. The patient may not remember accurately how long muscle paralysis has been present, so suppleness of the joints may be a more useful criterion. Patients with severe contractures or stiff joints are not suitable, although physiotherapy or surgery can reverse some contractures. There should be no infection of the skin such as scabies, and any deep cracks, wounds or ulcers at the time of referral. National Leprosy Operational Guidelines 38 Eradication Program for DPMR

Leprosy treatment criteria Patients should have completed the scheduled course of MDT or at least a minimum of 6 months MDT. Patients should be free from reactions and symptomatic neuritis for at least 6 months. Patients should not have taken steroids in the immediate past (about 4 to 6 months) unless the surgery is for neuritis. There should be no tenderness of any major nerve trunk in the limbs. The proposed surgical procedure and its positive consequences should be

balanced against the consequences of not doing surgery. This should be discussed with the patient and the decision whether to undergo surgery should be taken by the patient. Methods of managing to live with the deformities without causing further damages to the affected parts should be explained to patients who do not want or are not suitable for surgery. For most patients there is a period of few years during which surgery is most

likely to be beneficial. This starts when the disease is stable (free of reactions and neuritis), MDT course is completed and the muscle paralysis is not likely to progress or recover. Motivation is a key factor as patients may need to be in hospital for at least six weeks and will have to work at physiotherapy. Patients in whom surgery will make a difference are considered for referral. Priorities for reconstructive surgery Operations for lagophthalmos are usually considered as a high priority

because of the possibility of secondary damage to the eye leading to blindness. Feet are usually considered the next priority for mobility followed by hands but this may depend on the needs of individual patients. Operational Guidelines National Leprosy for DPMR Eradication Program 39

Physiotherapy Physiotherapy is helpful in restoring the normal tone of muscles and preserving the physiological properties of paralysed muscles. It also helps in preventing muscle atrophy and the over stretching of paralysed muscle. Its main aim is to prevent contractures and keeping joints mobile, keeping the skin soft and supple and improve the blood circulation of the part. Physiotherapy comprises exercises, oil massage, wax baths, hydrotherapy,

splinting, electrical stimulation of muscles, shortwave diathermy, ultrasonic massage etc. Physiotherapy is very useful in the management of deformities and is essential in both pre as well as post-operative care of deformity patients. RCS requires the patient to use a different muscle in place of the paralysed muscles. The operated part is still vulnerable, and patient needs post-operative muscle training and instructions in the use of anaesthetic

extremities. Instructions given by surgeon at the time of discharge should be followed. In general, the common postoperative muscle exercises are as follows: Type of paralysis Active Exercises Passive Exercises Claw hand Stabilize the MCP (Metacarpo-Phalangeal) Straighten the clawed fingers repeatedly joint between the hand & the fingers at using the other hand. 90 degrees with palm of other hand. Keep the wrist straight. Extend the fingers keeping the same position.

Repeatedly bend and straighten the fingers of the weak hand. For the thumb Use other hand to hold the weak thumb Straighten the weak thumb at the distal steady at the (MCP) joint between hand joint (IP) and hold it straight for a few and thumb. seconds. Straighten the paralysed thumb using his other hand and pull it away from the first finger towards the palm. Foot drop Practice lifting the fore foot upwards and Sit with the leg straight. holding it for a few seconds. Pull the foot up using a towel.

Repeat this movement several times. Lagophthalmos Think & blink. With the index finger on the skin at the Close the eyes as strongly as possible corner of the eye, gently pull outwards, so that the eye closes. Do this procedure as often as possible. National Leprosy Operational Guidelines 40 Eradication Program for DPMR

Minimum Essential Splints Finger loop splint Used for: Stabilising the MP joint to enable PIP joint extension. Helps: Keep MP flexion post-op, prevent contracture of skin and joints, correct or improve claw deformity, strengthen extensor expansion, stretch out mild to moderate stiffness pre and post op. Precaution: Change the loops if redness of skin or friction ulcer develops on the dorsum of the finger. Gutter splint (dynamic, flexible) Used for:

Hold the PIP joint in extension, passive stretching of volar skin at the level of PIP joints. Helps: To maintain the gain in range of movement and position maintenance as night splint, to overcome mild to moderate contracture of volar skin and stiffness of joints. Precaution: Do not use gutter splint in fixed deformity of PIP joint, discontinue its use if redness or ulceration develops on the dorsum of the PIP joint of the finger. Adductor band splint Used for:

Obtaining adduction of fingers, prevent splaying after 4 FMT Helps: To obtain adduction in splayed out fingers postoperatively. To adduct the fingers post-op in claw correction and hold fingers with unaffected fingers. Opponens splint Used for: Keeping the thumb in abduction. Helps: Maintain abduction after opponensplasty. To prevent thumb web contracture in ‘Ape-thumb’ deformity, Precaution: To get abduction make a double loop of the rubber band. Operational Guidelines National Leprosy

Self-care Empowerment of patients with kit or materials Considering the fact that majority of ulcers undergo cleaning and debridement in the operation theater, its dressing on regular basis becomes necessary either till it heals or it becomes fit for RCS. Often patients are discharged with advice on dressing as OPD Case. In place of that empowerment of patients in their self-care has been suggested and is practiced over a decade. Self-care

forms a vital part of the program and considering the fact today that nearly 60% cases have ulcers and wounds on anesthetic extremities, educating the patient on self-care is of paramount importance. ‘Self-care Kit’ has necessary tools and materials with which self-care is made compliant, patients can be educated, empowered and even homemade materials can be replaced in the kit if necessary. Good results have been obtained with this technique.

and replaced after a month. All patients are also given MCR footwear at the end of the session. Technique of using the Self-Care Kit 1. Soak the feet 2. Scrape the sole of the foot and margin of the ulcer 3. Wipe the feet dry between toes 4. Apply antiseptic ointment on the ulcer 5. Apply moisturising cream in dry areas of foot and leg 6. Put two sterile gauze pieces on ulcer and apply bandage 7. Wear MCR footwear National Leprosy Operational Guidelines 42 Eradication Program for DPMR

Coordination and Linkages Medical officer will coordinate with district nucleus for effective referrals, training, and logistics. Primary care institutions will maintain direct linkage with the District Hospital unit (secondary level) for referral of all types of cases. The referral slip should be marked to the district nucleus unit, which will be the linkage point amongst primary, secondary and tertiary level centres. The secondary care level institutions will maintain direct linkages with the identified

tertiary care institutes for referral of cases for RCS and other complications. Secondary level and tertiary level units will refer back cases after diagnosis and initiation of treatment to the primary care level units with proper instructions for maintenance of treatment and follow-up. To perform various activities of DPMR satisfactorily it is mandatory to have close coordination with the various divisions of health services like PHC

units and hospital services. Coordination with district nucleus is crucial in procurement of drugs, consumables, aids & appliances, consolidate information and generate reports. The District Nucleus will coordinate and provide linkages amongst the primary, secondary and tertiary level centres for all other issues. Similarly, on clinical aspects the Dermatologist / Physician of the District hospital will need to coordinate with the ophthalmology, orthopaedic surgery, and

physiotherapy departments of the institution for internal referral of cases. Linkages The district nucleus need to have good linkages with the local NGOs working in the area as well as national NGOs which support the NLEP. The linkage with Ministry of Social Welfare is necessary to rehabilitate patients economically after RCS or recovery from deformity. Other types of linkages necessary are with special investigative facilities like PCR, serological tests,

histopathology and mouse footpad innoculations to study drug resistance or viability of M. leprae and so on. In view of ICMR giving preference to leprosy research including reconstructive surgery, it is utmost important that NLEP liaison with tertiary care centers for result oriented output for eradication of leprosy. National Leprosy Operational Guidelines 44 Eradication Program for DPMR

IMPLEMENTATION OF DPMR SERVICES AT PRIMARY LEVEL Goal Primary level functionaries Disability burden due to leprosy is reduced. Patient / PAL, family members, community Objectives Village, VH&SC, ASHA 1. To prevent disability in new leprosy cases, Sub-center 2. To prevent new disability or worsening of disability in under treatment Sector PHC cases and in the cases who have completed the treatment, Block CHC RKS Strategies 1. Empowerment of community, patients and community level functionaries

Secondary level like GKS (VH&SC) to take ownership of eliminating disability in leprosy in their village by increasing the awareness for early self-reporting functionaries District HQ Hospital 2. Strengthening of capacity of ASHA at village level to suspect early neuritis and reactions in leprosy cases and their referral, monitoring Apex Group of self-care practices and ulcer dressing carried out by people affected DLO with leprosy himself, MO DN

3. Strengthening of Sub center and sector PHC to ensure coordination and RKS supportive supervision of works carried out by ASHA, 4. Strengthening of Block CHC to function as nodal referral center at Tertiary level functionaries primary level to carry out preventive, curative and referral services to Medical College Hospitals prevent new disability and worsening of disability in people affected PMR Institutions with leprosy. 5. Simplification of information system in respect of DPMR activities

6. Provision of materials like MCR foot wear, grip aids, self-care kits, splints for hands and feet, POP, ulcer dressing kits to all needy patients Operational Guidelines National Leprosy for DPMR Eradication Program 45

Operating Procedures 1. Patient Mobilization Patients are either reporting directly or referred by GKS/ASHA/AWW, Health workers/MO PHC/Ayush MO. The family members or other persons affected by leprosy may also refer the patient to PHC/CHC. 2. Service Components  Diagnosis and treatment: All reported and referred cases will be examined following standard procedure:  History taking o Duration of lesion o Duration of disability if any o Family history/ contact history o Previous treatment

o For initiation of MDT Operational Guidelines National Leprosy for DPMR Eradication Program 47

 Look for lid gap or inability to close one or both eyes (Lagophthalmos) and check for normal strength of eye closure. Measure the gap in millimeter.  Check the visual acuity of each eye separately, using a Snellen’s chart or by counting fingers at 6 meters. If the person cannot read the top line of the chart, or count fingers at 6 meters, they are visually impaired and have grade 2 disability in that eye. National Leprosy Operational Guidelines 48 Eradication Program for DPMR

Sensory Testing (ST): Impairment of Sensation is a main cause of disability and deformity in leprosy. General Practices: The objective of the ST is to detect easily nerve damage. It is very important I. All the activities below Block to pick up the skill of eliciting sensory loss in skin supplied by nerve. level will be implemented in  You will need a ball point pen (with plastic body) integrated manner with existing health functionaries.

Suspecting complications at field level How to suspect cases of leprosy reaction, neuritis, relapse, insensitive hands & feet by the ASHA or Health Workers / Ayush MO and refer to the Primary level Health Centers (CHC) for diagnosis: All patients affected by leprosy, ASHA, health workers will be trained to suspect leprosy reactions, neuritis, relapses and Grade 1 & 2 disability. Clinical features to identify each are as under:  Lepra reaction is the sudden appearance of signs of inflammation in the

skin lesions or nerves or eyes of a person with leprosy. There is redness, swelling and sometimes tenderness of the skin lesions. New skin lesions or symptoms suggestive of new nerve damage, such as numbness, or muscle weakness in the hands or feet may appear. Crop of subcutaneous nodules may appear. Above signs and symptoms may be seen in new patients, patients under MDT and also persons who have completed full course of MDT.  Neuritis is a common problem. During neuritis patients present pain in

nerves, sudden development of anaesthesia or sudden increase in area of anaesthesis, sudden weakness or paralysis of muscles of eye, hand and foot, tingling sensation over extremeties.  Relapse is defined as the re-occurrence of the disease at any time after the completion of a full course of treatment. Relapse is indicated by the gradual appearance of new skin lesions. Signs of inflammation or neuritis are usually not there.  Insensitive hands & feet can be identified by sensory testing in that area.

Insensitive palms and soles are prone to develop ulcers due to abnormal pressure on part or due to external injury. Look for any red or bluish spot on feet which is the first sign of blister and ulcer development. National Leprosy Operational Guidelines 50 Eradication Program for DPMR

Identification and Management of Disability Grade 1 After assessing the disabilities and its grades, Medical Officer CHC should DPMR activities to be take care to contain and reverse the effects of disabilities. Cases with carried out at Primary level anaesthesia of palm/sole are to be assessed properly. If the duration of in Urban Areas disability grade 1 i.e. anaesthesia along the course of trunk nerve is recent  Involvement of following

(< 6 months), a course of Prednisolone is to be started to treat neuritis. If the personnel in urban areas will duration is more and anaesthesia is irreversible, Prednisolone will not help be ensured: but the condition is to be prevented to progress in to grade 2. Anaesthetic  RWA (Residence Welfare sole/palm is prone to injuries resulting into ulcer, wound, secondary infection Association) leading to mutilation & absorption of parts. To prevent this deterioration,  USHA

of self-care kit / material and counseling will enable a case to adopt self care  Strengthening coordination procedure. Village Health & Sanitation Committee / Gaon Kalyan Samiti of different players like State can also help to motivate persons affected by leprosy to adopt the self care Govt., Central Govt., Local practices on regular basis: Bodies and Private sectors.  Community / family members can help and encourage the person to do what is needed on a regular basis

 Other people affected by leprosy can also be exampled for how they have been able to look after themselves at home Self-care groups have been started in some places. A number of people with self-care need to meet together regularly to discuss the practicalities of self care. These groups are often supportive and can be very motivating for members. Special efforts / counseling will be needed for those cases which are reluctant to adhere to ‘self-care’ practices Patients having Cataract in the Eye

Leprosy patients with cataract (visual acuity < 6/60) should be referred for cataract extraction with IOL so that with improved vision they are able to protect their anaesthetic hands/feet also. Operational Guidelines National Leprosy for DPMR Eradication Program 51

Operational Aspects Activities at community level Level of Institution Key Activities/Jobs/ Referral Supports required Operation and Person Responsibilities responsible Person Family Self referral to 1. If person does not PAL/Family members/ having members nearest health facility experience any benefits community need to be signs and of people or nearest health of Self-care practice educated about Self- symptoms affected with personal, Acquire or Ulcer does not start care practices and

of leprosy/ leprosy and knowledge and skills healing within complications of leprosy person(s) person him/ for carrying out 15 days or any having Gr-1 herself Self-care practices worsening noticed or Gr-2 and carry out those disability/ regularly, use of MCR 2. New signs and persons footwear regularly, symptoms of neuritis/ having regular dressing of neural pain/increase in trophic ulcer area of anaesthesia/ ulcers weakness of muscles of hand, feet or any eyes problem noticed

National Leprosy Operational Guidelines 52 Eradication Program for DPMR

Activities at institution level and referral mechanism: Institution Implementation Referral Functionary/Person and Level (Activities to be carried out) (conditions for referral) responsible VH&SC/GKS • Identification of suspects having • All suspects having VH&SC/GKS, ASHA at Village signs of leprosy, neuritis, nerve signs of leprosy, function impairment and old neuritis, nerve cases having disability function impairment • Monitoring of treatment and old cases having completion disability,

• Monitoring of Self-care practices • Patient requires MCR carried out by patient foot wear • Monitoring of use of MCR foot wear by patient supplied MCR foot wear • Interpersonal communication for community empowerment and participation Sub Center • Delivery of MDT to under • All suspects having MPHW (M/F) treatment cases signs of leprosy, Level • Maintain the case card LF-01 neuritis, nerve • Update the sector register on function impairment the day of sector meeting and old cases having

• Identification of early signs disability, of neuritis, reaction and • Patient requires MCR other complications of under foot wear treatment cases at SC • Supervision/Monitoring of treatment completion • Supervision/Monitoring of Self- care practices carried out by patient • Supervision/Monitoring of use of MCR foot wear by patient supplied MCR foot wear • Interpersonal communication for community empowerment and participation Sector PHC • Delivery of MDT to under • All suspects having MO Sector PHC. Ayush

treatment cases at PHC signs of leprosy, Doctor and MPHS • Delivery of prednisolone to neuritis, nerve patients undergoing treatment function impairment for neuritis and reactions and old cases having • Supply of dressing materials to disability, patients having ulcers • Patient requires MCR • Maintain the sector treatment foot wear register and up-date the master register at CHC Operational Guidelines National Leprosy for DPMR Eradication Program 53

Institution Implementation Referral Functionary/Person and Level (Activities to be carried out) (conditions for referral) responsible • Identification of early signs of neuritis, reaction and other complications of under treatment cases at PHC • Supervision/Monitoring of treatment completion • Supervision/Monitoring of Self-care practices carried out by patient • Supervision/Monitoring of use of MCR foot wear by patient supplied MCR foot wear • Interpersonal communication for community empowerment and

participation CHC • Diagnosis of disease in all • Pt not responding MO in charge of CHC suspects referred from village/ to steroid or has supported by PHC or directly reporting at CHC developed dependency PMW/HS having signs of leprosy, neuritis, • Pts having other nerve function impairment and associated diseases old cases having disability like Tb, HIV/ • Initiate treatment with AIDS, Diabetes/ appropriate counseling Hypertension • Provide other supportive requiring prednisolone

treatments like POP, splints, treatment for neuritis slings, MCR foot wear and reactions • Detail assessment of all cases • Complicated ulcers having nerve function impairment requiring surgery and recording of findings • Patients fit for RCS • Advise and demonstrate self and willing for surgery care practices • Pt having eye • Slit skin smear examination for complication AFB from suspected LL cases Any problem in eye of and relapse cases person noticed in affected

• Ulcer management/dressing persons will be referred • Supply of dressing materials and directly to Ophthalmologist ulcer dressing kit to patients of DHH • Counseling to pts/family member/community members • Planning training programs for Health Workers/ASHA and other GKS members and execution of training • Supervision and monitoring • Record maintenance and submission of monthly reports National Leprosy Operational Guidelines 54 Eradication Program for DPMR

Referral Protocol Implementation Referral Village Health & • Supervision Self-care practices • Neuritis sanitation Committee • Supervision Use of MCR • Reaction • Supervision of ulcer & dressing • Disability (GKS) ASHA, PAL carried out by patient • Ulcer Implementation • Self-Care advice Referral Sub Centre • Advice to RCS cases • Reaction • Disability • Monitoring & Supervision of • Neuritis ASHA Activities. • Ulcer • Follow up Sector PHC Implementation Referral • Manage Reactions

• Lepra Reactions difficult to manage • Ulcer dressing/technology transfer • Complicated ulcer • Identify or refer patient needing RCS Block PHC • Eye problems • Supply MCR foot wear to needy patient • Reconstructive Surgery cases • Advice to Reconstructive surgery cases • Persons needing Gr-II foot-wear • Advise to self care • Follow up of RCS, Lepra Reaction • Counseling Implementation • Management of complicated ulcers Referral • Management of Lepra • Refer difficult ulcer

District Hospital/ Reactions cases apex Group • Screening cases for RCS • Refer for • Diagnosis of difficult to Reconstructive diagnose cases/Relapse surgery case/Skin smear/RCS Referral Implementation • Refer for • Management of Lepra Reconstructive Reactions surgery/follow • Supply of foot-wear up of RCS. District Nucleus Implementation • Reconstructive surgery/Amputation/RCS Training Reconstructive Surgery Centre • Follow up after Reconstructive surgery • Implementation

• Referral • Supply of foot wear to District Nucleus. Operational Guidelines National Leprosy for DPMR Eradication Program 55

Job responsibilities - Primary Level for DPMR activities SI. No. Staff/facility Job responsibility 1. ASHA/GKS • Identification and referral of suspects having signs of leprosy, neuritis, nerve function impairment and old cases having disability to MO CHC • Monitoring treatment completion • Monitoring Self-care practices carried out by patient • Monitoring use of MCR foot wear by patient supplied MCR foot wear • Interpersonal communication for community empowerment and participation

2. MPHW (M/F) • Delivery of MDT to under treatment cases • Maintain the case card LF-01 • Update the sector register on the day of sector meeting • Identification and referral cases with early signs of neuritis, reaction and other complications of under treatment cases at SC • Referral of Gr-I & II RFT cases to PMW CHC for registration and SCP advices and assessment using P-III • Referral of suspected relapse to MO CHC • Referral cases requiring MCR foot wear to PMW CHC

• Supervision/Monitoring of treatment completion at village level • Supervision/Monitoring of Self-care practices carried out by patient at village level • Supervision/Monitoring of use of MCR foot wear by patient supplied MCR foot wear at village level • Interpersonal communication for community empowerment and participation at village level 3. Sector • Delivery of MDT to under treatment cases at PHC MO/Ayush • Delivery of prednisolone to patients undergoing treatment for neuritis and MO/MPHS reactions

• Supply of dressing materials to patients having ulcers • Maintain the sector treatment register and up-date the master register at CHC • Identification of early signs of neuritis, reaction and other complications of under treatment cases at PHC treat them on emergency-basis and refer them to MO CHC • Referral of Gr-I & II RFT cases to PMW CHC for registration and SCP advices and assessment • Referral of suspected relapse to MO CHC • Referral cases requiring MCR foot wear to PMW CHC

• All referral to be done using P-III • Supervision/Monitoring of treatment completion • Supervision/Monitoring of Self-care practices carried out by patient • Supervision/Monitoring use of MCR foot wear by patient supplied MCR foot wear • Interpersonal communication for community empowerment and participation National Leprosy Operational Guidelines 56 Eradication Program for DPMR

SI. No. Staff/facility Job responsibility 4. PMW • Support MO CHC in Diagnosis of disease in all suspects referred from village or directly reporting at CHC having signs of leprosy, neuritis, nerve function impairment and old cases having disability • Support MO CHC in Initiation of treatment with appropriate counseling • Provide other supportive treatments like POP, splints, slings, MCR foot wear • Detail assessment of all cases having nerve function impairment and

recording of findings in case card and Form –PII • Advise and demonstrate self care practices • Slit skin smear examination for AFB from suspected LL cases and relapse cases • Ulcer management/dressing • Supply of dressing materials and ulcer dressing kit to patients • Counseling to pts/family member/community members • Planning training programs for ASHA and other GKS members and execution of training • Supervision and monitoring • Record maintenance in P-I and submission of monthly reports

• Logistic planning/indenting and supplies 5. MO CHC • Diagnosis of disease in all suspects referred from village or directly reporting at CHC having signs of leprosy, neuritis, nerve function impairment and old cases having disability • Initiate treatment with appropriate counseling • Providing guidance to PMW in carrying out all jobs assigned to PMW • Planning training programs for ASHA and other GKS members and execution of training • Supervision and monitoring

• Referral of patients not responding to steroid of developed dependency • Referral of patients having other associated diseases like TB, HIV/AIDS, Diabetes/Hypertension and requiring prednisolone treatment for neuritis and reactions • Referral of Complicated ulcers requiring surgery • Referral of Patients fit for RCS and willing for surgery • Referral of cases with eye complications • Cross check Disability Register • Generate P-2 of MPR every month and submit it to District Leprosy Officer

Supervision of Record maintenance and submission of monthly reports Operational Guidelines National Leprosy for DPMR Eradication Program 57

Capacity Building of personnel at primary level: Level Personnel to be What to be trained Who? will Duration of trained impart training training Village PAL, Family How to suspect early case, early neuritis, By trained Hands on member of reaction, do self care practice, ulcer HWs, MO training in the PAL, GKS, dressing, use of MCR footwear-they will be PHC, AYUSH field community level trained about presentation of leprosy like MO ASHA functionaries patch over body, sudden appearance of new and MO I/C

patches, redness, swelling and tenderness in CHC during existing cases, pain in peripheral nerves, red village eye, self-care of eyes having lagophthalmos, visits in an insensitive hand and feet, simple techniques integrated of ulcer dressing, use of ulcer dressing manner kits, use of MCR footwear for PAL having insensitive foot CHC AII ASHA, How to suspect early case, early neuritis, MO I/C CHC 4 hrs during HWs, reaction, and PAL having disability problems integrating training live

Supervisors, and refer them to MO CHC promote self with other patients will be AYUSH MO, care practice, ulcer dressing, use of training demonstrated PHC MO MCR footwear-they will be trained about programmes. while training presentation of leprosy like patch over body, MO DN /DLO (must) sudden appearance of new patches, redness, will also be swelling and tenderness in existing cases, as resource pain in peripheral nerves, red eye, self care persons of eyes having lagophthalmos, insensitive

hand and feet, simple techniques of ulcer dressing, use of ulcer dressing kits, use of MCR footwear for PAL having insensitive foot District MO I/C PHC, History taking, Clinical examination of all DLO/MO DN, 2 days training Level PMW, cases mainly focusing on methods of nerve SLO Physiotherapist examination, conduction of Sensory Test and other (ST) and Voluntary Muscle Test (VMT), supervising Assessment disability and filling up the P-II, officers, BPOs special attention on cases at risk, Monitor

and conduct nerve assessment of at risk cases in every month, diagnosis of neuritis, reaction and management, techniques of simple ulcer management, How to run DPMR clinic at CHC and PHC, logistic arrangement, record keeping, identifying cases required referral to Secondary level and refer them follow up of referral cases, post-operative care of RCS cases, supervision National Leprosy Operational Guidelines 58 Eradication Program for DPMR

Supervision, Monitoring, Evaluation Medical Officer I/C CHC will supervise and monitor activities of the ASHA, Health Worker, Supervisors and Pharmacist. The District Nucleus under the DLO will supervise and monitor DPMR activities in the primary care level. Supervision: Supervision is extension of training, intensified immediately after training to ensure that health workers have fully acquired the skills taught and to provide any guidance needed.

It is systematic process for increasing the efficiency of health workers by 1. Developing their knowledge 2. Perfecting their skills 3. Improving their attitudes towards their work & 4. Increasing their motivational levels It is carried out in direct contact with the health worker and it is aided by programme monitoring. All health workers need help to solve problems and overcome difficulties. They also need feedback on their performance and

encouragement in their work. The supervisor’s personality is important. Good supervisors have a pleasant and friendly manner, and are quick to establish rapport with health workers of all categories. They are ready to listen with an open mind to any problems and to seek solutions that will take into account the suggestions of the health worker concerned. Two main levels of supervision can be distinguished  Supervision of activities at Village / sub-centre / Addl. PHC by Block level MPS / Medical Officer

 Supervision of activities at CHC / PHC by the district authorities / District Nucleus Problem-solving: If a health worker is unable to perform a task adequately because of lack of knowledge, then the supervisor should demonstrate that particular activity and ask the health worker to repeat it in the presence of the supervisor, such a coaching on the spot would solve the problem permanently. If solution is not available readily then it should be discussed

with the seniors. Conclusion should be written in the health facility register to take necessary measures. Operational Guidelines National Leprosy for DPMR Eradication Program 59

Supervisory visit to Primary health units by the Block: Frequency: Hospitals and health centres with a large number of outpatients should be visited once a month and those health facilities with fewer patients may be visited once in 2-3 months. The visit should be on regular basis and based on the performance. A checklist has to be formulated considering the following issues. 1. Review of disability status, initial and its follow-up 2. Observation of health workers doing their work, for example palpating

the nerve, method of doing ST and VMT, vision test, Active / Passive exercises, dressing the ulcer and counseling 3. Discussion with the health workers: the supervisor should talk to each category of staff separately, identify their problems, and establish its cause and try to solve them with the cooperation of each worker, particularly about referral of cases and follow up of cases returned from referral centres 4. Control of supplies: the supervisor should check the availability of

essentials such as drugs, dressing materials, foot wears etc. 5. Discussion with the patients: The supervisor should also talk with individual patients, cross check about their knowledge of the disabilities and its management Supervision visits to health units by the district: Frequency of visit to: Hospitals and health centres will depend on cases load and problems identified. Items to check: A checklist has to be formulated considering the following issues.

1. Review of disability initial/follow-up records 2. Observation of health workers doing their work, for example palpating the nerve, method of doing VMT, vision test, Active / Passive exercises, dressing the ulcer and counseling 3. Discussion with ASHA, health workers: the supervisor should talk to each category of staff separately, identify their problems, establish its cause and try to solve them with the cooperation of each worker, particularly about referral of cases and follow up of cases returned

from referral centres National Leprosy Operational Guidelines 60 Eradication Program for DPMR

4. Control of supplies: the supervisor should check the availability of essentials such as drugs, dressing materials, foot wears etc. 5. Discussion with the patients: The supervisor should also talk with individual patients, cross check about their knowledge of the disabilities and its management 6. Reports: look for accuracy, completeness and timely submission 7. Discussion in detail about new disability produced in any case Monitoring:

It is also to ascertain whether activities are being accomplished as planned; Methods of supervision & monitoring: it is a daily management activity, to identify problems early so that they  Record and report review can be solved without any delay. It indicates where we stand and how far we are from the goal, so that we can make a plan of action to rectify. We  Direct observation make interventions as per the plans made, monitoring helps assessing the  Discussion with health worker

impact of these interventions. It provides objectives indicators to assess if  Discussion with patients they were effective, or ineffective, and help identify the problems and plan  ASHA: To monitor self care corrective actions. practices and use of MCR footwear by PAL The main objective of monitoring is to identify and resolve operational  ANM: She will supervise work problems as soon as they emerge. Realistic solutions to operational problems of ASHA

will call for identification of causes and corrective action.  MPHW (M/F) will monitor/ supervise work of ASHA During the implementation phase of DPMR initiative, important activities like coverage of training, provision of logistics, information management  PMW/NMS will supervise the job of ANM at subcenter and system, communication, advocacy and laboratory services, nursing and ASHA of village level and will theatre services should be monitored. play the lead role in monitoring the program

Different aspects of each activity need to be monitored like Quality of work  MO will take an overall performance, quantity of certain outputs or outcomes, and the timeline with responsibility of monitoring the which an activity is accomplished. program. Operational Guidelines National Leprosy for DPMR Eradication Program 61

Performance Indicators and Aspects to Monitor Key performance Indicators Aspects to monitor POD Services provided Training 1. No. of different category of staff trained 2. Quality of training (duration, % of time devoted to practical, trainee: trainers ratio) Logistics 1. Stocks of Steroids, loose Clofazimine 2. Consumables 3. Forms and Registers, etc. Communication 1. No. of posters on hand care, feet care & eye care 2. No. of participatory methods of ulcer care conducted in a monthwith

patients & families Advocacy 1. No. of coordination meetings conducted with like minded agencies Supervision 1. Frequency of supervisory visits at health units/districts/state 2. Whether visits are made on schedule 3. Whether visits resulted in corrective action to solve the identified problems Operational indicator 1. No. of cases with disability - grade I and grade II 2. No. of cases developing new disability 3. No. of reaction cases put on Prednisolone 4. No. of cases undergone surgery

5. Multi drug treatment completion rates 6. No. of Relapse cases suspected and referred Logistics & Supplies All primary care level institution should have: MDT, Prednisolone, MCR foot-wear and Dressing materials Treatment protocol (symptoms and signs guide) Learning materials and Flash cards Recording and reporting formats and Referral slips Records & Reports Records to be maintained at Primary level are as under:  Disability Register: Form – P-1  Assessment of Disability and Nerve Function: Form – P-2

 Record of Lepra Reactions/Neuritis Cases – P-3  Prednisolone Card: Form – P-4  Referral Slip for ASHA/HW/PHC/CHC to CHC/District: Form – P-5  The Monthly Progress Report (MLF-04) submitted by PHC to District: MLF-04 (Page 2) National Leprosy Operational Guidelines 62 Eradication Program for DPMR

IMPLEMENTATION OF DPMR SERVICES AT SECONDARY LEVEL Objectives 1. To prevent disability in new leprosy cases, 2. To prevent new disability or worsening of disability in under treatment cases and in the cases who have completed the treatment. Strategy  Formation of District Apex Group at District HQ Hospitals headed by Dermatologist / Physician along with specialists of Orthopedics / General Surgery, Ophthalmology, assisted by Physiotherapist & Laboratory

Technician and coordinated & facilitated by MO DN / DLO.  All District Hospitals will be strengthened with provision of skin smear examination facility and physiotherapy unit.  Some District Hospitals will be strengthened to provide RCS services.  Some District Hospitals will be strengthened / outsourced to manufacture customized foot-wears. Activities at Secondary level 1. Validation and Diagnosis:  Validation of cases diagnosed at PHC/CHC level on sample basis to

assess quality of diagnosis and disability status  Diagnosis of directly reporting and Difficult to diagnose cases referred from primary level  Confirmation of suspected relapse cases referred by primary level  Reaction and neuritis cases referred 2. Treatment:  Initiation of treatment of all cases diagnosed at secondary level  Reaction and neuritis cases referred  In-patient management of severely ill cases Operational Guidelines National Leprosy for DPMR Eradication Program 63

3. DPMR Services:  Assessment of disability status  Management of Lepra Reactions  Management of complicated ulcers  Management of eye complications  Physiotherapy including Pre and post-operative care  Follow up of cases treated at tertiary level  Supply of customized footwear  Supply of ulcer dressing kits, Aids, splints and appliances  Self-care counseling  Outreached services to leprosy colonies  Screening of cases for RCS  Reconstructive surgery*  Amputation surgery* 4. Lab. Services:

 Skin smear examination and other investigations required  Blood examination for LFT, Sugar etc.  X-ray Training and Capacity building:  Assess training need  Organize training as per requirement of MO PHC/CHC and others Cases referred from primary care Referral: units may be of following types:  Recurrent ENL cases  Cases difficult to diagnose leprosy, and in need of  Severe reaction or complicated cases like pt. having hepatitis, nephritis confirmation or multi organ involvement

 Cases with Severe Lepra Reaction  Patients requiring further investigations like histopathology/  Cases with suspected relapse microbiology/other investigation required  Cases with adverse effects of MDT  Cases with disability grade II  Cases fit for RCS requiring medical or surgical  Eye cases could not be managed at secondary level treatment National Leprosy Operational Guidelines 64 Eradication Program for DPMR

Monitoring and Supervision:  Cases requiring Physiotherapy and counseling services  Record and report  Cases requiring material  Field visits support, like MCR foot-wear, crutches, protective goggles etc.  Monthly / review quarterly meetings  Laboratory facilities for smear examination  Inter-sectorial Coordination and linkages:  CBR Financial activity:  Procurement of prednisolone, aids/appliances and supportive drugs  Payment of incentives/loss of wages Source of patients

Patients referred by primary health care units and voluntarily reporting patients. Service functionaries A. Apex group at district hospitals / district referral centers B. District Nucleus Team (DNT) Operational Guidelines National Leprosy for DPMR Eradication Program 65

A) Apex Group at District Hospitals/ Referral Centers District Referral centre is meant to function to address the needs of patients referred from primary health centres and community and private health providers. The purpose of the centre is to provide specialized treatment services to persons affected by leprosy and to function as a clinical training resource for the Medical Officers and Para-medics in the district. MODN/DLO/LT/Physiotherapist/Physician at district hospital is to

coordinate DPMR services there. A ‘District Apex Group’ will consist of Dermatologist / Medical Specialist, Orthopedic Surgeon, Ophthalmologist and Physiotherapist/LT. The MODN/DLO after receiving the referred or directly reporting patient will refer the patient to concerned member of the Apex Group. These patients will be clinically assessed, hospitalized and treated or referred to tertiary care unit as per need. MODN/DLO/NMS will receive the referred cases or directly reporting cases

at the district hospital through common registration counter of OPD and the patient will then be referred to the concerned member of the apex group to get services. District Apex Group at district hospital i.e. District Referral Centre (DRC) will  Provide treatment to cases of Lepra reaction/neuritis referred or reported,  Provide treatment to eye complications in consultation with Ophthalmologists,  Provide treatment to cases with ulcers and deformities,

 Provide surgical treatment to cases with eye complications, abscess, foot drop and other surgeries possible at district hospital,  Get all the treated cases recorded in the treatment register,  Refer the cases to tertiary referral centres, which cannot be managed in district hospitals e.g. major surgery, laboratory investigations, expert’s opinion, etc.  Ensure pre and post-operative physiotherapy,  Refer back the operated cases to PHC with follow up instructions,

 Develop linkage with PHC and Tertiary Hospitals,  To prepare the required reports with assistance from PT / NMS and assess DPMR activity. National Leprosy Operational Guidelines 66 Eradication Program for DPMR

How to Manage Complicated Cases: The secondary level institutions will get complicated disability cases from the primary level for assessment and further necessary actions. Management of reactions has already been described earlier. Cases with severe reactions must be admitted and investigated appropriately. Majority of disability grade 2 cases referred to the secondary level care institutions. The treatment of eye complications has also been described earlier and all such cases should

be referred to ophthalmology department. Disability assessment – Disabilities are to be assessed to judge the extent, whether reversible / irreversible and prognosis with or without treatment. Careful clinical examination –  By taking history of duration of disability, previous treatment & its response  By sensory testing over the area  By examination of nerves through palpation & voluntary muscle testing  Eyes are to be examined for acuity of vision, redness, blink and proper closure of eye lids

 Oral and nasal examination should be done in cases of lepromatous leprosy  Disabilities assessed are to be graded and recorded Management of complicated ulcers: All wounds are the result of tissue stress. Common causes of ulcer include:  Sudden injury (e.g. sharp objects that cut or pierce through the skin like Note: thorns or broken glass) All grade 2 cases referred to district  Repetitive pressure, friction or shear forces (e.g. foot ulcers from walking hospital should be directed to

or hand ulcers from using unprotected hand tools) physiotherapy department for splintage and pre and post-operative  Burns care.  Secondary infection in macerated skin of web space with candidiasis can lead to deep abscess  Rarely rat bite can also lead to ulcer There are a few major principles that should be remembered when planning ulcer management. If these principles are followed, simple ulcers will heal without any medication:  Rest  Good wound environment  Hygiene  Protection Rest:

Operational Guidelines National Leprosy for DPMR Eradication Program 67

Almost all wounds will heal if they are rested. Almost all wounds will get worse if they are not rested. Regardless of the cause of injury, the first line in treatment of wounds is to remove the cause of tissue stress and then to allow the injured part to rest so that damaged tissue can repair itself. So long as the person with a wound is healthy, damaged tissue will repair itself. Rest doesn’t necessarily mean that the patient must stay in bed (although for foot ulcers this is often the

best option). If the person is unable to rest it may still be possible to rest the injured body part by – Splinting It will rest hand and finger wounds tissue is still being repaired. Crutches Walking with crutches (or even with a walking stick) – It will rest foot ulcers. Whatever the circumstances, the injured part should not be allowed to perform normal functions whilst the best option is for the person to spend as much time as possible, lying down with his foot raised above the level

of his heart (bed rest). However, this is very rarely possible amongst people who must struggle to feed themselves and their families, so other options should be explored. It is also very important to find out whether the person is able to change his activities so that he doesn’t need to walk so much: for example, can he temporarily swap work with another person? Other transport options should also be considered: for example, riding a bicycle. Topical antibiotics need

not be used in the treatment of ulcers in leprosy cases. Treating the ulcer is a great opportunity to reduce fear & stigma through demonstrating ulcer care without any discrimination. Family members are also encouraged to learn and practice the dressing of ulcer and nursing care of patient. Standard MCR Footwear use in leprosy: Leprosy leads to nerve damage resulting in loss of sensation of feet. Because of this, feet develop plantar ulcers which can damage the foot and lead

to deformities. Ulcers and deformities are the main reasons for stigma of leprosy. Appropriate footwear can protect feet, which have lost sensation from developing ulceration and consequent deformities. The prescribed footwear should fulfill the following criteria (1) Features: National Leprosy Operational Guidelines 68 Eradication Program for DPMR

(a) Acceptability: The footwear should be acceptable to the patient. Designs which are locally acceptable can be adopted by changing the pattern and colour of straps. (b) Well fitting: The footwear should fit snuggly with no play between the foot and footwear. Back-strap must be used in all anaesthetic feet in leprosy. The straps should have Velcro for fastening and should be adjustable to accommodate dressing or swelling of the foot.

(c) Durability: The quality of MCR should be of acceptable standards with regard to shore and longevity. Similarly the straps should have a similar longevity as that of the MCR. (2) Specifications of Materials to be used: (a) Insole: MCR should be used as an insole. MCR should not be too hard but have a shore of 15 degree. It should not be flattened, indented or hardened over a reasonable life of footwear (9/12-1 year). Different colours could be used to match outer-sole (under-sole).

(b) Outer Sole: The outer sole should be hard enough to prevent thorn/nail from piercing through it. It should be of light weight. (c) Upper Straps: Upper straps should be made of soft leather with an appropriate underlining. The straps should not harden on contact with water. (d) Velcro: Nails, buckles or clips should NOT be used. Only Velcro should be used as fasteners. Rehabilitation need assessment and Referral: The following are examples of interventions that may be available.

Problems Rehabilitation interventions Anatomical: Reconstructive surgery and Deformity of the hand physiotherapy Foot drop Ankle-foot orthosis, reconstructive surgery Amputation Prosthesis Psychological: Counseling Depression Functional: Occupational therapy Limitation of fine hand movements Mobility limitations Crutches or wheelchairs Social participation: Counseling Stigma in the family Operational Guidelines National Leprosy for DPMR Eradication Program 69

Problems Rehabilitation interventions Exclusion from community Education and advocacy functions Children with disability Promoting inclusive education Economic: Vocational training and/or Loss of employment placement Poverty Micro-credit for self-employment When to refer a case of severe reaction to tertiary care centre: Complicated cases of reactions, which need to be referred to tertiary care centres may be –  Those not responding to Prednisolone therapy  Contraindications for Prednisolone therapy

 Recurrent / repetitive ENL reaction  Lepra Reaction in children, pregnant woman, patient with diabetes, tuberculosis, osteomyelitis, infected ulcer, gastric or peptic ulcers  Lepra Reaction with undiagnosed associated disease under investigations  Lepra Reaction with nerve abscess or compressed nerve requiring surgical intervention Functioning of District Nucleus Team for DPMR District Nucleus Unit is the main coordination centre for activities under

DPMR. The District Leprosy Officer / District Nucleus Medical Officer is the nodal officer of this activity and he is responsible to receive DPMR reports from Primary, Secondary and Tertiary centres on various aspects of the programme. The role of the DNT will be: 1. District nucleus will receive all patients referred from primary level and after their registration these patients will be referred to concerned member of Apex Group for appropriate treatment. The treatment

provided at secondary level will be coordinated and recorded in appropriate record by District nucleus for future follow up.  District nucleus will also procure prednisolone and additional drugs, materials required for management of cases. National Leprosy Operational Guidelines 70 Eradication Program for DPMR

 District nucleus will maintain all records prescribed in the guidelines, for secondary level.  DN will screen cases for RCS, arrange RCS Camps and Workshops and also look after transportation and payment of incentives.  DN will be responsible for compilation of reports and its submission to state.  District nucleus will keep track with tertiary level institutions for services provision of referred cases and for their follow-up.  Overall programme planning, implementation, monitoring, supervision

and training will be responsibility of DN. 2. The District nucleus will maintain a Register of all such cases referred by PHCs. The secondary level centres will send a list of all disability cases registered by them as referred by PHCs or directly to the District nucleus every for record. Similarly tertiary level centre will also send a list of all disability cases registered by them directly to the District Nucleus for record. Caution is to be taken to avoid duplication of recording same cases.

3. While referring complicated cases from the secondary level to the tertiary level care centres, a copy of the referral slip will be marked to the District nucleus for record. 4. Tertiary level care centres will intimate the District nucleus, the leprosy cases operated upon; through a monthly report for updating their record and to facilitate payment of expenditures if any, to the patient or the institution as per GOI rules. 5. The District nucleus will be responsible to arrange procurement of all

drugs and materials required under DPMR and supply to the primary, secondary and tertiary centres as per GOI rules. Operational Guidelines National Leprosy for DPMR Eradication Program 71

Materials required at district level Aids and Appliances Protective aids (Goggles, eye shield): For using Lagophthalmos Pumice Stone/scrub: To remove the callous for protects from dust, sunlight and insects. and hard skin. Mittens, cotton glove, and Towels: To protect hands from Lumbrical splints: To prevent weaknesses of heat to prevent burns intrinsic muscles and to sustain post-operative Lumbrical/functional position.

Cylindrical Splints: To prevent / release skin and joint Gutter Splints: To prevent inter-phalangeal joint contractures contractures. Dynamic Splints: To keep the fingers mobile to prevent Adductor Band: To keep little finger in contractures. adduction position. Posterior Slabs (arm): To immobile elbow joint Posterior Slab (leg): To immobile knee joint and/or ankle joint. Thumb Spica: To prevent the thumb web contractures. To Crutches: To assist non-weight bearing gait.

protect thumb movements (Opponens to fingers) Physiotherapy Equipments Wax Bath To maintain the softness of the anaesthetic limbs Semmes-Wienstein Filaments Sensory testing Soaking Tubs For self-care practice Walking Parallel bar To monitor the walking styles (foot gait) Materials and Equipment Physical Surgical Instruments Shoe Unit Material Details of Rooms arrangements Auto clave Leather Sewing Machine Physiotherapy room Two Long benches size 18 x 12 ft size 6x3x0.6 ft

Sterilizer Grinding Machine (½ hp), grinding Stock room One Long table stone size 10 x 10 ft size 6x2x2.6 ft Artery Forceps (Artery, Iron shoe last, Gutum, Hammer, Shoe unit room Six Sitting stools Thumb, mosquito) Big scissors size 12 x 10 ft with (plastic) exhaust fan Probe Cutting blade, repair needles Two tables Surgical Scissors Leather cutting knifes, nose blare Two chairs B P scalpel Handles size Punch scar, curved edged knife, hole no. 4 and blade size 21 punch

Needle holder and Stitch Highlight punch, press machine remover POP cutter (Manual) Saw blade with stand Steel Tray with lid Wooden loses no. 5–10 Kidney Tray Oil Stones Harris mat MCR sheets, Leather, Outer sole material, Velcro, resin pasting solution, thread, buckles National Leprosy Operational Guidelines 72 Eradication Program for DPMR

Training Requirements Training will be needed for the Dermatologists, Physician, Ophthalmologist, Orthopaedic surgeons, physiotherapy technicians and lab. technicians as appropriate and needed under the program. Operational guidelines and DPMR–training module cum manual for the district hospital and district nucleus will be provided. Organizing training District nucleus will assess the training needs of GHC staff engaged in NLEP work and will be responsible for arranging formal & on the job trainings.

Trainers will consider the following points. 1. Plan for preparations, conducting and follow up of training courses should be prepared by the district in consultation with the State Leprosy Officer 2. Prepare ‘learning objectives’ according to job / task given to trainee / different category of staff and then design the curriculum 3. Concentrate on ‘how to achieve learning objectives’ through active learning process 4. Select appropriate teaching method for each session e.g. case

demonstration, role play, group exercises, case study etc. Select the content and teaching aids required 5. Try to remove barriers / factors distracting learning 6. Evaluate the training course, assess the participant’s reaction & learning at the end of the course and later on evaluate the performance on the job and effect of training after few months. Operational Guidelines National Leprosy for DPMR Eradication Program 73

Supervision & Monitoring The District Nucleus under the DLO will monitor the DPMR activities at the secondary level. The health care professionals should know the definitions and be able to differentiate between commonly used terminologies in the management of programme, such as supervision, monitoring and evaluation. Supervision: It is systematic process for increasing the efficiency of health workers by developing their knowledge, Perfecting their skills, Improving their attitudes

towards their work and increasing their motivational levels. Supervision is extension of training, intensified immediately after training, to ensure that health workers have fully acquired the skills taught and to provide any guidance needed. It is carried out in direct contact with the health worker and it is aided by programme monitoring. All health workers need help to solve problems and overcome difficulties. They also need feedback on their performance and encouragement in their work.

Supervisory visits to health units by the District Nucleus Team He should visit CHC/PHCs to verify records, reports and for validation of data at least once in a month. He should randomly validate some cases quality of diagnosis and management. He should provide hands on training to PHC/CHC/Sup/HW during supervisory visits. He should visit cases with disability to verify self-care practice carried out by patient. He should verify the use of splints. Self-care kits, MCR footwear and other

physical aids as well as make a need assessment. He should interact with ASHA, GKS members and patients and community to know the awareness regarding program. He should visit few RCS cases to know the outcome of operation. Monitoring The main objective of monitoring is to identify and resolve operational problems as soon as they emerge. Realistic solutions to operational problems will call for identification of causes and corrective action. Monitoring is essential for the following.

 to ensure implementation of planned activities  to measure the results through indicators  to check the records for correctness and completeness  to check the reports & compile them  to conduct review meetings National Leprosy Operational Guidelines 74 Eradication Program for DPMR

Secondary Level Job Responsibilities: Job responsibility of DLO / DNMO in District Nucleus Team:  Assist in planning & implementation of all NLEP activities in the district  Ensure timely submission of Monthly Progress Report (MPR) by Block PHCs to the district and its compilation  Ensure MDT, Prednisolone, foot-wear and other logistics are indented properly at all levels  Cross check newly detected cases with their disability status, in the district

 Ensure good liaison with the Dermatologist and members of District Apex Group, Tertiary institutions and State Leprosy Cell as well as peripheral institutions  Visit District Hospital and a reasonable sample of Block PHCs, Sector PHC and Sub-centres every month and submit an action taken report on integration, SIS Implementation, MDT stock management, case validation, Physiotherapy services, skin smear examination, IEC, DPMR & RCS activities, etc.

 Ensure that all the reports of the districts are timely submitted to the state  Provide technical and operational support to all the peripheral health institutions in the district using different innovative approaches Job Description of Physiotherapist/physio-technitian Job responsibilities 1. Undertake regular nerve function assessment and record the same 2. Maintain individual patient record and prioritize them according to the frequency of follow-up needed

3. Provide relevant physiotherapy for patients with deformities and ulcers 4. Teach self-care and provide information and demonstrate exercises to be carried out at home 5. Ensure pre and post-operative management and RCS referrals 6. Ensure podiatry applications, self-care demos and provide supplementary aids 7. Liaise with health staff and district nucleus staff for smooth coordination 8. Update records & registers and submit periodical reports to the concerned Operational Guidelines National Leprosy

Job Description of Footwear Technician Job responsibilities 1. Take the foot measurements, design and make footwear 2. Ensure proper alteration or repair of footwear 3. Proper storage of finished products and ensure its safety 4. Ensure prompt delivery of finished products 5. Report to the Medical Officer on the adequacy of stocks well in advance 6. Ensure safe disposal of waste materials 7. Submit periodic reports to concerned authorities Records & Reports

Records to be maintained at Secondary level are as under: (a) District Hospital (District Referral Centre)  Disability Register: Form – S 1  Disability Assessment Form: Form – S 2  Record of Lepra Reaction & Neuritis: Form – S 3  Prednisolone Card: Form – S 4  Referral Slip: Form – S 5  Record of Disabled / Complicated cases at District referral Centre: Form – S 6 (b) District Nucleus  Disability Register with District Nucleus: Form – S 7

 Monthly progress report from district to state: MLF 05 (Page-2) National Leprosy Operational Guidelines 76 Eradication Program for DPMR

IMPLEMENTATION OF DPMR SERVICES AT TERTIARY LEVEL Objectives for tertiary care centers  To provide DPMR services (mainly RCS) with provision of aids and appliances.  To hold camps and workshops for clearing of backlog of cases in need of RCS and training of surgeons.  To integrate DPMR/RCS services in to medical colleges, PMR institutes and District hospitals. Tertiary Level Institutions - Apex Centers South: Other support units (i) CLTRI, Chengalpattu, Tamil Nadu 1. Orthopedics and plastic surgery

(ii) DFIT Hospital, Nellore, Andhra Pradesh department of medical colleges 2. Identified NGO institutions (iii) CMC Vellore, Tamil Nadu 3. All national institutes under (iv) SLR&TC, Karigiri, Tamil Nadu Ministry of Social Justice and Empowerment North: 4. Contractual surgeons skilled (i) JALMA, ICMR, Agra, Uttar Pradesh in RCS and Rehabilitation Programme (ii) TLM Hospital, Naini, Uttar Pradesh 5. All PMR Institutes and (iii) TLM Hospital, Shahadra, Delhi dermatology, ophthalmology, microbiology, pathology

(iv) Plastic surgery department, medical college Lucknow departments of medical colleges East: 6. Leprosy Research Institutes (i) PMR Department, Patna Medical College, Bihar (ii) TLM Hospital, Kolkata (iii) RLTRI Raipur (iv) Leprosy Home and Hospital, Cuttack West: (i) J.J. Hospital, Plastic Surgery Department, Mumbai, Maharashtra (ii) All India Institute of Physical Medicine & Rehabilitation, Mumbai, Maharashtra Operational Guidelines National Leprosy for DPMR Eradication Program 77

State/UT wise GoI recognized Reconstructive Surgery (RCS) Centres State District Sr. No. RCS CENTRES Government NGO Andhra Chhittor 1 Emmaus Swiss Referral Hospital & Pradesh Leprosy Project Rajamundry 2 Rural India Self-Development Trust Nellore 3 Urban Leprosy Centre West Godavari 4 The Leprosy Mission Hospital, Narsapur 5 Damien Leprosy Center, Vegavara, Gopannapalem, Eluru Hyderabad 6 Sivanand Rehabilitation Home Vizianagaram 7 Philadelphia Leprosy Hospital East Godavari 8 The Leprosy Mission Hospital,

Ramchandra Puram Guntur 9 GRETNALTES, Morampudi, district Guntur Secunderabad 10 Gandhi Medical College & Hospital Sub-Total 10 1 9 Assam Guwahati 11 Guwahati Medical College & Hospital Sonitpur 12 Catholic Hospital Charitable Sub-Total 2 1 1 Bihar Muzaffarpur 13 The Leprosy Mission Hospital Patna 14 Patna Medical College Dharbhanga 15 Dharbhanga Medical College Sub-Total 3 2 1 Chhattisgarh Janjgir 16 Bethesda Leprosy Home and Hospital Bilaspur 17 Chandkhuri Leprosy Hospital and Home

Raipur 18 Regional Leprosy Training & Research Institute Sub-Total 3 1 2 Chandigarh Chandigarh 19 Government Medical College Sub-Total 1 1 0 Delhi North East 20 The Leprosy Mission Hospital, Delhi Shahdhara Sub-Total 1 0 1 Goa Panaji 21 Goa Medical College Hospital Sub-Total 1 1 0 Gujarat Vadodra 22 S.S.G. Hospital Ahmedabad 23 Civil Hospital Sub-Total 2 2 0 Haryana Rohtak 24 Post Graduate Institute of Medical Secince Sub-Total 1 1 0 National Leprosy Operational Guidelines 78 Eradication Program for DPMR

State District Sr. No. RCS CENTRES Government NGO Jharkhand Ranchi 25 Regional Institute of Medical Science Jamshedpur 26 MGM Medical College Hospital Ranchi 27 Radharani Rehabilitation Centre * Giridih 28 Holy Cross Hospital Sub-Total 4 2 2 Karnataka Dharwad 29 Hospital for Handicapped, Hubli Tumkur 30 Sri Ramakrishna Sewa Ashram SVIRHC, Pavagada Belgaum 31 The Leprosy Mission Hospital, Vengurla Road, Hindalga Sub-Total 3 0 3 Madhya Khargaon 32 St. Joseph Leprosy Centre, Sanawad

Pradesh Bhopal 33 Government Medical College Hospital Jabalpur 34 Seth Govind Das Govt. District Hospital Sub-Total 3 2 1 Maharashtra Mumbai city 35 Acworth Municipal Hospital for Leprosy Wadala, Mumbai* 36 Sishu Prem Samaj, 101/C – Mountana Building, Road No- 2, Lokandwala Complex, Andheri West 37 All India Institutes of Physical Medicine and Rehabilitation 38 Grant Medical College & J.J. group of hospitals* 39 Vimla Dermatological Centre, Yari Road, Varsova, Nagpur 40 N.K.P. Salve Institute of M.S. and

Lata Mangeshkar Hospital, Amravati 41 Kothara Leprosy Hospital, P.O. Paratwada, District Amravati Sangli 42 Richardson Leprosy Hospital, Miraj, District Sangli Raigad 43 Parbhani 44 Civil Hospital, Parbhani Dhule 45 Medical College, Dhule Aurangabad 46 Medical College, Aurangabad Bhandara 47 Govt. General Hospital Pune 48 Dr. Bandorwalla Leprosy Kondwa, Yevalewadi Pune 49 Sasoon Hospital Sub-Total 14 9 5 Operational Guidelines National Leprosy for DPMR Eradication Program 79

State District Sr. No. RCS CENTRES Government NGO Manipur Imphal 50 Regional Institute of Medical Sciences Sub-Total 1 1 0 Orissa Cuttack 51 Cuttack Medical College Hospital 52 Leprosy Home & Hospital Cuttack Ganjam 53 Berhampur Medical College Sambalpur 54 V.S.S. Medical College & Govt. Hospital, Burla* Jharsuguda 55 District Hospital * Rayagada 56 HOINA Leprosy Research Trust, Muniguda Baragarh 57 Mission Hospital, Baragarh Mayurbhanj 58 District Hospital Sonepur 59 District Hospital

Bhubaneshwar 60 Hi-tech Medical College & Hospital 61 SSB Hospital 62 IMSS & SUM Hospital Koraput 63 District Hospital Bolangir 64 District Hospital Sub-Total 14 9 5 Puducherry Puducherry 65 General Hospital Sub-Total 1 1 0 Sikkim Gangtok 66 STMN Govt. Hospital Sub-Total 1 1 0 Tamilnadu Vellore 67 Schieffelin Leprosy Research & Training Centre, Karigiri Tanjore / 68 Sacred Heart Leprosy Centre, Thanjavur Sakkotai Tiruchiorappalli 69 Holy Family Hansenorium, Fathimanagar Salem 70 Leprosy Relief Rural Centre,

Chettipatty Chennai 81 GREMALTES, Shenoynagar Villupuram 72 The Leprosy Mission Hospital, Vadathorsalurl Sivaganga 73 Dayapuram Leprosy Centre, Manamadurai Kancheepuram 74 Central Leprosy Teaching & Research Institute, Chengalpattu Chennai 75 Stanley Medical College Hospital Sub-Total 9 2 7 National Leprosy Operational Guidelines 80 Eradication Program for DPMR

State District Sr. No. RCS CENTRES Government NGO Uttar Pradesh Faizabad 76 The Leprosy Mission Hospital, Motinagar Allahabad 77 The Leprosy Mission Hospital, Naini Agra 78 JALMA – ICMR Lucknow 79 King George Medical College Varanasi 80 Pt. Deen Dayal Upadyay Hospital Sub-Total 5 3 2 Uttarakhand Dehradun 81 District Hospital Dehradun Sub-Total 1 1 0 West Bengal Purulia 82 Purulia Leprosy Home and Hospital Kolkata 83 SSKM Hospital Premananda Memorial Leprosy Hospital 84 R.G. Kar Medical College

85 N.R.S. Medical College Midnapur West 86 Jhargram S.D. Hospital Burdwan 87 Durgapur S.D. Hospital South Dinajpur 88 Balurghat District Hospital North Dinajpur 89 Raiganj District Hospital Coochbehar 90 MJN District Hospital Sub-Total 10 8 2 Total 90 49 41 Operational Guidelines National Leprosy for DPMR Eradication Program 81

Guidelines for Surgeons Reconstructive surgery aims to restore function and form as far as possible and to prevent further disability. It also plays an important role in the prevention of disability and rehabilitation process. Some patients can benefit from reconstructive surgery but not all patients are suitable. Pre and post-operative physiotherapy is essential for a successful outcome of surgery and needs to be arranged. Leprosy leads to physical,

functional, social and/or economic problems. Physical rehabilitation includes physiotherapy and occupational therapy, orthotics and prosthetics services, assistive and protective devices and reconstructive surgery. Persons affected by Leprosy with disability and deformity can be referred to specialist for surgical correction. The following are the major points in the guideline on RCS:  Besides completion of treatment and being free from reactions,

the joints should be mobile. In case any stiffness is noted pre-operative physiotherapy and splintage needs to be carried out.  In case patient is undergoing nerve decompression surgery for neuritis the corticosteroid treatment should be stopped at least before 2 to 3 weeks. Despite that anesthetist or the operating surgeon must be aware of patient having been on steroid therapy. A single dose of steroid at the time of surgery may prevent any complication arising. Post operatively too if any

problems due to steroid withdrawal is encountered patient must be given steroid overriding the fact of delayed healing or marred result. By and large, for tendon transfers patient should not be undergoing steroid therapy and should have completed steroid therapy at least six months prior to being taken up for surgery.  There should be no focus of infection like ulcer or blister on the limb to be operated. The patient should not have any complicated ulcers of the other limbs or in another part of the body.

 The patient should be willing to be admitted for the surgery, be willing to spend one week preoperatively for physiotherapy if indicated and three weeks in plaster cast and later be admitted for a period of four weeks for post-operative physiotherapy. He may go home in between these periods with the permission of surgeon. For the foot drop the duration must be at least one year of deformity and it may take as long as six weeks in plaster and another six weeks for physiotherapy.

National Leprosy Operational Guidelines Operational Guidelines National Leprosy 82 Eradication Program for DPMR for DPMR Eradication Program 83

 In cases of contractures or restricted mobility, the surgeon may decide on surgical and or non-surgical like serial POP splintage or continuous use of dynamic (elastic) gutter splints to release these contractures, make the skin soft and then take the patient up for tendon transfer surgery.  In the cases with lagophthalmos if cornea is exposed and there is threat to eye, immediate surgery of tarsorraphy may be done overriding other precautions but for tendon transfer same rules

like hand apply. Only different advice is that he/she will be put on liquid diet for three weeks post-op. However, some recent operations (not tendon transfers) do not need such advice.  Resurfacing for sole of the foot for plantar ulcer may require much longer duration of hospitalisation for skin graft or flap cover and patient shall be informed about the same.  While operating on the nose for collapsed or depressed nose a good clinical examination is necessary to rule out presence of ulcers in

the mucosa. As this deformity generally occurs in MB and smear positive cases, they should have completed at least 12 months of MDT and duration of collapse also should be longer than 12 months. A negative nasal smear report is must before surgery.  Septic surgery threatening the life of patient like gangrene may be dealt with as emergency in septic OT and previously mentioned guidelines do not apply to these cases. Criteria for Surgical Management  Unemployed - RCS

Deformities requiring RCS Primary Deformities Primary deformities arise due to involvement of peripheral nerves or follow the infiltration of the skin or mucosa by M. leprae. Neural involvement is generally seen in the tuberculoid type while mucosal and cutaneous involvement is seen in the lepromatous type. However, nerves can also be involved in the lepromatous type during the episode of reaction as well as at a later stage of the disease. In the neuritic type, primary and/or early affection

of the nerves may occur. The examples of primary deformities which result from neural involvement are claw hand, foot drop and lagophthalmos. Cutaneous involvement leads to the loss of eyebrow, wrinkling or sagging of facial skin and thickening of ear lobules. The nasal mucosal involvement and its subsequent sequelae produce the characteristic depressed nose. All these features constitute the prominent stigma of the disease. Secondary Deformities

Secondary deformities occur due to failure of realisation that the anaesthetic areas such as the hands, feet and cornea require special attention. Deformities of hands occur following unnoticed and uncared for injuries that may result from burns due to holding hot utensils, pressure necrosis, injuries at work, etc. the anaesthetic skin being dry, cracks easily and secondary bacterial infection in these cracks leads to formation of abscesses, inflammation of

synovial sheaths, or osteomyelitis of the phalanges. In the foot, plantar ulcers occur due to pressure damage and other unnoticed accidental injuries. These ulcers if neglected lead to osteomyelitis with sequestrum formation and finally shortening of the limb. In affection of eyes, keratitis, corneal opacities and other eye complications are likely to occur due to suppression of blinking reflex or due to lagophthalmos. Reconstruction of sole following plantar ulcers

In the recent years lot of momentum is gained for resurfacing the sole of the foot following plantar ulcers. Right from skin grafts to local transposition flaps, from myocutaneous flaps to neurovascular island pedicle flaps have revolutionised the surgery for plantar ulcers. Therefore, it is important to understand that such cases may need prolonged hospitalisation, immobilisation in the POP casts, walking with crutches for non-weight bearing even while in the hospital and specialised

footwear after healing has taken place. National Leprosy Operational Guidelines Operational Guidelines National Leprosy 84 Eradication Program for DPMR for DPMR Eradication Program 85

Charcot’s foot The clinician should remember that the most common problem affecting the anaesthetic foot and ironically the most commonly overlooked Indications for Surgery in Brief diagnosis is that of acute neuropathic disintegration of the foot or chronic 1. Diagnostic: skin and nerve neuropathic disintegration of the foot. The patients do not complain of biopsy. any problem or it may be only of swollen foot. On palpation, if the foot 2. Prevention of primary

is warm or ‘hot’ this is the earliest sign of the hot foot. The condition deformity – : nerve decompression. should be suspected whenever a swollen anaesthetic foot is seen and is confirmed by palpation. Regardless of X – ray findings treatment should 3. Correction of primary deformity. be immediately instituted otherwise the ankle may dislocate and present with an ugly abnormal foot which may finally end up in an amputation. 4. Cosmetic Reasons

The management includes total contact POP cast for 2-3 months Depressed nose followed by graduated walking (Partial Weight Bearing-full Weight Bearing) Facial wrinkling and watching for recurrence of swelling or heat. If it recurs, then POP should Ear lobule be reapplied and patient will probably require a Fixed Ankle Brace (FAB). Loss of eyebrows Nerve decompression surgery Empty thumb web space It has been established that peripheral nerves passes through the fibrous tunnel 5. Functional Benefits

at certain points in their course. The sites of predilection of nerve affection Ulnar claw hand in leprosy are near these tunnels. Being an anatomical structure it does not Total claw hand (thumb expand to accommodate the thickened nerve and thereby causes compression deformity) on the nerves resulting in the loss of conduction power of axons. Foot drop Ideally, if in leprosy nerves can be treated early deformities can be prevented. Claw toes

Nerve decompression is one such modality which is used by the surgeons Lagophthalmos to get some results in cases with compression and no improvement with 6. Correction of Secondary steroid therapy. Its indications are varied but can be summarised as to relieve deformities pain and tenderness, drain an abscess and if there is deterioration in nerve Plantar ulcers function. Patient may or may not be on MDT or in reaction as its outcome Contractures is not dependent on it. Joint stiffness

Patients who have chronic pain and swelling in peripheral nerves which Post-operative complications does not respond to analgesics and a course of steroids should be considered for nerve decompression. National Leprosy Operational Guidelines Operational Guidelines National Leprosy 84 Eradication Program for DPMR for DPMR Eradication Program 85

List of Instruments Required for RCS 1. Tendon Tunneller 13” cvd 2 Nos. 2. Tendon Tunneller 13” st 2 Nos. 3. Tendon Tunneller 7” cvd 2 Nos. 4. Tendon Tunneller 7” st 2 Nos. 5. Tendon hooks 2 Nos. 6. Skiin hooks 4 pairs (8 Nos.) 7. Metzebaum scissors 5” cvd, fine 4 Nos. 8. Metzebaum scissors 7” cvd 4 Nos. 9. Metzebaum scissors 7” st 4 Nos. 10. Adson’s forceps - toothed 6 Nos. 11. Thumb forceps 6” toothed 4 Nos. 12. SS Spatula (as per sample) 2 Nos. 13. Artery forceps 5” (mosq – fine) 8 Nos.

14. Artery forceps 6” cvd,ord 6 Nos. 15. Artery forceps 6” st,ord 8 Nos. 16. Artery forceps 5” (mosq – rt. angled) 2 Nos. 17. Kocher’s forceps 6” 4 Nos. 18. BP Handle No. 3 4 Nos. 19. BP Handle No. 4 4 Nos. 20. Fascia lata stripper 2 Nos. 21. Senn’s retractor 4 Nos. (2 pairs) 22. Cat’s paw retractor 4 Nos. 23. Iris scissors cvd 2 Nos. 24. Needle holders 8 Nos. (2 fine & 2 blunt) 25. Plaster cutting scissors (as per sample) 4 Nos. 26. Heath’s suture cutting scissors 4 Nos.

27. Engel’s Plaster cutting saw 4 Nos. 28. POP Shears 2 Nos. (1 Bohler & 1 Guy’s shears) 29. Plaster cast spreader – Henning 2 Nos. 30. Plaster bender – Bohler 2 Nos. National Leprosy Operational Guidelines Operational Guidelines National Leprosy 86 Eradication Program for DPMR for DPMR Eradication Program 87

Outreach Services for DPMR and RCS Organisation of Camps Recently, there has been increasing focus on reaching expert services to the grass root level through camps. These camps are basically of two types. One is where disabled patients are rendered services as well as patients in need of RCS are identified and referred to nearby tertiary care center. Another type of camp is for carrying out training of local surgeons at their own set up by sending a team of surgeons and holding the RCS camp in which few

demonstration surgeries are performed. The following tasks are undertaken at RCS selection and DPMR service camps. Assessment of risk status Patients with multiple skin patches, painful nerves, reactions etc. are at high risk for developing disability. A separate list is made and given to district authorities for their follow up. Children are examined separately by senior doctor. They are advised to report immediately in case of any nerve pain,

loss of sensation, weakness of muscles, appearance of numbness tingling/ paraesthesia in the hand, face and foot and also involvement of eye. Those who come with disability are told how to take care of themselves and to recognize signs and symptoms of worsening of disability. Providing DPMR services Besides teaching physiotherapy in group and providing splints to hand deformity cases, few patients with absorption of fingers may need Instant Grip-Aid Kit. Instant Grip-Aid Kit for advanced Instant Grip-Aids

hand deformity These are required mainly for patients staying in colonies and have long term leprosy with advanced deformities of the hand. With absorption and amputations of fingers they face difficulty in holding and using articles of daily use like for eating, drinking, brushing teeth, combing, toilet visits etc. The “Instant Grip-Aid Kit” is a tremendous boon for such cases. This kit is also used to overcome handicap in other disabilities like burns and amputation of

fingers thereby, integrating its use in the standard tertiary care hospital. Patients with foot drop are given the foot drop splint and patients suffering from ulcers are provided with self-care kit. These patients are then given a demonstration on the use of the self-care kit. Each of these patients with ulcers on the foot is also provided with MCR footwear at the camp. Tertiary care institutes need to have liaison for getting MCR footwear.

National Leprosy Operational Guidelines Operational Guidelines National Leprosy 86 Eradication Program for DPMR for DPMR Eradication Program 87

Self-Care Kit / Ulcer dressing kit Most patients are very poor and cannot afford to buy the materials needed to care for their feet. Providing patients with the self-care kit free of charge overcomes this obstacle. The self-care kit motivates patients to take care of their feet and gives them the tools to do so. It also has a very positive synergistic impact, as they witness the improvement and are motivated to continue to use it. They also feel more in control of their disabilities and remove their

self-perception as an “invalid” who needs to visit a clinic or doctor regularly. In the event of a recurrence, the patient knows how to deal with it and uses any remaining materials from the kit and contacts the health services Precaution immediately, thereby promoting healing in a shorter period and preventing It must be understood that the self-care kit is not meant for large worsening of the disability. ulcers which at once can be recognised

Patients may become dependent on the service provides for replacement as in need of surgery. It may be used without scraper as dressing material and a discontinuation in the supply may lead to a sense of dejection/rejection. till admission for surgery, particularly Hence follow-up services must be an integral part of the program. As the for chronic ulcers as seen in patients kit is useful in any home, there is often a demand for it as a “first aid kit”. residing in leprosy colonies. On no

account expectations are raised by Pilferage of kits may occur at all levels of distribution, leading to the escalation cure with the kit in such cases. of costs. MCR footwear Special MCR foot-wear is not recommended routinely for all patients. Any suitable foot-wear with prerequisites such as soft inner sole, hard outer sole (to prevent piercing of thorns/nails), that fits snugly and also has adjustable straps preferably with a back-strap can be used.

The foot-wear should be stuck or stitched by thread and not by nails. Also it should be comfortable, locally available and socially acceptable of different designs. However, if there is a provision available for MCR then it should be indented as per the number of cases with grade 1 & grade 2 disabilities of foot. Goggles & Loose Materials Patients with lagophthalmos are given the goggles and advised as necessary to prevent corneal ulceration. There are also such patients

who require only some loose materials. Accordingly some Vaseline, liquid paraffin, oil, gauze pieces, anti-septic ointments etc. are also taken and distributed at the camps. National Leprosy Operational Guidelines Operational Guidelines National Leprosy 88 Eradication Program for DPMR for DPMR Eradication Program 89

Minimum 50 patients are expected to attend each of these DPMR camps. All these patients are followed up monthly to substitute the given materials and are assessed for the result after four months. It is only the regular services which increase the confidence of patients and family in the health system. They tend to come forward easily later on if they have any problems. Selection for RCS All patients with deformities and mobile joints fall in to category for

selection of RCS provided they have fulfilled the other criteria. They are given a date for operation and referred to the tertiary care center or district hospital as decided earlier between chief surgeon and superintendent of the hospital. National Leprosy Operational Guidelines Operational Guidelines National Leprosy 88 Eradication Program for DPMR for DPMR Eradication Program 89

 Training of primary and secondary level staff at tertiary care institutes.  Training curriculum and its duration to be decided by core committee for each category. Training to be given by resource persons from established surgical units with demonstrations and trainee assisting the operations. National Leprosy Operational Guidelines Operational Guidelines National Leprosy 90 Eradication Program for DPMR for DPMR Eradication Program 91

Logistics and Supplies All tertiary care institutes should have:- 1. Fully equipped operation theatre and Medical Rehabilitation Centre. 2. All instruments, gadgets, aids and appliances required. 3. Adequate stock of Medical supplies like steroids, loose Clofazimine, Thalidomide, POP, dressing material etc. Procurement of materials The State Leprosy Societies will procure all materials required under DPMR plan and arrange to supply same to the concerned Govt. and Non-ILEP

institutions through the concerned District Leprosy Society as decided by the State Implementation Committee. Concerned ILEP organization will procure all materials required for their respective tertiary care centres. Drugs Prednisolone, Loose Clofazimine, Thalidomide and other supportive drugs. Prednisolone Reactions in Leprosy are medical emergencies. Immediate treatment is essential to prevent disability. Steroids are the drug of choice in managing

Lepra – reactions, usage in the form of Prednisolone is desirable. Total number of 5 mg tablets of Prednisolone, required to treat an episode may be 336-462-518 tablets as per the recommended schedule of 3-6 months. Loose Clofazimine It should be made available in loose form as 100 mg capsules apart from its routine availability in MDT Blister Calendar Packs. It has good anti- inflammatory properties in 300 to 400 mg per day in divided doses. But it

takes nearly a month to act hence steroids should be the first line of treatment. Clofazimine is useful especially in weaning a patient from steroid therapy. Also it can be combined with steroids in patients who require prolonged doses of steroids to control repeated reactions. It should be started as thrice daily for one/two months, twice daily for one and tapered off. National Leprosy Operational Guidelines Operational Guidelines National Leprosy

Thalidomide It is an effective drug in the treatment of severe ENL in leprosy. Thalidomide must be administered under the strictest possible supervision. Procurement of Thalidomide and its use may be as per GOI directions. Other supportive drugs Antacids, H2 receptor blockers, de-worming tablets, calcium supplements, soluble insulin for diabetic patients, antibiotics etc. requirement needs to be anticipated and kept ready. Physical Aid Materials

Provision of splints, crutches, grip-aid, self-care kit etc. is also required in most of the cases and these should be arranged depending on the total load of grade 2 cases in the community. Supply chain, particularly for MCR footwear distribution twice in a year needs to be established. ANNEXURES OF FORMS Form T-1: Disability register Form T-2: Record form for Disability & Nerve Function Impairment, Motor and Sensory Form T-3: Lepra reactions Form T-4: Prednisolone card

Form T-5: Record of cases at tertiary level Form T-6: Special discharge card with follow-up Form T-7: RCS follow-up form Form T-8: RCS monthly report form Form T-9: Monthly report of Grade II cases registered directly at tertiary care institutes. Form T-10: Record of patients on Thalidomide treatment National Leprosy Operational Guidelines Operational Guidelines National Leprosy 92 Eradication Program for DPMR for DPMR Eradication Program 93

Form P1/S1 Disability Register PHC/ CHC _________________ District ____________________ State ___________________________ Sr. Name of the patient Age/ Address New MB/ New Case Disability Site of disability No. Sex Village/ UTI/Old PB (NC)/ Gr.-I/II Eye Hand Foot Sub-centre/ Case UT case/ PHC RFT Gr-0 Gr-II Gr-I Gr-II Gr-I Gr-II 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Ulcer EHF Neuritis Reaction/ DPMR Services Provided Refer to secondary with date Simple/ Type-I/

Steroid/ Self-care Ulcer Other RCS Complicated Eye Reaction not Complicated Type-II dose/ practice Dressing if any Ulcer responding to duration steroid 15 16 17 18 19 20 21 22 23 24 25 26 New Disability developed after Referral Services provided/ starting of prednisolone Follow up taken up/Remarks Eye Hand Foot (Gr-II) (Gr-I/ (Gr-I/ Gr-II) Gr-II) 27 28 29 30 National Leprosy Operational Guidelines Operational Guidelines National Leprosy 92 Eradication Program for DPMR for DPMR Eradication Program 93

Form P2/S2/T2 Disability Assessment form Assessment of Disability & Nerve Function Name ...................................................... Village ................................. Dt. of Regn ................................ S/o.W/o.D/o. .......................................... Sub Centre .......................... Dt. of RFT .................................. Gender/Age ............................................ MDT No. .............................. Referred by ................................

Occupation ............................................. MB/PB ................................ Date of assessment ................... RIGHT LEFT Date Vision (0,1,2) Light Closure lid gap in mm. Blink Present / Absent Little Finger Out Thumb Up Wrist Extension Foot Up Disability Grade Hands Disability Grade Feet Disability Grade Eyes On date Max. (WHO) Disability Grade EHF score Signature of Assessor Muscle power: Score of vision: counting fingers at 6 meters S = Strong 0 = Normal

W = Weak 1 = Blurred vision P = Paralysed 2 = Unable to count fingers This form should be filled-in at the time of registration and repeated after 3 months (once in 2 weeks in case of neuritis/reaction) National Leprosy Operational Guidelines Operational Guidelines National Leprosy 94 Eradication Program for DPMR for DPMR Eradication Program 95

SENSORY ASSESSMENT National Leprosy Operational Guidelines Operational Guidelines National Leprosy 94 Eradication Program for DPMR for DPMR Eradication Program 95

Form P3/S3/T3 Record of Lepra Reaction / Neuritis Cases Name of Hospital ............................................. District ...................................... State ............................... Col. Col. No. 2 Col. No. 3 Col. No. 4 Col. No. 5 Col. No. 6 No. 1 Type of leprosy Lepra reaction Date of MDT No./ S. No. Name of the patient Type Neuritis registration registration No. MB PB I II Y N Col. No. 7 Col. No. 8 Col. No. 9 Col. No. 10 New disability Treatment given developed after start Remarks

of Prednisolone Prednisolone doses issued with dates Other drugs Yes No from upto How to fill the Form T III Column 1 : Serial no. of reaction cases is to be given Column 2 : Complete name with surname along with son / daughter / wife of should be written Column 3 : Date of registration of MDT is to be written Column 7 : Doses of Prednisolone in milligram with date of issue to be filled Column 8 : Enter Clofazimine, Analgesics, Mebandazole, or any other drug given

National Leprosy Operational Guidelines Operational Guidelines National Leprosy 96 Eradication Program for DPMR for DPMR Eradication Program 97

P4/S4/T4 - Prednisolone Card Prednisolone Card (This card should be kept with the patient) Other drugs issued ............................................. NATIONAL LEPROSY ERADICATION PROGRAMME ........................................................................... PREDNISOLONE – CARD ........................................................................... Name of the patient ............................................. ...........................................................................

Reg. No./MDT No. ............................................... Progress / Remarks ........................................... Type ............................................MB / PB ........................................................................... Date/due Date of RFT .......................................... ........................................................................... Indication for Prednisolone therapy:

........................................................................... ............................................................................ Signature of MO ................................................. Name ................................................................. Date of starting Prednisolone ............................... Place ................................................................. Signature of MO / Supervisor ...............................

INSTRUCTIONS PREDNISOLONE RECORD • Take Prednisolone tablets as single dose Dosage Date of Next due Signature daily with milk/food but never on empty issue date stomach 40mg x 2 wk. • Restrict salt intake till on Prednisolone 30mg x 2 wk. • Inform soon if you notice black stool 20mg x 2 wk. (malena), pain upper abdomen or vomiting • Inform immediately if discharge in planter Do (if required) ulcer, any focus of infection, persisting 15mg x 2 wk. cough, mild fever or any deterioration

• Don’t stop Prednisolone before impletion Do (if required) of regimen, even if there is improvement or deterioration. 10mg x 2 wk. Do (if required) 5mg x 2 wk. Do (if required) National Leprosy Operational Guidelines Operational Guidelines National Leprosy 96 Eradication Program for DPMR for DPMR Eradication Program 97

Form P5/S5 Form – P-III Referral Slip (To be used by ASHA/HW/MO PHC/MOCHC) Name of Hospital ......................................... District ............................. Date .............. Name of the person to be referred : ................................................................................................... SL. No. in referral register : ................................................................................................................

Referred to ......................................................................................................................................... Referred by : ...................................................................................................................................... (Designation & place/Signature) Action taken at referral centres: ..........................................................................................................

Referred back by ................................................................................................................................ (Dr. ......................................................................Designation & place ............................................) Signature & date: ............................................................................................................................... National Leprosy Operational Guidelines Operational Guidelines National Leprosy

MLF 04 - (Page 2) NLEP – Monthly Progress Report PHC / Block PHC / CHC to District Name of PHC / BLOCK PHC / CHC________________________________________________________________________________________________ Month___________________________ Sr. DPMR activity During the Cumulative No. month total From April till date 1 No. of Reaction cases recorded 2 No. of Reaction cases managed at CHC – at District Hospital – 3 No. of suspected relapse cases referred

4 No. of Relapse cases, confirmed at district hospital 5 No. of patients provided with foot-wear 6 No. of patients provided with self-care kit 7 No. of patients referred for RCS to tertiary units 8 No. of patients – RCS done 9 No. of ulcer case managed 10 No. of ulcer case referred to secondary level 11 No. of cases developed new disability 12 No. of cases provided regular MCR footwear 13 No. of cases referred for customised footwear

14 No. of cases referred for skin smear examination for AFB to secondary level 15 No. of cases found AFB + ve 16 No. of ASHA/HW trained 17 No. of new cases referred / confirmed by ASHA Operational Guidelines National Leprosy for DPMR Eradication Program 99

MLF 05 - (Page 2) NLEP - Monthly Progress Report (From District to State) District————————————————— Month———————————————————— Sr. DPMR activity During the Cumulative No. month total From April till date 1 No. of Reaction cases recorded 2 No. of Reaction cases managed at CHC – at District Hospital – 3 No. of suspected relapse cases referred by PHC 4 No. of Relapse cases, confirmed at district hospital 5 No. of patients provided with foot-wear 6 No. of patients provided with self-care kit

7 No. of patients referred for RCS to tertiary units 8 No. of patients – RCS done 9 No. of ulcer case managed 10 No. of ulcer case referred to secondary level 11 No. of cases developed new disability 12 No. of cases provided Gr-I MCR footwear 13 No. of cases referred for Gr-II MCR footwear 14 No. of cases referred for skin smear examination for AFB to secondary level 15 No. of cases found AFB + ve 16 No. of cases attended DPMR clinic 17 No. of ASHA / HW trained

18 No. of new cases referred / confirmed by ASHA National Leprosy Operational Guidelines 100 Eradication Program for DPMR

Form S6 Record of Disabled / Complicated Cases treated at District Referral Centre District hospital—————————————————— State——————————————— Date Sr. Name of Patient Age / Sex Address Referred by / Disability / Treatment Remarks No. Direct Complication 1 2 3 4 5 6 7 8 9 Form S7 Disability Register with District Nucleus District————————————— State————————————— Sr. Name of Age /Sex Address Registered Date of Regn. Type of Deformity No. Patient at Action Taken (PHC / DH) Eye Hand Foot Ulcer

1 2 3 4 5 6 7 8 9 10 11 Operational Guidelines National Leprosy for DPMR Eradication Program 101

National Leprosy Operational Guidelines 102 Eradication Program for DPMR 1 T - mroF retsigeR ytilibasiD ———————————————etatS —————————————————tcirtsiD ——— —————————————————latipsoH eht fo emaN ytilibasiD sutats )TDM( tnemtaerT fo epyT fo etaD sserddA latsoP xeS/egA tneitaP eht fo emaN .rS edarG )nekat PCB fo .oN( ysorpeL noitartsigeR .oN .oN nmuloC 8 7 6 5 4 3 2 1 ot derrefeR ssergorp / egnahC dedivorp secivreS eyE teeF sdnaH etad htiw deciton etad htiw .oN nmuloC 62 52 42 32 22 12 02 91 81 71 61 51 41 31

21 11 01 9 segnahC etaD secivreS etaD 1 T mroF eht pu llif ot woH .nevig eb ot si sesac delbasid ot .on laireS : 1 nmuloC nettirw eb dluohs fo efiw / rethguad / nos htiw gnola emanrus htiw eman etelpmoC : 2 nmuloC dessessa eb dluohs ega ,ega eht llet ot elbanu si tneitap fI : 3 nmuloC nevig eb ot NIP / kramdnal htiw sserdda latsop etelpmoC : 4 nmuloC nettirw eb ot si DM rof noitartsiger fo etaD : 5 nmuloC nettirw eb ot si BM ro BP : 6 nmuloC nettirw eb dluohs TDM ,PCB fo rebmun latoT : 7 nmuloC ereht eb yam

ytilibasid 1 naht erom ,detceted ytilibasid no kram kciT : 12 ot 9 nmuloC .setad evitcepser htiw gnola deretne eb yam .cte level yradnoces ot refer ,seohs RCM gniussI ,yregrus ,erac reclu ,gniniart erac fles sa hcus secivreS : 32-22 nmuloC .cte deciton degamad evren wen detaroireted noisiv ,depoleved lautcartnoc ,derrucer reclu ,delaeh reclu ekil segnahC : 52-42 nmuloC eyE deR noisiV woL somlahthpogaL )tooF( seitilibasid rehtO seot fo noitprosbA tooF - reclU pord tooF elos aisehtseanA ytilibasid rehto ynA

Form T5 Record of Disabled / Complicated Cases treated at Tertiary Level Name of the Hospital——————————————————————————————— District———————— State———————— Date Sr. Name of Age / Sex Address Referred by / Direct Diagnosis Services Status at No. Patient Provided discharge, with date / Referred back to 1 2 3 4 5 6 7 8 9 Form T6 Discharge slip with follow-up instructions Name of the Institution ———————————————————————————————————————————————————

Name of the Patient ————————————————————————————————————————————————————— Age ——— Sex ————— Address —————————————————————————————————————————————————————————— –—————————————————————————————————————————————————————————————— –—————————————————————————————————————————————————————————————— Referred From ———————————————————————————————————————————————————————— Indication / complication for which referred —————————————————————————————————————————— –——————————————————————————————————————————————————————————————

Investigation done and reports ———————————————————————————————————————————————— –—————————————————————————————————————————————————————————————— Treatment given ——————————————————————————————————————————————————————— Instructions to follow ————————————————————————————————————————————————————— –—————————————————————————————————————————————————————————————— –—————————————————————————————————————————————————————————————— Name and Signature of MO / Supervisor ———————————————————————————————————————————

Date of Discharge –————————————————————————————————————————————————————— Operational Guidelines National Leprosy for DPMR Eradication Program 103

Form T7 Postoperative Follow up of RCS in Leprosy Name of the Institute:.........................................................................................................................Hosp. / MDT No:........................... Name:............................................................................................................Sex:....................Age:............Occupation.:..........................

Date of operation:........................................Type of operation:............................................. Follow-up (date): 3rd month 6th month Yearly: 1st 2nd 3rd 4th 5th         H A N D Fully open hand Hyperextension of MCP Jts. absent Yes No Fully closed hand possible Yes No Lumbrical position possible Yes No Grasp Good grasp of opposite forearm possible Yes No a. Abduction & Opposition possible Yes No Thumb b. Pulp to pulp pinch possible Yes No F O O T

Drop foot correction Heel to toe walking gait Yes No Claw toes correction Straight toes Yes No E Y E Lagophthalmos correction Able to fully close eye/s Yes No MCP Jts.: Metacarpophangeal Joints Post operative follow-up: 1st: 3 months after discharge, 2nd: 6 months after discharge, 3rd: 12 months after discharge then onwards: Yearly once for 5 years Signature of MO.....................................Signature of PT......................................... National Leprosy Operational Guidelines

Form T8 Operational Guidelines National Leprosy for DPMR Eradication Program 105 IIIV T mroF ertnec eht ta tuo deirrac yregruS CR rojam no troper ylhtnoM —————————— etatS ————————————————————tcirtsiD ———————————————————latipsoh eht fo emaN fo doirep dna etaD yregruS noitazilatipsoh fo epyT /CHP( sserddA latsoP / egA .rS skrameR tneitap eht fo emaN detcudnoc ytilibasid )latipsoH .tsiD xeS .oN dr3 dn2 ts1

Form T9 Monthly Report - List of Grade II cases Registered directly at Tertiary Level Care Centres Name of the hospital:—————————————————————— District:—————————— State:—————————————— Sr. Name of Patient Age/Sex Address Date of Registration Type of Deformity No. 1 2 3 4 5 6 National Leprosy Operational Guidelines 106 Eradication Program for DPMR

List of Acronyms ANM ............................................................................................Auxiliary Nurse Midwife ASHA ................................................................................Accredited Social Health Activist ASLO ...................................................................................Assistant State Leprosy Officer AWW ...................................................................................................Angan Wadi Worker

BCP.....................................................................................................Blister Calendar Pack BEE ..............................................................................................Block Extension Educator CHC ...........................................................................................Community Health Centre CLTRI ..........................................................Central Leprosy Training & Research Institute

CMO .................................................................................................Cheif Medical Officer DLO................................................................................................District Leprosy Officer DDRO ..................................................................District Disability Rehabilitation Officer DPMR........................................................Disability Prevention & Medical Rehabilitation

DRPD .....................................................Disability Rehabilitation Programme for Disabled DRPA ..................................................................................Disability Rights Protection Act DLP................................................................................................Disabled Leprosy Person DLS .................................................................................................District Leprosy Society

EHF Score ..........................................................................Eye Hand Feet disability Scoring GOI......................................................................................................Government of India GHCS ......................................................................................General Health Care System ILEP ...................................................International Federation of Anti-leprosy Associations

PWD ..................................................................................................Person with Disability LT .....................................................................................................Laboratory Technician LTC ...............................................................................................Leprosy Training Centre MB/PB ................................................................................Multi Bacillary / Pauci-Bacillary

MDT ....................................................................................................Multi Drug Therapy MO ..............................................................................................................Medical Officer MOHFW ...................................................................Ministry of Health & Family Welfare MPHW ...................................................................................Multipurpose Health Worker

NCLCA ................................................Novartis Comprehensive Leprosy Care Association NGO ................................................................................Non-Governmental Organisation NLEP ..................................................................National Leprosy Eradication Programme NRHM ................................................................................National Rural Health Mission

PHC ..................................................................................................Primary Health Centre PMW ..................................................................................................Para Medical Worker PMR .............................................................................Physical Medicine & Rehabilitation POD ................................................................................................Prevention of Disability

POWD .......................................................................Prevention of Worsening of Disability PR ................................................................................................................Prevalence Rate PRI .............................................................................................Panchayati Raj Institutions PT ...............................................................................Physio Therapist / Physio Technician

RCS ................................................................................................Re Constructive Surgery RLTRI ........................................................Regional Leprosy Training & Research Institute RSU ..........................................................................................Reconstructive Surgery Unit Operational Guidelines National Leprosy for DPMR Eradication Program 107

Glossary Accompanied MDT Provision of more than 1 BCP of MDT at a time. Anaesthesia Loss of sensation. Blindness Refers to a condition (WHO) where a person suffers from any of the following conditions, viz., (i) total absence of sight; or (ii) visual acuity not exceeding 6/60 or 20/200 (Snellen’s method) in the better eye with correcting lenses; or (iii) limitation of the field of vision subtending an angle of 20 degrees or worse. Case of Leprosy

A case of leprosy is a person with clinical signs of leprosy, who requires chemotherapy(MDT). CBR A strategy within general community, for the rehabilitation, equalisation of opportunities and social inclusion of all people disabilities. Clawing Deformity wherein there is hyperextension of the joints between the fingers and the palm (MP joint) and flexion of the joints of the fingers. Corticosteroids A group of drugs known for their ability to suppress inflammatory response. Crack

Discontinuity of the epidermis, usually seen in joint folds or on the sole where the skin is thick. Defaulter An individual who fails to complete treatment within the prescribed time frame Deformity Abnormal appearance, disfigurement Disability Broad term covering any impairment, activity limitation or participation restriction affecting a person. Foot-Drop Inability to move the foot up i.e., dorsiflexion, caused by the paralysis of the muscles which lift the foot. Indicator

Measureable aspect of a programme, which can indicate the level of performance and/or changes in performance. Impairment Any loss or abnormality of anatomical structure or function caused by the disease or injury. It may be visible or invisible, temporary or permanent and progressive or regressive. Primary impairment may progress to the development of secondary impairments. Example: plantar ulcer, defective vision, contractures in fingers. National Leprosy Operational Guidelines

Lagophthalmos Inability to close the eye Leprosy cured person Any person who has completed a prescribed course of MDT (6 months for PB/12 months for MB Regimen). MDT Multi-Drug Therapy. Multi-bacillary cases A leprosy patient with 6 or more skin patches. Nerve function impairment A loss of normal nerve function demonstrated by loss of sensation in the skin or reduced muscle power in its area of distribution. New case

A case of leprosy who has never been previously registered/treated with anti-leprosy chemotherapy. Orthoses A treatment device especially for hands and feet, such as splints and MCR footwear. Prosthesis Artificial limb. Pauci-bacillary cases Case having 1-5 skin patches, with definite loss of sensation/involvement of one nerve trunk. Passive movement Movement produced by assistance/an external force. Person with low Vision Having vision less than 6/18 with glasses. Lepra Reaction

The sudden appearance of symptoms and signs of inflammation in the skin or nerves or eyes of a person with leprosy. Rehabilitation Includes all measures aimed at reducing the impact of disability for an individual, enabling him or her to achieve independence, social integration, a better quality of life and self-actualisation. Relapse The re-occurrence of the disease at any time after the completion of a full course of treatment. RFT

Release from treatment; this occurs when treatment with MDT has been successfully completed. Operational Guidelines National Leprosy for DPMR Eradication Program 109

Self-Help Group “A small, economically homogeneous and affinity group of rural/urban persons, voluntarily formed to save and contribute to a common fund to be lent to its members as per the groups decision and for working together for social and economic uplift of their families and community.” Social integration The active participation of persons with disabilities in the mainstream of community life. Ulcer Discontinuity of the skin or mucous membrane. Wrist Drop

Inability to move the wrist into extension. WHO Disability Grade 1 Loss of sensation in palm / soles due to damage of main peripheral nerve trunk supplying that area. WHO Disability Grade 2 Visible disability / deformity or damage of hand & foot; or person cannot count fingers at a distance of 6 feet, lagophthalmos, iridocyclitis, and corneal opacity. National Leprosy Operational Guidelines 110 Eradication Program for DPMR

Acknowledgements The Central Leprosy Division, of the Directorate General of Health Services, Government of India fully appreciates the following who contributed towards preparation of the Operational Guidelines (2012) on Disability Prevention and Medical Rehabilitation:  The World Health Organisation for the financial support to organise the three days workshop on Disability Prevention and Medical Rehabilitation and all the participants of the workshop held in June 2011.

 Dr. M. A. Arif, Country Coordinator, Netherland Leprosy Relief Association, Dr. Sunil Anand, Director, The Leprosy Mission, India and Dr. B. N. Barkakaty, National Consultant, NLEP for their full support in organising the workshop and follow up action thereafter.  The core group for restructuring and rewriting the Operational Guidelines on DPMR (2012) consisting of Dr. P. K. B. Patnaik, State Leprosy Officer, Odisha, Dr. S. N. Pati, State Co-ordinator

of Odisha from LEPRA Society, Dr. Atul Shah, Director, Novartis Comprehensive Leprosy Care Association, Dr. P. R. Manglani, National Consultant, NLR and Dr. P. K. Pattanayak, National Consultant, GoI.  Dr. Atul Shah for amalgamating the primary, secondary and tertiary care guidelines and Novartis Comprehensive Leprosy Care Association for printing the Guidelines.  Mrs. Jyoti Dayal, Office Executive, Central Leprosy Division and Ms. Zarna Patel, NCLCA, for the secretarial assistance.

The whole exercise was possible only through active support and approval of the Directorate General of Health Services (Ministry of Health & Family Welfare), Government of India, which is gratefully acknowledged. Operational Guidelines National Leprosy for DPMR Eradication Program 111

Reference Materials 1. G lobal Strategy for Further Reducing the Leprosy Burden and Sustaining Leprosy Control Activities, Operational Guidelines, 2006-2010, World Health Organisation. 2. P revention of Disabilities in Patients with Leprosy, A Practical Guide by H. Srinivasan, published by World Health Organisation, Geneva, Switzerland, 1993. 3. Essential Surgery in Leprosy, by Srinivsan & Palande, published by World Health Organisation, Geneva, Switzerland, 1997.

4. D isability Prevention & Medical Rehabilitation, Operational Guidelines, published by Central Leprosy Division, Government of India, 2007. 5. Leprosy A Concise Text by K. K. Koticha, published by D. K. Koticha, Mumbai, India, 1990. 6. Guidelines for the Social & Economic Rehabilitation of People Affected by Leprosy, published by ILEP, London, 1999. 7. M DT Questions and Answers Revised, 1997, published by World Health Organisation, Geneva, Switzerland.

8. WHO Operational Guidelines for the Enhanced Global Strategy, 2011-2015, published by World Health Organisation. 9. Global Strategy for Further Reduction of Leprosy Burden & Sustaining Leprosy Control Activities 2006-2010 Operational Guidelines. 10. Prevention of Disability in Leprosy, ILEP Guides 1, 2, 3. 11. I Can Do It Myself, by Hugh Cross, published by World Health Organisation Regional Office for South East Asia, Delhi, India, 2007.

12. Essential Action to Minimise Disability in Leprosy Patients by Jean Watson with Illustrations by J. Cole, published by ILEP, London, 1991. 13. Prevention and Correction of Claw Hand By Splintage – A New Approach to Deformity Care by Dr. Atul Shah, Published by Ciba-Geigy Leprosy Fund, 1991. 14. Facilitating Activities of Daily Living by Instant Grip-Aid Application in Cases with Advanced Hand Deformities, by Ms. Neela Shah, under publication by Novartis Comprehensive Leprosy Care Association, 2011.

15. S kin Biopsy in Leprosy by Ridley D. S., published by Ciba-Geigy, Basle, Switzerland. 16. Leprosy for Medical Practitioners and Paramedical Workers by S. J. Yawalkar, 8th revised edition, edited by S. K. Noordeen and Atul Shah, published by Novartis Foundation for Sustainable Development, Basle, Switzerland, 2009. 17. “Self-care Kit”, An Aid to Empowerment in Self-care of Feet in Leprosy, by Atul Shah, Neela Shah, Published by Novartis Comprehensive Leprosy Care Association, Mumbai, India, 2010.

18. Surgical Reconstruction and Rehabilitation in Leprosy by Fritschi E. P., published by The Leprosy Mission, India, 1984. National Leprosy Operational Guidelines 112 Eradication Program for DPMR

Background Document Hypertension Screening, Diagnosis, Assessment, and Management of Primary Hypertension in Adults in India March 2016 Ministry of Health & Family Welfare Government of India 1

Page no. TABLE OF CONTENTS Section 1 Introduction 3 Section 2.1 Executive summary of key issues for providers and programme 8 Section 2.2 Summary of Recommendations on Screening, Diagnosis, 10 Assessment, and Management Section 3 Methodology of Development of Guideline 30 Section 4 Scope and Objective of Guideline 45 Section 4 Screening and Diagnosis of Hypertension –detailed 48 recommendations Section 5 Education and Assessment of Patients with Hypertension-detailed 61 recommendations

Section 6 Management of Hypertension –detailed recommendations 72 Section 7 Pathways/Algorithms in screening, diagnosis, assessment 108 ,management of hypertension in India Annexure 1 Glossary of terms and abbreviations 117 Annexure 2 Lifestyle modifications in patients with hypertension 121 Annexure 3 Formulary of Essential Medicines for management of 131 hypertension in India Annexure 4 Bibliography 137 Annexure 5 Sample of Patient information leaflet (in English) 143 2

Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Section -1 INTRODUCTION 3 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Hypertension is the number one health related risk factor in India,with the largest contribution to burden of disease and mortality(3, 4). It contributes to an estimated 1.6 million deaths annually in India, due to ischemic heart disease and stroke(6) . Fifty seven percent of deaths related to stroke and 24% of deaths related to coronary heart disease are related to hypertension(7). Hypertension is one of the commonest non-communicable

diseases in India, with an overall prevalence of 29.8% (95% CI: 26.7, 33.0) and a higher prevalence in urban areas (33.8% vs. 27.6%, p=0.05), according to recent estimates(8).India’s demographic transition with an increasing proportion of elderly people and a sedentary lifestyle and obesity associated with increasing urbanisation, and other lifestyle factors like high levels of salt intake, alcohol and tobacco consumption, are contributing to this burden of hypertension.

Hypertension is a major modifiable risk factor for cardiovascular and renal disease in India, and improved detection and treatment of hypertension in India would reduce a preventable burden of cardiac (congestive heart failure, coronary artery disease), cerebrovascular (ischemic and haemorrhagic stroke) and renal (chronic kidney disease) disease related to hypertension. It has been estimated that a 2 mm population wide

decrease in systolic blood pressure in India, would prevent 151,000 deaths due to coronary artery disease and 153,000 deaths due to stroke would be prevented.(7) Awareness of hypertension in India is low while appropriate treatment and control are even lower: Hypertension is a chronic, persistent, largely asymptomatic disease. A majority of the patients with hypertension in India are unaware of their condition. This is because of

low levels of awareness and the lack of screening for hypertension in adults -either as a systematic programme or as an opportunistic exercise during visits to healthcare providers. The prevalence of awareness of hypertension is only in a quarter of rural and two-fifths of urban Indians, and only a quarter and a third of those identified in rural and urban India receive treatment for it. Those who are identified as hypertensive often receive

inappropriate care or fail to adhere to therapy, and remain uncontrolled (8). The prevalence of controlled hypertension is only in around 10% and 20% of rural and urban patients with hypertension respectively.(8) Apart from undiagnosed, uncontrolled hypertension, there is also the challenge of misdiagnosis of hypertension in India. This is because of poorly standardized techniques of BP measurement, poorly calibrated measurement devices,

reliance on single readings taken on a single visit for diagnosis rather than multiple readings confirmed by elevated readings on follow up. The need for a standard guideline for hypertension in India. The published literature consists of guidelines on diagnosis and management of hypertension, some of which are based on a rigorous review of the evidence, while others in addition, have also incorporated consensus based recommendations to address areas of uncertainty. Most guidelines are

national in scope (NICE, JNC 8, Canadian Hypertension Education Program, Australian), while others are focused on a wider regional or international audience (European Society of Hypertension guidelines, American Society of Hypertension/International Society of 4 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Hypertension). The contexts for the screening, diagnosis, evaluation and management of hypertension in India are different from countries where awareness of hypertension in the general population is high, screening for hypertension is a routine part of primary care, practitioners are trained in delivering lifestyle interventions and medical management of hypertension, and patients are aware of the need and have the means to adhere to therapy.

In view of the above stated reasons a standard guideline was developed for the management of hypertension in the Indian context. The purpose and approach of the guideline: The National Health Mission has commissioned this guideline to enable a systematic cost-effective approach to the screening, detection, evaluation and management of hypertension in India. This guideline and its accompanying implementation tools in the form of a quick reference guide, algorithms, patient information

leaflet and quality standards are intended for use by the healthcare providers, patients and administrators. The guideline has a primary care focus and a public health approach. The focus on primary care is crucial since our biggest challenge is that the majority of hypertensives are undiagnosed because of the asymptomatic nature of the disease, and increased detection can only be accomplished by a sustained effort to measure BP in adults

at a clinic or by a healthcare provider closest to them. Hypertension is a primary care problem which is therefore best detected, managed and followed up at a primary care level by a primary care team led by a physician. The involvement of the community level health workers including the 2.3 million village health workers in India who are trained, supervised, provided logistical support, and suitably compensated, is crucial if we wish to

improve detection, assessment, therapy and control of hypertension in India. The evidence of the potential of community health workers to effectively contribute to control and management of non-communicable diseases is emerging from a number of low and middle income countries (9-14). Overall this guideline emphasises a public health approach to hypertension, which envisages population based strategies which could decrease the burden of hypertension, increased

detection of hypertension by non-physician staff, education of the patient to improve outcomes of treatment, use of cost-effective diagnostic tools and a core list of 5 efficacious, safe and economical anti-hypertensives, and suggests systemic mechanism to maintain adherence. It is a tool to empower healthcare providers, especially those in primary care, to manage hypertension. It builds on the technical and operational platform suggested by the

guidelines of the National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular diseases and Stroke(15). It also incorporates elements of the Indian Public Health Standards as they relate to the assessment and management at public health facilities in India(16).Improved detection of hypertension is a public health imperative in India, and management of hypertension is one of the most important and cost-effective interventions in primary care.

A public health approach to hypertension in India would involve the five components detailed below. This includes 5 population level interventions for prevention of hypertension of which reduction of obesity, salt intake and cessation of tobacco use are the most important; screening of the adult population at 5 points of care for hypertension by trained staff using standardised BP measurement with validated devices, and management 5

of hypertension with lifestyle modifications combined with therapy using representativedrugs from five classes of anti-hypertensives, which should be made available in the public health system: 1. Prevention: Promotion of a five point population wide intervention on weight reduction in the obese, increasing exercise levels in the sedentary, decrease in salt intake, cessation of tobacco use, moderation of alcohol use. 2. Screening: Screening for hypertension in all adults will involve opportunistic

screening of people > 18 years of age at every point of contact with health professionals or allied health staff. This will include all points and levels of care – the village/multipurpose health worker, trained non-physician staff at sub-centres, primary health centre, community health centre, and referral hospital (District hospital, Medical College). This screening will also enable people with high normal BP to be identified, so that they can be prevented from developing hypertension by

use of appropriate lifestyle modifications. Since healthcare facilities may not be accessed by all potential hypertensives, the guideline also suggests a targeted screening initiative at the community level aimed at detection of hypertension in those in which hypertension is most prevalent and poses the maximum risk. This includes people with age > 50 years, those who are obese, diabetic, current smokers, those who have history of any cardiovascular

disease (coronary artery diseases, stroke etc.), or a history of hypertension or premature cardiovascular disease in the family. We recommend that one validated electronic BP device and at least 1 trained person per village should be made a reality, so that these high risk group can be screened for hypertension at least once every 2 years. Screening will involve BP measurement using a standardised procedure and persons will receive advice and/or referral appropriate to the BP level.

3. Diagnosis: Diagnosis and evaluation of hypertension will be made at the PHC level which will also serve as the point of follow up for patients diagnosed at higher level facilities. Assessment will focus on target organ damage related to hypertension, comorbidities like diabetes, and correctable risk factors. Initiation of treatment whenever required, should take precedence over referral for detailed laboratory evaluation. The guideline envisages integration of care of hypertension with care of

other non-communicable diseases. 4. Management: Ensure availability of representative drugs from a core list of 5 medications – diuretics, calcium channel blockers, ACE inhibitors, Angiotensin Receptor blockers, and beta-blockers. 5. Monitoring and Adherence: Enable a hypertension registry accessible to all healthcare providers in the local public health system, promote adherence to therapy by simplified regimens, and monitoring by allied health staff.

Hypertension can be easily diagnosed using inexpensive technologies, and easily treated with medications which are effective and safe.(17) Management of hypertension can be of the one most cost-effective public health interventions. The current cost of provision of antihypertensive therapy with 2 drugs viz. a calcium channel blocker and an ACE 6 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

inhibitor,along with aspirin and a statin in a pooled public procurement based system is as low as under a rupee a day. This guideline while emphasising a primary care led approach also recommends creation of a continuum of care for this chronic disease, with referrals proceeding in both directions in the health system. The suggested model for the screening, diagnosis and management of hypertension offers scope for integration of initiatives for other chronic diseases e.g.

diabetes mellitus, while lifestyle interventions suggested in this guideline would also have a salutary effect on incidence of other chronic diseases. The accompanying patient information material for patients with hypertension will be of value to patients with hypertension as well as the general population, to increase awareness of this common disease which can be easily diagnosed and treated. 7 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

SECTION 2.1 EXECUTIVE SUMMARY OF ISSUES FOR PROVIDERS AND PROGRAMME Key issues for the Providers: 1. Most people with hypertension in India are unaware of their condition. To improve rates of detection of hypertension, all adults over the age of 18 should undergo opportunistic screening for hypertension during visits to non-physician health staff as well as health facilities. In addition, community based health workers should also do targeted screening of high risk groups under their

care – elderly > 60 years, diabetic, obese, those with any cardiovascular disease, family history of premature cardiovascular disease. 2. Screening for hypertension should involve measurement of blood pressure using a validated device ( mercury or digital) with an appropriate sized cuff, following a standardised procedure on a relaxed patient, seated with arm supported at the heart level with the legs uncrossed. Diagnosis of

hypertension should be based on a minimum of 2 sets of readings on 2 different occasions, which are at least 1-4 weeks apart, except in the case of hypertensive emergencies and urgencies. Hypertension in persons <80 years of age is diagnosed on documentation of persistent elevation of systolic BP of > 140 mm and/or 90 mm diastolic. 3. Patients should be educated about the nature of the disease and its therapy, about lifestyle

modifications that can reduce BP and cardiovascular risk. Patients should undergo assessment for cardiovascular risk factors, target organ damage related to hypertension, associated clinical conditions like diabetes, chronic kidney disease, and cardiovascular disease ( e.g. coronary artery disease, stroke). Most of these assessments which involve history, clinical examination, and examination for proteinuria, diabetes, serum creatinine, lipids and ECG will be possible to complete

at the PHC and CHC levels with the advent of the free diagnostics initiative. 4. Hypertension is a primary care issue and best managed at the primary care level with a team approach involving physicians, and allied staff. .Hypertension should be managed using a combination of lifestyle modifications and use of drug therapy with ACE inhibitors, Calcium channel blockers and thiazide diuretics, either alone or in combination. The benefit of treatment is related to

reduction of BP rather than the use of a particular drug. All drug classes have equivalent effects but some are preferred in the presence of compelling indication. Both Calcium channel blockers and ACE inhibitors are effective, have few side effects, and have no adverse metabolic consequences or high requirements for monitoring. 5. The target BP should be less than < 140 mm systolic in persons < 80 year old and < 150 mm

systolic in those over 80 years old, while the target diastolic BP is < 90 mm Hg. To achieve the target BP especially in those with Grade 2 and Grade 3 Hypertension may require the use of 2 or even drugs. Grade 1 HT which is uncomplicated, may be given a trial of lifestyle modifications alone for 3 months, 6. Efforts should be made to promote follow up and adherence to long term therapy to antihypertensive. In selected patients especially those with associated cardiovascular disease, both

statin and aspirin may be given along with antihypertensive to reduce risk of CV event. In patients with diabetes, statins may be indicated. 8 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Key issues for the programme: 1. Hypertension is a major modifiable health related risk factor in India, contributing to the top causes of death in the country. Detection and proper management of hypertension could lead to substantial decrease in the burden of coronary artery disease, heart failure, stroke, and renal failure in the country. Hypertension can be prevented by minimising risk factors like obesity, physical

inactivity, and high salt intake, moderate to high alcohol consumption at the population level. 2. Hypertension is a non-communicable disease whose diagnosis can be accomplished non- invasively, which does not require frequent laboratory assessment, and which can be managed using a core list of 3-4 safe, efficacious and cost-effective drugs. 3. The improved detection, assessment, and management of hypertension will require availability of

a trained community health worker and a BP measurement device – preferably a digital device which will obviate the need for auscultation. Such personnel can also receive training in the education of patients with hypertension. We recommend that the Bureau of Indian Standards validates the digital BP devices available in the market using international validation protocols. 4. The assessment of patients with hypertension will require upgradation of diagnostic services at

the primary and community health centres. The key investigations required will be screening tests for diabetes and proteinuria and an ECG machine at the PHC level, and facilities for lipid profiles and renal function tests at CHC level. 5. The programme should ensure adequate quantities of a list of first line antihypertensives – amlodipine, enalapril, hydrochlorothiazide, at all times in the public health system. Some other

drugs like atenolol, losartan, may sometimes be required for individual patients. To deal with hypertensive emergencies, the public health system will require availability of intravenous frusemide, oral clonidine, and intravenous labetalol. Adjunctive drugs like statin, and aspirin will also be required. The entire package of antihypertensive and adjunctive drugs is available to quality assured public procurement programme at less than a rupee a day. Detection and management of

hypertension can be a truly cost-effective intervention in public health. 6. We recommend the creation of a hypertension registry at the PHC level which will generate data on burden of hypertension in the community, facilitate follow up of patients especially those with severe hypertension, and allow analysis of outcomes. It will also create a template which can be used for other non-communicable diseases. 9 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Section 2.2- KEY RECOMMENDATIONS 10 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

KEY RECOMMENDATION: SCREENING 1: Target population, and operational procedure of screening 1.1. We recommend an ongoing initiative to increase awareness of hypertension as a widely prevalent but asymptomatic disease associated with many adverse outcomes like heart attacks, strokes, kidney failure. Most patients with hypertension in India are unaware of their status and remain undetected. Early diagnosis and effective control of BP can save people from much morbidity, mortality and disability.

1.2. All adults above the age of 18 years should undergo opportunistic screening by healthcare providers at all points of care in India, either during the course of their visits to the health facilities, or separately as a screening examination if requested by the person. Targeted screening at the community level of high-risk groups like the elderly (>60 years), obese, current smokers, those with diabetes, those with existing cardiovascular disease, and those with a strong family history of heart

disease or stroke can be undertaken by trained non-physician staff. 2: Standardised BP measurement procedure 1.3. The screening of hypertension should be done by a physician or trained non physician staff, using an automated BP instrument or any other validated device, and following a standardised BP measurement procedure. 1.4. Blood pressure should be measured a few (5) minutes after the patient is in a relaxed state, is seated with the arm at the level of the heart, with legs uncrossed.

The cuff should have a bladder whose length is about 80% and whose breadth is about 40% of the arm circumference. If the auscultation based method is being used, the then the cuff should initially be inflated to at least 30 mm Hg beyond the point of disappearance of the radial pulse. It should then be deflated at a rate of 2- 3 mm per second. The first and the last audible Korotkoff sounds should be taken at the systolic BP and diastolic BP respectively. The column should be read to the nearest 2 mm Hg.

1.5. At least 2 readings should be taken at each visit with an interval of at least 1 minute between the measurements. If the two readings are substantially different a third reading should be taken. The lower of the two readings should be taken as the representative SBP and DBP. 3. Rescreening, reassessment, and referral of individuals found to be normal or elevated BP on screening by allied health staff 11 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

1.6. Depending on the BP readings, the person may be advised review up on an annual or 2 yearly basis, or referral (immediate or deferred) for diagnosis or treatment of hypertension. 1.6.1 Persons with normal BP (<130/80) should be advised a recheck in 2 years. 1.6.2 Persons with high normal BP: systolic BP of 130-139 mm Hg and diastolic of 80-89 mm Hg should be advised a recheck in 1 year, or sooner if indicated due to other risk factors or diseases.

1.6.3 Persons with BP > 140 mm Hg systolic and/or greater than 90 mm Hg diastolic should be rechecked within 1-2 weeks and then classified as hypertensive or high normal. 1.6.4 Persons with BP of >160 mm Hg systolic and/or greater than 100 mm Hg diastolic should be advised early referral to the primary health centre if measurements have been made at a peripheral health facility below the level of a primary health centre, for confirmation of the diagnosis of hypertension.

1.6.5 Persons with BP of >180 mm Hg systolic and/or greater than 110 mm diastolic if documented by a non-physician staff, should be immediately referred to the primary health centre or community health centre (whichever is nearer to the residence) for further investigation to exclude any acute target organ damage, and for initiation of treatment,which is required on an immediate basis. Patients documented with this level of BP in a health facility

would require assessment for target organ damage, and gradual reduction of BP over hours and days if there is no acute target organ damage. 1.6.6 Hypertensive emergencies are potentially life-threatening situations where hypertension (usually severe and > 180 mm systolic and >120 mm diastolic associated with the presence of recent onset and progressive target organ damage resulting in cardiovascular, neurologic, renal and visual dysfunction.

These situations may include severe hypertension associated with acute coronary syndrome (chest pain), acute left ventricular dysfunction (shortness of breath), and hypertensive encephalopathy (altered sensorium), stroke (focal weakness), and renal failure. It is most often associated with severe hypertension, except in children and pregnant women where hypertensive emergencies can occur with lower elevations of BP. 1.7 All persons who are screened for hypertension should be advised lifestyle measures

including maintaining a daily salt intake appropriate to their occupation, advice on diet and exercise in case the person is obese, stopping use of tobacco and moderating consumption of alcohol to reduce their blood pressure and to reduce their overall risk of cardiovascular complications. 12 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

KEY RECOMMENDATION: DIAGNOSIS AND CLASSIFICATION OF HYPERTENSION 2.1 Diagnosis of hypertension should be made at primary health centres and facilities above that level using validated and calibrated BP measurement devices and following the standardised BP measurement procedure. 2.2 Diagnosis of hypertension should be based on at least 2 measurements taken in the clinic or by a healthcare provider on at least 2 visits, which are at least 1-4 weeks apart, except in the case of hypertensive urgencies and

hypertensive emergencies, where hypertension is diagnosed during the first visit itself. Ambulatory blood pressure monitoring and home based BP monitoring is not feasible for diagnosis for most patients with hypertension in India and is therefore not recommended. 2.3 Hypertension should be diagnosed when BP is persistently above a systolic of 140mm and/or diastolic of 90 mm. 2.4 Patients with hypertension should be classified in the following manner:

• Grade 1 Hypertension: systolic 140-159 mm and/or diastolic 90-99 mm • Grade 2 Hypertension : systolic 160-179 mm and/or diastolic 100-109 mm • Grade 3 Hypertension : systolic 180 or above and/or diastolic 110 or above • Isolated systolic hypertension: systolic > 140 mm but diastolic <90 mm. • Hypertensive urgency: Severe asymptomatic hypertension ( usually Systolic > 180 mm , Diastolic >120 mm) • Hypertensive emergency: Severe hypertension accompanied by cardiac

(e.g. acute left ventricular failure), neurological (e.g. hypertensive encephalopathy), or renal dysfunction. KEY RECOMMENDATIONS: PATIENT EDUCATION AND ASSESSMENT 3.1 Patients should be counselled about the nature of the disease, and the management of hypertension, before being subjected to laboratory evaluation and drug treatment. The education and assessment of the patients should be tailored to their understanding, preferences and social circumstances. 13

3.1.1 Patients should be counselled about hypertension being an asymptomatic condition which can lead to disabling and life-threatening complications like stroke, heart attack and renal failure. Patient should be counselled about need for long-term therapy, need for regularity of drug intake, informed about the targets for BP control, and encouraged to monitor efficacy of therapy through regular check-ups which can include home based monitoring of BP.

3.1.2 The patient should be counselled about the important role of lifestyle measures in reducing hypertension and reducing risks of cardiovascular disease. 3.2 The effective control of blood pressure by initiation of therapy, if required, should not be delayed if laboratory evaluation is delayed or cannot be done. 3.3 The assessment of a patient with hypertension is aimed at assessing overall cardiovascular risk for cardiovascular events like stroke, ischemic heart disease, heart

failure, peripheral artery disease. 3.3.1 The risk of clinical events in a patient with hypertension depends on • the level of blood pressure • risk factors (diabetes or impaired glucose tolerance, smoking, dyslipidemia, obesity, male gender, age >55 years in male, ) , • target organ damage(heart, kidney, retina), • Presence of associated clinical conditions [clinical cardiovascular disease (coronary artery disease, cerebrovascular disease, PAD), kidney disease].

3.4 The risk factors, target organ damage and associated clinical conditions can be detected on history, physical examination (including ophthalmoscopy), and investigations like blood glucose, lipids, serum creatinine, urinalysis, and ECG. 3.4.1 Physicians and allied health staff should assess and evaluate patients for cardiovascular risk factors like smoking, obesity, diabetes. Reduction of risk by adoption of healthy living habits-(dietary changes, exercise,

smoking cessation) is to be reinforced by all cadres of health workers. Screening for hyperlipidemia can be suggested and carried out in patients at PHC/CHC especially in those who are obese, or have family history of premature coronary artery disease, or have existing cardiovascular disease. 14 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

3.4.2 Physicians and allied staff can detect target organ damage by eliciting symptoms of shortness of breath, decreased urine output, and noting signs of heart failure like swelling of feet, and other signs of heart failure. Target organ damage can also been detected by testing urine for proteinuria, noting evidence of left ventricular hypertrophy on ECG, and features of hypertensive retinopathy on ophthalmoscopy. These signs of target organ damage can all be detected at PHC/CHCs.

3.4.3 Physicians and allied staff can detect associated clinical conditions like clinical cardiovascular disease and chronic kidney disease by eliciting history of chest pain suggestive of angina and/or pain in the lower limbs on walking suggestive of claudication, and/or history of stroke with weakness of limbs. CKD can be detected by persistently abnormal serum creatinine measured at the CHC level. 3.5 The overall risk of cardiovascular events can be assessed from these assessments as follows:

Level of blood pressure: Grade 2 Hypertension even in isolation confers moderate risk (20-30% risk of CV event over 10 years), while Grade 3 hypertension confers high risk (Over 30% risk of CV event over 10 years). Risk factors: Presence of 3 or more risk factors confers moderate to high risk even in a patient with Grade 1 hypertension, while even fewer risk factors increase risk in Grade 2 hypertension. TOD/Diabetes/CKD/Clinical cardiovascular disease: Presence of any target

organ damage, diabetes, chronic kidney disease or clinical cardiovascular disease confers high to very high risk on patients. 3.6 The level of BP and results of the assessment will influence the following: • when to start antihypertensive therapy, • Whichantihypertensive to use. • whether statins and/or aspirin are indicated, to reduce cardiovascular risk • Which other associated conditions will need management (diabetes, clinical cardiovascular disease, chronic kidney disease).

3.7 Screening for diabetes (which is to be available at all health facilities under the free diagnostics initiative) is an integral part of evaluation of hypertension because of the 15 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

common association of hypertension and diabetes. The care of diabetes should be integrated with management of hypertension. 3.8 All patients should be asked about tobacco use and advised to stop it. 16 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

KEY RECOMMENDATIONS: THERAPEUTIC RECOMMENDATIONS Lifestyle modifications and initiation of drug therapy 4.1. Overall aim: The overall aim of the management of hypertension is not only reduction of BP to target levels but also to lower the cardiovascular risk of the patient. Management of hypertension should be tailored to the individual and his or her circumstances. 4.2. Lifestyle measures including reduction of salt intake, stopping tobacco

intake, and reduction of body weight in those who are obese, are part of management of all patients with hypertension. 4.2.1 These lifestyle measures may be sufficient for treatment of Grade 1 hypertension, may reduce the doses required for control of hypertension, and will also reduce the cardiovascular risk in all grades of hypertension. 4.2.2. A trial of lifestyle measures should be monitored for 1-3 months following diagnosis of Grade 1 hypertension. The lower range of

durations should be considered in the presence of other risk factors like age, obesity, lipid levels, and smoking status. 4.3.1 Drug therapy is indicated in patients with Grade 1 hypertension with • Any sign of target organ damage (LVH on ECG, proteinuria on urinalysis, hypertensive retinopathy on fundus examination). • Any evidence of coronary artery disease, congestive heart failure, cerebrovascular disease (clinical cardiovascular disease), PAD • Diabetes • Presence of chronic kidney disease

• Patients with 3 or more risk factors1 (including age, gender, smoking, obesity, dyslipidemia, diabetes, impaired fasting glucose, family history of premature coronary artery disease). 4.3.2 Drug therapy in patients with grade I hypertension uncomplicated by any organ damage, without coexisting diabetes mellitus, clinical cardiovascular 1 Age > 55 in men, >65 in women; Male gender; smoking; diabetes; obesity including abdominal obesity;

impaired fasting glucose ( FBS 100-125 mg/dl); dyslipidaemia (high LDL, high TG, low HDL); family history of premature coronary artery disease 17 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

disease should be initiated after a trial of 1-3 months of lifestyle modifications. 4.3.3. Drug therapy is indicated in all patients with Grade 2 and Grade 3 hypertension and should be combined with lifestyle measures. 4.3.4. Drug therapy is initiated in patients with Grade 2 hypertension on confirmation of the diagnosis on repeat BP measurements in the visits subsequent to the initial visit when Grade 2 HT was first detected. If the initial

screening by the non-physician medical staff revealed Grade 2 hypertension, then therapy can be initiated on the first visit of the patient to the primary health centre/community health centre. 4.3.5. Drug therapy in patients with Grade 3 hypertension is initiated after repeat measurements in the initial visit confirm the severe elevation of the blood pressure. 4.4. Treatment goals for management of hypertension: 4.4.1 The current target for control of BP for patients under 80 years of age should

be systolic blood pressure less than 140 mm and diastolic blood pressure less than 90 mm. 4.4.2 The current target for control of BP for patients 80 years or older should be less than 150 mm systolic and less than 90 mm diastolic. 4.4.3 A recent trial (SPRINT trial) in non-diabetic population at high cardiovascular risk has shown a reduction in cardiovascular mortality in patients in the intensive treatment group where the goal BP was less than 120 mm systolic

and 80 mm diastolic. However this was accompanied by more than 2 fold increased frequency of serious adverse events and increase in serum creatinine. Based on the currently available evidence we do not recommend this lower target generally for physicians and patients in India, except for individual patients and physicians in situations who have agreed upon these targets and where close monitoring for adverse effects is feasible. 4.4.4 Current evidence based on trials of BP targets of <130 mm and < 85 mm

diastolic in patients with diabetes have failed to show significant overall benefit on cardiovascular disease outcomes, and have been accompanied by increased frequency of serious adverse events. Therefore we currently recommend the standard BP target of <140 mm systolic and <90 mm in patients with diabetes in India. 18 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

4.5Classes of antihypertensive drugs & preferred choices 4.5.1 The primary issue in treatment of hypertension is reduction of cardiovascular risk by effective control of blood pressure. Overall the benefits of antihypertensive treatment are due to lowering of blood pressure rather than choice of therapy. Many patients will require more than one drug for control of hypertension. 4.5.2. All classes of drugs- calcium channel blockers, ACE inhibitors/ARBs, diuretics;

beta-blockers have approximately the same efficacy on lowering of blood pressure, and on outcomes, although beta-blockers have been associated with lesser protection against strokes. All combinations of drugs are not however similarly efficacious, and some are preferred. 4.5.3. The different classes of drugs have differing side effect profiles and requirements for monitoring, which may influence their use and prescription in the health system.

4.5.4 In the absence of any associated clinical conditions (noted below) providing a compelling indication for the use of a particular drug , a long acting calcium channel blocker, a low dose thiazide diuretic, or a low cost ACE inhibitor may be used as the initial antihypertensive drug. 4.5.5The presence of associated clinical conditions (diabetes, clinical cardiovascular disease, chronic kidney disease) in a patient may provide compelling indication for the use of specific classes of drugs.

4.5.5.1. Preferred drugs for treatment of patients with diabetes and hypertension are ACE inhibitors, especially in those with proteinuria. Calcium channel blockers /low dose diuretics may be used in addition if required to achieve control. 4.5.5.2. Preferred drugs for patients with heart failure and hypertension are ACE inhibitors, diuretics (including loop diuretics) and beta-blockers. 4.5.5.3. Preferred drugs for patients with coronary artery disease and

hypertension are beta-blockers, ACE Inhibitors or calcium channel blockers. 19 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

4.5.6. The specific drugs within these classes recommended on the basis of availability and affordability include amlodipine, (a long acting calcium channel blocker); enalapril or lisinopril, (ACE inhibitor); low dose hydrochlorothiazide, (thiazide) and if required and losartan, (a low cost angiotensin II receptor blocker). 4.5.7. Angiotensin receptor blockers have a mode of action, efficacy and indications similar to ACE inhibitors, but are currently more expensive than them. They

should therefore be used in the place of ACE inhibitors, in case there are side effects with ACE inhibitors like cough, angioedema. 4.6 The treatment regimen and the use of combinations: 4.6.1 In patients with Grade 1 or Grade 2 hypertension, therapy can be initiated with one drug (CCBs, ACE inhibitors, thiazide diuretics) in combination with lifestyle modifications. Average initial doses can be 5 mg of amlodipine, 5 mg of enalapril and 12.5 mg of hydrochlorothiazide.

4.6.2 In patients with Grade 3 hypertension, the therapy should be initiated with two drugs, in combination with lifestyle modifications. The combinations can be calcium channel blocker (amlodipine) + ACE inhibitor (enalapril) or calcium channel blocker (amlodipine) + thiazide diuretic (hydrochlorothiazide) or ACE inhibitor (enalapril) + thiazide diuretic (hydrochlorothiazide). 4.6.3 The dose of drugs can be increased or a new drug added at approximately 2- to

4-week intervals. This frequency can be faster or slower depending on the clinical circumstances of the patient and the judgment of the practitioner. 4.6.4 The addition of a new drug in patients with Grade 1 or Grade 2 hypertension may be preferable to maximising the dose of the initial drug. In case a calcium channel blocker (amlodipine) has been used as initial therapy, the add-on drug can be ACE inhibitor (enalapril) or a thiazide diuretic. Similarly if ACE inhibitors

have been used as initial therapy, a calcium channel blocker or a diuretic can be used as add on therapy. When used as an add on therapy, the initial dose of amlodipine should be 2.5 mg. Similarly if an ACE inhibitor like enalapril is added to a diuretic, the initial dose used may be 2.5 mg to avoid hypotension. 4.6.5. If the second drug in a usual dose also fails to reduce BP to target levels then the third class of drug previously unutilised should be added. An optimal 3 drug

combination in case it is required is a calcium channel blocker with a low dose thiazide diuretic and an ACE inhibitor (e.g. amlodipine+ enalapril+ hydrochlorothiazide). 20 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

4.6.6. The preferred 2 drug combinations are combination of calcium channel blockers with ACE inhibitors, ACE inhibitors with low dose diuretics, and calcium channel blockers with low dose diuretics. 4.6.7. Prescription of a single pill combination of antihypertensive drugs in a defined proportion may be considered if available, after BP has been stabilised with a dose of two drugs given singly in the same proportion. 4.6.8. The practitioner should aim for patients to reach target BP levels with an

effective treatment regimen, whether 1, 2, or 3 drugs, within 6 to 8 weeks. 4.6.9. Add-on drugs for control of BP drugs should be added at intervals of 2-4 weeks. 4.6.10. Negative recommendation: ACE Inhibitors should not be combined with Angiotensin receptor blockers. 4.6.10 Negative recommendation: Avoid prescribing a combination of beta-blockers and diuretics as they can increase the risk of diabetes mellitus in those at risk, e.g. persons with impaired glucose tolerance or obesity and metabolic

syndrome. 4.6.11. If the BP is not controlled despite use of 3 anti-hypertensives, then the hypertension should be termed resistant and the patient should be referred to a specialist at the medical college for further evaluation and management. 4.7. Recommendation: Review and respond to possible causes of poor response to BP medications 4.7.1 When a patient does not respond to two drugs given in full doses, the physician should review the underlying issues -related to § BP measurements,

§ poor adherence to drug and lifestyle modifications, including stoppage of medicines due to belief in other systems of medicine § suboptimal treatment regimens, § presence of associated conditions, § use of non-antihypertensive drugs which can interfere with the action of anti-hypertensives, and § Consider the possibility of secondary hypertension. 21 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

4.8 Therapy of hypertension and associated conditions: 4.8.1 Diabetes mellitus: 4.8.1.1 Patients with diabetes mellitus should be initiated on drug treatment when the SBP is greater than 140 mm Hg, and the target for control should be a SBP of less than 140 mm Hg, and a diastolic BP of less than 90 mm Hg. 4.8.1.2 ACE inhibitors are preferred as initial therapy and calcium channel blockers and diuretics may be used as add on therapy. Thiazide diuretics can be associated with glucose intolerance.

4.8.1.3 Drugs which inhibit the renin angiotensin systems- ACE inhibitors and ARBs should be used if the patients have proteinuria (or microalbuminuria). 4.8.2 Heart disease: 4.8.2.1 Beta-blockers should be prescribed in patients with hypertension and a recent myocardial infarction. These patients should also receive an ACE inhibitor. 4.8.2.2. In patients with angina, beta-blockers and calcium channel blockers, should be considered among the antihypertensive drugs for their effect on symptoms.

4.8.2.3 In patients with heart (4.5.2.1) failure and hypertension, ACE inhibitors, thiazide diuretics, and beta-blockers, and mineralocorticoid receptor antagonists are recommended for reduction in mortality and hospitalization. 4.8.3 Kidney disease (diabetic or non-diabetic): 4.8.3.1 The target for BP reduction should be a SBP of less than 140 mm Hg, but a SBP of less than 130 mm Hg should be considered for those with overt proteinuria.

4.8.3.2 ACE inhibitors /ARBs are effective in reducing albuminuria and should be used in patients with hypertension and overt proteinuria (or microalbuminuria). Monitoring serum creatinine and potassium in the first week of therapy is advisable after initiation of therapy or any increase in the dose of ACE inhibitors. 22 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

4.8.3.3 Use of ACE inhibitors and Thiazide or thiazide like diuretics should be used as other antihypertensive agents, and in the presence of volume overload, loop diuretics like frusemide may be used. 4.8.4 Cerebrovascular disease: 4.8.4.1 Prevention of stroke can occur with all classes of antihypertensive drugs if BP is effectively controlled. 4.8.4.2 In patients with a history of stroke or TIA, initiation of drug treatment should be considered even with Grade 1 hypertension, and a systolic BP

of less than 140 mm Hg should be targeted. An ACE inhibitor/ARB is considered an initial drug. 4.8.4.3 In the first 72 hours of an ischemic stroke, do not administer antihypertensive treatment, since excessive lowering of BP can exacerbate the existing ischemia. 4.8.4.4 In patients who are not undergoing thrombolytic therapy for ischemic stroke, extreme values of BP, e.g. systolic BP > 220 mm Hg or diastolic BP > 120 mm Hg should be treated by agents to reduce mean arterial

pressure by about 15% in the first hour and no more than 25% in the first 24 hours and with gradual reduction thereafter. In patients who are candidates for thrombolytic therapy, BP above systolic of 185 mm Hg and diastolic of 110 mm Hg should be treated cautiously and maintained below these levels. 4.8.4.5 In patients with intracerebral haemorrhage, with SBP > 200 mm Hg or MAP2>150 mm Hg, aggressive reduction of blood pressure with intravenous infusion of antihypertensives is indicated and the patient

should be examined every 5 minutes. 4.8.4.6 In patients with intracerebral haemorrhage , with SBP >180 mm Hg or MAP > 130 mm Hg, modest reduction of BP to 160/90 is indicated using an intermittent or continuous IV infusion with frequent re-examination is indicated. 4.8 Hypertension in the elderly: 2 MAP = Mean arterial pressure which is calculated as follows MAP = SBP +2(DBP)where SBP is systolic blood pressure and DBP is diastolic blood pressure 3 23

4.9.1Postural hypotension is more common in elderly people. Assess patients for postural hypotension at diagnosis and on follow up by checking BP in sitting and in standing position after 2 minutes. Postural fall of >20 mm in systolic and >10 mm diastolic indicates postural hypotension is a risk factor for falls. 4.9.2 In a patient with postural hypotension titrate target according to standing BP. 4.9.3 Start therapy with lower doses of drugs and change doses or add drugs at a slower

rate in elderly patients. 4.9.4 In elderly patients less than 80 years of age, the blood pressure target for control may be <140 mm systolic and <90 mm diastolic if the patient is fit and the treatment is well tolerated. 4.9.5. In elderly patients more than 80 years (the very elderly), the blood pressure target for control is <150 mm systolic and <90 mm diastolic. 4.9.6.The drug of choice for initiation of therapy in the elderly is a long acting calcium

channel blocker, or a low dose thiazide diuretic in the absence of compelling indications. 4.9.7 There is a higher likelihood of certain side effects in the elderly- e.g. hyponatremia in the case of thiazides, and hyperkalemia in the case of ACE inhibitors. 4.9.8 There is a likelihood of drug –drug interactions in the elderly who often receive other drugs; e.g. .NSAIDs for arthritis interferes with action of ACE inhibitors, and diuretics. 4. 10. Hypertensive emergencies:

4.10.1 Hypertensive emergencies are those in which severe hypertension (elevations of systolic >180 mm Hg) and/ or diastolic (> 120 mm Hg) is associated with symptoms and signs of acute ongoing organ damage. Such elevations of blood pressure may be associated with neurologic emergencies (hypertensive encephalopathy, cerebral infarction, and cerebral haemorrhage), cardiac emergencies (acute left ventricular failure, acute coronary syndrome), renal emergencies like acute renal failure, and

obstetric emergencies like eclampsia (symptoms and signs of such dysfunction are referred to under the mnemonic of ‘ABCDEFG’ in pathway on assessment and management on hypertensive crisis). Eclampsia can occur even at levels of BP less than 180 mm systolic and/or 120 mm diastolic. 24 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

4.10.2 The magnitude and rate of reduction of BP varies according to the organ involvement in the hypertensive emergency. In many hypertensive emergencies including hypertensive encephalopathy reduction of mean arterial pressure of ≤ 25 percent in the first hour, with a gradual reduction to 160 mm systolic and diastolic of 110-120 mm Hg over 2-6 hours, and gradual normalization of blood pressure over 24-48 hours is recommended. Parenteral agents like IV labetalol, nicardipine may be

used initially with a change to oral agents later. 4.10.3 In patients with ischemic stroke as noted earlier, reduction of systolic BP below 220 mm Hg and 120 mm Hg are not treated, unless the patient is being considered for thrombolytic therapy. 4.10.4 Negative recommendation: Oral or sublingual nifedipine may cause excessive, abrupt fall of blood pressure which may result in cardiac, cerebral or renal ischemic complications. It is not recommended in the treatment of any hypertensive emergency.

4.10.5 In the case of acute left ventricular failure reduction of the elevated BP is indicated with a parenteral loop diuretic like frusemide in addition to vasodilators like nitroglycerine. In patients with acute coronary syndrome with severe hypertension, intravenous nitroglycerine may be used in association with intravenous beta-blockers like esmolol or labetalol. 4.10.6 Patients with a hypertensive emergency should be examined for any

clinical clues to the presence of secondary hypertension and be evaluated for the same. 4.11. Hypertensive urgencies 4.11.1 This refers to situations when severe hypertension (SBP > 180 mm, DBP> 110 mm) is not associated with any signs of acute or ongoing organ damage (cerebral, cardiac, renal, visual), and the patient is relatively asymptomatic except for a mild headache (patient has none of the symptoms or signs referred in the mnemonic ‘ABCDEFG’ in the pathway on assessment and

management of hypertensive crisis). Patients with severe hypertension should be assessed clinically and by laboratory investigations, and target organ damage should be excluded before hypertensive urgency is diagnosed. 4.11.2. Hypertensive urgencies may occur in patients with chronic hypertension in a number of situations. This includes non-adherence to therapy, after sudden withdrawal of beta-blocker or clonidine therapy, after ingestion of large quantity of salt, or due to anxiety. 25

4.11.3. There is no benefit from rapid reduction of BP in patients with severe but asymptomatic hypertension and the BP should be reduced over a period of hours and days. 4.11.4. Nursing the patient in a quiet room and relief of anxiety may reduce BP to a certain extent. 4.11.5 Negative recommendation: Do not attempt excessive, rapid and uncontrolled reduction of blood pressure in hypertensive urgencies, with intravenous drugs or oral or sublingual nifedipine. This aggressive

reduction of BP in a patient with severe asymptomatic hypertension may cause fall of BP below the threshold of auto regulation in vascular beds, and cause serious cerebral and cardiac complications related to ischemia. 4.11.6 Re-institution of therapyor intensification of therapy by increasing the dose of drugs or adding a diuretic may suffice for gradual reduction of blood pressure in a patient who has developed severe asymptomatic hypertension on the background of chronic hypertension.

4.11.7 If BP reduction over few hours is required in view of imminent cardiovascular events, then oral frusemide, oral clonidine can be used. These can be followed by long term therapy with CCBs, ACE inhibitors or diuretics. 4.12 Integration with other interventions to reduce cardiovascular risks 4.12.1 The treatment of hypertension should be integrated with treatment of associated risk factors like lipid lowering therapy and antiplatelet therapy, apart from lifestyle interventions already mentioned.

4.12.2 Antiplatelet therapy with low-dose aspirin (75 mg/day) is recommended in patients with controlled hypertension who have previous history of cardiovascular event (previous MI, stroke, angina, bypass surgery or coronary angioplasty), because of a favourable benefit –harm ratio. 4.12.3 Low dose aspirin may be considered for those hypertensives who are well controlled and have a high cardiovascular risk (Grade 3 hypertension, 3 or more risk factors, target organ damage).

4.12.4 Negative recommendation: Do not use low-dose aspirin in hypertensive patients without cardiovascular disease and who are at low-moderate risk as the risk of major bleeds (intracranial and gastrointestinal) outweighs the potential benefit. 26 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

4.12.5 The use of low dose aspirin in patients with diabetes without cardiovascular or cerebrovascular disease is not recommended in view of the uncertain risk-benefit ratio. 4.12.6 Statins are recommended, regardless of presence/absence of hypertension in the following patient groups3 • Patients with overt atherosclerotic cardiovascular disease (coronary artery disease, cerebrovascular disease, and peripheral arterial disease), regardless of age.

• Patients with age with≥ 21 years, where LDL –cholesterol is more than 190 mg/dl, and where secondary cause of hyperlipidemia has been excluded. • In patients who are diabetic and in the age group of 40-75 years, and LDL cholesterol is between 70-189 mg/dl 4.12.7. Statins are indicated in hypertensive patients aged more than 40 years with high cardiovascular risk (3 or more of a list of 11 cardiovascular risk factors)4 4.12.8. Hypertensive patients who smoke or chew tobacco should be provided

advice to stop smoking and chewing tobacco. KEY RECOMMENDATION: MONITORING, FOLLOW UP AND IMPROVING ADHERENCE TO THERAPY 5.1 A simplified regime using long acting drugs which can be used once a day may improve adherence. 5.2 The patients should be monitored for efficacy of the regimen, both at the clinic and community level. In patients who are yet to achieve target BP, follow-up visits at 1-2 weeks can be scheduled till target BP is achieved.

Thereafter the patient can be seen by a physician at a frequency determined 3Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology. 2014; 63(25_PA):2889-2934.

4Daskalopoulou SS, Rabi DM, Zarnke KB, et al. The 2015 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, and assessment of risk, prevention, and treatment of hypertension. Canadian Journal of Cardiology. 2015; 31(5):549-568. 27 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

by the severity of the hypertension, presence of co morbidities, target organ damage. Streamlined methods to collect drugs should be allowed to enable compliance by the patient. 5.3 The patients should be monitored for side effects of drugs. 5.3.1. The common side effect of calcium channel blockers is peripheral edema, which is dose dependent and may subside with reduction of dose or combination with ACE inhibitor. 5.3.2. The common side effects of diuretics are metabolic side effects like

hypokalemia, hyperglycemia but which are less frequent when these are used in doses of 12.5 mg and when they are combined with ACE inhibitors.. A particular concern is of thiazide induced hyponatremia which is commoner in the elderly, those with a low body weight. This can develop rapidly and manifest as altered consciousness, and even seizures, and may require hospitalisation and administration of normal or hypertonic saline. 5.3.3. The common side effect of ACE inhibitors is dry cough, which may

necessitate withdrawal of therapy. There is a risk of hypotension when ACE inhibitors are started on patients who are on diuretics, or are on very low salt diet. A small rise in serum creatinine can occur on ACE inhibitors, which is reversible. Hyperkalemia can develop with high doses of ACE inhibitors, but also more commonly in patients with renal insufficiency, diabetes, concurrent use of potassium sparing diuretics, and the elderly. Angiotensin receptor blockers have a lower

rate of drug-induced cough but higher rate of hypotension. 5.4 Consider the use of pill counts, participation of a family member in supervision of drug intake, periodic counselling and provision of patient information leaflets to improve adherence and control. 5.5 Diagnosis and management of hypertension in India, needs to be embedded in the system of primary care. A team approach to management of hypertension needs to be evolved which involves the physicians, allied staff and community

based health workers. 5.6 Community based health workers can be trained to play a critical role in meeting the challenge of undetected, untreated and uncontrolled hypertension in India. They can improve detection, promote lifestyle modifications, monitor response and ensure adherence to therapy. They can also help prevent hypertension by advising appropriate lifestyle modifications in those who have a high normal BP (130-139 mm Hg systolic and 85-89 mm Hg diastolic) 28

5.7 We strongly recommend creation of a hypertension registry at the PHC & CHC level to ensure tracking of patients and create a system of recall which can involve the community based health workers. 5.8 Patients with hypertension should be encouraged to consider home blood pressure monitoring using an automated device which has been validated with a clinic based device. 5.9 All patients with hypertension, should undergo an annual review of control of BP,

implementation of lifestyle modifications (e.g. maintenance of body weight), target organ damage (proteinuria), review of treatment including side effects of drugs. 5.10 All patients with high normal BP should also be encouraged to undergo an annual review, and advised appropriate lifestyle modifications e.g. dietary changes, weight maintenance, and abstinence from tobacco. 29 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

SECTION 3: METHODOLOGY OF DEVELOPMENT OF GUIDELINE 30 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

A Task Force was constituted in December 2014 to guide the development of Standard Treatment Guidelines (STG) in India for application in the National Health Mission. The Task Force subsequently approved the draft STG development manual of India (Part 1) for development of adapted guidelines. In addition, it approved a list of 14 topics recommended by a subgroup of the task force appointed to select prioritized topics for STG

development. These 14 topics are from 10 clinical specialties for which the first set of STGs will be developed. The topic of Detection, Assessment, Management of Essential Hypertension was included in this first list and was the dealt with by the Internal Medicine clinical subgroup. 1. Formation of the STG group: A multidisciplinary group composed of a mix of primary care practitioners, family medicine practitioners, teaching faculty, practising and academic cardiologists, nurse

practitioners, voluntary sector representatives, and a patient representative was formed by June 2015. The composition of the subgroup is mentioned in the table below. Scoping the STG: The scope of the STG was discussed at the first clinical subgroup meeting in Delhi in July 2015 and was finally subsequently in an online consultation held with all members of the subgroup, since some were unable to attend the meeting in Delhi.

Facilitator Anurag Bhargava, Professor, Dept. of Medicine, Yenepoya Medical College, Mangalore, Karnataka Writing team Anurag Bhargava, RajkumarRamasamy, Ambuj Roy, KartikKalyanram, Rakesh Biswas, Reginald Alex Expert Ambuj Roy, Additional Professor, Department of Cardiology, All India Institute of Medical Sciences, New Delhi Primary Care RajkumarRamasamy, (KC Patty Primary Health Care Centre, KC Patty, Kodaikanal practitioners Taluk, Tamil Nadu),KartikKalyanram, Rishi Valley Rural Health Centre,Venkatesh ,

Department of Family Medicine, Christian Medical College, Vellore Physician Rakesh Biswas,Professor, L.N.Medical College, Bhopal Reginald Alex, Professor, Department of Emergency Medicine 31 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Private Prashant Jagtap, Wockhardt Hospital, Nagpur Practitioner Nursing Mercy Oomen, Department of Nursing, Christian Fellowship Hospital, Practitioner Bissamcuttack,Orissa Patient SouravDutta,Bhopal representative Public health John Oomen, Department of Community Medicine, Christian Fellowship specialist Hospital,Bissamcuttack, Orissa NGOs KartikKalyanram, RajkumarRamasamy (affiliations as mentioned above) Others SurajitNundy ( Physician, and Expert on Health Information systems, New Delhi)

The induction and orientation session was held on 21st July 2015 in which the facilitator (Chair) welcomed all the members of the subgroup, and set up the rules of operation based on the STG development manual, on the consistent use of terminology and definitions, using the structured power-point presentation provided by NHSRC/NICE. None of the members report any conflict of interest in the development of this guideline and have all signed their declarations

2. Search and selection of evidence based guidelines: In view of the paucity of time available to develop this guideline, a decision was taken by the Task Force for the Development of STGs for the National Health Mission that these STGs would be adopted and/or adapted from existing evidence based guidelines to make them relevant to our context, resource settings and priorities. A search was conducted for evidence based guidelines on primary hypertension, which

had been published within the past 5 years and which had been framed using evidence based methodology and using international guideline development criteria. The National Guidelines Clearinghouse (NGC) website was used since the guidelines have already gone through a rigorous ‘quality’ sifts based on international standards (http://www.guideline.gov/). The criteria for Inclusion of Clinical Practice Guidelines in NGC are based on the Institute of Medicine (IOM) Clinical Guidelines Standards 2011 and

IOM systematic review standards 2014. The guidelines available on the database have 32 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

been developed, reviewed, or revised within the past five years. The NGC entry criteria are similar to the AGREE II Instrument criteria5. Three of these guidelines were listed on the National Guidelines Clearinghouse , viz: Hypertension: Clinical management of primary hypertension in adults NICE guidelines [CG127]: National Institute for HealthCare Excellence; 2011 from the UK(18), The 2015 Canadian Hypertension Education Program recommendations for blood pressure

measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension(19); the 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8),from USA.(20) An additional guideline selected was the 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH)

and of the European Society of Cardiology (ESC).(21) This guideline was evaluated by a methodology expert from NICE UK, who opined that its methodology was evidence based and its formulation was in concordance with the AGREE 2 instrument. There were some other guidelines e.g. Indian Guidelines on Hypertension-3, and the National Heart Foundation of Australia (National Blood Pressure and Vascular Disease Advisory Committee).Guide to management of hypertension 2008. Updated December 2010,

which were not evidence based and did not follow the criteria for development of guidelines; which were therefore not followed. We also referred to the WHO /International Society of Hypertension guidelines of 2003 and the seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. The scope of our guideline was broad and to address the evidence base for certain

sections e.g. screening and cardiovascular risk prevention, we searched other evidence based guidelines like the US Preventive Services Task Force guideline for screening for high blood pressure,(22) and the European guidelines on cardiovascular disease prevention in clinical practice.(23) We also utilised the Cochrane database of Systematic Reviews for certain issues like the use of aspirin for primary and secondary prevention of cardiovascular diseases.

Some of the issues in the management of patients of hypertension are a matter of judgement since there is no supporting data from randomised controlled trials. For example, whether the best strategy for optimisation of BP control is to add drugs sequentially, or to maximise the dosage of the first. We therefore also utilised some recommendations from a consensus based guideline developed for international use by the American Society of Hypertension and the International Society for Hypertension. (24)

3. Search and select recommendations: Each of the guidelines referred to above was searched for recommendations relevant to the scope of our guidelines, and there were significant areas of consensus between evidence based guidelines. It was found that there was no single guideline which 5 AGREE II Instrument http://www.agreetrust.org/ 33 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

couldbe adopted fully to suit our requirements. For example, the NICE guideline had many recommendations applicable to our setting but considered ambulatory blood pressure monitoring as the gold standard for diagnosis. The assessments recommended for hypertensives varied between guidelines and different cardiovascular risk estimation tools were in use which were based on data on cohorts of the local population e.g. QRISK2 in UK, SCORE in Europe, pooled cohort equation based tool in USA. Therefore for

each issue mentioned in the scope document we searched all the evidence based guidelines for recommendations and selected them on the basis of the suitability to our settings in terms of contexts, resources and our priorities. 4. Adaptation and adoption of recommendations: The clinical sub-group decided in the meeting to adapt recommendations in existing evidence based guidelines by paraphrasing them & paying close attention to the

integrity of the recommendation, rather than quote verbatim. This decision was taken for a number of reasons explained here. As mentioned in the preceding paragraph we selected recommendations from a number of guidelines for the purpose of our STG. The different guidelines had differing purpose, different target audiences, and differing presentation and linguistic styles. While NICE guidelines used a user-friendly format in terms of language, other guidelines made recommendations with mention of strength of

evidence. Also the population, the healthcare setting and the resources available, the assessment tools and therapies available are different in the Indian context. For these reasons and in order to harmonise these different formats and linguistic styles, and have a uniformity of presentation in our STG, we decided to adapt existing evidence based guidelines. The quotation of recommendations verbatim would have also involved intellectual property related issues.

The table below outlines some key recommendations in these guidelines, their source and some comments related to their adaptation. Key recommendation Source guideline(s) Comment All adults above the age of 18 US Preventive Services Adapted. We added the years should undergo Task Force. Screening for component of opportunistic screening for high blood pressure: US opportunistic screening hypertension by healthcare Preventive Services Task and screening by both

providers at every point of Force recommendation physicians as well as contact with health services. statement. non-physician staff. Screening of hypertension NICE, European society of Adopted. should be done using an Cardiology guidelines automated BP instrument or any other validated device, using a standardised BP measurement procedure. Depending upon the readings Joint National Committee Adapted. 34 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

the person may be advised on Prevention, Detection, We have used the term review on an annual or 2 yearly Evaluation and Treatment “high normal” for SBP of basis or referral within a few of High Blood Pressure – 130-139 mm Hg and for diagnosis or treatment of Seventh Report DBP of 85-89 mm Hg hypertension used in WHO/ISH guideline and the ESC/ESH Guideline, instead of the term “pre-hypertension” used in JNC 7 Diagnostic standard for ESC/ESH guidelines Adapted. Reworded. hypertension It is based on clinic

based measurement using a standardised BP measurement procedure. Recording the measured BP : NICE guidelines 2011 Adapted. average measurement vs. Original lower measurement recommendation.” If blood pressure measured in the clinic is 140/90 mmHg or higher: Take a second measurement during the consultation. If the second measurement is substantially different from the first, take a third measurement. Record the lower of the last two measurements as the clinic blood pressure.” In the Indian setting,

with the proposed BP measurement by non- physician health workers , taking the lower instead of the average reading is more feasible and will avoid calculation errors. Classification of hypertension ESC/ESH 2013 guideline. Adopted. WHO/ISH guideline 2003 We retained the Grade 3 hypertension category (SBP >180 mm Hg &/or DBP >110 mm Hg). This category is mentioned 35 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

in the ESC/ESH guidelines and was part of the WHO/ISH guidelines. Even in guidelines like NICE which do not mention this grade, this level of SBP and DBP is classified as severe in these guidelines. This category has both prognostic and therapeutic importance. Prognostically, grade 3 hypertension is associated with high cardiovascular risk. Therapeutically it is important as it indicates need for immediate referral and initiation of therapy. The assessment of a patient ESC/ESH, WHO/ISH Adopted. We used the

with hypertension should same framework of include assessment for risk assessment of risk factors, target organ damage, factor, target organ and associated clinical damage, which along conditions (diabetes, with the presence of cardiovascular disease, associated clinical cerebrovascular disease, conditions, determine chronic kidney disease, the overall peripheral arterial disease) cardiovascular risk. Management of hypertension : ESC/ESH guidelines Adapted.

Lifestyle measures NICE guidelines ESC/ESH recommend reduction of salt intake, moderation of alcohol consumption, reduction of BMI to <25 kg/m2 , eating a diet with plenty of vegetables, moderate intensity exercise, advice on smoking cessation as Class I recommendations. We have used an optimal BMI cut-off of less than 23 kg/m2, in view of the lower cut-offsfor defining obesity in 36 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Indians(defined as BMI>25 kg/m2 )compared to the cut off for obesity of BMI>30 kg/m2 in western population. Indications for drug therapy in NICE guidelines Adapted. Grade I hypertension We followed the NICE recommendation of initiating therapy except the one which recommended initiation in those with a 10 year cardiovascular risk equivalent of 20% or greater. This is because there is no formal cardiovascular risk estimation tool which has been validated in an Indian population, and the variables required

for these estimates are not available at the primary care level. BP targets NICE guidelines Adapted. Reworded. General population : <140/90 The original mm Hg in people under 80 recommendation is years “aim for a target clinic <150/90 mm Hg in people 80 BP below 140/90 in years and over people aged less than 80 years with treated hypertension.” And “Aim for a target clinic BP below 150/90 in people aged 80 years and over, with treated hypertension.” BP targets JNC 8 guidelines Adapted

Diabetes Cochrane database of Original JNC8 Systematic reviews recommendation: (Arguedas JA, Leiva V, and “In the population aged Wright JM. Blood pressure ≥18 years with diabetes, targets for hypertension in initiate pharmacologic people with diabetes treatment to lower BP mellitus. Cochrane at SBP 37 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Database Syst Rev. 2013; ≥140 mm Hg or DBP ≥90 10:CD008277). mm Hg and treat to a goal SBP <140 mm Hg and goal DBP <90 mm Hg. (Expert Opinion – Grade E)” The Cochrane review noted some reduction of stroke mortality in the lower SBP target group, (RR:0.58, absolute risk reduction - 1%), there was an increase in risk of serious adverse with a RR of 2.58, and an increase of absolute risk of 2%.The Cochrane review on the subject concluded” At the present time, evidence from randomized trials

does not support blood pressure targets lower than the standard targets in people with elevated blood pressure and diabetes. More randomized controlled trials are needed, with future trials reporting total mortality, total serious adverse events as well as cardiovascular and renal events”. Choice of drugs JNC 8 guidelines Adapted. General population without ESC/ESH guidelines JNC 8 recommendation: compelling indications: “In the general nonblack population, including those with diabetes,

initial antihypertensive treatment should include a thiazide type diuretic, calcium channel blocker (CCB), angiotensin converting enzyme 38 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

inhibitor (ACEI), or angiotensin receptor blocker (ARB). (Moderate Recommendation – Grade B) ESC/ESH: “Diuretics (thiazides, chlorthalidone and indapamide), beta- blockers, calcium antagonists, ACE inhibitors, and angiotensin receptor blockers are all suitable and recommended for the initiation and maintenance of antihypertensive treatment, either as monotherapy or in some combinations with each other.” (Class I Level A) Choice of drugs : ESC/ESH guidelines Adapted. Original

Compelling indications recommendation. “Some agents should be considered as the preferential choice in specific conditions because used in trials in those conditions or because of greater effectiveness in specific types of OD.(Class II a Level C)” Treatment strategy for ESC/ESH guidelines Adapted. Reworded. A achieving control combination of 2 drugs is recommended with very marked elevation of BP. We have recommended initiation of therapy with 2 drugs 39

in patients with Grade 3 hypertension. Treatment of Hypertension CHEP guidelines for Adapted reworded with associated clinical treatment of hypertension conditions with stroke, chronic kidney disease, heart disease Review poor response to BP CHEP guidelines Adapted. medications Supplemental table 10 describes factors that underlie poor response to therapy. The scope of the guideline, an illustrative format of the guideline developed by the Medicine

sub-group was presented in a Task Force meeting on 26.8.2015. This scope was developed after extensive online consultation on an ongoing basis. 5. Submission of the draft STG for peer review: We submitted the draft STG inclusive of annexure to the Task Force in November 2015. 6. Peer review: We received general and specific comments In January 2016, which helped improve the clarity of our draft. Some of the comments were of a substantive nature and are

discussed in the following table. Many others were pointed in the text of the guidelines and included requests for references etc. S.No Comment Response INTRODUCTION NICE What population is recommended The population groups at high risk are for targeted screening? If high older adults (>50 - 60 years), persons risk population, request to define with diabetes, obesity especially those it and also document the evidence with a higher abdominal circumference,

on which recommendation is current smokers, those with any based cardiovascular disease, and those with family history of premature cardiovascular disease. Predictors for the presence of hypertension have been developed in Indian cohort studies and these risk scores are again based on age, current smoking, presence of abdominal obesity 40 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

IHG Salt intake recommendation to be We have mentioned a dietary intake of 6 corrected and uniform throughout gm. salt per day for the general the document. population, and have added a qualifier that this limit may be reconsidered in some patients who are engaged in heavy manual labour under hot climatic conditions, where substantial loss of salt in sweat may occur, as seen in some studies. IHG The age cut off for screening This lower cut-off is based on the US

should be 30 years, rather than 18 Preventive Services Task Force years. recommendations. A cut off above 30 years conveys an impression that younger adults (including pregnant women) cannot have hypertension. This is not so as explained below: 1. Hypertension including essential hypertension may present earlier than 30 years. Studies have shown that hypertension was prevalent in 15% of children in the 5-16 year age group (NMJI 2007 Raj et al). 2. Patients with secondary hypertension including chronic

renal disease may present before thirty years 3. Pregnancy induced hypertension: We envisage that this guideline will be followed by a guideline on pregnancy induced hypertension. This is a major cause of maternal morbidity and mortality, and all pregnant women in India (most of them less than 30 years) need to be screened for hypertension as part of antenatal care. This guideline will create the platform for screening of antenatal women. A large number of persons with high

normal BP may be identified by screening who can progress to hypertension. IF the recommendations of this guideline on weight reduction, tobacco cessation, and salt reduction are implemented, we might prevent their progression to essential hypertension with them. SCOPE OF HT GUIDELINE IHG The choice of BP measuring device India is committed to phasing out should be discussed with Health mercury and alternatives have to be Technology Assessment and considered. Electronic digital

finalized. oscillometric devices are emerging as the clinical standard for BP measurement worldwide, and have proved to be 41 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

accurate and robust. Aneroid sphygmomanometers need frequent calibration. Both mercury and aneroid sphygmo3manometers need an auscultation based measurement which may be less feasible for non-physician health staff. LIST OF RECOMMENDATIONS NICE Ambulatory BP/ HBP are the gold Addressed standard and may be possible in urban areas. Perhaps both recommendations can be put along with clearly stating that in the absence of ambulatory BP, clinic BP is recommended as an alternative.

IHG Definition of Obesity The Indian cut off for BMI defining obesity is ≥ 25.0 kg/m2 and is mentioned Age for BP cut-off for 80 years and The cut off of elderly as per the JNC above the group opines that 80 guidelines was in fact 60 years, and not years is too high a cut-off for 65 years as the reviewers have indicated. Indian population. may consider The cut off of 80 years for defining elderly 65 years as per JNC guidelines is purely for the purpose of the target BP

level. In JNC 8 guidelines a higher target of <150 mm systolic was considered for people over 60 years of age. This was one recommendation on which the committee failed to reach consensus. The findings of the recently published SPRINT trial included a high proportion of those over 60 years, and presents evidence in favour of an even lower target BP of <120/80. The higher target of 150/90 for a patient for example aged 62 years, will be even more problematic in this light. THERAPEUTIC RECOMMENDATIONS

IHG The Group commented on a table In the introduction of the guideline itself of commonly used we had indicated our requirement for antihypertensive drugs including only 1 representative drug from each their doses. class, and our choice of these drugs are Western guidelines tend to reflected in the formulary – amlodipine, mention high doses of drugs e.g. enalapril/Lisinopril , thiazide, low cost enalapril dose is 5-40 mg. The ARB ( losartan), and atenolol. Losartan

group also wanted atenolol, needs to be retained as a possible low thiazide like diuretic and losartan cost ARB option in case of cough due to to be removed from the list. ACE inhibitors. We have now indicated lower doses of enalapril 42 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

IHG Re look at recommendation for We have mentioned fixed dose FDC, the group feels should not combinations mainly because many include it here in the national guidelines now refer to them. guidelines We have clarified in the guideline that FDCs are to be considered for use only after stabilisation of blood pressure. In fact their use as initial therapy creates problems of titration of drug dosages. FDC use in the National Health Mission will also create problems of a logistical

nature in terms of ensuring stocks of multiple combinations. IHG Add interval for monitoring and These have been added dose increase or decision to add another drug IHG The guideline may clearly mention Phrasing has been changed that aspirin is not indicated for primary prevention, instead of “ it is of uncertain value” IHG Criteria for starting statins in This criterion is mentioned in the CHEP patients with more than 3 risk guidelines. Also the ESC/ESH mentions

factors is difficult to apply in the that presence of 3 risk factor confers high absence of hyperlipidemia risk of cardiovascular disease IHG Suggested only atorvastatin as a We agreed statin IHG Suggested chronic review We agree feedback in tabular form IHG We’re not sure about whether a We strongly feel that a guideline to be a formulary is required in a stand –alone document useful in all guideline settings in India, needs to have information on indications, contraindications, side effects of a drug,

so that drugs are used rationally and safely. IHG Also include foods to be We agree. encouraged. Elaborate on salt intake 43 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

FULL GUIDELINE Hypertension: Screening, Diagnosis, Assessment and Management of Primary Hypertension in Adult Men and Women in India. 44 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

SECTION 4: SCOPE AND OBJECTIVE OF THE GUIDELINE. a) To increase detection of hypertension in adults in India using a systematic, primary care led approach based on standardised measurements of BP and their follow up. b) To provide guidance on assessment of persons with hypertension appropriate to different levels of care in India. c) To provide a structured , simplified and standardised treatment guideline for hypertension in adults in India, along with implementation tools(quick reference

guide, quality standards, patient information leaflets) d) To provide guidance on availability of a core list of medications in the public health system for treatment of hypertension. e) To outline research issues related to hypertension in India. 1. Population Groups that will be covered a) Adults at risk of hypertension (18 years and older) b) Adults with hypertension (18 years and older) with or without cardiovascular disease. c) People with diabetes

d) People with severe hypertension or high blood pressure in emergency care settings. Groups that will not be covered a) Children and young people (younger than 18 years). b) Pregnant women c) Secondary causes of hypertension: For example, chronic kidney disease, endocrine causes of hypertension [Cushing’s syndrome, pheochromocytoma] and renovascular hypertension. However clues to suspect of secondary causes of hypertension will be mentioned. 2. Healthcare setting

a) Community( 2se) t tings: These would be involved in promoting awareness of cardiovascular risk facto rs and their modification by a healthy lifestyle. Screening of hypertension at this level so through trained non-physician staff is a major point of emphasis in this guideline b) Sub-centres: These would be involved in screening for hypertension, patient education and assessment, and follow up of diagnosed patients.

c) Primary health centres. These would be involved in diagnosis, patient education, assessment with simple laboratory tests, management and follow up of patients. 3. Detection, diagnosis, assessment and clinical management of hypertension in India. d) Community Health Centres: These would be involved in diagnosis, patient education, assessment by physician and biochemical investigations (including renal function and lipid profile), and 45 management and follow up of patients.

Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document e) District Hospitals, Medical Colleges: These would be involved in diagnosis, assessment, management of hypertension including those with severe/resistant hypertension.

Key clinical issues that will be covered in the guideline A. Screening for hypertension in adults in India: a) Age at screening b) Health care settings for screening and role of non-physician staff. c) BP devices for measurement: sphygmomanometers or oscillometric devices or aneroid devices d) Standardised BP measurement procedure and sources of error. B. Diagnosis of hypertension in India: a) Number of measurements required for diagnosis b) Classification of hypertension in India according to BP levels.

c) Time frame for recheck and review of elevated BP readings in case of grade 1 and Grade 2 hypertension. C. Patient education and assessment of persons with hypertension in India: a) Education of the patient regarding nature of disease, its treatment, and the importance of adherence to treatment. b) Assessment for target organ damage at different levels of care. c) Assessment of associated clinical conditions at different levels of care d) Assessment of cardiovascular risk at different levels of care.

e) Patient assessment to rule out secondary hypertension. D. Management of hypertension 1. Initiation of treatment in different grades of hypertension. 2. Targets for BP control. 3. Classes of antihypertensive drugs and preferred choices. 4. Treatment regimens and strategies to achieve effective control of BP including optimisation of drug dosages and addition of other medications. 5. Treatment of hypertension associated with other conditions like diabetes, heart disease, cerebrovascular disease.

6. Reasons for poor response to therapy. 46 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

7. Integration of interventions to reduce global cardiovascular risk including cessation of tobacco use, antiplatelet therapy and lipid lowering therapy. 8. Improving adherence to therapy and systems for long term follow up of patients. Specialist management of secondary hypertension (that is, hypertension arising from other medical Clinical issues that will not be reviewed conditions). 1. Outcome and quality indicators Outcomes:

The evidence based guidelines sourced by this guideline for its preparation have relied on the following clinical cardiovascular outcomes occurring in hypertensive individuals to frame recommendations- 1. Fatal or non-fatal stroke. 2. Myocardial infarction 3. Heart failure and other cardiovascular deaths. Annexure: I. Lifestyle intervention for exercise: brief description II. Lifestyle intervention for weight control: brief description.

III. Lifestyle intervention for reducing salt intake (recommendations for intake in summer?): brief description. IV. Lifestyle intervention for reducing alcohol and tobacco consumption. V. Lifestyle intervention for stress management. Relaxation techniques including Yoga. VI. Formulary pages: 2 pages for each class of drugs with indications, cautions, contraindications, use in hepatic, renal impairment, pregnancy and breast- feeding, side-effects, dosages (initial and increments) of representative drugs of

that class. 47 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

1. Screening: Detailed recommendations: 1: Target population, and operational procedure of screening 1.1. We recommend an ongoing initiative to increase awareness of hypertension as a widely prevalent but asymptomatic disease associated with many adverse outcomes like heart attacks, strokes, kidney failure. Most patients with hypertension in India are unaware of their status and remain undetected.Early diagnosis and effective control of BP can save people from much morbidity, mortality and disability.

disease or stroke can be undertaken by trained non-physician staff. Background: Hypertension is a commonly prevalent disease in adults in India, affecting more than a 65 million persons, most of whom are unaware of their hypertension status.(8) The prevalence of hypertension increases with increasing age and more than half of people over the age of 60 years may be affected(25). It is asymptomatic in most of its course and symptoms are present only in the stage of complications. Patients with lower

grades/stages of hypertension are also likely to progress to more severe forms of hypertension. Detection of people with hypertension helps in identification of people at higher cardiovascular risk and effective treatment can provide significant protection from stroke, heart attacks, congestive heart failure and kidney disease, without causing significant harm. The availability of automated (oscillometric) BP measurements and their acceptance as a

clinical standard(26) has created opportunities for measurement of BP by non-physician aides, since these do not require training on auscultation. Implementation: The implementation of the screening programme on hypertension will require that opportunistic screening for hypertension is offered to all adults during the course of their visits to health facilities or healthcare providers – i.e. the health care providers should use the opportunity provided by the visit to screen for hypertension, and record 48

the measurement in a patient card. Systematic and sustainable practical methods need to be developed to screen the asymptomatic population for hypertension and can be integrated with screening of other non-communicable diseases. Allied health staff should be trained to check hypertension using automated validated BP apparatus and follow the referral guidelines on screening measurements. The high risk groups which may be focused on are those with age >50 years years)(25, 27)

as well as those with diabetes(28) where prevalence of hypertension has been noted to be more than 30-50%, and yet often remains undetected(27, 29). Studies in India have also shown that the risk of hypertension is higher in those who have general or abdominal obesity and those who consume tobacco or alcohol.(30)There is a need to spread awareness of these risk factors for hypertension and cardiovascular disease, through the National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular

Diseases and Stroke. The major risk factors for hypertension and cardiovascular disease can be summarised as ABCDE as shown below- The ABCDEs of risk of hypertension and cardiovascular disease in India A: Age e.g. > 50 years B: Body mass index – Obesity (BMI >25 kg/m2) which is related to diet and activity levels, and especially abdominal obesity(waist circumference >90 cm in men,>80 cm in women) C: Consumption of tobacco and alcohol D: Diabetes, Dyslipidemia E: Excess salt in diet

Implementation of the screening program will require training of the non-physician aides in the measurement of blood pressure, the availability of an automated (oscillometric) BP measurement device, and preferably cuffs of 2 sizes to enable measurement of BP in obese patients too. Implementation will also require that the Bureau of Indian Standards develop a quality standard for the digital (oscillometric) devices in the market, on the lines of the standards and validation procedures in UK,

USA and Europe. This will ensure that validated devices are available in the Indian market. At present the Bureau of Indian Standards has quality standards only for mercury and aneroid sphygmomanometers. Rationale: Benefit outweighs harm: The evidence of the benefits and the harms of screening for hypertension have been systematically reviewed (U.S. Preventive Services Task Force. Screening for high blood pressure: U.S. Preventive Services Task Force recommendation

statement. Ann Intern Med 2007:147-783-786) and found to have a net benefit. The USPTF therefore recommended “screening for high blood pressure in adults 18 and over”. 49 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Screening by non-physician health workers: The operational guidelines of the National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular diseases and Stroke envisages that screening for hypertension is to be done at sub- centre by non-physician health workers like ANM or male health worker.(31) There is emerging evidence from India and other low-income Asian countries that community based interventions to assess cardiovascular risk factors,(13) task shifting to non-physician

health workers should be considered,(32) and finally that delivery of a package of interventions for non-communicable diseases including screening by non-physician health workers is both feasible and effective.(11). Groups at high risk of hypertension are easily identifiable:Cohort studies in south India have identified risk factors which can be helpful in identifying groups at particular risk of developing hypertension. These include persons with age≥ 35 years, current

smokers, persons with central obesity (measured by waist circumference), persons with previous record of high normal BP.(33, 34). All these risk factors can be identified by non- physician healthcare workers and can help prioritise groups who require targeted screening. The age threshold for screening: The age related threshold for screening has been previously suggested to be 30 years in India under the operational guidelines of the

National Programme for Prevention and control of cancer, diabetes, cardiovascular diseases and stroke.(31) However systematic reviews of the evidence have suggested a lower threshold and the US Preventive Services Task Force “recommends screening for high blood pressure in adults in adult 18 and over”. The lower threshold suggested may also be considered in light of other factors. Patients with essential hypertension can present even at an age less than 30 years, especially in those with a family history of

hypertension or increased body mass index. In a study of apparently normal 10-16 year old school children in south India ,a prevalence of 6.6% of essential hypertension which was associated with high BMI was noted(35). Patients with secondary forms of hypertension including chronic kidney disease can also present below 30 years of age. There are special populations like pregnant women who may be below 30 years of age, but should also be screened for hypertension to prevent maternal and foetal

complications. Indians have a lower age of presentation of cardiovascular events like coronary artery disease than their western counterparts.(36) Persons even below the age of 30 years may have prevalence of other risk factors like obesity in which prevalence of hypertension is higher, or smoking or alcohol consumption which will increase their risk for future cardiovascular disease. Measurement of BP in persons aged 18 years and

above offers opportunities for prevention of hypertension by identifying persons with high normal BP in whom progression to hypertension may be prevented by lifestyle modifications. Use of digital (oscillometric) devices:Guidelines like NICE,(18) ASH/ISH(24), ESC(21), now suggest the use of electronic BP measurement instruments based on the oscillometric approach to record BP in both clinic as well as home based settings. Protocols for the

validation, and a list of instruments validated by organisations like the British Hypertension Society, European Society of Hypertension, and Association for Advancement of Medical Instrumentation are also available.(37, 38)In evidence based systematic review, oscillometric devices were considered appropriate for use in adults 50 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

(Level A recommendation) including for those with trauma and shock, and were given a Level B recommendation for use in adults with hypertension, because of discrepancies accruing from increased arterial stiffness. Oscillometric However other studies have cited concerns about their accuracy.(39) In a study of validated digital devices in practice settings, 88% of digital devices had measurement within 3 mm Hg of the reference standard compared to 95% of mercury sphygmomanometers, suggesting that digital

devices can have accuracy equivalent to mercury sphygmomanometers.(40). The World Health Organisation recommends the use of electronicdevices, which are affordable and reliable and which have the capacity for manual settings.(41) Key Recommendation: Standardised BP measurement procedure 1.3 The screening of hypertension should be done by a physician or trained non physician staff, using an automated BP instrument or any other validated device, and following a standardised BP measurement procedure.

1.4 Blood pressure should be measured a few (5) minutes after the patient is in a relaxed state, is seated with the arm at the level of the heart, with legs uncrossed. The cuff should have a bladder whose length is about 80% and whose breadth is about 40% of the arm circumference. If the auscultation based method is being used, the then the cuff should initially be inflated to at least 30 mm Hg beyond the point of disappearance of the radial pulse. It should then be deflated at a rate of 2-

3 mm per second. The first and the last audible Korotkoff sounds should be taken at the systolic BP and diastolic BP respectively. The column should be read to the nearest 2 mm Hg. 1.5 At least 2 readings should be taken at each visit with an interval of at least 1 minute between the measurements. If the two readings are substantially different a third reading should be taken. The lower of the two readings should be taken as the representative SBP and DBP. Background

Hypertension is a condition which requires life-long monitoring and management. This diagnosis is based on measurement of blood pressure in the clinic setting and it is essential that this measurement be made as reliable as possible. A number of factors- the level of training of the observer, the setting for the measurement of BP (home or clinic), timing of the day, preceding caffeine intake or smoking, the position of the

patient during the procedure, the accuracy of the BP measuring instrument, the size and placement of the cuff, the number of readings taken, all affect the readings and thereby the reliability of this measurement.(2)It is important that the provider is trained, the BP measurement device is accurate and validated, the patient conditions for measurement of BP are met, and the procedure of recording the BP is standardised. We recommend

the use of both existing mercury BP sphygmomanometers and digital oscillometric BP devices. Implementation 51 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

We suggest that for expanding the access to screening, diagnosis and monitoring of blood pressure, digital BP devices be made available, especially at levels of care delivered by non-physicians. A WHO expert committee meeting on measurement of blood pressure in low resource settings concluded that “Given the serious inherent inaccuracy of the auscultatory technique, validated and affordable electronic devices, that have the option to select manual readings, seem to be a suitable solution for low

resource settings.”(41). The technical specifications recommended were “high accuracy, adoption of electronic transducers and solar batteries for power supply, standard rates of cuff inflation and deflation, adequate cuff size, digital display powered by solar batteries, facilities for adequate calibration, environmental requirements, no need of memory function, resistance to shock and temperature changes, and low cost”.(37)We

recommend that the Bureau of Indian Standards undertakes a validation of the devices being marketed in India according to internationally accepted protocols.(37). The accuracy can be re-checked periodically against a reference mercury sphygmomanometer in the PHC/CHC retained for this purpose. We recommend that the healthcare providers be trained in the use of these devices and the standardised conditions and procedure for measuring BP. The chosen device for BP measurement

should also undergo periodic calibration. BP measurement procedure: (ref: (2)) Auscultation based procedure: Patient preparation and position: Allow the patient to be seated 5 minutes before taking the BP measurement. BP should be measured with the patient in a relaxed state, sitting with the back supported, the arm at the level of the heart, and with the legs uncrossed. There should not have been caffeine intake in the preceding 1 hour and smoking in the

preceding 30 minutes. The patient should remove all clothing which may interfere with the placement of the cuff and have a constrictive effect. BP device: The device should be a validated device with an appropriate cuff size. Cuff size and placement: The cuff should have a bladder whose length is at least 80% of the arm circumference, and a width that is at least 40% of the arm circumference. The cuff should be placed with its midline over the pulsations of the brachial artery,

identified by palpation above the antecubital fossa. If the patient is obese then a large adult size cuff will be preferable. If an auscultation based method is being used for measurement of BP, a 2-3 cm space should be available between the lower end of the cuff and the antecubital fossa. Procedure: If the BP measurement involves auscultation, then the cuff should initially be inflated to at least 30 mm Hg beyond the point of disappearance of the radial pulse. It

should then be deflated at a rate of 2- 3 mm per second. The first and the last audible Korotkoff sounds should be taken at the systolic BP and diastolic BP respectively. The column should be read to the nearest 2 mm Hg. No. of measurements: At least 2 readings should be taken at each visit with an interval of at least 1 minute between the measurements. We suggest, in line with the new recommendation in the 52 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

NICE guidelines (2011), that the physician or non-physician measuring the BP records the lower of the 2 measurements as the representative systolic and diastolic BP. This will also avoid the calculation error involved in averaging the 2 measurements. Because of the variability of BP measurements, the diagnosis of hypertension should be only made after multiple readings over at least a week confirm the diagnosis of hypertension,

except in the case of hypertensive emergencies and urgencies where the diagnosis may be established with another BP recording in the same visit. If the patient is above 65 years of age, or a diabetic then the patient should have the BP checked in supine and 2 minutes after assuming the standing position. A fall in systolic Recommended cuff sizes for accurate measurement of Blood Pressure(source: Ref(2)) Patient (by arm circumference) recommended cuff size 22 to 26 cm 12 x 22 cm (small adult)

27 to 34 cm 16 x 30 cm (normal adult) 35 to 44 cm 16 x 36 cm (large adult) BP more than 20 mm Hg and 10 mm or more in the diastolic pressure suggests the presence of postural hypotension.(2) Source of measurement Comment (2) error (2) Back is not supported Diastolic BP may increase by 6 mm Arm is not at level of Dangling the hand unsupported increases BP by 10-12 mm Hg. heart Legs are crossed Systolic BP increases by 2-8 mm Hg Caffeine in the last 1 hour Transient increase in BP

Smoking in the previous Transient increase in BP half an hour Cuff size not appropriate May overestimate systolic BP by 10-50 mm in obese persons in whom a smaller cuff has been used 53 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Rapid deflation greater May underestimate systolic BP and overestimate diastolic BP than 3 mm/sec Patient’s anxiety/ This may result in elevated BP readings, which may be normal conditional response to when recorded by a nurse or when recorded at home. This “ an unusual situation in white coat hypertension” or “isolated office hypertension” may the presence of a constitute 32% of hypertensive subjects in 4 population based physician surveys.(42) White coat effect and white coat hypertension:

The white coat effect can occur in all patients with hypertension and can result in higher BP readings in clinic settings than outside it.(43) It may result in misclassification of severity of hypertension. The effect varies from minimal to marked increases in clinic BP readings compared to ambulatory or home recording with an overall mean increase of 27 mm Hg in the systolic BP observed in one study.(44) White coat hypertension or isolated clinic

hypertension occurs in persons who are normotensives on out of clinic measurements. The white coat effect is due to an alerting reaction and reflex activation of the sympathetic nervous system.(43) Rationale Use of oscillometric devices and the involvement of non-physician community health workers: Measurement of BP with a mercury sphygmomanometer is considered a gold standard, but India is a signatory to the Minamata convention and has committed to the phasing

out of mercury in healthcare, because of environmental concerns. Mercury based sphygmomanometers are also prone to breakages. Aneroid BP instruments are an alternative but they require frequent calibration. Both mercury and aneroid devices require an auscultation based procedure, which has its inaccuracies and more intensive requirements for training. Digital BP devices based on oscillometric approach are now considered the “clinical standard” and are being widely used in both clinic and home

settings in developed countries.(26)They have the advantages of lower training requirements facilitating use by non-physicians, portability. In a large study measurements with these oscillometric devices had a mean underestimation of less than 2 mm Hg,(45) and in a clinic based observational study, the accuracy was found to be acceptable.(40) Preliminary studies support the use of electronic devices by community health workers.(46)A mercury sphygmomanometer will still need to be retained at each

facility to check the accuracy of these devices.(2) A number of studies have shown that with proper training, supervision,and community based workers can measure blood pressure and assess cardiovascular risk factors accurately. 54 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Rescreening, reassessment, and referral of individuals found to have normal or elevated BP on screening by allied health staff 1.6. Depending on the BP readings, the person may be advised review up on an annual or 2 yearly basis, or referral (immediate or deferred) for diagnosis or treatment of hypertension. 1.6.1 Persons with normal BP (<130/80) should be advised a recheck in 2 years. 1.6.2 Persons with high normal BP: systolic BP of 130-139 mm Hg and diastolic of

80-89 mm Hg should be advised a recheck in 1 year, or sooner if indicated due to other risk factors or diseases. 1.6.3 Persons with BP > 140 mm Hg systolic and/or greater than 90 mm Hg diastolic should be rechecked within 1-2 weeks and then classified as hypertensive or high normal. 1.6.4 Persons with BP of >160 mm Hg systolic and/or greater than 100 mm Hg diastolic should be advised early referral to the primary health centre if measurements have been made at a peripheral health facility below the level

of a primary health centre, for confirmation of the diagnosis of hypertension. 1.6.5 Persons with BP of >180 mm Hg systolic and/or greater than 110 mm diastolic if documented by a non-physician staff, should be immediately referred to the primary health centre or community health centre (whichever is nearer to the residence) for further investigation to exclude any acute target organ damage, and for initiation of treatment,which is required on an

immediate basis. Patients documented with this level of BP in a health facility would require assessment for target organ damage, and gradual reduction of BP over hours and days if there is no acute target organ damage. 1.6.6 Hypertensive emergencies are potentially life-threatening situations where hypertension (usually severe and > 180 mm systolic and >120 mm diastolic associated with the presence of recent onset and progressive target organ

damage resulting in cardiovascular, neurologic, renal and visual dysfunction. These situations may include severe hypertension associated with acute coronary syndrome (chest pain), acute left ventricular dysfunction (shortness of breath), and hypertensive encephalopathy (altered sensorium), stroke (focal weakness), and renal failure. It is most often associated with severe hypertension, except in children and pregnant women where hypertensive emergencies can occur with lower elevations of BP.

1.7 All persons who are screened for hypertension should be advised lifestyle measures including maintaining a daily salt intake appropriate to their occupation, advice on diet and exercise in case the person is obese, stopping use of tobacco and 55 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

moderating consumption of alcohol to reduce their blood pressure and to reduce their overall risk of cardiovascular complications. Implementation: The health care staff will need to be trained not only in the measurement of BP using a standardised procedure, but also to interpret the measurements of normal or elevated BP readings and take appropriate actions. This will be facilitated by the availability of key messages for the detection, assessment and management of hypertension in a

flyer and quick reference guide. Suggested response to BP readings: Initial BP reading on screening Advice and Recommendations for Follow up SBP mm Hg DBP mm Hg <<130 <<85 Advise lifestyle modifications esp. smoking, weight reduction if possible : Recheck in 2 years 130-139 85-89 Advise lifestyle modifications: Recheck in 1 year 140-159 90-99 Recheck BP within 1-2 weeks. Advise lifestyle modifications. Refer to nearest health facility within 1 month for diagnosis, assessment.

160-179 100-109 Recheck BP within 1 week. Advise lifestyle modifications. Refer to nearest health facility for confirmation of diagnosis and initiation of treatment. >180 >110 Check for any symptoms/signs of any acute target organ damage (assess symptoms and signs referred to in the mnemonic ‘ABCDEFG’mentioned in pathway on assessment and management of hypertensive crisis). In cases of acute target organ damage, treat as hypertensive emergency. Refer to PHC/CHC for evaluation and

treatment immediately after confirming elevated readings in this range. Initiate therapy before referral, if seen at PHC. TABLE 3: SUGGESTED RESPONSE TO INITIAL BP READINGS :Adapted from references (29, 47) Rationale: There is no evidence from randomised controlled trials regarding the appropriate rescreening intervals for people screened for hypertension.(47) Recently the US Preventive Services Task Force published recommendations regarding rescreening

intervals. The weighted mean incidence of hypertension over rescreening intervals varying between 1 and 5 years was found to range between 2.5% and 13.8% 56 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

respectively. In studies persons with even a single risk factor like high normal BP (SBP 130-139 mm and DBP 85-89mm), persons who are obese or overweight , and those with age >40 years are at greater than 20% risk of developing hypertension within the next 3- 5 years, and therefore such persons should be screened annually for hypertension. The intervals suggested for confirmation and evaluation at a source of care have been adapted from the recommendations of the JNC 7.(29) 57

KEY RECOMMENDATION: DIAGNOSIS AND CLASSIFICATION OF HYPERTENSION 2.1 Diagnosis of hypertension should be made at primary health centres and facilities above that level using validated and calibrated BP measurement devices and following the standardised BP measurement procedure. 2.2 Diagnosis of hypertension should be based on at least 2 measurements taken in the clinic or by a healthcare provider on at least 2 visits, which are at least 1-4

weeks apart, except in the case of hypertensive urgencies and hypertensive emergencies, where hypertension is diagnosed during the first visit itself. Ambulatory blood pressure monitoring and home based BP monitoring is not feasible for diagnosis for most patients with hypertension in India and is therefore not recommended. 2.3 Hypertension should be diagnosed when BP is persistently above a systolic of 140mm and/or diastolic of 90 mm.

2.4 Patients with hypertension should be classified in the following manner: • Grade 1 Hypertension: systolic 140-159 mm and/or diastolic 90-99 mm • Grade 2 Hypertension : systolic 160-179 mm and/or diastolic 100-109 mm • Grade 3 Hypertension : systolic 180 or above and/or diastolic 110 or above • Isolated systolic hypertension: systolic > 140 mm but diastolic <90 mm. • Hypertensive urgency: Severe asymptomatic hypertension ( usually Systolic > 180 mm , Diastolic >120 mm) 58

• Hypertensive emergency: Severe hypertension accompanied by cardiac (e.g. acute left ventricular failure), neurological (e.g. hypertensive encephalopathy), or renal dysfunction. Background The diagnosis of hypertension depends on multiple BP measurements taken in the office setting over a period of time. Diagnosis of hypertension should be based on at least 2 measurements taken in the clinic or by a healthcare provider on at least 2 visits, which

are at least 1-4 weeks apart, except in the case of hypertensive urgencies and hypertensive emergencies, when the diagnosis of hypertension is made during the first visit itself. Classification of hypertension is important for therapy and prognosis as the level of cardiovascular risk and the risk of target organ damage increases with the severity of hypertension. Implementation: Diagnosis of hypertension will be made at primary health centres and facilities above

that level using validated and calibrated BP measurement devices and following a standardised BP measurement procedure. Hypertension should be diagnosed when BP is persistently above a systolic of 140 mm and/or diastolic of 90 mm. The classification of patients into those with optimal BP, Normal BP and different grades of hypertension is made as per the table below. In India, for the diagnosis of most patients with hypertension, ambulatory blood pressure

monitoring and home based BP monitoring is not feasible and is therefore not recommended. Rationale: All guidelines define hypertension for the general population as persistent elevation of SBP higher than 140 mm and/or DBP higher than 90 mm Hg. However the classification of hypertension varies across guidelines. While the WHO/ISH guidelines(48) and the ESH/ESC guidelines (21)mention the grades of hypertension referred in the table, the

JNC 7(29) and JNC 8 and NICE guidelines define only 2 stages of hypertension, collapsing the Stage 3 hypertension category into Stage 2,considering them to be therapeutically similar. The nomenclature of BP levels below 140 mm and 90 mm also differ. The ESC/ESH guidelines define normal as <130 mm systolic and/or <85 mm diastolic, the JNC7 guidelines define normal as <120 and or 80 mm and categorise all persons with BP of 120-139 mm SBP and 80-89 mm diastolic as having “pre-hypertension”.

We adopted the ESC/ESH guidelines for the classification of hypertension because of a consensus that Category 3 mentioned in these guidelines is retained and the category of pre-hypertension mentioned in JNC is avoided. Category 3 mentioned in the ESC/ESH guidelines was part of the WHO/ISH guidelines.(48) Even in guidelines like NICE which do not mention this grade, this level of SBP and DBP is classified as severe in these

guidelines. This category has both prognostic and therapeutic importance. Prognostically, grade 3 hypertension is associated with high cardiovascular risk. Therapeutically it is important as it indicates need for immediate referral and initiation of therapy. We 59 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

agreed that life-style modifications be advised to all persons with persons above 120 mm Hg systolic and/or 80 mm Hg diastolic but felt that the label of “pre-hypertension” may become a source of anxiety. Category SBP(mm Hg) DBP(mm Hg) Optimal <120 and/or <80 Normal 120 – 129 and/or 80 – 84 High Normal 130 – 139 and/or 85 – 89 Grade 1 Hypertension 140 – 159 and/or 90 – 99 Grade 2 Hypertension 160 – 179 and/or 100 – 109 Grade 3 Hypertension > 180 and/or >110 Isolated Systolic > 140 and < 90 Hypertension

Hypertensive urgency >180 and/or >110 Severe asymptomatic hypertension with no evidence of acute target organ damage Hypertensive emergency >180 and /or >110-120 Severe hypertension associated with cardiovascular dysfunction (e.g. Left ventricular failure, cerebral dysfunction (e.g. Hypertensive encephalopathy, stroke),renal dysfunction (acute renal failure), or Grade III-IV hypertensive retinopathy(haemorrhages, exudates, papilledema) 60

KEY RECOMMENDATIONS: PATIENT EDUCATION AND ASSESSMENT 3.1 Patients should be counselled about the nature of the disease, and the management of hypertension, before being subjected to laboratory evaluation and drug treatment. The education and assessment of the patients should be tailored to their understanding, preferences and social circumstances. 3.1.1 Patients should be counselled about hypertension being an asymptomatic condition which can lead to disabling and life-threatening complications like

stroke, heart attack and renal failure. Patient should be counselled about need for long-term therapy, need for regularity of drug intake, informed about the targets for BP control, and encouraged to monitor efficacy of therapy through regular check-ups which can include home based monitoring of BP. 3.1.2 The patient should be counselled about the important role of lifestyle measures in reducing hypertension and reducing risks of cardiovascular disease.

3.2 The effective control of blood pressure by initiation of therapy, if required, should not be delayed if laboratory evaluation is delayed or cannot be done. 3.3 The assessment of a patient with hypertension is aimed at assessing overall cardiovascular risk for cardiovascular events like stroke, ischemic heart disease, heart failure, peripheral artery disease. 3.3.1 The risk of clinical events in a patient with hypertension depends on • the level of blood pressure

• risk factors (diabetes or impaired glucose tolerance, smoking, dyslipidemia, obesity, male gender, age >55 years in male, ) , • target organ damage(heart, kidney, retina), • Presence of associated clinical conditions [clinical cardiovascular disease (coronary artery disease, cerebrovascular disease, PAD), kidney disease]. 3.4 The risk factors, target organ damage and associated clinical conditions can be detected on history, physical examination (including ophthalmoscopy), and investigations

like blood glucose, lipids, serum creatinine, urinalysis, and ECG. 3.4.1 Physicians and allied health staff should assess and evaluate patients for cardiovascular risk factors like smoking, obesity, diabetes. Reduction of risk by adoption of healthy living habits-(dietary changes, exercise, 61 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

smoking cessation) is to be reinforced by all cadres of health workers. Screening for hyperlipidemia can be suggested and carried out in patients at PHC/CHC especially in those who are obese, or have family history of premature coronary artery disease, or have existing cardiovascular disease. 3.4.2 Physicians and allied staff can detect target organ damage by eliciting symptoms of shortness of breath, decreased urine output, and noting signs of heart failure like swelling of feet, and other signs of heart

failure. Target organ damage can also been detected by testing urine for proteinuria, noting evidence of left ventricular hypertrophy on ECG, and features of hypertensive retinopathy on ophthalmoscopy. These signs of target organ damage can all be detected at PHC/CHCs. 3.4.3 Physicians and allied staff can detect associated clinical conditions like clinical cardiovascular disease and chronic kidney disease by eliciting history of chest pain suggestive of angina and/or pain in the lower limbs

on walking suggestive of claudication, and/or history of stroke with weakness of limbs. CKD can be detected by persistently abnormal serum creatinine measured at the CHC level. 3.5 The overall risk of cardiovascular events can be assessed from these assessments as follows: Level of blood pressure: Grade 2 Hypertension even in isolation confers moderate risk (20-30% risk of CV event over 10 years), while Grade 3 hypertension confers high risk (Over 30% risk of CV event over 10 years).

Risk factors: Presence of 3 or more risk factors confers moderate to high risk even in a patient with Grade 1 hypertension, while even fewer risk factors increase risk in Grade 2 hypertension. TOD/Diabetes/CKD/Clinical cardiovascular disease: Presence of any target organ damage, diabetes, chronic kidney disease or clinical cardiovascular disease confers high to very high risk on patients. 3.6 The level of BP and results of the assessment will influence the following:

• when to start antihypertensive therapy, • Which antihypertensive to use. • whether statins and/or aspirin are indicated, to reduce cardiovascular risk 62 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

• Which other associated conditions will need management (diabetes, clinical cardiovascular disease, chronic kidney disease). 3.7. Screening for diabetes (which is to be available at all health facilities under the free diagnostics initiative) is an integral part of evaluation of hypertension because of the common association of hypertension and diabetes. The care of diabetes should be integrated with management of hypertension. 3.8 All patients should be asked about tobacco use and advised to stop it.

Key recommendations: Background: Hypertension is most often asymptomatic and the benefits of treatment are not immediately apparent to a patient. The therapy of hypertension involves costs (indirect as well as direct), and occasional experience of adverse effects, and is often lifelong which may create barriers to adherence to therapy. Improving adherence to long-term treatment is a key part of management. The patient is more likely to adhere to

medications, lifestyle modifications if he/she understands the nature of the condition and its management. The assessment of cardiovascular risk factors, target organ damage due to hypertension, associated clinical conditions all help in assessment of cardiovascular risk and guide therapy of hypertension. These can be assessed by a relevant history, examination and appropriate investigations, many of which can be evaluated even by non-physician staff.

It may also indicate the need for other therapies like low-dose aspirin and statin to reduce cardiovascular risk. Decisions on initiation of therapy, choice of medications, BP targets for control are dependent on these factors as much as the severity of hypertension. Grade 1 hypertension may be managed with lifestyle modifications alone in the absence of other risk factors. Implementation of patient education and assessment

Patient education related to hypertension is a part of the initial care and should be reinforced during the continuing care of patients with hypertension, e.g. during annual reviews. It can be delivered by both physician and non-physician staff and can be supported by aids like patient information leaflets (attached). Non-physician staff at the community level can reinforce messages related to healthy living, monitoring of BP and adhering to treatment.

Patient education: Patient education will facilitate the patient’s participation and cooperation in the management of a life-long disease. They should understand the following features of the disease and its management: • The disease is asymptomatic but is a risk factor for serious consequences like heart attacks, strokes, heart and kidney failure, which can be prevented by controlling hypertension to a target BP which is usually less than 140 mm systolic 63

and 90 mm diastolic. The disease is persistent and although it cannot be cured it can be controlled. • Healthy living habits (lifestyle modification) like stopping smoking, eating a healthy diet lower in salt and saturated fat, exercising losing weight has many benefits with no cost. It can reduce blood pressure, may suffice for the management of grade 1 hypertension, reduce the dosage of medicines required for control of grade 2 and 3 hypertension, and help reduce the overall risk of

heart attacks and stroke. • The assessment of damage to the heart, kidney, vessels in the eye, and to detect the presence of associated conditions like diabetes are needed to determine the overall risk of cardiovascular and to frame an effective treatment regime. • Medications may have to be taken lifelong, and monitoring with regular checks of blood pressure is required to note their efficacy. Taking medications regularly without BP checks is suboptimal, as is checking BP regularly without regular

intake of medications. Most drugs can be given only once a day and can control BP with minimal side effects. Patient education should be given in an empathic and culturally appropriate manner. It should elicit their views of the disease, and their expectations from treatment. It can be given by both physicians and non-physician staff. Assessment of a patient with hypertension has the following 5 components a. Assessing the lifestyle related and other cardiovascular risk factors in

patients with hypertension and the capability each patient’s capacity or willingness to change these factors; e.g. b. Assessing the target organ damage related to hypertension. c. Assessing the presence of associated clinical conditions like diabetes, kidney disease or symptomatic cardiovascular disease. d. Assessing the clues to a secondary cause of hypertension. e. Assessment of overall cardiovascular risk of a patient To assess patients for each of the above components the healthcare provider should ask

relevant questions, look for relevant features on physical examination, and carry out appropriate laboratory investigations, which may be available at that level of care or may require referral .Some of these assessments can be done at any level of care, while others are only possible at a community health centre level. The tables below have been made keeping in mind the resources and level of training of healthcare providers in India and are not exhaustive.

a. Assessment of lifestyle and other cardiovascular risk factors: This is mentioned in table 1. 64 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Assess lifestyle factors and other cardiovascular risk factors History: Smoking history Dietary consumption of salt, saturated fats Exercise pattern Alcohol consumption Family history of premature coronary artery disease Examination: Weight & Height and calculation of BMI. Laboratory evaluation: Blood glucose, Lipids Table 1: Assessment of lifestyle and other cardiovascular risk factors Table 2: Risk factors for cardiovascular disease Risk factors for cardiovascular disease(5) (Apart from hypertension):

1. Male sex 2. Age (men >55 years, women>65 years). 3. Smoking. 4. Dyslipidemia (LDL > 115 mg/dl and/or Total cholesterol >190 mg/dl and/or HDL < 40 mg/dl and/or Triglycerides > 150 mg/dl). 5. Diabetes 6. Obesity (BMI> 25 kg/m2), abdominal obesity with waist circumference >90 cm in men and >80cm in women. 7. Fasting plasma glucose 100-125 mg/dl or abnormal glucose tolerance test A comprehensive list of risk factors is given in table 2. It is vital to ask every hypertensive

patient about their smoking history, confirm it with a relative, since it is often underreported, and advise on cessation of tobacco use. Tobacco use is an independent and powerful predictor of cardiovascular diseases. The diet with regard to fat and salt content and exercise pattern should be enquired. On examination, body weight and height should be measured and the body mass index [weight in kg/ (height in metre) 2]calculated. In laboratory evaluation, the blood glucose should be checked to rule out

undetected diabetes (currently available at CHCs), and the lipid profile should be carried out whenever feasible. Detection of associated diabetes should be an integral part of evaluation of hypertension and diabetes care should be integrated with the care of hypertension. b. Assessment of target organ damage related to hypertension is described in table 2. 65 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Assess target organ damage: Heart (heart failure), Kidney, and Retina History Breathlessness on effort Swelling on feet Examination Raised Jugular venous pressure, edema, gallops on auscultation (heart failure) Funduscopic evidence of hypertensive retinopathy-hemorrhages, exudates, papilledema Laboratory evaluation ECG: SV1 +RV6 > 3.5 Mv (LVH) Urine protein, Serum creatinine Table3: Assess target organ damage The target organs affected by hypertension are the brain, heart, kidney, and eye.

• A history of breathlessness on walking briskly or climbing stairs may indicate its effect on the heart, as does the complaints of swelling over both feet. • On examination the presence of pulsatile elevation of jugular venous pressure, presence of edema on the feet, and presence of changes of hypertensive retinopathy (Grade II or higher) indicate target organ damage. • ECG if feasible may show changes suggestive of left ventricular hypertrophy.

Microalbuminuria with an increased urine protein/creatinine ratio on spot urine is an early marker of renal damage, but is not widely available. However macroalbuminuria detected by a dipstix or serum creatinine estimation must be done whenever possible. Referral for assessment of TOD: Patients with Grade 2 hypertension and above, and those with diabetes, should be referred early to the community health centre to enable evaluation by ophthalmoscopy, ECG, urinalysis and creatinine

estimation, after initiation of treatment. Patients with Grade 3 hypertension should be referred on an urgent basis after initiation of treatment. Those who have Grade 3 hypertension and clinical features of hypertensive emergencies (papilledema with proteinuria) should be referred to an emergency department of a secondary level centre, after initiation of treatment. b. Assessment of associated clinical conditions/clinical cardiovascular disease:

Hypertension often occurs in association with other clinical conditions e.g. coronary artery disease (myocardial infarction or angina pectoris), cerebrovascular disease (history of ischemic or haemorrhagic stroke), and chronic kidney disease (diabetic or non-diabetic). A patient with hypertension may have been already been diagnosed with these conditions. Thepresence of these conditions determine choice of therapy and may favour particular classes of drugs. . For example, although beta-blockers are 66

no longer considered the first choice drugs in hypertension, but they are preferred drugs in the presence of angina or past history of infarction. These associated conditions can be assessed by eliciting history as shown in table. On examination, significant pallor in the presence of hypertension may indicate presence of chronic kidney disease. ECG may show signs of ischemia, infarction, and conduction system disturbances. Urinalysis may be abnormal and creatinine may be elevated in kidney disease.

Assess associated clinical conditions: Myocardial infarction, Stroke, Chronic Kidney disease History: Episode of chest pain at rest (Myocardial infarction) in past Weakness on one half of body (Stroke) in the past Examination: Significant pallor in the presence of HT– chronic kidney disease Laboratory: S. Creatinine ECG: Ischemia, infarction, conduction disturbances, arrhythmias (atrial fibrillation) Table 4: Assessment ofassociated clinical conditions Assess clues to presence of secondary hypertension

History:Abrupt onset of hypertension below the age of 30 years and above the age of 60 years (renovascular hypertension) Paroxysms of palpitations, pain(headache), perspiration( pheochromocytoma)(1) Snoring at night, breathing pauses reported by partner, daytime sleepiness (sleep apnoea) Drug intake: NSAIDs, Steroids, Oral contraceptive pill Examination: mooning of facies, striae: Cushing syndrome Unequal pulses: diminished/absent radial pulses- Takayasu’s arteritis

Diminished & delayed in lower limb: Coarctation of aorta. Tachycardia and postural hypotension (pheochromocytoma) Bruit over renal arteries: renal artery stenosis (renovascularhypertension) Laboratory investigations: Abnormal urinalysis (proteinuria, haematuria), elevated creatinine. Abnormal kidneys on USG- renal parenchymal disease Table 5: Assessment of clues to presence of secondary hypertension 67 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

c. Assessment of clues to secondary hypertension: There are clues to the presence of secondary causes of hypertension which may be noticed during the evaluation of the patient. These are important to recognise because an underlying secondary cause may result in difficult to control hypertension. Sometimes addressing the underlying cause e.g. renal artery stenosis may result in cure of hypertension. Long term therapy with oral steroids, often given

inappropriately for asthma, arthritis and skin disorders, is common in India and may result in Cushing’s syndrome. Takayasu arteritis is also seen in India and should be suspected in the presence of diminished or absent pulses in the upper limb. Grade 1 HT Grade 2 HT Grade 3 HT No risk factor Low risk Moderate risk High risk 1-2 risk factor* Moderate risk Moderate to High risk high >3 risk factor* Moderate to High High High risk risk Organ damage, High risk High risk Very high risk diabetes, CKD stage 3

Symptomatic CVD( Very high risk Very high risk Very high risk stroke, coronary artery disease), diabetes with organ damage, CKD>stage 4 Table 6: Overall Assessment of cardiovascular risk (5): Using this table the overall risk in a patient with Grade 1 hypertension can vary from low to very high depending upon the above factors. E.g. a non-smoking, non-obese 50 year old man with grade 1 hypertension may be low risk, a smoking male aged 60 years is at

moderately to high risk while a diabetic irrespective of other factors is at high risk. Framework for assessment of patients with hypertension in the health system in India: It is clear that patients with hypertension require a continuum of care with participation of healthcare providers at all levels. The non-physician staff with some training can play an important role in detection, assessment, management and long term care of patients with

hypertension. Their role in monitoring of blood pressure, adherence to healthy living habits and use of medications is crucial. We also feel that hypertension and many other chronic diseases are best managed at the primary care level and re-training of primary care providers in the prevention, screening, diagnosis and management of these conditions will provide a foundation for programs for these diseases. The health system will also need

strengthening in terms of availability of diagnostic tests. In this context, the proposed free 68 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

diagnostics initiative of the Government will make the basic evaluation of the patient with hypertension possible at the sub-centre, PHC and CHC level. The table below details the role that the different cadres of health workers can play in the assessment of patients. Much information on cardiovascular risk factors, target organ damage, detection of associated clinical conditions, and suspecting secondary causes of hypertension, can be obtained from the history, and general examination.

Village(Village Sub PHC(Primary CHC(Specialist) health centre(Traine health care worker) d auxiliaries) physician) History of √ √ √ √ cardiovascular risk factors: smoking, diet, exercise, diabetes. History suggestive of √ √ √ √ target organ damage(heart) History of associated √ √ √ √ clinical conditions, coronary artery disease, stroke History of secondary Suspect in case Suspect in case √ √ [ may also causes of of of refer in case of hypertension hypertension hypertension hypertension

not responding not responding non-response] to medicines. to medicines. Refer. Refer. Examination for risk Obesity : Obesity : Obesity : Obese: Weight, factors Weight, Height Weight, height Weight, height, height waist Diabetes: fasting circumference plasma glucose Fasting capillary Hyperlipidemia: blood glucose lipid profile Examination for end Edema(heart, Edema(heart, Clinical signs of Clinical signs + organ kidney) kidney) heart failure Investigations damage/secondary Clinical clues to for selected

causes of secondary causes like hypertension hypertension kidney disease. Refer to medical college for evaluation of other causes. Investigations Motivate Motivate Urinalysis : Fasting plasma patient to patient to proteinuria, glucose undergo undergo abnormal Serum evaluation evaluation sediment creatinine Fasting capillary Lipid profile blood glucose 69 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Table 7:Role of different cadres of health workers in patient assessment Guidelines for assessment of patients with hypertension in developed countries recommend performance of a panel of diagnostic tests (biochemical investigations, urinalysis, ECG, ophthalmoscopy) in all patients, even though this recommendation is based on weak evidence. In our context, this is not currently feasible or cost-effective because of low yields

of certain tests (e.g. serum creatinine, serum electrolytes), and we suggest a graded pragmatic approach to assessment. Three approaches to assessment – essential in all patients with Grade 1 HT, desirable in those with grade 2 HT or those with diabetes and/or proteinuria, and optimal in those with Grade 3 HT, or those with diabetic complications,CKD,heart failure, or with a suspicion of secondary hypertension are suggested.

Essential evaluation: Should be done in all patients attending primary care facilities,also in patients with Grade 1 hypertension History and physical examination for risk factors (smoking, obesity-diet and exercise patterns, family history of premature CVD), clinical cardiovascular disease (angina, heart failure, stroke) Fasting capillary blood or plasma glucose. FCG > 126 mg/dl or FPG >126 mg/dl is abnormal and

suggestive of diabetes. Abnormal fasting capillary glucose needs to be checked against a fasting plasma glucose obtained in the laboratory Urinalysis for proteinuria: Presence of proteinuria doubles the risk of morbidity and mortality for a certain BP and is an independent predictor of all-cause mortality in hypertension. Table 8: Essential and desirable steps in evaluation Rationale/Evidence: A comprehensive history and physical examination have been considered useful in assessing

risk factors, target organ damage, associated clinical conditions, providing potential clues to secondary hypertension and determination of overall cardiovascular risk, across guidelines.(5, 29)This is therefore being recommended as an essential part of the evaluation of a patient with hypertension in India. Evaluation for diabetes has similarly been Desirable assessment: Desirable in patients with Grade 2 hypertension and above, with family

history of premature cardiovascular disease, in patients with diabetes and in patients with proteinuria Essential assessment plus History and physical examination: Serumcreatinine: Abnormality more often seen in patients with severe hypertension, diabetic nephropathy, chronic kidney disease or occasionally in patients on ACE inhibitors. Lipids: more often abnormal in patients who are obese, in diabetics, in patients with

cardiovascular disease. Commonest abnormality in India is low HDL, increased triglycerides ECG: Low sensitivity for detection of LVH. LVH if present however indicates increased 70 Sccraerednioinvga,s cDuialagrn roisskis., LAVsHse wssitmh esntrta, iann sdt rMonagn apgreemdicetnotr o off P hreimaratr fya Hiluyrpee.r tMenasyi oynie-l dFu ellv iDdoecnucme eonf t ischemic heart disease, conduction system disturbance or arrhythmias.

recommended based on substantial evidence from randomised trials, in most guidelines.(5, 19, 49) The performance of ECG, and serum creatinine, lipids is recommended in all patients in most guidelines, although the evidence on which this is based is largely on consensus of experts and observational studies. (5, 19) Even the performance of some of these tests is suboptimal , e.g. the sensitivity of ECG for detection of left ventricular hypertrophy is

low.(5)Some tests like albumin-creatinine ratio on morning spot urine, which can give clue to the presence of microalbuminuria are not available in the public health system. The graded pragmatic approach to assessment outlined above is based on the importance and utility of the test, its current availability and feasibility in the Indian public health system, and the clinical circumstances of the patient. Detection of diabetes is important and

is emphasised. A patient with diabetes is also directly a candidate for statin therapy according to current recommendations.(50) Proteinuria is an independent risk factor which doubles the risk of a cardiovascular event can be done at all levels of the healthcare system.(51) Patients with Grade 2 HT and above, those who are obese, who are diabetic and proteinuric will need estimation of serum creatinine, and lipids, while in the case of patients

with grade 3 HT, CKD, or heart failure, there is a need for ophthalmoscopy, estimation of serum electrolytes. The overall cardiovascular risk can be estimated in absolute terms, using different risk Comprehensive evaluation: In patients with Grade 3 hypertension, patients with CKD, heart failure Desirable evaluation plus History and physical examination: exclude signs of secondary hypertension Serum sodium and potassium: hypokalemia clue to secondary hypertension (renovascular, primary hyperaldosteronism)

Ultrasound kidney: for evidence of CKD Echocardiography: in case of suspected heart failure (on basis of history, physical examination) calculators viz. the Framingham risk score, the Systematic Cerebrovascular and Coronary Risk Evaluation (SCORE), QRISK2 etc. In this guideline we avoided the calculation of absolute risk over a period of time-e.g.20% over 10 years for the following reasons. These calculations have not been developed using Indian data, including data on prevalence and

mortality risk. In a study on patients presenting with a first myocardial infarction, it was seen that the international scoring systems like WHO/ISH, Framingham risk score, ACC/AHA had insufficient accuracy in predicting cardiovascular risk in Indian patients.(52) Calculations of this risk scores may not be possible in clinic settings in India because of a variety of reasons including lack of laboratory resources for estimating lipid levels. Therefore

a semi-quantitative approach based on presence of risk factors, target organ damage, presence of associated clinical conditions, mentioned in the European Society of Cardiology/European Society of Hypertension guidelines.(5) 71 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

4. Therapeutic Recommendations 4.1. Overall aim: The overall aim of the management of hypertension is not only reduction of BP to target levels but also to lower the cardiovascular risk of the patient. Management of hypertension should be tailored to the individual and his or her circumstances. 4.2. Lifestyle modifications 4.2.1 Lifestyle measures including reduction of salt intake, stopping tobacco intake, and reduction of body weight in those who are obese, are part of

management of all patients with hypertension. 4.2.1.1. These lifestyle measures may be sufficient for treatment of Grade 1 hypertension, may reduce the doses required for control of hypertension, and will also reduce the cardiovascular risk in all grades of hypertension. 4.2.1.2 A trial of lifestyle measures should be monitored for 1-3 months following diagnosis of Grade 1 hypertension. The lower range of durations should be considered in the presence of other risk factors like age, obesity, lipid levels,

and smoking status. 4.3 Initiation of drug therapy 4.3.1Drug therapy is indicated in patients with Grade 1 hypertension with • Any sign of target organ damage (LVH on ECG, proteinuria on urinalysis, hypertensive retinopathy on fundus examination). • Any evidence of coronary artery disease, congestive heart failure, cerebrovascular disease (clinical cardiovascular disease), PAD • Diabetes • Presence of chronic kidney disease • Patients with 3 or more risk factors6 (including age, gender,

smoking, obesity, dyslipidemia, diabetes, impaired fasting glucose, family history of premature coronary artery disease). 4.3.2. Drug therapy in patients with grade I hypertension uncomplicated by any organ damage, without coexisting diabetes mellitus, clinical 6 Age > 55 in men, >65 in women; Male gender; smoking; diabetes; obesity including abdominal obesity; impaired fasting glucose ( FBS 100-125 mg/dl); dyslipidaemia (high LDL, high TG, low HDL); family history of premature coronary artery disease 72

cardiovascular disease should be initiated after a trial of 1-3 months of lifestyle modifications. 4.3.3. Drug therapy is indicated in all patients with Grade 2 and Grade 3 hypertension and should be combined with lifestyle measures. 4.3.3.1 Drug therapy is initiated in patients with Grade 2 hypertension on confirmation of the diagnosis on repeat BP measurements in the visits subsequent to the initial visit when Grade 2 HT was first detected. If the initial screening by the non-physician medical staff.

4.3.3.2. Drug therapy in patients with Grade 3 hypertension is initiated after repeat measurements in the initial visit confirm the severe elevation of the blood pressure. Background: The management of elevated BP involves lifestyle modifications and drug therapy when indicated. Hypertension is a major modifiable risk factor for mortality due to stroke, myocardial infarction.(53) In India for example the incidence of stroke is 119-145 per 100,000

population with a case fatality which varies between 27-42%.(54)There is evidence from multiple randomised controlled trials and meta-analysis that BP reduction leads to reduction in CAD, stroke and total mortality. The meta-analysis suggested a linear relationship with increasing reduction in SBP and DBP resulting in greater CHD and stroke reduction.(5, 55) Implementation: Advice on lifestyle modification can be given by both physician and trained non-physician

staff, and brief descriptions of this advice are given in the annexure of this guideline. Initiation of drug therapy can be done at any facility starting at the PHC level and above after confirming the diagnosis of hypertension and severity of hypertension (grade 1 or grade 2 or grade 3). Before initiation of therapy the patient will be educated about hypertension, and assessed for other cardiovascular risk factors (e.g. diabetes), presence of target organ damage, and

associated clinical conditions (coronary artery disease, stroke or TIA, and renal disease) as discussed in the section on assessment. The drug therapy to be initiated will depend on the presence of compelling indications related to these associated clinical conditions, and in case there are no compelling indications for the use of a specific class of drugs, any drug from the first line classes of antihypertensives like calcium channel blockers, ACE inhibitors/Angiotensin receptor

blockers, and low dose thiazide diuretics may be used. The availability of a core list of 4 drugs representative of the main groups of anti-hypertensive drugs need to be ensured at all health facilities. These include a long acting calcium channel blocker(amlodipine), ACE inhibitor (enalapril), low dose thiazide diuretic (hydrochlorothiazide), and a cardioselective beta-blocker(atenolol) all of which are listed in the National List of Essential Medicines 73

2015(56). In addition a representative drug of the class of Angiotensin receptor blockers like Losartan should be available in case the patient develops adverse effects like cough due to ACE inhibitors. The National List of Essential Medicines (NLEM) 2011 had losartan on its list, but in the NLEM 2015 this has been replaced by telmisartan, while generic lower cost versions of losartan are being procured by state procurement agencies, is therapeutically

similar but currently more expensive in India compared to losartan. Rationale: Lifestyle interventions have efficacy in lowering BP to a varying extent with the most significant decreases occurring with weight loss - 0.5-2 mm reduction of systolic BP per kg of weight loss, and 6-15 mm reduction in systolic BP with dietary sodium restriction. (29) In patients with grade 1 hypertension, therefore lifestyle modifications with weight reduction

and dietary sodium restriction, alone may be efficacious in lowering BP below target levels over a period of time. There is agreement among guidelines about the initiation of drug therapy in those with Grade 1 hypertension and those with target organ damage, cardiovascular disease, and other CV risk factors. (19, 49) There is variation in the duration of the trial of lifestyle modification in those with Grade 1 hypertension with no target organ

damage, no associated clinical conditions, no diabetes or CKD. While some guidelines mention a trial of up to 6-12 months of lifestyle modification in Grade 1 hypertension(5), other do not specify any time period. In view of the difficulties in accessing the health system, the higher cardiovascular risk in Indians, and likelihood of loss of follow up in patients in India, we felt it reasonable to advise a 3 month trial of lifestyle modification in

patients with Grade 1 hypertension who are low risk, without diabetes, target organ damage and clinical cardiovascular disease. A similar recommendation has been made in an advisory issued by the American Heart Association/American College of Cardiology and Center for Disease Control ( AHA/ACC/CDC).(57). At any level of blood pressure, Indians are considered to be at a higher cardiovascular risk. Profile of patient Advice Rationale 50 year with multiple BP records in the range of Drug therapy + Patient has

170/100 Grade 2 HT and Life style rx is indicated. modification 60 year old with BP readings in the range of 180-190 Immediate Patient has systolic & 110-120 diastolic drug therapy Grade 3 HT and with 2 drugs at rx is indicated half maximal dosages + lifestyle modification 45 year non-smoking female with BP of 150/96 , Lifestyle Grade 1 HT with obese, with normal fasting glucose modification obesity, no for 3 months diabetes and multiple risk 74

factors 66 year old smoker, obese, male with BP of 154/96 Drug therapy+ Grade 1 HT with multiple risk Lifestyle factors (male, modifications age > 65,smoker, obesity) 60 year old non-smoker with diabetes with BP of ~ Drug therapy + Grade I HT with 150/90 mm Hg on multiple readings lifestyle diabetes modifications 50 year old female with Grade 1 HT. Fundus shows Drug therapy Grade 1 HT with Grade 2 hypertensive retinopathy, and urine shows +lifestyle target organ 1+ proteinuria modifications damage(eye,

kidney) 75 year old female with recent history of stroke with Drug therapy Grade 1 HT with Grade 1 HT +lifestyle clinical modifications cardiovascular disease (stroke) Table 9: Translation of recommendation into practice 75 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

4.4. Treatment goals for management of hypertension: 4.4.1 The current target for control of BP for patients under 80 years of age should be less than systolic blood pressure less than 140 mm and diastolic blood pressure less than 90 mm. 4.4.2 The current target for control of BP for patients 80 years or older should be less than 150 mm systolic and less than 90 mm diastolic. 4.4.3 A recent trial (SPRINT trial) in non-diabetic population at high cardiovascular

risk has shown a reduction in cardiovascular mortality in patients in the intensive treatment group where the goal BP was less than 120 mm systolic and 80 mm diastolic. However this was accompanied by more than 2 fold increased frequency of serious adverse events and increase in serum creatinine. Based on the currently available evidence we do not recommend this lower target generally for physicians and patients in India, except for individual patients and physicians in situations who have agreed upon these

targets and where close monitoring for adverse effects is feasible. 4.4.4 Current evidence based on trials of BP targets of <130 mm and < 85 mm diastolic in patients with diabetes have failed to show significant overall benefit on cardiovascular disease outcomes, and have been accompanied by increased frequency of serious adverse events. Therefore we currently recommend the standard BP target of <140 mm systolic and <90 mm in patients with diabetes in India. Background:

Healthcare providers and patients alike need to know the target BP to be achieved as part of control of hypertension. This has been an evolving area of debate and investigations, and this issue has been addressed by recent guidelines like the JNC 8 which have systematically reviewed the evidence. The interim results of a recent study – the Systolic Blood Pressure Intervention Trial (SPRINT) which involved intensive reduction of BP < 120 mm are

provocative in terms of potential for reduction of mortality, which have to be weighed against increased incidence of serious adverse events noted.(58) Implementation: The target BP may be achieved at 6-8 weeks, for which the patient can be assessed at 2-4 weekly intervals for achievement of target BP. At each visit lifestyle interventions can be emphasised, adherence may be assessed and reinforced. If the BP does not show a

downward trend on the follow up, medicines from other classes may be added to achieve the target BP. Rationale: 76 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Target BP: There is agreement among all evidence based guidelines for the targets of Systolic BP ≤ 140 and diastolic BP ≤ 90 mm Hg in the general adult population. (18-21) We have therefore adopted the same targets. A recent study the Systolic Blood Pressure Intervention trial (SPRINT) has examined the effect of reduction of systolic blood pressure below 120 mm on cardiovascular outcomes in non-diabetic patients who were considered at

high risk for cardiovascular outcomes.(58) There was a 25% relative risk reduction in the primary outcome, but this was achieved with a mean of 3 antihypertensive drugs, and there was a significantly increased frequency of serious adverse events including hypotension, syncope, electrolyte abnormalities. Also there was a three-fold higher risk of more than 30% decline in GFR in the intensive treatment group.(58) Since the trial excluded diabetics, the

generalisation of these results to diabetics is questionable, especially with the lack of benefit on outcomes in the ACCORD trial which examined the role of intensive BP reduction in diabetics.(59)We feel that these results deserve a nuanced discussion about their generalisability in the context of our health system, where intensive monitoring and access to care is particularly challenging for a large part of our population. Therefore we continue to propose the targets of <140 mm systolic for the general.

Targets for elderly: The definition of elderly differs across guidelines, as JNC 8 guidelines categorised as elderly as those over 60 years (20), while all other guidelines have defined the elderly as people above 80 years of age. (18, 19, 21) . There is agreement among all guidelines, based on data from the HYVET study,(60) that the target for BP of systolic BP of ≤150 mm and diastolic BP ≤90 mm Hg should be considered for patients above 80 years of age.

Targets for patients with diabetes: Earlier guidelines like the JNC 7(29) recommended target BP of <130 mm Hg systolic and <80 mm Hg diastolic for patient populations e.g. diabetics, but recent evidence based guidelines like JNC 8 revised these targets to <140 mm systolic and <90 mm diastolic, based on appraisal of evidence from randomised controlled trials (20). A large randomised controlled trial – the ACCORD (Action to Control Cardiovascular Risk in

Diabetes) found that there was no significant cardiovascular benefit in the intensive BP reduction group where BP was lowered less than 120 mm Hg except a reduction in stroke. (59) In the intensive treatment group there was a more than 2 fold higher risk of serious adverse effects (hypotension, hyperkalemia, angioedema) and elevation of serum creatinine. The most recent Cochrane review on this subject has recommended the standard BP target of <140 mm Hg and <90 mm Hg since “evidence from randomized trials

does not support blood pressure targets lower than the standard targets in people with elevated blood pressure and diabetes.”(61). 4.5 Key recommendation: Classes of antihypertensive drugs & preferred choices 4.5.1 The primary issue in treatment of hypertension is reduction of cardiovascular risk by effective control of blood pressure. Overall the benefits of antihypertensive treatment are due to lowering of blood pressure rather than choice of therapy. Many patients will require more than one drug for

control of hypertension. 4.5.2. All classes of drugs- calcium channel blockers, ACE inhibitors/ARBs, diuretics; beta-blockers have approximately the same efficacy on lowering of blood 77 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

pressure, and on outcomes, although beta-blockers have been associated with lesser protection against strokes. All combinations of drugs are not however similarly efficacious, and some are preferred. 4.5.3. The different classes of drugs have differing side effect profiles and requirements for monitoring, which may influence their use and prescription in the health system. 4.5.4 In the absence of any associated clinical conditions (noted below) providing a

compelling indication for the use of a particular drug , a long acting calcium channel blocker, a low dose thiazide diuretic, or a low cost ACE inhibitor may be used as the initial antihypertensive drug. 4.5.5. The presence of associated clinical conditions (diabetes, clinical cardiovascular disease, chronic kidney disease) in a patient may provide compelling indication for the use of specific classes of drugs. 4.5.5.1 Preferred drugs for treatment of patients with diabetes and hypertension

are ACE inhibitors, especially in those with proteinuria. Calcium channel blockers /low dose diuretics may be used in addition if required to achieve control. 4.5.5.2 Preferred drugs for patients with heart failure and hypertension are ACE inhibitors, diuretics (including loop diuretics) and beta-blockers. 4.5.5.3 Preferred drugs for patients with coronary artery disease and hypertension are beta-blockers, ACE Inhibitors or calcium channel blockers.

4.5.6 The specific drugs within these classes recommended on the basis of availability and affordability include amlodipine, (a long acting calcium channel blocker); enalapril or lisinopril, (ACE inhibitor); low dose hydrochlorothiazide, (thiazide) and if required and losartan, (a low cost angiotensin II receptor blocker). 4.5.7 Angiotensin receptor blockers have a mode of action, efficacy and indications similar to ACE inhibitors, but are currently more expensive than them. They

should therefore be used in the place of ACE inhibitors, in case there are side effects with ACE inhibitors like cough, angioedema. Background: Current guidelines suggest that all the 4 drug classes of antihypertensive drugs–thiazide diuretics, calcium channel blockers, ACE inhibitors, Angiotensin receptors blockers for initiation as well as add-on agents to control BP.(20) Beta-blockers are not considered first 78 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

line drugs in most guidelines, but may be used in patients with hypertension and associated coronary artery disease or heart failure. Many patients will require combination of drugs for control of hypertension. Implementation: In a general patient where hypertension is the only or main condition, any of the 4 classes of drugs can be used as initial therapy, except in the case of elderly patients with isolated systolic hypertension, where a calcium channel blocker or diuretic would be preferred. In

case hypertension is associated with other clinical conditions detected during assessment of a patient with hypertension– diabetes, hypertension associated with previous myocardial infarction or stroke, heart failure, angina, and then some drugs would be preferred as mentioned in table 9. Consideration should also be given to the compelling and possible contraindications to the use of each class of these drugs before initiation of therapy, mentioned in table 10.

Clinical condition Drug to be preferred as Second drug if Third drug if needed to first drugs needed to achieve achieve BP control BP control Isolated systolic CCB/Thiazide Diuretic ACE Inhibitor* Thiazide diuretic + ACE hypertension ( elderly) CCB Inhibitor*+ CCB Hypertension and ACE inhibitor* CCB or thiazide ACE inhibitor* + CCB+ diabetes diuretic thiazide diuretic Hypertension and chronic ACE inhibitor*where CCB or thiazide ACE inhibitor*

kidney disease(defined as close clinical and diuretic (loop +CCB+ thiazide diuretic albuminuria or an eGFR< biochemical diuretic if eGFR is 60 ml/min/1.73 m2 for > 3 monitoring is possible. below 30 ml/min) months) Otherwise CCB may be preferable Hypertension and BB, ACE Inhibitor* CCB or diuretic previous myocardial infarction Hypertension associated Thiazide/ loop diuretic, BB Spironolactone with heart failure ACE Inhibitor* Hypertension associated ACE inhibitor* Diuretic or CCB ACE Inhibitor* +CCB+

with previous stroke diuretic Table 10: Clinical conditions which may be associated in a patient with hypertension and the drugs to be preferred *Angiotensin receptor blockers (ARBs) may be used for this indication if there is intolerance to ACE inhibitors (cough, angioedema)Abbreviations: ACE inhibitor: angiotensin converting enzyme inhibitor; CCB, calcium channel blocker; BB, beta-blocker.Notes: Examples of representative drugs: ACE inhibitors - Enalapril, Calcium

channel blockers-Amlodipine, Thiazide diuretic- Hydrochlorothiazide, Beta-blocker- Atenolol § Source: adapted from ref.(21) Angiotensin converting enzyme inhibitors (ACE inhibitors) and Angiotensin receptor blockers (ARBs) both act by targeting the renin-angiotensin system. Both are generally well tolerated, have similar indications and contraindications for their use, although ACE inhibitors have a more robust evidence base with regard to reduction of cardiovascular mortality.(62) ARBs are 79

preferred if patients develop cough, or angioedema with the use of ACE inhibitors. Many individual ACE inhibitors and ARBs are available. The choice should be guided by considerations of cost, and lower cost ACE inhibitors like enalapril/lisinopril and lower cost ARBs like losartan, may be used. Beta-blockers are not preferred as first line drugs in isolated cases of hypertension as recent meta-analysis have stated that the benefits of CVD protection especially stroke reduction

are lower with it than other class of drugs, and their use may be associated with fatigue, sexual dysfunction, and increased incidence of new onset diabetes.(63) Patients occasionally may require the use of other drug classes for control of severe hypertension. These include vasodilators (minoxidil), central alpha-agonists (clonidine), and alpha blockers (prazosin) Table 11: Compelling and possible contraindications to the use of antihypertensive drugs#

Drug Compelling contraindication Possible contraindication Diuretics Gout Metabolic syndrome, glucose intolerance, hypokalemia, hypercalcemia Beta-blockers Asthma, AV block (grade 2 or 3) Metabolic syndrome, glucose intolerance, chronic obstructive pulmonary disease Calcium channel Tachyarrhythmia, heart failure blockers(dihydropyridines) Calcium channel blockers(non- AV block (Grade 2 or 3),severe dihydropyridines) left ventricular dysfunction, heart failure ACE inhibitors Pregnancy Women with childbearing

Hyperkalemia potential Bilateral renal artery stenosis Angiotensin receptor blockers Pregnancy Women with childbearing Hyperkalemia potential Bilateral renal artery stenosis Mineralocorticoid receptor Acute or severe renal failure antagonists ( e.g. (eGFR<30 ml/min) spironolactone) Abbreviations: AV, atrioventricular; eGFR, estimated glomerular filtration rate Source: ref.(21) Rationale: All major guidelines recommend the four main classes of antihypertensive drugs for the

treatment of hypertension. (18-21) As the benefits of antihypertensive treatment is related to reduction of BP and is independent of the drug being used, there is no need to distinguish between drugs within a particular class. (21) In the NICE guidelines thiazide like diuretics viz. chlorthalidone, and indapamide have been preferred over thiazide diuretics like hydrochlorothiazide,(18)in view of greater evidence for the clinical outcome benefits (like

reduction of strokes and major cardiovascular events) with these drugs, but other guidelineslike the ESH/ESC do not consider this evidence substantial enough to prefer them 80 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

over thiazides.(21) All guidelines recommend calcium channel blockers or a diuretic for initiation of therapy in blacks, (18-21) but whether a similar differential response to these agents exists with regard to Indians is not clear. The recommendations for the use of specific drugs for use in associated clinical conditions are broadly similar in all major guidelines.(18-21) 81 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

4.6Key recommendation: The treatment regimen and the use of combinations: 4.6.1 In patients with Grade 1 or Grade 2 hypertension, therapy can be initiated with one drug (CCBs, ACE inhibitors, thiazide diuretics) in combination with lifestyle modifications.(Step 1 in table 13) Average initial doses can be 5 mg of amlodipine, 5 mg of enalapril and 12.5 mg of hydrochlorothiazide. 4.6.2 In patients with Grade 3 hypertension, the therapy should be initiated with two

drugs, in combination with lifestyle modifications (Step 2 in table 13). The combinations can be calcium channel blocker (amlodipine) + ACE inhibitor (enalapril) or calcium channel blocker (amlodipine) + thiazide diuretic (hydrochlorothiazide) or ACE inhibitor (enalapril) + thiazide diuretic (hydrochlorothiazide). 4.6.3 The dose of drugs can be increased or a new drug added at approximately 2- to 4- week intervals. This frequency can be faster or slower depending on the clinical

circumstances of the patient and the judgment of the practitioner. 4.6.4 The addition of a new drug in patients with Grade 1 or Grade 2 hypertension may be preferable to maximising the dose of the initial drug. In case a calcium channel blocker (amlodipine) has been used as initial therapy, the add-on drug can be ACE inhibitor (enalapril) or a thiazide diuretic. Similarly if ACE inhibitors have been used as initial therapy, a calcium channel blocker or a diuretic can be used as add on

therapy. When amlodipine is used as an add-on therapy, the initial dose used should be 2.5 mg. Similarly if an ACE inhibitor like enalapril is added to a diuretic, the initial dose used may be 2.5 mg to avoid hypotension. 4.6.5. If the second drug in a usual dose also fails to reduce BP to target levels then the third class of drug previously unutilised should be added (Step 3 in table 13). An optimal 3 drug combination in case it is required is a calcium channel blocker with a

low dose thiazide diuretic and an ACE inhibitor (e.g. amlodipine+ enalapril+ hydrochlorothiazide). 4.6.6. The preferred 2 drug combinations are combination of calcium channel blockers with ACE inhibitors, ACE inhibitors with low dose diuretics, and calcium channel blockers with low dose diuretics. 4.6.7. Prescription of a single pill combination of antihypertensive drugs in a defined proportion may be considered if available, after BP has been stabilised with a dose of

two drugs given singly in the same proportion. 4.6.8. The practitioner should aim for patients to reach target BP levels with an effective treatment regimen, whether 1, 2, or 3 drugs, within 6 to 8 weeks. 82 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

4.6.9. Add-on drugs for control of BP drugs should be added at intervals of 2-4 weeks. 4.6.10. Negative recommendation: ACE Inhibitors should not be combined with Angiotensin receptor blockers. 4.6.11. Negative recommendation: Avoid prescribing a combination of beta-blockers and diuretics as they can increase the risk of diabetes mellitus in those at risk, e.g. persons with impaired glucose tolerance or obesity and metabolic syndrome.

4.6.12. If the BP is not controlled despite use of 3 anti-hypertensives in optimal doses, then the hypertension should be termed resistant and the patient should be referred to a specialist at the medical college for further evaluation and management. Implementation: The initiation of drug therapy will be with monotherapy with any of the 3 classes of drugs (CCBs, low dose thiazides, ACE Inhibitors) or with two drugs representing 2 different drug classes. Choice of initial drugs in primary care:

Long acting Calcium channel blockers can be used in general population (especially the elderly) as well as patients with diabetes, cardiovascular disease and CKD. They can be used as a once a day drug, have no serious side effects, do not affect the glucose and lipids, and have no need for laboratory based monitoring. The common side effects like pedal edema and tachycardia are not of a serious nature. ACE inhibitors can similarly be used in general population (except in pregnant women), as

well as in patient groups with diabetes, (especially those with proteinuria) cardiovascular disease and CKD, and do not affect glucose and lipids. In general population, they do not require laboratory monitoring. However in patients with diabetic nephropathy and CKD they may require monitoring of potassium and creatinine as these levels can show a rise after initiation of therapy. They can be used on a once daily basis. Thiazide diuretics can be used in the general population (including elderly), as well as

patients with diabetes, CKD. However they can because metabolic side effects which include modest increases in glucose, total cholesterol, hypokalaemia. These side effects are dose related and are seen in doses exceeding 25 mg. The increase in antihypertensive effect between the doses of 12.5 mg and 25 mg are marginal,(64) and therefore the preferred dose is 12.5 mg once a day. Hyponatremia is a potentially life threatening complication

associated with thiazide use(65, 66) and is more common in elderly patients, and those with low body weight.(67) Thiazide diuretics potentiate the effect of ACE inhibitors, calcium channel blockers and some of the side effects like hypokalemia are also minimised when they are used in combination. In patients with metabolic syndrome, the risk of new onset of type 2 diabetes is increased with the use of thiazides, especially in combination with beta- blockers.(68)

Calcium channel blockers are efficacious agents which can used once daily, have no effect on glucose, lipids, electrolytes, and can be used in both general populations and patients 83 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

with diabetes. If patients have diabetes with proteinuria, or CKD, ACE inhibitors are indicated but may require monitoring of serum creatinine and potassium after initiation of therapy. Once a day Requirement Drug-drug Cost dosing for laboratory interactions monitoring: effect on glucose, lipids, electrolytes Calcium channel Yes Nil: no effect on Nil Low in public blockers lipids, glucose, procurement electrolytes system ACE inhibitors Yes (may No effect on Effect decreased Low in public

require BD lipid, glucose. by NSAIDS procurement dosing) Potassium, system serum creatinine may rise in some patients Thiazide Yes Small rise in Effect decreased Low in public diuretics glucose, by NSAIDs. procurement cholesterol, system hypokalemia in higher doses Table 12 : Comparison of 3 first line anti-hypertensive drugs Table 13 mentions the 3 initial drugs and their 6 combinations, which can be prescribed. In general the therapy can be started at half the maximal dose-e.g. 5 mg of amlodipine, 12.5

mg of hydrochlorothiazide, and 5 mg of Enalapril or 50 mg of Losartan. On review after 2-4 weeks if BP control has not been achieved, then a second drug from one of the classes that has not been used (CCB, diuretic, ACE inhibitor, ARB), and the patient reviewed again for BP control. The doses of drugs to be used as initial or add-on therapy is mentioned in table 5 Certain combinations e.g. of CCB with ARBs/ACE inhibitors or diuretics with ARBs/ACE

inhibitors are preferred, while combinations of ACE inhibitors with ARBs, and diuretics with beta-blockers are avoidable. The combination of ACE inhibitors with ARBs has an increased risk of end-stage renal failure and stroke as documented in trial settings, (69) and is advised against by all guidelines.(18-21)The combination of thiazide and beta-blockers is also effective but since both these drugs can elevate blood glucose concentration, the combination should

be used with caution in those with a higher risk of developing diabetes (obese, positive family history, glucose intolerance).(24, 68) If the BP is not at goal even after optimal doses of 2 drugs and with regular adherence, then a 3rd drug may be added. According to most guidelines the preferred 3 drug combination is 84 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

of a calcium channel blocker along with ACE inhibitor and a diuretic. (CCB+ACE Inhibitor +diuretic). 85 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Table 13: Initial drug therapy, preferred drug combinations and combinations to be avoided Initial drug Preferred combination Combinations for use in Combinations to be (as initial or add on Limited settings avoided therapy) CCB CCB + ACE Inhibitor* CCB CCB (dihydropyridines)+ (verapamil/diltiazem) beta-blocker [use in + beta-blocker patients with HT and coronary artery disease] CCB + thiazide diuretic Diuretic Thiazide diuretic +ACE Diuretic + beta- Inhibitor* blocker Thiazide Diuretic +CCB

ACE inhibitor ACE Inhibitor* + diuretic ACE Inhibitor + ACE Inhibitor* +ARB mineralocorticoid antagonist(potential for hyperkalemia) ACE Inhibitor* + CCB *Angiotensin Receptor blockers (ARBs) can be used if there is intolerance to ACE inhibitors (cough, angioedema) Abbreviations: CCB, calcium channel blocker; ACE Inhibitor, Angiotensin converting enzyme inhibitor; ARB, Angiotensin receptor blocker. In patients who qualify for initiation of drug therapy, 2-4 weekly follow up would be needed

to be advised to monitor response to therapy and achievement of BP target. The doctor at the PHC/CHC can record the initial BP in the patient record, and the patient can be monitored for response at the field level by health auxiliaries, or again at the health facility, according to the circumstances. If the patient achieves reduction of BP to target levels, then they would continue the same therapy and be monitored every 2-3 monthly at the PHC

level. In case the target BP is not achieved, then increasing the dose or addition of a new drug would be considered. The administration of two drugs in patients in grade 3 hypertension should initially be as two separate pills. Once target BP has been achieved, then a combination pill with the individual drugs in the same proportion, i.e. a single pill combination (SPC), if available, may be considered. A single pill combination should be considered for use in patients with hypertension, if it is

available and afterthe patient has been stabilised on the individual components in the same proportions. 86 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Table 14: Initial and maximal doses for initiation and titration of therapy for Indian patients with hypertension: (source: adapted from ref (24), (70) and product monographs listed at health Canada www.health-sc.gc.ca) Drug class Low dose Usual Initial Maximal Doses in certain dose dosage per day situations suggested suggested for for Indian Indian patients with patients with hypertension hypertension Calcium channel blockers Dihydropyridines Amlodipine 2.5 mg* 5 mg 10 mg 1

Angiotensin converting enzyme inhibitors Enalapril 2.5 mg§ 5 mg 10-20 mg 1-2 Lisinopril 5 mg 10 mg 1 Angiotensin receptor blockers Losartan 25 mg # 50 mg 100 mg 1-2 Telmisartan 40 mg 80 mg 1 Diuretics Thiazides 1 Hydrochlorothiazide 12.5 mg 25 mg 1 Thiazide-like Chlorthalidone 12.5 mg 25 mg 1 Beta-blockers Atenolol 25 mg 50 mg 100 mg 1 Metoprolol succinate 50 mg 100 mg 2 *Reduce dose of amlodipine to 2.5 mg once a day when it is started in low body weight

elderly patients, and when amlodipine is added to another antihypertensive medication. § Reduce dose to enalapril 2.5 mg when it is used in elderly (>65 years) and when the patient has been on diuretic therapy. # Use dose of 25 mg in patients less than 50 kg (Canadian labelling) 87 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Rationale: Use of initial monotherapy: Most of the evidence based guidelines like CHEP, ESC/ESH recommend therapy with a single drug in the case of grade 1 hypertension(19, 21), and with a combination of 2 drugs in patients with grade 2 hypertension. NICE however recommends treatment of grade 2 patients with a single drug initially (18), while JNC 8 recommends that the physician may at his/her discretion, initiate treatment of both grade 1 and grade 2

hypertension with one or two drugs.(20)We decided on the basis of consensus, to recommend a single drug therapy in grade 1 & 2 and with 2 drugs in the case of grade 3 hypertension, in India. Therapeutic strategy to achieve control of BP: There is no RCT based evidence on the best therapeutic strategy to achieve the target BP. The JNC 8 report has suggested the following strategies for achievement of target BP. These are as follows

1. Select a drug from one of the following classes: calcium channel blocker, ACE inhibitors or ARBs, or thiazide diuretics. 2. Select one of the following strategies to achieve control i. Start one drug, titrate to maximal dose, and then add drug from another class. ii. Start one drug, add drug from another class if not controlled. Finally titrate to maximal dose of initial drug. iii. Start with 2 drugs initially as individual drugs or as a single pill combination.

3. Add a drug from a third class. Maximise doses till control of BP is achieved. We suggest the following strategy based on the above recommendation in this guideline: Step 1 therapy: In patients with Grade 1 and Grade 2 hypertension, we suggest initiation with the usual doses of ACE inhibitors/Calcium channel blockers/Thiazide diuretics mentioned in table. Step 2 therapy: This involves either use of 2 drugs or using maximal doses of the initial

drug. Maximising drug doses of the initial drug is less preferable because of the dose plateau relationship in antihypertensive drugs, and because of the likelihood of appearance of adverse effects at high doses. We recommend Step 2 therapy for control of BP in either failure of Step 1 therapy in Grade 1 HT or Grade 2 HT or as initial treatment of patients with Grade 3 HT. Step 3 therapy: This involves addition of a drug from a third class of drugs 88

Initiation Initiation with 2 drugs or titration of drugs in a patient Use of three with single not controlled on a single drug : Step 2 drugs in a drug CCB Diuretic ACE patient not Step 1 (amlodipine) (hydrochlorothiazide) inhibitor controlled (enalapril) with 2 drugs Step 3 ACE Enalapril 5 mg+ Enalapril 5 mg + Enalapril10 ACE inhibitor inhibitor Amlodipine 2.5 Hydrochlorothiazide mg (less (Enalapril Enalapril5 mg , later raise to 12.5mg preferred 5/10mg ) mg 5 mg strategy) + CCB Or Amlodipine

Amlodipine 5 mg + Amlodipine 5/10 mg) CCB Amlodipine 10 Thiazide 12.5 mg 5 mg Amlodipine 5 mg +Enalapril 5 + mg (less preferred mg Thiazide Or strategy) Hydrochlorot Diuretic + CCB Hydrochlorothiazide Hydrochlor hiazide Thiazide (Amlodipine 2.5 25 mg (less preferred othiazide 12.5mg/25 diuretic mg, later 5 mg) strategy) 12.5 mg mg) Hydrochloro- Enalapril thiazide 12.5 2.5 mg , mg later 5 mg Table 15: Medication pathway in this guideline evolving from Step 1 (single drug) to Step 2

Single pill combinations:The use of single pill combinations has been suggested as they reduce the number of pills to be taken and have been associated with modest improvements in compliance, and non-significant improvement in persistence of therapy and efficacy.(71).If SPCs are used as initial therapy then titration of dose is difficult since increased dose of one is not possible without increasing the dose of the other. Other factors

which need to be considered are availability of 3 combinations in the public health system, the often higher cost of these combinations compared to their constituent drugs in India, and the logistics of maintaining stocks of both single ingredient and combinations of certain drugs. At the moment there is uncertain availability of even single ingredient antihypertensives in public health facilities in India.(72) We therefore recommend the imp

Doses of drugs: The doses recommended need some explanation. In the case of some drugs like thiazide diuretics, it has been seen that the antihypertensive efficacy does not increase at a dose beyond 25 mg while the metabolic side effects escalate with increase in dose.(70) In the case of ACE inhibitors little added antihypertensive efficacy has been noted for example with enalapril above the dose of 10 mg, (73) although doses of up to 40 mg for

hypertension have been mentioned in guidelines.(24)A lower dose of some drugs has been 89 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

mentioned for elderly (> 65 years) in the case of enalapril and amlodipine (especially if the patient has low body weight and is frail). Time period to achieve BP target: Control of BP to target BP without causing adverse effects can improve adherence to treatment by gaining the patient’s confidence. The evidence based guidelines do not address the question of the time period over which target BP should be reached specifically. However the ASH/ISH guidelines, on the basis of

consensus, mentions that an effective treatment regime should be established within 6-8 weeks,(24)and we have adopted this recommendation. Drug doses may be increased or additional drugs introduced at 2 weekly intervals. 90 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Review and respond to possible causes of poor response to BP medications 4.7. Key Recommendations: When a patient does not respond to two drugs given in full doses, the physician should review the underlying issues -related to § BP measurements, § poor adherence to drug and lifestyle modifications, including stoppage of medicines due to belief in other systems of medicine § suboptimal treatment regimens, § presence of associated conditions,

§ use of non-antihypertensive drugs which can interfere with the action of anti-hypertensives, and § Consider the possibility of secondary hypertension. When a patient does not respond to two drugs, the physician should review the underlying issues -related to BP measurements, poor adherence to drug and lifestyle modifications, suboptimal treatment regimens, presence of associated conditions, drug interactions, and consider the possibility of secondary hypertension. Background:

Although the means to control BP effectively now exist, only a minority of patients are well controlled on therapy. In India BP reduction to target levels was achieved in only 11% of rural Indians and 20% of urban Indians who are hypertensive.(8).This is undesirable as control of BP is a highly cost-effective intervention for the prevention of cardiovascular mortality, heart attack and stroke. Most patients can be controlled with 1 or 2 antihypertensives, especially combinations of

ACE inhibitors with calcium channel blockers or diuretics. Some patients have resistant hypertension which may even require more than 3 antihypertensive drugs to control. However more commonly we may have “pseudo resistant” hypertension as a result of measurement, patient, and drug therapy related factors mentioned above. Once these factors have been excluded, there may be secondary causes of hypertension underlying the difficult to control hypertension. 91

Implementation: When a patient is not responding to BP medications, as determined by persistently high BP readings on repeat visits, the physician should pay attention to the following factors: 1. Issues related to BP measurement in the clinic: This may include “white coat effect” because of which the clinic based BP measurements by a doctor may be higher than those obtained at home or by another healthcare provider. Improper size of cuff and improper technique may also give falsely elevated BP readings.

2. Adherence to medications: In a chronic disease, which are asymptomatic, patients often miss doses or even discontinue medications, and the regularity of drug intake should be enquired about from the patient and their relatives. The reasons for non- adherence should also be explored which may include doubts about the diagnosis, belief in lifestyle modifications being sufficient, cost of therapy, or side effects related to medicines. Belief in other systems of medicine may also lead to stoppage

of medicines 3. Adherence to lifestyle modifications: Excessive salt intake, excessive alcohol consumption, tobacco use, obesity all can contribute to poor control of hypertension. 4. Suboptimal treatment regimens: This can be the result of low doses, or use of inappropriate combinations. Drug dosages should be optimised. The combinations should be of medicines which are complementary in action. Addition of diuretics in patients not responding to a combination of drugs, usually results in good control.

5. Presence of associated conditions: Presence of sleep apnea, chronic pain can all impair control of BP. 6. Drug interactions: Some commonly used drugs like non-steroidal anti-inflammatory drugs (NSAIDs), oral contraceptives, corticosteroids and anabolic steroids, and common cold remedies which contain sympathomimetics can all result in higher BP. NSAIDs ( including cyclooxygenase-2 inhibitors) can cause salt retention and interfere with the action of all antihypertensives except calcium channel blockers.

Addition of a diuretic may mitigate their effect. 7. Secondary hypertension: The most frequent cause of secondary hypertension is chronic kidney disease, which can be diagnosed on the abnormal urinalysis& blood chemistries, at the level of the CHC. The other causes of secondary hypertension would include endocrine causes (pheochromocytoma, Cushing’s’ syndrome), vascular causes (renovascular hypertension, coarctation of aorta, Takayasu’s arteritis); which will require evaluation at a medical college level.

92 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Rationale/Evidence: The factors underlying poor response to antihypertensives have been enumerated in the CHEP guidelines, and have been adapted from this source. (19) 4.8. Therapy of hypertension and associated conditions: 4.8.1 Diabetes mellitus: 4.8.1.1 Patients with diabetes mellitus should be initiated on drug treatment when the SBP is greater than 140 mm Hg, and the target for control should be a SBP of less than 140 mm Hg, and a diastolic BP of less than 90 mm Hg.

4.8.1.2 ACE inhibitors are preferred as initial therapy and calcium channel blockers and diuretics may be used as add on therapy. Thiazide diuretics can be associated with glucose intolerance. 4.8.1.3 Drugs which inhibit the renin angiotensin systems- ACE inhibitors and ARBs should be used if the patients have proteinuria (or microalbuminuria). 4.8.2 Heart disease: 4.8.2.1 Beta-blockers should be prescribed in patients with hypertension and a

recent myocardial infarction. These patients should also receive an ACE inhibitor. 4.8.2.3. In patients with angina, beta-blockers and calcium channel blockers, should be considered among the antihypertensive drugs for their effect on symptoms. 4.8.2.3 In patients with heart failure and hypertension, ACE inhibitors, thiazide diuretics, and beta-blockers, and mineralocorticoid receptor antagonists are recommended for reduction in mortality and hospitalization. 4.8.3 Kidney disease (diabetic or non-diabetic):

4.8.3.1 The target for BP reduction should be a SBP of less than 140 mm Hg, but a SBP of less than 130 mm Hg should be considered for those with overt proteinuria. 4.8.3.2 ACE inhibitors /ARBs are effective in reducing albuminuria and should be used in patients with hypertension and overt proteinuria (or microalbuminuria). Monitoring serum creatinine and potassium in the first 93 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

week of therapy is advisable after initiation of therapy or any increase in the dose of ACE inhibitors. 4.8.3.3 Use of ACE inhibitors and Thiazide or thiazide like diuretics should be used as other antihypertensive agents, and in the presence of volume overload, loop diuretics like frusemide may be used. 4.8.4 Cerebrovascular disease: 4.8.4.1 Prevention of stroke can occur with all classes of antihypertensive drugs if BP is effectively controlled.

4.8.4.2 In patients with a history of stroke or TIA, initiation of drug treatment should be considered even with Grade 1 hypertension, and a systolic BP of less than 140 mm Hg should be targeted. An ACE inhibitor/ARB is considered an initial drug. 4.8.4.3 In the first 72 hours of an ischemic stroke, do not administer antihypertensive treatment, since excessive lowering of BP can exacerbate the existing ischemia. 4.8.4.4 In patients who are not undergoing thrombolytic therapy for ischemic stroke,

extreme values of BP, e.g. systolic BP > 220 mm Hg or diastolic BP > 120 mm Hg should be treated by agents to reduce mean arterial pressure by about 15% in the first hour and no more than 25% in the first 24 hours and with gradual reduction thereafter. In patients who are candidates for thrombolytic therapy, BP above systolic of 185 mm Hg and diastolic of 110 mm Hg should be treated cautiously and maintained below these levels. 4.8.4.5 In patients with intracerebral haemorrhage, with SBP > 200 mm Hg or

MAP7>150 mm Hg, aggressive reduction of blood pressure with intravenous infusion of antihypertensives is indicated and the patient should be examined every 5 minutes. 4.8.4.6 In patients with intracerebral haemorrhage , with SBP >180 mm Hg or MAP > 130 mm Hg, modest reduction of BP to 160/90 is indicated using an intermittent or continuous IV infusion with frequent re-examination is indicated. 4.8.4.7 In patients presenting with intracerebral haemorrhage and a SBP of 150-220

mm Hg, BP can probably be lowered to a SBP of 140 mm Hg safely. 7 MAP = Mean arterial pressure which is calculated as follows MAP = SBP +2(DBP)where SBP is systolic blood pressure and DBP is diastolic blood pressure 3 94 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Background: Patients with hypertension often have associated conditions like diabetes, clinical cardiovascular disease with ischemic heart disease or cerebrovascular disease, or chronic kidney disease. Some classes of antihypertensive drugs have special roles in the presence of such conditions, some drugs are best avoided in the presence of conditions like chronic kidney disease, while in other conditions like acute stroke, reduction of elevated BP in general by any class of drugs, should be cautious.

Implementation: The evaluation of these clinical conditions would be best done at the CHC level, where in addition to the history and physical examination, the patient could be subjected to Investigations like X-ray chest (cardiomegaly in case of heart failure), ECG (reveal changes suggestive of ischemic heart disease), renal function tests (abnormal in patients with chronic kidney disease) and urinalysis. Patients with chronic kidney disease and heart disease may

require monitoring and follow up at the CHC level, while patients with diabetes and previous cerebrovascular disease may be followed up at the PHC level with periodic review at the CHC. The group recommends that the doctors at the PHC level need to be empowered to deal with hypertension and diabetes, and the patients should get access to investigations like serum creatinine, lipids and ECG through a referral arrangement with the CHC. Rationale:

The issue of treatment of associated conditions is addressed by guidelines like ESC/ESH, JNC 8 and CHEP, though not specifically by NICE. There is broad consensus between these guidelines on the choice of drugs for the treatment of hypertension in the presence of associated conditions. Diabetes:However there is some variation in the targets for BP control across guidelines. CHEP guidelines for example recommend lower systolic and diastolic BP targets for patients

with diabetes (systolic BP < 130 mm Hg and diastolic BP < 80 mm Hg),(19) while the European guidelines recommend a diastolic BP target of less than 85 mm Hg while recommending the same systolic BP target of 140 mm Hg. The JNC 8 guideline specifically reviewed the evidence from randomised controlled trials in favour of lower targets for systolic and diastolic BP in diabetics and concluded that there was insufficient evidence supporting

them, and suggested similar targets as for the general population.(20) We decided to adopt the JNC 8 recommendation in light of the evidence presented in them and the conclusions of a recent Cochrane review which were similar to the JNC 8 recommendations.(61) Also a similar target for BP control in diabetics as well as the general population would favour guideline implementation. Cerebrovascular diseases: The recommendations regarding antihypertensive treatment in

patients with ischemic stroke has been adopted from the CHEP guidelines,(19)the ESC/ESH guidelines and the Seventh Report of the JNC. The recommendations related to blood 95 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

pressure management in patients with spontaneous intracerebral haemorrhage has been adapted from a recent guideline from the American Heart Association/American Stroke Association.(74) Recent studies have demonstrated the lack of an ischemic penumbra in hemorrhagic strokes, and the reduction of BP in the acute phase of stroke can be safely undertaken. 4.9 Hypertension in the elderly: 4.9.1 Postural hypotension is more common in elderly people. Assess patients for postural

hypotension at diagnosis and on follow up by checking BP in sitting and in standing position after 2 minutes. 4.9.2 Postural fall of >20 mm in systolic and >10 mm diastolic indicates postural hypotension is a risk factor for falls. 4.9.3 In a patient with postural hypotension titrate target according to standing BP. 4.9.4 Start therapy with lower doses of drugs and change doses or add drugs at a slower rate in elderly patients.

4.9.5 In elderly patients less than 80 years of age, the blood pressure target for control may be <140 mm systolic and <90 mm diastolic if the patient is fit and the treatment is well tolerated. 4.9.6 In elderly patients more than 80 years (the very elderly), the blood pressure target for control is <150 mm systolic and <90 mm diastolic. 4.9.7 The drug of choice for initiation of therapy in the elderly is a long acting calcium channel blocker, or a low dose thiazide diuretic in the absence of compelling

indications. 4.9.8 There is a higher likelihood of certain side effects in the elderly- e.g. hyponatremia in the case of thiazides, and hyperkalemia in the case of ACE inhibitors. 4.9.9 There is a likelihood of drug –drug interactions in the elderly who often receive other drugs; e.g. .NSAIDs for arthritis interferes with action of ACE inhibitors, and diuretics. 4.10 Hypertensive emergencies: 4.10.1 Hypertensive emergencies are those in which severe hypertension (elevations of

systolic >180 mm Hg) and/ or diastolic (> 120 mm Hg) is associated with symptoms and signs of acute ongoing organ damage. Such elevations of blood pressure may be associated with neurologic emergencies (hypertensive encephalopathy, cerebral infarction, and cerebral haemorrhage), cardiac emergencies (acute left ventricular 96 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

failure, acute coronary syndrome), renal emergencies like acute renal failure, and obstetric emergencies like eclampsia (symptoms and signs of such dysfunction are referred to under the mnemonic of ‘ABCDEFG” in pathway on assessment and management on hypertensive crisis). Eclampsia can occur even at levels of BP less than 180 mm systolic and/or 120 mm diastolic. 4.10.2 The magnitude and rate of reduction of BP varies according to the organ

involvement in the hypertensive emergency. In many hypertensive emergencies including hypertensive encephalopathy reduction of mean arterial pressure of ≤ 25 percent in the first hour, with a gradual reduction to 160 mm systolic and diastolic of 110-120 mm Hg over 2-6 hours, and gradual normalization of blood pressure over 24-48 hours is recommended. Parenteral agents like IV labetalol, nicardipine may be used initially with a change to oral agents later.

4.10.3 In patients with ischemic stroke as noted earlier, reduction of systolic BP below 220 mm Hg and 120 mm Hg are not treated, unless the patient is being considered for thrombolytic therapy. 4.10.4 Negative recommendation: Oral or sublingual nifedipine may cause excessive, abrupt fall of blood pressure which may result in cardiac, cerebral or renal ischemic complications. It is not recommended in the treatment of any hypertensive emergency.

4.10.5 In the case of acute left ventricular failure reduction of the elevated BP is indicated with a parenteral loop diuretic like frusemide in addition to vasodilators like nitroglycerine. In patients with acute coronary syndrome with severe hypertension, intravenous nitroglycerine may be used in association with intravenous beta- blockers like esmolol or labetalol. 4.10.6 Patients with a hypertensive emergency should be examined for any clinical clues to

the presence of secondary hypertension and be evaluated for the same. 4.11 Hypertensive urgencies: 4.11.1 This refers to situations when severe hypertension (SBP > 180 mm, DBP> 110 mm) is not associated with any signs of acute or ongoing organ damage (cerebral, cardiac, renal, visual), and the patient is relatively asymptomatic except for a mild headache(none of the symptoms or signs referred in the mnemonic ‘ABCDEFG’ in the pathway on assessment and

management of hypertensive crisis). Patients with severe hypertension should be assessed clinically and by laboratory investigations, and target organ damage should be excluded before hypertensive urgency is diagnosed. 97 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

4.11.2. Hypertensive urgencies may occur in patients with chronic hypertension in a number of situations. This includes non-adherence to therapy, after sudden withdrawal of beta- blocker or clonidine therapy, after ingestion of large quantity of salt, or due to anxiety. 4.11.3 There is no benefit from rapid reduction of BP in patients with severe but asymptomatic hypertension and the BP should be reduced over a period of hours and days.

4.11.4. Nursing the patient in a quiet room and relief of anxiety may reduce BP to a certain extent. 4.11.5. Negative recommendation: Do not attempt excessive, rapid and uncontrolled reduction of blood pressure in hypertensive urgencies, with intravenous drugs or oral or sublingual nifedipine. This aggressive reduction of BP in a patient with severe asymptomatic hypertension may cause fall of BP below the threshold of autoregulation in vascular beds, and cause serious cerebral and cardiac

complications related to ischemia. 4.11.6 Re-institution of therapy or intensification of therapy by increasing the dose of drugs or adding a diuretic may suffice for gradual reduction of blood pressure in a patient who has developed severe asymptomatic hypertension on the background of chronic hypertension. 4.11.7 If BP reduction over few hours is required in view of imminent cardiovascular events, then oral frusemide, oral clonidine can be used. These can be followed by long term

therapy with CCBs, ACE inhibitors or diuretics. Background: Severe elevations of BP can be asymptomatic and can occur in those with undiagnosed, uncontrolled hypertension or in hypertensive patients who were on therapy but were non-adherent or have stopped some agents like beta-blockers or clonidine suddenly. Such asymptomatic severe elevation of BP termed “hypertensive urgencies” demand reduction of BP over hours and days. Severe hypertension may be associated with life-

threatening events involving cardiac, cerebral or renal systems, in which case the term “hypertensive emergency” is used and BP is reduced appropriately over minutes to hours. Appropriate management of hypertension in these situations can prevent morbidity and mortality, while inappropriate management which includes sudden excessive reduction of BP may result in serious complications. Implementation: Physicians will need to be trained in the clinical and laboratory assessment of severe

hypertension and to distinguish between hypertensive urgency and an emergency 98 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Patients with hypertensive emergencies have symptoms, signs, and laboratory abnormalities suggestive of cardiac, cerebral, renal complications, listed in the table below, and will need care at a secondary/tertiary care facility. However treatment should not be delayed and the patient should be referred after an initial reduction of BP. The healthcare facility will need to keep stock of certain essential medicines for the management of hypertensive urgencies and emergencies. These are indicated in the

table below. A minimum list would contain IV frusemide, IV labetalol, and IV nitroglycerine. Rationale:There is no good quality evidence from randomised controlled trials to guide the management of patients with acute severe hypertension with/without complications, and current recommendations The and are based on the Seventh Report.(29) Hypertensive emergencies Cardiac conditions Acute left ventricular failure Acute myocardial infarction Renal conditions Acute glomerulonephritis Renovascular hypertension

Cerebrovascular conditions Hypertensive encephalopathy Cerebral infarction Intracerebral hemorrhage Subarachnoid hemorrhage Head injury Accelerated hypertension with exudates and/or papilledema Obstetric conditions Eclampsia Surgical conditions Postoperative hypertension Severe burns Excess catecholamine Pheochromocytoma Abrupt withdrawal of clonidine, beta- blockers Table16: Conditions presenting as hypertensive emergencies Drug Dose Onset of Adverse effects Comments action

IV Frusemide 20-40 mg in 5-15 min Hypovolemia, May be used in 1-2 min hypokalemia combination with other drugs to maintain their efficacy. Indicated in acute left ventricular failure IV labetalol 20-80 mg IV 5-10 min Scalp tingling, Can be used in many dizziness, nausea, hypertensive heart block emergencies. Avoid 99 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

in acute heart failure IV Nicardipine 5-15 mg per 5-10 min Tachycardia, Can be used in many hour as IV headache, nausea, hypertensive tachycardia emergencies. Avoid in acute heart failure IV 5-100 2-5 min Headache, vomiting, Useful in myocardial Nitroglycerine µg/min methemoglobinemia, ischemia with tolerance hypertension Table 17: Selected intravenous drugs useful in management of hypertensive emergencies 4.12 Integration with other interventions to reduce cardiovascular risks

4.12.1 The treatment of hypertension should be integrated with treatment of associated risk factors like lipid lowering therapy and antiplatelet therapy, apart from lifestyle interventions already mentioned. 4.12.2 Antiplatelet therapy with low-dose aspirin (75 mg/day) is recommended in patients with controlled hypertension who have previous history of cardiovascular event (previous MI, stroke, angina, bypass surgery or coronary angioplasty), because of a favourable benefit –harm ratio.

4.12.7 Low dose aspirin may be considered for those hypertensives who are well controlled and have a high cardiovascular risk (Grade 3 hypertension, 3 or more risk factors, target organ damage). 4.12.8 Negative recommendation: Do not use low-dose aspirin in hypertensive patients without cardiovascular disease and who are at low-moderate risk as the risk of major bleeds (intracranial and gastrointestinal) outweighs the potential benefit. 4.12.9 The use of low dose aspirin in patients with diabetes without

cardiovascular or cerebrovascular disease is not recommended in view of the uncertain risk-benefit ratio. 4.12.10 Regardless of presence/absence of hypertension statins are recommended in the following patient groups8 8Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. A Report of the American College of

Cardiology/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology. 2014;63(25_PA):2889-2934. 100 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

• Patients with overt atherosclerotic cardiovascular disease (coronary artery disease, cerebrovascular disease, and peripheral arterial disease), regardless of age. • Patients with age with≥ 21 years, where LDL –cholesterol is more than 190 mg/dl, and where secondary cause of hyperlipidemia has been excluded. • In patients who are diabetic and in the age group of 40-75 years, and LDL cholesterol is between 70-189 mg/dl 4.12.7. Statins are indicated in hypertensive patients aged more than 40 years with

high cardiovascular risk (3 or more cardiovascular risk factors)9 4.12.11Hypertensive patients who smoke or chew tobacco should be provided advice to stop smoking and chewing tobacco. Background Aspirin is used for its antiplatelet effect in patients for prevention of cardiovascular outcomes including myocardial infarction (MI) and stroke, and cardiovascular disease (CVD) death. Aspirin use however also carries a risk of increase in incidence of major bleeds – gastrointestinal or intracranial.

Lowering lipid levels to target levels lowers cardiovascular risks in those with moderate to high cardiovascular risk. The relative benefits of lowering statins are greatest in those who are also diabetic. However they contribute the highest additional costs to antihypertensive treatment. Where the cost factor may be a major cause for default from treatment, the costs benefits of adding statins should be carefully considered and discussed with the patient. Implementation:

Aspirin: Aspirin in a dose of 75 mg should be available in the public health system for use in well controlled hypertensives that have had a previous cardiovascular event like previous MI or angina, bypass surgery or angioplasty, or stroke. In patients without cardiovascular disease , aspirin should be considered in those with a high cardiovascular risk – as discussed in the section on assessment, these would be patients with controlled Grade 2 /Grade 3

hypertension, with 3 or more risk factors, or with organ damage. Statins: Some statins e.g. atorvastatin are off-patent and available in quality assured public pooled procurements for as low as Rs. 0.22 for a 10 mg 9Daskalopoulou SS, Rabi DM, Zarnke KB, et al. The 2015 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, and assessment of risk, prevention, and treatment of hypertension. Canadian Journal of Cardiology. 2015; 31(5):549-568. 101

tablet(seehttp://www.tnmsc.com/tnmsc/new/user_pages/drugtender.php?drugcat=drug20 15). The indications for statin use are fairly clear cut for three categories of patients – Those with existing cardiovascular disease, those with diabetes in the age group of 40-79 years, and those with a LDL-C of > 190 mg/dl. Physicians at the PHC and CHC level can be trained in the use of statins and recognise these indications for statin therapy. With the availability of

statins of generic origin and trained health personnel, risk reduction with statins in terms of all-cause mortality, nonfatal MI and stroke, for patients with hypertension with cardiovascular disease in India is feasible in the public health system. Rationale: Use of Aspirin: Aspirin due to its antiplatelet effect has the potential to reduce cardiovascular outcomes including myocardial infarction, stroke and other such

complications. However its use is also associated with higher risk of gastrointestinal and extracranial bleeds. It should be used therefore when the benefit outweighs the possible harm. Evidence based guidelines like the ESH/ESC, after reviewing the data from recent large meta-analysis(75), have indicated the situations where the potential benefit outweighs the harms, and recommended aspirin in the secondary prevention of cardiovascular

disease.(21) We have adopted these recommendations. When aspirin is used for primary prevention, it does reduce the risk of MI, but its effect on reducing risk of stroke and CVD death is inconclusive, whereas the possibility of harm remain.(76) The prescription of aspirin for primary prevention of cardiovascular disease is based on judgement of the healthcare provider who must weight possible benefit against the risk of major bleeding.(76) In patients

with diabetes, the existing data suggests that aspirin use is associated with a modest but not statistically significant reduction in stroke and myocardial infarction.(77) Aspirin should only be given for risk reduction after the BP has been well controlled Statin therapy: Statin therapy has been recommended as part of global vascular protection or treatment of associated risk factors in some of the guidelines e.g. CHEP and the ESC/ESH

guidelines. There is consensus that these are effective in lowering mortality, risk of myocardial infarction and stroke in patients with cardiovascular disease.(19, 21)In such patients statins are an adjunct to diet, exercise, effective control of hypertension and smoking cessation.(19)The use of statins may increase the absolute risk of diabetes by 1%, especially in those with features of the metabolic syndrome, and are associated with a risk

of muscle damage.(78) Myositis occurs in about 5-10% of recipients. The use of statins in patients without cardiovascular disease requires discussion of the possible adverse effects of statins with the patients. Use of statins in such individuals has been recommended for example if the 10 year risk of cardiovascular disease exceeds a threshold determined by risk assessment tools. The caveats with this calculation based approach are that the pooled

cohort equation and the data, on which these risk assessment tools are modelled, are not based on the Indian population. The CHEP guidelines have however defined a high risk individual as someone with 3 or more cardiovascular risk factors out of a list of 11 factors.(19) This is an approach that might be feasible to implement in a public health programme in India. 102 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Cardiovascular risk factors for consideration of statin therapy in patients with hypertension: Consider if 3 or more risk factors are present 1.Male sex 2. Smoking 3. Family history of premature cardiovascular disease 4. Diabetes mellitus 5. Left ventricular hypertrophy 6. Family history of premature cardiovascular disease 7. Total cholesterol to high-density lipoprotein ratio ≥ 6 8. Other ECG abnormalities: Left bundle branch block, left ventricular strain, pattern, abnormal Q-

waves or ST-T changes, compatible with ischemic heart disease 9. Microalbuminuria or proteinuria 10. Previous stroke or transient ischemic attack 11. Peripheral arterial disease Table 18: Cardiovascular risk factors for consideration of statin therapy in patients with hypertension 103 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Cessation of tobacco use: Key recommendations: Hypertensive patients who smoke or chew tobacco should be provided brief advice to stop smoking and chewing tobacco. Background: Tobacco use which includes smoking and chewing tobacco is a major avoidable and modifiable risk factor for cardiovascular disease.(79) In the INTERHEART study which examined the risk of myocardial infarction with tobacco use in 52 countries, the odds ratio

for myocardial infarction associated with current smoking cigarettes, smoking beedies, and chewing tobacco were 2.95, 2.89, and 2.23 respectively. The highest risk was associated with current smokers who also chewed tobacco (OR: 4.09).(79) Studies suggest smoking causes up to 60% of cardiovascular disease in urban men in India which is higher than in richer countries.(80) Cessation of tobacco use is therefore an integral component of global vascular protection for patients with hypertension.

Implementation:Assess history of tobacco use as smoking or chewing, and consider appropriate brief interventions as an integral part of hypertension management, which have been well described in the operational guidelines of the National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular diseases and Stroke.(15) This part of treatment can be done by non- medical staff if they are provided information and skills in this area. Rationale:

Systematic reviews of a large number of randomized controlled trials have established that brief physician advice to stop smoking can lead to significant increases in smoking cessation.(81) Brief interventions using non-judgemental and evidence based methods are effective, feasible, cost nothing and carry large benefits to those with hypertension. Also combining advice on tobacco cessation with pharmacotherapy (nicotine replacement

therapy, administration of bupropion, and varenicline) also resulted in a higher likelihood of sustained quitting. 104 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

5. Monitoring, follow up and improving adherence to therapy Key Recommendations: 5.1 A simplified regime using long acting drugs which can be used once a day may improve adherence. 5.2 The patients should be monitored for efficacy of the regimen, both at the clinic and community level. In patients who are yet to achieve target BP, follow-up visits at 1-2 weeks can be scheduled till target BP is achieved. Thereafter the patient can be seen by

a physician at a frequency determined by the severity of the hypertension, presence of comorbidities, target organ damage. Streamlined methods to collect drugs should be allowed to enable compliance by the patient. 5.3. The patients should be monitored for side effects of drugs. 5.4. The common side effect of calcium channel blockers is peripheral edema, which is dose dependent and may subside with reduction of dose or combination with ACE inhibitor.

5.4.1. The common side effects of diuretics are metabolic side effects like hypokalemia, hyperglycemia but which are less frequent when these are used in doses of 12.5 mg and when they are combined with ACE inhibitors.. A particular concern is of thiazide induced hyponatremia which is commoner in the elderly, those with a low body weight. This can develop rapidly and manifest as altered consciousness, and even seizures, and may require hospitalisation and administration of normal or hypertonic saline.

5.4.2. The common side effect of ACE inhibitors is dry cough, which may necessitate withdrawal of therapy. There is a risk of hypotension when ACE inhibitors are started on patients who are on diuretics, or are on very low salt diet. A small rise in serum creatinine can occur on ACE inhibitors, which is reversible. Hyperkalemia can develop with high doses of ACE inhibitors, but also more commonly in patients with renal insufficiency, diabetes, concurrent use of potassium sparing diuretics, and the elderly.

5.5. Consider the use of pill counts, participation of a family member in supervision of drug intake, periodic counselling and provision of patient information leaflets to improve adherence and control. 5.6 Diagnosis and management of hypertension in India, needs to be embedded in the system of primary care. A team approach to management of hypertension needs to be evolved which involves the physicians, allied staff and community based health workers. 105

5.7 Community based health workers can be trained to play a critical role in meeting the challenge of undetected, untreated and uncontrolled hypertension in India. They can improve detection, promote lifestyle modifications, monitor response and ensure adherence to therapy. They can also help prevent hypertension by advising appropriate lifestyle modifications in those who have a high normal BP ( 130-139 mm Hg systolic and 85-89 mm Hg diastolic)

5.8 We strongly recommend creation of a hypertension registry at the PHC & CHC level to ensure tracking of patients and create a system of recall which can involve the community based health workers. 5.9. Patients with hypertension should be encouraged to consider home blood pressure monitoring using an automated device which has been validated with a clinic based device. 5.10. All patients with hypertension, should undergo an annual review of control of BP,

implementation of lifestyle modifications (e.g. maintenance of body weight), target organ damage (proteinuria), review of treatment including side effects of drugs. 5.11 All patients with high normal BP should also be encouraged to undergo an annual review, and advised appropriate lifestyle modifications e.g. dietary changes, weight maintenance, and abstinence from tobacco. Background: Screening and initiation of therapy for hypertension is worthwhile only if it can

be sustained. Many patients commenced on treatment remain with uncontrolled hypertension because of poor treatment adherence. Since adherence is a multi-dimensional phenomenon, poverty, poor access to care, patient’s perceptions about the need and benefit of lifelong therapy, availability of medications in the public health system, the quality of interactions and communication between healthcare providers and patients, concerns about costs and side effects of therapy all demand careful consideration in the

management of patients with hypertension Monitoring of ongoing treatment compliance and recalls are necessary to help treatment compliance. Community based health workers can assist in recalls. Implementation: Patient education about the need and benefits of therapy in preventing life-threatening complications is essential for adherence and healthcare providers would need to be trained in providing guidance to patients with hypertension. In patients where this is possible, home

BP monitoring may aid adherence to the regime. The patient may be asked to tailor his intake of pills to fit his daily habits. A simplified regime using long acting drugs which can be used once a day may improve adherence. When multiple anti-hypertensives are being given, a single pill combination can be considered. The use of pill counts, participation of a family member in supervision of drug 106 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

intake, periodic counselling and provision of patient information leaflets may be considered to improve adherence and control. A sample patient information leaflet is provided. The patients should be monitored for efficacy as well as safety of the regimes used. They should be aware of the common side effects of the drugs being used. A paper or computer based monitoring system for chronic diseases should be maintained for the target population of a primary health care provider which recognises failure to

adhere to treatment. There should be an organised system of interventions when a patient defaults, so that default is not due to lack of knowledge, financial resources or lack of access to health services. Recall systems are effective if they are non-judgemental and respectful of patient choices. Rationale: The framework for adherence and the evidence for action have been developed in a WHO document which this guideline draws upon. (82) Among the hypertension related guidelines

the CHEP and ESC/ESH guidelines have recommended the multipronged and team approach for management of hypertension, although the evidence base is weak. The above points for action are adapted from these guidelines. According to a systematic review , the involvement of community health workers can improve the control of blood pressure, appointment keeping and adherence to medications, healthcare utilisation and even cardiovascular outcomes.(83) 107

PATHWAYS IN SCREENING, DIAGNOSIS, CLASSIFICATION, ASSESSMENT AND MANAGEMENT OF HYPERTENSION: Screening by non-physician medical staff or physician Targeted screening at community level, Any person > 18 years of age seeking of age>50 years, obese, smokers, those care at clinic level with any CVD, or family history of hypertension/ premature CVD 2 sets of BP readings on 2 occasions using validated device and standardised BP measurement procedure are > 140 mm systolic and/or >90 mm diastolic (>150/90

mm in those >80 years) Assess Risk Factors -Advice on lifestyle modifications-Urgent referral if BP >180 mm systolic &/or >110 mm diastolic Referral to PHC for diagnosis, assessment and management Patient referred back to primary care Register in HT registry team for follow up and monitoring 1. Screening pathway 108

Standard Procedure for BP measurement 1.Patient Patient should be in a relaxed state for 5 minutes before preparation and measurement of BP. Patient should not have had caffeine in the past position 1 hour or smoked in the past 30 minutes. Patient should be seated comfortably with back supported, with arm at heart level, and legs in an uncrossed position. 2.Choice of BP Mercury sphygmomanometer or any other device (including device electronic digital oscillometric devices) which has been validated

using a standard protocol, and has been calibrated regularly. 3.Cuff size and The cuff size should be appropriate for the patient. Length of placement bladder should be 80% of arm circumference and width should be 40% of arm circumference, and a large adult cuff should be used for an obese patient. Patient should not wear any constrictive clothing. Place the midline of the cuff over the pulsations of the brachial artery, at a distance of 2-3 cm above the cubital fossa.

4. Procedure to Palpate the radial pulse and then inflate the cuff to 30 mm beyond measure systolic the disappearance of the radial pulse. Deflate the cuff at 2-3 mm per and diastolic blood second and record the first and the last sounds as the systolic and pressure( applicable diastolic blood pressure respectively. in case of In oscillometric devices the systolic and diastolic BP will be displayed auscultation based automatically.

BP measurement) If the patient is diabetic or above 65 years measure the BP in supine and 2 minutes after assuming the standing position to check for postural hypotension. 5.No. of 1.1. At least 2 readings should be taken at an interval of 1 measurements and minute. If the readings differ by more than 5 mm Hg takes a recording the result third reading. The lower of the two readings should be taken as the representative SBP and DBP. 109

Grade 1 HT SBP: 140-159 mm Hg &/or DBP: 90-99 mm Hg Grade 2 HT SBP: 160-179 mm Hg &/or Patient with SBP > 140 mm DBP: 100-109 mm Hg and/or DBP >90 mm documented by at least 2 Hypertensive urgency: severe readings each on 2 visits using a Grade 3 HT asymptomatic hypertension standardised BP measurement SBP : >180 mm Hg procedure &/or Hypertensive emergency: DBP: >110 mm Hg severe HT with acute cardiac /neurologic/renal/retinal dysfunction Isolated Systolic hypertension:

SBP > 140 mm Hg (if age<80years), >150 mm Hg (ifage >80 years) AND DBP < 90 mm Hg Pathway 3: Classification pathway 110

History for risk factors, cardiovascular disease Grade 1 HT Essential evaluation Examination for clinical cardiovascular disease (angina, heart failure, stroke) Screening for diabetes, proteinuria History and examination as in Essential evaluation Desirable evaluation Grade 2 HT Screening for diabetes + lipids Patient with Urinalysis,Serum creatinine,ECG hypertension History and examination as in Essential evaluation + evidence of secondary Grade 3 HT or patient HT,Ophthalmoscopy: Comprehensive

<40 years and >60 Blood glucose, lipids, serum creatinine, serum evaluation years or Resistant HT sodium and potassium,Ultrasound if suspicion of renal parenchycmal or renovascular disease,ECHO: in case of ? heart failure Pathway 4: Assessment pathway 111 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Blood pressure > 140/90 mm Hg,in adults aged 18-79 years,on multiple occasions using standardized procedure (for age > 80 years blood pressure >150/90 ) Lifestyle modifications (Dietary change-salt restriction,low fat diet, reduce weight, Stop smoking) in all patients. Trial of lifestyle modifications in uncomplicated Grade 1 HT for 3 months before initiation of drug therapy. Grade 1 hypertension with TOD/DM/associated clinical ! Grade 2 HT and Grade 3 HT conditions or > 3 risk factors Start Drug therapy

Patients without compelling Patients with compelling indications indications (Hypertension with associated clinical (Hypertension alone ) conditions) Grade 1 HT(SBP 140-159, DBP 90-99) Grade 3 HT (SBP >180, Grade 2 HT (SBP 160-179, DBP 100- DM: A /C, D DBP > 110) 109) # Start with One drug CAD: B + A , C A or C* or D Increase A or CorD to USE TWO DRUGS (preferred strategy) CHF: D+ A+ B, MRA maximal dose (less A+ C OR C+ D OR A+ D preferred strategy) § CKD: A, C, D USE 3 drugs A+C +D

NO response to 3 drugs -Resistant HT- Consider Specialist referral Pathway 5 A.: Management pathway (algorithm form) Drugs are added only if they are required to achieve the target BP of <140/90 mm Hg (in patients <80 years old) or BP <150/90 mm Hg(in patients >80 years of age) Abbreviations: SBP : Systolic blood pressure, DBP: Diastolic blood pressure, TOD :target organ damage, DM: diabetes mellitus, CAD: coronary artery disease,CHF: Congestive heart

failure, CKD: Chronic kidney disease. Drug abbreviations: A : Angiotensin converting enzyme(ACE) inhibitors (e.g. enalapril) or Angiotensin II receptor blockers(ARBs)(e.g. losartan) onlyif intolerance to ACE inhibitors, C: Calcium channel blocker(e.g. amlodipine), D: Thiazide diuretics(e.g. hydrochorothiazide), B: Beta-blockers(e.g. atenolol), MRA : Mineralocorticoid receptor antagonist (e.g. spironolactone). Footnotes :! Other Risk factors(apart from hypertension) : age ( > 55 years in men, 65 years

in women), male gender, diabetes mellitus,smoking,obesity(including abdominal obesity), dyslipidemia, impaired glucose tolerance, family history of premature coronary artery disease. * calcium channel blockers are antihypertensives of choice in the elderly (> 60 years).# 112

Patients with CAD and history of myocardial infarction should receive both beta-blockers and ACE inhibitors.§ Patients with CKD may require loop diuretics if the Glomerular filtration rate is low. Those patients who are started on ACE inhibitorswill require monitoring of serum creatinine and potassium after initiation of treatment.Based on references(24, 49) 113 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

MANAGEMENT OF HYPERTENSION - target BP <140/90 mmHg in those < 80 years, 150/90 in those over 80 years. ALL PATIENTS REQUIRE LIFE-LONG LIFESTYLE MODIFICATION Dietary change to Heart-healthy diet– salt < 5 g/day, low-fat diet Regular exercise, Maintain weight – target BMI 18.5-22.9 kg/m2 Stop smoking Patients with Grade 1 hypertension may require only lifestyle modification, which should be tried for 3 months. GRADE 1 HYPERTENSION (SBP 141-159 mm, DBP 91-99mm ) with

Inadequate control after 3 months of lifestyle modification OR more than 3 risk factors Male Age: men >55 years ,women > 65 years smoking obesity, including abdominal obesity dyslipidaemia impaired glucose tolerance family history of early coronary artery disease Drug therapy – A or C 1 or D Add second drug - A+C or C+D or A+D if response not adequate within 2-4 weeks Add third drug – A+C+D if response not adequate within 2-4 weeks GRADE 2 HYPERTENSION (SBP 141-159, DBP 91-99) Drug therapy – A or C or D

Add second drug - A+C or C+D or A+D if response not adequate within 2-4 weeks Add third drug – A+C+D if response not adequate within 2-4 weeks GRADE 3 HYPERTENSION (SBP >180, DBP >110) Use two drugs - A+C or C+D or A+D Add third drug – A+C+D if response not adequate within 2-4 weeks ALL GRADES OF HYPERTENSION WITH ASSOCIATED CLINICAL CONDITIONS CAD: coronary artery disease - B+A 2 , C CHF: congestive heart failure - D+A+B, MRA CKD: chronic kidney disease – A or C or D 3 DM: diabetes mellitus – A or C, D

Drugs are added only if they are required to achieve the target BP of <140/90 mm Hg (in patients <80 years old) or <150/90 mm Hg (in patients >80 years of age) Abbreviations: CAD: coronary artery disease, CHF: congestive heart failure, CKD: chronic kidney disease, DBP: diastolic blood pressure, DM: diabetes mellitus, SBP: systolic blood pressure, TOD: target organ damage. Drug classes: A: Angiotensin converting enzyme (ACE) inhibitors, (e.g. enalapril) or Angiotensin II receptor blockers

(ARBs) (e.g. losartan) only if intolerance to ACEinhibitors, B: Beta-blockers (e.g. atenolol), C: Calcium channel blockers (e.g. amlodipine), D: thiazide diuretics (e.g. hydrochorothiazide), MRA: mineralocorticoid receptor antagonist (e.g. spironolactone). Drug doses: Doses for initiation of therapy: A : enalapril 5 mg; B: Atenolol 50 mg; C: Amlodipine 5 mg ( 2.5 mg in elderly); D: Hydrochlorthiazide 12. 5 mg.

Add-on doses: A : enalapril 5 mg (reduce in elderly or in those on diuretics), C: amlodipine 2.5 mg, D: hydrochlorthiazide 12.5 mg Maximal doses: A : enalapril 20 mg; B: Atenolol 100 mg C: Amlodipine 10 mg; D: Hydrochlorthiazide: 25 mg Footnotes : 1 Calcium channel blockers are antihypertensives of choice in the elderly (> 60 years). 2 Patients with CAD and history of myocardial infarction should receive both beta-blockers and ACE inhibitors

3 Patients with CKD may require loop diur etics if the glomerular filtration rate is low. Patients on ACE inhibitors will require 114 monitoring of serum creatinine and potassium. Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document Based on references {, 2011 #138;Weber, 2014 #85}

non physician health staff- screen-refer for diagnosis-educate- assess-advise on lifestyle &adherence- monitor-follow up Physician at PHC/CHC diagnose-classify-educate-assess (TOD, associated clinical conditions), advise- register -initiate therapy-refer if indicated, follow up Referrals to District 1. In case of hypertensive emergency after initiation of treatment 2. For evaluation of resistant hypertension. 3. For management of certain associated clinical conditions -Ischemic heart disease

SBP>180 DBP>110-120 Assess for following* A: Altered consciousness B: Breathlessness C: Chest Pain (ischemic) D: Deficit (weakness in one or more limbs) or Decreased urinary output E: Edema F: Fundus if feasible-hemorrhages, exudates, papilledema G: Generalised seizures Asymptomatic : One or more of symptoms No A/B/C/D/E/F/G /signs in A-G HYPERTENSIVE HYPERTENSIVE URGENCY EMERGENCY Reduce BP over hours Cardiac Neurologic to days. emergencie emergencies s Use oral drugs Renal Accelerated DO NOT USE

emergenci Malignant SUBLINGUAL es Hypertension NIFEDIPINE Surgical Obstetric Reduce BP (only rarely to normal) over minutes to hours -according to type of emergency Use parenteral drugs : choice depends upon type of emergency DO NOT USE SUBLINGUAL NIFEDIPINE Pathway 7: Assessment and management pathway in a patient with hypertensive crisis (> 180 mm systolic, >110-120 mm diastolic) *Also investigate as appropriate: Serum creatinine (in all), X-ray chest, ECG, CT scan if indicated.

Cardiac emergencies: Acute left ventricular failure, Myocardial infarction, unstable angina Neurologic emergencies: Hypertensive encephalopathy, Ischemic stroke, Intracerebral haemorrhage, subarachnoid haemorrhage, Head injury Renal emergencies: Acute glomerulonephritis#, renovascular hypertension Surgical emergencies: Post-operative hypertension, severe burns Obstetric: Eclampsia# #: Hypertensive emergency may occur even at BP levels lower than 180 mm systolic and 110 mm diastolic 116

ANNEXURES 117 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Annexure 1: Glossary and Abbreviations Abdominal obesity, also known as central obesity, is when excessiveabdominal fat around the stomach and abdomen has built up to the extent that it is likely to have a negative impact on health. It is assessed by measuring the waist circumference or calculating the ratio of the circumference at the waist to that at the hip (waist-hip Abdominal ratio). Abdominal obesity has been strongly linked to risk of obesity cardiovascular disease.

ACC/AHA American College of Cardiology/American Heart Association Angiotensin-Converting Enzyme Inhibitor. These slow down the effect of the angiotensin converting enzyme (ACE) and reduce the levels of angiotensin II. These are used in treatment of hypertension and heart ACE Inhibitor failure. Examples include enalapril, lisinopril. Angiotensin II Receptor Blocker. They are used in treatment of hypertension, kidney disease and heart failure and act by blocking the

effect of angiotensin II on the receptors in the blood vessels. ARB Examples include losartan, and telmisartan. Body mass index is the weight in kilograms divided by the square of the height in metres. Cut offs exist to define thinness, normal weight, BMI overweight, obesity. Calcium channel blocker. A group of drugs used in treatment of hypertension and angina. Examples include amlodipine,nifedipine, CCB diltiazem and verapamil. CHC community health centre CHEP Canadian Hypertension Education Program

Chronic kidney disease: disease in which kidneys start failing in their function of filtering waste, removing water and salt. It can result from a variety of causes, among which hypertension and diabetes are CKD common. Cardiovascular disease. It is a class of disease affecting the heart or vessels. It may manifest as angina or myocardial infarction (heart CVD attack), heart failure, stroke or disease of the arteries in the limbs. Diastolic blood pressure-the pressure in the arteries during the

DBP relaxation of the heart, between beats. A class of drugs which promotes the production of urine. They are Diuretic used in treatment of hypertension, heart failure and kidney disease. Diabetes mellitus - a disease in which there is abnormal handling of DM the sugar in the body. Abnormal amount of lipids (fats) in the blood, usually cholesterol, Dyslipidemia triglycerides. ECG Electrocardiogram ESH/ESC European Society of Hypertension/European Society of Cardiology

Hyperlipidemia excess of cholesterol and other fats in the blood Hypertension High blood pressure Hypertensive Hypertensive emergency is a situation where the blood pressure is 118 emergency severely elevated [systolic blood pressure 180 or higher or diastolic Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

pressure 110 or higher), along with symptoms , signs and other evidence of associated organ damage which may manifest as altered consciousness, stroke, breathlessness, chest pain, kidney failure, visual disturbance. Hypertensive urgency is a situation where the blood pressure is Hypertensive severely elevated [systolic blood pressure 180 or higher or diastolic urgency pressure 110 or higher), but there is no associated organ damage Internal Harmonisation Group- a group of experts constituted by the

National Health Systems Resource Centre, New Delhi to harmonise IHG guideline development ISH Internal Society of Hypertension Joint National Committee is a group of experts in the United States which has provided periodically, guidelines on prevention, detection, JNC evaluation and treatment of hypertension Lifestyle modifications Changes in lifestyle which are healthier left ventricular hypertrophy -an enlargement of the left side of the LVH heart due to high blood pressure

The National Institute for Health and Care Excellence is an executive non-departmental public body under the Department of Health in the United Kingdom, reputed for its formulation of guidelines for clinical NICE practice. Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have a negative effect on health. The international cut-off is a BMI of 30 kg/m2 or higher, but a Obesity lower cut off of 25 kg/m2 for Indians has been suggested.

This is a BP measuring device which uses electronic pressure sensors Oscillometric and an algorithm to estimate the systolic and diastolic blood device pressures which are available as a numerical readout. PHC primary health centre It is the usual form of hypertension that by definition has no Primary(essential) identifiable cause. It is linked to genetics, dietary factors, inactivity hypertension and obesity the presence of abnormal quantities of protein in the urine, which

Proteinuria may indicate damage to the kidneys damage to the retina and the circulation of the retina due to high Retinopathy blood pressure Systolic Blood pressure- the pressure produced in the arteries during SBP the contraction of the heart Screening, in medicine, is a strategy used in a population to identify the possible presence of an as-yet-undiagnosed disease in individuals Screening without signs or symptoms. It is the less common form of hypertension where the hypertension is

Secondary associated with an underlying medical condition of the kidneys, hypertension arteries, or endocrine system. A medical emergency when either clogging of arteries or bleeding in Stroke the brain may result in death of brain cells and appearance of 119 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

weakness or numbness of the body, trouble with speech, vision. Hypertension is a major risk factor for strokes, which can result in death or disability. Target organ damage usually refers to damage occurring in Target organ major organs fed by the circulatory system (heart, kidneys, brain, damage eyes) which can sustain damage due to uncontrolled hypertension. The white coat refers to the coats traditionally worn by doctors. This effect is present when the blood pressure readings recorded in a visit

to the clinic are consistently higher than those recorded at home. This effect may be seen in both treated and untreated forms of White coat effect hypertension. This is a situation where people with normal BP outside the clinic White coat setting have hypertension during measurement of BP by doctors and hypertension nurses. WHO World Health Organisation 120 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

ANNEXURE 2: LIFE STYLE MODIFICATIONS IN HYPERTENSION Life style changes recommended for patients diagnosed to have hypertension and for those at risk of developing hypertension Background: Lifestyle modifications are an integral part of the management of persons with hypertension, regardless of severity of hypertension. Reduction of BP following lifestyle modifications may suffice for the control of grade I hypertension, while they may aid the

control of hypertension and reduce the dosages of drugs required for control of other grades of hypertension. Lifestyle modifications also help to reduce the overall cardiovascular risk in a person with hypertension. Lifestyle modifications are also an integral part of the prevention of hypertension at both an individual and the population level, and may help prevent progression of high normal BP to hypertensive levels. 1. Physical Activity (adapted from ref. (84))

• Physical activity includes daily activity like walking and cycling, household work, work related activity, and leisure activity. Moderate intensity physical activity of 30 minutes per day or at least 2.5 hours (150 mins) per week, which can be performed in bouts of 10 minutes or more in 4-7 sessions per week, should be advised to all individuals for its cardio-protective effect . Moderate intensity physical activity includes any activity which can increase the heart rate, make

the breathing rapid and make the body warmer such as brisk walking (at 3-4 mph), stair-climbing, light swimming, walking the treadmill at 3-4 mph, or . 45 minutes (accumulated) exercise per day is recommended for cardiovascular fitness, while 60 minutes (accumulated) per day is recommended for weight reduction. The specific form of physical activity chosen by or for the patient should be enjoyable and sustainable. § Alternatively persons can indulge in 75 minutes of vigorous physical activity like

running (at 6-8 mph), cycling at 12-14 mph. This kind of activity makes the 121 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

breathing very hard, the heartbeat rapid and makes it difficult to carry on a conversation comfortably. § All adults should include physical activities to improve muscle strength at least twice a week. § Regular aerobic exercises can reduce the systolic blood pressure average of 4 mmHg and diastolic BP by an average of 2.5 mmHg.(29) § Epidemiologic evidence suggests that physical activity reduces cardiovascular morbidity and mortality. There is strong evidence that regular physical activity

has an independent cardio protective effect. Physical activity improves cardiorespiratory fitness, lowers SBP and DBP, improves insulin sensitivity and glycemic control, helps reduce and control weight, and lowers markers of inflammation.(53) § Chronically sedentary individuals should not start a program of vigorous activity suddenly, but should gradually increase the duration and intensity of physical activity, starting for example with 10 minutes of moderate activity per session

.(85) This is done to minimise the risk of a sudden cardiac event and musculoskeletal injuries. Any patient experiencing chest discomfort, jaw pain, palpitations, syncope or dyspnea, should undergo evaluation before continuing with exercise. Patients with decompensated heart failure and acute coronary syndromes should not embark on an exercise program. 122 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Source: Ref: (85) Source : ref(85) 2. Weight Reduction: achieve and maintain desirable body weight. All individuals who are overweight or obese should be encouraged to lose weight 123 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

through a combination of a reduced calorie diet, increased physical activity and behaviour modification. Dietary changes and recommendations for physical activity are mentioned in other sections. Overweight or obesity is assessed by measuring body mass index (BMI), which is calculated as weight in kg/height in meter2. For Indian population 18.5 to 22.9 BMI is normal, 23 to 24.9 is considered as overweight and BMI of ≥25 kg/m2 is considered as

obesity in Indians.10 Apart from BMI which is a measure of general adiposity, it is also important to measure the abdominal adiposity, which is also associated with a higher cardiovascular risk. Abdominal adiposity can be measured by measurement of the waist circumference and the waist-hip ratio. The waist circumference is measured at the end of several consecutive natural breaths, midpoint between the top of the iliac crest and

the lower margin of the last palpable rib in the mid axillary line. Waist circumference should be <90 cm for men and <80 cm for women. Another measure of central obesity is Waist Hip Ratio (WHR), which is the waist circumference divided by the hip circumference. The hip circumference is measured at the maximum circumference of the buttocks. Normal WHR is <0.85 for women and <0.90 for men. 10Misra A, Chowbey P, Makkar B, et al. Consensus statement for diagnosis of obesity, abdominal obesity and

the metabolic syndrome for Asian Indians and recommendations for physical activity, medical and surgical management. JAPI. 2009;57(2):163-170. 124 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

3. Alcohol Consumption § Reducing alcohol intake can lower the blood pressure substantially. On other hand moderate drinking and binge drinking increases the blood pressure and risk of developing hypertension. § Zero alcohol consumption is recommended for women who are pregnant or planning to have pregnancy and also for those hypertensives that had already suffering from a complication due to hypertension like stroke, heart disease or renal disease.

§ Alcohol consumption is measured in terms of units of alcohol (UK) or standard drinks (e.g. Australia, USA). 1 unit of alcohol is 10 ml ethanol (around 8 gms ethanol), while 1 standard drink contains 10 g ethanol (Australia) or 14 g ethanol (USA). § The no. of units consumed per day can be calculated using the drink volume and the Alcohol by volume which is mentioned as a percentage on the container. E.g. Beer may be around 5% ABV, wine is around 12.5%, while whisky and vodka are around 40% ABV.

§ The number of units of alcohol = Drink volume x ABV /1000. Therefore 100 ml of whisky will be 100 x 40/1000= 4 units. § Healthy adults should not regularly drink more than 3-4 units per day in the case of men and 2-3 units in the case of women. If there has been heavy alcohol consumption, there should be no alcohol intake for 48 hours. § Tips on cutting down should be offered to patients and should be employed in an incremental fashion(86) : These include keeping track of alcohol intake (

including counting and measuring) and keeping intake within recommended limits, setting goals for consumption, drinking slowly and preferably with some food in the stomach. In patients who have decided to quit, avoiding triggers, dealing with urges, and refusing offers of drinks politely are of vital importance. Talking and enlisting the support of spouses, non-drinking friends, and mutual support groups like alcoholics anonymous are also very helpful. 125

4. Tobacco cessation Non-smokers should be encouraged not to start smoking.(87)All smokers should be encouraged to quit smoking, and should be supported by the health professional in their efforts to do so.(87) Patients who use other forms of tobacco should be motivated to stop doing so. § Smoking cessation may not reduce the blood pressure directly but markedly reduces overall cardiovascular risk. The risk of myocardial infarction is 2–6 times

higher and the risk of stroke is 3 times higher in people who smoke than in non- smokers. Smokers who quit reduce their risk of coronary heart disease. § Brief advice from health professionals is effective in helping persons to quit smoking, increasing quit rates. Even 3–5 minutes taken to encourage smokers to attempt to quit can increase success rates. § The WHO has recommended a 5 As approach to aid in smoking cessation in routine practice- The patient should be asked about smoking status at every

opportunity. Then the patient should beadvised about to quit smoking, and assessed about his degree of addiction and readiness to quit. The health professional should assist in formulating a smoking cessation strategy including setting a quit date, counselling and other measures, and finally arrange a follow up visit. § Pharmacotherapy to stop smoking with nicotine replacement therapy, bupropion, nortryptiline and varenicline are effective and should be offered to

motivated smokers who fail to quit with counselling. The risk of adverse effects is small and is generally outweighed by the significant risk of continuing to smoke. 126 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Ref: (23) 127 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

5. Dietary Recommendations All patients should be encouraged to adopt a heart healthy diet. Fat: All individuals should be strongly encouraged to reduce total fat and saturated fat intake. Total fat intake should be reduced to about 30% of calories, saturated fat to less than 10% of calories, trans-fatty acids ( present in margarine and bakery products )intake should be reduced as much as possible or eliminated and most dietary fat should

be polyunsaturated (up to 10% of calories) or monounsaturated (10–15% of calories). Salt: All individuals should be strongly encouraged to reduce daily salt intake by at least one third and, if possible, to <5g or <90mmol per day. Fruits, vegetables, fibre: All individuals should be encouraged to eat at least 400 g a day of a range of fruits and vegetables as well as whole grains and pulses. 128 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

6. Salt Intake All patients should be strongly encouraged to limit their salt intake to < 5 g salt(or 90 mmol) per day as per WHO recommendations.(87) There is lack of representative data on salt intake in India, although in a study in urban India, the mean intake was found to be 8.5 g salt per day.(88) Reduction of salt intake can be accomplished by not adding additional salt in diet, choosing foods processed without salt, avoiding high-salt processed foods, salty snacks,

takeaway foods high in salt and salt added during cooking or at the table. Preparations which are high in salt and need to be moderated are: Pickles, chutneys, sauces and ketchups, papads, chips and salted biscuits, cheese and salted butter, bakery products and dried salted fish. The above recommendation for dietary salt restriction may have to be individualised in the case of certain occupational exposures. Acclimation to heat occurs rapidly; thus,

within a few days of exposure to hot and humid conditions, individuals lose only small amounts of sodium through sweat. But in the case of workers performing intense physical activity under conditions of heat stress, may lose significant amounts of fluid and salt in sweat. In a study it was estimated that a 10 hour shift of working in moderately hot climatic conditions(350C) can result in loss of 10-15 g salt.(89) 129 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

7. Stress management § In hypertensive patients in whom stress may be contributing to blood pressure elevation, stress management should be considered as an intervention. § A recent systematic review and meta-analysis of Yoga concluded that there were clinically important effects on cardiovascular disease risk factors and that Yoga could be considered an ancillary intervention to reduce cardiovascular risk.(90)With regard to its role in hypertension management, another systematic

review concluded that there was emerging but low-quality evidence for Yoga as an adjunct to medical therapy, but larger confirmatory studies were required. (91) 130 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

ANNEXURE 3: FORMULARY 131 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Calcium channel blockers (CCBs) with focus on amlodipine. Pharmacology of CCBs: These drugs interfere with the inward movement of calcium ions through the slow channels of cell membranes in the heart and the vascular smooth muscle. They are divided into 2 major classes , the dihydropyridines CCBs which includes amlodipine,nifedipine, felodipine) which do not have a major negative inotropic effect and no antiarrhythmic activity, and the non-dihydropyridines like verapamil, and diltiazem,

which have both significant negative inotropic and anti-arrhythmic activity. Amlodipine: Amlodipine has a very long elimination half- life (35 to 48 hours) and can be given once daily. It has a good safety profile, very few drug interactions, and no adverse effect on glucose, lipid levels. Other agents in this class like cilnidipine, nicardipine, lercanidipine, have no major advantage over amlodipine whose outcome benefits have

been established in large trials. An isomer of amlodipine, S-Amlodipine is also marketed in India, along with the amlodipine in its racemic form. The limited high quality data available suggests that there is no difference in therapeutic efficacy as well as adverse effects between the two forms(92). The S-Amlodipine form is more expensive. The racemic amlodipine is available in various forms – amlodipine besilate, amlodipine mesilate, and amlodipine maleate, but these are interchangeable.

Indications for amlodipine: Used alone or in combination for hypertension, chronic stable angina, coronary artery disease without heart failure or an ejection fraction <40% Dose, titration, and use in combinations Initial dose: 5 mg once daily. In elderly, small patients, and patients with hepatic impairment, the initial dose may be 2.5 mg once daily. The dose of 2.5 mg may also be used when adding amlodipine to other antihypertensive agents. Dose may be increased at

intervals of 7-14 days to achieve BP goals. Doses may be increased up to a maximum of 10 mg once daily. Amlodipine can be used in combination with ACE inhibitors/ARBs, and low dose diuretics for treatment of hypertension. Use in combination with beta-blockers is of benefit in patients with chronic stable angina. Contraindications: Cardiogenic shock, unstable angina, significant aortic stenosis. Worsening angina or increased risk of myocardial infarction may be seen Cautions:

Drug interactions: Beta-blockers enhance hypotensive effect of amlodipine. Amlodipine increases exposure to simvastatin (dose of simvastatin should not exceed 20 mg per day). Amlodipine also increases exposure to ciclosporin and tacrolimus. 132 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Side effects: Generally well tolerated. Side effects are dose related and commoner in women. Pedal edema is the chief side effect, seen in around 10% of people on 10 mg daily, and may be decreased in patients receiving angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Headache and flushing related to vasodilation may disappear after a few days. Use in Pregnancy and breast feeding Pregnancy Class C. Use if potential benefits outweigh risk. Avoid in lactation.

Hepatic impairment: may need dose reduction Renal impairment: No modification of drug dose is required. 133 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Angiotensin converting enzyme inhibitors with focus on enalapril and its use in hypertension Pharmacology: Angiotensin converting enzyme (ACE) inhibitors are drugs which inhibit the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor) and the degradation of bradykinin. They represent a real advance in cardiovascular therapy and have broad spectrum of proven beneficial effects in heart failure, hypertension, renal disease and

cardio-protection after myocardial infarction. They are generally well tolerated with no effect on blood glucose or lipids, with adverse effects which are occasional (e.g. cough), or quite rare (e.g. Angioedema). These adverse effects are not dose related. Some adverse effects are seen when administered in patients with heart failure on high dose diuretics (first dose hypotension), or pre-existing renal parenchymal and vascular disease (rise in

creatinine, hyperkalaemia), which may be dose related. Use of all ACE inhibitors is contraindicated in pregnancy. Indications for enalapril: Hypertension, heart failure (all stages), nephropathy (non-diabetic and diabetic), cardio- protection in early phase acute MI and post-MI LV dysfunction. Dose, titration, and use in combinations Initial dose in hypertension: 5 mg in one or two divided doses daily. In patients who have

received diuretics, those who were elderly, the initial does may be 2.5 mg11. The dose may be usually increased to 10 mg above which the additional benefit may be minimal12, although the maximum dose mentioned for hypertension is 20 mg per day. Enalapril can be used in combination with low dose diuretics, calcium channel blockers for treatment of hypertension. ACE inhibitors should not be combined with ARBs. Contraindications: Pregnancy is a contraindication for use of ACE inhibitors. Bilateral renal

artery stenosis. History of hypersensitivity (including angioedema). Cautions: Renal function may be assessed before starting therapy. In patients receiving diuretics especially high dose diuretics, there is a risk of first dose hypotension, which may be minimised by using a low dose of enalapril, close medical supervision. Up to 30% increase in serum creatinine may occur on starting ACE inhibitors, which is reversible. Hyperkalemia can

occur if there is renal impairment, is on potassium containing salt substitutes. Side effects: Generally well tolerated. Cough is the most common side effect; angioedema is rare and may be potentially serious. Breast feeding: Limited information. Do not use enalapril for the first few weeks of life, especially in the case of preterm infants because of risk of neonatal hypotension 1170. Opie L.H, Gersh B.J, editors. Drugs for the Heart. 8th ed: Saunders; 2013. 1270. Ibid. 134

Pregnancy Class D Use in second and third trimesters confers risk of oligohydramnios, and birth malformations. Hepatic impairment: may need dose reduction, and close monitoring. Renal impairment: may need dose reduction when creatinine clearance is less than <30 ml/min (approximate serum creatinine 3 mg/dl), when dose should be 2.5 mg once a day.13 13 US FDA full prescribing information for enalapril. 135 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

Thiazide diuretics for use in hypertension with special focus on low dose hydrochlorothiazide: They act by increasing sodium excretion. Thiazide diuretics are useful agents in the therapy of hypertension as first line drugs and as add on therapy when initial therapy with calcium channel blockers, ACE inhibitors does not achieve target for BP control. Benefits on cardiovascular outcomes have been proven for hydrochlorothiazide, chlorthalidone and

indapamide. They are long acting agents effective as once a day therapy. In high doses(25 mg and above) thiazides have metabolic side effects like glucose intolerance, worsening of lipids, hypokalaemia, but given in low doses (12.5 mg) they exert near maximal lowering of BP without producing biochemical changes as noted above. Thiazide like agents like chlorthalidone, indapamide are also available, which are longer acting than

hydrochlorothiazide, and have beneficial outcomes on cardiovascular mortality documented in clinical trials. Indications for thiazides: Hypertension, Heart failure Dose, titration, and use in combinations in hypertension Dose in hypertension: 12. 5 mg once daily. Increasing the dose to 25 mg daily may not increase antihypertensive effect but can increase risk of hyperglycemia. Low dose hydrochlorothiazide can be used in combination with calcium channel blockers,

and ACE inhibitors for treatment of hypertension. The combination of thiazide diuretics with beta-blockers is not preferred as it increases the risk of new onset diabetes as well has an adverse effect on lipids. Contraindications: severe hypokalemia, hyponatremia, hypercalcemia. Cautions Thiazides can worsen glycemiccontrol and gout. Side effects: Gastro-intestinal disturbances, orthostatic hypotension, altered plasma lipid concentration, metabolic and electrolyte disturbances (including hypokalaemia,

hyponatraemia, hypomagnesaemia, hypercalcaemia, hyperglycaemia). Occasional thrombocytopenia, impotence. Pregnancy: Not used to treat hypertension in pregnancy. Administration in third trimester carries risk of neonatal thrombocytopenia. Hepatic impairment: Avoid in severe liver disease; hypokalemia may precipitate hepatic encephalopathy Renal impairment: Avoid if creatinine clearance is less than <30 ml/min (approximate serum creatinine 3 mg/dl), when they may be ineffective. 136

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meta-analysis of yoga for hypertension. Am J Hypertens. 2014 Sep;27(9):1146-51. 92. Liu F, Qiu M, Zhai SD. Tolerability and effectiveness of (S)-amlodipine compared with racemic amlodipine in hypertension: a systematic review and meta-analysis. Curr Ther Res Clin Exp. 2010 Feb;71(1):1-29. 142 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

ANNEXURE 5: PATIENT INFORMATION LEAFLET HYPERTENSION OR HIGH BLOOD PRESSURE (BP)- patient information leaflet Why is high blood pressure called a silent killer? In the past most illnesses made us feel unwell. We know we are ill because we get symptoms like diarrhoea or fever or cough. We see the doctor to get help. But when we have high blood pressure there are no symptoms for many years. It’s like a silent killer who comes quietly behind you and stabs you. High

BP slowly damages the important blood vessels in our body without us knowing it. Later wecan become suddenly very sick. Only then we know we had hypertension but it may be too late to treat it by then. What is hypertension? The pressure of air in a bus tyre must not be too high or too low. If it is too high it may burst without warning. If the pressure of water in a hose is too high it may suddenly burst. In the same way our blood flows to different parts of the body in blood vessels. If the pressure

in the blood vessels is too high the blood vessels will become damaged over time. We do not always know why some people get high blood pressure. In a few people there are reasons like kidney disease and alcohol overuse. If hypertension causes no symptoms of disease at the start, how can we find hypertension early? The only way to check blood pressure is through blood pressure machines. What is the normal blood pressure? Our heart is a pump that first fills

with blood and then pumps it to the blood vessels. It then fills again and then pumps again. So blood pressure readings have 2 numbers. The first number or systolic BP is when the heart is pumping blood. The second number or diastolic BP is when it is filling. The normal blood pressure is 130 systolic and 80 diastolic and we write that as 130/80. Readings lower than 130/80 can be normal. However the blood pressure of every person

can vary from time to time. When we are exercising or worried it can increase. When we are resting it can be lower. So your blood pressure may need to be repeated s few times when you are resting if it was found to be high. Anyone who keeps having readings over 140/90 has high blood pressure. What are the effects of high blood pressure on the body? If untreated high blood pressure damages the blood vessels to different parts of the body causing • Strokes- we get sudden paralysis or numbness of one

side of the body or speech which may not get better • Heart attacks- sudden blockage of blood vessel in the heart can cause severe chest pain and sudden death • Kidney failure • Damage to vision and many other problems • Sadly these problems may happen very suddenly without warning. 143 Screening, Diagnosis, Assessment, and Management of Primary Hypertension- Full Document

When should I have my blood pressure checked? You should check your blood pressure even if you feel well because in the early stages it causes no symptoms. All those over 18 years should have the blood pressure checked every 2 years. If you are overweight, have diabetes, do little exercise, smoke, drink alcohol, or have family members with high blood pressure you should have it checked once a year. Your health centre nurse or health worker can check your BP. You do not need to see a doctor to check BP.

If I have high blood pressure what can I do to help it myself? There are several things you can do • Stop smoking: smoking markedly increases the damage caused by high blood pressure. • If you already do not do hard work, do some exercise you enjoy doing that makes you a little short of breath for at least 30 minutes each day. • If you are overweight reducing your weight by even 5 kg over 6 months can lower blood pressure. • If you work hard and sweat a lot just avoid salty food. Otherwise reduce the

salt you add in cooking by half. • Avoid fatty food like oils or oily fried food, fatty meat (take off the fat before you cook goat or take the skin off chicken). Eat more vegetables and fish. • Do not take excessive alcohol. • Don’t drink more than 2 glasses of coffee each day. Do I need to take tablets? How long will I need to take these tablets? People with high blood pressure of 160/100 or higher and those for whom changing lifestyle does not work need

tablets to lower blood pressure. Disease like pneumonia, typhoid can be cured by taking tablets for only a limited time. But blood pressure tablets do not cure the disease but control it only as long as you take them. It’s like dying your hair which has turned grey as you get older. It will become black only as long as you keep dying it black! You must keep taking the tablets regularly and not stop them without asking your doctor. Most tablets can be taken once a day either in the morning or night. It

should become a routine like brushing your teeth. Make sure you get more tablets before your last lot run out. Remember that treating high BP will be one of the best things you can do to protect your health in the future. Treatment of hypertension may not help always make you feel better straight away. Will the tablets cause harm? Blood pressure tablets are usually very safe. If you do get side effects there are many different medications to choose from and the doctor will find one that suits you. The

doctor may ask you take other medicines like aspirin and some tablets to lower your blood cholesterol which is a chemical in blood that can worsen the effects of high blood pressure. How often do I need to see the doctor? Till your blood pressure is controlled the doctor may see you once a month. Once the blood pressure is controlled you only need to see the doctor once in 6 months. Continue your medications and you can see the doctor at any time if you

have any worries over your treatment. Remember- take your medications regularly. TOGETHER WE CAN STOP THE SILENT KILLER AND PREVENT UNNECESSARY SUDDEN DEATHS AND DISABILITY. 144

National Programme for Prevention and Management of Burn Injuries (NPPMBI) Courtesy: Bihar Burn & Trauma research centre Directorate General of Health Services Ministry of Health and Family Welfare Government of India BURNS PREVENTION IS THE ONLY WAY TO REDUCE INCIDENCE OF BURNS.

Index S No Topic Page No 1. Skin & its properties 1-2 2. Burns-causes & modes of injury 3-4 3. Chemical Burns (With special reference to Acid attack) 5-7 4. First Aid and Transportation 8-9 5. Burns –Extent & Severity 10-16 6. Pathophysiology of Burn Shock 17-21 7. Local Wound Management 22-25 8. Infection Control in Burn Patients 26-27 9. Burns of Special Sites 28-29 10. Burns of Special Types 30-32 11. Nutrition in Burns 33-34 12. Prevention of Deformities and Contractures 35-36

13. Management of Burn Deformities 37-38 14. Ten Commandments of Burns Management 39 15. A brief Practical Guide to Management of Burn Patient 40-42 16. Suggested Books for further reading 43 17. Appendix 44-48 a. Blood Hematology - Normal Values b. Blood Serum Chemistry - Normal Values c. Nutritive value of common food items Fruits

1. SKIN & ITS PROPERTIES UNDERSTANDNG SKIN AND ITS RELATIONSHIP WITH BURN WOUND HEALING Skin is a composite structure and the largest organ of human body with multifocal activities. Functions of skin are: • Physical barrier & infection control • Sensation • Water & electrolyte balance • Temperature regulation The skin consists of two layers with different properties. The covering layer/epidermis is the layer which finally completes wound healing. The deeper layer is called the dermis, which is the

layer providing strength and stability to the skin. Also this layer contains the pilosebaceous elements. Figure-1 Anatomy of skin & its layers Epidermis: Epidermis is ectodermal by origin and has the capability of complete regeneration and forms the replica of original. Therefore burn which is confined to the epidermis will heal without any tell- tale story in the form of scar. The basal layer of epidermis encroaches onto the dermis and is seen as papillary structures.

These encroachments are often described as dermal elements though in true sense these are epidermal elements. This portion of dermis is described as papillary dermis. Because of the Page 1 of 48

presence of these epidermal structures this portion of the dermis shows the property of regeneration in combination with repair. Dermis: Dermis which is devoid of these dermal elements is described as reticular which has no property of regeneration and will always require a reparative process. Burns involving up to this layer heal mostly by reparative process and may develop hypertrophic scars. The proportion of papillary dermis and reticular dermis markedly vary in different parts of the

body. For sake of simplification we can say that the amount of papillary dermis is higher on the flexor aspects of the body and amount of reticular dermis is more in proportion on extensor surfaces of the body. However, this is not universal. Face has a rich layer of papillary dermis with comparatively very small layer of reticular dermis; therefore, most burns of the face heal spontaneously. Because of the limited amount of the epithelial tissue in the deeper layer and because of the

limited reticular layer these wounds quickly contract and lead to marked deformation of the facial structure. This is justifiably seen in the formation and development of ectropion in the upper and lower eyelids, webbing around the medial canthus, contraction of nasolabial fold, shortening and contractures of the upper and lower lip with circumoral contraction. Similarly, limitations of reticular dermis which is basically a storing protective layer leads to quick

development of contractures of neck on the flexor aspect. Availability of thick layer of reticular dermis in the back and buttock region is responsible for practically no contracture in the region of back, buttocks and nape of the neck. SUMMARY FOR NURSES & PARAMEDICS • Skin is an essential organ of our body & performs many vital functions. • Skin is composed of epidermis & Dermis. • Burns confined to epidermis & superficial part of dermis heal well with no or minimal scarring.

• Burns involving deep dermis heal with hypertrophy and contractures. • With burns, all vital functions of skin are lost. • Facial burns almost always heal well due to presence of high proportion of papillary dermis. They should be protected from sunlight. • Reticular layer of dermis protects against formation of contractures; thin layer over face, eyelid & neck is responsible for development of contractures & thick layer over buttocks & back protects against developing same. Page 2 of 48

2. BURNS - CAUSES & MODES OF INJURY The various modes for sustaining burns are: • Flames • Scalds • Chemical • Electrical Flame burns Mostly accidental, they are frequently due to leaking gas pipe or cylinder and sometimes due to use of kerosene pressure stove. The correct method of lighting the stove is to first sprinkle some spirit over the burner & them pump kerosene vapors below after igniting ; but due to shortage of

spirit ,people over-pump kerosene vapor which gets sprayed on the face, clothes & nearby inflammables which compounds the burn injury. Cooking at floor level along with overcrowding & playing of toddlers in the vicinity are the risk factors for burn injury among children. Lighting of crackers during “Diwali” carelessly or as a part of competition among children often leads to mishaps. Lack of adult supervision associated with adornment of synthetic clothing adds to the problem.

Similar conditions are seen in a ‘pandal’ fire where use of tents in constrained areas during weddings/functions etc. along with improper makeshift kitchens and improper lighting may lead to fire breakout. Scalds Scald is the most common cause of burns in children. Scalds are often due to negligence by the caregiver when a small child ventures near a vessel containing hot liquid and spills it on himself or herself. Storing of hot water in bathrooms where toddler may accidently slip into the bucket is

also a risk factor. Overcrowding with too many children playing in the same room where mother is cooking on the floor is the most common history elicited when children burns occur. Chemical burns They are often seen as accidental burns due to spillage of strong sulfuric acid or nitric acid which are majorly used as toilet cleaning agents and available in every household. They are often very devastating injuries claiming vision, appearance or sometimes even the life of the victim. They

are also seen as suicidal or homicidal burns when used in order to threaten, demoralize or seek revenge from someone. Page 3 of 48

Electrical burns Almost always accidental, they are most commonly seen in overcrowded localities with illegal electrical wiring, defective electrical sockets and other contributing factors. They are also seen in sub-urban areas as a part of ‘stealing’ electricity by throwing a live wire onto a high tension electric cable. People travelling on train tops have also sustained electrical injury. Apart from this, ignorant

unsupervised children playing at home are often victims of electric burns due to exposed “live” wires or short circuits. SUMMARY FOR NURSES & PARAMEDICS • Flame burns are most common cause of burns. All activities involving fire, including cooking should be carried out with utmost care & presence of mind. • Overcrowding should be avoided; toddlers should be kept away from cooking area. • Faulty cooking gadgets & illegal cylinders should not be used.

• Hot water should never be stored in buckets, should be used only when required. • Electric circuits at home should be carefully insulated and kept out of reach of small children. • In the event of gathering or function, tents should be well planned so that cooking area is away from the crowd specially children. • Chemicals used for cleaning should be labeled well, kept in closed cupboards and taken out only under supervision. Page 4 of 48

3. CHEMICAL BURN (With special reference to Acid attack) Chemical burn is caused by corrosive substances such as acids and alkalis. These chemicals are known to cause significant tissue damage when they come in contact with skin surface. A pH of 7 is neutral. Acids are lower in pH and alkalis are higher in pH. Litmus paper can be used to confirm the type of chemical. Chemicals causing burn: 1. Acids- Accidental or due to violence 2. Toilet cleaner 3. Sulphuric acid 4. Hydrochloric acid

5. Chemicals in the industries- a. Chemical industries b. Mining industries c. Fabrication industries d. Medical manufacturing units e. Cotton industries Pathophysiology: • Most of the acids produce coagulation necrosis by denaturing proteins. It forms coagulum or eschar. This coagulum is thick leathery layer of dead skin. • Alkalis though look mild, but produce more severe injury. They cause liquefaction of the tissue. This involves denaturation of proteins and saporification of fat. The effect of alkali

remains ongoing and cause increasing depth of damage. Depth and severity of burn depend upon: 1. PH of the chemical 2. Concentration of the agent 3. Duration of the contact with the agent 4. Volume of the agent used 5. Physical form of the chemical agent 6. Involvement of the organ. Mode of Injury: The effect of the chemicals depend upon the mode of chemical injury. The vitriolage or acid violence is deliberate throwing of acid on someone causing burn over face and upper part of the Page 5 of 48

body. This is aimed at maiming or disfigure the women and children. Often the eyes are affected because of the direct contact of acid to the cornea and eye ball. The chemical injuries caused in the industries affect hands and lower part of the body. The chemicals in the industries may have irritant fumes, which cause respiratory burn. Ingestion of chemicals may cause burn of oral cavity, pharynx and oesophagus. Clinical features or effects of corrosives:

The chemical burn is characterised by discoloration of skin with clear line of demarcation. It is brown or black with sulphuric acid and yellow with nitric acid. The trickle marks are the special features. There is absence of blisters. The chemical substance may be present over the surface and the clothings. The acid burn victim suffers from severe pain and burning. In case of acid attack, the corrosives may enter in the eyes and cause corneal damage. This causes severe pain in the affected eye.

Prehospital approach to chemical burn: S.A.F.E. approach is recommended- S – Shout for help A – Assess the scene quickly F – Free from danger of violence E – Evaluate the casualty Initial management of chemical burn: • Removal of smeared clothes • Removal of metallic ornaments in and around acid burn area. • Manual removal of solid chemicals with no touch technique • Removal or capping of source of chemical • Irrigation with copious plain water for 15 – 20 minutes

• Do not try to neutralize the chemical as it may cause exothermic reaction and more damage. • The rescuer must be careful not to cause harm himself/herself. • The water should not spill over rest of the normal body parts especially eyes, nose, mouth and ears. • Many chemical may cause inhalation injury due to toxic chemical vapours. The source of chemical should be capped or removed from the scene. All chemical burn victims should be rushed to the nearest specialised medical care units at the earliest.

Management in the hospital: 1. Copious washing to continue till litmus test is negative. 2. Chemical inhalation burn should be assessed and managed. 3. Treatment of burn area is management of any other burn injury. One has the choice of early surgical excision or conservative therapy. 4. Early excision is preferred for early and better recovery. 5. These burns heal with bad scars and deformities of face and neck 6. These may require secondary surgeries for correction of deformities.

7. Psychological support at every stage of management is essential part of treatment. 8. Finally rehabilitate to get back to society. Prevention: The concerted efforts of media, non-governmental organisations and administration may prevent this social evil of acid attack. The efforts of NGOs has resulted in reduction in the incidence in Bangladesh. They have been able to force many legislative reforms over past few years. The

restricted availability of acid and chemicals for general public is one of the effective steps in prevention. Page 7 of 48

4. FIRST AID & TRANSPORTATION On site care: A burn is because of flame and fire; more the contact with fire more is the extent and depth of burn. First & foremost priority is to safely extinguish the fire expeditiously. Pouring plain water on fire is the easiest way to douse the flame; however when the burns is due to electricity sand is a better option than water. If water is not available, victim should drop and roll till fire is extinguished.

In case of electrical burns, putting the main switch off as soon as a person has come in contact with an electrical circuit. Futhermore, any attempt to manually separate the victim from electrical source may result in electric burns to the rescuer too; therefore a wooden scale or rod should be used to push the victim away from electricity. In case of chemical burns, washing the area with copious amounts of ordinary running water for

at least half to one hour; reduces the effect of chemical by simple dilution and at the same time removes it from the body. First aid: Once the patients is away from fire, cooling with running plain water for a short period may help but attempt should be made to quickly transport the patient to the hospital. During the process one must see that the patient’s airway is maintained. Patients who have sustained burn injuries in

a closed chamber may develop carbon monoxide poisoning and may require quick cleaning of the throat and putting oxygen mask during transportation. Sometimes in case of electrical injuries, patient may have respiratory/cardiac arrest for which cardiac massage; mouth to mouth breathing/Ambu bag must be used during transportation. Electrical burns respond well to these measures. Transportation: Transportation of burn victims should be done as quickly as possible, so that

the “golden period” of resuscitation is not wasted. At the site of injury all attempts should be made to maintain the airway so that the patient is transported safely. At the same time all fractures and probable spinal injuries should be adequately fixed by appropriate collar or neck splintage. An injured limb should be properly splinted so that no further damage is done during transportation. During transportation a burnt patient, especially infants and children should be

kept well covered to avoid excessive heat loss and resulting hypothermia. Page 8 of 48

SUMMARY FOR NURSES & PARAMEDICS • Always take the victim away from site of burns. • Rescuer should take care of his/ her own safety. • Electrical injury patients require close monitoring for cardiac arrhythmias. • Ensure A-Airway-Breathing & C-Circulation before transportation to higher center. • Always rule out head injury, cervical spinal injury, other limb injury before transporation; if any of these is present, shift with adequate precaution in the form of cervical brace, limb splint etc.

• In case of chemical burns, wash the wound with copious saline. Page 9 of 48

5. BURNS-EXTENT & SEVERITY UNDERSTANDING ESTIMATION EXTENT & SEVERITY OF BURNS Burns is a three dimensional injury. Severity of burns depends upon quantum of tissue burnt and depth. Whole body surface area is taken as 100%. Proportion of surface burn is represented as %age. Estimation of surface area There are many ways to estimate surface area burned. None of these are 100% accurate. Rule of Nine which was popularized by A.F. Wallace of Edinburgh remains the most popular method of

describing the surface area burn. In this, body is divided into 11 equal parts making this 99% and 1% is given to perineum. (Figure 2) Figure-1 ‘Rule of Nine’ for estimation of TBSA burned In new borns and children, because of the larger size of head and small body surface area of limbs, the Rule of Nine is not applicable. Lund and Browder chart simplifies the calculation of total body surface area burn in children. This takes into account the variation in the body surface

area of different parts of the body in different age group. Also, it is common to see patchy burns making calculations a difficult proposition. For this, more elaborate chart was proposed by Lund and Browder which also takes in consideration the patient’s age for calculation of surface area of burns involved. This appears to be the most Page 10 of 48

accurate method so far available but it requires availability of well written charts and is difficult to remember. (Figure 3) Figure-2 Lund & Browder chart One closed hand of an individual is equal to his 1% body surface area. This hand must be of the person concerned who sustains burns. A hand consists of all the fingers and thumb brought together in extended position, which include palm and all the fingers. This is applicable

universally in every age group. This is popularly known as the ‘Rule of Palm’. (Figure 4) Page 11 of 48

Figure-3 Rule of Palm (1%) UNDERSTANDING THE DEPTH OF BURN First degree burn is epidermal burn alone which normally present as erythema/redness only. Typical example is sunburn. Burns due to any other cause is rarely a true first degree burn. They are very painful. There is no blister formation. It resolves in 3-5 days without scarring. Second degree burn involves epidermis and a portion of dermis but not the complete dermis. This is further divided into superficial or deep.

Second degree superficial is associated with involvement of epidermis & papillary dermis. It is characterized by severe pain, hyperaesthesia and blister formation. It heals in 10-20 days with minimal scarring. Second degree deep or deep dermal burn involves epidermis, papillary dermis & a part of reticular dermis. Wound is waxy white, soft & elastic. It heals in 3-5 weeks and usually causes hypertrophic scar. They are in danger of getting converted to full thickness due to infection or drying.

Third degree burn is also known as full thickness burn which involves the full thickness of skin, whole epidermis and dermis. It appears as tough, dry, inelastic, translucent & parchment like eschar. Page 12 of 48

Figure 4 – Histological presentation of Depth of burn Any involvement beyond dermis is normally included in full thickness burns but is sometimes described as fourth degree burn. This involves subcutaneous tissues as well. Various depths of burn are well illustrated in figure 5. As we climb up the ladder from 1st degree to 4th degree, pain is remarkably decreasing as with more depth more nerve endings are destroyed.

For the sake of convenience and practical utility burns are classified into two broad types: 1. Burns which heal on their own and do not require surgeon’s knife, called as partial thickness burns. 2. Burns which do not heal on their own and require a surgeon’s help are known as full thickness burns. Partial thickness burns depending upon the amount of dermis involved are called superficial dermal /superficial partial thickness burns or deep dermal / deep partial thickness burns. Diagnosing the depth

Diagnosing different type of burns may not be easy. History: History regarding cause of burns helps in diagnosing to some extent as in flame burns contact of fire is for a longer period of time; it’s likely to lead to full thickness burns. Scalds from hot water spilling may be a superficial burn while a scald from falling into a hot water tub is likely to be deep because of prolonged contact. A scald from ghee, oil or any fat may

likely to be deep because of high latent heat and viscosity of these substances. Page 13 of 48

Similarly chemical & electrical burns are almost always deep as compared to thermal burns of same extent; requiring intensive monitoring of vital parameters & more aggressive wound management. Second history related fact is the age of the patient. At extremes of age (i.e. infants and older people), burns are likely to be deep because of thinness of skin – atrophy of dermis and epidermis in old age and lesser formation of dermis and epidermis in children. Examination: Table 1: Physical appearance of Burns

Superficial Deep Appearance Pink, soft White, yellow or brown Blanches on pressure Yes Fixed red or salt & pepper appearance Hair follicles Firmly fixed, provide Pulled easily resistance to pull Pain Hyperalgesia to needle touch Analgesia to needle touch. Visible thrombosed capillaries, venules, or other blood vessels are sure sign of full thickness burn. Normally there is no difficulty in recognizing superficial partial thickness and full thickness

burns but there is a lot of overlap in understanding deep partial thickness and full thickness burns. Superficial partial thickness burns heal by the process of epidermal regeneration with minimum or reparative process. Thus, there is minimal or no scarring in these burns. Deep partial thickness burns heal by reparative process with minimal amount of regenerative process involved. These burns heal with excessive fibrosis and result in hypertrophic scarring.

Surgical importance of identification of depth of burns: Early estimation of depth of burns allows surgical intervention to be taken up at an appropriate time which ultimately reduces morbidity and mortality. Invariably, these partial thickness burns are treated with surgery. These burns are tangentially excised till the bleeding point or up to the viable reticular dermis; and the resulting raw area is skin grafted. In full thickness burns, the entire area is excised either up to the subcutaneous plane or

sometimes up to deep fascia and the resulting raw area is skin grafted. In this way, treatment modality of deep partial thickness and full thickness burns may appear to be similar. Page 14 of 48

JUDGING THE SEVERITY Every burn patient looks normal and well oriented on arrival so much so that one may get confused and think of it as a simple injury. Any burn above 5% should be taken seriously. All the burns above 10% in infants and children and all burns above 15% in adults are considered major burns and need hospitalization and fluid resuscitation. For the sake of convenience burns can be classified as: Table 2: Burns classification based on severity Children Adult

Partial Full thickness Partial thickness Full thickness Thickness Minor <10% TBSA --- <15%TBSA <2%TBSA Moderate 10-15% 1-3%TBSA 15-25%TBSA 2-10%TBSA TBSA Critical >15%TBSA >3%TBSA >25%TBSA >10%TBSA Minor burns (to be treated on out-patient basis) • Burns less than 15% in adults and 10% in children (excluding chemical, electrical burns and burns of face, hands and perineum). Moderate burns • Require hospitalization for resuscitation and/or excisional therapy. • Burns between 15-25% in adults.

• Full thickness burns between 3-10% in adults and 1-3% in children. Critical burns • Burns above 25% in adults, 15% in children and 5% in newborn and infants. • Full thickness burns above 15% in adults and any extent in children. • Electrical burns • Chemical burns. • Respiratory burns. • Burns associated with other injuries. o Orthopaedic injury. o Chest injury. o Abdominal injury o Head injury. Escharotomy: In hospital, close watch should be kept for tight eschar bands on the chest and neck which

increases the resistance of lungs. Escharotomy on the neck and chest should be done in all these cases removing any constriction & allowing lungs to expand. Page 15 of 48

Similarly tight eschar around limbs should be seen & compartment syndrome anticipated. Escharotomy on the limbs should be done either in central plane or mid-axial line. All these procedures should be undertaken in O.T in complete sterile conditions and after ensuring a patent i.v. line with adequate prior resuscitation. Inhalational Injury: History of burn in closed space points towards risk of inhalational injury. Patient’s respiratory

status should also be assessed. Excessive oral secretions, pale/angry looking mucosa, singeing of nostril hairs and soot particles in oro-pharynx denote respiratory involvement. If it is associated with wheezing and brochospasm one must not hesitate to intubate these patients and give a bronchial lavage, if necessary. These patients should be put on positive pressure ventilation with PEEP if one finds signs of lung edema. If that is not available, patient should be put on T-piece

and humidified oxygen. When intubation is not possible due to any reason one should perform tracheotomy. SUMMARY FOR NURSE & PARAMEDIC • Burn is a 3 dimensional injury, assessed as Total Body Surface Area burns (TBSA). • Rule of Nine is used for calculating the extent. • Rule of Nine is not applicable in newborns, infants and children, where Lund & Browder chart is applicable. • First degree burn is epidermal burn only – doesn’t require treatment, heals with no scarring.

• 2nd degree burn: 2nd degree superficial burn heals in less than 2 weeks is painful. • 2nd degree deep dermal heals in 3 weeks & have less pain. • 3rd degree burn or full thickness burn doesn’t heal by itself. It requires skin replacement. • 2nd degree deep dermal and 3rd degree burns are relatively painless. • Thrombosed capillaries and blood vessels are signs of full thickness burns. • All moderate and major burns require hospitalization and critical care.

• Escharotomy should be considered as a limb salvage procedure only after adequate resuscitation has been done. Page 16 of 48

6. PATHOPHYSIOLOGY OF BURN SHOCK A burn injury not only destroys the cutaneous barrier protecting the patient from a hostile environment, but it also leads to profound changes in almost all other organ systems. The deleterious effects of burn injury on the organ systems are proportional to the extent of burns. Mechanism of thermal injury: • Agent: Temperature & duration of exposure of the burning agent. There is an inverse relationship between these two parameters i.e.as temperature rises, a progressively

shorter duration of exposure is required to inflict the same injury & vice versa. • Host: Physical property of skin in the form of its thickness, water content, pigmentation, presence of hair, oil, dirt all influence severity of injury. • Environment: Temperature and humidity also determine the severity of burn injury. Page 17 of 48

Figure-6 Pathophysiology of Burns Burns Increase capillary permeability Increased evaporative Loss of water Loss of plasma from intravascular compartment Haemoconcentration Burn hypovolemia Body compensatory mechanisms Vasoconstriction all over the body Splanchnic constriction Compensation su ccessful Circulation mainta ined Compensation fails, Circulation not maintained Urine output drops, Urine outpu t remains normal To be corrected No. i.v. fluids Fluid therapy Resuscitation, i.v Circulation maintained,

Systemic manifestation of burn/body response to thermal injury Burn Shock--Burns is a mechanism of heat transfer from high source to a low source. In non animated object it goes in a predictable manner with more energy transfer from source at higher temperature to source at lower temperature. However, this response is not so linear in living creature and humans; being modulated by different body responses through many different chemical mediators.

In addition to gross changes seen at local site of burns there are marked circulatory changes in the form of increased capillary permeability. This increased capillary permeability in major burns is not confined to the site of burns alone but to the whole body. Exact cause of this increased capillary permeability is not clearly understood. At times it is so great that colloidal substance of molecular weight as great as 15,000 daltons are ready to escape out from capillaries

to the extra vascular space. This is seen maximum in the first 12 hours and then slowly phases out but still remains high up to 24-36 hours. This increased capillary permeability creates a situation of hypovolemic shock which is seen in the form of: • Increased pulse rate (Tachycardia) • Dryness of mouth and skin (Dehydration) • Cold clammy extremities (Hypothermia) • Fall of blood pressure (Hypotension) • Decreased urine output(Oliguria)

Initially body tries to compensate this by generalized vasoconstriction and constriction of splanchnic circulation to maintain cardiac output. However, soon this compensatory mechanism fails if no attempt is made to correct the fluid loss. Further, loss of covering envelope of the body increases the evaporative losses which may be as much as 20 times that of normal. Correction of this shock stage is essential and should be done as soon as possible. Main thrust

remains to maintain intra vascular compartment, so that cardiac output can be brought to normal. Initially it was thought that the patient loses plasma too, therefore patient should be infused with plasma along with primary resuscitation fluid. Britishers persisted with this theory and their main thrust of resuscitation remained plasma replacement. The Americans reasoned that because of increased capillary permeability in the first 24 hrs, whatever is given is likely to come out into

the extra vascular space; therefore one must maintain intravascular compartment with crystalloid solution only. Page 19 of 48

Though the controversy of colloid and crystalloid is not fully resolved, it appears that ease of availability of crystalloid world over has made the use of crystalloid as a primary resuscitation fluid. Some of the important fluid resuscitation system along with fluid is given below- Table-3 Parkland fluid resuscitation formula Duration Formula Colloid Crystalloid Maintenance First 24 hours 4ML/KG/%BSA NIL RINGER NIL from time of LACTATE burn Second 24 2ML/KG/%BSA NIL RINGER NIL hours LACTATE

• Fluid therapy is monitored by maintaining hourly urine output. If Ringer lactate is not available, Normal saline may also be used for resuscitation. The role of soda bicarbonate is also reported in cases where metabolic acidosis occurs. Although Parkland formula is widely accepted, it has been associated with “fluid creep”; which is accumulation of fluid in the extracellular & third space. Therefore, Parkland formula is modified in many burn

centers in many ways for initial resuscitation. Thereafter, fluid requirement is titrated according to hourly urine output. Best & least invasive method to see adequate perfusion is urine output. A urine output of 0.5ml- 1ml/kg/hr denotes adequate perfusion. Thus, for an average person of 70kg, a urine output of 35ml/hour is regarded as adequate. For children, urine output of 1-2 (1.5)ml/kg/hr is considered optimal. Fluid loss is maximum in first 8 hrs, therefore half of calculated amount is infused in

first 8 hrs and rest is infused in next 16 hours. Maintaining a good IV line is the lifeline of burns resuscitation. Sometimes it may be difficult to put a peripheral line; in such cases, a long line in subclavian or external jugular vein should be introduced. A peripheral cut down which was routine done previously should be avoided as far as possible and should be performed as the last resort. Femoral lines either long or peripheral should be avoided for fear of DVT and its related complication.

All patients should be catheterized to monitor and see hourly urine output which is required for proper assessment and adequacy of fluid management. After 24 hrs the resuscitation fluid is nearly half of first 24 hrs. It is recommended that before stopping resuscitative measure patient should start taking sufficient amount of fluids orally. This should be equal to the increased evaporative losses from the body plus normal daily requirements for the patient.

Initial oral fluid given should be small part of daily normal requirement and this should be slowly increased to normal daily requirement, including water loss from burn surface. Oral rehydration Solution (ORS) which is available in all hospitals for the treatment of diarrhoea, is also considered an optimum oral resuscitation fluid for burns. Its composition is as follows: Page 20 of 48

Table-4: Composition of ORS NaCl 2.6gm(0.092oz) Trisodium Citrate Dihydrate 2.9gm(0.10oz) KCl 1.5gm(0.053oz) Anhydrous Glucose 13.5gm(0.48oz) Above constituents are per Litre of Fluid. Evaporative water loss can be calculated using a complicated nomogram using body surface area based upon height and weight. SUMMARY FOR NURSES & PARAMEDICS • Following burns, there is massive Increase in capillary permeability causing rapid escape of fluid & electrolytes into extra vascular space.

• Primary treatment of burns is fluid, fluid & fluid. • No role of colloid in first 24 hours, Ringer lactate is the intravenous fluid of choice. • First & foremost importance in burns management is a secure wide bore i.v.line through which RL can be given rapidly. • Parkland formula most widely accepted for calculating burn resuscitation fluid is 4 X wt.(kg) X %TBSA burns. • Hourly urine output is the most reliable indicator of adequate resuscitation. Other

parameters are pulse rate, hydration& blood pressure. • Half of fluid calculated for first 24 hrs is given on 2nd day which may be supplemented with colloids. • Fluid to be given parenterally till patient starts taking orally adequately. • Oral fluids should be encouraged after initial resuscitation. • ORS is a good fluid for oral supplementation. Page 21 of 48

7. LOCAL WOUND MANAGEMENT All burn areas are cleaned and loose dead skin is removed. Blisters are de-roofed, collected plasma removed and an appropriate dressing is applied. Biological dressing is preferred dressing material if available. Collagen is cheap and good skin substitute for partial thickness burns. If this is not available then a non-adhesive dressing in the form of paraffin gauze impregnated with

1% SSD, colloidal silver, ionic silver cream or silver nitrate cream is applied. Dressing is further supported with absorbent cotton pads (Gamgee). Dressing needs to be changed at regular intervals. Early change of dressing is advised if: • Dressing becomes wet, smelly • Becomes contaminated with urine or stool • Patient shows any signs of infection like fever, vomiting, altered sensorium, distension of abdomen, decreased urine output-signs generally belong to septicemia or SIRS.

• Pain not explained by extent of burns. These dressings should be opened and wound inspected to see for any local signs of wound infection. Burn wound is a potential source of infection. Sepsis remains the main cause of mortality in burns. Routine prophylactic use of systemic antibiotics have been found to lead to development of resistant strains of bacteria and in long term failed to provide any reduction in sepsis related

complication of burns. Use of topical antiseptic material reduces local growth of bacteria and reduces systemic septic complications. Tetanus prophylaxis should be given as a rule in all burn patients. Late in 60s, Fox made a compound which uses both silver nitrate and sulfonamide compound that is Silver sulfadiazine. This compound is stable; least absorbed systemically and does not lead to any systemic complications. Today, all over the world this is the most common topical

agent used for burn wound dressings. Silver sulfadiazine (SSD) cream stood the test of time because of its broad spectrum range, ease of application, no side effects and extremely low systemic absorption properties. But of late, bacterial resistance to SSD has emerged. Since superficial burns have shown satisfactory outcome even with other topical antibiotics, like Framycetin (Soframycin) & Neosporin, the use of SSD has to be judicious. It should be selectively used for deep dermal, full

thickness, infected & old neglected burns. BIOLOGICAL DRESSINGS – These are the materials derived from human or animal tissues. • For partial thickness or deep partial thickness burns: Page 22 of 48

o Collagen dressings are available in dry and wet forms. Collagen is good skin substitute especially in partial thickness burns and should be a dressing of choice. o Amniotic membrane has been found to be very useful in our country however, because of fear of diseases caused by transmission of body fluids including HIV and AIDS these should be applied only when serological screening has confirmed negative report. o In current scenario when all pregnant women are often subjected to serum

marker testing beforehand, use of amniotic membrane is found to be safe & acceptable. Its use is also NOT dependent on the fact that childbirth is vaginal or via C-section. • For full thickness burns: o All above mentioned products can be applied as a temporary cover for full thickness burns after excisional therapy has been done & skin grafting cannot be done because of limited or non availability of donor site. o Best dressing is patient’s own skin graft (autograft). Therefore the role of

excisional surgery & grafting is of great consequence in deep burns. o Sometimes when donor site is inadequate; especially in children, skin graft from parent/sibling (homograft) can be taken to provide temporary cover in order to reduce the septic load & promote the onset of anabolic phase of healing. But, homograft has to be always replaced with an autograft in due course of time. Excision surgery & skin grafting in burns

• All full thickness burns require excision of dead skin. Douglas Jackson of Birmingham hospital of U.K. was probably amongst initial few people who suggested surgical intervention in burn patients. Zora Janzekovic of Yugoslavia was amongst the first who suggested the concept of tangential excision of burns which was initially implemented for deep dermal burns. Gradually, same theory was extended for full thickness burn also and it was called as sequential excision.

• In case where burns are limited in size and site, these excision give an excellent result. Excision of localized full thickness burn up-to a living plane of subcutaneous tissue or deep fascia gives excellent result. As these areas are grafted quickly and wound closure is done fast, the patient recovery is quick. • However these surgical procedures should not be taken as lightly in case of extensive burns. Excision of these cases should be done by expert only and should be done after

complete resuscitation probably after 4th day of burn trauma. Sufficient blood must be available before embarking on the surgery. For each 5% burn excision at least 1 unit of blood should be ready. Normally one should not attempt to excise more than 10% area at a time. Though extensive excision today are performed by experts where facilities are Page 23 of 48

excellent with cover by medical and anesthetic teams. In all cases the complete picture of bacterial colonization of wound should be assessed preoperatively and proper antibiotic should be given during surgery and 3 days after surgery. In full thickness burns it is better to perform direct excisional surgery rather than going for sequential surgery which may cause more blood loss. • Blood loss in these patients must be quickly corrected because these patients have poor reserve.

• Raw area created must be covered with autograft. The autografts can be expanded by using different type of meshers, normally one should opt for expansion of 1:2 or 1:3. • Meek Micro Graft- In this technique, grafts are cut into two planes dividing it into squares of 1-2 mm in size which are expanded on an adherent synthetic expandable sheet. Meek micro graft differs from mesh graft in that it looks like a postage stamp

which expands on its lateral sides from all edges, while in case of mesh skin the central area heals by epithelialisation. • Mesh graft is more popular than meek graft. Before embarking on excisional surgery, one should examine for donor area. In case of limited area, graft can be harvested from scalp, buttock, neck and sole area. Graft taken should be thin so that the next crop can be taken from the same area. Proper splintage should be given for proper immobilization. Skin substitutes

• A variety of skin substitutes are available commercially. Different burn wounds are dressed with different synthetic bio-substitutes. These include transparent bio-adhesive presterilized sheets eg. Tegaderm or opsite. These are good materials for partial thickness burns as they control evaporative water loss to some extent. • Secondly, improvements on these synthetic materials have been made which partly incorporate and also help in formation of dermal bed. These are usually applied on full

thickness burns after excision on the resulting bed. These are Integra, Therafoam, Bio- brain, Omniderm, Trancyte etc. • These materials are extremely good for application after excision of deep dermal or full thickness burns. However, their cost is exceptionally high. Hence, it has not been used routinely in our patients. SUMMARY FOR NURSES & PARAMEDICS • All burn patients should be given tetanus prophylaxis. • Burn wound should be cleaned well. • Burn dressing is an integral part of burn management.

• Topical antibiotic creams like SSD, Soframycin, Neosporin should be used judiciously. Page 24 of 48

• Ideally burn dressings should be changed every day; sometimes earlier when they are soaked, contaminated or too tight causing pain. • Biological dressings should be reserved for superficial burns especially in small children. • Best dressing over burn wound is skin. All deep dermal wounds should be aimed for subsequent excision & grafting for definitive closure. • For full thickness burns, sequential excision & grafting should be considered.

• All excision surgeries should be well planned. Patient should be adequately resuscitated, all parameters should be normal & blood should be arranged in addition to expert surgical & anaesthesia facilities. Page 25 of 48

8. INFECTION CONTROL IN BURN PATIENTS Role of prophylactic antibiotics: All the burn wounds are sterile up to 24 hrs so there is no need for antibiotic in first 24 hrs. Prophylactic use of antibiotics normally should be avoided as it has not been found to reduce chances of infection. All the procedures like catheterization, IV Line and Ryle’s tube should be done with no-touch technique. Whenever a patient presents with Burns, his/her tetanus immunization status should be known.

When this is not available, Injection tetanus toxoid & tetanus immunoglobulin should be given for passive immunity. Hand-washing is a vital step in preventing burn infection. The caregivers should always wash hands before & after touching any Burn patient. Also the use of disposable sterile gloves before performing any intervention on the patient including dressings, cannulation etc. is always advocated. Proper Hand-washing Technique

• A drop of liquid soap from dispenser should be taken on palm & both hands should be cleaned for minimum 30-60 seconds. • Cleaning should be done over palm, dorsum, between fingers & thumb. Wrist should be cleaned as well. • After seeing each patient, medical personnel should wash his hands or use chlorhexidine scrub. Antibiotic therapy: Units where patient are treated, must have their own antibiogram and sensitivity patterns whenever antibiotics are to be started fearing invasive sepsis.

Antibiotic should cover the entire bacterial flora found on patient’s wound surface. If that is not available, antibiotics are required to cover both gram –ve and gram +ve bacterias. In some long standing cases fungal cover may also be required. It is not uncommon to see the patients kept nil orally with H blocker given intravenously. This 2 process enhances the translocation of bacteria from gut and creates a situation of invasive sepsis. Page 26 of 48

SUMMARY FOR NURSES & PARAMEDICS • Infection control is of utmost importance in burns. • All burn wounds are sterile initially therefore all aseptic precautions should be followed in order to prevent cross infection from caregivers. • Early closure of burn wounds either by serial dressings or by excision & grafting is the definitive goal of treatment. Page 27 of 48

9. BURNS OF SPECIAL SITES Some areas of body require special mention as management of burns in these areas is a different and formation of these area may completely devastate patient’s life. Burns of face Face is the most important part of the body. Facial skin has got large papillary dermis with minimum amount of reticular dermis and is rich in vascularity. This area has tendency of rapid healing with quick deformation of face. Majority of burns of face are managed by exposure

method & an expectant policy. Cheeks, lips & forehead burns may undergo hypertrophic, atrophic & depigmented scarring following burns. However if timely seen, diagnosed and splinted much of deformation can be prevented. Areas to be watched are lips and nasolabial folds, where one should not hesitate to quickly shave of these areas and provide full thickness skin graft so that contracting bands are minimized. Proper face mask with lateral pull from circumoral area markedly reduces deformity in this area.

Practical tips: Open dressing, repeated cleaning, local antibiotic ointment application, early pressure garment, chin strap, face mask application. Burns of eyelid Eyelid is an important structure which preserves the cornea and eye. If eyelid burns are full thickness in nature and these burns are a part of extensive burns to the rest of the body, one should be ready to perform tarsorraphy to preserve the cornea. Our experience shows that in case

of extensive burns of other parts of body one often forgets about this area and ends up with exposed cornea and subsequent perforation. The common post burn sequelae of the eyelids are ectropion, loss of eyelid and symblepheron; ectropion being the commonest. An eyelid ectropion can lead to exposure keratitis, corneal ulceration and ultimately loss of vision. Till skin graft can be done over raw area, cornea is protected by ointment, pad and bandage. One

should visit this area again when the patient’s condition improves. Skin graft is applied over the corrected defect. This delayed method saves both the patient and his eyes. Always overcorrection of the ectropion should be done preferably of one eyelid only. Symblepheron occurs commonly after acid burns. In such cases one should evaluate whether the eye has vision or not. These cases have variable degrees of conjunctival loss which makes reconstruction very complicated. Page 28 of 48

Ear burns External ear has a special position and particularly prone to thermal injury. Lack of subcutaneous tissue & thin overlying skin closely adherent to cartilage further worsen the damage. Ear cartilages survive by plasmatic imbibitions from either side. Burn edema separates the skin from cartilage leading to devascularization of cartilage. Some of the post burn injuries of ear are: • Ear abscess • Scarring of pinna • Adhesion of ear to scalp • Loss of helical rim

• Loss of upper or lower half of pinna • Loss of entire pinna In case of partial thickness burns, ear should be cleaned & all contours are filled up with acriflavine wool and soft adaptive firm dressing is applied. Whenever full thickness burns are present, it is excised along with dead cartilage and rest of the area is treated as a case of partial thickness burn. Whenever abscess occurs it should promptly be drained with compression dressing. Whenever

minor deformities occur, simple release & skin grafting can be done. Reconstruction of pinna is a multi-staged procedure and should be embarked upon only if surrounding skin & soft tissues are spared. Prosthetic ears can also be used in long term wherever patient is not a candidate for surgery. Many patients may be satisfied by masking the defect with a change in hairstyle. Perineal burn Perineal burns especially in children require special care. All these burns are treated by exposure

methods. Patients are put in special bars so that abducted legs and thighs do not rub against scrotum or penis and buttocks are kept apart. All areas are cleaned and satisfactory position is maintained. SSD cream is used as topical agent. Usually stool and urine do not create much problem in wound healing. These areas rarely require skin grafting. Page 29 of 48

10. BURNS OF SPECIAL TYPES Electrical burns In India incidence of electrical burns is rising at a high rate. In year 1993 electrical burns formed 3% of all admissions in burns unit. In the year 2000 it rose up to 12%. Electrical burns are of two types- a) domestic type/low tension burn and (b)from transmission cables where current is greater than 1000 volts these are called high tension electric burns. Damage from electrical current is proportional to the current flow into the human body. More the

voltage, more the current & more is the damage. Current flows through the fluid medium that is through blood vessels and muscles. Nerves are supposed to be good conductors & they get burnt out immediately from high voltage of current. On the contrary, dry skin & bone are poor conductors. The severity of proximal tissue damage decreases as distance from the contact site increases. It is commonly believed that damage from electrical current is progressive in nature and

therefore any definitive surgery is not indicated in acute stage. The contrary view is that there is no progressive damage from electrical current. The late effects seen are because of the secondary effects from already damaged structures. Early intervention in electrical burns may prevent secondary damage. Therefore all electrical burns should be thoroughly examined about their cardiac status, neurological status and limb vascularity from direct damage due to the electrical current.

Cardiac arrhythmias and tetanic muscle spasms are more readily produced by alternating current. Alternating current is the mainstay of electricity in common households. Majority of people die from muscle damage. Myoglobin released from damaged muscle is highly toxic and also a cardiac depressant. All these dead areas should be quickly excised and wherever possible, decompression should be performed by fasciotomy. Involved major vessel should be ligated proximal to the site of injury.

Development of compartment syndrome should also be recognized early. By decompression of fascia, further compression of venous system is avoided and further progress of damage is minimised. Most patients with significant electrical injury have large fluid requirements. It is very important to give enough intravenous fluid to help maintain at least 2-5 ml/kg/hr of urine output. Higher output is necessary to clear the pigment from the circulation. Page 30 of 48

If myoglobin or free hemoglobin is present in urine, the urine output should be maintained at twice the desired volume. To prevent myoglobin precipitation in renal tubules, Sodium bicarbonate infusion at 12.5gm i.v. bolus followed by 12.5gm/hr i.v. until urine is clear of pigments. Electrical burns are often associated with limb loss and amputations may also be required whenever indicated. Chemical burns Chemical burns amount to 0.3% of all burns unit admission. Acids as well as alkalis can cause

chemical burns. Acids lead to protein de-naturation of cell wall protein and this prevents further absorption reducing further risk of systemic damage. Alkalis come in contact with lipid moiety of cell wall protein leading to saponification and destruction of lysosomes with release of lysosomal enzymes causing cell damage. Therefore damage in case of alkali is perpetuating and may have late systemic effects. Worst chemical burns are homicidal in nature where acid is thrown on face of the victim. These

should be taken very seriously, eye should be washed thoroughly and tension in eyeball is reduced by giving Acetazolamide (Diamox). Thus perforation of cornea and loss of the eye is avoided. Whenever possible these burns should be primarily excised and grafted. In case of chemical burns of any nature, one should rush to shower quickly to dilute the chemical and to wash it away with a jet of water if available. No attempt should be made to neutralize by antidote, as neutralization leads to further damage

to structure from the heat generated from chemical reaction. TAR BURNS Hot coal tar burns are seen quite commonly in labourers paving the roads. Tar has thermoplastic properties and it liquefies when heated. It becomes solid when applied to skin as the temperature cools. It is difficult to remove manually and may remove underlying viable skin. Household materials like ghee and butter have been found to be useful for separating the tar from

skin. Apart from them, Neosporin ointment when applied liberally helps in dissolving tar adherent to skin. BURNS IN PREGNANCY Women in the child bearing age group (18-45 years) constitute a substantial proportion of burned patients in our country. Thermal injury sustained during pregnancy presents special management problems. Prognosis of burns in pregnancy is poor & pregnancy may terminate spontaneously prior to death of the patient. A large majority of pregnant burned patients who survive can go on

to full term delivery. Several complications encountered in the management of pregnant burned patients which are detrimental to the foetus are: • Hypotension & Hypovolemia • Hypoxia • Septicemia • Dilutional hyponatremia • Drug induced problems Pregnancy must be confirmed. Ultrasound is the most widely accepted modality to monitor fetal parameters during pregnancy. Measuring urine output is again the single most essential parameter to judge adequacy of

resuscitation. Because of the physiological anemia of pregnancy, the normal hemoglobin values are 11-12g /dl, the need for blood transfusion is also decided by taking these parameters into consideration. In first trimester of gestation, fetal death rate is high and it does not appear to be directly related to the extent of burns. Fetal survival is better in the second trimester. In the third trimester, it is the gestational age which is the important determining factor in fetal survival.

Healed burn scars on abdomen are of no consequence in a subsequent pregnancy. Abdominal enlargement in pregnancy is very gradual and the scars also stretch under the influence of maternal hormones. Breast burns: Burns of breast in childhood may cause scars which may compress, distort or displace the breast tissue. This may require surgical release & correction. Such breasts may get engorged and lead to discomfort following delivery. There is no technique which can restore lactation in such breasts.

11. Nutrition in Burns Aggressive nutritional support is recommended following burn injury. All patients with burns should start oral feeds as soon as possible after initial. Oral fluids given should be 1/4th of daily normal requirement and this should be slowly increased to normal daily requirement which should include extra water loss from burn surface. All burn patients after 24-48 hrs should start on oral hyper-alimentation. Many formulae are

available for protein and caloric requirement of the patients. Table-5 Curreri formulae for calorie & protein requirement in burns Calorie Protein Adult 20Kcal X Body wt.(kg) +70 Kcal X 1gm X body wt.(kg) + 3 gm X % TBSA burns %TBSA burns Children 60Kcal X Body wt.(kg) +35 Kcal X 3gm X body wt.(kg) + 1 gm X % TBSA burns %TBSA burns This high requirement is difficult to maintain orally, therefore in initial phase balanced diet of

high protein and high calories is given intravenously to supplement oral intake. Protein should form 25% of energy requirement of burn patients. Glucose reduces the extent of hypermetabolic response and protein breakdown. Hence carbohydrate should form major part of the diet. It is recommended to give 50% of energy requirement as carbohydrate. Adults may be given 5 mg/kg/min and children 5-7 mg/kg/min. One of the recommendation is to give very little

fat. In adults 4% and in children 2-3% of total energy requirement should be met with fat. Each unit must be able to prepare diet formula depending upon local feeding habits. These formulae should be designed in consultation with a dietician. Whenever diet is prepared, one must see the proportion of carbohydrate and protein. One should see that the proteins are properly assimilated and they are used as building blocks not as a source of energy provider.

Minimum of 100 calories are required for assimilation of 1 gm of nitrogen. Patient should be regularly weighed and patient must not be allowed to lose weight for more than 5%. If patient loses 20% of its original weight, the outcome of such patient is unfavourable. Attention should be given to timely measurement of serum albumin and electrolytes. These parameters should be kept to near normal level. Burns patients tend to develop low immunity

both humoral and cellular, therefore immuno-modulators are given to these patients. A good protein diet containing Glutamine, Arginine and other micronutrients like vitamins, iron, Page 33 of 48

calcium, zinc, selenium, copper & intravenous immunoglobulins especially IgG & IgM given to burn patients has shown to improve their survival. Early we are able to close burn wounds, the rapid is the recovery of immune and other systemic problems. SUMMARY FOR NURSES & PARAMEDICS • Apart from IV fluids, oral resuscitation should be started in form of early enteral feeds wherever permissible, to prevent endotoxemia. • Patients taking orally should be provided with adequate calories & proteins as per their

increased requirements due to burns. • Feeding regime should be individualized for the patient. Page 34 of 48

12. PREVENTION OF DEFORMITIES & CONTRACTURES Following are the causes of post burn deformities and contractures: 1. Loss of organ or tissue due to very deep burn. 2. Loss of special organs like nose, ear, eye, eyelids, hands, feet, external genitalia etc. 3. Limbs are amputated due to vascular compromise, more common in electrical burn. 4. Delay in resurfacing of the raw area. 5. Use of very thin split skin graft. 6. Lack of use of Postoperative pressure garment and appropriate splints.

7. Recurrent ulceration in the area of burn. 8. Lack of physiotherapy and occupational therapy. 9. Involvement of the muscles, tendons and joints. Prevention of deformities and contracture is an integral part of burn management. All burn patients receive active physiotherapy of all major joints and these joints should be kept in optimum positioning of function i.e. neck should be placed in slight extension without lateral

rotation and in alignment with the thorax; axilla should be kept at 90 degree abduction, shoulder in 10 degree flexion and neutral rotation; elbow should be kept in extension and mid prone position, wrist at dorsiflexion, MCP AT 90 degree flexion, IP joint at neutral and thumb at abducted extended and opposed position. The moment all areas are healed, they should be lubricated and proper physiotherapy and splintage given to avoid contracture formation. Compression garment and silicone gel sheet are

provided to avoid scar hypertrophy and contracture formation resulting in deformity of limb and joint. Prevention of complication and rehabilitation of burn victims Majority of complications of burn areas arise due to the inability to foresee the problems at early stages. Majority of contractures can be prevented if they are given splintage and physiotherapy. Gross deformation of hands and knees are because of not using splints. These contractures

would require surgical correction in order to restore optimum position. Use of compression garment helps in reducing hypertrophy.They increase local oxygen demand and thus prevent itching and hypertrophy. Page 35 of 48

Prevention of hypertrophy and itching Exact cause of hypertrophy and itching is not well known. However, it is found that it is because of the histamine release and increased oxygen demand. Frequent massage of burn scar with a non scented lubricant like coconut oil, often helps in preventing hypertrophy. Use of compression garment and sometimes excision and grafting followed by compression therapy helps in reducing

hypertrophy and itching. Topical application of silicone gel or silicone gel sheet is helpful. Local injection of Triamcinolone helps in quick resolution of hypertrophy. SUMMARY FOR NURSES & PARAMEDICS 1. Recognise the causes of secondary deformities. 2. Prevent the deformities by appropriate postoperative management. 3. Postoperatively lubrication, massage and pressure garments are essential to prevent or minimise the deformities. 4. Appropriate surgical management of the post burn sequelae is possible.

5. Similar rehabilitation regime is followed after surgery for post burn deformities. Page 36 of 48

13. MANAGEMENT OF BURN DEFORMITIES When primary management of burn is compromised, there is very high risk of development of deformities. Following deformities may occur as sequelae to burn: 1) Post burn unsightly, hypopigmented, hyperpigmented and hypertrophic scars. 2) Post burn contractures. 3) Fixed flexion deformities. 4) Loss of limb and organs. 5) Heterotrophic ossification. 6) Facial deformities. 7) Hand and feet deformities. 8) Post burn alopecia and 9) Many more.

Of all these deformities, the commonest is the hand deformities and thereafter face & neck. Once the deformities develop, they need to be managed timely and appropriately. Many factors are considered for management of the deformities. Age, sex, occupation, area of deformity, duration since wound healing etc decide the time and type of surgical management. Most of these deformities are disabling for the patient as well as matter of great

concern for all the family members. Hence these should be managed on priority basis as and when it is fit for surgical intervention. For loss of the organs appropriate reconstruction can be carried out. Most of the deformities are correctable to a large extent. But the burn scar is difficult to get rid of. One needs to discuss with the patient and his/her family members while managing the secondary deformities based on their choice as well as on the technical priorities. For example if severe

contracture of neck is associated with contracture of axilla, technically the neck contracture gets priority even if patient wants correction of axillary deformity for the anaesthetic safety of the patient. Along with surgical management of the deformity burn care givers should assess the psycho-social problems of the patient and appropriate treatment and psychological support should be provided. Page 37 of 48

SUMMARY FOR NURSES & PARAMEDICS 1. There are many causes for occurrence of post burn defect and deformities. 2. Some of the deformities are preventable with appropriate post burn care. 3. Timely reconstruction of lost organ is desired. 4. Post burn deformities can be surgically managed by judicious surgical treatment. 5. One should remember that once scar is always a scar. We can minimize the burn scar but it may not be possible to remove it completely. Page 38 of 48

14. TEN COMMANDMENTS OF BURN MANAGEMENT Acute burn care requires meticulous planning and attention to details. Often, small things escape attention and result in avoidable mortality and morbidity. Care of burn victim can be significantly improved if certain principles are adhered to. It has been proposed as "The Ten Commandments" of burn care. It is believed that these commandments will help and guide the young surgeon treating burns in far and remote corners of this vast continent. Ten commandments are:

1. Maintain circulation and blood pressure (shock management) 2. Maintain airway 3. Increase body resistance 4. Avoid bacterial toxemia 5. Avoid auto-toxemia 6. Watch for renal complications and multiple organ dysfunctions 7. Maintain nutrition 8. Abide by principles of biomechanical physiotherapy and rehabilitation 9. Attend to psychological, emotional aspects and counseling 10. Analyze factors for reducing mortality. Adherence to these principles and commandments can help us decrease the morbidity and

mortality in this unfortunate set of patients. These commandments have been dealt with in details in earlier chapter as well as in a publication. (Ref: Gupta JL. Ten Commandments in Burn Management. Indian J Burns 2012;20:7-10) Page 39 of 48

15. A BRIEF PRACTICAL GUIDE TO MANAGEMENT OF BURN PATIENT ON SITE MANAGEMENT 1. If patient’s clothes are on flames – ask him to stop, lie on the ground and roll to douse the flames or rescuer douses the flames with water or by wrapping with a blanket and removing the blanket as soon as the flames are put off. 2. Rescuer to check for ABC (airway, breathing and circulation) and deliver CPR accordingly. 3. Burned body part to be put under running water or immersed in a bucket of water for 10-

15 minutes or till burning pain subsides. Do not immerse whole body in water. Do not use ice or ice cold water. 4. Cover with a clean cloth and shift to nearest medical centre. 5. Do not apply any local agent on the wounds. 6. If patient has extensive burns and is conscious, may be given sugar and salt solution orally. 7. In case of electric burns – switch off the main electric supply. 8. In case of chemical burns – wash the affected area with running water continuously for

20 min and then shift to hospital. MANAGEMENT IN BURNS CASUALTY 1. As soon as patient arrives, asses for ABC and CPR to be given accordingly. 2. Remove all clothes and assess patient for extent and depth of burn as per “Rule of nine” or Lund and Browder chart. 3. Weigh the patient. 4. Start wide bore I/V lines for infusing ringer lactate. 5. Remove all constricting objects like rings bangles etc. 6. Eschorotomy or fasciotomy to be done in circumferential burns.

7. Oxygen inhalation to be started if evidence of inhalation injury. 8. Dress the wounds with SSD or dressing material available. 9. Give Tetanus prophylaxis, preferably tetanus globulin. 10. Admit all major burns in the ICU. 11. Minor burns to be discharged with prescription of oral pain-killers and fluid intake and instructions for early return and follow up visits. 12. Maintain the records in detail. 13. Police information to be sent. 14. Medico legal formalities to be completed. Page 40 of 48

MANAGEMENT IN ICU 1. I/ V fluids to be calculated and infused as per formula. 2. Monitor applied to measure vitals. 3. Assess airway for inhalation injury and intubate if required or give moist oxygen inhalation. 4. Catheterize the patient for monitoring urine output and aim at output of 0.5 – 1 ml /kg / hr in adults and 1 – 1.5 ml/kg /hr. 5. Assess extremities, neck and chest for circulation in case of circumferential full thickness

thermal burns or electrical contact burns. To give escharotomy/ fasciotomy incisions as per requirements to improve circulation or respiration. 6. Arterial blood gas to be recorded in inhalation injury. 7. Nil orally till patient is out of shock, and then the patient can start oral sips only. Iincrease fluid and start semisolid diet after 24 to 48 hours once patient recovers from hypovolemic shock phase. 8. ECG monitoring for electric burns patient is essential.

9. If peripheral line not adequate put in a central line for fast fluid infusion and CVP monitoring. 10. Chest physiotherapy and extremity positioning and physiotherapy should be started from second day onwards. 11. Hemoglobin, hematocrit , Serum electrolytes , KFT and Blood sugar should be done daily or as per requirement. 12. I/ V fluids to be continued as per daily losses and requirements. 13. Monitor intake output chart.

14. Dressing to be done with 1 % SSD, collagen or silver dressings depending on availability and changed every 3 -5 days as per indication. 15. Tangential excision should be performed within 3 to 5 days for deep dermal burns or to continue conservative management if extensive burns. 16. Shift to HDU or step down ICU once patient’s general condition and oral intake improve. 17. No antibiotics are needed during initial period.

18. Systemic antibiotic to be given based on symptoms, wound and blood culture sensitivity and ward antibiogram. 19. Oral or parenteral analgesics and sedation for pain management are prescribed as per requirement. MANAGEMENT IN HDU AND WARD 1. Oral intake to be increased with high calorie and high protein diet. I/ V fluids to be supplemented as per intake / output chart. 2. Parenteral nutrition to be given based on oral intake. Page 41 of 48

3. Blood transfusion to be given as and when indicated. 4. Monitor blood investigations every 3rd day – haemogram, electrolytes, KFT, Blood sugar and serum proteins . 5. Dressings to be changed every 3rd to 5th day or earlier if needed after a shower. 6. Active physiotherapy for limbs to continue. 7. Once slough separates and raw area is healthy, to be taken up for split thickness skin grafting. 8. Once all wounds covered and patient mobile, may be discharged and called for follow up in OPD.

MANAGEMENT IN FOLLOW UP OPD 1. Dressings to be done as required. 2. Once all wounds have healed – advice for massage with oil or moisturiser, active physiotherapy, cervical collar, splints and pressure garments. 3. Check for compliance at regular intervals. 4. Counseling to be done. 5. Psychological support and rehabilitation. 6. Secondary surgery for correction of deformities after six months or as per indication. Page 42 of 48

16. SUGGESTED BOOKS FOR READING 1. Herndon D. Total Burn Care ; 4th Edition. Saunders 2009. 2. McCauley RL. Functional and aesthetic reconstruction of burned patients; Taylor and Francis Publishers 2005. 3. Kumar P. Fundamentals of Burn Management. 2nd Edition 2009. 4. Principles and practice of burn care. Sarabahi S, Tiwari VK, Goel A, Gupta LC (eds). Jaypee Brothers Medical Publishers (P) Ltd. New Delhi. 2010. 5. Salisbury RE. Thermal burns. In: McCarthy JM, ed: Plastic surgery. Philadelphia,

6. Paediatric Burns: Total Management of the Burned Child. Ed: Marella L. Hanumadass, K. Mathangi Ramakrishnan. New Delhi, Paras Medical Publisher,2011 Page 43 of 48

17. APPENDIX 17 a. APPENDIX Blood Hematology - Normal Values Measure (abbreviations, synonyms) Typical Normal Range Whole Blood Hematocrit (HCT; packed cell volume) 38-54% (men) 36-47% (women) Hemoglobin (Hb) ….. …… …. 14-18 g/dL (men) 12-16 g/dL (women) 12-14 g/dL (children) 14.5-24.5 g/dL (newborns) Complete Blood Count (CBC) per mm 3 percentage Erythrocytes (Red blood cells; RBCs) 4.5-6 x104 (men) 4.3-5.5x104 (women) Reticulocytes ….. …… …. 0-1% of RBCs Leukocytes (total) 5000-10000

Myelocytes 0 0% of leukocytes Juvenile neutrophils 0-100 (0-1%) Band neutrophils 0-500 (0-5%) Segmented neutrophils 2500-6000 40-60%) Lymphocytes 1000-4000 20-40%) Eosinophils 50-300 (0-5%) Basophils 0-100 (0-1%) Monocytes 200-800 (4-8%) Platelets ….. …… …. 200,000-500,000 RBC Measurements Diameter 5.5-8.8 µm Mean corpuscular volume (MCV) 80-94 µm3 Mean corpuscular hemoglobin (MCH) 27-32 pg Mean corpuscular hemoglobin concentration 33.4-35.5 g/dL Miscellaneous Prothrombin time (PT) 10-20 seconds 0.8-1.2 INR

(International Normalized Ratio) Activated Partial Thromboplastin Time (aPTT) 30-45 seconds Notes: The normal ranges in each laboratory depend on the local population, test methodology and conditions of assay, units, and a variety of other circumstances. The ranges above are typical, but the normal values established for each laboratory should be used for most purposes. Normal ranges for newborns often vary from the adult ranges. Page 44 of 48

17 b. APPENDIX Blood Serum Chemistry - Normal Values Electrolytes Bicarbonate (total) 18-30 mEq/L Calcium (total) 9-11 mg/dL; 4.5-5.5 mEq/L Chloride 98-106 mEq/L Magnesium 1.8-3.6 mg/dL; 1.5-3.0 mEq/L Phosphorus 3-4.5 mg/dL; 1.8-2.3 mEq/L (adults) 4-6.5 mg/dL; 2.3-3.8 mEq/L (children) Potassium 3.5-5.5 mEq/L Sodium 135-147 mEq/L Enzymes* Alkaline Phosphatase 50-160 U/L Amylase 53-123 U/L Creatine Kinase (CK, CPK) 38-174 U/L (males) 96-140 U/L (females) Lipase 10-150 U/L ALT (GPT) 0-30 U/L

AST (GOT) 0-40 U/L Others Albumin 3.5-5.5 g/dL Bilirubin <1.0 mg/dL total <0.4 mg/dL direct (glucuronide- or sulfate-conjugated) Cholesterol <225 mg/dL (depends on age) Creatinine 1.0-2.0 mg/dL Globulin 1.5-3.5 g/dL Glucose 80-120 mg/dL Protein (Total) 6.3-8.0 g/dL Triglycerides 40-200 mg/dL Urea 20-40 mg/dL Uric Acid 2.0-4.0 mg/dL Notes: The normal ranges in each laboratory depend on the local population, test methodology

and conditions of assay, units, and a variety of additional circumstances. * The units for enzyme activities are especially sensitive to such circumstances. The normal ranges above are typical, but the normal ranges established for each laboratory should be used for most purposes. The units g/dL (grams per deciliter) and mg/dL are sometimes expressed as g% and mg%, or g/100 mL and mg/100 mL. Page 45 of 48

17 c. APPENDIX Nutritive value of common food items Fruits S.No. Foodstuff Energy Protein Carbohydrate Fat Fibre Calcium Iron Apple 59 0.2 13.4 0.5 0.3 10 0.66 Banana 116 1.2 27.2 0.3 0.4 17 0.36 Dates, Fresh 144 1.2 33.8 0.4 3.7 22 0.96 Grapefruit 45 1 10 0.1 30 0.2 Grapes 71 0.5 16.5 0.3 2.9 20 0.52 Guava 51 0.9 11.2 0.3 5.2 10 0.27 Jackfruit 88 1.9 19.8 0.1 1.1 20 0.56 Lemon 57 1 11.1 0.9 1.7 70 0.26 Litchi 61 1.1 13.6 0.2 0.5 10 0.7 Lime, Sweet, Mosumbi 43 0.8 9.3 0.3 0.5 40 0.7

Mango 74 0.6 16.9 0.4 0.7 14 1.3 Musk Melon 17 0.3 3.5 0.2 0.4 32 1.4 Orange 48 0.7 10.9 0.2 0.3 26 0.32 Papaya 32 0.6 7.2 0.1 0.8 17 0.5 Pears 52 0.6 11.9 0.2 1 8 0.5 Pineapple 46 0.4 10.8 0.1 0.5 20 2.42 Sapota (Chikoo) 98 0.7 21.4 1.1 2.6 28 1.25 Water Melon 16 0.2 3.3 0.2 0.2 11 7.9 GRAINS Maize 342 11.1 66.2 3.6 2.7 10 2.3 Oatmeal 374 13.6 62.8 7.6 3.5 50 3.8 Rice (Raw) 345 6.8 78.2 0.5 0.2 10 0.7 Rice(Par-Boiled) 346 6.4 79 0.4 0.2 9 1 Wheat (Whole) 346 11.8 71.2 1.5 1.2 41 5.3

Wheat Flour (Whole) 341 12.1 69.4 1.7 1.9 48 4.9 PULSES Bengal gram (dal) 372 20.8 59.8 5.6 1.2 56 5.3 Kesari Dal 345 28.2 56.6 0.6 2.3 90 6.3 Lentils 343 25.1 59 0.7 0.7 69 7.58 Peas (Dry) 315 19.7 56.5 1.1 4.5 75 7.05 Rajmah 346 22.9 60.6 1.3 4.8 260 5.1 Red gram (Dal) 335 22.3 57.6 1.7 1.5 73 2.7 Soyabean 432 43.2 20.9 19.5 3.7 240 10.4 SPICES Cardamon 229 10.2 42.1 2.2 20.1 130 4.6 Chillies, Dry 246 15.9 31.6 6.2 30.2 160 2.3 Page 46 of 48

Cloves, Dry 286 5.2 46 8.9 9.5 740 11.7 Coriander Seeds 288 14.1 21.6 16.1 32.6 630 7.1 Cumin Seeds 356 18.7 36.6 15 12.1 1080 11.7 Garlic, Dry 145 6.3 29.8 0.1 0.8 30 1.2 Ginger, Fresh 67 2.3 12.3 0.9 2.4 20 3.5 Peper, Dry 304 11.5 49.2 6.8 14.9 460 12.4 Turmeric 349 6.3 69.4 5.1 2.6 150 67.8 OILS AND FATS Butter 729 81 Cooking Oils (Gingelly) Groundnut, Mustard, Coconut 900 100 Ghee (Buffalo) 900 100 Hydrogenated fat (fortified) 900 100 LEAFY VEGETABLES Bathua 30 3.7 2.9 0.4 0.8 150 4.2

Bengal gram leaves 97 7 14.1 1.4 2 340 23.8 Cabbage 27 1.8 4.6 0.1 1 39 0.8 Coriander Leaves 44 33 6.3 0.6 1.2 184 1.42 Spinach 26 2 2.9 0.7 0.6 73 1.14 ROOT VEGETABLES Carrot 48 0.9 10.6 0.2 1.2 80 1.03 Colacasia (Arbi) 97 3 21.1 0.1 1 40 0.42 Onion 59 1.8 12.6 0.1 0.6 40 1.2 Potato 97 1.6 22.6 0.1 0.4 10 0.48 Raddish 17 0.7 3.4 0.1 0.8 35 0.4 OTHER VEGETABLES Bittergourd 25 1.6 4.2 0.2 0.8 20 0.61 Bottlegourd 12 0.2 2.5 0.1 0.6 20 0.46 Brinjal 24 1.4 4 0.3 1.3 18 0.38 Capsicum 24 1.3 4.3 0.3 1 10 0.56

Cauliflower 30 2.6 4 0.4 1.2 33 1.23 Cucumber 13 0.4 2.5 0.1 0.4 10 0.6 Drumsticks 26 2.5 3.7 0.1 4.8 30 0.18 French Beans 26 1.7 4.5 0.1 1.8 50 0.61 Jack Fruit, Tender 51 2.6 9.4 0.3 2.8 30 1.7 Ladies Finger 35 1.9 6.4 0.2 1.2 66 0.35 Lotus Stem (Dry) 234 4.1 51.4 1.3 25 405 60.6 Peas 93 7.2 15.9 0.1 4 20 1.5 Plaintain, Green 64 1.4 14 0.2 0.7 10 6.27 Page 47 of 48

Pumpkin 25 1.4 4.6 0.1 0.7 10 0.44 Tomato 20 0.9 3.6 0.2 0.8 48 0.64 Water Chestnut (Fresh) 115 4.7 23.3 0.3 0.6 20 1.35 FISH, MEET AND POULTRY PRODUCTS Fowl 109 25.9 0.6 25 Goat Meat 118 21.4 3.6 12 Liver 150 19.3 1.3 7.5 10 6.3 Pork 114 18.7 4.4 30 2.2 Egg 173 13.3 13.3 60 2.1 Mutton 194 18.5 13.3 150 2.5 Pomfret fish 87 17 1.8 1.3 200 0.9 Pork 114 18.7 4.4 30 2.2 Buffalo's milk 117 4.3 5 6.5 210 0.2 Cheese (Processed) 348 24.1 6.3 25.1 790 2.1 Cow's milk 67 3.2 4.4 4.1 120 0.2 Curds 60 3.1 3 4 149 0.2

Khoa, Whole Buffalo Milk 421 14.6 31.2 650 5.8 Milk, Cow's 67 3.2 4.4 4.1 120 0.2 Milk, Human 65 1.1 7.4 3.4 28 Milk,Bufflalo's 117 4.3 5 6.5 210 0.2 Skimmed Milk 29 2.5 4.6 0.1 120 0.2 OTHERS Biscuits, salted 534 6.6 54.6 32.4 Biscuits, sweet 450 6.4 71.9 15.2 Bread 245 7.8 51.9 0.7 11 1.1 Cane Sugar 398 0.1 99.4 0 12 0.15 Fish Liver Oil 900 100 Honey 319 0.3 79.5 0 5 0.69 Jaggery 383 0.4 95 0.1 80 2.64 168 Page 48 of 48

STANDARD TREATMENT GUIDELINES Management of Snake Bite Quick Reference Guide July 2016 Ministry of Health & Family Welfare Government of India 1 Quick Reference Guide Final version

Table of Content 1. INTRODUCTION ............................................................................................... 4 2. INCIDENCE OF SNAKE BITE IN INDIA .................................................................... 5 3. WHEN TO SUSPECT/RECOGNIZE SNAKEBITE........................................................ 6 4. RECOMMENDATIONS .......................................................................................... 7

4.1 FIRST AID MEASURES .......................................................................................... 7 4.2 SIGN & SYMPTOMS .............................................................................................. 10 4.2.1 Asymptomatic (i.e., non Venom related symptoms) .................................. 11 4.2.2 Dry Bite ..................................................................................................... 12

4.2.3 Neuroparalytic (Progressive weakness; Elapid envenomation) .................. 12 4.2.4 Vasculotoxic (haemotoxic or Bleeding) ...................................................... 13 4.2.5 Locked in syndrome (LIS) ........................................................................... 15 4.2.6 Life threatening complications ................................................................... 15

4.2.6 Painful Progressive Swelling (PPS) .............................................................. 17 4.2.7 Myotoxic ................................................................................................... 17 4.2.8 Occult snakebite ........................................................................................ 17 4.3. ASSESSMENT ................................................................................................... 18

4.3.1 Critical Arrival: Patient assessment on arrival ............................................ 18 4.3.2 Patient assessment: ................................................................................... 20 4.4 LAB INVESTIGATIONS ........................................................................................ 21 4.4.1 Bedside 20 minute whole blood clotting test (20 WBCT) ............................. 21

4.4.5- Rationale and interpretation of the tests .................................................. 24 5. ANTI SNAKE VENOM (ASV) THERAPY ................................................................ 25 5.1 ANTISNAKE VENOM (ASV) ..................................................................................... 26 5.2 ANTISNAKE VENOM (ASV) DOSE ............................................................................ 26

5.3 MONITORING OF PATIENTS AND PRECAUTIONS DURING ASV ADMINISTRATION ................ 27 5.4 ASV DOSE IN PREGNANCY ....................................................................................... 28 5.5 ASV DOSE IN CHILDREN .......................................................................................... 28 5.6 ASV DOSAGE IN VICTIMS REQUIRING LIFE SAVING SURGERY ............................................ 29

5.7 REPEAT DOSE OF ASV ............................................................................................ 29 5.9 VICTIMS WHO ARRIVE LATE ..................................................................................... 29 5.10. ASV REACTION .................................................................................................. 30 6. MANAGEMENT NEUROTOXIC (NEUROPARALYTIC) ENVENOMATION ............... 32

7. MANAGEMENT OF VASCULOTOXIC SNAKEBITE ................................................. 34 7.1 VOLUME REPLACEMENT IN SNAKE BITE: ..................................................................... 34 7.2 FORCED ALKALINE DIURESIS (FAD) .......................................................................... 34 2 Quick Reference Guide Final version

7.6 IN CASE OF SHOCK, MYOCARDIAL DAMAGE ................................................................ 36 8. MANAGEMENT OF SEVERE LOCAL ENVENOMING ............................................. 37 9. RECOVERY PHASE .............................................................................................. 38 10. OTHER MEASURES ......................................................................................... 39

10.1 SURGICAL PROCEDURES IN SNAKEBITE...................................................................... 39 10.1.1 Debridement of necrotic tissue ................................................................ 39 10.1.2 Compartmental syndrome ....................................................................... 40 10.1.3 Criteria for fasciotomy in snakebite limb .................................................. 40

11. DISCHARGE .................................................................................................... 41 11.1 FOLLOW-UP ...................................................................................................... 41 11.2 REHABILITATION ................................................................................................. 41 12. REFERRAL CRITERIA ....................................................................................... 42

13. REFERENCES................................................................................................... 45 ANNEXURE 1. SNAKE BITE EXAMINATION PERFORMA .............................................. 48 ANNEXURE 2. SNAKE BITE MANGEMENT DIFFERENT LEVELS OF HEALTHCARE ......... 50 3 Quick Reference Guide Final version

1. Introduction Snakebite is an acute life threatening time limiting medical emergency. It is a preventable public health hazard often faced by rural population in tropical and subtropical countries with heavy rainfall and humid climate. There are more than 2000 species of snakes in the world and about 300 species are found in India out of which 52 are venomous. The venomous snakes found in India belong to three families Elapidae, Viperidae and hydrophinae (Sea

Snakes). The most common Indian elapids are Naja naja (Indian Cobra) and Bungarus caeruleus (Indian Krait), Daboia russalii (Russells’ Viper) and Echis carinatus (Saw scaled viper) (Alirol et al 2010). Clinical effects of envenoming by same species of snake are almost similar except a few regional variations. Kraits are active during night hours, often biting a person sleeping on floor bed. Maximum Viper and Cobra bites occur during the day or early darkness, while

watering the plantation or walking bare foot in grown grass or soybean crops. Although total number of bites may be more than 5-6 lakhs but only 30% are venomous bites. On the basis of Million Death Study), non-fatal bites may be as high as 1.4 million per year. Though snakebite is a life threatening centuries old condition, it was included in the list of neglected tropical diseases (Warrell and WHO 2009; Bawaskar HS 2014). With its triad of high mortality, high disability,

and substantial psychological morbidity, snake bite warrants high priority research (lancet 2015). Currently, treatment quality is highly varied, ranging from good quality in some areas, to very poor quality treatment in others. The high fatality due to Krait bite is attributed to the non-availability of antisnake venom (ASV), delayed and inappropriate administration of ASV, lack of standard protocol for management and inexperienced doctors and non-availability of ventilator or

bag and valve (Bawaskar et al 2008). In India, there has always been a crisis of antivenom supply (Bawaskar HS and Bawaskar PH 2001). On one hand there is shortage of ASV but on the other hand scarce ASV is being wasted due to excessive dosage of ASV in the absence of a Standard Treatment Guideline. Victims are not only misdiagnosed as - abdominal colic, and vomiting due to indigestion, appendicitis, stroke, head injury, ischemic heart disease, food

poisoning, trismus, hysteria and Guillain-Barre´ syndrome but also subjected to unnecessary investigations including MRI scans of the brain and lumbar 4 Quick Reference Guide Final version

puncture thus causing undue delay in ASV therapy. Delayed administration of ASV or waiting until victim develops systemic manifestations i.e., a 6 h wait results in systemic envenoming and high fatality (Bawaskar et al 2008). Morbidity and mortality depends on the age and size of victim (children receive larger envenomation relative to body size), co-morbid conditions (elderly patients succumb more easily to snake venom) as well as nature of first aid

given. Factors not contributing to outcome are size of the snake and time of bite (day/night) 2. Incidence of Snake Bite in India There is a huge gap between the number of snakebite deaths reported from direct survey and official data. Only 7.23% snakebite deaths were officially reported (Majumdar, 2014 and Mohapatra 2011). Earlier hospital based reports estimated about 1,300 to 50,000 annual deaths from snakebites per year in India. Mohapatra et al, 2011, reported direct estimates from a national

mortality survey of 1.1 million homes in 2001–03. The study found 562 deaths (0.47% of total deaths) were assigned to snakebites, mostly in rural areas, and more commonly among males than females and peaking at ages 15–29. This proportion represents about 45,900 annual snakebite deaths nationally or an annual age-standardized rate of 4.1/100,000, with higher rates in rural areas (5.4) and with the highest rate in the state of Andhra Pradesh (6.2). Annual

snakebite deaths were greatest in the states of Uttar Pradesh (8,700), Andhra Pradesh (5,200), and Bihar (4,500). Other Indian states with high incidence of snakebites cases are Tamil Nadu, West Bengal, Maharashtra and Kerala. Because a large proportion of global totals of snakebites arise from India, global snakebite totals might also be underestimated (Mohapatra et al 2011). In a retrospective study conducted in one district of West Bengal only 22.19% of the

snakebite victims attended the hospitals (Majumder et al, 2014). This is because even today most of the victims initially approach traditional healers for treatment and many are not even registered in the hospital. Singh et al reported among the snakebite victims, about 60.76% received first aid at the site of incident, and 20.25% of them sought hospital care after consulting the traditional healers (ozhas, or mantrik and tandrik). Time lapsed for seeking

hospital treatment was less than 4 h in 55.69% of the cases and more than 12 h 5 Quick Reference Guide Final version

in 7.59% of the cases. Most (41.79%) patients were frightened, but no local or systemic symptoms had appeared when they reported the emergency (Singh A et al 2015). 3. WHEN TO SUSPECT/RECOGNIZE SNAKEBITE CLINICAL PRESENTATION: Clinical presentation of snakebite victim depends upon species of snake, amount of venom injected, season of the bite, whether snake is fed or unfed, site of bite, area covered or uncovered, dry or incomplete bite, multiple bites,

venom injection in vessel, weight of the victim and time elapsed between the bite and administration of ASV. Venom concentration and constitution depends on environmental conditions as well as snake’s maturity and darkness of colour of snake (Bawaskar HS et al 2014). Patient can present in any of the four clinical syndromes or with overlapping syndrome i.e. progressive weakness (neuroparalytic/neurotoxic), bleeding (vasculotoxic/haemotoxic), myotoxic and painful progressive Swelling (Figure 1). 6

Suspected snake bite •Neuroparalytic Overt bite Occult bite Krait s n y o m lo p c t a o l m si s g w ns ith History of bite No history of bite •Severe Nonvenomous (70%) / venomous (30%) abdominal pain, vomiting Asymptomatic Dry bite Symptomatic* 1. ASV Predominant symptom manifestation 2. AN*** Anxiety, palpitations, 3. Ventilation tachycardia, Paraesthesia Progressive painful Neuroparalytic Vasculotoxic Myotoxic Observe for swelling 24 hours Cobra •Russel’sviper Flat tailed

Viper Krait Saw Scale viper Sea snake •Ptosis •Bleeding •Muscle ache •Diplopia •Demonstrable •Muscle swelling •Local necrosis •Dysarthia coagulopathy (20WBCT •Involuntary •Ecchymosis •Dysphonia incoagulable) contractions of •Blistering •Dyspnoea •Shock muscles •Painful •Dysphagia •Acute kidney injury •Compartment swelling •Paralysis (not seen with Saw syndrome •Compartment scale viper) syndrome 1. ASV**¥ 1. ASV**¥ 1. ASV** 2. Supportive treatment 2. Supportive ASV# 2. AN*** 3. Dialysis treatment

3. Ventilation 4. Blood transfusion 3. Dialysis * Even though present as predominant manifestation but there may be overlap of syndrome as well. # ASV indicated in rapidly developing swelling only. Purely localized swelling with or without bite marks is not an indication of ASV. ** For reaction to antisnake venom (ASV) Dose of Adrenaline 0.5 mg IM (in children 0.01 mg/kg) ¥ Specific ASV for sea snake and Pit viper bite is not available in India. However, available ASV may

have some advantage by cross reaction. *** ‘AN’ injection Atropine 0.6 mg followed by neostigmine(1.5mg) IV stat (In children Inj. Atropine 0.05 mg/kg followed by Inj. Neostigmine0.04 mg/kg IV.)Repeat neostigmine0.5 mg (in children 0.01mg/kg) with atropine every 30 minutes for 5 doses. Thereafter taper dose at 1 hour, 2 hour, 6 hours and 12 hour. Positive response is measured as 50% or more recovery of the ptosis in one

hour. If no response after 3rddose stop AN injection. No AN injection in confirmed krait bite • The snake specie shown above are indicative only. Russell’s viper envenoming in Tamil Nadu and some other areas commonly causes paralysis –the venom of this species varies considerably across its range in India. Figure 1. Four presenting clinical syndromes of snakebite i.e. progressive weakness (neuroparalytic/neurotoxic), bleeding (vasculotoxic/haemotoxic),

myotoxic and painful progressive Swelling and its management. 4. Recommendations 4.1 FIRST AID MEASURES 4.1.1 - By bystander or victim- Immediately transfer after providing first aid to a health facility where optimal medical care with antisnake venom (ASV) is available, close observation and definite treatment can be provided. 4.1.2 At The Community or Village Level • Check history of snakebite and look for obvious evidence of a bite (fang 7 Quick Reference Guide Final version

puncture marks, bleeding, swelling of the bitten part etc.). However, in krait bite no local marks may be seen. It can be noted by magnifying lens as a pin head bleeding spot with surrounding rash. • Reassure the patient as around 70% of all snakebites are from non- venomous species. • Immobilize the limb in the same way as a fractured limb (Apply splint extending to the entire length of the limb, immobilizing all of the joints of the limb) in the recovery position (prone, on the left side) with his/her

airway protected to minimize the risk of aspiration of vomitus. Use any rigid object as a splint e.g. spade, piece of wood or tree branch, rolled up newspapers etc.), but do NOT block the blood supply or apply pressure. • Nil by mouth till victim reaches a medical health facility. • Shift the victim to the nearest health facility (PHC or hospital) immediately. • Arrange transport of the patient to medical care as quickly, safely and passively as possible by vehicle ambulance (toll free no. 102/108/etc.),

boat, bicycle, motorbike, stretcher etc. Motorbike may be a feasible alternative for rural India where no other transport is available but third . person must sit behind the patient • Victim must not run or drive himself to reach a Health facility. • Remove shoes, rings, watches, jewellary and tight clothing from the bitten 8 Quick Reference Guide Final version

area as they can act as a tourniquet when swelling occurs. • Leave the blisters undisturbed. • Inform the doctor of any symptoms such as progress of swelling, ptosis or new symptoms that manifest on the way to hospital. • If patient is being referred if possible medical officer can accompany with patient to know the progress, manifestation of the new symptoms (such as progress of swelling, ptosis or new symptoms) and management and treatment of shock and cardiopulmonary resuscitation (CPR) on the way.

4.1.3 Important don’ts Do not attempt to kill or catch the snake as this may be dangerous. l Traditional remedies have NO PROVEN benefit in treating snakebite. l Some of them may produce confusing signs and symptoms. Discard traditional first aid methods (black stones, scarification) and l alternative medical/herbal therapy as they have no role and do more harm than good by delaying treatment. Do not wash the wound or interfere with the bite wound (incisions, l

suction, rubbing, tattooing, vigorous cleaning, massage, application of herbs or chemicals, cryotherapy, cautery) as this may introduce infection, increase absorption of the venom and increase local bleeding. Do NOT apply or inject antisnake venom (ASV) locally. l Do not tie tourniquets as it may cause gangrenous limbs. l If victim is expected to reach the hospital in more than 30 minutes but l less than 3 hours crepe bandage may be applied by qualified medical

personnel only till the patient is shifted to the hospital. The bandage is wrapped over the bitten area as well as the entire limb with the limb placed in a splint. It should be capable of admitting a finger beneath it See Figure 2.) If trained personnel is not present , Do NOT try) 9 Quick Reference Guide Final version

Figure 2: Pressure immobilization (Sutherland method) modified (Sutherland 1979) 4.1.4 At A Health Care Facility – Secure IV line in PHC itself and use normal saline to keep IV access open. – Start fluids, if patient is in shock. – Admit all victims of snakebite confirmed or suspected and keep under observation for 24 hours. – Provide first-aid measures and supportive measures immediately. – Observe for signs of envenomation. – Administer ASV therapy as soon as there is evidence of envenomation.

4.2 Sign & Symptoms The clinical presentation of a snakebite victim varies with the age and size of the patient, the species of snake, the number and location of the bites, and the quantity and toxicity of the venom. See figure 1 for presenting clinical syndromes of venomous snakebite. There may be considerable overlap of clinical features. 10 Quick Reference Guide Final version

Victims of snakebite may suffer any or all of the following (WHO 2015 adopted): 1. No physical effects other than the fang/tooth puncture due to bites by non-venomous snakes, animals other than snakes (lizards, fish, rodent, spiders), dry bite by venomous snake. Examination of the bite site Examine the bite site and look for fang marks, or any signs of local envenomation. Fang mark or their patterns have no role to determine whether the biting species was venomous or non venomous or

amount of venom injected, severity of systemic poisoning and nature of poisoning – Elapidae or viperidae venom etc. Some species like Krait may leave no bite marks. 2. Local envenoming confined to the bitten part of the body. These effects may be transient, resolving in hours or a few days; may persist for few weeks or debilitating, some time permanently due to local necrotic effects of venom and complicating infections. 3. Systemic envenoming involving organs and tissues distant from the

bitten part of the body. These effects may be transient, persistent, life threatening and debilitating, sometimes permanently. 4. Effects of anxiety prompted by frightening experience of being bitten (real or imagined) and by exaggerated beliefs about the potency and speed of action of snake venoms. The symptoms may mislead the treated personnel. 5. Effects of first-aid and other pre-hospital treatments that may cause misleading clinical features. 4.2.1 Asymptomatic (i.e., non Venom related symptoms)

Patients many a times present with nonspecific symptoms related to anxiety. Common symptoms in these patients are: – Palpitations, sweating, tremulousness, tachycardia, tachypnoea, elevated blood pressure, cold extremities and paraesthesia (pins and needles pricking sensation of the extremities). These patients may have dilated pupils suggestive of sympathetic over activity. Other may develop vasovagal shock (faintness and collapse with profound slowing of heart) after the bite or suspected bite. 11

– Differentiate from symptoms and signs of envenomation listed below. – Redness, increased temperature, persistent bleeding and tenderness locally. However, local swelling can be present in these patients due to tight ligature. 4.2.2 Dry Bite Bites by nonvenomous snakes are common and bites by venomous species are not always accompanied by the injection of venom (dry bites). – The percentage of dry bites ranges from 10–80% for various venomous snakes.

– Even in case of dry bite, symptoms due to anxiety and sympathetic over-activity (as above) may be present. As symptoms associated with panic or stress sometimes mimic early envenoming symptoms, clinicians may have difficulties in determining whether envenoming occurred or not. – Some people who are bitten by snakes (or suspect or imagine that they have been bitten) or have doubts regarding bite may develop quite striking symptoms and signs, even when no venom has been injected

due to understandable fear of the consequences of a real venomous bite. 4.2.3 Neuroparalytic (Progressive weakness; Elapid envenomation) – Neuroparalytic snakebite patients present with typical symptoms within 30 min– 6 hours in case of Cobra bite Many species, particularly the Krait and the hump-nosed pit viper are known for delayed appearance of symptoms which can develop after 6–12 hours; however, ptosis in Krait bite have been recorded as late as 36 hours after hospitalization.

– These symptoms can be remembered as 5 Ds and 2 Ps. • 5 Ds – dyspnea, dysphonia, dysarthria, diplopia, dysphagia • 2 Ps – ptosis, paralysis – In chronological order of appearance of symptoms – furrowing of forehead, Ptosis (drooping of eyelids) occurs first (Figure 3), followed by Diplopia (double vision), then Dysarthria (speech difficulty), then Dysphonia (pitch of 12 Quick Reference Guide Final version

voice becomes less) followed by Dyspnoea (breathlessness) and Dysphagia (Inability to swallow) occurs. All these symptoms are related to 3rd, 4th, 6th and lower cranial nerve paralysis. Finally, paralysis of intercostal and skeletal muscles occurs in descending manner. – Other signs of impending respiratory failure are diminished or absent deep tendon reflexes and head lag. – Additional features like stridor, ataxia may also be seen. – Associated hypertension and tachycardia may be present due to hypoxia.

Figure 3. Ptosis with neuroparalytic snakebite – To identify impending respiratory failure bedside lung function test in adults viz. • Single breath count – number of digits counted in one exhalation - normal >30 • Breath holding time – breath held in inspiration – normal > 45 sec • Ability to complete one sentence in one breath. – Cry in a child whether loud or husky can help in identifying impending respiratory failure. – Bilateral dilated, poorly or a non-reacting pupil is not the sign of brain

dead in elapid envenoming (Figure 3). – Refer patients presenting with neuroparalytic symptoms immediately to a higher facility for intensive monitoring after giving Atropine Neostigmine (AN) injection (schedule of AN injection described below). 4.2.4 Vasculotoxic (haemotoxic or Bleeding) 13 Quick Reference Guide Final version

General signs and symptoms of Viperine envenomation (Vasculotoxic bites are due to Viper species. They can have local manifestations as well as systemic manifestations. Local manifestations – These are more prominent in Russel’s viper bite followed by Saw scaled viper and least in Pit viper bite. Local manifestations are in form of: • Local swelling, bleeding, blistering, and necrosis. • Pain at bite site and severe swelling leading to compartment

syndrome. Pain on passive movement. Absence of peripheral pulses and hypoesthesia over the fuels of nerve passing through the compartment helps to diagnose compartment syndrome. • Tender enlargement of local draining lymph node. Systemic manifestations – • Visible systemic bleeding from the action of haemorrhagins (Figure 4) e.g. gingival bleeding, epistaxis, ecchymotic patches, vomiting, hematemesis, hemoptysis, bleeding per rectum, subconjunctival

hemorrhages, continuous bleeding from the bite site, bleeding from pre-existing conditions e.g. haemorrhoids, bleeding from freshly healed wounds. • Bleeding or ecchymosis at the injection site is a common finding in Viper bites. • The skin and mucous membranes may show evidence of petechiae, purpura ecchymoses, blebs and gangrene. • Swelling and local pain. • Acute abdominal tenderness may suggest gastro-intestinal or retro peritoneal bleeding.

• Lateralizing neurological symptoms such as asymmetrical pupils may be indicative of intra-cranial bleeding. • Consumption coagulopathy detectable by 20WBCT, develops as early as within 30 minutes from time of bite but may be delayed. 14 Quick Reference Guide Final version

Figure 4. Local and systemic Vasculotoxic (haemotoxic or Bleeding) manifestations of Viperine envenomation. 4.2.5 Locked in syndrome (LIS) Locked in syndrome (LIS) is defined as quadriplegia and anarthria with preserved consciousness. Patients retain vertical eye movement, facilitating non-verbal communication. In complete locked in syndrome (LIS) patient cannot communicate in any form. Central LIS is seen commonly due to lesions in the ventral pons (Smith and Delargy 2005; Prakash 2008; Poovazhagi 2013).

Peripheral causes of LIS are severe acute polyneuropathies, neuromuscular junction blockade due to myasthenia gravis toxins and snakebite (Prakash 2008). Knowing the peripheral causes are very important as one may make a wrong diagnosis of brain death and is treatable and complete recovery can be possible with timely intervention. Confirmatory tests like EEG, cerebral blood flow, nerve conduction velocities are recommended to avoid misdiagnosis of coma or brain death.

Peripheral LIS usually occurs in Elapidae bites, especially Krait bite and hence increasing ones suspicion rate is important as they can be referred to a centre with ventilator support. 4.2.6 Life threatening complications • Acute Kidney Injury (AKI) e.g. declining or no urine output, deteriorating renal signs such as rising serum creatinine, urea or potassium. Some species e.g. Russell’s viper (Daboia sp) frequently cause acute Kidney Injury.

Patient presents with bilateral renal angle tenderness, albuminuria, 15 Quick Reference Guide Final version

hematuria, hemoglobinuria, myoglobinuria followed by oliguria and anuria with AKI. • Hypotension due to hypovolaemia or direct vasodilatation or direct cardiotoxicity aggravates acute kidney injury. • Parotid swelling, conjunctiva oedema, sub-conjunctival haemorrhage, renal failure, acute respiratory distress syndrome [leaking syndrome] and refractory shock. • Long term sequelae e.g. pituitary insufficiency with Russell’s viper (Daboia sp), Sheehan’s syndrome or amenorrhea in females.

Systemic Capillary Leak Syndrome (SCLS) Idiopathic systemic capillary leak syndrome (ISCLS) is a rare disorder characterized by episodes of severe hypotension, hypoalbuminemia, hemoconcentration without albuminuria due to profound derangement of the vascular endothelium resulting in leakage of plasma and proteins into the interstitial compartment. Capillary leak syndrome is a sinister complication of Daboia russelii bite as it is beset

with an excess of morbidity and mortality. Manifestations like parotid swelling, conjunctival chemosis, myalgia, thirst and systemic hypotension observed in patients of Daboia russelii bite indicate capillary leak syndrome. It is seen in more commonly in males as compared to females. Hemoconcentration, increased HCT, leukocytosis, pleural effusion are early laboratory and radiological markers of capillary leak syndrome and should alert the clinician to seek urgent interventions in Daboia russelii bite.

A B C D Figure : A) 17 year old patient with viper bite at admission. B) & C) Same patient with Periorbital swelling, Conjunctival chemosis and icterus 24 hours later. D) Another patient with viper bite developing parotid swelling 24 hours later. 16 Quick Reference Guide Final version

4.2.6 Painful Progressive Swelling (PPS) Progressive painful swelling is indicative of local venom toxicity. It is prominent in Russel’s viper bite, Saw scaled viper bite and Cobra bite. This is associated with • Local necrosis which often has a rancid smell. Limb is swollen and the skin is taut and shiny. Blistering with reddish black fluid at and around the bite site. Skip lesions around main lesion are also seen. (Figure 5). • Ecchymoses due to venom action destroying blood vessel wall.

• Significant painful swelling potentially involving the whole limb and extending onto the trunk. • Compartment syndrome will present invariably. • Regional tender enlarged lymphadenopathy. Figure 5. Snakebite marks and local swelling and necrosis 4.2.7 Myotoxic This presentation is common in Sea snakebite. Patient presents with: • Muscle aches, muscle swelling, involuntary contractions of muscles. • Passage of dark brown urine. • Compartment syndrome, cardiac arrhythmias due to hyperkalaemia, acute

kidney injury due to myoglobinuria, and subtle neuroparalytic signs. 4.2.8 Occult snakebite • Krait bite victims often present in the early morning with paralysis with no local signs with no bite marks. 17 Quick Reference Guide Final version

• Snakebite victim gets up in the morning with severe epigastric/umbilical pain with vomiting persisting for 3 – 4 hours and followed by typical neuroparalytic symptoms within next 4- 6 hours. There is no history of snakebite. • Unexplained respiratory distress in children in the presence of ptosis or sudden onset of acute flaccid paralysis in a child (locked-in syndrome) is highly suspicious symptoms in endemic areas particularly of Krait bite

envenomation. Sometimes patients may present with throat, chest or joint pain. Early morning symptoms of acute pain abdomen with or without neuroparalysis can be mistaken for a acute appendicitis, acute abdomen, stroke, GB syndrome, myasthenia gravis and hysteria (Bawaskar 2002). Krait bite envenoming is diagnosed by developing descending neuroparalysis while GB syndrome is by ascending paralysis. Strong clinical suspicion and careful examination can avoid not only costly and

unnecessary investigations such as CT scan, MRI, nerve conduction studies, CSF studies and many others but also help in avoiding undue delay in initiation of a specific treatment with ASV. Atropine neostigmine (AN) test helps to rule out myasthenia gravis. Snakebite is a medical emergency, history, symptoms and signs must be obtained rapidly. ON PRESENTATION, PATIENTS CAN BE CRITICAL OR NON CRITICAL (See FIGURE 1). 4.3. ASSESSMENT 4.3.1 Critical Arrival: Patient assessment on arrival

1. Assess circulation, airway and breathing and deal with any life threatening symptoms on presentation. Vasculotoxic patients presenting with bleeding from multiple orifices with hypotension, reduced urine output, obtunded mentation (drowsy, 18 Quick Reference Guide Final version

confused), cold extremities need urgent attention and ICU care for volume replacement, pressor support, dialysis and infusion of blood and blood products (See following sections). Neuroparalytic patients presenting with respiratory paralysis, tachypnoea or bradypnoea or paradoxical respiration (only moving abdomen), obtunded mentation, and peripheral skeletal muscle paralysis need urgent ventilator management with endotracheal intubation, ventilation bag or ventilator assistance.

Other patients can be evaluated to decide severity of their illness (see non- critical arrival below). 2. Establish large bore intravenous access and start normal saline slow infusion. 3. Before removal of the tourniquet/ligatures, test for the presence of a pulse distal to the tourniquet. If the pulse is absent ensure a doctor is present before removal or ligatures. 4. In case of clinically confirmed venomous bite, remove tourniquet only after starting of loading dose of ASV and keep Atropine Neostigmine

injection ready. In case of multiple ligatures, all the ligatures can be released in Emergency Room EXCEPT the most proximal one; which should only be released after admission and all preparations. 5. Carry out a simple medical assessment including history and physical examination and record (see Annexure 2) and repeat all above, every 1-2 hourly – bite site local swelling, painful tender and enlarged local lymph glands, persistent bleeding from the bite wound, blood pressure, pulse

rate, bleeding (gums, nose, vomit, stool or urine), level of consciousness, drooping eyelids (ptosis) and other signs of paralysis. The Glasgow Coma scale cannot be used to assess the level of consciousness of patients paralyzed by neurotoxic venom. – Check for and monitor the following: Pulse rate, respiratory rate, blood pressure and 20 minutes Whole Blood clotting test (20 WBCT) every hour for first 3 hours and every 6 hours for remaining 24 hours.

– Check distal pulses and monitor, if there is presence of gross swelling. The presence of a pulse does not rule out compartment syndrome. Pain on passive movement, pallor, pulseless limb, hypoaesthesia over the sensory nerve passing through the compartment are suggestive of compartment 19 Quick Reference Guide Final version

syndrome (see compartment syndrome below for details). 4.3.2 Patient assessment: Non critical arrival and Critical patients after stabilization: patient assessment – Determine the time elapsed since the snakebite and as to what the victim was doing at the time of the bite, history of sleeping on floor bed in previous night. – Determine if any traditional medicines have been used. – Obtain a brief medical history (e.g., date of last tetanus immunization, use

of any medication, presence of any systemic disease, and history of allergy) Examination of pregnant women - Monitor uterine contractions and foetal heart rate. Lactating women who have been bitten by snakes should be encouraged to continue breast feeding. 4.3.3 Differential identification of type of snakebite based on the symptoms and signs Though to a large extent the manifestation of snakebite depends upon the species of snake, unfortunately, in many cases the biting snake is not seen, and

if it is, its description by the victim is often misleading (Harris et al 2010). Therefore identification of the type of snake should not hold the treatment. At times the bite mark might not be visible (e.g., in the case of Krait). The clinical manifestations of the patient may not correlate with the species of snake brought as evidence. Examine carefully the snake, if brought, and identified (Figure 6), if possible. Discourage bringing the killed snake into the emergency

department. Identification of the species even if killed should be carried out carefully, since crotalids can envenomate even when dead. If snake is not available for identification in such a situation showing specimens of snakes preserved in formalin in glass jars or pictures of snakes would help the patient or the witness to recognize the offending snake which facilitates the judgment of the clinician. One smart phone photograph of the snake, dead

or alive, if can be taken safely, for confirmation by an expert would help in identifying the snake. 20 Quick Reference Guide Final version

Inspection of local bite site and bitten limb can also help to identify snake’s species. Local swelling, bleeding, blistering, necrosis suggests Cobra bite. Minimum local changes indicate Krait bite. Local bleeding suggests Nilgiri Russel’s viper. Pain in abdomen and hyper peristalsis indicates Krait bite. Figure 6. Snake identification by the patient Clues for severe snake envenomation are: • Rapid early extension of local swelling from the site of the bite. In Cobra

bite on finger, necrosis may start in few minutes. • Early tender enlargement of local lymph nodes, indicating spread of venom in the lymphatic system • Visible signs of neurological impairment such as ptosis, muscular weakness, respiratory distress or respiratory arrest. • Early spontaneous systemic bleeding especially bleeding from the gums, bite site, haematuria, haemoptysis, epistaxis or ecchymoses. • Unconsciousness either with or without respiratory arrest. • Passage of dark brown urine

• Snake identified as a very venomous one i.e., Cobra, Russel’s viper. 4.4 LAB INVESTIGATIONS 4.4.1 Bedside 20 minute whole blood clotting test (20 WBCT) Place 2 ml of freshly sampled venous blood in a small glass test tube and leave undisturbed for 20 minutes at ambient temperature. Gently tilt the test tube to see if the blood is still liquid; the patient has hypofibrinogenaemia (“incoagulable” blood or “not clotted”) as a result 21 Quick Reference Guide Final version

of venom-induced consumption coagulopathy (Figure 7). Caution: Use clean new dry glass test tube only to avoid false positive tests. If blood clot is formed and signs and symptoms of neurotoxic envenomation present, classify as neurotoxic envenomation. In case where the 20WBCT result is inconsistent with the patients’ clinical condition, repeat the test in duplicate, including a “control” (blood from a healthy person). If the blood is solid i.e. has clotted the patient has

passed the coagulation test and no ASV is required at this stage. 20 WBCT may remain negative (clotting) in patients with evolving venom – induced DIC, therefore, the patient is re-tested every hour for the first three hours and then 6 hourly for 24 hours until either test result is not clotted or clinical evidence of envenomation to ascertain if dose of ASV is indicated. Antivenom treatment should not be delayed if there is other evidence of spontaneous systemic bleeding distant from the bite site. In

case test is non-clotting, repeat 6 hour after administration of loading dose of ASV. In case of neurotoxic envenomation repeat clotting test after 6 hours. (Expert Consensus) Counsel patient and relatives in the beginning that, 20WBCT may be repeated several times before giving any medication. Figure 7. 20 minute whole blood clotting test (20 WBCT). The first blood drawn from the patient should be typed and cross-matched, as the effects of both venom and ASV can interfere with later cross-matching. 22

Other investigations that may assist in the management of snake bite at various levels of healthcare 4.4.2 – Other Lab tests at Primary health centre – Peak flow meter in patients (adolescents and adults) presenting with neuroparalytic syndrome. – If Peak flow meter is not available in PHC then assess respiratory function using bedside tests - single breath count, breath holding time and ability to complete one sentence in one health as described earlier.

– Urine examination for albumin and blood by dipstick. 4.4.3 Others lab test at District Hospital In addition to the above – Prothrombin time – Serum Amylase – Platelet count, – Blood sugar – Clot retraction time – ECG – Liver function test (LFT) – Abdominal ultrasound – Renal Function test (RFT) – 2D Echo (if available) 4.4.4 Others Lab test at Tertiary Health Care Centre In addition to the above – In neuroparalytic envenomation • Arterial blood gases. Caution: Arterial puncture is contraindicated in

patients with haemostatic abnormalities. • Pulmonary function tests – In Vasculotoxic venomation • For coagulopathy- BT, CT, PT, APTT, Platelet, Serum Fibrinogen, FDP D- Dimer assay, LDH, peripheral blood smear • Hemolysis -Urine for myoglobin, Urine haemoglobin • For renal failure- Urine microscopy for RBC, casts, RFT, urinary proteins, creatinine ratio • Hepatic injury – LFTs including SGOT, SGPT, Alkaline phosphatase, serum proteins • Cardiotoxicity- CPK-MB, 2D Echo, BNP

• Myotoxic – CPK, SGOT, Urine myoglobin, compartment pressure 23 Quick Reference Guide Final version

• Infection- Serum procalcitonin, culture (blood, urine, wound) and sensitivity – Arterial blood gases and urine examination should be repeated at frequent intervals during the acute phase to assess progressive systemic toxicity). 4.4.5- Rationale and interpretation of the tests 1. Hemogram: The hemogram may show transient elevation of hemoglobin level due to hemoconcentration (because of the increased capillary leak) or may show anemia (due to hemolysis, especially in viper bites). Presence of

neutrophilic leucocytosis signifies systemic absorption of venom. Thrombocytopenia may be a feature of viper envenomation. 2. Platelet count: This may be decreased in victims of envenoming by vipers. 3. White blood cell count: An early neutrophil leucocytosis is evidence of systemic envenoming from any species. 4. Blood film: Fragmented red cells (“helmet cell”, schistocytes) are seen when there is microangiopathic haemolysis. 5. Plasma/serum: May be pinkish or brownish if there is gross

haemoglobinaemia or myoglobinaemia. 6. Serum creatinine: This is necessary to rule out acute kidney injury after viper and sea snakebite. 7. Serum creatinine phosphokinase (CPK): Elevated levels of these markers suggests muscle damage (caution for renal damage) and raised amylase suggests pancreatic injury. In patients who develop capillary leak syndrome meticulous monitoring of CPK and blood pressure control is necessary to avoid the inception of renal failure.

8. Prothrombin time (PT) and activated partial thromboplastin time (aPTT): Prolongation may be present in viper bite (to be repeated 6 hourly, if abnormal). 9. Fibrinogen and fibrin degradation products (FDPs): Low fibrinogen with elevated FDP is present when venom interferes with the clotting mechanism. 10. Urine examination for Proteinuria/ RBC/ Haemoglobinuria/ Myoglobinuria: The colour of the urine (pink, red, brown, black) should be noted and the 24 Quick Reference Guide Final version

urine should be tested by dipsticks for blood or haemoglobin or myoglobin. Standard dipsticks do not distinguish blood, haemoglobin and myoglobin. Haemoglobin and myoglobin can be separated by immunoassays but there is no easy or reliable test. Microscopy will confirm whether there are erythrocytes in the urine. 11. Electrocardiogram (ECG): Common electrocardiographic changes seen are sinus tachycardia, sinus arrhythmia, sinus bradycardia, tall T-wave in V2,

pattern suggestive of acute anterior wall infarction with reciprocal changes, myocardial ischemia, non-specific ST-T changes and atrioventricular block (Nayak et al 1990). 12. Electroencephalogram (EEG): EEG changes have been noted in up to 96% of patients bitten by snakes. However, rarely needed for patient management. These changes start within hours of the bite but are not associated with any features of encephalopathy. 62% showed grade I changes, 31% cases manifested grade II changes (moderate to severe

abnormality), and the remaining 4% showed severe abnormality (grade III). These abnormal EEG patterns were seen mainly in the temporal lobes (Ramachandran S et al 1995). 13. Pulse oximetry for oxygen in patients with respiratory failure or shock. 14. Electrolyte determinations: These tests are necessary for patients with respiratory paralysis and systemic symptoms. 15. Arterial blood gases and pH may show evidence of respiratory failure

(neurotoxic envenoming) and acidaemia (respiratory or metabolic acidosis). 16. X-Ray/ CT/ Ultrasound (The use of X-Ray and ultrasound are of unproven benefit, apart from identification of bleeding in Viperine bites). 5. ANTI SNAKE VENOM (ASV) THERAPY 1. If ASV is indicated i.e. signs and symptoms of envenomation with or without evidence of laboratory tests, administer FULL dose without any delay. Do NOT wait for any test report. In a patient with a history of Bite;

known or unknown, if there is spontaneous abnormal bleeding beyond 20 minutes from time of bite, start ASV, do NOT wait for 20 WBCT report. 2. Carry out a more detailed clinical and laboratory assessment including biochemical and haematological measurements, ECG or radiography, as indicated to get a baseline data. 25 Quick Reference Guide Final version

3. There are no absolute contraindications to ASV. However, do not routinely administer ASV to any patient claiming to have bitten by a snake as ASV exposes such patients to the risks of ASV reactions unnecessarily; besides wastage of valuable and scarce stocks of ASV. However, at the same time do not delay or withhold ASV on the grounds of anaphylactic reaction to a deserving case. Do NOT give incomplete dose. 4. Purely local swelling, even if accompanied by a bite mark from an

apparently venomous snake, is not a ground for administering ASV. Swelling, a number of hours old is also not a ground for giving ASV. However, rapid development of swelling indicates bite with envenoming requiring ASV. 5.1 Antisnake venom (ASV) – Antisnake venom treatment is the only specific treatment, it should be given as soon as it is indicated. It may reverse systemic envenomation abnormality even when this has persisted for several days or, in the case of

haemostatic abnormalities, persisting for two or more weeks. The dosage required varies with the degree of envenomation. – In the presence of coagulopathy, Polyvalent ASV freeze-dried (heat stable; to be stored at cool temperature; shelf life 3-5 years) or neat liquid ASV (heat labile; ready to use; requires reliable cold chain (2-8oC and NOT frozen) with a refrigeration shelf life of 2 years but costlier) whichever is available may be used before expiry date. If integrity of the cold chain is

not guaranteed use of lyophilized ASV is preferred. However, in patients with severe envenoming recently expired antivenoms may be used if there is no alternative (WHO 2015). 5.2 Antisnake venom (ASV) DOSE Reconstitute ASV supplied in dry powder form by diluting in 10 ml of distilled water/normal saline. Mixing is done by swirling and not by vigorous shaking. Caution: Do not use, if reconstituted solution is opaque to any extent. Dose of ASV for neuroparalytic snakebite – ASV 10 vials stat as infusion

over 30 minutes followed by 2nd dose of 10 vials after 1 hour if no improvement within 1st hour. 26 Quick Reference Guide Final version

Dose of ASV for vasculotoxic snakebite - Two regimens low dose infusion therapy and high dose intermittent bolus therapy can be used. Low dose infusion therapy is as effective as high dose intermittent bolus therapy and also saves scarce ASV doses (Expert Consensus). Low Dose infusion therapy – 10 vials for Russel’s viper or 6 vials for Saw scaled viper as stat as infusion over 30 minutes followed by 2 vials every 6 hours as infusion in 100 ml of normal saline till clotting time

normalizes or for 3 days whichever is earlier. OR High dose intermittent bolus therapy - 10 vials of polyvalent ASV stat over 30 minutes as infusion, followed by 6 vials 6 hourly as bolus therapy till clotting time normalizes and/or local swelling subsides. No ASV for Sea snakebite, confirmed Green Pit snakebite even if with signs of envenomation as available ASV do not contain antibodies against them. The range of venom injected is 5 mg-147 mg. The total required dose range is

between 10 and 30 vials as each vial neutralizes 6 mg of Russell’s Viper venom. Depending on the patient condition, additional vials can be considered. Patients with capillary leak syndrome required higher dose of ASV compared to those without it. Early recognition and effective treatment like infusion of fresh frozen plasma and reduction of hemoconcentration may play a key role to reduce its gruesome mortality (Menon and Joseph 2014; Atkinson, et al 1977).

5.3 Monitoring of Patients and Precautions during ASV Administration • Give ASV only by the IV route, and slowly, with the physician at the bed side during the initial period to intervene immediately at the first sign of any reaction. Observe all patients carefully every 5 min for first 30 min, then at 15 min for 2 hours for manifestation of a reaction. At the earliest sign of an adverse reaction suspend temporarily. • The rate of infusion can be increased gradually in the absence of a reaction

until the full starting dose has been administered (over a period of ~1 hour). • Give prophylactic epinephrine 0.25 mg of 0.1% solution by subcutaneous injection (Children 0.005 mg/kg body weight of 0.1% solution) except in 27 Quick Reference Guide Final version

known hypertensive or patients with cardiovascular disease and draw Epinephrine (adrenaline) in readiness in two syringes before ASV is administered. • NEVER give ASV by IM route and do NOT inject the ASV locally at the bite site. • Take all aseptic precautions before starting ASV to prevent any pyrogenic reactions to ASV. • Maintain a strict intake output chart and note colour of urine to detect acute kidney injury early. ASV in syringe 10 vials of AVS dissolved in 100 ml of distilled water and added to

400ml of normal saline Mention date and time of starting infusion Administer 10 vials of ASV in first hour. Maintain slow drip for 24 hours Figure 8. ASV infusion and dosage schedule Each vial of AVS be dissolved in 10 ml of distilled water and added to an infusion medium such as normal saline (i.e. 10 vials of AVS dissolved in 100 ml of distilled water and added to 400ml of normal saline). The volume of infusion is reduced according to the body size and the state of hydration of the patient. In oliguric

patients restrict fluids and use infusion pump to give full dose of ASV over 30 minutes. 5.4 ASV dose in pregnancy Pregnant women are treated in exactly the same way as other victims. The same dosage of ASV is given. Refer the victim to a gynecologist for assessment of any impact on the foetus. 5.5 ASV dose in children Children also are given exactly the same dose of ASV as adults as snakes inject the same amount of venom into children and adult. 28 Quick Reference Guide Final version

Infusion: liquid or reconstituted ASV is diluted in 5-10 ml/kg body weight of normal saline. However, reduce amount of fluid in running bottle to 200 ml to avoid fluid over load. 5.6 ASV dosage in victims requiring life saving surgery Rarely patient may develop intracranial bleeding for which a life saving surgery is required. In such cases, before surgery, coagulation must be restored to avoid catastrophic bleeding and higher initial dose of ASV (up to 30 vials) can be administered. 5.7 Repeat dose of ASV

Repeat dose: in Vasculotoxic or haemotoxic envenomation Repeat clotting test every 6 hours until coagulation is restored. Administer ASV every 6 h until coagulation is restored. In patients who continue to bleed briskly repeat ASV within 1-2 hours (WHO 2015). Envenomation by the Hump- nosed Pit viper does not respond to normal Indian polyvalent ASV and coagulopathy may continue for up to 3 weeks. If 30 vials of ASV have been administered reconsider whether continued administration of ASV is serving

any purpose, particularly in the absence of proven systemic bleeding. If large doses have been administered and the coagulation abnormality persists, give fresh frozen plasma (FFP) or cryoprecipitate (fibrinogen, factor VIII), or give fresh whole blood, if both FFP and cryoprecipitate are not available. Repeat dose: neuroparalytic or neurotoxic envenomation Initial dose of ASV 10 vials stat as infusion to be followed by 2nd dose of 10 vials

if no improvement within 1st hour. Repeat 2nd dose may be required even after 2-3 hours if relapse of signs of neurotoxicity are noted (may be due to delayed absorption). Maximum dose is 20 vials of ASV for neurotoxically envenomed patients. 5.9 Victims who arrive late Sometimes victims arrive late after the bite, often after several days, usually with acute kidney injury. Determine current venom activity such as bleeding in case of viperine envenomation. Perform 20WBCT and determine if any

coagulopathy is present then administer ASV. If no coagulopathy is evident, treat kidney injury, if any. 29 Quick Reference Guide Final version

5.10. ASV reaction – NO ASV TEST DOSE MUST BE ADMINISTERED. – SKIN/CONJUNCTIVAL HYPERSENSITIVITY TESTING DOES NOT RELIABLY PREDICT EARLY OR LATE ANTISNAKE VENOM REACTIONS AND IS NOT RECOMMENDED. – Rarely patients may develop severe life-threatening anaphylaxis characterized by hypotension, bronchospasm, and angioedema. However, 20%-60% patients treated with ASV develop either early or late mild reactions (Deshpande et al.2013; Deshmukh et al 2014.

– Early anaphylactic reactions occurs within 10–180 min of start of therapy and is characterized by itching, urticaria, dry cough, nausea and vomiting, abdominal colic, diarrhoea, tachycardia, and fever. A minority of these patients may develop severe life-threatening anaphylaxis, hypotension, bronchospasm and angio-oedema (WHO 2015) – Pyrogenic reactions usually develop 1–2 h after treatment. Symptoms include chills and rigors, fever, and hypotension. These reactions are

caused by contamination of the ASV with pyrogens during the manufacturing process. – Any new sign or symptom after starting the ASV in drip should be suspected as a reaction to ASV. – Late (serum sickness–type) reactions develop 1–12 (mean 7) days after treatment. Clinical features include fever, nausea, vomiting, diarrhoea, itching, recurrent urticaria, arthralgia, myalgia, lymphadenopathy, immune complex nephritis and, rarely, encephalopathy. 5.11 Premedication with Adrenaline (epinephrine)

Routine use of prophylactic adrenaline is recommended before ASV, except in known hypertensive, and if patient presents with blood pressure more than 140/90 in adult victims or if evidence of suspicion of underlying cardiovascular disease. The adult dose of adrenaline (epinephrine) is 0.25 mg of 0.1% solution by subcutaneous injection (Children 0.005 mg/kg body weight of 0.1% solution). Use of histamine, anti-H1 and anti-H2 blockers, corticosteroids and the

rate of intravenous infusion of antivenom between 10 and 120 minutes), 30 Quick Reference Guide Final version

do not affect the incidence or severity of early antivenom reactions. (de silva 2011) 5.12 Treatment of Early ASV reaction 1. Stop ASV temporarily. 2. Oxygen 3. Start fresh IV normal saline infusion with a new IV set 4. Administer Epinephrine (adrenaline) (1 in 1,000 solution, 0.5 mg (i e 0.5 ml) in adults intramuscular over deltoid or over thigh; In children 0.01 mg/kg body weight) for early anaphylactic and pyrogenic ASV reactions. 5. Administer Chlorpheniramine maleate (adult dose 10 mg, in children 0.2

mg/kg) intravenously. – Hydrocortisone can be given but it is unlikely to act for several hours. – Once the patient has recovered, re-start ASV slowly for 10-15 minutes keeping the patient under close observation. Then resume normal drip rate. For high risk patients In patients with history of hypersensitivity or exposure to animal serum such as equine ASV, tetanus-immune globulin or rabies-immune globulin in past, severe atopic conditions: • Give ASV only if they have signs of systemic envenoming.

• Give Inj. Hydrocortisone 200 mg and Chlorpheniramine maleate 22.75 mg prior to the administration of ASV. Treatment of Late (serum sickness–type) reactions – Inj. Chlorpheniramine 2 mg in adults (In children 0.25 mg/kg/day) 6 hourly for 5 days. – In patients who fail to respond within 24–48 h give a 5-day course of Prednisolone (5 mg 6 hourly in adults and 0.7 mg/kg/day in divided doses in children. Desensitization procedure only in case of severe anaphylaxis reaction to ASV

with shock and generalised anasarca after injection of very few ml of ASV usually less than 5 ml of diluted ASV. – Change the batch of ASV – Pre-medication: Administer Inj. Hydrocortisone 100 mg I.V. and Inj. Adrenaline 0.5 ml subcutaneously/ intramuscularly (± Promethazine) Table 1. Steps of dilution of ASV 31 Quick Reference Guide Final version

Steps of Instructions Total Solution Dilution dilution Volume 1. Dilute 1 ml of ASV in a vial 10ml A with 10 ml of normal saline 2. 1ml of solution A + 9 ml of 10 ml B 1: 10 saline 3. 1ml of solution B+ 9 ml of 10 ml C 1: 100 saline 4. 1ml of solution C + 9 ml of 10 ml D 1: 1000 saline 5. 1ml of solution D + 9 ml of 10 ml E 1: 10,000 saline After dilution and preparation of Solution E, 6. MANAGEMENT NEUROTOXIC (NEUROPARALYTIC) ENVENOMATION

Antisnake venom treatment alone cannot be relied upon to save the life of a patient with bulbar and respiratory paralysis. Administer following in addition: 1. Oxygen 2. Assisted ventilation. If the patient has evidence of bulbar or respiratory paralysis, insert endotracheal tube with the help of the anesthesiologist, if available or by a trained medical personnel or use laryngeal mask airway (LMA). If there is evidence of respiratory failure, assist ventilation manually

by anaesthetic bag or mechanical ventilator. The duration of mechanical 32 Quick Reference Guide Final version

ventilation in snakebite victims is usually short since neuroparalysis reverses quickly with prompt administration of ASV. Manual ventilation (self ventilating anaesthetic bag) is also effective if mechanical ventilator is not available. Prolonged assisted ventilation with room air or oxygen is followed by complete recovery in case of Guillain-Barre syndrome and delayed neuropathy following snakebite. 3. Administer ‘Atropine Neostigmine (AN)’ schedule described as below. Give

one dose of “AN” injection before transferring to the higher centre. Rapid deterioration of Cobra bite neurotoxic syndrome may kill the patient on the way during transfer. Some patients go into a deep coma state but recover completely. Hence, diagnosis of brain death should not be considered. Do not give AN in case of confirmed krait bite. 4. Initial dose of ASV is administered over 1 hour. If ASV not available refer to a higher facility where ASV is available or if no improvement after initial dose.

6.1 Atropine neostigmine (AN) dosage schedule – Atropine 0.6 mg followed by neostigmine (1.5mg) to be given IV stat and repeat dose of neostigmine 0.5 mg with atropine every 30 minutes for 5 doses (In children, Inj. Atropine 0.05 mg/kg followed by Inj. Neostigmine 0.04 mg/kg Intravenous and repeat dose 0.01 mg/kg every 30 minutes for 5 doses). A fixed dose combination of Neostigmine and glycopyrolate IV can also be used. – Thereafter to be given as tapering dose at 1 hour, 2 hour, 6 hours and 12

hour. Majority of patients improve within first 5 doses. Observe the patient closely observed for 1 hour to determine if the neostigmine is effective. After 30 minutes, any improvement should be visible by an improvement in ptosis. Positive response to “AN” trial is measured as 50% or more recovery of the ptosis in one hour. – Stop Atropine neostigmine (AN) dosage schedule if: • Patient has complete recovery from neuroparalysis. Rarely patient can have recurrence, carefully watch patients for recurrence.

• Patient shows side effects in the form of fasciculations or bradycardia. • If there is no improvement after 3 doses. – Improvement by atropine neostigmine indicates Cobra bite. A few Nilgiri Russel’s viper bites victims also improve with this regimen. 33 Quick Reference Guide Final version

– If there is no improvement after 3 doses of atropine neostigmine, this indicates probable Krait bite. Krait affects pre-synaptic fibres where calcium ion acts as neurotransmitter. Give Inj. Calcium gluconate 10ml IV (in children 1-2 ml/kg (1:1 dilution) slowly over 5-10 min every 6 hourly and continue till neuroparalysis recovers which may last for 5-7 days. 7. MANAGEMENT OF VASCULOTOXIC SNAKEBITE 1. Strict bed rest to avoid even minor trauma.

2. Screen for hematuria, hemoglobinuria, myoglobinuria by Dipstick method. Dipstick test is positive in all three presentations listed above. Centrifuged urine showing pink color indicates hemoglobinuria, clear supernatant (RBCs settle down as deposit) indicates myoglobinuria. 3. Closely monitor urine output and maintain 1 ml/kg/h urine output. 4. If the patient is bleeding severely irrespective of full dose of ASV or is already seriously anaemic give transfusion of blood or fresh frozen plasma

or transfer where facility is available. 5. Prompt recognition of organ dysfunction and immediate intervention may reverse organ impairment and improve the outcome. 7.1 Volume Replacement in snake bite: If the patient has intravascular volume depletion, indicated by supine or postural hypotension, or empty neck veins, proceed as follows: 1. Establish intravenous access. 2. Give fluid challenge: In adult patient 200 ml in saline in 5 minutes first,

check BP response, if positive additional fluid given over 30 min or until the jugular venous pressure/central venous pressure has risen to 8-10 cm above the sterna angle (with the patient propped up at 450). 3. Observe the patient closely while this is being done. The fluid challenge must be stopped immediately if pulmonary oedema develops. 7.2 Forced Alkaline Diuresis (FAD) If urine output does not improve or dipstick positive for blood give a trial

of FAD within first 24 hours of the bite to avoid pigment nephropathy leading to acute tubular necrosis (ATN). Delayed FAD has no role. Sequence of FAD in adults is as follows: 34 Quick Reference Guide Final version

i. Inj. Frusemide 40 mg IV stat ii. Inj. Normal saline 500 ml + 20 ml of NaHCO over 20 minutes 3 iii. Inj. Ringer’s lactate 500 ml + 20 ml of NaHCO over 20 minutes 3 iv. Inj. 5% dextrose 500 ml + 10 ml of Potassium Chloride over 90 minutes v. Inj. Mannitol 150 ml over 20 min – Whole cycle completes in 2 h 30 min and urine output of 3 ml/min is expected. – If patient responds to first cycle continue for 3 cycles. FAD converts oliguria into polyuria and avoid ATN and acute kidney injury needing

dialysis in more than 75% patients. – If there is no response to furosemide discontinue FAD and refer patient immediately to a higher center for dialysis. 7.3 Detection and management of hyperkalemia Hyperkalaemia (>7 mmol/l or hyperkalaemic ECG changes- tall peaked T waves, prolonged P-R interval, absent P wave, wide QRS complexes) 1. Give 10 ml of 10% calcium gluconate intravenously over 2 minutes (with ECG monitoring if possible) repeated up to 3 times.

2. Give 50 ml of 50% dextrose with 10 units of soluble insulin intravenously 3. Sodium bicarbonate 40 ml of 8.4% by slow intravenous infusion and Salbutamol aerosol by inhaler may also be used. 7.4 Management of severe acidosis If the patient is hypotensive and profoundly acidotic (deep sighing “Kussmaul” respirations, very low plasma bicarbonate levels or very low pH <7.10, administer sodium bicarbonate 1. Calculate bicarbonate deficit

2. Administer 2-3 ampoules (40 ml of 8.4% sodium bicarbonate equivalent to 1 mmol/ml) in 55 dextrose water or half of the calculated deficit can be replaced in 3-4 hours. Caution: Intravenous bicarbonate may precipitate profound hypocalcaemia and seizures, especially in patients with rhabdomyolysis. 35 Quick Reference Guide Final version

3. Severe acidosis in snakebite is usually associated with acute renal failure. Volume expansion by sodium bicarbonate can cause fluid overload. If no clinical improvement dialysis is indicated. 7.5 Indications for dialysis • Absolute value of Blood urea >130 mg/dl (27 mmol/L) (BUN 100 mg/dl), Sr. Creatinine > 4 mg/dl (500 μmol/L) OR evidence of hypercatabolism in the form of daily rise in blood urea 30 mg/dl (BUN > 15), Sr. Creatinine > 1 mg/dl, Sr. Potassium > 1 mEq/L and fall in bicarbonate >2 mmol/L

• Fluid overload leading to pulmonary oedema • Hyperkalaemia (>7 mmol/l or hyperkalaemic ECG changes- tall peaked T waves, prolonged P-R interval, absent P wave, wide QRS complexes) • Unresponsive to conservative management. • Uremic complications – encephalopathy, pericarditis. – Haemodialysis is preferable in cases of hypotension or hyperkalaemia. Peritoneal dialysis can be performed at a secondary health care center. Continuous renal replacement therapies and intermittent hemodialysis

are equivalent in patients with severe sepsis and acute renal failure because they achieve similar short-term survival rates. – Continuous therapies are recommended to facilitate management of fluid balance in hemodynamically unstable patients. An efficient dose for continuous renal replacement therapy would be 20 to 25 mL/kg/h of effluent generation. 7.6 In case of Shock, myocardial damage 1. Correct hypovolaemia with colloid/crystalloids, controlled by observation of the central venous pressure.

2. Infusion of isotonic crystalloids or albumin, with boluses of up to 20 ml/kg for crystalloids (or albumin equivalent) over 5 to 10 min (in children over 30 min) titrated to reversing hypotension, increasing urine output, and attaining normal capillary refill, peripheral pulses and level of consciousness without inducing lung crepitations or hepatomegaly. 36 Quick Reference Guide Final version

3. If hepatomegaly or rales develop, initiate inotropic support with dopamine or dobutamine. If patient doesn’t respond to fluid resuscitation, inotropic support must be given. 4. In sepsis, noradrenaline is the inotropic agent of choice. Treat patients with hypotension associated with bradycardia with atropine. 5. For coagulopathy – in case of prolonged CT, PT, aPTT administer fresh frozen plasma (FFP) infusion. Associated low platelets indicates consumptive coagulopathy and disseminated intravascular

coagulopathy (DIC). To confirm fibrinogen level FDP should be estimated. Low fibrinogen and high FDP will require fibrinogen/FFP supplementation. Bleeding leads to anaemia, PCV of 30% must be maintained, therefore, measure serial PCV every 4 – 6 h depending upon bleeding severity of patients. If PCV is lower than 30 needs blood transfusion/PCV transfusion. 6. Avoid intramuscular injections. 7. FFP administration after ASV administration results in more rapid

restoration of clotting function in most patients, but no decrease in discharge time. Early FFP administration (< 6-8 h) post-bite is less likely to be effective. Administer 10-15 ml/kg of FFP within over 30–60 min within 4 hours of ASV administration. The aim should be a return of coagulation function, as defined by an INR of < 2.0, at 6 h after ASV administration was commenced. Non –response to FFP can occur with use of FFP that has low activity of FV and FVIII, because of either poor

storage or premature thawing (> 24 hours) prior to administration. Heparin is ineffective against venom-induced thrombosis and may cause bleeding on its own account. It should never be used in cases of snakebite. Antifibrinolytic agents are not effective and should not be used in victims of snakebite. 8. MANAGEMENT OF SEVERE LOCAL ENVENOMING 1. Local necrosis, intracompartmental syndromes and even thrombosis of major vessels is more likely in patients who cannot be treated with ASV.

2. Surgical intervention may be needed but the risks of surgery in a patient with consumption coagulopathy, thrombocytopenia and enhanced 37 Quick Reference Guide Final version

fibrinolysis must be balanced against the life-threatening complications of local envenoming. 3. Give prophylactic broad-spectrum antimicrobial treatment for cellulitis after completion of first 10 vials of ASV) is as following. Inj. Amoxiciilin+ clavulanic acid 1.2 g IV thrice daily for first 7 days then switch to oral therapy Tab. Amoxiciilin+clavulanic acid 625 mg three times a day for further 3-7 days; In children, the dose is 100 mg/Kg/day

in three divided doses intravenously; for oral therapy, the dose is 50 mg/kg/day in three divided doses. Reduce dose of Amoxiciilin+ clavulanic acid and Ceftriaxone in case of acute kidney injury due to Viper bites. Alternatively Inj Ceftriaxone 1 g IV twice daily (in children the dose is 100 mg/kg/day in two divided doses) for 7 days. • Inj. Metronidazole 400 mg IV infusion thrice daily for 7 days; in children- 30 mg/kg/day in 3-4 divided doses. 9. Recovery phase

Observation of the response to adequate dose of antisnake venom • Response to infusion of ASV is marked by normalization of blood pressure. Within 15–30 min bleeding stops, though coagulation disturbances may take up to 6 h to normalize. • Neurotoxic envenoming of the postsynaptic type (Cobra bites) begins to improve within the first 30 min, but patients may require 24–48 h for full recovery. Envenoming with presynaptic toxins (Kraits and sea snakes) do

not respond in this way usually takes a considerable time to improve. Recovery of respiratory muscles is reflected by improvement of neck flexors where flexing the neck against gravity indicates timing to wean off ventilation. Prophylactic antibiotics are unnecessary. • Nausea, headache and generalized aches and pains may disappear very quickly. • In shock patients, blood pressure may increase within the first 30-60 minutes and arrhythmias such as sinus bradycardia may resolve.

• Active haemolysis and rhabdomyolysis may cease within a few hours and the urine returns to its normal colour. However, red colour urine may 38 Quick Reference Guide Final version

persist for several days in spite of adequate ASV treatment, does not require further ASV. • Patient in deep coma recover fully provided there is no hypoxic brain damage. Autonomic dysfunctions are transient and don’t need treatment. Sometimes treatment might be harmful e.g. treating with antihypertensive drugs to lower the increased blood pressure due to sympathetic hyperactivity. 10. Other measures 1. Clean the bitten site with povidone-iodine solution, but do not apply any dressings.

2. Leave blisters alone. Allow them to break spontaneously and heal. If there is local necrosis, excise and apply saline dressings. Surgical decompression may be necessary in some cases. 3. Administer booster dose of Tetanus toxoid injection, if not vaccinated earlier or vaccination history is not reliable after correction of coagulopathy. 4. For mild pain, in adults Paracetamol 500-1000 mg (in children 10-15 mg/kg) every 4-6 hourly orally. Do not use aspirin or other non steroidal

anti-inflammatory drugs (NSAIDs). In case of severe pain in adults, Tab. Tramadol 50 mg or Inj. Tramadol 50 mg IV and in children Ibuprofen cautiously 5-10 mg/kg/dose every 8 hourly. Avoid drugs such as sedatives, pethidine, morphine and neuromuscular blocking agents in neurotoxic envenomation. A deeply sedated patient may create confusion regarding level of neuro-paralysis. 5. Maintain hydration and nutrition. 6. If there is local pain and spreading oedema, elevate the affected limb

and allow it to rest on a sand bag. 10.1 Surgical procedures in snakebite 10.1.1 Debridement of necrotic tissue Wait for 5-7 days before commencing debridement of necrotic tissue in order to specify the line of demarcation between viable and non-viable tissue. Refer patients requiring skin grafting and amputation of a 39 Quick Reference Guide Final version

necrotic digit/limb to a Surgeon after completion of ASV treatment. 10.1.2 Compartmental syndrome Clinical features of a compartmental syndrome (5 ‘P’) – • Pain (severe) • Pallor • Paraesthesia • Pulselessness • Paralysis or weakness of compartment muscle. 10.1.3 Criteria for fasciotomy in snakebite limb • Clinical evidence of an intracompartmental syndrome • Intra-compartmental pressure >40 mmHg of normal saline (in adults). Compartment pressure can be measured bed side using 3 way cannula – 16

G needle attached to one end, BP apparatus attached to 2nd end and saline infusion on 3rd side (Figure 9). • This can be confirmed by vascular Doppler and rising CPK in thousands. Timely fasciotomy decreases the need for repeated dialysis. • Haemostatic abnormalities have been corrected (with ASV or without clotting factors), otherwise the patient may bleed to death. Early treatment with antisnake venom (ASV) remains the best way of preventing irreversible muscle damage. Antisnake venom may also be

helpful in reducing severe limb oedema (Rojnuckarin et al., 2006). Corticosteroids should not be used as they are not effective in ameliorating local effects of envenoming and carry the risk of side-effects (Reid et al., 1963; Nuchprayoon et al., 2008). The limb can be raised in the initial stages to see if swelling is reduced. However, this is controversial as there is no trial evidence to support its effectiveness. • Persistent moderate swelling of the limb after viper bite can be successfully

managed by systemic broad spectrum antibiotics and repeated Magnesium Sulphate compresses (in the layers of wet bandage, changed 2-3 times a day) for 5-7 days. Compartment pressure measurement procedure is shown in Figure 10. 40 Quick Reference Guide Final version

Insert a 16 no. needle in the suspected compartment at a depth of 1 cm and connect to a simple tubing irrigated with normal saline. Measure rise in the saline column in the tubing. A rise more than 40 cm of saline corresponds to 30mm Hg of lymphatic/ capillary pressure and is suggestive of compartment pressure. This necessitates fasciotomy procedure. Figure 10. Compartment pressure measurement procedure. – Refer the patient to a surgical specialist but it is worth the treating clinician

ensuring that objective criteria are used to assess the actual intracompartmental pressure in the limb (A2). 11. Discharge If no symptoms and signs develop after 24 hours the patient can be discharged. Keep the patient under observation for 48 hours if ASV was infused. 11.1 Follow-up 1. A snakebite victim discharged from the hospital should continue to be followed up. 2. At the time of discharge patient should be advised to return to the

emergency, if there is worsening of symptoms or signs such as evidence of bleeding, worsening of pain and swelling at the site of bite, difficulty in breathing, altered sensorium, reduced or increased urine output etc. 3. The patients should also be explained about the signs and symptoms of serum sickness (fever, joint pain, joint swelling) which may manifest after 5-10 days. 11.2 Rehabilitation 1. In patients with severe local envenoming, maintain limb in a functional

position. For example, in the leg, equinus deformity of the ankle should be prevented by application of a back slab. 2. Start simple exercises while the patient is still in hospital for restoration of normal function in the bitten part. Conventional physiotherapy after discharge from hospital may accelerate functional recovery of the bitten limb. Give a time table of rehabilitation activities. 41 Quick Reference Guide Final version

3. Functional effects of local envenoming range from persistent stiffness and induration to severe deformity, tissue loss, especially dermonecrosis, requiring skin grafting and gangrene requiring debridement and amputation. 12. REFERRAL CRITERIA Vasculotoxic envenomation Neurotoxic Envenomation If no ASV is available, transfer to a Progressive neuroparalysis - transfer hospital (where ASV availability is with life support in ambulance for confirmed over the phone). mechanical ventilation (Battery

operated Transport Ventilator) If 20 WBCT is “not clotted” after operated by qualified staff or ambu loading dose of 10 vials of ASV as in bag as a last resort to a hospital case of Viper bite. where facility of a ventilator is available. If patient is continuing to bleed even after full dose of ASV transfer to a The key criteria to determine need for tertiary care medical college or higher mechanical ventilation is the ‘neck lift’ level of health facility. to elicit broken neck sign.

Progressive septicaemia Check frequently on patient’s ability to perform a neck lift. Signs of kidney injury or abnormal kidney function test transfer to a If they are able to carry out the neck tertiary care medical college or higher lift action continue treatment until level of health facility. recovery in the PHC. If patient cannot perform neck lift action, immediately refer the patient to a hospital with a mechanical ventilator. Very young children may not be able to follow commands for neck lift.

Other tests which indicate descending paralysis are declining single breath 42 Quick Reference Guide Final version

count, pooling of saliva. Oxygen saturation <90% using pulse oximetry indicates requirement for ventilator support. Figure 11. ‘‘Broken neck’’ sign observed in a 14-year-old girl bitten by a Russell’s viper in India. Envenoming by cobras, kraits and—in some areas—by Russell’s viper frequently leads to progressive descending paralysis. In this case, neuroparalysis persisted for five days despite antivenom treatment, but without progression toward respiratory failure.

H. S. Bawaskar. doi:10.1371/journal.pntd.0000603.g002 Instructions while referring – Inform the need for referral to the patient and/caregiver (family member or the accompanying attendant). – Give prior intimation to the receiving centre using available communication facilities. – Arrange for an ambulance. Call Emergency helpline 102/108 etc. Transport in an ambulance equipped with transport ventilator. If ventilator is not available tight-fitting face mask connected to an anaesthetic (Ambu) bag

should be available. However, do not waste time to get an ideal ambulance. Motorbike is a practical alternative in rural areas for rapid transport but third person must sit behind the patient to support on bike. 43 Quick Reference Guide Final version

– If ASV is not available at First contact centre transfer to the nearest health facility where ASV is available after confirmation by telephone. – Transfer to a higher health facility (Secondary Care Hospital or Tertiary Care Hospital) where facilities for mechanical ventilator and dialysis are available, if required after completion of ASV infusion only. – During transfer, continue life-supporting measures and provide airway support with the help of an accompanying staff, if required.

– Do not insert nasogastric tube routinely. It is indicated only if victim has obtunded mentation and or gag reflex is poor. If this is not possible give head up position to victim during transport to avoid aspiration of gastric contents. – Send the referral note with details of treatment given clearly mentioning the clinical status at the time of referral. See Annexure II for management of snakebite at various levels of healthcare 44 Quick Reference Guide Final version

13. References A Module on the “Management of Snakebite Cases” For Medical Officers. Developed By Public Health Branch of the Directorate of Health Services & Institute of Health & Family Welfare Kolkata. Department of Health & Family Welfare. Government of West Bengal. A2 Snakebite Management in Asia & Africa Guidelines produced by: Pakistan Medical Research Council, Pakistan Medical Association; National Program for Family Planning and Primary Health Care and Indian Journal of Emergency Pediatrics, 2011.

Alirol E, Sharma SK, Bawaskar HS, Kuch U, Chappuis F. Snake Bite in South Asia: A Review. PLoS Negl Trop Dis 2010; 4(1): e603. doi:10.1371/journal.pntd.0000603. Atkinson, JP, Waldmann, TA, Stein, SF, et al. Systemic capillary leak syndrome and monoclonal IgG gammopathy; studies in a sixth patient and a review of the literature. Medicine (Baltimore) 1977; 56:225. Bawaskar HS, Bawaskar PH and Bawaskar Parag H. Premonitory signs and symptoms of envenoming by common krait (Bungarus caeruleus). Tropical

Doctor 2014, Vol. 44(2) 82–85. Bawaskar HS, Bawaskar PH, Punde DP, Inamdar MK, Dongare RB and Bhoite RR. Profile of snakebite envenoming in rural Maharashtra, India. J Assoc Physicians India 2008; 56: 88–95. Bawaskar HS, Bawaskar PH. Call for a global snake-bite control and procurement of funding [letter]. Lancet. 2001; 357:1132–1133. Bawaskar HS. Aphasia in a farmer after viper bite. Lancet Vol 360 November 23, 2002. www.thelancet.com

Bawaskar HS. Snake bite poisoning: A neglected life-threatening occupational hazard. Indian J Crit Care Med 2014; 18: 123-4. de Silva HA, Pathmeswaran A, Ranasinha CD, Jayamanne S, Samarakoon SB, Hittharage A, et al. Low-Dose Adrenaline, Promethazine, and Hydrocortisone in the Prevention of Acute Adverse Reactions to Antivenom following Snakebite: A Randomised, Double-Blind, Placebo-Controlled Trial. PLoS Med (2011) 8(5): e1000435. doi:10.1371/journal.pmed.1000435

Deshmukh Vinod S, Motghare Vijay M, Gajbhiye Dharmendra, Birajdar SV, Deshpande Rushikesh, Pise Harshal, Jaykare Swapnil. Study on acute adverse drug reactions of antisnake venom in a rural tertiary care hospital 45 Quick Reference Guide Final version

Asian J Pharm Clin Res, Vol 7, Issue 5, 2014, 13-15 Deshpande Prabhakar Rushikesh, Motghare Vijay Motiram, Padwal Sudhir Laxman, Pore Rakesh Ramkrishna, Bhamare Chetanraj Ghanshyam, Deshmukh Vinod Shivaji, Pise Harshal Nutan. Adverse drug reaction profile of anti-snake venom in a rural tertiary care teaching hospital. Journal of Young Pharmacists 5 (2013) 41e45 Harris JB, Faiz MA, Rahman MR, Jalil MA, Ahsan MF, et al. Snakebite in Chittagong Division, Bangladesh: a study of bitten patients who developed

no signs of systemic envenoming. Trans R Soc Trop Med Hyg.2010 May;104(5):320-7. doi: 10.1016/j.trstmh.2009.12.006. Epub 2010 Jan 22. Jaideep C Menon and Joseph K Joseph. Complications of Hematotoxic snake bite in India. Clinical Toxinology in Asia Pacific and Africa, Springer Reference edited by P Gopalakrishna Kone 2015 p-209-232; Majumder D, Sinha A, Bhattacharya SK, Ram R, Dasgupta U, Ram A. Epidemiological profile of snakebite in South 24 Parganas district of West

Bengal with focus on underreporting of snakebite deaths. Indian J Public Health 2014;58:17-21. Maurya PK, Kalita J, Paliwal VK, Misra UK. Manual AMBU ventilation is still relevant in developing countries. QJM 2008; 101: 990-991. Mohapatra B, Warrell DA, Suraweera W, Bhatia P, Dhingra N, Jotkar RM Rodriguez PS, Mishra K, Whitaker R, Jha P, for the Million Death Study Collaborators. Snakebite Mortality in India: A Nationally Representative Mortality Survey. PLOS Tropical Neglected Diseases. 2011. DOI:

10.1371/journal.pntd.0001018 Nayak KC, Jain AK, Sharda DP, Mishra SN. Profile of cardiac complications of snakebite. Indian Heart J. 1990; 42:185–8. Nuchprayoon I, Pongpan C, Sripaiboonkij N. The role of prednisolone in reducing limb oedema in children bitten by green pit vipers: a randomized, controlled trial. Ann Trop Med Parasitol. 2008; 102: 643-9. Poovazhagi Varadarajan,Thankavelu Shankaerlingam et al. Peripheral Locked in syndrome following snake envenomation. Pediatric on call July- Sept

2013 Vol 10 issue 3. Prakash S .Mathew C, Bhagath S, Locked in syndrome in snake bite. J Assoc. Physicians India 2008;56;121-122. 46 Quick Reference Guide Final version

Ramachandran S, Ganaikabahu B, Pushparajan K, Wijesekara J. Electroencephalographic abnormalities in patients with snakebites. Am J Trop Med Hyg. 1995;52:25–8. Reid HA, Chan KE & Thean PC. Prolonged coagulation defect (defibrination syndrome) in Malayan viper bite. Lancet. 1963; i: 621-626. Rojnuckarin P et al. A randomized, double-blind, placebo-controlled trial of antivenom for local effects of green pit viper bites. Trans R Soc Trop Med Hyg. 2006; 100: 879-84.

Singh A, Goel S, Singh AA, Goel AK, Chhoker VK, Goel S, Naik SM, Kaur M. An epidemiological study of snakebites from rural Haryana. Int J Adv Med Health Res 2015;2:39-43. Smith E, Delargy M, Locked in syndrome. BMJ 2005; 330; 406-409 Snakebite- the neglected tropical diseases. Editorial. Lancet 2015; 386:1110 Suri V, Sharma N, Bhalla A, Mahi S. Ambu Bag - Basic Life Support Saves the Day. Emergency Medicine 2006; 23: 23-25. Sutherland SK, Coulter AR, Harris RD (1979) Rationalisation of first-aid

measures for elapid snakebite. Lancet 1: 183–185. Warrell and WHO 2009 11-Http://www.who.int/neglected _diseases.EB132_R7_en.pdf). Warrell DA. Guideline for Management of Snakebite. World Health Organization 2010. 47 Quick Reference Guide Final version

Annexure 1. SNAKE BITE EXAMINATION PERFORMA Name …………………………………….. Age ……………………….. Sex M/F Address ……………………………………………………………………………………………………….. Date ……………….time of bite ………………..Activity at time of bite …………………… Sleeping on floor bed … Yes/No …. Cot …… Yes/No ……… Mosquito net Yes/No Snake Seen Yes/No Killed Yes/No Specimen photo in mobile Yes/No Identification of snake in photos specimen as ………………………….………………….. Confirmed specimen of snake ………………………………………….……………………………. Local site

Repeat 20WBCT Clotted /Not clotted Time………….……… ASV administered ……………………. Dose given ……………vials Time………..….…..… Repeat 20WBCT after ASV Clotted /Not clotted Time………….…………………… 48 Quick Reference Guide Final version

Progress after ASV 20WBCT at 1h ………….2h…………..3h……………6h…………12h……….18h……..24h… Progress INR ……………………………………………....APTT ……………………..………………… Blood urea ………………………………Serum creatinine …………….………………….. Urine ………………………………………………………….. Haematuria /hemoglobinurea Haemogram …………………………………………Platelet count………………………………… Blood transfusion, if any ……………………………………………………………………………… Fresh Frozen Plasma (FFP), if any ………………………………………………………………… Dialysis, if any ……………………………………………………………………………………………..

Compartment syndrome Present/Not present Neuroparalytic symptoms Bilatral Ptosis ……………………………………. Opthalmoplegia ………………………………… Bulbar palsy ………………………..……. Respiratory rate ………………../min sPO ……………% One minute count …………. 2 Muscle power on arrival Upper limb ……………………lower limb …………………….. Progress ………………………… Pelvic girdle …………………………………………………………………………………………………….. Reflexes Planter on arrival …………………….Progress ……………………………………….…. Voice on arrival ………………………………………………………………………………………………..

Distance between Inter teeth margin …………On arrival ………….. Progress ………… Protrude of tongue in relation to teeth margin …………On arrival ……….progress Pupil size …………. reacting to light…………… On arrival…………………………..... Progress after ASV total dose ……………….After Repeat dose ………………………….. Intubation time ………………..Ambu bag ventilation/ Mechanical ventilator Follow up Recovery time in days……………… Total ASV dose given…………………….... Blood transfusion given/not given FFP given/not given Dialysis days………..

Ventilations total days ……………… Disability………………………………. Hypoxic brain injury ………………….. Amputation of limb ……………………. Plastic surgery 49 Quick Reference Guide Final version

Annexure 2. SNAKE BITE MANGEMENT DIFFERENT LEVELS OF HEALTHCARE AT A PRIMARY HEALTH CARE CENTER (PHC) Patient Arrival & Assessment 1. Assess circulation, airway and breathing and deal with any life threatening symptoms on presentation. 2. Establish large bore intravenous access and start normal saline slow infusion. 3. Before removal of the tourniquet/ligatures, test for the presence of a pulse distal to the tourniquet. If the pulse is absent ensure a doctor is present before removal or ligatures.

4. In case of clinically confirmed venomous bite, tourniquet should be removed only after starting of loading dose of ASV and keep Atropine Neostigmine injection ready. In case of multiple ligatures, all the ligatures can be released in Emergency Room EXCEPT the most proximal one; which should only be released after admission and all preparations. 5. Carry out a simple medical assessment including history and simple physical examination – local swelling, painful tender and enlarged local lymph

glands, persistent bleeding from the bite wound, blood pressure, pulse rate, bleeding (gums, nose, vomit, stool or urine), level of consciousness, drooping eyelids (ptosis) and other signs of paralysis. The Glasgow Coma scale cannot be used to assess the level of consciousness of patients paralyzed by neurotoxic venoms. 6. The snake, if brought, should be carefully examined and identified, if possible. (One smart phone photograph of the snake, dead or alive, if

available, should be taken for confirmation by an expert). 7. Clotting test ‘20WBCT’ in clean, new, dry, glass test tubes should be carried out to diagnose vasculotoxic envenomation. Report should be given as Clotted or Not Clotted. Never write Positive/negative. If clotted continue every 1 hour for the 1st 3 hours from the time of hospitalization and then 6 hourly for 24 hours. If a neurotoxic snakebite is confirmed, clotting test can

be repeated after 6 hours. If not clotted administer antisnake venom (ASV). 8. Give analgesia by mouth if required: Paracetamol (acetaminophen) (adult dose 500 mg to 1 g maximum 4 g in 24 hours; children 10-15 mg/kg/dose 50 Quick Reference Guide Final version

(maximum 100mg/kg/day). Do NOT give aspirin or non-steroidal anti- inflammatory drugs which can cause bleeding and renal dysfunction. 9. Assess the need and feasibility of transporting the patient to a higher level of the health service (see A above). 10. If the necessary skills, equipment, antivenom and other drugs are available, give intravenous fluid to correct hypovolaemic shock. These skills include ability to diagnose local and systemic envenoming, set up

intravenous infusion or intravenous injection, identify the early signs of anaphylaxis. 11. If the patient fulfils criteria for antivenom treatment, give ASV. If no ASV is available, transfer to a health facility where ASV is available. 12. Give premedication with Adrenaline 0.25 mg (0.1% solution) and in Children 0.005 mg/kg body weight of 0.1% solution subcutaneously except in hypertensive and patients with cardiovascular disease. Adrenaline is

made ready in two syringes of 0.5mg (1:1000) for IM administration if symptoms of any adverse reaction appear. If symptoms do appear, ASV is temporarily suspended while the reaction is dealt with and then recommenced (for details see treatment of early ASV reactions). If the patient has evidence of respiratory paralysis, give oxygen by mask or laryngeal mask airway (LMA), and intubate the patient and make arrangements for transfer to a higher facility accompanied by a Medical

Officer carrying an Ambu bag, additional endotracheal tubes, oxygen, facemasks and basic drugs for resuscitation (Suri et al 2006; Maurya et al. 2008) 13. During the journey the endotracheal tube may slip into right bronchus leading to left lung collapse and right side pneumothorax may also occur. To prevent the tube being bitten, a mouth gag should be inserted. The tube may get obstructed due to secretions or kinking leading to cyanosis and resistance to Ambu-ventilation. Then the tube should be pulled out

immediately and Ambu- ventilation could be continued with a face mask. 14. Administer Atropine and Neostigmine before transferring to a hospital as recommended above. 15. It is assumed that assisted ventilation other than by a tight-fitting face mask connected to an anaesthetic (Ambu) bag will not be possible at this 51 Quick Reference Guide Final version

level. 16. Injection Tetanus Toxoid to be given after ruling out or correction of coagulopathy. 17. Patient should be placed under observation for 24 hours (even if the victim gives a history of a nonvenomous snakebite. The bite victim becomes so frightened and confused immediately after a bite, many a time gives false identification history). If no symptoms develop after 24 hours the patient can be discharged. 6. Discourage the use of ineffective and potentially harmful drugs such as

corticosteroids, antihistamines, and heparin. SNAKE BITE MANGEMENT AT THE DISTRICT HOSPITAL Proceed as in PHC above in addition to the followings: 1. If ASV indicated and had not been given already start without any delay, do not wait for any test report. 2. Carry out a more detailed clinical and laboratory assessment including biochemical and haematological measurements, ECG or radiography, as indicated to get a baseline data. 3. If the patient is bleeding severely irrespective of full dose of ASV or is

already seriously anaemic give transfusion of blood or fresh frozen plasma or transfer where facility is available. 4. Reassess analgesia (see B above) and, if required, consider giving Tramadol 50 mg orally. In case of severe pain administer Inj. Tramadol 50 mg IV. Avoid pethidine or morphine in neurotoxic envenomation. A deeply sedated patient may create confusion regarding level of neuro-paralysis. 52 Quick Reference Guide Final version

5. Give tetanus toxoid booster (if not given already), to all snakebite victims provided coagulation is restored. 6. In case of cellulitis consider antibiotics, and consider surgical debridement of dead tissue. 7. If the patient has evidence of acute kidney injury (AKI), treat with dialysis. If this is not available, transfer to a specialized hospital. For details see Annexure. 8. If the patient has evidence of bulbar or respiratory paralysis, insert

endotracheal tube with the help of the anesthesiologist if available or by a trained medical personnel or laryngeal mask airway (LMA). If there is evidence of respiratory failure, assist ventilation manually by anaesthetic bag or mechanical ventilator. 9. Initial dose of ASV is administered over 1 hour. The first blood drawn from the patient should be typed and cross-matched, as the effects of both venom and ASV can interfere with later cross-matching.

10. Atropine neostigmine “AN” challenge test is administered using 0.6mg of atropine IV first followed by 1.5 mg of neostigmine IV (Schedule described above). Rarely, if patient require more than 2nd dose of AN test. Stop after 3rd dose if there is no response. In Krait bite practice of continuing Neostigmine drip till ptosis persists beyond 24 h is not beneficial. Pre-synaptic blockage by Krait venom does not respond to AN injection. 11. If after 2 hours from the end of the first dose of ASV, the patient’s

symptoms have worsened i.e. paralysis has descended further, a second full dose of ASV is given over 1 hour. SNAKE BITE MANGEMENT AT THE TERTIARY CARE OR MEDICAL COLLEGE Proceed as in PHC and District hospital above in addition to the following: 1. In the ICU, the standard protocol should be followed during assisted ventilation and the patient should be monitored for all parameters including level of consciousness. Avoid drugs such as sedatives, morphine and neuromuscular blocking

agents. Some patients go into a deep coma state but recover completely. Hence, diagnosis of brain death should not be considered. Recovery of respiratory muscles is reflected by improvement of neck flexors 53 Quick Reference Guide Final version

where flexing the neck against gravity indicates timing to wean off ventilation. Prophylactic antibiotics are unnecessary. 2. Multiple organ failure. Management is supportive, and prevention of organ damage in those at risk are therefore crucial. Aggressive early resuscitation, adequate antivenom therapy, excision of devitalized tissue and treatment of infection are important. Prompt recognition of organ dysfunction and immediate intervention may reverse organ impairment and improve the outcome.

3. If the patient has evidence of acute kidney injury peritoneal or haemodialysis or haemofiltration. Indications for dialysis as described above. 4. More advanced surgical management of local necrosis (e.g. split skin grafting). 5. More advanced investigations including bacterial cultures and imaging (CT scans) as indicated. 6. CNS complication and intracranial bleeding to be managed according to the standard practice. Neurosurgical opinion may be requested according to

intracranial pathology. However, haemostatic abnormalities must be corrected. 7. Coma, autonomic dysfunctions. Patient in deep coma recovers fully provided there is no hypoxic brain damage. Autonomic dysfunctions are transient and don’t need treatment. Sometimes treatment might be harmful e.g. treating with antihypertensive drugs to lower the increased blood pressure due to sympathetic hyperactivity. 8. Uncommon complications such as hepatic dysfunction, pancreatitis,

endocrine insufficiency and deep venous thrombosis should be managed according to the standard practice. 9. Implement rehabilitation by physiotherapists. 54 Quick Reference Guide Final version

STANDARD TREATMENT GUIDELINES The Diabetic foot Prevention and management in India Full Background document (Draft) January 2016 Ministry of Health & Family Welfare Government of India The Diabetic Foot – Full Background Document Ver. 3.0 (Draft)

The Diabetic Foot: Full background document TABLE OF CONTENTS pp Section 1 Introduction 1.1 Definition and burden of disease 2 1.2 Morbidity and mortality 2 Section 2 Financial burden and costs, Current practices in India 3 Section 3 Need for a Standard Treatment Guideline 3 Section 4 Recommendations (Moves from primary to tertiary) 4.0 Key terms used 4 4.1 Prevention 5 4.2 Assessment, Classification, Referral 6 4.3 Infection 7 4.4 Wound care 8 4.5 Footwear 9 4.6 Diabetic foot with Osteomyelitis 9

4.7 Charcot’s foot 10 4.8 Surgical intervention and revascularization 11 Section 5 Way forward for India 13 Section 6 How this guideline has been developed 13 Section 7 References 24 Annexure 1 Glossary of terms 26 Annexure 2 Risk grading tables for decision making 30 Annexure 3 Adapt/ Adopt Tables 38 National Standard Treatment Guidelines 1

The Diabetic Foot: Full background document Section 1. INTRODUCTION 1.1.a Definition Diabetic foot as defined by the World Health Organization is, “The foot of a diabetic patient that has the potential risk of pathologic consequences, including infection, ulceration, and/or destruction of deep tissues associated with neurologic abnormalities, various degrees of peripheral vascular disease, and/or metabolic complications of diabetes in the lower limb”. 1, 2 1.1.b Burden of disease

India is set to become the diabetes capital of the world with a projected 109 million individuals with diabetes by 2035. India ranks second (after China) with more than 66.8 3 million diabetics in the age group of 20-70. The prevalence of Diabetes in India is 8.6% 4 and, as of 2013, more than 1 million Indians die each year due to diabetes related causes. 5 Diabetic Foot (DF) is one of the most common complications for admissions imposing

tremendous medical and financial burden on our healthcare system. The lifetime risk of 6 7 a person with diabetes having a foot ulcer could be as high as 25% and is the commonest 8 reason for hospitalization of diabetic patients (about 30%) and absorbs about 20% of the total health-care costs, more than all other diabetic complications. The prevalence of foot 9, 10 ulcers in diabetics attending a centre managing diabetic foot (both indoor and outdoor

setup) in India is 3%. Foot ulcers among outpatient and inpatient diabetics attending 11, 12 hospitals in rural India was found to be 10.4%. 13 Peripheral vascular disease (PVD) occurs in about 3.2% diabetics below 50 years of age and rises to 55% in those above 80 years of age. 15% of those with diabetes for a 14 decade suffer from diabetic foot, where as it increases to almost 50% by another decade. 15 1.2: Morbidity and mortality

Approximately, 85% of non-traumatic lower limb amputations are seen in patients with prior history of diabetic foot ulcer. Each year, more than 1 million people with diabetes 16,17 lose at least a part of their leg due to diabetic foot. It shows that every 20 seconds a limb is lost in the world somewhere. In India, though recent population based data is not 18 available, it is estimated that approximately 45,000 legs are amputated every year in India.

The vast majority (75%) of these are probably preventable because the amputation often results from an infected neuropathic foot. More than half of all foot ulcers become 19 infected, requiring hospitalization, while 20% of infections result in amputation. After a 20 major amputation, 50% of people will have the other limb amputated within two years’ time. People with a history of diabetic foot ulcer have a 40% greater 10-year death rate than people with diabetes alone. 21 Section 2:

2.1 Financial burden and costs For treating a simple and complex diabetic foot ulcer in low Income countries like India can be equivalent to 5.7 years of average annual income . However, pain and suffering, 22 loss of mobility, even life-long dependence on others and limitations imposed by the change of role is incalculable . 23 National Standard Treatment Guidelines 2

The Diabetic Foot: Full background document The management of diabetic foot requires a holistic and rigorous approach without which there will be high levels of relapse, morbidity and even mortality. The expenditure on care for amputation has tow fold burden on patient as well as health care system with requirement for surgery, postoperative care followed by rehabilitation and the need for adaptations to home and prostheses fitting. However, prevention is clearly more cost

effective than cure in diabetic foot management. 2.2 Current practice in India Diabetic foot care is one of the most ignored aspects of diabetes care in India. 24 Due to social, religious, and economic compulsions, many people walk barefoot. Poverty and lack of education lead to usage of inappropriate footwear and late presentation of foot lesions. Many non-medically qualified persons are interfering in the treatment of diseases,

including diabetes. Patients also try home remedies before visiting their physicians. It 24 estimated that 90% of diabetic patients in India do not see a specialist in their lifetime. 25 Problem is further worsened by a delay in accessing healthcare due to patient approaching informal care providers and alternative medicine prescribers. Section 3 3.1 Need for a Standard Treatment Guideline There is a lack of a good evidence-based standard guideline on Diabetic foot are in India.

Currently, diabetic feet are treated by individual practitioners. Physicians, General surgeons, orthopaedic surgeons, primary care physicians, endocrinologists and podiatrists all look after the diabetic feet. But neither their roles, responsibilities nor the protocols are clearly defined in the public domain. Moreover, in the Indian context, due to the pronounced variability in the health care system, a common national guidance for

providing curative as well as preventive methods to curb the growth of diabetic foot in the future is essential. Hence, it is a public health imperative to create an integrated framework for comprehensive management of diabetic foot. 3.2 The purpose of the guideline This standard treatment guideline aims to provide evidence-informed guidance on the key components of care of people with diabetic foot from community care to hospital admission both in the public and the private sector.

3.3 Who this guideline is for This guideline is intended to be relevant to hospital staff caring for patients with diabetic foot problems in referral centres, non-specialized carers who provide secondary and primary care, prevention podiatrists and patient and their care givers. National Standard Treatment Guidelines 3

The Diabetic Foot: Full background document SECTION 4: RECOMMENDATIONS National Standard Treatment Guidelines 4

The Diabetic Foot: Full background document Divided into subsections: 1. Prevention 2. Assessment 3. Infection 4. Wound care 5. Footwear and follow up 6. Charcot’s foot 7. Surgical intervention and Revascularization Key terms used: Peripheral Neuropathy: The presence of symptoms or signs of peripheral nerve dysfunction in people with diabetes, after exclusion of other causes. Peripheral Artery Disease (PAD): Obstructive atherosclerotic vascular disease with clinical

symptoms, signs or abnormalities on non-invasive vascular assessment, resulting in disturbed or impaired circulation in one or more extremities. 4. 1: PREVENTION Overview: 1. Identification of the at-risk foot 2. Regular inspection and examination of the at-risk foot 3. Education of patient, family and healthcare providers 4. Routine wearing of appropriate footwear 5. Treatment of pre-ulcerative signs 4.1.1 Prevention of Diabetic foot problems

4.1.1 To identify a person with diabetes at risk for foot ulceration, examine the feet annually / six monthly / quarterly / monthly (depending on patient’s risk category) to seek evidence for signs or symptoms of peripheral neuropathy and peripheral artery disease. IWGDF 2015 (Adapted) Risk Classification System and preventive screening frequency Category Characteristic Frequency 0 No peripheral neuropathy Once a year 1 Peripheral neuropathy Once every 6 months

2 Peripheral neuropathy with peripheral artery Once every 3-6 months disease and/or a foot deformity National Standard Treatment Guidelines 5

The Diabetic Foot: Full background document 3 Peripheral neuropathy and a history of foot Once every 1-3 months ulcer or lower-extremity amputation source : The IWGDF guidelines 2015 4.1.2 In a person with diabetes who has peripheral neuropathy, screen for: a history of foot ulceration or lower-extremity amputation; peripheral artery disease; foot deformity; pre-ulcerative signs on the foot; poor foot hygiene; and ill-fitting or inadequate footwear. (Strong; Low) IWGDF 2015 (Adopted)

4.1.3 Treat any pre-ulcerative sign on the foot of a patient with diabetes. This includes: removing callus; protecting blisters and draining when necessary; treating ingrown or thickened toe nails; treating haemorrhage when necessary; and prescribing antifungal treatment for fungal infections. (Strong; Low) IWGDF 2015 (Adopted) 4.1.4 To protect their feet, instruct an at-risk patient with diabetes not to walk barefoot, in socks, or in thin-soled standard slippers, whether at home or when outside. (Strong;

Low) IWGDF 2015 (Adopted) 4.1.5 Instruct an at-risk patient with diabetes to: daily inspect their feet and the inside of their shoes; daily wash their feet (with careful drying particularly between the toes); avoid using chemical agents or plasters to remove callus or corns; Adopted use emollients to lubricate dry skin; and cut toe nails straight across. (Weak; Low) IWGDF 2015 (Adopted) 4.1.6 Instruct an at-risk patient with diabetes to wear properly fitting footwear to

prevent a first foot ulcer, either plantar or non-plantar, or a recurrent non-plantar foot ulcer. When a foot deformity or a pre-ulcerative sign is present, consider prescribing therapeutic shoes, custom-made insoles, or toe orthosis. (Strong; Low) IWGDF 2015 (Adopted) 4.1.7 Instruct a high-risk patient with diabetes to monitor foot skin temperature at home to prevent a first or recurrent plantar foot ulcer. This aims at identifying the early signs of

inflammation, followed by action taken by the patient and care provider to resolve the cause of inflammation. (Weak; Moderate) IWGDF 2015 (Adopted) 4.1.8 To prevent a first foot ulcer in an at-risk patient with diabetes, provide education aimed at improving foot care knowledge and behaviour, as well as encouraging the patient to adhere to this foot care advice. (Weak; Low) IWGDF 2015 (Adopted) 4.1.9 To prevent a recurrent plantar foot ulcer in an at-risk patient with diabetes,

prescribe therapeutic footwear that has a demonstrated plantar pressure relieving effect during walking and encourage the patient to wear this footwear. (IWGDF 2015 (Adapted) 4.1.10 To prevent a recurrent foot ulcer in an at-risk patient with diabetes, provide integrated foot care, which includes professional foot treatment, adequate footwear and education. This should be repeated or re-evaluated once every one to three months as necessary. (Strong; Low) IWGDF 2015 (Adopted)

4.2.1: Assessing the risk of developing a diabetic foot problem National Standard Treatment Guidelines 6

The Diabetic Foot: Full background document 4.2.1a Evaluate a diabetic patient presenting with a foot wound at 3 levels: the patient as a whole, the affected foot or limb, and the infected wound. IDSA 2012 guidelines (Adapted) 4.2.1b Assess the affected limb and foot for arterial ischemia (strong, moderate), venous insufficiency, presence of protective sensation, and biomechanical problems. IDSA 2012 guidelines (Adapted)

Explanatory note: Biomechanical problems means anatomical and physiological disturbances of the foot. i.e., structural changes which happen in the bones, joints and muscles of the foot of diabetics and the changes in the blood circulation and nerve sensation of the foot of diabetics. 4.2.2. Classification of Diabetic foot 4.2.2a Assess the severity of any diabetic foot infection using the Infectious Diseases Society of America/ International Working Group on the Diabetic Foot Classification

system. (Strong; Moderate) IWGDF 2015 (adopted) (Refer to Annexure below for IDSA/IWGDF classification system -Table 1) 4.2.2b Do not use the Wagner classification system to assess the severity of a diabetic foot ulcer. (Adopted) (NICE 2015 Guidelines on Diabetic foot problems: prevention and management.) 4.2.3 Referral for Diabetic foot problems 4.2.3a Initially hospitalize all patients with a severe infection, selected patients with a

moderate infection with complicating features (eg, severe peripheral arterial disease [PAD] or lack of home support), and any patient unable to comply with the required outpatient treatment regimen for psychological or social reasons. Also hospitalize patients who do not meet any of these criteria, but are failing to improve with outpatient therapy. IDSA 2012 guidelines (Adapted) (Also refer to Table-3 and 4 in the Annexure below, for explanatory notes.)

4.2.3b Prior to being discharged, make sure that a patient with a DFI (Diabetic Foot Infection) is clinically stable; has had any urgently needed surgery performed; has achieved acceptable glycemic control; is able to manage (on his/her own or with help) at the designated discharge location; and has a well defined plan that includes an appropriate antibiotic regimen to which he/she will adhere, an off-loading scheme (if needed), specific wound care instructions, and appropriate outpatient follow-up. IDSA

2012 guidelines (Adapted) 4.3: DIABETIC FOOT INFECTIONS 4.3.1 Consider the possibility of infection occurring in any foot wound in a patient with diabetes. Evidence of infection generally includes classic signs of inflammation (redness, warmth, swelling, tenderness, or pain) or purulent secretions, but may also include additional or secondary signs (e.g., non-purulent secretions, friable or discoloured granulation tissue, undermining of wound edges, foul odour). IDSA 2012 Guidelines (Adapted)

4.3.2 Be aware of factors that increase the risk for diabetic foot infections (DFI) and especially consider infection when these factors are present; these include a wound for which the probe-to-bone (PTB) test is positive; an ulceration present for >30 days; a history of recurrent foot ulcers; a traumatic foot wound; the presence of peripheral vascular disease in the affected limb; a previous lower extremity amputation; loss of National Standard Treatment Guidelines 7

The Diabetic Foot: Full background document protective sensation; the presence of renal insufficiency; or a history of walking barefoot. IDSA 2012 guidelines (Adapted) 4.3.3 Take plain radiographs of the affected foot of all patients presenting with a new Diabetic Foot Infection to look for bony abnormalities (deformity, destruction) as well as for soft tissue gas and radio-opaque foreign bodies. IDSA 2012 Guidelines (Adapted) 4.3.4 When and how to obtain culture from Diabetic foot patients?

4.3.4a For clinically uninfected wounds, do not collect a specimen for culture. IDSA 2012 guidelines (Adapted) 4.3.4b Send a specimen for culture that is from deep tissue, obtained by biopsy or curettage and after the wound has been cleansed and debrided. Avoid swab specimens, especially of inadequately debrided wounds, as they provide less accurate results. IDSA 2012 guidelines (Adapted) Explanatory note: Wash the wound with saline and the surrounding skin with antiseptic solution before

taking culture to avoid contamination of the specimen obtained for culture. 4.3.4c Do not obtain repeat cultures unless the patient is not clinically responding to treatment. IWDGF 2015 Guidance Document (Adapted) Explanatory note - Expert consensus says that if the signs of inflammation do not subside even after 72 hours of starting treatment, then it should be considered that patient is not responding. 4.3.4d For infected wounds, send appropriately obtained specimens for culture prior to

starting empiric antibiotic therapy, if possible. Cultures may be unnecessary for a mild infection in a patient who has not recently received antibiotic therapy. IDSA 2012 guidelines (Adapted) 4.3.5. Selection of Antibiotic and when should it be modified? 4.3.5a Do not treat clinically uninfected wounds with antibiotic therapy. IDSA 2012 Guidelines (Adapted) 4.3.5b Prescribe antibiotic therapy for all infected wounds but caution that this is often

insufficient unless combined with appropriate wound care. IDSA 2012 guidelines (Adapted) 4.3.5c Base the route of therapy largely on infection severity. Prefer parenteral therapy for all severe, and some moderate DFls, at least initially, with a switch to oral agents when the patient is systemically well and culture results are available. Use highly bioavailable oral antibiotics alone in most mild, and in many moderate, infections and

topical therapy for selected mild superficial infections. IDSA 2012 guidelines (Adapted) 4.3.5d Select an empiric antibiotic regimen on the basis of the severity of the infection and the likely etiologic agent(s). a. For mild to moderate infections in patients who have not recently received antibiotic treatment, therapy just targeting aerobic gram-positive cocci (GPC) is sufficient. b. For most severe infections, start broad-spectrum empiric antibiotic therapy,

pending culture results and antibiotic susceptibility data. c. Empiric therapy directed at P. aeruginosa is usually unnecessary except for patients with risk factors* for true infection with this organism. National Standard Treatment Guidelines 8

The Diabetic Foot: Full background document d. Consider providing empiric therapy directed against MRSA in a patient with a prior history of MRSA infection; when the local prevalence** of MRSA colonization or infection is high; or if the infection is clinically severe. IDSA 2012 guidelines (Adapted) Explanatory notes: * Risk factors for true infection with Pseudomonas aeruginosa include Immunocompromised status, Chronic Kidney Disease, warm climate and frequent exposure of foot to water.

**The local prevalence of MRSA (i.e., percentage of all Staph. aureus clinical isolates in that locale that are methicillin resistant) is high enough (perhaps 50% for a mild and 30% for a moderate soft tissue infection) that there is a reasonable probability of MRSA infection. 4.3.5e Give an initial antibiotic course for a soft tissue infection of about 1–2 weeks for mild infections and 2–3 weeks for moderate to severe infections. IDSA 2012 guidelines (Adapted)

4.3.5f Continue antibiotic therapy until, but not beyond, resolution of findings of infection, but not through complete healing of the wound. IDSA 2012 guidelines (Adapted) 4.3.5g Administer parenteral therapy initially for most severe infections and some moderate infections, with a switch to oral therapy when the infection is responding. (Strong; Low) IDSA 2012 guidelines (Adopted) 4.4: WOUND CARE 4.4.1 Clean ulcers regularly with clean water or saline*, debride them when possible in

order to remove debris from the wound surface and dress them with a sterile, inert dressing in order to control excessive exudate and maintain a warm, moist environment in order to promote healing**. (Strong; Low)IWGDF 2015 (Adopted) Explanatory note: *Clean water is boiled cooled water (distilled water) ** Do not use hydrogen peroxide, EUSOL (Edinburgh University Solution), povidone iodine, chlorhexidine, etc 4.4.2 Select dressings principally on the basis of exudate control, comfort and cost.

(Strong; Low) IWGDF 2015 (Adopted) 4.4.3 Do not use antimicrobial dressings with the goal of improving wound healing or preventing secondary infection. (Strong; Moderate) IWGDF 2015 (Adopted) 4.4.4 Do not offer the following to treat diabetic foot ulcers, unless as part of a clinical trial: · Electrical stimulation therapy, autologous platelet-rich plasma gel, regenerative wound matrices and dalteparin. · Growth factors (granulocyte colony-stimulating factor [G-CSF], platelet-derived

growth factor [PDGF], epidermal growth factor [EGF] and transforming growth factor beta [TGF-β]). · Hyperbaric oxygen therapy. NICE clinical guideline NG19 (Adopted) National Standard Treatment Guidelines 9

The Diabetic Foot: Full background document 4.4.5 Consider dermal or skin substitutes as an adjunct to standard care when treating diabetic foot ulcers, only when healing has not progressed and on the advice of the multidisciplinary foot care service. NICE clinical guideline NG19 (Adopted) 4.4.6 1f Consider negative pressure wound therapy after surgical debridement for diabetic foot ulcers, on the advice of the multidisciplinary foot care service. NICE clinical guideline NG19 (Adopted)

4.4.7 Do not select agents reported to improve wound healing by altering the biology of the wound, including growth factors, bioengineered skin products and gases, in preference to accepted standards of good quality care. (Strong; Low) IWGDF 2015 (Adopted) 4.4.8 Do not select agents reported to have an impact on wound healing through alteration of the physical environment, including through the use of electricity, magnetism, ultrasound and shockwaves, in preference to accepted standards of good

quality care. (Strong; Low) IWGDF 2015 (Adopted) 4.4.9 Do not select systemic treatments reported to improve wound healing, including drugs and herbal therapies, in preference to accepted standards of good quality care. (Strong; Low) IWGDF 2015 (Adopted) 4.4.10 Redistribution of pressure off the wound to the entire weight-bearing surface of the foot (“off-loading”). While particularly important for plantar wounds, this is also

necessary to relieve pressure caused by dressings, footwear, or ambulation to any surface of the wound. (Strong; High) IDSA 2012 guidelines (Adopted) 4.4.11 When deciding about wound dressings and offloading when treating diabetic foot ulcers, take into account the clinical assessment of the wound and the person’s preference, and use devices and dressings with the lowest acquisition cost appropriate to the clinical circumstances. NICE clinical guideline NG19 (Adopted) 4.5 : FOOTWEAR

4.5.1 To heal a neuropathic plantar forefoot ulcer without ischemia or uncontrolled infection in a patient with diabetes, offload with a non-removable knee-high device with an appropriate foot-device interface. (Strong; High) IWGDF 2015 (Adopted) Non-removable (cast) walker: Same as removable (cast) boot/walker but then with a layer(s) of fibreglass cast material circumferentially wrapped around it rendering it irremovable (also known as "instant total contact cast")

4.5.2 When a non-removable knee-high device is contraindicated or not tolerated by the patient, consider offloading with a removable knee-high walker with an appropriate foot- device interface to heal a neuropathic plantar forefoot ulcer in a patient with diabetes, but only when the patient can be expected to be adherent to wearing the device. (Weak; Moderate) IWGDF 2015 (Adopted) Removable (cast) boot/walker: Prefabricated removable knee-high boot with a rocker or roller outsole

configuration, padded interior, and an insertable and adjustable insole which may be total contact. 4.5.3 When a knee-high device is contraindicated or cannot be tolerated by the patient, consider offloading with a forefoot offloading shoe, cast shoe, or custom-made temporary shoe to heal a neuropathic plantar forefoot ulcer in a patient with diabetes, National Standard Treatment Guidelines 10

The Diabetic Foot: Full background document but only and when the patient can be expected to be adherent to wearing the shoes. (Weak; Low) IWGDF 2015 (Adopted) 4.5.4 Instruct an at-risk patient with diabetes to wear properly fitting footwear to prevent a first foot ulcer, either plantar or non-plantar, or a recurrent non-plantar ulcer. When a foot deformity or a pre-ulcerative sign is present, consider prescribing therapeutic shoes, custom-made insoles, or toe orthosis*. (Strong; Low) IWGDF 2015 (Adopted)

*Toe orthosis:- An in-shoe orthosis to achieve some alteration in the function of the toe. 4.5.5 To prevent a recurrent plantar foot ulcer in an at-risk patient with diabetes, prescribe therapeutic footwear that has a demonstrated plantar pressure relieving effect during walking and encourage the patient to wear this footwear. IWGDF 2015 (Adapted) 4.5.6 Instruct a patient with diabetes not to use conventional or standard therapeutic footwear to heal a plantar foot ulcer. IWGDF 2015 (Adapted)

Explanatory note: Use footwear with following features - Sandals: should have adjustable straps, insole, full heel counter and rigid outsole. Shoes: should have wide toe box extra depth and without laces. 4.5.7 Consider using shoe modifications, temporary footwear, toe spacers or orthoses to offload and heal a non-plantar foot ulcer without ischemia or uncontrolled infection in a patient with diabetes. The specific modality will depend on the type and location of the

foot ulcer. (Weak; Low) IWGDF 2015 (Adopted) 4.5.8 If other forms of biomechanical relief are not available, consider using felted foam* in combination with appropriate footwear to offload and heal a neuropathic foot ulcer without ischemia or uncontrolled infection in a patient with diabetes. (Weak; Low) IWGDF 2015 (Adopted) Felted foam - A fibrous, unwoven material backed by foam with absorbing and cushioning characteristics.

The foam is generally ‘rubber foam’ or ‘PU foam’ which is formed by either a polyester or polyether polyol resin, in conjunction with water and Toluene di Isocyanate, along with various catalysts and blowing agents and colouring pigments to give the desired compression. 4.6: Diabetic foot with osteomyelitis and CHARCOT’S FOOT 4.6 Treatment of Diabetic foot with osteomyelitis 4.6.1 For an infected open wound, perform a probe-to-bone test; in a patient at low risk

for osteomyelitis a negative test largely rules out the diagnosis, while in a high risk patient a positive test is largely diagnostic. (Strong; High)IDSA 2012 guidelines (Adopted) 4.6.2 Markedly elevated ESR is suggestive of osteomyelitis in suspected cases. IWGDF 2015 (Adapted) Explanatory note: Tests for serum inflammatory markers are costly and not widely available, except ESR. Also these tests are not diagnostic of DFO.

4.6.3If osteomyelitis is suspected in a person with diabetes but is not confirmed by initial X-ray, consider an MRI to confirm the diagnosis. In places where MRI is unavailable, diagnose osteomyelitis by the PTB test (clinically) and/or taking a Bone biopsy and culture. (Adapted from NICE clinical guideline NG19 and Expert group discussion) Explanatory note: Expert Consensus says that as availability of MRI is limited across the country, it is

recommended to use MRI wherever available. At the primary and secondary health centre levels, the PTB test and bone biopsy and culture are more feasible and economical and reasonably accurate. National Standard Treatment Guidelines 11

The Diabetic Foot: Full background document 4.6.4 A definite diagnosis of bone infection usually requires positive results on both histological and microbiological examinations of an aseptically obtained bone sample, but this is usually required only when the diagnosis is in doubt or determining the causative pathogen’s antibiotic susceptibility is crucial. (Strong; Moderate) IDSA 2012 guidelines (Adopted) 4.6.5 Avoid using results of soft tissue or sinus tract specimens for selecting antibiotic

therapy for osteomyelitis as they do not accurately reflect bone culture results. (Strong; Moderate) IDSA 2012 guidelines (Adopted) 4.6.6 When a radical resection leaves no remaining infected tissue*, we suggest prescribing antibiotic therapy for only a short duration (2–5 days). When there is persistent infected or necrotic bone, we suggest prolonged (≥4 weeks) antibiotic treatment. (weak, low) IDSA 2012 guidelines (Adapted)

Explanatory note: *A proximal bone histopath to be done if available to get a clear margin and confirm that no infected bone remains. 4.6.7 For specifically treating Diabetic foot osteomyelitis, we do not currently support using adjunctive treatments such as hyperbaric oxygen therapy, growth factors (including granulocyte colony stimulating factor), maggots (larvae), or topical negative pressure therapy (eg, vacuum-assisted closure). (weak, low) IDSA 2012 guidelines (Adapted)

Also refer to Table 4 and 5 in the Annexure below, for explanatory notes. 4.7. Charcot’s Foot 4.7.1 Suspect acute Charcot arthropathy if there is redness, warmth, swelling or deformity (in particular, when the skin is intact), especially in the presence of peripheral neuropathy or renal failure. Think about acute Charcot arthropathy even when deformity is not present or pain is not reported. NICE clinical guideline NG19 (Adopted)

4.7.2 Refer the person with suspected charcot’s foot early (within one week) to the - Diabetic Foot care centre to confirm the diagnosis, and offer non-weight-bearing treatment until definitive treatment can be started. NICE clinical guideline NG19(Adapted) Diabetic Foot care centre:- In India, since there are no minimum standards of services offered to the diabetic foot patients, in our recommendations we have used this term to denote this facility, which may

exist at the General Practitioner’s office, Primary health centre, Secondary care centre or at a tertiary care centre. Preferably, the diabetic foot care centre should consist of atleast a surgeon, a physician, and an orthotist. 4.7.3 If acute Charcot arthropathy is suspected, X-ray the affected foot. Consider an MRI if the X-ray is normal but clinical suspicion still remains. NICE clinical guideline NG19 (Adopted) 4.7.4 Distinguishing the bony changes of osteomyelitis from those of the less common

entity of diabetic neuro-osteoarthropathy (Charcot foot) may be particularly challenging and requires considering clinical information in conjunction with imaging. IDSA 2012 guidelines (Adopted) 4.7.5 Clinical clues supporting neuro-osteoarthropathy in this context include midfoot location and absence of a soft tissue wound, whereas those favoring osteomyelitis include presence of an overlying ulcer (especially of the forefoot or heel), either alone or

superimposed on Charcot changes. IDSA 2012 guidelines (Adopted) National Standard Treatment Guidelines 12

The Diabetic Foot: Full background document 4.7.6 If the films show classic changes suggestive of osteomyelitis (cortical erosion, periosteal reaction, mixed lucency, and sclerosis), and if there is little likelihood of neuro- osteoarthropathy, it is reasonable to initiate treatment for presumptive osteomyelitis, preferably after obtaining appropriate specimens for culture. IDSA 2012 guidelines (Adopted) 4.7.7 If the Diabetic Foot care centre suspects acute Charcot arthropathy, offer treatment

with a non-removable off-loading device. Only consider treatment with a removable off- loading device if a non-removable device is not advisable because of the clinical or the person’s circumstances. NICE clinical guideline NG19 (Adapted) 4.7.8 Do not offer bisphosphonates to treat acute Charcot arthropathy, unless as part of a clinical trial. NICE clinical guideline NG19 (Adopted) 4.7.9 Monitor the treatment of acute Charcot arthropathy using clinical assessment. This

should include measuring foot–skin temperature difference and taking serial X-rays until the acute Charcot arthropathy resolves. Acute Charcot arthropathy is likely to resolve when there is a sustained temperature difference of less than two degrees centigrade between both feet and when X-ray changes show no further progression. NICE clinical guideline NG19 (Adapted) 4.7.10 People who have a foot deformity that may be the result of a previous Charcot

arthropathy are at high risk of ulceration and should be cared for by the. Diabetic Foot care centre. NICE clinical guideline NG19 (Adopted) 4.7.10 The Diabetic Foot care centre should care for people who have a foot deformity resulting from a previous Charcot’s arthropathy as they are at high risk of ulceration. NICE clinical guideline NG19 (Adapted) 4.8: SURGICAL INTERVENTIONS AND REVASCULARIZATION 4.8.1 Consult a surgical specialist in all cases of diabetic foot infections that are moderate

or severe. IWGDF 2015 (Adapted) 4.8.2 Perform urgent surgical intervention in cases of deep abscesses, compartment syndrome and necrotizing soft tissue infections. IWGDF 2015 (Adapted) 4.8.3 Debride any wound that has necrotic tissue or surrounding callus; the required procedure may range from minor to extensive. IWGDF 2015 (Adapted) 4.8.4 Perform urgent surgical intervention for most foot infections accompanied by gas in the deeper tissues, an abscess, or necrotizing fasciitis, and less urgent surgery for

wounds with substantial nonviable tissue or extensive bone or joint involvement. IDSA 2012 guidelines (Adapted) Additional note: In those with a non-severe infection, carefully observing the effectiveness of medical therapy and the demarcation line between necrotic and viable tissue before operating may be prudent. National Standard Treatment Guidelines 13

The Diabetic Foot: Full background document 4.8.5 Consider surgical intervention in cases of osteomyelitis accompanied by: spreading soft tissue infection; destroyed soft tissue envelope; progressive bone destruction on X- ray; or, bone protruding through the ulcer. IWGDF 2015 (Adapted) 4.8.6 Remove slough, necrotic tissue & surrounding callus with sharp debridement in preference to other methods, taking relative contraindications such as severe ischemia into account. IWGDF 2015 (Adapted)

4.8.7 Consider digital flexor tenotomy to prevent a toe ulcer when conservative treatment fails in a high-risk patient with diabetes, hammertoes and either a pre- ulcerative sign or an ulcer on the toe. (weak; low) IWGDF 2015 (Adopted) 4.8.8 Consider Achilles tendon lengthening, joint arthroplasty, single or pan metatarsal head resection or osteotomy to prevent a recurrent foot ulcer when conservative treatment fails in a high-risk patient with diabetes and a plantar foot ulcer. (weak; low)

IWGDF 2015 (Adopted) Management of Peripheral Artery Disease in patients with Diabetic foot problems 4.8.9 Examine a patient with diabetes annually for the presence of peripheral artery disease (PAD); this should include, at a minimum, taking a history and palpating foot pulses. (Strong; low) IWGDF 2015 (Adopted) 4.8.10 Evaluate a patient with diabetes and a foot ulcer for the presence of PAD. Determine, as part of this examination, ankle or pedal Doppler arterial waveforms;

measure both ankle systolic pressure and systolic ankle brachial index (ABI). (Strong; Low) IWGDF 2015 (Adopted) 4.8.11 Use bedside non-invasive tests to exclude PAD. No single modality has been shown to be optimal. Measuring ABI (with <0.9 considered abnormal) is useful for the detection of PAD. Tests that largely exclude PAD are the presence of ABI 0.9-1.3, toe brachial index (TBI) ≥0.75 and the presence of triphasic pedal Doppler arterial waveforms. IWGDF 2015 (Adapted)

4.8.12 In patients with a non-healing ulcer with either an ankle pressure <50mmHg or ABI <0.5 consider urgent vascular imaging and revascularisation. (Strong; Low) IWGDF 2015 (Adopted) 4.8.13 Consider vascular imaging and revascularisation in all patients with a foot ulcer in diabetes and PAD, irrespective of the results of bedside tests, when the ulcer does not improve within 6 weeks despite optimal management. (Strong; Low) IWGDF 2015 (Adopted)

4.8.14 Do not consider Diabetic microangiopathy to be the cause of poor wound healing in patients with a foot ulcer. IWGDF 2015 (Adapted) 4.8.15 To obtain anatomical information when revascularisation is being considered, use one of these tests - Colour Doppler ultrasound, CT-angiography, MR-angiography or intra-arterial digital subtraction angiography. Evaluate the entire lower extremity arterial circulation, with detailed visualization of below-the-knee and pedal arteries. IWGDF 2015 (Adapted)

The Diabetic Foot: Full background document 4.8.16 Offer duplex ultrasound as first-line imaging to all people with peripheral arterial disease for whom revascularization is being considered. Take the decision of revascularisation on the basis of colour doppler findings and use DSA for defining the vascular anatomy prior to the procedure. (Adapted from NICE 2012 PAD Guidelines, last modified August 2015) 4.8.17 The aim of revascularisation is to restore direct flow to at least one of the foot

arteries, preferably the artery that supplies the anatomical region of the wound, and adequate revascularization should be assessed post-operatively with a colour Doppler wave-fronts (preferable) or a hand held Doppler probe used bedside. IWGDF 2015. (Adapted) 4.8.18 A centre treating patients with a foot ulcer in diabetes should have liaison / association with a centre having the expertise necessary to diagnose and treat PAD; both

endovascular techniques and bypass surgery should be available. (Adapted) IWGDF 2015 4.8.19 The multidisciplinary team should treat the patient after a revascularisation procedure for a foot ulcer in diabetes, as part of a comprehensive care plan. (Strong; Low) IWGDF 2015 (Adapted). 4.8.20 There is inadequate evidence to establish which revascularisation technique is superior and a multidisciplinary team should decide the technique of revascularization for

a patient based on a number of individual factors, such as morphological distribution of PAD, availability of autogenous vein, patient co-morbidities and local expertise. (Strong; Low) IWGDF 2015 (Adapted) 4.8.21 Give emergency treatment to patients with signs of PAD and a foot infection as they are at particularly high risk for major limb amputation. IWGDF 2015 (Adapted) 4.8.22 Avoid revascularisation in patients in whom, from the patient perspective, the

risk-benefit ratio for the probability of success is unfavourable*. (Strong;Low) IWGDF 2015 (Adopted) Explanatory note: Unfavourable risk benefit ratio would indicate those patients who are frail, elderly, bed ridden, having low life expectancy, multiple co-morbidities imposing high risk for surgical intervention, etc 4.8.23 All patients with diabetes and an ischemic foot ulcer should receive aggressive cardiovascular risk management including support for cessation of smoking, treatment of

hypertension and prescription of a statin as well as low-dose aspirin or clopidogrel. (Strong;Low) IWGDF 2015 (Adopted) 4.8.24 Do not offer major amputation to people with critical limb ischaemia unless all options for revascularisation have been considered by a vascular multidisciplinary team. Major amputation without giving a chance for revascularization is indicated only in lifesaving situations like foot causing septicemia, wet gangrene, or completely destroyed

foot (post charcot’s or osteomyelitis etc). (Adapted) NICE 2012 PAD guidelines, last modified August 2015 THE WAY FORWARD FOR INDIA National Standard Treatment Guidelines 15

The Diabetic Foot: Full background document In keeping with the rising burden, India will need to plan for a foot protection service at the primary and community level, to implement the proven cost-effective preventive interventions which are learnings from other countries. The lesser referrals to the hospital hopefully will in the future be treated by a multidisciplinary foot care service at the hospital level, using a more robust protocolized care pathway, built on Indian audited

data and cost-impact analysis research. Professionals for this interdisciplinary foot care service will include, Diabetes physicians and nurses, podiatrists, orthotists, microbiologists, interventional radiologists, vascular surgeons, wound care nurses, plastic surgeons and disability specialists. National Standard Treatment Guidelines 16

The Diabetic Foot: Full background document Section 6. How This STG was Developed National Standard Treatment Guidelines 17

The Diabetic Foot: Full background document Background A Task Force was constituted in December 2014 to guide the development of Standard Treatment Guidelines (STG) in India. The Task Force subsequently approved the draft STG development manual of India (Part 1) for development of adapted guidelines. In addition, it approved a list of 14 topics recommended by a subgroup of the task force appointed to select prioritized topics for

STG development. These 14 topics are from 10 clinical specialties for which the first set of STGs will be developed. The topic diabetic foot is included in this first list and was the dealt with by the General Surgery clinical subgroup. Overview The STG on Diabetic foot management, was developed by a team of experts and relevant stakeholders. The recommendations in the STG were adopted/ adapted from four source guidelines which are the IWGDF (2015), IDSA (2012) and NICE guideline (26th August, 2015)

on diabetic foot, and the NICE guidelines on PAD (Peripheral Arterial Disease) November 2014. Available from and full reference below: http://www.iwgdf.org/files/2015/ http://www.idsociety.org https://www.nice.org.uk/guidance/NG19 https://www.nice.org.uk/guidance/cg147 1. 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections 26 2. The National Institute for Health and Care Excellence (NICE) guidelines- Diabetic foot

problems: prevention and management (NG19) (Published: 26 August 2015) 27 3. International Working Group on the Diabetic Foot (IWGDF) 2015 - Prevention and Management of Foot Problems in Diabetes Guidance Documents and Recommendations 28 4. NICE guideline- Lower limb peripheral arterial disease: diagnosis and management (NICE clinical guideline 147) (Issued: August 2012 last modified: August 2015) 29 The processes and methods used in developing this STG draw on those outlined in the STG

development manual of India (Part 1) for development of adapted guidelines and summarized in National Standard Treatment Guidelines 18

The Diabetic Foot: Full background document the Stepwise guide on STG development. The figure below contains a schematic of the process followed and each of the steps are detailed in subsequent sections below. The NHSRC with technical support from NICE international carried out a training workshop in May 2015 to guide the STG group members and chairs on the methodology to follow in developing adapted STGs suitable for the Indian context. This workshop was conducted on 29th & 30th May,

2015 and two members (NR, MK) of the surgery STG team attended. Subsequently, NHSRC facilitated the STG development process by providing resources approved by the Ministry of Health & family welfare to the expert group. To assist widespread implementation of the diabetic foot STG, three implementation tools have been developed in addition to the STG document. They include: ● The Quick Reference Guide to help the clinical practitioner (Clinical pathways)

● An information document for the public to create patient awareness about the disease and ● the quality standards developed from key priority recommendations. Steps followed during the development of the STG on diabetic foot are as follows: 1) Diabetic foot STG Subgroup established A multi-disciplinary group consisting of health professionals, subject matter experts in various fields and a patient representative undertook the development of this evidence-based STG on

diabetic foot. Official letters of invitation were sent from the NHSRC head office. The members of the task force who worked for the Government experienced delays and difficulties in procuring permissions from their respective departments for this work. Subsequently, there were drop outs National Standard Treatment Guidelines 19

The Diabetic Foot: Full background document and new experts invited. The names of the 14 group members in the STG sub-group on diabetic foot, their specialities and organization affiliation are listed here: Task Force: The STG Subgroup on Diabetic foot None of the members report any conflict of interest in the development of this guideline and have all signed their declarations. Facilitator Nobhojit Roy, Prof & Head, Dept of Surgery, BARC hospital (HBNI University), Mumbai

Rapporteurs/Writing team Monty Khajanchi, Assistant Prof, Dept of Surgery, KEM Hospital and G S Medical college, Mumbai Satish Mishra, Associate Prof, Dept of Surgery, BARC Hospital, (HBNI University), Mumbai Kunal Chhatbar, Senior registrar, JRH Hospital, Mumbai Dikpal Singh Jadhav, BARC Hospital, (HBNI University), Mumbai Aditi S Kashikar, MGIMS Wardha (Research assistant) Expert Arun Bal, President, Diabetic Foot Association of India and Raheja Hospital for Diabetes.

Physician Usha Menon, Prof of Clinical Endocrinology, Amrita Institute of Medical Sciences, Kochi-682041, Kerala, India. Private Practitioner Sanjay Vaidya, Plastic surgeon, Hinduja Hospital DFSI Exec committee member Paramedic Gautham Gopalakrishna,Principal senior Scientist & Head, /Nurse/Rehabilitation Footwear Design and Development, Central Leather Institute, Experts Chennai Primary Care Practitioners Trupti Patil, Chembur CHSS dispensary, Chembur, Mumbai

Patient Right Group/NGO Raman Kataria, Surgery, Jan Swasthya Sahyog, Ganiyari Village, Bilaspur District, Chhattisgarh Nandakumar M, Senior secondary care surgeon, Ashwini, Gudalur, Tamil Nadu Sushil Patil, JSS, Ganyari, Chattisgarh Expert Adviser: Dr. Raghuram Sekhar, Vascular surgeon, Kokilaben Hospital, Mumbai Dr Abha Mehndiratta was the technical person providing oversight and guidelines in the meetings. Satish Mishra and Sushil Patil were the patient right representatives in the group.

The STG Subgroup met twice face-to-face and all meetings (including the smaller weekly ones were quorate (50%=7 members). The working group met every tuesday evening, before and after each of these meetings over a period of two months. Some of the members joined the small group meetings via video-conference. In the induction and orientation session held on 21st July 2015, the facilitator (Chair) welcomed all the members of the subgroup, and set up the rules of operation

based on the STG development manual, on the consistent use of terminology and definitions, using the structured powerpoint presentation provided by NHSRC/NICE. National Standard Treatment Guidelines 20

The Diabetic Foot: Full background document The induction and orientation session was held on 21st July 2015 in which the facilitator (Chair) welcomed all the members of the subgroup, and set up the rules of operation based on the STG development manual, on the consistent use of terminology and definitions, using the structured power-point presentation provided by NHSRC/NICE. The STG Subgroup met face-to-face twice between July 2015 to November 2015. The writing team

met every week, on Tuesday evening during the same time period. All these meetings were quorate (50% = 7 members). Those who could not attend physically joined in via video conferencing (Skype). Also, the individual members in the writing team kept in touch via e-mails and Whatsapp. In the initial few meetings the recommendations were drafted, and in the subsequent meetings, the recommendations were edited as per the peer review comments from the NHSRC/NICE. 2) Scope the STG

To develop the scope of this STG we followed the principle of what the scope will include and exclude. It also identifies only the key aspects of care that “must” be included, set the “boundaries” of the development work and provide a clear “framework” to enable work to stay within the agreed priorities, inform the development of the clinical questions and search strategy, inform “professionals” and the “public” about expected content of the

guideline, keep the STG to a “reasonable size” to ensure that its development can be carried out within the “allocated period”. Based on these principles, the scope of the STG underwent multiple revisions. In the 28th July 2015 meeting, the first draft of scope of the diabetic foot guideline was discussed. The scope of the STG on diabetic foot was initially drafted by the working group described above in step 1 and was subsequently reviewed and approved by the STG sub group on diabetic foot.

It was decided that this guideline will not include cost-effectiveness analysis and cost impact analysis. The costing task force instituted by the Ministry of Health & Family Welfare may carry out a cost impact analysis of the STG subsequent to its finalization. The main deliberation was whether to expand the scope beyond diabetic foot, and include prevention, glycaemic control, footwear, prosthesis and regional anaesthesia techniques

for diabetic foot. The group were in favour of including all these topics, though other international guidelines have not included it in their scope. The final version of the SCOPE of this guideline is as follows: What will be covered: Adult (18 years and older) diabetics with foot at risk or with a foot ulcer. This STG addresses primary, secondary and tertiary care of diabetic foot patients and includes prevention in the community.

Ensuring relevance to India, this guideline provides clear, appropriate and relevant clinical pathways to the healthcare provider and in plain language explain diabetic foot to the patients, who are the target audience. Prevention and Footwear are included. This STG remains brief and precise and it will be updated every three years. What this guideline does not include: Children and young people (younger than 18 years) will not be covered. Pregnant women will not be included.

The Diabetic Foot: Full background document Glycaemic control will be briefly included in the form of an annexure. Regional Anaesthesia techniques and Prosthesis are not covered 3) Search & select guidelines The STG working group searched for existing evidence based guidelines on diabetic foot. They searched the National Guideline Clearinghouse (NGC), NICE website, WHO website, Uptodate and also performed a Google search to obtain the available guidelines which were not on the

guideline.gov website. These included the Australian guidelines on diabetic foot and the Indian guidelines by the Diabetic foot society of India. In the 28th July 2015 meeting, the writing group expressed discontent about finding only two guidelines on the guideline.gov site and felt they were not enough. After the preliminary search, more guidelines were found in literature, but the evidence was not graded as per the AGREE2 method (Appraisal of Guidelines Research and Evaluation).

Both situations were not fully acceptable. The group deliberated that instead of reinventing the wheel, they would exhaust the two available evidence-based guidelines completely, and only thereafter seek answers to unanswered questions through other guidelines. 4) Compare & sift guidelines After sifting through all the available guidelines, the group selected four guidelines as the primary source guidelines viz. IWGDF (2015), IDSA (2012) and NICE guideline (26th August, 2015) on

diabetic foot, and the NICE guidelines on PAD (Peripheral Arterial Disease) November 2014. Following a review of all the selected guidelines against international criteria. In addition, the selected guidelines were compared in terms of relevance to the topic and key clinical issues listed in the scope, evidence ratings, target population and also their applicability or relevance to the Indian context. Currency of the selected guideline was ensured by including only guidelines

published/ updated in the last 5 years. The selected four guidelines were subsequently approved as source guidelines by the full STG sub group on diabetic foot. Before the first face-to-face meeting of the STG sub-group, the working group prepared a draft scope for the STG (refer to step 2), performed background research on available evidence based source guidelines (refer to step 3), compared & sifted the guidelines to select evidence based guidelines developed according to the

international methodology for guideline development (refer to step 4) and subsequently created a draft table with proposed recommendations (adopted/ adapted) selected from the selected source guideline (refer to step 5). The first draft of guidelines adopted or adapted from the source guidelines were ready and the group met on 4th August 2015, and went through each of the recommendations, presented by members of the group who were writing editors of sub-sections within the Diabetic foot guideline.

Guidelines available Selected /Not Rationale Selected Frykberg RG, Zgonis T, Armstrong Not selected, though DG, Driver VR, Giurini MSJM, this guideline was Kravitz SR, et al. Surgery DIABETIC well constructed, FOOT DISORDERS : A CLINICAL since it was about a PRACTICE GUIDELINE ( 2006 decade old. revision ) DIABETIC FOOT DISORDERS : The Journal of foot and ankle surgery. 2006;45(5):1–66 International Working Group on the Selected GRADE compatible Diabetic Foot (IWGDF) 2015 - and very well

Prevention and Management of Foot structured guideline available on the National Standard Treatment Guidelines 22

The Diabetic Foot: Full background document Problems in Diabetes Guidance guideline.gov website. Documents and Recommendation Easy to adapt to the Indian context. International consensus on the Not selected, as this Diabetic Foot, by the International guideline was old, working group on the though informative. Diabetic Foot, 1999. 2012 Infectious Diseases Society of Selected America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections

The National Institute for Health and Selected. This The don’ts are firmly Care Excellence (NICE) guidelines- guideline was stated in these Diabetic foot problems: prevention and available to us, after guidelines, and these management (NG19) (Published: 26 we had nearly NICE clearly August 2015) completed our first delineates the roles draft. The previous and responsibilities at version of the NICE each provider level, DF guideline was not including the patient. very useful in the India context, but

this new one was extensively used by our group. NICE guideline- Lower limb peripheral Referenced for Only used for PAD arterial disease (PAD): diagnosis and specific sections section management (NICE clinical guideline 147) (Issued: August 2012 last modified: August 2015) https://www.nice.org.uk/guidance/cg147 Lipsky B a, Berendt AR, Cornia PB, et Selected This guideline was al (2012) 2012 Infectious Diseases GRADE compatible, Society of America clinical practice and was excellent for

guideline for the diagnosis and Diabetic foot treatment of diabetic foot infections. infections, which is a Clin Infect Dis. doi: predominant problem 10.1093/cid/cis346 in India. Diabetic foot society of India (DFSI) This was our first National Guidelines for the starting point, as this Management of Diabetic foot (2007) was developed in India, by expert consensus. However, modifying these guidelines, adding evidence in keeping with the NICE and GRADE standards proved to be very difficult. It was more

The Diabetic Foot: Full background document feasible to contextualize to India, from guidelines which were already GRADE compatible. 5) Search & select recommendations Each key clinical issue defined in the scope of the STG was reviewed and relevant recommendations were searched for in each of the 4 selected guidelines. It was found that none of the 4 guidelines individually covered the whole STG scope, so recommendations

from all 4 guidelines were used. They were chosen according to their applicability to the Indian context (for example available expertise and resources for implementing them in practice). Each recommendation listed in the draft was circulated 3 days before the meeting and subsequently discussed with the full sub-group during the meeting of the STG sub-group on diabetic foot surgery on 14th August 2015 from 11.30 am to 4.00 pm in BARC Hospital Conference Room, Anushakti Nagar, Mumbai. All group members

declared and signed conflict of interest forms, before the meeting. 6 Adopt/ adopt recommendations Recommendations selected from various source guidelines are considered adaptations of existing guidelines and should maintain the standards (evidence) used in the original guideline. A systematic approach was followed to ensure high quality of the process. The STG clinical sub group was required to make a series of judgments on the new STG

recommendations. The meetings of 25th August and 1st September (with Dr Abha over Skype) were completely dedicated to these discussions. In between these meetings, the subsection editors contacted external experts and advisers for matters arising, which could not be resolved within the group. There was clear documentation of the deliberations and the reasons for each recommendation being adapted in the process in order to maintain quality assurance. This led to several options:

a) Adopted recommendation - this entailed transferring a recommendation verbatim to the new STG. b) Adapted recommendation – This ranged from a minor edit in order to ensure local compatibility with India, or adding precisions to the wording to clarify the recommendation. It is important that when adapting a recommendation the evidence underpinning the recommendation remains intact. Implementation challenges were considered when decisions were made to adopt or adapt

recommendations. Factors considered included public/ private health infrastructure available and affordability and primary, secondary and tertiary care. We started with tertiary care recommendations in the initial discussions (July and early August) and then handed them over to the secondary care members of the group and then to the primary care member/patient representatives (late August - early September) for feasibility in the

primary care setting. At the end, before submission we collated all the recommendations and chose the top six recommendations for implementation, the quick reference guide and the patient information sheet. National Standard Treatment Guidelines 24

The Diabetic Foot: Full background document The working group compiled a list of the proposed recommendations which was reviewed by the STG sub-group. Each proposed recommendation was discussed and debated before a decision was taken on whether it can be adopted or needed adapting to the Indian context. Few recommendations were excluded as they were considered inappropriate in view of the required resources/cost and/or feasibility. There was much debate about the

use of MRI, and the consequences of making it the standard of care in India, triggering widespread transfers of all diabetic foots from primary to tertiary care institutions. The details of adopted and adapted recommendations and the rationale for adaptation are available in the Annexure named “Adopt/Adapt guidelines”. Note on STG sub group meetings: The First Face-to-face Meeting - The STG sub-group on diabetic foot met on 14th August 2015

from 11.30 am to 4.00 pm in BARC Hospital Conference Room, Anushakti Nagar, Mumbai. The members who attended the meeting were: Dr. Arun Bal Dr.Sanjay Vaidya Dr. Abha Mehndiratta Dr. Monty Khajanchi Dr. Satish Mishra Dr. Kunal Chhatbar Dr. Raman Kataria (via Skype) Dr. Sushil Patil (via Skype) Dr. Nandakumar M (via Skype) Mr. Santosh Tirlotkar Aditi S Kashikar Dr. Nobhojit Roy (Facilitator) Apologies were sent by: Dr. Usha Menon (draft submitted by email) Dr. Dikpal Jadhav Dr. Trupti Patil

Mr. Gautham Gopalakrishna The agenda of the meeting & details of the key issues discussed are included in an annexure. The quorum (50%) of members was maintained during the meeting and all the members of the STG sub group declared whether they had any conflict of interest/ financial interest in the development of the STG on diabetic foot. Subsequently, all the members of the group were oriented by Dr Abha (NICE-India) on the methodology

defined in the STG development manual of India (Part 1) for development of adapted guidelines and summarized in the Stepwise guide on STG development. The sub-group reviewed and approved the draft scope of the diabetic foot STG compiled by the smaller group. Subsequently the sub-group had a brief discussion on the source guidelines selected by the smaller group and arrived at a consensus agreement of approval of all the 4 selected guidelines since they conformed to the international criteria for

guideline development and were either published/ updated in the last 5 years. The sub group subsequently reviewed individual recommendations on prevention, diagnosis, management and rehabilitation of diabetic foot patients collated as a draft by the smaller group in preparation for the meeting. Each recommendation was discussed and debated National Standard Treatment Guidelines 25

The Diabetic Foot: Full background document before a decision was taken on whether it can be adopted (verbatim without any changes) or can be included after adaptation to the Indian context. Few recommendations were not included at all since they were considered absolutely inappropriate in view of the required resources/cost and/or feasibility. Discussions over the electronic media: Subsequent to the STG sub group meeting the recommendations in the STG document

were revised based on the decisions made by the expert group. The document was shared with all the members by utilizing technology like Google Docs and personal e-mails wherever required. Any changes made in the document were shared with all the group members. In the event of any areas of uncertainty requiring a discussion, opinion was sought over electronic media and all issues were addressed after developing mutual consensus. A group was also created on Whatsapp to enable organization of meetings and

discussion of issues. The working group of the sub group members entrusted with the responsibility of writing the STG continued to meet weekly. The Second Face-to-Face STG Subgroup meeting was held on 8th September from 5pm to 12 AM in the BARC Hospital, Anushakti Nagar, Mumbai to review the final list of recommendations. Some of the members were available in person and some joined via skype. The implementation tools were developed using Google doc, by a consensus process and

finalized in a Face-to-face meeting on 6th of October 2015. During the entire development of the STG, the diabetic foot sub group has deliberately chosen the most up-to-date and robust evidence base available. In addition, to ensure a patient and carer focus, the concerns of patients and carers regarding health and social care have been considered in at all subgroup meetings and throughout the development of the guideline. 7. Writing the STG: Compiling all recommendations (adopted/ adapted) and developing

the implementation tools This was the final step of the ‘adaptation process’ and involved compiling and writing the adopted, adapted, updated in the final STG (Standard Treatment Guideline). The STG document was written by a smaller group comprising members of the STG group and 1 research assistant. The STG comprises of the following documents: I. The Background Document II. Implementation tools a) The Quick Reference Guide (QRG) b) The Patient’s Information Document c) The Quality Standard

The Diabetic Foot: Full background document The background document contains details about how the STG was developed i.e the process by which key recommendations were chosen either by adoption or adaptation from recommendations in selected guidelines (developed according to the international guideline development criteria). It is aimed at peer reviewers and all those who are interested to understand how the STG was developed, including who was involved, the

evidence (guidelines) underpinning the recommendations, how decisions were made. This document provides information to demonstrate that the STG has been developed according to international criteria and is therefore of good quality. The implementation tools included here are: a. The Quick Reference Guide (QRG) that summarizes the recommendations in an easy-to-use format aimed at healthcare providers (doctors, nurses) for use in

practice. The QRG is a practical resource to use on a day-to-day basis and includes all the recommendations. It presents the STG recommendations in a concise, easy- to-use format and utilizes a chart of a care pathway (represented in the form on an algorithm) containing the clinical decisions (recommendations) described in the STG. We expect that this will be the most read part of the DF STG guideline. b. The Patients Information Document summarises the recommendations in the

STG in everyday language, and is aimed at patients, their families and carers, and the wider public. It does not describe the condition or interventions in detail. We have done this in Hindi and Marathi too. c. We have developed seven Quality Standards, which are aimed at all those involved in the care of patients: ● Payers (governments, health insurers, and often patients themselves) ● Regulatory bodies ● Provider organizations ● Healthcare professionals (doctors, nurses, pharmacists, allied health

professionals) They were derived from key priority for implementation. They aim to enhance implementation of STGs and maximize impact in terms of efficiency, effectiveness and ethical considerations, prioritizing quality improvement in areas where existing clinical practice is likely to be poor, highly variable, or disadvantages particular populations (such as tribal groups, or other groups who may not have geographical access to specialist care

at central-level hospitals). The Quality Standards were developed as per the methodology listed in the STG development manual for India (Part 1), which is aligned to the principles listed in the Guide on developing quality standards in Low and Middle Income Countries developed by NICE International. 1. Review. Review 1: The STG was reviewed by Francoise Cluzeau (NICE UK) and Abha Mehndiratta (NICE India) to ensure the process followed by the STG sub group on

diabetic foot was as per the methods and processes listed in the Stepwise guide on STG development and the Manual on STG development for India (part 1). After ensuring the robustness of the process followed, the STG was sent for peer review. 63 comments were received, mainly about methodology, referencing and each of the comments were addressed by five STG group members on 11th, 12th and 13th of September 2015 and resolved by consensus. National Standard Treatment Guidelines 27

The Diabetic Foot: Full background document Review 2: Peer review received on 16th October 2015, from NHSRC internal peer-review committee: Recommendations- 1. Scope of the guidelines not provided in the guidelines. “Scope of STG” at Page 19 refers to final version of scope is given in an annexure. But no such document is included in annexure. This was an inadvertent error in attachment. At any rate, now the scope is a part of this main document, as advised and not an annexure (as advised by the

previous peer-review) 2. Priority recommendation may be shifted after listing all recommendations (Page 4) – Priority recommendations have been deleted altogether, as the previous NICE peer review by Dr. Cluzeau and Dr.Mehndiratta advised that these need to metamorphose into Quality Recommendation guidelines (QRGs). The priority recommendations are now QRGs in this document, in keeping with the QRG template provided by NICE. 3. Photos of the group should not be included in the guidelines. Later on we can

include these in process document for STG taskforce. – These have been removed, as advised. 4. Rationale for including or excluding clinical questions while defining scope should be should be given in section 2 (Page 19, Scope) rather than giving details of meetings. – The details of the meetings was in the template provided to us previously, but this has been modified this section to include the discussion about the scope; and including or excluding clinical questions while defining scope.

5. Rationale of selecting the two guidelines should be given in objective manner. It may be illustrated in a comparison table with three columns – first listing of all available guidelines, second column with selected guidelines and third with rationale for selecting guidelines for adoption/adaptation (Search & Select Guidelines) – The three column format has been created to describe why a particular guideline was selected over the other.

6. Level of evidence should be mentioned against each recommendation based on the level in source guidelines. (STG Adopt-Adapt Annexure) – We had removed the Level of Evidence in the previous submitted version, as advised by the previous NICE peer review. Only two guidelines are GRADE compatible, and the NICE guideline (Aug 2015) does not have Level of Evidence (LOE) included with each recommendation. Also recommendations 4.6.2, 4.7.4, 4.7.5, 4.7.6 are without grades and levels even though they are

from the GRADEd IDSA 2012 guidelines. As per the advice of this peer-review committee, we have reinserted the level of evidence in each recommendation. However, since not all adopted/adapted recommendations have a level of evidence, please find that these are missing in places, giving rise to an inconsistent way of writing the recommendations in this version. 7. Risk categories should be defined with a matrix (Page 4)This matrix was in the

annexure, and has been brought under the relevant recommendation, as advised. We must admit, that this looks a bit odd, as all the recommendations are clean, and all explanations and grading being available only in Annexures. But here it is. 8. Definitions for key terms should be given at the beginning of guidelines. List Acronyms and abbreviations with explanation should be given in annexure. Acronym/ Abbreviation should be expanded while it is used for the first time in

the text.The key termshave been given in the beginning of the guideline. We have revised this point 8 in this version, however, there may be a need for more shuffling terms from annexures to main document. 9. Semantics – Recommendations should start with an active verb. – All recommendations now start with an active verb. However, this violates the “ad verbatim” National Standard Treatment Guidelines 28

The Diabetic Foot: Full background document principle of not changing the original guideline recommendation and the words. In this version, in the Adapt-adopt table, we have mentioned that we have changed the recommendation to start with an active verb. 10. Avoid phrases like “We Recommend”Names of all contributors can be written at one place. –Similar to point 9, ‘we recommend’ was the writing style of one of the guidelines,

and we had retained it. But for the sake of consistency, we have removed ‘we recommend’ in this version. Review 3: Peer review comments on the Full Background Document and the Adopt- Adapt Tables received on 19th October 2015 from the NHSRC internal harmonization group. The comments on the Quick Reference Guide (clinical pathways) and the Quality Standards received on 31st October 2015. The STG team members met twice (via Skype on 6th November 2015 and face-to-face on

17th Novermber 2015) to discuss these comments. All these comments were in track changes mode in the Microsoft word document. The suggestions have been carried out and appropriate changes made in the relevant places in the documents. National Standard Treatment Guidelines 29

The Diabetic Foot: Full background document References 1. Frykberg Rg, Zgonis T, Armstrong Dg, Driver Vr, Giurini Msjm, Kravitz Sr, Et Al. Surgery Diabetic Foot Disorders: A Clinical Practice Guideline (2006 Revision ) Diabetic Foot Disorders : The Journal of Foot and Ankle Surgery. 2006;45(5):1–66. 2. International Working Group on the Diabetic Foot (2015) In: International consensus on the diabetic foot. International Working Group on the Diabetic Foot, The

Netherlands, pp 20–96 Available from:http://iwgdf.org/guidelines/definitions- criteria-2015/ 3. Indian Heart Association Why South Asians Facts Web. 30 April 2015. <http://indianheartassociation.org/why-indians-why-south-asians/overview/> 4. International Diabetes Federation Regional Fact Sheet 6th edition 2014. http://www.idf.org/sites/default/files/DA-regional-factsheets-2014_FINAL.pdf 5. WHO Global Health Observatory Data Repository, eff date; 2014-09-05

6. Reiber G, Lipsky B, Gibbons G. The burden of diabetic foot ulcers. Am J Surg. 1998;176(2A Suppl):5S–10. doi: 10.1016/S0002-9610(98)00181-0 7. Wu SC, Driver VR, Wrobel JS, Armstrong DG. Foot ulcers in the diabetic patient, prevention and treatment. Vascular health and risk management . 2007 Jan;3(1):65–7 8. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA [Internet]. 2005 [cited 2015 Feb 12];293:217–28. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15644549

9. Thomson FJ, et al. A team approach to diabetic foot care: the Manchester experience. Foot 1991;1:75-82. 10. Williams R, Airey M. The size of the problem: economic aspects of foot problems in diabetes. In: Boulton AJM, Connor H, Cavanagh PR, eds. The Foot in Diabetes, 3rd edn. Chichester: Wiley, 2000:3-17 11. Pendsey SP, Epidemiological aspects of Diabetic Foot. Int. J Diab. Dev Countries 1994; 14:37-38. Available from: http://diabetes.org.in/journal/1994_april-june/article1.pdf

12. International consensus on the Diabetic Foot, by the International working group on the Diabetic Foot, 1999. 13. Evaluation of foot problems among diabetics in rural population. Mehra BR, Thawait AP, Karandikar SS, Gupta DO, Narang RR. Indian J Surg. 2008 Aug; 70(4):175- 80.[PubMed] [Ref list] 14. Palumbo PJ, Melton LJ. Peripheral vascular disease and diabetes in M. I. Harris and R. F. Hamman (Eds), Diabetes in America, NIH 1985; publ no.85 – 1468. Washington:US Government Printing Office, 1985;XVI-21.

15. Janka H U, StandI E and Mehnert H. Peripheral vascular disease in diabetes mellitus and its relation to cardiovascular risk factor : screening with Doppler ultrasonic technique. Diabetes Care 1980; 3: 207. 16. Larsson J, Apelqvist J. Towards less amputations in diabetic patients: Incidence, causes, cost, treatment, and prevention—a review. Informa UK Ltd UK; 2009 [cited 2015 Aug 31]; Available from: http://informahealthcare.com/doi/abs/10.3109/17453679508995520

17. Reiber G, Lipsky B, Gibbons G. The burden of diabetic foot ulcers. Am. J. Surg. [Internet]. 1998 [cited 2015 Aug 4];176:5S – 10S. Available from: http://www.sciencedirect.com/science/article/pii/S0002961098001810[PubMed] [Cross Ref] National Standard Treatment Guidelines 30

The Diabetic Foot: Full background document 18. Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of diabetic foot disease. Lancet 2005 Nov 12;366(9498): 1719-1724 http://www.iwgdf.org/files/2015/website_development.pdf 19. Pendsey S. Clinical Profile of Diabetic Foot in India. The international journal of lower extremity wounds9. 2010;9(4):180–4. 20. Pendsey S. Reducing diabetic foot problems and limb amputation: An Experience

from India. In: Dinh T, editor. Global Perspective on Diabetic Foot Ulcerations. Croatia: InTech; 2011. p. 15-24 21. Diabetic foot ulcers double death rate: Study. http://timesofindia.indiatimes.com/city/ahmedabad/Diabetic-foot-ulcers-double- death-rate-Study/articleshow/25783943.cms 22. Cavanagh P, Attinger C, Abbas Z, Bal A, Rojas N, Xu Z-R. Cost of treating diabetic foot ulcers in five different countries. Diabetes. Metab. Res. Rev. [Internet]. 2012 [cited 2015 Aug 31];28 Suppl 1:107–11. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/22271734 23. Meaney B. Diabetic foot care: prevention is better than cure. Journal of renal care. 2012 Feb;38 Suppl 1:90–8. 24. Shankhdhar K, Shankhdhar LK, Shankhdhar U, Shankhdhar S. Diabetic foot problems in India: an overview and potential simple approaches in a developing country. Current diabetes reports. 2008 Dec;8(6):452–7. 25. Pendsey S. Clinical Profile of Diabetic Foot in India. The international journal of lower extremity wounds9. 2010;9(4):180–4.

26. Lipsky B a, Berendt AR, Cornia PB, et al (2012) 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. doi: 10.1093/cid/cis346 27. Diabetic foot problems: prevention and management | Guidance and guidelines | NICE. 28. The 2015 IWGDF Guidance documents on prevention and management of foot problems in diabetes: development of an evidence-based global consensus.

http://www.iwgdf.org/files/2015/website_development.pdf. Accessed 13 Sep 2015 29. Lower limb peripheral arterial disease: diagnosis and management | Guidance and guidelines | NICE. 30. Nalini Singh, David Armstrong et al. JAMA. 2005;293(2):217-228. doi:10.1001/jama.293.2.217. Preventing Foot Ulcers in Patients. http://jama.jamanetwork.com/article.aspx?articleid=200119 National Standard Treatment Guidelines 31

The Diabetic Foot: Full background document Glossary of terms and definitions used in this guideline NICE National Institute for Health and Clinical Excellence – a special health authority set up within the NHS to develop appropriate and consistent advice on health care technologies, and to commission evidence-based guidelines. DFI Diabetic Foot Infection PAD Peripheral Artery Disease PTB test Probe to Bone test IWGDF International Working Group on the Diabetic Foot- was founded in

1996, and consists of experts from almost all disciplines involved in the care of patients with diabetes and foot problems. IDSA Infectious Disease Society of America Critical Limb Persistent rest pain requiring regular analgesia for more than 2 Ischaemia weeks; ulceration or gangrene attributable to objectively proven peripheral artery disease. Claudication Pain in a foot, thigh or calf that occurs during walking and is relieved by rest, due to peripheral artery disease.

Rest pain Severe and persistent pain localized to the foot due to peripheral artery disease, that can, at least partially, be relieved by putting the foot in a dependent position. Diabetic The presence of symptoms or signs of peripheral nerve dysfunction neuropathy in people with diabetes, after exclusion of other causes. Loss of Inability to sense light pressure, e.g. as applied with a 10 gram Protective Semmes-Weinstein monofilament. Sensation

Offloading Redistribution of pressure off the wound to the entire weight- bearing surface of the foot. Foot deformity Structural abnormalities of the foot such as hammer toes, mallet toes, claw-toes, hallux valgus, prominent metatarsal heads, residuals of neuro-osteoarthropathy, amputations or other foot surgery. Total contact A well-moulded, minimally padded, below-the-knee non-removable cast fibreglass or plaster cast that maintains total contact with the entire

plantar surface and lower leg. The cast is often worn with an attachable sole to facilitate walking. National Standard Treatment Guidelines 32

The Diabetic Foot: Full background document Non removable Same as removable cast boot/walker but then with a layer(s) of cast walker fibreglass cast material circumferentially wrapped around it rendering it irremovable (also known as “instant total contact cast”). Necrosis Devitalized (dead) tissue. Gangrene Death of tissue in all tissue layers (cutis, tendon, fascia, muscle) due to insufficient blood supply. Without infection this generally results

in dry and black tissue, frequently called dry gangrene; when the tissue is infected, with accompanying putrefaction and surround cellulitis, it is often called wet gangrene. Callus Hyperkeratosis caused by excessive mechanical loading. Foot protection The foot protection service is usually based outside the hospital, for service example, in a health centre or GP clinic. The foot protection service specialises in providing foot care for people with diabetes,

preventing diabetic foot problems and dealing with foot problems that don't need to be treated in hospital. The foot protection service should be led by a podiatrist (someone trained to look after your feet; sometimes called a chiropodist) with special training in dealing with diabetic foot problems. PAD Obstructive atherosclerotic vascular disease with clinical symptoms, signs or abnormalities on non-invasive vascular assessment, resulting in disturbed or impaired circulation in one or more extremities.

Therapeutic Some form of customization to the patient’s foot regarding insole, Footwear shoe, and/or orthosis. Diabetic Foot A localised injury to the skin and/or underlying tissue, below the ulcer ankle, in a person with diabetes. (NICE 2015 Guidelines) Monofilament Done with 10 g monofilament.First touch the fiber on palm and test make him familiar with the kind of sensation. Then make the patient in a position that he does not see his sole. Then tell the patient that

you are going to touch the bottom of his feet at different points and ask him to count. The monofilament is pressed at a point till it buckles and the contact should be for one second. Fig: showing the monofilament test and the most sensitive sites (90%-blue, other recommended sites-white) JAMA2005;293(2)30 National Standard Treatment Guidelines 33

The Diabetic Foot: Full background document To minimize bias, test the different sites in random sequences and pause in between and see the patient response . If the patient fails to respond at a particular site, retest it once more later in the exam. If he fails the second time also, then are diagnosed this area as insensate. Out of 10 tested sites, 4 or more insensate sites diagnoses a moderate sensory neuropathy or in other words, LOPS (loss of protective sensation).

The monofilament should not be used for more than 50 applications per day. If you test more than this, the fiber fatigues and fails to apply 10 g force. It should then be rested for 24 hours. In general, monofilaments should be replaced every three months, or immediately if they are bent. Vibration test The vibration perception threshold can be determined by a simple tuning fork that vibrates at 120 Hz. The two sites tested are bony prominence at base of great toe and the medial malleolus. Ideally

patient should be able to perceive the vibration till it is perceived by the examiner. ABPI (Ankle Ankle brachial index using a hand held Doppler. Brachial Ankle brachial index is ratio of systolic BP ankle and systolic BP at Pressure Index) arm. Posterior tibial artery runs behind the medial malleolus. First of all, apply the bP cuff at ankle in such a way that the lower margin of the cuff is just above the ankle in the tendinous portion of the

leg. Before insufflating the BP cuff, apply jelly on the area of artery, National Standard Treatment Guidelines 34

The Diabetic Foot: Full background document put the Doppler probe and move it around till you hear a clear sound. Then with other hand insufflate the cuff. As the cuff pressure exceeds the systolic pressure, the sound will disappear. Then start releasing the insufflated air slowly. At one point, you will start getting the sound on Doppler. This is systolic BP. Now deflate the BP cuff completely and apply jelly over the area of dorsalis pedis artery, and similarly measure the systolic pressure.

In a similar way you can measure the systolic brachial in both the forearms. The highest recorded pedal pressure in one lower limb, regardless of the vessel, is divided by the highest of the two extremity pressures. This is called ABPI. Probe to bone When there is high clinical suspicion of osteomyelitis , any sterile (PTB) test blunt instrument can be used as probe and inserted into the wound, if bone can be sound then it is considered as positive test. negative test largely rules out osteomyelitis

Ipswich Touch Done at home by a nonprofessional (friend, relative, or caregiver) Test following written instructions. The test comprised light touching of the tips of the patient's 1st, 3rd, and 5th toes of each foot with the tip of the tester's index finger for 1 to 2 seconds while the patient's eyes were closed. The patient indicated whether they felt the touch by responding right or left, and results were recorded on a foot diagram. National Standard Treatment Guidelines 35

The Diabetic Foot: Full background document ANNEXURE 2: Risk grading tables for decision making Table 1. Infectious Diseases Society of America and International Working Group on the Diabetic Foot Classifications of Diabetic Foot Infection Clinical Manifestation of Infection PEDIS IDSA Grade Infection Uninfected: 1 Uninfected No symptoms or signs of infection Infected: 2 Mild At least two of the following items are present: • Local swelling or induration • Erythema >0.5cm around the wound

• Local tenderness or pain • Local warmth • Purulent discharge (thick, opaque to white or sanguineous secretion) Exclude other causes of an inflammatory response of the skin (eg, trauma, gout, acute Charcot neuro-osteoarthropathy, fracture, thrombosis, venous stasis). Local infection involving only the skin and the subcutaneous tissue (without involvement of deeper tissues and without systemic signs as described below). An erythema, must be </=2 cm around the ulcer.

Local infection (as described above) with erythema > 2 cm, or 3 Moderate involving structures deeper than skin and subcutaneous tissues (eg, abscess, osteomyelitis, septic arthritis, fasciitis), and No systemic inflammatory response signs (as described below) Local infection (as described above) with the signs of SIRS, as 3 Severea manifested by ≥2 of the following: • Temperature >38°C or <36°C • Heart rate >90 beats/min • Respiratory rate >20 breaths/min or PaCO2 <32 mm Hg

• White blood cell count >12,000 or <4000 cells/µL or ≥10% immature (band) forms Abbreviations: IDSA, Infectious Diseases Society of America; PaCO2, partial pressure of arterial carbon dioxide; PEDIS, perfusion, extent/size, depth/tissue loss, infection, and sensation; SIRS, systemic inflammatory response syndrome. a.Ischemia may increase the severity of any infection, and the presence of critical ischemia often makes the infection severe. Systemic infection may sometimes manifest

with other clinical findings, such as hypotension, confusion, vomiting, or evidence of metabolic disturbances, such as acidosis, severe hyperglycemia, and new-onset azotemia. Source: IWGDF 2015 National Standard Treatment Guidelines 36

The Diabetic Foot: Full background document Table 2: Risk Classification System and preventative screening frequency Category Characteristic Frequency 0 No peripheral Once a year neuropathy 1 Peripheral neuropathy Once every six months 2 Peripheral neuropathy Once every 3-6 months with peripheral artery disease and/or a foot deformity 3 Peripheral neuropathy Once every 1-3 months and a history of foot ulcer or lower- extremity amputation source : from The IWGDF guidelines 2015

Table 3: Characteristics suggesting a more serious diabetic foot infection Table 4: Factors indicating that hospitalization may be necessary source : from The IWGDF guidelines 2015 National Standard Treatment Guidelines 37

The Diabetic Foot: Full background document Annexure 1 Adapt / Adopt Tables National Standard Treatment Guidelines 38

The Diabetic Foot: Full background document ADAPT – ADOPT TABLES 4.1 Prevention of Diabetic Foot problems MoHFW guideline Adopted/ Original Guideline Remarks Adapted 4.1.1 To identify a Adapted IWGDF 2015 Expert person with diabetes Guidance Document consensus at risk for foot says - recommends ulceration, examine To identify a person more frequent the feet annually / six with diabetes at risk follow ups for monthly / quarterly / for foot ulceration, high risk

monthly (depending examine the feet patients of DF. on patient’s risk annually to seek Risk category*) to seek evidence for signs or stratification evidence for signs or symptoms of and frequency symptoms of peripheral of follow up has peripheral neuropathy neuropathy and been and peripheral artery peripheral artery mentioned in disease. disease.(Strong; the Annexure Low) table-2. 4.1.2 In a person with Adopted IWGDF 2015 diabetes who has Guidance document peripheral neuropathy, screen for: a history of

foot ulceration or lower-extremity amputation; peripheral artery disease; foot deformity; pre- ulcerative signs on the foot; poor foot hygiene; and ill-fitting or inadequate footwear.(Strong; Low) 4.1.3 Treat any pre- Adopted IWGDF 2015 ulcerative sign on the Guidance document foot of a patient with diabetes. This includes: removing callus; protecting blisters and draining when necessary; treating ingrown or thickened National Standard Treatment Guidelines 39

The Diabetic Foot: Full background document toe nails; treating haemorrhage when necessary; and prescribing antifungal treatment for fungal infections.(Strong; Low) 4.1.4 To protect their Adopted IWGDF 2015 feet, instruct an at-risk Guidance document patient with diabetes not to walk barefoot, in socks, or in thin-soled standard slippers, whether at home or when outside.(Strong; Low) 4.1.5 Instruct an at- Adopted IWGDF 2015 risk patient with Guidance document diabetes to: daily inspect their feet and

the inside of their shoes; daily wash their feet (with careful drying particularly between the toes); avoid using chemical agents or plasters to remove callus or corns; use emollients to lubricate dry skin; and cut toe nails straight across.(Weak; Low) 4.1.6 Instruct an at- Adopted IWGDF 2015 risk patient with Guidance document diabetes to wear properly fitting footwear to prevent a first foot ulcer, either plantar or non-plantar, or a recurrent non- plantar foot ulcer. When a foot deformity

or a pre-ulcerative sign is present, consider prescribing National Standard Treatment Guidelines 40

The Diabetic Foot: Full background document therapeutic shoes, custom-made insoles, or toe orthosis.(Strong; Low) 4.1.7 Instruct a high- Adopted IWGDF 2015 risk patient with Guidance document diabetes to monitor foot skin temperature at home to prevent a first or recurrent plantar foot ulcer. This aims at identifying the early signs of inflammation, followed by action taken by the patient and care provider to resolve the cause of inflammation. (Weak; Moderate) 4.1.8 To prevent a first Adopted IWGDF 2015

foot ulcer in an at-risk Guidance document patient with diabetes, provide education aimed at improving foot care knowledge and behaviour, as well as encouraging the patient to adhere to this foot care advice. (Weak; Low) 4.1.9 To prevent a Adapted IWGDF 2015 Expert recurrent plantar foot guidance document Consensus says ulcer in an at-risk says - that no patient with diabetes, To prevent a footwear prescribe therapeutic recurrent plantar manufacture footwear that has a foot ulcer in an at- can mention

demonstrated plantar risk patient with the quantity of pressure relieving diabetes, prescribe pressure effect during walking therapeutic reduction as it and encourage the footwear that has a depends on the patient to wear this demonstrated height and footwear. plantar pressure weight of the relieving effect patient as well during walking as the pattern (i.e.30% relief of foot strike. National Standard Treatment Guidelines 41

The Diabetic Foot: Full background document compared to plantar pressure in standard of care therapeutic footwear) and encourage the patient to wear this footwear. (Strong; Moderate) 4.1.10 To prevent a Adopted IWGDF 2015 recurrent foot ulcer in Guidance document an at-risk patient with diabetes, provide integrated foot care, which includes professional foot treatment, adequate footwear and education. This should be repeated or re- evaluated once every one to three months as necessary.(Strong; Low)

* Risk category and frequency of follow up is given in the annexure document. 4.2.1: Assessing the risk of developing a diabetic foot problem MoHFW guideline Adopted/ Original Guideline Remarks Adapted 4.2.1a Evaluate a Adapted IDSA 2012 Guidelines Rephrasing diabetic patient says – done for presenting with a foot Clinicians should using active wound at 3 levels: the evaluate a diabetic verb. patient as a whole, patient presenting with the affected foot or a foot wound at 3 levels:

limb, and the infected the patient as a whole, wound. the affected foot or limb, and the infected wound. (Strong; Low) 4.2.1b Assess the Adapted IDSA 2012 Guidelines Rephrasing affected limb and foot says - done for for arterial ischemia, We recommend using active venous insufficiency, assessing the affected verb. presence of limb and foot for National Standard Treatment Guidelines 42

The Diabetic Foot: Full background document protective sensation, arterial ischemia and biomechanical (strong, moderate), problems*. venous insufficiency, presence of protective sensation, and biomechanical problems. (Strong; Low) * Biomechanical problems means anatomical and physiological disturbances of the foot, i.e., structural changes which happen in the bones, joints and muscles of the foot of diabetics and the changes in the blood circulation and nerve sensation of the foot of diabetics.

4.2.2 Classification of Diabetic foot MoHFW guideline Adopted/ Original Remarks Adapted Guideline 4.2.2a Assess the Adopted IWGDF 2015 Classification has severity of any Guidance been provided in diabetic foot infection Document the Annexure Table- using the Infectious 1. Diseases Society of America/ International Working Group on the Diabetic Foot Classification system. (Strong; Moderate) 4.2.2b Do not use the Adopted NICE 2015 Wagner classification Wagner classification Guidelines on does not take into

account the presence of system to assess the Diabetic foot neuropathy and size of severity of a diabetic problems: the lesion. These factors foot ulcer. prevention and can have a pronounced management effect on the treatment and potential outcome. (Reference – Podiatry Today – A Guide to Understanding the Various Wound Classification Systems – by Kathleen Satterfield – vol. 19 – Issue 6 – June 2006) 4.2.3 Referral for Diabetic foot problems (Admission criteria and Discharge criteria)

The Diabetic Foot: Full background document MoHFW guideline Adopted/ Original Guideline Remarks Adapted 4.2.3a Initially Adapted IDSA 2012 Guidelines Rephrasing hospitalize all patients says - done for with a severe infection, We recommend that all using active selected patients with a patients with a severe verb. moderate infection infection, selected with complicating patients with a features (eg, severe moderate infection peripheral arterial with complicating

disease [PAD] or lack of features (e.g., severe home support), and PAD or lack of home any patient unable to support), and any comply with the patient unable to required outpatient comply with an treatment regimen for appropriate outpatient psychological or social treatment regimen for reasons. Also psychological or social hospitalize patients reasons be hospitalized who do not meet any of initially. Patients who these criteria, but are do not meet any of failing to improve with these criteria but are

outpatient therapy. failing to improve with outpatient therapy may also need to be hospitalized (Strong, low). 4.2.3b Prior to being Adapted IDSA 2012 Guidelines Rephrasing discharged, make sure says - done for that a patient with a We recommend that using active Diabetic Foot Infection prior to being verb. is clinically stable; has discharged, a patient had any urgently with a DFI should be needed surgery clinically stable; have performed; has had any urgently achieved acceptable needed surgery

glycemic control; is performed; have able to manage (on achieved acceptable his/her own or with glycemic control; be help) at the designated able to manage (on discharge location; and his/her own or with has a well defined plan help) at the designated that includes an discharge location; and appropriate antibiotic have a well defined regimen to which plan that includes an he/she will adhere, an appropriate antibiotic National Standard Treatment Guidelines 44

The Diabetic Foot: Full background document off-loading scheme (if regimen to which needed), specific he/she will adhere, an wound care off-loading scheme (if instructions, and needed), specific appropriate outpatient wound care follow-up. instructions, and appropriate outpatient follow-up. (Strong, low). 4.3 Diabetic Foot Infections MoHFW guideline Adopted/ Original Guideline Remarks Adapted 4.3.1 Consider the Adapted IDSA 2012 Guidelines Rephrasing possibility of infection says – done for

occurring in any foot Clinicians should using active wound in a patient consider the possibility verb. with diabetes. Evidence of infection occurring of infection generally in any foot wound in a includes classic signs of patient with diabetes. inflammation (redness, Evidence of infection warmth, swelling, generally includes tenderness, or pain) or classic signs of purulent secretions, inflammation (redness, but may also include warmth, swelling, additional or secondary tenderness, or pain) or

signs (e.g., nonpurulent purulent secretions, secretions, friable or but may also include discolored granulation additional or secondary tissue, undermining of signs (e.g., non- wound edges, foul purulent secretions, odour). friable or discoloured granulation tissue, undermining of wound edges, foul odour). (Strong; Low) 4.3.2 Be aware of Adapted IDSA 2012 Guidelines Rephrasing factors that increase says – done for the risk for diabetic Clinicians should be using active

foot infections (DFI) aware of factors that verb. and especially consider increase the risk for infection when these diabetic foot infections factors are present; (DFI) and especially these include a wound consider infection National Standard Treatment Guidelines 45

The Diabetic Foot: Full background document for which the probe-to- when these factors are bone (PTB) test is present; these include a positive; an ulceration wound for which the present for >30 days; a probe-to-bone (PTB) history of recurrent test is positive; an foot ulcers; a traumatic ulceration present for foot wound; the >30 days; a history of presence of peripheral recurrent foot ulcers; a vascular disease in the traumatic foot wound; affected limb; a the presence of

previous lower peripheral vascular extremity amputation; disease in the affected loss of protective limb; a previous lower sensation; the presence extremity amputation; of renal insufficiency; loss of protective or a history of walking sensation; the presence barefoot. of renal insufficiency; or a history of walking barefoot. (Strong; Low) 4.3.3 Take plain Adapted IDSA 2012 Guidelines Rephrasing radiographs of the says – done for affected foot of all We recommend that all using active

patients presenting patients presenting verb. with a new Diabetic with a new DFI have Foot Infection to look plain radiographs of for bony abnormalities the affected foot to look (deformity, for bony abnormalities destruction) as well as (deformity, for soft tissue gas and destruction) as well as radio-opaque foreign for soft tissue gas and bodies. radio-opaque foreign bodies (strong, moderate). 4.3.4 When and how to obtain culture from Diabetic foot patients

MoHFW guideline Adopted/ Original Guideline Remarks Adapted 4.3.4a For clinically Adapted IDSA 2012 Guidelines Rephrasing uninfected wounds, says – done for using do not collect a For clinically active verb. specimen for culture. uninfected wounds, we National Standard Treatment Guidelines 46

The Diabetic Foot: Full background document recommend not collecting a specimen for culture (strong, low). 4.3.4b Send a Adapted IDSA 2012 Guidelines Rephrasing specimen for culture says – done for using that is from deep We recommend active verb. tissue, obtained by sending a specimen for biopsy or curettage culture that is from and after the wound deep tissue, obtained has been cleansed by biopsy or curettage and debrided. Avoid after the wound has swab specimens, been cleansed and

especially of debrided. We suggest inadequately avoiding swab debrided wounds, as specimens, especially they provide less of inadequately accurate results.* debrided wounds, as they provide less accurate results (strong, moderate). 4.3.4c Do not obtain Adapted IWDGF 2015 says – Infection repeat cultures Do not obtain repeat control unless the patient is cultures unless the surveillance of not clinically patient is not clinically resistant responding to responding to pathogens

treatment. treatment, or may not be occasionally for possible at all infection control levels. surveillance of resistant pathogens (Strong; Low) 4.3.4d For infected Adapted IDSA 2012 Guidelines Rephrasing wounds, send For infected wounds, done for using appropriately we recommend that active verb. obtained specimens clinicians send for culture prior to appropriately obtained starting empiric specimens for culture antibiotic therapy, if prior to starting possible. Cultures empiric antibiotic

may be unnecessary therapy, if possible. for a mild infection in Cultures may be a patient who has not unnecessary for a mild recently received infection in a patient antibiotic therapy. who has not recently National Standard Treatment Guidelines 47

The Diabetic Foot: Full background document received antibiotic therapy (strong, low). *Wash the wound with saline and the surrounding skin with antiseptic solution before taking culture to avoid contamination of the specimen obtained for culture. 4.3.5 Selection of Antibiotic and when should it be modified MoHFW guideline Adopted/ Original Remarks Adapted Guideline 4.3.5a Do not treat Adapted IDSA 2012 Rephrasing done for clinically Guidelines says – using active verb. uninfected wounds We recommend

with antibiotic that clinically therapy. uninfected wounds not be treated with antibiotic therapy (strong, low). 4.3.5b Prescribe Adapted IDSA 2012 Rephrasing done for antibiotic therapy Guidelines says – using active verb. for all infected We recommend wounds but prescribing caution that this is antibiotic therapy often insufficient for all infected unless combined wounds but with appropriate caution that this is wound care. often insufficient unless combined with appropriate wound care (strong, low).

4.3.5c Base the Adapted IDSA 2012 Rephrasing done for route of therapy guidelines says – using active verb. largely on infection We suggest basing severity. Prefer the route of parenteral therapy therapy largely on for all severe, and infection severity. some moderate We prefer DFls, at least parenteral therapy initially, with a for all severe, and switch to oral some moderate agents when the DFIs, at least patient is initially (weak, systemically well low), with a switch

The Diabetic Foot: Full background document and culture results to oral agents are available. when the patient is Clinicians can systemically well probably use and culture results highly bioavailable are available. oral antibiotics Clinicians can alone in most mild, probably use and in many highly bioavailable moderate, oral antibiotics infections and alone in most mild, topical therapy for and in many selected mild moderate, superficial infections and infections. topical therapy for selected mild

superficial infections (strong, moderate). 4.3.5d Clinicians Adapted IDSA 2012 Rephrasing done for should select an Guidelines says using active verb. empiric antibiotic that – regimen on the We recommend basis of the that clinicians severity of the select an empiric infection and the antibiotic regimen likely etiologic on the basis of the agent(s). severity of the a. For mild to infection and the moderate likely etiologic infections in agent(s). (Strong; patients who have Low) not recently a. For mild to

received antibiotic moderate treatment, therapy infections in just targeting patients who have aerobic gram- not recently positive cocci received antibiotic (GPC) is sufficient. treatment, we b. For most suggest that severe infections, therapy just start broad- targeting aerobic spectrum empiric gram-positive antibiotic therapy, cocci (GPC) is pending culture sufficient. (Weak; results and Low) antibiotic b. For most susceptibility data. severe infections, National Standard Treatment Guidelines 49

The Diabetic Foot: Full background document c. Empiric we recommend therapy directed at starting broad- P. aeruginosa is spectrum empiric usually antibiotic therapy, unnecessary pending culture except for patients results and with risk factors* antibiotic for true infection susceptibility data. with this organism. (Strong; Low) d. Consider c. Empiric providing empiric therapy directed at therapy directed P. aeruginosa is against MRSA in a usually patient with a unnecessary

prior history of except for patients MRSA infection; with risk factors* when the local for true infection prevalence** of with this organism. MRSA colonization (Strong; Low) or infection is high; d. Consider or if the infection is providing empiric clinically severe. therapy directed against MRSA in a patient with a prior history of MRSA infection; when the local prevalence** of MRSA colonization or infection is high; or if the infection is clinically severe. (Weak; Low).

4.3.5e Give an Adapted IDSA 2012 Both the sentences initial antibiotic Guidelines says – of this original course for a soft We suggest guideline can tissue infection of continuing themselves be an about 1–2 weeks antibiotic therapy individual for mild infections until, but not recommendation and 2–3 weeks for beyond, resolution and hence we have moderate to severe of findings of split them for ease of infections. infection, but not understanding through complete without changing

healing of the the meaning or the wound (weak, message to be low). We suggest conveyed. an initial antibiotic National Standard Treatment Guidelines 50

The Diabetic Foot: Full background document course for a soft Also, rephrasing tissue infection of done for using active about 1-2 weeks verb. for mild infections and 2-3 weeks for moderate to severe infections (weak, low). 4.3.5f Continue Adapted IDSA 2012 Both the sentences antibiotic therapy Guidelines says – of this original until, but not We suggest guideline can beyond, resolution continuing themselves be an of findings of antibiotic therapy individual infection, but not until, but not recommendation

through complete beyond, resolution and hence we have healing of the of findings of split them for ease of wound. infection, but not understanding through complete without changing healing of the the meaning or the wound (weak, message to be low). We suggest conveyed. an initial antibiotic Also, rephrasing course for a soft done for using active tissue infection of verb. about 1-2 weeks for mild infections and 2-3 weeks for moderate to severe infections (weak, low). 4.3.5g Administer Adopted IDSA 2012

parenteral therapy Guidelines initially for most severe infections and some moderate infections, with a switch to oral therapy when the infection is responding. (Strong; Low) * Risk factors for true infection with Pseudomonas aeruginosa include Immunocompromised status, Chronic Kidney Disease, warm climate and frequent exposure of foot to water. National Standard Treatment Guidelines 51

The Diabetic Foot: Full background document **The local prevalence of MRSA (i.e., percentage of all S. aureus clinical isolates in that locale that are methicillin resistant) is high enough (perhaps 50% for a mild and 30% for a moderate soft tissue infection) that there is a reasonable probability of MRSA infection. 4.4 Wound care techniques and dressings MoHFW guideline Adopted/ Original Remarks Adapted Guideline 4.4.1 Clean ulcers regularly with Adopted IWGDF clean water* or saline, debride 2015

them when possible in order to Guidance remove debris from the wound document surface and dress them with a sterile, inert dressing in order to control excessive exudate and maintain a warm, moist environment in order to promote healing**. (Strong; Low) 4.4.2 Select dressings principally Adopted IWGDF on the basis of exudate control, 2015 comfort and cost. (Strong; Low) Guidance document 4.4.3 Do not use antimicrobial Adopted IWGDF dressings with the goal of 2015 improving wound healing or Guidance

preventing secondary infection. document (Strong; Moderate) 4.4.4 Do not offer the following to Adopted NICE 2015 treat diabetic foot ulcers, unless Guidelines as part of a clinical trial: on Diabetic · Electrical stimulation Foot (NG19) therapy, autologous platelet-rich plasma gel, regenerative wound matrices and dalteparin. · Growth factors (granulocyte colony-stimulating factor [G-CSF], platelet-derived growth factor [PDGF], epidermal growth factor [EGF] and transforming growth factor beta [TGF-β]).

· Hyperbaric oxygen therapy. National Standard Treatment Guidelines 52

The Diabetic Foot: Full background document 4.4.5 Consider dermal or skin Adopted NICE 2015 substitutes as an adjunct to Guidelines standard care when treating on Diabetic diabetic foot ulcers, only when Foot (NG19) healing has not progressed and on the advice of the multidisciplinary foot care service. 4.4.6 Consider negative pressure Adopted NICE 2015 wound therapy after surgical Guidelines debridement for diabetic foot on Diabetic ulcers, on the advice of the Foot (NG19) multidisciplinary foot care

service. 4.4.7 Do not select agents Adopted IWGDF reported to improve wound 2015 healing by altering the biology of Guidance the wound, including growth document factors, bioengineered skin products and gases, in preference to accepted standards of good quality care. (Strong; Low) 4.4.8 Do not select agents Adopted IWGDF reported to have an impact on 2015 wound healing through alteration Guidance of the physical environment, document including through the use of electricity, magnetism,

ultrasound and shockwaves, in preference to accepted standards of good quality care. (Strong; Low) 4.4.9 Do not select systemic Adopted IWGDF treatments reported to improve 2015 wound healing, including drugs Guidance and herbal therapies, in document preference to accepted standards of good quality care. (Strong; Low) 4.4.10 Redistribute the pressure Adopted IDSA 2012 Rephrasing off the wound to the entire Guidelines done for weight-bearing surface of the foot using active

(“off-loading”). While particularly verb National Standard Treatment Guidelines 53

The Diabetic Foot: Full background document important for plantar wounds, this is also necessary to relieve pressure caused by dressings, footwear, or ambulation to any surface of the wound. (Strong; High) 4.4.11 When deciding about Adopted NICE 2015 wound dressings and offloading Guidelines when treating diabetic foot ulcers, take into account the clinical assessment of the wound and the person’s preference, and use devices and dressings with the lowest acquisition cost appropriate to the clinical

circumstances. *Clean water is boiled cooled water (distilled water) **Do not use H2O2, EUSOL, etc 4.5 Footwear MoHFW guideline Adopted/ Original Remarks Adapted Guideline 4.5.1 To heal a Adopted IWGDF 2015 Non-removable neuropathic plantar Guidance (cast) walker: Same forefoot ulcer Document as removable (cast) without ischemia or boot/walker but then uncontrolled with a layer(s) of infection in a fibreglass cast patient with material diabetes, offload circumferentially with a non- wrapped around it

removable knee- rendering it high device with an irremovable (also appropriate foot- known as "instant device interface. total contact cast") (Strong; High) 4.5.2 When a non- Adopted IWGDF 2015 Removable (cast) removable knee- Guidance boot/walker: high device is Document Prefabricated contraindicated or removable knee-high not tolerated by the boot with a rocker or patient, consider roller outsole National Standard Treatment Guidelines 54

The Diabetic Foot: Full background document offloading with a configuration, removable knee- padded interior, and high walker with an an insertable and appropriate foot- adjustable insole device interface to which may be total heal a neuropathic contact. plantar forefoot ulcer in a patient with diabetes, but only when the patient can be expected to be adherent to wearing the device. (Weak; Moderate) 4.5.3 When a knee- Adopted IWGDF 2015 high device is Guidance contraindicated or Document

cannot be tolerated by the patient, consider offloading with a forefoot offloading shoe, cast shoe, or custom-made temporary shoe to heal a neuropathic plantar forefoot ulcer in a patient with diabetes, but only and when the patient can be expected to be adherent to wearing the shoes. (Weak; Low) 4.5.4 Instruct an at- Adopted IWGDF 2015 risk patient with Guidance diabetes to wear Document properly fitting footwear to prevent a first foot ulcer, either plantar or non-plantar, or a recurrent non-

The Diabetic Foot: Full background document a foot deformity or a pre-ulcerative sign is present, consider prescribing therapeutic shoes, custom-made insoles, or toe orthosis. (Strong; Low) 4.5.5 To prevent a Adapted IWGDF 2015 Expert Consensus recurrent plantar guidance says that no footwear foot ulcer in an at- document says - manufacture can risk patient with To prevent a mention the quantity diabetes, prescribe recurrent plantar of pressure reduction

therapeutic foot ulcer in an at- as it depends on the footwear that has a risk patient with height and weight of demonstrated diabetes, the patient as well as plantar pressure prescribe the pattern of foot relieving effect therapeutic strike. during walking and footwear that has encourage the a demonstrated patient to wear this plantar pressure footwear. relieving effect during walking (i.e.30% relief compared to plantar pressure in standard of care therapeutic footwear) and encourage the patient to wear

this footwear. (Strong; Moderate) 4.5.6 Instruct a Adapted IWGDF 2015 Rephrasing done for patient with Guidance better understanding diabetes not to use Document says – of the conventional or Do not prescribe, recommendation. standard and instruct a Also, the Expert therapeutic patient with consensus felt the footwear to heal a diabetes not to word “shoes” should plantar foot ulcer.* use, conventional be replaced with or standard “footwear” as many therapeutic shoes people in India wear

The Diabetic Foot: Full background document to heal a plantar chappals and foot ulcer. sandals, instead of (Strong; Low) shoes. Also, it means – Use footwear with following features – Sandals: should have adjustable straps, insole, full heel counter and rigid outsole. Shoes: should have wide toe box extra depth and without laces 4.5.7 Consider Adopted IWGDF 2015 using shoe Guidance modifications, Document temporary footwear, toe spacers or orthoses to offload and heal a non-plantar foot ulcer without

ischemia or uncontrolled infection in a patient with diabetes. The specific modality will depend on the type and location of the foot ulcer. (Weak; Low) 4.5.8 If other forms Adopted IWGDF 2015 Felted foam - A fibrous, unwoven material backed by of biomechanical Guidance foam with absorbing and relief are not Document cushioning characteristics. available, consider The foam is generally using felted foam** ‘rubber foam’ or ‘PU foam’ which is formed by either a in combination polyester or polyether

with appropriate polyol resin, in conjunction footwear to offload with water and Toluene di and heal a Isocyanate, along with various catalysts and neuropathic foot blowing agents and ulcer without colouring pigments to give ischemia or the desired compression. uncontrolled infection in a patient with National Standard Treatment Guidelines 57

The Diabetic Foot: Full background document diabetes. (Weak; Low) *Use footwear with following features - Sandals: should have adjustable straps, insole, full heel counter and rigid outsole. Shoes: should have wide toe box extra depth and without laces. ** Felted foam - A fibrous, unwoven material backed by foam with absorbing and cushioning characteristics. The foam is generally ‘rubber foam’ or ‘PU foam’ which is formed by either a polyester

or polyether polyol resin, in conjunction with water and Toluene di Isocyanate, along with various catalysts and blowing agents and colouring pigments to give the desired compression. 4.6 Diabetic foot with osteomyelitis & Charcot’s Foot MoHFW guideline Adopted/ Original Remarks Adapted Guideline 4.6.1 For an Adopted IDSA 2012 infected open Guidelines wound, perform a probe-to-bone test; in a patient at low risk for osteomyelitis a negative test largely rules out the diagnosis, while in a

high risk patient a positive test is largely diagnostic. (Strong; High) 4.6.2 Markedly Adapted IWDGF 2015 says - Tests for serum elevated ESR is Markedly elevated inflammatory suggestive of serum markers are costly osteomyelitis in inflammatory and not widely suspected cases. markers, especially available, except erythrocyte ESR. Also these sedimentation tests are not rate, are suggestive diagnostic of DFO. of osteomyelitis in suspected cases. 4.6.3 If osteomyelitis Adapted NICE 2015 Expert Consensus

is suspected in a Guidelines on says that as person with diabetes Diabetic Foot availability of MRI but is not confirmed (NG19) says that – is limited across by initial X-ray, If osteomyelitis is the country, it is consider an MRI to suspected in a recommended to National Standard Treatment Guidelines 58

The Diabetic Foot: Full background document confirm the person with use MRI wherever diagnosis. In places diabetes but is not available. At the where MRI is confirmed by primary and unavailable, initial X-ray, secondary health diagnose consider an MRI to centre levels, the osteomyelitis by the confirm the PTB test and bone PTB test (clinically) diagnosis. biopsy and culture and/or taking a are more feasible Bone biopsy and and economical culture. and reasonably accurate. 4.6.4 A definite Adopted IDSA 2012

diagnosis of bone Guidelines infection usually requires positive results on both histological and microbiological examinations of an aseptically obtained bone sample, but this is usually required only when the diagnosis is in doubt or determining the causative pathogen’s antibiotic susceptibility is crucial. (Strong; Moderate) 4.6.5 Avoid using Adopted IDSA 2012 results of soft tissue Guidelines or sinus tract specimens for selecting antibiotic therapy for osteomyelitis as they do not accurately

reflect bone culture results. (Strong; Moderate) 4.6.6 When a radical Adapted IDSA 2012 A proximal bone resection leaves no Guidelines says – histopath to be remaining infected done if available to National Standard Treatment Guidelines 59

The Diabetic Foot: Full background document tissue*, prescribe When a radical get a clear margin antibiotic therapy resection leaves no and confirm that for only a short remaining infected no infected bone duration (2–5 days). tissue, we suggest remains. When there is prescribing Also, rephrasing persistent infected antibiotic therapy done for using or necrotic bone, for only a short active verb. give prolonged (≥4 duration (2-5 weeks) antibiotic days) (weak, low'). treatment. When there is

persistent infected or necrotic bone, we suggest prolonged (2:4 weeks) antibiotic treatment (weak, low). 4.6.7 For Adapted IDSA 2012 Rephrasing done specifically treating Guidelines says for using active Diabetic foot that – verb. osteomyelitis, do not For specifically Also refer to Table use adjunctive treating DFO, we 4 and 5 in the treatments such as do not currently Annexure below, hyperbaric oxygen support using for explanatory therapy, growth adjunctive notes. factors (including treatments such as

granulocyte colony hyperbaric oxygen stimulating factor), therapy, growth maggots (larvae), or factors (including topical negative granulocyte colony pressure therapy stimulating factor), (eg, vacuum-assisted maggots (larvae), closure). (weak, low) or topical negative pressure therapy (eg, vacuum- assisted closure). (weak, low) *A proximal bone histopath to be done if available to get a clear margin and confirm that no infected bone remains. 4.7 CHARCOT’S FOOT :-

MoHFW guideline Adopted/ Original Guideline Remarks Adapted National Standard Treatment Guidelines 60

The Diabetic Foot: Full background document 4.7.1 Suspect acute Adopted NICE 2015 Charcot arthropathy guidelines on if there is redness, Diabetic Foot warmth, swelling or (NG19) deformity (in particular, when the skin is intact), especially in the presence of peripheral neuropathy or renal failure. Think about acute Charcot arthropathy even when deformity is not present or pain is not reported. 4.7.2 Refer the Adapted NICE 2015 Urgently (within 24 person with Guidelines on hours) may not be

suspected Charcot’s Diabetic Foot possible in Indian foot early (within (NG19) says - context. So the one week) to the Refer the person word early (within multidisciplinary urgently (within 24 one week) is used. foot care service hours) to the Diabetic Foot care Diabetic Foot care multidisciplinary centre:- In India, since centre to confirm the foot care service to there are no minimum standards of services diagnosis, and offer confirm the offered to the diabetic

non-weight-bearing diagnosis, and offer foot patients, in our treatment until non-weight- recommendations we have used this term to definitive treatment bearing treatment denote this facility, which can be started. until definitive may exist at the General treatment can be Practitioner’s office, Primary health centre, started. Secondary care centre or at a tertiary care centre. Preferably, the diabetic foot care centre should consist of atleast a surgeon, a physician, and an orthotist.

4.7.3 If acute Adopted NICE 2015 Charcot arthropathy guidelines on is suspected, X-ray Diabetic Foot the affected foot. (NG19) Consider an MRI if the X-ray is normal but clinical National Standard Treatment Guidelines 61

The Diabetic Foot: Full background document suspicion still remains. 4.7.4 Distinguishing Adopted IDSA 2012 the bony changes of Guidelines osteomyelitis from those of the less common entity of diabetic neuro- osteoarthropathy (Charcot foot) may be particularly challenging and requires considering clinical information in conjunction with imaging. 4.7.5 Clinical clues Adopted IDSA 2012 supporting neuro- Guidelines osteoarthropathy in this context include midfoot location and absence of a soft tissue wound,

whereas those favoring osteomyelitis include presence of an overlying ulcer (especially of the forefoot or heel), either alone or superimposed on Charcot changes. 4.7.6 If the films Adopted IDSA 2012 show classic Guidelines changes suggestive of osteomyelitis (cortical erosion, periosteal reaction, mixed lucency, and sclerosis), and if there is little likelihood of neuro- osteoarthropathy, it National Standard Treatment Guidelines 62

The Diabetic Foot: Full background document is reasonable to initiate treatment for presumptive osteomyelitis, preferably after obtaining appropriate specimens for culture. 4.7.7 If the Diabetic Adapted NICE 2015 As foot care centre guidelines on multidisciplinary suspects acute Diabetic Foot foot care service is Charcot (NG19) says that – not available at arthropathy, offer If the present, we suggest treatment with a multidisciplinary “Diabetic foot care non-removable off- foot care service centre” as the

loading device. Only suspects acute alternative. It has consider treatment Charcot been described with a removable arthropathy, offer above in off-loading device if treatment with a recommendation a non-removable non-removable off- no. 4.7.2 device is not loading device. advisable because of Only consider the clinical or the treatment with a person’s removable off- circumstances. loading device if a non-removable device is not advisable because of the clinical or the person’s circumstances.

4.7.8 Do not offer Adopted NICE 2015 bisphosphonates to guidelines on treat acute Charcot Diabetic Foot arthropathy, unless (NG19) as part of a clinical trial. 4.7.9 Monitor the Adapted NICE 2015 Unit of measuring treatment of acute Guidelines on temperature is Charcot arthropathy Diabetic Foot specified as using clinical (NG19) says - Centigrade as per assessment. This Monitor the expert opinion. should include treatment of acute measuring foot–skin Charcot National Standard Treatment Guidelines 63

The Diabetic Foot: Full background document temperature arthropathy using difference and clinical assessment. taking serial X-rays This should include until the acute measuring foot– Charcot arthropathy skin temperature resolves. Acute difference and Charcot arthropathy taking serial X-rays is likely to resolve until the acute when there is a Charcot sustained arthropathy temperature resolves. Acute difference of less Charcot than two degrees arthropathy is centigrade between likely to resolve

both feet and when when there is a X-ray changes show sustained no further temperature progression. difference of less than 2 degrees centigrade between both feet and when X-ray changes show no further progression. 4.7.10 The diabetic Adapted NICE 2015 Rephrasing done foot care centre guidelines on for using active should care for Diabetic Foot verb. people who have a (NG19) says that – Also, as a dedicated foot deformity People who have a foot protection resulting from a foot deformity that service is not

previous Charcot’s may be the result available in the arthropathy as they of a previous country at present, are at high risk of Charcot hence the diabetic ulceration. arthropathy are at foot care centre is high risk of used as an ulceration and alternative. should be cared for by the foot protection service 4.8 Surgical intervention and revascularisation MoHFW guideline Adopted/ Original Guideline Remarks Adapted National Standard Treatment Guidelines 64

The Diabetic Foot: Full background document 4.8.1 Consult a Adapted IWGDF 2015 Guidance Expert surgical specialist document says that :- consensus in all cases of Consult a surgical preferred to diabetic foot specialist in selected replace the infections that are cases of diabetic foot word “selected” moderate or infections that are with “all” so as severe. moderate, and in all avoid confusion cases that are severe. as to which (weak; low) cases would fall under the category “selected”.

4.8.2 Perform Adapted IWGDF 2015 Guidance Expert urgent surgical document says – consensus says intervention in Perform urgent that all cases of cases of deep surgical intervention is abscesses, abscesses, necessary in most cases compartment compartment of deep abscesses, syndrome and syndrome and compartment necrotizing soft necrotizing soft syndrome and virtually tissue infections tissue infections. all necrotizing soft will require tissue infections surgical (Strong; Low) intervention. As such the words

“most cases” and “virtually all”used in the original guideline are likely to create confusion, and hence better dropped off in rephrasing. 4.8.3 Debride any Adapted IWGDF 2015 says – Rephrasing wound that has Clinicians should done for using necrotic tissue or debride any wound active verb. surrounding callus; that has necrotic tissue the required or surrounding callus; procedure may the required procedure range from minor may range from minor to extensive. to extensive. (strong, low)

4.8.4 Perform Adapted IDSA 2012 Guidelines In those with a urgent surgical says – non-severe National Standard Treatment Guidelines 65

The Diabetic Foot: Full background document intervention for We recommend urgent infection, most foot infections surgical intervention carefully accompanied by for most foot infections observing the gas in the deeper accompanied by gas in effectiveness of tissues, an abscess, the deeper tissues, an medical therapy and the or necrotizing abscess, or necrotizing demarcation line fasciitis, and less fasciitis, and less urgent between necrotic urgent surgery for surgery for wounds and viable tissue

wounds with with substantial before operating substantial nonviable tissue or may be prudent. nonviable tissue or extensive bone or joint Also, rephrasing extensive bone or involvement (strong, done for using joint involvement.* low). active verb. 4.8.5 Consider Adapted IWGDF 2015 says – Rephrasing surgical Consider surgical done for using intervention in intervention is usually active verb. cases of advisable in cases of osteomyelitis osteomyelitis accompanied by: accompanied by:

spreading soft spreading soft tissue tissue infection; infection;destroyed soft destroyed soft tissue tissue envelope; envelope;progressive progressive bone bone destruction on X- destruction on X- ray; or,bone protruding ray; or, bone through the ulcer protruding through (Strong;Low) the ulcer. 4.8.6 Remove Adapted IWGDF 2015 says – Rephrasing slough, necrotic In general remove done for using tissue & slough, necrotic tissue active verb. surrounding callus & surrounding callus with sharp with sharp

debridement in debridement in preference to other preference to other methods, taking methods, taking relative relative contraindications contraindications such such as severe as severe ischemia into ischemia into account.(Strong; Low) account. 4.8.7 Consider Adopted IWGDF 2015 Guidance digital flexor Document National Standard Treatment Guidelines 66

The Diabetic Foot: Full background document tenotomy to prevent a toe ulcer when conservative treatment fails in a high-risk patient with diabetes, hammertoes and either a pre- ulcerative sign or an ulcer on the toe. (weak; low) 4.8.8 Consider Adopted IWGDF 2015 Guidance Achilles tendon Document lengthening, joint arthroplasty, single or pan metatarsal head resection or osteotomy to prevent a recurrent foot ulcer when conservative treatment fails in a high-risk patient with diabetes and a plantar foot

ulcer.(weal; low) * In those with a non-severe infection, carefully observing the effectiveness of medical therapy and the demarcation line between necrotic and viable tissue before operating may be prudent. Management of PAD in diabetic foot patients :- MoHFW guideline Adopted/ Original Guideline Remarks Adapted 4.8.9 Examine a Adopted IWGDF 2015 patient with Guidance document diabetes annually for the presence of peripheral artery disease (PAD); this should include, at a minimum, taking a history and

The Diabetic Foot: Full background document pulses. (Strong; low) 4.8.10 Evaluate a Adopted IWGDF 2015 patient with Guidance document diabetes and a foot ulcer for the presence of PAD. Determine, as part of this examination, ankle or pedal Doppler arterial waveforms; measure both ankle systolic pressure and systolic ankle brachial index (ABI). (Strong; Low) 4.8.11 Use bedside Adapted IWGDF 2015 says – Rephrasing done non-invasive tests We recommend the for using active

to exclude PAD. No use ofbedside non- verb. single modality has invasive tests to been shown to be exclude PAD. No optimal. Measuring single modality has ABI (with <0.9 been shown to be considered optimal. Measuring abnormal) is useful ABI (with <0.9 for the detection of considered PAD. Tests that abnormal) is useful largely exclude PAD for the detection of are the presence of PAD. Tests that ABI 0.9-1.3, toe largely exclude PAD brachial index (TBI) are the presence of ≥0.75 and the ABI 0.9-1.3, toe

presence of brachial index (TBI) triphasic pedal ≥0.75 and the Doppler arterial presence of waveforms. triphasic pedal Doppler arterial waveforms. (Strong; Low) 4.8.12 In patients Adopted IWGDF 2015 with a non-healing Guidance document ulcer with either an ankle pressure <50mmHg or ABI National Standard Treatment Guidelines 68

The Diabetic Foot: Full background document <0.5 consider urgent vascular imaging and revascularisation. (Strong;low) 4.8.13 Consider Adopted IWGDF 2015 vascular imaging Guidance document and revascularisation in all patients with a foot ulcer in diabetes and PAD, irrespective of the results of bedside tests, when the ulcer does not improve within 6 weeks despite optimal management. (strong; low) 4.8.14 Do not Adapted IWGDF 2015 says – Rephrasing done consider Diabetic Diabetic for using active

microangiopathy to microangiopathy verb. be the cause of poor should not be wound healing in considered to be the patients with a foot cause of poor ulcer. wound healing in patients with a foot ulcer. (Strong; Low) 4.8.15 To obtain Adapted IWGDF 2015 says – Rephrasing done anatomical Colour Doppler for using active information when ultrasound, CT- verb. revascularisation is angiography, MR- being considered, angiography or use one of these intra-arterial digital tests - Colour subtraction

Doppler ultrasound, angiography can CT-angiography, each be used to MR-angiography or obtain anatomical intra-arterial digital information when subtraction revascularisation is angiography. being considered. Evaluate the entire The entire lower lower extremity extremity arterial National Standard Treatment Guidelines 69

The Diabetic Foot: Full background document arterial circulation, circulation should with detailed be evaluated, with visualization of detailed below-the-knee and visualization of pedal arteries. below-the-knee and pedal arteries. (Strong; Low) 4.8.16 Offer duplex Adapted NICE 2012 PAD As per Expert ultrasound as first- Guidelines, last Consensus, in line imaging to all modified August most vascular people with 2015 says that – centres MRI or CT peripheral arterial Offer duplex is not done

disease for whom ultrasound as first- routinely for revascularization is line imaging to all planning being considered. people with intervention as Take the decision of peripheral arterial MRI is costly and revascularisation on disease for whom the quality and the basis of colour revascularization is reporting are doppler findings being considered. highly machine and use DSA for Offer contrast- and operator and defining the enhanced magnetic radiologist vascular anatomy resonance dependent. An

prior to the angiography to average quality procedure. people with MR does not peripheral arterial contribute. CT is disease who need cheaper but again further imaging as Indians have (after duplex highly calcified ultrasound) before vessels, CT has considering limitation that it revascularization. may not be able to Offer computed differentiate a tomography calcification and angiography to contrast. people with peripheral arterial disease who need further imaging (after duplex ultrasound) if

contrast enhanced magnetic resonance angiography is contraindicated or not tolerated. National Standard Treatment Guidelines 70

The Diabetic Foot: Full background document 4.8.17 The aim of Adapted IWGDF 2015 Tests to measure revascularisation is Guidance document skin perfusion to restore direct says that – pressure, toe flow to at least one The aim of pressure and of the foot arteries, revascularisation is TcPO2 are very preferably the to restore direct costly and not artery that supplies flow to at least one easily available the anatomical of the foot arteries, even in metro region of the preferably the cities.

wound, and assess artery that supplies A hand held for adequate the anatomical Doppler used revascularization region of the bedside is less post-operatively wound, with the aim accurate as it can with a colour of achieving a pick up signals Doppler wave- minimum skin from an adjacent fronts (preferable) perfusion pressure arterial branch or a hand held ≥40mmHg; a toe also, hence giving Doppler probe used pressure ≥30mmHg; a false bedside. or, a TcPO2 ≥25 reassurance. mmHg. (Strong; Low)

4.8.18 A centre Adapted IWGDF 2015 Most of the treating patients Guidance document secondary and with a foot ulcer in says that - some tertiary diabetes should A centre treating centres in India have liaison / patients with a foot don’t themselves association with a ulcer in diabetes have the centre having the should have the infrastructure expertise necessary expertise in and necessary for to diagnose and rapid access to revacularisation treat PAD; both facilities necessary and hence a

endovascular to diagnose and collaboration is techniques and treat PAD; both recommended. bypass surgery endovascular should be available. techniques and bypass surgery should be available. (Strong; Low) 4.8.19 The Adapted IWGDF 2015 says – Rephrasing done multidisciplinary After a for using active team should treat revascularisation verb. the patient after a procedure for a foot revascularisation ulcer in diabetes, procedure for a foot the patient should ulcer in diabetes, as be treated by a

part of a multidisciplinary National Standard Treatment Guidelines 71

The Diabetic Foot: Full background document comprehensive care team as part of a plan. comprehensive care plan. (Strong; Low) 4.8.20 There is Adapted IWGDF 2015 says – Rephrasing done inadequate There is inadequate for using active evidence to evidence to verb. establish which establish which revascularisation revascularisation technique is technique is superior and a superior and multidisciplinary decisions should be team should decide made in a the technique of multidisciplinary

revascularization team on a number for a patient based of individual factors, on a number of such as individual factors, morphological such as distribution of PAD, morphological availability of distribution of PAD, autogenous vein, availability of patient co- autogenous vein, morbidities and patient co- local expertise. morbidities and (Strong; Low) local expertise. 4.8.21 Give Adapted IWGDF 2015 says – Rephrasing done emergency Patients with signs for using active treatment to of PAD and a foot verb.

patients with signs infection are at of PAD and a foot particularly high infection as they are risk for major limb at particularly high amputation and risk for major limb require emergency amputation. treatment. (Strong; Moderate) 4.8.22 Avoid Adopted IWGDF 2015 Unfavourable risk revascularisation in Guidance document benefit ratio patients in whom, would indicate from the patient those patients who perspective, the are frail, elderly, risk-benefit ratio for bed ridden, having the probability of low life

success is expectancy, unfavourable.* multiple co- (Strong; Low) morbidities National Standard Treatment Guidelines 72

The Diabetic Foot: Full background document imposing high risk for surgical intervention, etc 4.8.23 All patients Adopted IWGDF 2015 with diabetes and Guidance document an ischemic foot ulcer should receive aggressive cardiovascular risk management including support for cessation of smoking, treatment of hypertension and prescription of a statin as well as low-dose aspirin or clopidogrel. (Strong; Low) 4.8.24 Do not offer Adapted NICE 2012 PAD Expert consensus

major amputation guidelines, last recommends that to people with modified August there is merit in critical limb 2015 says that - considering major ischaemia unless all Do not offer major amputation in life options for amputation to saving situations revascularisation people with critical and destroyed have been limb ischaemia foot. considered by a unless all options vascular for multidisciplinary revascularisation team. Major have been amputation without considered by a giving a chance for vascular

revascularization is multidisciplinary indicated only in team. lifesaving situations like foot causing septicemia, wet gangrene, or completely destroyed foot (post Charcot’s or osteomyelitis etc). National Standard Treatment Guidelines 73

The Diabetic Foot: Full background document *unfavourable risk benefit ratio would indicate those patients who are frail, elderly, bed ridden, having low life expectancy, multiple co-morbidities imposing high risk for surgical intervention, etc National Standard Treatment Guidelines 74

Standard Treatment Guidelines Detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants Quick Reference Guide October 2016 1

Table of contents S. Topic Page No. No. 1. Introduction 3 2. The purpose of the guideline 4 3. The approach of the guideline 5 4. Full Guideline Title 6 5. Key Clinical issues that will be covered in this guideline 6 6. Key recommendations 7 7. What should be the screening protocol for detection of jaundice in neonates? 7 8. Which neonates are at a higher risk of hyperbilirubinaemia? 7 9. Approach to an infant with jaundice 8

10. What is the accuracy of transcutaneous bilirubinometry in recognising neonatal 9 hyperbilirubinaemia and how should it be done? 11. Clinical Examination for jaundice 9 12. Transcutaneous and total serum bilirubin 10 13. How will you interpret serum bilirubin levels and manage hyperbilirubinaemia? 11 14. Guidelines for phototherapy in hospitalized infants of 35 or more weeks 12 gestation 15. Guidelines for phototherapy in hospitalized infants of 35 or more weeks 13 gestation

16. What should be optimum discharge and follow-up timing and the assessment 14 policy to minimize the subsequent risk of severe hyperbilirubinemia and kernicterus? 17. What should be included in the formal assessment of a neonate with neonatal 15 hyperbilirubinaemia? 18. How can we prevent severe hyperbilirubinemia? 16 19. Phototherapy for the management of hyperbilirubinemia 17 20. Tips for delivering safe and effective phototherapy 18 21. Exchange transfusion for management of hyperbilirubinemia 19

22. Other modalities for management of hyperbilirubinemia 19 23. What information and support should be given to parents/carers of babies with 20 neonatal hyperbilirubinaemia? 24. References 21 25. Phototherapy units available in the market 23 2

Introduction Jaundice refers to the yellow discoloration of the skin and the sclera caused by the accumulation of a pigment (bilirubin) in the skin and mucous membranes. It is seen in neonates when the serum bilirubin levels exceed 5-7 mg/dL. Approximately 60% of term and 80% of preterm infants develop jaundice in the first week of life, and about 10% of breastfed infants are still jaundiced at 1 month. Visible jaundice usually appears between 24 to 72 hours of age. The total serum

bilirubin (TSB) level usually rises in term infants by 3 days of age and then falls. In preterm infants, the peak level occurs around 3 to 7 days after birth. It may take weeks before the TSB levels falls under 2 mg/dL in both term and preterm infants. Jaundice is not an indication of an underlying disease for most infants, and this early jaundice (termed 'physiological jaundice') is generally harmless. Hyperbilirubinemia typically refers to serum bilirubin levels beyond the normal range

and is a common problem in neonates. (1)A significant proportion of these neonates develop pathological jaundice (jaundice requiring treatment) during the first week of life (2). It is also one of the leading causes of hospitalization in the first week of life globally (3- 5).The overall incidence of hyperbilirubinemia (>15 mg/dL) has been reported as 3.3% in intramural neonates and 22.1%in extramural neonates(2). Timely and appropriate treatment with phototherapy and/or exchange transfusion is

effective in decreasing excessive bilirubin levels. However, failure of instituting appropriate therapy results in acute bilirubin encephalopathy (ABE) which if not treated immediately, might go on to develop kernicterus and other long term neurological deficits including cerebral palsy, sensorineural hearing loss, intellectual difficulties or gross developmental delays (6-10). It is estimated that nearly 5,00,000 term and late preterm neonates globally

are affected by severe hyperbilirubinemia annually and around one-fourth of them die and 63,000 survive with neurological disability (11). Three-fourth of these affected infants reside in sub-Saharan Africa and South Asia (12). 3

The purpose of the guideline There is a need for a standard guideline for the management of neonatal hyperbilirubinemia in term and late preterm newborn infants in India. The context for the detection, management and prevention of neonatal hyperbilirubinemia in India is different from other countries. The published evidence based guidelines on early detection, management and prevention of neonatal hyperbilirubinemia by various bodies including American Academy

of Pediatrics (13) and National Institute for Health and Clinical Excellence (14)primarily takes care of the need of high income countries. The low and middle-income countries including India are following these guidelines due to dearth of literature and absence of such evidence based guidelines from their own setting. There is an increased incidence of significant hyperbilirubinemia in India due to various risk factors including racial and genetic factors, widespread practice of exclusive

breastfeeding, higher prevalence of G6PD deficiency in some parts of the country, more neonates with low albumin at birth, higher bilirubin levels in summer season due to dehydration, blood group incompatibilities and infections(15, 16). Lack of knowledge among mother and family members about jaundice (17) and poor transport facilities especially in rural areas often results in delay in seeking medical advice. The situation is further

compounded by “why worry” attitude among healthcare professionals especially in the dearth of substantial data documenting bilirubin induced neurological dysfunction (BIND)on arrival to health facility(18). Inadequate knowledge among healthcare professionals, limited facilities for clinical investigations, lack of standardised protocol for management (including absence of monitoring serum bilirubin while under phototherapy) and inconsistent

functional status of available phototherapy devices, often results in inappropriate treatment thus resulting in BIND(19-22). Even the lack of exchange transfusion facilities at majority of the healthcare setting due to non-availability of blood or expertise results in permanent neurological dysfunction which could be easily avoided by doing early exchange transfusion. Though the guidelines published by National Neonatology Forum,India (NNF 2010)

(22) have tried to provide a practical framework for managing neonatal hyperbilirubinemia in Indian setting, these guidelines are meant for only tertiary care health facilities. In view of the above stated reasons and opening of Special Care Newborn Units (SCNUs) and private health facilities delivering level II neonatal care in a big way; the current guideline has been 4

developed for the management of neonatal hyperbilirubinemia in late preterm and term infants in the Indian context for health care facilities at all levels. Approach of the guideline The guidelines have been commissioned to enable a systematic cost-effective approach for the detection, management and evaluation of neonatal hyperbilirubinemia in late preterm and term infants in India. This guideline and its accompanying implementation

tools in the form of a quick reference guide, flow charts, and quality standards will serve as a valuable reference material for healthcare providers, patients and administrators. While formulating these guidelines the main outcome measures taken into consideration have been mortality, incidence of acute bilirubin encephalopathy, incidence of chronic bilirubin encephalopathy, hearing Loss, incidence of exchange transfusion, incidence of severe

hyperbilirubinemia, duration of phototherapy and incidence of readmissions required for hyperbilirubinemia • This guideline has a primary care focus and a public health approach. The focus of the primary care is to improve the early detection and the timely treatment to prevent long term neurological deficits. Increasing awareness among public especially mother and family members at the time of discharge about the need for jaundice evaluation in first week of life in face of early discharges from health

facilities in India will improve this dismal situation and result in improving intact survival. • These guidelines will also facilitate effective advocacy and mobilisation of requisite resources for the optimal care of newborn infants with hyperbilirubinemia at all levels. • The guideline presented covers detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants in primary, secondary and tertiary care setting and includes an algorithmic approach (figure 1) to a

Full Guideline Title: Detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants Population Groups that will be covered a) Neonates ≥ 35 weeks Groups that will not be covered a) Preterm neonates < 35 weeks b) Neonates with conjugated hyperbilirubinemia Health Care Setting a) Primary care b) Secondary and tertiary care Disease or risk condition At risk or having jaundice Key Clinical issues that will be covered in this guideline I. Screening and Diagnosis

1.1 What should be the screening protocol for detection of jaundice in neonates? 1.2 Which neonates are at a higher risk of hyperbilirubinaemia? 1.3 What is the accuracy of transcutaneous bilirubinometry in recognising neonatal hyperbilirubinaemia and how should it be done? 1.4 How will you interpret serum bilirubin levels and manage hyperbilirubinaemia? 1.5 What should be optimum discharge and follow-up timing and the assessment policy

to minimize the subsequent risk of severe hyperbilirubinemia and acute bilirubin encephalopathy? 1.6 What should be included in the formal assessment of a neonate with neonatal hyperbilirubinaemia? 1.7 How can we prevent severe hyperbilirubinemia? II. Treatment of hyperbilirubinemia 2.1 Phototherapy 2.2 Exchange transfusion 2.3 Other modalities 2.4 What should be the frequency of long term follow up of neonates with hyperbilirubinemia and what all should be evaluated at follow up?

2.5 Information and support which should be given to parents/caregivers of neonates with neonatal hyperbilirubinaemia? 6

Key recommendations 1. Screening and assessment 1.1 What should be the screening protocol for detection of jaundice in neonates? (14,22) Recommendation 1. Healthcare professionals should all look for jaundice (visual inspection) in babies (Figure 1) 2. Assessment of all newborns for jaundice should be done every 12 hours especially in the initial 3 to 5 days. 3. Monitoring for development of severe neonatal jaundice may be needed till end of first week of postnatal life.

1.2 Which neonates are at a higher risk of hyperbilirubinaemia? (13, 22) Recommendation Identify neonates as being more likely to develop significant hyperbilirubinaemia if they have ANY of the following factors: • Gestational age under 38 weeks • A previous sibling with neonatal hyperbilirubinaemia requiring phototherapy • Mother's intention to breastfeed exclusively • Visible jaundice in the first 24 hours of life. • Visible jaundice at discharge • Setting of blood group incompatibility

• High prevalence of G6PD deficiency, primipara mother • Weight loss at discharge >3% per 24 h of age or >7% cumulative weight loss 7

Figure 1: Approach to an infant with jaundice Perform visual assessment (VA) of jaundice: every 12 h during initial 3 to 5 days of life. VA can be supplemented with transcutaneous bilirubinometry (TcB), if available Step 1: Does the baby have serious jaundice*? Yes No Step 2: Does the infant have significant jaundice to Start require TSB measurement#? phototherapy$ Yes No Measure TSB level and determine if baby Continued observation every

requires phototherapy or exchange transfusion 12 to 24 hr for initial 3 to 5 (refer to Management) days Step 3: Determine the cause of jaundice(Table 2)and provide supportive and follow up care *Serious jaundice (Any one of following): #Measure serum bilirubin if: a. Presence of visible jaundice in first 24 h a. Jaundice in first 24 hour b. Yellow palms and soles anytime b. Beyond 24 hr: if on visual assessment or by

c. Signs of acute bilirubin encephalopathy or kernicterus: transcutaneous bilirubinometry, TSB is likely to hypertonia, abnormal posturing such as arching, be more than 12 to 14 mg/dL or approaching retrocollis, opisthotonus or convulsion, fever, high phototherapy range or beyond. pitched cry) c. If you are unsure about visual assessment d. IF AVAILABLE: Serum bilirubin or TcB value more than 95thcentile as per age specific nomogram( 23)

$Though it is important to start immediate phototherapy, it is also important to document serum bilirubin simultaneously. 8

1.3 What is the accuracy of transcutaneous bilirubinometry in recognising neonatal hyperbilirubinaemia and how should it be done? 1.3.1 Clinical examination for jaundice Essential steps for screening and assessment of jaundice* 1. Examine the baby in bright natural light. Alternatively, the baby can be examined in white fluorescent light. Make sure there is no yellow/ off white background. 2. Make sure the baby is naked. 3. Examine blanched skin and gums or sclerae

4. Depth of jaundice (degree of yellowness) should be carefully noted as it is an important indicator of level of jaundice and it does not figure out in Kramer’s rule ) (figure 2) A deep yellow staining (even in absence of yellow soles or palms) is often associated with sever jaundice and therefore TSB should be estimated in such circumstances. *Important notes 1 Visual inspection of jaundice is believed to be unreliable, but if it is performed properly (i.e. examining a naked baby in bright

natural light and in absence of yellow background), it has reasonable accuracy particularly when TSB is less than 12 to 14 mg/dL 2 Absence of jaundice on visual inspection reliably excludes the jaundice. 3 All newborns with visible jaundice should be evaluated with TcB or TSB 4 If transcutaneous bilirubinometer is available, use it in babies with a gestational age of 35 weeks or more and postnatal age of more than 24 hours and if it indicates a bilirubin level greater 14 mg/dL, check serum bilirubin.

1. Face 5-7 mg/dL 2. Chest 8-10 mg/dL 3. Lower abdomen/thigh 12 to 15 mg/dL 4 4. Arms/ lower legs 15 to18 mg/dL 5. Soles/Palms >15 mg/dL Figure 2: The extent of jaundice (Kramer’s rule)(24) 9

1.3.2 Transcutaneous and total serum bilirubin Measurement of bilirubin Transcutaneous bilirubinometry (TcB) 1. TcB is a useful adjunct to TSB measurement, and routine employment of TcB can reduce need for blood sampling by nearly 30%. 2. Current devices are costly and have a significant recurring cost of consumables such as disposable tips etc. 3. TcB can be used in infants of 35 weeks or more of gestation after 24 hr. 4. TcB becomes un reliable once TSB level goes beyond 14 mg/dL.

5. Hour specific TcB can be used for prediction of subsequent hyperbilirubinemia. TcB value below 50th centile for age would rule out the risk of subsequent hyperbilirubinemia with high probability (high negative predictive value)(23) 6. Trends in TcB values by measuring 12 hr apart would have a better predictive value than a single value. Measurement of TSB a. Indication of TSB measurement: i. Jaundice in first 24 hour ii. Beyond 24 hr: if visually assessed jaundice is likely to be more than

14 mg/dL or approaching the phototherapy range or beyond. iii. If you are unsure about visual assessment iv. During phototherapy, for monitoring progress and after phototherapy to check for rebound in select cases (such as those with hemolytic jaundice) b. Frequency of TSB measurement depends upon the underlying cause (hemolytic versus non-hemolytic) and severity of jaundice as well as host factors such as age and gestation. In general, in non-hemolytic

jaundice in term babies, TSB can be performed every 12 hr depending upon age of the baby. As opposed to this, a baby with Rh isoimmunisation would require TSB measurement every 6 to 8 hours during initial 24 to 48 hours or so. c. Methods of TSB measurements i. Biochemical: High performance liquid chromatography (HPLC) remains the gold standard for estimation of TSB. However, this test is not universally available and laboratory estimation of TSB is

usually performed by Vanden Bergh reaction. It has marked inter laboratory variability with coefficient of variation being up to 10 to 12 percent for TSB and over 20 percent for conjugated fraction. (25) ii. Micro method for TSB estimation: It is based on spectrophotometry and estimates TSB on a micro blood sample. It is useful in neonates, as bilirubin is predominantly unconjugated and can be done bedside. 10

1.4 How will you interpret serum bilirubin levels and manage hyperbilirubinaemia? Re commendation In terpret serum bilirubin levels according to the baby's postnatal age in hours an d manage hyperbilirubinaemia as per the guidelines. 1. American Academy of Paediatrics (AAP) criteria should be used for making decision regarding phototherapy or exchange transfusion in these infants. AAP provides two age-specific nomograms- one each for phototherapy and

exchange transfusion. The nomograms have lines for three different risk categories of neonates (Figure 2 and 3). These lines include one each for lower risk babies (38 wk or more and no risk factors), medium risk babies (38 wk or more with risk factors, or 35 wk to 37 wk and without any risk factors) and higher risk (35 wk to 37 wk and with risk factors). 2. TSB value is taken for decision making and direct fraction should NOT be reduced from it. The babies at lower and higher risk have their cut-offs at

approximately 2 mg/dL higher or 2 mg/dL lower than that for medium risk babies, respectively. 3. Risk factors include presence of isoimmune hemolytic anemia, G6PD defici ency, asphyxia, temperature instability, hypothermia, sepsis, significant letha rgy, acidosis and hypoalbuminemia.* *Routine estimation of serum albumin is not recommended 11

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1.5 What should be optimum discharge and follow-up timing and the assessment policy to minimize the subsequent risk of severe hyperbilirubinemia and acute bilirubin encephalopathy? (22) In India, healthy neonates are usually discharged after 24-48 h of normal delivery. In some facilities with high obstetric case load or absence of adequate manpower neonates are discharged even before completing first 24 h of age. Discharge after

delivery by cesarean section is more variable with length of stay varying from 3 to 7 days. Due to continuing rise of bilirubin and absence of supervision for ensuring optimal feeding, neonates discharged home before completing 48-72 h of age are at high risk of developing undetected pathological hyperbilirubinemia. In India, this risk may be further aggravated due to absence of any formal system of follow-up home- visits by health care personnel (e.g. public health nurse) and due to traditional

practice of confinement of mother-baby dyad at home for first few weeks after delivery. Neonates delivered at home are also at high risk of undetected pathological hyperbilirubinemia due to same reasons. The strategy of follow up of all neonates although desirable, is not feasible due to relative shortage of health care personnel and inability of some families to return for follow-up. Therefore follow-up plan may be devised based on pre-discharge risk assessment (Table 1).

Table 1: Suggested follow-up policy (13) Scenario Age at discharge Follow-up None of risk factors* 24-72 h 48 h after discharge present >72 h Follow-up optional Any risk factor* present 24-48 h 24 h after discharge After 48 hours 48 h after discharge *History of jaundice needing treatment in previous sibling, setting of blood group incompatibility, visible jaundice at discharge, gestation <38 completed weeks, high prevalence of G6PD deficiency, primipara mother, weight loss at discharge >3% per 24 h

of age or >7% cumulative weight loss, **may need a repeat visit depending on physician’s assessment 14

1.6 What should be included in the formal assessment of a neonate with neonatal hyperbilirubinaemia? (14) Recommendation All neonates should undergo a complete clinical examination including evaluation of intensity of jaundice (24), breast feeding adequacy#, pallor, splenomegaly, cephalhematoma or other signs of birth trauma, and evaluation for lethargy, poor feeding, general activity and tone. 1. All pregnant women should be tested for ABO and Rh (D) blood types. (14)

2. If a mother has not had prenatal blood grouping or is Rh-negative, a direct anti- body test (or Coombs’ test), blood type, and an Rh (D) type on the infant’s (cord) blood are strongly recommended. (14) 3. DO NOT use the albumin/bilirubin ratio when making decisions about the management of hyperbilirubinaemia (14) 4. Do not subtract conjugated bilirubin from total serum bilirubin when making decisions about the management of hyperbilirubinaemia. (14)

5. In addition to a full clinical examination by a suitably trained healthcare professional, carry out the following tests in babies with hyperbilirubinaemia (Table 2) as part of an assessment for underlying disease and treatment threshold graphs. Table 2: Tests to be done in babies with hyperbilirubinaemia Indications Assessments I nfant receiving phototherapy Measure TSB; blood type and DCT (if mother is ‘O’ or Rh negative); G6PD status; peripheral smear and reticulocyte count

J aundice present beyond 3 weeks Total and direct (or conjugated) o f age* bilirubin level, thyroid profile (T3, T4, TSH), urine for reducing substances (galactosemia), urine r/m, urine c/s Important Note* • Exclude cephalohematoma on examination • Exclude Rh isoimmunisation • Excessive weight loss (more than 10%) • Breast feeding jaundice due to inadequate breast feeding is common • Presence of direct hyperbilirubinemia (direct bilirubin more than 2 mg/dL at any age) requires

specific investigations and care which is beyond the scope of this guideline # Breast feeding is considered adequate if infant passes urine 6 to 8 times in 24 hours, sleeps for 2 to 3 hours after feeds and gains weight adequately after initial 7 to 10 days. 15

1.7 How can we prevent severe hyperbilirubinemia?(13, 14) Recommendation 1. All women should be encouraged to breastfeed 8 to 12 times a day 2. Supplementation is recommended only for dehydrated newborns and where weight loss from birth is >10%. Expressed breastmilk is the preferred supplementation. 3. Routine supplementation with intravenous fluids, honey or dextrose water for newborns with jaundice is not recommended 4. No interruption of breastfeeding should be done for any jaundice. 16

• Management and treatment Therapeutic options in management of hyperbilirubinemia 2.1 Phototherapyfor the management of hyperbilirubinemia (14)* • Phototherapy can be delivered by light - emitting diode (LED) or fibreoptic or fluorescent lamps or tubes or bulbs.# • Do not use sunlight as treatment for hyperbilirubinaemia. Exposing the baby to sunlight does not help in treatment of jaundice and is associated with risk of sunburn and therefore should be avoided. *

Rash, overheating, dehydration and diarrhoea are the most common side effects of phototherapy. It has photo oxidative effects and hence the parenteral nutrition fluid and some drugs need to be adequately covered during phototherapy #See Appendix A for different phototherapy equipment available in Indian Market Starting phototherapy • Use serum bilirubin levels ONLY for decision making for starting phototherapy • Intensive phototherapy must be ensured for neonates nearing exchange

transfusion threshold. Phototherapy can be intensified by adding another light source or increasing the irradiance of the initial light source used. • Increase the area of exposure to light by using double surface phototherapy for severe jaundice.* • It is not necessary to measure spectral irradiance before each use of phototherapy; however it is important to perform periodic checks of phototherapy units to make sure that an adequate irradiance is being delivered.

• Phototherapy thresholds presented on seventh day may be used for rest of the neonatal period. *Severe jaundice defined earlier Stopping phototherapy • There is no standard for discontinuing phototherapy. For infants who are readmitted after their birth hospitalization (usually for TSB levels of 18 mg/dL or higher), phototherapy may be discontinued when the serum bilirubin level falls below 13 to 14 mg/dL. Discharge and follow up after phototherapy

• If phototherapy is used for infants with hemolytic diseases or is initiated early and discontinued before the infant is 3 to 4 days old, a follow-up bilirubin measurement within 24 hours after discharge is recommended. • For infants who are readmitted with hyperbilirubinemia and then discharged, significant rebound is rare, but a repeat TSB measurement or clinical follow- up 24 hours after discharge is a clinical option. • Checking serum bilirubin 24 h after discharge to check for rebound is optional 17

Tips for delivering safe and effective phototherapy • Protect the eyes with eye patches/covers • Keep the baby naked with a small nappy to cover the genitalia • Place the baby as close to the lights as the manufacturers’ instructions allow. • Routine position change while the baby is under phototherapy is not recommended. • Phototherapy does not have to be continuous and can be interrupted for feeding, clinical procedures, and to allow maternal bonding.#

• Using white cloth or aluminum foil around the light source to reflect light back onto the baby, making sure not to impede the airflow that cools the bulbs is optional • Do not place anything over the top of the phototherapy unit. This may block air vents or light and items may fall on the baby • Encourage frequent breastfeeding. Unless there is evidence of dehydration, supplementing breastfeeding or providing IV fluids is unnecessary

• Giving frequent feeding will prevent excessive weight loss and temperature from rising • Visual assessment of jaundice during phototherapy is unreliable • Ensure all phototherapy equipment is maintained and used according to the manufacturers’ guidelines. # Important note • The guideline notes that there is no evidence to support the safe use of intermittent phototherapy at moderate or high levels of serum bilirubin (mild hyperbilirubinemia defined as a total bilirubin level of up to 12 mg/dL and

high defined as levels above 20 mg/dL in full-term infants. Bilirubin levels between these values indicated moderate hyperbilirubinemia) • Change tube lights every 6 months (or usage time >1200 hrs) whichever is earlier; or if tube ends blacken or if tubes flicker. Life of Compact Fluorescent lamps is 3000 hours while that of LED bulbs is 30,000 to 50,000 hours. Failure of phototherapy (22) • For those infants in the exchange or pre-exchange bilirubin zone, failure of

phototherapy has been defined as an inability to observe a decline in bilirubin of 1-2 mg/dL after 4-6 hours and/or to keep the bilirubin below the exchange transfusion level. • Exchange transfusion is recommended if the TSB rises to these levels despite intensive phototherapy. • For readmitted infants, if the TSB level is above the exchange level, repeat TSB measurement every 2 to 3 hours and consider exchange if the TSB remains above

the levels indicated after intensive phototherapy for 6 hours. However, an exchange transfusion (ET) should be performed at the slightest suspicion of bilirubin encephalopathy irrespective of the bilirubin value. 18

2.2 Exchange transfusion for management of hyperbilirubinemia (14) • Exchange transfusion should be done by central or peripheral route aiming replacement of double the baby’s blood volume and by skilled personnel in a well-equipped centre. • Immediate EBT is recommended if infant shows signs of ABE or if TSB is ≥25 mg/dL above the recommended age and risk specific cut off TSB • For Rhesus isoimmunization, the best choice would be O (Rh) negative packed cells

suspended in AB plasma. O (Rh) negative whole blood or cross-matched baby’s blood group (Rh negative) may also be used. • For ABO isoimmunization, O group (Rh compatible) packed cells suspended in AB plasma or O group whole blood (Rh compatible with baby) should be used. • In other situations baby’s blood group should be used. All blood must be cross matched against maternal plasma. • Blood volume used: 2 x (80-100 ml/kg) x birth weight in kg. 2.3 Other modalities for management of hyperbilirubinemia (14)

• No role of phenobarbitone, tin mesoporphyrin, Agar, Albumin, charcoal, cholestyramine, clofibrate, glycerine, chinese herbs, homeopathy, acupuncture, riboflavin or manna in management of hyperbilirubinemia • Routine use of Intravenous immunoglobulin (IVIg) for Rhhaemolytic disease of newborn and ABOdisease is not recommended as evidence from studies with lowrisk of bias indicates no benefit in Rhhaemolytic disease of newborn and studies suggesting benefit

in ABO incompatibility had a high risk of bias. (26) 2.4 What should be the frequency of long term follow up of neonates with hyperbilirubinemia and what all should be evaluated at follow up? • When infants with hyperbilirubinemia are identified and treated appropriately, the outcome is excellent with minimal or no additional risk for adverse neurodevelopmental sequelae. • Neonates with hyperbilirubinemia requiring exchange transfusion require:

o Follow up (at 3 months and 18 months postnatal age) for formal development assessment o Hearing evaluation of these neonates by brain stem evoked response audiometry (prior to 3 months) • Subsequent follow up of these neonates is 6 monthly (or more frequently (if the developmental assessment mandates the same • Other follow up (for vaccination, growth and feeding can continue as for a normal neonate) 19

2.4 What information and support should be given to parents/care givers of babies with neonatal hyperbilirubinaemia? Offer parents or care givers information about neonatal jaundice but should be tailored to their ne eds and expressed concerns. This information should be provided through verbal discuss ion backed up by written information whenever possible. (14) Care sh ould be taken to avoid causing u nnecessary anxiety to parents or care-givers. Information should include:

• factors that influence the development of significant hyperbilirubinaemia • how to check the baby for jaundice • what to do if they suspect jaundice • the importance of recognising jaundice in the first 24 hours and of seeking urgent medical advice • the importance of checking the baby’s nappies for dark urine or pale chalky stools • the fact that neonatal jaundice is common, and reassurance that it is usually transient and harmless when treated appropriately

• reassurance that breastfeeding should continue Information about treatment including phototherapy • anticipated duration of treatment • reassurance that breastfeeding, nappy-changing and cuddles can usually continue. • Encourage mothers of with jaundice to breastfeed frequently, and to wake the baby for feeds if necessary. • Provide lactation/feeding support to mothers whose baby is visibly jaundiced. • why phototherapy is being considered

• why phototherapy may be needed to treat significant hyperbilirubinaemia • the possible adverse effects of phototherapy • the need for eye protection and routine eye care • reassurance that short breaks for feeding, nappy changing and cuddles will not alter course of jaundice and efficacy of phototherapy • what might happen if phototherapy fails • rebound jaundice • potential long-term adverse effects of phototherapy Information on exchange transfusion

• Offer parents or care givers information on exchange transfusion including: • the baby be admitted to an intensive care bed • why an exchange transfusion is being considered • the possible adverse effects of exchange transfusions • when it will be possible for parents or care givers to see and hold the baby after the exchange transfusion. • when it will be possible for parents or carers to see and hold the baby after the exchange transfusion. 20

References: 1. Ip S, Chung M, Kulig J, et al. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics 2004;114:e130-53 2. Report 2002-2003: National Neonatal Perinatal Database Network. New Delhi: National Neonatology Forum of India; 2004. 3. The Young Infants Clinical Signs Study Group. Clinical signs that predict severe illness in children under age 2 months: a multicentre study. Lancet. 2008;371:135–42.

4. Burke BL, Robbins JM, Bird TM, Hobbs CA, Nesmith C, Tilford JM. Trends in hospitalizations for neonatal jaundice and kernicterus in the United States, 1988– 2005. Pediatrics. 2009;123:524–32. 5. Tomashek KM, Crouse CJ, Iyasu S, Johnson CH, Flowers LM. A comparison of morbidity rates attributable to conditions originating in the perinatal period among newborns discharged from United States hospitals, 1989–90 and 1999–2000. Paediatr Perinat Epidemiol. 2006;20:24–34.

6. Mwaniki MK, Atieno M, Lawn JE, Newton CR. Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review. Lancet. 2012;379:445–52. 7. Gladstone M. A review of the incidence and prevalence, types and aetiology of childhood cerebral palsy in resource-poor settings. Ann Trop Paediatr. 2010;30:181– 96. 8. Amin SB, Smith T, Wang H. Is neonatal jaundice associated with autism spectrum disorders: a systematic review. J Autism Dev Disord. 2011;41:1455–63.

9. Olusanya BO, Somefun AO. Sensorineural hearing loss in infants with neonatal jaundice in Lagos: a community-based study. Ann Trop Paediatr. 2009;29:119–28. 10. Maulik PK, Darmstadt GL. Childhood disability in low- and middle-income countries: overview of screening, prevention, services, legislation, and epidemiology. Pediatrics. 2007;120Suppl 1:S1–55. 11. Olusanya BO, Ogunlesi TA, Kumar P, Boo NY, Iskander IF, Almeida DF, Vaucher YE, and Slusher TM. Management of late-preterm and term infants with

hyperbilirubinaemia in resource-constrained settings. BMC Pediatr. 2015; 15: 39. 12. Bhutani VK, Zipursky A, Blencowe H, Khanna R, Sgro M, Ebbesen F, et al. Neonatal hyperbilirubinemia and Rhesus disease of the newborn: incidence and impairment estimates for 2010 at regional and global levels. Pediatr Res. 2013;74Suppl 1:86– 100. 13. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation.

Pediatrics. 2004 Jul;114(1):297-316. 14. Neonatal Jaundice 2010 Available at https://www.nice.org.uk/guidance/cg98/evidence/full-guideline-245411821. Accessed on 18 May, 2016 15. Narang A, Gathwala G, Kumar P. Neonatal jaundice: an analysis of 551 cases. Indian Pediatr 1997;34:429-32. 16. Olusanya BO, Ogunlesi TA, Slusher TM. Why is kernicterus still a major cause of death and disability in low and middle-income countries? Arch Dis Child. 2014;99:1117–21. 21

17. Bhutani VK, Johnson LH. Managing the assessment of neonatal jaundice: importance of timing. Indian J Pediatr. 2000 Oct;67(10):733-7. 18. Bhutani VK, Cline BK, Donaldson KM, Vreman HJ. The need to implement effective phototherapy in resource-constrained settings. Semin Perinatol. 2011;35:192–7. 19. Cline BK, Vreman HJ, Faber K, Lou H, Donaldson KM, Amuabunosi E, et al. Phototherapy device effectiveness in Nigeria: irradiance assessment and potential for improvement. J Trop Pediatr. 2013;59:321–5.

20. Pejaver RK, Vishwanath J. An audit of phototherapy units. Indian J Pediatr. 2000;67:883–4. 21. Owa JA, Ogunlesi TA. Why we are still doing so many exchange blood transfusion for neonatal jaundice in Nigeria. World J Pediatr. 2009;5:51–5. 22. NNF 2010. Available at http://aimaonline.org/iap-neochap-2013/uploads/acd- corner/nnf_guidelines-2011.pdf. Accessed on 18th May, 2016 23. Bhutani VK, Stark AR, Lazzeroni LC, Poland R, Gourley GR, Kazmierczak S, Meloy L,

Burgos AE, Hall JY, Stevenson DK; Initial Clinical Testing Evaluation and Risk Assessment for Universal Screening for Hyperbilirubinemia Study Group. Predischarge screening for severe neonatal hyperbilirubinemia identifies infants who need phototherapy. J Pediatr. 2013 Mar;162 (3):477-482 24. Kramer LI.Advancement of dermal icterus in jaundiced newborn.Am J Dis Child 1969;118:454-8. 25. van Imhoff DE, Dijk PH, Weykamp CW, Cobbaert CM, Hulzebos CV; BARTrial Study

Group. Measurements of neonatal bilirubin and albumin concentrations: a need for improvement and quality control. Eur J Pediatr 2011;170:977-82. 26. Louis D, More K, Oberoi S, Shah PS. Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2014 Jul;99(4):F325-31. Epub 2014 Feb 10. 22

Appendix A Phototherapy units available in the market S.No. Type of unit Principals Dealer Unit cost (Rs.) A. White fluorescent tube * * 20,000 (6 to 8; 20w) Double surface 35,000 Fluorescent B. Compact fluorescent Medela Rohit Surgials 60.000 lights (6 to 8; 21w) Phoenix Phoenix 25,000 Nice Neotech SBP Mediare 20,000 SS Technomed Global Medical Sys 20,000 Meditrin Meditrin 25,000 C.* Blue light (2 to 4; 20w) Atom Vishal Surgical 40,000-2,00,000 and white (2 to 4; 20w) Medela Rohit Surgical Drager Drager

Wyer Rustagi Surgical Ameda Medisphere Heraeus Medex Choongwae Global Medical Phoenix Phoenix D. Halogen bulb Datex-Ohmeda Phoenix 60,000-90,000 (Single; 150w; 21v) Olympic Rustagi Surgical Hillrom Phoenix E. Bili-Blanket Fibreoptic Ginevri Global Med 1,00,000-2,50,000 Bili BedTM Wallaby System Medela Global Med. Olympic System Datex- Rohit Surgical Ohmeda Rohit Surgical Ibis medical Ibis medical Principals Dealer • LED Shrichitra Shrichitra 40,000 • Lullaby LED GE GE 60,000

• LED high intensity spot Fanem Fanem 80,000 (Bilitron 3006/ Bilitron bed 5006/ Bilitron sky 5006) • LED high intensity spot Phoenix Phoenix 40,000 • Sunshine LED SS technomed 40,000 • Ibis medical Ibis Medical 50,000 23

National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Disease and Stroke (NPCDCS) A Manual for Medical Officer Developed under the Government of India – WHO Collaborative Programme 2008-2009 1

Contents: Page No. 1. Introduction 3 2. Risk factors of NCDs and their relationship 5 3. Role of medical officer to promote healthy lifestyle in community 6 4. Cardiovascular disease risk assessment and management 8 5. Treatment guidelines for 5.1. Diabetes 18 5.2. Hypertension 29 5.3. Hypercholesterolemia 34 5.4. CAD 38 5.5. Stroke 48 5.6 Cancer 52 6. Suggested Reading 79 7. List of Experts and Institutions involved 80 2

Section 1: INTRODUCTION Non-communicable diseases (NCD), also known as chronic diseases include cardiovascular diseases, diabetes, stroke, most forms of cancers and injuries. Such diseases mainly result from lifestyle related factors such as unhealthy diet, lack of physical activity and tobacco use. Changes in lifestyles, behavioural patterns, demographic profile (aging population), socio-cultural and technological advancements are leading to sharp increases in the prevalence of NCD. These

diseases by and large can be prevented by making simple changes in the way people live their lives or simply by changing our lifestyle. Magnitude of NCD burden in India During the year 2005, NCD accounted for 53% of all the deaths in the age group 30-59 years in India. Of these, 29% were due to cardiovascular diseases; It is estimated that, by 2020, cardiovascular disease will be the largest cause of disability and death, as a proportion of all

deaths in India. In 2003 alone, in India, there were approximately 30 million people suffering from coronary heart disease. It is estimated that the overall prevalence of diabetes, hypertension, Ischemic Heart Diseases (IHD) and Stroke is 62.47, 159.46, 37.00 and 1.54 respectively per 1000 population of India. There are an estimated 25 Lakh cancer cases in India. Diabetes which is a major risk factor for chronic disease on its own causes increased death and

disability. According to the Diabetes Atlas 2006 published by the International Diabetes Federation, the number of people with diabetes in India is currently around 40.9 million and is expected to rise to 69.9 million by 2025, unless urgent preventive steps are taken. Similarly, 118 million people were estimated to have high blood pressure in the year 2000 which is expected to go up to 213 million in 2025. Not only this, Indians succumb to diabetes, high blood pressure

and heart attacks 5-10 years earlier than their western counterparts, during their most productive years. This leads to considerable loss of productive years, to the country. It has been estimated that, by the year 2030, India will lose approximately 17.9 million potentially productive years which is higher than the expected combined loss in China, Russia, USA, Portugal and Brazil. This translates into a huge economic loss as high as 237 billion dollars by the

year 2015. Development of diabetes and heart attacks at an early age is not largely because of 3

environmental causes such as low consumption of fresh fruits and vegetables along with other unhealthy diet, increasing use of tobacco, and higher prevalence of sedentary life-style. To contain the increasing burden of Non-Communicable Diseases, Ministry of Health and Family welfare, Government of India, has revised the National Cancer Control Programme (NCCP) and formulated an integrated National Programme for Prevention and Control of Cancers,

Diabetes, Cardiovascular Diseases and Stroke (NPCDCS). The NPCDCS will focus on health promotion and prevention, strengthening of infrastructure including human resources, early diagnosis and management and integration with the primary health care system through NCD cells at different levels for optimal operational synergies. Objectives of NPCDCS: a. Prevent and control common NCDs through behaviour and life style changes, b. Provide early diagnosis and management of common NCDs,

c. Build capacity at various levels of health care for prevention, diagnosis and treatment of common NCDs, d. Train human resource within the public health setup viz doctors, paramedics and nursing staff to cope with the increasing burden of NCDs, and e. Establish and develop capacity for palliative & rehabilitative care Strategies The Strategies to achieve above objectives are as follows: 1) Prevention through behaviour change 2) Early Diagnosis 3) Treatment 4) Capacity building of human resource

5) Surveillance, Monitoring & Evaluation The strategies will be implemented in 20,000 Sub-Centres and 700 Community Health Centres (CHCs) in 100 Districts across 21 States/UTs 4

Section 2: RISK FACTORS OF NCDS What gives rise to major NCDs (Diabetes, cardiovascular diseases, Stroke, Cancer)? Major NCDs are caused by a set of risk factors like unhealthy diet (low fruit and vegetable intake), physical inactivity, tobacco use, harmful use of alcohol and stress. High blood pressure, dyslipidemia (high levels of total cholesterol, LDL-cholesterol, and triglycerides and low level of HDL-Cholesterol) overweight/obesity (both generalized and central) is other physiological risk

factors. Other putative but not well proven factors include air pollution, food preservatives, adulterants, artificial color and indoor smoke from solid fuels. Alcohol consumption, specifically binge drinking, leads to acute hypertension, stroke and in some individuals atrial fibrillation and cardiomyopathy. Risk factors and level of NCD prevention and management Behavioral RF Physiological RF Disease Outcome (cid:149) Unhealthy Diet (cid:149) BMI (Obesity) (cid:149) Diabetes

(cid:149) Physical (cid:149) Hypertension (cid:149) Heart disease inactivity (cid:149) Hyper- (cid:149) Stroke (cid:149) Tobacco cholesterolemia (cid:149) Cancer (cid:149) Alcohol (cid:149) High Blood sugar (cid:149) Chronic (cid:149) Stress level respiratory disease Primary Prevention Secondary Prevention Tertiary Prevention Health promotion Case management & HP Case management Some attributes of risk factors

(cid:216) Risky lifestyle behaviors are responsible for the risk factors. Risk factors are cumulative and operate on a life course perspective. (i.e. they influence the risk throughout the life course. For example childhood obesity is a major risk factor for adult obesity and consequently diabetes and CVD). (cid:216) Normally, for all practical purposes it is seen that these risk factors occur together. A person who has high blood sugar levels may also have high blood pressure, dyslipidemia and

(cid:216) Risk factors operate in a continuum. This means that even within the normal ranges, people with higher level have higher risks. For example individuals with systolic blood pressure of 140 mmHg have a higher risk of CVD, stroke and future death than those with 120 mmHg even though both are within ‘normal’ range. This applies to all the risk factors of CVD and Stroke (cid:216) The risk factors are additive. This means cumulative small elevations of risk factors are

much more harmful than isolated elevation of single risk factors. It is important to note that all these risk factors are amenable to modification through lifestyle changes. In nutshell, today’s risky behaviors are tomorrow’s risk factors. Today’s risk factors are tomorrow’s disease. Thus, primary and secondary prevention of chronic diseases and their common risk factors provide the most sustainable and cost-effective approach to chronic disease prevention and control 6

Section 3: ROLE OF MEDICAL OFFICER IN NPCDCS 1. Health promotion activities - Educate regarding common risk factors, increased intake of healthy foods (ii) increased physical activity through sports, exercise, etc. (iii) avoidance of tobacco and alcohol and (iv) stress management. 2. Risk assessment and management through opportunistic screening 3. Motivate and create role models in the community 4. Work closely with other sectors/ departments for NCD prevention

5. Management of patients suffering from Cancer, Diabetes, CVDs and Stroke referred from different centers 6. Establish an effective referral mechanism (two way) with the nearest medical colleges 7. Supervision of the activities undertaken by paramedical workers 8. Assist resource centers/ institution in organizing the training for different cadre of health workers 7

Section 4: RISK ASSESSMENT AND MANAGEMENT This section provides evidence-based guidelines on how to reduce the occurrence of first clinical events of coronary heart disease (CHD), cerebrovascular disease (CeVD) and peripheral vascular disease (PVD) in the population. The evidence-based recommendations given in these guidelines provide guidance on which specific preventive actions to initiate, and with what degree of intensity. The accompanying

World Health Organization/ International Society of Hypertension (WHO/ISH) risk prediction charts enable the estimation of total cardiovascular risk of people in the first category. 4.1. What are the goals of implementing these guidelines? The goals are to prevent CHD, CeVD and PVD events and Cancer by lowering risk. The recommendations assist people to: (cid:216) Quit tobacco use, or reduce the amount smoked, or not just start the habit (cid:216) Make healthy food choices (cid:216) Be physically active

(cid:216) Reduce body mass index, waist hip ratio/waist circumference (cid:216) Lower blood pressure (cid:216) Lower blood cholesterol and low density lipoprotein cholesterol (LDL-cholesterol) (cid:216) Control hyperglycemia (cid:216) Take anti platelet therapy when necessary. 4.3. Who needs referral to a specialist facility? Referral is required if there are clinical features suggestive of: (cid:216) Acute cardiovascular events such as: heart attack, angina, heart failure, arrhythmias,

stroke, and transient ischemic attack. (cid:216) Secondary hypertension, malignant hypertension. (cid:216) Diabetes mellitus (newly diagnosed or uncontrolled). (cid:216) Established cardiovascular disease (newly diagnosed or if not assessed in a specialist facility). (cid:216) Suspected lesions for Cancer (cid:216) People needing medical therapy to quit smoking. 8

Once the condition of the above categories of people (except with suspected lesion) is assessed and stabilized, they can be followed up in a primary care facility based on the recommendations provided in these pocket guidelines. They will need periodic reassessment in specialty 4.3. When is grading cardiovascular risk using charts unnecessary for making treatment decisions? Some individuals are at high cardiovascular risk because they have established cardiovascular

disease or very high levels of individual risk factors. Risk stratification is not necessary for making treatment decisions for these individuals as they belong to the high risk category; all of them need intensive lifestyle interventions and appropriate drug therapy . They include people: (cid:216) With established cardiovascular disease (cid:216) Without established CVD who have a total cholesterol ≥ 320 mg/dl or low density lipoprotein (LDL) cholesterol ≥ 240 mg/dl or TC/HDL-C (total cholesterol/high

density lipoprotein cholesterol) ratio >8 (cid:216) Without established CVD who have persistent raised blood pressure of ≥160/ ≥100 mmHg (cid:216) With renal failure or renal impairment. 4.4. Instructions for using WHO/ISH risk prediction charts These WHO/ISH risk prediction charts indicate 10-year risk of a fatal or nonfatal major cardiovascular events (myocardial infarction or stroke), according to age, gender, blood pressure,

smoking status, total blood cholesterol and presence or absence of diabetes mellitus. There are two sets of charts. One set can be used in settings where blood cholesterol can be measured. The other set is for settings in which blood cholesterol cannot be measured. The charts provide approximate estimates of CVD risk in people who do not have established coronary heart disease, stroke or other atherosclerotic disease. They are useful as tools to help

identify those at high cardiovascular risk, and to motivate persons, particularly to change behaviour and, when appropriate, to take antihypertensive, lipid-lowering drugs, and aspirin. 9

4.5. How do you use the charts to assess cardiovascular risk? (cid:216) If blood cholesterol can be measured, refer to chart 1. (cid:216) If blood cholesterol cannot be measured due to resource limitations, refer to chart 2. (cid:216) Before applying the chart to estimate the 10 year cardiovascular risk of an individual, the following information is necessary * ●● Presence or absence of diabetes ●● Gender ●● Smoker (All current smokers and those who quit smoking less than 1 year **

before the assessment) or non-smoker ●● Age *** ●● Systolic blood pressure (SBP) ●● Total blood cholesterol. * A person who has diabetes is defined as someone taking insulin or oral hypoglycemic drug(s), or with a fasting venous plasma glucose concentration ≥126 mg/dl or a postprandial (approximately 2 hours after a main meal) venous plasma glucose concentration ≥ 200 mg/dl on two separate occasions. For very low resource settings urine sugar test may be used to screen for diabetes if blood

glucose assay is not feasible. If urine sugar test is positive a confirmatory blood glucose test needs to be arranged to diagnose diabetes mellitus. ** All current smokers and those who quit smoking less than 1 year before the assessment are considered smokers for assessing cardiovascular risk. *** Systolic blood pressure, taken as the mean of two readings on each of two occasions, is sufficient for assessing risk but not for establishing a pre-treatment baseline. 10

Once the above information is available proceed to estimate the 10-year cardiovascular risk as follows: Step 1 Select the appropriate chart depending on the presence or absence of diabetes Step 2 Select male or female tables Step 3 Select smoker or non smoker boxes Step 4 Select age group box (if age is 50-59 years select 50, if 60-69 years select 60 etc) Step 5 Within this box find the nearest cell where the individual’s systolic blood pressure (mm Hg) and total

blood cholesterol level (mg/dl) cross. The colour of this cell determines the 10 year cardiovascular risk. 11

4 .6. WHO / ISH Risk prediction CHARTS Chart 1: 10 year risk of a fatal or non fatal cardiovascular event by gender, age, and systolic blood pressure, total blood cholesterol, smoking status and presence or absence of diabetes mellitus 12

Chart 2: 10 year risk of a fatal or non fatal cardiovascular event by gender, age, systolic blood pressure, smoking status and presence or absence of diabetes mellitus 13

4.7. Practice Points Please note that CVD risk may be higher than indicated by the charts in the presence of the following: • Already on antihypertensive therapy • Premature menopause • Approaching the next age category or systolic blood pressure category • Obesity (including central obesity) • Sedentary lifestyle • Family history of premature CHD or stroke in first degree relative (male <55 years, female < 65 years) • Raised triglyceride level (≥150 mg/dl)

• Low HDL cholesterol level (≤40mg/dl in males, ≤ 50 mg/dl in females) • Fasting glycaemia, or impaired glucose tolerance • Microalbuminuria • Socioeconomic deprivation. 4.8. Recommendations for prevention of cardiovascular disease in people with cardiovascular risk factors (according to individual total risk) 10 year risk of Risk classification Intervention cardiovascular event Risk <10% LOW RISK Low risk does not mean “no” risk. Conservative management focusing on lifestyle an intervention is suggested.

Risk assessed after 5 years unless significant change in health status. Risk 10% to <20% MODERATE Monitor risk profile every 2 years. RISK Risk 20% to <30% HIGH RISK Monitor risk profile yearly. Risk ≥30% VERY HIGH Individuals in this category are at very high risk of RISK fatal or non-fatal vascular events. Monitor risk profile every 3–6 months. Note: Reassess a person after six months of lifestyle modification if there is isolated elevation of single risk factor. 14

4.9. LIFESTYLE MODIFICATION a. DIET (cid:216) Increase intake of green leafy vegetables and fresh fruits. (cid:216) Consume less salt; avoid adding/sprinkling salt to cooked and uncooked food. (cid:216) Preparations which are high in salt and need to be moderated are: Pickles, chutneys, sauces and ketchups, papads, chips and salted biscuits, cheese and salted butter, bakery products and dried salted fish. (cid:216) Restrict all forms of sugar free and refined carbohydrates for example biscuits, breads,

naan, kulchas, cakes, mathris etc. (cid:216) Steamed and boiled food should be preferred over fried food. (cid:216) Have fresh lime water instead of carbonated drinks. (cid:216) Avoid eating fast/junk foods and aerated drinks. Instead of fried snacks, eat a fruit. (cid:216) In practice, it is best to use mixture of oils. Either buy different oils every month or cook different food items in different oils. (cid:216) Oils which can be mixed and matched are mustard oil, soya bean oil, groundnut oil, olive

oil, sesame oil, and sunflower oil. (cid:216) Ghee, vanaspati, margarine, butter and coconut oil are harmful and should be moderated. (cid:216) If you are a non vegetarian, try to take more of fish and chicken. They should not be fried. Red meat should be consumed in small quantities and less frequently # b. PHYSICAL ACTIVITY (cid:216) Physical activity is a key determinant of energy expenditure. (cid:216) Regular exercise is important for promoting weight control or weight loss.

(cid:216) Exercise regularly (moderate to vigorous) for 5-7 days per week; start slowly and work up gradually o At least 30 minutes (accumulated) of physical activities per day for cardiovascular disease protection. o 45 minutes/ day (accumulated) for fitness. o 60 minutes/ day (accumulated) for weight reduction. (cid:216) Discourage spending long hours in front of TV. (cid:216) Encourage outdoor activities like cycling, gardening etc. 15

(cid:216) Yoga: A holistic life style which includes Asanas and all other components of healthy life style like low fat vegetarian diet (Satvik diet), stress management, tobacco avoidance and physical exercise. They have the potential for primary and secondary prevention of heart disease. c. WEIGHT CONTROL All individuals who are overweight or obese should be encouraged to lose weight through a combination of a low calorie diet and dynamic physical activity.

Overweight or obesity is assessed by measuring body mass index (BMI), which is calculated as 2 weight in kg/height in meter . For Indian population 18.5 to 22.9 BMI is normal, 23 to 24.9 is considered as overweight and BMI of ≥25 is considered as obesity. Waist circumference is also an important measurement of central obesity and it should be <90 cm for men and <80 cm for women. Another measure of central obesity is Waist Hip Ratio (WHR). Normal WHR is <0.85 for women and <0.95 for men.

# Patients with uncontrolled hypertension (≥200/≥110), uncontrolled diabetes (FBS ≥ 250 mg/dl), diminished vision due to diabetic/hypertensive retinopathy or for other reasons, recent myocardial infarction/unstable angina or stroke (within 6 weeks), and with uncontrolled angina (class III or more) are not advised to go for physical exercise. d. TOBACCO CESSATION • All non-smokers should be encouraged not to start smoking.

• All smokers should be strongly encouraged to quit smoking by a health professional through Lifestyle modification including YOGA and supported in their efforts to do so. • It is suggested that those who use other forms of tobacco be advised to stop. The following flow chart depicts the protocol for counseling on tobacco cessation using the 5 steps -5 A approach 16

PROTOCOL FOR COUNSELING ON CESSATION OF TOBACCO USE (5 STEPS– 5As) D o you use No Reinforce message that tobacco? tobacco increase risk of heart disease & cancer Yes Advise to quit in a clear, strong and personalized manner Tobacco use increases the ri sk of developing a heart attack, stroke and/or cancer Quitting tobacco use is the o ne most important thing you can do to protect your heart and health, you have to quit now” Are you willing to make a quit attempt now? Yes No • Set quit date P rovide

• Inform family and fr iends Information on health • Ask for their suppor t hazards of tobacco to the • Remove cigarettes/to bacco patient. • Remove objects/art icles that prompt you to smoke • Arrange follow up v isit at 1, 3 and 5 months. A t Follow up Visit Congratulate success and reinforce I f p a t i e n t h a s relapsed, consider more intensive follow-up and support from family Use 5 steps- 5 as- ask, advise, assess, assist, arrange e. ALCOHOL INTAKE

4.10. PHARMACOTHERAPY 10year risk of Risk Anti-hypertensive drugs Lipid lowering drugs Antiplatelet drugs cardiovascular event classification Risk <10% LOW RISK (cid:149) Persistent blood pressure (cid:149) individuals with total (cid:149) Aspirin should not be ≥140/90 mmHg should cholesterol at or above 320 given to individuals in continue non pharmacologic mg/dl this low-risk category. therapy like lifestyle strategies (cid:149) To follow a non

(cid:149) Total cardiovascular risk pharmacologic therapy i.e., reassessed every five years lifestyle modification Risk 10% to <20% MODERAT (cid:149) Persistent blood pressure (cid:149) individuals with total (cid:149) Aspirin should not be E RISK ≥140/90 mmHg should cholesterol at or above 320 given to individuals in continue non pharmacologic mg/dl this risk category. therapy like lifestyle strategies (cid:149) To follow a non (cid:149) Total cardiovascular risk pharmacologic therapy i.e.,

reassessed every two years lifestyle modification Risk 20% to <30% HIGH (cid:149) Persistent blood pressure Adults >40 years with (cid:149) Aspirin should not be RISK ≥140/90 mmHg should persistently high serum given to individuals in continue non pharmacologic cholesterol (>200 mg/dl) and/or this risk category. therapy like lifestyle strategies LDL cholesterol >120 mg/dl, (cid:149) Total cardiovascular risk despite a lipid-lowering diet reassessed every year and other lifestyle measures for

(cid:149) First line antihypertensive a year, should be given a statin. therapy may be considered. Risk ≥30% VERY (cid:149) Persistent blood pressure Adults >40 years with (cid:149) Aspirin should be given HIGH RISK ≥130/80 mmHg should persistently high serum to individuals in this risk continue non pharmacologic cholesterol (>200 mg/dl) and/or category. therapy like lifestyle strategies LDL cholesterol >120 mg/dl, (cid:149) Total cardiovascular risk despite a lipid-lowering diet

reassessed six months and other lifestyle measures for (cid:149) First line antihypertensive a year, should be given a stain. therapy may be considered. 18 Note: Reassess a person after six months of lifestyle modification if there is isolated elevation of single risk factor.

Section 5: MANAGEMENT GUIDELINES 5. 1. PREVENTION AND MANAGEMENT OFDIABETES What is diabetes? Diabetes is a disease in which the body does not produce or properly use the hormone insulin. The body needs insulin to convert sugar, starches and other foods into energy. Impairment of insulin secretion and action in the body leads to abnormally elevated levels of glucose in blood, a condition classically termed as diabetes. What are the different "types" of diabetes?

Diabetes is classified into three types namely Type 1 Diabetes, Type 2 Diabetes and gestational diabetes. A description of each of these types is give below while guidelines for management elaborated in the following sections are specific to type 2 diabetes. Type 1 diabetes (T1DM): Usually occurs in younger people, children and adolescents. The diagnosis of T1DM can be made throughout childhood but it is more likely below 15 yrs of age. The onset is usually acute and

severe and insulin is required for survival Type 1 diabetes results from autoimmune destruction of the beta cells in the pancreatic islets. Family history of diabetes is rare in T1DM. Presence of features of associated autoimmunity (autoimmune disorders, vitiligo) and absence of obesity and acanthosis nigricans are characteristics of T1DM. In addition, urine of T1DM patients with uncontrolled hyperglycemia is positive for ketone bodies. Type 2 diabetes (T2DM):

Is the commonest type of diabetes. It usually occurs after the age of forty years but occurs frequently even at lower age among Indians. T2DM was previously known as non-insulin dependent diabetes mellitus. The onset is usually insidious and may be mild to severe. The family history is usually positive and strong. Obesity, metabolic syndrome and acanthosis nigricans are usually seen in these patients while there is no evidence of autoimmunity. Further, there is no

When is a person at high risk for diabetes? 1. If he/she is of above the age of 30 years 2 2. If he/she is overweight (BMI is more than 23kg/m ). 3. If he/she is physically inactive, that is, he or she exercises less than 3 times a week. 4. If he/she has high blood pressure 5. If he/she has impaired fasting glucose or impaired glucose tolerance. 6. If his/her triglyceride and/or cholesterol levels are higher than normal. 7. If his/her parents/siblings or grandparents have or had diabetes.

8. If she delivered a baby whose birth weight was 4 kgs or more. 9. If she has had diabetes or even mild elevation of blood sugars during pregnancy. When to suspect diabetes? • Symptoms of uncontrolled hyperglycemia: excess thirst, excess urination, excess hunger with loss of weight • Frequent infections • Non-healing wounds • Unexplained lassitude • Fatigue • Impotence in men Criteria for diagnosing T2DM The criteria for diagnosing T2DM, as defined by the World Health Organization in 1999, are

depicted in table-5.1.1. Table-5.1.1: Criteria for diagnosis of T2DM using venous blood samples* Fasting Glucose 2-hour Post-Glucose Load (mg/dl) (mg/dl) Diabetes Mellitus >=126 >=200 Impaired Glucose Tolerance < 110 >140 to <200 Impaired Fasting Glucose >=110 to <126 *WHO Definition 1999 20

Management of Diabetes Management of T2DM should be initiated as soon as diagnosis is established even if the patient is asymptomatic. Initial assessment and management of the patients has to be carried out at Community Health Centre (CHC) level or at secondary care level. Management of T2DM comprises initial assessment, initial management and follow-up visits. Each of these components is elaborated here. 1. Initial assessment of individuals suspected of having T1DM need to be subjected to risk

assessment which include: • History and physical examination; • Assessment of blood glucose level; • Presence of CVD risk factors (lipid profile); and • End-organ damage (urine for protein/ ECG/ fundus examination) Assessment of history and physical examination of the patient is elaborated in table-5.1.2. 2. Initial management include: • Pharmacotherapy for the management of hyperglycemia and any other co-morbid conditions e.g. high blood pressure, dyslipidemia etc.;

• Therapeutic lifestyle management (please refer the earlier section); and • Diabetes patient Education and counseling by dietician 21

Table-5.1.2 Initial Assessment of Diabetic Patients History (Ask for) Physical Examination (Look for) Symptoms of hyperglycemia Weight Duration since onset of symptoms Body Mass Index Precipitating factors such as recent infections, Waist circumference, Waist-hip ratio stress, change in dietary habits or physical activity levels Symptoms of Micro- and Macro-vascular Acanthosis nigricans * Complications: visual disturbances, edema, breathlessness, angina, intermittent claudication, numbness, paraesthesiae

Hypertension, pre-existing cardiovascular Blood pressure diseases Drug history Peripheral pulses Feet: calluses, ulcers, prominent Diet veins, edema, injuries # Physical Activity: type, frequency Fundus examination Family History Cardiovascular system -Diabetes and complications Peripheral nervous system -Age at onset Thyroid -Cardiovascular disease *Acanthosis nigricans is a brown to black, poorly defin ed, velvety hyperpigmentation of the

skin, usually present in the posterior and lateral folds of the neck, the axilla, groin, umbilicus, and other areas. This occurs due to insulin spillover (from excessive production due to obesity or insulin resistance) into the skin which results in its abnormal growth, and the stimulation of color producing cells. The most common cause would be insulin resistance, usually from type-2 diabetes mellitus. # Details of Fundus examination are provided in a later section 22

T2DM: Principles of Management Lifestyle management (diet and physical activity) accompanied by drug therapy or insulin are the corner stone of diabetes management. Apart from this other concurrent complications should be addressed. The basic principles in the management of type-2 diabetes are: • Modify Lifestyle: diet and physical activity • Reduce Insulin Resistance through reduction in weight, specifically reduction of fat mass • Pharmacological treatment (if inadequate control):

(cid:252) Sulfonylureas/ Metformin • Treatment for high blood pressure: (cid:252) ACE-Inhibitors, Calcium channel blockers such as amlodipine and diuretics such as hydrochlorothiazide (cid:252) For details refer the section on hypertension • Lipid control with statins The targets of control in Diabetes management in depicted in the Box 5.1.1 Box 5.1.1: Ideal Targets of control in the management of Diabetes Fasting blood glucose : 80-110 mg/dl Post meal blood glucose : 120-140 mg/dl HbA : < 7% 1C

Total cholesterol : < 180 mg/dl LDL-chol : < 100 mg/dl HDL chol : > 45 mg/dl Blood pressure : < 130/80 mmHg Serum TG : <150 mg/dl Source: ICMR Note: The targets for diabetic population are lower than the non-diabetes 23

Box 5.1.2: Glycosylated haemoglobin (HbA ) 1C A fraction of hemoglobin in the RBCs is found to be in a glycosylated form i.e. has glucose attached to it. The HbA1c level is proportional to average blood glucose concentration over the previous two to three months and therefore is an excellent indicator of how well the patient has managed his/her diabetes over the last four weeks to three months. Glycated hemoglobin is recommended for monitoring blood sugar control in diabetic patients.

American Diabetes Association (ADA) recommends an HbA1c goal of less than 7% for people with diabetes in general. Pharmacotherapy (cid:252) BIGUANIDES (Metformin) Mechanism of Action: Insulin sensitizer Dose: The dose of metformin varies from 250mg to 2000mg/day. Since patients may complain of nausea and gastric irritation, the dose can be administered after a major meal. Dose of metformin can be titrated based on blood glucose monitoring at intervals of 2-4 weeks.

Currently the preferred approach is to start the patient on metformin and increase the dose to at least 1g/day. If despite this dose, optimum glucose control is not achieved, a suphonylurea should be added (see box-7 for targets of control. Advantages § No weight gain; some patients may experience weight loss. Hence metformin is useful in large majority of patients who are overweight § No hypoglycaemia § For monotherapy in obese patients

§ Can be combined with other anti-hyperglycemic agents including insulin Contraindications § r enal (Creatinine ≥ 1.5mg% in men; Creatinine ≥ 1.4mg% in women) / hepatic disease § cardiac / respiratory insufficiency; other hypoxic condition o severe infections § alcohol abuse § history of lactic acidosis § Use of I/V radiographic contrast media Pregnancy § Temporarily withhold: surgery, acute illness Caution: Phenformin is a banned drug and is not recommended 24

(cid:252) SULPHONYLUREAS (Glibenclamide) § The dose of glibenclamide varies from 2.5-20mg/day given in one or two doses. The dose can be titrated based on blood glucose monitoring at intervals of 1-2 weeks § General rule: glucose lowering effect plateaus after half-maximal recommended dose § APPROVED INDICATIONS: monotherapy; in combination with metformin and insulin § Caution: Hypoglycemia can occur most likely to effect among elderly, those with

worsening renal function and among those with irregular meal schedules General Guidelines for using oral anti-diabetic agents: The treatment should be individualized and the points mentioned below are only broad based Guidelines. The necessity of diet, exercise and life style modifications needs to be emphasized; in some cases these measures alone would suffice. When pharmacological treatment becomes necessary, the following points may be considered: (i) Non-obese people with type 2 diabetes:

§ In non-obese people with diabetes, start with a sulphonylurea / meglitinide or glitazone. If even after two to four weeks of initiation of treatment, symptoms still persist or blood sugar is not sufficiently controlled then a drug from another group like metformin can be added. If the initial blood sugar levels are very high, the symptoms are very severe or acute complications like ketosis are present, insulin has to be considered for treatment even at the onset, for a brief period.

§ If the initial assessment shows presence of complications like diabetic retinopathy or nephropathy, this indicates a long period of undiagnosed diabetes and insulin therapy on a continuous basis should be considered. (ii) Obese people with type 2 diabetes: § In obese people with diabetes, the starting drug is ideally metformin. § Similar Guidelines as mentioned above can be used to achieve good metabolic control with addition of other drugs like sulphonylureas/ meglitinides or glitazones and/ or insulin.

(iii) Lean people with type 2 diabetes: § In India, many subjects with type 2 diabetes are lean or low body weight (BMI 2 <18.5kg/m ). In these people with diabetes, metformin is better avoided and the use 25

of glitazones and sulphonylureas may be considered as first line of management. Quite often, such people with diabetes may require insulin for better control. § With increasing duration of diabetes, most oral anti-diabetic agents tend to be less effective and hence poly-pharmacy becomes inevitable, with use of drugs from multiple classes. However, insulin use should not be delayed and, if and when necessary, insulin should be introduced for tight glycemic control. Combination of oral drugs with insulin

When the glycemic control is not achieved with the maximum dose of an oral agent/combination therapy, this is called "secondary failure to oral hypoglycemic agents (OHA). It has been the experience of most physicians in India that combination of oral drugs and insulin helps to achieve good control of diabetes. While using combination therapy, the oral drugs may be continued in optimal doses, while intermediate acting/long acting/short acting insulin is

added either at bed time or in the morning depending on the blood sugar profile of person with diabetes. However, if indicated, one should not hesitate to use insulin in multiple doses to achieve tight metabolic control. When to recommend hospitalization • Uncontrolled infections; • Severe cellulitis, • Unresponsive UTI or other deep seated infections including bad diabetic foot needing intravenous antibiotics, • Recurrent UTI not responding to oral antibiotics, • Presence of ketones in urine

Diabetes patient education and diet counseling Patient education on diabetes management and life style modifications is the corner stone of effective diabetes control and management and prevention of complications. If a ‘diabetes educator’ is available then the patients and their families must visit him/her. At PHC level, nurses/multipurpose health workers can be trained to undertake this activity. At sub-district and

district level hospital, dietician/counselor and nurses can undertake diabetes patient education. Counseling on diet need to be provided by a trained dietician at district and sub-district level hospital. Patient education topics that can be covered in the initial visit and follow-up visits are depicted in the table-5.1.3. 26

Table-5.1.3: Patient education topics to be covered in the initial and follow-up visits Initial Visits Follow-up Visits What is Diabetes? Importance of Glycaemic Control Why does it occur? Prevention of Complications Lifestyle measures: Diet, Exercise Foot Care (see box-5.1.3) Detailed lifestyle advice Newer modalities of treatment Use of Oral Drugs Marriage Counseling Advice on identifying signs and symptoms of Pre-conceptional counseling regarding the

hypoglycaemia and hyperglycaemia and their importance of good glucose control prior to management pregnancy Patient should be informed about the importance of factors other than glucose control: cholesterol, blood pressure, stopping smoking,/tobacco, etc Box 5.1.3: Foot Examination Foot care advice to the patients Inspect your feet daily for cracks, blisters, infections, and injuries. You may be able to see a problem before you feel it. If you can't see the bottoms of your feet easily, use a mirror. A

magnifying glass also may help you see better. If you can't check your own feet, have someone else do it for you. Cleanse your feet daily as you bathe or shower, using warm water and mild soap. Dry your feet with a soft towel making sure to dry between the toes. Don't use hot water. You may burn your skin as you may not be able to feel the hotness of the water. Moisturize dry skin by using oil. If it causes redness or irritation, discontinue its use and inform

your doctor. If you are currently using a cream or lotion that keeps your skin soft and free of cracks, continue using it. Clip toenails straight across. Use a nail cutter; don't use a scissor and also smooth down the edges. If you can't easily reach your feet for have thick nails, have someone experienced trim your nails. Always wear something on your feet (socks, slippers, shoes) to protect from injury - even in your house.

Choose soft good shoes. Let them be a size bigger that what you feel is appropriate. Wear socks made of cotton or wool (in winter). 27

Treat minor breaks in the skin promptly. Cleanse the area with soap and water, dry, and cover with clean gauze. Observe for signs of infection such as redness, swelling, warmth, pain or drainage. Don't put weight on the foot that has an injury. See your doctor to check your feet during your regular visits for diabetes care. Take off your shoes and socks at every visit. For more information and visual guidance visit http://www.healthy-india.org/preventdiabetes5.asp 3. Follow-up visits

Annual assessment of the patients has to be carried out at CHC/secondary care level for follow-up of blood glucose, urinary microalbuminuria, fundus examination, blood lipids, creatinine, feet examination and patient education. Primary care physicians need to follow up the diabetic patients regularly for compliance with medicines, lifestyle management, blood glucose control, blood pressure control and control of other risk factors. Eye Care in diabetes

The Retina/fundus of all diabetes patients need to be checked at least once a year by a trained ophthalmologist even if there are no eye symptoms and the vision is 6/6. The patient needs to be accordingly referred for the same to the CHC, where ophthalmologist is available. Early retinal problems don’t show up as visual symptoms and a good vision should not mean that a fundus examination is not required. Diabetes can damage blood vessels throughout our bodies. The vessels in the eyes seem

especially vulnerable to damage. In the early stages of retinopathy, fluid can leak from small blood vessels in the retina. If this leaking occurs in the macula, then objects may appear blurry. However early damage can be diagnose through a retina/fundus examination and the blood vessels can be sealed with laser and vision can be saved and preserved. Proliferative retinopathy is an advanced form of retinopathy. Proliferative retinopathy occurs

when abnormal blood vessels grow on the retina and sometimes into other parts of the eye. If these vessels bleed into the vitreous - the clear fluid in the centre of the eye, light can't reach the retina and vision can become cloudy. The blood may be slowly reabsorbed and vision can return to normal but if the bleeding continues, vision may be cloudy until the problem is treated. Tissue can also grow along with the abnormal blood vessels, distorting vision or making objects

appear blurry. Over time, the tissue can shrink, pulling the retina away from its base. 28

If the blood doesn't reabsorb or if the tissue affects vision, the vitreous may need to be surgically removed to avoid loss of vision. All these problems of the eyes can be prevented if prevention is started early. Checklist for preventing of diabetes complications Every 3-6 months the patient should have a physical review by the physician. Checklist for the follow-up is as follows: 1. Test blood sugar levels 2. Test glycosylated haemoglobin levels(HbA ) (if facilities are readily available) 1C

3. Examine feet for sensations and circulation; Also for calluses, dryness, sores, infections, injuries 4. Check blood pressure. 5. Help the patient to give up tobacco, if he/she continues to use tobacco 6. Reinforce of life style measures- increase physical activity levels and improve diet (please refer the earlier section on therapeutic lifestyle management). Preconception counselling Counselling on pregnancy must start before conception. All women with diabetes must know that

they should not conceive till their blood glucose is well controlled for at least 2-3 months before conception as ascertained by HbA . Hyperglycemia at conception increases the risk of 1C complications during pregnancy as well as congenital defects in the foetus. A summary of services for diabetes management, appropriate at each levels of care, is depicted in the table 5.1.4: Table-5.1.4: Management of Diabetes at each levels of care Services Levels of Care Secondary CHCs PHCs care level

Screening for Diabetes √ √ √ History and Physical Examination √ √ √ Initial Assessment √ √ X Diabetic Patient Education √ √ √ Pharmacotherapy Initiation √ √ X Follow-up √ √ √ Foot care √ √ √ Eye care √ √ X Annual Assessment √ √ X Pre-conception Counseling √ √ √ Marriage Counseling √ √ √ 29

5.2. PREVENTION AND MANAGEMENT OF HYPERTENSION Introduction Abnormally elevated blood pressure is a pathological condition which increases the work load on the heart. This condition is termed as high blood pressure or hypertension. Based on the etiology, high blood pressure is of two types: Primary/essential: Primary or "essential" hypertension has no known cause, however many of the above said lifestyle factors are associated with this condition. This constitutes majority of the

high blood pressure in the world today. Secondary: Secondary hypertension is caused by some other medical conditions/problem or the use of certain medications. Secondary hypertension is seen only in very few individuals in the community. The causes of secondary hypertension include: kidney diseases: reno-vascular disease and chronic renal disease, endocrine disorders: hyperthyroidism, cushing's syndrome and pheocromocytoma, sleep disorders, coarctation of the aorta and non specific aorto-arteritis. Some

of these causes are often curable, and many others treatable. Criteria for diagnosing high blood pressure The table-5.2.1 provides a classification of blood pressure for adults ages 18 and older. The classification is based on consistent elevation during two or more properly measured BP readings in sitting position. Table-5.2.1: Criteria for diagnosing high blood pressure Category Systolic Diastolic Normal Less than 120 Less than 80 Pre-hypertension 120-139 80-89 High Blood Pressure Stage 1 140-159 90-99

Stage 2 160 or higher 100 or higher Source: JNC VII classification 30

MANAGEMENT OF HYPERTENSION: The Risk assessment should cover: o Assessment of medical history o Physical Examination o Laboratory Investigation (cid:216) Assessment of medical history: Ask for: a. Risk factors o Lack of physical activity (or sedentary lifestyle). o Obesity or being overweight o Abdominal obesity o High sodium intake/high salt intake o Excess alcohol consumption b. Family history c. Symptoms of consequences of hypertension d. Frequent intake of pain relieving drugs (NSAIDS)

e. Steroid intake for asthma f. Breathing difficulty particularly on exertion g. Swelling of feet h. Urinary difficulties, history of passing stones in the past (cid:216) Physical examination: Physical examination should include a. BP measurement at least in one upper and one lower limb (Refer Appendix- for the procedure) b. Measurement of Body weight and height to obtain BMI c. Measurement of Waist circumference d. Palpating all peripheral pulses

e. Auscultation for bruit (renal, carotid, abdominal and others) f. Eye evaluation if ophthalmology facility is available 31

(cid:216) Laboratory Tests: Essential: • Blood Sugar • Urine analysis for proteinuria Desirable: (at CHC/sub-district/district level hospitals depending upon the available facilities for laboratory investigations) • Haemogram, • Serum creatinine • Serum sodium and potassium levels • Lipid profile • Complete Urine analysis • Electrocardiogram(ECG) • X-Ray chest Based on risk assessment, the management of high blood pressure cases can be initiated. The management should include the following:

• Therapeutic life-style management (refer to section on lifestyle modification) • Drug Therapy Drug Therapy Whether a person requires medicines for his high blood pressure and which medicine is best for the patient would depend on: • The blood pressure reading • Whether the high blood pressure has already affected target organs in the body such as heart, kidneys, eyes and arteries • Concurrent medical conditions such as diabetes, heart disease, kidney disease and other

risk factors like use of tobacco, obesity and high blood fat levels(lipid profile) etc. • Other considerations will be age, gender (male/female) and body weight. Treatment Goals Refer to the risk assessment section to manage hypertension. 1. Initial aim should be to obtain blood pressure level less than 130/85 mms of Hg 2. Ideally the aim should be to get to blood pressure levels of less than 120/80 without bothersome side-effects. 3. Don't accept blood pressure levels of 140/90 mms of Hg or more

4. Maintain healthy blood pressure throughout the person’s lives 32

5. Prevent and control risk factors which could give rise to high blood pressure. 6. Always make sure that risk factors are controlled. 7. Prevent and control risk factors which could increase risk of complications due to high blood pressure. In the Indian context, diuretics (hydrochchlorthiozide), calcium channel blockers (amlodipine) and ACE inhibitors (Enalapril) are relatively cheap. Drug therapy should be started in individuals at the time of diagnosis if they have blood pressure more than

160/100mmHg (despite non-pharmacological interventions) or if the blood pressure is more than 140/90 in diabetic subjects or end organ damage such as protinuria, high blood urea, ECG evidence of left ventricular hypertrophy, presence of heart diseases and evidence of retinopathy. In all other individuals life style modification should be tried for atleast six months before initiating drug therapy. Medicines are tailored depending on the following factors • Blood pressure level

• Patient characteristics (like age, body weight, occupation) • Co-existing risk factors • Type and extent of target organ damage • Other associated diseases • Affordability It is better to start with calcium channel blockers (specifically if the person is older than 55 years) and ACE inhibitors if less than 55 years. Recheck the BP in 2 weeks. If BP is not under control adding diuretics (Hydrochlorothiazide 12.5 mg a day) may be helpful. Normally this should bring

the BP under control. If the BP is not controlled by the combination of Amlodipine 10mg + Hydrochlorothiazide 25mg a day or Enalapril 10mg and Hydrochlorothiazide 25mg a day, a referral to a higher center may be necessary. Life style advice is advocated for the first six month after the diagnosis of high BP in the following situations: (cid:149) If the BP is less than 160/100 mm of Hg (cid:149) There is no diabetes, co-existing heart disease stroke or peripheral vascular disease

(cid:149) No evidence of LVH on ECG (cid:149) Absence of urinary proteinuria and (cid:149) Serum creatinine <1.6mg/dl 33

Table-5.2.2: Dosage and contraindications of Common anti-hypertensive medications Drug Dose Contra- Cautions indications ACE-Inhibitors Enalapril: 5-40mg/day Pregnancy Renal impairment Captopril: 25-150mg/ day Renovascular Peripheral vascular Ramipril: 2.5-20mg/day diseases disease Calcium- Amlodipine: 2.5-10mg/day - Painless swelling of Channel Nifedipine (Sustained the feet and ankles blockers Release): 30-60mg/day may occur leading to its withdrawal in a few patients Thiazides Hydrochlorothiazide: Gout

12.5-50 mg/day Beta-Blockers Metoprolol (Sustained Asthma or chronic Heart failure Release): 50-200mg/day obstructive (symptomatic) Atenolol: 25-100mg/day pulmonary disease, Peripheral vascular advanced disease, Heart block Diabetes (except with coronary heart disease) The summary of services for hypertension management, appropriate at each levels of care is depicted in table -5.2.3. Table-5.2.3: Management of Hypertension at different levels of care Levels of Care Services Secondary care CHCs PHCs

Screening for Hypertension √ √ √ Initial Risk Assessment Assessment of Medical History √ √ √ Physical Examination √ √ √ Laboratory Investigation Essential √ √ √ Desirable √ √ Therapeutic Lifestyle Management √ √ √ Pharmacotherapy Initiation (Uncomplicated cases) √ √ √ Initiation (Complicated cases) √ √ √ Follow-up √ √ √ Annual Assessment √ √ √ 34

5. 3. PREVENTION AND MANAGEMENT OF DYSLIPIDEMIA What is Dyslipidemia? Dyslipidemia is characterized by elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high density lipoprotein (HDL) level that contributes to the development of atherosclerosis. Cholesterol is a fatty substance (lipid) that is present in cell membranes and is a precursor of bile acids and steroid hormones. Cholesterol exists largely as LDS-cholesterol, VLDL cholesterol, and

HDL cholesterol. Along with triglycerides they are tightly packed in a central core and surrounded by surface lipoprotein particles. Several large epidemiological investigations of human populations incriminate high levels of cholesterol as being atherogenic. The positive relationship between serum cholesterol levels and the development of first or subsequent attacks of CHD is observed over a broad range of LDL-cholesterol levels; the higher

the level, the greater the risk. Prospective study data suggest that the risk of CHD plateau at lower cholesterol levels, but this apparent plateau has disappeared in larger studies. In other words the risk of CHD is continuous at all levels of blood cholesterol therefore any definition is weighted based on risk-benefit and cost-effectiveness ratio and management is based on individualized risk of CHD. Definition of High Blood Cholesterol

The definition of abnormal blood cholesterol is as indicated in the table 5.3.1. These are based on the Adult Treatment Panel (ATP) III recommendations of the USA as there are no indigenous Indian prospective epidemiological data on risks of high blood cholesterol on CHD. Low HDL cholesterol is an important risk factor for CHD while high HDL cholesterol has a protective effect and is considered a negative risk factor. 35

Table-5.3.1. Classification of blood lipid levels for therapeutic interpretation Blood Lipids Serum Level (mg/dl) Total Cholesterol Desirable <200 Borderline High 200-239 High >240 Among Indians, based in the normal mean levels of cholesterol, it is preferred to have total cholesterol less than 160mg/dl LDL Cholesterol Optimal <100 Near Optimal 100-129 Borderline High 130-159 High 160-189 Very High ≥190 Serum Triglycerides Normal <150 Borderline High 150-199 High 200-499 Very High ≥500

MANAGEMENT OF HIGH BLOOD CHOLESTEROL Management of high blood cholesterol would depend on the overall risk profile of an individual. The broad guidelines to assess management would be based on: 1. Ascertaining whether patient has established Cardiovascular Disease like previous heart attack/ stroke/angina/peripheral vascular disease. 2. is a diabetic or not 3. what other CVD risk factors (hypertension/smoking/age/obesity) are present

4. Blood sugar/ total cholesterol/ HDL/LDL cholesterol levels(where available) Treatment Goals PHC Level 1. All patients with established CVD or diabetes should be counseled about non pharmacology treatment and also initiated on statins (Atorvastatin /Simvastatin). 2. Other patients should be counseled about non pharmacology treatment CHC Level 1. All patients with established CVD or diabetes should undergo lipid profile (where a

detailed profile is not available total cholesterol should be done). They must be counseled about non pharmacology treatment and also initiated on statins (Atorvastatin /Simvastatin) to achieve a LDL cholesterol of less than 100 mg/dl or Total cholesterol of less than 200 g/dl. Patients not achieving these goals with statins alone or developing complications due to them should be referred to higher centre. 2. Other patients with 2 or more CVD risk factors should undergo lipid profile/ total

cholesterol testing. Their risk level should be assessed by using risk assessment chart and manage accordingly. 3. Patients with one or no risk factors should be counseled about non pharmacology treatment only. 37

Drug Treatment Several classes of hypolipidemic drugs are available. However, statins are by far the most widely used first line drugs as most of evidence of proven benefit of lowering cholesterol on CVD is based on trials using them. Table-5.3.2: Summary of Statins Lipid effects LDL cholesterol - ↓ 18–55% HDL cholesterol - ↑ 5–15% Triglycerides - ↓ 7–30% Contraindications Active or chronic liver disease Major side/adverse effects Myopathy, increased liver transaminases

5.4 MANAGEMENT OF CAD Definitions Coronary artery disease is a condition in which there is an inadequate supply of blood and oxygen to a portion of the myocardium. It typically occurs when there is an imbalance between myocardial oxygen supply and demand. The most common cause of myocardial ischemia is atherosclerotic disease of an epicardial coronary artery or arteries (fig.5.4.1) sufficient to cause a regional reduction in myocardial blood flow and inadequate perfusion of

the myocardium supplied by the Fig 5.4.1: The coronary circulation representing involved coronary artery. specific arterial territory of the heart • Coronary Artery disease (CAD): Fifty percent or more stenosis of epicardial coronary arteries. • Acute Coronary Syndrome (ACS): A spectrum of clinical conditions from unstable angina to ST-elevation MI consequent to myocardial ischemia. Clinically, acute chest pain, typical in character, lasting more than 15 minutes. ‘Typical’ defined as retrosternal discomfort

(heaviness), brought about or increased with exertion and reduced with rest or nitrates. • Unstable Angina (UA): A clinical syndrome subset of ACS defined by ECG ST-segment depression or prominent T wave inversion and no elevation of cardiac biomarkers of necrosis (Troponins T/I or CPK ). MB • NSTEMI: A clinical syndrome subset of ACS defined by ECG ST-segment depression or prominent T wave inversion and/or positive biomarkers of necrosis in the absence of ST- segment elevation.

• STEMI: A clinical syndrome subset of ACS characterized by ST-segment elevation or new onset LBBB due to myocardial necrosis. • Chronic Stable Angina: Chronic manifestation of CAD described as retrosternal discomfort (heaviness), brought about or increased with exertion and reduced with rest or nitrates lasting less than 10 minutes. The clinical spectrums of CAD are shown in the diagram below (fig.5.4.2). 39

Fig.5.4.2: Flowchart showing the spectrum of CAD D efinition of myocardial infarction MI was defined by a combination of two of three characteristics: typical symptoms (i.e., chest discomfort), enzyme rise and a typical ECG pattern. Pathologically, MI is defined as infarction of an area of the heart muscle, usually as a result of occlusion of an epicardial coronary artery. P athogenesis and patho physiology Coronary artery occlusion is a dynamic process from deposition of atherosclerotic plaque and

partial occlusion to complete artery occlusion (fig 5.4.3). Deposition of plaque in coronary arteries Atherosclerosis Partial occlusion of coronary arteries Stable angina Rupture of Plaque Thrombus formation Unstable angina ACS Sub occlusive intracoronary clot Complete occlusion Myocardial infarction Figure 5.4.3 Spectrum of coronary artery disease 40

Fig.5.4.4: Figures showing the usual and unusual site of pain of angina Clinical Chest pain (angina) is the commonest symptom (cid:149) Typical angina: Substernal pressure radiating to neck, jaw, arm (Fig. 4) with duration <20-30 minutes which may be associated with dyspnea, diaphoresis, palpitations, nausea- vomiting, or lightheadedness; increases with exertion, decreases with rest or NTG. (Note: Rest angina is angina occurring at rest and prolonged, usually greater than 20 minutes)

(cid:149) MI: Has increased angina intensity and duration >30 min. Twenty five percent of MIs are clinically silent. Proportion of painless STEMIs is greater in patients with diabetes mellitus and increases with age. Associated symptoms: Weakness, nausea/vomiting, sweating, apprehension, anxiety, sense of impending doom. Other presentations, with or without pain • Sudden-onset breathlessness, loss of consciousness confusional state or sensation of profound weakness

• Rhythm abnormalities or unexplained decrease in arterial pressure • Evidence of peripheral embolism Features not characteristics of myocardial ischemia: • Sharp pain brought by respiratory movement or cough, 41

• Pain that may be localized by the tip of one finger, particularly over the left ventricular apex or a costochondral junction. • Very brief episode of pain that lasts a few seconds • Pain reproduced by movement or palpation over the chest • Constant pain that lasts for many hours without other ischemic symptoms Physical examination (cid:149) Focused clinical examinations for evidence of heart failure, peripheral hypo-perfusion

(pallor, diaphoresis, cool extremities), heart murmur, elevated JVP, pulmonary edema should be noted quickly without delaying treatment. (cid:149) The presence of severe underlying coronary disease is suggested in patients with clinical evidence of LV dysfunction, congestive heart failure (cid:149) Pulse rate and blood pressure: Arterial pressure is variable. In most transmural infarctions, systolic pressure decreases by approximately 10–15 mmHg from the preinfarction state.

– Many patients have normal pulse rate and blood pressure within the first hour of STEMI. – Patients with large infarctions have hypotension (systolic blood pressure <100 mmHg and/or sinus tachycardia >100/min) – Anterior infarction: About one-fourth of patients have manifestations of sympathetic nervous system hyperactivity (tachycardia and/or hypertension). – Inferior infarction: Up to half of patients show evidence of parasympathetic hyperactivity (bradycardia and/or hypotension).

(cid:149) In right ventricular (RV) infarction, Jugular venous distention is common. (cid:149) Look for signs of ventricular dysfunction – Third and fourth heart sounds – Decreased intensity of the first heart sound – Paradoxical splitting of the second heart sound (cid:149) Transient mid-systolic or late systolic apical systolic murmur due to dysfunction of the mitral valve apparatus may be present. New, loud (≥Gr 3/6) precordial systolic murmur

may be present in ruptured ventricular septum and mitral regurgitation (cid:149) Pericardial friction rub in pericarditis (usually develops 24-96 hours after MI) 42

Electrocardiogram in ACS • A 12 lead resting ECG (± RV3, RV4 for right ventricular MI) should be obtained immediately in patients with ongoing chest pain as rapidly as possible with in 10 minutes of presentation • A normal ECG does not exclude the presence of severe CAD, and should be repeated if strong suspicion in every 4-6 hrs or earlier • ECG abnormality includes: – Resting ST segment changes (depression ≥ 0.5 mm horizontal or down sloping in

NSTEACS, convex elevation > 1mm in ≥2 consecutive leads in STEMI, pseudo normalization of ST segment or dynamic changes) – New pathological Q-waves (>0.4 seconds) is considered diagnostic of MI, but may occur with prolonged ischemia – T wave-inversion(≥ 2 mm symmetrical) or a peaked upright T waves may be the first ECG manifestations of Myocardial Ischemia – Recent onset LBBB – RVMI is diagnosed with ST segment elevation in lead V4R, ST elevation in V1 in the presence of ST elevation in inferior leads

– Non-specific ST and T changes: ST depression <0.5 mm, T wave inversion <2mm, isoelectric T wave or asymmetric T inversion is less suggestive of myocardial ischemia. • The range of normal ST-segment deviation differs between men and women. ST- elevation (concave upwards) in the V2 or V3 leads of 2·0 mV or less in men and 1·5 mV or less in women, or 1·0 mV or less in other leads, is normal • ECG changes that mimic MI may result from pre-excitation, pericarditis, myocarditis,

cardiomyopathy, COPD, pulmonary embolism, cholecystitis, and hyperkalemia; thus the treating physician should be aware. Figure 5.4.5. Evolution of ECG changes in Myocardial infarction 43

Laboratory studies (depending upon the facilities available): (cid:149) Blood samples should be sent for cardiac enzymes (biomarkers Troponin I or T and CK- MB)-for diagnosis of ACS; Hemogram, blood urea, creatinine, electrolytes, FBS -for monitoring and Fasting lipid profile- for secondary prevention. Cardiac specific troponin is the preferred biomarker (Table 5.4.1) for diagnosis of STEMI. Table 5.4.1: Time course of serum markers in acute MI Test Onset Peak Duration

Creatine kinase - total and MB 3-12 hours 18-24 hours 36-48 hours Troponins 3-12 hours 18-24 hours Upto 10 days • A portable chest radiograph is useful to exclude other causes of acute chest pain but it should not delay the initiation of therapy • Imaging: (if facilities are available) 2D echocardiography and Doppler echocardiography: Algorithm for the Evaluation and Management of Patients with chest pain Because symptoms are similar, the differentiation of CSA, UA/NSTEMI and STEMI from that of

a non coronary chest pain requires medical evaluation and judgment (figure 5.4.6). * History, ECG, stress tests Figure 5.4.6. Algorithm for Evaluation and Management of Patients with Chest Discomfort. 44

1. Management of Chronic stable angina: A. History: Clinical Classification of Chest Pain • Typical angina (definite if all 3 present) 2. Retrosternal chest discomfort with a characteristic quality and duration that is 3. Provoked by exertion or emotional stress and 4. Relieved by rest or nitroglycerin • Atypical angina (probable) Meets 2 of the above characteristics • Non-cardiac chest pain Meets ≤1 of the typical angina characteristics Figure 5.4.7. Management Algorithm of chronic stable angina 45

Table 5.4.2: Summary of Management of Chronic Stable Angina at Various Level of Health Care Level 1 Level 2 Level 3 Level 4 (Medical colleges (PHC) (CHCs, Sub-divisional (District Hospitals) with facilities for PCI and hospitals) Tertiary centers) Diagnose and (cid:149) Detailed history (cid:149) Management same as (cid:149) Management same as refer as soon (cid:149) Investigation level 2 for new patient level 2 for new patient as possible - ECG (cid:149) Echocardiography for (cid:149) Angiography and

- Blood sugar, Serum creatinine, LV Function revascularization if Cholesterol facilities are available - Chest X ray for refractory cases (cid:149) Treatment - Nitroglycerin (Sublingual)- sos - Oral nitrates - Beta blockers - Aspirin - Statins and ACE inhibitors - Reduce cholesterol < 200 mg/dl - Reduce LDL < 100 mg/ dl (cid:149) Refer to level 3/ 4, if angina is not controlled despite medication 2. Initial management of ACS at emergency department Chest pain suggestive of ACS

Immediate assessment within 10 Minutes Initial tests Emergent care Assessment – 12 lead ECG • IV access o Read ECG – Blood sample for: • Cardiac o Establish monitoring diagnosis CPK-MB, Oxygen Identify • o lipids, RFT, glucose, Aspirin and/or complications • -- CXR clopidogrel o Assess for Nitrates reperfusion / Optimum treatment • Figure 5.4.8: Flow chart for initial emergency m easur es in management of ACS 46

3. Management of Acute Coronary Syndrome (ACS) * At sub-centre: give Tab. Aspirin 300mg stat with prompt referral to nearest Level 1 care **Markers of successful lysis: decrease in chest pain, ST resolution of 50% or more and the development of a terminal negative T wave in the lead with the highest ST elevation 47

4. Medication Dosing and Administration: A spirin • 300 mg chewed and swallowed (150 mg × 2) upon presentation, then 150 mg daily indefinitely. C lopidogrel • 300-mg oral loading dose, then 75 mg PO daily for 9 to 12 mo. H eparin • LMWH (Enoxaparin1 mg/kg SC Q12 h or Dalteparin 120 IU/kg SC (max 10,000 IU) Q12h or, until PCI or till hospital admission) ß-Blockers (should be initiated in first 24 hours if no contraindications in small doses) • Oral Metoprolol 25-50 mg PO BD.

• Carvedilol 6.25-25mg BD. ( if LV dysfunction) • Patient with early contraindication should be reevaluated for b-blocker therapy for secondary prevention N itroglycerin • 0.4 mg sublingual Q 5 min × 3 for persistent ischemic pain or IV infusion starting at 5- 10 μg/min with up titration for persistent ischemic pain. Oral long acting nitrates once/twice daily. M orphine sulfate • 2–4 mg IV every 5–10 minutes until pain is relieved or side effects develop

•Side effects: Nausea, vomiting, respiratory depression and hypotension. O xygen • 2–4 L/min by nasal cannula to maintain oxygen saturation > 90% A CE inhibitors • Captopril 6.25 mg TID, titrate up as tolerated • Ramipril 2.5-5mg BD • ARBs, (Valsartan 20-160 mg BD) in patients intolerant to ACE inhibitors with evidence of LV dysfunction. • Aldosterone blockers (spironolactone 25mg OD, eplerenone 25-50 mg OD) • Post-STEMI patients who meets the following

• No significant renal failure (Cr < 2.5 men or 2.0 for women) • No hyperkalemia > 5.0 • LVEF < 40% • Symptomatic Congestive heart failure or Diabetes Mellitus Insulin consider insulin infusion in first 48 hours to normalize blood glucose 48

5.5. PREVENTION AND MANAGEMENT OF STROKE What is a Stroke? A stroke means that part of the brain is suddenly damaged. If an artery in the brain becomes blocked by a thrombus, it causes a stroke. If an artery in the brain leaks then too it damages the brain and causes a stroke. Atheroma is also known as 'atherosclerosis' or 'hardening of the arteries'. Patches of atheroma are also called 'plaques' of atheroma. Patches of atheroma are like small fatty lumps that

develop within the inside lining of arteries (blood vessels).The thrombus usually forms over some atheroma. A temporary lack of blood supply to a part of the brain is known as TIA or transient ischemic attack. Prevent Strokes Stroke can be prevented by controlling high blood pressure, avoiding tobacco use and leading a healthy life style. Simple tips include the following: • Keeping blood pressure well under control. • In case of positive family history of stroke yearly evaluation of risk factors such as

hypertension and diabetes. • Eating healthy (plenty of whole grains, fruits and vegetables in the daily diet). • Avoiding refined flours, sugars and foods rich in trans fat such as biscuits, deep fried foods etc. Educate the patients that if there are stroke symptoms, including sudden weakness of the face or a limb, a blurring of vision, dizziness, or an intense headache, he/she should seek immediate medical attention 49

Box 5.5.1: Practical advice to patients on how strokes can be prevented (cid:216) Know the blood pressure. Have the blood pressure checked at least once a year, and, if it is elevated, treat it diligently, to keep it under control (cid:216) Stopping the use of both smoking and non-smoking forms of tobacco. (cid:216) It is preferable to avoid alcohol due to several other ill effects on health. However for individuals who consume alcohol the consumption should be

moderate (daily consumption of not more than a glass of wine or 30-50ml of hard drinks such as whisky, brandy or similar products with high alcohol content). Avoid binge drinking. It is a major risk factor for stroke because it can acutely elevate blood pressure. (cid:216) Including exercise in the daily routine (cid:216) Consuming a low-salt, low-fat diet (cid:216) Preferring whole grains and whole pulses and eating 10-40 gms of unsalted non-fried nuts every day. (cid:216)

Identifying circulatory problems that could increase the risk of stroke and Atrial fibrillation (cid:216) Screening for hypercholesterolemia. If more than 200mg/dl, lower it by lifestyle changes like regular exercise and change in diet along with statins. (cid:216) Controlling diabetes, if present concurrently. (cid:216) Avoiding deep vein thrombosis. If a patient is recovering from illness or a surgery and is in bed, then make sure he/she exercises the legs by raising it up and down 10-15 times every day

Management Patients of stroke presenting within 6 hours of onset of symptoms should be referred to a secondary care for initial assessment and management. The follow-up of patients presenting with a completed stroke not requiring acute care (such as respiratory distress) can be managed at the PHC level. 50

Identification of an acute event o Sudden onset of weakness of one half of body or one part of body o Sudden onset of inability or difficulty in speech o Sudden onset of imbalance o Sudden onset of blindness o Sudden onset of dizziness or spinning o Sudden severe headache o Seizures o Sudden loss of consciousness All patients with above symptoms should be examined by qualified medical practitioners Guidelines for stroke treatment at a secondary health care level

1. If available a plain CT scan should be done in all cases; contrast if indicated. 2. Secure the airway by keeping the patients head to a side; if breathing is compromised assisted ventilation to be provided and circulation should be maintained by securing a good IV line and infusing 5% dextrose. 3. Elevated blood pressure should be managed by nitroprusside, labetalol (under monitoring) or captopril in titrated doses. In most places only captopril will be

available and this can be given sublingually too. The BP should not be brought down rapidly. The systolic should be around 140 mmHg and diastolic between 80-90 mmHg. 4. Avoid cerebral decongestants (mannitol, glycerol) unless there is evidence of raised Intra-Cranial-Pressure with signs of decerebration. 5. Provide supportive care to prevent deep vein thrombosis by prophylaxis with 5000 units heparin BD (or equivalent units of low molecular weight heparin if available and affordable).

6. Acute rehabilitation includes proper positioning, dysphasia management, passive movements of limbs, bowel/bladder care with active involvement of family members Guidelines for referral to a tertiary health care level 1. If CT shows significant pressure effect, or middle cerebral artery (MCA) dense sign suggesting massive infarction, refer to tertiary centre 2. If CT shows intra-parenchymal hemorrhage with midline compression, or a cerebellar infarct or hemorrhage refer to higher centre.

3. If CT shows primary subarachnoid hemorrhage refer to higher centre 51

Guidelines for follow-up of stroke at all levels 1. First follow up at 2 weeks. Follow up to be kept at 3 or 6 monthly intervals depending on individual merits of the case. 2. Look for Functional recovery, 3. Check blood pressure and blood sugars, 4. Monitor compliance with rehabilitation measures. 5. Continue Aspirin. Use of clopidogrel or combination antiplatelet agents such as low dose aspirin plus extended release dypiridamole to be instituted on individual merits of

the case after risk stratification at the secondary or tertiary care centers. Cardio-embolic strokes will need oral anticoagulants with monitoring of prothrombin time. 6. Dietary and lifestyle modification. Counseling regarding vocational guidance eventual return to work Guidelines for stroke prevention: 1. Identification of those at high risk • High blood pressure , • History of heart disease, • History of TIA, • Past history of stroke • Diabetes, • Tobacco users,

• Family h/o increased risk for vascular disease, • Obesity- sedentary life style , • On oral contraceptives, • Hyperlipidemia, • Family history of stroke Individuals belonging to the above category are at a higher risk for stroke. Such individuals have to undertake preventive measures for stroke. Refer the section on ‘Therapeutic lifestyle management’ for lifestyle changes. Subjects with established vascular diseases have to take extra precautions as described below.

2. Primary prevention in high risk individuals Advise to adopt a healthy life style and please refer to section on healthy life style. 52

5.6. PREVENTION AND MANAGEMENT OF CANCERS Cancer is a group of diseases characterized by uncontrolled cell multiplication which can occur in any living tissue in any site in the human body. Cancer develops in several phases depending on the type of tissue affected. Figure 5.6 .1 shows the phases in cancer development. (Source- National Cancer Control Programmes – Policies and Managerial Guidelines. World Health Organization.2nd Edition, 2002)

Incidence of cancer is the most reliable indicator of occurrence of cancer and is generated from population based cancer registries (PBCRs). PBCRs also provide data on cancer survival and mortality. Prevalence (number of persons living with the disease at any given time) of cancer can be estimated using the information on cancer incidence and survival. Global scenario Cancer is emerging as a major problem globally; both in more developed and in less developed

countries. Annually there are over 10 million new cases of cancer and more than 6 million deaths due to cancer (12% of all deaths) worldwide. The contribution of the developing world to this figure is more than half. By 2020, the number of new cancer cases is expected to reach at least 15 million a year and cancer deaths 10 million a year. National scenario As per the latest National Cancer Registry Programme ( Two Year Population Based

Cancer Registry 2004-2005) collected from eight PBCRs there were 70,600 cancer cases out of which 49.66% (35,061) were males and 50.34% (35,539) were females. 53

Prevention of Cancer Table 5.6.1 illustrates approaches for some common groups of cancers. Table 5.6.1 Approaches in cancer control Prevention Tobacco-related Tobacco control/ cessation cancers Early detection Oral/Breast/Cervix Propagation of awareness and self-examination Opportunistic examination Diagnostic support Diagnosis and treatment Common cancers Training Treatment guidelines Infrastructure Referral practices Palliative care All advanced cancers Oral morphine availability, Human resource

development Community participation (cid:216) Primary Prevention Primary Prevention aims to reduce the incidence of disease by risk factor modification. A risk factor for a disease is an attribute or exposure that increases the probability of getting the disease. As exogenous risk factors including personal habits play a major role in the etiology of cancer, modifying risk factor exposure may prevent many cancers. Among the activities for prevention, emphasis should be placed on: ● Tobacco control

● Health education relating to sexual and reproductive factors associated with cancer ● Avoiding alcohol use ● Healthy diet ● Physical activity and avoidance of obesity Tobacco Tobacco is the single most important modifiable risk factor for cancer. Of all cancers in India, 34% are due to tobacco (48% of cancers in men and 20% of cancers in women). Tobacco smoke contains approximately 4000 chemicals of which at least 438 can cause cancer. Tobacco

smoking causes cancer of the lung, larynx and oesophagus. Smoking is also associated with 54

cancers of the pancreas, bladder, pelvis of the kidneys, ureter and squamous cell carcinoma of the uterine cervix. Tobacco chewing is the most important risk factor for cancer of the oral cavity. Inhalation of secondary smoke, known as “passive smoking” is a unique feature of smoking. It results in increased risk of cancers among non- smokers exposed to tobacco smoke. (cid:216) Alcohol Increasing alcohol consumption is associated with cancers of the mouth, pharynx (excluding

nasopharynx), larynx, oesophagus and liver. The risk relationship between cancer and alcohol is nearly a linear relationship with the risk increasing with increasing amount of alcohol consumed. Co-existence of tobacco habits can have a multiplicative effect on development of cancer. Control of alcohol requires actions similar to those for tobacco control. The actions should be targeted towards individual and community and include taxation, general public education,

encouraging highly vulnerable groups like young people to avoid starting consumption etc. Sexual and Reproductive Factors Sexual and reproductive factors are associated with cancer of the uterine cervix and breast. Sexual behaviour factors, like young age at first sexual activity, multiple sexual partners and poor sexual hygiene, are associated with cancer of the uterine cervix. Human Papilloma Virus (HPV) has now been identified as the etiological agent responsible for cervical cancer. HPV

prevalence increases with high risk sexual behaviour and poor sexual hygiene. Late age at marriage, nulliparity, and late menopause have been linked to breast cancer, but the underlying mechanism is probably uninterrupted exposure to oestrogen for prolonged periods in all these cases. Education regarding sexual hygiene and safe sexual behaviour may be provided for prevention of cancer cervix. Safe sexual behaviour protects women from the risk of cervical cancer by

preventing infection with HPV. Breast cancer is not preventable to any large extent. Early detection of breast cancer is the main strategy for improving survival in breast cancer. 55

Diet Various studies in the past two decades suggest the role of diet in human cancers. It is generally agreed that diets rich in animal fats, especially red meats, increase the risk for cancer. It is also widely accepted that diets high in fresh vegetables and fruits, and fibre reduce risk for cancer. Certain basic measures may help in reducing risk of cancer: ● Avoid being underweight or overweight ● Engage in regular physical activity ● Consumption of alcohol is not recommended

● Limit consumption of salted foods ● Choose predominantly plant based diets rich in fruits and vegetables Occupation Occupational cancers constitute 5-10% of all cancers. Increased risk of lung cancer has been seen in workers engaged in manufacture of rubber tyres in developing countries, textile workers, ship and dockyard workers and wood workers. Higher risk of bladder cancer was seen in workers of chemical and pharmaceutical plants. Limiting exposure to potentially

carcinogenic substances through protective gear, frequent rotation of workers, mechanized handling of such chemicals and similar mechanisms may help reduce cancers from occupational exposures. Infection Infections with various agents are implicated in the aetiology of certain cancers. Control of cancers caused by or associated with infections depends upon success in combating the infection concerned. Measures include eliminating reservoirs and source of infection,

preventing transmission, increasing host immunity through vaccination, and effective treatment of those infected. 56

(cid:216) Early Detection Early detection of cancer is the detection of disease at a stage in its natural history where the chance of cure is high. Early detection is only part of a wider strategy that includes diagnosis, treatment and follow-up. Many cancers that are potentially curable at early stages are detected only in advanced stages. Diagnosis of such cancers at a stage where treatment is effective could have a major impact on

the disease outcome. Certain symptoms and signs may be early indicators of some cancers. Warning signals for Cancer C hange in bowel or bladder habits A wound that does not heal U nusual Bleeding or discharge T hickening or Lump in the breast or elsewhere I ndigestion or difficulty in swallowing O bvious change in a wart or mole N aging cough or hoarseness of voice All people should be aware of these warning signs. The presence of any of these features does

not mean a definitive diagnosis of cancer. Such changes may occur in other benign conditions also. However, any such sign not responding to appropriate treatment warrants immediate medical attention and prompt management. It is also important to train people to detect cancers in the early stage with self-examination of the oral cavity and breast. Screening Screening is the presumptive identification of unrecognized disease or defects by means of

tests, examination or other procedures that can be applied rapidly. Screening is based on the concept that there is a detectable pre-clinical phase of the disease being screened, and detection at this stage markedly alters disease prognosis. The success of screening depends on having 57

sufficient numbers of trained personnel to perform the screening tests with adequate coverage of target populations, and on the availability of facilities that can undertake subsequent diagnosis, treatment and follow-up. Screening is recommended for cancers of uterine cervix and breast, only if resources permit. Screening for Cervical cancer Cervical smear cytology is the standard screening test for cervical cancer. It is an easy and

effective method revealing the presence of pre-cancerous lesions as well as in situ or very early invasive cancer. Screening should preferably begin at 35 years of age, as at younger ages dysplasia detected through screening rarely progresses to cancer, but adds to programme cost in treatment .The important requirement for cervical cytology is the availability of good laboratory services so that accurate diagnosis is possible. Fig 5.6.3 shows phases of cervical cancer and screening.

Fig 5.6.3: Phases and Screening for cervical cancer (cid:216) Diagnosis and Treatment Diagnostic Methods The diagnostic procedures in oncology are for diagnosis, determining the extent of the disease, deciding the treatment options available and evaluating the patient during follow- up. Clinical evaluation is the first and the most important step in the diagnosis of malignancy. It requires the health professional to be alert to the early warning signals. A thorough history and clinical

examination of any suspicious symptom or sign is mandatory. Clinical suspicion of malignancy 58

can be confirmed by various diagnostic methods described below. Radiological Evaluation Various imaging methods are: ● X ray ● Fluoroscopy ● Mammography ● Ultrasound ● C.T.Scan ● Magnetic Resonance Imaging Medicine ● Positron Emission Tomography Nuclear ● Radio nuclide scan and Radioactivity uptake studies e.g. Thyroid, Bone Biochemical Evaluation This is generally done to know the organ functions, like liver function tests, and renal function tests. Endoscopy In oncology endoscopy is useful to:

● Detect the site of primary cancer ● Evaluate the extent of lesion ● Perform biopsy ● Perform certain therapies like endoprosthesis for oesophageal stenosis, laser therapy, etc. Pathological Evaluation Pathological evaluation is an important method for confirmation of clinical diagnosis and includes: ● Haematological Examination: Examination of peripheral blood smear and bone marrow. ● Cytological Examination: § Exfoliative cytology: examination of exfoliated cells; e.g. female genital tract,

oral cavity, urinary tract (urine examination), gastrointestinal lesions (gastric lavage) etc. § Fine Needle Aspiration Cytology (FNAC): to obtain material from organs that do not shed cells spontaneously. Example: Breast, Thyroid, etc. § Aspiration of body fluids: to rule out or confirm malignant effusions. Example: pleural fluid, peritoneal fluid. 59

● Biopsy: A small chunk of tissue is removed from the suspicious site and subjected to histopathological examination. It may be: § Excisional biopsy in small tumours § Incisional / Punch biopsy in skin and mucosal lesions Cone biopsy in uterine cervix § Needle biopsy in bone marrow, solid tumours of abdomen and pelvic organs. Immunological Evaluation Some cancers release biologic or biochemical substances, in the form of hormones, enzymes,

and antigens, into the circulation. The measurement of these substances in blood can be useful in the detection and diagnosis of some types of cancers. Such chemicals are called tumour markers. Some common tumour markers and the conditions in which they may be raised are listed in Table 5.6.2 Tumour marker Malignancies Non-malignant conditions Alpha feto protein (AFP) Hepatoblastoma, Cirrhosis, Hepatitis Nonseminomatous germ cell tumour testis, Non- dysgerminomatous germ cell tumour ovary,

Hepatocellular carcinoma, Beta human chorionic Choriocarcinoma, Testicular Hypogonadism, gonadotrophin (B-hCG) germ cell tumours Hydatidiform mole Carcino embryonic Colorectal cancers, Breast Smoking, Fatty liver, antigen (CEA) cancer, Cholangiocarcinoma, Hepatitis Stomach cancer CA-125 Epithelial ovarian cancer Pregnancy, Menstruation, Endometriosis, Ascites, Pleural effusion Prostate specific antigen Prostate cancer Prostatitis, Benign prostatic hyperplasia, Prostatic manipulation

Table 5.6.2 Some common tumour markers and the conditions in which they may be raised 60

Staging of cancer Staging is used to assess the extent of the spread of the disease in the body. It is an Indication of prognosis, and is used as a guide to determine the type and extent of treatment required. TNM classification- The TNM classification for tumours has been adopted by the International Union against Cancer, and has been extended for many sites of cancer. This is a detailed clinical staging which is arrived at by the clinician by ascertaining the extent of the

primary tumour (T), lymph node involvement (N), and presence of metastases (M). The information so obtained is scored. The details of scoring are specific to each type of cancer. Other systems of staging include the FIGO (International Federation of Gynaecology and Obstetrics) staging for cancers of the uterine cervix and body of the uterus, and the Duke’s system of staging for cancer of the rectum. Principles of Treatment

The primary goals of cancer treatment are cure ideally, prolongation of useful life if possible, and improvement in quality of life always. The principal methods of treatment are surgery, radiotherapy, and chemotherapy (including hormonal manipulation). Each of these modalities has a well-established role, and can be used for cure or for palliation. Appropriate combination and sequencing of these modalities can be adopted for specific cancers. Surgery

Surgery plays an important role in the diagnosis, staging and treatment of localised cancers. Where other modalities form the mainstay of treatment, surgery can contribute through removal of tumour masses, palliation and treatment of some complications. Surgery requires the support of other specialties including anaesthesiology, blood transfusion services, pathology (specially oncopathology) and critical care nursing. In early stage solid

tumours, surgery that encompasses a sufficient margin of normal tissue is curative. These include early stage cancers of the breast, oral cavity, uterine cervix, colon, prostate and the skin. Surgery is also used post chemotherapy or radiotherapy to provide local cancer control and better chances for adjuvant therapy. In certain solid tumours, surgery is critical for reducing bulk (cytoreduction). Surgery is valuable in oncology emergencies, to relieve bowel

obstruction, promote cessation of bleeding, close perforations, relieve compression, and drain ascites or pleural effusions. Apart from treatment, surgery for reconstruction and rehabilitation can improve function and cosmetic appearance and enhance quality of life for patients. 61

Radiotherapy Radiotherapy is one of the most important methods of curing local cancer. Radiotherapy is the method of treating diseases with “ionising radiation”. The ionising radiation causes damage to certain vital structures within the cells. The cells are either damaged or are rendered incapable of further multiplication. These damaging effects on normal cells are less and reversible whereas the damage in the abnormal cell is irreversible. This differential is the principle of

radiotherapeutic treatment. Radiotherapy may be teletherapy (administered from a distance) or brachytherapy (treatment with radioactive substances within body cavities or tissues). Teletherapy may be administered by cobalt machines or by accelerators. Clinical outcomes are identical with both machines. Brachytherapy may be delivered by low dose rate (LDR) devices using caesium and high dose rate (HDR) devices using iridium or cobalt. HDR can be used for treatment of a wider variety

of cancers than LDR and reduces the need for hospital bed occupancy, but demands more expertise and has higher costs. Radiotherapy is one of the most important methods of curing local cancer. It is also often administered before or after surgery. Such treatment either facilitates surgery or consolidates surgical gains, and reduces local recurrence of disease. Palliative radiotherapy is of value in cases of pain secondary to bone metastasis and tumours causing bleeding or compressive syndromes.

Radiotherapy can cause various side effects. Patients may notice loss of appetite, nausea, and occasionally vomiting persisting for a week. The symptoms are mild in nature and seen in about 10% of patients, and are easily controlled by medicines. Other side effects depend on the site irradiated and can include mucositis and bone marrow depression. Long-term side effects are also observed. 62

Chemotherapy Chemotherapy is the use of cytotoxic drugs against cancer. Cancer cells are damaged to the extent that they cannot survive. Normal cells are also damaged but to a lesser degree. Chemotherapy is curative in certain cancers e.g. Hodgkin disease, high-grade non-Hodgkin lymphomas; palliative in many cancers, and used as adjuvant therapy for some cancers including breast cancer, ovarian cancer and colorectal cancer. The goal of adjuvant therapy

(treatment given in addition to primary definitive therapy in the absence of macroscopic residual disease) is to avoid metastases, prolong life and improve quality of life. Chemotherapy is ineffective in hepatobiliary cancers, pancreatic cancer, thyroid cancer, and central nervous system cancers among others. Acute side effects of chemotherapy are usually self-limited and reversible. Fall in blood count, hair loss, nausea, vomiting, constipation, diarrhea, anaemia, and depression of the immune

system are some of the side-effects. There may be drug specific side effects like cardiotoxicity, nephrotoxicity, neurotoxicity. Palliative care Palliative care is an approach that improves the quality of life of patients and their families facing a life-threatening illness. This is done through prevention and relief of suffering by means of early identification, accurate assessment and treatment of pain and physical,

psychosocial and spiritual problems. Palliative care involves a multidisciplinary team approach. Further details on palliative care are provided in the Manual on Palliative Care In summary, primary prevention, early detection, prompt diagnosis and appropriate treatment, and palliative care are the main strategies for cancer control. Each cancer requires a distinctive mix of these strategies for its control. The matrix given in Table 5.6.3 suggests the options on

a prevention-treatment-palliation continuum, for each cancer. Tobacco-related cancers like cancers of the lungs, pharynx, and oral cavity are highly amenable to primary prevention. Early detection and treatment is possible for cancers of the oral cavity, uterine cervix, and breast. Palliative care is a key intervention for all types of 63

cancers. Cancers of the oral cavity, uterine cervix, and breast are discussed in detail subsequently in view of the opportunity they offer for early detection and treatment with curative intent. Table 5.6.3: Relative importance of various interventions in different cancers Cancer Early Surgery Radiation Chemotherapy/ Palliative Care Detection Hormonal adjuvant the Mouth/Pharynx + ++ +++ + +++ Oesophagus - + ++ - +++ Stomach + + - - +++ Colon/Rectum ++ +++ ++ +++ +++ Liver - + - - +++ Lung - + ++ - +++

Breast +++ +++ ++ +++ +++ Cervix +++ ++ +++ - +++ Key: — = no role; + = small role; ++ = modest role; +++ = major role (Source- National Cancer Control Programmes – Policies and Managerial Guidelines. World Health Organization.2nd Edition, 2002) Issues that need to be kept in mind for all cancers (cid:216) Prompt referral of patients with any suspicion of cancer for appropriate management (cid:216) Compliance of the patient with medical advice

(cid:216) Provision of psychosocial services for the patient, and the family (cid:216) Rehabilitation: Physical, psychological and social rehabilitation so that the affected individual is able to take care of self, be emotionally stable, and be able to work and socialize, to the extent possible. 64

Key messages Primary prevention ●● Avoid use of tobacco in any form ●● Avoid alcohol ●● Promote physical activity ●● Eat plenty of fruits and vegetables ●● Practise Safe sexual behaviour Early detection of cancers ●● Breast awareness ●● Awareness in community regarding early warning signs of common cancers (Oral/Breast/Cervix) ●● Opportunistic check up for oral, breast and cervical cancer ●● Prompt referral and appropriate management

●● Prompt referral of any suspicious case is the most important step towards cure. Diagnostic methods: ●● Clinical history & examination – first and most important ●● Radiological examination ●● Pathological examination ●● Diagnostic procedures help us to know: The type of cancer The extent (staging) of cancer Treatment options and prognosis Follow-up evaluation Treatment Modalities: ● Surgery ● Radiotherapy ● Chemotherapy

●● Treatment modalities can be used with intention of cure or palliation, and alone or in combination depending on type and extent of disease. ●● Goal of treatment is ideally cure if possible and improvement in quality of life always 65

Role of Health Professionals in Cancer Prevention and Control Health professionals have the following roles to play for prevention and control of Cancer Prevention of cancers • Create awareness about the ills of tobacco and advocate avoidance • Encourage and assist habitual tobacco users to quit the habit • Promote healthy dietary practices and physical activity Early detection of cancers • Create awareness about the early warning signs of cancer • Encourage breast awareness

• Encourage oral self-examination • Create awareness about symptoms of cervical cancer • Examine, as a routine, the oral cavity of patients with history of tobacco use • Offer clinical breast examination to any woman over 35 years presenting to the health centre • If facilities exist, perform a pap smear test for every woman at least once in her lifetime, between 35 and 40 years of age • Promptly refer any person with a suspicious lesion for accurate diagnosis and appropriate treatment Treatment of cancers

• Ensure that every patient complies with therapy advised • If follow up care is required at the health centre level, make sure that detailed instructions are provided by the treating institution Palliative care • Ensure that the patient is free from pain as far as possible. Learn and practice the WHO step-ladder approach of pain management; refer to the appropriate centre for oral morphine • Achieve control of unwanted symptoms to the extent possible

• Provide psychological support to the patient to accept the diagnosis and treatment • Involve the family in diagnosis, treatment and care as far as possible 66

Common Cancers 1. Cancer of the Oral Cavity Oral cancer is one of the ten most common cancers in the world. In India, oral cancer, including cancers of the lip, tongue, gum and floor of mouth, is one the most common cancers, and may be the commonest in many regions. Oral cancer is both preventable and curable. There is usually a long natural history and most cases of oral cancer arise from pre-cancerous lesions. Therefore there is ample opportunity for intervention before actual malignancy

develops. Also oral cancer responds well to surgery and radiation if detected early. Risk factors Tobacco chewing is the single most important risk factor for oral cancer. Other risk factors include alcohol use, betel nut chewing, and chronic trauma to oral mucosa by sharp tooth or ill- fitting dentures. Chronic exposure to these risk factors causes changes in the oral mucosa and these changes are visible as pre-cancerous lesions. Over time, malignancy may develop in these lesions. Pre-cancerous lesions

Pre-cancerous lesions or conditions are local or generalized disturbances that predispose to malignancy in a particular site. Leucoplakia, erythroplakia, palatal changes associated with reverse smoking or beedi smoking and submucous fibrosis are local pre-cancerous lesions. Plummer Vinson syndrome, syphilis, and erosive lichen planus are generalized pre-cancerous conditions. All these conditions are amenable to early diagnosis, and treatment is possible in many cases. Leucoplakia

This is defined as a white patch that cannot be characterized as any other disease clinically or pathologically (Figure 5.6.4). They can be of 4 types: a. Homogeneous leucoplakia: Low risk of cancer b. Ulcerated or erosive leucoplakia: High risk of cancer Figure 5.6.4: Homogeneous c. Speckled or nodular leucoplakia: High risk of cancer leukoplakia involving dorsum and d. Verrucous leucoplakia: Very high risk of cancer right lateral border of tongue Two or more types of leucoplakia may be present 67

in the oral cavity at the same time. Confirmatory diagnosis is by biopsy Erythroplakia: This is a bright, velvety area sometimes surrounded by faint plaques which cannot be characterized as any other lesion clinically or Figure 5.6.5: Erythroplakia pathologically (Figure5.6.5). About 90% of these lesions show cellular dysplasia or malignancy. The risk of malignancy in erythroplakia is higher than in leucoplakia. The most common cancer seen in the oral cavity is squamous cell carcinoma. It presents

as a painless ulcer, mass or fissure. As the disease advances, patient may have excessive salivation, trismus, and difficulty in chewing, swallowing or cervical lymphadenopathy. Distant metastases are uncommon in oral cancers. Early detection: This is important for detecting oral lesions at an early stage I. Self Examination of oral cavity Figure 5.6.6: Self Examination of oral cavity II. Examination by a health professional

Utilize every opportunity to examine the oral cavities of tobacco users. All parts of the oral cavity should be examined; oral cavity includes lip, anterior 2/3 of tongue, floor of mouth, buccal mucosa, gingival mucosa, hard palate and retromolar trigone (Figure 5.6.7). Figure 5.6.7 Oral Cavity 68

Management of Oral Cancer Management may be through surgery, radiotherapy, chemotherapy, or a combination of modalities. Figure 5.6.8 presents a flow chart of management of any person with a suspicious oral lesion. Figure 5.6.8: flowchart for management of patient with an oral lesion 69

2. Cancer of the Uterine Cervix Cervical cancer is the third most common cancer among women in the world and the leading cause of death from cancer among women in developing countries. In India more than 100,000 new cases of cervical cancer occur each year and nearly 75,000 women die annually from this disease. Human Papilloma virus infection, which is a sexually transmitted infection, is the primary cause of this cancer. HPV prevalence increases with multiple sexual partners for both spouse,

and poor genital hygiene of both partners. Symptoms of cancer of the uterine cervix: In the early stages, there will be no symptoms. By the time symptoms appear, disease may have already spread. Common symptoms are: ● Post-menopausal bleeding ● Post-coital bleeding ● Intermenstrual bleeding ● Blood stained discharge per vaginum ● Excessive seropurulent discharge ● Backache ● Lower abdominal pain Screening for Cervical Cancer

Screening for cervical cancer can be considered in women aged 30 to 59 years, as the chances of detecting pre-cancerous lesions are maximum in this age group. Regular population Based Screening using Pap Smear cytology is internationally accepted screening method for cervical cancer. In low resource setting, Visual Inspection with Acetic Acid is a useful alternative to categorise women as “high risk’ and “low risk”. Pap smear:

The ectocervix and the endocervix are scraped to collect cells that are spread on a glass slide, stained in the laboratory and examined under microscope. Depending on the features of the cells seen under microscope the cytopathologist (or a trained technologist) can report the smear as ‘negative’ (normal) or ‘positive’ (abnormalities suspicious of low grade or high grade CIN). 70

Requirement for Pap smear • Examination gloves • Speculum (Cusco’s self-retaining type preferred) • Ayre’s spatula (Figure5.6.9) and endocervical brush (if available) • Glass slide • Diamond tipped pencil to write on glass slide (if the glass slide has frosted edge an ordinary pencil can be used to label it) • Focusing light • Coplin’s jar • 95% ethyl alcohol • Cytology form Figure 5.6.9: Cusco's Speculum and Ayer’s Spatula Procedure: • Procedure should be explained to the woman.

• Clean a glass slide with dry cotton and label it. • The woman should lie down on her back with legs folded (lithotomy position not required). • Insert the speculum gently and expose the cervix. • Note any abnormal discharge, bleeding or growth in the cervix. • Insert the long tip of theAyre’s spatula into the os so that the curvature touches the ectocervix. Figure 5.6.10: Preparation of smear Maintaining gentle pressure, rotate the spatula a full 360 degrees circle (Fig. 5.6.10).

• Spread the content of either side of the spatula on one side of the glass slide by one or two swipes. 71

Visual Inspection using 4% Acetic acid (VIA): Acetic acid causes dehydration of the cells and some surface coagulation of proteins thereby reducing the transparency of the epithelium. These changes are more prominent in abnormal epithelium and can be easily distinguished on naked eye inspection. Requirements: • Examination gloves • Speculum (Cusco’s self-retaining type preferred) • Cotton tipped swabs • Freshly prepared 5% acetic acid (to be produced at least once a week by

diluting 5 ml of glacial acetic acid with 95 ml of distilled water) • Focusing light (with halogen bulb Figure 5.6.11: Normal Cervix preferred) Procedure: • Procedure should be explained to the woman. • The woman should lie down on her back with legs folded (lithotomy position not required). • Insert the speculum gently and expose the cervix. • Note any abnormal discharge, bleeding or growth in the cervix. • Apply adequate amount of acetic acid to

the cervix using the cotton swabs. Figure 5.6.12: Visual inspection with • Wait for 1 minute to note the changes. acetic acid showing acetowhitening • Identify the squamo-columnar junction(SCJ) as the line joining the pink Table 5.6.4 gives the detailed criteria smooth squamous epithelium with the red v e l v e t l i k e c o l u m n a r e p i t h e l i u m categorizing VIA test results as negative • L o o k f o r w h i t e p a t c h e s . or positive or invasive cancer • If there are no white patches in the

ectocervix the test is negative’ • All the aceto-white patches are not considered positive. • If there is a white patch, its density, margin and the relationship to the SCJ should be noted. 72

Criteria for categorizing VIA test results as negative or positive or invasive cancer VIA category Description Negative • No aceto-white lesions • Transparent lesions or faint patchy lesions without definite margins • Nabothian cysts becoming aceto-white • Faint line like aceto-whitening at the junction of columnar and squamous epithelium • Aceto-white lesions far away from the transformation zone Positive • Distinct, opaque aceto-white area ● Margin should be well defined, may or may not be raised

● Abnormality close to the squamocolumnar junction in the transformation zone and not far away from the os. Invasive cancer Obvious growth or ulcer in the cervix. Acetowhite area may not be visible because of bleeding 73

Management of women with abnormal tests All cases of suspicious smears or visual inspections should be subjected to colposcopy for better visualization. Biopsy, either by endocervical curettage or cervical cone biopsy should be done in all suspicious cases on colposcopy. For such investigations, women should be promptly referred to the nearest centre performing these investigations. Figures 5.6.13and5.6.14 depict the sequential management of women with abnormal test results on Pap and VIA. PAP

NORMAL INFLAMMATION ASCUS/AGUS CIN/DYSPLASIA 48 Re –Screen Repeat after 6 months after 5 Yrs Normal Abnorma l Colposcopy Normal & satisfactory Abnormal Unsatisfactory Cryotherapy at same setting Biopsy LEEP LEEP Normal CIN Repeat pap after1 Yr Cryotherapy LEEP CIN: Cervical Intraepithelial neoplasia LEEP: Loop Electricosurgical Excisional Procedure ASCUS: Atypical Squamous cells of unspecified significance AGUS: Atypical glandular cells of unspecified significance 74

Figures 5.6.13: Sequential management with abnormal test results on Pap

VIA Negative Positive 48 Re –Screen after 5 Yrs Colposcopy Pap if available Normal & satisfactory Abnormal Unsatisfactory Biopsy LEEP LEEP Cryotherapy at same setting Management as in Normal CIN fig: 5.6.13 Repeat VIA after1 Yr Cryotherapy LEEP Figures 5.6.14: Sequential management with abnormal test results on VIA 75

3. Cancer of the Breast Breast cancer is the commonest cancer among women all over the world. In India, it is the second most common cancer among women after cancer of the uterine cervix and is emerging as the commonest cancer in urban centres. Data from Hospital Based Cancer Registry (HBCR) show that only about 15% of patients present in localized stage. Regional Lymph nodes are involved in around 75% at the time of presentation and about 10% have distant metastases at the time of presentation

Risk factors Some of the risk factors for breast cancer are • Reproductive and hormonal factors – the older a woman is when she has her first child, the greater her chance of having breast cancer. Women who begin menstruation early (before age 12), have menopause late (after age 55) or never had children are also at greater risk. Women who take menopausal hormone therapy (oestrogen and progesterone) for five years or more after menopause also appear to have an increased risk.

• Family History: Risk of cancer increases in women with a first-degree relative with bilateral breast disease • Other factors: Being obese after menopause: women who are obese after menopause are at higher risk of breast cancer. Physical inactivity: women who are physically inactive throughout life have a greater risk of having breast cancer. Alcohol intake: some studies suggest that the risk of breast cancer increases with increased intake of alcoholic beverages.

Prompt diagnosis of breast cancer in the early stage is very important. This is possible by increasing the level of awareness among women and health care professionals. The following methods may be used for early detection 76

Breast awareness and breast self examination (BSE): The first person to detect any lump in the breast is the woman herself. For this, it is essential that every woman be aware of the size, shape and consistency of her breasts, and know when there is an abnormal change in any of these Every woman should be aware of the following signs – ● A change in size ● A nipple that is pulled in or changed in position or shape ● A rash on or around the nipple ● Discharge from one or both nipples

● Puckering or dimpling of skin ● Lump or thickening in the breast ● Constant pain in the breast or armpit In case a woman notices any such change, she should promptly visit the health centre or a health professional. Clinical Breast Examination (CBE): This is to be performed by a physician, trained nurse or a health worker. It is recommended that women may be examined for any lump in the breast when they have come for other reasons. Fig.5.6.15 Sign and Symptoms of Breast Cancer 77

Management of breast cancer Breast cancer is managed by surgery, radiotherapy, chemotherapy (including hormone therapy), or a combination of the three. Figure 5.6.10 shows the management of a person with a suspicious breast lump in a flowchart. Figure 5.6.16: Flowchart of management of a suspicious breast lump 78

SUGGESTED READING: • World Health Organization. Preventing chronic diseases: a vital investment. Geneva, 2005. • Reddy KS, Shah B, Varghese C, Ramadoss A. Responding to the threat of chronic diseases in India. The Lancet 2005; 366(3498):1744-1749. • Mohan V, Sandeep S, Deepa R, Shah B, Varghese C. Epidemiology of type 2 diabetes: Indian scenario. Indian J Med Res 2007; 125(3):217-230. • Manual for Health Professional,National Control Programme,Dte.G.HS.,Ministry of Health & Family Welfare,goi ,2005

• Report of the Joint International Society and Federation of Cardiology/World Health Organization Task Force on Standardization of Clinical Nomenclature. Nomenclature and criteria for diagnosis of ischemic heart disease. Circulation 1979; 59: 607–9. • World Health Organization. Prevention of Cardiovascular disease; Pocket guidelines for assessment and management of cardiovascular risk. Geneva 2007. • Reddy KS, Naik N, Prabhakaran D. Hypertension in the developing world: a

consequence of progress. Curr Cardiol Rep 2006; 8(6):399-404. • Guidelines for prevention of Ischemic Heart Disease in India by cardiology society of India.2003. • World Health Organization. WHO CVD risk assessment and management for low and medium resource settings. Geneva, 2002. th th • Integrated management of cardiovascular risk. A report of WHO meeting 9 – 10 July. Geneva. (Link: http://www.who.int/cardiovascular_diseases/media/en/635.pdf)

• World Health Organization. Prevention of recurrent heart attacks and strokes in low and middle income populations. Evidence based recommendations for policy makers and health professionals. Geneva, 2003. • World Health Organization. Avoiding heart attacks and strokes. Don’t be a victim protect yourself. Geneva 2005. • Thygesen, K, Alpert, JS, White, HD, et al. Universal definition of myocardial infarction: Kristian Thygesen, Joseph S. Alpert and Harvey D. White on behalf of the

Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Eur Heart J 2007; 28:2525. • White HD. Evolution of the definition of myocardial infarction: what are the implications of a new universal definition? Heart 2008; 94: 679–84. 79

Acknowledgements 1. Dr R K Srivastava, DGHS ,GOI 2. Dr. Jagdish Prasad,Addl.D.G.H.S, GOI 3. Dr Harsh Wardhan, Head, Cardiology Dr RML hospital PGIMER, New Delhi 4. Dr D C Jain, DDG ,Dte.G.H.S,GOI 5. Dr Sudhir Gupta, CMO (NCD), Dte.G.H.S,GOI 6. Dr W D Bhutia, CMO (WDB), Dte.G.H.S,GOI 7. Prof. K K Talwar, Director PGIMER, Chandigarh 8. Dr J S Thakur, Cluster Focal Point, NMH Cluster WHO – India 9. Dr D Prabhakaran, Executive Director ,Center for Chronic Disease Control, New Delhi

10. Dr Shiv Bagga, Assistant Professor, Cardiology , PGIMER, Chandigarh 11. Dr Binod Patro, Assistant Professor, School of Public Health, PGIMER, Chandigarh 12. Dr Ranjit Nath, Assistant Professor, Cardiology, Dr RML hospital PGIMER, New Delhi 13. Dr. Mithila Dayanithi,Consultant Cancer,MoH&FW,GOI 14. Dr Ritu Rana, Consultant-NCD,MoH&FW,GOI 15. Dr Sitanshu Kar, National Consultant, NMH Cluster WHO – India 80

GUIDELINES FOR PRE-OPERATIVE, OPERATIVE AND POST OPERATIVE PRECAUTIONS FOR INTRA OCULAR EYE SURGERY Post-Operative Endophthalmitis is a devastating and serious complication of Intraocular Surgery. Fortunately, in recent times, due to better surgical techniques and improved sterilization and aseptic methods, the incidence has come down to very low levels. However, sometimes despite all precautions, infections do occur. The risk factors for developing post- operative endophthalmitis are multifactorial.

It is essential to understand the difference in causes or risk factors that lead to cluster or sporadic endophthalmitis. For sporadic, it is usually contamination from the patient’s own conjunctival flora or deficiency of the aseptic protocols like pre op antibiotics, gloving, gowning, patient hygiene, OT ventilation systems and surgical techniques. In cluster endophthalmitis, it is usually due to sterilization failure or contaminated surgical supplies. (A) Operation Theatre

Surgery for the patients selected for surgery should be preferably organized in a dedicated routine functional eye care facility having an enclosed, air-conditioned, functional eye-OT with operating microscope and separate scrub area with running and tested water facility. The following layout is preferable to ensure aseptic processes and minimize contamination. (B) Operation Theatre Layout To be arranged in levels Level-I  Restricted Entry  Changing rooms/offices/record keeping

 Shoes/footwear to be removed and clothes changed. Level-II  Entry only after changing for both patients and staff.  Caps/masks to be worn.  Scrub room/gloving and gowning. Level-III  Sterile area (Separate slippers)  Entry restricted to minimal staff  Fumigated areas  Ultra-violet light at night if possible  Floors, walls, surfaces to be scrubbed and carbolised  OT must be air-conditioned 1

Level-IV  Waste disposal area  Sterilization room  Instrument maintenance (Under supervision of the Staff Nurse/OT Technician  Cleaned and washed with Savlon/soap ultrasonic cleaning  Examined under magnification for defect/for repair/packing for sterilization  No. of sets: Minimum 5 sets (more if volume increases)  One set to one patient only  Sharps to be cleaned and Autoclaved (ETO sterilization/  Tubes to be rinsed, air dried, flushed, air injected and then autoclaved.

(C) Patient Screening & precautions: A screening eye camp to be held at least 1day prior to scheduled surgery date. (D) General Examination (i) Thorough checkup (Physician’s referral if required) Investigations  Blood pressure.  Blood sugar  ECG – (especially of cardiac and hypertensive cases).  Urine (R/M, Albumin) (ii) Check up for systemic illness  Diabetes  Chronic Pulmonary Conditions (COPD)  Hypertension & Cardio vascular Condition  Renal conditions etc.

All High risk patient including patients with uncontrolled systemic illness like diabetes, hypertension, CAD etc. should not be enrolled for surgery when doing on a mass scale and should be advised to consult a physician before surgery. (E) Ocular Examination  Special care should be taken for all the one eyed patients, where surgery will be performed in their only functioning eye.  Chief complaints and History of the problem. Complete ophthalmic examination  Intraocular pressure 2

 All patients should be screened to ensure patent nasolacrimal duct and negative regurgitation test. A blocked nasolacrimal duct/positive regurgitation test should not be enrolled for cataract surgery and referred for further examination  Syringing – Not to be done on day of surgery.  Adnexal infections present to be treated with systemic antibiotics.  Lid conditions & Sac related conditions such as entropion, trichiasis, and Daryocystitis to be treated first.

 Intraocular surgery to be delayed by at least three weeks after these surgeries.  All investigations including contact biometry to be done at least 1 day prior to surgery, thus avoiding contact procedure on the day of surgery.  Pre-op topical second or fourth generation fluoroquinolone group of antibiotics should be started in both eyes, 4-6 times a day starting at least 1 day prior to the surgery.  A written-informed consent should be taken in all cases undergoing surgery after

explaining the procedure and the risks involved.  On the day before surgery date, patient should have thorough face wash with soap and if required head bath and shaving. (F) OPERATION THEATRE PREPARATION (i) Sterilization of OT, instruments and consumables:  Floors of the operating room should be mopped on the day before surgery with antiseptic solutions, used for OT cleaning purpose.  On the day before surgery, the surgical instruments, required linen must be

autoclaved using long sterilization cycle parameters following the standard protocol.  Proper functioning of the sterilization process like autoclave should be monitored by the operating surgeon and the senior nurse by checking the colour change of the sterilization indicator.  A minimum of 4-5 instruments sets (trays) per OT should be autoclaved and kept available.  Proper sterility of the consumables like dyes, viscoelastic solution, irrigating fluid

should be ensured by checking for expiry date, suspended or floating particles.  The surface of trolleys, operation tables should be wiped each day with antiseptic solutions prior to starting the surgery. 3

 After each day, all the instruments and linen after thorough cleaning and drying should be autoclaved.  OT air conditioner filters must be removed and cleaned once a month.  The irrigating fluid bottle batch number should be noted. Lab report of random sample from the batch of all intraocular use solution like irrigating solution/ viscoelastics should be made available to the surgeon team. (ii) Sterilization of instruments between surgeries

 Strictly avoid chemical sterilization using either Glutaraldehyde or Acetone.  A high speed sterilizer or flash autoclave should be used for sterilization of surgical instruments (trays) in between the cases, thus rotating the 4-5 instruments sets (trays) per table, providing uninterrupted supply of autoclaved instruments for each surgery and to sustain high volume of surgeries.  For phacoemulsficiation, the phaco needles for every five cases and sleeves and

irrigation/aspiration (I/A) handpieces for every case should be sterilized. (iii) Documentation of sterilization process  For each load, additional sterilization indicators should be placed individually in the surgical bins or in linen packs. These additional indicator stickers should be pated in a register maintained for the purpose.  Similarly, for each instruments set, there must be indicator tapes, which should be pasted in the case record with load details and date.

 Date of fumigation of OT should be documented in registers (iv) Surgical supplies 1. Irrigating Solutions:  Both Ringer lactate solution (RL) or balanced salt solution (BSS)) can be used for the cataract surgery as intraocular irrigating solution. To use only those which are packaged in flexible bag or in bottle container. Should not use solutions supplied in rigid, plastic, non- transparent containers.  If packaged in flexible bag, then it should be supplied with outer flexible sterile steam

permeable pouch / nylon pack for aseptic handling in OT. The outer pouch should be opened only inside the OT. The circulating nurse should check for any visible suspended particles or any leaks and if found the solution should be discarded. 4

 If glass bottles are used, the bottle should be checked and autoclaved on the previous day. Before autoclaving, the bottle should be inspected for the quantity, any crack and for any suspended particles. If the quantity is less or a crack or any suspended particles are seen it should be discarded. The bottle should be autoclaved on the day before surgery. The outer surface of the bottle should be cleaned before autoclaving. The parameters for autoclaving

bottles is 121⁰ C temperature, 21 PSI pressure for 20 minutes.  Any leftover solution should be discarded at the end of the day after the surgeries. Should not be stored nor reused on the following day. 2. Ocular Viscoelastic Device, dyes, and other sterile consumables ( HPMC, NaHy, Trypan blue) Packaging: Should be packed in glass syringe / glass vial to maintain uniform sealing integrity to maintain the sterility. The glass syringe/vial should be packed further by sterile outer pouch

pack for aseptic handling in OT. OVD packed in plastic disposable syringes should be avoided due to its compromised sealing integrity which may lead sterility failure. Also it will lead to severe sterile reactions due to chemical leachable of plastic syringe get in to the OVD. (Variation in PH, inorganic impurities etc., which cause undue toxicity) Handling: The outer pouch should be opened in OT and the syringe/vial shall be received by

the sterile OT staff or placed in a sterile tray. Scissors or other instruments should not be used to open the pouch For any intraocular injection, including trypan blue dyes packed in the glass vial can be used for multiple times in the same day provided the aluminium seal should not be removed from the vial. The rubber bung is self sealable for maximum ten pricks. After that it should be discarded. HPMC is made up of plant cellulose and prolong exposure may attract and enhance aerobic

microbes. Hence, any leftover solution should be discarded after the surgeries. Should not be stored and reused 3. Others:  Cannulas used for viscoelastic solution should not be reused, as it is difficult to clean the cannulas of viscoelastic.  10% Povidone iodine shall be used for surface painting/cleaning. This should not be diluted in OT for any other purpose.  5% Povidone iodine solution used as eye drops shall be used for conjunctiva sac cleaning.

Once the container is opened, use the solution in 48 hours to avoid iodine loss and its efficacy as it lacks strong stabilising agents.  The batch numbers of the supplies used must be noted down in the case sheet and also a designated register. 5

(G) Patient preparation: (i) On the day of surgery  On the day of surgery, patient shall continue to receive topical antibiotics before and after surgery.  Each patient should be given protective cap and booties before entering the preoperative holding area/operating room.  In the preoperative holding area, the periocular skin should be cleaned with povidone-iodine 10% solution prior to administering the regional anesthetic block. (ii) Scrubbing and gowning`

 Surgeon should wear washed OT clothes, OT slippers, cap and mask. Other staff working inside the OT area also to wear sterile OT gown  Surgeon should perform 3 scrubs with a solution equivalent to 4% w/v of chortexidine gluconate for at least 3 to 5 minutes under tested running water.  A clock to be placed in the washing area.  To proceed in a methodical manner from distal to proximal i.e. Hand/Palms/fingers/ Medial,

lateral, dorsal, ventral aspects. Fore arm-Medial, lateral, anterior, posterior up to beyond elbow. Scrubbing from distal to proximal.  Hands always above waist and elevated so that water drains away from hand. (iii) Cleaning & Draping  5% providone iodine for instillation into cul de sac with contact time of at least 3 min. Surgical area should be draped using sterile linen and separated plastic eye-drape for each

patient to isolate the field. The eye to be washed with Ringer lactate or BSS before the start or surgery.  Separate instruments trolley lined with sterile cotton linen and covered by sterile plastic sheet should be used. The linen and plastic sheets should be changed if it gets wet due to spill over of fluid. (iv) During surgery  Wounds which are unstable and leak should be sutured to avoid hypotony and thereby minimizing risk of infection.

 Subconjunctival injection of antibiotic / (and steroid) should be administered at the completion of surgery in all cases.  At the completion of surgery, topical fluoroquinolone antibiotic should be instilled in the conjunctival sac before the eye is bandaged. 6

 Minimal handling of tissues  Instruments used for extra ocular manipulation not to be used inside eye  No wick left into anterior chamber-uvea/capsule/vitreous and complete removal and formation of anterior chamber with irrigating fluid/Air.  No foreign material to be left in surgical area.  Gloves to be changed after every case and scrubbing and gowning to be done after every 5-6 cases. If no touch techniques used, but if gown gets wet due to accidental contact with

unsterile area, it should be changed immediately.  Separate surgical set to be used for all patients.  Intra-cameral antibiotics may be administered in high volume surgeries.  Sharps – Keratomes/blades/needle not to be reused unless sterilization procedure undertaken.  Intraocular instruments and cannulas not to be reused if possible unless properly sterilized. Disposables, wherever possible, to be disposed after single use.

 The operative time should be limited to continuous eight hours after which a minimum break of two hours may be given for cleaning, sterilization and fumigation of the Operation Theatre. (H) Post-operative precautions:  Proper lid hygiene should be maintained in the post-op period  Topical fluoroquinolone antibiotics 4-6 times per day should be administered for 7 to 10 days along with topical steroids in tapering doses for 6 to 8 weeks. Cycloplegics if required as prescribed by the surgical team.

 All patients should be given a discharge card mentioning the surgical details and postoperative instructions including date for follow up examination and location.  Regular follow-up of the patients is necessary. Patients should be referred to a referral centre immediately upon early symptoms (e.g. pain, redness, dimness of vision, discharge) and signs (e.g. circumcorneal congestion, anterior chamber cells and flare, hypopyon, reduced fundal glow, vitreous exudates) of infection/endophthalmitis.

 Personal hygiene to emphasized.  Avoid dust, smoke and sunlight.  Wear protective dark glasses outdoors.  Frequency of instillation of Eye drops as advised to be ensured.  Regular follow-up of the patients is necessary as below:  1st post Operative day by surgeon mandatory.  2nd or 7th day 7

 30 to 25 day with refractive correction. (I) Emergency Consultation  Patients should be referred to a referral centre immediately upon early symptoms:  Excessive pain & Redness.  Watering/discharge  Sudden Blurring of vision/Decreased or loss of vision  Floaters/Flashes  Excessive photo phobia (J) Waste Disposal All Doctors and staff (Medical & Paramedical) should receive formal training in Biomedical waste Management. Segregation  Infected material to be handled only by gloved staff.

 OT to be washed /scrubbed before use and surfaces carbolized.  Fumigation at frequently timed intervals or after an infected case has been done/large volume cases operated.  Bi-weekly cultures of the OT to be sent from specified points of the OT.  Ultraviolet light is recommended for overnight use.  Infected cased to be done in a separate OT along with other extra ocular surgeries. (K) POINTS TO REMEMBER Pre-operative, Operative Precautions  Preoperative antibiotic drops.

 Bath for patients/Head wash/Face wash.  Special note of eye brow/medical canthus area/nasal area.  Eye to be washed with BSS and Betadine 5%.  Sharps – Keratomes/blades/needle not to be reused unless sterilization procedure undertaken.  Intraocular instruments and canulas not to be reused if possible unless properly sterilized Disposables wherever possible to be used.  OT to be washed/scrubbed before use and surfaces carbolized.

 A drop of Beta-dine to be put in conjunctiva before starting the surgery. Post-Operative Precautions  Sub-conjunctival Antibiotics, single Drops of 5% Betadine in the conjunctivital Sac after completion of surgery. 8

 Systemic antibiotics only if adnexal infections present.  Topical antibiotics to be given post operatively with anti-inflammatory-steroidal/non steroidal agents.  Personal hygiene to be emphasized to the patient  The patient should avoid dust, smoke and sunlight.  The patient should wear protective dark glasses outdoors.  Routine weekly/ if necessary, more frequently postoperative visits should be ensured.  Frequent instillation of Eye drops to be ensured.

 Dilating drops once daily to keep pupil mobile. (L) Minimum Equipments / Infrastructure that should be available in Eye OTs for sterilization and for maintaining aseptic standards; 1. Horizontal autoclave 2. High speed autoclave for sterilization in between surgeries 3. Ethylene Oxide sterilizer 4. Basic RO water plant 5. Large drums for boiling of water 6. Chemical sterilization indicators 7. Indicator guns (M) Training of OT staff in Eye OTs in district hospitals

It will be appropriate to plan a systematic auditing of the facilities in the district hospitals to identify the areas of deficiency and also institute appropriate training for the staff. At least two of the staff members must be well trained in sterilization techniques. Sr. Members of the Committee Signature No 1 Dr.Arun Kumar Panda, Additional Secretary, Ministry of Health & FW, Government of India. 2 Prof. Atul Kumar, Professor, AIIMS, New Delhi 3 Prof. J.S. Titiyal, Professor, AIIMS, New Delhi

4 Prof. T.P Lahane, Dean Grants College, Mumbai 5 Dr. Ramesh Dhankad, DPM, Haryana 6 Dr. Ravindran, Arvind Eye system, Madurai 7 Dr. Alok Sen, HOD, Sadguru Netralaya, Chitrakoot 8 Dr. N.K. Agarwal, DDG (o), Dte.GHS, Nirman Bhavan, New Delhi 9 Dr. V. Rajshekhar, AC (NPCB) MOH&FW, Member Secretary of the Committee 9

GUIDELINES FOR THE MANAGEMENT OF CRITICAL CARE Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 ACUTE EXACERBATION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD 3 2 ACUTE SEVERE ASTHMA 13 3 ACUTE RESPIRATORY FAILURE 20 4 ACUTE RESPIRATORY DISTRESS SYNDROME 30 5 ACUTE LIVER FAILURE 36 6 BRAIN DEATH TEST AND ICU MANAGEMENT 45 7 EVALUATION OF NEW FEVER IN THE CRITICALLY ILL PATIENT 57 8 HEMODYNAMIC MONITORING IN THE ICU 63 9 ACUTE PULMONARY EMBOLISM (PE) 78 10 SEVERE SEPSIS AND SEPTIC SHOCK 87 11 SEVERE COMMUNITY ACQUIRED PNEUMONIA 98 12 STATUS EPILEPTICUS 102

13 INITIAL MANAGEMENT OF SEVERE TRAUMA 113 14 TRAUMATIC BRAIN INJURY 122 ACUTE EXACERBATION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE 2

(COPD) Rajesh Chawla, Consultant Physician and Intensivist, Indraprastha Apollo Hospital, Delhi I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Chronic obstructive pulmonary disease (COPD) refers to a group of disorders characterized by chronic airflow obstruction/limitation. The airway obstruction is persistent and largely irreversible. It includes two distinct pathophysiological processes - chronic bronchitis and emphysema. Acute exacerbations of these disorders occur during the natural history of

progression of this disease. Exacerbations are frequent, more so during winter, resulting in progressive loss of the functional capacity of the lungs leading to progressive dyspnea. b) Case definition: For both situations of care (mentioned below*) There are many definitions for what represents an acute exacerbation of COPD. One of the most widely used definitions evaluates the severity of exacerbation based on three symptoms: i. worsening dyspnea ii. increase in sputum purulence

iii. an increase in sputum volume Type I exacerbation (severe) have all three symptoms and Type 2 exacerbations (moderate) exhibit two of three symptoms. Type 3 exacerbation (mild) include one of the symptoms and at least one of the following: upper respiratory tract infection within the past 5 days,fever without apparent cause, increased wheezing, increased cough, or a 20% increase in respiratory rate or heart rate over baseline. II INCIDENCE OF THE CONDITION IN OUR COUNTRY

COPD is currently the fourth leading cause of death worldwide behind cardiovascular disease,cancer and cerebrovascular diseases. The Global Burden of Disease Study estimated that in 1990, the worldwide prevalence of COPD was 9.34 per 1000 men and 7.33 per 1000 women. Depending on the severity of the disease, the 5-year mortality rate for patients with COPD varies from 40%to 70%. The three major causes of death have been identified as COPD itself, lung cancer and cardiovascular disease. 3

The prevalence rates of COPD in males varied from 2.12% to 9.4% in studies conducted in north India and from 1.4% to 4.08% in south India. The respective ranges for females were 1.33%– 4.9% in north India and 2.55%– 2.7% in south India. A majority of cases with chronic COPD (57.4%) were found to suffer from a mild form and only 16% had severe COPD. A large-scale study in Hyderabad city and its surrounding municipalities, covering a population

of more than 54 lakh and 28 hospitals/health posts, was done in 2001 to collect cause-specific morbidity data. The rates of hospital admissions of cases with COPD showed an age differential. While the rate was 47.84/100,000 persons at the community level, it was 57.28 for those 18–64 years of age and 546.17 for those above 65 years of age. Treatment cost of a patient with COPD per year (in Rs)· according to Guidelines is Rs 2126 for moderate to severe disease and Rs 10,538 for acute exacerbation.

III DIFFERENTIAL DIAGNOSIS Acute exacerbation of COPD should be differentiated from the following disorders • Congestive cardiac failure • Bronchial asthma • Bronchiectasis • Interstitial lung disease • Chronic thromboembolic pulmonary disease • Obesity induced dyspnea • Chronic destructive lung disease due to old tuberculosis • Occupational lung disease IV PREVENTION AND COUNSELING Avoidance of smoking is the single most important factor in prevention of exacerbation of

COPD. Yearly influenza vaccine and 5 yearly Pneumococcal vaccine has also been found to be helpful. Education regarding starting early antibiotics with evidence of exacerbation. Avoidance of pollution is advisable Early consultation with physician should be strongly encouraged and patient should be educated about the warning signs of acute exacerbation. V OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA 4

*Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: Patient usually presents with a history of chronic cough and exertional breathlessness with recent increase in cough,breathlessness, increased volume and purulence of sputum. There are usually associated constitutional symptoms like fever, malaise and lack of appetite. Patient may be orthopneic and have swelling of feet,

On examination there is increase in respiratory rate, tachycardia, flapping tremor and drowsiness ( if retention of carbon dioxide) . Some patients who have predominant chronic bronchitis show features of chronic corpulmonale (Blue Bloaters) like pedal edema, raised jugular venous pressure, puffy face, central cyanosis, loud pulmonary heart sound and parasternal heave due to right ventricular hypertrophy. On the other patient with predominant

emphysema (Pink Puffers) are usually thin built, plethoric due to associated secondary polycythemia, disproportionately dyspneic, features of hyper-inflated lungs like obliteration of liver and cardiac dullness, silent chest. b) Investigations: • Chest Xray – To rule out Pneumothorax. Look for consolidation, pleural effusion,cardiomegaly and features of lung hyperinflation.Look for features of past tuberculosis • Pulse Oximetry • Sputum for gram stain, Culture and sensitivity, Acid Fast Bacilli stain.

• Hemogram, blood urea, serum creatinine, serum electrolytes • Electrocardiogram c) Treatment: • Oxygen therapy: Controlled humidified oxygen therapy with a Venturi mask (fixed performance device) or low oxygen flow (1-2 litres) with nasal cannula or simple face mask (variable performance device) to keep Spo2 90-92%. Higher oxygen saturation and high concentration of inspired oxygen should be avoided. • Bronchodilators: o Nebulised beta 2 adrenergic receptor agonists (salbutamol) in patients who are

very dyspneic – 2.5-5 mg nebulised every 4-6 hours and as necessary. Watch for tachycardia or arrhythmias 5

o Inhaled beta 2 adrenergic receptor agonists in patients who are able to take metered dose inhalers (180 mcg) every 2-4 hours o Nebulised anticholinergic agent (ipratropium bromide) 0.5 mg every 4-6 hrs o Inhaled Ipratropium bromide 18-36 mcg every 2-4 hours • Corticosteroids: Five to 10 days of oral or intravenous corticosteroids is advocated in most cases. Prednisolone 40-60 mg orally or methylprednisolone 60-120 mg intravenously may be used. Appropriate stress ulcer prophylaxis with Ranitidine or

Proton Pump inhibitors should be started. Inhaled corticosteroids may be added later when patient has stabilized. • Antibiotics: The most common organisms identified in acute exacerbation are Streptococcus pneumonia, moraxellacatarrhalis and hemophilus influenza.In patients with more severe and recurrent disease gram negative organisms like Klebsiella pneumonia and Pseudomonas aeruginosa should also be considered. Initial antibiotic

choice is empirical. Usually a macrolide antibiotic like azithromycin or clarithromycin or a quinolone like levofloxacin or moxifloxacin is given. Broader spectrum antibiotics are used for severe disease. • Methylxanthines like aminophylline. Though commonly used in India but given the frequent and severe side effect profile,narrow therapeutic window and lack of evidence demonstrating improved outcomes routine use of these agents is not recommended

• There is no role of mucolytic or chest physiotherapy commonly used practices in acute exacerbation of COPD. d) Referral criteria: Following category of patient should be referred to higher centre. • Patient who will benefit from non invasive ventilation and if this facility is not available in the primary centre • Patients in need for intubation and mechanical ventilation • Patient with hemodynamic instability • Patient not responding to maximal medical treatment

• Patient with acute exacerbation complicated by associated pneumonia,pneumothorax. • Patient in whom diagnosis is uncertain and needs further investigation. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical Diagnosis: As in situation 1 b) Investigations: • Arterial Blood gas analysis – look for hypercarbia and respiratory acidosis • Echocardiogram- Low ejection fraction 6

• D DIMER, Pro BNP – bio markers for venous thromboembolism and congestive cardiac failure respectively • CT scan of Chest – look for other pulmonary disease, pulmonary thrombus • Venous Doppler of legs- to rule out deep venous thrombosis c) Treatment: • Noninvasive ventilation should be applied simultaneously to a patient in acute respiratory failure in addition to the rest of the treatment based on the clinical criteria, provided there is no contraindication

Non-invasive Positive Pressure Ventilation (NIPPV) is indicated in patients with appropriate diagnosis with potential reversibility and if patient has any two of the following clinical criteria are fulfilled. • Moderate to severe respiratory distress • Tachypnea, (RR more than 25 / min) • Accessory muscle use or abdominal paradox • Blood gas derangement pH < 7.35, PaCO2 > 45 mm Hg • PaO2 / FiO2 < 300 or SPO2 < 92% with FiO2 0.5 CONTRAINDICATIONS

There are no absolute contraindications for the use of NIPPV. Some contraindications have, however, been suggested  Non-availability of trained medical personnel  Inability to protect the airways -Comatose patients, patients with CVA or bulbar involvement, confused and agitated patients. Upper airway obstruction  Hemodynamic instability- uncontrolled arrhythmia, patient on very high doses of inotropes, recent myocardial infarction.

 Inability to fix the interface -Facial abnormalities, facial burns, facial trauma, facial anomaly. • Severe GI Symptoms – vomiting, obstructed bowel. Recent GI Surgery., Upper G.I. Bleed  Life threatening hypoxemia  Copious secretions  Conditions where NIPPV has not been found to be effective 7

Protocol for application of NIPPV For successful noninvasive ventilation. a) Patient interface –Nasal or oronasal mask b) Mode of ventilation: 1) Bi-level positive airway pressure--Spontaneous or spontaneous timed mode in portable pressure ventilators or NIV option on conventional ventilators 2) Pressure support /Pressure control /Volume control – conventional ventilators c) Ventilator settings Explain therapy and its benefit to the patient in detail. Also discuss the possibility of intubation.

a) Choose the correct size interface. Oronasal mask in acute respiratory failure is preferred. b) Set the NIPPV portable pressure ventilator in spontaneous or spontaneous /timed mode. , c) Start with very low settings. Start with low inspiratory positive airway pressure (IPAP) of 6 – 8 cm H 0 with 2 to 4 cm H 0 of EPAP (Expiratory positive airway pressure). The 2 2 difference between IPAP and EPAP should be at least 4 cm H 0. 2 d) Administer oxygen at 2 liters per minute.

e) Hold the mask with the hand over his face. Do not fix it. f) Increase EPAP by 1-2 cm increments till all his inspiratory efforts are able to triggers the ventilator. g) If the patient is making inspiratory effort and the ventilator does not respond to that inspiratory effort, it indicates that the patient has not generated enough respiratory effort to counter auto PEEP and trigger the ventilator (in COPD patients). Increase EPAP

further till this happens. Most of the patients require EPAP of about 4 to 6 cm H2O.Patient who are obese or have obstructive sleep apnea require higher EPAP. h) When all the patient’s efforts are triggering the ventilator, leave EPAP at that level. i) Now start increasing IPAP in increments of 1-2 cm up to a maximum pressure, which the patient can tolerate without discomfort and there is no major mouth or air leak. j) In some NIPPV machine, inspiratory time (Ti) can be adjusted. Setting the Ti at one

k) Now secure interface with head straps. Avoid excessive tightness. If the patient has a nasogastric tube put a seal connector in the dome of the mask to minimize air leakage. l) After titrating the pressure, increase oxygen to bring oxygen saturation to around 90%. m) As the settings may be different in wakefulness and sleep, readjust them accordingly. When NIPPV is being initiated for acute respiratory failure, close monitoring and the capability

to initiate endotracheal intubation and other resuscitation measures should be available in the same setup. Start NIPPV preferably in the ICU or in the emergency room in acute respiratory failure. Application of NIPPV using a Critical Care Ventilator a) The first step is to select a ventilator, which is capable of fulfilling the needs of the patient. b) Explain the therapy to the patient c) Choose the appropriate mode. Usually pressure support or pressure control modes are

preferred. Standard critical care ventilators using flow by system ( non invasive mode option ) allow the patient to breathe without expending effort to open valves. In selected patients like those suffering from neuromuscular diseases, volume assist or volume control mode may be used. d) Choose an appropriate interface e) Silent ventilator alarms f) Keep FiO2 0.5 Using pressure support/control approach • Start with low settings like inspiratory pressure support at 5-6 cm H2O and PEEP at 2 cm H2O.

• Initiate NIPPV while holding the mask in place and confirm optimum fit. If it is big or small or loose, change it. • Hold the mask .do not fix the headgear • Now increase PEEP till all his inspiratory efforts are able to triggers the ventilator 9

• If the patient is making inspiratory effort and the ventilator does not respond to that inspiratory effort, it indicates that the patient has not generated enough respiratory effort to counter auto PEEP and trigger the ventilator (in COPD patients). Increase PEEP further till this happens. • Once the patient’s all inspiratory efforts are triggering the ventilator then start increasing pressure support further, keeping certain patient’ comfort in mind.

(Reduce respiratory rate, reduced use of accessory muscle etc. Ensure that there are no major leaks. • When there is significant mouth leak, there may be asynchrony. In that case, pressure control will be the preferred mode of NIPPV and one can set up the inspiratory time to avoid asynchrony. • After adequate ventilation has been achieved, increase fraction of oxygen concentration to maintain Oxygen saturation more than 90%.

• Secure interface with headgear. It should be tight, but not over-tight. Small leaks are acceptable • A peak inspiratory pressure more than 25 cm is rarely required in COPD, but higher pressures can be used when using NIPPV for other indications. PEEP is usually titrated between 5-10 cm H2O to improve triggering and oxygenation. Patient must be monitored very closely clinically. Look for sensorium,dyspnoea, respiratory

rate ,respiratory distress, use of accessory muscles, abdominal paradox, Mask comfort and vital signs pulse , blood pressure, ECG monitoring and arterial oxygen saturation, All this must be documented every 15 minutes for the first hour in the clinical notes. Patient will show improvement in parameters if NIPPV is effective. Arterial blood gas sample should be sent after 30mts to 1 hr after the application of NIPPV. In ventilator setting look for air leaks and patient–ventilator interaction.

Monitoring of noninvasive ventilation for acute respiratory failure Subjective • Mask comfort 10

• Tolerance of ventilator settings • Respiratory distress • Physical findings • Respiratory rate Other vital signs • Accessory muscle use • Abdominal paradox • Ventilator parameters • Air leaking • Adequacy of pressure support • Adequacy of PEEP • Tidal volume (5–7 mL/kg) • Patient-ventilator synchrony Gas exchange • Continuous oximetry (until stable) • ABGs, baseline and 1–2 hrs, then as indicated Initially give NIPPV continuously or as long as possible. Once patient is tolerating periods off

NIPPV, start discontinuing during day time and give during nighttime. In two to three days patient can be weaned off from the NIPPV. • Intubate and initiate mechanical ventilation in following group of patients o Those who have failed NIV trial. o Those who have contraindications of NIV o Excessive secretions o Hemodynamic instability o Extreme obesity • Initial Ventilator settings in COPD patient should take into account patients need for

prolonged expiration. Appropriate initial ventilator settings would be volume assist control, Tidal volume 8 ml/kg predicted body weight, rate 10-12/min, PEEP of 0-5 cm f H O , FiO2 2 titrate for SpO2 90-92 % . High peak flow 70-90 L/min to keep I:E ratio 1:4 or more . • Attempt should not be made to attain normal blood gas but to aim for patient’s baseline values. • Monitor for development of auto PEEP by end expiratory manouever or analyzing ventilator graphics.

• Neuromuscular blockers should be avoided • Deep venous thrombosis prophylaxis, Stress ulcer prophylaxis and nutritional needs should be addressed. VI FURTHER READING / REFERENCES • Hill NS, Brennan J (2007) Noninvasive ventilation in acute respiratory failure.Crit Care Med 35(10):2402–2407 • Stoller JK (2002) Clinical practice. Acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 346(13):988–994 • SnowV (2001) Evidence base for management of acute exacerbations of chronic

obstructive pulmonary disease. Ann Intern Med 134(7):595–599 • Confalonieri M, Garuti G, Cattaruzza MS, et al (2005) A chart of failure risk for noninvasive ventilation in patients with COPD exacerbation. EurRespir J 25(2):348–355 • K.J.R. MURTHY, J.G. SASTRY. Economic burden of chronic obstructive pulmonary disease.NCMH Background Papers Burden of Disease in India 12

ACUTE SEVERE ASTHMA Rajesh Chawla, Consultant Physician and Intensivist, Indraprastha Apollo Hospital, Delhi II. WHEN TO SUSPECT/ RECOGNIZE? c) Introduction: It is a chronic inflammatory disease of the airways characterized by airway hyper reactivity and inflammation, bronchoconstriction and mucus hyper-secretion. Asthma is associated with considerable patient morbidity, a diminution in productivity and increase in health care utilization. d) Case definition: For both situations of care (mentioned below*)

Acute severe asthma or status asthmaticus is defined as a prolonged episode of severe asthma that is unresponsive to initial standard medical therapy and may lead to respiratory failure. The episode may be rapid in onset (in a matter of hours) or more typically progress during several hours to days. The former is referred to as asphyxic asthma and occurs in a minority of cases. III. INCIDENCE OF THE CONDITION IN OUR COUNTRY

The estimated prevalence of asthma in India is 2468 per 100,000 population. Prevalence of acute asthma in age group 15-59 was found to be 40 per 1000,000 populations in India. Prognosis of asthma in general is good but 10-20% of patents continue to have severe attacks throughout their lives. Approximately 10% of patients hospitalized with asthma are admitted to the intensive care unit and 2% are intubated. Mortality rate ranges from 0.5-3% in hospitalized patients. 13

IV. DIFFERENTIAL DIAGNOSIS The following should be should be considered in patients with severe breathlessness • Upper airway obstruction • Epiglottitis • Vocal Cord Dysfunction • Foreign Body aspiration • Congestive heart failure V. PREVENTION AND COUNSELING Morbidity and mortality from asthma disproportionately affects the economically disadvantaged, due to prehospital factors such as access to health care, inadequate preventive therapy or delay in seeking medical treatment

Rapid onset asthma is often triggered by exposure to allergens, irritants, exercise, psychosocial stress, and inhaled illicit drugs. It may also develop after exposure to aspirin, non steroidal anti-inflammatory drugs, or beta blockers in susceptible individuals. Asthma attacks may be triggered by viral or atypical pulmonary infections. Proper counseling regarding prevention of allergen or precipitating factors should be done.

Compliance with anti asthmatic drugs should be ensured and education in its proper use should be done. Early consultation with physician during acute attack is advocated. VI. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: b) History and Physical Examination

Clinically patients present with dyspnea, cough, chest tightness and wheezing . Severity of asthma may be assessed by the following • Unable to speak full sentences 14

• Increased Respiratory rate • Use of accessory muscle • Increased Pulse rate • Pulsus paradoxus ( Inspiratory decrease in systolic blood pressure) • Decrease in sensorium, fatigue • Auscultation: Wheezes and crackles; silent chest signifies very severe airflow obstruction b) Investigations: • Peak expiratory flow rate (PEFR) is an objective measure of airflow obstruction: <30% of baseline/predicted would indicate likelihood of respiratory failure. Initially

check every half hour to assess response to therapy • SPO2: Hypoxia is usually correctable with supplemental oxygen. Refractory hypoxia should trigger search for pneumothorax, atelectasis, pneumonia or occult sepsis. • Chest x-ray; To rule out pneumothorax, look for degree of hyperinflation, or any lung infiltrate suggestive of atelectasis or collapse consolidation. c) Treatment: Initial medical management • Oxygen supplementation is continued to keep Spo2 more than 90%.

• Nebulized salbutamol 2.5 mg (0.5 ml of 5% solution in 2.5 ml saline) or levosalbutamol, repeat every 20 mins for 3 doses then less frequently dictated by patent’s clinical response. • More frequent and even continuous nebulization of salbutamol at a dose of 10 to 15 mg can be used within limits of toxic effects such as tachycardia and tremors. • Ipratratropium 0.5 mg nebulization every 20 mts should be included in initial treatment concomitantly with salbutamol for better bronchodilatation

• If nebulizer is not available use 4 puffs of salbutamol MDI through a spacer device. Treatment concomitantly with salbutamol for better bronchodilatation 15

• Cortcosteroids should be initiated at the earliest to prevent respiratory failure.. The usual doses are: Inj Hydrocortisone 100 mg every q 6 hourly or methylprednisolone 60-125 mg q 6-8 hourly. Oral prednisolone 60 mg is equally effective. • Aminophylline may be used as a second-line agent although its role is much debated. A loading dose of 5-6 mg/kg is followed by a continuous infusion of 0.6 mg/kg/hr. Avoid loading dose in case patient has been on oral theophyllines earlier.

• Antibiotics are not required routinely in bronchial asthma exacerbation and should be given only if there is evidence of infection. Quinolones or macrolide may be used only if there is evidence of infection, though most of these are viral in origin. d) Referral criteria: The following patients should be referred to higher centre as they have a probability of developing respiratory failure and respiratory arrest. • Breathless at rest inspite of bronchodialtaors • Pulsus paradoxus > 25 mm Hg

• Peak expiratory flow < 60% predicted • Oxygen saturation < 90% • Patient getting drowsy or confused • Bradycardia (<60/min) • Severe work of breathing and fatigue. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available d) Clinical Diagnosis: as per situation 1 e) Investigation: • Arterial blood gases: In asthma normal or elevated PaCO signifies respiratory 2 failure due to respiratory muscle fatigue. pH < 7.28 would raise the need for ventilatory support

• Doppler Echocardiogram – to rule out cardiac cause of breathlessness 16

f) Treatment: • Non-Invasive Ventilation: inspite of medical treatment if respiratory status worsens NIV may be tried as a temporizing measure. IPAP reduces work of breathing and EPAP overcomes auto PEEP. Extended trials of NIV may be warranted if the sensorium and patient comfort are improving. NIPPV is more useful in patients with COPD; there is limited data on its use in acute severe asthma. • Monitor respiratory rate, SPO2, heart rate and blood pressure continuously. Reassess

every 30 mins until patient is stable and comfortable. Nursing attendance should be continuous. • Intubate if indicated o Impending respiratory arrest o Hypotension o Altered sensorium: progressive drowsiness, agitation or severe restlessness o In a conscious patient no improvement or deterioration after 3-4 hours of optimal medical therapy and NIV support o PCO2> 55 mmHg and Ph < 7.28. However more than the absolute values the

general appearance and degree of distress and fatigue of the patient are important. • Orotracheal intubation: As far a possible a tube size of 8 or more is employed and therefore orotracheal route is preferred • Sedation and paralysis: At the time of intubation short acting sedative or anaesthetic such as ketamine, propofol or midazolam and short acting neuromuscular blocking agent (succinylcholine or rocuronium) are used. For maintenance of sedation to assist MV

midazolam/ propofol infusion can be used. Neuromuscular blocking agents should be avoided as infusion to prevent critical illness neuropathy. • Initial ventilator settings Setting Recommendation Respiratory rate 10-15 breaths/rain Tidal volume 8-10 ml/kg Minute ventilation 8-10 l/min PEEP 0 cm H O 2 Inspiratory flow ≥100 l/rain I:E ratio ≥1:3 FiO2 1.00 17

The goals of ventilation are to • Maintain oxygenation (SpO2 > 90%) • Reduce work of breathing • Minimise auto-PEEP • Accept hypercarbia, do ont increase respiratory rate and tidal volume to reduce PaCO2 if it increases auto-PEEP • Monitor: Hypotension is usual after mechanical ventilation due to dehydration,use of sedative and intrinsic PEEP . It should be managed by giving fluid challenge • Pplat (plateau pressure) reflects PEEPi or dynamic hyperinflation and should be kept <

30 cmH2O. Peak airway pressure reflects only proximal airway pressure and is generally high. • Magnesium sulfate 2gms infusion over 20 mins can also be tried in refractory cases although its role is unproven. • Liberation from mechanical ventilation: o Once the airway resistance decreases as reflected by decrease in Pplat and hypercarbia, spontaneous breathing is then allowed by discontinuing paralysis and deep sedation. o PEEP may be titrated cautiously to counteract auto PEEP for easier triggering

o The patient is given spontaneous breathing trials with a T-piece or low CPAP (equal to or less than 8 cm H2O). After 30 -120 mins, if the trial is successful the ventilator is withdrawn. o In the event of failure of the trial, the patient is placed on assist-control or Pressure support modes. While on spontaneous breathing a PEEP of 5-8 cmH2O may be applied to reduce inspiratory threshold load imposed by PEEP. o Further attempts at liberation are carried out after 24 hours to allow for return of

diaphragmatic function. • Supportive Therapy. Adequate DVT prophylaxis and stress ulcer prophylaxis is mandatory in these patients. Adequate nutrition support with less carbohydrate proportion to decrease CO2 production in COPD patient is desirable. 18

VII. FURTHER READING / REFERENCES 1. Oddo M, Feihl F. Management of mechanical ventilation in acute severe asthma: practical aspects. Intensive Care Med. 2006 Apr;32(4):501-10 2. Hill NS, Brennan J, Noninvasive ventilation in acute respiratory failure. Crit Care Med. 2007 Oct;35(10):2402-7 3. K.J.R. MURTHY, J.G. SASTRY Economic burden of asthma. NCMH Background Papers·Burden of Disease in India 19

ACUTE RESPIRATORY FAILURE FN Kapadia, Consultant Physician & Intensivist, PD Hinduja National Hospital, Mumbai Minal Jariwala, Associate Intensive Care Unit Consultant, PD Hinduja National Hospital, Mumbai I. WHEN TO SUSPECT/ RECOGNIZE? e) Introduction: Respiratory Failure includes any condition that affects breathing and ultimately results in failure of the lungs to function properly. The main tasks of the lungs and chest are to get oxygen into the bloodstream from air

that is inhaled (breathed in) and, at the same to time, to eliminate carbon dioxide (C0 ) from the bloodstream through air that is exhaled (breathed 2 out). In respiratory failure, either the level of oxygen in the blood becomes dangerously low, and/or the level of C0 becomes dangerously high. 2 f) Case definition: Respiratory failure is defined as a failure of gas exchange manifestedeither as hypoxemia (PO2 <60mm Hg on room air) i.e. inadequate blood

oxygenation or hypercapnia (PaCO >45 mm Hg) i.e. excess of circulating 2 carbon dioxide or frequently a combination of both types of gas exchange abnormalities. Practically/ clinically diagnosed as respiratory fatigue. VIII. INCIDENCE OF THE CONDITION The problem in US 1. 360,000 cases per year 2. 137 cases per 100,000 population 3. With 36% failing to survive the hospitalization 20

The problem in India: not known but respiratory failure is a common occurrence either as a complication of other diseases or as a terminal event IX. DIFFERENTIAL DIAGNOSIS/ TYPES: Type 1 Type 1 respiratory failure is defined as hypoxemia without hypercapnia, and indeed the P CO may be normal or low. The basic defect in type 1 respiratory a 2 failure is failure of oxygenation characterized by: P O low (< 60 mmHg (8.0 kPa) on room air a 2 P CO normal or low a 2

This type of respiratory failure is caused by conditions that affect oxygenation such as: • Parenchymal disease (V/Q mismatch) • Diseases of vasculature and shunts: right-to-left shunt, pulmonary embolism • Interstitial lung diseases: ARDS, pneumonia, emphysema. Type 2 The basic defect in type 2 respiratory failure is characterized by: P O decreased a 2 P CO increased a 2 Type 2 respiratory failure occurs as a result of alveolar hypoventilation and

results in inability to effectively eliminate carbon dioxide. The commonest cause of type II respiratory failure is COPD. Other causes are: 21

1. Impaired central nervous system drive to breathe  Drug over dose  Brain stem injury  Sleep disordered breathing  Hypothyroidism 2. Impaired strength with failure of neuromuscular function in the respiratory system  Myasthenia Gravis  Guillian Barre Syndrome  Amyotrophic Lateral Sclerosis  Phrenic nerve injury  Respiratory muscle weakness secondary to myopathy,electrolyte imbalance, fatigue 3. Increased loads on the respiratory system

 Resistive-bronchospasm (Asthma ,Emphysema, Chronic Obstructive Pulmonary Disease)  Decreased lung compliance-Alveolar edema, Atelectasis, Auto peep  Decreased chest wall compliance- Pneumothorax, Pleural effusion, Abdominal distension  Increased minute ventilation requirement- pulmonary embolism by increase in dead space ventilation, sepsis and in any patient with type I respiratory failure with fatigue. Type 3 and 4 occur in setting of perioperative period due to atelectasis and

muscle hypoperfusion respectively. X. PREVENTION AND COUNSELING Treatment of underlying disease. XI. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA 22

*Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited e) Clinical Diagnosis: Dyspnoea at rest, tachypnoea, tachycardia, hypertension, nasal flaring, pursed lip breathing, using accessory muscle of respiration.Evidence of central / peripheral cyanosis, asterexis or severe drowsiness in case COPD is feature of severe hypercapnia f) Investigations: Pulse oxymetric assessment of SpO2 to assess blood oxygen content /

hypoxia. Chest x-ray:Details regarding evidence of consolidation, pulmonary edema, COPD and various other pathology Complete blood count, electrolytes Electrocardiogram g) Treatment:  Oxygen therapy: In the hypoxic self-ventilating patient, delivery of oxygen to the alveoli is achieved by increasing the environmental oxygen fraction (FiO2), which involves application of supplemental oxygen. Oxygen therapy will suffice if muscle strength or vital capacity is reasonable and upper airway is not compromised.

Pulse oxymetry is used to quickly titrate to the preferred levels of oxygen administration Various oxygen delivery devices: 1. Variable performance: Nasal cannula delivers oxygen at low gas flow 1-6lpm with FiO2 from 21-44 %. Best device for patient with high PCO2as no rebreathing. 23

Face maskdelivers oxygen at low gas flow 6-10lpm with FiO2 upto 50%. Nonrebreathingface maskwith reservoir bag delivers oxygen at flow rates 9-15 lpm with FiO2 from 85-90%. Delivery of oxygen is dependent on the patient inspiratory flow rates. 2. Fixed performance: Venture type mask –ensures fixed FiO2 above fixed flow. • Nebulised bronchodilators to relieve bronchospasm • Appropriate early antibiotics in case of pneumonia or in case of infective exacerbation of COPD or antimalarials or antivirals as per

case requirement. • IV steroids for acute exacerbation of COPD or bronchial asthma. • IV diuretics for acute pulmonary edema. h) Referral criteria:  Need for invasive mechanical ventilation in cases of worsening hypoxemia or respiratory muscle fatigue in spontaneous breathing patient or on NIV. (Non-invasive ventilation in secondary care hospitals to be offered only if backed up by invasive mechanical ventilation)  Need for non-invasive ventilation for worsening hypercapnic

respiratory failure in COPD patients.  Unable to wean the patient off the ventilator in 48-72 hrs in small set up.  Need for specialized treatment. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available g) Clinical Diagnosis: As per situation 1 b)Investigations:  Arteial blood gas analysis  Echocardiogram  Lung Function test (Spirometry) 24

 Ventilation Perfusion Scan  CT scan of Chest  Other investigations to look for underlying cause of respiratory failure g) Treatment:  Non invasive positive pressure ventilation or CPAP: Using a comfortable reasonably tight nasal or full face mask with ventilators used in cases of hypercapnic/ type II respiratory failure like COPD, sleep apnoea, bronchial asthma and hypoxemic respiratory failure as in acute cardiogenic pulmonary edema.  Mechanical ventilation with endotracheal intubation: Indications:

1. Type I /hypoxemic respiratory failure where the patient is unable to meet the oxygen requirements of the body or is able to do so only at a very high cost that results in haemodynamic and metabolic compromise. 2. Type II/ hypercapnic respiratory failure where the ventilarory pump has failed. Goals of mechanical ventilation • Correct hypoxemia-PO2 ~60 mmHg/ SpO2 90% • Correct hypercapnic-PCO2 ~ 40mmHg • Reduce work of breathing • Reversal of respiratory muscle fatigue.

Complication of mechanical ventilation: 1. Related to intubation: • Loss of protective airway reflexes leading to aspiration • Autonomic stimulation causing either tachycardia and hypertension or bradycardia • Hypotension in fluid depleted patients post induction with sedations. 25

2. Complication secondary to endotracheal tube:blocked ,kinked and misplaced tube,unrecognised esophageal intubation 3. Pneumothorax 4. Ventilator associated pneumonias 5. Ventilator associated lung injury like volutrauma, atelectotrauma and barotrauma. Supportive care: 1. Suctioning: Maintains airway patency Increases oxygenation and decreases work of breathing Stimulates cough and prevents atelectasis. 2. Nebulisation: Inline jet nebulizer / MDI Delivery of bronchodilator drugs in aerosolised form.

3. Humidification:Prevents drying of secretions and maintains mucociliary function. 4. Physiotherapy: Prevents atelectasis, facilitates postural drainage, and prevents complication of mechanical ventilation. 5. Care of ETT: Proper fixing of the tube, measuring cuff pressure and maintaining it less than 25 mm of Hg. 6. Nutritional support: early enteral feeding, provide adequate calories, protein, electrolytes, vitamins and fluids, care of feeding tube.

7. Stress ulcer prevention: Early enteral feeding, H2 blockers or proton pump inhibitors for prophylaxis, minimise use of steroids and NSAIDS 8. DVT prevention: DVT prevention either by low molecular weight heparin or conventional heparin or by graduated compression stockings or sequential compression device in patient where heparin is contraindicated. 9. Head end elevation of 35-45°. 10.Bowel bladder care 11. Care of eyes 12. Daily sedation interruption

13. Prevention of pressure sore: positioning, prevent soiling, use of air mattress, meticulous cleaning and good wound care. 14. Adequate Analgesia for pain 15. Infection control. 26

Weaning: Weaning is a gradual process, which involves withdrawal of mechanical ventilation and removal of artificial airway. It represents the period of transition from total ventilatory support to spontaneous breathing. Indications for weaning and extubation: 1. Resolution of disease and its acute phase 2. Patient is able to breathe spontaneously 3. Patient able to oxygenate 4. Patient able to protect the airway Criteria for weaning 1. Resolution of disease and its acute phase

2. Patient has adequate cough 3. Adequate oxygenation: PaO2 >60 mm Hg on a) FiO2 < 0.5-0.6 b) PEEP < 5-10 cm of H2O 4. Stable haemodynamics without recent increase pressor requirement. 5. Adequate mentation or no recent deterioration in neurological status. The best way to determine suitability for discontinuation of mechanical ventilation is to perform spontaneous breathing trial, which can be performed in following ways, 1. Check respiratory rate and tidal volume on no pressor- support and

calculate Rapid Shallow Breathing Index and extubate. (RSBI=respiratory rate/tidal volume in L) If RSBI <105 breaths/min/L then patient is suitable for extubation 2. A T-piece trial involves patient to breathing through T piece for a set period of time (30 min to max 180 min) The chances of successful extubation are high if patient passes the T-piece trial. 27

3. An alternative variant is the use of CPAP(continuous positive airway pressure) via an endotracheal tube, which overcomes the imposed work of breathing through ETT and prevents airway collapse. During spontaneous breathing trial (SBT) presence of any of the following amounts to failure of SBT: a. Change in mental status-somnolence, coma, agitation b. Onset or worsening of discomfort c. Severe diaphoresis d. Signs of increased work of breathing- Use of accessory muscles, thoraco- abdominal paradox.

e. Increase in heart rate >20 bpm or blood pressure > 20 mm of Hg, or any evidence of haemodynamic instability or new onset arrhythmias. If a patient fails an SBT, then it is important to look for a reason like occult heart failure, neuromuscular pathology, etc. Suitability for extubation: 1. All of the above 2. The patient with adequate cough and gag reflexes. Extubation failure: The use of post extubation non invasive ventilators has decreased the use need for re-intubation. Tracheostomy:

Tracheostomies to be considered if mechanical ventilation is expected for more than 7-10 days. 28

XII. FURTHER READING / REFERENCES • Epstein SK (2011) Acute respiratory failure. In: Bope: Conn’s Current Therapy 2011, 1st ed. Saunders: Elsevier, Section 4, pp. 233–238. • Goldman L (2011) Goldman’s Cecil Medicine, 24th ed. Saunders: Elsevier, Chapter 104, pp. 629–638. • Lellouche F (2007) Non-invasive ventilation in patients with hypoxemic acute respiratory failure. CurrOpinCrit Care 13(1):12–19. • Baudouin S, Blumenthal S, Cooper B, et al. (2002) Role of non-invasive

ventilation in management of acute respiratory failure in emergency department.Thorax 57:192–211. 29

ACUTE RESPIRATORY DISTRESS SYNDROME JV Divatia, Professor & Head, Department of Anaesthesia, Critical Care and Pain, Tata Memorial Hospital, Mumbai WHEN TO SUSPECT/ RECOGNIZE? Introduction: The acute respiratory distress syndrome (ARDS) is a sudden, life-threatening lung failure caused by an inflammatory injury to the lung that is characterized clinically by acute hypoxemic respiratory failure accompanied by pulmonary infiltrates.

Clinical disorders associated with the development of ARDS are divided into those associated with direct injury to the lung and those that cause indirect lung injury (summarized in Table 1). Severe sepsis from any cause is a common underlying disease. Falciparum malaria, leptospirosis,H1N1 influenza pneumonia,hantavirus infection, scrub typhus and severe pneumonias due to Legionella and the pneumococcus are common causes of ARDS and multiorgan failure in India.

Table 1. Clinical Disorders Associated with the Development of ARDS DIRECT LUNG INJURY INDIRECT LUNG INJURY Common causes Common causes Pneumonia Sepsis Aspiration of gastric contents Severe trauma with shock and Less common causes Multiple transfusions Pulmonary contusion Less common causes Fat emboli Cardiopulmonary bypass Near-drowning Drug overdose Inhalational injury Acute pancreatitis Reperfusion pulmonary edema after lung Transfusion of blood products transplantation or pulmonary embolectomy 30

Case definition: The American–European Consensus Conference Committee definition is commonly used. It defines a spectrum of severity ranging from a milder form of lung injury, Acute Lung Injury (ALI), to a more severe Acute Respiratory Distress Syndrome (ARDS) Table 2. 1994 American–European Consensus Conference Committee Definitions Condition Timing Oxygenation Chest Radiograph Pulmonary Artery Occlusion Pressure Acute Acute Onset PaO2/FiO2 <300 torr Bilateral Infiltrates on < 18 mmHg. when

Lung Frontal chest measured or no clinical Injury radiograph evidence of left atrial (ALI) hypertension Acute Acute Onset PaO2/FiO2 <200 torr Bilateral Infiltrates on < 18 mmHg. when Respiratory Frontal chest measured or no clinical Distress radiograph evidence of left atrial Syndrome hypertension (ARDS) INCIDENCE OF THE CONDITION IN OUR COUNTRY An early estimate by the National Institutes of Health (NIH) suggested that the annual incidence

in the United States was 75 per100, 000 population. Most studies report a mortality of 40 %-60% from ARDS with most deaths being attributed to sepsis and multi-organ failure rather than a primary respiratory cause. Recent studies have shown a decreasing mortality from this disease to as low as 36% and 34%. This may be probably related to improved and more effective strategies for ventilation and treatment of sepsis and better supportive care of the critically ill patients.

There are no reliable data from India. DIFFERENTIAL DIAGNOSIS/ TYPES:  Cardiogenic pulmonary edema  Fluid overload  Bronchopneumonia  Aspiration pneumonia  Viral pneumonia  Alveolar hemorrhage  Pulmonary contusion  Miliary tuberculosis 31

 Extensive pulmonary metastases  Vasculitis PREVENTION AND COUNSELING  Management of the underlying condition  Early mangement and control of sepsis  Prognosis is guarded with mortality of about 50% OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited Clinical Diagnosis:  Features of the underlying condition

 Breathlessness, tachypnea, respiratory distress, cyanosis, sweating, mental obtundation  Pulse oximetry show SpO2 below 90%, or is maintained above 90% only with high flow oxygen Investigations:  Blood count, cultures, Ultrasonography and other investigations to diagnose the underlying  Chest X-ray : Bilateral parenchymal infiltrates  Arterial blood gases: low PaO2, low PaO2 / FiO2 ratio  Echocardiography: normal left ventricular function, may show signs of pulmonary

hypertension and right ventricular dysfunctionin severe cases Treatment:  Treatment of the underlying illness  ALI / ARDS is not a disease of the lung alone; it is often a part of multiorgan dysfunction in systemic inflammation and sepsis. Thus ventilatory and pulmonary management are part of the overall management of the patient. Identifying and treating the inciting clinical disorder is of utmost importance while supportive therapy with mechanical ventilation gives time for the lungs to heal.

o Use tidal volume of 6 ml/kg ideal body weight (approximately 350-400 ml for average height Indian male, and 300ml for average height Indian female), respiratory rate 15-30/min o Give 5-10 PEEP  Increase PEEP and FiO2 to maintain the following goals: o Plateau Pressure Pplat< 30 cm H2O o pH of 7.25-7.35 • PaO2 55mmHg – 70mmHg, or SpO2 88%-95%  Avoid ventilator induced lung injury: do not exceed tidal volume and plateau pressure limit

 Supportive care as outlined in Chapter on Respiratory Failure and Mechanical Ventilation  Avoid fluid overload, use basic hemodynamic monitoring (see chapteron Hemodynamic Monitoring)  Mechanical Ventilation settings for Protective Lung Ventilation Variable Protocol Ventilator mode Volume assist-control Tidal volume < 6 mL/kg ideal body weight Plateau pressure Pplat< 30 cm H2O Ventilation set rate/min 6–35/min, adjusted to achieve arterial pH goal pH of 7.25-7.35 pH of 7.25-7.35 considered acceptable.

Inspiratory flow, I:E Adjust flow to achieve I:E of 1:1–1:3 Oxygenation goal PaO255-80mmHg 88% < SpO2 < 95% Fio2/PEEP 0.3/5, 0.4/5, 0.4/8, 0.5/8, 0.5/10, 0.6/10, (mm Hg) 0.7/10, 0.7/12, 0.7/14, 0.8/14, 0.9/14, combinations 0.9/16, 0.9/18, 1.0/18, 1.0/22, 1.0/24 Weaning Attempts to wean by pressure support required when FiO2/PEEP are .40/8 33

Referral Criteria  Undiagnosed underlying condition  Severe underlying illness and multiple organ dysfunction (e.g., severe sepsis, renal failure, etc)  Associated polytrauma with head injury  High FiO2 and PEEP requirement (FiO2 > 0.5 and PEEP > 10)  Requirement of deep sedation and neuromuscular blockade to allow smooth mechanical ventilation  High plateau pressures > 30 cmH2O despite tidal volume of 6 ml/kg  Development of complications such as pneumothorax, ventilator-associated pneumonia

 Inability to wean patient *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available Clinical Diagnosis: As per situation 1 b) Investigations: as per situation 1 plus  Investigations to find the source of sepsis / underlying cause of ARDS  CT scan of the Chest: alveolar filling, consolidation, and atelectasis occurring predominantly in dependent lung zone. lung injury in ARDS is non-homogeneous, and

basal, dependent lung regions are more severely affected by edema and consolidation. Treatment:  As in Situation 1 plus  Continue protective lung ventilation strategy, high FiO2 and PEEP  Permissive hypercapnia  Deep sedation and neuromuscular blockade  Recruitment manoeuvres  Prone ventilation  Nitric oxide  High frequency oscillation  Extracorporeal membrane oxygenation  Steroids may be considered but not recommended for routine use  Continue supportive Care

 Prevent ventilator induced lung injury and ventilator associated pneumonia  Start weaning the patient as soon as possible 34

Further reading: 1. Bernard GR, Artigas A, Brigham HL, et al. The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J RespirCrit Care Med. 1994;149:818-824. 2. Ware L, Matthay M. The acute respiratory distress syndrome. N Engl J Med 2000; 342:1334 3. Kollef MH, Schuster DP. The acute respiratory distress syndrome. N Engl J Med. 1995;332:27-37.

4. Pinhu L, Whitehead T, Evans T, Griffiths M. Ventilator-associated lung injury. Lancet 2003; 361: 332–40 5. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome: The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342:1301-1308. 6. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in

patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 2010;303:865e73 7. Sud S, Friedrich JO, Taccone P, et al. Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis. Intens Care Med 2010; DOI 10.1007/s00134-009-1748-1 8. The Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO)

Influenza Investigators. Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome. JAMA. 2009; 302(17):(doi:10.1001/jama.2009.1535) 9. Peek GJ, Mugford M, Tiruvoipati R, et al.Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009; DOI:10.1016/S0140-6736(09)61069-2

10. Pipeling MR, Fan E. Therapies for Refractory Hypoxemia in Acute Respiratory Distress Syndrome. JAMA. 2010;304(22):2521-2527 11. The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Efficacy and Safety of Corticosteroids for Persistent Acute Respiratory Distress Syndrome. N Engl J Med 2006;354:1671-84. 35

ACUTE LIVER FAILURE AK Baronia, Professor & Head, Department of Critical Care Medicine, SGPGI, Lucknow Introduction Acute Liver Failure (ALF) is defined as acute hepatitis (elevation in AST/ALT) accompanied by elevation in INR >1.5 and any degree of mental alteration (encephalopathy) within 12 weeks of onset of symptoms, in the absence of chronic liver disease. Its presentation is rapid, dramatic and frequently leads to death over the course of a few days in the absence of emergency liver transplantation.

Incidence The exact incidence of ALF in the Indian subcontinent is not known. However, viral hepatitis leading to acute liver failure is the commonest cause in our country. In western countries, the commonest cause of ALF is paracetamol poisoning and it is a relatively uncommon disease (e.g., it affects about 2500 patients in the United States each year). Since there is a high load of hepatotropic viruses in India, the incidence of ALF may probably be higher. Prognosis

ALF carries a high mortality rate with 15-20% survival without orthotopic liver transplantation (OLT). In developed countries, liver transplantation has revolutionized the prognosis of this disease and survival rates are in the range of 59 to 79%, with liver transplantation. Moreover, it accounts for about 5-11 % of liver transplants among adults. Hepatitis A, paracetamol overdose and ischemic insults typically present as hyper acute liver failure, and

have a relatively good spontaneous survival rate of 36%, whereas idiosyncratic drug reactions and indeterminate causes present later, with only a 14% survival rate without OLT. The other etiologies with very poor prognosis include acute hepatitis B (and other non-hepatitis A viral infections), autoimmune hepatitis, Wilson’s disease and Budd-Chiari syndrome. Patients presenting in grade III/IV encephalopathy also have a very poor prognosis. Differential diagnosis

Differential diagnosis includes severe malaria, leptospirosis, rickettsial diseases, enteric fever, and Hanta virus infection. Clinical features The initial clinical features of ALF may be non-specific, and may include anorexia, fatigue, abdominal pain, jaundice and fever before progressing to hepatic encephalopathy. Hepatic encephalopathy is graded from I to IV based on clinical features and neurological signs. 36

Grades of Hepatic encephalopathy I Changes in behaviour with minimal change in level of consciousness II Gross disorientation, drowsiness, possibly asterixis, inappropriate behaviour III Marked confusion, incoherent speech, sleeping most of the time but arousable to verbal stimuli IV Comatose, unresponsive to pain, decorticate or decerebrate posturing This grading is clinically robust and increasing grades of hepatic encephalopathy have a strong negative

correlation with outcome. The evolution to grade III/IV HE is a grave prognostic sign as this group is at risk of intracranial hypertension, and subsequent brain herniation. Clinical signs suggestive of increasing intracranial pressure include worsening of hepatic encephalopathy, systemic hypertension and bradycardia (Cushing reflex), altered pupillary reflexes and decerebrate rigidity. All of these clinical signs occur late in the clinical course. Causes Etiological category Specific causes

Viral HAV, HBV±HDV, HRV, HSV Human herpes virus 6, CMV, EBV, VZV, Parvovirus B19, Yellow fever Drug/toxin induced Paracetamol, Amanita phalloides, tetracyclines, Bacillus (dose dependent) cereus, carbon tetrachloride Drug/toxin induced Halothane, anti-tubercular therapy, co-amoxiclav, macrolides, (idiosyncratic) ofloxacin, phenytoin, valproate, statins, NSAIDs, disulfiram, metformin, dapsone, amiodarone, labetolol, methyl dopa, HAART, etoposide, ecstasy/amphetamines, cocaine, herbal remedies, etc

Vascular Ischemic hepatitis, Budd Chiari syndrome, right heart failure, veno-occlusive disease Metabolic Wilson’s disease, acute fatty liver of pregnancy, HELLP 37

Miscellaneous Autoimmune hepatitis, malignant infiltration, sepsis, heat stroke Others Cryptogenic Criteria for hospital admission All patients with clinical or laboratory evidence of moderate to severe acute hepatitis should have immediate measurement of prothrombin time and careful evaluation for subtle alterations in mentation. If the prothrombin time is prolonged by >4-6 seconds or more (INR>1.5) and there is any evidence of

altered sensorium, the diagnosis of ALF is established and hospital admission is mandatory. Criteria for ICU admission Patient with any one of the following:  Altered sensorium: Patients in grade I and perhaps, grade II encephalopathy, could be managed in a ward. However, rapidly worsening encephalopathy or grade III/IV encephalopathy warrants ICU admission.  Respiratory distress, i.e., respiratory rate >30/m.  Any evidence of gastrointestinal bleeding  Any hemodynamic instability

Optimal diagnostic criteria, investigations, treatment and referral A. Non metro/ Secondary hospital Investigations 2) Prothrombin time(PT)/INR 3) Chemistries: serum sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate, glucose 4) Liver function test: AST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin 5) Renal function test : serum creatinine, blood urea nitrogen 6) Arterial blood gas (with arterial lactate, if possible) 7) Complete blood count 8) Blood type and screen

9) Viral hepatitis serologies: anti-HAV IgM, HBsAg, anti-HEV. 10) Ultrasound abdomen to look at the echotexture of the liver and rule out chronic liver disease/ Budd-Chiari syndrome. 11) Blood culture 12) Blood smear for malaria, serology for Dengue and Widal test in selected cases (based on clinical suspicion) 38

Laboratory monitoring Frequency to repeat tests Tests Twice daily Blood glucose (bedside glucostix adequate) Daily PT, serum sodium and potassium Arterial blood gas Alternate day Blood count, serum creatinine Twice weekly Magnesium, phosphate Treatment 1) Nutrition: A carbohydrate rich diet with protein restriction (60 g/day) is recommended. If enteral feeds are not tolerated, dextrose infusion should be started. A record of intake and output should

be maintained and a positive balance of no more than 500 ml is acceptable. 2) Bowel decontamination with lactulose and antibiotic for gut sterilization (ampicillin / metronidazole / rifaximin) 3) Intravenous ranitidine or proton pump inhibitors. 4) Rehydration is required in many patients as they may be dehydrated at admission due to vomiting and anorexia. Subsequently, maintain euvolemia. 5) Careful and repeated neurological examination for grade of encephalopathy and evidence of

cerebral edema is mandatory. 6) Avoid sedation in grades 1 and 2 encephalopathy. 7) All patients in grade 3 or 4 hepatic encephalopathy should be intubated electively for airway protection. In addition, respiratory support and mechanical ventilation should be provided for those with inadequate respiratory effort. 8) Treatment for clinical evidence of cerebral edema includes: 1. Elevation of head end of the bed to 15-30° 2. Head in neutral position 3. Limiting all nonessential physical examination

4. Maintaining normotension (mean arterial pressure atleast 70-80 mm Hg) 5. Hydrotherapy for fever control; judicious use of paracetamol to control fever 6. Prevent hypo and hyperglycemia 7. Parenteral mannitol (for raised ICP) in 0.5-1 gm/kg boluses 8. Look for and correct hypercapnia and hypoxemia 9) Give one dose of vitamin K. Fresh-frozen plasma transfusion is required for bleeding manifestations, as and when required. Platelet transfusion is required for platelet counts

<10,000/mm3 or invasive procedures. 10) N acetyl cysteine should be given in patients with acetaminophen induced ALF. 11) The role of antibiotics is not definitive. However, in grades 3 and 4 encephalopathy, prophylactic antibiotics may be advisable. Third generation cephalosporin, e.g., Ceftriaxone, is adequate. 39

Referral The following are reasons for referral to a higher centre: 1) Liver transplantation: Planning for transfer to a transplant center should begin in patients with grade I or II encephalopathy because they may worsen rapidly. Early transfer is important as the risks involved with patient transport may increase or even preclude transfer once stage III or IV encephalopathy develops. 2) Renal replacement therapy: Renal replacement therapy forms an integral part of care given to all

patients with renal failure. Continuous modes of dialysis such as continuous veno-venous hemofiltration are better as hemodynamic stability is maintained and fluctuations in intracranial pressure are avoided. 3) Transfusion requirement: Patients with significant gastrointestinal bleed should be referred to an institution where blood products can be arranged adequately. B. Metro/ Super specialty situation Investigations All those listed in the previous section. In addition, the following may be added:

1) Toxicology screen including acetaminophen level 2) Serum Ceruloplasmin 3) Serum ammonia ( if possible) 4) Autoimmune markers: Antinuclear antibody, anti smooth muscle antibody, anti liver-kidney microsomal antibodies, Immunoglobulin G level 5) HIV status (liver transplant) 6) Liver biopsy (via the transjugular route) may be done, if expertise with this technique is available. Laboratory monitoring Frequency to repeat tests Tests Four times a day Blood glucose (bedside glucostix adequate)

Twice daily Serum sodium and potassium, Arterial blood gas Daily PT/INR, blood count Alternate day Serum creatinine, magnesium Twice weekly Serum phosphate, Liver function tests 40

Treatment Treatment enumerated in the previous section should be instituted. The following are recommended, in addition. 1) Enteral nutrition is preferred and should be started through a nasogastric tube. Total parenteral nutrition may be considered, in case enteral nutrition is not tolerated or there are contraindications. However, the risk of fungal infections increases with parenteral nutrition. 2) Invasive hemodynamic monitoring in the form of intra-arterial blood pressure and central venous

pressure monitoring. 3) Maintenance of adequate cerebral perfusion pressure - Keeping mean arterial pressure >80mm Hg. - PaCO in the range of 30-35 mm Hg. 2 4) In ventilated patients, sedation should be instituted to avoid coughing and bucking on endotracheal tube. Bolus of lignocaine and sedation should be given prior to suctioning. 5) Pts with renal failure should be started on continuous renal replacement therapy to minimize fluctuations in intracranial pressure during dialysis.

6) Urgent hepatic transplantation is indicated in acute liver failure where prognostic indicators suggest a high likelihood of death. 7) Artificial and bio-artificial liver devices may be used as bridge to liver transplant Complications Infection If antibiotics are not given prophylactically, surveillance for infection (including chest radiography and periodic cultures of sputum, urine and blood for bacterial and fungal organisms) should be undertaken. In

case the patient develops ascites, spontaneous bacterial peritonitis should be ruled out. A low threshold for starting appropriate anti-bacterial or anti-fungal therapy should be maintained. Bleeding Replacement therapy for thrombocytopenia and/or prolonged prothrombin time is recommended only in the setting of hemorrhage or prior to invasive procedures. Prophylactic platelet transfusions are needed only for platelet count <10,000/mm3. Criteria for referral for liver transplant

Several prognostic indicators suggest a high likelihood of mortality and in these patients, liver transplantation is the only option. Currently available prognostic scoring systems do not adequately predict outcome; neverthless, the King’s college hospital criteria (KCH criteria) have been most commonly used and most frequently tested of the several criteria proposed. 40

Kings College Hospital Criteria Etiology of ALF Criteria predicting death Acetaminophen overdose Arterial pH <7.30 OR All of the following: PT > 100 seconds (INR > 6.5) Creatinine level > 3.4 mg/dL Grade III/IV encephalopathy Non-acetaminophen PT > 100 seconds (INR > 6.5 ) overdose OR Any three of the following: Non A non B hepatitis/drug/halothane Jaundice to encephalopathy interval > 7 days Age < 10 years or > 40 years PT >50 seconds (INR >3.5) and bilirubin level >17.4 mg/dL

Prevention & Counseling: Hepatitis A & E, which spread mainly by faeco-oral contamination, can be controlled by clean and safe water supply & other hygienic measures. . Universal precautions, viral screening of blood for Hepatitis B & C should be made mandatory. Recycling of syringes should be discouraged and declared unlawful. References 1. Acharya SK, Dasarathy S, Kumer TL, Sushma S, Prasanna KS, Tandon A et al. Fulminant

hepatitis in a tropical population: Clinical course, cause, and early predictors of outcome. Hepatology 1996; 23:1448–1455. 2. Khuroo MS, Kamili S. Aetiology and prognostic factors in acute liver failure in India. Journal of Viral Hepatitis 2003; 10:224–231. 3. Dhiman RK, Seth AK, Jain S, Maheshwari U , Bhalla A, Sharma N et al. Early indicators of prognosis in fulminant hepatic failure: An assessment of the Model for End-Stage Liver

Disease (MELD) and King’s College Hospital Criteria. Liver transplantation 2007; 13:814- 821. 4. R. Todd Stravitz. Critical management decisions in patients with acute liver failure. Chest 2008; 134:1092-1102. 41

5. Trotter FJ. Practical management of acute liver failure in intensive care unit. Current Opinion in Critical Care 2009; 15:163-167. 6. O’Grady JG, Schalm SW, William R. Acute liver failure: redefining the syndromes. Lancet 1993; 342:273–5. 7. Polson J and Lee WM. AASLD Position Paper: The Management of acute liver failure. Hepatology 2005; 41:1179-1197. 8. Craig DG, Lee A, Hayes PC, Simpson KJ. Review article: Current management of acute liver

failure. Alimentary Pharmacology & Therapeutics. 2010; 31(3):345-58. 42

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1)Non- 1. Gastroenterologist 1) Once : GE serology Drugs: 3 generation Monitor with ECG, metro or a general cephalosporin, proton pump NIBP, SpO 2 physician on daily 2) Daily: PT, serum inhibitor, lactulose, sodium, potassium, ABG

basis mannitol. 3) Twice daily: blood Fentanyl ,midazolam, Ventilator glucose atracurium 2. One nurse per shift 4) Alternate day: blood Consumables : count, serum creatinine Blood Gas Analyzer 18 G velflon (2), Foley’s 5) Twice weekly: LFT, catheter, uroflow meter. 3. Intensivist for Magnesium, phosphate, those who develop Chest x- ray Ventilator tubings, grade III – IV HME(2), Endotracheal COST: 1st day: Rs. 2500- encephalopathy tube, 3000 catheter mount, suction catheters

Subsequent days: COST: 1st day: Rs. 3000- 5000 Rs. 1000-1500/day Subsequent days: Rs. 1000-2000/day 2)Metro As in situation 1 1) Four times a day Blood All of the above plus As in situation 1 glucose (bedside glucostix adequate) 7 fr triple lumen Central venous catheter, mersilk, Plus Plus 2) Daily: PT/INR, blood tegaderm, single lumen count, serum sodium, CVC, 20g velflon. potassium, Pressure Transducers(2) 4. Surgeon with Dialysis machines , 3) Twice daily : Serum expertise in liver Liver Transplant

transplant Arterial blood gas Angiography sheet and Fully equipped advance ICU with 4) Alternate day: Serum Surgical gown. ventilator creatinine, magnesium 5. Anaesthetist with expertise in liver 5) Twice weekly :Serum COST: 1st day*: Rs. 8000- transplant phosphate, Liver function 10000 tests Subsequent days*: 6) Once :special Rs. 2000-4000 per day investigations as listed in above document 6. Radiologist COST: 1st day: Rs. 3000- *Excluding dialysis 5000 7. Nephrologist Cost of each session of

Subsequent days: Rs.1000- CRRT= Rs. 15, 000 3000/day Note: Cost calculated above does not include oxygen/ventilation costs/hospital and physician charges 44

BRAIN DEATH TEST AND ICU MANAGEMENT FN Kapadia, Consultant Physician & Intensivist, PD Hinduja National Hospital, Mumbai Rishi Kumar Badgurjar, Associate Intensive Care Unit Consultant, PD Hinduja National Hospital, Mumbai WHEN TO SUSPECT/ RECOGNIZE? Introduction: It is important to recognize and diagnose brain death especially in patients who are potential organ donors. Early diagnosis, documentation and initiation of the organ donation process and

appropriate management of brain-dead organ donorsforms an important part of intensive care unit management. Definition Brain death is defined as the irreversible loss of all function of the brain, including the brainstem. The three essential findings to confirm brain death are coma (known irreversible cause), absence of brainstem reflexes, and apnea. An evaluation for brain death should be considered in patients who have suffered a massive,

irreversible brain injury of identifiable irreversible cause as established by history, clinical exam, lab testing or neuroimaging (CT scan or MRI). Once brain death criteria are met a person clinically determined to be brain dead is legally dead in the context of organ donation under the Transplantation of Human Organ Act 1994. Always consider Medico legal, philosophical and religious perspective. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA

Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited The diagnosis of brain death is primarily clinical. No other tests are required if the full clinical examination, including each of two assessments of brain stem reflexes and a single apnea test, are conclusively performed. In the absence of either complete clinical findings consistent with

brain death, or confirmatory tests demonstrating brain death, brain death cannot be diagnosed. 45

Differential Diagnosis Neurologic states that can mimic brain death • Locked-in syndrome (Present in case of GBS); Patient cannot move the limbs, grimace or swallow, but blinking and vertical eye movements remains intact. • Vegetative state; No awareness of self and environment using a series of stimuli after CPR may take 1 month to become fully apparent and is permanent if no change after 3 months is observed. Investigation Brain death Examination Exam prerequisites

1. Irreversible loss of clinical brain function. (Definitive cause leading acute brain catastrophe compatible with diagnosis of brain death evidenced on clinical or neuroimaging) 2. Achieve Systolic Blood Pressure>100mmHg and core body temperature C (>90°F). 3. Exclusion of confounding factorin prognostication. • Drugs (sedatives or neuromuscular blocking agents). • Intoxication. • Hypothermia (induced hypothermia therapy). • Shock. Brain death test

• Sufficient time period has been passed to exclude possibility of possible recovery of meaningful neurological function, several hours to days as per clinical factors. • The relevant family member or appropriate party has been notified of the intention to initiate the determination of brain death. • Neurological exam then proceeds with aim of determining three principle findings in brain death: coma, absence of brainstem reflexes and apnea (coma and apnea must coexist).

• Two physician as per local institutional protocol do the brain death test • The second physician should not be involved in the patient’s care. • Neither physician should be involved with organ transplantation. • Intensivist, neurologist or any physician competent doing brain death test appointed by the institute as per local law can do the brain death test, both physician do the test individually. Determination of unresponsiveness(Coma)

• Absence of supraspinal motor response to pain in all extremities and no eye opening to pain (standardized painful stimuli - supraorbital pressure, TMJ pressure, sternal rub and nail bed pressure) Glasgow coma scale 3/15. 46

Examination of brain stem reflex Pupillary reflex • Dilated pupils at mid position (4–6 mm). • Absence of bilateral pupillary responses to light. Ocular movement • Absent oculocephalic reflex (doll’s eye ) • Absent cold caloric responses (vestibulo-ocular reflex) Absent Facial sensory and motor response Absent Pharyngeal reflex and Tracheal reflex • Absence of gag reflex. • Absence of coughing in response to tracheal suctioning. Apnea test Prerequisites • SBP>100mmHg.

• Core body temperature >36.5°C(>97°F). • Euvolemia with appropriate fluid balance in the previous 6 hours. • Normal PaO2. • Normal PaCO2. Procedure • Connect SpO2 probe and preoxygenation at 100% Fio2 for 10 minutes, draw baseline ABG, Pao2 >200 mmHg and Paco2 ~40mmHg (may require to reduce ventilator rate to get eucapnia) is needed. • Disconnect the ventilator. • Delivering oxygen by tracheal catheter at carina with flow of 6 liters per minute or T-

piece system using 12 l/min O2 flow or use CPAP of 10 cmH2O (less hypoxia with CPAP method). • Observe the chest and the abdominal wall movement for respiration for 8 to 10 minutes and monitor the patient for changes in vital functions. • Rate of rise of PaCO2 is 3mmHg per minute so 8 – 10 minutes are sufficient for apnea test to get rise of 20 mmHg of PaCO2. • Draw post test ABG and then reconnect the ventilator. • Positive apnea test - Absence of respiratory drive at a Paco2 of 60 mm Hg or 20 mm Hg

above normal base-line values, apnea is confirmed. • If respiratory movement occurs or any sign of hemodynamic instability, abandon the test, draw sample for ABG and then reconnect the ventilator. 47

Ancillary test Routine use is not recommended. Observation period between two examination Depends on the age of the patient; • 7 days to 2 month old minimum 48 hr interval. • 2 month to 1 year old minimum 24 hr interval. • >1 year to <18 years old minimum 12 hr interval. • >18 years old, interval is optional, minimum 6 hr. Number of Confirmatory tests • Neonate < 7 days Brain death testing is not valid. • 7 days to 2 months old, 2 confirmatory tests. • >2 months to 1 year old, 1 confirmatory test.

• >1 year to <18 years old, optional. • >18 years old, optional. Brain death declaration • If clinical criteria’s are met. • No need of confirmatory test. Documentation of brain death • Etiology and irreversibility of condition. • Absence of brainstem reflexes. • Absence of motor response to pain. • Absence of respiration with Paco2 ≥ 60 mm Hg. • Timing of first and repeat neurologic examination. • Justification for confirmatory test and result of confirmatory test.

• Brain death time - time of rise of Pao2 >60mmHg after second set of test. • Two physician signatures should be obtained. Primary or secondary health care centre • Brain death test are clinical. • Brain death can be declared at these centers if all three criteria’s are fulfilled. Communication with family and further decision making After the clinical criteria of brain death have been met, the physician should inform the next of

kin, who can be approached about organ donation. The physician is required to abide by state law with respect to organ donation. Treatment • Basic intensive care, cardivascular, respiratory, hemodynamic and metabolic support Routine ICU care and monitoring • Nursing care. • Skin care. 48

• Turning and positioning. • Care of lines. • Ryle’s tube to prevent risk of aspiration. • Pulse oximetry. • Arterial and central venous pressure monitoring. • Pulmonary artery catheter placement If necessary. • Foleys catheter for urine out put monitoring. • Core temperature monitoring. • Antibiotic therapy. • Anticipation of complications. • Prevention and treatment of complications. • Frequent assessment and titration of therapies. • Nutrition. • Maintenance of vital organ function; • Resuscitation.

• Oxygen delivery to the tissues. • Hydration and perfusion. • Routine laboratory testing ABG, CBC, SE, BUN, Cr and LFT. • Testing for HIV, HBV & HCV on all donors after first apnea test. • Additional tests may be necessary as per local protocol. • Support of the family. Counseling • The family should be counseled that the patient cannot recover • Family should be counseled for organ donation • If the patient cannot become an organ donor, withholding or withdrawing of life support

may be discussed with the family. Referral Criteria • If the patient is a potential organ donor, he should be transferred to a tertiary level centre that is certified by the competent authority and is capable of supporting the brain dead organ donor • If in some cases further diagnostic studies are required to confirm brain death o Difficulty to determine coma. o Incomplete brain stem reflex testing. o Incomplete apnea testing. o Toxic drug levels. o Facial trauma. o Preexisting pupillary abnormality.

o Sleep apnea or severe pulmonary disease resulting in chronic retention of CO 2 . o Children younger than 1 year old (<1 year age not recommended). o As required by institutional policy. 49

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical Diagnosis: As per situation 1 b) Investigations: as per situation 1 plus • EEG • Bispectral index (BIS) • SSEP • Neuroimaging • Cerebral angiography (CTA, MRA) when ICP exceeds MAP angiography demonstrates absence of blood flow beyond carotid bifurcation. • Cerebral scintigraphy (technetium tc-99m brain scan) o Noninvasive study also knownas a cerebral blood flow study.

o Absent uptake of isotope in brain parenchyma is supportive of a diagnosis of brain death- Hollow skull phenomenon. o Single photon emission computed tomography(SPECT) at 48 hrs is 100 % diagnostic. • In case of barbiturate coma neuroimaging can be used without the necessary wait (5 half life provided normal renal and hepatic function) for the medication to leave the system. • Transcranial Doppler Ultrasonography However, the clinical criteria of brain stem death are considered adequate under the

Transplantation of Human Organ Act and special investigation are not mandatory to declare brain stem death in India. Treatmentas in Situation 1 above plus ICU management of Brain dead organ donor ICU management of the potential organ donor plays a key role in maintaining and increasing current number of donor organs aim is to improve organ survival. • Early identification of potential donors; o Critically ill patient in an intensive care unit - severity of acute brain injury is

such that there is a high probability of brain death occurring. • Early notification of Organ Procurement Organization(OPO), State Authorization Committee, Zonal Transplant Coordinating Centre (ZTCC) or Local Authorization Committee(LAC)as per institutional protocol. • Designated requestor – OPO or LAC coordinator, as per institutional protocol. • Requesting consent to organ donation from the family are ethical and professional responsibilities of the intensive care specialist. • Preparation of the family.

• Consider family’s psychological, religious and cultural needs. • Enquiring about the stated wishes of the patient. • Ensuring the wishes, dignity and privacy of the donor are respected. 50

• Provide sufficient information and time. • Support family to make an informed decision concerning organ donation without undue pressure. • Clarification of ongoing physiologic support despite brain death. • The family should have adequate emotional and social support after giving consent to organ donation and during the follow up period. • Details of all discussions with the families should be documented. Supportive treatment should start early as soon as brain death has been recognized irrespective of

the consent.Switch the focus of the management for elevated intracranial pressure and brain protection, to preservation of organ function and optimization of tissue oxygen delivery. Hemodynamic support Hypertension • Hypertension and bradycardia preceding brain death characterize the Cushing’s response. • Ischemia of the vagal nucleus in the medulla oblongata results in uncontrolled sympathetic stimulation- catecholamine “storm” results in systemic hypertension,

tachycardia and possibly tissue ischemia including; o Pituitary ischemia. o Myocardial injury - right and/or left ventricular dysfunction. • Duration and severity of this “storm “ varies but within hours results in depletion of catecholamine with subsequent generalized vasodilatation and homodynamic collapse. • Initial period of severe HTN – short acting ß-blocker esmolol. Hypotension Most common problem seen in brainstem dead organ donors.

• Chronic maintenance phase of brain stem dead donors is frequently characterized by hypotension. • Invasive monitoring of arterial and central venous pressure should be instituted. • Proper fluid management is the cornerstone of therapy; o Fluid resuscitation may require several liters of fluid. o Combination of crystalloids and colloids is used. o Relying on urine output alone to determine adequacy of fluid resuscitation is misleading because of polyuria due to diabetes insipidus. • Vasopressors;

o If possible use of vasopressors should be minimized because of their splanchnic vasoconstrictive effects. o The first choice is usually Dopamine, preferably at a dose below 10mcg/kg/min. o Dobutamine should be used for impaired myocardial contractility; and o Norepinephrine or Epinephrine for severe systemic vasodilatation. • In donors who remain unstable despite routine management, pulmonary artery catheterization may help in determining the problem.

• Rule of 100’s for management of brain death organ donor; o SBP 100 mmHg o U/O 100 ml/hr o PaO2 100 mmHg 51

o Hb 100 g/L Arrhythmias • Brady arrhythmias and tachyarrhythmia are common after brain death. • Brady arrhythmias occurring as part of the Cushing reflex, during coning, do not require treatment. • Correct acidosis, electrolyte abnormalities and try to optimize Inotropes. • Atropine is ineffective for Brady arrhythmias after brain death has occurred. Respiratory support Ventilatory support • Increase ET cuff pressure immediately after BD declaration. • HOB up 30°. • Turning q2h. • Pulmonary toilet.

• Paco2 should be maintained in the normal range. • Routine use of PEEP at 5 cm H2O in brainstem dead organ donors is recommended to prevent microatelectasis. • Plateau pressures should <35cmH2O to reduce the risk barotrauma. • FiO2 <0.6 to reduce the risk of oxygen toxicity. • PaO2 of >100 and a saturation >95%. • Monitor ABG’s q2h or as required. • Chest X-Ray. • Bronchoscopy in some cases. • CT chest in some cases Renal support • Maintain urine output 1-3 ml/kg/hr. • Avoid nephrotoxic drug.

• Maintain Euvolemia. • Oliguria; o Despite adequate filling pressures and blood pressure, loop diuretics or osmotic diuretics should be used to initiate diuresis. • Polyuria, a frequent finding in brainstem dead organ donors; • Diabetes insipidus. • Osmotic diuresis due to mannitol or hyperglycemia. • Physiologic diuresis due to massive fluid resuscitation. • Hypothermia. • Hypokalemia. 52

Neuro-Endocrine changes As neurologic death occurs, alteration in the hypothalamic-pituitary-adrenal axis (HPA axis) is inevitable. Diabetes insipidus • DI results in problems with homodynamic stability and fluid and electrolyte balance; o Urine volumes exceed 300ml/hr (or 7ml/kg/hr). o Hypernatremia (serum sodium greater than 150mEq/l). o Serum osmolality (>310mOsm/L). o Low urinary sodium concentration. • Desmopressin (dDAVP) preferred; o (DDAVP) 1 mcg IV, may repeat x 1 after 1 hour.

o 1-4 mcg every 8 to 12hrly SC. o Nasal spray. • Vasopressin - splanchnic and renal vasoconstrictive effects. o 1-4 units/hr. • Hypernatremia (>155mEq/L) o Free water, i.e. D5% or half strength 0.45% Saline. Hyperglycemia • Insulin 0.05-0.1U/kg/hour titrated to maintain glucose at 80-120. • Hourly glucose checks so as to avoid hypoglycemia. Thyroid hormone replacement • Thyroid hormone administration typically with T3 (triiodothyronine) which is the active form of thyroid hormone.

• T3 is converted from T4 and T3 is 4 X more active than T4 • Use T3 preferably if not available use T4 (T3 dose 0.05-0.15 mcg/kg/hour) titrate to keep SBP >100 • Monitor Potassium levels closely. Steroid • Protocols may use hydrocortisone 1.5 mg/kg IV Q 6 hours (max dose of 100 mg) or single dose of methylprednisolone 15 mg/kg in adults and 1 mg/kg in children (max dose of 2 gm). • The use of hormonal replacement therapy, Thyroxin, triiodothyronine (T3), corticosteroid

and insulin, has been advocated to improve cardiovascular stability. At present, such therapies are regarded as experimental. Studies regarding ACTH and cortisol levels inconclusive. Unclear whether steroids make any significant improvement in organ preservation. Hypothermia • Core temperature should be monitored using rectal thermometers. • Maintain above 35°C. • If core temperature <35°C 53

• Warm inspired gas. • Warmed IV fluids. • Warming lights. • Warming blankets. • Hot packs in the axilla. Infection • Systemic infection is a relative contraindication to organ donation. • All unnecessary indwelling devices should be removed. • All lines and catheters must be inserted aseptically. • Care of dressings and wounds is vital. • Tracheal suction should be done with sterile precautions. • Appropriate samples from suspected sources of infection should be sent for culture and sensitivity.

• Prophylactic antibiotics are indicated only immediately prior to organ retrieval. Coagulopathy • If clinically significant mucocutaneous bleeding, treatment with appropriate blood components is required. • Keep hematocrit > 30%. Ischemic reperfusion injury • Keep FiO2 <0.6. • Avoid hyperthermia (>37°C). • Avoid hyperglycemia (>180 mg/dl). • Steroid and N-acetylcysteine may have sort term and long organ survival. Absolute Contraindications to organ donation

• Malignancy (except primary brain tumors, low grade skin malignancies and carcinoma in situ of the cervix). • Uncontrolled sepsis. • Active viral infections-hepatitis A and B, CMV, HSV, AIDS. Age and Organ Harvesting • Corneas 0 - 100 years (poor eyesight is not a contraindication). • Heart Valves 0 - 60 years (Heart Attack not a contraindication). • Trachea 15 - 60 years. • Skin 16 - 85 years. • Kidneys 0 - 75 years (Pediatric donors consider weight and size).

• Liver 0 - 70 years (size matching is usually recommended). Organ Preservation Time • Heart – 4 to 6 hours. • Lungs – 4 to 6 hours. 54

• Small Intestines – 4 to 6 hours. • Liver - 12 hours. • Pancreas – 12 to 18 hours. • Kidneys-72 hours. Documentation • Cause of irreversible brain injury. • Absence of other potentially reversible causes of coma. • Clinical and other findings that confirmed brain death. • Time of brain death. • Information to the patient's family on brain death and organ donation. • Consent for organ or tissue donation. • Signatures required • Medical officer treating the patient.

• Neurologist/Neuro Surgeon (Where Neurologist/Neurosurgeon are not available, then anaesthetist/intensivist). • Authorized Specialist (from panel of experts approved by the Appropriate Authority). • Medical Administrator In charge of the hospital. Conclusion A severe shortage of organs the world over has led to increased pressure on the intensive care staff for early identification of the brain dead donor and optimum management of this condition.

The diagnosis of brain death as per the Transplantation Human Organ Act 1994 is based on simple clinical bedside tests,no need of routine confirmatory test. This Act has made it possible in India to use this pool of patients for organ retrieval and transplantation. The process of organ donation and transplantation requires co-ordination between multidisciplinary teams operating almost simultaneously and sometimes in different locations like getting surgeons from different

specialties together for both donor and recipient surgery. Further reading • Evidence-based guideline update: Determining brain death in adults : Report of the Quality Standards Subcommittee of the American Academy of Neurology Eelco F.M. Wijdicks, Panayiotis N. Varelas, Gary S. Gronseth, et al. Neurology 2010;74;1911 • The Dead Donor Rule and Organ Transplantation Robert D. Truog, M.D., and Franklin G. Miller, Ph.D. N Engl J Med 2008; 359:674-675

• Transcranial Doppler Ultrasonography to confirm brain death: a meta-analysis Louisa M. MonteiroCasperW. BollenAlexanderC. vanHuffelenRobG.A. AckerstaffNicolaas J. G. Jansen Adrianus J. van Vught Intensive Care Med (2006) 32:1937–1944 • NEW YORK STATE DEPARTMENT OF HEALTH, GUIDELINES FOR DETERMINING BRAIN DEATH, DECEMBER 2005 55

• Donohue KJ, Frey KA, Gerbaudo VH, Nagel JS, Shulkin B. Society of Nuclear Medicine Procedure Guideline for Brain Death Scintigraphy. J Nucl Med. 2003 May; 44(5): 846- 51. • Wijdicks EF. The diagnosis of brain death. N Engl J Med. 2001 Apr 19; 344(16): 1215- 21. • The Role of Thyroid Hormone Administration in Potential Organ Donors Ali Salim, MD; PantelisVassiliu, MD; George C. Velmahos, MD; Jack Sava, MD; James A. Murray, MD;Howard Belzberg, MD; Juan A. Asensio, MD; DemetriosDemetriades,

MD Arch Surg. 2001;136:1377-1380 • Wijdicks EF. Determining brain death in adults. Neurology. 1995 May; 45(5): 1003-11. • Reliability in diagnosis of brain death A. Paolin,A. Manuali,F. Di Paola,EBoccaletto, P. Caputo, R Zanata, G.P. Bardin,G. Simini Intensive Care Med (1995) 21:657-662 • Brain death: timing of apnea testing in primary brain stem lesion, G. Schwarz , G. Litscher , G. Pfurtscheller , H.V. Schalk , E. Rumpl and G. Fuchs Intensive Care Med (1992) 18:315-316 56

EVALUATION OF NEW FEVER IN THE CRITICALLY ILL PATIENT Subhash Todi, Consultant Physician and Intensivist, AMRI Hospital, Kolkata 1. When to suspect? Recognize? a. INTRODCTION:New onset of fever in Intensive care unit is a very common finding, and triggers a response of various investigations and addition of new antibiotics which may not be needed many times. This leads to increasing cost and adds to increased utilizations of resources. All new fevers in ICU should be

evaluated in a prudent and cost effective manner. b. CASE DEFINITION. i. In non-immunosuppressed patient two consecutive temperature (core) of more than 101° F warrants further investigation. ii. In neutropenic patient a single temperature of 101° F should be considered important iii. New onset of fever below this range, in a hemodynamically stable patient requires a bedside assessment to look for a source of infection and non infectious fever and sending investigation appropriately. iv. Recording fever

1. All patients in ICU should have hourly recording of temperature and recorded in nursing chart. 2. Uniformity of scale (Centigrade or Fahrenheit should be maintained) 3. The site of temperature recording should be recorded (Oral, axillary, rectal or tympanic) 4. Larger ICUs should have access to core temperature (rectal, tympanic or bladder) measurement device 5. The instrument should be properly calibrated and sterilized. Thermometers should not be shared between patients to reduce cross infection

2. Incidence of the condition in our country 30% patients become febrile during hospitalizations. Up to 90% critically ill patients with severe sepsis experience fever during ICU stay. ICU patients will generally present a newly elevated temperature at some point during their stay. Fever in ICU could be infectious, non-infectious or mixed origin and confirmation of source is difficult. A prudent, cost-effective assessment is necessary. 3. Differential diagnosis: Non-infectious causes of fever

b. Cardiac: MI, Pericarditis c. Pulmonary: Atelectasis, PE, fibro-proliferative phase of ARDS d. Hepatobiliary & GIT: Acalculus cholecystitis, acute pancreatitis, active Crohn’s disease, toxic megacolon, alcoholic hepatitis e. Rheumatologic syndromes: Vasculitis, SLE, RA, Good pasture's syndrome f. Endocrine: Hyperthyroidism, adrenal insufficiency, phaeochrocytoma g. Other miscellaneous non-infectious causes: i. Drug fever ii. Transfusion reactions iii. Neoplasms iv. Malignant hyperthermia

v. Neuroleptic malignant syndrome vi. Serotonin syndrome vii. Opioid withdrawal syndrome viii. Alcohol withdrawal syndrome ix. Devitalized tissue secondary to trauma x. Hematoma h. Infectious causes of fever i. CNS: Meningitis, Encephalitis, Brain abscess, Epidural abscess ii. Head & Neck: Acute suppurative parotitis, Acute sinusitis, ASOM, Para and retropharyngeal abscesses. iii. CVS: Endocarditis, Catheter related infection iv. Pulmonary & Mediastinal: Pneumonia, Empyema, Mediastinitis

v. Hepatobiliary & GIT: Appendicitis, Diverticulitis, Peritonitis, Intraperitoneal abscess, Perirectal abscess, Infected pancreatitis, Acute cholecystitis, Cholangitis, Hepatic abscesses, Acute viral hepatitis vi. Genitourinary: Bacterial or fungal cystitis, Pyelonephritis, Perinephric abscess, Tubo-ovarian mass, Endometritis, Prostatitis vii. Breast: Mastitis, abscess viii. Cutaneous: Cellulitis, Suppurative wound infection, Necrotizing fasciitis, Bacterial myositis, Herpes zoster

ix. Osseous: Osteomyelitis 4. Prevention & Counseling Staff working in the ICU should be familiar with drug fever and non- infectious causes of fever. Strict asepsis, hand hygiene measures & universal precautions can bring down the infection related fevers. Regular surveillance can help in identifying non-compliant staff, which can be appropriately counseled. 5. Optimal Diagnostic Criteria, Investigations, treatment & referral criteria

*Situation1: At secondary Hospital/ Non-Metro situations: Optimal standards of treatment in situations where technology & resources are limited. a. Clinical Diagnosis: 58

i. Patients are not febrile: euthermic or hypothermic (cid:224) with life-threatening infection: 1. Elderly 2. Open abdominal wound 3. Large burns 4. Patients on ECMO, CRRT 5. CHF 6. End-stage liver disease, CRF 7. Patients on anti-inflammatory or antipyretic drugs. ii. Symptoms and signs in the absence of fever, which mandate a comprehensive search for infection and aggressive, immediate empirical therapy: Unexplained hypotension, tachycardia, tachypnea, confusion,

rigors, skin lesions, respiratory manifestations, oliguria, lactic acidosis, leukocytosis, leukopenia, immature neutrophils (i.e., bands) of 10%, or thrombocytopenia a. Key elements in evaluation: History & physical examination. Look at wounds, surgical incision sites, vascular access and pressure ulcers. Obtain/review Chest Xray, look for new infiltrates or effusions. Appropriate lab studies: Cultures, WBC, PBS. Remove CVC > 96 hrs

Send tip for semi quantitative culture.Send stool sample in patients on ABx for> 3 days.C difficile toxin. Diagnostic thoracocentesis, paracentesis, LP, Ultrasound/CT 4. INITIAL ASSESSMENT a. Focused history and bedside review of nursing chart and patients notes should be done. A detailed medication history, line manipulation, blood transfusion, appearance of new rash, diarrhea, or any new procedure performed should be enquired

b. Focused physical examination should be performed looking for any source of sepsis or non-infectious cause of fever. c. Common infectious causes of new fever in ICU Hospital acquired or Ventilator associated pneumonia- Intubated for more than 48 hours. New fever, purulent secretion, bronchial breathing Central line sepsis-Line in place for more than 48 hours Erythema, purulent discharge at central line site. Urinary catheter related infection – Catheter more than 48 hours in place,suprapubic

tenderness cloudy urine Surgical site infection – purulent discharge from wound site Sinusitis- Nasogastric or nasotracheal tube, purulent nasal discharge 59

Parotitis- poor oral hygiene, unilateral tender parotid swelling A calculus cholecystitis- abdominal tenderness, intolerance of feed d. Common non infectious causes of fever in ICU Rash- drugs (antibiotics,antiepileptics, NSAIDSetc.) Unilateral painful swelling of limb- Deep Venous thrombosis Thrombophlebitis 5. INVESTIGATION Investigation to be performed (in all facilities) a. Total and differential white count b. Peripheral smear for toxic granules c. CRP

d. Blood culture – All ICUS should have a protocol for sending blood culture. Recommendation for blood cultures: • CULTURE NUMBER- Obtain 3 to 4 blood cultures within the first 24 hrs of the onset of fever (cid:224) first cultures before the initiation of antimicrobial therapy (cid:224)drawn consecutively or simultaneously, (cid:224)endovascular infection (cid:224) separate venipunctures by timed intervals can be drawn to demonstrate continuous bacteremia.

• Additional blood cultures to be drawn only: (cid:224)clinical suspicion of continuing or recurrent bacteremia or fungemia or(cid:224)? for test of cure, (cid:224) 48–96 hrs after initiation of appropriate therapy for bacteremia/fungemia. • Additional cultures should always bepaired. • For patients- without an indwellingvascular catheter(cid:224) at least 2 blood cultures using strict aseptic technique from peripheral sites (cid:224) by separate venipunctures after appropriate disinfection of the skin.

• For cutaneous disinfection, 2% chlorhexidine gluconate in 70% isopropyl alcohol is the preferred skin antiseptic; tincture of iodine is equally effective. Both require -30 secs of drying time before the culture procedure. Povidone iodine is an acceptable alternative; (cid:224)it must be allowed to dry for 2 mins. 60

e. Wound swab for gram stain, culture and sensitivity f. Endotracheal suction for gram stain C & S (semiquantitative) g. Urine for gram stain C&S (semi-quantitative) h. Central line tip for C&S i. Chest x-ray j. Abdominal USG k. X-ray sinus l. Transthoracic echocardiogram Investigation to be performed in tertiary care center. a. Procalcitonin b. Chest CT c. Bronchoscopy with lavage d. CT sinus e. CT abdomen for any collection f. Four sets of blood culture g. Blood for fungal culture

h. Stool for c. difficile toxin e. MIC or e-test of antibiotics f. Venous Doppler of legs g. Transesophageal Echocardiogram 6. MANAGEMENT. It will depend on the underlying cause. Non specific treatment with antipyretic should be instituted in patients with central nervous system disorder, extremes of age, poor cardiac reserve. Referral Criteria: If higher diagnostic tests and imaging techniques are not available and the patient is not improving, transfer to well equipped centres should be undertaken.

Suggested Reading 1. Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases Society of America. Naomi P. O’Grady, MD; Philip S. Barie, MD, MBA, FCCM; John G. Bartlett et al 61

Crit Care Med 2008; 36:1330–1349 2. Fever in ICU. Paul E Marik. CHEST 2000; 117:855–869 3. Clinical practice guidelines for the diagnosis and management of intravascular catheter- related infection: 2009 Update by the Infectious Diseases Society of America. Mermel, LA, Allon, M, Bouza, E, et al Clin Infect Dis 2009; 49:1. 4. CDC/NHSN surveillance definition of healthcare-associated infection and criteria for specific types of infections in the acute care setting. Horan, TC, Andrus, M, Dudeck,

HEMODYNAMIC MONITORING IN THE ICU JV Divatia, Professor & Head, Department of Anaesthesia, Critical Care and Pain, Tata Memorial Hospital, Mumbai Sheila NainanMyatra, Associate Professor, Department of Anaesthesia, Critical Care and Pain, Tata Memorial Hospital, Mumbai WHEN TO SUSPECT/ RECOGNIZE? h) Introduction: Hemodynamic monitoring is an integral part of ICU care. Need for invasive monitoring should be assessed carefully. Attention to technical details correct interpretation of data, and its

application in selecting therapy should be individualized within the clinical context. a) Case definition: For both situations of care Basic hemodynamic monitoring: In any Secondary Hospital / non-Metro setup • Clinical examination- Central and peripheral pulses, Manual blood pressure- look at the trend, compare with patients normal values, capillary refill, core temperature, peripheral temperature at extremities • Noninvasive- Noninvasive blood pressure, Pulse oximetryplethysmographic signals

• Intraarterial pressure • Central venous pressure • Hourly urine output • Screening Echocardiography • Base deficit (ABG) • Central venous oxygen saturation 63

Advanced hemodynamic monitoring in selected cases: In Superspeciality facility in a Metro location • These should be initiated in patients on high vasopressors, high ventilator support, compromised cardiac and renal function, and where empirical fluid challenge may be harmful. These modalities include o Cardiac output- minimally invasive Pulse contour analysis (e.g. Flotrac, PICCO, LiDCO) Esophageal Doppler • Pulmonary artery catheter o Pulmonary artery occlusion pressure o Continuous cardiac output

o Continuous mixed venous oxygen saturation (SvO2) o Derived and calculated variables o Pulse pressure/ Stroke volume variation o Continuous Scvo2 monitoring o Lactate levels Standard Operating Procedure *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited ARTERIAL CANNULATION The ability of invasive blood pressure monitoring to identify beat to beat variability and long term trends

is unsurpassed by any other currently available technology. In addition, presence of arterial catheter enables frequent sampling of arterial blood without arterial punctures in critically ill patients. INDICATIONS: a) Hemodynamic monitoring - beat to beat monitoring of blood pressure • acutely hypertensive or hypotensive patients (shock) • use of vasoactive drugs • cardiac and cardiovascular surgery • induced hypotension - pulse contour cardiac output monitoring

b) Frequent arterial blood gas sampling: critically ill patients including ventilated patient c) Arterial administration of drugs, thrombolytics d) Intra aortic balloon pump use 64

e) Noninvasive blood pressure monitoring not possible – e.g., too obese, burned extremity ABSOLUTE AND RELATIVE CONTRAINDICATIONS:  Severe injury to the limb  Lack of collateral circulation  Coagulopathy  Arteriovenous fistula in the same limb • Pre-existing vascular insufficiency (Raynaud’s phenomenon)  History of surgery disrupting lymphatic drainage to that limb e.g., mastectomy with lymph node dissection Equipment:  Appropriate intravascular catheter

 Fluid filled noncompliant tubing with stopcocks  Transducer  A constant flush device  Electronic monitoring equipment Site selection:  The common sites of arterial line insertion are the radial, femoral, and dorsalis pedis arteries.  Other sites: axillary dorsalis pedis brachial, ulnar, posterior tibial and superficial temporal arteries Arterial Cannulation:  The arterial line can be inserted using a simple catheter-over-needle arrangement (with or

without a guidewire) or a set based on the Seldinger technique.  Doppler or ultrasound can be helpful for difficult line insertion. Set up of the pressure tranducing system o The pressure transducing assembly consists of a coupling system, pressure transducer, amplifier and signal conditioner, analog to digital converter, microprocessor which convert the signal received from the vein or artery into a waveform on the a bedside monitor

o The flushing system – is set up using a 500 ml saline bottle encased in a bag 65

pressurized to 300 mm Hg. At this pressure the catheter will be flushed with 3 ml saline per hour and help keep the catheter patent. Heparinised saline is no longer routinely used • The reference point is usually at the level of the heart where the transducer is zeroed. RESOURCES REQUIRED FOR ONE PATIENT/PROCEDURE (PATIENT WEIGHT 60 KGS) SITUATION HUMAN INVESTIGATION DRUGS AND EQUIPMENT RESOURCES OF 4-6 WEEKS CONSUMABLES FOR 4- 6 FOR 4-6 WEEKS WEEKS 66 noitautis ortem-non/latipsoh yradnoces tA .1

One Each: Once a week or 1. Drugs for 4-6 1. Ultra more for 4-6 week week- Rs. 2000 sonography 1. Intensivist / long therapy machine Anaesthetist 2. Lab a. Ultrasound investigation- Rs. 2. Invasive 2. ICU 2000 arterial Technician 1. Doppler of the pressure cannulated artery 3. Consumables- monitor Rs.7000 2. For arterial One in each canulation shift: b. Arterial tip 1. ICU/Ward culture (femoral Doctor arterial line) 2. Nurse c. Blood culture 3. Attendant

67 noitacol ortem ni ytilicaf ytlaiceps repus tA .2 As in situation As in situation 1 a. For simple As in situation 1 situation 1 with 1. drugs for 4-6 1. Long arterial weeks-Rs.2000 catheter 2. Lab 2. Arterial investigation-Rs. catheter with 5000 guide wire b. For difficult situation 1. use of long catheter for arterial canulation- Rs.6,000 2. USG guided arterial canulation and using special arterial catheters with wire-guide - Rs.8,000 RESOURCES REQUIRED FOR ONE PATIENT/PROCEDURE (PATIENT WEIGHT 60 KGS)

REFERENCES: 1) Textbook of critical care, 5th edition. Fink MP, Abraham E, Vincent JL, Kochanek PM. 2) Intensive care medicine, 6th edition - Irwin and rippe’s 3) Anaesthesia and analgesia, Ahmed F Ghouri, Aug 2002. 4) Clinical anaesthesiology, 5th edition – Morgan, Mikhail, Murray. 5) Arterial Line Placement (Anesthesia): Editor(s): Lee A. Fleisher, MD, FACC, FAHA | Robert Gaiser, MD 6) March 1973 - Volume 38 - Issue 3> Complications of Percutaneous Radial-artery

Cannulation: 1973 American Society of Anesthesiologists, Inc. 7) Journal of the American College of Surgeons Volume 201, Issue 1 , Pages 18-22, July 2005

Central venous catheter insertion and Central Venous Pressure Monitoring Definition: Insertion of a catheter in a central vein, usually the superior vena cava, but also in the inferior vena cava or right atrium. Indications: In recent years, central venous cannulation is practiced increasingly in anaesthesia and intensive care for a variety of indications Measurement of Central Venous Pressure (CVP)  Major surgery  Anticipated major blood loss  Anticipated major fluid shifts

 Significant cardiac disease  Significant pulmonary disease  Pulmonary hypertension Intravenous access  Rapid administration of fluids and blood  Administration of Vasoactive agents and concentrated potassium infusions  Measurement of central venous oxygen saturation during resuscitation from shock  Measurement of cardiac output using some semi-invasive techniques  Total parenteral alimentation  Administration of Chemotherapeutic and other irritant drugs  Frequent blood sampling

 Insertion of a pulmonary artery catheter  Inability to cannulate peripheral veins Therapeutic procedures  Insertion of transvenous pacemaker  Insertion of catheters for haemodialysis and plasmapheresis  Aspiration of air emboli Sites of central venous cannulation: The subclavian and internal jugular veins are the most commonly cannulated veins. Other veins that may be used are the arm veins (basilic, cephalic), external jugular and femoral veins. Equipment Required In all situations:

 Appropriate intravascular catheter o catheter over guidewire using the Seldinger technique o cather through needle or cannula o long cannula over needle  Fluid filled noncompliant tubing with stopcocks  Transducer  A constant flush device  Electronic monitoring equipment  Chest X-ray at the end of the procedure to confirm position of the CVC and rule out pneumthorax In a superspeciality hospital in a Metro: in addition to the above  Location of the internal jugular vein by ultrasound

• Portable ultrasound machine with a high frequency probe • Ultrasound probe with or without a needle guide • Sterile jelly • Sterile sleeve for ultrasound probe • Antibiotic coated catheter may be used in case there is high risk of catheter related blood stream infection o Immunosuppressed patient o High baseline CRBSI rate in the unit o Anticipated prolonged duration of cannulation Clinical Utilization of CVP Measurement

 CVP is influenced not only by the volume status, but also by myocardial contractility, afterload, intrathoracic and intra-abdominal pressures.  A single measurement of the CVP helps somewhat in defining circulatory status but leaves considerable overlap in possible interpretations. Hence single values of CVP should not be relied upon. Instead, response to fluid challenge and the trend of values should be used in clinical decision making,  It is best not to remove PEEP for measurements.

• DO NOT subtract half or any other proportion of PEEP value to the CVP measurement to get an approximate of “true” CVP  In a non mechanically ventilated patient CVP of 8 -10 mm Hg is judged to be adequate. Fluid Challenge  A controlled fluid challenge and response of CVP is the best method of interpreting volume status. The fluid challenge is performed in 4 steps: o Select the type of fluid: usually normal saline or a colloid

o Infuse rapidly. Rate of infusion: 500ml of crystalloid or 200 ml of colloid over 20-30 minutes o Target the Desired therapeutic response: the parameters are set empirically by the physician. These could be mean arterial pressure (MAP >70mmHg), HR <100/min, hourly urine output > 0.5ml.kg/hr. 69

o Set the Danger / safety limits. Again set empirically by the physician. E.g. CVP 16mmHg, or 4-5mmHg more than the baseline value o Assess the response to the initial bolus of fluid o Repeat bolus infusion of fluid if § Therapeutic target not reached AND § Danger CVP value is not reached o Discontinue fluid infusion if § Therapeutic target is achieved OR § Danger value of CVP is reached o Reassess at frequent intervals  Another way to perform a fluid challenge is to see the change in CVP in response to a

fluid bolus. As a rule of thumb if the increase in CVP measured before and 5 minutes after a fluid bolus is 0-3 mmHg, more fluid should be given. If it is 3-5 mmHg he is probably adequately filled. If the CVP increases >5mmHg after the fluid bolus, fluid loading should be stopped. 70

RESOURCES REQUIRED FOR ONE PATIENT/PROCEDURE (PATIENT WEIGHT 60 KGS) SITUATION HUMAN INVESTIGATION DRUGS AND EQUIPMENT RESOURCES OF 4-6 WEEKS CONSUMABLES FOR 4- 6 FOR 4-6 WEEKS WEEKS 71 ortem-non/latipsoh yradnoces tA .1 noitautis One Each: Once a week or 1. Drugs for 4-6 1.Ultra more for 4-6 week week- Rs. 2000 sonography 1. Intensivist / long therapy machine Anaesthetist 2. Lab a. Ultrasound investigation- Rs. 2.Muliparameter 2. ICU 2000 monitor with Technician 1. Doppler of the invasive pressure

vein 3. Consumables- monitoring One in each Rs.8000 shift: 2. For CVC: 1. ICU/Ward a. Blood count Doctor b. CVC tip culture c. 2. Nurse Blood culture 3. Attendant ortem ni ytilicaf ytlaiceps repus tA .2 noitacol As in situation As in situation 1 a. For simple As in situation 1 1 situation with 1. drugs for 4-6 weeks-Rs.2000 2. Lab investigation-Rs. 7000 b. For difficult situation 1. antibiotic coated catheter 2000-4000 2. USG guided canulation

Echocardiography  While resuscitation efforts are underway , a quick assessment with bedside echocardiogram can guide clinician in rationalizing use of volume resuscitation, inotropes and vasopressors . This can be repeated to assess response to therapy.  Using bedside Echocardiogram one can assess o The Left ventricular (LV) function, o Right Ventricular (RV) function, o Presence of pericardial effusion and tamponade, o Pre load assessment, fluid responsiveness o Valve lesions. Equipment requirement

Portable Echocardiography / Ultrasound machine with Probe : Rs. 15,00,000.00 *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available Pulmonary artery catheter insertion and monitoring Introduction: Swan &Ganz introduced the balloon tipped pulmonary artery catheter into clinical practice in early seventies. This brought the catheter out of the domain of radiologists and at the

bedside of the patients in intensive care. Notwithstanding the controversies regarding the utility of pulmonary artery catheter in improving outcome, the clinician in the operating room and ICU needs to conversant with the use of pulmonary artery catheter. Indications for insertion of PAC: Pulmonary artery catheterization can be used for diagnostic purpose, to monitor therapy, and to evaluate the effects of drugs. The indications for PAC insertion are:  Management of complicated myocardial infarction

• Hypovolemia vs cardiogenic shock • Ventricular septal rupture (VSR) vs acute mitral regurgitation • Severe left ventricular failure • Right ventricular infarction • Unstable angina 72

• Refractory ventricular tachycardia  Assesment of respiratory distress • Cardiogenic vs non-cardiogenic pulmonary edema  Primary vs secondary pulmonary hypertension  Assessment of type of shock  Assessment of therapy • Afterload reduction • Vasopressors • Beta blockers • Intra-aortic balloon counterpulsation  Assessment of fluid requirement in critically ill patients • Hemorrhage • Sepsis • Acute renal failure • Burns  Management of postoperative open heart surgical patients

• Assessment of valvular heart disease • Assessment of cardiac tamponade/constriction  Contraindications / Cautions: • Coagulopathy • Inexperienced clinician • Pulmonary hypertension Pulmonary artery catheter insertion can only be performed at well equipped tertiary care centres. Use of the Pulmonary Artery Catheter The 4 most important measurements obtained from the PAC are • Pulmonary artery occlusion pressure (PAOP) • Pulmonary artery diastolic pressure (PADP) • Thermodilution cardiac output

• Mixed venous oxygen saturation • The fluid challenge (as described with CVP) remains the best method of assessing the PAOP during mechanical ventilation with PEEP. Mixed venous oxyen saturation (Svo2) / Central venous oxygen saturation (ScvO2)  . An SvO below 65% implies low oxygen delivery, while a value below 60% indicates 2 that there is a serious risk of tissue hypoxia if corrective measures are not taken.  A low SvO (< 40 % ) implies critical oxygen supply / demand imbalance. In some 2

disease states, cells in some tissues are unable to assimilate and/or process the needed oxygen. 73

 If SvO is high(>80%) then the demand has declined, the O supply has increased, or the 2 2 cells are unable to utilize oxygen.  Thus a falling or low SvO is an important indicator that the oxygen delivery is 2 compromised and is deficient relative to the needs of the tissues.  An alternative is to measure central venous oxygen saturation (ScvO ). Central venous 2 catheterisation is a simpler and safer procedure, and is commonly used.

 In this case a catheter is positioned in the Superior vena cava or upper Right atrium.  The goals of early resuscitation , within six hours of septic shock is to keep SVo2 > 65% or Scvo2 > 70%  SvO2 and ScvO2 can be measured continuously with oximetric catheters, or blood can be drawn intermittently and the analysed using a co-oximeter on the blood gas machine Cardiac Output monitoring Cardiac output is the amount of blood being pumped to the body by the heart every minute. In

some patients, cardiac output monitoring may be useful to ake a diagnosis and to refine therapy. Cardiac output monitoring should be perfromed only in well equipped tertiary care centres. Indications  Management of complicated myocardial infarction • Hypovolemia vs cardiogenic shock • Severe left ventricular failure  Assessment of type of shock  Septic shock  Assessment of therapy • Afterload reduction • Vasopressors • Beta blockers • Intra-aortic balloon counterpulsation

 Assessment of fluid requirement in critically ill patients • Hemorrhage • Sepsis • Acute renal failure • Burns  Management of postoperative open heart surgical patients Methods of monitoring cardiac output  Thermodilution (intermittent or continuous) using the pulmonary artery catheter has been the classical method of cardiac output monitoring. However insertion of a pulmonary artery catheter is demanding and complicated. Other less invasive methods include 74

 PiCCO: usingbolustranspulmonary thermodilution cardiac output and pulse contour derived continuous cardiac output measurement are obtained. A central venous catheter, special thermistor tipped femoral artery catheter and monitor are required.The main advantages over the pulmonary artery catheter is PiCCO is far less invasive, easy to place requiring routine skills of placing a central line and arterial line. The additional

advantages are the values of extravascular lung water, global end-diastolic volume and the stroke volume variation (a dynamic measure of preload).  Lithium Dilution Cardiac Output (LidCO): uses lithium dilution technique, instead of transpulmonary thermodilution (used by PiCCO). The principle of pulse contour analysis for continuous cardiac output measurement is similar. o Advantages: Existing arterial line and venous lines can be used, even central

venous access is not mandatory. Therefore cardiac output monitoring can be established fast. o Disadvantages: requires lithium injection  Flotrac: Arterial Pressure based Cardiac output (APCO) system calculates the stroke volume from pulse pressure, which is the standard deviation of blood pressure. A special transducer is connected to an existing arterial line and the cardiac output monitor. o Advantages: does not require a central venous catheter or any bolus injection to

estimate cardiac output, easy and rapid set up Preload Responsiveness  Preload responsiveness is the increase in cardiac putput in response to fluid loading.  Dynamic parameters predict the response to fluid loading without having to give a fluid challenge. Hence they may avoid the potential hazards of a fluid challenge.  Stroke volume variation, Systolic pressure variation and Pulse pressure variation with respiratory cycle and are referred to as dynamic indicators of preload responsiveness.

 Values>13% is indicative of fluid responsiveness  These parameters are available on minimally invasive cardiac output monitors such as Flotrac, PICCO, LIDCO.  Visible variation in the diameter of the inferior vena cava on echocardiography can also be used to predict fluid responsiveness.  SPV, PPV and SVV cannot be used in patients with spontaneous breathing activity and / or with arrhythmias. They are not reliable in patients ventilated with low tidal volume

and in patients with increased intraabdominal pressure  In these cases Passive leg raising is an alternative choice.  Passive leg raising maneuver is an endogenous fluid challenge. A continuous monitor of stroke volume or SVV / PPV is required. Increase in stroke volume > 10%, increase of Aortic blood flow >10% in response or decrease in SVV / PPV after PLR predict a good response to fluid loading 75

A comparison of the costs of Disposables required for the Pulmonary artery catheter (PAC), Flotrac and PICCO is given in Table 2: Table 2: Costs of Disposables for cardiac output monitoring PAC PiCCO Flotrac (Cost in Rs) (Cost in Rs) (Cost in Rs) Essential disposables 9500 9000 9500 (CCO-SvO2catheter ) Transducers 2 1 0 Total cost 1500 750 0 CVC 0 1000 0 Art. Line 70 0 70 Saline, syringes 400 200 200 Total Initial Set up 11,470 12750 9770 Cost (Does not Add Presep include capital cost of continuous

hemodynamic ScvO2 catheter monitors) 8000 Total: 17700 Daily monitoring cost 4500-5000 4500-5500 3500-4000 (based on an average of 3 days monitoring, 6000-7000 does not include including professional fees) Presep Further reading: 1. Otto CW. Central venous pressure monitoring. In, Blitt CD, Hines RL (editors). Monitoring in Anesthesia and Critical Care Medicine, 3rdedn, Churchill Livingstone, New York. 76

2. Leatherman J, Marini JJ. Pulmonary artery catheter: pressure monitoring. In, The pulmonary artery catheter: methodology and clinical applications, Sprung CL, editor, 2nd edition, 1993. 3. Pinsky MR. Pulmonary artery occlusion pressure Intensive Care Med (2003) 29:19-22 4. Pinsky MR. Clinical significance of pulmonary artery occlusion pressure Intensive Care Med (2003) 29:175-178 5. Chaney JC, Derdak S. Minimally invasive hemodynamic monitoring for the intensivist:

Current and emerging technology Crit Care Med 2002; 30:2338 –2345 6. Berton C, Cholley B. Equipment review: New techniques for cardiac output measurement – oesophageal Doppler, Fick principle using carbon dioxide, and pulse contour analysis. Critical Care 2002, 6:216-221 7. Leatherman J, Marini JJ. Pulmonary artery catheter: pressure monitoring. In, The pulmonary artery catheter: methodology and clinical applications, Sprung CL, editor, 2nd edition, 1993.

8. Jardin F. Cyclic changes in arterial pressure during mechanical ventilation. Intensive Care Med 2004; 30:1047–1050 9. Antonelli M, Levy M, Andrews PJF, et al. Hemodynamic monitoring in shock and implications for management International Consensus Conference, Paris, France, 27–28 April 2006. Intensive Care Med 2007; 33:575–590 10. Reinhart K, Kuhn HJ, Hartog C, Bredle DL Continuous central venous and pulmonary artery oxygen saturation monitoring in the critically ill. Intens Care Med 2004; 30:1572-8

11. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M. Early goal directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368–1377. 12. De Backer D. Lactic acidosis. Intens Care Med 2003; 29: 699-702. 77

ACUTE PULMONARY EMBOLISM (PE) Rajesh Chawla, Consultant Physician and Intensivist, Indraprastha Apollo Hospital, Delhi I. WHEN TO SUSPECT/ RECOGNIZE? i) Introduction: Venous thromboembolic conditions leading to acute respiratory failure is common in critically ill medical and surgical patients. This may be the presenting diagnosis on ICU admission or may develop secondarily in patient admitted to ICU for other conditions. PE presentation is variable

presenting suddenly as a cardio respiratory arrest or may be asymptomatic .Mortality can be reduced by prompt diagnosis and therapy . Despite significant advances in the prevention and treatment of VTE, pulmonary embolism remains the most common preventable cause of hospital death, being responsible for approximately 150,000 to 200,000 deaths per year in the United States j) Case definition: For both situations of care (mentioned below*)

PE refers to obstruction to main pulmonary artery or one of its branches by material (e.g., thrombus, tumor, air, or fat) that originated elsewhere in the body. This topic review focuses on PE due to thrombus. PE can be classified as acute or chronic. Patients with acute PE typically develop symptoms and signs immediately after obstruction of pulmonary vessels. In contrast, patients with chronic PE tend to develop slowly progressive dyspnea over a period of years due to pulmonary hypertension

II. INCIDENCE OF THE CONDITION IN OUR COUNTRY The incidence of DVT in India as reported is one percent of the adult population after the age of forty and is 15% to 20% in hospitalized patients. The risk of DVT is 50% in patients undergoing orthopedic surgery, particularly involving the hip and knee, and it is 40% in patients undergoing abdominal or thoracic surgery. 1/100 who developed DVT can develop PE which can be fatal. As per India-specific ENDORSE data presented at Geneva, 1 of 2

hospitalized patients in India is at high risk of developing VTE at any point in time. 78

 An autopsy data from PGI Chandigarh, where 1,000 consecutive autopsies were performed between 1997 and 2002. 14.4% showed evidence of pulmonary thromboembolism (PTE). 1.45 % of all hospital deaths were due to PTE  The mean age was 37 years with a male preponderance in the ratio of 1.82:1  Clinical suspicion was present in 29.17 % of cases  The most common underlying cases were o Sepsis (40.28%) o Respiratory illness (10.42%) o Malignancies (9.72%) o Renal disease (8.3%) o Hepatobiliary disease (7.64%)

o Cardiovascular disorder (6.94%) o Gastrointestinal tract disorder (3.47%) o Vasculitis (2.78%) III. DIFFERENTIAL DIAGNOSIS /TYPES Acute PE can be further classified as massive or sub massive: • Massive PE causes hypotension, defined as a systolic blood pressure <90 mmHg or a drop in systolic blood pressure of ≥40 mmHg from baseline for a period >15 minutes. It should be suspected anytime there is hypotension accompanied by an elevated central venous pressure (or

neck vein distension), which is not otherwise explained by acute myocardial infarction, tension pneumothorax, pericardial tamponade, or a new arrhythmia.  All acute PE not meeting the definition of massive PE are considered submassive PE.  A saddle PE is a PE that lodges at the bifurcation of the main pulmonary artery into the right and left pulmonary arteries. Most saddle PE are submassive.  Acute PE should be differentiated from other causes of acute breathlessness o Pneumonia o Pneumothorax

o Acute Left Ventricular failure o Acute exacerbation of COPD o Acute bronchial asthma IV. PREVENTION AND COUNSELING 79

Most of the acute PEs originate from deep venous thrombosis (DVT) of legs. Assessing patients at risk for DVT and preventing its occurrence decreases the incidence of acute PE Assess the risk factors for PE and deep venous thrombosis (DVT) from past medical history as mentioned below:  Prior venous thromboembolism. • Immobility for more than 48 hours—congestive heart failure, septic shock, surgery with general anesthesia, on mechanical ventilation.  Abdominal or lower extremity surgery or trauma.

 Hypercoagulable states.  Malignancy.  Spinal cord injury.  Heparin-induced thrombocytopenia.  Pregnancy or use of oral contraceptives.  Indwelling central venous catheters  Obesity  Congestive heart failure Initiate adequate DVT prophylaxis  Unfractionated heparin(UFH) 5,000 I.U. twice or thrice daily subcutaneously. • Fractionated Low molecular weight heparin – enoxaparin 40 mg sub cut once daily or equivalent  Fondaparinaux

 In patients with high risk of bleeding mechanical methods like intermittent pneumatic compression or graduated stockings may be tried. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited i) Clinical Diagnosis: 80

• PE should be suspected in all patients who present with new or worsening dyspnea, chest pain, or sustained hypotension without any other obvious cause • ASSESS CLINICAL PROBABILITY OF PE: Clinical probability of PE is based on either clinical judgment or clinical decision rules (Wells and Revised Geneva Score) mentioned below. Therevised Geneva score: F Age older than 65 years (1 point) F Previous deep venous thrombosis or pulmonary embolism (3 points) F Surgery or fracture within 1 month (2 points)

F Active malignant condition (2 points) F Unilateral lower limb pain (3 points) F Hemoptysis(2 points) F Heart rate F 75 to 94 beats/min (3 points) or F 95 beats/min or more (5 points) F Pain on lower-limb deep venous palpation and unilateral edema (4 Points) The probability is assessed as follows: F Heart rate Low-probability (0 to 3 points) F Intermediate-probability (4 to 10 points) F High-probability (> or =11 points) j) Investigations:

 ECG, XRAY CHEST (PA view) and ABG should be ordered in all these patients. Although these tests are nonspecific they do increase the index of suspicion. k) Treatment:  Provide oxygen to maintain saturation at more than 90% 81

 If the patient is hypotensive, administer 500 to 1000 ml isotonic crystalloid. Any more volume resuscitation should be given with caution as it may increase RV wall tension and cause ischemia and worsening of shock.  While diagnostic confirmation is awaited, anticoagulant treatment withsubcutaneouslow molecular weight heparin or intravenousunfractionated (UFH) heparin should be initiated as soon as possible in patients with a high clinical probability of PE if there are no contraindications.

 UFH is preferred in hemodynamically unstable patients in whom thrombolytic therapy is being planned. UFH is also preferred in critically ill patients in the ICU with PE requiring numerous procedures. It is also preferred in patients with renal failure. Patients are considered to be hemodynamically unstable if they are in shock or have a systolic blood pressure of less than 90 mm Hg or a drop in systolic pressure of more than 40 mm Hg for more than 15 minutes in the

absence of new onset arrhythmia, hypovolemia, or sepsis Most patients with acute PE are candidates for initial anticoagulant treatment with subcutaneous low- molecular-weight heparin or fondaparinux or intravenous UFH. LMWH and Fondaparinux are preferred over UFH. The usual doses of Anticoagulation for PE are: 1) UFH: Bolus of 80units IV/kg or 5000 IU followed by infusion at 18 units IU /kg/hr. Keeping APTT between 1.5 and 2.5 to normal. 2) Weight based normogram of heparin infusion 3) Fondaparinux:

- Weight < 50kg - 5mg s/c once a day. - Weight 50-100kg - 7.5mg s/c once a day - Weight >100 kg – 10mg s/c once a day. 4) Enoxaparin: 1 mg /kg s/c twice a day. 82

a) Referral criteria: • All patients with massive PE should be referred to a higher centre The risk of adverse outcome is also more in the following situations and these patients should be referred : o Shock (SBP < 90mmof Hg) and/or BP drop >= 40mm of Hg for >15min and sustained hypotension. o Immobilization due to neurological disease. o Age 75 years or more. o Cardiac, renal or respiratory disease or cancer

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available h) Clinical Diagnosis: As per situation 1. i) Investigations: • If the patient has a high probability of PE clinically or on the basis of a high probability score, and is safely transferable to CT room and is in a position to cooperate with breath holding, he should undergo multidetector CT (MDCT) for CT Pulmonary Angiography irrespective of his hemodynamic status.

• If the patient is hemodynamically unstable and has a high probability of PE clinically or on the basis of a high probability score and who is critically ill and can not be shifted, he should be subjected to Trans-esophageal Echo (TEE,), lower extremity ultrasonography and his blood sample sent for a D- Dimer level.A negative Echo and Venous Doppler, however, do not rule out clinically significant PE.Efforts should be made to stabilize this

patient hemodynamically and once the patient stabilizes, he should be sent for MDCT CT Pulmonary Angiography, if doubt still remains about the diagnosis. • If the patient is hemodynamically stable and has a low or medium probability score then order a high sensitivity D- Dimer level (ELISA). If it is positive (level more than 500ng/ml) further testing with CT chest is indicated. 83

• If it is negative the risk of PTE is very low (0.14%) and no further testing is required. • A V/Q scan may be done in patients with a high probability of PE and where there is a contraindication for CT like renal failure or if CT scanning is not available. • In pregnant women with clinical findings suggestive of PE, an MDCTchest should be done. The concern about radiation is overcome by the hazard of missing a potentially

fatal diagnosis or exposing the mother and fetus to unnecessary anticoagulant treatment. Multidetector CT delivers a higher dose of radiation to the mother but a lower dose to the fetus than V/Q scanning. Venous ultrasonography can be done in these patients before MDCT. j) Treatment: CONSIDER THROMBOLYSIS: a) If the patient is hemodynamically unstable: i. Admit in ICU ii. Start anticoagulation, preferably IV unfractionated heparin or LMWH. Keep APTT time 1.5-2.5 to normal.

iii. Administer thrombolytic therapy if there are no contraindications (Table1). iv. Other supportive measure to stabilize the patient. b) Hemodynamically stable patients with right myocardial dysfunction and injury suggested by TEE and markers (raised Troponin and BNP) can also be given thrombolytic therapy if there are no contraindications (Table 2). CONSIDER SURGICAL TREATMENT Table 1 Thrombolytic therapy regimens for acute pulmonary embolism Drug Protocol

Streptokinase 250,000 U IV (loading does during 30 mins; then 100,000 U/h for 24 hours 84

Urokinasea 250,000 U IV (loading does during 10 mins; then 2,000 U/lb/h for 12 to 24 hours IV, intravenous; tPA, tissue-type plasminogen activator. 100 mg IV during 2h Hemodynamically stable patient with PE without myocardial dysfunction or injury: (cid:216) Admit in ward. (cid:216) Anti-coagulate with LMWH or Fondaparinux or UFH. (cid:216) Closely watch for vitals and respiratory distress. Consider early mobilization. Table2 Contraindication for thrombolytic therapy: Absolute contraindications

§ Prior intracranial hemorrhage (ICH) § Known structural cerebral vascular lesion § Known malignant intracranial neoplasm § Ischemic stroke within 3 months § Suspected aortic dissection § Active bleeding or bleeding diathesis (excluding menses) significant closed-head trauma or facial trauma within 3 months Relative contraindications § History of chronic, severe, poorly controlled hypertension § Severe uncontrolled hypertension on presentation (SBP >180 mm Hg or DBP >110 mm Hg)

§ Traumatic or prolonged (>10 min) CPR or major surgery less than 3 weeks § Recent (within 2-4 wk) internal bleeding § Non compressible vascular punctures § For streptokinase/anistreplase - Prior exposure (more than 5 d ago) or prior allergic reaction to these agents § Pregnancy § Active peptic ulcer § Current use of anticoagulant (e.g., warfarin sodium) that has produced an elevated international normalized ratio (INR) >1.7 or prothrombin time (PT) >15 seconds 85

INITIATE VITAMIN K ANTAGONIST (WARFARIN) THERAPY: (cid:216) Vitamin K antagonist should be initiated as soon as possible preferably on the first treatment day and Heparin should be continued. Heparin should be discontinued when INR reaches a level of 2.0 or higher for at least 24 hours. Duration of treatment is from 3 to 6 months. (cid:216) LMWH is preferred over Warfarin in Cancer and in pregnant women for longterm treatment. : Inferior vena caval filters are indicated in the following conditions:

(cid:216) Recurrent thromboembolism despite anticoagulant therapy (cid:216) Contraindication to anticoagulation therapy (cid:216) Bleeding while on anticoagulants. Patient should be put on long term anticoagulant treatment in the following conditions: (cid:216) Idiopathic pulmonary embolism (cid:216) Recurrent PE (cid:216) Cancer VI. FURTHER READING / REFERENCES 1. Kakkar N, Vasishta RKPulmonary embolism in medical patients: an autopsy-based study. ClinApplThrombHemost. 2008 Apr;14(2):159-67

2. Giancarlo Agnelli and Cecilia Becattini. Acute Pulmonary embolism .N Engl J Med 2010;363:266-74 3. Jamie l Todd and Victor F Tapson. Thromolytic therapy for pulmonary embolism Chest 2009;135:1321-1329 4. Antithrombotic therapy for venous thromboembolic disease. Chest2008; 133:454-545. 86

SEVERE SEPSIS AND SEPTIC SHOCK FN Kapadia, Consultant Physician & Intensivist, PD Hinduja National Hospital, Mumbai Rishi Kumar Badgurjar, Associate Intensive Care Unit Consultant, PD Hinduja National Hospital, Mumbai I. WHEN TO SUSPECT/ RECOGNIZE? k) Introduction: Sepsis(from Greek sepein = to rot, putrefy)is a significant problem worldwide in the intensive care unit both in terms of the burden on the healthcare and the morbidity and the mortality it

causes. Despite the advances in the treatment and the understanding of the pathophysiology of sepsis, the mortality has remained unforgivably high. The site of infection is difficult to estimate and even among those patients where the site is strongly suspected, cultures might be negative or of questionable significance. Though a positive blood culture would be diagnostic, the rate of positivity is only 30 to 50 % percent. It is easy to confuse the diagnosis of sepsis with conditions

that simulate it such as pancreatitis or anaphylactic reactions or drug fever. Early identification and prompt treatment is the key to reduce mortality a) Case definition: Till 2001 there was no clear definition of sepsis. As a result there was no uniformity in the treatment guidelines. International sepsis forum defined sepsis in the following way Systemic inflammatory response Two or more of the following variables syndrome (SIRS) (1) fever > 38°C (100.40°F) or hypothermia <36°C (96.80°F)

(2) tachypnea (>20 breaths/min) or PaCO2 < 32 mmHg (3) tachycardia (heart rate >90 beats/min) (4) Leukocytosis or leucopeniai.eWBC > 12,000 cells/mm3, < 4,000 cells/mm3 or > 10% immature band forms 87

Sepsis Systemic inflammatory response syndrome that occurs due to a “known or suspected” pathogen (bacteria, virus, fungal or parasite) Severe sepsis Sepsis plus evidence of organ dysfunction or tissue hypoperfusion as follows – (1) Altered mental status. (2) ALI PaO2/FIO2 <250 (3) Thrombocytopenia < 100,000/ (4)Bilirubin >2mg/dl (5) INR >1.5 or aPTT> 60 seconds. (6) Urinary output of 0.5 ml/kg for at least 2hr or Scr>2mg/dl despite fluid resuscitation.

(7) Tissue hypoperfusion as suspected by mottled skin, Capillary refilling time ≥ 2 seconds or lactate >4 mmol/l (8) Hypotension Systolic blood pressure ≤90 mmHg or mean arterial pressure ≤70 mmHg. Sepsis induced hypotension SBP<90mmHg or MAP<70mmHG or SBP decrease >40mmHg Septic shock Sepsis induced hypotension despite adequate fluid resuscitation. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY The incidence of sepsis and the number of sepsis-related deaths are increasing,

although the overall mortality rate among patients with sepsis is declining. The mortality rates associated with severe sepsis and septic shock are 25% to 30% and 40% to 70% respectively Though we do not have exact statistics from India, one Indian study showed incidence of SIRS without organ dysfunction as 51.60%, SIRS with organ dysfunction as 17.10% patients, of which 76.50% were due to sepsis and 23.50% were not due to sepsis. ICU mortality of all admissions was 13.90% and that of severe 88

sepsis was 54.10%. Hospital mortality and 28-day mortality of severe sepsis were 59.30% and 57.60%, respectively. III. DIFFERENTIAL DIAGNOSIS Severe Sepsis and Septic shock should be differentiated from other common cause of fever and shock in ICU or hospital like - 1) Acute pancreatitis. 2) Drug fever. 3) Anaphylaxis and anaphylactoid reactions. 4) Adrenal crisis. 5) Cardiogenic shock, hemorrhagic shock or neurogenic shock. 6) Pulmonary embolism or pulmonary infarct. 7) Myxedema coma. 8) Thyrotoxicosis.

9) Poisoning or insect bite. 10) Burn, major surgery 11) SLE crisis. 12) Macrophage activation syndrome. Although making the distinction of the above conditions from true sepsis becomes difficult, using different biomarkers and imaging studies might be helpful in making the diagnosis. Close monitoring and optimising the patient physiological variables will give us time to identify the exact insult. IV. PREVENTION AND COUNSELING

Sepsis is a medical emergency. Awareness and recognition are the key of survival.The following action plan should be used to reduce global mortality from severe sepsis.  Build awareness of sepsis. 89

 Follow standards guidelines of care.  Improve early and accurate diagnosis.  Increase the use of appropriate treatments and interventions.  Educate staff about sepsis diagnosis, treatment and management.  Data collection for the purposes of audit and feedback V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited Clinical Diagnosis:

The presentation of sepsis varies. The most important step towards improving survival is to identify the signs of sepsis very early. General variables:  Altered mental status.  Fever.  Hypothermia.  Tachycardia.  Tachpnea.  Hyperglycaemia (plasma glucose >120 mg/dL or 7.7mmol/L) in the absence of diabetes.  Positive fluid balance. Inflammatory variables:  Leukocytosis.  Leukopenia.  Normal WBC count with >10 % band forms. Organ dysfunction variables: • Respiratory –Decreased oxygen saturation

• Renal – Acute oliguria urine output <0.5ml/kg/hr for atleast 2 hrs or rise in Creatinine > 0.5 mg/ dL. • Haematological- Thrombocytopenia (platelet count <100,000/ µL) or coagulation abnormalities: International Normalised Ratio INR >1.5 or activated partial thromboplastin time aPTT > 60 sec.  Liver - Hyperbilirubinemia (plasma total bilirubin>4.0 mg/ dL or 70 mmol/ L). Tissue perfusion variables: 90

 Decreased capillary refill or mottling Haemodynamic variables: Arterial hypotension, Systolic Blood Pressure SBP <90 mm Hg, Mean Arterial Blood Pressure MAP <70 mm Hg, or SBP decrease >40 mm Hg. l) Investigations: Investigations should be directed at diagnosis, assessing the focus of sepsis, and the severity of the sepsis. 1) Hb 2) TLC 3) DLC 4) Blood Glucose. 5) Renal function tests (SE,BUN,Cr) 6) Liver function test (Bi,AST,ALT,ALKP,GGT,PT,INR,PTT) 7) Cultures with gram stain 8) Urine R/M 9) X-Ray

10) ECG m) Treatment: Standard Operating procedure a. In Patient Sepsis should be treated in the ICU, if recognized out side the ICU. Immediately start fluid resuscitation, collect blood culture and give broad spectrum antibiotics within 1 hr, culture collection should not delay antibiotic administration, and simultaneously organize ICUtransfer. b. Out Patient Resuscitation with fluid in the emergency department collect blood culture and give

broad spectrum antibiotics within 3hrs , culture collection should not delay antibiotic administration, and shift the patient in the ICU. c. Day Care Do not admit septic patient in Day care setting. 91

n) Referral criteria: Generally, patients can be considered for transfer for diagnosis, source control or further monitoring when they are hemodynamically stable with or without vasoactive drugs and when oxygenation and ventilation is maintained. a) Need Invasive monitoring devices such as arterial lines, centralline, flow trac. b) Mechanical ventilation, dialysis or CRRT required. c) Modern surgical facilities. d) Ultrasound and CT scan or MRI

Always communicate with receiving hospital physician, document the reason for transport and arrange appropriate staff, medication and instrument for transportation. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available k) Clinical Diagnosis: As per situation 1 l) Investigations: ABG SCVO . 2 Serum lactate Procalcitonin (PCT) These biomarkers may be useful to distinguish between infectious and non-infectious causes of

SIRS.PCT can be used to assess the severity of infection and prognostication. It also acts as a tool to guide Antimicrobial Therapy.  Ultrasonography (source identification)  CT scan if it is safe to do(source identification) • USG or CT guided sample from the source – minimally invasive approach is advisable to prevent change in physiology and keep in mind the risk of transportation to imaging department. 92

m) Treatment: Follow the Surviving Sepsis Campaign (SSC) International guidelines for management of severe sepsis.Rapid diagnosis, expeditious treatment multidisciplinary approaches are critical and necessary in the treatment of sepsis. The management of patients with sepsis starts on arrival at the emergency room prior to ICU admission. Special focus on fluid and hemodynamic resuscitation and early antibiotics. (1) Within the first 6 hours (Early goal-directed therapy) Fluid therapy

1. Start resuscitation with fluid boluses if hypotension or serum lactate >4mmol/L to maintain § Central venous pressure (CVP) more than or equal to 8-12 mm Hg and 12-15mmHg in mechanically ventilated patient or intra abdominal hypertension. § Mean arterial pressure (MAP) more than >65 mm Hg § Urine output more than 0.5 ml/kg/hr § Mixed venous oxygen saturation Svo2 >65% and central venous oxygen saturation (Scv02). § Rate of fluid administration should be reduced if cardiac filling

pressures increase without concurrent hemodynamic improvement. § If mixed venous oxygen saturation Svo2 <65% transfuse packed red blood cells to achieve a hematocrit of >30% and/or dobutamine infusion (up to a maximum of 20 µg/kg/min). Diagnosis 1) Cultures with gram stain- Obtain appropriate cultures before starting antibiotics provided this does not significantly delay antimicrobial administration. • Two or more blood cultures. • One or more BCs should be percutaneous.

• One BC from each vascular access device in place for >48 hours. • Other site cultures as clinically indicated Eg. Tracheal culture, sputum culture, ascetic fluid culture, Urine cultures. (should be sent in lab within one hour) Antibiotic therapy 1. Begin intravenous antibiotics early within the first hour of recognizing Severe sepsis or septic shock. o Broad-spectrum agents o Active against likely bacterial/fungal pathogens o Good penetration into the source 93

2. Reassess antimicrobial regimen daily 3. Combination therapy in Pseudomonas infections and in neutropenic patient. 4. De-escalation after culture sensitivity report. Early and appropriate antibiotic therapy and control of the source of infection arethe major therapies shown to improve survival in sepsis. Source identification and control 1. Source of infection should be established as rapidly as possible and start measures to

control the source within the first 6 hours of presentation as soon as the initial resuscitation is done e.g. abscess drainage, tissue debridement and removal of central line. In pancreatitis avoid early surgical intervention. 2. Source control measures must be directed at achieving maximal efficacy with minimal physiological upset. Vasopressor 1. Use norepinephrine or dopamine through central line to keep MAP ≥ 65mmHg administered as the initial vasopressors of choice.

2. Epinephrine, phenylephrine, or vasopressin should not be used as the initial vasopressor in septic shock 3. Vasopressin 0.01 to 0.04 units/min may be subsequently added. 4. Epinephrine as the first alternative agent in septic shock when norepinephrine is not effective. 5. Do not use low-dose dopamine for renal protection. 6. In patients requiring vasopressors arterial catheter should be put as soon as practical. Inotropic support

1. In case of myocardial dysfunction as evidenced by increased cardiac filling pressures and decreased cardiac output dobutamine can be used. 2. Dobutamine infusion (up to a maximum of 20 µg/kg/min) if mixed venous oxygen saturation Svo2 <65%. 3. Do not target predetermined supranormal levels of cardiac index. (2) After initial resuscitation (24 hours goal) Steroid 1. Consider use of low dose intravenous Hydrocortisone (≤300mg/day) 94

a. Septic shock poorly responsive to fluid and vasopressors b. Endocrine or corticosteroid history warrants it 2. Do not use steroids to treat sepsis in the absence of shock and wean it once vasopressors are no longer required 3. Hydrocortisone is preferred to dexamethasone 4. There is no role of ACTH stimulation test while determining whether the patient should receive hydrocortisone to treat septic shock. Blood product administration

1. Packed red blood cells should be given to patients with hemoglobin less than 7.0 g/dL (<7.0 g/L). Achieve target hemoglobin of 7.0 -9.0 g/dL in adults.In certain special circumstances, A higher hemoglobin level may be required. (e.g.: myocardial ischemia, severe hypoxemia, acute hemorrhage, cyanotic heart disease, or lactic acidosis) 2. Erythropoietin must not be used to treat sepsis-related anemia 3. In case of active bleeding, fresh frozen plasma may be used. But its use for correcting

laboratory clotting abnormalities is contraindicated unless an invasive procedure is planned. 4.platelets should be transfused in case of - - Counts< 5000/ µL regardless of bleeding. - Counts between 5000 to 30,000/ µL and there is significant bleeding risk. - Higher platelet counts ≥ 50,000/ µL in case of surgery or invasive procedures. Mechanical ventilation of sepsis-induced acute lung injury (ALI)/ARDS 1. Target a tidal volume of 6mL/kg (predicted) body weight and plateau pressure

≤30cmH2O in patients with ALI/ARDS. 2. Positive end expiratory pressure (PEEP) should be set according ARDS NET protocol to avoid extensive lung collapse at end expiration and prevent over distention of normal lung. 3. Allow permissive hypercapnia if needed, to minimize plateau pressures and tidal volumes 4. Weaning protocol and a spontaneous breathing trial (SBT) regularly to evaluate the potential for discontinuing mechanical ventilation.(1A) • Daily SBT (spontaneous breathing trial)

• Before the SBT, patients should: – be arousable – be hemodynamically stable without vasopressors – have no new potentially serious conditions – have low ventilatory and end-expiratory pressure requirement – require FiO2 levels that can be safely delivered with a face mask or nasal cannula 5. Do not use a pulmonary artery catheter for the routine monitoring. 6. Consider early prone position or rescue therapy for refractory hypoxia. 95

7. Use a conservative fluid strategy for patients with established ALI/ARDS after initial resuscitation. Lung protective ventilation strategy using low tidal volume ventilation reduces ventilator- induced lung injury like volutrauma, barotrauma, atelectrauma and biotrauma. This is the only ventilator manipulation that has been shown definitively to reduce injury and absolute mortality reduction of 9%. Sedation, analgesia, and neuromuscular blockade in sepsis

1. Use sedation protocols with a sedation goal for critically ill mechanically ventilated patients. 2. Avoid neuromuscular blockers where possible. Monitor depth of block with train- of-four when using continuous infusions. Glucose control 1.Aim to keep blood glucose 150 - 180mg/dL using a validated protocol for insulin dose adjustment. Renal replacement 1. Consider early renal replacement therapy 2. Intermittent hemodialysis and continuous veno-venous hemofiltration (CVVH) are considered equivalent.

3. CVVH offers easier management in hemodynamically unstable patients. Bicarbonate therapy 1.Do not use bicarbonate therapy to improve hemodynamics or reducing vasopressor requirements with lactic acidemia and pH < 7.15. Deep vein thrombosis (DVT) prophylaxis 1. Use either low-dose unfractionated heparin (UFH) or low-molecular weight heparin (LMWH), unless contraindicated. 2. Use a mechanical prophylactic device, such as compression stockings or an intermittent

compression device, when heparin is contraindicated. 3. Combination of pharmacologic and mechanical therapy high risk for DVT. Stress ulcer prophylaxis 1.Provide stress ulcer prophylaxis using H2 blocker or proton pump inhibitor. 96

Consideration for limitation of support 1.Discuss advance care planning with patients and families. Describe likely outcomes and set realistic expectations. VI. FURTHER READING / REFERENCES References 1. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock. Crit Care Med2008; [published correction appears in Crit Care Med 2008; 36:1394-1396] 36:296- 327

2. Todi et al. Critical Care 2007 11(Suppl 2):P65 doi:10.1186/cc5225 3. Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J: Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial.Am J Respir Crit Care Med 2008, 177:498-50 4. Hausfater P, Juillien G, Madonna-Py B, Haroche J, Bernard M, Riou B.Serum procalcitonin measurement as diagnostic and prognostic marker in febrile adult patients presenting to the emergency department. Crit Care. 2007;11(3):R60. 97

SEVERE COMMUNITY ACQUIRED PNEUMONIA Subhash Todi, Consultant Physician and Intensivist, AMRI Hospital, Kolkata 1. When to suspect/Recognize? a. Introduction Community acquired pneumonia affects 2 to 3 million patients per year and carries high mortality of around 30% in severe cases. As life expectancy is increasing and many patients with chronic diseases like cardiac failure,COPD are living longer , more patients in community like oncology and transplant with immunosuppressive therapy , incidence of

community acquired pneumonia is increasing and distinction from hospital acquired pneumonia is getting blurred as these patients visit hospital frequently. b. Case Definition Patient usually presents with a constellation of respiratory symptoms like cough, purulent sputum and sometimes pleuritic pain associated with constitutional symptoms like fever, lack of appetite and myalgia. Chest x-ray revealing new infiltrate usually clinches the diagnosis. c. Incidence of the condition

Community-acquired pneumonia is a major cause of morbidity and mortality, worldwide Lower respiratory tract infections, including CAP, were ranked third in a list of the 30 leading causes of death worldwide. About 4 million CAP cases occur annually in the US; with about 20% requiring hospitalization. High mortality trends observed in patients hospitalized for CAP (5-20%) and in CAP patients admitted in ICU (up to 50%). Overall mortality rate of CAP is about 7.3%.

Typical CAP- Sudden onset fever, chills, pleuritic pain, productive cough.Raised TLC, ESR, CRP. Chest x-ray shows diffuse patchy opacities. 60-80% produced by bacteria like -Strep pneumoniae, Staphylococcus, Kleibseilla, Haemophilus Atypical CAP- The organisms: virus, mycoplasma, legionella, chlamydia psittaci, Coxeillaburnetii. Presentation: Preceding airway symptoms, myalgias, fever without chills, headache, unproductive cough. TLC, ESR, CRP are either normal or show a mild rise. Chest x-

ray shows- diffuse, patchy or ground glass shadows Assessment of Severity This is a crucial step as it will help in identifying patient who are prone to get complication and should be admitted in intensive care unit. CURB 65 is a useful mnemonic for this 98

• Confusion • Urea > 20 mg/dl • Respiratory Rate >30/min • Blood Pressure Systolic <90 mmHg • Age > 65 years INVESTIGATIONS a. Investigations to be sent in all facilities 1. Complete Blood Count 2. CRP 3. Urea ,Creatinine 4. Liver Function Test 5. Blood Culture – Two sets 6. Prothrombin Time 7. Na, K 8. Sputum for microscopy, gram stain, AFB stain, fungal stain, cytology 9. Sputum for culture and sensitivity 10. Chest X-ray 11. ECG b. Investigation to be done at a higher centre 1. Procalcitonin

2. Chest CT scan 3. Chest ultrasound 4. Bronchoscopy with lavage 5. Echocardiogram 6. Urine for legionella and pneumococcal antigen 7. Serology for H1N1, HIV, ANCA , Legionella 8. Nasal Swab for MRSA,Viral Panel 9. NT PRoBNP 10. Venous Doppler legs 11. D Dimer Treatment: Initial Choice of Antibiotic A detailed history should be taken to identify patients who are at high risk of drug resistant infection. • Previous hospitalization in 9 months • Previous antibiotic in 3 months

• Comorbidity – steroid use, liver failure, renal failure, COPD 99

Cover common organisms responsible for pneumonia: both typical and atypical • Strep pneumoniae • Legionella • Staph aureus (MSSA) • Gram negative bacilli (non ESBL) • Hemophilus Antibiotic choices in these patients A beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) + azithromycin OR A beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) + a respiratory Fluoroquinolone (levofloxacin or equivalent) OR For penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam

Additional organisms to be considered in patients at risk of drug resistantInfection If ESBL or pseudomonas is a concern- Anantipneumococcal, antipseudomonal beta-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) + either ciprofloxacin or levofloxacin (750 mg) OR The above beta-lactam PLUS an aminoglycoside and azithromycin OR The above beta-lactam PLUS an aminoglycoside and an antipneumococcalfluoroquinolone (for penicillin-allergic patients, substitute aztreonam for above beta-lactam)

If MRSA is a concern- Add vancomycin or linezolid. Availability of other cephalosporin with betalactamase inhibitors combination (Cefoperazone – sulbactam, Cefepime Tazobactam, cetriaxone-sulbactam) and Class 1carbapenem- Ertapenem can be used to cover ESBLs as per the hospital antibiotic policy andlocal antibiogram. Duration of Antibiotic therapy: Duration of antibiotic should be individualized based on clinical response,type of organismbiomarker response, development of complications and

comorbidities. Minimum five days ofantibiotic is recommended. Prolonged antibiotics upto two 100

weeks should be considered inselected cases like slow responders, pseudomonas and staph infection,lung abscess , empyema,metastatic infection. Identification of Non-Responders With appropriate antibiotic therapy some improvement in patients clinical course should beseen within 48 to 72 hours. This should be assessed clinically as radiographic resolution takes alonger time. For non- responders following conditions should be considered. 1. Organism not covered by empiric choice of antibiotic

2. Atypical organisms – Tuberculosis, strongyloidosis, meliodosis , H1N1 influenza etc 3 Complicated pneumonia- Lung abscess, empyema. Obstruction, Resistant organism 4. Nosocomial problem- Secondary infection. Differential diagnosis: Heart failure, cryptogenic organizing pneumonia (COP), Malignancy, Pulmonary embolism, Pulmonary eosinophilia pneumonia, Hypersensitivity pneumonitis, vasculitis –Wegners granulomatosis Referral Criteria

• Non-responders should be managed at a higher facility for appropriate workup. • CAP patients with shock, multi-organ dysfunction Suggested Reading 1. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Mandell, LA, Wunderink, RG. Clin Infect Dis 2007; 44 Suppl 2:S27. 2. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Lim, WS, Baudouin, SV. Thorax 2009; 64 Suppl 3

3. Canadian guidelines for the initial management of community-acquired pneumonia: An evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis. 2000; 31:383. 4. Recent advances in community-acquired pneumonia: inpatient and outpatient .Niederman MS Chest. 2007 Apr; 131(4): 1205-15. 101

STATUS EPILEPTICUS FN Kapadia, Consultant Physician & Intensivist, PD Hinduja National Hospital, Mumbai Prashant Walse, Associate Intensive Care Unit Consultant, PD Hinduja National Hospital, Mumbai I. WHEN TO SUSPECT/ RECOGNIZE? l) Introduction: Status epilepticus (SE) is a state of continuous seizure without return of consciousness. Any seizure type can progress to status epilepticus. Status epilepticus is a serious medical and neurological emergency which requires efficient management as delay is

associated with worse outcome. The prognosis depends predominantly on the cause and duration of the SE and is good in rapidly reversible causes. Overall mortality is 15.8 %.( 1) Additional 10 to 23% of patients who survived from status epilepticus are left with disability. Case definition: For both situations of care (mentioned below*) Clinically definition of SE based on manifestations of continuous seizure activity and incomplete recovery of consciousness between seizures for a ‘particular duration’. The

criterion for duration is still ambiguous and evolving issue. For all practical purposes, a patient should be considered in status epilepticus if seizure activity lasting more than 5 minutes as very few single seizures will last this long. Refractory Status Epilepticus (RSE): Appropriate definition is still not available. RSE is commonly defined as seizure activity that continues after failure of first and second line antiepileptic drug therapy (AED) therapy. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY

Chin et al in a recent systemic review reported incidence rates of SE between 3.86 to 38 per 100,000 per year in children and 6 to 27 per 100000 per year in adults in Europe. (2) Incidence has bimodal distribution with peaks in children less than a year (135 to 156 per 100000 per year) and elderly (14.6 to 86 per 100000 per year).The annual incidence of Non convulsive status epilepticus (NCSE) is 2.6 and 7.8 per 102

100000. NCSE was documented in 8 % of all comatose patients without signs of seizure activity. Frequency of refractory status epilepticus in patients with SE ranged from 31 to 44 %. There is hardly any incidence data available in India. In a recent study NCSE was documented as a cause of altered mental status in 10.5% of comatose patients without signs of seizure activity. The incidence of RSE in SE patients in Indian series ranges between 12 and 19 %. (3) III. DIFFERENTIAL DIAGNOSIS

Disorders that may mimic seizures are benign conditions like myoclonus, fasciculations, tremors, tics, panic attack, psychogenic seizures and potentially dangerous conditions like basilar artery transient ischemic attack, metabolic encephalopathy and syncope. When doubt regarding diagnosis is present one should always request neurological consultation and electroencephalogram (EEG). Video- EEG monitoring may be useful for detection of ongoing subclinical seizures

and should be considered in critically ill patient with unexplained altered mental status.(4) IV. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: SE is best divided into three categories: 103

Convulsive status epilepticus (CSE) Non convulsive status epilepticus (NCSE) Partial status epilepticus (PSE) CSE is the most common form of SE characterized by rhythmic jerking of the body, limbs, tongue biting and loss of consciousness. With increasing seizure duration the movements may become reduced although generalized electrical activity continues in the brain. NCSE may be difficult to diagnose and may be more common in the elderly

population. Although there is no accepted classification of NCSE, two major types are partial complex –which is subdivided on the basis that whether the patient has underlying epilepsy or is in coma and petit mal. In partial complex SE stereotypical movements such as lip smacking, chewing or picking at ones’ clothes may occur and alteration of consciousness lasts more than 30 minutes as result of abnormal cortical electrical activity.

Physical examination should look for signs of occult head trauma, substance abuse, fever, meningismus and diabetes. Always check for Medical Alert bracelets or wallet information and try to contact relatives to determine prior medical and seizure history. b) Basic Investigations Complete blood count , electrolytes ,Blood urea nitrogen(BUN),serum creatinine,glucose,liver function test c) Treatment Initial general management: • Assess basic life support • Start supplemental oxygen, monitor oxygen saturation

• Initiate seizure precautions (e.g., padding bed rails) • Monitor vital signs and ECG • Adequate venous access and liberal hydration should be started with normal saline to prevent dehydration and rhabdomyolysis. • Blood pressure should be monitored closely, especially if seizures persist for more than 30 minute • Consider thiamine 100 mg IV and dextrose 25-50 g IV if blood 104

glucose is less than 60 mg/dl • Treat fever with acetaminophen and icepacks Initial Antiepileptic drug treatment • In the setting of acute brain injury, treatment usually should be initiated after a single self limited seizure. Initial AEDs (viz. Lorazepam and phenytoin) should be given as soon as possible. • Management of SE should begin within 5 minutes of seizure activity or after two seizures without full recovery in between.

• Give IV Lorazepam 0.1 mg/kg IV at 2mg/minIf Lorazepam is not immediately available, diazepam 10-20 mg or midazolam 2-5 mg can be substituted • Midazolam given intramuscularly is the promising treatment in prehospital settings • Start phenytoin 20 mg/kg IV load at <= 50 mg/min Referral criteria: Patients of SE can be considered for transfer to superspeciality center if seizures are not controlled with benzodiazepine and first line antiepileptic drugs or patient has recurrent

seizures after initial stabilization. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical diagnosis (as per situation 1) b) Investigation • Blood and urine toxicology screen and when indicated pregnancy test and arterial blood gases, serum ammonia level • Anticonvulsant medication levels • CT or MRI scan and lumbar puncture may be necessary to establish underlying diagnosis once seizures are controlled. • NCSE can only be diagnosed by EEG.

Common Aetiologies of seizures in critical care unit: Neurological : Cerebrovascular disease: infarct, haemorrhage, vascular malformation Vasculitis Infection: meningitis, encephalitis, brain abscess Head trauma Anoxia Brain tumours Neurosurgical procedure Hypertensive encephalopathy/eclampsia/posterior reversible encephalopathy syndrome Complication of Critical illness: Acute systemic insult, sepsis, hypotension Electrolytes imbalances: hyponatremia, hypocalcaemia, hypomagnesaemia,

hypophosphatemia (especially in alcoholics), hypoglycaemia Toxins Illicit drug use, especially cocaine Organ failure: renal, hepatic Medications /substance withdrawal: Benzodiazepine, barbiturates, alcohol If none of the above causes are identified consider following less common aetiologies:Anti NMDA receptor limbic encephalitis(LE),Anti glutamate receptor LE,Paraneoplastic LE,Hashimotos' encephalopathy.(5) 110

c) Treatment Additional general management • Consider intubation to maintain airway patency • Monitor for arrhythmias, hypotension and respiratory failure Antepileptic drug treatment • Start phenytoin 20 mg/kg IV load at <= 50 mg/min or Fosphenytoin at 20 mg phenytoin equivalents (PE)/kg at =< 150 mg PE/min • Seizure activity not resolving with two anticonvulsants: • Give Phenobarbital 10-20 mg/kg IV at <70 mg/min. • Call for continuous EEG monitoring • Consider neurological consultation

• Consider administration of following alternative agents: • Midazolam drip: 0.2 mg/kg slow IV push, followed by 0.1-2 mg/kg/hr to stop electrographic and clinical seizures or • Propofol: 2 mg/kg load and 2-10 mg/kg/hr to stop clinical and electrographic seizures or maintain burst suppression on EEG • Valproate 15 mg/kg IV load may be useful as an adjunctive agent. • Pentobarbital 3-5 mg/kg IV to induce burst suppression; in most adults

pentobarbital bolus 400 mg over 15 min. every 15-30 min. until burst suppression appears is well tolerated, followed by infusion at 0.3-9.0 mg/kg/hr to maintain burst suppression.(7),(8) • For all infusions, decrease infusion rate periodically to check EEG burst suppression pattern; if electro cerebral silence occurs, decrease the dose till bursts are seen again.(4) V FURTHER READING / REFERENCES 1. Li JM, Chen L.Convulsive status epilepticus in adults and adolescents of

southwest china: Epilepsy Behav 2009, Jan; 14(1)146-9 2. Chin RFM,Neville BGR.A systemic review of the epidemiology of status epilepticus:Eur J Neurol.2004;11:800-10 3. Narayan JT,Murthy JMK. Nonconvulsive status epilepticus in a neurological ICU; profile in developing country: Epilepsia 2007;48;900-6 4. Vadi S,Gursahani R,Kapadia F N. Utility of electroencephalogram in altered state of consciousness in intensive unit care patients: Ind J Critical Care Medicine 2005;9:19-21 111

5. Thomas P. Bleck. Less common etiologies of status epilepticus: Epilepsy currents, vol.10, No 2(March/April) 2010; 31-33 6. Lowenstein D H. Management of refractory status epilepticus: Epilepsia 2006; 47(1); 35-40 7. Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: A systematic review. Epilepsia 2002; 43:146-53. 8. Von Ness PG. Pentobarbital and EEG burst suppression in treatment of status

epilepticus refractory to benzodiazepines and phenytoin. Epilepsia 1990; 31:61-7. 112

INITIAL MANAGEMENT OF SEVERE TRAUMA Subhash Todi, Consultant Physician and Intensivist, AMRI Hospital, Kolkata 1. When to suspect/Recognize? a. Introduction: There is an increasing incidence of accidents and crimes in India with increasing urbanization and attendant emergency admission of trauma victims. A comprehensive trauma care is lacking in majority of places. As this malady affects predominantly young patients it is a heavy burden to the exchequer.

Improving organized trauma care with easy accessibility is an urgent need in our country. b. Case definition: The American Trauma Society defines trauma as an injury caused by a physical force. More often, trauma is the consequence of motor vehicle crashes, falls, drowning, gunshots, fires and burns, stabbings, or blunt assaults. Lot of emphasis has been placed on aggressive initial management of trauma. The concept of prehospital car is highlighted by the Golden Hour, which may be

defined as the period during which all efforts are made to save a life before irreversible pathological changes can occur thereby reducing or preventing death in the second and third phase. This period may range from the time of injury to definitive treatment in a hospital. The first platinum 10 minutes becomes important to make this golden hour effective and should be distributed as follows to make it fruitful. Time lines: Assessment of the victim & primary survey- 1-minute, Resuscitation

& stabilization – 5 min, Immobilization & transport to nearby hospitals 4 minutes. 2. Incidence of the condition in our country India contributes to 10% of world trauma with vehicular accident every 3 min & death every 10 min. Road traffic injuries are a major cause of mortality responsible for 22.8% of death related to injuries.The lower and middle-income group countries, including India contribute about 90% of the global burden of injury mortality.

Uncontrolled bleeding is a leading cause of death in trauma. In fact, death in trauma follows a trimodal distribution of death. First peak occurs immediately after an accident. Second peak occurs 1-4 hours later and the third peak occurs 1-5 weeks later. 113

The initial management is usually done by paramedics, and an adequately trained team with skills in maintenance of airway, control of external bleeding and shock, immobilization of the patient and transportation. This has to be tied to early arrival of trauma ambulance and a system of triaging and notifying the receiving hospital with a central coordination. 3. Differential diagnosis: In Polytrauma, the assessment of the extent of injuries is very important. A head to

toe examination facilitates identifications of brain & cervical spine trauma, thoracic or abdominal or major skeletal trauma. If shock persists after resuscitation, patient must be evaluated for any other covert internal injuries. All patients with head injury should be assumed to have a cervical spine injury as well unless proved otherwise clinically or radiologically. 4. Prevention & Counseling: Road safety & pedestrian safety are two important issues. Most of the trauma victims

are either pedestrians or bicyclists. Strict implementation of traffic rules and measures like wearing helmets, lane driving and implementing speed limits are important issues that need to be uniformly applied across India. A robust prehospital ambulance system manned by qualified emergency medical technicians will help in improving survival significantly. Trauma victims are generally young and bread winners for their families. Any such

death or disability is associated with significant financial and psychological trauma to the victim and his family. Adequate counseling and support is required for the trauma patients and their families. 5. Optimal diagnostic criteria, investigations, treatment & referral criteria *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited Facilities required

1. Medical Personnel with basic training in airway management and resuscitation 2. Basic Airway management equipment 3. Cervical collar 4. Spine Board 5. Scoop stretcher 6. Basic Volume resuscitation items like i.v fluids and i.v cannulas 7. Continuous oxygen supply and suction 8. Chest tube drainage system 9. Fracture stabilization material 114

10. Surgical sutures and hemostatic forceps. 11. X-ray & ultrasound facilities 12. Abdominal paracentesis equipment 13. Access to Blood Bank 14. Routine hematology, biochemistry, coagulation testing facility 15. Transport to higher center. Clinical diagnosis: This remains the mainstay of diagnosis. Investigations: Facilities like CT scan/MRI etc. are not available. Simple x-ray & Ultrasound should be available. Basic investigations like hematology, biochemistry, coagulation parameters should be available.

Treatment: Quick identification and assessment of the extent of external injuries should be made. Basic care like intravenous access, fluid or blood resuscitation should be done. Splinting & bandaging of injured extremity or scalp should be done. Airway, breathing & circulation should get priority. Internal injuries and head injuries cannot be managed and should be referred to higher centres. These centers should have a clear policy on transfer of trauma patients and all

patients who cannot be managed there should be shifted after initial treatment and resuscitation. At Super Specialty Facility in Metro location where higher-end technology is available Facilities required 1. Trauma Team with an on call rota and quick response time. The team should consist of a trauma surgeon or a general surgeon, intensive care or emergency medicine physician, Neurosurgical team, cardiothoracic team, orthopedician& anaesthesiologist.

2. The trauma team should be adequately supported by trained nurses and paramedical staff 3. Focussed abdominal ultrasound in trauma (FAST) 4. Portable X-ray facility 5. CT scan& MRI 6. Transport ventilator 7. Spine board 8. Scoop stretcher 9. Cervical immobilization devices 10. Difficult airway management equipment 11. Thoracotomy equipment 12. Portable echocardiogram 13. On site blood bank 14. Intravenous fluid warmed 15. Rapid i.v. infusion system 115

16. Central lines 17. Round the clock OT facility 18. Pericardiocentesis equipment 19. Trauma protocol to guide management The principles followed in clinical diagnosis, investigations & treatment are same as above. However a more organized approach is used, which is described below. 1. TRIAGE :Triage is a process of determining the priority of patients’ treatment based on the severity of their condition and the resources available to provide that treatment. . In

multiple casualty incidents, the number of patients and the severity of their injuries do not exceed the ability of the trauma care facility. The patients with life-threatening injuries are treated first. In mass casualty incidents, the number of patients and the severity of their injuries exceed the capacity of the trauma care facility. Here, the patients with the greatest chance of survival are treated first. 2. Primary Survey and Resuscitation: Primary survey involves rapid early assessment of

the patient. The life threatening conditions are identified and treatment priorities are established based on their injuries, vital signs and injury mechanisms. During the primary survey, the following aspects are assessed and rapid corrective measures taken. a) Airway maintenance with C-Spine Control b) Breathing and Ventilation c) Circulation and /hemorrhage Control d) Disability/ Neurological Status e) Exposure/ Environmental Control Airway with C-spine control

The patency of the airway should be assessed with special attention to foreign body or maxillo- facial fractures that may result in airway obstruction. Chin-lift or Jaw-thrust maneuver may be used to achieve airway patency simultaneously protecting the cervical spine. A definitive airway is warranted in a patient with an altered level of consciousness or a Glasgow Coma Score of 8 or less. It is critical to protect the spine. Spinal injury should be assumed in any patient of trauma

unless specifically excluded. Breathing and Ventilation The patient’s chest should be exposed to adequately assess chest wall excursion. Auscultation to detect adequate air entry, percussion to exclude air or blood in chest and visual inspection and palpation to detect injuries to chest wall should be carried out. Specific life threatening problems 116

such as tension pneumothorax, massive hemorrhage, flail chest and cardiac tamponade should be identified immediately and addressed during the primary survey Circulation with Hemorrhage Control Hemorrhage is the primary cause of shock in trauma patients. Rapid and accurate assessment of the patient’s hemodynamic status and identification of the site of hemorrhage is therefore essential. It is critical to establish adequate intravenous access in a trauma patient. While the

primary survey is going on, two intravenous lines should be established with short broad gauge cannula, preferably in the upper extremities, and resuscitation started with crystalloids. Disability / Neurological Status A rapid neurological evaluation is carried out at the end of primary survey after the resuscitation and before rapid sequence intubation. This assesses the patient’s level of consciousness, papillary

size and reaction and focal neurological deficit. The level of consciousness may be described in terms of Glasgow Coma Scale (GCS). Exposure / Environmental Control The patient should be completely undressed to facilitate thorough examination and assessment. At the same time care should be taken to prevent hypothermia to the patient. Adjuncts to Primary Survey and Resuscitation a) ECG Monitoring: The appearance of dysrhythmias may indicate blunt cardiac injury.

Pulseless electrical activity, the presence of cardiac rhythm without peripheral pulse may indicate cardiac tamponade, tension pneumothorax or profound hypovolemia. b) Urinary Catheter: Urine Output is a sensitive indicator of the volume status of the patient and reflects renal perfusion. All trauma victims should be catheterized to enable monitoring of the urine output and plan intravenous fluid therapy. Transurethral catheterization is contraindicated in patients urethral transaction is suspected.

c) Gastric Catheter: A gastric tube is indicated to reduce stomach distension and decrease the risk of aspiration. It should be passed via the orogastric route in patients with head injury and suspected base skull fracture. d) X-rays and Diagnostic Studies: The chest and pelvis x-ray help in the assessment of a trauma patient. Any trauma patient entering the red area of the emergency should undergo blood sampling. The blood should be sent for cross-match and arranging for

packed cells, and important diagnostic parameters such as hemoglobin, renal parameters, ABG should be checked. Pulse oximetry is a valuable adjunct for monitoring oxygenation in injured patients. 117

e) FAST: Focused Assessment by Sonography in Trauma is a rapid non- invasive tool used to assess free fluid in the abdomen, blunt abdominal injury and cardiac tamponade. f) CT scan & MRI: For brain, spinal cord trauma and in injury to internal organs. Secondary Survey Once the primary survey is accomplished, life- threatening conditions are managed and resuscitative efforts are underway, secondary survey is carried out. This is head to toe

evaluation of trauma patient, which includes a complete history and physical examination and reassessment of all the vital signs. Each region of the body is completely examined. The care continues with regular re-evaluation of the patient for any deterioration and new findings, so that appropriate measures can be taken. Reevaluation After the completion of the secondary survey, the patient should be reevaluated beginning with the ABCs and thorough physical examination and examined for any missed injury such

as fractures. Constant monitoring of the severely injured patient is required and may necessitate rapid transfer to the surgical intensive care unit, operating room or to another centre having better specialized facilities. The transfer to another centre should not be delayed for the want of investigations. 118

RESOURCES REQUIRED SITUATI HUMAN INVESTIGATIO DRUGS AND EQUIPMENT ON RESOURCES N OF 4-6 CONSUMABLES FOR 4- 6 WEEKS FOR 4-6 WEEKS WEEKS 1. At One Each: a. X-ray a. Intravenous a. X-ray seconda fluids- machine 1. Casualty b. Ultrasound ry Crustalloids- (portable) Medical hospital/ Normal saline b. Ultrasoun c. Hematology Officer non- 50 , Ringer d machine (CMO) metro d. Biochemistry lactate 50 c. Orthopedi situatio b. Intravenous c splints 2. X-ray n e. Blood grouping fluid- d. Spine Technician

& cross matching Colloids- board (1) Hemaccel, e. Scoop HES 5 bottles stretcher One in each each (1) shift: c. IV canula: f. Ambu bag 24,22,20,18,16 (2) 1. CMO ,14 gauge ( 10 g. Bain each) circuit (2) 2. Nurse d. IV drip sep- h. Oxygen 3. Attendant 25 cylinders e. Compression (10) bags for fast i. Bllod fluid delivery staroage (5) rfrigerato f. Bandages (1-2 r 1 drums) j. Dressing g. Dressing set (1) material (1-2 k. Suturing drums) set (1) h. POP ( 100) l. Cevical i. Blood set (10) collar

j. Leucoplast (5 m. Ambulanc rolls) e for k. Dynaplast (5 transport rolls) l. ICD tubes (10) different 119

sizes m. Underwater seal (5) n. Nasopharyng eal & oropharyngea l airway (all sizes) 2. At super As in situation As in situation 1 In addition to all As in situation 1 specialty 1 a. + items listed above: with facility in Emergency a. CT scan 1. Arterial 1. Well metro Consultant-1 b. MRI canulae (10) equipped location b. CMO-2 c. ECHO 2. Central OT with d. Coagulatio venous lines C-arm c. n (10) 2. Airway & Techanician-1 parameter 3. Cardiac breathing s monitors equipmen d. Nurses- 3

e. Blood and 4. Defibrillator t per shift in other fluid 5. 3. Transport addition to cultures ventilator Incharge (Microbiol 4. ACLS d. Ward boys ogy) ambulanc 2 e with ventilator, e. monnitor, Housekeeping defibrillat 2 or f. Multiprofesio nal Trauma team as per the composition listed in the text. 120

Referral Criteria • Patients should have basic control of airway, breathing and circulation, and surgery to stop bleeding if possible before contemplating transfer • Need for specialized surgery: thoracic, cardiac surgery • Need for advanced intensive care after initial stabilization Reference 1. American College of Surgeons Committee on Trauma. Resources for optimal care of the trauma patient. Chicago: American College of Surgeons; 1998

2. American College of Surgeons Committee on Trauma. Advanced trauma life support program for doctors, 8thed, chapter1, Initial assessment and management. Chicago: American College of Surgeons Committee on Trauma; 2008:1-18. 3. Super G, Groth S, Hook R, et al. START: Simple Triage and Rapid Treatment Plan. Newport Beach, CA: Hoag Memorial Presbyterian Hospital; 1994. 4. Flint L, Meredith JW, Schwab C, eds. Trauma: Contemporary Principles and Therapy. 1st Ed. Lippincott Williams & Wilkins; 2008

5. Moore EE, Feliciano DV, Mattox KL, eds. Trauma, 5thed, chapter 47, New York: McGraw-Hill; 2004: 1067-1068 121

TRAUMATIC BRAIN INJURY S. Srinivas, Head, Critical Care Medicine, Care Hospital, Hyderabad I. a) When to suspect / recognize? Traumatic Brain Injury is usually associated with road traffic accidents or criminal assault. It could also happen due to a fall or due to industrial mishaps. Nevertheless the disorder is usually obvious and history is generally clinching. In situations where the history is not forthcoming any injury or mishap associated with the change in the

level of consciousness of the individual should be deemed to be associated with brain injury unless proved otherwise. b) Case definition: The term TBI is self explanatory. However the course in hospital for a patient with TBI is characterized by 2 major injuries – Primary and Secondary Primary injury is the injury sustained by the patient and is related to the mechanism of injury. Secondary injuries are those sustained during the transport and treatment of

patients with TBI. This is the more common cause of altered consciousness amongst TBI patients. Some of the causes of secondary injury are 1. Seizures 2. Hypotension 3. Hypertension 4. High and Low blood sugars 5. Elevated body temperature. 6. Electrolyte imbalance. 7. Hypoxia II. Incidence of the condition in our country Incidence of road traffic accidents in India is amongst the highest in the world, and is rising. As per the report of the National Crime Records Bureau 2001, 2,710,019

accidental deaths, 108,506 suicidal deaths and 44,394 violence-related deaths were reported in India. A significant proportion of the deaths due to accidents and violence are due to head injuries. A study from NIMHANS revealed that minor, moderate and severe brain injuries (due to RTIs) were recorded in 60%–65%, 16%–20% and 15%– 20% of cases as per the Glasgow Coma Scale (GCS) grading. Mortality was higher among those with severe brain injuries. Polytrauma was documented in 1%–21% of

cases. Facial, chest, abdominal and limb injuries were documented in 48%, 3%, 1% and 10% of cases, respectively. 122

III. Differential Diagnosis: The differential diagnosis of traumatic brain injury is generally straight forward. However when the history is not forthcoming, differential diagnosis should include • Ischemic stroke • Sub arachnoid hemorrhage • CNS infections • Toxic encephalopathies IV. Optimal Diagnostic criteria, investigations, treatment and referral criteria: Situation 1: In non metro situation with limited resources: Investigations: • CT Scan of the brain with or without contrast • Serum electrolytes

• Blood sugar • Chest X-ray Treatment • Maintenance of oxygenation and blood pressure: Hypoxia and hypotension are common causes of secondary brain injury. Mortality amongst patients whose saturations are < 60% is close to 50%. Duration of hypoxia is also a determinant of adverse outcomes. o Intubation when GCS < 8 is recommended. Mechanical ventilation is instituted to maintain PaO2 and control PaCO2 • Similarly, both pre and intra hospital hypotension are predictors of adverse

outcomes. It is recommended that systolic blood pressure should not be less than 90 mm Hg. If hypotension does occur initially, all precautions need to be taken to avoid recurrent episodes. In resource limited settings management of TBI on the basis of Cerebral Perfusion Pressure may not be feasible and is recommended as an optional strategy. • Hyperosmolar therapy: 20% Mannitol and Hypertonic Saline.Their use is indicated when raised intracranial pressure is suspected.Mannitol can either be

used as a single short term agent or as a continuous therapy. However, repeated use of Mannitol over several days is not known to be effective. • Surgery, indicated for evacuation of extradural or subdural hematoma, intracranial hemorrhage, depressed skull fracture, other surgery in case of associated polytrauma 123

• Anaesthesia, analgesia and sedation: Providing adequate analgesia and sedation is crucial for a patient with TBI with or without raised ICP. Morphine and midazolam can be used. • Infection Prophylaxis: Prevention of other systemic infections is also important in TBI. Early extubation is recommended if the patient has an intact gag and cough reflex. • Thromboprophylaxis: Patients with TBI are at a high risk of deep venous thrombosis. This risk increases with the increase in the severity of brain injury.

Prophylaxis is either mechanical or pharmacological or both. The use of mechanical intermittent pneumatic compression (IPC) devices is strongly recommended for all patientswith TBI except when there are coexistent lower extremity injuries. • A combination of IPC with low molecular weight heparin is superior to using either modality alone. However, initiating LMWH or Heparin within 24 hrs of surgery is not recommended. No specific agent is superior to the others. However, the use of pharmacoprophylaxis

might be associated with a higher chance of intra cranial bleeding. • Anti Seizure Prophylaxis: Post traumatic seizures can be early onset (<7 days) or late onset (>7 days). Both need to be prevented. Risk factors for PTS include • GCS<10 • Cortical contusion • Depressed fracture • Sub dural hematoma • Epidural hematoma • ICH • Penetrating head wound • Seizure within 24 hrs of injury. Phenytoin can be used for preventing early onset PTS. No role can be made out for

prophylactic drugs to prevent late PTS. Valproate is as effective as Phenytoin in preventing PTS but is associated with higher mortality. • Hyperventilation: Prophylactic hyperventilation is not recommended. It is a temporary measure. Whenever Hyperventilation is frequently required monitoring of SjVO2 or brain tissue oxygen tension is recommended. Therefore such patients need to be referred to a centre with facilties to do so. • Steroids: No role in the management of TBI Transfer / Referral Criteria

• Non-availability of CT scan or neurosurgical expertise • Persistent unconsciousness with GCS < 8, seizures • Persistent high intracranial tension, clinically and on CT scan, despite medical and initial surgical management 124

• Polytrauma, especially associated chest trauma • Ongoing requirement of mechanical ventilation, hemodynamic instability • Requirement for intracranial pressure monitoring Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical Diagnosis: As per situation 1 b) Investigations: as per situation 1 plus • MRI • Intracranial pressure and cerebral perfusion pressure monitoring • Serum osmolality • EEG monitoring c) Treatment: as in situation 1 plus:

• Hyperosmolar therapy: hypertonic saline. A close monitoring of the serum osmolality is warranted. A central venous access is preferable for administration of hypertonic saline • Intra cranial pressure (ICP) Monitoring: Indications: • Patients with TBI who have a GCS < 8 and for those who have an abnormal CT scan. The abnormalities include hematomas, contusion, oedema, herniation and compressed basal cisterns. • Age of the patient is > 40 years, patient has systolic pressure <90mm Hg or

there is abnormal motor posturing. The need for ICP monitoring is an indication for transferring the patient to a facility with the expertise in the technique. It is not recommended for use in non metro areas and resource limited settings. ICP Monitoring methods: The ventricular catheter connected to an external strain gauge is the best available tool for ICP monitoring. It is the least expensive and currently most accurate. It also

gives a therapeutic option of CSF drainage. Fibreoptic transduced monitors are also accurate but more expensive. • ICP Thresholds: Measures to regulate ICP should be initiated if the pressure exceeds 20 mm Hg. Treatment should be tailored on the basis of clinical and CT findings with ICP as a guide. • CPP Thresholds: CPP should be maintained between 50-70 mmHg. Attempts to achieve CPP>70 are associated with a higher incidence of ARDS. CPP<50mm Hg should be avoided.

• Brain oxygen monitoring: Wherever facilities for jugular saturation monitoring are available, SjVO2 should be maintained >50%. If brain tissue oxygen tension is monitored 125

then PbtiO2 should be maintained > 15mm Hg. Jugular venous oxymetry is recommended when hyperventilation is used with a therapeutic intent. • Anaesthesia, analgesia, sedation, neuromuscular blockade • Propofol is recommended in moderate doses as a sedative for its beneficial effects on ICP and cerebral perfusion pressure. High dose propofol infusion can trigger Propofol Infusion Syndrome and is therefore not recommended. • Opioid analgesics and benzodiazepines are recommended. Morphine and

Midazolam can be combined with opioid analgesics for sedation. • Barbiturate infusions are recommended for control of raised ICP. • If ICP remains high neuromuscular blocking agents may be considered. • Continuous EEG monitoring may be used wherever available to titrate the dose of sedatives. • Prophylactic Hypothermia: The use of prophylactic hypothermia in patients with raised ICP is based on the fact that hypothermia decreases the metabolic activity of

the injured brain. This reduces the cerebral metabolic rate for oxygen and minimizes the extent of brain injury. The target temperature is 32-330C to be maintained for atleast 48 hrs. However, monitoring patients on hypothermia regimen needs core temperature monitoring and may not be available in resource limited settings. If patients are considered fit for transport, it is advisable to transfer them to a centre with the facilities and experience in using hypothermia. d) References

1. Guidelines for the management of severe traumatic brain injury 3rd edition. Brain trauma foundation 2. Heegard W, Biros M. Traumatic brain injury Emerg Med Clin N Am 25 (2007) 655– 678 126

GUIDELINES FOR THE MANAGEMENT OF COMMON MENTAL DISORDERS Ministry of Health & Family Welfare Government of India 1

List of contributors Dr. R.C. Jiloha Dr Rajesh Rastogi Director Professor & Head Consultant and Head Department of Psychiatry Department of Psychiatry G.B. Pant Hospital & Maulana Azad Safdarjung Hospital & VM Medical Medical College College New Delhi New Delhi Dr Rajesh Sagar Dr. Sanjeev Jain Professor Professor Department of Psychiatry Department of Psychiatry All India Institute of Medical Sciences National Institute of Mental Health and (AIIMS) Allied Sciences (NIMHANS) New Delhi New Delhi

Dr. Daya Ram, Dr. Deepak Kumar, MD (Psychiatry) Director, Deputy Medical Superintendent Central Institute of Psychiatry, Institute of Human Behaviour & Allied Kanke, Sciences (IHBAS), Ranchi New Delhi Dr. Om Prakash Dr Anukriti Verma Consultant Geriatric Psychiatrist & Senior Resident Associate Professor of Psychiatry Department of Psychiatry, Institute of Human Behaviour & allied Safdarjung Hospital & VM Medical Sciences (IHBAS) college, New Delhi New Delhi Dr Prerna Kukreti Dr Priyanka Yadav

Senior Resident of Psychiatry Senior Resident of Psychiatry Institute of Human Behaviour & allied Department of Psychiatry, Sciences (IHBAS), All India Institute of Medical Sciences New Delhi (AIIMS) New Delhi Dr. Amrita Kansal, Dr Ankur Sachdeva Program Officer, Senior Resident WHO Country Office, Department of Psychiatry New Delhi Safdarjung hospital & VM Medical College New Delhi List of contributors from Directorate General of Health Services Dr. (Prof) Jagdish Prasad Dr. Sujeet K. Singh

TABLE OF CONTENTS CHAPTER TITLE PAGE NO. I Psychosis 4 II Depression and other Affective disorders 15 III Anxiety disorders 29 IV Somatoform disorders 39 V Emotional and Behavioural problems in children and 44 adolescents VI Psychiatric problems in elderly 57 VII Epilepsy 64 VIII Psychiatric Emergencies 72 IX Alcohol use and Drug use disorders 81 3

PSYCHOSIS Introduction Broadly, psychiatric illnesses presenting in general health care settings can be classified into two groups, ‘Common Mental Disorders’(CMDs) e.g. depression, anxiety disorders and ‘Severe Mental Illnesses’(SMIs) which refers to a group of mental illnesses causing marked disruption in socio occupational life i.e. schizophrenia and bipolar disorder. Psychosis (Greek word, ‘psyche" refers to mind/soul; and ‘-osis’ refers to abnormal condition

or derangement) means ‘an abnormal condition of the mind’. Psychosis refers to a state characterized by an individual’s loss of contact with reality. It may involve abnormality in thinking and perceptions, as well as disturbances in emotions. It is categorized as a severe mental disorder causing dysfunction in the life of the patient and family. Schizophrenia and other forms of psychoses that affect young people represent a

major public health problem. It is common myth in general public to consider it due to religious and supernatural causes than illness, which often leads to delay in treatment seeking. Moreover, due to stigma attached to mental health services, there is often a delay in reaching to the psychiatrists. Thus, general physicians can be effective bridge in diagnosing, managing and effectively referring such patients. Psychosis occurs in a number of psychiatric disorders e.g. depression, bipolar disorder

(manic-depressive illness), puerperal psychosis and sometimes with drug and alcohol abuse. It can also occur in a number of medical and neurological conditions and caused due to medications. Clinical features Patients can present with following complaints related to psychosis:  Abnormal/disorganized behavior /unusual appearance  Un-understandable talk/Non-sensible speech 4

 False beliefs (e.g. ‘’people are planning to kill me’’)  False perception (e.g. hearing voices of people not around)  Social withdrawal  Neglect of usual responsibilities related to work/school/domestic chores  Talking to self  Violent/aggressive behavior  Restless and running here and there Clinical symptoms and signs for evaluation of psychosis for ease of understanding can be divided into following two groups:

1. Positive symptoms: They are called ‘positive’ since the person’s thoughts, beliefs or sensations seems to be ‘’abnormally expanded or greater’’ than normal. They suggest person having lost contact from reality and of having created one’s false world. They include: - Hallucinations: It refers to perceiving any sensations in absence of a real stimulus, e.g. hearing or seeing things that are not there. - Delusion: It refers to false beliefs that are held with extraordinarily conviction and are not

shared by other members of the society. - Formal Thought disorder: It refers to the disorganization in thought as reflected by speech or sentences which are disjointed or cannot be understood e.g. while speaking person looses chain of thought or one thought has no connection with other. 2. Negative symptoms: They are called ‘negative’ since they involve ‘decrease’ in a person’s usual experiences and functioning. They include: - Little/ no drive to do things - Lack of energy and interest

Diagnosis There are no laboratory tests available for diagnosis of psychosis. Diagnosis is entirely clinical. The following set of symptoms when present together can be helpful in making diagnosis: Schizophrenia More than two symptoms of the following if present for more than one month duration causing disturbance in functioning: 1. Delusions 2. Hallucinations 3. Disorganized speech 4. Grossly disorganized or catatonic behavior 5. Negative symptoms Subtypes of schizophrenia

1. Paranoid Schizophrenia: Delusions; Hallucinations (e.g. belief people are making plans to kill me or hearing of voices; most common subtype; better prognosis 2. Catatonic Schizophrenia: Stupor; Rigidity; Mutism; Maintaining odd postures for long time; Good prognosis 3. Hebephrenic Schizophrenia: Disorganized speech; Self care and behavior e.g. vagabonds on street; Poor prognosis 4. Simple schizophrenia: Negative symptoms; gradual onset; Long lasting; Poor prognosis

5. Residual schizophrenia: Earlier fulfill criteria for Schizophrenia; Partially attenuated form mainly as negative symptoms 6

Acute Psychosis It is characterized by appearance of psychotic symptoms within 2 weeks. It usually has rapidly changing clinical picture and complete improvement within 1 to 3 months, spontaneously or with effective treatment. Persistent delusional disorder It is characterized by the presence of delusion, usually centered on one theme with absence of hallucinations. Person’s social and occupational functioning in all areas other than the theme

of delusion is unaffected. Delusion can be persecutory (e.g. suspicious or fearful of being harmed), grandiose (e.g. believes self to be in possession of extra power, worth knowledge, ability or identity) or somatic (e.g. false belief of having an abnormal somatic sensation or illness). Affective psychosis Mania with psychotic symptoms Presence of psychotic symptoms in background of following symptoms for 1 week: Markedly elevated or irritable mood Excessive energy and activity Excessive talking

Usually psychotic symptoms are grandiose delusion and auditory hallucinations Depression with psychotic symptoms Presence of psychotic symptoms in the background of following symptoms for 2 weeks: Depressed mood 7

Decreased energy and activity Usually psychotic symptoms are nilhistic delusion (belief of having every body organ inside having decayed) and auditory hallucinations Organic Psychosis due to general medical condition Psychosis associated with medical or surgical condition/ drug-induced Assessment Good clinical history, thorough medical examination and mental status examination are the keys to make diagnosis. Take history from patient, accompanying caregivers and screen

relevant treatment and investigation records. Cover following points in your questions to assess symptoms and other relevant history: a. What is the nature of the hallucination or delusion? b. What is the time span? c. Is there a recurring theme? d. Is there insight into it being unreal? e. Is there history of any medical illness? f. Have there been any recent major life-events? g. Is there a history of substance abuse (alcohol or drugs)?

h. Does the patient's past behavior suggest psychological vulnerability, e.g. irritability, uneasiness, suspiciousness and withdrawn mood? i. Is there a family history of mental illness? While taking the history it is possible to make an assessment of the patient's mental state: a. Is there loss of touch with reality; are there delusions or hallucinations? b. Is thought or speech disorganized, abstract or vague? c. Is emotion normal and appropriate? Remember that such experiences will naturally cause

extreme anxiety but are there inappropriate emotional outbursts? 8

d. Is there excitement or confusion? e. Is there depression or suicidal ideation? Investigations Though no specific test is diagnostic, but depending on the possible list of differentials for causes of organic psychosis, investigations can be advised. Look for concurrent conditions e.g. alcohol use, signs or symptoms suggestive of stroke/ diabetes/ hypertension/ HIV or AIDS/ cerebral malaria/ medications usage (e.g. steroids, ATT). Treatment A comprehensive treatment program includes:

1. Antipsychotic medication, which forms the cornerstone of treatment of psychosis 2. Education of the individual about his/her illness and treatment 3. Family education and support 4. Support groups and social skills training 5. Rehabilitation to improve the activities of daily living 6. Vocational and recreational support Pharmacological management After identification of the case, antipsychotic medications should be started depending on

clinical status. The treatment can be broadly divided into two phases acute and maintenance. The goals of acute phase of treatment are to reduce symptoms, to prevent harm to self/others and improve biological functions. The goal of maintenance phase of treatment is to prevent relapse and to help patient improve one’s level of functioning. 9

Selection of antipsychotic drug: Two classes of antipsychotic drugs are available, typical antipsychotics (haloperidol, chlorpromazine, trifluoperazine) and atypical antipsychotics (risperidone, olanzapine, quetiapine). Both the groups are equally effective, but differ in their side effect profiles. In typical antipsychotics, high potency drugs (e.g. haloperidol) have more extrapyramidal side (EPS) effects and low potency drugs (e.g. chlorpromazine, fluphenazine,

trifluoperazine) have more anticholinergic side effects (e.g. dryness of mouth, urinary retention, constipation) and cardiovascular side effects (e.g. tachycardia, postural hypotension). Managing side effects Monitoring for common acute side effects is essential: 1. Extrapyramidal side effects (drooling of saliva, rigidity, fine tremors in hands), acute dystonia (sudden sustained contraction of a group of muscles, most commonly neck

and oral musculatures are affected), oculogyric crisis (sudden up rolling of eyeballs), rabbit syndrome (fine perioral tremors). Manage extrapyramidal side effect by reducing antipsychotic dosage or addition of oral anticholinergic drug e.g. trihexyphenidyl or acutely by giving injection promethazine. 2. Cardiovascular side effects (hypotension, bradycardia, QTc prolongation in ECG): These side-effects require reducing dosage or switching to other agents. 10

Antipsychotic Adult dose range (mg/day) Side effects Acute Maintenance phase Chlorpromazine 100-1600 mg 50-40 mg oral Sedation, postural hypotension oral; 25-400 mg IM Trifluoperazine 4-40 mg oral 5-20 mg oral Sedation, extra pyramidal side effects Fluphenazine 12.5-50 mg IM (deaconate, fortnightly) Haloperidol 5-20mg oral; 1-5 mg oral; Sedation, extra pyramidal side effects, dystonia, akathisia, amenorrhea 5-20mg IM 25-200 mg IM (deconate, monthly) Risperidone 4-6 mg oral Sedation, extra pyramidal side

effects, amenorrhea Olanzapine 7.5-30 mg oral Sedation, postural hypotension, weight gain Quetiapine 300-800 mg oral Sedation, postural hypotension, dizziness 11

Non pharmacological management Psycho-education: Discuss with the patient and family regarding: -The person’s ability to recover; -The importance of continuing regular social, educational and occupational activities, as far as possible -the suffering and problems can be reduced with treatment -the importance of taking medication regularly; -the right of the person to be involved in every decision that concerns his or her treatment

-Importance of staying healthy (e.g. following healthy diet, staying physically active, maintaining personal hygiene). -Additional messages to family members of people with psychosis --The person with psychosis may hear voices or may firmly believe things that are untrue --The person with psychosis often does not agree that he or she is ill and may sometimes be hostile --The importance of recognizing the return/worsening of symptoms and of coming back for re-assessment should be stressed

--The importance of including the person in family and other social activities should be stressed --Family members should avoid expressing constant or severe criticism or hostility towards the person with psychosis. --person with psychosis may have difficulties recovering or functioning in high-stress working or living environments. --It is best for the person to have a job or to be otherwise meaningfully occupied. 12

Follow up care People with psychosis require regular follow-up. In this phase, particularly general physicians can be of great help. Once a patient is in remission, or behaviourally stable, can continue to follow up locally with nearest general physician. Subsequently, patient can be referred to specialised mental health services only on need basis. Follow up frequency: Acute phase: Follow up once or twice weekly. Maintenance phase: Follow up every one to three month.

Follow up assessment: During follow up visits, assess for the following: -Level of symptoms -Side-effects of medications -Treatment adherence: Treatment non-adherence is common, address it -Assess for and manage concurrent medical conditions -Assess for the need of psychosocial interventions at each follow-up -Maintain realistic hope and optimism during treatment -Involvement of carers is critical during such periods Referrals

In following situations, consider need for referral to specialized mental health services: 1. Nature of illness -Severe level of symptoms and distress -Suicide or risk of harm to others -Marked violent aggressive behavior -Catatonic symptoms -Poor general medical status 13

-Refusal to accept orally (meals/ medications) 2. Nature of treatment -Partial or no response to treatment -Need to start modified electroconvulsive therapy -Need to start clozapine -Need of specific psychological therapies or vocational rehabilitation 3. Support system -Poor social support system (e.g. homelessness) -Family needs psycho-education about nature of illness and need of treatment 14

DEPRESSION AND OTHER AFFECTIVE DISORDERS Affective disorders encompass all disorders of mood that are persistent and pervasive and lead to socio- occupational dysfunction. By far, Depression is the most commonly encountered mental disorder by a general practitioner and hence a comprehensive understanding of the disorder is indispensable. This is the broad classification of affective disorders. Affective disorders Recurrent Manic depressive episode episode Bipolar Depressive affective episode disorder

Introduction and epidemiolo gy Mood disorders mainly manifest as either manic or depressive episodes. The lifetime risk of depression varies from 10-15% with the risk being twice more in w omen than men. Depression has a multifactorial aetiology as depicted b elow. The disorder may manifest at any age but the incidence seems to peak in 20s. The disorder may have a variable course but if untreated can run a chronic and

disabling course. Thus early identification and treatment increases the likelihood of remission and recovery. 15

Risk factors for depression neuro endocrine  Female sex  Age <40 years  Impaired interpersonal psycho relationships neuro depression chemical etiology f s a o c c to ia r l s  Divorced, widowers  Family history of depression  Negative life events genetics Diagnosis: For a depressive episode: diagnostic criteria Symptoms should be causing For at least 2 weeks, has the person had at significant socio occupational least 2 of the following core symptoms: dysfunction

Depressed mood (most of the day, almost Rule out bereavement in past 2 every day), (for children and adolescents- months irritability or depressed mood) Rule out the possibility of bipolar Loss of interest or pleasure in activities that depression. (Ask about prior episode are normally pleasurable of manic symptoms such as elevated, Decreased energy or easily fatigued expansive or irritable mood, increased activity and talkativeness, flight of ideas, decreased need for

sleep, grandiosity, distractibility, loss During the last 2 weeks has the person had of social inhibitions and extreme at least 2 other features of depression optimism leading to reckless behaviours. Reduced concentration and attention If 2 other features Mild depressive episode Reduced self-esteem and self-confidence Ideas of guilt and unworthiness If 3 other features Moderate depressive Bleak and pessimistic view of the future episode Ideas or acts of self-harm or suicide

If 3 of the core features and 4 other Disturbed sleep symptoms Severe depressive episode It Diminished appetite may be with or without psychotic features 16

An episode can be with or without Somatic syndrome (4 or more of the following) loss of interest in activities and lack of emotional reactivity, Loss of appetite, Weight loss, Insomnia mainly as early morning awakening, depression worse in morning, Low libid0, Psychomotor retardation or agitation Recurrent depressive Repeated episodes of depression with current disorder episode being mild, moderate or severe A chronic depressive state that does not meet criteria

for a depressive episode anytime and lasts for at least Dysthymia 2 years 17

Clinical features As seen in the diagnostic criteria the clinical features of depression encompass domains of psychological, somatic and psychotic symptoms if severe. psychological somatic psychotic suicidal thoughts •sadness •weight loss or gain •delusions (pertaining •always enquire about •hopelessness •insomnia or to ideas of sin, ideas of self harm •helplessness hypersomnia poverty, deserved proactively punishment, •worthlessness •loss of libido imminent disasters •present plan

•guilt •psychomotor for which patient •available means slowing or agitation •pessimism feels responsible) •previous attempt •anhedonia •hallucinations( •family history of suicide •difficulty usually auditotory of •any implusive act concentrating accusations and •how impulse is resisted •loss of interest defamation or •any psychotic feature olfactory of rotting leading to such ideas things) •overall risk of suicide •stupor (if marked slowing)

Following medical conditions, drugs and psychiatric disorders may be comorbid with depression and should always be explored and only then can the patient be treated holistically. General medical conditions Other psychiatric disorders Endocrine Anxiety disorders Thyroid / glucocorticoid disturbance Substance use disorders Infections 18

Meningitis, encephalitis, syphilis, HIV Systemic( UTI, pneumonia, sepsis) Drugs Cardiovascular Shock, cardiac failures Withdrawal of Cerebrovascular caffeine, nicotine, sedatives, amphetamines Infarcts, haemorrhage Prolonged use of Metabolic Antihypertensive drugs Dyselectrolytemia, renal/hepatic failures, hypo/hyperglycaemia Anti-inflammatory/ analgesics Nutritional Steroids Vitamin B12, Folate deficiency Antineoplastic drugs Tumours Anti-parkinsonism drugs Cerebral/systemic Antipsychotics

Trauma Sedatives Subdural haematoma, cerebral contusions Many antibacterial/ antifungals Mental status examination Generalised psychomotor retardation ( or agitation in elderly), stooped posture, slow spontaneous movements, downcast gaze, decreased rate of speech with increased reaction time, depressed mood and restricted affect, with delusions or hallucinations in perceptual disturbance may be seen. Thought process may be slow with poverty of ideas. Though sensorium is intact memory may be

impaired with increased impulsivity (assess for suicide) with impaired judgement (too pessimist) and insight may be impaired. Usually the classic triad of pessimist thoughts about self, future and others may be seen. A differential diagnosis needs to be done from the comorbid conditions as listed above as treating the underline cause may change the course of Depression. Also the distinction of unipolar and bipolar depression is inevitable for optimal treatment. 19

Management: Goals  Psychoeducation  Relieve the symptoms of present episode (remission)  Frequent follow ups until remission and also later  Restore premorbid functioning of individual  Maintain treatment to prevent relapse (usually if no or minimal depressive symptoms for 9 – 12 months and ability to carry out routine activities for that time period consider tapering and stopping the antidepressant) PHARMACOLOGICAL Tricyclic antidepressants(TCA): Imipramine,

Amitryptyline Selective Serotonin Reuptake PSYCHOLOGICAL Inhibitors(SSRI): Fluoxetine, Sertraline, Psychoeducation, cognitive behavioural Escitalopram Serotonin Norepinephrine receptor inhibitors: Venlafaxine therapy (CBT) Others: Mirtazepine PSYCHOSOCIAL Psychoeducation, address current psychosocial stressors, reactivate social networks, activity scheduling, physical activity 20

At primary health care level, it may be feasible to  Select a drug from national formulary and give according to instructions given below.  Give psychosocial interventions along with, depending on severity of depressive symptoms.  Exploring the psychosocial stressors of patient in privacy, empathetically and helping problem solve them may be needed. Family and friends can be used to build up support system for patient. Any pertinent stress like abuse may need to be dealt with in patient’s environment.

 Patient should be encouraged to resume the earlier pleasurable hobbies and social meetings to reactivate his social circuits.  Patient may need to be helped with a schedule according to his strengths and weaknesses and appropriately rewarded and applauded for the same with the help of family members initially.  Some sort of physical activity or yoga may be advised (45 minutes 3-5 times/week)  Any comorbid medical condition should be treated adequately at primary health care level

Select an antidepressant from the WHO Formulary. Fluoxetine and amitriptyline (as well as other tricyclic antidepressants (TCAs) are antidepressants mentioned in the WHO Formulary. In the national list of essential medicines Fluoxetine, Imipramine and Amitriptyline have been mentioned. National formulary of India advices use of Fluoxetine, Escitalopram, Imipramine and Amitriptyline. Following table summarises the drug information. SSRI’s TCA

Common side-effects (mostly self-limiting) Common side-effects (mostly self-limiting) Restlessness, nervousness, insomnia, anorexia, Orthostatic hypotension (fall risk), dry mouth, gastrointestinal disturbances, headache, sexual constipation, difficulty urinating, dizziness, dysfunction blurred vision and sedation. Risk of switching to mania in people with Serious side-effects: cardiac arrhythmia. bipolar disorder. Risk of switching, lethal in overdose, sedating Time to response: 4 – 6 weeks after adequate

Time to response: 4 – 6 weeks after adequate dose dose Dose for fluoxetine: Initiate treatment with 20 21

mg daily (if not tolerated even 10 mg) once Dose of amitriptyline: daily and increase to 20 mg if the medication is Start with 50 mg at night and reach up to 100- tolerated. If no response in 4 – 6 weeks or 150 by 4-6 week and if no/partial response partial response in 6 weeks, increase dose by increase further(maximum 200 mg) 20 mg (maximum dose 60 mg) Do not prescribe for adolescent population For children and elderly start with 10 mg and increase gradually to 20 mg. wait for 6-12

For elderly start low with 25 mg and go slow weeks before up titration. with wait up to 12 weeks and maximum dosage being 100 mg. Monitor for emergence of suicidal ideation in adolescent population and refer to specialist if DO NOT prescribe TCA to people at risk of no response. serious cardiac arrhythmias or with recent myocardial infarction. Monitor blood pressure for all cardiovascular patients on TCA. Special population Individuals with Pregnancy and breast children Elderly concurrent feeding conditions

Treat both the Avoid psychotropic in Offer Avoid Tricyclic depression and the pregnancy, and pharmacotherapy antidepressants, concurrent condition manage with non- with fluoxetine watch for drug pharmacological (> 12𝑦𝑟𝑠) only if non interactions, expect means, however pharmacological slower response, weigh the risk benefit treatments fail. increase dosages ratio of continuing an Monitor for gradually and treat antidepressant during emergence of suicidal with lower dosages pregnancy. Avoid long ideation.

acting fluoxetine during breast feeding When to refer  Patient has severe depression with psychotic features  Suicidal ideations  Failure of 2 or more antidepressants  Psychological intervention needed ( lack of resources)  Bipolar affective disorder  Multiple comorbid conditions  Special population if not manageable  Any other emergency comorbid with mood disorder 22

Bipolar affective disorder (BAD) BAD is characterised by an episode of mania or hypomania. It may or may not be followed by a subsequent mood episode. About 5-10% of patients with initial diagnosis of major depressive episode have a manic episode later on. Dianostic criteria Mania Elevated, expansive or irritable mood + 3 of the following (4 if mood is irritable)  Increased activity, restlessness, excitement Multiple symptoms, lasting for at least 1 week  Increased talkativeness

 Loss of social inhibitions Severe enough to interfere significantly with  Decreased need for sleep work and social activities or requiring  Overspending or other reckless behaviours hospitalization  Distractibility  Elevated sexual energy Hypomania Same features as mania but with a lesser severity and Some symptoms, lasting for at least 4 days duration. Cause some interference with work and social activities but do not require hospitalization or have psychotic features

So a bipolar disorder may manifest as single manic episode or a manic/hypomanic episode with depression. 23

BAD present episode hypomanic bipolar BAD manic affective current episode disorder episode (BAD) manic BAD current episode depression Clinical features and MSE Mood Changes as elation, euphoria or Irritable. The level of goal directed and pleasurable activities increase that are usually reckless and involve risk. Patient is distractible with poor concentration. Speech is rapid and patient jumps from one topic to another. Patient may have delusions mainly

grandiose delusions of power, worth or identity. There is decrease in need of sleep and still high levels of energy, increased appetite, increased libido and sexual activity, increased desire for substances. Also the disorder may be comorbid with other general medical conditions as depicted under depression. Comorbid psychiatric conditions and substances are mentioned here. PREDICTORS OF BIPOLARITY Other psychiatric disorders  Early age of onset with marked psychomotor Anxiety disorders retardation)

 Postpartum depression Substance use disorders  Rapid onset and offset of depressive episodes  Recurrent depression (5 or more episodes)  Atypical symptoms (increase in appetite and sleep)  Bipolar family history Drugs  Antidepressant induced hypomania  Seasonal episodes Withdrawal of Sedatives, alcohol Prolonged use of Amphetamines, cocaine 24

Stimulants (methylphenidate) Steroids Bromocriptine, levodopa Baclofen opioids Management Goals  Psycho education  Treat the present episode  Prevent relapse by maintenance treatment ( at least 2 years after last bipolar episode )  Know when to refer  rehabilitation (appropriate economic, social, cultural and educational activities) Begin treatment of acute mania with mood stabilizer (lithium, valproate, and If present episode is carbamazepine) or with antipsychotics* mania/hypomania

Consider short-term benzodiazepine* such as diazepam for behavioural disturbance or agitation. Discontinue any antidepressants. Begin treatment with a mood-stabilizer If present episode is depression but there is history of past Consider antidepressant combined with bipolar affective disorder or mood stabilizer for moderate / severe past manic /hypomanic episode depression with monitoring of switching in history to mania. However, referral to a specialist should be done. Consider non

pharmacological management of mild bipolar depression along with mood stabilizer. 25

*National formulary of India- Antipsychotics for acute mania (Olanzapine, Haloperidol, Chlorpromazine, Fluphenazine) and short term Benzodiazepines (Diazepam, Lorazepam, Alprazolam, Nitrazepam) When to refer  If acute episode is severe and not being controlled at primary health care setting  A patient with bipolar depression  Medical emergencies comorbid with Bipolar mood disorder  Special population like elderly, pregnant women and children and adolescent  Toxicity with drugs

Primary mood stabiliser can be lithium, valproate or carbamazepine as shown in the table below. 26

Lithium* valproate Carbamazepine* Starting dose: 300 Starting dose: 500 Starting dose: 200 Usual dose : 600-1200 Usual dose : 1000-2000 Usual dose : 400-600 Levels: 0.6 – 1.0 mEq / litre Avoid in pregnancy and advice contraception Mania: 0.8 – 1.0 mEq / litre to woman of chil d bearing age along with folate supplementation. Lithium also Maintenance: 0.6 – 0.8 mEq / associated with birth defects (mainly cardiac) litre. though at a lower rate than antiepileptic drugs Regular serum level

monitoring critical. Monitor TSH and S. creatinine levels also. Side effects: Tremors, sedation, weight Tremors, sedation, weight Tremors, sedation, weight gain gain, hepatotoxicity, gain, leukopenia, leukopenia. Watch for hepatotoxicity. Watch for Impaired coordination, hepatitis, pancreatitis, diplopia, impaired polyuria, polydipsia, cognitive thrombocytopenia, coordination, rash, liver problems, enzyme cardiac arrhythmias, diabetes Elevations, Stevens-Johnson insipidus, hypothyroidism

syndrome, aplastic anaemia. No level monitoring required. START if both lithium and Get hepatic status before START only if clinical and valproate ineffective or not initiating. Ex-plain the signs laboratory monitoring is tolerated. Monitor blood and and symptoms of blood and available. hepatic parameters. liver disorders. Monitor Effective against the relapse of hepatic and blood indices. both mania and depression Educate about lithium toxicity 27

 Take plenty of fluids (summers) with no salt restriction  Reduce or stop lithium temporarily on developing fever, loose motions, vomiting or any condition leading to fluid loss  ACE inhibitors, diuretics and NSAIDs along with Lithium increase risk of toxicity  Gastrointestinal upset, dysarthria, ataxia, coarse tremor followed by impaired consciousness, fasciculation, myoclonus, seizures, and coma are signs of toxicity  Monitoring for features of lithium toxicity should be routinely done and

appropriate referral done accordingly. *Carbamazepine and Lithium carbonate are included in National formulary of India while Lithium and Valproate are mentioned in national list of essential medicines. Special population should be referred to psychiatrist. Females of child bearing age on antiepileptic mood stabiliser should receive folate supplementation and be advised to practice contraception. Even for Lithium a risk benefit assessment needs to be done before continuing in pregnancy as it is

also associated with teratogenic effects though less than that of antiepileptic mood stabilisers. Thus a referral needs to be done. 28

ANXIETY DISORDERS INTRODUCTION AND EPIDEMIOLOGY ANXIETY : diffuse, vague, unpleasant sense of apprehension that is felt as psychic tension and restlessness or autonomic arousal like palpitation, perspiration, headache, chest tightness, abdominal discomfort, inability to sit still. It is usually insidious to an unknown, internal, vague, conflictual threat. FEAR: response to external, known, definite, non conflictual threat that alerts the individual

Anxiety is normal if it is alerting in response to external stress and leads to optimal performance. However, if anxiety leads to excessive arousal and impairment in the ability to function normally it is pathological and should be treated. It is said that the 12-month prevalence rate of anxiety disorder is 17.7 percent with women having more prevalence then men. Patients seeking treatment for somatic and cognitive symptoms of anxiety may be most commonly encountered by a GP. TYPES OF ANXIETY DISORDERS

 Phobic anxiety disorder  Panic disorder  Generalised anxiety disorder  Obsessive compulsive disorder  Acute stress disord er  Post-traumatic stress disorder  Anxiety disorders due to general medical condition and substances  29

PHOBIC ANXIETY DISORDER These are by far one of the commonest mental disorders, with females more afflicted then males and onset usually seen in teens. It can be of 3 types broadly 1. Agoraphobia 2. Social phobia 3. Specific phobia AGORAPHOBIA DIAGNOSTIC CRITERIA AND CLINICAL FEATURES Agoraphobia Marked and consistent fear or avoidance of at least two of the following situations: crowds; public places; travelling alone; travelling away from home.

Symptoms of anxiety in the feared situation at some time since the onset of the disorder, with at DIleAaGstN twOoS TsyImCp CtoRmITs E RIA AND CLINICAL FEATURES Autonomic arousal symptoms Palpitations, Sweating Trembling, Dry mouth Symptoms concerning chest and abdomen Difficulty breathing, Feeling of choking, Chest pain or discomfort, abdominal distress Symptoms concerning mental state Feeling dizzy or light-headed. Feelings that objects are unreal (derealisation), or that one's self is

unreal (depersonalization), Fear of losing going crazy, Fear of dying. General symptoms Hot flushes or cold chills, Numbness or tingling sensations. Significant emotional distress due to the avoidance or the anxiety symptoms, and a recognition that these are excessive or unreasonable. Symptoms predominate in the feared situations or when thinking about them. Agoraphobia CAN BE without panic disorder 30

SOCIAL PHOBIA DIAGNOSTIC CRITERIA AND CLINICAL FEATURES Social phobias A. Either (1) or (2): (1) Marked fear of being the focus of attention, or fear of behaving in a way that will be embarrassing or humiliating (2) Marked avoidance of being the focus of attention or situations in which there is fear of behaving in an embarrassing or humiliating way. These fears are manifested in social situations (eating or speaking in public; encountering

known individuals in public; or entering or enduring small group situations, such as parties, meetings and classrooms) At least two symptoms of anxiety in the feared situation at some time since the onset of the disorder, as defined in Agoraphobia and in addition one of the following symptoms: Blushing; Fear of vomiting; Urgency or fear of micturition or defecation. Significant emotional distress due to the symptoms or to the avoidance and recognition that

the symptoms or the avoidance are excessive or unreasonable. Symptoms predominate in the feared situation or when thinking about it. SPECIFIC PHOBIA DIAGNOSTIC CRITERIA AND CLINICAL FEATURES Specific (isolated) phobias Either (1) or (2): (1) marked fear of a specific object or situation other than agoraphobia or social phobia (2) marked avoidance of such objects or situations (animals, birds, insects, heights, thunder, flying,

small enclosed spaces, sight of blood or injury, injections, dentists and hospitals) B. Symptoms of anxiety in the feared situation at some time since the onset of the disorder, as defined in agoraphobia. Significant emotional distress due to the symptoms or the avoidance, and a recognition that these are excessive or unreasonable. So precisely, phobic anxiety disorders are characterised by excessive, irrational fear or avoidance of

a p Sayrmticputloamr ssi tauraet iroens torric ttheidn gto ( atlhoen fge wariethd psihtuyasitcioanl ,s yomr wphtoemn sth oinf kainnxgi eatbyo iuft s iut.c Iht tchainn gbse a: raen eimndaul rteydp)e, (e.g. insects, dogs); nature-forces type (e.g. storms, water); blood, injection and injury type; situational type (e.g. elevators, tunnels); other type 31 It can be: animal type (e.g. insects, dogs); nature-forces type (e.g. storms, water); blood,

injection and injury type; situational type (e.g. elevators, tunnels); other type

DIFFERENTIALS Phobias need to be differentiated from normal shyness, substance induced anxiety symptoms, central nervous symptoms pathologies. Schizophrenia patients may have specific or social phobia but as part of their broader psychosis. PANIC DISORDER The lifetime prevalence of this disorder id 1-4% with women being twice more likely to be affected. Mean age of presentation is 25 years. DIAGNOSTIC CRITERIA AND CLINICAL FEATURES

Recurrent panic attacks that are not consistently associated with a specific situation or object and often occurring spontaneously The panic attacks are not associated with marked exertion or with exposure to dangerous or life- threatening situations. A panic attack is characterized by all of the following:(a) it is a discrete episode of intense fear or EXPLAINING THE VIGNETTE discomfort; (b) it starts abruptly; (c) it reaches a crescendo within a few minutes and lasts at least

some minutes; (d) at least four symptoms of anxiety must be present as described in phobic disorder above Panic disorder is characterised by unexpected discrete episodes of fear and physical symptoms of anxiety that swarm in a few minutes and subside in next few. Usually they are mistaken for acute cardiac events and patients may have several emergency visits before being diagnosed as panic disorder as seen in this case. So a detailed history and thorough

medical workup may help bring upon timely intervention for the patient. Also, this patient is self-treating his anticipatory anxiety with alcohol. Substance abuse may be comorbid with anxiety disorders. COMMON DIFFERENTIALS Mostly panic attacks are confused with acute cardiac syndromes like anaemia, cardiac failure, arrhythmias or angina and most of the initial workup is done on that line. Respiratory emergencies like asthma should be ruled out. Endocrine disorders like thyrotoxicosis,

Pheochromocytoma, hypoglycaemia, menopausal or premenstrual syndromes may manifest as extreme anxiety. Some drug intoxication or withdrawal states or allergic states like anaphylaxis should be ruled out 32

GENERALISED ANXIETY DISORDER (GAD) They constitute one fourth of all anxiety disorder with onset seen in late adolescence and more in females. DIANOSTIC CRITERIA AND CLINICAL FEATURES A period of at least six months with prominent tension, worry and feelings of apprehension, about every-day events and problems. Four symptoms out of the following list Autonomic arousal symptoms Palpitations, Sweating Trembling, Dry mouth Symptoms concerning chest and abdomen

Difficulty breathing, Feeling of choking, Chest pain or discomfort, abdominal distress Symptoms concerning mental state Feeling dizzy or light-headed. Feelings that objects are unreal (derealisation), or that one's self is unreal (depersonalization), Fear of losing going crazy, Fear of dying. General symptoms Hot flushes or cold chills, Numbness or tingling sensations. Symptoms of tension Muscle tension or aches and pains, Restlessness and inability to relax, Feeling keyed up, or

on edge, or of mental tension, A sensation of a lump in the throat, or difficulty with swallowing. Other non-specific symptoms Being startled easily, Difficulty in concentrating, or mind going blank, because of worrying OoBrS aEnxSieStIyV, PEe rCsiOsteMntP irUriLtaSbIilVityE, DDifIfiScuOltRy DgeEttRin g to sleep because of worrying. It is the fourth most common psychiatric disorder with equal prevalence in men and women and mean age of onset in 20 years. 33

DIANOSTIC CRITERIA AND CLINICAL FEATURES Either obsessions or compulsions (or both), present on most days for a period of at least two weeks. Obsessions (thoughts, ideas or images) and compulsions (acts) share the following features (1) They are acknowledged as originating in the mind of the patient and are not imposed by outside persons or influences. (2) They are repetitive and unpleasant, and at least one obsession or compulsion must be present that is acknowledged as excessive or unreasonable.

(3) The subject tries to resist them but at least one obsession or compulsion must be present which is unsuccessfully resisted. (4) Carrying out the obsessive thought or compulsive act is not in itself pleasurable. The obsessions or compulsions cause distress or interfere with the subject's social or individual functioning, usually by wasting time. ACUTE STRESS DISORDER A young male patient was brought to the OPD as he was very agitated after hearing the news

of death of his wife suddenly in an accident few minutes back. Relatives reported on hearing the news he did not respond and after a while started saying irrelevant things and occasionally misnamed relatives. On being asked he even abused and became violent with his brother. Patient appeared confused, disoriented, dizzy and restless and every now and then used to pace around in the room. He had tachycardia, flushing and sweating and shortness of breath. He had no past history of any illness.

Exposure to an exceptional mental or physical stressor. Followed by an immediate onset of symptoms (within one hour) (Two groups of symptoms) are given (1) The criteria for symptoms as mentioned in generalized anxiety disorder (2) Withdrawal from expected social interaction; narrowing of attention; apparent disorientation; anger or verbal aggression; despair or hopelessness; purposeless over-activity; uncontrollable and excessive grief (judged by local cultural standards).

If the stressor is transient or can be relieved, the symptoms must begin to diminish after not more than eight hours. If the stressor continues, the symptoms must begin to diminish after not more than 48 hours. 34

Post-traumatic stress disorder Exposure to a stressful event or situation of exceptionally threatening or catastrophic nature, which is likely to cause pervasive distress in almost anyone. Persistent remembering or reliving the stressor by intrusive flash backs, vivid memories, recurring dreams, or by experiencing distress when exposed to circumstances resembling or associated with the stressor. Avoidance of circumstances resembling or associated with the stressor Either (1) or (2):

(1) Inability to recall, either partially or completely, some important aspects of the period of exposure to the stressor (2) Persistent symptoms of increased psychological sensitivity and arousal shown by any two of the following: difficulty in falling asleep, irritability, difficulty in concentrating; hyper-vigilance; exaggerated startle response. Symptoms occurred within six months of the stressful event, or the end of a period of stress.

These symptoms are seen in patients who are exposed to some life threatening event like natural calamities followed by a triad of re-experiencing, avoidance and increased arousal. MANAGEMENT Pharmacological Non pharmacological  Short term treatment with  Psycho education about the disorder benzodiazepines (BZD’s)  Exploring the concomitant stressors  Withdraw BZD’s after initial 2-4 and addressing the worries in a weeks. reassuring, empathic and neutral  Always taper BZD’s manner

 Long term treatment with  Cognitive behavioural therapy antidepressants preferably Selective (CBT) ( include relaxation, Serotonin Reuptake biofeedback and addressing Inhibitors(SSRI’s) followed by cognitive distortions) tricyclic antidepressants and MAO  Supportive psychotherapy inhibitors  Insight oriented psychotherapy  Regular exercises, yoga, breathing exercises may be advised along with 35

Phobic anxiety disorder: pharmacotherapy with SSRI’s, beta blockers (performance anxiety) or CBT ( systematic desensitisation) Panic disorder: pharmacotherapy with SSRI’s, beta blockers or CBT involving relaxation training and cognitive remodelling Generalised anxiety disorder : short term management with BZD’s + long term CBT or SSRI’s Obsessive compulsive disorder: Either CBT as Exposure and Response Prevention (ERP) or antidepressants ( SSRI’s or Clomipramine) or a combination of both

Acute stress disorder: short term BZD’s + Debriefing in groups post trauma or pharmacotherapy Post-traumatic stress disorder: CBT ( systematic desensitisation), eye movement desensitisation and reprocessing (EMDR) or pharmacotherapy ( SSRI’s or imipramine, amitriptyline) COMORBID CONDITIONS WITH ANXIETY DISORDERS General medical conditions Other psychiatric disorders Endocrine Substance use disorders Hyperthyroidism, hypoparathyroidism, Cushing’s syndrome, Schizophrenia

hypoglycaemia, Pheochromocytoma, Addison’s disease Mood disorders 36

Pulmonary Asthma, hyperventilation Drugs Cardiovascular Anaemia, cardiac failures, mitral valve prolapse, hypertension, Withdrawal of angina, myocardial infarction Alcohol, opiates, sedatives, Neurological hypnotics Infarcts, haemorrhage, epilepsy, migraine, Wilson’s disease, Intoxication basal ganglia disease like Sydenham’s chorea and Huntington’s Nicotine, amphetamine, cocaine, disease(OCD) theophylline, amyl nitrite, Metabolic hallucinogens Dyselectrolytemia, renal/hepatic failures Nutritional

The following table is an outline for the use of drugs for treating anxiety disorders. Group of drug Dosages (mg/day) Adverse effects Selective serotonin reuptake inhibitors (SSRI’s) Sertraline 50-200 Sleep disturbance, Escitalopram* 10-20 gastrointestinal side effects, headache, Paroxetine anxiety, prolonged bleeding time, 20-50 hyponatremia, sexual dysfunction, Citalopram discontinuation syndrome 20-40 Fluoxetine* 20-60 Fluvoxamine 100-300 Tricyclic antidepressants sedation, hypotension, cardiac side

(TCA) effects mainly prolonged QT interval, 75-300 anticholinergic effects, weight gain Clomipramine 75-300 Imipramine* 75-200 Amitriptyline Benzodiazepines (BZD’s) Clonazepam 0.5-2 On long term use-Tolerance, dependence and withdrawal, ataxia, Alprazolam* 0.5-4 dizziness, daytime drowsiness, amnesia, in overdose respiratory depression Lorazepam* 1-4 Diazepam* 5-15 Beta-blockers Propranolol 10 – 20 mg bid or tds Hypotension, bradycardia, worsening of asthma and hypoglycaemia, GI side effects

*In National formulary of India WHEN TO REFER  If 2 adequate trial of treatments {antidepressant(usually 8-16weeks) or psychotherapy or combination} fails  Need for specialised psychological intervention and lack of resources 38  Severe or chronic disorders or those with comorbid psychiatric conditions that need multidimensional approach  Secondary depressive features are severe enough to warrant independent attention

SOMATOFORM DISORDERS Introduction Somatoform Disorders are a broad group of illnesses that have bodily signs and symptoms as a major component. According to ICD – 10 [International Classification of Diseases – 10th revision], Somatoform Disorders are described as ‘Repeated Presentation of physical symptoms together with persistent requests for medical investigations, although patients have been reassured by their

Physicians that the symptoms have no physical basis'. In people who have a somatoform disorder, history and physical examination do not indicate the presence of a medical condition. Medical test results are either normal or do not explain the person's symptoms. Patients are convinced that their symptoms result from some type of undetected and untreated bodily derangement. These complaints are not imaginary and patients do actually experience these symptoms. These disorders

encompass mind – body interactions in which the brain sends various signals that impinge on the patient’s awareness, indicating a severe problem in the body. Epidemiology Somatoform Disorders are more common in females as compared to males with approximate ratio of 4: 1. The overall prevalence of these disorders varies from 1-5 %. It is found in 5-10 percent of patients presenting to General Practitioners, hence it is important to identify at

primary level. Usually, the symptoms begin appearing during adolescence, and patients are diagnosed before the age of 30 years. They are more common in people with low education & low income. Symptoms are sometimes similar to those of other illnesses and may last for several years before initial presentation. Symptoms may occur across cultures and gender. Clinical Features The ICD – 10 classifies Somatoform Disorders into various categories with a common underlying pre-

occupation with bodily signs and symptoms. These categories are Somatization disorder, Hypochondriacal disorder, Un-differentiated somatoform disorder, Somatoform autonomic dysfunction, Persistent somatoform pain disorder and others. Somatization disorder - The main features are multiple, recurrent, and frequently changing physical symptoms, which have usually been present for several. The patients believe they have been sick

most of their lives. Most patients have a long and complicated history of contact with both primary 39

and specialist medical services, during which many negative investigations or operations may have been carried out. Symptoms commonly involve gastrointestinal sensations (pain, belching, regurgitation, vomiting, nausea, etc.), abnormal skin sensations (itching, burning, tingling, numbness, soreness, etc.), headache and blotchiness. Sexual, menstrual and neurologic problems may also be reported. The course of the disorder is chronic and fluctuating. People with this disorder tend to be

referred to various specialists, and have many tests and investigations. Dependence upon or abuse of medication (usually sedatives and analgesics) is often found. Hypochondriasis - This is a disorder where people fear that minor symptoms may be due to a serious disease. For example, that a minor headache may be caused by a brain tumor, or a mild rash is the start of skin cancer. People with this disorder have many such fears and spend a lot of time thinking about their symptoms.

Body dysmorphic disorder - People with this disorder are obsessed and exaggerate a physical flaw. Patients may also imagine a flaw they don't have. The preoccupation may involve any part of the body such as wrinkles, hair, or the size or shape of the eyes, nose, or breasts. Some people consult a cosmetic surgeon to have the imagined or trivial defect corrected. Pain disorder - The predominant complaint is of persistent, severe, and distressing pain, which

cannot be explained fully by a physiological process or a physical disorder. Pain usually starts with a psychological stress or trauma. For example, they develop an unexplained, chronic headache after a stressful life event. Somatoform autonomic dysfunction - The symptoms are presented by the patient as if they were due to a disorder of a system or organ that is under autonomic innervations i.e. the cardiovascular,

gastrointestinal, or respiratory system although there is no evidence of a significant disturbance. Presenting symptoms usually are palpitations, sweating, flushing, tremor, sensations of fleeting aches and pains, burning, heaviness, tightness, and sensations of being bloated. Somatoform disorder not otherwise specified - People with this type do not meet the full criteria for any other somatoform disorders. Example includes pseudocyesis (mistaken belief of being

pregnant based on other signs of pregnancy, including an expanding abdomen; feeling labor pains, nausea, fetal movement etc.) Somatoform Disorders are commonly associated with other psychiatric disorders, namely Personality Disorders, Substance related Disorders, Generated Anxiety Disorder and Phobia. Suicidal threats are common but actual suicide is rare. Patient’s medical histories are usually vague, inconsistent and confusing. Patients classically described their complaints in a dramatic, emotional

and exaggerated fashion. They would emphasize the need for further investigations or examinations. Assessment and Diagnosis The general practitioners and medical officers play a vital role in the management of patients with somatoform disorders. They act as the 'gatekeeper' and have the potential to limit the patient's access to specialized hospital resources, many of which are not only expensive, but also carry the 40

possibility of iatrogenic harm. Appropriate and timely diagnosis in primary care combined with collaborative psychiatric and medical interventions may decrease significant long-term morbidity and suffering. The assessment aims to clarify patient's somatic symptoms and their effects on daily life, Understand what patient wants from treatment, Elicit fears and beliefs about illness, Exclude organic disease, Identify relevant psychosocial Stressors, Identify co-morbid psychiatric disorders, Risk of

suicide and Dependence on medications. Previous referrals, investigations and treatment history needs detailed assessment (Box - 1). Doctors may need to perform laboratory tests to rule out other possible causes before they diagnose somatoform disorder. Box - 1: Objectives in assessment interview  Clarify patient's complaints  Understand what patient wants  Elicit fears and beliefs about illness  Previous referrals, investigations and treatments  Exclude organic disease

 Identify relevant psychosocial Stressors  Order relevant investigations  Identify drug misuse  Identify psychiatric disorders and risk of suicide Differential Diagnosis  Malingering (Intentionally producing symptoms to achieve an environmental goal)  Factitious disorder (Fabrication of symptoms or self-inflicted injury to assume the sick role)  Psychosomatic illness (A real medical condition affected by stress or psychological factors)  Depression Treatment of Somatoform Disorders

Somatoform disorders are difficult to treat as patients often cling to the belief that their symptoms have an underlying physical cause. Reassurance by a doctor does not usually help as they feel their doctors cannot find the cause for their symptoms. 41

A strong doctor-patient relationship is a key to getting help in patients with somatoform disorders. Seeing a single health care provider with experience managing somatoform disorders can help cut down on unnecessary tests and treatments (Box - 2). The focus of treatment is on improving daily functioning, not on managing symptoms. Stress reduction is often an important part of getting better. Stress management techniques,

Counseling for family and friends, Promotion of self-care activities, Relaxation and breathing exercises, Lifestyle change and Occupational Counseling may be useful and can be done at primary level. Medications do not have much of a role except if the disorder is associated with underlying mental illnesses such as depression, anxiety or substance abuse. Still, antidepressants such as amitriptyline, imipramine and selective serotonin reuptake inhibitors

(SSRIs) along with short-term antianxiety agents such as benzodiazepines have been found effective. Box - 2 : Specific treatments for somatoform disorders  General advice Lifestyle change Relaxation  Drug treatments Antidepressants Anti-Anxiety drugs (short duration)  Occupational and social Occupational counseling Problem-solving for social problems  Psychological treatments Cognitive-behavioral and other therapies  Regular appointments at fixed, pre-arranged intervals  Minimize use of drugs 42

When to Refer? Some important indicators that should guide the primary care provider to refer to psychiatrists include;  Diagnostic dilemma  Chronic & Severe illness  Suicidal threats and attempts.  Co-morbid Psychiatric problems like severe depression and substance abuse.  No relief on initial treatment 43

EMOTIONAL AND BEHAVIOURAL PROBLEMS IN CHILDREN & ADOLESCENTS INTRODUCTION The child is continually developing. Symptoms & Behaviour problems change with developmental changes, as do emotional needs. The developmental stage can influence the presentation, significance & course of a psychiatric disorder. It is essential that all individuals involved in the care of children have at least a basic understanding of ‘normal’ and ‘abnormal’ childhood experience and behaviour.

Transient symptoms and behavioural disturbances are common in children of all ages. Parents are becoming increasingly aware of emotional health problems in Children and seek help for various concerns regarding their children. Parents may seek help for various concerns regarding their children. These concerns may include children not able to sit still, not able to pay attention, not able to engage in verbal, non-verbal, or social communication with others, seems to be withdrawn, depressed, angry,

and violent, poor scholastic performance, drug abuse etc. The major epidemiological features of childhood psychiatric disorder are:  Boys are affected twice as often as girls for most diagnoses.  Commonest diagnoses are emotional and conduct disorder.  Disorders are commoner in children with mental retardation, epilepsy or medical illness. ETIOLOGY IN CHILD PSYCHIATRY  The same broad range of etiological factors operates in childhood as in adulthood.

 There is a genetic component to most disorders, mediated partly through its influence on intelligence & temperament. The disorders involve interplay of genetic and environmental factors.  The major environmental factors are the family & social circumstances. The family factors include parenting styles, parental conflict/ separation and social factors include deprivation. A deprived child is one who is: Without proper parental care or control, subsistence, education as

required by law, or other care or control necessary for his physical, mental, or emotional health or morals, has been placed for care or adoption in violation of law, has been abandoned by parents or other legal custodian, is without a parent, guardian, or custodian.  Other factors like medical disorder (Epilepsy) might also increase the risk. RANGE OF CHILDHOOD PSYCHIATRIC DISORDERS The Mental Health problems affecting children and adolescents may be considered from a

number of perspectives. The disorders listed below are identified as priority areas based on 44

higher frequency of occurrence and degree of associated impairment, therapeutic possibilities and long-term care consequences. EARLY CHILDHOOD MIDDLE CHILDHOOD ADOLESCENCE    LearBnien g Disorders Tic disorders Depression and associated suicide  (Tourette’s  Pervasive Development Anxiety Disorders Dis order (autism) Syndrome)  Psychosis  Hyperkinetic Disorders  Attachment Disorders (ADHD)  Conduct Disorder  Substance Abuse  Eating Disorders

Internalising behavioural problems are characterised by an overcontrol of emotions and include being withdrawn, demanding attention, being too dependent or clingy and feeling worthless or inferior. DESCRIPTION OF CHILDHOOD PSYCHIATRIC DISORDERS (A) LEARNING DISORDERS: Learning disorders have a high incidence and prevalence with serious implications for future productivity. Learning disorders are diagnosed when the individual’s academic achievement in reading,

mathematics, or writing is substantially below what would be expected for age, schooling and intellectual ability (APA, 1994). Specific Learning Disorder (SLD) is a disorder in one or more of the basic psychological processes involved in understanding or in using spoken or written language. The disability may be exhibited as an imperfect ability to listen, think, speak, read, write, spell, or do mathematical calculations. Types of Learning Disorders:

Reading disorders:  Reading skills significantly below expectancy  Significantly interferes with academic achievement or activities requiring reading skills Mathematics disorders:  Mathematics skills significantly below expectancy  Significantly interferes with academic achievement or activities requiring mathematics skills Disorder of written  Writing skills significantly below expectancy expression  Significantly interferes with academic achievement or activities requiring mathematics skills 45

The most common treatment for learning disabilities is special education. Other professionals such as speech and language therapists also may be involved. This usually requires referral to a higher center. (B) PERVASIVE DEVELOPMENTAL DISORDERS These are Developmental disorders where the development follows a deviant path and there is a deviation in development of communication and socialization. The disorders included in this category are  Autism  Aspergers disorder  Retts disorder

 Other disintegrative disorders  PDD unspecified AUTISM: Autism is a pervasive developmental disorder and characterized by significant problems in all three domains of:  Communication  Social interactions  And stereotyped patterns of behaviour Characteristic features:  Difficulties with social interactions  Marked impairment in the use of non-verbal behaviours, such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction

 A decrease or lack of spontaneous seeking to share enjoyment, interests, or achievements with other people  Decreased or lack of social or emotional reciprocity  Failure to develop peer relationships appropriate to developmental level  Impairments in communication  Delay or total lack of development of spoken language  Stereotyped or repetitive use of language or idiosyncratic language  Lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level.

Common co-occurring conditions in autism:  Mental Retardation: up to 75% of people with autism have mental retardation  Seizures: 25% of autistic individuals also develop seizures, some in early childhood and others as they go through puberty Treatment:  Behavioural, psychotherapeutic as well as pharmacologic approaches can be used to address numerous problems, but unfortunately there is no cure for the core disorder

 The goal of treatment is not merely to lessen symptoms, but to help the individual achieve the maximally feasible quality of life 46

(C) MENTAL RETARDATION/ INTELLECTUAL DISABILITY:  Mental retardation is one of the most prevalent of the developmental disorders, occurring in approximately 1 – 3% of school-aged children and estimated to be 2.5%.  Mental Retardation or Intellectual disability involves impairments of general mental abilities that impact adaptive functioning in three domains, or areas. These domains determine how well an individual copes with everyday tasks:

 The conceptual domain includes skills in language, reading, writing, math, reasoning, knowledge, and memory.  The social domain refers to empathy, social judgment, interpersonal communication skills, the ability to make and retain friendships, and similar capacities.  The practical domain centers on self-management in areas such as personal care, job responsibilities, money management, recreation, and organizing school and work tasks. CATEGORY IQ RANGE LEVEL OF FUNCTIONING

Mild MR 50-70  Individuals educable.  Can be minimally self supporting.  Can acquire basic social and vocational skills. Moderate MR 35-49  They are trainable.  Able to perform academic activities comparable to a child in Grade two. Severe MR 20-34  Seriously impaired in their motor and speech development  Only learn basic language and practice hygiene after age six. Usually permanently dependent on others and therefore spend their lives with family, in community homes or in institutions.

Profound MR Less Than 20  Fully reliant on caregivers.  Often diagnosed with a neurological disorder and epilepsy, spasticity and mutism. 47

Etiology: Mental retardation may be the end result of one of the following categories of risk.  Biomedical- these are factors that have a deleterious impact on the child’s central nervous system  Social- inadequacies in the social and/or family environment can diminish cognitive and social growth and development  Behavioral- these include trauma, maternal substance abuse  Educational- the availability and quality of training programmes can affect intellectual

development and influence whether or not the child functions in the range of mental retardation.  Interaction between risk factors Assessment of mental retardation: The diagnosis of the cause of mental retardation involves pediatricians and pediatric neurologists The assessment of a child with suspected mental retardation encompasses: - Making the diagnosis - Evaluating concurrent psychiatric problems Management: Mental retardation is rarely treatable and management is aimed at maximizing potential and

quality of life, and treating concurrent psychiatric problems. The physician should help the family to prepare for the future. The clinician should ensure, that over time, the family accepts the prognosis and has realistic expectations for the child’s future. (D) HYPERKINETIC DISORDER:  It is also called ADHD: Attention Deficit Hyperactivity Disorder.  Prevalence of this disorder is estimated to be around 3-5% in pre-pubertal children.  It is much more common in boys than girl (4:1)

 The onset is usually in early childhood (before age 7) but the problem is usually identified when the child starts going to school. Characteristic features: This disorder is characterized by: Hyperkinetic behaviour and poor attention span.  The main feature is hyperkinetic behaviour:  The second characteristic is poor attention As children they are: span - Restless and cannot sit still. - These children do not concentrate on - Fiddle with everything around any task and leave most tasks

- Emotionally excitable unfinished. - Show episodes of rage or crying - These patients may have many other - Impulsive associated symptoms like impulsivity, - Show temper tantrums emotional lability, poor scholastic progress and antisocial behaviour. 48

Etiology:  Genetic factors seem to play some part.  Majority of these patients do show developmental delays. Soft neurological signs are common.  Others believe that the disorder occurs due to maturational lag of the central nervous system. The condition improves with maturation.  Psychosocial factors may play some part. This disorder is more common in orphanages where proper raring atmosphere is not available. Diagnosis:

 Based on presence of hyperactivity and poor attention span, which is out of proportion of the age and intelligence of the child.  Some children may show conduct disorders in form of truancy, lying, aggression etc. Course and Prognosis: - About three - fourths improve by adolescence. - Some may continue to have poor attention span. - Others may continue showing both hyperactivity and poor attention. - However, a small group may develop dissocial personality disorder and other may persist with

difficulties in social adaptation. MANAGEMENT  Pharmacotherapy: - The CNS stimulants: These drugs reduce hyperactivity and improve attention span. - Dextroamphetamine and Methylphenidate are the drug of choice. They are to be given in the morning and at noon because nighttime dose may produce sleep difficulty. - Dextroamphetamine is given in a dose of 5-10 mg/day. - Methylphenidate in doses of 0.25-1 mg/kg/day is effective. - Non-stimulant: Atomoxetine (1- 1.4 mg/kg qd)  Psychological Treatment

The parents and teachers are advised not to retaliate against the child but their hyperactivity could be channelized into outdoors sports and their poor attention can be improved by appropriate educational technology. (E) CONDUCT DISORDER: Characterized by repetitive and persistent dissocial and aggressive/ defiant behaviour. This behaviour should be persistent and should not be limited to one or two situations. 0.5 to 1% children may show conduct disorder before 18 years of age. Etiology:

iii) Socio-cultural Factors iv) Psychological Factors v) Neurological Factors Clinical Features These children may show any one or more of the following: - excessive level of fighting or bullying; - cruelty to animals or other people; - fire setting; - stealing; - repeated lying; - truancy from school and running away from home - frequent and severe temper tantrums; defiant provocative behavior and persistent severe disobedience Conduct disorders

Conduct disorders can be further subdivided into the following: a) Conduct disorder confined to family context - Dissocial acts in relation with their family members b) Unsocialized Conduct Disorders – These children find it difficult to develop enduring relationship with peers. They are usually isolated. c) Socialized Conduct Disorder – These children become part of a delinquent group and indulge in antisocial activities as described earlier. Basically these children are able to form stable

relationship with other children. They may establish relationships with normal children or with children from delinquent gangs. Management:  Conduct disorders require psychological management. Following principles are to be kept in mind: - If conduct disorder is associated with family disruption or poor parenting, the child may have to be shifted to some other place or a children\s home - Family should always be involved and attempt should be made to help the family to provide consistent upbringing

- These children may be involved with a group of normal children which may provide them proper role models to emulate - Behaviour modification with positive reinforcement may be helpful  Medication may be needed to control aggressiveness or hyperactivity. Haloperidol in small doses & anticonvulsant (carbamazepine) may be helpful. (F) DISORDER OF SOCIAL FUNCTIONING WITH ONSET SPECIFIC TO CHILDHOOD AND ADOLESCENCE These disorders usually develop in response to disturbed environment. Common disorders

included are:  Non-Organic Enuresis: Majority of children become dry by 4 to 5 years. Enuresis is seen in around 1% of children after this age. Enuresis is characterized by involuntary voiding of urine by 50

day or night. If it is caused by neurological or other organic factors then it is called organic enuresis. Enuresis is divided into primary and secondary: Etiology Definite etiology is not known. Genetic factors may play a role. Some children may have excessive production of urine due to reduced activity of antidiuretic Hormone. Psychological factors are more important in secondary enuresis. In primary enuresis, reactive psychological problems may lead to poor self-image and familial tensions.

Clinical Picture These children wet the bed at night or in the daytime. The frequency can be varying from daily to once or twice a week. These children usually become self-conscious and tense. They may avoid going to places where they have to pass the night. Family tensions may also develop. Differential Diagnosis Organic causes of enuresis like spina-bifida-occult, cystitis, seizures etc. should be excluded. Management - Behavioural treatment has been found effective. The children should be made to void

urine before going to bed. Evening intake of fluid should be restricted. The child may be woken up in the middle of night and made to pass urine.. - Pharmacology: Imipramine in dosage of 25 to 50 mg at bedtime reduces enuresis. But many children relapse after stopping the drug. - Psychological Treatment: This is effective only in secondary eneuresis. These children should be helped to overcome their anxiety and feelings of insecurity by providing them stable parental relationship.  Non-Organic Encopresis:

This is characterized by passing of stools at inappropriate places even after the age of bowel control has been attained (5 years). These children may pass stool in their underwear. This condition should be differentiated from organic encopresis e.g. overflow incontinence resulting from constipation and, ganglionic megacolon (Hirschprung’s disease). These children do not have any desire to defecate yet they may have incontinence. Encopresis is usually associated with some other psychiatric disorders like

pervasive developmental disorders. Management: These children are usually very tense and families are disturbed. The tension should be eased out by explaining to them that this is a disorder and we should help the child to have change of underwear’s without much fuss. Behavioural training is useful. Treatment of associated psychiatric condition can be helpful. 51

G. Emotional Disorders ( with specific onset to childhood) Separation anxiety disorder Anxiety on separation from a primary care giver is a developmentally normal phenomenon in children less than 1 yr and may last until 2 yrs of age. When developmentally inappropriate and excessive anxiety concerning separation from home or primary care giver occurs, it is referred to as Separation Anxiety Disorder. Clinical features:

Its onset may be during preschool years or commonly between age of 6-7 yrs. The onset has to be prior to 18 yrs of age The anxiety is expressed as:  Excessive distress when separation occurs  Excessive worry about anticipated separation  Reluctance to be in a situation in which separation is anticipated. Eg: School, sleeping alone  Physical symptoms as stomachache, headache etc. Management:  Detailed assessment of child’s temperament, Mothers attitude towards the child and their

bonding as well as the psychosocial background in the family  Multimodal treatment is advised – includes CBT, family education, and psychosocial intervention with the family.  Graded contact as a form of behaviour modification SCHOOL REFUSAL Many children try to avoid going to school from time to time. Some do it regularly. School refusal is not a psychiatric disorder, but it is a common cause of referral to child psychiatrists and is frequently attributable to an emotional disorder.

ASSESSMENT OF SUSPECTED SCHOOL REFUSAL  Why is the child absent from school?  What does the school refusal reflect? Reluctance to leave home (i.e. secondary to separation anxiety) A specific ‘school-phobia’ (e.g. of getting there or of being bullied) A more generalized disorder (e.g. social phobia, depressive disorder) 52

 What are the other factors affecting the presentation of management? Recent life events (e.g. bereavement) Recent events at school (e.g. change of class) Parental characteristics: (e.g. overprotective). Management is aimed at a rapid return to school before avoidance is too ingrained. Sometimes a graded re-exposure is needed. Address any specific fears of stresses, and treat any associated psychiatric disorder. The prognosis in younger children is good. In older children, the problem may become prolonged

and other psychiatric problems may emerge. CHILDHOOD AND ADOLESCENT DEPRESSION Childhood major depressive disorder (MDD) is characterized by a significant, often recurrent emotional and behavioral change from baseline to a dysphoric or irritable mood, loss of pleasure or fun, and with decreased functioning at home, school and with peers. Incidence figures are hard to measure in this population.  Infants and preschoolers- 1%. It mainly presents as failure to thrive, as well as attachment,

separation and behavioral problems  School age children- 2%. Closer fit to adolescent/ adult criteria. It typically has a more protracted, recurrent or severe course. Suicide attempts and completions uncommon to rare.  Adolescents- 5% or more. Presents more like the adult syndrome and typically require evaluation of suicidality and substance use. Etiology and contributing factors These include genetic factors(biological offspring’s of depressed parents more likely to have

depression), environmental factors, organic factors, developmental and transactional factors. Making the diagnosis-  Infant/ toddler- both the persistently passive, unresponsive infant and the irritable, unsoothable, crying infant may suffer from the mood dysregulation associated with depression. Their clinical presentation may evolve into a quiet, inhibited toddler with arrested social development or an overactive, impulsive and irritable preschooler.

 School age- in school age children with MDD there may be humiliation, defeat, irritability and self-doubt. The child may become sad, isolated, rejected and accident-prone. Temper 53

tantrums or morbid preoccupations with bodily injury, illness, abandonment or death may emerge. There may be multiple somatic complains.  Adolescents- they may have difficulty containing intense negative feelings. They may have direct negative actions inwards towards themselves by disregarding food, sleep and hygiene. Some turn to alcohol and drugs or engage in self-destructive behavior. Adolescents with MDD often appear irritable, angry and resentful. This age group should be given special

attention considering the harmful behavior they may indulge in. Management Mild or moderate cases of depression can be safely cared for as outpatients. Urgent psychiatric consultation is indicated when the child or adolescent might be acutely suicidal, abusing substances, having psychotic features or otherwise difficult to manage. The treatment strategies include-  Medications –SSRI’s (Fluoxetine) are the drugs of choice for this population, but they have to be used with caution

 Cognitive behavior therapy  Family therapy  Environmental manipulation  Parental guidance. Psychological issues related to Adolescence: Adolescence is not just a blend of childhood and adulthood; it is a stage with unique biological and social characteristics of its own. Biological factors defining adolescence includes the achievement of sexual maturity as well as the physical and cognitive changes resulting from hormonal shifts.

Behavioural problems and disorders during this period of “stress and storm” often represent exaggerations or unresolved versions of the normal development tasks of adolescence. Some of the psychological and social tasks of adolescence include : identity formation (a strong sense of differentiated self in the individual and includes a social/sexual/work and moral identity), self determination, and the dual process of exploration (“keeping options open”) and commitment

.Some societies provide structured rituals to assist adolescent with the transition from childhood to adulthood. Disorders of adolescence are classified in terms of:  Residual childhood problems (e.g. conduct disorder)  Problems of adolescent transition (eating disorder, Para suicide, drug abuse)  Early adult disorders (e.g. Schizophrenia, bipolar disorder, OCD) 54

Consider referral when: Problem Refer to Mental retardation Pediatrician, neurologist, Psychologist Autism Psychiatrist, Psychologist Significant learning/ academic problems Psychiatrist Suicidal or self-injurious behaviour, severe aggression, Psychiatrist Substance abuse Psychotic symptoms Psychiatrist Attention Deficit hyperactivity disorder Psychiatrist, psychologist Mood disorder, anxiety disorder Psychiatrist, psychologist GENERAL PRINCIPLES OF MANAGEMENT IN CHILD PSYCHIATRY

Management of children with psychiatric disorder is based upon several principles: i. Take the child’s developmental stage and overall level of functioning into account. ii. Most problems are treated initially with reassurance, support and behavioural interventions. iii. Whatever the treatment, involve the family. iv. Avoid removal from school or home wherever possible v. Medication has a limited role in most disorders.

General principles of behaviour therapy: Behaviour therapy may not be feasible at PHC level and might require referral to a higher centre. However, some of the following principles may be useful in management:  Behaviour modification in children can be brought about by using behavioural principles.  Every behaviour is determined by an Antecedent (what happens before a behaviour) and a Consequence (what happens after a behaviour).  Antecedent or Consequence can be altered to alter a behaviour.

 Desired behaviours need to be reinforced and unwanted behaviour should be decreased 55

 Positive reinforcement is used to promote desired behaviours. It involves the use of rewards which include Tangible rewards as food,objects,etc and social rewards as praise.  Initially tangible rewards may be used as reinforcement and later replaced by social rewards to sustain the change in behaviour. Rewards must be chosen on the basis of child’s preferences .  Unwanted behaviours can be decreased by ignoring them or taking away existing privileges

or reinforcement. For example: withholding TV viewing or a regular excursion.  Punishment should not be used or only sparingly used to bring about a behaviour change  If wanted behaviours are reinforced at the same time ignoring the unwanted behaviours, which is also called differential reinforcement the benefits may be marked.  One has to be consistent in providing reinforcements and they should be contingent to the behaviour. 56

PSYCHIATRIC PROBLEMS IN ELDERLY Introduction The elderly population of India is steadily increasing. It is projected that by 2050, proportion of persons who are of age 60 years and above living in India will rise to 19% from current 8% of total population (United Nations Population Division, 2010). The demographic profile depicts that in the years 2000-2050, the overall population in India will grow by 55% whereas aged population 60 years and above will increase by 326% (United Nations 2002). This has

resulted in “Greying of India”. Despite improvement in health care system, Indian elderly is facing a huge burden of communicable and non-communicable diseases. This vulnerable population is more prone to psychiatric problems. These psychiatric problems in elderly are more complex and challenging than those encountered in young- and middle-aged patients due to host of medical and environmental conditions. Most common psychiatric illnesses in Indian elderly

population are depression, dementia and anxiety disorders which need attention of General Practitioners. Clinical picture Dementia Dementia is also known as ‘chronic brain failure’, more frequent after 65 years of age. Dementia is a syndrome characterised by concurrent impairment in cognition, behaviour and activities of daily living. Its cardinal feature is memory impairment in the presence of clear consciousness. It can be understood through ‘ABC of dementia’: 57

A- Problems in Activities of Daily Living (ADL) B- Problems in Behaviour i.e. Behavioral & Psychological symptoms of Dementia (BPSD) C- Problems in Cognition i.e. memory impairment A: Dementia interferes with activities of daily routine like dressing, washing, eating, personal hygiene & toilet training. B: Psychological symptoms in dementia assessed on the basis of interviews with patients and caregivers include delusions, paranoia, hallucinations, anxiety and depressed mood.

Behavioural symptoms identified on the basis of observation of the patient include physical aggression, screaming, restlessness, agitation, wandering, sexually inappropriate behaviours, and hoarding. C: Patients with dementia have problems in cognition i.e. memory, more particularly learning new information. There is a definitive decline in memory from previous state reported by caregivers. Other problems associated with cognitive decline include language, orientation,

judgment, executive function and thinking. Memory loss is usually progressive with prevalence doubling every 5 years after the age of 60 years. Delirium Delirium or acute confusion is a transient organic brain syndrome, a type of medical emergency encountered in health care settings, characterised by an alteration in consciousness caused due to underlying medical conditions. This clinical condition is acute in onset and shorter in duration (few hours to days). Patient with delirium is presented with

global impairment of cognitive function (i.e. confused state of mind, disorientation to 58

time/place and disturbance in sleep-awake cycle). This condition has a diurnal variation, more worsening in night hours (‘Sun downing phenomenon’). Emotional disturbances like anxiety, fear, irritability, anger, apathy and withdrawn, may be associated with delirium in elderly. Mortality among hospitalized patients is high as much as 40%. Hence, clinicians need serious attention to identify and manage this medical emergency Depression

Depression is considered to be ‘Disorder of losses’-loss of mood (sadness of mood); loss of interest in pleasurable activities (anhedonia); and loss of energy (easy fatigability). Depressed/sad mood remains the most common presentation of depression in elderly but may not be spontaneous complaint. In addition to weight loss, persistent anhedonia is common reported symptom in elderly. Psychotic symptoms may also present in elderly depressives.

Appetite loss and suicidal ideation or acts may also present in old age depression. Depression may be associated with medical conditions. Elderly patients often report bodily symptoms (aches & pains, gastro-intestinal disturbances) rather than sadness of mood. They also report subjective experience of forgetfulness or memory loss and slow thinking (Pseudo-dementia; ‘dementia of depression’) which should be differentiated from dementia. They may also

present with anxiety symptoms, agitation and psychotic symptoms. There is always a high risk of suicide associated with depression in late life. Late-onset anxiety disorders Anxiety disorders in elderly may be associated with medical disorders or exist as independent disorders (Generalised anxiety disorder, panic disorder & obsessive compulsive disorder). They may be presented with physical symptoms like palpitation, chest pain, choking,

giddiness, and tingling numbness; and psychological symptoms like worrying, nervousness, tension, apprehension, anticipatory fear, lack of concentration. 59

Late-onset psychosis Elderly may also prone to psychosis like young adults. In late-onset psychosis (also called ‘Paraphrenia’), delusions of persecution & reference and auditory & visual hallucinations are usually present. Management Assessment Dementia Diagnostic exercise of patient with memory problem starts with a good history from both family members and the patient regarding chronological presentation of symptoms and

problem behaviours. Evaluation includes questions related to memory loss like becoming lost in a familiar place, asking food again and again, and losing objects. A thorough evaluation of medical history and examination of bodily systems, including neurological examination is must for patient with memory loss. The nature and degree of the cognitive function and activities of daily living should be assessed with Hindi adaptation of Mini-Mental State

Examination (HMSE) and Everyday Abilities Scale for India (EASI). The laboratory tests to rule out reversible causes for dementia are: thyroid stimulating hormone, vitamin B12 & folate levels, electrocardiogram, blood sugar & creatinine. Computed tomography of brain is required for patients with memory loss. Delirium Delirium is seen more in intensive medical and surgical units and among patients recovering from surgery or on multiple medications. It needs thorough clinical evaluation, including

intoxication, electrolyte disturbances, infections, hypoxia, hypoglycaemia, physical restraint, bladder catheter use and concomitant medications. 60

Depression Older persons may not reveal depressive symptoms so easily, hence needs good observation and clinical skills. More focus of interview is towards motor activity, hopelessness, worthlessness, hallucinations, suicidal ideations and memory problems. The laboratory tests to rule out co-morbid medical conditions are: complete blood counts, thyroid stimulating hormone, vitamin B12 & folate levels (vegetarians), electrocardiogram, Fasting blood sugar,

serum electrolytes, blood urea & creatinine. Computed tomography of brain is optional for suspected cases of cerebro-vascular lesions. Late-onset anxiety disorders Anxiety symptom may be part of medical and psychiatric disorders like hypoglycaemia, hyperthyroidism, cardiac arrhythmias, pulmonary emboli, delirium, depression, dementia and psychotic disorder. It could be related to medications like ephedrine, anticholinergic drugs and benzodiazepine withdrawal. Late-onset psychosis

Psychotic symptoms in the form of suspiciousness, delusions, hallucinations and agitation are present in schizophrenia and delusional disorders. Family members should be interviewed to explore behavioural disturbances. Treatment approaches Once the psychiatric problem is formulated by the clinician, the usual treatment approaches must be individualized depending on clinical status and also targeted to reverse the underlying disorder. Emphasis should be on identifying above mentioned problems early and

referring appropriately. Also, the assessment should include evaluation of psychiatric and comorbid medical illnesses, which is a rule rather than exception in the elderly. It is also essential to include drug history keeping in mind the drug-drug/ drug-disease interactions. 61

Counselling & education regarding disorder as well as diet and medicines is the mainstay for the successful treatment. Dementia Early identification and treatment may delay or arrest the process of cognitive decline. Treatment of dementia is based on the cholinergic hypothesis of memory. Cholinesterase inhibitors like donepezil, rivastigmine and galantamine are indicated for patients with dementia. Donepezil should be started with dosage of 5mg/day which may titrate to

10mg/day in 2 weeks. Antipsychotics may be indicated for controlling aggressive behaviour, psychotic symptoms and severe agitation. Risperidone(1 to 3 mg) and quetiapine (25 to 400 mg) may be used. Delirium For patients with delirium, initial treatment includes medical support i.e. maintenance of vital parameters (adequate airway, blood pressure, pulse and temperature). The cause of delirium is established through history, physical examination, and laboratory tests. Specific

therapy/intervention is started after identification of precipitant of confusional state. Clinicians also look after and manage excess and confused environmental stimuli present in the vicinity of patient. Patient should be kept in quiet, well-lighted and simply furnished room. Family members and hospital staff should regularly acquaint the patient regarding time, place and person. Restraints should be avoided. For agitated behaviour, low dose

antipsychotics (Haloperidol or Risperidone, either oral or intramuscular) may be prescribed. Depression Antidepressants remain mainstay for treatment of geriatric depression. Newer antidepressants, Specific Serotonin Reuptake Inhibitors (SSRIs) like fluoxetine, sertraline, citalopram and escitalopram can be initiated at lower doses (preferably half of young adult dosage). Gastrointestinal disturbances, weight loss and agitation are commonly reported side 62

effects with SSRIs. Tricyclic antidepressants may be avoided due to postural hypotension and anticholinergic side-effects. Elderly depressives who do not respond to or tolerate antidepressants may better respond to Electroconvulsive Therapy (ECT). Families should be involved for support building and motivating patient in activities. Late-onset anxiety disorders Short-acting benzodiazepines like alprazolam (0.125-0.25mg) and lorazepam (2-4mg) may be

indicated in patients with anxiety disorders. SSRIs (Escitalopram, citalopram and sertaline) are useful in treatment of anxiety disorders. Late-onset psychosis Patient with psychosis requires a safe environment. Agitated and suspicious elderly needs inpatient hospitalization. Antipsychotic medications used in late-onset psychotic disorders are risperidone (1-3 mg/day), quetipine (25-300mg/day) and haloperidol (0.5-10mg/day). Guidelines for referral Refer patients of following conditions to specialist care:

1. Dementia with behavioural and psychological symptoms 2. Complicated delirium 3. Depression not responding to antidepressants 4. Suicidal patient 5. Depression with psychotic/cognitive symptoms 6. Anxiety disorders not responding with medications 7. Agitated and suspicious elderly patient 63

EPILEPSY After completing this chapter, the participants should be able to: 1. Identify a case of Epileptic seizure 2. Classify the patients in different types of epilepsy 3. Understand about the management strategy of epilepsy:  How long the medications (AED) is to be continued  When to initiate and stop the treatment  When to Refer the cases of epilepsy INTRODUCTION  Epilepsy is one of the common neuropsychiatric conditions encountered in general

practice It is a diagnosis which carries social stigma and hence the diagnosis should not be made without thorough consideration. For some patients, epilepsy might be a lifelong disorder requiring indefinite treatment.  Epilepsy is characterized by Recurrent Seizures. Seizures occur due to episodic excessive, abnormal neuronal activity in the brain that produces a sudden change in the neurological functions.  Its incidence is about 5-8/1000. However, increased incidence is seen in neonates,

children, and elderly. CLASSIFICATION Summary of international classification of epileptic seizures I. Partial (Focal) seizures a) Simple partial seizures (consciousness not impaired) b) Complex partial seizures (temporal lobe or psychomotor seizures, consciousness impaired) c) Partial seizures evolving to secondarily generalized seizures [tonic-clonic (grand mal), tonic or clonic] II. Generalized seizures (convulsive or nonconvulsive) a) Absence (petit mal) seizures b) Myoclonic seizures c) Tonic seizures

d) Atonic seizures e) Clonic seizures f) Tonic-clonic (grand mal) seizures III. Unclassified epileptic seizures 64

CLINICAL FEATURES SIMPLE PARTIAL SEIZURES  Sudden onset and cessation  Due to focal cortical pathology  No alteration in consciousness  Focal symptoms or signs: - Motor - Sensory or special sensory - Psychic (dysphasic, dysmnestic, cognitive, affective, illusions, hallucinations)  Partial seizures may progress to Complex Partial Seizure (CPS) or to generalized tonic clonic seizures COMPLEX PARTIAL SEIZURES (TEMPORAL LOBE/ PSYCHOMOTOR EPILEPSY)

Seizure may begin with no warning or with motor, sensory, autonomic, psychic signs & symptoms  Sudden onset and gradual recovery  Aura (focal symptoms/signs as in simple partial seizures)  Altered consciousness-motionless stare & unresponsiveness  Automatism (chewing, lip smacking, fiddling, rubbing of hands, circling, running, mimicry, gestural, ambulatory, verbal, responsive), co-ordinated involuntary motor activity  Amnesia

 CPS patients may have combination of Aura and altered consciousness and automatism  CPS may progress to generalized tonic clonic seizures  Due to focal cortical pathology  Temporal lobe CPS-60% extra temporal, especially frontal cortex -30% TYPICAL ABSENCE SEIZURES (PETIT MAL)  Sudden onset and cessation, (few seconds, average:10 seconds)  Cessation of motor activity: Blank stare  Blinking of eyes, jerking and brief automatism may be present  Impaired responsiveness, Posture and tone preserved

 Several 100/day especially with sleep awake cycle  EEG –Generalized 3/sec spike and wave pattern  Precipitated by hyperventilation  Easily controlled with AED ATYPICAL ABSENCE SEIZURES  Absence (blank stare)  impaired responsiveness  Focal signs prominent, include tone changes, clonic jerking, motor spasm, automatism  Onset and cessation often gradual, and seizure may be prolonged  In-patients with diffuse cerebral damage, mental retardation  Difficult to control 65

MYOCLONIC SEIZURES  Brief jerk, singly or in series + induced by stimulus  Intensity varies from slight tremor to massive jerk  Distribution varies, from single muscle to generalized jerking  Consciousness preserved  Rapid onset and cessation on waking or going off to sleep  Myoclonus may precede a generalized tonic clonic seizure  EEG generalized spike and polyspike and wave discharge  Occurs as part of: Idiopathic generalized epilepsy (JME), progressive myoclonus epilepsy; or in

patients with diffuse cerebral damage associates with mental retardation PRIMARILY GENERALIZED TONIC-CLONIC SEIZURES (GRAND MAL) Ictus  Loss of consciousness-shrill cry-tonic phase (10-30 sec)  Respiration ceases  Clonic phase, labored breathing,  Tongue bite, frothing, incontinence, cyanosis, vocalization, autonomic features (30-60 sec)  Flaccidity of muscles (2-30 minutes)  Sudden onset and gradual recovery Post ictal  Confusion, drowsiness, sleep, headache, muscle pain

 May be modified with treatment-tonic, clonic or atonic  May have precipitating factors or diurnal variation FEBRILE CONVULSIONS  Seizures are associated with fever  Common (2-5% of all children) (3 months-6 years)  Peak age of onset (6 month-2 years)  Simple, complex types, febrile SE-young children  Recurrence – early age of onset & positive febrile history  Seizure usually at onset of febrile illness  Complex febrile convulsion: > 30 min; partial seizure, recur within 24h

 Risk of continuing epilepsy is small DIAGNOSIS The first step in the evaluation of a patient with possible epilepsy is to determine whether the patient does or does not have seizures.  History from the patient and eyewitness: The history obtained from the patient and a reliable informant/eye witnesses is often the most important information in establishing diagnosis of a seizure disorder.  Questions related to parts of a seizure: Begin by asking in detail about the events before, during

o Aura o Ictus o Post-ictal o Inter-ictal  To determine the cause (etiology) of the seizure, determine: o Whether there is a family history of epilepsy o Personal history of head trauma, birth complications, febrile convulsions, middle ear or sinus infection, alcohol or drug abuse or symptoms of cancer  Physical examination: A thorough physical examination: look for disorders associated with epilepsy as well as signs of head trauma, infections of middle ear or sinuses, congenital

malformations, alcohol or drug abuse and symptoms of cancer.  Electroencephalographic studies (EEG): In approximately 50% of patients with epilepsy, a single EEG may show no abnormalities at all. An EEG provides information about: o Confirmation regarding presence or absence of abnormal electrical activity o Information regarding type of seizure disorder o Location of seizure focus Laboratory tests and Neuro-imaging: The following tests are done to determine the cause of newly diagnosed seizure disorder:

 Electrolyte and liver function test  EEG in sleeping and waking states  MRI or CT brain: to rule out serious structural lesion  Screening tests for toxic substances if alcohol or drug abuse or withdrawal is suspected  Lumbar puncture performed if fever or cancer suspected Note: The request for the investigations by the medical officers should be judicious. A high degree of clinical suspicion should govern the need for investigations for the patients with seizure disorder.

These should include for eg. Cases of recurrent seizures even on regular & adequate treatment, persons with first episode of seizure, post encephalitic sequalae, history of head injury etc. DIFFERENTIAL DIAGNOSIS: Disorders that must be differentiated from epilepsy:  Non-epileptic attack disorder (Pseudo seizures)  Syncopal attacks  Transient Ischaemic attacks (TIA)  Breath holding spells Non Epileptic Attack Disorder or Pseudo-seizure  Attacks with motor phenomenon  Thrashing of limbs (people around)

 Distractability/interactions with the environment  Excessive salivation, teeth clenching  Commoner in females than males  Obvious secondary gains  Overt psychiatric illness may be there Syncopal Attacks  Evidence of precipitant factors  Lightheadedness, dizziness, nausea  Ringing in the ears  Bilateral loss of vision  Pallor & Collapse  Some twitching tonic movement  Irregular myoclonic jerking  Rapid recovery when supine  Sweating, subsequent flushing Transient Ischaemic Attacks

 Focal Neurological Deficit  Loss of consciousness – rare  May not be repetitive Breath Holding Spells CAUSES OF SEIZURES ACCORDING TO AGE: Neonate-3 years 3-20 years 20-60 years >60 years - Prenatal injury - Genetic - Brain tumor - Vascular disease - Perinatal injury predisposition - Trauma - Brain tumors - Post natal - Infection - Vascular disease - Trauma trauma - Trauma - Infection - Metabolic Disorders - Metabolic def. - Cong. - Infections - Congenital Malformation Malformation. - Metabolic def.

- CNS Injury Features of in increased risk of seizure recurrence  Seizure types (e.g. partial, tonic and atypical absence seizures etc).  High previous seizure frequency  Long duration of epilepsy  Structural abnormality or Psychiatric disorder  Epileptic syndromes (e.g. JME, LGS etc)  Inadequate AED/Misdiagnosis 68

Neuro-imaging in Epilepsy: Indications for structural imaging include:  Partial seizures or grossly abnormal EEG  Fixed/progressive neurological or psychological deficit  Generalized seizures before the age of 1 year and after 20 years  Refractory seizures/status epilepticus/seizures in elderly Treatment: The initiation of antiepileptic drug treatment: Always ask  Is the diagnosis of epilepsy certain?  What are the risks of recurrence of seizures without treatment?

 What are the risks of recurrence of seizures with treatment?  Are the presences of precipitating factors relevant?  Are the seizure characteristics relevant?  What are the risks of side effects to treatment? Consider drug therapy after a first unprovoked seizure if:  The patient has a neurological deficit  The EEG shows unequivocal epileptic activity  The patient or their family/carers consider the risk of having a further seizure unacceptable  Brain imaging shows a structural abnormality

Choice of Anti Epileptic Drugs (AEDs) for different seizure types: Seizure type First choice Second choice Partial seizures Carbamazepine, valproate Phenytoin, Lamotrigine, Simple partial, complex Clobazam, Phenobarbitone partial, secondarily generalized Generalized seizures Valproate Lamotrigine, Tonic-clonic, clonic Carbamazepine Clobazam, Phenobarbitone Absence Valproate, Ethosuximide Lamotrigine, Clonazepam Acetazolamide 69

Atypical absences, atonic, Valproate Lamotrigine, Clobazam tonic Clonazepam, Acetazolamide Phenobarbitone, Phenytoin Myoclonus Valproate Clonazepam, Phenobarbitone The newer drugs (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and vigabatrin) are recommended for managing epilepsy in people who have not benefited from treatment with the older antiepileptic drugs or for whom the older

antiepileptic drugs are unsuitable. However this should be carried out at higher centres under specialist care. Anti Epileptic Drugs: starting and maintenance doses for adults AED Starting dose (mg) Average maintenance Doses/day dose (total mg/day) Carbamazepine 100 600-1800 2-3 (retard:2) Clobazam 10 10-30 1-2 Clonazepam 0.5 0.5-3 1-2 Ethosuximide 250 500-1500 1-2 Lamotrigine 50 200-400 2 Oxcarbazepine 300 900-2400 2-3 Phenobarbitone 60 60-180 1 Phenytoin 200-300 200-400 1-2 Valproate 500 1000-2500 1-2

Note:  The clinician should be aware of the special populations with seizure disorders (children elderly and women with pregnancy).The doses of antiepileptics need to be adjusted accordingly. Also the common drug interactions with AEDs like Phenytoin, Carbamazepine and valproate should be made note of, while prescribing them.  All women on anticonvulsants should start taking folic acid supplements of 5 mg per day well before the pregnancy. 70

 Anticonvulsant drugs can increase the risk of fetal malformation, although the absolute risk is low. The risk is particularly increased in women taking valproate and phenytoin.  Women with epilepsy (and their partners if appropriate) should receive accurate information and counseling about contraception, conception, pregnancy, caring for children, breast feeding, and the menopause.  STEPWISE ‘AED’ PLAN FOR NEWLY DIAGNOSED PATIENT Step 1: Precipitating factors: fever, fatigue, alcohol and drug abuse

Step 2: Reasons for AED treatment, expectations, limitations, duration of therapy, need for regular tablet taking, AED do not provide a cure for epilepsy, have to be taken for a long time, 70-80% of patients seizures controlled by regular medication Step 3: Start with small dose of AED (1st line), dose increments gradually to therapeutic level, may increase to the maximum tolerated dose, if necessary Step 4: If seizures continue in spite of maximally tolerated dose of a first-line AED:

 Review the diagnosis of epilepsy  If there is any underlying structural lesion: imaging of the brain  Whether patient is complaint by non-confrontational enquiry of patient and carers  Counting the number of tablets, measurement of serum drug level: Low serum AED suggests non-compliance.  Start the 2nd AED and taper the first AED. Duration of treatment:  Patients are more likely to remain free from seizures if they have been free from seizures for more than two years while taking antiepileptic drugs

 Decision to withdraw anticonvulsant should be done under the guidance of a specialist. Referral to specialist care:  Refer patients with first episode seizure to specialist care  Refer patients with prolonged seizures, status epilepticus  Refer if there may be difficulties in monitoring the patient’s condition 71

PSYCHIATRIC EMERGENCIES Introduction: A psychiatric emergency is defined as any disturbance in thoughts, feelings or actions for which immediate therapeutic interventions are necessary. Such patients may cause harm to themselves or others or suffer immense acute distress which is intolerable .These are clinical situations which are unique as they may pose risk and danger not only for the patient but also for the people around him. The emergent task at hand is triage, evaluation,

formulation and disposition or thereafter referral. The challenge is ensuring the safety of the patient, others and oneself. The handling of a psychiatric emergency can be very intimidating for a medical professional, however the management becomes much simpler if they understand the nature of the underlying psychiatric disorder and follow some simple steps. The management of a psychiatric emergency is a team effort in which both

medical professionals and hospital staff have crucial roles .Prompt and appropriate management of psychiatric emergencies saves lives. A psychiatric emergency can include any of the following clinical scenarios:- Box No. 1: PSYCHIATRIC EMERGENCIES 1. Suicidal patient 2. Violent patient 3. Substance withdrawal 4. Severe anxiety / panic attack. 5. Drug toxicity / intoxication 6. Drug induced parkinsonism The fo llowing text discusses the presentation and management of two of the most common

and important psychiatric emergencies in detail, namely suicide and violence and briefly discusses the others. 72

SUICIDE Introduction Suicide is the termination of one’s life intentionally. It is the third leading cause of death between ages 15 and 24. A suicidal patient is one who has attempted or tried to attempt or frequently thought of attempting suicide. A suicidal patient needs emergent intervention as this can prevent a completed suicide. As opposed to popular belief suicide is more often a culminating event of an underlying psychiatric disorder ( in 95% of cases)

than of any circumstantial life event. The prevalence of suicide is 10-15% in patients of depression, 10% in schizophrenia and this number rises when alcoholism complicates the picture. Hence the evaluation for an underlying psychiatric disorder is a must in all such patients. Slitting of wrist, hanging, overdose of sleeping pills are some common means applied by such patients. Risk assessment is an integral part of evaluation and management. Presentation of a suicidal patient :

Such patients have either frequently thought of/ contemplated suicide or have planned the act or have attempted suicide . They are often brought by family. Box No. 3- Warning signs of suicide Warning signs of suicide • A person talks about death , threatens of commitingor discusses suicide. • Discusses different methods of suicide. • A person mentions suicidal ideation. • A person attempts any act of deliberate self harm. • A person is seen making goodbye gestures or

communications, writing of will or other acts suggestive of a suicidal plan. • A person has suffered recent major loss of life or property . • Hopelessness. • Severe agitation/anxiety 73

Suicidal risk: anyone can attempt suicide however a few risk factors pre-dispose an individual to attempt / commit suicide. The presence of a psychiatric disorder however is the single most important and common risk factor for suicidal behavior. Fig.No. 1 enlists the risk factors increasing the risk of suicide: Risk factors for Suicide 1.female gender 2. elderly age group 8. family history 7. chronic physical illness 3. clinical 4.poor 5.single 6.Alcohol depression social status abuse support

Suicidal Risk-Assessment: this is an integral part of management of such patients. This establishes the severity of the situation and the likelihood of future death by suicide. Box No. 4 –Types of suicidal risk  Lo w suicidal risk: such patients have less severe psychiatric illnesses, better social support , fewer attempts, have employed attempted less lethal means of suicide like superficial cut marks on wrist.  Moderate suicidal risk: presence of psychiatric disorder, multiple attempts ,

attempts in last few days, low-moderate lethality attempts like pills , alcoholism +/-  High suicidal risk : severe psychiatric illness, attempt in last few hours, lethal attempt like hanging/gunshot/ pesticide, poor social support Two important terms in suicide: 1. Intentionality: this refers to the intent to commit suicide. Patients with high intentionality make elaborate plans and try to ensure that the attempt of suicide leads to definite death.

2. Lethality: this refers to the means adopted to commit suicide. High lethality of suicide is indicative in the use of firearms, hanging or use of pesticide as means. 74

Fig No 2- factors associated with high suicidal risk. Suicidal Risk is high if Psychotic symptoms Lethal Suicidal attempt intent Suicidal risk is High if: Accesibl Suicidal e plan weapon Alcohol use Management of a Suicidal patient • A suicidal patient either thinks attempting suicide or has already attempted suicide. • The goal of intervention is to prevent completed suicide. • Suicide is preventable if intervention is done timely. • Assessment of suicidal risk is important. 75

Following simple steps must always be followed:- Steps in Management of Suicide Step 1 Assess the physical condition of the patient. ( check vitals, pallor , cyanosis , higher mental functions, local injury/wound etc.) Step 2 if found medically stable then calm down patient ,and do a risk assessment as per the above points mentioned. Step 3 Evaluate for underlying psychiatric illness by taking history and mental status examination. Step 4 Once suicidal risk is established it is best to admit the patient.

proceed by instructing for 24 hr strict vigilance by hospital staff and family members. No potentially harmful object should be near the patient and all medication given should be supervised. Prevention of Suicide Suicide is preventable condition. Early recognition of risk factors for suicide .Early diagnosis and prompt treatment of mental disorders like depression, schizophrenia, bipolar disorder and substance abuse .Not ignoring warning signals

such as talks, threats, thoughts or previous attempts of deliberate self harm. Directly asking patient about death wishes, suicidal ideation and intentions helps in assessing the risk.24 hr strict vigilance is advised till the underlying psychiatric illness responds to treatment. When to Refer a suicidal patient ? • All suicidal patients require psychiatric evaluation once medically stable. • Hospitalization in psychiatric ward is recommended for all patients who have made

lethal attempts of deliberate self harm or who exhibit high risk of suicide. • Early psychiatric intervention can prevent suicide. 76

Violent patient Introduction: Violence is associated with many psychiatric disorders. Violence may include physical assault/ threat or breaking of property and verbal abuse. Serious threat may be posed to others and the treating team by a violent patient .Violence can occur in any psychiatric disorder however is more common in patients of psychosis, mania, schizophrenia or substance intoxication .Organic causes like neurological insult can

also present with violence. These patients are sufferers themselves first and perpetrators of violence only later. Also care should be taken not to violate the human rights of any patient by forceful restraint or injection unless as last resort. Causes of violence in medical practice: Box No. 4 Some medical conditions that can present with violence • Ictal or post ictal states • Head injuries • Frontal & temporal lobe pathologies • Dyselectrolemias • Delirium and dementiasrenal / hepatic failure

Psychiatric factors that underlie violent behavior include :- • Manic hyper excitement and agitation • Exacerbation of psychosis • Paranoid delusions and fear • Substance intoxication or withdrawl • Delirium • Catatonic hyperexcitement • Mental retardation with behavioral problems Management of violent behavior in clinical settings The management of a violent patient can be challenging. It requires patience, vigilance, team

effort and preparedness. Following box enlists steps in the approach to a violent patient. Box No. 5: Approach to a violent patient includes • Ensuring the safety of others including oneself • Restrain or seclusion may be required • To rule out organicity and look for treatable medical cause • Medication oral or parentral to control agitation • Psychiatric assessment by history and MSE to establish underlying diagnosis • Treat underlying psychiatric disorder 78

Special precautions in dealing with a violent patient: • Do not approach a violent patient alone. Other staff should be present. • Ensure the removal of potentially harmful objects with the patient or in the vicinity. • Assess for the possibility of possession of weapon by the patient. • In case of uncontrollable violence a suitable escape door must be present • Do not intimidate, argue or pose any threat to the patient • Approach the patient in a benign , non threatening and calm manner.

• Maintain atleast3 to 6 feet distance from the patient. • If patient agrees to speak with you sit him down and ask him about his problem. Listen to him and let him know u are there only to help him and he need not fear . Steps in Management of violence in clinical settings: 1) Try to talk to the patient if possible and calm him with your words. 2) Urge or convince him to take oral medication. 3) If he declines your request consider injectable drugs to calm him down.

4) Restrain or seclusion may be required in very severe cases. However keep a concern for the human rights of the patient. Box No. 6: – psychotropic drugs used in management of violence M EDICATION AND DOSAGE NOTES • Lorazepam , 2-4mg, PO or I/M or diazepam effective particularly in non psychotic 5-10mg iv/ im • Olanzapine ,10 mg, PO or I/M indicated in psychosis • Haloperidol 5-10mg + Promethazine 25-50mg very effective in rapid effect in IM rapid control of psychotic agitation 79

When to refer a violent patient • All suspected cases of organicity should be investigated and referred to concerned speciality. • All others should be stabilized and referred to psychiatrist for evaluation and management. • The medical condition must be examined and stabilized before a psychiatric referral. • Very severe cases need inpatient management. Other psychiatric emergencies Substance withdrawl particularly complicated alcohol withdrawal is an emergency where

patient may have seizures or in rare instance go into delirium tremens (DT). 20% of untreated cases of DT die hence prevention and timely intervention is crucial. Patients dependent on opioids may also have very distressing withdrawal symptoms but they are less likely to cause serious consequences like alcohol withdrawal. Management is with benzodiazepines and thiamine oral or in injection in alcohol withdrawal. Panic attacks are discrete episodes of severe anxiety associated with autonomic symptoms

like breathlessness, palpitations, and heaviness of head and sense of impending doom. Such patients frequent casualty settings often thinking they’re having a heart attack. Use of benzodiazepines is indicated. Patients should be referred thereafter to psychiatrist. Drug induced acute dystonias, occulogyric crisis, extrapyramidial symptoms often present as psychiatric emergencies. Such patients are usually on an antipsychotic (mostly typical

antipsychotics like haloperidol). IM/IV Promethazine 25-50 mg is treatment of choice. 80

ALCOHOL USE AND DRUG USE DIORDERS INTRODUCTION Almost all cultures have used psychoactive substances to facilitate social interaction, to alter consciousness, to heal. Our society’s expanded chemical manipulation simply represents large technical capacity, more wealth, leisure and individual choice. Among many ills which have plagued the human society today, the drug abuse is of greatest social relevance. To begin with, let us understand what a drug is. World Health Organization (WHO) defines a drug as

any substance that, when taken into the living organism, may modify one or more of its functions. This definition conceptualizes ‘drug’ in a very broad way, including not only the medicines but also the other pharmacologically active agents. A psychoactive drug is one that is capable of altering mental functioning. Drug-addiction is a chronic, often relapsing brain disease characterized by compulsive drug seeking and use despite harmful consequences to the user and the people around. Repeated drug exposure

leads to changes in structure and function of the brain. Initial decision of drug-intake may be voluntary but repeated drug exposures affect person’s self-control and ability to make sound decisions. There are four important patterns of drug use disorders, which may overlap each other. These are as follows: 1. Acute Intoxication 2. Withdrawal State 3. Dependence Syndromes 4. Harmful Use 1. Acute Intoxication is a transient condition following the administration of alcohol or other

psychoactive substance, resulting in disturbances in level of consciousness, cognition, perception, affect or behaviour, or other psycho-physiological functions and responses. This is usually associated with high blood levels of the drug. Sometimes even a low dose of the drug or alcohol is sufficient to cause intoxication. This may occur either due to low threshold (i.e. chronic renal failure) or due to idiosyncratic sensitivity. As the time passes, the intensity

of intoxication lessens and the symptoms eventually disappear in the absence of further use of the substance. The recovery is generally complete except in cases where tissue damage or other complications have occurred. 81

2. Withdrawal State comprises a cluster of symptoms that are specific to the drug used and develops on total or partial withdrawal of the drug usually after repeated and/or high-dose use. Withdrawal syndrome is generally short lasting ranging from few hours to few days. Withdrawal symptoms are relieved if the drug is taken. The withdrawal states are further classified as: (i) Uncomplicated (ii) With convulsions (iii) With delirium

3. Dependence syndrome is a condition, which generally develops on regular and continued use of a drug. When a person becomes dependent on a particular drug, he has a compulsive need to obtain and use the drug, each time requiring a higher dose of the drug to get the same effect because of development of tolerance. In case the drug is not available or available in lesser quantity, withdrawal symptoms develop. This behaviour is detrimental to

personal and social life of the individual. According to the International Classification of Diseases (ICD-10), the dependence syndrome is a cluster of physiological, behavioural, cognitive phenomena in which the use of a substance or a class of substances taken on a much higher priority for a given individual than other behaviours that once had greater value. The dependence syndrome is characterized by a strong, often over-powering desire to

take a psychoactive drug (may or may not have been prescribed medically). The definite diagnosis of dependence should usually be made only if at least three of the following have been experienced or exhibited at some time during the previous year; (i) A strong desire or sense of compulsion to take the substance. (ii) Difficulties in controlling substance-taking behaviour in terms of its onset, termination or levels of use. (iii) A physiological withdrawal state occurs when the substance use has ceased or

reduced, (iv) Evidence of tolerance is seen in dependent users. In order to achieve the effects of the drug obtained with low doses initially, he person has to take the higher doses. (v) Progressive neglect of alternative pleasures o interests because of substance use occurs and the individual spends more time in procuring and using the psychoactive drug. (vi) There is persistence with the substance despite of harmful effects caused by the drug on various body organs

4. Harmful Use of a drug can be classified as follows: (i) Continuous drug use, despite the awareness of harmful medical and/ or social effect of the drug being used. (ii) A pattern of physically hazardous use of drug 9i.e. driving during intoxication) The diagnosis of ‘Harmful use requires that the actual damage is caused to the physical or the mental health of the user. If the patient qualifies for the diagnosis of dependence syndrome then

harmful use is not diagnosed. ICD-10 includes other syndromes associated with psychoactive 82

substance use such as psychotic disorder, amnesic syndrome, and residual and late-onset psychotic disorder. The major dependence producing drugs are as shown in Table I. TABLE I: PSYCHOACTIVE SUBSTANCES 1. Alcohol 2. Opioids i.e. opium, heroin 3. Cannabinoids, i.e. Cannabis, Marihuana 4. Cocaine 5. Amphetamines and other sympathomimetic drugs 6. Hallucinogens i.e. Lysergic acid diethylamide (LSD), Phencyclidine (PCP) 7. Sedatives and hypnotics i.e. barbiturates 8. Inhalants i.e. volatile solvents

9. Nicotine, and 10. Other Stimulants i.e. Caffeine AETIOLOGY OF SUBSTANCE USE DISORDER IS A COMPLEX INTERPLAY OF MULTIPLE FACTORS. BIOLOGICAL, PSYCHOLOGICAL AND SOCIAL FACTORS ARE IMPLICATED AND SHOWN IN TABLE II. TABLE II: AETIOLOGICAL FACTORS IN SUBSTANCE USE DISORDERS 1. Biological Factors (i) Genetic Vulnerability (ii) Co-morbid psychiatric disorder or personality disorder (iii) Co-morbid medical disorders (iv) Reinforcing effects of the drugs (v) Withdrawal effects and craving (vi) Biochemical factors

2. Psychological Factors (i) Curiosity, need for novelty seeking (ii) General rebelliousness and social non-conformity (iii) Early initiation of alcohol and tobacco (iv) Poor impulse control (v) Sensation-seeking (high) (vi) Low self-esteem (anomie) (vii) Concerns regarding personal autonomy (viii) Poor stress management skills (ix) Childhood trauma or loss (x) Relief from fatige or boredom (xi) Escape from reality (xii) Lack of interest in conventional goals (xiii) Psychological distress 3. Social Factors

(i) Peer pressure (often more important than the parental factor (ii) Role model: imitating the ego-ideal. 83

ALCOHOL DEPENDENCE Complications Alcohol dependence has its effect not only on the consumer’s body but also on the social and personal life of the individual leading to several complications both medical and social. These are as follows: 1. Acute Intoxication After initial excitation for a brief period, there is generalized Central Nervous System depression with alcohol use. With increasing intoxication, there is increased reaction time, slowed thinking

and distractibility and poor motor control. Later, dysarthria, ataxia and in-co-ordination occur. There is progressive loss of self control with frank disinhibited behaviour. The duration of intoxication depends on the amount and the rapidity with which alcohol is ingested. The signs of intoxication are obvious with blood alcohol levels of 150-200 mg%. Increasing drowsiness followed by coma and respiratory depression develop at the blood level of 300-450 mg%. When

the bllod levels reach between 400-800 mg%, death is likely to occur (Table III). TABLE III: BLOOD ALCOHOL LEVELS AND BEHAVIOUR Blood Alcohol Concentration Behavioural Correlated 25-100 mg% Excitement 80 mg% Is the legal limit for driving in UK whilr in India this limit is Serious intoxication, slurred speech, in-coordination, nystagmus. 100-200 mg% Hypothermia, dysarthria, cold sweats 300-350 mg% Coma 350-400 mg% Death may occur 84

>400 mg% Urinary alcohol Diagnostic Equivalent Blood Alcohol Concentration Concentration Use >120 mg% Suggestive 80 mg% 150 mg >200 mg% Diagnostic Sometimes a small dose of alcohol may produce active intoxication in some persons. It is an idiosyncratic reaction to alcohol and not related to blood levels. This condition is known as pathological intoxication. Sometimes an individual develops complete amnesia of the acute intoxication known as blackouts. 2. Withdrawal Syndrome

In a dependent alcoholic when the blood levels decrease withdrawal symptoms appear. The most common with drawal syndrome is a hangover on the next morning. Mild tremors, nausea, vomiting, weakness, irritability, insomnia and anxiety are other common withdrawal symptoms. Sometimes withdrawal syndrome is more severe characterized by one of the following three: alcoholic hallucinosis, alcoholic seizures, and delirium tremens. (i) Alcoholic hallucinosis: During partial or complete abstinence, a dependent

alcoholic experiences hallucinations (usually auditory). The hallucinations are generally accusatory or threatening in nature. It occurs in about 2% of the cases. These hallucinations persist after the withdrawal syndrome is over, and classically occur in clear consciousness. Usually recovery occurs within one month and the duration is very rarely more than six months. (ii) Alcoholic seizures (rum fits): Generalized tonic clonic seizures occur in about 10%

of alcohol dependent patients, usually 12-48 hours after a heavy bout of drinking. Often, these patients have been drinking alcohol in large amounts on a regular basis for many years. Multiple seizures (2-6 at one time) are more common than single seizures. Sometimes status epilepticus may be precipitated. In about 30% of the cases, delirium tremens follows. (iii) Delirium tremens (DT): It is the most severe alcohol withdrawal syndrome. It

occurs usually within 2-4 days of complete or significant abstinence from heavy alcohol drinking in about 5% of patients, as compared to acute tremulousness which occurs in about 34% of the cases. The course of delirium tremens is short and recovery generally occurs within 37 days. This is an acute organic brain syndrome with the following characteristic clinical features: (a) Clouding of consciousness with disorientation in time and place. (b) Poor attention span and distractibility 85

(c) Visual (and also auditory) hallucinations and illusions, which are often vivid and very frightening. Tactile hallucinations of insects crawling over the body may occur. (d) Marked autonomic disturbance with tachycardia, fever, sweating, hypertension and papillary dilatation are the usual features encountered. (e) Psychomotor agitation and ataxia may be present. (f) Insomnia, with a reversal of sleep-wake pattern can be seen. (g) Dehydration with electrolyte imbalance is present.

Death may occur due to cardiovascular collapse, infection hyperthermia or self-inflicted injury. At times, medical illness like pneumonia, fractures’ liver disease and pulmonary tuberculosis may complicate the clinical picture. 3. Neuropsychiatric complications of chronic alcohol use (i) Wernicke’s encephalopathy: This is an acute reaction occurring in response to severe deficiency of thiamine, commonest cause being chronic alcohol intake.

The onset of this disorder characteristically occurs after a period of persistent vomiting. The important clinical features are: (a) Ocular signs: Course nystagmus and ophthalmoplegia, with bilateral external rectus muscle paralysis occur early. In addition, papillary irregularities, retinal hemorrhages and papilledema can occur, causing an impairment of vision. (b) Higher mental function disturbance: Disorientation, confusion, recent memory disturbances, poor attention span and distractibility are the

common impairments of higher mental functions. Other early symptoms seen are apathy and ataxia. Peripheral neuropathy and serious malnutrition are generally co-existent. Neuropathological findings show neuronal degeneration and hemorrhage in thalamus, hypothalamus, mammillary bodies and midbrain. (ii) Korsakoff’s psychosis: Korsakpff’s psychosis often follows Wernicke’s encephalopathy and to-gether they are referred as the Wernicke-Korsakoff

Syndrome. Clinical manifestations of Korsakoff’s psychosis include an organic amnestic syndrome, characterized by gross memory disturbances with confabulation and impaired insight. Neuropathological findings show widespread lesion and the most consistent changes are seen in bilateral dorsomedial nuclei of the thalamus and mammillary bodies. The changes are also seen in periventricular and periequiductal grey matter, cerebellum and

parts of brainstem. The cause is usually severe, untreated thiamine deficiency secondary to chronic alcohol use. (iii) Marchiafave-Bignami disease: This disorder is probably caused by alcohol- related deficiency with pathological changes in the form of wide-spread demyelination of corpus callosum, optic tract and cerebellar peduncles. Clinical manifestations include disorientation, epilepsy, ataxia, dysarthria, 86

hallucinations, spastic limb paralysis, and deterioration of personality and intellectual functions. This is a rare disorder. (iv) Other Complications of Alcohol Use include (a) Alcoholoc dementia (b) Cerebellar degeneration (c) Peripheral neuropathy (d) Central Pontine myelinosis (e) Optic atrophy (particularly with methyl alcohol) Treatment: Following steps should be considered before starting treatment for alcohol dependence: (iv) Look for the possibility of a physical disorder.

(v) Look for the possibility of a psychiatric diagnosis. (vi) Patient’s motivation to undergo treatment should be assessed. (vii) Assessment of the social support the patient enjoys should be done. (viii) Personality characteristics of the patient should be assessed in details. (ix) Level of current and past occupational and socials functioning should be assessed. The treatment comprises two broad components i.e. detoxification and treatment of alcohol dependence. 1. Detoxification

Treatment of alcohol withdrawal symptoms is detoxification. Symptoms that are produced due to non-availability or lesser availability of alcohol to a dependent alcohol user are withdrawal symptoms and the constellation of symptoms form withdrawal syndrome. The usual duration of uncomplicated withdrawal syndrome is 7-14 days. The aim of detoxification is the symptomatic management of the emergent withdrawal symptoms. Benzodiazepines are the drugs of choice for symptomatic detoxification. Chlordiazepoxide is

generally used in the dosage range of 80-200 mg per day in three to four divided doses. Another drug used is diazepam, its dose being 40-80 mg per day in divided doses. The typical dose of chlordiazepoxide in moderate alcohol dependence should be as follows: - 1st day, 20 mg four times - 2nd day 15 mg four times - 3rd day 10 mg four times - 4th day 5 mg four times - 5th day 5 mg two times and then stop. In severe dependence, higher doses are required for longer period (up to

10 days. In some countries drugs like chlormethiazole (1-2 g/day) and carbamazepine (600- 1600 mg/day) are also used for detoxification. These drugs follow a standard dose regime 87

with dosage steadily decreasing and stopping on 10th day. Nutritional deficiency is generall associated with alcohol dependenc therefore, vitamins should be given. 2. Treatment of alcohol dependence After the detoxification process is over further management is done with the aim to prevent the patient from restarting alcohol consumption. Several methods are available to choose that suit best to the patient. Some of these important methods are as follows: (i) Behaviour therapy (ii) Psychotherapy

(iii) Group therapy (iv) Deterrent therapy (v) Other medications (vi) Psychosocial rehabilitation OPIOID USE DISORDER The natural alkaloids of opium and their synthetic preparations are highly dependence producing drugs (Table IV). The dried exude obtained from unripe seed capsules of Papaver somniferum is a highly dependence producing and is abused for centuries. In the last few decades, the use of opioids has tremendously increased all over the world. India being the transit point for illicit drug trade

between golden triangle (Burma-Laos-Thailand) and golden crescent (Iran-Afghanistan-Pakistan) is among the worst effected countries. Addition of heroin to Indian streets some two decades ago has caused devastating effects on the adolescents and youth of the country. TABLE IV: OPIOID DERIVATIVES 1. Natural Alkaloids of opium (i) Morphine (ii) Codeine (iii) Thebaine (iv) Noscapine (v) Papaverine 2. Synthetic Compounds (i) heroin (ii) Nalorphine (iii) Hydromorphine (iv) Methadone (v) Dextropropoxyphene

(vi) Meperidine (Pethidine) (vii) Cyclazocine (viii) Levallorphan (ix) Diphenoxylate 88

Morphine and heroin are the most potent dependence producing derivatives; they bind to mu opioid receptors. The other opioid receptors are kappa (for pentazocin), delta (for a type of encephalin), sigma (for phencyclidine), epsilon and lamda. Heroin (diacetyl-morphine) is two times more potent than morphine in injectable form. Apart from the parentral mode of administration, heroin can also be smoked or chased (chasing the dragon), often in impure form (popularly known

as smack or brown sugar in India. Due to its higher addictive potential than morphine, heroin causes dependence after a short period of exposure. Tolerance to heroin occurs rapidly and can be increased to up to more than 100 times the first dose needed to produce an effect. Acute Intoxication Acute intoxication due to opioids is characterized by apathy, bradycardia, hypotension, respiratory depression, sub-normal core body temperature and pin-point pupils. Subsequently,

reflexes become delayed, pulse becomes thready and coma may occur in case of a large overdose. In severe intoxication, mydriasis may occur due to hypoxia. Withdrawal Syndrome Withdrawal symptoms generally appear within 12-24 hours, reach their peak within 24-72 hours and subside within 7-10 days of the last dose of opioids. He characteristic symptoms include lacrimation, rhinorrhoea, papillary dilatation, sweating, diarrhea, yawning, tachycardia, mild hypertension,

onsomnia, raised body temperature, muscle cramps, generalized bodyache, severe anxiety, piloerectio, nausea, vomiting and anorexia. There can be marked individual differences in manifestation of withdrawal symptoms. Withdrawal syndrome with heroin is more severe as compared to the one seen with morphine. Complications Chronic opioid use may lead to several complications. The important ones are listed here. One may experience one or more of the following complications:

(i) Complications due to illicit use are quite common. Illicit drug is usually contaminated with some toxic additives. Complications generally seen are, parkinsonism, degeneration of globus pallidus, peripheral neuropathy, amblyopia, transverse myelitis. (ii) Complications due to intravenous use are quite common if the needles are exchanged. The user gets exposed to the risk of various infections. The complications generally seen

are, AIDS, skin infections, thrombophlebitis, pulmonary embolism, septicemia, viral hepatitis, tetanus, endocarditis. (iii) Drug pedaling and criminal activities may become a part of chronic users’ life leading to various social and legal complications. Production, manufacture, import, export, sale, purchase and even use of opioids is illegal and is liable to be penalized with severest of punishment (under Narcotic Drugs and Psychotropic substances Act 1985 in India).

Chronic use also leads to financial and occupational difficulties leading to marital discord and other social problems. 89

Treatment Before starting treatment correct diagnosis should be established on the basis of detailed history of drug intake, the examination and laboratory tests. These tests provide an evidence of drug use. These tests include, Naloxone challenge test to precipitate withdrawal symptoms and urinary opioid testing with radio-immunoassay (RIA), free radical assay technique (FRAT), thin layer chromatography (TLC), gas liquid chromatography (GLC), high pressure liquid chromatography

(HPLC) or enzyme-multiplied immuno-assay technique (EMIT). After confirming the diagnosis, the treatment can proceed on three lines: 1. Treatment of overdose 2. Detoxification 3. Maintenance therapy 1. Treatment of opioid overdose Narcotic antagonists (i.e. naloxone, naltrexone) are generally used to treat opioid overdose. Intravenous injection of 2 mg Naloxone followed by repeated injection in 5-10 minutes, causes

reversal of overdose. Since naloxone has a short half-life, repeated doses are required every 1-2 hour. General supportive care should be provided along with. 2. Detoxification is the process in which an opioid dependent person is “freed” from opioids. This is usually done by abruptly stopping the opioid, and managing the emergent withdrawal symptoms. Detoxification of opioid dependents is highly successful, relatively cheaper, applicable on a very large

scale, associated virtually with no morbidity or mortality and acceptable to almost all patients. Following methods are available for the management of the withdrawal symptoms: (i) Use of substitution drugs such as methadone is quite common though this drug is not available in India, to control withdrawal symptoms. Methadone is relatively less addicting, has longer half-life, decreases possible criminal behaviouir and has much

milder withdrawal symptoms when stopped. The aim is to gradually taper the patient from methadone. Relapse rates are quite high when methadone is stopped. It is also argued that one dependence is replaced by another. (ii) Clonidine is an alfa2 agonist that acts by inhibiting norepinephrine release at the presynaptic alfa2 receptor. The usual dose of clonidine is 0.3-1.2 mg. Per day, and it is tapered off within 10-14 days. It is started after stopping the opioid. Clonidine causes

excessive sedation and postural hypertension, therefore the treatment is ideally started in the indoor setting. Regular blood pressure monitoring should be done. (iii) Naltrexone in combination with clonidine is used for the treatment of opioid dependence. Naltrexone is a orally available narcotic antagonist blocking the action of opioids in a dependent person and thus causing withdrawal symptoms. These withdrawal symptoms are managed with addition of clinidine for a period of 10-14 days

and then stopping it. Subsequently the patient continues on naltrexone alone. Now if 90

the person takes an opioid, there are no pleasurable experiences as the opioid receptors are blocked by naltrexone. Therefore, this method can be regarded as the combination of detoxification and maintenance treatment. The usual dose of naltrexone is 100 mg orally, administered every alternate day. (iv) Other drugs are also used as detoxification agents. These are: (a) LAAM (levo-alpha-acetyl-methadol) is not in wide use for opioid dependence and its

use as a long-term treatment agent began in late 1960s. Its analgesic effect and delayed action and longer duration of action were first noted in animals in 1948. With subcutaneous injection of 10-30 mg LAAM analgesic effect is produced after 4- 6 hours lasting for 48-72 hours. Intravenous administration also produces similar results, while with oral administration effect appears much quicker (within 1-2 hours) and persists for 72 hours. (b) Propoxyphene (c) Diphenoxylate

(d) Buprenorphine is a long-acting partial mu-agonist and is commonly used for both detoxification and maintenance treatment. (e) Lofexidine is a alpha2 agonist like clonidine 3. Maintenance therapy After the patient is detoxified, the next step is to put the patient on maintenance therapy. The patient is maintained on one of the following regimes: (i) Methadone maintenance (Agonist substitution therapy) (ii) Opioid antagonists (iii) Other methods (iv) Psychosocial rehabilitation CANNABIS USE DISORDER

Cannabis is derived from hemp plant Cannabis sativa and different parts of the plant yield the products popularly known as grass, hash or hashish, marihuana, charas, bhang etc. The plant carries more than 400 identifiable chemicals of which about 50 are cannabinoids, the most active being TABLE V: CANNABIS PREPARATION AND THC CONTENT Cannabis Part of the plant from where THC content Potency as compared (%) to Bhang preparation It is obtained Hashish/Charas Resinous exudates from the flowering tops 8-14% 10

of cultivated plants Ganja Small leaves and brackets of inflorescence 1-2% 2 91

of highly cultivated plants Bhang Dried leaves, flowering shoots and cut tops 1% 1 of uncultivated plants Hash oil Lipid soluble plant extract 15-40% 25 COCAINE USE DISORDER Cocaine is an alkaloid derived from the coca bush, Erythroxylum coca, found in Bolivia and Peru. It was isolated by Albert Neimann in 1860 and was used y Karl Koller, a Friend of Sigmund Freud in 1884 as the first effective local anaesthetic agent. In the last few decades, cocaine has gained

popularity as a street drug, crack and can be administered in the body orally, intranasally, by smoking or parenterally, depending upon the preparation available. Commonest forms used are, cocaine hydrochloride and free base alkaloid. Both intravenous use and free base inhalation produce a ‘rush’ of pleasurable sensations. Cocaine is central stimulant, which inhibits the reuptake of dopamine, along with the reuptake of

noreponephrine and serotonin. In animals, cocaine is the most powerful reinforcer of the drug- taking behaviour. Cocaine is sometimes used in combination with opiates like heroin (‘speed ball’) or at times amphetamines. Cocaine has started making its presence felt in India’s bigger cities. Acute effects are due to central stimulant and sympathomymetc effects as euphoria, confidence, increased energy, increased heart rate and blood pressure, dilated pupils, constriction of peripheral

blood vessels and rise in body temperature and metabolic rate. In an intoxicated state, the user presents with papillary dilatation, tachycardia, hypertension, sweating and nausea or vomiting. A hypomanic picture with increased psychomotor activity, grandiosity, elation of mood, hypervigilance and increased speech output may be present. Later, judgment is impaired and there is impairment of social and occupational; functioning.

In various trials it has been found that the effects of cocaine on heart, blood pressure respiratory rate, and mood increase as the dose is raised from 4 mg. To 30 mg. Major effects are observed with the dose 16 mg and above. In higher doses cocaine can cause depression of the medullary centres and death from cardiac, and more often respiratory arrest. Because cocaine causes increased energy and confidence and can produce irritability and paranoia, it may lead to physical aggression and crime. 92

Chronic effects are generally not marked if cocaine is used for 2-3 times a week for recreational purposes. Taken daily in fairly large amounts, it can disrupt eating and sleeping habits, produce minor psychological disturbances including irritability and difficulty in concentration, and create a serious psychological dependence. Perceptual disturbances (especially pseudohallucinations), paranoid thinking and rarely psychosis also occur in chronic users of cocaine. A runny and clogged

nose is common to be seen and that can be treated with nasal decongestant sprays. Less often, the nose can become inflamed, swollen or ulcerated. Rarely, perforated nasal septum is also reported. Dependence potential varies with the route of administration. Intravenous cocaine use is most powerful drug-reinforcer. Withdrawal syndrome Cocaine does not produce physical dependence in the sense that alcohol and heroin does but

sometimes- mild withdrawal symptoms such as anxiety and depression arise. Physical dependence is very mild if it is there but the psychological dependence is very strong. TABLE VI: COMPLICATIONS DUE TO COCAINE USE The complications of chronic cocaine withdrawal include: 1. Acute anxiety reaction 2. Uncontrolled compulsive behaviour 3. Psychotic episode (with persecutory delusions and yactile and other hallucinations 4. Delirium and delusional disorder 5. seizures (especially with high dose)

6. Respiratory depression 7. Cardiac arrythmias 8. Coronary artery occlusion 9. Myocardial infarction 10. Lung damage 11. Gastrointestinal necrosis 12. Fetal anoxia 13. Nasal septum perforation. INHALANTS Volatile solvents have the capacity to intoxicate those who deliberately inhale them. Hundreds of intoxicating volatile products are available in the homes as well as market place much within the reach of adolescents and young people. Use of inhalants is found more common among school going

adolescents and inhalation of these agents is a peer-originated and peer-perpetuated activity. There is a wide range of inhalants commonly abused: 93

(i) Airplane glue (ii) Fingernail polish remover (iii) Gasoline (iv) Paint thinner (v) Liquid shoe polish (vi) Plastic cement (vii) Cleaning fluid (viii) Wax strippers (ix) Petrol (x) Kerosene oil Causes (i) Indulgence in inhalant use behavior is generally caused by unsuccessful and unrewarding school experiences. (ii) Personality deficiencies are reported to be important predisposing factors in confirmed inhalant abusers. (iii) Youngsters overwhelmed with anxiety, depression, or both; boarder-line or over

schizophrenia; and those with character disorders employ inhalants in effect at self- treatment for their intrapsychic and interpersonal distress. (iv) Social disorganization within the community also contribute to this practice Consequences (i) Psychiatric features of acute intoxication resemble those of alcohol intoxication except for its brief duration. The period of relative stimulation and of disinhibited behaviour is

also similar to that of alcohol. This can result in accidental injury or death and the releasing of aggressive impulses against one’s self or others. Cognitive deficit may occur with extensive and prolonged inhalant abuse. Psychological maturation gets arrested and aberrant behaviour is not uncommon. School-dropout is a usual consequence of inhalant abuse. (ii) Physical symptoms may occur due to the toxic effects of the inhalants. Some of the

volatile solvents are the known poisons. Carbon tetrachloride is so toxic that it has been removed from the commercial trade, and benzene’s use is limited for the same reason. Hexane and leaded gasoline can cause a serious polyneritis, and the latter is capable of producing encephalopathy. Toluene is involved in dysfunction of kidney, nervous system and bone marrow. Metallic spray paints and other aerosols may have dangers caused by

secondary ingradients rather than by solvent themselves. Sudden sniffing deaths have been reported. Ventricular fibrillation and other arrhythmias occur. BENZODIAZEPINES AND OTHER SEDATIVE-HYPNOTIC USE DISORDER These drugs are generally used in the treatment of anxiety and insomnia. Currently, these are the most often prescribed drugs. Chlordiazepoxide was discovered by Sternbach in 1957 and since then benzodiazepines have replaced other sedative-hypnotic drugs. Benzodiazepines produce their

effects by acting on benzodiazepine receptors (GABA-Benzodiazeine receptor complex), thereby indirectly increasing the action of GABA, the chief inhibitory neurotransmitter in the human bran. 94

Bnzodiazepine (or other sedative-hypnotic) use disorder can either be iatrogenic or originating with illicit drug use. Dependence, both psychological and physical, can occur and tolerance is usually moderate. TOBACCO Tobacco is a plant product derived mainly from Nicotiana tobaccum and Nicotiana rustica grown all over the world and used by people in almost all countries. Tobacco plant is a native of Americas and was brought by the European navigators on their discovery of Americas in 1492. Tobacco leaves

contain an active alkaloid, which is highly toxic and develops resistance to its own action and hence highly addictive. Tobacco is used in smokeless form and it is smoked as cigarette, beedi etc. Withdrawal symptoms include restlessness, nervousness, anxiety, insomnia, increased weight. For tobacco-cessation, pharmacological and behavioural techniqiues are used. First line treatment includes Bupropion (150 mg per day for 3 days and then 150 mg twice a day for 6-7 weeks). Nicotine

replacement therapy in the form of nicotine patches, nicotine spray, nicotine lozenges is available. Second-line treatment includes clonidine and amitriptyline. Behaviour therapy and counseling are used along with pharmacotherapy or independently. 95

STANDARD TREATMENT GUIDELINES GENERAL SURGERY Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 BLUNT ABDOMINAL TRAUMA 4 2 CHOLECYSTECTOMY D 7 3 CIRCUMSION 15 4 COLECTOMY 21 5 FISTULA IN ANO 34 6 HAEMORRHOIDS 40 7 HERNIA 44 8 HYDROCELE 48 9 PAROTID NEOPLASM 51 10 PEPTIC ULCER PERFORATION 53 11 SKIN AND SOFT TISSUE LESIONS 60 12 SMALL BOWEL PERFORATIONS 63 13 VARICOSE VEINS SURGERY 66 2

Group Head Coordinator of Development Team Dr Ajit Sinha Department of Surgery Safdarjung Hospital New Delhi 3

BLUNT ABDOMINAL TRAUMA Dr Sanjay Gupta Professor, Department of Surgery University College of Medical Sciences, Delhi 1. Name of the condition: Blunt abdominal trauma 2. When to suspect/ recognize? a. Introduction: Blunt abdominal trauma (BAT) is an increasingly common problem encountered in the emergency department. The usual causes of BAT include vehicular accident, assault, falls, sports injuries and natural disasters. b. Case definition: BAT is suspected in any patient involved in above situations and

presents with abdominal pain, distention or shock. It should be looked for in patients of polytrauma. 3. Incidence of the condition in our country: One study has reported 2.1% incidence of BAT amongst all surgical patients admitted to a tertiary hospital during 1 year. 4. Differential diagnosis:Abdominal trauma forms adifferential diagnosis of any patient presenting with acute abdomen. 5. Prevention and counseling: Use of appropriate safety measures during various activities

associated with BAT can significantly reduce its incidence. 6. Optimal diagnostic criteria, investigations, treatment and referral criteria: a. Situation 1 At Secondary Hospital/ Non-metro situation: Optimal standard of treatment in situations where resources are limited I. Clinical diagnosis:This is based on a. High level of suspicion of intra-abdominal injury b. Presence of wounds/ bruising on the abdomen c. Abdominal guarding/ tenderness d. Presence of free gas/ fluid in the peritoneal cavity

e. Presence of fracture of lower ribs and/ or pelvis increases the likelihood of intra- abdominal injury f. Note should be made of altered mental state, drug or alcohol intoxication and distracting injuries which may mask the features of BAT g. Repeated examination increases the accuracy of diagnosis II. Investigations: a. All hemodynamically stable patients with suspected BAT should undergo Focused Abdominal Sonography in Trauma (FAST)or Diagnostic Peritoneal Lavage (DPL)

b. Urgent laparotomy is indicated in patients with evidence of BAT who remain hemodynamically unstable despite initial resuscitation III. Treatment (Standard operating procedure): a. Inpatient: 4

i. All patients should have initial cervical stabilization and resuscitation, if required ii. Initial fluid resuscitation should be done with 2L warmed Ringer Lactate solution infusedrapidly through 2 peripheral lines iii. A nasogastric tube and a Foley catheter should be put iv. Laparotomy should be done, if indicated on the basis of clinical features, FASTor DPL v. Laparotomy should be done through a long midline incision vi. Bleeding should be controlled by clamping/ packing till definitive control

is possible vii. Hollow viscus should be repaired viii. In case the intra-abdominal injuries are extensive, patient is very sick and OT facilities/ surgeon’s experience is suboptimal, Damage Control Surgery may be done. Definitive surgery should be done subsequently under improved circumstances or at a higher center. b. Outpatient: Not indicated c. Day care: Not indicated IV. Referral criteria: After Damage Control Surgery if the local facilities are inadequate.

b. Situation 2 At Superspecialty Facility in Metro location where higher end technology is available 1. Clinical diagnosis: Same as 6a 2. Investigations: a. Same as 6a b. CECT abdomen is preferred investigation in all hemodynamically stable patients with BAT c. Angiography and angioembolization may be considered in hemodynamically stable patients with solid organ injury who are suitable for non-operative management 3. Treatment (Standard operating procedure): a. Inpatient: i. Same as 6a

ii. In case the intra-abdominal injuries are extensive, patient is very sick and surgeon’s experience is suboptimal, Damage Control Surgery may be done. Definitive surgery should be done subsequently under improved circumstances iii. Angiography and angioembolization may be considered in hemodynamically stable patients with solid organ injury who are suitable for non-operative management b. Outpatient: Not indicated c. Day care: Not indicated 4. Referral criteria: Not indicated 5

7. Who does what and timelines: a. Doctor: Does initial evaluation, subsequent monitoring, decision regarding investigations and therapeutic intervention. b. Nurse: Assists in resuscitation, monitoring, investigation and treatment. c. Technician: Assists in resuscitation, investigation and treatment. 8. Further reading/ references a. Udeani J, Steinberg SR. Blunt abdominal trauma. URL: http://emedicine.medscape.com/article/433404-print

b. Joint theatre Trauma System Clinical Practice Guideline: Blunt abdominal trauma. URL: http://www.usaisr.amedd.army.mil/cpgs/Blunt%20Abdominal%20Trauma%2030%20Ju n%2010.pdf c. M. Swarnkar, P. Singh & S. Dwivedi : Pattern Of Trauma In Central India: An Epidemiological Study With Special Reference To Mode Of Injury. The Internet Journal of Epidemiology. 2010 Volume 9 Number 1 6

CHOLECYSTECTOMY Dr. Arun Prasad INTRODUCTION: Cholecystectomy is one of the commonest elective surgical procedure performed in India. Most are performed to address symptoms related to biliary colic from cholelithiasis, to treat complications of gallstones (eg, acute cholecystitis, biliary pancreatitis), or as incidental cholecystectomies performed during other open abdominal procedures. Currently, most cholecystectomies are done using the

laparoscopic technique in cities; however, the open technique is required in places where facilities or trained staff are not available. DEFINITION: Cholecystectomy implies the surgical resection the gall bladder. INDIAN INCIDENCE In India, the incidence of gall stones is around six percent in the total population. It is 10 per cent in women and three per cent in men. In elderly people it may go up to 20 percent. INDICATIONS: Asymptomatic patients

Cholecystectomy is not indicated in most patients with asymptomatic stones because only 2-3% of these patients go on to become symptomatic per year. To properly determine the indications for elective cholecystectomy, the risk of the operation (taking into account the age and comorbid factors of the individual patient) must be weighed against the risk of complications and death without operation. The widespread use of diagnostic abdominal ultrasonography has led to the increasing detection of

clinically unsuspected gallstones. This, in turn, has given rise to a great deal of controversy regarding the optimal management of asymptomatic (silent) gallstones. Patients who are immunocompromised, are awaiting organ allotransplantation, or have sickle cell disease are at higher risk of developing complications and should be treated irrespective of the presence or absence of symptoms. Additional reasons to consider prophylactic cholecystectomy include the following:

• Calculi >3 cm in diameter, particularly in individuals in geographical regions with a high prevalence of gallbladder cancer • Chronically obliterated cystic duct • Nonfunctioning gallbladder • Calcified (porcelain) gallbladder • Gallbladder polyp >10 mm or showing rapid increase in size 7

• Gallbladder trauma • Anomalous junction of the pancreatic and biliary ducts • Morbid obesity is associated with a high prevalence of cholecystopathy, and the risk of developing cholelithiasis is increased during rapid weight loss. Routine prophylactic cholecystectomy prior to gastric bypass (RYGB) is controversial, but cholecystectomy should clearly precede or be performed at the time of RYGB in patients with a history of gallbladder pathology. Symptomatic gallstone disease

Biliary colic with sonographically identifiable stones is the most common indication for elective cholecystectomy. Acute cholecystitis, when diagnosed within 72 hours from the onset of symptoms, can and usually should be treated by surgery. Once 72 hours pass after the onset of symptoms, inflammatory changes in the surrounding tissues are widely believed to render dissection planes more difficult. Interval cholecystectomy after 4-6 weeks or percutaneous cholecystostomy are other options.

Biliary dyskinesia should be considered in patients who present with biliary colic in the absence of gallstones, and a cholecystokinin–diisopropyl iminodiacetic acid (CCK-DISIDA) scanning should be obtained. The finding of a gallbladder ejection fraction <35% at 20 minutes is considered abnormal and constitutes another indication for cholecystectomy. Complex gallbladder disease Gallstone pancreatitis Cholecystectomy can be safely performed during the same hospitalization after the clinical signs of mild

to moderate biliary pancreatitis have resolved. Patients diagnosed with gallstone pancreatitis should first undergo imaging to rule out the presence of choledocholithiasis. Cholecystectomy should be delayed in cases of acute moderate to severe biliary pancreatitis (5 Ranson criteria). Choledocholithiasis The following treatment options are available for patients found to have choledocholithiasis: Preoperative ERCP with sphincterotomy Postoperative ERCP with sphincterotomy

Laparoscopic intraoperative cholangiogram with laparoscopic common bile duct (CBD) exploration Open CBD exploration and T-tube placement Mirizzi syndrome Mirizzi described an unusual presentation of gallstones that, when lodged in either the cystic duct or the Hartmann pouch of the gallbladder, externally compressed the common hepatic duct, causing symptoms of obstructive jaundice. 8

Although an initial trial of dissection may be performed by an experienced laparoscopic biliary surgeon, one must be prepared for conversion and for biliary reconstruction. Endoscopic stone fragmentation at ERCP, with papillotomy and stenting, is a viable alternative to operative surgery to treat Mirizzi syndrome in the acute setting.[24 ]Subsequent cholecystectomy may be performed.[25 ] Cholecystoduodenal fistula

Patients with cholecystoduodenal fistula leading to gallstone ileus should undergo exploratory laparotomy and removal of the stone, followed by exploration of the remainder of the gastrointestinal tract for additional stones. The fistula may be addressed at the time of the initial procedure but is probably better addressed at a second operation (3-4 wk postoperatively) after inflammation has subsided.[25 ] Cholecystenteric fistula does not represent an absolute contraindication to laparoscopic surgery,

although it does require careful visualization of the anatomy and good laparoscopic suturing skills. Acalculous cholecystitis A greater proportion of patients with acalculous cholecystitis are too ill to undergo surgery. In these situations, percutaneous cholecystostomy guided by CT or ultrasonography is advised. Ninety percent of these patients demonstrate clinical improvement. Once the patient has recovered, the cholecystostomy

tube can be removed, usually at 6 weeks, without sequelae. Interval cholecystectomy is not necessary.[27 ] Incidental gallbladder cancer Gallbladder cancer may be an incidental finding at cholecystectomy, with an incidence ranging from 0.3- 5.0%. Uncertainty of diagnosis, uncertainty of the degree of tumor spread, or postoperative identification of cancer on pathological examination of a routine cholecystectomy specimen should engender early reoperation.

Before reoperation, distant metastases should be excluded by a detailed clinical examination including a per-rectal/per-vaginal examination, examination for supraclavicular lymph nodes, and CT/MRI of the chest and abdomen. Special situations Children Cholecystectomy is a safe and effective treatment for most children diagnosed with biliary disease (BD). Cirrhosis Cholecystectomy in safe in patients with Child class cirrhosis. 9

Diabetes mellitus The presence of diabetes mellitus, in and of itself, does not confer sufficient risk to warrant prophylactic cholecystectomy in asymptomatic individuals. However, consider that acute cholecystitis in a patient with diabetes is associated with a significantly higher frequency of infectious complications such as sepsis. Pregnancy The treatment of biliary colic or uncomplicated cholecystitis in a pregnant patient is conservative

management followed by elective cholecystectomy. Using antibiotics, analgesics, and antiemetics help most pregnant women avoid surgical intervention. Surgery is generally indicated for patients with recurrent acute cholecystitis who have failed maximal medical therapy. Classically, the second trimester is considered the safest time for surgery. This is because of the findings of increased risk for spontaneous abortion and teratogenesis during the first trimester, and the

increased risk for premature labor and difficulties with visualization in the third trimester. Pregnancy was formerly considered to be an absolute contraindication to the laparoscopic approach because of concern for potential trocar injury to the uterus and the unknown effects of pneumoperitoneum to the fetal circulation. However, this has not been borne out in the literature, and cholecystectomy is now considered safe.

Recommendations for pregnant patients who undergo laparoscopic cholecystectomy include placing them in the left lateral recumbent position to shift the weight of the gravid uterus off the vena cava and maintenance of insufflation pressures between 10 and 12 mm Hg. In addition, maternal PaCO 2 monitoring must be performed by measuring either arterial blood gases or end-tidal CO 2 , but arterial PaCO 2 may be more accurate.

Other recommendations include avoiding rapid changes in intraperitoneal pressures, avoiding rapid changes in patient position, and using open technique for the umbilical port placement. Distance from medical centres In India, another indication can be distance from a treating hospital as long travel that may be needed can lead to complications. INVESTIGATIONS: § Haemogram § Liver Function Tests § Blood sugar § Serum creatinine § Bleeding time, clotting time and prothrombin time § Xray chest 10

§ ECG § USG abdomen § In patients with dilated common bile duct or raised liver functions, MRCP or ERCP may be indicated based on availability. Alternatively, an on table cholangiogram or CBD exploration may be done during surgery. Patient can be referred to another centre in case of non availability of expertise or experience. OPERATIVE TECHNIQUES: Principles of surgery remain the same regardless of whether it is being done by open or laparoscopic technique. • Safe access to abdomen.

• Clear definition of anatomy in the calots triangle showing either the continuity between cystic duct and gall bladder or junction between cytic duct and common bile duct. • Avoiding diathermy close to common bile duct. • Securing cystic artery safely and close to the gall bladder. • Dissection from liver bed staying close to gall bladder. • Early conversion to open procedure in case of a difficult laparoscopic surgery. REFERRAL CRITERIA: • Common bile duct stones if no facilities for management available.

• Suspected gall bladder cancer. • Bile duct injury during surgery. Patient should be referred to a tertiary centre as soon as possible. WHO DOES WHAT? Doctor: a) Surgeon: diagnosis & work up Pre operative planning Operative procedure Post operative follow up 11

b) Anesthetist: PAC, anesthesia, post op ICU management NURSE: • Dressing of the wound • Pre & post operative care TECHNICIAN: • Pre op equipment and drugs to be checked and kept ready • Assist anesthetist in the OT • Assist the surgeon, positioning of the patient RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (Patient weight 60 Kgs) Human Resources Investigations Drugs/Consumables Equipment Surgeon – 1 Haemogram Antibiotics OT Table & lights Medical Officer / LFT Analgesic Instrument trolley

Assistant Surgeon – 1 Blood Sugar I.V. Fluids Laparoscopic Surgery set Anesthetist – 1 S. Electrolytes Sutures General Surgery Set Pathologist – 1 KFT Drains Cautery Staff Nurse – 1 ECG Catheters Suction Technician – 1 X-Ray – Chest Anesthetic drugs Anesthetic Equipment Nursing Orderly – 1 USG Dressings Monitors Sweeper – 1 Histopathology 12

REFERENCES 1.↵ Sama C, Labate AM, Taroni F, Barbara L. Epidemiology and natural history of gallstone disease. Semin Liver Dis. 1990; 10:149-58. 2.↵ Newman HF, Northup JD. The autopsy incidence of gallstones. Internat Abstr Surg. 1959; 109:1-13. 3.↵ The MICOL Group. Prevalence of gallstone disease in 18 Italian population samples: first results from the MICOL study. In: Capocaccia L, Ricci G, Angelico F, Angelico M, Attili AF, Lalloni F; eds. Recent

Advances in the Epidemiology and Prevention of Gallstone Disease. Boston: Kluwer; 1991:37-44. 4.↵ Cucchiaro G, Watters CR, Rossitch JC, Meyers WC. Deaths from gallstones. Incidence and associated clinical factors. Ann Surg. 1989; 209:149-51. 5.↵ Godrey PJ, Bates T, Harrison M, King MB, Padley NR. Gallstones and mortality: a study of all gallstone related deaths in a single health district. Gut. 1984; 25:1029-33. 6.↵ French EB, Robb WA. Biliary and renal colic. Br Med J. 1963; 2: 135-8.

7.↵ Thistle JL, Cleary PA, Lachin JM, Tyor MP, Hersh T. The natural history of cholelithiasis: the National Cooperative Gallstone Study. Ann Intern Med. 1984; 101:171-5. 8.↵ Glambek I, Arnesio B, Soreido O. Correlation between gallstones and abdominal symptoms in a random population. Scand J Gastroenterol. 1989; 24:277-81. 9.↵ Jorgensen T. Abdominal symptoms and gallstone disease: an epidemiological investigation. Hepatology. 1989; 8:856-60. 10.↵ Price WH. Gallbladder dyspepsia. Br Med J. 1963; 2:138-41.

11.↵ Health and Policy Committee, American College of Physicians. How to study the gallbladder. Ann Intern Med. 1988; 109:752-4. 12.↵ Hutcheon DF, Bayless TM, Gadacz TR. Postcholecystectomy diarrhea. JAMA. 1979; 241:823-4. 13.↵ Ros E, Zambon D. Postcholecystectomy symptoms. A prospective study of gallstone patients before and two years after surgery. Gut. 1987; 28:1500-4. 14.↵ Lasson A. The postcholecystectomy syndrome: diagnostic and therapeutic strategy. Scand J Gastroenterol. 1987; 22:897-902.

15.↵ Bishop YM, Mosteller F. Smoothed Contingency-Table Analysis. In: Bunker JP, Forrest WH Jr, Mosteller F, Vandam LD,; eds. The National Halothane Study. Bethesda, Maryland: National Institute of General Medical Sciences; 1969:238-72. 16.↵ Commission on Professional and Hospital Activities. Hospital Mortality, PAS Hospitals, United States, 1972-73. Table F. Ann Arbor, Michigan: Commission on Professional and Hospital Activities; 1975. 13

17.↵ Commission on Professional and Hospital Activities. Hospital Mortality, PAS Hospitals, United States, 1974-75. Table F. Ann Arbor, Michigan: Commission on Professional and Hospital Activities; 1977. 18.↵ Ransohoff DF, Gracie WA, Wolfenson LB, Neuhauser D. Prophylactic cholecystectomy or expectant management for persons with silent gallstones. A decision analysis to assess survival. Ann Intern Med. 1983; 99:199-204.

19.↵ Roos LL, Fisher ES, Sharp SM, Newhouse JP, Anderson G, Bubolz TA. Postsurgical mortality in Manitoba and New England. JAMA. 1990; 263:2453-8. 20.↵ Gilliland TM, Traverso LW. Modern standards for comparison of cholecystectomy with alternative treatments for symptomatic cholelithiasis with emphasis on long-term relief of symptoms. Surg Gynecol Obstet.1990; 170:39-44. 21.↵ Morgenstern L, Wong L, Berci G. Twelve hundred open cholecystectomies before the laparoscopic

era. A standard for comparison. Arch Surg. 1992; 127:400-3. 22.↵ Andren-Sandberg A, Alinder G, Bengmark S. Accidental lesions of the common bile duct at cholecystectomy. Ann Surg. 1985; 201:329-32. 23.↵ Raute M, Schaupp W. Iatrogenic bile duct injuries at cholecystectomy: treatment and results. Langenbecks Arch Chir. 1988; 373:345-54. 24.↵ Cuschieri A, Dubois F, Mouiel J, Mouret P, Becker H, Buess G, et al. The European experience with laparoscopic cholecystectomy. Am J Surg. 1991; 161:385-7.

25.↵ Dubois F, Berthelot G, Levard H. Laparoscopic cholecystectomy: historic perspective and personal experience. Surg Lap Endos. 1991; 1:52-7. 26.↵ Grace PA, Quereshi A, Coleman J, Keans R, McEntee G, Broe P, et al. Reduced postoperative hospitalization after laparoscopic cholecystectomy. Br J Surg. 1991; 78:160-2. 27.↵ Perissat J, Collet D, Vitale G, Belliard R, Sosso M. Laparoscopic cholecystectomy using intracorporeal lithotripsy. Am J Surg. 1991; 161:371-6.

28.↵ Peters JH, Gibbons GD, Innes JT, Nichols KE, Front ME, Roby SR, et al. Complications of laparoscopic cholecystectomy. Surgery. 1991; 110:769-778. 29.↵ Southern Surgeons Club. A prospective analysis of 1518 laparoscopic cholecystectomies. N Engl J Med. 1991; 324:1073-8. 30.↵ Spaw AT, Reddick J, Olsen DO. Laparoscopic laser cholecystectomy: analysis of 500 procedures. Surg Lap Endos. 1991; 1:2-7. 14

CIRCUMSION INTRODUCTION: Religious male circumcision is considered a commandment from God in Judaism widely practiced in Islam and customary in Christian churches in Africa. Virtually all the current policy statements from specialty societies and medical organizations do not recommend routine neonatal circumcision The opponents to circumcision consider it a violation of human rights CASE DEFINITION: The words “circumcision” is derived from the Latin circum (meaning “around”) and coedre (meaning “to

cut”). Male circumcision is the removal of some or the entire foreskin (prepuce) from the penis MEDICAL INDICATIONS: • In infants and young boys – true phimosis caused by BXO (Balanitis xerotica obliterans) • Recurrent balanoposthitis • Recurrent UTI’s with an abnormal upper urinary tract • Phimosis may result from misguided attempt by parents to expose the glans forcibly • In adult – inability to retract prepuce for intercourse • Splitting of an abnormally tight frenulum • Balanitis

• Before radiotherapy for carcinoma penis • Paraphimosis • Diabetes mellitus with recurrent balanoposthitis • HIV • UTI INCIDENCE: Proportion of males circumcised worldwide vary from one sixth to a third Circumcision is most prevalent in the Muslim countries of the world In India too, it is nearly 100% among Muslims 15

PREVENTION AND COUNSELLING: Physiological adhesion between the foreskin and glans penis may persist until 6 years of age and be mistaken for phimosis. Forcible retraction of the skin is not recommended in physiological phimosis. At 4-5 years of age, topical corticosteroid cream may be used for 6 weeks if phimosis continues to exist. Circumcision – is done if it is • Resistant to topical steroid therapy • If patient requires treatment for balanitis

• When there is urinary obstruction due to very high prepuce Carcinoma penis should be ruled out. When confined to prepuce, circumcision may be adequate treatment but regular follow up is necessary Similarly chancre which may present as phimosis should be ruled out Balanitis xerotica obliterans – normal foreskin becomes thickened and does not retract Has increased susceptibility to carcinoma and hence requires early treatment Treatment is circumcision OPTIMAL DIAGNOSTIC CRITERIA:

Phimosis is diagnosed by inability to retract the prepucial skin SITUATION 1: i. PHIMOSIS: clinical features • Inability to retract the prepuce • Ballooning of prepuce (second bladder) in children • Balanoposthitis because of inability to clean the glans ii. PARAPHIMOSIS: clinical features Retracted prepuce cannot be pulled forward; forms a tight ring and acts as constriction. Venous congestion increases with swelling of glans and can result in ulceration and gangrene of the glans

iii. History of diabetes with recurrent attacks of balanophosthitits iv. History of bleeding and short duration of lack of retractibility would suggest carcinoma v. History of STD; sexual history to r/o chancre 16

DIFFERENTIAL DIAGNOSIS: 1. Chancre 2. Cancer 3. Meatal stenosis (masked by prepuce) INVESTIGATION: Simple phimosis is a clinical diagnosis and requires no investigation for confirmation Routine investigation before surgery such as Blood sugar Haemogram Urine r/m X Ray and ECG may be done as per anaesthetic indication Biopsy of underlying lesion if any USG of the abdomen and pelvis to evaluate the entire urinary tract in cases of UTI TREATMENT:

Medical treatment in children 5-6 years with congenital phimosis – topical steroid cream Surgical treatment – circumcision PROCEDURE: In infant: Applying a clamp (or bone forcepts) across the prepuce distal to the glans with blind division of the foreskin is to be condemned Perform a proper circumcision under direct vision as in an adult ANAESTHESIA – GA – in children, infants and neonates Dorsal penile nerve block, Ring block and / or EMLA (lidocaine/prilocaine) topical cream may be used in adults 17

Razmus et al reported that newborns circumcised with the dorsal block and ring block in combination with oral cucrose had lowest pain scores Wg et al found EMLA cream in addition to local anaesthetic effectively reduces the sharp pain induced by needle puncture In adults frenular stretch must to avoid bleeding from frenular artery Histopathology: should be done when there is suspicion of malignancy or other associated conditions POST OP: Analgesic Antibiotic: perioperative dose

Abstinence for 4-6 weeks in adults The patient should be reviewed 5-7 days post op Retract and clean any skin covering the glans to prevent adhesion COMPLICATINS OF CIRCUMCISION: • Bleeding most common • Infection • Scar • Meatal stenosis • Phimosis in later life – if insufficient skin is removed in a child during the first sugery • Skind bridge formation in infants SOP: Day care REFERAL CRITERIA: The patient should be referred to a higher centre for treatment of associated conditions if any, such as

malignancy Patient with bleeding disorders and co morbidities may be safely operated in a higher centre SITUATION 2: DIAGNOSIS: Clinical as in situation 1 INVESTIGATIONS: as in situation 1 18

HbA1C Coagulation profile if bleeding disorder is suspected TREATMENT: As in situation 1 Additional procedures: Devices are available for infant circumcision – Plastibell, Gomco clamp, or Mogen clamp used together with a restraining device 1. Frenulum may need to be broken or crushed and cut from the corona near the urethra to ensure that the glans can be freely and completely exposed SOP: Day care WHO DOES WHAT? AND TIMELINES a. Doctors: • Clinical examination • Diagnosis • Planning surgery • Surgery

• Post op care • Anesthesia b. Nurse: • Pre & post operative care • Assisting during surgery c. Technician: • Pre op equipment and drugs to be cechked and kept ready • Assist anaesthetist in the OT • Assist the surgeon 19

REFERENCES: 1. Circumcision –Wikipedia, the free encyclopedia 2. Williams N S, Bulstrode CJK, O’Connell P K, Bailey & Love’s Short Practice of Surgery 25th edition 3. K Rajgopal Shenoy, Manipal Manual of Surgery, second edition, reprint 2009. CBS publishers and distributors (pvt) ltd., India RESOURCE REQUIRED FOR ONE PATIENT / PROCEDURE (Patient weight 60 kgs.) Situation Human Investigations Drugs/Consumables Equipment Resources 1 Surgeon -1 Haemogram Antibiotics OT Table and

Medical officer/ Urine analysis Analgesics lights Assistant surgeon Blood sugar Iv fluids Autoclave – 1 Sutures Instrument trolley Staff nurse – 1 Anesthetic drugs General surgery Technician – 1 Lignocaine set Nursing orderly – dressings Cautery 1 Suction Sweeper – 1 Pulse oximeter Anesthetic equipment 2 Consultant – 1 Same as above + Same as above Same as above + Resident – 1 hbA1C Plastigell / gomco Staff nurse – 1 coagulation / vogen clamps Technician – 1 profile Nursing orderly – ECG 1 X-Ray chest

COLECTOMY Dr. Ajit Sinha & Dr. V. Ramesh INTRODUCTION: Sir William Arbuthnot was one of the early proponents of the usefulness of total colectomies. Colectomy is commonly performed for the treatment of colon cancer. DEFINITION: Colectomy implies the surgical resection of any extent of the large intestine (colon). Based on the segment of colon removed colectomies are termed as 1. Right hemicolectomy. 2. Extended right hemicolectomy 3. Transverse colectomy 4. V resection 5. Left hemicolectomy

6. Extended left hemicolectomy 7. Sigmoidectomy 8. Proctosigmoidectomy 9. Total colectomy 10. Total proctocolectomy 11. Subtotal colectomy INDIAN INCIDENCE: not documented DIFFERENTIAL DIAGNOSIS: • Polyps • Inflammatory bowel disease-ulcerative colitis, Crohn’s disease • Tuberculous stricture of the large bowel with obstruction 21

• Vascular malformations with lower gastro intestinal bleeding • Amoebiasis PREVENTION: In familiar situations like FAP & HNPCC early colectomy is advised. It is important to understand the carcinogenesis in colorectal cancer & the associated molecular events. ENVIRONMENTAL FACTORS also pay an important role, particularly dietary factors & estrogen replacement. Association between hyperplastic polyposis & colorectal cancer & adenomas called sporadic MIS tumuors

Colorectal cancers: are Sporadic in 75% cases & Genetic in 25% (younger age at diagnosis) Positive Familial history is present in 15%-20%. HNPCC (5%)-80% risk FAP(less than 1%)-100% risk of development of CRC – prophylactic total colectomy/proctocolectomy COUNSELLING: GENETIC COUNSELLING PREDISPOSITION SHOULD BE COUNSELLED & SCREENED FOR COLON CANCER. Screening colonoscopy and polypectomy – reduces colon cancer mortality. 1. OPTIMAL DIAGNOSTIC CRITERIA: Situation 1 Clinical Diagnosis

Anatomical locations and clinical manifestations of colon cancer Distribution % Ascending / Transverse Descending/Sigmoid Caecum Manifestations Bleeding Abdominal pain Changing bowel habit Anemia Obstruction Obstruction Malena Mass Mass Abdominal pain Abdominal Mass pain obstruction Mass 22

Diarrhoea obstruction Perforation Low back pain INVESTIGATIONS: § Haemogram § Colonoscopy – investigation of choice § - Biopsy & HPE - Brush cytology if biopsy is not possible • X-ray abdomen – if patient presents with features of large bowel obstruction • Double contrast barium enema : - When colonoscopy is contra indicated or not available - Findings – constant irregular filling defect - Detects associated lesions - Small ulcerative lesions can be diagnosed • USG abdomen

• Endoluminal ultrasound – if available • CECT – if available is used in large palpable abdominal masses = To determine local invasion • Urograms – when evidence of hydronephrosis on USG/ CT in left sided tumours TREATMENT: 1. Pre op evaluation of staging, respectability, patient’s operative risks are mandatory. 2. Accurate localization of tumour – of particular importance. a. Sometimes known cancer may not be apparent on serosal aspect. b. Localization by tattooing during colonoscopy, Barium enema.

c. Pre op CT, USG assessment of iver metastasis should be done PRE OP PREPARATION: Mechanical bowel preparation Prophylactic antibiotics 23

Blood grouping and cross matching Thromboembolism prophylaxis OPERATIVE TECHNIQUES: Resection should follow Standard oncological principles: • Proximal ligation of primary arterial supply at its margins • Adequate proximal & distal margins(5 cm) determined by area supplied by the primary feeder artery • Appropriate lymphadenectomy – harvesting of minimum 12 nodes • Extent of resection is an important prognostic factor (SAGES guidelines 2000)

• Any tumour not removed intraoperatively strongly influences prognosis & therapy Ro – absence of residual tumour, margins free histologically R1 – no gross residual tumour but margins histologically positive R2 – residual gross disease remains unresected RADIAL MARGIN: T4 lesions are a complex group & should be considered separate from other T groups Radial tumour free margins should be resected. Radial margin should be histologically free of disease for resection to be curative.

Specimen labeling, marking are important for a good pathological report R1 & R2 resection – incomplete resection for cure affects curability though TNM stage remains same LATERAL CIRCUMFERENTIAL MARGIN: In addition to radial, proximal & distal margins, circumferential margins should also be pathologically assessed. Positive margins are associated with increased rate of local and distal failure. Disease free survival and mortality significantly related to margin involvement after TME ADJUVANT Ro stage:

Adjuvant therapies require complete resection A case is not Ro if it is 24

§ Non enbloc resection § Radial margins positive for disease § Bowel margin positive for disease § Residual lymph node disease present or § Nx (incomplete staging) LYMPHADENECTOMY: Should be radical (up to the level of origin of primary feeding artery) Apical nodes positive for disease may have prognostic significance in addition to number of positive lymph nodes ENBLOC RESECTION of adherent tumours : En bloc removal of adjacent organs locally invaded by

cancer colon can achieve survival rates similar to patients with tumour that do not invade an adjacent organ, provided negatgive resection margins are achieved. PERFORATION OF TUMOUR SHOULD BE AVOIDED (SAGES GUIDELINE) Inadvertent full thickness perforation of rectum would probably classify tumour as T4 and resection as R1 Perforation at the site of cancer, as opposed to an area remote from the tumour has a greater impact on survival & local recurrence.

Inadvertent local perforation predisposes to local recurrence and warrants post-operative radiotherapy. INTRAOPERATIVE SPILLAGE: HAS AN INDEPENDENTT EFFECT ON PROGNOSIS Adjuvant radiotherapy may be considered to decrease rates of local recurrence NO TOUCH TECHNIQUE: Value inconclusive 25

SURGICAL PROCEDURES: Anatomical Resection of Colon Cancer Tumour location Vascular Ligation Colon resection Anastamosis Caecum, ascending ileo-colic, right colic Right hemicolectomy ileotransverse colon colostomy Hepatic flexure, ileocolic right, middle Extended right iIeodescending Proximal transverse colic hemicolectomy with colostomy colon omentectomy Distal transverse ileocolic right, middle Extended right ileosigmoid colostomy colon splenic or left branch of hemicolectomy with or Transverse sigmoid

flexure middle colic, left colic omentectomy or Left colostomy hemicolectomy Descending colon Inferior mesenteric or Left hemicolectomy Transverse colorectal left colic anastamosis Sigmoid colon Inferior mesenteric or Left colectomy or Transverse colorectal sigmoid Sigmoid resection anastamosis or descending colorectal anastamosis Colectomy may be performed by the i) Conventional open technique REFERRAL CRITERIA: Patients suspected of colon cancer & biopsy proven should be referred to a higher centre for

further evaluation and treatment when 1) Adequate surgical facilities are not available / surgeon does not have sufficient experience in colon cancer surgery. 2) Competent pathologist to report on malignant lesions as per standard oncological guidelines is not available. 3) For adjuvant / neo-adjuvant radio and chemo therapy TREATMENT: Patient requiring colectomy for biopsy proven cancer are best referred to a super specialty centre 26

In view of the need for multi modality treatment. SITUATION 2: All investigations as in situation 1 • Spiral CT in elderly patients more than 80 years • CT colonoscopy also called virtual colonoscopy – 6 mm polyps may be picked up effectively • CEA – fetal glycoprotein - Increased pre op CEA in node positive Ca – indication for chemotherapy • MRI : • PET : detection of metastasis • SPECT – if single photon emission is studied, such as technetium or thallium

• FDG-PET – useful in evaluation of recurrent colorectal cancer -Differentiates post op changes from recurrent / residual disease -Useful diagnostic tool but prohibitive cost • CT-PET – fusion tests provide the most powerful integrated images • NUCLEAR MEDICINE IMAGING: -Using 131 I , 111 I n , 99m T cbound to monoclonal antibodies, leucocytes & erythrocytes. TREATMENT: As outlined in situation 1. Laparoscopic resection is gaining popularity. However it is not freely available & performed as per protocols.

SPECIAL CONSIDERATIONS 1. Synchronous malignancies or polyps Patients with synchronous malignancies should be considered for subtotal colectomy depending on the distance between lesions Colonic cancer with multiple adenomatous polyps – subtotal colectomy 27

(Due to increased risk of metachronous lesion and to facilitate surveillance of the remaining colon) Factors that influence the decision to perform prophylactic subtotal colectomy -number -location -size of accompanying polyps -age -compliance of patient 2. Cancer is a polyp Complete endoscopic removal of polyp with cancer in situ – no further treatment Histoplathology shows invasive carcinoma: Ensure that endoscopic polypectomy was complete

Specimen was submitted with proper orientation to the pathologist for histopathology Carcinoma at margin of resection requires formal resection Carcinoma with free margins – a. thorough pathological review, b. identification of adverse histological features i. poor differentiation, ii lymphatic or venous invasion iii invasion into the stock of the polyp – formal resection It is difficult to locate the previous polypectomy site during surgery

Even if polyp is not removed it may be soft and difficult to palpate through the colon wall 28

Endoscopic distance (from anal verge or dentate line) misleading Polypectomy site should be videotaped for later review and marked with vital dye that can be seen serosally at the time of surgery 3. Obstructing Cancers- 2% of colorectal cancers Partial obstruction – Gentle bowel preparation over several days-Elective surgery Total obstruction - Rt colon cancers – Rt Hemi colectomy – immediate ileocolostomy - Lt colon cancers 1) Endoscopic decompression by laser passed beyond the obstructed

Segment – This allows mechanical preparation and elective resection. - This is possible only when the narrowed lumen can be traversed by the endoscope. - It is not possible when obstruction is complete 2) Primary resection and immediate anastamosis with on- table colonic washout with or without proximal colostomy. 3) Primary resection with colostomy. Anastamosis at second stage. 4) Subtotal colectomy with primary anastamosis 5) Decompressive colostomy followed by formal colonic resection

4. Adjacent organ involvement- 10% Locally advanced tumours are potentially curable with multi organ resection.-Do not necessarily Portend a dismal prognosis. -A non metastasizing variant of colon cancer grows to a large size without spreading to regional nodes -Separation of adhesions adjacent to a malignancy can lead to dissemination of tumour cells. 29

-Enbloc resection of these tumours, depending on location can lead to five year survivals of 70% Hepatic metastases – 10% at the time of exploration. -Solitary metastasis amenable to –wedge resection with clear margins can be removed concomitantly. -Formal hepatic lobectomy done as a second stage procedure. 5. Ovarian metastasis – 7% at the time of colon resection Oophorectomy: at the time of colorectal surgery Indications

i) Large ovarian metastasis (Krukenbergt’s tumour) which are symptomatic (prevents second surgery for the metastasis, benefit of preventing primary ovarian cancer) ii) Direct ovarian involvement iii) Post menopausal women – prophylactic oophorectomy 6. Inadvertent Perforation -Predisposes to local recurrence -Warrants post op radiotherapy Follow up Aim: Early detection of recurrence or metachronous lesion History Physical examination Faecal occult blood } CBC every 3 months-first 3 years

Tumour markers (CEA) - monthly – 3 years, 3 monthly-next 2 years Colonoscopy – first colonoscopy within 6-12 months of surgery, yearly-next 2 years, 2-3 yearly thereafter. CXR CT abdomen and pelvis – if primary loco regionally advanced -LFT ↑ -CEA ↑ % of recurrence of colon cancers occurs in the first two years. SOP All patients should be admitted when a colectomy is planned WHO DOES WHAT? Doctor: c) Surgeon: diagnosis & work up Pre operative planning Operative procedure Post operative follow up

d) Radiotherapist : radiotherapy – neoadjuvant & adjuvant e) Medical oncologist : Chemotherapy f) Anesthetist: PAC, anesthesia, post op ICU management NURSE: • Siting of colostomy when required by some nurse • Care of stoma • Dressing of the wound • Pre & post operative care 31

TECHNICIAN: • Pre op equipment and drugs to be checked and kept ready • Assist anesthetist in the OT • Assist the surgeon, positioning of the patient REFERENCES 1. The Scottish Intercollegiate network (SIGN) 2003 Colorectal cancer Quick reference Guide. 2. National cancer Institute guidelines 2000 for colon and rectal cancer surgery. Nelson H, Sargent D, Karlin A, CoutureJ, Fleshman J, Guillon J, Miedema B, Ota D, Petrelli M. 3. Sages and ACRS Guidelines for laparoscopic resection of curable rectal

and colon Cancer . 4. Shackelford’s Surgery of the Alimentary Tract 6th Edition by Charles j. Yeo MD Saunders | 2006 | ISBN: 1416023577 RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (Patient weight 60 Kgs) Situ Human Resources Investigations Drugs/Consumables Equipment atio n 1 Surgeon – 1 Haemogram Antibiotics OT Table & lights Medical Officer / Urine Analysis Analgesic Instrument Assistant Surgeon – 1 Blood Sugar I.V. Fluids trolley Anesthetist – 1 S. Electrolytes Sutures General Surgery Set

Pathologist – 1 KFT Drains Cautery Staff Nurse – 1 ECG Catheters Suction Technician – 1 X-Ray – Chest Anesthetic drugs Anesthetic Nursing Orderly – 1 USG Dressings Equipment 32

Sweeper – 1 Histopathology Stoma bags Monitors 2 Consultant – 1 Same as above + Same as above Same as above + Residents – 1 HbA1C Laparoscopic Set Anesthetist – 1 CEA Pathologist – 1 Coagulation Harmonic Profile Scalpel Medical Oncologist – 1 Colonoscopy Endo GI Radiotherapist – 1 Staplers EUS Staff Nurse – 2 CT Scan Stoma therapist – 1 CEA Technician – 1 Microbiology Nursing Orderly – 1 Sweeper - 1 ABG Immunology PET 33

FISTULA IN ANO WHEN TO SUSPECT/RECOGNIZE? When a patient presents with a discharging opening gin the perianal region, on e should suspect a fistula in ano INTRODUCTION: A fistula is an abnormal communication between two epithelial surfaces. DEFINTION: By definition a fistula in ano is a communication between the anal canal and skin by a tract which may be straight and simple or complex with ramifications or a horse shoe tract involving the right and / or

left halves. The discharge may be pus, fecal matter, flatus or serosanguinous. Fistula are classified as low or high Based upon their relationship to the anal sphincter complex, anal fistulas are categorized into: 1. Intersphincteric 2. Trans sphincteric 3. Supra sphincteric 4. Extra sphincteric Treatment options are based upon these classifications INCIDENCE: Indian incidence is not documented DIFFERENTIAL DIAGNOSIS: Furunculosis Crohn’s disease Pilonidal sinus Tuberculosis 34

Actimycosis Lymphogranuloma venereum Granuloma inguinale Perianal abcess PREVENTION: Adequate drainage of anorectal abscesses may prevent fistula formation Predisposing causes 1. Crohn’s disease 2. Malignancy 3. Chlamydia In the presence of a complex, recurrent, non healing fistula these should be suspected. COUSELLING: Surgical treatment alone offers permanent cure. So patients should be counseled for early surgey when it is a simple fistula so that it does not become complex. OPTIMAL DIAGNOSTIC CRITERIA:

SITUATION 1: CLINICAL DIAGNOSIS: Patients with anal fistula commonly present with complaints of • Discharge from external or internal opening, the external opening may be single or multiple • Pain • Swelling • Fever The presentation may be acute when there is acute perianal sepsis A chronic anal fistula presents with periodic exacerbation and pus discharging openings around the anus per rectal exam and proctoscopy should be done to visualize both the internal and external openings.

INVESTIGATIONS: Fistulogram may be done when branching is suspected, in recurrent fistulae and when internal opening is not appreciable. Examination under anesthesia Probe test, caution may cause now internal opening Injection technique is useful in delineating the tract Biopsy when specific cause is anticipated Barium enema – when co existing disease is suspected Blood sugar – to r/o diabetes mellitus Complete blood count Urine r/m X ray chest – to rule out TB TREATMENT:

Simple low fistulae can be managed in a secondary hospital where a surgeon is available SURGICAL PROCEDURES: Surgical options are dictated by the type of fistula. Aim is to drain the septic focus and remove the fistula with minimal injury to the sphincter complex Fistulotomy Fistulectomy Seton Combination of the above: Fistulotomy (of superficial position), with seton division (of the cephalad position) Staged procedures may be required in high anal fistulae

Fistula presenting as perianal abscess would require drainage, analgesics and antibiotics followed subsequently by a definitive procedure Fistulotomy and curettage / Fistulectomy – low anal fistula 36

Trans sphincteric fistula that involve =<30 percent of sphincteric muscle – sphincteromy without risk of incontinence High Trans sphincteric fistulas – seton placement REFERRAL CRITERIA: Complex/recurrent/high anal fistulae may need referral to a higher centre for adequate investigation and management. Colostomy and staged procedure may be required. Co existing conditions like rectal cancers, Crohn’s disease, TB fistulae, HIV infection require referral SOP: In patient SITUATION 2:

Clinical diagnosis as in situation 1 INVESTIGATION: All investigations as in situation 1 Additional investigations: MRI, MR Fistulogram in complex, high, trans sphincteric, supra and extrasphincteric fistulae Colonoscopy – associated ulcerative colitis, carcinoma, TB etc HIV test in suspected cases Biopsy when multiple openings are present, malignancy or specific cause is suspected prothrombin time HbA1C in cases of diabetes mellitus TREATMENT: as in situation 1

Colostomy – when significant sphincter involvement is present, or non healing ulcer Multiple procedures – complex fistula with multiple tracts SOP: Day Care – Low fistulae – subcutaneous / submucous fistula All others – should be admitted 37

WHO DOES WHAT? Doctor: Clinical examination Diagnosis Planning surgery Post op care Anesthesia Nurse: Siting of colostomy when required, by stoma nurse Care of stoma Dressing of the wound Pre & post operative care Assisting during surgery Technician: Pre op equipment and drugs to be checked and kept ready Assist anesthetist in the OT Assist the surgeon, positioning of the patient REFERENCES Owen G, Keshava A, Stewart P, Patterson J, Chapuis P, Bokey E, Rickard M.

Plugs unplugged. Anal fistula plug: the Concorf experience. ANZ J Surg. 2010 May, 80 (5):341-3 Department of Colorectal Surgery, Concord Repatriation General Hospital, Hospital Road, Concord, NSW 2139, Australia. Owen_g@optusnet.com. ajgopal Shenoy, Manipal Manual of Surgery second edition; reprint 2009. CBS Publishers and Distributors (Pvt.) Ltd., India 38

Shackelford’s Surgery of the Alimentary Tract 6th Edition by Charles J. Yeo MD Saunders 2006 ISBN: 1416023577 RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (Patient weight 60kgs) Situation Human Resources Investigations Drugs/Consumables Equipment 1 Surgeon – 1 Haemogram Antibiotics OT Table and Medical Officer / Urine Analysis Analgesics lights Assistant Surgeon Blood Sugar I V Fluids Autoclave – 1 Sutures General surgery Staff Nurse – 1 Anesthetic drugs set Technician – 1 Lignocaine Cautery

Nursing Orderly – dressings Suction 1 Pulse Oximeter Sweeper - 1 Anesthetic equipment 2 Consultant – 1 Same as above + Same as above + Same as above Resident – 1 hbA1C stoma bag Staff nurse – 1 coagulation Technician – 1 profile Nursing Orderly – ECG 1 X-Ray chest Sweeper - 1 39

HAEMORRHOIDS When to suspect / recognize? When a patient presents with an h/o passing fresh blood per rectum INTRODUCTION: Three haemorrhoidal cushions are found in the left lateral, right anterior and right posterior positions of the anal canal. Bleeding results when these cushions are engorged and subjected to raised intra abdominal pressure while straining during defecation. DEFINITION: Haemorrhoids are cushions of submucosal tissue containing venules, arterioles and smooth muscle

fibers located in the anal canal Treatment is indicated only if they become symptomatic due to venous engorgement of the haemorrhoidal plexus INCIDENCE: Haemorrhoids is a common condition but the exact incidence in our country is not documented DIFFERENTIAL DIAGNOSIS: • Prolapsed rectum • Anal fissure • Anal polyp • Carcinoma anal canal • Rectal varices due to portal hypertension • Perianal abscess • Proctitis PREVENTION AND COUNSELLING:

Excessive straining, increased intra abdominal pressure and hard stools increase venous engorgement of haemoohoidal plexus. Avoidance of these would prevent the development of haemoorhoids OPTIMAL DIAGNOSTIC CRITERIA: Situation 1: Diagnosis is largely clinical 40

Symptoms: • Bleeding per rectum, bright red, painless • Anemia due to frequent bleeding • Mass prolapsing per rectum • Pain on prolapsed • Mucous discharge • Pruritus • Skin tag EXAMINATION: DIRECT VISUALISATION: thrombosed/prolapsed haemorrhoids, external haemorrhoids & skin tags be visualized. DIGITAL RECTAL EXAMINATION: Thrombosed haemorrhoids, as well as other associated conditions such as anal cancer, BPH may be felt per rectum. PROCTOSCOPY:

Internal haemorrhoids occur in 3, 7 & 11 “o” clock positions. These are visualized during prctoscopy. Haemorrhoids are classified into 4 graes by descent Grade Presentation 1. Bleeding 2. Protrusion below the anal verge while straining with spontaneous reduction 3. Protrusion regressing with manual reduction 4. Irreducible protrusions Based on their location, haemorrhoids can be classified into External – located distal to dentate line, covered by anoderm, painful, arise from inferior haemorrhoidal plexus

Internal – located prominal to dentate line, covered by insensuate anorectal mucosa, painless, may prolapsed or bleed Interno – external – features of both INVESTIGATIONS: Hb Peripheral smear 41

TLC, DLC, ESR Blood grouping and Rh typing USG abdomen TREATMENT: MEDICAL: • Laxatives • Haematinics if anemia is present • Sitz bath • Ointment • Antibiotics when infection or complications are present • Emergency transfusion when presentation is of profuse haemorrage or severe anaemia due to chronic blood loss SURGICAL: I. Minor Outpatient procedures: 1. Sclerotherapy – for grade 1 & II haemorrhoids and bleeding haemorrhoids

2 to 5 ml of 5% phenol in almond oil injected around pedicle in the submucosa aseptically 2. Banding – gr II & III haemorrhoids by modified Barron’s band applicator above the dentate line II. In patient GR III & IV haemorrhoids 1. Haemorrhoidectomy • Open: MILLIGAN – MORGAN operation • Closed: HILL – FERGUSON operation 2. Excision of thrombosed pile mass: ANESTHESIA: GA/Spinal/Caudal block REFERRAL CRITERIA: Patients who opt for stapled haemorrhoidopexy Patients with portal hypertension

Patients with co-morbidities that may require ICU care SOP Outpatient / day care procedures: Minor procedures for Grade I & II In Patient: Operative procedures for Grade III & IV Situation 2: CLINICAL DIAGNOSIS – Same as in situation 1 INVESTIGATIONS – As in situation 1 + Colonoscopy – to r/o other conditions (malignancy) and co-existing when required Coagulation profile TREATMENT As in situation 1 & Outpatient procedures: 1. Photocoagulation – 1&II degree haemorrhoids

Infrared coagulation probe applied to the apex of each haemorrhoid to coagulate the underlying venous plexus In-patient procedures: 1. Stapled haemorrhoidectomy: for grade III haemorrhoids. May be done as a day care procedure or as an in-patient SOP: In-patient Day care procedure – depending on the education and awareness of the patient WHO DOES WHAT? AND TIMELINES a. Doctor • Clinical examination • Diagnosis • Planning surgery • Surgery 42

• Post op care • Anesthesia b. Nurse • Pre & post operative care • Assisting during surgery c. Technician • Pre operatively equipment and drugs to be checked and kept ready • Assist anesthetist in the OT • Assist the surgeon, positioning of the patient REFERENCES Bailey and Love’s Short Practice of Surgery 25th edition Shackelford’s Surgery of the Alimentary Tract 6th Edition by Charles J. Yeo MD Saunders 2006 ISBN: 1416023577 RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (Patient weight 60 Kgs)

Situation Human Resources Investigations Drugs/Consumables Equipment 1 Surgeon – 1 Haemogram Antibiotics OT Table & lights Medical Officer / Urine Analysis Analgesics Autoclave Assistant Surgeon Blood sugar IV fluids General surgery - 1 Sutures set Staff Nurse – 1 Anesthetic drugs Cautery Technician – 1 lignocaine Suction Nursing Orderly – Anesthesia 1 equipment Sweeper - 1 2 Consultant – 1 Same as above + Same as above Same as above Resident – 1 HbA1C Staff nurse – 1 Coagulation Technician – 1 Profile

HERNIA I. Introduction A hernia is an area of weakness or disruption of the fibromuscular tissue of body wall. Often hernia is also defined as an actual anatomical weakness or defect. Strictly it is defined as “an abnormal protrusion of a viscus or a part of viscous through an opening – artificial or natural with a sac covering it. II. Incidence 75% of the abdominal hernias are groin hernia. 15 % males and 5% females will develop groin hernia. Femoral hernia incidence is 17%.

Incidence of Umbilical hernia is 8.5%. Others type of hernias are seen in 1.5%. These figures exclude incisional hernias which can form after any surgery through abdominal wall or lumbar area. III. Differential Diagnosis a. Hydrocele – Infantile, Encysted, Large vaginal and bilocular – absence of cough impulse, getting above the swelling and transillumination. The swelling is not reducible. b. Undescended testis – the corresponding half of the scrotum is empty and underdeveloped.

c. Femoral Hernia- the sac is below and laterals to the pubic tubercle. d. Lipoma of cord – the localized swelling moves with pulling of the spermatic cord. Cough impulse is absent and the swelling can not be reduced. e. Groin abscess- May mimic small strangulated hernia. Signs of acute inflammation are present. Cough impulse is absent and it can not be reduced. IV. Prevention and Counseling No specific preventive measures except in incisional hernia where various factor can lead to

development of incisional hernia. All patients having hernia other than direct inguinal hernia or hernia with wide neck are counseled to undergo surgery at the earliest convenience to prevent any chance of complications like obstruction and strangulation etc. V. Optimal diagnostic criteria, Investigations, Treatment and referral criteria ( Situation 1 ) a) CLINICAL DIAGNOSIS A swelling in groin or abdominal wall exhibiting cough impulse and showing sign of

reducibility is clinically diagnosed as hernia. The clinical spectrum includes :- (cid:216) Epigastric hernia exhibiting above features in a swelling in epigastric region. (cid:216) Umblical and para-umblical hernia- in umbilical and para-umblical area. 44

(cid:216) Incisional hernia or ventral hernia (cid:216) Inguinal hernia ( Direct ,Indirect and Congenital hernia ) presenting in groin area. (cid:216) Femoral hernia also presenting as a swelling of variable dimension in groin area. In congenital hernia the inguino-scrotal swelling is present since birth or during childhood . b) INVESTIGATIONS In most of the cases practically no investigations are required to confirm the diagnosis of

hernia. Clinical diagnosis is enough. Ultrasound of whole abdomen may be done in cases of hernia to rule out other abdominal pathology . c) TREATMENT i. In-Patient – Principles of Hernia surgery include reduction of hernia , excision of the sac and repair of wall. Repair may be done by suture or mesh. o Congenital inguinal hernia is treated by herniotomy alone. o Direct and indirect inguinal hernia is treated by herniorrhaphy or hernioplasty using a mesh by various techniques.

o Epigastric hernia with small defect may be treated by suture repair using double breasting technique . When the defect is large , hernioplasty using a mesh may be done. o Umblical and Para-umblical hernia – approach is same as for epigastric hernia. o Femoral hernia – Same principles of hernia repair are applied by High, Low or inguinal approach depending upon the case and expertise of surgeon. o Incisional hernia – An anatomical repair or mesh repair may be considered

depending upon individual case and expertise of the surgeon. ii. Out-patient – None iii. Day-care – In appropriate situation and setting viz local anesthesia, small size hernia , patient residing within approachable distance etc . day care practice may be considered. 45

d) REFERRAL CRITERIA Referral can be considered from situation 1 in hernia only if the patient has associated severe co-morbidities requiring special care. Optimal diagnostic criteria, Investigations, Treatment and referral criteria (Situation 2) a) CLINICAL DIAGNOSIS Same as situation 1. b) INVESTIGATIONS Same as situation 1. c) TREATMENT i. In-patient – Same as for situation 1. In addition, patient can be offered laparoscopic repair , particularly in bilateral and recurrent hernia after

informed patient consent provided that the infrastructure, equipment and expertise is available. ii. Out-patient – None iii. Day-care – Same as situation 1. d) REFERRAL CRITERIA None VI. Who does what ? and timelines a. Doctor (cid:216) The job of diagnosis, treatment including surgery, post-operative care and follow up. b. Nurse (cid:216) Pre-operative care, operative assistance, post-operative care, administration of treatment instructed by the doctor and monitoring as instructed. c. Technician

(cid:216) Keeps all machines and equipments in order and assist the anesthetist during operation. VII. Further reading 1. Bailey & Love’s Short Practice of Surgery 2. Schwartz’s Textbook of Surgery 3. Abdominal Operations by Maingot 46

Resources required for one patient/procedure Situation Human resources Investigations Drugs etc Equipment 1 Surgeon – 1 X-ray I/V fluids, Broad General surgery set, Medical officers - USG spectrum antibiotics, Anesthesia equipment 2 Biochemistry analgesics, Monitors, Cautery, Staff Nurses -2 Hematology Vasopressors,anesthesia Suction, OT Tables & Technician – 1 Urine analysis drugs, sutures, Mesh, lights, Autoclave, Ward boy -1 drains & catheters, O2 Trolleys Sweeper - 1 cylinder etc

2 Consultant – 1 Same as above Same as above plus Same as above plus all Sr. Resident – 1 plus Microbiology HDU/ICU back up equipment for Jr. Resident -2 ABG HDU/ICU, Laparoscope Staff Nurses -2 Technician – 1 Ward boy -1 Sweeper - 1 47

HYDROCELE I. Introduction Hydrocele is collection of fluid between two layers of tunica vaginalis of testis. It can be congenital or acquired which is further of two types i.e. primary or secondary. II. Incidence Hydrocele is quite a common condition with little high incidence in zones or areas affected by filariasis. Those present since birth are called congenital hydrocele where the processus vaginalis is essentially patent. Secondary hydrocele is most commonly due to tuberculosis,

malignancy or chronic infection. III. Differential Diagnosis Primary hydrocele in adults has to be differentiated from a. Inguinal Hernia- One can not get above swelling and transillumination is absent (except congenital hernia ). b. Epididymal cyst – The testis is palpable separately. c. Spermatocele – The testis is palpable separately. d. Testicular tumor - The consistency is firm to hard, Testicular sensation and fluctuations are absent and transillumination can not be elicited.

IV. Prevention and Counseling There are no specific preventive measures for both congenital and adult hydrocele except that wherever filariasis is endemic or prevalent, anti filarial prophylaxis may be taken or whenever the person suffers from it, prompt and proper treatment should be taken. V. Optimal diagnostic criteria, Investigations, Treatment and referral criteria ( Situation 1 ) a) CLINICAL DIAGNOSIS For primary hydrocele in adults, 3 classical signs i.e. can get above the swelling,

presence of fluctuations and transillumination are diagnostic of hydrocele. Secondary hydrocele is generally very small and soft and signs of primary pathology may be present. In congenital variety, classical history of no scrotal swelling in morning and full blown swelling in the evening coupled with above signs is diagnostic. b) INVESTIGATIONS In most of the cases practically no investigations are required to confirm the diagnosis

of primary hydrocele and congenital hydrocele. At the most, ultrasound may be done to find out testicular morphology . For secondary hydrocele , complete battery of investigation consisting of ultrasound, FNAC, CT scan and investigations for tuberculosis and tumor markers etc will be required depending upon the possible primary pathology. 48

This battery is unlikely to be available in situation 1; hence referral to higher centre would be advisable. c) TREATMENT i. In-Patient – Congenital hydrocele is treated surgically by herniotomy through inguinal approach. Adult hydrocele (primary) is treated by eversion or excision or plication depending upon size of hydrocele and thickness of the sac. Since hematoma is a very common complication , hence perfect hemostasis must be achieved in this surgery. ii. Out-patient – None.

iii. Day-care – For congenital hydrocele , overnight stay is routine. For adult hydrocele , in appropriate setting , the operative procedure can be considered on day care basis if surgery has been done under local anesthesia. d) REFERRAL CRITERIA Referral may be considered in secondary hydrocele if the primary cause turns out to be testicular malignancy. Optimal diagnostic criteria, Investigations, Treatment and referral criteria (Situation 2) a) CLINICAL DIAGNOSIS Same as situation 1. b) INVESTIGATIONS

Same as situation 1. c) TREATMENT i. In-patient – Same as situation 1. ii. Out-patient – None iii. Day-care – All the surgical options mentioned for congenital and primary variety of adult hydrocele can be considered on day care basis in situation 2 . d) REFERRAL CRITERIA None VI. Who Does What? and Timelines a. Doctor (cid:216) The job of diagnosis, treatment including surgery, post-operative care and follow up. b. Nurse 49

(cid:216) Pre-operative care, operative assistance, post-operative care, administration of treatment instructed by the doctor and monitoring as instructed. c. Technician (cid:216) Keeps all machines and equipments in order and assist the anesthetist during operation. VII. Further reading 1. Bailey & Love’s Short Practice of Surgery 2. Schwartz’s Textbook of Surgery Resources required for one patient/procedure Situation Human Investigations Drugs etc Equipment resources

1 Surgeon – 1 X-ray I/V fluids, Broad General surgery Medical officer USG spectrum antibiotics, set -1 Biochemistry analgesics, Anesthesia Staff Nurses -1 Hematology Vasopressors,anesthesia equipment Technician – 1 Urine analysis drugs, sutures, drains & Monitors, Cautery, Ward boy -1 catheters, O2 cylinder Suction, OT Tables Sweeper - 1 etc & lights, Autoclave, Trolleys 2 Consultant – 1 Same as above plus CT Same as above plus Same as above Jr. Resident -2 Scan , Pathology,

Staff Nurses -1 Immunology,Microbiology Technician – 1 ABG Ward boy -1 Sweeper - 1 50

PAROTID NEOPLASM Dr Sanjay Gupta Professor, Department of Surgery University College of Medical Sciences, Delhi 1. Name of the condition: Parotid neoplasm 2. When to suspect/ recognize? a. Introduction: Parotid gland is the commonest site of salivary gland neoplasms. b. Case definition: Neoplasms of parotid gland may be benign or malignant. 3. Incidence of the condition in our country: Not reported 4. Differential diagnosis: Skin, soft tissue and lymph node swellings form an important differential

diagnosis of parotid neoplasm. 5. Prevention and counseling: Parotid lesions should be investigated and treated early to prevent morbidity of facial nerve injury and mortality due to advanced parotid malignancy. 6. Optimal diagnostic criteria, investigations, treatment and referral criteria Situation 1 At Secondary Hospital/ Non-metro situation: Optimal standard of treatment in situations where resources are limited I. Clinical diagnosis:

a. Painless, slow growing swelling in front of or below the ear. Occasionally, there may be a bulge in the tonsillar region if deep lobe is involved. Presence of pain or facial paralysis may suggest malignancy. II. Investigations: a. Fine Needle Aspiration Cytology is necessary to confirm the diagnosis and as a prelude to radical parotidectomy. III. Treatment (Standard operating procedure) a. Inpatient: i. Superficial parotidectomy is the treatment of choice for benign

neoplasms located in the superficial lobe of parotid. ii. Isolated deep parotidectomy or total parotidectomy with preservation of facial nerve is indicated for benign neoplasms located in the deep lobe of parotid. iii. For malignant neoplasms of the parotid gland total parotidectomy with excision of adjacent involved structures, facial nerve and ipsilateral neck dissection, if required, should be done. b. Outpatient: Not indicated c. Day care: Not indicated

IV. Referral criteria: Patient should be referred to a higher center if frozen section or nerve grafting of the facial nerve are anticipated. 51

Situation 2 At Superspecialty Facility in Metro location where higher end technology is available I. Clinical diagnosis: a. Painless, slow growing swelling in front of or below the ear. Occasionally, there may be a bulge in the tonsillar region if deep lobe is involved. Presence of pain or facial paralysis may suggest malignancy. II. Investigations: a. Fine Needle Aspiration Cytology is necessary to confirm the diagnosis and as a prelude to radical parotidectomy.

b. CECT/ MRI should be done to evaluate the nature of lesion, involvement of adjacent structures and presence of significant lymphadenopathy. III. Treatment (Standard operating procedure) a. Inpatient: i. Superficial parotidectomy is the treatment of choice for benign neoplasms located in the superficial lobe of parotid. ii. Isolated deep parotidectomy or total parotidectomy with preservation of facial nerve is indicated for benign neoplasms located in the deep lobe of parotid.

iii. For malignant neoplasms of the parotid gland total parotidectomy with excision of adjacent involved structures, facial nerve and ipsilateral neck dissection, if required, should be done. iv. Ipsilateral neck dissection is indicated in the presence of significant lymphadenopathy. v. Frozen section biopsy is indicated if operative findings are suspicious of malignancy, even if it was not suspected preoperatively. vi. Nerve grafting should be done when facial nerve needs excision.

b. Outpatient: Not indicated c. Day care: Not indicated IV. Referral criteria: Not indicated 7. Who does what and timelines: a. Doctor: Clinical evaluation, treatment planning and execution. b. Nurse: Assisting in evaluation and treatment. c. Technician: Assisting in investigations and operation. 8. Further reading/ references: a. Day TA, Deveikis J, Gillespie MB, Joe JK, Ogertmen B, Osguthorpe JD et al. Salivary gland neoplasms. Current Treatment Options in Oncology 2004, 5:11–26

b. Meyers MN, Ferris RL (Eds.). Salivary gland disorders. Springer Verlag Berlin 2007. 52

PEPTIC ULCER PERFORATION Dr. Arun Prasad INTRODUCTION: Lau and Leow have indicated that perforated peptic ulcer was clinically recognized by 1799, but the first successful surgical management of gastric ulcer was by Ludwig Heusner in Germany in 1892. In 1894, Henry Percy Dean from London was the first surgeon to report successful repair of a perforated duodenal ulcer. Wangensteen et al reported that in a patient with perforation but without evidence of

pneumoperitoneum, one can safely assume that perforation has sealed off on its own. They advocated a nonoperative approach for such patients. However, they too supported operative treatment in patients with perforated ulcer and evidence of pneumoperitoneum. Berne and Donovan emphasized the use of a water-soluble upper GI study to demonstrate spontaneous sealing of the perforation. They demonstrated that as many as 40% of perforated peptic ulcers had no

evidence of leak on upper GI contrast studies. Berne and Donovan concluded that these patients can be observed safely as long as peritonitis does not develop. Mortality rates were 6% and 3% in the operative and nonoperative groups, respectively. Donovan et al proposed dividing patients based on their Helicobacter pylori infection status and recommended nonoperative treatment in all patients except those without H pylori infection and those in whom prior treatment of H pylori infection had failed.

Despite strong arguments favoring nonoperative treatment of patients with perforated PUD, delaying the initiation of surgery more than 12 hours after presentation was demonstrated to worsen the outcome. Therefore, when definitely indicated, a laparotomy should be performed as soon as possible. INDIAN INCIDENCE There are no statistics available on this topic. SYMPTOMS • Sudden, sharp and severe pain in upper abdomen • Spreading of pain to rest of abdomen • Pain gets worse after oral ingestion or movements

• Feeling of giddiness and fainting • Fever • Weakness SIGNS Tachycardia Fever Pallor 53

Reduced abdominal wall movements COMPLICATIONS INVESTIGATIONS • Haemogram • Liver Function Tests • Blood sugar • Serum creatinine • Bleeding time, clotting time and prothrombin time • Xray chest • ECG • USG abdomen • Upper GI endoscopy MANAGEMENT Resuscitation Fluid resuscitation should be initiated as soon as the diagnosis of peptic ulcer disease (PUD) is made. Essential steps include insertion of a nasogastric tube to decompress the stomach and a Foley catheter

to monitor urine output. Intravenous infusion of fluids is begun, and broad-spectrum antibiotics are administered. In select cases, insertion of a central venous line or a Swan-Ganz catheter may be necessary for accurate fluid resuscitation and monitoring. As soon as the patient has been adequately resuscitated, emergent exploratory laparotomy should be performed. Conservative Treatment Wangensteen et al reported that in a patient with perforation but without evidence of

evidence of leak on upper GI contrast studies. Berne and Donovan concluded that these patients can be observed safely as long as peritonitis does not develop. Mortality rates were 6% and 3% in the operative and nonoperative groups, respectively. Donovan et al proposed dividing patients based on their Helicobacter pylori infection status and recommended nonoperative treatment in all patients except those without H pylori infection and those in whom prior treatment of H pylori infection had failed. 54

Despite strong arguments favoring nonoperative treatment of patients with perforated PUD, delaying the initiation of surgery more than 12 hours after presentation was demonstrated to worsen the outcome. Therefore, when definitely indicated, a laparotomy should be performed as soon as possible Surgical Treatment The appropriate surgical procedure depends on the location and nature of the ulcer. Many authorities recommend simple oversewing of the ulcer, with treatment of the underlying H pylori infection or

cessation of nonsteroidal anti-inflammatory drugs (NSAIDs) for bleeding PUD. Additional surgical options for refractory or complicated PUD include vagotomy and pyloroplasty, vagotomy and antrectomy with gastroduodenal reconstruction (Billroth I) or gastrojejunal reconstruction (Billroth II), or a highly selective vagotomy. The patient is placed in the supine position. A midline incision provides the most expeditious entry into

the abdominal cavity. The incision can be extended to the symphysis pubis if necessary. Once the abdomen is entered, the stomach and duodenum are carefully examined to determine the site of perforation. If the anterior surfaces of the stomach and duodenum show no abnormalities, the gastrocolic ligament is serially divided between clamps to allow entrance into the lesser sac and inspection of the posterior surface of the stomach.

The choice of operative procedure depends on variables such as the presence of shock, the presence of life-threatening comorbid conditions, the degree of contamination of the upper abdomen, the amount and duration of perforation, and whether the patient has a history of, or currently has intraoperative evidence of, chronic peptic ulceration. In the presence of life-threatening comorbid conditions and severe intra-abdominal contamination, the

safest technique for an acute anterior duodenal perforation is a simple closure with a Graham patch, using omentum. Several full-thickness simple sutures are placed across the perforation, using 2-0 or 3-0 silk sutures. A segment of omentum is placed over the perforation. The silk sutures are secured. If contamination of the upper abdomen is minimal and the patient is stable, a definitive ulcer procedure can be performed. For a perforated duodenal ulcer, this may include a highly selective vagotomy, a

truncal vagotomy and pyloroplasty, or vagotomy and antrectomy. For a perforated gastric ulcer, the procedure performed depends on the patient's condition. If the patient is moribund, the ulcer is best excised by grasping it with multiple Allis clamps and using a linear stapler. Alternatively, the ulcer can be excised with electrocautery; the defect is approximated with a 2- layer closure with inner continuous 3-0 absorbable sutures and outer interrupted Lambert sutures using 2-0 or 3-0 silk sutures.

In a stable patient, the ulcer is excised and sent for frozen section analysis to exclude malignancy. For a benign gastric ulcer, a distal gastrectomy with either a Billroth I gastroduodenostomy or a Billroth II gastroduodenostomy is performed. Post Operative Care & Complications 55

The nasogastric tube can be discontinued on postoperative day 2 or 3, depending on the return of GI function, and diet can be slowly advanced. Patients who are found to have H pylori infection should receive the appropriate antibiotic regimen. Patients with high serum gastrin levels should undergo an evaluation for Zollinger-Ellison syndrome. Patients should undergo upper endoscopy to evaluate the area of ulcer and healing of the perforation site 4-6 weeks after surgery.

Surgical complications include pneumonia (30%), wound infection, abdominal abscess (15%), cardiac problems (especially in those >70 y), diarrhea (30% after vagotomy), and dumping syndromes (10% after vagotomy and drainage procedures). REFERRAL CRITERIA: • ICU care may be needed in patients who present late with severe sepsis and have other systemic illnesses. • Patients with recurrence of perforation few days after surgery may need ICU care, parenteral

nutrition, investigations for gastrinoma and further surgery. MEDICOLEGAL: • Failure to detect / investigate or refer a patient of suspected peptic ulcer perforation. • Delay in treatment. • Delay in diagnosing complications and taking corrective action. WHO DOES WHAT? Doctor: g) Surgeon: diagnosis & work up Pre operative planning Operative procedure Post operative follow up h) Anesthetist: PAC, anesthesia, post op ICU management NURSE: • Dressing of the wound • Pre & post operative care 56

TECHNICIAN: • Pre op equipment and drugs to be checked and kept ready • Assist anesthetist in the OT • Assist the surgeon, positioning of the patient RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (Patient weight 60 Kgs) Human Resources Investigations Drugs/Consumables Equipment Surgeon – 1 Haemogram Antibiotics OT Table & lights Medical Officer / LFT Analgesic Instrument trolley Assistant Surgeon – 1 Blood Sugar I.V. Fluids Laparoscopic Surgery set Anesthetist – 1 S. Electrolytes Sutures

General Surgery Set Pathologist – 1 KFT Drains Cautery Staff Nurse – 1 ECG Catheters Suction Technician – 1 X-Ray – Chest Anesthetic drugs Anesthetic Equipment Nursing Orderly – 1 USG Dressings Monitors Sweeper – 1 Histopathology REFERENCES 1. Fineberg HV, Pearlman LA. Surgical treatment of peptic ulcer in the United States: trends before and after the introduction of cimetidine. Lancet 1981; i: 1305-7. 2. Paimela H, Oksala NKJ, Kivilaakso E. Surgery for peptic ulcer today. Dig. Surg. 2004; 21: 185-91.

3. Svanes C. Trends in perorated peptic ulcer: incidence, etiology, treatment, prognosis. World J. Surg. 2000; 24: 277-83. 4. McConell DB, Baba GC, Deveney CW. Changes in surgical treatment of peptic ulcer disease within a veteran hospital in the 1970s and the 1980s. Arch. Surg. 1989; 124: 1164-7. 5. Lena GM, Blomgren MD. Perforated peptic ulcer: long-term results after simple closure in the elderly. World J. Surg. 1997; 21: 412-15. 57

6. Svanes C, Salvesen H, Stangeland L, Svanes K, Soreide O. Perforated peptic ulcer over 56 years. Time trends in patients and disease characteristics. Gut 1993; 34: 1666-71. 7. Armstrong CP, Blower AL. Non-steroidal anti-inflammatory drugs and life-threatening complications of peptic ulceration. Gut 1987; 28: 527-32. 8. Nogueria C, Silva AS, Santos JN et al. Perforated peptic ulcer. Main factors of morbidity and mortality. World J. Surg. 2003; 27: 782-7.

9. Hermansson M, Von Holstein CS, Zilling T. Surgical approach and prognostic factors after peptic ulcer perforation. Eur. J. Surg. 1999; 165: 566-72. 10. Testini M, Portincasa P, Piccini G, Lissidini G, Pellegrini F, Greco L. Significant factors associated with fatal outcome in emergency open surgery for perforated peptic ulcer. World J. Gastroenterol. 2003; 9: 2338-40. 11. Chou NH, Mok KT, Chang HT et al. Risk factors of mortality in perforated peptic ulcer. Eur. J. Surg. 2000; 166: 149-53.

12. Zittel TT, Jehle EC, Becker HD. Surgical management of peptic ulcer disease today - indication, technique and outcome. Langenbecks Arch. Surg. 2000; 385: 64-96. 13. Makela JT, Kiviniemi H, Ohtonen P, Laitinen SO. Factors that predict morbidity and mortality in patients with perforated peptic ulcers. Eur. J. Surg. 2002; 168: 446-51. 14. Kum CK, Chong YS, Koo CC, Rauff A. Elderly perforated peptic ulcers: factors affecting morbidity and mortality. J. R. Coll. Surg. Edinb. 1993; 38: 344-7.

15. Sillakivi T, Lang A, Tein A, Peetsalu AE. Evaluation of risk factors for mortality in surgically treated perforated peptic ulcer. Hepatogastroenterology 2000; 47: 1765-8. 16. Kujath P, Schwandner O, Bruch HP. Morbidity and mortality of perforated peptic gastroduodenal ulcer following emergency surgery. Langenbecks Arch. Surg. 2002; 387: 298-302. 17. Svanes C, Lie RT, Svanes K. Adverse effects of delayed treatment for perforated peptic ulcer. Ann. Surg. 1994; 220: 168-75.

18. Svanes C, Lie RT, Lie SA, Kvale G, Svanes K, Soreide O. Survival after peptic ulcer perforation: a time trend analysis. J. Clin. Epidemiol. 1996; 49: 1363-71. 19. Walt R, Katschinski B, Logan R, Ashley J, Langman M. Rising frequency of ulcer perforation in elderly people in the United Kingdom. Lancet 1986; 3: 489. 20. Agrez MV, Henry DA, Senthiselvan S, Duggan JM. Changing trends in perforated peptic ulcer during the past 45 years. ANZ J. Surg. 1992; 62: 729.

21. Bulut O, Rasmunsen C, Fischer A. Acute surgical treatment of complicated peptic ulcer with special reference to elderly. World. J. Surg. 1996; 20: 574-7. 22. Irvin TT. Mortality and perforated peptic ulcer: a case for risk stratification in elderly patients. Br. J. Surg. 1989; 76: 215. 23. O'Riordain DS, O'Dwyer PJ, O'Higgins NJ. Perforated duodenal ulcer in the elderly patients. J. R. Coll. Surg. Edinb. 1990; 35: 93.

24. Kulber DA, Hartunian S, Schiller D, Morgenstern L. The current spectrum of peptic ulcer disease in the older age groups. Am. Surg. 1990; 56: 737. 25. Svanes C, Soreide JA, Skartein A et al. Smoking and ulcer perforation. Gut 1997; 41: 177-80. 26. Duggan JM, Zinsmeister AR, Kelly KA. Long-term survival among patients operated on for peptic ulcer disease. J. Gastroenterol. Hepatol. 1999; 14: 1074-82. 27. Reinbach DH, Crusikshank G, McColl KEL. Acute perforated duodenal ulcer is not associated with

Helicobacter pylori infection. Gut 1993; 34: 1344-7. 28. Smedley F, Hickish T, Taube M, Yale C, Leach R, Wastell C. Perforated duodenal ulcer and cigarette smoking. J. R. Soc. Med. 1988; 81: 92-4. 29. Doll R, Peto R, Wheathly K, Gray R, Sutherland I. Mortality in relation to smoking: 40 years' observation on male British doctors. BMJ 1994; 309: 901-11. 30. Svanes C, Sothern RB, Sorbye H. Rhythmic patterns in incidence of peptic ulcer perforation over 5.5 decades in Norway. Chronobiol. Int. 1998; 15: 241-64.

31. Illingworth CFW, Scott LDW. Acute perforated peptic ulcer. Frequency and incidence in the West of Scotland. BMJ 1944; 2: 655-9. 32. DeBakey M. Acute perforated gastroduodenal ulceration. Surgery 1940; 8: 852-84. 33. Sonnenberg A, Wasserman IH, Jacobsen SJ. Monthly variation of hospital admission and mortality of peptic ulcer disease: a reappraisal of ulcer periodicity. Gastroenterology 1992; 103: 1192-8. 58

34. Boey J, Choi SKY, Alagaratnam TT, Poon A. Risk stratification in perforated duodenal ulcers, a prospective validation of predictive factors. Ann. Surg. 1987; 205: 22-6. 35. Hodnett RM, Gonzalez F, Chapman L, Nance FC, Deboisblanc R. The need for definitive therapy in the management of perforated gastric ulcers. Ann. Surg. 1989; 209: 36-9. 36. Svanes C, Salvesen H, Espehaug B, Soreide O, Svanes K. A multifactorial analysis of factors related to

lethality after treatment of perforated gastroduodenal ulcer. Ann. Surg. 1989; 209: 418-23. 37. Hamby LS, Zweng TN, Strodel WE. Perforated gastric and duodenal ulcer: an analysis of prognostic factors. Am. Surg. 1993; 59: 319-23. 38. Chao TC, Wang CS, Chen MF. Gastroduodenal perforation in cancer patients. Hepatogastroenterology 1999; 46: 2878-81. 39. Kujath P, Schwander O, Brunch HP. Morbidity and mortality of perforated peptic gastroduodenal ulcer

following emergency surgery. Langenbecks Arch. Surg. 2002; 387: 298-302. 40. Welch CE, Rodkey GV, Gryska PR. A thousand operations for ulcer disease. Ann. Surg. 1986; 204: 454- 67. 41. Hewitt PM, Krige J, Bormann PC. Perforated gastric ulcers: resection compared with simple closure. Am. Surg. 1993; 59: 669-73. 42. Ng EKW, Lam YH, Sung J, Yung MY, To KF, Chan ACW. Eradication of Helicobacter pylori prevents

recurrence of ulcer after simple closure of duodenal ulcer perforation: randomized controlled trial. Ann. Surg. 2000; 231: 153-8. 43. Al-Assi MT, Graham DY. Peptic ulcer disease, Helicobacter pylori, and the surgeon: changing of the guard. Curr. Opin. Gen. Surg. 1994: 120-4. 44. Lunevicius R, Morkevicius M. Systematic review comparing laparoscopic and open repair for perforated peptic ulcer. Br. J. Surg. 2005; 92: 1195-207.

45. Lau H. Laparoscopic repair of perforated peptic ulcer. A meta-analysis. Surg. Endosc. 2004; 18: 1013-21. 59

SKIN AND SOFT TISSUE LESIONS Dr Sanjay Gupta Professor, Department of Surgery University College of Medical Sciences, Delhi 1. Name of the condition: Skin and subcutaneous lesions 2. When to suspect/ recognize? a. Introduction: There are a large number of skin and subcutaneous lesions, both benign and malignant. The aim of the surgeon is to identify those which are malignant or carry malignant potential and institute appropriate treatment.

b. Case definition: All lesions identified clinically as occurring in skin or subcutaneous tissue. 3. Incidence of the condition in our country: The condition is very common. However, the exact incidence is not reported. 4. Differential diagnosis: 60

5. Prevention and counseling:Specific to each lesion 6. Optimal diagnostic criteria, investigations, treatment and referral criteria: a. Situation 1 At Secondary Hospital/ Non-metro situation: Optimal standard of treatment in situations where resources are limited 61

V. Clinical diagnosis: Based on clinical features specific for each lesion. VI. Investigations: a. FNAC b. Incision biopsy (for larger lesions) c. Excision biopsy (for smaller lesions) VII. Treatment (Standard operating procedure) a. Inpatient: Not indicated b. Outpatient/ Day care: These lesions can be treated on day care or outpatient basis. All lesions do not need treatment. i. Confirm diagnosis by investigations ii. Excise the lesion under LA with appropriate margin.

iii. For large lesions or in children general anesthesia may be used. iv. Skin is closed by primary suturing/ grafting. VIII. Referral criteria: Not indicated. b. Situation 2 At Superspecialty Facility in Metro location where higher end technology is available: Same as “a” V. Clinical diagnosis VI. Investigations VII. Treatment (Standard operating procedure) a. Inpatient b. Outpatient c. Day care VIII. Referral criteria 7. Who does what and timelines

a. Doctor: Clinical diagnosis, investigations and treatment b. Nurse: Assisting the surgeon in investigations and treatment c. Technician: Assisting in investigations and treatment 8. Further reading/ references: a. Luba MC, Bangs SA, Mohler AM, Stulberg DL. Common benign skin tumors. AmFamPhy 2003. 67(4):729-738. b. Skin lesions. URL info.wirral.nhs.uk/document_uploads/evidence.../SkinLesions.pdf 62

SMALL BOWEL PERFORATIONS I. Introduction Small perforation is breach in seromuscular continuity of small intestine ie from D-J junction to ileocaecal junction. It can be single or multiple and of varying sizes depending on nature and stage of pathology causing it. It may even be associated with gangrenous segment of variable length of small intestine. II. Incidence of the condition in our country In India, the commonest cause of small bowel perforation is enteric fever and tuberculosis.

Rapidly increasing incidence of vehicular trauma contributes to another category of perforation called traumatic perforation. Penetrating injury caused by knife, gunshot etc also adds to the etiology of these perforations. Rarely these perforations can be associated with long standing small intestinal volvulus or near the site of band compressing the gut causing ischemia and perforation. Iatrogenic perforations too can occur during conduct of various other abdominal

operations and even gynecological operations. III. Differential diagnosis The common conditions that should be considered in any patient presenting with features of peritonitis (apart from small bowel perforations):- 1. Acute Pancreatitis 2. Duodenal perforation 3. Appendicular perforation with peritonitis 4. Mesenteric vascular ischemia IV. Prevention and counseling Timely medical advice and treatment for conditions like enteric fever and tuberculosis. In case of

injury whether blunt or penetrating, seek hospitalization without any delay. Using of seat belts during travel (wherever possible) is also a good preventive step V. Optimal diagnostic criteria, Investigations, Treatment & Referral Criteria( Situation 1) a. Clinical diagnosis (cid:216) Small bowel perforation is suspected clinically in any patient presenting with history of fever, trauma, abdominal pain, vomiting, distension of tummy, inability to pass flatus

and feces of variable duration depending on type and duration of pathology. (cid:216) Clinical examination will reveal features of peritonitis which is mostly generalized but rarely may be localized also. Hippcratic facies will be present. The patient may be in shock ( hypovolemic or septic) or may even be having septicemia at the time of presentation. 63

b. Investigations (cid:216) Plain X-ray abdomen in erect posture shows gas under one or both domes of diaphragm (cid:216) USG evidence of fluid collection showing internal echoes (cid:216) Abdominal paracentesis , not routinely but only where X-ray provides some doubt (cid:216) Additional serological tests like Widal may be carried out. c. Treatment ( Standard operating procedure ) i. In Patient (cid:216) Hospitalization followed by resuscitation followed by investigation followed by

optimization for surgery which essentially consists of • Laparotomy • Closure of perforation/Ileostomy/resection and anastomosis depending on condition of the patient, condition of the bowel, location and multiplicity of pathology.( If single perforation with healthy bowel and condition of the patient is not bad , primary closure; otherwise ileostomy. In the event of multiple perforations with healthy bowel and good condition of the patient , resection and

anastomosis ; otherwise ileostomy is advised . Once a while exteriorization may be considered if the condition of bowel and patient demands this procedure ) • Thorough peritoneal lavage • Closure after providing adequate drainage tubes Postoperative Care in ward and involves - I/V fluids, antibiotics, pain killers and monitoring - Oral allowance after bowel movements - Stitch removal at appropriate time ii. Outpatient None iii. Day Care None d. Referral criteria

(cid:216) If any of the facilities, infrastructure or expertise to carry out any of the above step is not available either at diagnostic level or treatment level or at the level of post- operative care, then the case must be referred to higher centre. Optimal diagnostic criteria, Investigations, Treatment & Referral Criteria (Situation 2) a. Clinical diagnosis (cid:216) Same as in situation 2 b. Investigations (cid:216) Same as in situation 1 plus CT scan and diagnostic laparoscopy if any equivocality is

involved despite already mentioned investigations. c. Treatment (Standard operating procedures ) i. In Patient (cid:216) Same as in Situation 1 with addition of Laparoscopic procedure in following situations: • Facilities and infrastructure available 64

• Expertise is available (cid:216) Post-operative care of the patient in HDU or ICU if the patient is unstable . ii. Out patient – None iii. Day care – None d. Referral criteria – None from situation 2 VI. Who does what and Timeliness? a. Doctor (cid:216) The job of diagnosis, treatment including surgery, post-operative care and follow up. b. Nurse (cid:216) Pre-operative care, operative assistance, post-operative care, administration of treatment instructed by the doctor and monitoring as instructed.

c. Technician (cid:216) Keeps all machines and equipments in order and assist the anesthetist during operation. VII. Further reading a. Bailey & Love’s Short Practice of Surgery b. Schwartz’s Textbook of Surgery c. Abdominal Operations by Maingot Resources required for one patient/procedure Situation Human resources Investigations Drugs etc Equipment 1 Surgeon – 1 X-ray I/V fluids, Broad Exploratory laparotomy Medical officers - USG spectrum antibiotics, equipments

2 Biochemistry analgesics, Anesthesia equipment Staff Nurses -2 Hematology Vasopressors,anesthesia Monitors, Cautery, Technician – 1 Urine analysis drugs, sutures, drains & Suction, OT Tables & Ward boy -1 catheters, O2 cylinder lights, Autoclave, Sweeper - 1 etc Trolleys 2 Consultant – 1 Same as above Same as above plus Same as above plus all Sr. Resident – 1 plus Microbiology HDU/ICU back up equipment for Jr. Resident -2 ABG HDU/ICU, Laparoscope Staff Nurses -2 Technician – 1 Ward boy -1 Sweeper - 1 65

VARICOSE VEINS SURGERY Dr. Arun Prasad INTRODUCTION: The description of varicose veins as a clinical entity can be traced back as early as the fifth century BC. Forefathers of medicine including Hippocrates and Galen described the disease and treatment modalities, which are still used today. Throughout the centuries, surgical treatments have evolved from large, open surgeries to minimally invasive approaches. Varicose veins represent a significant clinical

problem and are not just a “cosmetic” issue because of their unsightly nature. The problem arises from the fact that varicose veins actually represent underlying chronic venous insufficiency with ensuing venous hypertension. This venous hypertension leads to a broad spectrum of clinical manifestations, ranging from symptoms to cutaneous findings like varicose veins, reticular veins, telangiectasias, swelling, skin discoloration, and ulcerations. DEFINITION:

When veins become abnormally thick, full of twists and turns, or enlarged, they are called varicose veins. Generally, the veins in the legs and thighs have a tendency to become varicosed. INDIAN INCIDENCE In India, the incidence of varicose veins is reportedly less than in the Western countries. This could be genuinely less or underreported as culturally the society does not permit exposure of legs and therefore it may not be bothering many people. INDICATIONS:

Surgical removal or obliteration of varicose veins is often for cosmetic reasons alone. Noncosmetic indications include symptomatic varicosities (e.g., pain, fatigability, heaviness, recurrent superficial thrombophlebitis, bleeding), or for the treatment of venous hypertension after skin or subcutaneous tissue changes, such as lipodermatosclerosis, atrophie blanche, ulceration, or hyperpigmentation, have developed.

Conservative treatment with stockings and external compression is an acceptable alternative to surgery, but worsening cutaneous findings or symptoms despite these measure usually warrant intervention. Nonetheless, a patient's desire for surgical management over conservative treatment or for cosmetic purposes alone are both reasonable relative indications for surgery. TESTS FOR REFLUX Trendelenburg test: This physical examination technique distinguish patients with reflux at the SFJ from

those with incompetent deep venous valves. The leg is elevated until the congested superficial veins have all collapsed. Direct pressure is used to occlude the GSV just below the SFJ. The patient stands with the occlusion still in place. If the distal superficial varicosities remains empty or fills very slowly, the 66

principal entry point of high pressure into the superficial system is at the SFJ. Rapid filling despite manual occlusion means that some other reflux pathway is involved. Doppler auscultation: A Doppler transducer is positioned along the axis of a vein with the probe at an angle of 45° to the skin. When the distal vein is compressed, audible forward flow exists. If the valves are competent, no audible backward flow is heard with the release of compression. If the valves are

incompetent, an audible backflow exists. These compression-decompression maneuvers are repeated while gradually ascending the limb to a level at which the reflux can no longer be appreciated. Venous refilling time (VRT): This is a physiologic test, again using plethysmography. The VRT is the time necessary for the lower leg to become infused with blood after the calf-muscle pump has emptied the lower leg as thoroughly as possible. In healthy subjects, venous refilling is greater than 120 seconds. In

patients with mild and asymptomatic venous insufficiency, VRT is between 40 and 120 seconds. In patients with significant venous insufficiency, VRT is abnormally fast at 20-40 seconds. Such patients often complain of nocturnal leg cramps, restless legs, leg soreness, burning leg pain, and premature leg fatigue. A VRT of less than 20 seconds is markedly abnormal, and is nearly always symptomatic. If the VRT is less than 10 seconds, venous ulcerations are likely.

Duplex US with color-flow imaging (sometimes called triplex ultrasound): This is a special type of 2- dimensional ultrasound that uses Doppler-flow information to add color for blood flow in the image. Vessels in the blood are colored red for flow in one direction and blue for flow in the other, with a graduated color scale to reflect the speed of the flow. Venous valvular reflux is defined as regurgitant flow with Valsalva that lasts great than 2 seconds. INVESTIGATIONS: § Haemogram § Blood sugar

§ Serum creatinine § Bleeding time, clotting time and prothrombin time § Xray chest § ECG § Doppler of lower limb venous system to rule out any DVT RELEVANT ANATOMY The greater saphenous vein (GSV) originates on the medial foot as part of the venous arch and receives tributaries from deep veins of the foot as it courses upward along the anterior aspect of the medial malleolus. From the ankle, the GSV continues along the anteromedial aspect of the calf to the knee and

into the thigh, where it is found more medially. From the upper calf to the groin, the GSV is usually contained within an envelope of thin fascia. Visualization of this fascial envelope is an important way of identifying the GSV with duplex ultrasound. This fascial envelope often prevents the GSV from becoming significantly dilated, even when large volumes of reflux pass along its entire length. A normal GSV is typically 3-4 mm in diameter in the mid thigh. 67

Along its course, a variable number of named perforating veins may connect the GSV to the deep system at the femoral, posterior tibial, gastrocnemius, and soleal veins. The Cockett perforators, between the ankle and the knee, are a special group of perforating veins. Rather than directly connecting the superficial to deep venous systems, they connect the subfascial deep system with the posterior arch vein, which then empties into the GSV.

Besides perforating veins, the GSV has numerous superficial tributaries as it passes through the thigh. The most important of these are the posteromedial and anterolateral thigh veins, found at the level of the mid thigh, and the anterior and posterior accessory saphenous veins at the level of the canal of Hunter in the upper thigh, where a perforating vein often connects the GSV to the femoral vein. Just below the SFJ, the GSV receives several additional important tributary veins. These include the lateral

and medial femoral cutaneous branches, the external circumflex iliac vein, the superficial epigastric vein, and the internal pudendal vein. These tributaries are frequently involved in the reflux that leads to the appearance of surface varicose veins on the lower thigh or upper calf. The termination point of the GSV into the common femoral vein is called the saphenofemoral junction in the English literature but is known as the crosse (i.e., shepherd's crook) in the French medical literature.

The terminal valve of the GSV is located within the junction itself. In most cases, at least one additional subterminal valve is present within the first few centimeters of the GSV. Most patients have a single subterminal valve that can be readily identified approximately 1 cm distal to the junctional valve. Reflux at or near the SFJ does not always come through the terminal valve of the GSV, nor does it always involve the entire trunk of the GSV. Reflux can enter the GSV below the subterminal valve or even

immediately below the junction, passing through a failed subterminal valve to mimic true SFJ incompetence. Reflux can also pass directly into any of the other veins that join the GSV at that level, or it may pass a few centimeters along the GSV and then abandon the GSV for another branch vessel. When a perforating vein is the primary site of reflux, dilatation of the vessel proceeds both proximally and distally. When dilatation reaches the most proximal portion of the vein, the saphenofemoral or

saphenopopliteal junction is often recruited as a secondary point of reflux. Although most large varices are tributaries off of an incompetent GSV or SSV, failed perforating veins or connecting veins can also give rise to independent varices in the greater saphenous distribution without involving the saphenous system itself. Identifying the originating point and the primary pathway of reflux in the thigh is often difficult, which is why duplex ultrasound has become so helpful in varicose vein workup.

OPERATIVE TECHNIQUES: 1. Safenofemoral ligation with long saphenous vein removal for long saphenous vein varicosities. Surgical removal of the GSV has evolved from large open incisions to less invasive stripping. Original methods of stripping used different devices and variations of techniques. The Mayo stripper was an extraluminal ring that cut the tributaries as it was passes along the vein. The Babcock device was an intraluminal stripper with an acorn-shaped head that pleated up the vein 68

as it pulled the vessel loose from its attachments. The Keller device was an internal wire used to pull the vein through itself, as is done today with perforation-invagination (PIN) strippers. Currently, the technique of PIN stripping begins with a 2- to 3-cm incision made at the groin crease. The femoral vein and SFJ are exposed with dissection and all tributaries of the SFJ must be identified and flush-ligated to minimize the incidence of reflux recurrence.

After ligation and division of the junction, the stripping instrument (usually a stiff but flexible length of wire or plastic) is passed into the GSV at the groin and threaded through the incompetent vein distally to the level of the upper calf. The stripper is brought out through a small incision (5 mm or smaller) approximately 1 cm from the tibial tuberosity at the knee. An inverting head is attached to the stripper at the groin and is secured to the proximal end of the

vein. The vessel is then inverted into itself, tearing away from each tributary and perforator as the stripper is pulled downward through the leg and out through the incision in the upper calf. If desired, a long epinephrine-soaked gauze or ligature may be secured to the stripper before invagination, allowing hemostatic packing to be pulled into place after stripping is complete. An older technique of stripping to the ankle (rather than to just the knee) has fallen into disfavor

because of a high incidence of complications, including damage to the saphenous nerve, which is closely associated with the vein below the knee 2. Subfacial ligation with below knee removal of long saphenous vein for below knee varicosities associated with incompetent perforators. 3. Removal of the short saphenous vein is complicated by variable local anatomy and risk of injury to the popliteal vein and peroneal nerve. The saphenopopliteal junction must be located by

duplex examination before beginning the dissection, and adequate direct visualization of the junction is essential. After ligation and division of the junction, the stripping instrument (often a more rigid stripper that facilitates navigation) is passed downward into the distal calf, where it is brought out through a small incision (2-4 mm). The stripper is secured to the proximal end of the vein, which is invaginated into itself as it is pulled downward from knee to ankle and withdrawn from below.

4. Stab phlebectomy (or ambulatory phlebectomy) Performed by Galen as early as the second century, this procedure came back into modern favor during the 1960s and has increased in popularity ever since. This procedure is extremely useful for the treatment of residual vein clusters after saphenectomy and for removal of nontruncal tributaries when the saphenous vein is competent. Ambulatory phlebectomy is a treatment for

superficial varicose veins. The procedure involves the removal of the varicose veins through small 2–3 mm incisions in the skin overlying the veins. The procedure may be performed in hospital or outpatient settings. The procedure may be performed with tumescent local anesthesia, such as with lignocaine. 69

A microincision is made over the vessel using a tiny blade or a large needle, a phlebectomy hook is introduced into the microincision, and the vein is delivered through the incision. With traction, as long a segment as possible is pulled out of the body until the vein breaks or cannot be pulled any further. Another microincision is made and the process is begun again and repeated along the entire length of the vein to be extracted. Short segments of veins can be

removed through tiny incisions without ligatures, and skin closure is not necessary. NEWER METHODS 1. Endovenous laser 2. Radiofrequency ablation 3. Sclerotherapy 4. Cutaneous electrodesiccation 5. Subfascial endoscopic perforating vein surgery POST SURGERY INSTRUCTIONS After treatment of large varicose veins by any method, a 30- to 40-mm Hg gradient compression stocking is applied and patients are instructed to maintain or increase their normal activity levels.

Most practitioners also recommend the use of gradient compression stockings even after treatment of spider veins and smaller tributary veins. Activity is particularly important after treatment by any technique because all modalities of treatment for varicose disease have the potential to increase the risk of DVT. Activity is a strong protective factor against venous stasis. Activity is so important that most venous specialists will not treat a patient who is unable to remain active following treatment.

COMPLICATIONS A correct diagnosis of superficial venous insufficiency is essential. Veins should be treated only if they are incompetent and if a normal collateral pathway exits. Removal of a saphenous vein with a competent termination will not aid in the management of nontruncal tributary varices. In the setting of deep system obstruction, varicosities are hemodynamically helpful because they provide a bypass pathway for venous return. Hemodynamically helpful varices must not be removed

or sclerosed. Ablation of these varicosities will cause rapid onset of pain and swelling of the extremity, eventually followed by the development of new varicose bypass pathways. The most annoying minor complications of any venous surgery are dysesthesias from injury to the sural nerve or the saphenous nerve. Subcutaneous hematoma is a common complication, regardless of treatment technique used. It is easily managed with warm compress, NSAIDS, or aspiration if necessary. 70

WHO DOES WHAT? Doctor: i) Surgeon: diagnosis & work up Pre operative planning Operative procedure Post operative follow up j) Anesthetist: PAC, anesthesia NURSE: • Dressing of the wound • Pre & post operative care TECHNICIAN: • Pre op equipment and drugs to be checked and kept ready • Assist anesthetist in the OT • Assist the surgeon, positioning of the patient RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (Patient weight 60 Kgs) Human Resources Investigations Drugs/Consumables Equipment

Surgeon – 1 Haemogram Antibiotics OT Table & lights Medical Officer / Blood Sugar Analgesic Instrument trolley Assistant Surgeon – 1 S. Electrolytes I.V. Fluids General Surgery Set Anesthetist – 1 S. Creatinine Sutures Cautery Staff Nurse – 1 ECG Drains Suction Technician – 1 X-Ray – Chest Anesthetic drugs Anesthetic Equipment 71

Nursing Orderly – 1 Doppler Dressings Monitors Sweeper – 1 REFERENCES 1. Royle J, Somjen GM. Varicose veins: Hippocrates to Jerry Moore. ANZ J Surg. Dec 2007;77(12):1120-7. [Medline]. 2. Coon WW, Willis PW 3rd, Keller JB. Venous thromboembolism and other venous disease in the Tecumseh community health study. Circulation. Oct 1973;48(4):839-46. [Medline]. 3. Callam MJ. Epidemiology of varicose veins. Br J Surg. Feb 1994;81(2):167-73. [Medline].

4. Carpentier PH, Maricq HR, Biro C, Ponçot-Makinen CO, Franco A. Prevalence, risk factors, and clinical patterns of chronic venous disorders of lower limbs: a population-based study in France. J Vasc Surg. Oct 2004;40(4):650-9. [Medline]. 5. Shami SK, Sarin S, Cheatle TR, Scurr JH, Smith PD. Venous ulcers and the superficial venous system. J Vasc Surg. Mar 1993;17(3):487-90. [Medline]. 6. Recek C. Conception of the venous hemodynamics in the lower extremity. Angiology. Oct-Nov 2006;57(5):556-63. [Medline].

7. Sales CM, Bilof ML, Petrillo KA, Luka NL. Correction of lower extremity deep venous incompetence by ablation of superficial venous reflux. Ann Vasc Surg. Mar 1996;10(2):186-9. [Medline]. 8. Naoum JJ, Hunter GC. Pathogenesis of varicose veins and implications for clinical management. Vascular. Sep-Oct 2007;15(5):242-9. [Medline]. 9. Weiss RA, Feied CF, Weiss MA. Vein Diagnosis & Treatment: A Comprehensive Approach, 1st ed. New York, NY: McGraw-Hill; 2001.

10. Pappas PJ, Lal BKL, Cerveira JJ, et al. The Management of Venous Disorders. In: R. B. Rutherford, ed. Vascular Surgery. Philadelphia, Pennsylvania: Elsevier; 2005:2220-2302. 11. Hafner J, Ramelet AA, Schmeller W, et al. Management of Leg Ulcers. New York, New York: Karger Publishers; 1999. 12. Eklöf B, Rutherford RB, Bergan JJ, Carpentier PH, Gloviczki P, Kistner RL, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg. Dec 2004;40(6):1248-52.

[Medline]. 13. Kalra M, Gloviczki P. Surgical treatment of venous ulcers: role of subfascial endoscopic perforator vein ligation. Surg Clin North Am. Jun 2003;83(3):671-705. [Medline]. 14. Caggiati A, Allegra C. Historical Introduction. In: The Vein Book. New York, New York: Elsevier; 2006:1- 14. 15. Dwerryhouse S, Davies B, Harradine K, Earnshaw JJ. Stripping the long saphenous vein reduces the rate of reoperation for recurrent varicose veins: five-year results of a randomized trial. J Vasc Surg. Apr

1999;29(4):589-92. [Medline]. 16. Johnson CM, McLafferty RB. Endovenous laser ablation of varicose veins: review of current technologies and clinical outcome. Vascular. Sep-Oct 2007;15(5):250-4. [Medline]. 17. Subramonia S, Lees T. Randomized clinical trial of radiofrequency ablation or conventional high ligation and stripping for great saphenous varicose veins. Br J Surg. Mar 2010;97(3):328-36. [Medline].

18. Rabe E, Otto J, Schliephake D, Pannier F. Efficacy and safety of great saphenous vein sclerotherapy using standardised polidocanol foam (ESAF): a randomised controlled multicentre clinical trial. Eur J Vasc Endovasc Surg. Feb 2008;35(2):238-45. [Medline]. 19. Wright D, Gobin JP, Bradbury AW, et al. Varisolve® polidocanol microfoam compared with surgery or sclerotherapy in the management of varicose veins in the presence of trunk vein incompetence: European

randomized controlled trial. Phlebectomy. 2006;21:180-90. 20. O'Hare JL, Stephens J, Parkin D, Earnshaw JJ. Randomized clinical trial of different bandage regimens after foam sclerotherapy for varicose veins. Br J Surg. May 2010;97(5):650-6. [Medline]. [Full Text]. 21. Lurie F, Creton D, Eklof B, Kabnick LS, Kistner RL, Pichot O. Prospective randomised study of endovenous radiofrequency obliteration (closure) versus ligation and vein stripping (EVOLVeS): two-year

follow-up. Eur J Vasc Endovasc Surg. Jan 2005;29(1):67-73. [Medline]. 72

22. Rasmussen LH, Bjoern L, Lawaetz M, Blemings A, Lawaetz B, Eklof B. Randomized trial comparing endovenous laser ablation of the great saphenous vein with high ligation and stripping in patients with varicose veins: short-term results. J Vasc Surg. Aug 2007;46(2):308-15. [Medline]. 23. Morrison N. Saphenous ablation: what are the choices, laser or RF energy. Semin Vasc Surg. Mar 2005;18(1):15-8. [Medline]. 73

STANDARD TREATMENT GUIDELINES OPTHALMOLOGY Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 REFRACTIVE ERRORS 4 2 STRABISMUS AND AMBLYOPIA 23 3 CONJUNCTIVITIS 35 4 MICROBIAL KERATITIS 45 5 CATARACT 57 6 DIABETIC RETINOPATHY 68 7 AGE RELATED MACULAR DEGENERATION (AMD) 81 8 GLAUCOMA 88 9 ANGLE CLOSURE DISEASE 89 10 PRIMARY OPEN ANGLE GLAUCOMA 103 11 INFECTIVE ENDOPHTHALMITIS 113 12 CHRONIC DACRYOCYSTITIS 124 13 RETINOBLASTOMA 133 2

Group Head Coordinator of Development Team Dr. Venkatesh Prajna Chief- Dept of Medical Education, Aravind Eye Hospitals, Madurai 3

NAME OF CONDITION: REFRACTIVE ERRORS I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: An easily detectable and correctable condition like refractive errors still remains a significant cause of avoidable visual disability in our world. A child, whose refractive error is corrected by a simple pair of spectacles, stands to benefit much more than an operated patient of senile cataract – in terms of years of good vision enjoyed and in

terms of overall personality development. In developing countries, like India, it is estimated to be the second largest cause of treatable blindness, next only to cataract. Measurement of the refractive error is just one part of the whole issue. The most important issue however would be to see whether a remedial measure is being made available to the patient in an affordable and accessible manner, so that the disability is corrected. Because of the increasing realization of the enormous need for helping

patients with refractive error worldwide, this condition has been considered one of the priorities of the recently launched global initiative for the elimination of avoidable blindness: VISION 2020 – The Right to Sight. b) Case definition: i. Myopia or Short sightedness or near sightedness ii. Hypermetropia or Long sightedness or Far sightedness iii. Astigmatism These errors happen because of the following factors: a. Abnormality in the size of the eyeball – The length of the eyeball is too long in

myopia and too short in hypermetropia. b. Abnormality in the curvature of the cornea – The curvature of the cornea is too steep in myopia and too flat in hypermetropia. In addition, irregularity of the corneal surface may give rise to astigmatism. c. Abnormality in the refractive index – Light passes through the major refracting surfaces like the cornea and lens, before impinging on the retina. A high refractive index may cause myopia, while a low refractive index may cause hypermetropia.

Of all these factors, the abnormality of the size of the eyeball is most common in producing refractive errors. 4

Myopia Myopia is a form of refractive error, wherein parallel rays of light come to a focus in front of the retina, when the eye is at rest. It is the commonest cause of refractive error and usually detected in the younger age group. It consists of two main types: Simple myopia: is just a variant of the normal and is not a major problem. Apart from the refractive error, no anatomical or functional complications of the ocular structures occur.

The progression of myopia, more commonly happens during the growing phase of one’s life. The maximum growth happens between the ages of 12 and 20 years. Frequent change of glasses maybe required during these years and the myopic error usually stabilizes after the age of 20. Hence permanent surgical procedures like laser surgery have to be performed only after documented stabilization of the myopia. Pathological (or progressive) myopia: also called as degenerative myopia, as the name

suggests is of a more serious nature a type of severe, progressive nearsightedness characterized by changes in the fundus of the eye, posterior staphyloma, and deficient corrected acuity. Refractive error is greater than -8.00 diopters, and axial length is greater than 32.5 mm. In pathological myopia the retina becomes very thin and is stretched at the periphery. The peripheral retina is at risk of developing tears or holes. Hypermetropia

Hypermetropia is a form of refractive error, wherein parallel rays of light come to a focus behind the retina, when the eye is at rest. In this condition, the person is unable to see near objects well. The eye tries to focus the images by increasing the refractive index of the lens (by making it thicker) - the process is called Accommodation. Astigmatism In this condition the eye is unable to form a point focus of light upon the retina. Instead of

a single focal point of the image being formed, there are two foci that are separated by a distance. Hence the person is unable to see an image clearly in one meridian when he is focusing on another meridian. - In regular astigmatism, the refractive power varies successively from one meridian to the next, and each meridian has a uniform curvature at every point across the entrance pupil. The meridians of greatest and least power, the so-called principal meridians, are

always located at meridians 90 degrees apart. - In irregular astigmatism, which can be clinically significant in conditions such as keratoconus and other corneal ectasias; corneal basement membrane and stromal dystrophies; corneal scarring; and post-surgical corneas (e.g., following penetrating 5

keratoplasty, radial keratotomy (RK), complicated refractive surgery), the magnitude and the axis of astigmatism vary from point to point across the entrance pupil. In addition to these refractive errors, there is another condition called as presbyopia which occurs in all people, usually above the age of 40 years. Presbyopia In this condition, the eye is unable to focus near objects. The problem in presbyopia is the aging of the lens and the accommodating system, which fail to focus near objects on the

retina. Although not truly a refractive error, presbyopia will be considered in this document because its correction has similarities to the correction of refractive errors. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY With blindness defined as presenting distance visual acuity <3/60 in the better eye, the prevalence of blindness due to refractive error has been reported to be as high as 0.2% in India, for all age groups in the population considered together. A recent survey shows an

increase in the incidence of refractive errors as a cause of social blindness from 12% to 15%, whereas the burden of cataract has actually decreased from 80% to 62% (Source: National Survey of Blindness 1986-89 and 2001-02). III. DIFFERENTIAL DIAGNOSIS: Patients with refractive errors often complain of defective vision, tiredness of eyes and headache. Even though refractive errors is the most common causative factor for defective

vision, other organic causes such as the following should be examined and ruled out by a comprehensive eye examination. i. Cataract ii. Retinal disorders iii. Optic nerve pathology iv. Glaucoma v. Other media opacities It should be once again emphasized that estimation of refractive errors should be a part of a complete ophthalmic evaluation. In addition, other causes of headache like sinusitis or migraine should be suspected especially when there are complaints of recurrent headache

in the setting of a normal refractive status. IV. PREVENTION AND COUNSELING For all practical purposes, there are no strategies which are effective in preventing this condition from occurring. However, counseling on the importance and compliance to treatment optimizes visual performance and prevents further deterioration of the functioning of the eye. Most myopic refractive errors develop and progress during childhood and adolescence, which corresponds to their general physical development. The 6

importance of school teachers in suspecting this condition cannot be over emphasized. They can be trained for screening of this condition and experience has shown that this system is very useful to identify children who need ophthalmic care and support at the school going level. The positive effect of outdoor activity for reducing myopic progression has been documented in numerous studies. Physical activity, sports, and low accommodative demands have been postulated as the cause of this protective effect.

V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: A proper history taking remains a cornerstone of the diagnosis of this condition. A child with uncorrected refractive error is restricted to the limits of its vision. Those who are not

so eloquent with their complaints would tend to read their books very close to their face and sit closer to the black board or the television. The frustrated child becomes an introvert, keeping away from other children of his age and avoids outdoor activities. The myope’s main complaint is that he /she don’t see distant objects clearly. The defect may also manifest as headache, watering from eyes and constant itching of the eyes – all

these symptoms are a result of the eyestrain induced by the refractive error. Conditions like pathological myopia, if not diagnosed early and followed up regularly can result in permanent loss of vision due to retinal scarring or retinal detachment. The progression of myopia happens more often in the growing phase of a person’s life. The maximum growth happens between the ages of 12 and 20. Frequent changes of spectacles may be required

during these years, and the myopic error usually stabilizes after the age of 20. The hypermetropes complain that they are unable to do near work very well. Headache and eyestrain following any prolonged near work like desk jobs or sewing can be accompanying symptoms. These symptoms are collectively termed asthenopia. Although hypermetropia can be detected at any age, it generally manifests more with increasing age Presbyopes are usually people in their fourth decade, who find it increasingly difficult to

read the newspaper at their usual working distance in dim light and tend to keep it at a distance to make out the letters. Simple tasks like threading a needle, putting one’s signature on a document or making out the fine print on a visiting card become increasingly difficult and sometimes embarrassing. For artists and artisans who depend on their near vision for livelihood, it can even become economically crippling. Headaches and eye – strain

may occur after long hours of near work. The uncorrected disability hampers his/her financial productivity and compromises their occupational skills. Left uncorrected, he/ she 7

loses interest in performing near work like reading and writing leading to a compromise in quality of life. The evaluation of refractive errors requires an assessment of both the refractive status of the eye, the patient’s current mode of correction, symptoms, and visual needs. As emphasized repeatedly, refraction is often performed in conjunction with a comprehensive ophthalmic evaluation. A thorough history with a special focus on the vocational needs of

the patient should be asked for and kept in mind before finalizing the prescription. The examination should include both undilated and dilated evaluations. While pupillary reactions, ocular alignment and movements, visual field evaluation (in indicated cases) and dynamic refraction can be performed on a reactive pupil, posterior segment evaluation and cycloplegic retinoscopy and refraction can be done after dilating the pupil. b) Investigations: 1. Visual acuity testing

Distance visual acuity is usually measured in a dimly lit room as the patient looks at a chart of high-contrast characters. It should be measured separately for each eye with current correction. For clinical purposes it is desirable that test chart luminance not be less than 80 cd/m2. It is desirable that the luminance level employed be specifiable. visual acuity testing conditions should be standardized in each examination room and

at each visit, so that the same viewing distance and lighting conditions are used. Near acuity is usually measured while the patient looks at a well-lit reading card of high- contrast characters held at a specified near working distance, typically 14 inches or 30 cm Nonverbal child (upto 1 year) Estimating visual acuity in a non verbal child is a challenge. It should comprise of assessing the following parameters. 1. The assessment for this age involves evaluation of ocular fixation and following to

appropriate visual stimuli: for an infant under 4 months of age, the examiner’s face or the parent’s face is used as a target. For older infants, appropriate toys can be used to induce fixation. Attempts should be made to assess the quality of the fixation response (central, eccentric, steady, unsteady, maintained) to the targets used. Even a subtle difference in the ocular fixation response of an infant with an otherwise normal eye examination requires monitoring to evaluate the presence or development of

amblyopia. 2. Ability to fixate a light held at 33cm.is assessed 3. Blink reflex in response to sound is observed. 8

Verbal but preliterate child (1 to 5 year) Preschool going children can be assessed by either of the following methods. 1. Ability to locate small objects (cake decorations). 2. Marble game test; in which child is asked to place marbles in holes of a card. 3. Illiterate E-card test. 4. Sheridan Gardiner (S-G) test. Literate child (>5 year) and adults These patients can be checked using a regular Snellen’s visual acuity chart. In illiterate

people, Landolt C chart or a tumbling E chart may be used. Near vision testing can be performed using a Jeager chart. 2. Refraction: Each eye should be evaluated independently. A dynamic refraction is done first for all adults followed by a cycloplegic refraction if necessary. Presbyopic correction is determined before applying dialating drops. All children, below the age of 15 years should be refracted only after applying cycloplegics to neutralize the effects of accomadation, to

identify accomadative spasm and to diagnose strabismus of accomadative aetiology. An objective retinoscope followed by a subjective refinement of refraction is preferred. Distance refraction should be performed with accommodation relaxed using manifest (noncycloplegic) refraction with fogging or other techniques to minimize accommodation with care not to provide excess minus power correction to the patient. The common dialating agents are tropicamide and cyclopentolate. Tropicamide provides a more rapid

onset of action and a shorter duration of effect while cyclopentolate provides greater cycloplegia that can allow a more accurate refraction but a longer duration of effect. A significant difference between manifest and cycloplegic refraction is frequent in children; In adults,a substantial difference between manifest and cycloplegic refraction may require a post-cycloplegic dynamic refraction on a subsequent day where the cycloplegic refraction

is used to guide the final manifest prescription. The post-cycloplegic refraction is performed when full accommodation has returned. 3. Measurement of interpupillary distance (IPD) to determine the distance in millimeters between the centre of the pupils of the two eyes for a given viewing distance with a ruler. IPD is to be measured for both distance and near. 4. Determination of vertex distance and precise astigmatic axis is especially important in patients with high refractive errors.

5. Determination of Muscle Balance This is done for people complaining of asthenopic symptoms 9

C) Treatment: Spectacle Correction: 1. Myopia: Full correction can be given to patients who are having visually demanding activities so that they can have a good distance vision. Over correcting myopic patients will cause excessive accommodation, which may create symptoms. Some patients may become symptomatic from increasing myopia at low levels of illumination. These patients may require increased correction for clear vision at night.

2. Hypermetropia: Slight under correction may be desirable in young and middle aged hypermetropes because there is some physiological accommodative tone. With the onset of presbyopia as the patient ages, full correction may be necessary to minimize difficulties with near vision. 3. Astigmatism: Full correction may not be needed for individuals with regular astigmatisms. Adults with astigmatism may not accept full cylindrical correction in their

first pair of spectacles, or in subsequent spectacles if their astigmatism has been only partially corrected or its oblique axis astigmatism. 4. Presbyopia: In presbyopic patients, accommodative amplitudes are measured to determine if the available accommodation is sufficient for the near task. It is suggested that half of the accommodative amplitude be held in reserve for comfort. Individuals with myopia must exert more accommodative effort when using contact lenses, or after

refractive surgery, than when using eyeglasses. Individuals with hyperopia must exert more accommodative effort when using eyeglasses than contact lenses. A brief note of the basics of spectacle fitting is given below: Frames The types of frames can be broadly classified into Metal and Plastic Frames. Metal Frames Alloys of varying constituents and consistencies are used to make frames. The most commonly used Nickel alloys, are cheap, strong and are tensile but may cause allergic

reactions in the skin and so are not advisable. Stainless steel is a good alternative as it is inert, less allergenic and lightweight at the same time. Aluminium is lightweight but soft, and is less allergenic. Metals such as Titanium are also becoming popular, as it is very strong but lightweight.. The color and protective coatings given to the frame are just as important as the base material. Electroplating is a sturdy and reliable way to coat the

frames. Cheaper frames are usually dipped or spray-painted – these coats usually peel off fast and may not be uniform. Powder coats on frames have a longer life as the coat is fused with the base metal. A final protective lacquer coat on top of the colour coat adds lusture and binds the color coat to the frame. 10

Plastic Frames Most ‘plastic’ frames are actually all natural. The common constituent of this frame is Cellulose acetate, which is derived from treated wood pulp. These are sometimes called “shell” frames since the tortoise shell was initially used to make frames and later bone and animal horns were also used. Though this practice no longer exists, the name has remained. All these shell frames are less allergenic, flexible and elastic – so they last longer. However,

low-grade plastic frames which are more thermosetting (become rigid with heating) tend to become brittle and cannot be reused. Thermoplastic frames on the other hand become pliable on heating and can be reused when one wants a change of lenses. Rimless Frame These frames are actually disjointed three parts of a frame – the two temples of the frame and the nose bridge. These are then attached to the lenses and held in place by screws.

These are available in both metal and shell frames. The advantage here is that the lens shape can be free form. However, these must be handled carefully as the lenses have no protection. Half-Rimless Frames These frames appear to have the frame rim running only along one side of the frame, but if at a closer look one can see a clear nylon wire running along a groove holding the lens in place. These are quite fashionable and are more reliable than rimless frames. Lenses

Once the frame is chosen the lenses need to be selected. Lenses are available in three basic materials: Glass Lenses Traditionally lenses were made out of glass. These had very high clarity and were easy to produce and fit into frames. Alternatives for lens materials were sought because glass was heavy and broke easily. This was a cause for concern where wearers had an active lifestyle. Plastic Lenses Lenses made of plastic are lightweight and do not break easily. However, as plastic is softer

than glass, it tends to scratch easily. But today with the developments of high quality scratch resistant coatings plastic is fast replacing glass in the market. Plastic lenses weight only 40% as much as glass and are especially suitable for an active lifestyle or a high refractive error. It is especially safe for children, as it does not shatter like glass lenses. Polycarbonate Lenses These are called “bulletproof” lenses and for good reason too. They are impact resistant,

that makes them long lasting and lightweight. They have a very high refractive index, which means that these lenses are very thin even for very high powers. Polycarbonates are usually used for sports eyewear. But their lightweight, longevity combined with a good scratch resistant coating make them one of the best choices. 11

Hi Index Lenses For a high myope heavy, thick ringed lenses make their eyes seem small and unsightly. An excellent alternative are hi-index lenses that give the same refractive power at half the thickness of the normal glass lens. These are available in both plastic and glass lenses. Lenses admit most of the light through them – but some of the incident rays are reflected off the surface of the lens. This causes glare, which is disturbing when driving in the night

with glasses on or while using the computer. Anti-Reflection Coatings (or ARC) that is applied onto the lens ensures that the lens admits up to 99% of the light. This not only gives clearer vision to the wearer, it is a cosmetically better choice as the ugly reflections on the lens surface are avoided and the eyes are visible to the onlooker. Correction for Presbyopia Presbyopes require glasses called bifocal lenses (two focal lengths); their main

disadvantages being discomfort if line of sight falls at the division in the lens; and being able to see clearly only at two focal lengths. To help them focus at all distances new lenses have been designed called ‘varifocals’. These are designed by increasing the focal power gradually (so also called Progressive Addition Lenses). They eliminate the discomfort caused by segments in the lenses and improve the quality of vision. Safety Lenses

These are special eyewear systems designed for protecting the eye from excessive heat, dust, light, harmful rays, or impact. This eyewear is suitable for people working in extremes of environment like welders, bikers, those living in extremes of weather, those handling harmful chemicals etc. Polarized lenses have long been known and proven to enhance visibility and reduce glare under all conditions. The lenses provide a sharper vision under any environmental

condition. Polarized lenses are the only lenses that provide visibility below the surface of the water in a marine environment. A polarized lens filters and eliminates annoying glare and transmits only efficient light to the eye. Wherever there are horizontal surfaces producing glare, the use of polarizing lenses is recommended because it reduces eye fatigue and maintains the health of your eyes while exposed to the sun. Ultra Violet Protection

UV Filter capacity of a lens is measured and certified. Lenses marked UV400 mean that they block 100% of UVA & UVB. As a result, your eyes are not subjected to any harmful rays. All sunglasses offer UV protection to some extent but not 100%. Exposure to UV rays accelerates development of cataract, degeneration of cornea and retina. It can also cause tumors of the eyelid. 12

Standard Operating procedure a. Inpatient Not applicable b. Out Patient: All patients are treated as outpatients. c. Day care Not applicable d) Referral criteria: The following patients can be referred to a higher centre for the following reasons: - Pathological Myopia - Refractive Error with associated Strabismus - Visual Acuity not improving with glasses - Oblique Astigmatism - Sudden refractive change - Amblyopia Those patients who desire contact lenses and refractive surgeries

*Situation 2: At Super Specialty Facility in Metro location where higher- end technology is available a) Clinical Diagnosis: Apart from the regular history and examinations, measured above, special emphasis on evaluating the visual expectations should be performed on patients seeking refractive surgery. b) Investigations: While regular patients seeking spectacle correction go through the same investigations mentioned above, patients with special needs such as contact lenses and laser

refractive surgeries have to undergo special procedures. The refraction may be done objectively by retinoscopy, with an autorefractor, or with a wavefront analyzer; or it may be done subjectively. In cooperative patients, subjective refinement of refraction using a phorometer or trial lens set is preferred c) Treatment: Contact Lenses: An attractive alternative to spectacles for correcting refractive errors, contact lenses are

also used for various therapeutic, pharmacological and cosmetic procedures. Modern contact lenses are polymers which are relatively safe, non-toxic and non-allergic. Since the cornea derives its oxygen supply mainly from the atmosphere, placing a lens on its surface can compromise its intake starving the cornea of oxygen. Newer lenses however, allow oxygen to pass through them to the cornea. There are basically three types of contact lenses: 13

Soft contact lens: These are well flexible lenses made of a polymer called HEMA (Hydroxy Ethyl Metha Acrylate). They are very comfortable to wear and permit oxygen to reach the cornea. Semi soft lenses or Rigid Gas Permeable Lenses: These lenses are made from special materials like Cellulose or Silicon acrylate. They are less flexible than soft contact lenses but allow some oxygen to pass through the cornea. Though less comfortable than soft

lenses, they can be used to correct steep corneas and high astigmatism. Hard contact lenses: Made of a polymer called PMMA (Poly Methyl Metha Acrylate), hard lenses are least flexible and permit almost no oxygen to pass through to the cornea. The advantage of a hard contact lens is its durability. Advantages of a contact lens: • A contact lens provides a larger field of vision than spectacles and a better range of mobility. Hence it is ideally suited for sportspersons and people engaged in outdoor

physical activities. • In people with high refractive error in one eye alone, spectacles will produce double vision due to the image size discrepancy. Contact lenses can be used for such people. • Cosmetically, they offer an advantage over spectacles. • Apart from correcting refractive errors, contact lenses are also used to deliver drugs to the eyes and to treat corneal diseases. • Nowadays contact lenses are also available in various colors and can be used by people

even with normal vision for the cosmetic appeal. Precautions With all these advantages, there are also some precautions to be taken before opting for contact lenses. • An ophthalmologist should examine the eyes to rule out infections and other disorders of the eye. • A qualified contact lens specialist alone should do the contact lens fitting. This includes measuring the corneal curvature and diameter and issuing a suitable pair of contact

lens. After wearing them, the specialist examines the eyes for a good, comfortable fit on the eyes. • Hand washing with soap before inserting and removing the contact lens from the eye is mandatory. • Proper maintenance of the contact lens by cleansing it with the appropriate lens fluid is necessary. • If the eyes are red or there is a white discharge from the eyes, the contact lens should not be used and the eye care professional should be contacted for further instructions. 14

• One should not sleep overnight with the regular daily wear contact lens on. The oxygen supply to the cornea is totally cut off during sleep by the contact lens. The oxygen deprived cornea is liable to damage and ulceration. • The eyes should be periodically examined by an eye care professional to look for any infections or corneal damage, possible due to contact lens wear. The latest innovation in the field is extended wear contact lenses which can be used over a

longer period of time. Wearing of contact lenses during waking and sleeping hours, i.e., continuous 24 hour wear for a specified number of days. NOTE: The FDA recommends no longer than six (6) consecutive nights wear for traditional extended-wear lenses. These lenses allow free passage of oxygen through them to the cornea, but even they must be used with care. Refractive Surgery for Myopia, Astigmatism and Hyperopia Refractive surgery may be considered when a patient wishes to be less dependent on

eyeglasses or contact lenses, or when there are occupational or cosmetic reasons not to wear eyeglasses. Patient expectation will be the main pillar around which all the other structures of the preoperative examinations should be built. The motives for desiring refractive surgery should be carefully discussed with the patient by the surgeon. Individuals who expect only 6/6 and nothing less should be discouraged from having refractive surgery, while patients

motivated by a desire to reduce their dependence on glasses or contact lenses, will be good candidates. Keratorefractive surgery can be applied to a broad range of refractive errors, but in some circumstances, the surgeon may consider an intraocular procedure like the placement of an intraocular lens (IOL) implant, either in front of the crystalline lens (phakic IOL) or in place of the crystalline lens (refractive lens exchange). Preoperative evaluation

1. Patients to discontinue contact lenses at least 1 week before surgery because of the possibility of contact lens induced corneal warpage. Toric soft contact lenses and rigid contact lenses should be discontinued for a longer period (atleast 2 weeks) because they are associated with a greater potential for corneal warpage and refractive instability. 2. Visual acuity without correction 3. Manifest, and where appropriate, cycloplegic refraction: The stability of the refraction

should be well documented. If the patient is seen for the first time, it may be prudent to ask for his previous refraction powers and compare with the present 4. Detailed anterior and posterior segment evaluation: A thorough anterior segment evaluation before and after pupillary dilation is crucial. Potential anatomical problems like a prominent brow, narrow palpebral fissure and peripheral vascular pannus should be looked for, since these may pose problems during microkeratome operation. As the 15

cornea is evaluated, close attention should be paid to any anterior membrane dystrophy, stromal scarring or vascularization that may influence the type of surgery or whether it should be done at all. Any variation in stromal thickness, as in pellucid or Terrien’s degeneration, keratoconus or stromal dystrophies should alert the surgeon to reconsider performing a refractive procedure. The crystalline lens should be examined in detail after full dilatation, especially in patients above the age of 40 years. A

progressive myopia, during middle age should alert the clinician about the early stage of immature cataract. In case of doubt, an axial length measurement can be estimated and if there is any discrepancy, further testing can then be ordered. A baseline intraocular pressure measurement, like the preoperative keratometry reading, serves as an useful adjuvant, since post lasik intraocular pressure measurement using Goldman’s applanation tonometry is less than accurate.

A detailed indirect ophthalmoscopic evaluation with and without indentation should be an integral component of the whole screening processes. Lattices with multiple holes and horse shoe tears can be subjected to barrage laser and laser surgery can be performed after a period of 1 month. Round atrophic holes and simple lattice degenerations need not be treated as a routine. Even as there is no proof of increased occurrence of retinal detachment following refractive surgery, it will be prudent to

treat any predisposing condition first. 5. Evaluation of tear film: The level of tear meniscus and the quality of the tear film should be assessed before any instrument touches the eye. Although mild dryness due to intolerance of contact lens wear may be an indication for refractive surgery, more significant dryness may pose a threat to successful epithelial healing. 6. Evaluation of ocular motility and alignment 7. Topography: for evidence of irregular astigmatism, corneal warpage, or abnormalities

suggestive of keratoconus or other corneal ectasias, because all may be associated with unpredictable refractive outcomes and latter with progressive ectasia following surgery. The detection of the posterior corneal elevation adds an extra safety dimension before Lasik procedure. 8. Pachymetry: To identify unusually thin corneas and estimate residual stromal bed thickness. Corneas with central corneal thickness values less than 500 μm should be considered potentially abnormal. Excimer Laser Systems

Laser assisted in situ keratomileusis (LASIK) is the most commonly performed refractive surgery worldwide. Good visual results, quick rehabilitation and negligible complication rates have been the main reasons for the widespread acceptance rate of this procedure. Technological advancements have brought in many evolutions from the initial era of broad beam lasers to the more recent ones using flying spot technology. These refinements have

helped the new generation lasers to have more accurate predictability than the earlier 16

ones. A recent addition in this field is the area of customized correction, by lasers using wave front technology. Even though the customized correction procedures are becoming popular by the day, controversies still surround many of its presumed theoretical advantages. Since conventional LASIK surgery by itself is a highly accurate procedure, it becomes all the more difficult to establish the superiority of the customized correction over the conventional one. Conventional

By varying the ablation pattern, the excimer laser can alter the anterior corneal curvature to modify a particular refractive error described by sphere and cylinder. The laser delivery methods currently being utilized to achieve the ablation pattern are broad beam, scanning slit, or flying spot systems. Eye-tracking technology is integrated into the current commercially available excimer laser systems and permits the ablation to remain centered on the pupil in the presence of small ocular movements.

Potential advantages of customized treatment Wave front based aberrometry has certain theoretical advantages, the notable one being the evaluation of whole eye optics. In certain instances, visual symptoms can be correlated with certain higher order aberrations. However the measurements of these aberrations are not reproducible. For example, it has been shown that Postoperative wavefront aberrations do not always correlate with contrast sensitivity measurements. The magnitude

of higher order aberrations have been documented to increase with increasing papillary size. Hence there is a theoretical beneficial effect of correcting higher order aberrations in people with large pupils, who have to work mainly in dim light conditions. Potential disadvantages of customized treatment 1. All aberrations are not treated: The aberrometer generates a lot of data from a human eye. Not all of these are treatable using customized LASIK procedure. In fact,

customized LASIK has been demonstrated to induce additional higher order aberrations as well. This again brings us to the notion that the significance of these aberrations is still not well understood at this point of time and further refinements are yet to be done in this field. 2. All aberrations are not reproducible: The aberrations generated from a human eye are not reproducible and this is one of the major draw backs. Daily fluctuations in wave

front aberrations have been noted in several studies and are attributed to accommodation, tone of the pupil and tear film distribution. 3. Wave front changes with age: The wave front measurements of the eye alter with age, because of changes that occur in the lens and cornea with age. Hence even if one performs customized corneal ablation, it will be interesting to watch whether these changes would be permanent. 4. Pupillary size: Pupillary alterations happen almost on a continuing basis in our day to

day routine. The output of the wave front images changes with minute changes in the 17

papillary size. If this be the case, it is interesting to speculate whether the treated area corrects the aberrations, over the entire spectrum of papillary dilatation and constriction, which happens during our day to day activities. 5. Limitation of the retina: Even if we correct all the aberrations of the eye, there is a biological limitation of the retina to see beyond approximately 6/3 vision. It is not clear whether the neural retina will be able to interpret the improved image.

6. Depth of field: Removing the eye’s higher order aberrations increases optical quality for objects that lie at the best focus. However, it reduces optical quality for objects that are far out of best focus. Exactly how this benefits and cost tradeoff functions in everyday vision has not yet been carefully studied. 7. Change in posture: It has to be understood that the wave front measurements are taken with the patient in a sitting position, while the treatment is performed in a

patient in a supine position. Since the wave front changes with these postural alterations, this factor needs to be studied in detail. Contraindications • Unstable refraction • Certain abnormalities of the cornea (e.g., keratoconus or other corneal ectasias, thinning, edema, interstitial or neurotrophic keratitis, extensive vascularization) • Insufficient corneal thickness for the proposed ablation depth • Visually significant cataract • Uncontrolled glaucoma

• Uncontrolled external disease (e.g., blepharitis, dry eye syndrome, atopy/allergy) • Uncontrolled connective tissue or autoimmune disease • Unrealistic patient expectations Relative Contraindications • Functional monocularity • Ocular conditions that limit visual function • Excessively steep or flat corneas • Abnormal corneal topography suggestive of forme fruste of keratoconus, keratoconus, or other corneal ectasias • Significant irregular astigmatism • Corneal stromal or endothelial dystrophies

• History of herpes simplex virus (HSV) or varicella zoster virus (VZV) keratitis • Significant dry eye syndrome • Prior incisional or lamellar keratorefractive surgery • Glaucoma • Diabetes mellitus • Pregnancy or lactation • Connective tissue or autoimmune diseases 18

• Certain systemic medications (e.g., isotretinoin, amiodarone, sumatriptan, levonorgestrel implants, colchicine) • Under 21 years of age (FDA labeling should be consulted for each laser) Surface Ablation Techniques Photorefractive Keratectomy In PRK, the central corneal epithelium is removed and the excimer laser is used to ablate Bowman’s membrane and superficial corneal stroma over the entrance pupil. Laser Epithelial Keratomileusis and Epi-LASIK

Laser epithelial keratomileusis (LASEK) is a modification of PRK that attempts to preserve the epithelium. After alcohol is applied to the corneal epithelium, an epithelial trephine and spatula are used sequentially to score, loosen, and roll up the epithelium, which remains attached at a nasal or superior hinge. Photoablation is then performed, and the epithelium is unrolled back over the central corneal stroma. A bandage contact lens is used for several days until the surface re-epithelializes.

An alternative surface ablation procedure to LASEK is epi-LASIK. Instead of using alcohol to loosen the epithelium, an epikeratome is used to dissect an epithelial sheet from Bowman’s membrane. The epikeratome is similar in design to a mechanical microkeratome used for LASIK. Instead of using an oscillating sharp blade to incise the cornea beneath Bowman’s membrane, the epikeratome uses a blunt oscillating separator that moves

across the cornea held under high pressure with a suction ring. This separator lifts a sheet of epithelium from Bowman’s membrane. The laser ablation is then performed and the epithelial sheet is either replaced or discarded. Visual recovery and discomfort with LASEK and epi-LASIK are similar to PRK and are prolonged relative to LASIK. Alternatives for patients who are Lasik Rejects: For eyes with THIN CORNEA · PRK / LASEK / EPI-LASIK · SBK (Sub Bowman’s Keratomileusis) · Intra corneal Rings

· Phakic IOL (ICL) For eyes with ABNORMAL SHAPE · Intra corneal Rings (INTACS, Kera rings ) · Phakic IOL Phakic IOLs Phakic IOLs fall into three broad categories: • Anterior chamber angle-fixated lenses, originally introduced by Baikoff and Joly • Anterior chamber iris-fixated lens, introduced by Fechner and Worst 19

• Posterior chamber sulcus- fixated lens introduced by Fyodorov and subsequently modified by other companies. Indications for phakic IOLs: • Correction of myopic errors of -8.00 D or more. • In eyes contraindicated for LASIK: - Relatively thin corneas, - Stable keratoconus; - Corneas steeper than 48.00 D or with expected post-LASIK keratometry readings flatter than 35.00 D. - in eyes with residual refractive errors after LASIK, corneal transplant, intrastromal

corneal ring segment (ICRS) implantation, corneal collagen crosslinking (CXL), and pseudophakia. Contraindications: • Unstable refraction • Visually significant cataract in the case of phakic IOLs • Corneal endothelial disease, including Fuchs dystrophy • Uncontrolled glaucoma • Uncontrolled external disease • Uncontrolled connective tissue or autoimmune disease • Unrealistic patient expectations Standard operating procedure a. In patient: Not applicable b. Out Patient: Not applicable

c. Day care: Refractive surgeries are done as day care procedures. d) Referral criteria: Not applicable VI. WHO DOES WHAT? And TIMELINES a. Doctor 1. History taking with examination of the patient 2. To carry out the necessary investigations 3. To satisfy the patient as per his/her needs b. Technician/Nurse Role of Ophthalmic Assistants is to 1. Test vision, conduct refraction and prescribe corrective lenses. 20

2. Assist medical officers in providing primary care including treatment for trachoma, ocular injuries, and conjunctivitis etc. 3. Assist in conducting eye camps at the primary health centre. 4. Help in organizing vision-screening programmes in schools. 5. Carry out eye health education activities. 6. Maintain the dark room and ophthalmic equipment in primary health centre. VII. FURTHER READING / REFERENCES 1. Caster AI, Hoff JL, Ruiz R. Conventional vs wavefront-guided LASIK using the

LADARVision4000 excimer laser [Internet]. Journal of Refractive Surgery (Thorofare, N.J.: 1995). 2005 ;21(6):S786-791.Available from: http://www.ncbi.nlm.nih.gov/pubmed/16329381 2. Frick KD, Riva-Clement L, Shankar MB. Screening for refractive error and fitting with spectacles in rural and urban India: cost-effectiveness [Internet]. Ophthalmic Epidemiology. 2009 ;16(6):378-387.Available from: http://www.ncbi.nlm.nih.gov/pubmed/19995203

3. Jose R, Sachdeva S. School eye screening and the National Program for Control of Blindness [Internet]. Indian Pediatrics. 2009 ;46(3):205-208.Available from: http://www.ncbi.nlm.nih.gov/pubmed/19346567 4. Limburg H, Kansara HT, d'Souza S. Results of school eye screening of 5.4 million children in India--a five-year follow-up study [Internet]. Acta Ophthalmologica Scandinavica. 1999 ;77(3):310-314.Available from: http://www.ncbi.nlm.nih.gov/pubmed/10406152

5. McLeod SD, Chuck RS, Hamilton DR, Katz JA, Rutzen AR, Vukich JA, et al. Prepared by the American Academy of Ophthalmology Refractive Management/Intervention Panel Refractive Management/Intervention Panel Members. 2007 ; 6. Pararajasegaram R. VISION 2020-the right to sight: from strategies to action [Internet]. American Journal of Ophthalmology. 1999 ;128(3):359-360.Available from: http://www.ncbi.nlm.nih.gov/pubmed/10511033

7. Shah S. LASIK--the Indian eye controversy [Internet]. Indian Journal of Ophthalmology. 2002 ;50(4):259-260.Available from: http://www.ncbi.nlm.nih.gov/pubmed/12532489 8. Contact lenses: Edited by James V. Aquavella, M. D., and Gullapalli N. Rao, M.D., with 15 contributors. Philadelphia: J.B. Lippincott Company, 1987. Pp. 278. $42.50 [Internet]. Available from: http://www.journals.elsevierhealth.com/periodicals/cev/article/0953- 4431(89)90035-0/abstract 21

RESOURCES REQUIRED Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1) Secondary 1)Doctor 1)Refraction 1)Mydriatics and 1)Retinoscope level 2)Nurse 2)Kerotometry 2)Cycloplegics 2)Trial set 3)Ophthalmic 3)Spectacle 3) Indirect ophthalmic Assistant frames and lenses with 20D lens 4)Antibiotic and 4) Slit Lamp steroid eye drops Biomicroscope with 5) Visual acuity charts 6) Keratometry 2) Tertiary 1) Doctor (with 1)Refraction 1)Mydriatics and 1) Retinoscope

level a refractive 2)Kertometry 2)Cycloplegics- 2) Trial set surgeon) 3)Pachymetry 3)Spectacle 3)Autorefractometer 2) Nurse - 1 4)Topography frames and lenses 4)Slit Lamp 3)Ophthalmic 4)Antibiotic and Biomicroscope Assistant - 1 steroid eye drops 5)Keratometer 4)OT Nurse - 1 5)Phakic IOL 6)Pachymeter INTACS 7)Topography 8)Indirect ophthalmic with 20D lens 9)Operating microscope 10) Visual acuity charts 11) Laser equipment 22

NAME OF CONDITION: STRABISMUS AND AMBLYOPIA I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Strabismus or amblyopia or both together may lead to failure to develop binocular vision which may prevent individual pursuing specific occupations. The associated cosmetic disorder may interfere with social and psychological development with potentially serious effects on individuals. Timely diagnosis and appropriate treatment of children with

strabismus and/or amblyopia is likely to reduce the prevalence of persistent amblyopia and ocular misalignment in adults. Rarely, strabismus and/or amblyopia may be the presenting symptom in children with a serious eye disease or systemic condition (e.g. retinoblastoma or hydrocephalus) when urgent referral to a specialist may be necessary. Amblyopia is the most common visual disability in children. It can present as early as 3 months of age. Its progression and

reversibility both are inversely proportional to child’s age. It is commonly unilateral. Nearly all amblyopic visual loss is preventable or reversible with timely detection and appropriate intervention. b) Case definition: Strabismus is a misalignment of the eyes in which the visual axes deviate from bifoveal fixation. Amblyopia is a unilateral or, less commonly, bilateral reduction of best-corrected visual acuity that cannot only and directly be attributed to the effect of a structural abnormality

of the eye or the visual pathways. For practical purposes, amblyopia is defined as at least 2 Snellen lines difference in visual acuity between the eyes, but amblyopia is truly a spectrum of visual loss, ranging from missing a few letters on the 6/6 (20/20) line to hand motion vision. It is a diagnosis of exclusion. Amblyopia is caused by abnormal visual experience early in life resulting from one of the following: • Strabismus • Anisometropia or high bilateral refractive errors (isometropia)

• Visual deprivation With timely intervention, the reduction in visual acuity caused by amblyopia can be completely or partially reversed. 23

II. INCIDENCE OF THE CONDITION IN OUR COUNTRY There are not many reports available from India about the prevalence of strabismus. One population based study from South India reported the prevalence as 0.43% among children. Another study in North India among school children reported it as 2.5%. The presence of strabismus is not a cosmetic issue only. Its presence says that the child is unable to use both eyes together and there could be some other ocular problem that is undetected.

Different studies from developed countries on amblyopia have an estimated prevalence in childhood of 1.2% to 4.4% depending on the defining criteria. III. DIFFERENTIAL DIAGNOSIS Strabismus • Pseudostrabismus • Nystagmus • Facial asymmetry Amblyopia • Nutritional/Toxic optic neuropathy • Malingering • Cortical blindness IV. PREVENTION AND COUNSELING Recent studies have shown that early detection and treatment of amblyopia are highly cost

effective when compared with other interventions in health care. The earlier amblyopia is detected and properly treated, the higher the likelihood of visual acuity recovery. Starting treatment at a young age also may increase the likelihood of compliance and the rate of vision recovery. The Amblyopia Treatment Study demonstrated that more than 75% of amblyopic children younger than 7 years can have significant improvement in the

amblyopic eye (to 20/30 or better) as the result of treatment. The purpose of periodic eye and vision screening is to detect pediatric eye disorders, especially amblyopia, at a sufficiently early age to allow effective treatment. All children should undergo eye and vision screening, because screening is most effective when performed periodically throughout childhood. In addition, children with risk factors for amblyopia should have a comprehensive

ophthalmic evaluation. Some risk factors include family history of amblyopia or strabismus, childhood cataract or glaucoma, premature birth of less than 30-week gestation or 1,500 grams, and delayed visual or neurologic maturation of unclear etiology. Reduction or prevention of risk factors such as premature birth and detrimental prenatal environmental 24

influences such as alcohol abuse and smoking can result in a decrease in the incidence of amblyopia. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: The initial strabismus and amblyopia evaluation (history and physical examination) includes

all components of the comprehensive pediatric ophthalmic evaluation, with special attention to the potential risk factors for amblyopia, such as a positive family history for strabismus, amblyopia, or media opacity. The examination of a patient who has childhood-onset strabismus includes all components of the comprehensive pediatric or adult ophthalmic evaluation in addition to the sensory, motor, refractive, and accommodative functions. History

Although a thorough history generally includes the following items, the exact composition varies with the patient's particular problems and needs: • The chief complaint and reason for the eye evaluation • Current eye problems • Ocular history, including prior eye problems, diseases, diagnoses, and treatments Systemic history: birth weight, prenatal (e.g., alcohol, tobacco, and drug use during pregnancy), and perinatal history (e.g. birth asphyxia, trauma) that may be pertinent,

past hospitalizations and operations, general health and development. • Pertinent review of systems, including history of head trauma and relevant systemic diseases • Current medications and allergies • Family history of eye conditions and relevant systemic diseases • Review of systems Examination The eye examination consists of an assessment of the physiological function and the anatomic status of the eye and visual system. Documentation of the child’s level of

cooperation with the examination can be useful in interpreting the results and in making comparisons among the examinations over time. In general, the examination may include the following elements: 25

• Assessment of visual acuity and fixation pattern • Ocular alignment and motility for near and distance Extraocular muscle function (ductions and versions including incomitance, such as A and V patterns) • Detection of nystagmus • Sensory testing • Red reflex or binocular red reflex (Brückner) test • Pupil examination • External examination • Anterior segment examination • Cycloplegic retinoscopy/refraction • Funduscopic examination • Binocularity/stereoacuity testing

Assessment of Visual Acuity and Fixation Pattern The method of evaluating visual acuity varies according to the child’s age and level of cooperation. Preverbal children should be checked for objection to cover and the presence of a fixation preference. When possible, monocular distance visual acuity should be determined utilizing a recognized optotype, such as the tumbling-E, Lea figures, or Snellen letters. Anomalous head posture is suggestive of peeking around the occluder. An occlusive patch

over the non-tested eye can distinguish between peeking and possible eccentric fixation. Monocular visual acuity testing for patients with nystagmus may require blurring of the contralateral eye with a high plus lens (+4.00 D to +5.00 D). Binocular and monocular testing also should be performed for patients with nystagmus. Testing visual acuity with isolated targets (figures or letters) is the quickest way to assess

the vision in preverbal children, but it does lead to falsely elevated visual acuities. Isolated acuities should be compared with visual acuities taken with linear targets or crowding bars. The difference between linear and isolated acuities should be noted at each visit, if possible. This difference is a way of quantifying the depth of amblyopia from visit to visit. Under ideal circumstances, visual acuity testing conditions should be standardized in each

examination room and at each visit, so that the same viewing distance and lighting conditions are used. Some children are more amenable to testing at shorter distances. Young children sometimes benefit from shorter testing distances, especially when a visual or attention deficit is suspected. The testing distance, type of optotype, and whether the optotype is presented a line at a time or isolated, should be documented. Patients should

be encouraged to learn optotype-equivalent tests at the earliest possible age. 26

Ocular Alignment and Motility Ocular alignment is assessed by using the corneal light reflection, the binocular red reflex (Brückner) test, or the cover test. Cover/uncover and alternate cover tests in primary gaze at distance and near accommodative targets are utilized when feasible; these tests require the patient's cooperation and interaction with the examiner in addition to sufficient vision to fixate on the target. Ocular versions and ductions should be tested even in the young

infant. In the inattentive or uncooperative patient, eye movements may be tested using the oculocephalic rotations maneuver (doll’s head) or assessed by spontaneous eye movements. Evaluating oblique muscle function in young children is important when examining a child with strabismus, but it may be difficult. When strabismus is suspected or revealed, a strabismus evaluation is warranted). Red Reflex / Binocular Red Reflex (Brückner) Test

The red reflex and/or binocular red reflex test should be performed to identify opacities of the ocular media. The red reflex of each eye is assessed by looking at each eye with a direct ophthalmoscope from a distance of about 18 inches. The examiner should answer three questions: 1. Is there a red reflex from each eye? 2. Are the red reflexes from each eye symmetrical? 3. Is the quality of the red reflex normal for the individual child (taking into account skin tone and race or ethnicity)?

The binocular red reflex (Brückner) test allows an assessment of the clarity of the visual axis and an indirect assessment of ocular alignment as well as large and/or asymmetric refractive errors. The binocular red reflex test is performed in a dimly lit room with the examiner at a distance of about 30 inches (0.75 meter) from the child. The examiner overlaps both pupils simultaneously, creating a binocular red reflex with the largest circular

light of a direct ophthalmoscope set to focus on the ocular surface, usually at zero. The examiner then assesses the quality of the redness seen within the child’s pupils. Normally, the red reflex from each eye should be of the same color and brightness. Abnormalities include asymmetric reflexes when one reflex is duller or a different color, a white reflex, a partially or totally obscured reflex, or crescents present in the reflex. Extraocular Muscle Function

Versions and ductions should be evaluated and any over- or underactions of extraocular muscles assessed and recorded. Inferior oblique muscle dysfunction, A or V patterns, or dissociated vertical or horizontal deviations may develop over time. The examiner should note any limitations in versions or ductions. The oculocephalic rotations maneuver (doll’s head) is particularly valuable in infants and young children and often reveals clinically

normal ductions that cannot otherwise be documented, even with patch testing. Detection of Nystagmus 27

Nystagmus in the patient with esotropia may be manifest or latent. Manifest nystagmus is constantly present and may be horizontal, vertical, or torsional. It is typically symmetrical, although it may vary in magnitude, speed, and wave form, depending on the direction of gaze and other specific viewing conditions. Latent nystagmus (sometimes called occlusion nystagmus) is conjugate, predominantly horizontal, jerk oscillations of the eyes that are

produced or exacerbated by monocular viewing. It is characterized by a slow drift away from the fixating eye, with rhythmic jerk redress movements to re-establish central fixation. The nystagmus is described as latent because it is typically perceptible or accentuated when one eye is occluded. Both manifest and latent nystagmus may coexist in the same patient. Sensory Testing The binocular sensory status should be assessed when feasible using Worth 4-dot testing

and stereoacuity tests. Reliable data may be difficult to obtain in younger children.In the older strabismic (especially esotropic) patient, more detailed sensory testing is occasionally useful, especially if there is a history of diplopia. An orthoptic evaluation may be useful to further define the sensory status of the child. Pupil Examination Even in small infants, the pupils should be assessed for direct and consensual response to

light and for the presence of a relative afferent defect. This can be done with a penlight, a direct ophthalmoscope, or a transilluminator. Pupil evaluation in infants and children may be difficult due to active hippus or shift in the patient’s fixation and accommodative status. In general, amblyopia is not associated with a detectable afferent pupillary defect. If an afferent pupillary defect is present, the examiner should thoroughly review etiologic causes

for asymmetric optic nerve function rather than attribute the finding to amblyopia External Examination External examination involves assessment of the eyelids, eyelashes, lacrimal apparatus, and orbit.The anatomy of the face (including the lids, interocular distance, and presence or absence of epicanthal folds), orbital rim, and presence of oculofacial anomalies should be noted. The position of the head and face (including head tilt or turn) should be noted.

Children with prominent epicanthal folds and normal ocular alignment may appear to have an esotropia (pseudo-esotropia). Distinctive features unusual for the family may suggest the presence of a congenital anomaly and merit an assessment of other physical abnormalities (e.g., ears, hands). Anterior Segment Examination To evaluate further opacities of the ocular media, the cornea, anterior chamber, iris, and lens should be evaluated with slit-lamp biomicroscopy if possible Slit-lamp biomicroscopic 28

evaluation is easily performed for older children or for younger children who are cooperative. In infants and young children, a hand-held slit-lamp biomicroscope may be helpful. Some children may need to be restrained, sedated, or undergo an eye examination under general anesthesia when apparent abnormalities warrant a detailed examination. Cycloplegic Retinoscopy/Refraction Determination of refractive errors is important in the diagnosis and treatment of amblyopia

or strabismus. Patients should receive an accurate cycloplegic refraction either by retinoscopy or by subjective refraction. Prior to cycloplegia, dynamic retinoscopy provides a rapid assessment of accommodative function and may be helpful in evaluating a child with high hyperopia or possible accommodative insufficiency. Cycloplegia is necessary for accurate refraction in children. Cyclopentolate is useful because it has a rapid onset and produces cycloplegia that approximates the effect of

topical ophthalmic atropine but with a shorter duration of action. Cyclopentolate 1% is more frequently used; cyclopentolate 2% is also available. The strength of cyclopentolate should be determined based on the child's weight, iris coloration, and dilation history. In eyes with heavily pigmented irides, adjunctive agents such as tropicamide and/or phenylephrine hydrochloride may be necessary to achieve adequate dilation. In rare cases,

topical ophthalmic atropine may be necessary to achieve maximal cycloplegia. The use of topical anesthetic prior to the cycloplegic makes the cycloplegic sting less and promotes its penetration into the eye. Funduscopic Examination Posterior segment structures should be examined, preferably with an indirect ophthalmoscope. The optic disc, macula, retina, vessels, and the choroid of the posterior regions should be examined Examination of the peripheral retinal and scleral indentation, if

indicated, may require sedation or general anesthesia (e.g., evaluation for retinoblastoma). Binocularity / Stereoacuity Testing Testing for binocular fusion (e.g., Worth 4-dot test) or the presence of stereopsis (e.g., Random-Dot E test or Stereo Fly test) may be useful in detecting ocular misalignment or amblyopia. Fusion and stereoacuity testing at distance (20 feet or 6 meters) as well as near (13 inches or 0.33 meter) may also be helpful. b) Investigations:

Strabismus and Amblyopia are mostly clinically diagnosed and treatment is planned based on routine examination and orthoptic check up. B scan ultrasonogram may be needed for associated media opacity and intra ocular tumors. Rarely CT scan and Electrophysiological tests are needed for assisting diagnosis. c) Treatment: 29

Amblyopia: Choice of Therapy The following therapies are used alone or in combination as required to achieve the therapeutic goal. • Optical correction: The amblyopic eye must have the most accurate optical correction possible. This should occur prior to any occlusion therapy because vision may improve with spectacles alone. Full cycloplegic refraction should be given to patients with accommodative esotropia and amblyopia. In other patients, a prescription less than the

full plus measurement that was refracted may be prescribed given that the decrease in plus is symmetric between the two eyes. Because accommodative amplitude is believed to be decreased in amblyopic eyes, one needs to be cautious about cutting back too much on the amount of plus. Refractive correction alone has been shown to improve amblyopia in up to 77% of patients. • Occlusion: Patching may be full-time or part-time. Standard teaching has been that

children need to be observed at intervals of 1 week per year of age, if undergoing full- time occlusion to avoid occlusion amblyopia in the sound eye . In addition to adhesive patches, opaque contact lenses, occluders mounted on spectacles, and adhesive tape on glasses have been used • Penalization: Penalization therapy was reserved for children who would not wear a patch or in whom compliance was an issue. The Amblyopia Treatment Studies,

however, have demonstrated that atropine penalization in patients with moderate amblyopia (defined by the study as visual acuity better than 20/100) is as effective as patching. The Amblyopia Treatment Studies were performed in children aged 3-7 year • Surgery to treat the cause of the amblyopia In general, occlusive adhesive patches should be used during the initial therapy in many cases of amblyopia; however, in mild to moderate amblyopia, penalization with atropine

drops has been shown to be an effective alternative Strabismus: Ocular alignment should be established as soon as possible, especially in young children, to maximize binocularity, prevent or facilitate treatment of amblyopia, and normalize appearance. In almost all cases, clinically important refractive errors should be corrected. Amblyopia treatment is usually started before surgery, because this may reduce the angle of strabismus or increase the likelihood of good postoperative binocularity.

The following treatment modalities are used alone or in combination as required to achieve the therapeutic goal: • Correction of refractive errors • Bifocals • Miotics 30

• Prism therapy • Amblyopia treatment • Extraocular muscle surgery: Except few conditions (like, accommodative esotropia), strabismus is corrected with surgery. Treatment plans are formulated in consultation with the patient and parents. The plans should be responsive to their expectations and preferences, including the family’s perception of the existing alignment, which may differ among ophthalmologist’s, and what they hope to achieve with treatment. It is important that the family and ophthalmologist

agree on the goals of treatment before surgery is performed. A particularly challenging situation can arise when the surgical intervention might worsen the appearance of the child. In patients for whom the potential for binocularity is poor, surgery to normalize appearance is still appropriate treatment. The amount of surgery and the choice of surgical technique may vary (e.g., methods of suture placement in the muscle and sclera, or measurement of recession or resection).

Although two-muscle surgery is most frequently performed, sometimes three- or four- horizontal-muscle surgery may be required for large-angle deviations. Results may be similar with different procedures; one method may be chosen over another on the basis of preoperative diagnosis, angle of deviation, technical ease, anatomical exposure, the need for an assistant, presence of scar tissue, and other factors such as physician preference and experience. Bilateral medial rectus muscle recessions are

commonly performed as the initial surgical procedure. Most surgeons prefer uniocular surgery (single-muscle recession or recession/resection) for patients with irreversible amblyopia or substantially reduced vision in one eye on an anatomic basis. Operating on both eyes may be preferable in specific clinical circumstances, such as V pattern esotropia with inferior oblique-muscle overaction or null-point nystagmus with compensatory face turn. Standard Operating procedure a. In Patient

• Patients preferring hospital stay for surgery because of distance and better care If decided by the anaesthesiologist • Patients needing some adjustment of sutures on the next day • Patients with post operative complications that need institutional care b. Out Patient Non surgical treatment Pre operative investigations Follow up c. Day Care If patients prefer and are able to reach the clinic easily if required d) Referral criteria: 31

• Cases needing specialized investigations (e.g USG B-Scan, Electrophysiological tests) • Cases not manageable by the facilities available . • Seeking second opinion • Complications needing specialized intervention. • Complex cases like torsional deviation, DVD, Duanes retraction syndrome etc.,needs referral *Situation 2: At Super Specialty Facility in Metro location where higher- end technology is available a) Clinical Diagnosis: Same as situation 1 plus better orthoptic examination.

b) Investigations: Same as situation 1. In addition, USG B Scan and electrophysiological tests are done if needed. Paediatric and neurological consultation back up and facility for relevant systemic investigations is required in indicated patients. c) Treatment: Same as situation1. In addition, the ophthalmologist should be able to take up complex surgeries. Interdiscipinary referral between the anterior and posterior segment specialists is required in certain cases. Low vision aids may be required in

some individuals Standard Operating procedure a. In Patient • Patients preferring hospital stay for surgery because of distance and better care If decided by the Anaesthesiologist • Patients needing some adjustment of sutures on the next day • Patients with post operative complications that need institutional care b. Out Patient Non surgical treatment; Pre operative investigations; Follow up c. Day Care If patients prefer and are able to reach the clinic easily if required d) Referral criteria:

• Patient History is taken and a Clinical Examination performed • Documenting the medical record • Plan treatment guidelines and counsel patients • Perform surgery. Explain and assure patients if complications occur. • Follow up • Referral in needed. • Monitoring the functional improvement and if needed guide parents in rehabilitation b. Nurse / Technician • Receive the patients and assist in clinical examination • Refraction • Orthoptic check up • Counseling whenever patients/ parents

• Prepare the patients for surgery • To monitor the patients who are admitted regarding pre and post operative care • To maintain separate inpatient and outpatient record • To maintain lab reports • Explain discharge advice to patients • Proactively ensure follow up through counseling. VII. FURTHER READING / REFERENCES 1. Madhu Gupta, Bhupinder P Gupta, Anil Chauhan, and Ashok Bhardwaj Ocular morbidity prevalence among school children in Shimla, Himachal, North India Indian J

Ophthalmol. 2009 Mar–Apr; 57(2): 133–138 2. Nirmalan PK, Vijayalakshmi P, Sheeladevi S, Kothari MB, Sundaresan K, Rahmathullah L.,The Kariapatti pediatric eye evaluation project: baseline ophthalmic data of children aged 15 years or younger in Southern India. Am J Ophthalmol. 2003 Oct;136 (4):703-9. RESOURCES REQUIRED 33

Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1] Secondary 1) Ophthalmologist 1)Refraction 1)Cycloplegics 1)Torch light level - 1 2)Orthoptic 2)Local 2)Trial set 2) OP Nurse check up Anaesthetics 3)Prism set – 1 3)Antibiotics 4)Retinoscope 3) Ophthalmic eye drops 5)Slit lamp - Assistant / biomicroscope 4)Optometrist 6)Direct trained in orthoptics Ophthalmoscope 1 7)+90 D lens 8)Indirect Ophthalmoscope with +20 D lens 2] Tertiary 1) Experienced 1)Refraction 1)Local 1)Torch light

level Ophthalmologist - 2)Strabismus anaesthetics 2)Trial set 1 assessment 2)Antibiotics 3)Prism set 2) OP Nurse 3)Biometry eye drops 4)RAF Rule – 1 4)USG B- Scan 3)Mydriatics 5)Synoptophore 3) Ophthalmic 5)Examination 4)General 6)Hess’s screen Assistant / under short GA 5)Anaesthetic 7)Retinoscope 4)Optometrist -1 medications 8)Slit lamp - 5)Orthoptist -1 biomicroscope 6)Anaesthesiologist 9)Direct -1 Ophthalmoscope 7) Assisting Nurse -1 10)+90 D lens 8) Counsellor - 1 11)Indirect Ophthalmoscope

12)Applanation tonometer (Perkin’s) 13)Gonioscope with +20 D lens 14)A-Scan Keratometer 15)USG B- Scan 16)Boyle’s apparatus 17)Pulse oxymeter 34

NAME OF CONDITION : CONJUNCTIVITIS I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Conjunctivitis is a highly contagious disease which occurs world wide both sporadically and epidemically. Most varieties of conjunctivitis are self limited, but some may progress and cause severe ocular and extra ocular complication. Even in self limited conditions, it causes a significant period of ocular morbidity and loss of work place efficiency. It affects all ages and all social strata. Approximately 2% of all

primary case visit and 1% of all emergency room visit are related to conjunctivitis. Appropriate prevention strategies are required to prevent this condition to spread and affect large number of people. b) Case definition: Conjunctivitis is a general term that refers to a diverse group of disorder, characterized by inflammation of the conjunctiva, as typified by congestion, pain, discharge, lid edema and gritty sensation of the eye. INCIDENCE OF THE CONDITION IN OUR COUNTRY

Conjunctivitis is considered extremely common in developing countries. Although there are no reliable figures that document the incidence or prevalence of conjunctivitis, this condition has been cited as one of the most frequent causes of patient self-referral. Adenoviral conjunctivitis is the most common cause of epidemic conjunctivitis accounting for 70% . It is highly seasonal, often following monsoons. It often assumes epidemic proportions in certain years. The morbidity is directly linked

to the virulence of the infecting virus. Rarely, chlamydia is the causative organism in 2% of cases of acute conjunctivitis and is the most common cause of chronic follicular conjunctivitis. Ophthalmia neonatorum, which denotes purulent conjunctivitis caused by gonococcus in infants, is a relatively rare phenomenon nowadays. II. DIFFERENTIAL DIAGNOSIS Conjunctivitis is a general term that refers to a diverse group of disorder, classified as

infectious and non infectious affecting the conjunctiva primarily. The cause of 35

infectious conjunctivitis include viral and bacterial while noninfectious conjunctivitis are allergic,mechanical/toxic/irritative,immune mediated, and neoplastic. Ophthalmia neonatorum [neonatal conjunctivitis]is often defined separately as it is caused by different group of organisms. It is important to understand that all red eyes are not necessarily due to conjunctivits and hence the role of an ophthalmologist is to differentiate from other important serious conditions like 1. Scleritis

2. Angle closure glaucoma 3. Keratitis 4. Acute anterior iritis 5. Masquerade syndromes like ocular squamous surface neoplasia, ocular cicatricial pemphigoid. III. PREVENTION AND COUNSELING The ophthalmologist plays a critical role in breaking the chain of transmission of epidemic conjunctivitis, primarily by educating the patient and family about proper hygiene. Infected individuals should be counseled to wash hands frequently along

with washing their eyes and use separate towels, and to avoid close contact with other family members during the period of contagion. Health care facilities have occasionally been associated with epidemic outbreaks of adenoviral keratoconjunctivitis. Paradoxically, eye hospitals may be a source of the disease transmission and hence steps have to be taken to prevent such instances from happening. Hand-washing procedures with antimicrobial soap and water and

disinfecting ophthalmic equipments in between every procedure may reduce the risk of transmission of viral infection. Exposed surfaces on equipment like the applanation tonometers can be decontaminated by wiping with sodium hypochlorite (a 1:10 dilution of household bleach] or with 70% isopropyl alcohol. Prevention of allergic conjunctivitis is possible by changing the environment of the patient or by avoiding exposure to allergen causing the allergy e.g., pollen, animal fur. Ophthalmia

neonatorum can be prevented by prenatal screening and treatment of the expectant mother suffering from sexually transmitted diseases and prophylactic treatment of the infant at birth by using 0.5% erythromycin or 1% tetracycline ointment . IV. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA 36

*Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: History taking, comprehensive evaluation of the eye and understanding of the general epidemic prevalence of this condition in the society is crucial to establish a diagnosis . Patients usually come with typical history of matting of eye lashes on waking, copious purulent discharge, redness, gritty foreign body sensation, itching

and rarely may even present with distortion of vision, photophobia and coloured haloes. Examination: The ocular examination includes recording visual acuity, an external eye examination and slit-lamp biomicroscopy. Visual acuity measurement: Due to acute infection of the involved eye, it is difficult to record visual acuity accurately. Although visual acuity is normal in patients with conjunctivitis, discharge sliding across the eye may cause visual disturbance vision

colored haloes resulting in under estimation of true visual potential. External examination: The following points should be looked for: 1. Abnormalities of skin like signs of eczema, roseacea, seborrhea. 2. Look for regional enlargement of lymph nodes (pre auricular). 3. Abnormalities of eye lid and adnexa like swelling, ulceration and discolouration and laxity. 4. Examination of conjunctiva to look for chemosis, sub conjunctival hemorrhage, discharge cicatricial changes and symblepharon.

Slit-lamp Biomicroscopy: Should include evaluation of the following: 1. Eye lid margins: To look for inflammation, ulceration, nodules, vesicles and keratinization. 2. Eye lashes: loss of eye lashes, crusting, scurf, nits and lice. 3. Lacrimal puncta and canaliculi for pouting and discharge 4. Tarsal and forniceal conjunctiva for presence and size of papillae and follicles, membranes, pseudo membranes, ulceration, masses, hemorrhages and cicatricial changes like foreshortening and symblepharon. 37

5. Bulbar conjunctiva and limbus for follicles, edema, nodules, chemosis, laxity, papillae, ulceration, scarring, phlyctenules, hemorrhages, foreign material, keratinization. 6. Cornea for coarse punctate keratitis, epithelial defects, filaments, ulceration, infiltrations including sub epithelial infiltrates and phlyctenules. Specific helpful clues in differentiating the causes of conjunctivitis are listed below. 1. Bacterial conjunctivitis

o Preauricular adenopathy sometimes occurs; chemosis (thickened, boggy conjunctiva) is common. o Discharge is copious; discharge quality is thick and purulent. Conjunctival injection is moderate or marked. 2. Viral conjunctivitis o Preauricular adenopathy is common in epidemic keratoconjunctivitis and herpes; chemosis is variable. o Discharge amount is moderate, stringy, or sparse; discharge quality is thin and seropurulent. Conjunctival injection is moderate or marked.

3. Chlamydial conjunctivitis tends to be chronic with exacerbation and remission. o Preauricular adenopathy is occasional; chemosis is rare. Discharge amount is minimal; discharge quality is seropurulent. Conjunctival injection is moderate 4. Allergic conjunctivitis is characterized by acute or subacute onset, no pain, and no exposure history. o Pruritus is extremely common. Clear, watery discharge is typical with or without a moderate amount of mucous production.

o An aggressive form of allergic conjunctivitis is vernal conjunctivitis in children and atopic conjunctivitis in adults. Vernal disease often is associated with shield corneal ulcers. Perilimbal accumulation of eosinophils (Horner-Trantas dots) typifies vernal disease. Vernal keratoconjunctivitis (VKC), usually affecting young boys, tends to be bilateral and occurs in warm weather. VKC is presumed to be a hypersensitivity to exogenous antigens and may be associated with or accompanied by keratoconus.

5. Giant papillary conjunctivitis resembles vernal disease. o This condition occurs mainly in contact lens wearers who develop a syndrome of excessive pruritus, mucous production, and increasing intolerance to contact use. o Bilateral disease typically is infectious or allergic. o Unilateral disease suggests toxic, chemical, mechanical, or lacrimal origin. o Intraocular pressure, pupil size, and light response are all normal. o Ciliary flush, corneal staining, and anterior chamber reaction is absent unless

a significant amount of keratitis is associated (as seen in EKC). 38

6. Nummular keratitis gives a clue for diagnosis as it is often caused by adenovirus and HZV b) Investigations: Conjunctivitis usually is diagnosed by history and physical examination. A regular microbiological useful in patients with recurrent conjunctivitis and in some cases of epidemic conjunctivitis the material is obtained by taking conjunctival swabs from lower forniceal and upper tarsal conjunctiva after instilling a topical anesthetic agent

(4% lignocaine). Two smears are initially prepared one with gram staining and the other with giemsa. Gram stain is considered the criterion standard for determining the bacterial cause of conjunctivitis. Eosinophils seen on Giemsa stain are indicative of allergic conjunctivitis but can be seen in parasitic causes also. Giemsa staining is also performed to look for the inclusion bodies of Chlamydia trachomatis. c) Treatment:

Treatment of conjunctivitis is ideally directed at the root cause. Indiscriminate use of topical antibiotics or corticosteroids should be avoided, because antibiotics can induce toxicity and corticosteroids can prolong adenoviral infections and worsen herpes simplex virus infections. A careful counselling of the dosages of the individual medicine should be adequately explained to the patient and an accompanying person so that it will be

applied in the right manner. Regular irrigation of the eye with clean water remains the corner stone of the treatment for all forms of conjunctivitis. The following table shows various modalities of management in different types of conjunctivitis. Type Management 1]Bacterial conjunctivitis • Chloramphenicol 0.5%eye drops (or) • Ciprofloxacin 0.3%eye drops Intensive instillation every 15 to 30 min until symptoms and signs are reduced and gradually tapered.

2]Viral conjunctivitis • Advice the patient to clean the eye by washing with normal saline frequently. • Cold compression. • Topical anti-histaminics • Frequent application of preservative free artificial tears. • Topical antibiotics in cases of suspected secondary bacterial infection. • Severe inflammation, presence of sub-epithelial infiltrate, 39

presence of membranes and pseudo membranes may necessitate a short course of topical steroids. • Herpetic conjunctivitis to be treated with topical acyclovir eye ointment. 3]Allergic conjunctivitis • Cold compression and ocular lubricants. • Topical and systemic anti-histaminics. • Topical mast-stabiliser • Topical NSAIDs • Topical steroids in short pulses 4] Chlamydial conjunctivitis In Neonates • Topical tetracycline1% or erythromycin ointment twice daily for 2 months

• Oral tetracycline1.5-2gm daily in divided doses for 2 weeks or oral azithromycin single dose or erythromycin50mg/kg in four divided doses for 2weeks In Adults • Oral azithromycin 1g single dose or doxycycline100mgBD for 7 days or tetracycline250mgqid for 7days or erythromycin 500mg qid for 7 days. 5] Gonococcal conjunctivitis In Neonates • I M Ceftriaxone 25-50mg/kg single dose In Adults • I M Ceftriaxone 1g single dose • I M Spectinomycin 2g single dose. • Chloramphenicol 1%eye ointment

• Use normal saline or cooled boiled water.Initially continuous irrigation will be needed. 6]Chemical conjunctivitis • Stop instilling the substances that has caused the reaction. • Lubricant ointment can be soothening. • Mild topical antibiotics like chloramphenicol will prevent secondary bacterial infection. standard operating procedure a. In Patient : • Admit patients if they develop complications secondary to conjunctivitis like orbital

cellulitis, keratitis ,scleritis, anterior uveitis ,especially if the patient cannot come for frequent follow up and who are non compliant. • Admit patients with hyperacute bacterial conjunctivitis if the entire cornea cannot be visualized, as there may be an early corneal ulceration. 40

b. Out Patient: All cases of simple conjunctivitis are almost exclusively treated on out patient basis. c. Day Care: Not applicable. d) Referral criteria: • Infants diagnosed to have ophthalmia neonatorum due to gonococci, chlamydia and HSV are referred as they need systemic evaluation and appropriate systemic treatment and more importantly need for counseling the parents. • Severe conjunctivitis, not responding to treatment to be referred for further laboratory evaluation in tertiary centre.

• When conjunctivitis appears to be a manifestation of auto immune systemic disease like Reiters ulcerative colitis etc., then patients should be referred for evaluation by an appropriate medical specialist. • Prolonged persistent conjunctivitis with development of complication like cicatrization, lid abnormalities, and dry eye, symblepharon and punctal anomalies. • Severe chemical conjunctivitis with limbal ischaemia and suspected intra ocular

penetration of toxic substances to be referred for further management in higher centre. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical Diagnosis: Apart from the regular history taking, care should be exercised to fully understand the treatment history of the patient, including all the medications along with the dosage schedules which were prescribed at the secondary centre. In fact, withdrawal

of strong topical antibiotics may be warranted. A fresh comprehensive clinical examination, as detailed in the previous section should be performed without being biased by the referral report. b) Investigation As the patients are referred from a secondary centre for a non responsiveness to treatment or when diagnosis is uncertain or especially in neonatal conjunctivitis which needs exact etiological diagnosis for initiation of treatment , additional micro

biological and immunological diagnostic tests may be required. • Culture: Culture and sensitivity of conjunctival scrapings are indicated in all cases of suspected neonatal conjunctivitis, persons who are immunosuppressed, when N gonorrhoeae is under consideration as the etiology, recurrent or severe purulent conjunctivitis and in cases where the conjunctivitis has not responded to medication. When performed, collect 41

exudate from the lower conjunctival fornix with a calcium alginate swab moistened with saline. Sheep blood and mannitol agar plates routinely are used. Expect viral and chlamydial causes in culture-negative conjunctivitis. • Viral diagnostic tests: Viral cultures are not routinely used to establish a diagnosis. A rapid, in-office immunodiagnostic test using antigen detection is available for adenovirus conjunctivitis. Immunodiagnostic tests may be available for other viruses.

Polymerase chain reaction (PCR) may be used to detect viral deoxyribonucleic acid. RPS adenodetector is a new rapid diagnostic test for identifying adeno viral conjunctivitis. • Chlamydial diagnostic tests: Suspected cases of adult and neonatal chlamydial conjunctivitis can be confirmed by laboratory testing. Immunologically based diagnostic tests are available, including a direct immunofluorescent antibody test and enzyme-linked immunosorbent assay.

• Biopsy: Conjunctival biopsy may be helpful in cases of conjunctivitis unresponsive to therapy. Because such eyes may harbor a neoplasm, directed biopsy may be both vision-saving and lifesaving. Conjunctival biopsy and immunofluorescent staining diagnostic tests may be helpful to establish the diagnosis of diseases such as ocular squamous surface neoplasia (OSSN), ocular mucous membrane pemphigoid (OMMP) and paraneoplastic syndromes.A biopsy of bulbar conjunctiva should be performed

and a sample should be taken from an uninvolved area adjacent to the limbus in an eye with active inflammation when OMMP is suspected. In cases of suspected sebaceous gland carcinoma, a full-thickness lid biopsy is indicated. When considering a biopsy, a preoperative consultation with the pathologist is advised to ensure proper handling and staining of specimens. c) Treatment: The treatment strategies should be revisited to check for adequacy,

appropriateness and affordability. If the culture and other tests show a different organism, then the treatment regimen should be modified. Surgical procedure includes: 1. Symblepharon: treated by dividing the symblepharon and to prevent the reformation of scar tissue during healing period. The formation of scar tissue in raw area is prevented by single pedicle conjunctival graft, mucous membrane graft, split skin graft or by amniotic membrane transplantation.

2. Correction of lid abnormality like cicatricial ectropion, cicatricial entropion, trichiasis etc., by appropriate surgical procedure. 3. Chemical conjunctivitis with severe ocular surface abnormality treated by ocular surface reconstruction by limbal stem cell graft, conjunctival autograts, 42

fornix reconstruction, optical penetrating keratoplasty and keratoprosthesis surgeries. STANDARD OPERATING PROCEDURE a. In Patient : • Infants diagnosed to have ophthalmia neonatorum due to gonococci chlamydia and HSV are admitted as they need systemic evaluation and appropriate systemic treatment. • Prolonged persistent conjunctivitis with development of complication like cicatrization, lid abnormalities, dry eye, symblepharon and punctal anomalies.

• Severe chemical conjunctivitis with limbal ischaemia and suspected intra ocular penetration of toxic substances. b. Out Patient: If the patient requires only modification of the topical anti- infectives, then he/she can be treated as an outpatient. c. Day Care: not applicable. d) Referral criteria: not applicable. V. WHO DOES WHAT? AND TIMELINES a. Doctor : • Patient history is taken and a clinical examination performed • Conjunctival infective material is obtained by scrapping and smear are prepared

and also materials are inoculated directly onto culture media • Documenting the medical record • Plan treatment guidelines and perform surgery if necessary. Monitoring, publication and reporting to department of health if there is an epidemic conjunctivitis and if there is an emergence of drug resistance pathogen. • He/she plays a critical role in breaking the chain of transmission of epidemic adenoviral conjunctivitis, primarily by educating the patient and family about proper hygiene.

• He/she should also ensure that needy patients receive necessary care directly or through referral to appropriate persons and facilities that will provide such care, and he or she supports activities that promote health and prevent disease. b. Nurse/Technician: • Prepare Slide, Media for smear and culture. • To monitor the patients who are admitted. • To maintain separate inpatient and outpatient record. • To maintain lab reports. 43

VI. FURTHER READING / REFERENCES 1. Bersudsky V, Rehany U, Tendler Y, Leffler E, Selah S, Rumelt S. Diagnosis of chlamydial infection by direct enzyme-linked immunoassay and polymerase chain reaction in patients with acute follicular conjunctivitis [Internet]. Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Für Klinische Und Experimentelle Ophthalmologie. 1999 ;237(8):617-620.Available from: http://www.ncbi.nlm.nih.gov/pubmed/10459609

2. Sambursky R, Tauber S, Schirra F, Kozich K, Davidson R, Cohen EJ. The RPS adeno detector for diagnosing adenoviral conjunctivitis [Internet]. Ophthalmology. 2006 ;113(10):1758-1764.Available from: http://www.ncbi.nlm.nih.gov/pubmed/17011956 Resources required Situation HUMAN RESOURCES INVESTIGATION DRUGS AND EQUIPMENT CONSUMABLES 1) Secondary 1)Ophthalmologist - 1 Smear test 1) Antibiotics eye 1 level 2)OP Nurse - 1 1)Gram stain drops )Slit lamp -

3)Refraction nurse - microscoscopy 2) Anti viral eye biomicroscopy -1 1(shared ) 2)Giemsa stain ointment 2)Light microscopy -1 3)Systemic 3)15# blade/ antibiotics and anti conjunctival swabs virals – 1 4) NSAID’S eye drops 4) Glass slide - 1 and steroids 5) Basic stains - 1 5) Anti allergic eye drops. 6) Cycloplegics 2) Tertiary level 1)Cornea specialist - 1 1)Smear test 1) Antibiotics eye 1) Slit lamp - 2)Refraction nurse - 2)Culture drops biomicroscopy -1

1 (shared ) medium 2) Anti viral eye 2) Light microscopy -1 3)OP Nurse - 1 3) Viral diagnostic ointment 3)15NO blade 4)lab technician – 1 tests like IF tests, 3)Systemic /calcium alginate 5)Scrub nurse 1 PCR, RPS adeno antibiotics and anti swabs 1 6) OT nurse 1 detector. virals 4) Glass slide - 1 7) Ward nurse - 1 4) Chlamydial 4) NSAID’S eye drops 5) Basic stains - 1 8) Counsellor - 1 diagnostic tests and steroids 6)Cultures like IF tests,ELISA. 5) Anti allergic eye 7)OT microsurgical

5) Conjunctival drops. instruments - 1 biopsy. 6) Cycloplegics 44

NAME OF CONDITION: MICROBIAL KERATITIS I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Microbial keratitis is an important cause of avoidable monocular blindness in India. Young adults in their prime working age group are most commonly affected and hence the loss of man years of productivity is extremely high. The therapeutic results are less than satisfactory even in the most optimistic situations. Even the so called successfully

treated cases end up with a corneal scar which might impair vision. The cost of treatment is compounded by the long treatment schedules and frequent follow ups to the hospital A significant percentage of patients fail medical treatment, and will require corneal transplantation. The availability of donor corneas in India is extremely low. Currently only 5% of the requirement is being met. Under these circumstances, it becomes very clear that adequate and appropriate therapy at all levels and more

importantly preventive strategies at the primary level will go a long way in preventing this unnecessary catastrophe. b) Case definition: A theoretical definition of a corneal ulcer is a loss of the overlying epithelium with underlying infiltration. However, for all practical purposes, microbial keratitis includes any condition which causes suppurative infection of the cornea. Further progress of the disease can cause necrosis of the deeper stromal tissue, resulting in perforation and loss

of intraocular contents. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY It is an extremely common condition causing significant ocular morbidity in our country. In fact, an editorial in the British Journal of Ophthalmology called it as an silent epidemic Gonzales et al found that the annual incidence of corneal ulceration in Madurai district in South India was 113 per 1,00,000 people. By applying the 1993 corneal ulcer incidence rate in Madurai district to whole of India, about 8,40,000 people are likely to

develop a corneal ulcer in a year Even this figure is quoted as an under estimation when compared to other SAARC countries. This figure is thirty times more than the number of corneal ulcers seen in the United States. III. DIFFERENTIAL DIAGNOSIS The term microbial keratitis is often reserved for conditions caused by microorganisms which results in suppuration. The common causative organisms can be bacteria, fungi or, parasites. Other conditions which can mimic a suppurative keratitis includes

b. Marginal keratitis caused by hypersensitivity reactions c. Ulcerative keratitis secondary to inherent connective tissue disorders d. Toxic keratitis e. Exposure and neurotrophic keratitis f. Corneal ulceration secondary to Vitamin A deficiency in children. IV. PREVENTION AND COUNSELING Avoiding exposure to predisposing factors may minimize the risk of microbial keratitis. The majority of corneal ulcers follow trivial corneal abrasions. The use of traditional eye

medicines (TEMs) is an important risk factor for corneal blindness, since they are often contaminated and provide a vehicle for the growth of pathogenic organisms. The common TEM’s used in our country includes breast milk, castor oil and leaf extracts. Training traditional healers in asepsis, banning harmful medicines and directing patients to appropriate health care facilities would be the first rewarding approach in preventing

corneal blindness due to red eye and corneal injuries. Ocular surface disease such as Trachoma, dry eye, lagophthalmos and Vitamin A deficiency should be treated. Routine use of prophylactic topical antibiotics in this setting is controversial because their efficacy has not been established and may promote growth of resistant organisms. Even though keratomalacia is rare, still we see children going blind due to Vitamin A deficiency. Proper

diet counseling and Vitamin A supplementation will totally eradicate keratomalacia from our country. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited 46

a) Clinical Diagnosis: An adequate history taking, coupled with a comprehensive evaluation goes a long way in establishing a clinical diagnosis which can then be confirmed by microbiological examination. Patients come with varying degrees of pain, photophobia, watering and redness of eyes and may also complain of defective vision, especially if the visual axis is involved. History Eliciting a proper history with regards to nature of trauma and use of TEM is crucial step in

the management of microbial keratitis. Trauma with vegetable matter such as paddy husks or onions are more likely to cause a fungal keratitis. Contact with contaminated or brackish water is likely to produce Acanthamoeba keratitis. In cases of contact lens wearers, it is imperative to take history of wearing schedule and lens care. Examination The ocular examination includes recording visual acuity, an external eye examination and slit-lamp biomicroscopy of affected and normal eye. Visual Acuity measurement

Due to acute infection of the involved eye, it is difficult to record visual acuity accurately. However, an approximate visual acuity with or without optical correction will give a baseline data to aid in the appropriate management strategy and also to monitor the healing process. External Examination An external examination should be performed with particular attention to the following: • General appearance of the patient • Facial examination • Eyelids and lid closure • Conjunctiva • Nasolacrimal apparatus

• Corneal sensation Slit-lamp Biomicroscopy Should include evaluation of the following: Eyelid margins: Inflammation, ulceration, eyelash, and abnormalities including trichiasis, irregularities, and lacrimal punctal anomalies. Conjunctiva: Discharge, inflammation, morphologic alterations (e.g. follicles, papillae, cicatrization, keratinization, membrane, pseudomembrane, ischemia, and foreign bodies). Sclera: Inflammation, (e.g. infectious, versus autoimmune), ulceration, scarring /

Cornea: Epithelium, including defects and punctate keratopathy, edema Stroma, including ulceration, thinning, perforation, and infiltrate (location [central, peripheral, perineural, surgical, or traumatic wound], density, size, shape [ring], number [satellite], depth, character of infiltrate margin [suppuration, necrosis, feathery, soft, crystalline], color), edema Signs of corneal dystrophies (e.g., epithelial basement membrane dystrophy)

Previous corneal inflammation (thinning, scarring, or neovascularization) Signs of previous corneal or refractive surgery Fluorescein (or, occasionally, rose bengal staining) of the cornea is usually performed and may provide additional information about other factors, such as the presence of dendrites, pseudodendrites, loose or exposed sutures, foreign body, and any epithelial defect. Clinical features suggestive of bacterial keratitis include dense suppurative stromal

infiltrate with distinct edges and edema. The symptoms are typically more prominent than the signs. Fungal keratitis presents with dry raised surface and feathery indistinct margins. Accompanying satellite lesions may be present in few cases. Acanthamoeba keratitis usually presents with a ring shaped stromal infiltrate, as a late clinical feature and commonly it is misdiagnosed as viral keratitis. It has to be emphasized however that all

these features are only suggestive of the organism and microbiological confirmation should be sought for proper identification. b) Investigations: Microbiological investigations: While characteristic clinical features have been described for ulcers caused by different microorganisms, it is difficult to confirm these, especially after the disease has become well established. Patients present late in our country and by this time, the clinical demarcation

between the ulcers caused by bacteria and fungi are usually lost. Since bacteria and fungi cause an almost equal proportion of keratitis in our country, it is highly essential to perform at least a smear test before initiating the treatment. Corneal infective material is obtained by scraping after instilling a topical anesthetic agent (4% lignocaine) and using a flame sterilized platinum spatula, blade or other similar sterile instrument. The material is

obtained from the advancing borders; ulcer base and edges. Two smears are initially prepared – one with Gram’s stain (for identifying bacteria, fungi, and Acanthamoeba) and the other with 10% potassium hydroxide (for fungus). 48

Biochemical investigations: A baseline evaluation for diabetes mellitus should be performed. Some of these patients have undiagnosed diabetes, which might hinder with the healing of the ulcer. c) Treatment: The treatment for suppurative keratitis is often prolonged. The importance of a regular follow up should be adequately emphasized to the patient before the initiation of the appropriate anti microbial therapy. A careful counseling of the dosages of the individual

medicine should be adequately explained to the patient and an accompanying person so that it will be applied in the right manner. The treatment strategy should be guided by the microbiological investigations and the clinical appearance of the ulcer. Bacterial Keratitis: Topical antibiotics are capable of achieving high tissue levels and are the preferred route in most cases. Ointments may be useful in children and at bedtime. Routine subconjunctival

antibiotics are not necessary unless the compliance of the patient is doubtful or poor. For severe keratitis (ulcer more than 5mm and deep), a loading dose at every 5 to 15 minutes during the first hour, followed by applications every 15 minutes to 1 hour during waking hours is recommended. It is ideal to treat the patient as inpatient. For non-severe keratitis, a regimen with less frequent dosing is appropriate. Cycloplegic agents may be

used to prevent synechia formation and to decrease pain. Small ulcers less than 2 mm and away from the visual axis do not need cycloplegics. Gram positive cocci are the most important cause of bacterial keratitis in our country. Topical eye drops of Chloramphenicol (0.5%) and Cefazolin (5 to 10%) are ideal for gram positive cocci. S. pneumoniae, which is the most common bacterial isolate in our country, has variable susceptibility to fluoroquinolones and hence fluoroquinolones may not be the

ideal antibiotic for monotherapy for gram positive organisms in our country . Gram negative bacilli respond very well to fluoroquinolones and aminoglycosides. Single drug therapy using a fluoroquinolone has shown to be as effective as combination therapy utilizing topical antibiotics that are commercially available. But recent reports do not recommend this in view of more drug resistance. The following table gives the dosage schedule of commonly used antibacterial agents. 49

Table 1: Antibiotic Therapy of Bacterial Keratitis Organism Antibiotic Topical Subconjunctival Concentration Dose No organism identified or Cefazolin with 50 mg/ml 100 mg in 0.5 ml multiple types of Gentamycin/ 3-14 mg/ml 20 mg in 0.5 ml organisms Tobramycin or Fluoroquinolones 3 mg/ml Gram-positive cocci Chloramphenicol 5 to 10 mg/ml Cefazolin 50 mg/ml 100 mg in 0.5 ml Vancomycin 15-50 mg/ml 25 mg in 0.5 ml Gram-negative bacilli Gentamicin/ 3-14 mg/ml 20 mg in 0.5 ml Tobramycin

Ceftazidime 50 mg/ml 100 mg in 0.5 ml Fluoroquinolones 3 mg/ml Non-tuberculous Gentamicin 14 mg/ml 20 mg in 0.5 ml Mycobacteria Amikacin 10 mg/ml Nocardia Amikacin 10 mg/ml 20 mg in 0.5 ml Trimethoprim/ 16 mg/ml Sulphamethoxazole 80 mg/ml Note: Systemic antibiotics are recommended only when the ulcer involves sclera or perforates. Fortified antibiotic therapy is a good armamentarium to treat bacterial keratitis. The preparation and the indication for such a therapy is described in the following paragraph

Preparation of fortified antibiotics: Gentamicin and Tobramycin Add 2 ml of injectable Gentamicin or Tobramycin to 5 ml commercial topical preparation in a sterile set up using disposable syringe. 5 ml commercial has - 15 mg Added drug - 80 mg Total in 7 ml - 95 mg 1 cc contains 13.5 mg or 1.35% Cefazolin: Add 5 ml or 10 ml of distilled water or sterile saline to 500 mg vial of cefazolin to obtain 10% or 5% solution. Use a dropper, which is available in the pharmacy or other source. Vancomycin:

Add 10 ml distilled water or saline to 500mg vial of Vancomycin and obtain a 5% solution. 50

Amikacin: 1% would be sufficient. Add 10cc distilled water to 100mg of Amikacin. Use a sterile empty Xylocaine vial and place the cap for ready use. All these solutions could be safely used for a week. If it is applied frequently as recommended it will not last more than a week. The treatment of fungal keratitis remains as a challenge. All the available antifungal agents are fungistatic and not fungicidal. The penetration of the drugs is poor particularly when

the epithelial defect is small. It leads to prolonged treatment, often leading to poor compliance with antifungal therapy. Natamycin (5%) and Amphotericin -B(0.15%-0.5%) are the most efficacious among the available topical antifungal agents against filamentous fungi. Voriconazole 1% is a recent addition in the treatment of filamentous fungi. A recently published randomized clinical trial demonstrated that the safety and efficacy of Natamycin

and Voriconazole are comparable when used for fungal keratitis .Use of systemic anti- fungals like imidazoles and triazoles are reserved for deep keratitis associated with scleritis and endophthalmitis. The following table gives the dosage schedule of commonly used antifungal agents. Table 2: Therapy of fungal Keratitis Organism Antibiotic Topical Systemic Fusarium a. Natamycin 5% suspension not available b. Amphotericin B 0.1 to 0.5 % I.V.use rarely Aspergillus a. Amphotericin B 0.15% to 0.5% ----

b. Imidazole 1 –2 % 200 mg to 400 mg (Prepare the suspension) daily - orally Candida (rare) a. Fluconazole 0.3% b. Nystatin ointment 1,00,000 m Other Drugs ¤ Itraconazole – oral – 300 mg daily (only 55 to 60 % efficacy) Several clinical features suggest the response to antimicrobial therapy. • Decreased pain. • Consolidation and sharper demarcation of the periphery of the stromal infiltrate. • Decreased density of the stromal infiltrate. • Reduction of stromal edema and endothelial inflammatory plaque.

• Reduction in congestion of bulbar conjunctiva • Visual improvement Topical therapy is tapered according to the clinical response, taking into account the baseline clinical picture and the virulence of the pathogen. Standard Operating Procedure a. In Patient • Severe keratitis (ulcer more than 5mm and deep) • No response to initial management • Doubtful compliance b. Out Patient • Small ulcers • Patients who can come for frequent follow up and those who understand the importance of compliance c. Day Care

• Not applicable d) Referral criteria: Immediate referral on presentation if there is • Immediate threat to vision • Ulcer involved in the only seeing eye • Pediatric patients needing anesthesia • Impending or actual perforation Referral following initial treatment if, Non healing or progressive ulcer inspite of adequate and appropriate anti microbial therapy, apart from all the points mentioned above. *Situation 2: At Super Specialty Facility in Metro location where higher- end technology is available

a) Clinical Diagnosis: Apart from the regular history taking, care should be exercised to fully understand the treatment history of the patient, including all the medications along with the dosage schedules which were prescribed at the secondary centre. This will avoid unnecessary wastage of medicines and help in formulating an ideal treatment strategy. A fresh comprehensive clinical examination, as detailed in the previous section should be performed without being biased by the referral report. 52

b) Investigations: Microbiology: Since the patient has been referred for a potentially serious condition, a comprehensive microbiological evaluation including additional culture, antibiotic sensitivity testing and if necessary, a corneal biopsy should be performed. A repeat smear examination should be ordered for and carefully looked for mixed organisms. Routine culture examinations are useful for the following reasons i. Gold standard that confirm gram stain microscopy (GSM)

ii. Provide sensitive data, including antibiotic sensitivity measurement to enable modification of initial therapy iii. It will serve as an useful tool to understand the causative organisms prevalent in the region The cultures should be selected to identify common organisms like fungi and bacteria. An ideal minimal culture tests would use blood agar and Sabouraud’s dextrose agar. Special culture medial such as non nutrient agar should be reserved for non responsive cases or

cases which show clinical suspicion of Acanthamoeba. Ocular bacterial cultures usually grow within 48 hours while the fungi from the ocular specimens grow within 7 days. Recommended Stains and Culture media for Microbial Keratitis Suspected Organisms Stain Media Aerobic bacteria Gram’s Blood agar Chocolate agar Thioglycollate broth Anaerobic bacteria Gram’s Anaerobic blood agar (Rarely involved) Thioglycollate broth Mycobacteria Gram’s Blood agar Acid fast Lowenstein – Jenson Fungi 10 % KOH Blood agar

Gram’s Sabouraud’s dextrose agar Calcofluorwhite Brain heart infusion Acanthamoeba 10 % KOH ------ Gram’s Giemsa Non-nutrient agar Calcofluorwhite with E.coli Note: Acridine orange – GMS – if facilities available, use it. Corneal biopsy: 53

It may be performed in the following conditions i. Deeper stromal lesions which are non accessible to routine corneal scrapings ii. Ulcers which show a negative culture, probably because of inadequate specimen. C) Treatment: The treatment strategies should be revisited to check for adequacy, appropriateness and affordability. If the culture grew a different organism, then the treatment regimen should be modified appropriately as recommended in the previous table. If the ulcers continue to

worsen in spite of correct treatment, then surgical options should be considered. Surgical Procedure may include: 1. Ulcer Debridement : • Enhance penetration of topical medication • Debulking of infective material 2. Tissue adhesive • Microperforation • Peripheral corneal ulcer with descematocoele 3. Dacryocystectomy if lacrimal sac infection in same eye 4. Penetrating Keratoplasty Therapeutic keratoplasty has to be performed when the ulcer progresses despite specific

anti-microbial therapy leading to descemetocele or perforation. The microperforation could be diagnosed by noticing a decrease in the size of the hypopyon, radial folds from the base of the ulcer and relief from pain. Sometimes it may seal spontaneously and healing will be faster. If the anterior chamber is formed within 48 hours with bandage or other supportive therapy therapeutic keratoplasty could be avoided or postponed. The goals of

the therapeutic keratoplasty are to eliminate the infection and restore the integrity of the globe. The size of the graft should be decided on the basis of the size of the ulcer and should include the infected edges. Fresh donor corneas give better results in Phakic eyes. Steroid in any form should be avoided post operatively in fungal ulcers. 5. Tarsorrhaphy: can be considered in neurotrophic and exposure keratitis Standard Operating Procedure a. In Patient i. Immediate threat to vision

ii. Ulcer involved in the only seeing eye iii. Pediatric patients needing anesthesia iv. Impending or actual perforation v. Any patients requiring surgery b. Out Patient 54

i. If the patient requires only modification of the topical antibiotics, then he/she can be treated as outpatients. c. Day Care Not applicable D) Referral criteria: Not applicable VI. WHO DOES WHAT? AND TIMELINES a. Doctor • Patient History is taken and a Clinical Examination performed • Corneal infective material is obtained by scrapping and smear are prepared and also materials are inoculated directly onto culture media • Documenting the medical record

• Plan treatment guidelines and perform surgery if necessary. • Monitoring, publication and reporting to department of health if there is an epidemic of drug resistant pathogen and iatrogenic corneal ulcer (Contact lens, refractive Surgery related) b) Nurse/Technician • Prepare Slide, Media for smear and culture • To monitor the patients who are admitted regarding application of eye drops and ensure compliance • To maintain separate inpatient and outpatient record • To maintain lab reports

VII. FURTHER READING / REFERENCES 1. Garg P, Sharma S, Rao GN. Ciprofloxacin-resistant Pseudomonas keratitis [Internet]. Ophthalmology. 1999 ;106(7):1319-1323.Available from: http://www.ncbi.nlm.nih.gov/pubmed/10406614 2. Prajna NV, Mascarenhas J, Krishnan T, Reddy PR, Prajna L, Srinivasan M, et al. Comparison of natamycin and voriconazole for the treatment of fungal keratitis [Internet]. Archives of Ophthalmology. 2010 ;128(6):672-678.Available from: http://www.ncbi.nlm.nih.gov/pubmed/20547942

3. Srinivasan M, Gonzales CA, George C, Cevallos V, Mascarenhas JM, Asokan B, et al. Epidemiology and aetiological diagnosis of corneal ulceration in Madurai, south India 55

[Internet]. The British Journal of Ophthalmology. 1997 ;81(11):965-971.Available from: http://www.ncbi.nlm.nih.gov/pubmed/9505820 4. Whitcher JP, Srinivasan M. Corneal ulceration in the developing world--a silent epidemic [Internet]. The British Journal of Ophthalmology. 1997 ;81(8):622- 623.Available from: http://www.ncbi.nlm.nih.gov/pubmed/9349145 RESOURCES REQUIRED Situation HUMAN RESOURCES INVESTIGATION DRUGS AND EQUIPMENT CONSUMABLES

1) Secondary 1)Ophthalmologist - 1 1) Smear test 1) Antibiotics eye 1) Slit lamp - level 2)OP Nurse 1 2) Gram stain drops biomicroscope -1 3)Refraction nurse - microscopy 2) Antifungal eye 2) Light microscope -1 1(shared ) 3) KOH smear drops 4) Blood sugar 3) Systemic 5) Lacrimal antibiotics and syringing anti fungal 4) Vitamin A 5) Cyclopiegics 2) Tertiary level 1)Cornea specialist - 1 1) Smear test 1) Antibiotics eye 1) Slit lamp - 2)Refraction nurse - 2) Culture drops/ointment biomicroscope -1

1(shared ) medium 2) Antifungal eye 2) Light microscopy -1 3)OP Nurse - 1 3) Antibiotic drops/Ointment 3)Confocal 4)lab technician – 1 sensitivity 3) Systemic microscope -1 5)Scrub nurse 1 4) Corneal biopsy antibiotics and 4)Specular 6) OT nurse 1 5) AC tap anti fungal microscope -1 7) Ward nurse - 1 6) PCR 4) Vitamin A 5) OT microsurgical 7) Blood sugar 5) Topical and instruments including 8) Lacrimal systemic trephines. syringing steroids 6) Well equipped 6) Suture materials microbiological

7) Needles and laboratory for smear, syringes culture and PCR) 7)Eye Bank equipment 56

NAME OF CONDITION: CATARACT I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Cataract is the commonest cause of blindness and visual impairment in India. It affects a significant number of elderly people’s quality life and economic productivity. This age related condition usually presents with gradual dimness of vision in both eyes. In the earlier stages, patients may experience glare, especially while driving at night. There may be

monocular diplopia or polyopia, reduced contrast sensitivity and altered colour perception. Over a period of time, the cataracts can advance and can cause total blindness. Very rarely, children can also have cataract. These children are born with this disorder or develop it at a very early age. The definitive treatment is always surgery with a very favourable risk reward ratio. In fact, cataract surgery is one of the most cost-effective public health interventions worldwide. b) Case definition:

A cataract is any opacity of the crystalline lens or its capsule leading to degradation of its optical quality, thereby causing decreased quality of vision. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY In India cataract has been reported to be responsible for 50-80% of the bilaterally blind in the country .Data from a population based longitudinal study of randomly selected communities in Central India have for the first time provided direct estimates of age

specific incidence of blindness from cataract. It estimated that 3.8 million persons become blind from cataract each year in India. The absolute number of cataract blind which was 7.75 million in 2001 is likely to reach 8.25 million in 2020 due to a substantial increase in the population above 50 years in India over this period. The 60+ population which stood at 56 million in 1991 will double by 2016.This increase in population means that the population 'at-risk' of blinding cataract will also increase

tremendously. The economic loss due to blindness and visual disability from cataract is enormous. Cataract blind people are unable to work and thus due to lack of productivity, the economic impact is a staggering 4.5 million rupees per year of every million population. Cataract in children, although rare, can still happen. The prevalence of blindness among children in different regions varies from 0.2/1000 children to over 1.5/1000 children with a

global figure estimated at 0.7/1000. In India this figure is approximately 1 per 1000 children. The proportion of blindness in children due to cataract varies considerably between regions from 10%-30%. Children who are blind have to overcome a lifetime of 57

emotional, social and economic difficulties which affect the child, the family and society. Timely recognition and intervention can eliminate blind-years due to childhood cataract, as the condition is treatable. III. DIFFERENTIAL DIAGNOSIS Cataract presents as a white reflex in the central part of the pupil. There are some other common conditions of the eye that show white reflex in the pupillary area and mimic cataract. • Endophthalmitis • Old Retinal Detachment • Intra ocular tumour

• Persistent hyperplastic primary vitreous IV. PREVENTION AND COUNSELING Cataract is mostly age related and there is no effective way of preventing this condition. However there are certain secondary types of cataract which can be prevented. • Traumatic cataract is very common in India especially among younger adults and children. Education about occupational safety and avoiding dangerous games (e.g. Bow and arrow) can reduce incidence of traumatic cataract.

• Drugs, commonly corticosteroids (either local or systemic) can produce cataract after prolonged use. This can be prevented by judicious application of the medicine. • Heredity plays a role in some families. Multiple children in a family are either born with cataract or develop cataract at a very young age. Genetic counseling has some role in prevention. Early eye check up for all the children in those families can be advocated.

• Maternal infections during pregnancy, most commonly rubella, can give rise to congenital cataract. This can be prevented by immunizing the target age group of women. • Smoking is known to be associated with nuclear cataract and hence preventing smoking is thought to be beneficial. • Ultraviolet-B radiation has been associated with lens opacities and hence protecting eyes from sun has some role in prevention. • Diabetes mellitus has a higher risk for cataract formation, and behavior modification

to reduce the risk of developing type 2diabetes may be effective. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA 58

*Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: History: Cataracts is an extremely common occurrence in the elderly. However, the key is to determine whether the cataract is the cause of functional disability for an individual. Careful history taking is important for assessing the quality of the visual impairment due to

this disability. Occupational and functional needs of the patients should be taken into consideration before planning for surgical intervention. History should also include ocular and systemic medications currently and previously used. Medical history about systemic diseases is important. Patients should be asked about any allergy to any food or medicine. Ocular examination: i. Presenting Visual acuity with and without present correction (if spectacle is available,

the power of the present correction should be recorded) is determined In advanced and mature cataract, perception and projection of light should be tested in all the four quadrants to rule out gross retinal problems. ii. Measurement of best-corrected visual acuity (with refraction when indicated). iii. External examination (lids, lashes, lacrimal apparatus, orbit). Pressure should be applied over the sac to look for any regurgitation. If regurgitation is

positive or dacryocystitis is suspected syringing of naso-lacrimal duct should be carried out. If duct is not free, with mucus or purulent discharge, dacryocystectomy or dacryocystorhinostomy is done and cataract surgery is done after one month. iv. Examination of ocular alignment and motility. v. Assessment of pupillary shape, size and reaction: This is a very important step and should be done very carefully, since it will help in determining the prognosis.

vi. Slit-lamp biomicroscopy of the anterior segment : Special emphasis should be made to examine the corneal endothelium for any guttata, pupil for pseudoexfoliation and the lens for any preoperative compromises on stability. vii. Dilated Examination of the lens opacity may reveal the extent of visual impairment. For example, opacity in the visual axis may cause more functional visual deficit than a peripheral cataract posterior sub-capsular opacity may cause more symptoms of glare

than a nuclear cataract. It helps in grading nuclear sclerosis and reveals any subluxation. Measuring amount of maximal dilation helps in planning the surgery. 59

viii. Dilated examination of the fundus including, optic disc, macula and vitreous. If clarity of media allows then the peripheral retina should be examined. This helps in planning the prognosis of the surgical intervention. ix. Indirect ophthalmoscopy is indicated for known myopes, eyes with past history of trauma or retinal detachment in other eye. b) Investigations: i. Measurement of intraocular pressure (preferably by Applanation tonometry)

ii. Gonioscopy is not done as a routine. It can be performed if anterior chamber appears shallow, IOP is raised, presence of any sign that can be related to secondary glaucoma (e.g. pseudoexfoliation) or known cases of glaucoma. iii. Keratometry and A scan biometry: It should be performed in both eyes. It should be repeated if needed for unusual powers of IOL. Appropriate formula should be used according to cases. In case of scarred cornea and irregular surface of cornea, the K

reading will not be possible. In this case the other eye should be taken into consideration. iv. Ultrasonogram of the posterior segment is indicated in traumatic cataracts, complicated cataracts and unilateral mature cataracts. v. Blood pressure vi. Screening for diabetes mellitus vii. Physician fitness is mandatory for cardiac patients and those with advanced systemic problems. viii. Patients who require general anesthesia need to undergo preanasthetic check up c) Treatment: Nonsurgical management

Patients with early cataract and all stages of nuclear cataracts may sometimes benefit by spectacles. If they do benefit, then subsequent follow ups can be planned to determine the timing of surgery, if required. Management of a visually significant cataract is primarily surgical. Indications for Surgery An individual who is unable to carry out his/her desired activities due to dimness of vision for which cataract surgery is likely to restore the visual function is the prime indication for

surgery. The other reasons for a cataract removal include the following: i. Clinically significant anisometropia in the presence of a cataract where cataract surgery is likely to facilitate binocularity. ii. Conditions in which the lens opacity is dense enough to interfere with evaluation and management of posterior segment conditions. iii. Lens induced ocular inflammation 60

iv. Lens induced glaucoma Prognosis of surgery should be clearly explained to the patient in an understandable language. Contra-indications for surgery: i) Patient not convinced about surgery ii) Patient has satisfactory functional vision either with or without visual aids iii) Cataract surgery is unlikely to improve vision iv) Patient is medically unfit Anesthesia Cataract surgery may be performed using a variety of anesthesia techniques that include

general and local (regional) anesthesia (e.g., retrobulbar, peribulbar, periocular, sub- Tenons injection, topical, and intracameral). Local (regional) anesthesia is generally used, with or without sedation/analgesia. Traditionally, a retrobulbar or peribulbar anesthesia is used for most of the extracapsualr cataract surgeries. Topical anesthesia can be used for patients undergoing clear corneal phacoemulsification. General anesthesia may be utilized

if needed for children and patients with medical, psychosocial, or surgical indications. The planned mode of anesthesia should be decided after interaction between patient and the doctor. The process should be discussed with the patient so that he/she will know what to expect in terms of pain, discomfort, consciousness level, visual experiences, and complications. Infection Prophylaxis Greatest concern of an ophthalmologist after successful surgery is the endophthalmitis

because of its serious consequences. Prevention remains the best measure to avoid it. Risk for endophthalmitis can be lessened by reducing the number of microorganisms on the ocular surface. Prophylactic strategies that are commonly practiced include using topical antibiotic eye drops before surgery, applying 5% povidone iodine to the conjunctival cul de sac, preparing the periocular skin with 10% povidone iodine, careful sterile draping of the eyelid margins

and eyelashes, and applying topical antibiotic eye drops after surgery. Taking care of personal hygiene of the patient is very important. A thorough face washes before surgery is recommended. A surgeon should stick to strict aseptic techniques of surgeries. Wound construction and closure should be meticulous. The surgery should end with a water tight incision and the surgeon should not hesitate to put sutures for security. Surgical Techniques

The preferred method to remove a cataract is extracapsular extraction by either of the following techniques: a. Manual small incision cataract surgery b. Conventional extracapsular cataract extraction. 61

c. Phacoemulsification. Visual results can be improved in all these types of surgeries by adhering to these common guidelines. • A well planned incision that minimizes surgically-induced astigmatism. • Safe and secure incision. • Ensuring minimal loss of the corneal endothelial cells • An appropriate posterior chamber IOL placed in the capsular bag. • Avoiding trauma to iris, and other ocular tissues. Incision location, size, and design may depend on several factors, including the patient's

orbital anatomy, the type of IOL to be implanted, the role of the incision in astigmatism management, and surgeon preference and experience. Manual small incision cataract surgery: This surgery is known to be extremely cost effective and visual improvements are comparable to other technique like phacoemulsification. This can be performed through superior incisions or temporal incisions. While superior incisions would be relatively safer with regard to the occurrence

of endophthalmitis (since the incision is protected by the lids), it causes a higher astimagtism than the temporal incision. If temporal incisions have to be performed because of excessive preoperative astigmatism, care should be taken to fashion a longer internal corneal valve and the tunnel may be secured with a couple of nylon sutures. While any type of anterior capsular opening techniques can be used alongside this procedure,

capsulorrhexis is preferred for better centration of the intraocular lenses and reduced inflammation. The cataractous lens can be taken out by irrigating vectis or by viscoexpression. Rigid or foldable lenses can be used as per the needs of the individual patient. Extra capsular cataract surgery: This surgery can be performed on hard cataracts, shallow anterior chambers or a bulky nucleus which may be difficult to express through a smaller incision. The decision to

perform this surgery has to be decided upon by the needs of the patients along with the comfort level of the surgeon. The main drawback of this surgery is the increased need for postoperative follow ups which may be necessitated due to problems associated with sutures. Astigmatism can also be a significant issue which may warrant a suture removal, in order to optimize good uncorrected visual acuity. Phacoemulsification: This surgery can be performed on early to intermediate level of

hardness of cataract and produces rapid visual recovery. It also eliminates the risk of regional anasthesia since it may be performed topically. There is a learning curve for surgeons and once it is mastered, it can be employed in a significant number of cases. Harder cataracts may require an experienced surgeon and a machine with good fluidics. 62

However, this procedure is expensive and sometimes may be difficult to perform in certain types of cataracts. In all these types of surgeries, there are chances of intraoperative complications. The most common causes are posterior capsular rupture and zonular dialysis. If this happens, the management of vitreous loss is crucial and should be managed by automated vitrectomy. Intraocular Lenses Posterior chamber IOLs (PC IOL) are the best choice unless contra-indicated. Other less

commonly used lenses are Anterior Chamber and Scleral Fixated IOLs. There is a wide range of PC IOLs with various value added optical and non optical characteristics. The most common materials used are polymethyl methacrylate (PMMA) and acrylic lenses. Even though they have comparable visual acuity outcomes, the rates of posterior capsular opacification (PCO) is lower in acrylic than PMMA. In patients, where there is more chance of posterior capsular opacification,as in children or diabetics or

others, acrylic lenses may be preferred. Acrylic lenses can be hydrophobic or hydrophilic. Another parameter which has been thought to influence PCO occurrence is the design of the intraocular lenses. Square edged lenses are known to cause a lower incidence of PCO. The ophthalmologist can choose any of these PCIOLs according to clinical indications, patient’s visual need and affordability. Anterior chamber lenses if used at all, should preferably be single-piece flexible open-loop.

Effective and safe use of an anterior chamber lens depends on appropriate sizing. Anterior chamber IOLs are used most often when there is inadequate capsule support for a posterior chamber IOL. Placement of an anterior chamber lens requires a peripheral iridectomy and proper anterior vitrectomy. The surgeon should have access to a variety of lens styles to select an appropriate IOL for an individual patient. Variations in the preoperative state of the eye, the surgical

technique, patient expectation, and surgeon experience and preference affect the decision. Post Operative Medication: i) Topical corticosteroid in a tapered fashion for 4 to 6 weeks. ii) Topical broad spectrum antibiotics for two weeks. iii) Cycloplegic drops, NSAID and anti glaucoma medications according to ophthalmologist’s clinical decision. Outcomes of cataract surgeries should be carefully monitored and results used for improvement of service. Presenting visual acuity, rather than best corrected visual

acuity should be taken as the standard for assessing visual success. Complications of Cataract Surgery should be carefully documented clearly explained to the patient in their own language and appropriate care given. 63

Standard Operating procedure a. In Patient i. Patients coming from a long distance ii. Traumatic cataracts iii. Cataracts with intraoperative complications: iv. Pediatric patients requiring anesthesia. v. Mono ocular patients. b. Out Patient Pre operative investigations Follow up C. Day Care Cataract surgery is ideally done as a day care procedure. d) Referral criteria: Cases needing specialized investigations before surgery (Specular microscopy) Cases not manageable by the facilities available

Seeking second opinion Complications needing specialized intervention (e.g. posterior vitrectomy) Detection of posterior segment disorder after cataract removal *Situation 2: At Super Specialty Facility in Metro location where higher- end technology is available a) Clinical Diagnosis: Same as situation 1 b) Investigations: Same as situation 1. Some additional investigations help in explaining prognosis and planning the surgery.

b. Corneal topography, corneal pachymetry and , specular microscopy for associated corneal disease. Specular microscopy is helpful for planning surgery in hard cataracts and in patients with suspected compromised corneas. c. Fluorescein angiography is helpful in vascular retinopathies and maculopathies if clarity of media permits. d. An automated field analyzer evaluation may be helpful in preoperative diagnosis of co-existing glaucoma. e. Conjunctival swab culture for suspected infections

f. Additional investigations for paediatric cataracts according to systemic conditions. 64

c) Treatment: Same as situation 1. Difficult cases should get individualized attention according to the merit of the case. Correction of pre-existing astigmatism can be taken either with selection of the incision sites, using toric intraocular lenses or by limbal relaxing incision. Patients desiring multifocal lenses should be counseled appropriately and then taken for surgery. Paediatric cataracts should be appropriately managed by trained surgeons. Standard Operating procedure a. In Patient

Patients preferring hospital stay for surgery because of distance and better care Children undergoing cataract surgery Patients with post operative complications that need institutional care g. Out Patient Pre operative investigations Follow up h. Day Care Ideal for cataract surgery. d) Referral criteria: Does not apply VI. WHO DOES WHAT? AND TIMELINES a. Doctor Patient History is taken and a Clinical Examination performed Documenting the medical record Plan treatment guidelines and counsel patients

Advise and Perform surgery. Explain and assure patients if complications occur. Follow up Referral in needed. Monitoring the infection control process Monitoring outcome and share the results with the team b. Nurse / Technician Receive the patients and assist in clinical examination Prepare the patients for surgery Counseling whenever necessary To monitor the patients who are admitted regarding application of eye drops and ensure compliance To maintain separate inpatient and outpatient record

Explain discharge advice to patients VII. FURTHER READING / REFERENCES 1. Minassian DC, Mehra V. 3.8 million blinded by cataract each year: projections from the first epidemiological study of incidence of cataract blindness in India [Internet]. The British Journal of Ophthalmology. 1990 ;74(6):341-343.Available from: http://www.ncbi.nlm.nih.gov/pubmed/2378840 2. Murthy G, Gupta SK, John N, Vashist P. Current status of cataract blindness and

Vision 2020: the right to sight initiative in India [Internet]. Indian Journal of Ophthalmology.2008;56(6):489-494.Availablefrom: http://www.ncbi.nlm.nih.gov/pubmed/18974520 3. Schein OD, Katz J, Bass EB, Tielsch JM, Lubomski LH, Feldman MA, et al. The value of routine preoperative medical testing before cataract surgery. Study of Medical Testing for Cataract Surgery [Internet]. The New England Journal of Medicine. 2000 ;342(3):168-175.Available from: http://www.ncbi.nlm.nih.gov/pubmed/10639542

4. Tseng VL, Greenberg PB, Scott IU, Anderson KL. Compliance with the American Academy of Ophthalmology Preferred Practice Pattern for Diabetic Retinopathy in a resident ophthalmology clinic [Internet]. Retina (Philadelphia, Pa.). 2010 ;30(5):787- 794.Available from: http://www.ncbi.nlm.nih.gov/pubmed/20168268 5. Childhood cataract: magnitude, management, economics and impact [Internet]. Community Eye Health / International Centre for Eye Health. 2004 ;17(50):17-

18.Available from: http://www.ncbi.nlm.nih.gov/pubmed/17491800 6. Preferred Practice Patterns : American Academy of Ophthalmology [Internet]. Available from: http://one.aao.org/CE/PracticeGuidelines/PPP.aspx?sid=17ec4816- d6f4-4af7-81fc-64919982bac4 66

RESOURCES REQUIRED Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1) Secondary 1) Ophthalmologist 1)B.P. recording 1)Local 1)Torch light level - 1 2)Tonometry anaesthetics 2)Trial set 2) OP Nurse 3)Sac syringing (if 2)Antibiotics eye 3)Retinoscope – 1 indicated) drops 4)Slit lamp - 3) Ophthalmic 4)Refraction 3)Steroid eye biomicroscope -1 Assistant / 5)Biometry drops 5)Direct Ophthalmoscope 4)Optometrist 1 6) USG B scan 4)Mydriatics 6)+90 D lens 5) OT Nurse Miotics 7)Indirect

6) Ward Nurse – 1 5)Viscoelastics Ophthalmoscope with 7) Counsellor - 1 6)Irrigating fluids +20 D lens 7)Intraocular 8)A-Scan lenses in various 9)Keratometer powers 10)BP apparatus 8) Dyes to stain 11)Schiotz Tonometer/ the capsule Applanation tonometer 9) Needles and 13)Gonioscope syringes 14)Operating microscope 10) Suture 15)Phacoemulscification materials machine 16)Anterior vitrectomy machine 17)Ultrasonogram 18) Microsurgical instruments 19) Nd: YAG laser machine (for capsulatomy)

2) Tertiary 1) Experienced 1)B.P. recording Similar Similar. level Ophthalmologist 2)ECG In addition, a specular - 1 3)Sac syringing (if microscope 2) OP Nurse indicated) and an automated field – 1 4)Refraction analyzer and equipments 3) Ophthalmic 5)Biometry for documenting fundus Assistant / 6)USG B- Scan pathologies. 4)Optometrist 1 7)Specular 5) OT Nurse microscopy 6) Ward Nurse – 8)Pachymetry 1 9)FFA 7) Counsellor - 1 10)HFA 67

NAME OF CONDITION: DIABETIC RETINOPATHY I. When to suspect/ recognize? a) Introduction: Diabetes Mellitus (DM) has established itself as a pandemic disease, projected to affect 438 million people by 2030 AD.. The exponential growth in the incidence and identification of systemic diabetes has projected diabetic retinopathy as one of the leading causes of visual loss globally. Diabetic retinopathy (DR) is one of the most frequent causes of blindness world-

wide. In India DR which was the 17th cause of blindness but has now ascended to the 6th position. Diabetic retinopathy screening is directed towards improving health care services for persons with diabetes and diabetic retinopathy. It is symptomless in its early stage; screening is the only way to identify these patients to prevent them from going blind. The number of DR patients’ increase with increase in the diabetic population, especially in developing countries where there is resource scarcity.

Timely treatment can prevent vision loss which means that all of the diabetics have to be regularly examined for DR. b) Case definition: Diabetic Retinopathy is primarily a microvascular disease. For all practical purpose fundus changes like micro aneurysms, hard exudates and hemorrhages in diabetic patients are to be considered as diabetic retinopathy until proved otherwise. The most common cause of visual loss in diabetic patients is due to macular edema

(DME) and advanced diabetic retinopathy (Vitreous hemorrhage and Retinal detachment). II. Incidence of the condition in our country Diabetic retinopathy is the leading cause of blindness among adults in the developing countries and is emerging as an important cause of blindness in the developing countries next to cataract. The longer the duration of diabetes higher is the incidence of developing diabetic retinopathy. In India, there is a paucity of data

on the prevalence of DR in type 1 diabetes mellitus, as a registry for prevalence of type 1 diabetes is only recently being set up in the country. The prevalence of diabetic retinopathy in India, according to various population based studies is in between 17.6% to 34.1%. An earlier study done in a clinic-based population reported an overall prevalence of 14 per cent of DR in a diabetic population examination. Of these, non proliferative diabetic retinopathy (NPDR) accounted for 6 per cent,

macular oedema accounted for 4 per cent and proliferative diabetic retinopathy accounted for rest of the 4 per cent. 68

III. DIFFERENTIAL DIAGNOSIS Diabetic retinopathy may present like or coexist with other conditions and hence one needs to be careful with making a diagnosis. The following disorders may also present similary and hence they have to be ruled out. 1. Hypertensive retinopathy 2. Vascular occlusive disorders 3. Inflammatory chorio retinopathy 4. Radiation retinopathy 5. Age related macular degeneration IV. PREVENTION AND COUNSELLING

o All the diabetic patients are the potential candidates for vision impairment. Strict control of blood glucose level and other risk factors like hypertension, hypercholesterolemia, anaemia will retard the development and progression of DR.. o Screening of all “known diabetic patients” for DR at their primary point of contact, by physicians/diabetologists as most of the diabetic patients come to the ophthalmologists only after experiencing considerable vision loss will detect early cases.

o All pregnant women with diabetes should have dilated eye examinations during each trimester of their pregnancy to check for retinopathy o Educating the community for regular eye check up and having good healthy diet, exercises and avoiding smoking goes a long way in preventing progression of diabetic retinopathy. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal

Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: History taking: Diabetic retinopathy often has no early warning signs. Patients usually presents with painless loss of vision. A thorough and complete history taking regarding past duration of diabetes, treatment history, family history and history of 69

associated risk factors is essential. Waiting for the diabetic to present with visual problems is not a good strategy. Many patients retain normal eyesight or experience a minimal (and sometimes unnoticeable) reduction of vision even in the presence of sight-threatening disease (diabetic maculopathy, proliferative disease). It is for this reason that screening for DR is mandatory. Sometimes, the patients may become aware of a problem (whether or not they are known diabetics) as in :

• A painless gradual reduction of central vision may be associated with any of the types of DR. The most common cause is diabetic macular oedema. Painless and gradual visual loss is also associated with coexistent cataract formation (diabetic or otherwise). • Haemorrhages result in the sudden onset of dark, painless floaters which may resolve over several days. • Severe vitreous haemorrhage may obscure the vitreous altogether resulting in a painless visual loss.

• An acute attack of glaucoma precipitated by rubeosis iridis is the one situation where the patient will present with acute pain; urgent referral is essential. Examination: a complete and comprehensive examination using a direct ophthalmoscope, indirect ophthalmoscope and slit lamp with 90 dioptre lens is essential for diagnosing and staging diabetic retinopathy. Careful staging and appropriate management goes a long way in preventing visual loss due to diabetic retinopathy.

International clinical diabetic retinopathy disease severity scale 5 levels for Diabetic Retinopathy – none, mild, moderate, severe and proliferative Proposed Disease Severity Level Findings Observable upon Dilated Ophthalmoscopy No Apparent retinopathy • No abnormalities Mild non-proliferative diabetic • Microaneurysms only retinopathy Moderate non-proliferative diabetic • Microaneurysms . dot shaped haemorrhages and retinopathy hard exudates but less than severe NPDR

Severe non-proliferative diabetic Any of the following : Retinopathy • More than 20 intra-retinal hemorrhages in each of 4 quadrants • Definite venous beading in 2+quadrants • Prominent IRMA in 1+ quadrant 70

And no signs of proliferative retinopathy Proliferative diabetic retinopathy One or more of the following: • Neovascularization of the Disc or else where • Vitreous / preretinal hemorrhage International clinical diabetic retinopathy disease severity of diabetic macular edema 2 Major levels, with subcategories for diabetic macular edema Proposed Classification Findings Observable upon Dilated Ophthalmoscopy Diabetic Macular Edema Absent No retinal thickening or hard exudates in posterior pole

Diabetic Macular Edema Present Some retinal thickening or hard exudates in posterior pole Diabetic macular edema is classified into three types based on FFA findings: • Focal exudative maculopathy • Diffuse exudative maculopathy • Ischaemic maculopathy. Term clinically significant macular edema(CSME) is considered ,if one of the following criteria are present on : (cid:252) Retinal edema or Thickening of the retina at or within 500µ of the centre of the fovea.

(cid:252) Hard exudates at or within 500 µ of the centre of fovea associated with adjacent retinal thickening (cid:252) Retinal thickening of size 1DD, at least a part of which is within 1DD of the foveal centre. Advanced diabetic eye disease. (cid:252) Vitreous and preretinal haemorrhages occur as new vessels grow forward from the retina and enter the vitreous where they bleed easily. (cid:252) Haemorrhages appear as reddish/dark opacities; preretinal or subhyaloid haemorrhages.

b) Investigations: Visual acuity test: This is done as a baseline investigation. Amsler’s grid evaluation is also useful to monitor macular disease Fundus examination with direct and indirect ophthalmoscope. The direct ophthalmoscope examination is essential for both community setting and general physicians. Indirect ophthalmosopy is done in case of advanced diabetic retinopathy. Slit lamp biomicroscopy with 78D or 90D is gold standard for diagnosis of diabetic maculopathy.

Fundus photography and Digital Retinal Screening Programs: Systematic programs for the early detection of eye disease including diabetic retinopathy are becoming more common, where all people with diabetes mellitus are offered retinal screening at least annually. This involves digital image capture and transmission of the images to a digital reading center for evaluation and treatment referral. Fluorescein Angiography This is a magnified photography of the retina involving the use of an injectable dye. It

helps to classify the condition and to record changes in the retinal blood vessels. It is also useful to rule out the ischemia of the macular region. The first angiogram is usually done during the first evaluation. Subsequent angiograms may be done to assess the progression of diabetic retinopathy and to decide on the mode of treatment C. Treatment: Medical Care Glucose control: One of the clinical trials, the Diabetes control and complications

trial (DCCT) has found that intensive glucose control in patients with insulin dependent diabetes mellitus (IDDM) has decreased the incidence and progression of diabetic retinopathy. Glycosylated hemoglobin levels of 6- 7% are ideal to prevent or at the very least to minimize the long-term complications of DM, including DM retinopathy. Surgical Care Laser photocoagulation is the standard technique for treating diabetic retinopathy.

In general, it is advised for patients with high-risk PDR, CSME, or neovascularization of the anterior chamber angle. Either argon or diode laser can be used for photocoagulation. Laser photocoagulation techniques can be classified as panretinal, focal, or grid. Panretinal photocoagulation, also referred to as scatter 72

photocoagulation, is used for the treatment of proliferative diabetic retinopathy. It may be done in more than one session. Focal and grid photocoagulation are used for the treatment of diabetic macular edema. DIABETIC MACULOPATHY: Argon laser photocoagulation: Indications: • All eyes with CSMO should be considered for laser photocoagulation irrespective of the level of visual acuity because treatment reduces the risk of visual loss by 50%.

• Pre-treatment FFA is useful to delineate the area of leakage and to detect ischaemic maculopathy which carries a poor prognosis. Focal treatment – burns are applied to microaneurysms and microvascular lesions in the centre of rings of hard exudates located 500 -3000µm from the centre of macula .The spot size is 50 - 100 µm , exposure time 0.1 sec with sufficient power to obtain gentle whitening or darkening of the lesions. Grid treatment – burns are applied to areas of diffuse retinal thickening more than

500 µm from the centre of the macula and 500 µm from the temporal margin of the optic disc.the spot size is 100 µm and exposure time is 0.1 sec giving a very light intensity burn. PROLIFERATIVE DIABETIC RETINOPATHY: Panretinal photocoagulation: Laser treatment is aimed at inducing involution of new vessels and preventing visual loss. Indications: • PDR with HRCs • Neovascularisation of irirs • Severe NPDR associated with : o Poor compliance for follow up o Before cataract surgery/YAG capsulotomy

o Renal failure o Pregnancy o One-eyed patient The recommended therapy is 1200-2000 burns 500µm in diameter delivered through the goldmann lens or the same number of 200 µm burns delivered through volk lens. The burns should be intense enough to whiten the overlying retina,which usually requires a power of 200 – 600mW and duration of 0.1 second. 73

Treatment of Diabetic Retinopathy Proliferative Retinopathy Clinically Significant Clinically Significant Macular Macular Oedema Oedema Retinal microaneurysms Retinal thickening & areas of non-perfusion Type of laser Argon green Green or yellow (577) Green or yellow (577) argon laser argon laser Spot size 200-500µm 50 - 100µm 100µm Power 0.2 - 0.8 watts 0.1 - 0.3 watts 0.1 - 0.3 watts Duration 0.2 seconds 0.1 seconds 0.05 - 0.1 seconds

End point Faint white burn at level of Faint whitening of RPE or Very faint white burn at level of retinal pigment epithelium darkening ofretinal pigment epithelium (RPE) (RPE) microaneurysm How to treat Do not overlap burns Apply burns directly to Place burns at least one burn Do not treat within temporal microaneurysms width apart, to make a grid which arcades includes the area of retinal Do not treat within one disc thickening diameter of optic disc Do not treat within 500m of

Do not treat within two disc fovea at first session diameters temporal to fovea Number of Approximately 2,000 Variable Variable burns Number of Two sessions. Treat the lower One One sessions half of the retina first (1,000 burns) Other Topical steroids and mydriatic after treatment Signs of New vessels regressing Less retinal Less retinal thickening resolution Reduced blood flow in new thickening/exudate vessels More fibrous tissue Less beading of retinal veins 74

Indications for Fresh new vessels on the Significant macular Significant macular oedema after retreatment optic disc or elsewhere in the oedema after 3 months 3 months fundus Failure of new vessels to regress Retreatment Between previous burns, Do not retreat areas lying Treat to within 100m of the edge avoiding retinal vessels in the macular-papular of the foveal avascular zone bundle Standard Operating procedure a. In Patient – No need b. Day Care – Not applicable c. Out Patient Procedure:

• Screening, diagnosis and disease management. • Providing treatment for diabetic retinopathy with lasers and other medical treatment. d) Referral criteria: If the patients are requiring further investigations/treatment such as vitrectomy, Retinal detachment surgery is referred to the tertiary level eye care provider. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical Diagnosis: Same as situation 1

b) Investigations: Same as situation 1. Some additional investigations help in explaining prognosis and planning the surgery (example Optical Coherence Tomography(OCT) c) Treatment: General Management Recommendations: Level of Retinopathy Evaluation Treatment Strategies Fluorescein PRP Focal Follow-up Angiography (months) Mild NPDR No macular edema No No No 12 Macular edema No No No 4-6 75

CSME Yes No Yes 2-4 Moderate NPDR No macular edema No No No 6-8 Macular edema (not CSME) No No No 4-6 CSME Yes No Yes 2-4 Severe NPDR No macular edema No Rarely No 3-4 Macular edema (not CSME) No Occasionally Occasionally 2-3 after focal CSME Yes Occasionally Yes 2-3 after focal Standard Operating procedure: The operating procedures like vitrectomy, retinal detachment surgeries and other intravitreal medications are done for those cases of advanced retinal detachment which

have been referred from secondary eye care. Surgical treatment in advanced diabetic eye disease: Laser photocoagulation allows effective treatment of moderate to severe PDR .Some eyes can progress to tractional retinal detachment and vision loss. Standard laser cannot be performed in eyes with vitreous hemorrhage precluding visualization of the retina. Pars plana vitrectomy is the main method of treating severe complications of PDR. The

diabetic retinopathy vitrectomy study ( DRVS) showed that early vitrectomy was beneficial for patients with visual acuity of 6/120 or better and having one of the following: (1) severe neovascularization and fibrous proliferation; (2) fibrous proliferation and moderate vitreous hemorrhage; or (3) moderate neovascularization, severe fibrous proliferation, and moderate vitreous hemorrhage. Role of vitrectomy: The most common indications for diabetic vitrectomy are : 1. Severe nonclearing vitreous haemorrhage,

2. Traction retinal detachment recently involving the macula, 3. Combined traction and rhegmatogenous detachment, 4. Progressive fibrovascular proliferation, 5. Rubeosis iridis and vitreous haemorrhage, with opacity preventing adequate laser. The DRVS study concluded that: 76

1. Early vitrectomy provides a greater chance for prompt recovery of visual acuity in eyes with recent severe vitreous haemorrhage. 2. For patients with IDDM, in whom severe vitreous haemorrhage occurred after a shorter duration of diabetes, early vitrectomy provides a greater chance of recovering good visual acuity 3. DRVS findings support early vitrectomy in eyes known or suspected to have very severe PDR as a means of increasing the chance to restoring or maintain good vision.

4. Vitrectomy for traction retinal detachment or macular traction: Progressive tractional RD threatening or involving the macula must be treated without delay. Other medications that are being used in clinical practice and in clinical trials include intravitreal bevacizumab (Avastin) and ranibizumab (Lucentis), These medications are VEGF antibodies and antibody fragments, respectively. They can help to reduce diabetic macular edema and also neovascularization of the disc or retina a. Out Patient

Diagnosis and disease management a. Investigations for diabetic retinopathy b. Fluorescein angiography c. Photography-scan ultrasonography d. Lasers for diabetic retinopathy b. In Patient: • Advanced diabetic retinopathy • Patient who need surgical treatment • Patient with neovascular glaucoma, complicated cataract and other ocular complication secondary to diabetes has to be admitted for further management. c. Day care d) Referral criteria: Not applicable 77

VI. Who does what? And timelines Doctor - history taking, clinical examination ,treatment plan - Follow up schedule - Need additional skills in indirect ophthalmoscopy, - Interpretation of Fluorescein angiography. - Handling retinal laser photocoagulation - Surgical management of DR. Nurse - Assist in conducting diagnosis and examination of patient and preparing them for treatment. - Attend and assist in diabetic retinopathy screening camps. Technician

- Undergo additional training in fundus photography and fluorescein angiography - FFA - Indications, technique complications -Basic ultrasonography 78

VII. FURTHER READING / REFERENCES 1. Alfaro DV, Liggett PE, Mieler WF, Quiroz-Mercado H, Jager RD, Tano Y. Age- Related Macular Degeneration: A Comprehensive Textbook [Internet]. 1 ed. Lippincott Williams & Wilkins; 2005. Available from: http://www.amazon.com/dp/0781738997 2. Kempen JH, O'Colmain BJ, Leske MC, Haffner SM, Klein R, Moss SE, et al. The prevalence of diabetic retinopathy among adults in the United States [Internet]. Archives of Ophthalmology. 2004 ;122(4):552-563.Available from:

http://www.ncbi.nlm.nih.gov/pubmed/15078674 3. Roy MS, Klein R, O'Colmain BJ, Klein BE, Moss SE, Kempen JH. The prevalence of diabetic retinopathy among adult type 1 diabetic persons in the United States [Internet]. Archives of Ophthalmology. 2004 ;122(4):546-551.Available from: http://www.ncbi.nlm.nih.gov/pubmed/15078673 4. Silva PS, Cavallerano JD, Sun JK, Aiello LM, Aiello LP. Effect of systemic medications on onset and progression of diabetic retinopathy [Internet]. Nature

Reviews. Endocrinology. 2010 ;6(9):494-508.Available from: http://www.ncbi.nlm.nih.gov/pubmed/20664533 5. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030 [Internet]. Diabetes Care. 2004 ;27(5):1047-1053.Available from: http://www.ncbi.nlm.nih.gov/pubmed/15111519 6. Grading diabetic retinopathy from stereoscopic color fundus photographs--an extension of the modified Airlie House classification. ETDRS report number 10. Early

Treatment Diabetic Retinopathy Study Research Group [Internet]. Ophthalmology. 1991 ;98(5 Suppl):786-806.Available from: http://www.ncbi.nlm.nih.gov/pubmed/2062513 79

RESOURCES REQUIRED Situation HUMAN INVESTIGATI DRUGS & EQUIPMENT RESOURCES ONS CONSUMABLES 1 Seconday 1) Ophthalmologist 1)FFA 1) Fluoresceing dye 1) FFA including retinal level – 1 2)USG 2) Antiangiogenic camera & imagenet - 1 2) Nurse - 1 3) Blood injections 2) Ultrasonography 3) Technician - 1 sugar 3) Mydriatics 3) Indirect 4) Counsellor - 1 4) Neeles and ophthalmoscope with 20D 5)Field coordinator syringes lens-1 - 1 4) Frequency double YAG laser with endolaser probe/slit lamp delivery

with all accessories- 1 2. Tertiary 1) Ophthalmologist 1) FFA 1) Fluoresceing dye 1) FFA including retinal level – 2 2) USG 2) Antiangiogenic camera & imagenet - 1 2) Retina specialist - 3) OCT injection 2) Ultrasonography-1 2 4) Blood 3) Irigating solution 3) Indirect 3) Nurse - 3 sugar 4) Intraocular gas ophthalmoscope with 20D 4) Technician – 1 and silicon oil lens -1 5) Counsellor - 2 5) Mydriatics 4) Frequency double YAG 6)Field coordinator 6) Needle s and laser with endolaser

- 1 syringes probe/slit lamp delivery 7) Suture materials with all accessories- 1 5) OCT – 6)ERG – 1 Surgical equipment: 1. Vitrectomy console 2. VR surgical instrument 3. Surgical operating microscope with CCTV attachment and observerscope–1 80

NAME OF CONDITION: AGE RELATED MACULAR DEGENERATION (AMD) I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Age related macular degeneration (AMD) is one of the leading causes of low vision in developed countries. However, this condition is being increasingly recognized in our country in recent times. It has been found to have significant impact on the individual’s quality of life. As the geriatric population of the country increases,

courtesy of improved medical services, the number of people afflicted with AMD will proportionately, increase. Understanding the epidemiology, risk factors and treatment modalities of AMD is essential to improve the overall ocular health of the individual. b) Case definition: Age-related macular degeneration is defined as a degenerative disease characterized by the presence of the following: drusen; retinal pigment epithelium (RPE) abnormalities; RPE and associated neurosensory detachment; retinal

haemorrhages; choroidal neovascularization; geographic atrophy, or retinal fibrous scarring in the absence of other retinal disorders. • Drusen are localized, discrete whitish-yellow deposits lying between the basement membrane of the RPE and Bruch’s membrane. • Abnormalities of the RPE include hyperpigmentation or hypopigmentation, without any visibility of the choroidal vessels as associated with drusen. • Geographic atrophy is defined as sharply delineated, confluent areas of

hypopigmentation or depigmentation or apparent absence of the RPE in which choroidal vessels are more visible than in surrounding areas. • Choroidal neovascularization is the growth of new blood vessels from the choroid, characterized morphologically by greenishgrey subretinal tissue, with or without subretinal haemorrhage or exudates. • Dry AMD is defined as the presence of drusen and RPE abnormalities, including geographic atrophy.

• Wet AMD is defined as the presence of any of the following: RPE detachments or serous detachment of the sensory retina; subretinal or sub-RPE neovascular membranes; subretinal haemorrhages, and epiretinal, subretinal, intraretinal or sub-pigment epithelial scar or glial tissue or fibrin-like deposits. Several classification systems have evolved over the years to define this entity and describe the various stages. The commonest ones used in epidemiological studies is 81

the Wisconsin ARMD grading system. The stages as defined by the Wisconsin group are: Category 1: No AMD No or a few small drusen(<63 microns in diameter) Category 2: Early AMD Many small drusen or a few intermediate sized drusen(63-124 microns in diameter) or macular pigmentary changes Category 3: Intermediate AMD Extensive intermediate drusen or at least one large drusen(≥125 microns), or geographic atrophy not involving the foveal center. Category 4: Advanced AMD

Geographic atrophy involving the foveal center (atrophic or dry AMD) Choroidal neovascularisation (wet AMD) or evidence for neovascular maculopathy (Sub retinal haemorrhage, serous retinal or RPE detachments, lipid exudates or fibrovascular scar). II. INCIDENCE OF THE CONDITION IN OUR COUNTRY : Several incidence and prevalence studies have been undertaken in various parts of India. These studies show an overall prevalence of AMD in India for early AMD is

similar to that seen in western countries. However, the incidence of late AMD is found to be comparatively less. The prevalences of early and late age-related macular degeneration were 2.7% (95% CI, 2.2%-3.2%) and 0.6% (95% CI, 0.4%-0.8%), respectively (ACES 2004). Another study found the overall prevalence of AMD in south India to be 1.87% (APEDS 2005). Most recent data show a prevalence of blindness in late AMD of 1.8% (INDEYE study).This data indicates that the condition is

rapidly increasing or is being increasingly recognized and is a significant health hazard and cause for blindness in our country. III. DIFFERENTIAL DIAGNOSIS The widely variable clinical presentation and sometimes unpredictable natural history are important confounding features in the correct diagnosis of AMD. Variable degenerative and dystrophic diseases of the retina and RPE, in which pigmentary mobilization or lipofuscin accumulation are major findings, share fundamental

clinical features with the dry form of the disease. The common differential diagnoses for dry AMD are • Bests disease • Pattern dystrophies of RPE • Cuticular drusen, pseudo vitelliform detachment • Stargardts disease. • Central serous retinopathy. • Chloroquine toxicity 82

• Dominant drusen • Membranoproliferative glomerulonephritis Type II Wet AMD has to be differentiated from • Angioid streaks • Sub retinal neovascular membranes • Myopic CNVM • Choroidal melanoma • Choroidal rupture • Parafoveal telangiectesia. IV. PREVENTION AND COUNSELLING • Prospective, randomized, controlled clinical trials support the use of antioxidant vitamins and minerals in patients with intermediate-risk AMD to reduce the rate of progression to advanced AMD.

• The role of antioxidant supplements in the prevention of AMD or in slowing progression of AMD for those with the early stages of the disease has not been adequately answered in randomized controlled trials. • Patients with intermediate AMD in one or both eyes and patients with advanced AMD in one eye only or vision loss due to AMD in one eye should consider taking antioxidants with zinc on a daily basis • Self screening by the use of Amslers grid should be taught to the patients,

specially those in stage of intermediate AMD. The warning signs have to be explained to them in order to recognise the shift to wet AMD earlier. • Regular follow up of the patients is essential. The interval depends on the stage of AMD. • Rehabilitation of the patients who are already in the stage of advanced AMD by use of low vision aids should form an important part of AMD management protocol. . V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA

*Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited The role of secondary level in diagnosis and treatment of AMD include: • Early diagnosis • Treatment • Prevention of progression 83

• Rehabilitation • Patient education • Human resource development • Documentation. a) Clinical Diagnosis: Diagnosis is mostly clinical. It requires good ophthalmic examination set up with basic instruments such as slit lamp, 90D lenses, Indirect ophthalmoscope. In its earliest stages, macular degeneration may cause the following symptoms:  Blurry distance and/or reading vision;  Distorted vision - straight lines will appear bent, crooked or irregular;  Dark gray spots or blank spots in vision;

 Size of objects may appear different for each eye;  Colours do not look the same for each eye. The disease can be classified according to the stages mentioned earlier and steps for prevention, treatment, rehabilitation or referral as required can be done. b) Investigations: Diagnostic tools such as slit lamp, indirect ophthalmoscope; procedures such as fluorescein angiography, Indocyanine green angiography, autofluoroscence and optical coherence tomography are used to obtain optimal diagnosis.

1. Amsler’s grid: is used to check macular vision and to detect any damage or disease to the macula, which is located at the center of the retina. Basically, it is a grid that consists of evenly spaced vertical and horizontal lines, resembling a piece of graph paper, with a large dot in the middle. While staring or focusing at the dot, patient will be asked if he sees any wavy lines or missing spaces. Any distortion in the perception of the grid could indicate the presence of macular disease or

degeneration. 2. Fundus Fluorescein Angiography (FFA): This is a test involving photography of retina after injecting fluorescein dye. This is usually performed to detect wet AMD. It helps to decide the mode of treatment. 3. Indocyanine Green Angiography (ICG): This is another test done using injectable dye. The helps to highlight the choroidal features well. As there is development of choroidal neovascular membrane in AMD, ICG angiography has good diagnostic value.

4. Optical Coherence Topography (OCT): OCT is a non-invasive, fast, non-contact imaging technique which readily displays intra-retinal, subretinal and sub-RPE fluid, but is limited in its imaging of the choroid due to poor penetration. Its role in CNV detection has a good sensitivity and specificity. c) Treatment: 84

Laser photocoagulation: laser photocoagulation is usually reserved for CNV outside the fovea and for treatment of the variants of exudative AMD, including retinal angiomatous proliferation (RAP) and polypoidal choroidal vasculopathy. Photodynamic therapy (PDT) Indications: 1. Sub foveal predominant classic CNVM (classic CNVM >50% of the area of entire lesion) 2. Small pure occult CNVM 3. Large occult CNVM with definitive decrease n visual acuity. 4. Mixed lesions

Technique :vertiporfirin (6 mg/kg BW) is infused intravenously over 10 minutes.non thermal laser is applied for CNVM for 83 sec ,spot size 1000µ larger than greater linear dimension of the lesion to ensure complete closure. Trans puppilary thermotherapy: uses infra red laser beam to induce neovascular tissue regression by hyper thermia but not coagulation. Technique : over lapping one minute application of 3mm diode laser beam ovar the

area of neovascular tissue ,adjust the power so that retinal blanching does not develop befre45 seconds. Anti angiogenic agents: (i) Bevacizumab (ii) Ranibizumab (iii) Pegatinib sodium. These medications are VEGF antibodies and antibody fragments, respectively. They can help to induce regression of new vessel. • Regular follow up once in 6 months if patient is in dry AMD stage. No specific treatment. Patient is taught about Amsler grid and its use in this stage.

• Anti oxidant and Zinc supplementation if patient is in intermediate AMD stage. • Referral to higher centre for treatment if patient is in exudative AMD stage. • Rehabilitation with low vision aids if there is atrophy or scarring. Standard Operating procedure a. In Patient: Not necessary b. Out Patient: Yes. For investigations and diagnosis. c. Day Care: Yes. For treatment. d) Referral criteria:  Exudative AMD  Difficulty in diagnosing with FFA 85

*Situation 2: At Super Specialty Facility in Metro location where higher- end technology is available a) Clinical Diagnosis: Using slit lamp, 90 D lens and indirect ophthalmoscope. b) Investigations: FFA OCT ICG angiography c) Treatment: • Laser • PDT • TTT • Anti VEGF therapy: Intra vitreal bevacizumab Intravitreal ranibizumab Intravitreal pegatanib sodium. Standard Operating procedure a. In Patient: Not necessary b. Out Patient: This is the standard operating procedure for diagnosis and

treatment such as laser, PDT. c. Day Care: This is required if intra vitreal injections are to be the mode of treatment. V. WHO DOES WHAT? AND TIMELINES Designation Role Doctor Diagnosis of AMD Interpretation of investigations Treatment: Requires skills in Intra vitreal injection and laser delivery. Nurse Vision recording Counselling for treatment and prevention Maintaining proper follow up Technician Fundus photography for documentation Performing FFA, ICGA,OCT . VI. FURTHER READING / REFERENCES 86

1. Bird AC, Bressler NM, Bressler SB, Chisholm IH, Coscas G, Davis MD, et al. An international classification and grading system for age-related maculopathy and age- related macular degeneration. The International ARM Epidemiological Study Group [Internet]. Survey of Ophthalmology. 1995 ;39(5):367-374.Available from: http://www.ncbi.nlm.nih.gov/pubmed/7604360 2. Krishnaiah S, Das T, Nirmalan PK, Nutheti R, Shamanna BR, Rao GN, et al. Risk factors

for age-related macular degeneration: findings from the Andhra Pradesh eye disease study in South India [Internet]. Investigative Ophthalmology & Visual Science. 2005 ;46(12):4442-4449.Available from: http://www.ncbi.nlm.nih.gov/pubmed/16303932 3. Nirmalan PK, Katz J, Robin AL, Tielsch JM, Namperumalsamy P, Kim R, et al. Prevalence of vitreoretinal disorders in a rural population of southern India: the Aravind Comprehensive Eye Study. [Internet]. Archives of ophthalmology. 2004

;122(4):581-6.Available from: http://www.ncbi.nlm.nih.gov/pubmed/15078677 RESOURCES REQUIRED Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1) 1)Ophthalmologist - 1 1)Amsler grid 1)Dilating drops 1)Slit lamp Secondary 2)OP Nurse 1 2)Fundus 2)Fluorescein dye 2)90 D lens level 3)Refraction nurse - 1 fluorescein 3) Needles and 3)20 D lens 4)FFA technician-1 angiography syringes 4)Indirect (optional) 5)ophthalmoscope Fundus camera

2)Tertiary 1)Ophthalmologist - 1 1) FFA 1)Dilating drops 1)Slit lamp level 2)OP Nurse 2 2) OCT 2 Fluorescein dye 2)90 D lens 3)Refraction nurse - 1 3) ICGA ICG dye 3)20 D lens 4)FFA technician-1 3) Anti VEGF 4)Indirect injections 5)Ophthalmoscope 4) Needles and 6)Fundus camera syringes 7)OCT machine 5) Suture materials 8) Laser equipment 9) Operating microscope 87

NAME OF CONDITION: GLAUCOMA Glaucoma is a group of eye diseases with multi-factorial etiology characterized by an acquired loss of retinal ganglion cells manifesting as progressive optic neuropathy with morphological abnormalities in the optic nerve head and retinal nerve fiber layer and visual field effects in which intraocular pressure (IOP) is a major risk factor. In short, it is a pressure sensitive optic neuropathy. It is estimated there are more than 60 million glaucoma cases

worldwide of which 12 million are in India. With a rapidly growing ageing population in India, this figure will increase to 16 million by 2020 and population-based studies in India suggest that more than 90% of glaucoma cases in our country remain undiagnosed. Hence glaucoma is a significant public health problem of our country and requires a concerted effort on part of the health care community to counter irreversible blindness caused by the disease.

There are three major theories regarding the pathogenesis of glaucoma: - • Mechanical (IOP related damage), • Vascular (decrease in blood supply to optic nerve head) and • Biochemical (decrease in neurotrophic factors / increased levels of neurotoxins) Therefore the three possible therapeutic options would be to decrease IOP, increase perfusion to the optic nerve head and provide neuro-protection to retinal ganglion cells. As

of today the only option available to us is to decrease IOP and treat systemic conditions which may compromise the vascular supply to the optic nerve head decreasing the perfusion pressure. Compliance to therapy, affordability of treatment and family history should be ascertained and all siblings of a glaucoma patient encouraged to get their eye checked up. The following table gives the guidelines of glaucoma management in general: Goals for Glaucoma Management

To achieve target IOP and reduce IOP fluctuations with minimal possible medications To administer glaucoma medication which have the least side effects on the quality of life of the patient To achieve this treatment at an affordable and sustainable cost for the patient Monitor the structure and function of the optic nerve for further damage and adjust the target IOP to a lower level if deterioration occurs. To treat non-IOP dependant systemic factors (systemic hypertension, low diastolic perfusion

pressures [diastolic blood pressure minus IOP], diabetes, hyperlipidemia, vasospasm) which may contribute to the development and worsening of glaucomatous optic neuropathy. To educate and involve the patient and his family in the management of the disease process 88

NAME OF CONDITION: ANGLE CLOSURE DISEASE I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: ‘Angle closure’ implies either appositional or synechial closure of the anterior chamber angle. This iridotrabecular contact (ITC) may or may not be associated with raised intraocular pressure (IOP) or glaucomatous optic neuropathy. Various mechanisms are postulated in pathogenesis of primary angle closure (PAC), of which pupillary block constitutes a key element. This results in obstruction of aqueous flow

from posterior chamber of eye to the anterior chamber, resulting in anterior bowing of iris and consequent crowding of the chamber angle. Prolonged apposition may lead to mechanical or functional obstruction to trabecular meshwork outflow and may result in formation of peripheral anterior synechiae (PAS), causing raised intraocular pressure and glaucomatous optic neuropathy. There are various other causes of ITC including position and thickness of ciliary body, iris thickness, lens

position and thickness. Secondary angle closure can also occur in neovascularization, inflammation and gas or oil tamponade of posterior chamber besides other causes. b) Case definitions: Angle closure disease had been classified earlier on the basis of presence or absence of symptoms into three subtypes as acute, intermittent and chronic angle closure .Intermittent and chronic angle closure have since then been reclassified into PAC and PACG as described above.

In recent years, there has been an effort to standardize diagnostic definitions of angle closure glaucomas based on suggestions by International Society of Geographical and Epidemiological Ophthalmology (ISGEO).1 More emphasis is placed on structural (optic nerve head) and functional (visual field) changes to diagnose glaucoma. The amount of ITC (apposition between iris and posterior trabecular meshwork) required to define primary angle closure has been debated. By

consensus, an eye with 180 degrees or more of ITC in dim illumination and non compressive gonioscopy is classified as one having primary angle closure disease.2 Based on associated findings this is further subclassified as: 89

Primary Angle Closure Suspect (PACS) An angle where more than 180(cid:176) of the posterior trabecular meshwork cannot be seen under dim illumination, which, in the presence of normal intraocular pressure and no disc/ field changes suggestive of glaucoma and no peripheral anterior synechiae is classified as primary angle closure suspect. Primary Angle Closure (PAC) An eye with PACS having peripheral anterior synechiae and/or raised intraocular pressure

with no glaucomatous optic neuropathy is classified as primary angle closure. Primary Angle Closure Glaucoma (PACG) An eye with PACS having evidence of glaucomatous damage in the form of glaucomatous disc changes and/or visual field changes is classified as primary angle closure glaucoma. It is not mandatory to have raised intraocular pressure or peripheral anterior synechiae. Secondary Angle Closure Secondary angle closure occurs from known causes which may or may not be associated with pupillary block.

Etiology: Secondary angle closure with pupillary block: • Swollen lens induced (Phacomorphic) • Anterior lens subluxation/ dislocation • Trauma, laxity of zonules, Marfan’s syndrome • Miotic induced secondary closure • Miotics relax the ciliary muscle, causing forward movement of iris-lens diaphragm and may precipitate angle closure. • Synechiae between iris and crystalline lens/ intraocular lens/cornea/ vitreous • These cause a physical obstruction to flow of aqueous from the posterior to anterior

chambers and may result in ‘iris bombe’. • Aphakic pupillary block Secondary angle closure with anterior pulling mechanism without pupillary block • Neovascular glaucomas • Iridocorneal endothelial syndromes • Inflammation • Post penetrating keratoplasty • Epithelial downgrowth • Aniridia Secondary angle closure with posterior pushing mechanism without pupillary block • Ciliary block glaucoma • Iridociliary cysts 90

• Intravitreal silicon oil/ gas induced • Ciliochoroidal effusions • Suprachoroidal haemorrhage • Scleral buckling II. INCIDENCE OF THE CONDITION IN OUR COUNTRY Reported prevalence differences between studies occur due to differing methodology and classification of angle closure in these studies. The estimates of number of people with angle closure glaucoma in 2010 were 15.4 million for the world with India accounting for 3.7 million cases. Estimates of angle closure

glaucoma in 2020 will rise to 21 million for the world and above 5 million for India. The reported prevalence for PACG in Vellore eye study (VES) was 4.32%. In Andhra Pradesh Eye Disease Study (APEDS), the reported prevalence for PACG was noted to be 1.08% with another 2.21% having ‘occludable angles’. The criteria for occulability was different between the studies-the VES considered one half or more angle to be narrow to be considered occludable while APEDS had a criteria of three quarters or

more. Moreover, VES incorporated PAC and PACG together into PACG. The actual prevalence of PACG would have been 0.5% alone. A similar prevalence of 0.5% for PACG was reported by Aravind Comprehensive Eye Survey (ACS). The Chennai Glaucoma Study (CGS), using the current ISGEO criteria reported higher rates for PACS, PAC and PACG in the urban cohort as compared to rural one. The prevalence of PACG was noted to be 0.87% in rural and 0.88% in urban cohorts.

Besides this, 6.3 % were classified as PACS and 0.7% as PAC in the rural cohort as compared to 7.2 and 2.8% in urban cohorts. The prevalence of PACS has been noted to be higher than PAC and PACG in these, implying that all patients of PACS do not necessarily progress to PAC and PACG and the slow rate of conversion for the same. III. DIFFERENTIAL DIAGNOSIS • Secondary pupillary block due to uveitis with iris bombe • Malignant glaucoma • Lens induced angle closure-phacomorphic/ subluxation/ dislocation

IV. PREVENTION AND COUNSELING The majority of patients are asymptomatic. Vision lost in glaucoma cannot be restored. The purpose of therapy is to preserve existing vision. Diagnosis of angle closure needs a detailed slit lamp examination, intraocular pressure assessment, indentation gonioscopy, optic nerve head assessment and investigations as required. Since cataract and glaucoma can coexist and the patient may attribute their vision loss to the former, it

is essential to have a comprehensive eye examination above the age of 40 years at least annually or biannually. Being a progressive blinding disorder, if glaucoma is detected in a patient, the patient is counseled and explained the need for regular eye examinations throughout life. The need to screen close family members of the patient with angle closure disease is stressed as glaucomas at times may be heritable and may show familial predisposition. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS,

TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: History: Most primary angle closure glaucoma in Indian eyes is asymptomatic. A patient may present with intermittent attacks of redness or pain with halos and blurred vision in eyes or may present with acute onset of such symptoms. Previous or concomitant use of

steroids in any form should be noted. Drugs likely to precipitate angle closure such as such as adrenergic and anticholinergic agents, tri and tetracyclic antidepressants, MAO inhibitors and sulfa based such as topiramate to be recorded along with any history of angle closure in family. IOP: Intraocular pressure is preferably assessed with Goldmann’s applanation tonometer. Gonioscopy: 92

A carefully done goniosopy for diagnosis of angle closure is crucial and helps in follow up and management of these patients. Preferably, indentation gonioscopy is done in patients suspected for angle closure to differentiate appositional from synechial closure. It is first done in dim illumination with a short slit beam avoiding the pupil and then on indentation with a bright light. Excessive compression on the gonioscope and/ or excess

light entering the pupil may artifactually open up the angle. Careful assessment of the angle structures with their exact anatomic documentation along with iris contour, iris processes, areas of peripheral anterior synechiae with pigmentation of the angle should ideally be done. Optic nerve head and visual fields assessment: Undilated disc assessment (if possible prior to laser peripheral iridotomy) with a +78/90 Dioptre lens under a slit lamp biomicrosope along with a dilated fundus examination

with nerve fiber layer and optic nerve head assessment. b) Investigations: Automated perimetry (preferably Humphrey 24-2 SITA Standard/ Octopus G1 test) form the gold standard tests for the diagnosis and follow up of the glaucoma patient. In patients with advanced visual field losses 10-2 or macular threshold test on Humphrey may be required. Since visual fields may have a learning curve, it is preferable to have two visual fields with replicable defects to establish a reliable baseline. Serial

stereoscopic disc photographs/disc drawings also form an important additional modality to follow up a patient. c) Treatment: Guidelines to therapy: Treatment for angle closure revolves around intraocular pressure control, assessment and therapy directed to the control of the angle and angle closure, prevention and treatment for acute primary angle closure, preventing progression of glaucoma and thus aiming to preserve a patient’s vision and quality of life. (1) Control of intraocular pressure:

Antiglaucoma medications are prescribed to control IOP for short term either before definitive therapy by laser or surgery and following the same for residual IOP elevation in the long term. All major classes of drugs can be used as for open angle glaucomas such as beta blockers, alpha agonists, carbonic anhydrase inhibitors, prostaglandin analogues, cholinergic agents and hyperosmotic agents can be used depending on their tolerability, side effects and contraindications. However Pilocarpine is usually

contraindicated in lens induced and retro lenticular mechanisms as it may cause forward movement of iris lens diaphragm and shallowing of chamber angle. At low doses, Pilocarpine can be used for relieving residual appositional closure after laser iridotomy or iridoplasty in plateau iris and angle closure patients. 2) Angle control: 93

Laser peripheral iridotomy/ Surgical iridectomy Preferably, a laser peripheral iridotomy (LPI) is done to alleviate pupillary block. It allows the aqueous to bypass the pupil, providing an alternative route for outflow from posterior to anterior chambers of the eye. Surgical iridectomy may rarely be needed in case of failures of laser iridotomy. Laser peripheral iridotomy: Technique The role and limitations and possible complications of laser iridotomy are explained to

the patient. To reduce the risk of post laser IOP spike and inflammation, apraclonidine 1% or brimonidine 0.15/ 0.2% can be used either before or after the procedure. Alternatively, oral/ topical carbonic anhydrase inhibitors or topical glycerine (in case of corneal epithelial edema secondary to raised IOP) can be used in selected patients. It is preferable to reduce IOP to a safe level prior to the procedure. To reduce the risk of

bleeding, selected patients on oral anticoagulants for systemic diseases should be counseled and may be asked to stop their anticoagulants for a few days prior to the procedure. Usually iridotomy is recommended between 11-1 o’ clock beneath the eyelids avoiding the 12 o’ clock position. However, others prefer 3 and 9 o’ clock positions. PI is avoided at lid margins to reduce symptoms of glare formed by tear meniscus. Successful penetration is seen with a gush of pigments in anterior chamber

with a visible deepening of anterior chamber. A minimum opening of 150-200 microns is aimed to ensure patency. Parameters (Nd-YAG laser) Energy: 2-5 mJ, 1-3 pulses/ burst It is preferable to choose a thin area of iris or an iris crypt to reduce the amount of energy and associated complications with the procedure. Pre treatment with pilocarpine to stretch and thin the peripheral iris is helpful. Use of Abraham or Wise lenses with

coupling agents is preferred to enhance magnification and focusing of the laser beam. Complications and follow up after LPI: Possible complications can include IOP spike, blurred vision, bleeding, damage to corneal epithelium or endothelium and rarely damage to lens capsule or the retina. Late complications include progression of cataract and iridotomy closure. Post laser IOP check is done within 1-6 hours and patient is advised tapering dose of topical steroids with antiglaucoma medications as needed.

Reassessment of the angle after pilocarpine effect wears off with documentation of areas of synechial and appositional closure is done. (3) Surgery: Surgery is usually considered in case of failure of medical/ laser management for IOP control or progression of glaucoma despite maximum medical management. Trabeculectomy alone or combined with cataract surgery 94

Cataract surgery alone-helps to reduce crowding of the angle and relative pupillary block. Treatment of primary angle closure disease: PACS As noted, not all patients of PACS progress to PAC or PACG. The treatment needs to be individualized in regards to laser iridotomy or a close follow up. An iridotomy may be considered to reduce the risk of angle closure in future or alternatively the patient may be monitored for IOP elevation and PAS over time. However an iridotomy can be

considered in the following situations: • Fellow eye of an eye with primary angle closure • Confirmed family history of angle closure glaucoma • Eyes requiring frequent dilation for retinal examination • When follow up is impractical or a poorly compliant patient • Symptomatic patient • Difficulty in opening the angle with compression, with areas of patchy trabecular meshwork pigmentation In case iridotomy is deferred, patients are warned about symptoms of angle closure and

are counseled for regular check ups. The possible risk of angle closure by medications such as decongestants and motion sickness is warned. PAC and PACG Laser peripheral iridotomy to relieve pupillary block is recommended as first line therapy. Appositional or synechial closure of the angle with concomitant damage to trabecular meshwork can cause rise in IOP. However, medical treatment should not be used as a substitution of laser in cases of PAC and PACG.

After component of pupillary block has been removed, further management on lines of open angle glaucomas is done to prevent pressure induced glaucomatous optic neuropathy and visual field progression by topical hypotensive agents and/or surgery. Plateau Iris Configuration/ Syndrome Elimination of element of pupillary block by LPI is recommended as first line of treatment. Iridoplasty helps opening up non synechial areas of the angle in selected

patients. Chronic use of low dose miotic therapy may prevent further closure of the angle. Acute Primary Angle Closure Initial treatment is medical to lower IOP to a level when definitive therapy by LPI can be performed. Medical therapy includes topical hypotensive agents and systemic agents to reduce IOP rapidly. However, topical mioics may not be effective at times in an ischemic pupillary 95

sphincter. Indentation with a 4 mirror gonioscope or a cotton tipped applicator has been used to break the acute attack. Laser iridectomy of the affected eye is the definitive management. It is done along with prophylactic iridectomy of the fellow eye, if narrow. This is done as nearly 50% of fellow eyes have been reported to develop acute closure within 5 years of the fellow eye. Following LPI, reassessment of the angles by gonioscopy

is done to determine extent of synechial closure. IOP is controlled by antiglaucoma medications and optic nerve head damage and visual field assessment is done to outline further management. In case of extensive synechial closure, incisional surgery for glaucoma can be considered for IOP control, although it carries a high risk of post operative complications such as shallow anterior chamber and malignant glaucoma. Treatment of secondary angle closure glaucomas:

The treatment of secondary glaucomas is directed to the primary event causing angle closure which is based on the underlying mechanism of angle closure—pupillary block, or non pupil block (anterior pulling/ posterior pushing) mechanisms. Thus, treatment of secondary glaucomas may require relief of pupil block (iris bombe/ lens induced) with YAG peripheral iridectomy and treatment of underlying in inflammatory disorder. Raised IOP is treated with topical/ oral antiglaucoma medications as needed.

Standard Operating procedure a) In Patient  Acute primary angle closure unresponsive to medical therapy/lasers  Lens induced (Phacomorphic glaucoma)  Symptomatic secondary angle closure requiring hyperosmotics for IOP control b) Out Patient  PACS, PAC, PACG, Secondary glaucomas  Acute primary angle closure (following laser iridotomy and the patient is asymptomatic) c) Day Care • Not applicable d) Referral criteria: immediate referral on presentation if there is

Acute primary angle closure with uncontrolled IOP on maximum therapy and facilities for laser peripheral iridotomy are not available Facilities for cataract surgery not available in lens induced glaucomas (phacomorphic) Children (acute intraocular pressure lowering measures initiated prior to referral; laser or surgical therapy to be done at higher centres) 96

Referral following initial treatment if,  Secondary glaucomas without facilities to treat the underlying cause (for example laser iridotomy for pupil block/ surgery (ex. in microspherophakia or lensectomy for subluxated crystalline lens)  Nanophthalmos requiring surgery  Previous failed trabeculectomy uncontrolled on maximum antiglaucoma therapy  Patients requiring tube implants  Only seeing eye  Post congenital cataract surgery with uncontrolled IOP on therapy

 Complications of filtration surgery requiring surgical intervention (cid:252) Failing bleb (cid:252) Large choroidal haemorrhage/ effusions (cid:252) Bleb leaks (cid:252) Blebitis and endophthalmitis *Situation 2: At Super Specialty Facility in Metro location where higher- end technology is available The clinical diagnosis and management is done on the same general guidelines as given above. a) Clinical Diagnosis: A Perkins tonometer or Tonopen (especially in case of corneal scarring precluding the

use of a Goldmann’s tonometer) may be used for IOP measurement. b) Investigations: Ancillary investigations which may aid clinical diagnosis and management include Imaging of anterior segment: A carefully done gonioscopy remains the gold standard for diagnosis of angle closure. There are various imaging tools to help evaluate the anterior segment of the eye. Anterior segment optical coherence tomography and ultrasound biomicroscopy play a key role in

selected patients with angle closure. Both allow qualitative and quantitative assessment of anterior segment of the eye, although AS-OCT is unable to assess structures posterior to the iris. Biometry To assess the axial length, lens thickness and anterior chamber depth (Refer ‘Risk factors’ above) Imaging of optic disc and nerve fibre layer Use of HRT, GDx and OCT (Retinal nerve fiber layer assessment) (if available) C)Treatment: (1) Control of IOP as outlined above (2) Angle control

Both Argon and Nd-YAG lasers can be used either alone or sequentially to achieve an iridotomy. Use of Nd-YAG laser for iridotomy has been described above. In sequential use, photocoagulative effects of argon laser are combined with photodisruptive effects of Nd- YAG laser. This is especially useful in cases of thick irides and to reduce the risk of bleeding. Argon laser is used first to thin the iris and then the Nd-YAG laser is used for penetration. Parameters (Argon laser) Stretch Burns:

Spot size: 200-500 µm Exposure time: 0.2-0.5 sec Power: 200-600 mW Penetration burns: Spot size: 50 µm Exposure time: 0.02 sec Power: 800-1000 mW Argon laser peripheral iridoplasty. (3) Surgery Trabeculectomy alone or combined with cataract surgery Cataract surgery alone-helps to reduce crowding of the angle and relative pupillary block. Tube implant surgery Management of complications of glaucoma surgery causing secondary closure of angle Malignant glaucoma

• Aqueous suppressants/ cycloplegics (miotics are contraindicated) • Nd-YAG hyaloidotomy along with posterior capsulotomy in pseudophakics • -Pars plana vitrectomy Secondary closure choroidal effusion -Topical steroids/ cycloplegics with or without systemic steroids - Choroidal drainage if conservative measures fail Acute primary angle closure Other modalities attempted include iridoplasty and paracentesis for temporary lowering of

IOP. In case LPI is not possible, iridoplasty or surgical iridectomy can be attempted. Cataract surgery alone or combined with goniosynechiolysis have been reported with varying success rates. This approach may be attempted in eyes not amenable to laser iridotomy or surgical iridectomy, however the risks and benefits should be weighed beforehand. Genetic counseling: This forms an important tool to educate and inform patients about higher risk of glaucoma in close relatives and children.

a. In Patient • Patients requiring surgical intervention • Acute primary angle closure with uncontrolled IOP on maximum therapy /laser peripheral iridotomy not complete (symptomatic patient) • Lens induced glaucomas (phacomorphic) • Blebitis and Endophthalmitis • Malignant glaucoma refractory to medical management b. Out Patient • PACS, PAC, PACG, Secondary glaucomas c. Day Care • Not applicable d)Referral criteria: • Not applicable VI .WHO DOES WHAT? and TIMELINES a. Doctor

• Clinical history and examination • Visual acuity • Intraocular pressure measurement • Gonioscopy • Undilated/ dilated fundus examination • ASOCT/ UBM • YAG peripheral iridotomy/ Iridoplasty • Surgery if indicated b. Nurse/Technician • Preparing the patient for laser treatment • Ancillary tests-Pachymetry, Visual fields, Disc photography • Compliance to therapy for inpatients VII FURTHER READING / REFERENCES: Please refer at the end of the chapter 99

RESOURCES REQUIRED: Situation HUMAN INVESTIGATION DRUGS & EQUIPMENT RESOURCES S CONSUMABLES 1) 1) Ophthalmologist 1) Visual fields 1) Antiglaucoma 1) Slit lamp Secondary -1 medications biomicroscope-1 2) Pachymetry level 2) Optometrist/ 2) Topical steroids 2) Goldmann applanation 3) Disc Technician -1 tonometer -1 photographs 3) Irrigating 3) OP Nurse -1 (desirable) Solutions 3) Indentation gonioscope -1 4) Viscoelastic (preferable Sussman/ agents Posner/ Zeiss) 5) Mydriatics & 4)90D/ 78 D lens-1

Cycloplegics 5) Indirect 6) Antibiotic eye ophthalmoscope-1 drops 6) Operating Microscope 7) Intraocular lenses 7) Microsurgical Instruments 8) Needle and syringes 8) Pachymeter 9) Suture 9)Nd-YAG laser materials 10) Lenses for PI-1 (Abraham/ Wise) 11) Automated perimeter-1 (preferably 12)Humphrey/ Octopus) 100

2) Tertiary 1) Glaucoma 1)Visual fields 1) Antiglaucoma 1) Slit lamp level specialist-1 medications biomicroscope-1 2)Pachymetry 2) Optometrist/ 2) Topical/Systemi 2) Goldmann applanation 3)Biometry Technician -1 c steroids tonometer-1 4)ASOCT 3) OP Nurse -1 3) Irrigating 3) Indentation (desirable) Solutions gonioscope-1 (preferable 4) Scrub nurse -1 Sussman/ Posner/ Zeiss) 5)UBM 4) Viscoelastic 5)OT nurse - 1 101

6) Ward nurse - 1 6)Ultrasound agents 4)90D/ 78 D lens-1 7) Counsellor - 1 6)Disc 5) Mydriatics & 5) Indirect photographs Cycloplegics ophthalmoscope-1 6) Antibiotic eye 6) Pachymeter drops 7)Ultrasound-1 7) Antimetabolites 8)Disc photography-1 8)Ologen 9) A Scan-1 9) Glaucoma 10) Diode laser with laser Drainage Devices delivery system / Cryo-1 10) Intraocular (recurring supplies lenses required for G probe for Diode) 11) Needles & Syringes 11) Nd-YAG laser-1 12) Suture 12) Automated

materials perimeter-1 (preferably Humphrey/ Octopus) 13) ASOCT-1 14) UBM-1 15) Lenses for PI / Iridoplasty -1 16) Operating Microscope 17) Microsurgical Instruments 102

PRIMARY OPEN ANGLE GLAUCOMA I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: POAG is most common form of glaucoma world wide. It is estimated that 45 million people worldwide have POAG. With the exception of Asia, Primary open angle glaucoma (POAG) is far more common than Primary angle-closure glaucoma (PACG) worldwide. b) Case definition: Definition: It is a chronic progressive anterior optic neuropathy characterised by

acquired loss of retinal ganglion cell loss, visual field loss, open angles with no obvious causative ocular or systemic condition. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY In India, Primary open angle glaucoma is estimated to affect 6.48 million persons. Aravind comprehensive eye survey found a prevalence (95% confidence interval) of POAG it was 1.7% (1.3, 2.1) in rural population. The prevalence of POAG in rural south

Indian population as evaluated by Chennai glaucoma study group 1.62%. The prevalence increased with age, and 98.5% were not aware of the disease. Vellore eye study found a prevalence (95% CI) of POAG 4.1 (0.08-8.1) in urban south Indian population. Andhra Pradesh eye disease study found a prevalence (95% confidence interval) of 1.62% (0.77%-2.48%) in urban south Indian population. Studies comparing the prevalence in urban and rural population – Chennai glaucoma study found prevalence of POAG in

south Indian urban population was 3.51%, higher than that of the rural population. Andhra Pradesh eye disease study also found the prevalence to be greater in urban population (4% vs 1.6%; P<0.001). III. DIFFERENTIAL DIAGNOSIS • Optic nerve anomalies: coloboma, pits, oblique insertion • Primary optic atrophy • Past history of steroid usage • Past history of trauma or surgery • Ischemic optic neuropathy (arteritic/non arteritic) IV. PREVENTION AND COUNSELING 103

Once the blindness of glaucoma has occurred there is no treatment that will restore the lost vision. In nearly all cases blindness from glaucoma is preventable, which requires early diagnosis and proper treatment. Detection depends on the ability to recognize the early clinical manifestations of various glaucomas. Appropriate treatment requires an understanding of the pathogenic mechanisms involved, detailed knowledge of drugs and operations that control IOP. Infact

sometimes, a patient needs to be followed up for an extended period of time before a decision to treat can be made. Retinal nerve fiber layer loss precedes measurable optic nerve head and conventional white on white perimetry changes in early glaucoma.Hence patients should be counseled regarding the asymptomatic nature of the disease, importance of treatment, correct technique of eye drop application and regular follow up. Each patient should be educated about different modalities of treatment.

V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited Clinical Diagnosis: Diagnosis: based on comprehensive initial ophthalmic evaluation- • History (ocular and systemic) • Family history of Glaucoma ( Severity and Outcome) • IOP recording by applanation tonometer.

• Larger diurnal variation in IOP either by daytime phasing or 24 hour diurnal phasing. • Gonioscopy to exclude angle closure disease and causes of secondary open angle glaucoma • Steroscopic ONH evaluation (Preferably through dilated pupil) with pictoric fundus diagram. Investigations: • Pachymetry : central corneal thickness affects IOP measurements with higher IOP in thick corneas and lower IOP in thin corneas. • Fundus photography aids in documentation of optic nerve head at baseline and

Treatment: M anagement Goals: • Stable ONH and RNFL status • Controlled IOP • Stable visual fields Standard Operating procedure a. In Patient :Surgical treatment is indicated • IOP not controlled with maximal medical therapy • Contraindication to medical therapy • Poor compliance Surgical options: Trabeculectomy and combined glaucoma and cataract surgery. b. Out patient : Medical management : Most appropriate medication with greatest

chance of reaching target IOP, with good safety profile, convenient dosing and affordable medication should be chosen. Details of the medications, dosage, its adverse effects and follow up schedule are mentioned below. c.Day Care Not applicable VI. Referral criteria: 1. High suspicion of secondary glaucoma is present requiring evaluation for secondary causes 2. For optimal investigations and treatment 3. For management of difficult cases and Post-operative complications 105

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical Diagnosis: Comprehensive ophthalmic evaluation including • History special attention to factors including systemic diseases that influence diagnosis, course and treatment of POAG. • Evaluation of visual function: with respect to difficulties in night driving, near vision and outdoor mobility. o Visual acuity measurement

o Pupil examination: to detect Relative afferent pupillary defect, which is a function of optic nerve o Anterior segment examination by Slit lamp biomicroscopy o Intraocular pressure measurement by Goldmann applanation tonometry o Gonioscopy: § Is pre-requisite for diagnosis of glaucoma to rule out secondary causes like angle closure, angle recession, pseudoexfoliation, pigment dispersion, peripheral anterior synechiae, new vessels, blood in schlemm’s canal and inflammatory precipitates.

• Optic nerve head and retinal nerve fiber evaluation by 90D stereopscopic examination: (cid:252) Disc size. (cid:252) Neuroretinal rim (cid:252) Disc haemorrhage (cid:252) Nerve fiber layer defect. (cid:252) Peripapillary atrophy. (cid:252) Vascular pattern. • Central corneal thickness measurement (CCT) Thicker CCT overestimates IOP readings and thinner CCT underestimates. There is no generally accepted correction formula. Thinner CCT is independent risk factor for

conversion of ocular hypertensive to POAG as proven in Ocular Hypertensive Treatment Study. • Visual field evaluation: characteristics of glaucomatous visual field defects (cid:252) Asymmetrical across horizontal midline. (cid:252) Located in midperiphery.(5-25 degrees from fixation). (cid:252) Reproducible. (cid:252) Not attributable to other pathology. (cid:252) Clustered in neighbouring test points. (cid:252) Defect should correlate with the ONH damage.

• Optic nerve head and retinal nerve fiber layer analysis (cid:252) Slit lamp indirect ophthalmoscopy using 90 D and 78 D lenses. (cid:252) Fundus diagrams. (cid:252) Stereoscopic disc photographs. (cid:252) Red free fundus photography. 106

(cid:252) Confocal scanning laser ophthalmoscopy.(HRT) (cid:252) Scanning laser polarimetry (GDx) (cid:252) Optical coherence tomography. POAG is chronic progressive optic neuropathy that is bilateral and asymmetric in presentation • Evidence of Optic Nerve Head damage (cid:216) Optic disc and retinal nerve fiber layer damage - Diffuse thinning, focal narrowing or notching of neuroretinal rim (NRR) especially at inferior or superior poles - Progressive thinning of NRR with increased cupping

- Diffuse or focal peripapillary nerve fiber layer defects especially at poles - Peripapillary splinter hemorrhages (cid:216) Reliable and reproducible visual field abnormality - Visual field defects corresponding to retinal nerve fiber layer damage (nasal step, arcuate scotoma, paracentral scotoma) - Adult onset (more than 18yrs of age) - Elevated Intraocular pressure > 22 mm Hg in majority of cases on two successive occasions - Diagnosis of exclusion (to exclude pigment dispersion, pseudoexfoliation

and other secondary open angle glaucomas) Severity of glaucoma: (cid:216) HAP Visual Field Severity Score (Based on visual field damage) Criteria for early defect § Mean deviation no worse than −6 dB § On pattern deviation plot, _25% of points depressed below the 5% level and _15% of points depressed below the 1% level § No point within central 5° with sensitivity _15 dB Criteria for moderate defect (cid:216) Mean deviation worse than −6 dB but no worse than −12 dB

(cid:216) On pattern deviation plot, _50% of points depressed below the 5% level and _25% of points depressed below the 1% level (cid:216) No point within central 5° with sensitivity _0 dB (cid:216) Only 1 hemifield containing a point with sensitivity _15 dB within 5° of fixation Criteria for severe defect • Mean deviation worse than −12 dB • On pattern deviation plot, _50% of points depressed below the 5% level or _25% of points depressed below the 1% level

• Any point within central 5° with sensitivity _0 dB • Both hemifields containing point(s) with sensitivity _15 dB within 5° of fixation b) Investigations:  Pachymetry 107

 Visual field  Optic nerve head and retinal nerve fiber layer analysis  Slit lamp indirect ophthalmoscopy using 90 D and 78 D lenses.  Fundus diagrams.  Stereoscopic disc photographs.  Red free fundus photography.  Confocal scanning laser ophthalmoscopy.(HRT)  Scanning laser polarimetry (GDx)  Optical coherence tomography.  Additional Investigations to rule out secondary causes:  B scan, UBM  Fluorescein angiography c) Treatment: Standard Operating procedure a. In Patient

Surgical treatment when (cid:252) target IOP not achieved with medical therapy (cid:252) Any contraindication to medical therapy exists. (cid:252) Has an edge over medical therapy in advanced glaucomas. (cid:252) Poor compliance Surgical options: Trabeculectomy, Combined cataract and glaucoma surgery, non penetrating glaucoma surgeries and aqueous drainage devices. b. Out Patient: Medical and laser therapy : Medical therapy. (cid:252) Effective for majority of patients. (cid:252) Most widely acceptable

(cid:252) Widely available. (cid:252) Most appropriate medication with greatest chance of reaching target IOP, with good safety profile, convenient dosing and affordable medication should be chosen Drug Methods of action IOP Side- effects Contraindications 108

Prostaglan Increased uveoscleral 25-33% Cystoids macular edema Macular edema dins outflow conjunctival injection history of herpes periocular keratitis hyperpigmentation eyelash growth iris colour change, uveitis possible herpes virus reactivation Beta- Decreased aqueous 20-25% Corneal toxicity COPD, asthma, blockers production allergic reactions bradycardia, first congestive heart failure degree heart block, bronchospasm Myasthenia gravis bradycardia CHF, hypotension depression impotence

Alpha- Non-selective: 20-25% Conjuctival injection, Monoamino oxide adrenergic improve aqueous allergic reaction, inhibitor therapy agonists outflow somnolosence, fatigue, infants and children Selective: decrease headache <2 yrs aqueous production, decrease episcleral venous pressure, increase uveoscleral outflow Carbonic Decrease aqueous 15- 20% Topical use: metallic taste Sulfonamide allergy, anhydrase production Corneal edema, allergic aplastic anemia, Renal

inhibitors dermatoconjunctivitis, calculi and Renal Systemic use: Steven failure, sickle cell Johnson syndrome, disease aplastic anemaia, thrombocytopenia, renal calculi,metallic taste, malaise, anorexia, gastric irritation, depression, serum electrolyte disturbance Parasyma Increased trabecular 20-25% Myopia, brow ache, Neovascular pathomim outflow decreased vision, cataract, glaucoma, malignant metic corneal toxicity, glaucoma, periodic agents dermatoconjunctivitis, retinal evaluation

Laser therapy: Selective Laser Trabeculoplasy by Frequency doubled Nd:YAG laser for ouflow enhancement and Diode Cyclophotocoagulation for end stage glaucoma POAG Target IOP not Target IOP achieved achieved Mild Moderate Severe Add or substitute second line medication. Reassess target IOP. Surgical treatment when Target not achieved Follow up - every 5-6months. Follow up every 4 months VF and ONH VF and ONH documentation documentation every 12 every 6 months months

ONH evaluation should be done every visit . ONH and RNFL changes should be documented whenever suspected by means of Stereoscopic fundus photography c. Day Care Trabeculectomy ,combined cataract and glaucoma surgeries, laser therapy, can be done on day care basis ensuring regular follow up. d) Referral criteria: Not applicable. 110

VII. WHO DOES WHAT? and TIMELINES a. Doctor : • Detailed history pertaining to ocular, systemic, past treatment should be obtained. • Visual acuity and refraction should be reviewed. • Detailed slit lamp evaluation with IOP recording, gonioscopy and stereoscopic optic nerve head evaluation should be performed. • Interpretation and clinical correlation of the investigations requested. • Accurate treatment as applicable and monitoring the follow up. b. Nurse / Technician

• Brief ocular history with respect to chief complaints, treatment, compliance should be obtained. • Visual acuity and refraction should be performed at each visit. • Should be trained in obtaining fundus photographs, perimetry and imaging. VIII. FURTHER READING / REFERENCES 1. Jacob A, Thomas R, Koshi SP, Braganza A, Muliyil J Prevalence of primary glaucoma in an urban south Indian population, Indian J Ophthalmol. 1998 Jun;46(2):81-6

2. Ramakrishnan R, Praveen NK, Krishnadas R, et al. Glaucoma in a rural population o southern India: the Aravind Comprehensive Eye Survey. Ophthalmology.2003;110:1484- 1490. 3. Lingam Vijaya,Ronnie George, M. Baskaran,Hemamalini Arvind, Prema Raju,. S.Ve Ramesh,Govindasamy Kumaramanickavel,Catherine McCarty. Prevalence of Primary Open-angle Glaucoma in an Urban South Indian Population and Comparison with a Rural Population: Ophthalmology Volume 115, Issue 4 , April 2008, 648-654.

4. Vijaya. L, George.R, Paul P, et al prevalence of open angle glaucoma in rural south Indian population. Invest Ophthalmol vis sci.2005;46:2261-4467. 5. Dandona L, Dandona R, Mandal P et al. Angle-closure glaucoma in an urban population in southern India. The Andhra Pradesh eye disease study. Ophthalmology. 2000 Sep;107(9):1710-6. 111

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation HUMAN INVESTIGATION DRUGS & EQUIPMENT RESOURCES S CONSUMABLES 1 Ophthalmologist Visual fields Antiglaucoma Slit lamp -1 Pachymetry medications biomicroscope-1 Optometrist/ Disc Topical steroids Goldmann Technician-1 photographs Topical applanation OP Nurse-1 (desirable) anaesthetics tonometer-1

Fluorescien strips. Indentation gonioscope-1 (preferable Sussman/ Posner/ Zeiss) 90D/ 78 D lens-1 Indirect ophthalmoscope-1 Pachymeter Automated perimeter-1 (preferably Humphrey/ Octopus) 2 Glaucoma Visual fields Antiglaucoma Slit lamp specialist-1 Pachymetry medications biomicroscope-1 Optometrist/ Topical/Systemic Goldmann Technician-1 OCT/GDX/HRT steroids applanation OPNurse-1 Fundus camera Topical tonometer-1 Scrub nurse anaesthetics. Indentation OT nurse Fluorescein strips gonioscope-1

Ward nurse Anti – (preferable Sussman/ metabolites. Posner/ Zeiss) 90D/ 78 D lens-1 Indirect ophthalmoscope-1 Pachymeter Disc photography-1 Automatedperimeter -1 (preferably Humphrey/ Octopus) Q switched frequency doubled Nd-Yag laser. Argon laser Diode laser. Glaucoma drainage devices 112

NAME OF CONDITION: INFECTIVE ENDOPHTHALMITIS I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Exogenous Endophthalmitis is a devastating complication, usually following intraocular surgery or open globe injury. Rarely, a hematogenous dissemination into the eye from a distant focus of injection within the body may be a cause and this form is termed as endogenous endophthalmitis in this condition, the internal structure of the eye are

invaded by replicating microorganisms, resulting in an inflammatory response that ultimately may involve all tissues of the eye. This serious condition can be effectively treated if diagnosed early and treated comprehensively. b) Case definition: Endophthalmitis is defined as a serious intraocular inflammation resulting from infection of the vitreous cavity. Exogenous endophthalmitis occurs when infective organisms gain entry into the eye by direct inoculation, such as from intraocular

surgery, intravitreal injections, penetrating trauma, or contiguous spread from adjacent tissues. Endogenous endophthalmitis occurs when infectious agents are hematogenously disseminated into the eye from a distant focus of infection. Initial intraocular signs and symptoms may include decreased visual acuity, afferent pupillary defect, pain, hypopyon, fibrinoid anterior chamber response, corneal edema, corneal/wound infiltrate, vitreous inflammation, retinitis, and/or retinal periphlebitis.

External signs of inflammation, such as ciliary injection, chemosis, and lid edema, may be present. If the infection has spread to orbit, restriction of extraocular motility and proptosis may occur. NCIDENCE OF THE CONDITION IN OUR COUNTRY The national survey on blindness and visual outcome after cataract surgery in 2001, carried out by the ministry of health, Government of India, found an incidence of 0.6%. In a study conducted by a major tertiary care centre, the incidence of post operative

endophthalmitis was found to be 0.09%. Traumatic endophthalmitis accounts for approximately 7% of open globe injuries and nearly a quarter of all endophthalmitis cases. Endogenous endophthalmits accounts for 2.6% of all culture positive endophthalmitis. III. DIFFERENTIAL DIAGNOSIS : The following are the differential diagnosis a) Sterile uveitis b) Phacoanaphylactic endophthtalmitis c) Sympathetic ophthalmia 113

Sterile inflammation may result from retained intraocular foreign material like cotton fibers, from toxic reaction to drugs or irrigating fluids, from operative trauma, from exacerbation of preexisting uveitis, and from other conditions like phacoanaphylactic endophthalmitis and sympathetic ophthalmia. Post trauma or post cataract surgery severe inflammation with true hypopyon can result from retained lens fragments. Ultrasonography may be helpful in establishing the diagnosis. The clinical presentation

depends on cause, therefore the history may be helpful, and should include the details of recent surgery, allergy history and uveitis history. IV. PREVENTION AND COUNSELING The mainstay of prevention of post operative endophthalmitis is maintenance of strict surgical asepsis during any intraocular surgery. The ocular surface and adnexa are the primary sources of microbes in culture positive cases of post operative endophthalmitis.

The use of topical 5% povidine iodine solution in the conjunctival fornices before performing intraocular surgery reduces the bacterial load and decreases the incidence of this condition. The second line of prevention is use of broad spectrum and bactericidial topical / periocular/ intracameral antibiotics. Numerous surgical studies have confirmed that prophylactic antibiotics are maximally effective preoperatively and less effective

postoperatively in preventing endophthalmits. In case of post operative endophthalmitis, prompt referral to a tertiary care centre in case of slightest doubt is mandatory. Investigations have to be immediately performed to rule out any intra ocular foreign body. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis:

The diagnosis of endophthalmitis is based on the clinical presentation, be it postoperative, post-trauma or endogenous. Any eye with inflammation greater than the usual postoperative or post-trauma clinical course should be suspected of having endophthalmitis. Symptomatically, typically the patient notes a sudden increase in pain and decrease in vision which may manifest after a variable time period after an intraocular surgery or open globe injury. Examination demonstrates conjunctival chemosis and 114

increased injection. The upper lid becomes edematous and the cornea shows variable degree of edema. The anterior chamber shows increased flare and cells, and hypopyon is often present in the inferior angle. Fundus view is obscured by focal or diffuse vitritis which manifests as a yellow glow. In more extreme cases the anterior chamber is filled with exudates and the cornea is white. If the infection has spread to orbit, restriction of extraocular motility and proptosis may occur. b) Investigations:

i) When measuring visual acuity, the technique of differentiating light perception from hand motions vision is most important, since this is a major factor in determining candidates most likely to benefit from vitrectomy in postoperative endophthalmitis. Hand motions vision should be determined no closer than 2 feet from the patient with light illumination originating from behind the patient. ii) A diligent clinical examination with slit lamp biomicroscopy should be done to look for

certain risk factors which influence the management. These include wound leak or dehiscence, suture abscess and vitreous incarceration in the wound in postoperative endophthalmitis. Additionally, presence of intraocular foreign body and lens disruption should be recognized in post-trauma endophthalmitis. iii) Ultrasound evaluation of the globe should be performed if significant media opacification prevents an adequate view of the fundus. Findings consistent with

endophthalmitis include dispersed vitreous opacities from associated vitritis and in advanced cases, chorioretinal thickening. The ultrasound examination should rule out associated retinal or choroidal detachment, dislocated lens material, or intraocular foreign bodies. iv) Ocular samples should be obtained for microbial identification. As there are no significant differences in yield of positive cultures among the needle tap, vitreous

biopsy, or pars plana vitrectomy techniques, the surgeon may decide the best possible sampling method based on the resources available. Retrobulbar anesthesia may be necessary but must be administered cautiously in the presence of recent ocular surgical wound or open globe injury. The eye is surgically prepared with povidone iodine 5% solution and rinsed thoroughly with sterile balanced salt solution or normal saline to remove residual antiseptic from the ocular surface. A surgical drape, lid

speculum and operating microscope may be used. A 30 gauge needle attached to a tuberculin syringe is inserted through the limbus into the anterior chamber and an aqueous specimen is aspirated without collapsing the anterior chamber. A quantity of approximately 0.1ml can usually be obtained. A vitreous specimen may be obtained either by vitreous needle tap or by vitreous biopsy with a vitreous cutter. After conjunctival incision, a vitrectomy probe attached to a tuberculin syringe is inserted

into the vitreous cavity through a sclerotomy incision placed 3mm posterior to the limbus. Approximately 0.1-0.3ml of vitreous is removed from the anterior vitreous cavity by using the automated cutting mechanism of the probe and slow, manual 115

aspiration into the syringe. The alternative method, vitreous needle tap, is performed by inserting a 27 to 23 gauge needle attached to a tuberculin syringe into the vitreous cavity through the pars plana, and slowly aspirating a similar volume of fluid vitreous. Samples collected should be sent immediately for Gram and KOH staining. It is ideal to inoculate the samples for culture (aerobic, anaerobic and fungal) within minutes of obtaining them to maximize the culture yield. c) Treatment:

i) Postoperative endophthalmitis: the main treatment is in the form of intravitreal antibiotics since it is the best way to achieve therapeutic concentration in the eye. An empirical treatment with broadspectum antibiotics is initiated concomitantly with the ocular fluid biopsy or core vitrectomy. The recommended combinations of antibiotics for empirical therapy are Vancomycin 1.0mg/0/1ml and Ceftazidime 2.25mg/0.1ml. Amikacin 400 microgm/0.1ml can be considered in exchange for ceftazidime in beta-

lactam sensitive patients. In cases of suspected fungal endophthalmitis intravitreal antifungal agents should be administered. In addition to eradication of viable organisms from the eye and sterilization of the vitreous cavity, control of intraocular inflammation is an important therapeutic goal. Inflammation can increase even when microbes are no longer viable. Corticosteroid administration at the appropriate time - no matter what route is chosen - is to be

administered to reduce the ocular inflammation and maintain the structural integrity of the globe. Immediate vitrectomy should be reserved for severe endophthalmitis with a presenting vision of perception of light. Such cases carry a significant, threefold improved chance of obtaining 6/12 vision in comparison to vitreous tap or biopsy according to endophthalmitis vitrectomy study. However, the procedure is not without risks such as vitreous haemorrhage, retinal tears and retinal detachment. Hence a

limited vitrectomy of the core of the vitreous is advocated by various investigators. Improved viewing systems and instrumentations have enabled surgeons to perform complete vitrectomies with claims of better visual results and fewer complications. It is highly recommended to choose the right amount of vitreous debulking depending on the visibility of the fundus structures and severity of the inflammation. The best way to avoid complications is to keep intraocular pressure at a constant level during the

entire procedure, thereby preventing hypotony. Post surgery management includes use of topical antibiotics based on the culture sensitivity. In situations where no organisms are grown on culture, a combination of antibiotic or a broad spectrum antibiotic should be chosen to cover both the gram 116

negative and gram positive spectrum of causative organisms. Role of systemic antibiotics are debatable considering its low intraocular bioavailability. After initial treatment of endophthalmitis a fraction of patients would require further treatment, mainly for worsening ocular infection or complication from the initial procedure. It typically requires more than 48hrs to observe an improvement in the clinical appearance after initial treatment. But one needs to keep in mind that the

treated eyes look somewhat worse 1 day after treatment before improving subsequently. ii) Traumatic endophthalmitis: When the diagnosis of traumatic endophthalmitis is established, aqueous and vitreous specimen should be obtained for culture and Gram stain. Intravitreal injection with appropriate antimicrobial agent may be given as an initial treatment. But the guidelines for postoperative endophthalmitis treatment may not be applicable for traumatic endophthalmitis because of the diversity of the

organisms encountered. Early closure of the wound, removal of foreign body and Vitrectomy in patients with severe vitritis should be the standard of care in all cases of traumatic endophthalmitis where the injury involves a rupture of ocular coats, or rupture of lens. Patients who do not respond after 48hrs or rapidly deteriorate in the first 24hrs following intravitreal antibiotics should also be treated with vitrectomy. Just

like postoperative endophthalmitis, the exact role of systemic antimicrobial therapy for traumatic endophthalmitis is unclear. Endogenous endophthalmitis: In contrast to postoperative endophthalmitis and traumatic endophthalmitis, systemic antibiotics are central to treatment of the endogenous endophthalmitis, since the source of infection is often remote to eyes. A detailed systemic workup including a general physical examination with special

attention to the heart, skin and extremities should be carried out to look for the source of origin of the infection. When the source of infection is not apparent, special diagnostic studies like echocardiogram, abdominal ultrasonography, culture of blood and urine should be done. Cases of endogenous endophthalmitis with mild inflammation (e.g., focal metastatic abscesses in the anterior or posterior segment) may be treated initially with topical and systemic therapy, using nonocular cultures to

guide treatment. Intravitreal antibiotic injection may be indicated if: 1) the inflammatory focus is in the anterior segment, and the eye is aphakic, or there is a dehiscence in the posterior capsule; or 2) the inflammatory focus is in the posterior segment, and there is significant vitritis. If no improvement is seen within a reasonable length of time or if nonocular cultures are negative, biopsy is indicated. Unlike cases of

postoperative or posttraumatic endophthalmitis, the vitreous may not be the principal 117

site of infection in endogenous endophthalmitis. For this reason, biopsies should be taken from the area that is the primary site of ocular inoculation/inflammation. List of commonly used antibiotics with recommended doses: Antibiotic Topical Subconjunctival Intravitreal Amikacin 20mg/ml 40mg/ml 400micgm Amphotericin B 0.15-0.5% - 5-10micgm Ampicillin 50mg/ml 100mg 5mg Cefazoline 50mg/ml 100mg 2.25mg Ceftazidime 50mg/ml 100mg 2.25mg Ciprofloxacin 0.3% 1mg 100-500micgm Clindamycin - 30mg 250micgm

Fluconazole 0.2% 2%-1ml 10-100micgm Gatifloxacin 0.3% - 400micgm Gentamicin 10-20mg/ml 20mg 200micgm Levofloxacin 0.5% - 625micgm Miconazole 10mg/ml 5mg 25micgm Moxifloxacin 0.5% - 400micgm Tobramycin 8-15mg/ml 20mg 200micgm Vancomycin 50mg/ml 25mg 1mg Voriconazole 1-2% - 100micgm Standard Operating procedure a. In Patient All patients with endophthalmitis should be admitted and treated as in patients b. Out Patient Not applicable c. Day Care Not applicable d) Referral criteria:

i) Postoperative endophthalmitis with presenting vision of light perceptions. ii) Severe postoperative endophthalmitis iii) Traumatic endophthalmitis with lens rupture and intraocular foreign body. iv) Endogenous endophthalmitis worsening in spite of maximum treatment v) Endophthalmitis in the only seeing eye vi) Paediatric patients needing general anaesthesia 118

*Situation 2: At Super Specialty Facility in Metro location where higher- end technology is available a) Clinical Diagnosis: The surgeon at the tertiary care center should elicit the history of the disease afresh to plug the missing links if any, especially in endogenous endophthalmitis. Postoperative and traumatic endophthalmitis history is generally straight forward. A detailed treatment history and the culture results if any should be noted. In culture negative cases fresh

investigations should be initiated to rule out phacoanphylactic endophthalmitis or retained intraocular foreign body. b) Investigations: Meticulous ultrasonogram of the eye may detect retained lens matter. Compuerised tomography may detect occult intraocular foreign bodies in traumatic endophthalmitis. Special investigations like polymerase chain reaction of the vitreous or aqueous samples may be an useful additional diagnostic tool in culture negative cases. A repeat smear and

culture of ocular fluids is mandated. The commonly used stains and culture media are mentioned below. Presumed organisms Stain Media Aerobic bacteria Gram Blood agar Giemsa Chocolate agar Thioglycolate broth Anaerobic bacteria Gram Anaerobic blood agar Thioglycolate broth Fungi 10%KOH Blood agar Gram Saboraud dextrose agar Calcofluor white Brain heart infusion c)Treatment: The culture sensitivity results help in choosing appropriate antibiotics for treatment.

1.Vancomycin and ceftazidime with or without dexamethasone stand as the preferred combinations of intravitreal drugs if no organisms are isolated. 2.A combination of vancomycin with amikacin is advocated as the empirical treatment in traumatic endophthalmitis. 3. In Soil contaminated foreign body injuries where bacillus caerus is suspected, combination of gentamicin with clindamicin in an option. 4. Pars plana vitrectomy remains the treatment of choice in severe endophthalmitis and in

cases where the disease progression is noted in spite of the initial antibiotic treatment. 119

The first technical problem that confronts the surgeon is placement of the infusion cannula. Because the media is almost always too cloudy for the surgeon to be able to visualize a pars plana port, this infusion cannot be used for the initial stages of the operation. Because the incision and placement of the infusion port are easier in a firm eye, it is often worthwhile placing an inferotemporal port with sutures, reserving its use for later in the procedure,

once the location of the tip in the vitreous cavity can be verified. The presence of the crystalline lens or a pseudophakos will determine placement of the canula (3.5mm from limbus in pseudophacos, 4mm in phakic eyes). If light is not needed during the initial portion of the procedure, a bent needle or other blunt infusion canula can be positioned in the center of the pupillary space, where its position can be monitored.

This infusion can be turned on at this stage so that the incision through the pars plana for the cutting instrument may be made in a firm eye. The anterior chamber often contains significant amounts of fibrin and hypopyon. Because the cornea invariably has some combination of epithelial edema, folds, and cells deposited on the posterior surface, the iris and central anterior vitreous are often impossible to visualize adequately. Initial incisions

may be made in the limbus at approximately the 9.30 and 2.30 clock positions, modifying the location as necessary depending on the condition of the previous surgical wound and on the presence of a filtering bleb. Fluid is infused into the anterior chamber as inflammatory debris is removed with the suction and cutting instrument. If an inflammatory membrane extends over the iris surface and the lens, a bent needle can be used to gently peel it off the surface. The vitrectomy is now progressively carried

posteriorly. The vitreous removal is performed initially in the center of the vitreous cavity. Pockets of more heavily infiltrated vitreous are sometimes located; in the aphakic eye, peripheral depression may be used to bring these into view. Aggressive removal of all infiltrated vitreous in the basal area should not be attempted because this often results in retinal tears. The presence of a posterior vitreous detachment, on the other hand, allows

more complete vitreous removal. If the vitreous is still attached, a judgment must be made about the amount of vitreous to be removed. The cutting of vitreous adjacent to inflamed or necrotic retina will often cause retinal breaks; these are difficult to seal and may result in failure of the case. In eyes with posterior vitreous detachment, a white mound of inflammatory debris may be visible over the posterior pole. This should be approached

with care and may be gently aspirated into the cutting port. If the mound proves to be solid and adherent, small amounts can usually be removed, but in most cases it is unwise to attempt to remove large portions. In some instances the material is flocculent and equivalent to an unorganized hypopyon; this can be gently sucked up with vacuum techniques. The procedure is completed by closing all incisions in a watertight manner and

injecting intraocular antibiotics. After closure of the conjunctival incisions, subconjunctival antibiotics are often injected. 120

Standard Operating procedure a. In Patient i) Postoperative endophthalmitis ii) Traumatic endophthalmitis iii) Endogenous endophthamitis b. Out Patient Not applicable C. Day Care Not applicable c) Referral criteria: Not applicable VI. WHO DOES WHAT? AND TIMELINES a. Doctor • Elicits patient history and performs clinical Examination • Collects ocular fluid sample and inoculates for smear and culture • Maintains medical records • Plans the appropriate treatment • Performs surgery

• Monitors, publishes and reports to department of health any emergence of drug resistant strains of microbes. b. Nurse • Maintains separate inpatient and outpatient record • Prepares the patient for operative procedures • Monitors the inpatients to ensure compliance c. Technician • Prepares slide, media for smear and culture • Maintains lab records • Performs ultrasonography when necessary and maintains records 121

FURTHER READING / REFERENCES 1. Brinton GS, Topping TM, Hyndiuk RA, Aaberg TM, Reeser FH, Abrams GW. Posttraumatic endophthalmitis [Internet]. Archives of Ophthalmology. 1984 ;102(4):547- 550.Available from: http://www.ncbi.nlm.nih.gov/pubmed/6704010 2. Doft BH, Kelsey SF, Wisniewski SR. Additional procedures after the initial vitrectomy or tap-biopsy in the Endophthalmitis Vitrectomy Study [Internet]. Ophthalmology. 1998 ;105(4):707-716.Available from: http://www.ncbi.nlm.nih.gov/pubmed/9544646

3. Jackson TL, Eykyn SJ, Graham EM, Stanford MR. Endogenous bacterial endophthalmitis: a 17-year prospective series and review of 267 reported cases [Internet]. Survey of Ophthalmology. 2003 ;48(4):403-423.Available from: http://www.ncbi.nlm.nih.gov/pubmed/12850229 4. Sternberg P, Martin DF. Management of endophthalmitis in the post-endophthalmitis vitrectomy study era [Internet]. Archives of Ophthalmology. 2001 ;119(5):754- 755.Available from: http://www.ncbi.nlm.nih.gov/pubmed/11346404

5. Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group [Internet]. Archives of Ophthalmology. 1995 ;113(12):1479-1496.Available from: http://www.ncbi.nlm.nih.gov/pubmed/7487614 122

RESOURCES REQUIRED Situation HUMAN RESOURCES INVESTIGATION DRUGS AND EQUIPMENT CONSUMABLES 1) Secondary 1)Ophthalmologist - 1 1)Smear test 1)Antibiotics 1) Slit lamp - level 2)OP Nurse 1 2)Gram stain eye drops biomicroscope -1 3)Refraction nurse - microscopy 2)Antifungal 2) Light microscope -1 1(shared ) 3)KOH smear eye drops 3)Disposable needles 3)Systemic 4)Tuberculin syringe- antibiotics 5 steroids and 5) Glass slide - 1 anti fungals 6) Basic stains - 1 4) Mydriatic clyclopigic 5) Needles and syringes

6) Basic stains 2) Tertiary 1) Retina specialist - 1 1)Smear test 1)Antibiotics 1) Slit lamp - level 2)Refraction nurse - 2)Culture eye drops biomicroscope -1 1(shared ) medium 2)Antifungal 2) Light microscop -1 3) OP Nurse - 1 3)Antibiotic eye drops 3) Ultrasonogram -1 4) Lab technician - 1 sensitivity 3)Systemic 4)Vitrectomy 5)Scrub nurse - 1 plates antibiotics and equipment -1 6) OT nurse - 1 4)Corneal anti fungal 5)OT microsurgical 7) Ward nurse -1 biopsy 4) Topical and instruments -1

8) Counsellor - 1 5)PCR systemic 6)PCR instruments -1 steroids 5) Mydriatic and cyclopigic 6) Irrigating solutions 7) Needles and syringes 8) Basic stains 123

NAME OF CONDITION: CHRONIC DACRYOCYSTITIS I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Chronic dacryocystitis is an inflammatory condition of the lacrimal sac most commonly associated with partial or complete obstruction of the nasolacrimal duct . Most chronic dacryocystitis present with watering and discharge, but some may progress and cause severe ocular and extra ocular complication. Even in mild conditions, it may cause a significant ocular morbidity and loss of work place

efficiency because watering can blur the vision momentarily, prevent a person from concentrating on some work and can be socially embarrassing. It affects all ages and all social strata but women are more likely to develop dacryocystitis because of their nasolacrimal ducts are anatomically narrower as compared to males. Approximately 3% of all the ophthalmic clinical visits and 1% of all emergency room visits are related to dacryocystitis. The underlying etiology, typical infectious organisms and

preferred treatments are important issues to understand in the management of this common disorder. b) Case definition: Dacryocystitis is defined as inflammation of the lacrimal sac. The sac is a part of the lacrimal excretory system whose function is to transport the tears from the eyes to the nose. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY Chronic dacryocystitis is a common ophthalmic problem. Although there are no reliable figures that document the incidence or prevalence of chronic dacryocystitis,

large studies from the west have documented it to be around 3% of all the clinical ophthalmic visits. Since the lacrimal system is prone to infections as it is contiguous with both conjunctiva and nasal mucosa, dacryocystitis is considered much more common in developing countries like India. The morbidity is much more than expected because of its chronic nature, social factors as discussed already, tendency for acute painful exacerbations and its complications. III. DIFFERENTIAL DIAGNOSIS

Although chronic dacryocystitis is not very difficult to diagnose, there could still be certain atypical cases which may masquerade in a similar fashion and needs to be kept in mind. They include bacterial conjunctivitis, pre-septal cellulitis, 124

miebomitis, blepharitis and canaliculitis. Points that differentiate and favour bacterial conjunctivitis included sudden onset redness with discharge and diffuse conjunctival congestion. Pre-septal cellulitis is an acute inflammation involving the eyelid, not associated with discharge or long standing epiphora. Meibomitis and blepharitis are usually bilateral associated with irritation of the lid margins and burning sensation. Canaliculitis can be differentiated by focal swelling

of the canalicular portion of the eyelid margin with pouting puncta and inspissated discharge. IV. PREVENTION AND COUNSELING There are no known preventive measures for chronic dacryocystitis. Infections and inflammations are the major known causes for it. Therefore a good hygiene can at least prevent secondary infections of the lacrimal sac from the conjunctiva and nasal mucosa. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA

*Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: History taking, comprehensive evaluation of the eye and understanding of the general epidemic prevalence of this condition in the society is crucial to establish a diagnosis . Patients usually come with typical history of chronic watering, matting of eye lashes on waking, discharge and redness of the eye.

Examination: The ocular examination includes recording visual acuity, an external eye examination and slit-lamp biomicroscopy. Visual acuity measurement: Although visual acuity is normal in patients with dacryocystitis, discharge sliding across the eye may cause visual disturbances. 125

External examination: The following points should be looked for: 1. Increased tear lake 2. Visible or palpable enlargement of the lacrimal sac 3. Discharge which at times may be copious. 4. Regurgitation on pressure over the lacrimal sac or ROPLAS test is a simple confirmatory test, which if positive is diagnostic of nasolacrimal duct obstruction and usually does not require further investigations. 5. Abnormalities of skin like crusting or eczematous lesions suggest chronic

changes caused by watering. Skin may also show a lacrimal fistula or a scar of past acute dacryocystitis or lacrimal abscess. Slit-lamp Biomicroscopy: Should include evaluation of the following: 1. Increased tear film height. 2. Matted lashes. 3. Lacrimal puncta and canaliculi for pouting and discharge 4. Variable types of discharge like clear, mucoid or muco-purulent. 5. Micro regurgitation with ROPLAS test as described earlier can be useful in cases where there is no frank regurgitation.

6. Conjunctival congestion Fluorescein Dye Disappearance test This is a very useful physiological test which is based on the principle of evaluation of residual fluorescien in the eye following instillation of one drop of fluorescein in unanesthetized conjunctival sac. This is a useful functional test specifically in children as it is easy to obtain results. STANDARD PROCEDURE: 1. One drop of 1-2% fluorescein is instilled into the lower fornix of each eye.

2. After 5 minutes the thickness of the fluorescent tear meniscus is measured with the help of cobalt blue filter. 3. Children should be held upright during the test. 4. The tears normally drain down in 5 minutes. The test is positive if residual fluorescein is present. 5. The residual fluorescein is graded as Grade 0- No fluorescence , Grade 1- Thin strip of fluorescence, Grade 2- Between grade 1 and 3, and Grade 3- Wide, brightly fluorescence strip. Diagnostic Probing and Syringing

This is a very simple clinical method which when employed appropriately give useful clues that helps the physician in knowing the presence, location and the form of 126

obstruction in the lacrimal excretory system. The test qualitatively establishes the patency or stenosis or complete obstruction of the canaliculi, lacrimal sac or nasolacrimal duct but does not give any information on functional insufficiencies. STANDARD PROCEDURE: 1. Place a drop of topical anesthetic in the conjunctival cul-de-sac. 2. The punctum and the ampulla are dilated with a punctual dilator. 3. A blunt lacrimal canula is placed in the inferior canaliculus and the lower eyelid is

pulled down and laterally to straighten the lower canaliculus and evert the punctum away from the ocular surface. 4. The tip is placed first vertically and then horizontally with the eyelid on stretch. The tip is advanced 6-7 mm into the canaliculi and sterile water is used as an irrigant. The irrigation should begin in the canaliculi so that the incoming passages are dilated and the mucosa is less traumatized. 5. Irrigation should be preferred when the tip is in the lacrimal sac. Simultaneous

probing can also be done with the same tip of the canula. A hard stop rules out canalicular obstruction whereas a soft stop is indicative of such obstructions. 6. Irrigation should now be interpreted. In a normal passage the saline is felt in the nose or the throat by the patient. Regurgitation through the opposite punctum with a hard stop suggests a nasolacrimal duct obstruction. Regurgitation through the opposite punctum with a soft stop suggests a common canalicular block. In

cases of upper or lower canalicular block, regurgitation is seen through the same puncta. Partial regurgitation is associated with partial blocks respectively. b) Investigations: Chronic dacryocystitis is usually diagnosed by history, physical examination and simple investigations where needed. Microbiological work up: A regular microbiological examination is not necessary unless there are recurrent attacks of acute dacryocystitis, lacrimal abscess or any

associated canaliculitis. If additional microbiological work up is needed or other imaging modalities like computed tomography or dacryocystography is the felt need than a referral to higher center must be thought of. c) Treatment: The treatment of choice in chronic dacryocystitis is dacryocystorhinostomy (DCR). Additional procedures along with dacryocystorhinostomy like intubation, use of adjunctive pharmacotherapy like mitomycin-C and canalicular trephining depends

upon multiple factors like presence of canalicular obstructions, intra-sac synechiae or 127

repeat surgeries. Dacryocystorhinostomy is a bypass procedure that creates an anastomosis between the lacrimal sac and the nasal mucosa via a bony ostium. It may be performed through an external skin incision or endo-nasally with or without endoscopic visualization or via the transcanalicular approach. The most commonly done approach is the External DCR which is still considered as a gold standard in management of chronic dacryocystitis. Standard procedure

1. Adequate nasal decongestion and nasal packing preoperatively is helpful. 2. Anesthesia can be local or general. Local anesthesia includes topical in conjunctival cul-de-sac, infratrochlear block and local infiltration. 3. Skin incision either straight or curvilinear can be used. 4. Periosteum over the anterior lacrimal crest is raised and the lacrimal sac is reflected laterally. 5. A large bony osteum is created respecting the anatomic boundaries.

6. Flaps of nasal mucosa and lacrimal sac raised. Posterior flaps are excised. 7. Adjunctive pharmacotherapy or intubation is done if needed. 8. Anterior flaps are sutured with 6-0 vicryl and skin is sutured with 6-0 silk or prolene. 9. Nasal packing is done to soak the blood and hemostasis. Standard Operating Procedure a. In Patient : • Admit patients after the surgical procedure to monitor the vitals and signs of bleeding especially if they are from far off places.

• Admit patients with complications like orbital cellulitis or severe acute dacryocystitis for intravenous antibiotics. b. Out Patient: Not applicable. c. Day Care: Patients after the surgical procedure are kept under observation for 4-5 hours for any bleeding and then can be discharged if they are stable. d) Referral criteria: • Lacrimal obstruction at multiple sites. • Failed Dacryocystorhinostomy. • Complications of chronic dacryocystitis like recurrent acute exacerbations or orbital cellulitis.

• Chronic dacryocystitis associated with systemic diseases like sarcoidosis or wegeners granulomatosis. 128

• Chronic dacryocystitis associated with suspected dacryolithiasis. • Chronic dacryocystitis where there is a suspicion of a lacrimal sac tumor. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical Diagnosis: Apart from the regular history taking, care should be exercised to fully understand the treatment history of the patient, including all the medications along with the

dosage schedules which were prescribed at the secondary centre. In fact, withdrawal of strong topical antibiotics may be warranted. A fresh comprehensive clinical examination, as detailed in the previous section should be performed without being biased by the referral report. DIAGNOSTIC NASAL ENDOSCOPY: Nasal examination especially nasal endoscopy is obligatory for every lacrimal patient. An endocsopy provides a clear diagnostic looks for nasal anatomical variations,

nasal polyps, deviated nasal septum or tumors of the lacrimal sac. It is a very important for clinical evaluation in postoperative patients and after failed lacrimal surgery. The procedures are performed through rigid or flexible 2.7mm or 4mm endoscopes. STANDARD PROCEDURE 1. Nasal mucosa is decongested and anesthetized with topical medications. 2. The patient either sits or lies in a relaxed position. 3. Nasal vestibule, inferior meatus, floor of the nose and nasopharynx are examined.

4. Middle turbinates and meatus is examined and then the scope is directed postero- superiorly to evaluate the spheno-ethmoidal recess and superior meatus. b) Investigation As the patients are referred from a secondary centre for a non responsiveness to treatment or when diagnosis is additional microbiological and imaging studies may be required. • Culture: Culture and sensitivity of the discharge is indicated specially in cases of orbital cellulitis or recurrent lacrimal abscess. When performed, collect

discharge with a calcium alginate swab moistened with saline. Apart from smears for grams and giemsa staining, culture onto blood and chocolate agar is 129

taken. • Imaging: CT Scans are useful in elucidating facial skeletal anomalies, fractures or foreign bodies as the cause of lacrimal disorder. It is also useful rule out occult malignancy or mass as a cause of dacryocystitis. Dacryocystography(DCG) with subtraction or CT-DCG is very sensitive to study the anatomy of the lacrimal sac and surrounding structures. Dacryoscintigraphy (DSG) is done with the help of Technetium 99 and gamma camera and is useful

in providing certain insights into the functional causes of epiphora. c) Treatment: The treatment strategies should be revisited to check for adequacy, appropriateness and affordability. If the culture and other tests show a different organism, then the treatment regimen should be modified. Surgical procedure includes: 1. External Dacryocystorhinostomy or repeat external DCR as described in the earlier section. 2. Endoscopic endonasal revision of past DCR. 3. Endoscopic guided secondary intubations

4. Canalicular trephining and use of monoka stents 5. Laser assisted DCR or Laser assisted revision of a failed DCR. 6. Conjunctival DCR with Jones tubes. 7. Balloon assisted DCR revision. 8. Balloon dacryoplasty and canaliculoplasty. STANDARD OPERATING PROCEDURE a. In Patient : • All procedures planned under general anesthesia. • Revision DCR’s as there is more tendency to bleed in postoperative period. • Patients with complications like orbital cellulitis on referral or postoperative severe bleeding.

b. Out Patient: Not applicable. c. Day Care: Patients after the surgical procedure are kept under observation for 4- 5 hours for any bleeding and then can be discharged if they are stable. d) Referral criteria: not applicable. 130

VI. WHO DOES WHAT? AND TIMELINES a. Doctor : • Patient history is taken and a clinical examination performed. • Infective material is obtained from discharge and smear are prepared and also materials are inoculated directly onto culture media • Documenting the medical record • Plan treatment guidelines and perform surgery if necessary . • He/she should also ensure that needy patients receive necessary care directly or through referral to appropriate persons and facilities that will provide such care,

and he or she supports activities that promote health and prevent disease. b. Nurse/Technician: • Prepare Slide, Media for smear and culture. • To monitor the patients who are admitted. • To maintain separate inpatient and outpatient record. • To maintain lab reports. VII. FURTHER READING / REFERENCES 1. Mills DM, Bodman GM, Meyer DL, et al. The microbiological spectrum of dacryocystitis: A national study of acute versus chronic infection. Ophthal Plast Reconstr Surg 2007;23:302-306.

2. Chaudhry IA, Shamsi FA, Rashed WA. Bacteriology of chronic dacryocystitis in a tertiary care center. Ophthal Plast Reconstr Surg 2005;21:207-210. 3. Kotlus BS, Rodgers R, Udell IJ. Dacryocystitis caused by community onset methicillin resistant staphylococcus aureus. Ophthal Plast Reconstr Surg 2005;21:371-375. 4. Linberg JV, McCormick SA. Primary acquired nasolacrimal duct obstruction: A clinico-pathological report. Ophthalmology 1986;93:1055-1062.

6. Bartley GB. Acquired lacrimal drainage obstructions: An etiologic classification system, case reports and review of literature. Ophthal Plast Reconstr Surg 1992;8:237-249. 131

6. Rosen N, Mordechai S, Moverman DC et al. Dacryocystorhinostomy with silicone tubes: Evaluation of 253 cases. Ophthalmic Surg 198920:115-119. 7. Dresner SC, Klussman KG, Meyer DR. Outpatient dacryocystorhinostomy. Ophthalmic Surg 1991;22:222-224. 8. Emmerich KH, Busse H, Meyer-Rusenberg HW. Dacryocystorhinostomia externa. Ophthalmologe 1994;91:395-39 Resources required Situation HUMAN RESOURCES INVESTIGATION DRUGS AND EQUIPMENT CONSUMABLES

1) Secondary 1)Ophthalmologist - 1 Smear test 1)Antibiotics eye 1Slit lamp - level 2)OP Nurse - 1 1)Gram stain drops and ointment biomicroscopy -1 3)Refraction nurse - 2)Giemsa stain 2)Steroid eye drops 2)Light microscopy -1 1(shared ) 3)Systemic 3)Alginate swabs – 1 4) OT Nurse -1 antibiotics and 4)Glass slide - 1 5) Scrub Nurse -1 NSAIDS 5) Basic stains - 1 6) Ward Nurse -1 4) Nasal 6) OT Headlight -1 7) Counselor -1 decongestant drops 7) Suction mach -1 5) Nasal steroid 8) Cautery -1

spray. 9) DCR SETS -2 6) Betadine 5% 2) Tertiary level 1)Ophthalmic plastics 1)Smear test 1)Antibiotics eye 1Slit lamp - specialist - 1 2)Culture drops and ointment biomicroscopy -1 2)Refraction nurse - medium 2)Steroid eye drops 2)Light microscopy -1 1 (shared ) 3)Drug sensitivity 3)Systemic 3)Alginate swabs – 1 3)OP Nurse - 1 4)Nasal antibiotics and 4)Glass slide - 1 4)lab technician – 1 endoscopy NSAIDS 5) Basic stains - 1 5)Scrub nurse 1 5) CT Scan 4) Nasal 6) OT Headlight -1

6) OT nurse 1 6) DCG/DSG decongestant drops 7) Suction mach -1 7) Ward nurse - 1 5) Nasal steroid 8) Cautery -1 8) Counselor - 1 spray. 9) DCR SETS -2 6) Betadine 5% 10)Nasal endoscope - 1 132

NAME OF CONDITION : RETINOBLASTOMA I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Retinoblastoma is the most common intraocular malignancy of childhood. It is second only to uveal melanoma in the frequency of occurrence of malignant intraocular tumors. Although it is highly malignant, it is eminently curable. The recent advances such as identification of genetic mutations, replacement of external beam radiotherapy by chemoreduction as the primary management modality, use of

chemoreduction to minimize the size of regression scar with consequent optimization of visual potential, identification of histopathologic high-risk factors following enucleation and provision of adjuvant therapy to reduce the incidence of systemic metastasis, protocol-based management of retinoblastoma with accidental perforation or intraocular surgery and aggressive multimodal therapy in the management of orbital retinoblastoma have contributed to improved outcome in

terms of better survival, improved eye salvage and potential for optimal visual recovery. Life salvage has improved from 30% in the 1930s to nearly 95% now. Early diagnosis and appropriate referral are the keys to better outcome. b) Case definition: Retinoblastoma is a malignant tumor arising from the retinal progenitor cell or the retinal stem cell during the period of retinal development and occurs predominantly in children under 3 years of age. II.INCIDENCE OF THE CONDITION IN OUR COUNTRY

The reported incidence of retinoblastoma ranges from 1 in 10,000 to 1 in 20,000 live births. There are no good epidemiological studies that provide the accurate data on incidence of retinoblastoma in India. It is estimated that 1500 new cases of retinoblastoma occur in India every year. The ICMR Indian Retinoblastoma Registry has recorded 1019 cases from 8 treatment centers between April 2009 to December 2010. There is no racial or gender predisposition in the incidence of retinoblastoma.

Retinoblastoma is bilateral in about 25 to 35% of cases. The average age at diagnosis is 18 months, unilateral cases being diagnosed at around 24 months and bilateral cases before 12 months. 133

III. DIFFERENTIAL DIAGNOSIS The typical clinical manifestation of retinoblastoma is leucocoria. There are several other causes for leucocoria in children that may clinically mimic retinoblastoma in children. Some of the common differential diagnosis are: 1. Coats’ Disease 2. Persistent Hyperplastic Primary Vitreous 3. Toxocara Retinal Granuloma 4. Congenital or Developmental Cataract 5. Endogenous Endophthalmitis 6. Retinal Dysplasia 7. Astrocytic Hamartoma

A good history regarding the time of onset and course of the disease, comprehensive ophthalmic examination often under anesthesia,ultrasonography B-scan and computed tomography scan can reliably help differentiate retinoblastoma from pseudoretinoblastomas. IV. PREVENTION AND COUNSELING Out of the newly diagnosed cases of retinoblastoma only 6% are familial while 94% are sporadic. Bilateral retinoblastomas involve germinal mutations in all cases.

Approximately 15% of unilateral sporadic retinoblastoma is caused by germinal mutations affecting only one eye while the 85% are sporadic. Genetic counseling is an important aspect in the management of retinoblastoma. In patients with a positive family history, 40% of the siblings would be at risk of developing retinoblastoma and 40% of the offspring of the affected patient may develop retinoblastoma. In patients with no family history of retinoblastoma, if the

affected child has unilateral retinoblastoma, 1% of the siblings are at risk and 8% of the offspring may develop retinoblastoma. In cases of bilateral retinoblastoma with no positive family history, 6% of the siblings and 40% of the offspring have a chance of developing retinoblastoma. The families are counseled to have every future sibling screened for retinoblastoma within 3 weeks after birth and periodically thereafter until at least 3 years of age. Apart from empiric genetic counseling as described

above, the current trend is to identify the mutation and compute specific antenatal risk. 134

The most important aspect in the management of retinoblastoma is early diagnosis. Early diagnosis can be achieved by increasing public awareness about the most common obvious signs (white reflex as seen externally or on a photograph of the child or squint) of retinoblastoma so that the parents bring the child to medical attention. Concurrent sensitization of the medical community, specifically the pediatricians, pediatric health care workers and general ophthalmologists about the

possible signs of retinoblastoma and the need for early initiation of management can not be overemphasized. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: A good history eliciting specific symptoms and also a family history of retinoblastoma

are essential. Leucocoria is the most common presenting feature of retinoblastoma, followed by strabismus, painful blind eye and loss of vision. The clinical presentation of retinoblastoma depends on the stage of the disease. Early lesions are likely to be missed, unless an indirect ophthalmoscopy is performed. The tumor appears as a translucent or white fluffy retinal mass. The child may present with strabismus if the tumor involves the macula or with reduced visual acuity.

Moderately advanced lesions usually present with leucocoria due to the reflection of light by the white mass in the fundus. Advanced tumors manifest with proptosis secondary to optic nerve extension or orbital extension and systemic metastasis. Retinoblastoma can spread through the optic nerve with relative ease especially once the lamina cribrosa is breached. Orbital extension may present with proptosis and is most likely to occur at the site of the

scleral emissary veins. Systemic metastasis occurs to the brain, skull, distant bones and the lymph nodes. 135

Some of the atypical manifestations of retinoblastoma include pseudohypopyon, spontaneous hyphema, vitreous hemorrhage, phthisis bulbi and preseptal or orbital cellulites. Examination: The ocular examination includes estimation of vision by age- appropriate means, an external examination, distant direct ophthalmoscopy, examination of the eye under good illumination and magnification, direct ophthalmoscopy and indirect ophthalmoscopy. A child with suspected

retinoblastoma necessarily needs examination under anesthesia. The intraocular pressure is measured and the anterior segment and fundus are examined. Direct visualization of the tumor by an indirect ophthalmoscope is diagnostic of retinoblastoma in over 90% of cases. Visual acuity measurement: Visual acuity assessment in children is difficult. A 3-12 month old child can only be assessed by fixation and following responses and by

determining if one eye is preferred. A child in the age range of 12 months to 36 months can be dynamically assessed using familiar toys. An older verbal child can be assessed by using picture chart and alphabets. External examination 1. Regional enlargement of lymph nodes 2. Eyelid and periocular edema 3. Proptosis and displacement Slit-lamp Biomicroscopy (Handheld slit-lamp in younger children) or Examination under illumination and magnification 1. Conjunctival congestion, circumciliary congestion

2. Anterior extraocular extension 3. Corneal horizontal diameter and clarity 4. Depth of anterior chamber, presence of tumor hypopyon 5. Iris neovascularization 6. Cataract Fundus Evaluation 1. Bilateral fundus examination with 360 degree scleral depression 2. Tumor location, size, morphology, vascularity 3. Extent and location of subretinal fluid, subretinal seeds and vitreous seeds 136

b) Investigations: Ultrasonography B-scan helps in confirming the clinical diagnosis when in doubt or if the tumor is not directly visible because of media haze. CT-scan is reserved only to rule out suspected extraocular extension and MRI to rule out optic nerve or intracranial extension and pinealoblastoma. Fundus fluorescein angiography is rarely performed. Bone marrow biopsy is performed to rule out systemic metastasis in cases with clinical or histopathological risk factors and CSF cytology to rule out

intracranial extension or CNS metastasis. Management: Classification International Classification of Intraocular Retinoblastoma Group A Small tumors (< 3 mm) outside macula Group B Bigger tumors (> 3 mm) or any tumor in macula or any tumor with subretinal fluid Group C Localized seeds (subretinal or vitreous) Group D Diffuse seeds (subretinal or vitreous) Group E Tumor touching the lens, Neovascular glaucoma, Tumor anterior to anterior vitreous face involving ciliary body or anterior segment,

Diffuse infiltrating retinoblastoma, Opaque media from hemorrhage, Tumor necrosis with aseptic orbital cellulitis, and Phthisis bulbi International Staging System for Retinoblastoma Stage 0 No enucleation (one or both eyes may have intraocular disease) Stage I Enucleation, tumor completely resected Stage II Enucleation with microscopic residual tumor Stage III Regional extension A Overt orbital disease B Preauricular or cervical lymph node extension Stage IV Metastatic disease A Hematogenous metastasis

B CNS Extension 1 Prechiasmatic lesion 2 CNS mass 3 Leptomeningeal disease C)Treatment A. Intraocular tumor, International Classification Group A to C, Unilateral or Bilateral Refer to retinoblastoma treatment center B. Intraocular tumor, International Classification Group D, Unilateral or Bilateral Refer to retinoblastoma treatment center C. Intraocular tumor, International Classification Group E, Unilateral or Bilateral 1. Primary enucleation with PMMA orbital implant

Special considerations for enucleation in retinoblastoma • Minimal manipulation • Avoid perforation of the eye • Harvest long (> 15 mm) optic nerve stump • Inspect the enucleated eye for macroscopic extraocular extension and optic nerve involvement • Harvest fresh tissue for genetic studies • Avoid biointegrated implant if postoperative radiotherapy is necessary 2. Send specimen for histopathology and high risk factors predictive of metastasis • Anterior chamber seeding • Iris infiltration

• Ciliary body infiltration • Massive choroidal infiltration • Invasion of the optic nerve lamina cribrosa • Retrolaminar optic nerve invasion • Invasion of optic nerve transection • Scleral infiltration • Extrascleral extension D. High risk factors on histopathology, International Staging, Stage II Refer to retinoblastoma treatment center 138

E. Extraocular tumor, International Staging, Stage IIIA Refer to retinoblastoma treatment center F. Regional Lymph Node Metastasis, International Staging, Stage IIIB Refer to retinoblastoma treatment center G. Hematogenous or Central Nervous System Metastasis, International Staging, Stage IV Refer to retinoblastoma treatment center Standard Operating Procedure a. In-Patient :Admit patients for enucleation b. Out Patient: All older children who can cooperate for examination

c. Day Care: All children undergoing examination under anesthesia c) Referral criteria: a) Intraocular tumor, International Classification Group A to C, Unilateral or Bilateral b) Intraocular tumor, International Classification Group D, Unilateral or Bilateral c) High risk factors on histopathology, International Staging, Stage II d) Extraocular tumor, International Staging, Stage IIIA e) Regional Lymph Node Metastasis, International Staging, Stage IIIB

f) Hematogenous or Central Nervous System Metastasis, International Staging, Stage IV Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical Diagnosis: A good history eliciting specific symptoms and also a family history of retinoblastoma are essential. Leucocoria is the most common presenting feature of retinoblastoma, followed by strabismus, painful blind eye and loss of vision. The clinical presentation

of retinoblastoma depends on the stage of the disease. Early lesions are likely to be missed, unless an indirect ophthalmoscopy is performed. The tumor appears as a translucent or white fluffy retinal mass. The child may present with strabismus if the tumor involves the macula or with reduced visual acuity. 139

Moderately advanced lesions usually present with leucocoria due to the reflection of light by the white mass in the fundus. As the tumor grows further, three patterns are usually seen: • Endophytic, in which the tumor grows into the vitreous cavity. A yellow white mass progressively fills the entire vitreous cavity and vitreous seeds occur. The retinal vessels are not seen on the tumor surface. • Exophytic, in which the tumor grows towards the subretinal space. Retinal

detachment usually occurs and retinal vessels are seen over the tumor. • Diffuse infiltrating tumor, in which the tumor diffusely involves the retina causing just a placoid thickness of the retina and not a mass. This is generally seen in older children and usually there is a delay in the diagnosis. Advanced tumors manifest with proptosis secondary to optic nerve extension or orbital extension and systemic metastasis. Retinoblastoma can spread through the

optic nerve with relative ease especially once the lamina cribrosa is breached. Orbital extension may present with proptosis and is most likely to occur at the site of the scleral emissary veins. Systemic metastasis occurs to the brain, skull, distant bones and the lymph nodes. Some of the atypical manifestations of retinoblastoma include pseudohypopyon, spontaneous hyphema, vitreous hemorrhage, phthisis bulbi and preseptal or orbital cellulites.

Examination: The ocular examination includes estimation of vision by age- appropriate means, an external examination, distant direct ophthalmoscopy, examination of the eye under good illumination and magnification, direct ophthalmoscopy and indirect ophthalmoscopy. A child with suspected retinoblastoma necessarily needs examination under anaesthesia. The intraocular pressure is measured and the anterior segment and fundus are examined. Direct

visualization of the tumor by an indirect ophthalmoscope is diagnostic of retinoblastoma in over 90% of cases. Visual acuity measurement: Visual acuity assessment in children is difficult. A 3-12 month old child can only be assessed by fixation and following responses and by determining if one eye is preferred. A child in the age range of 12 months to 36 months can be dynamically assessed using familiar toys. An older verbal child can be assessed by using picture chart and alphabets. External examination

1. Regional enlargement of lymph nodes 2. Eyelid and periocular edema 3.Proptosis and displacement 140

Slit-lamp Biomicroscopy (Handheld slit-lamp in younger children) or Examination under illumination and magnification 1. Conjunctival congestion, circumciliary congestion 2.Anterior extraocular extension 3.Corneal horizontal diameter and clarity 4..Depth of anterior chamber, presence of tumor hypopyon 5.Iris neovascularization 6.Cataract Fundus Evaluation 1. Bilateral fundus examination with 360 degree scleral depression 2.Tumor location, size, morphology, vascularity

3. Extent and location of subretinal fluid, subretinal seeds and vitreous seeds b) Investigations: Ultrasonography B-scan helps in confirming the clinical diagnosis when in doubt or if the tumor is not directly visible because of media haze. CT-scan is reserved only to rule out suspected extraocular extension and MRI to rule out optic nerve or intracranial extension and pinealoblastoma. Fundus fluorescein angiography is rarely performed. Bone marrow biopsy is performed to rule out systemic metastasis in

cases with clinical or histopathological risk factors and CSF cytology to rule out intracranial extension or CNS metastasis. Management: A. Intraocular tumor, International Classification Group A to C, Unilateral or Bilateral 1. Focal therapy (cryotherapy or transpupillary thermotherapy) alone for smaller tumors (< 3mm diameter and height) located in visually noncrucial areas 2. Standard 6 cycle chemoreduction and sequential aggressive focal therapy for

larger tumors and those located in visually crucial areas 3. Defer focal therapy until 6 cycles for tumors located in the macular and juxtapapillary areas. Transpupillary thermotherapy or plaque brachytherapy for residual tumor >6 cycles. 4. Focal therapy for small residual tumor, and plaque brachytherapy/external beam radiotherapy (>12 months age) for large residual tumor if bilateral, and enucleation if unilateral. 141

B. Intraocular tumor, International Classification Group D, Unilateral or Bilateral 1. High dose chemotherapy and sequential aggressive focal therapy 2. Periocular carboplatin for vitreous seeds 3. Consider primary enucleation if unilateral specially in eyes with no visual prognosis C. Intraocular tumor, International Classification Group E, Unilateral or Bilateral 1. Primary enucleation with PMMA orbital implant Special considerations for enucleation in retinoblastoma • Minimal manipulation

• Avoid perforation of the eye • Harvest long (> 15 mm) optic nerve stump • Inspect the enucleated eye for macroscopic extraocular extension and optic nerve involvement • Harvest fresh tissue for genetic studies • Avoid biointegrated implant if postoperative radiotherapy is necessary 2. Send specimen for histopathology and high risk factors predictive of metastasis • Anterior chamber seeding • Iris infiltration • Ciliary body infiltration • Massive choroidal infiltration

• Invasion of the optic nerve lamina cribrosa • Retrolaminar optic nerve invasion • Invasion of optic nerve transection • Scleral infiltration • Extrascleral extension D. High risk factors on histopathology, International Staging, Stage II 1. Standard 6 cycle adjuvant chemotherapy 2. High dose adjuvant chemotherapy and orbital external beam radiotherapy in patients with scleral infiltration, extraocular extension, and optic nerve extension to transection.

E. Extraocular tumor, International Staging, Stage IIIA 1. Baseline systemic evaluation for metastasis 142

2. High dose chemotherapy for 3-6 cycles, followed by enucleation or extended enucleation, external beam radiotherapy, and continued chemotherapy for 12 cycles F. Regional Lymph Node Metastasis, International Staging, Stage IIIB 1. Baseline evaluation for systemic metastasis 2. Neck dissection, high dose chemotherapy for 6 cycles, followed by external beam radiotherapy, and continued chemotherapy for 12 cycles G. Hematogenous or Central Nervous System Metastasis, International Staging, Stage IV

Palliative therapy in discussion with the family Standard Operating Procedure a. In-Patient : • Admit patients for surgery and chemotherapy • Admit patients with complications following chemotherapy b. Out Patient: All older children who can cooperate for examination c. Day Care: All children undergoing examination under anesthesia and focal treatment. c) Referral criteria: not applicable VI. WHO DOES WHAT? AND TIMELINES a. Doctor : • Patient history is taken and a clinical examination performed

• Documenting the medical record • Plan treatment guidelines and perform surgery if necessary. • Awareness of public and medical personnel b. Nurse/Technician: • Perform lab tests • To monitor the patients who are admitted • To maintain separate inpatient and outpatient record 143

• To administer medications as prescribed by the Physician VII. FURTHER READING / REFERENCES 1. Shields JA, Shields CL. Intraocular tumors – A text and Atlas. Philadelphia, PA, USA, WB Saunders Company, 1992. 2. Shields CL, Honavar SG, Shields JA, Demirci H, Meadows AT, Naduvilath TJ. Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Arch Ophthalmol. 2002;120:460-4.

3. Shields CL, Honavar SG, Meadows AT, Shields JA, Demirci H, Singh A, Friedman DL, Naduvilath TJ. Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation. Am J Ophthalmol. 2002;133:657-64. 4. Shields CL, Honavar SG, Meadows AT, Shields JA, Demirci H, Naduvilath TJ. Chemoreduction for unilateral retinoblastoma. Arch Ophthalmol. 2002;120:1653-8. 5. Murthy R, Honavar SG, Naik MN, Reddy VA. Retinoblastoma. In: Dutta LC, ed.

Modern Ophthalmology . New Delhi, India, Jaypee Brothers; 2004:849-859. 6. Honavar SG, Singh AD. Management of advanced retinoblastoma. Ophthalmol Clin North Am. 2005;18:65-73. 7. Vemuganti G, Honavar SG, John R. Clinicopathological profile of retinoblastoma in Asian Indians. Invest Ophthalmol Vis Sci 2000; 41(S):790. 8. Abramson DH, Frank CM, Susman M, Whalen MP, Dunkel IJ, Boyd NW 3rd. Presenting signs of retinoblastoma. J Pediatr. 1998; 132:505-8.

9. Ellsworth RM. The practical management of retinoblastoma. Trans Am Ophthalmol Soc 1969: 67: 462-534. 10. Shields CL, Shields JA. Basic understanding of current classification and management of retinoblastoma. Curr Opin Ophthalmol.2006;17:228-34. 11. Chantada G, Doz F, Antoneli CB, et al A proposal for an international retinoblastoma staging system Pediatr Blood Cancer 2006:47;801-805 12. Hungerford JL, Toma NMG, Plowman PN, Kingston JE. External beam radiotherapy

for retinoblastoma: I, whole eye technique. Br J Ophthalmol. 1995; 79: 112-117. 13. Ferris FL, 3rd, Chew EY. A new era for the treatment of retinoblastoma. Arch Ophthalmol 1996; 114:1412. 144

14. Kingston JE, Hungerford JL, Madreperla SA, Plowman PN. Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Archives of Ophthalmology 1996; 114:1339-43. 15. Gallie BL, Budning A, DeBoer G, Thiessen JJ, Koren G, Verjee Z, et al. Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 1996; 114:1321-8. 16. Murphree AL, Villablanca JG, Deegan WF, 3rd, Sato JK, Malogolowkin M, Fisher A,

et al. Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol 1996; 114:1348-56. 17. Shields CL, De Potter P, Himelstein BP, Shields JA, Meadows AT, Maris JM. Chemoreduction in the initial management of intraocular retinoblastoma. Arch Ophthalmol 1996; 114:1330-8. 18. Singh AD, Shields CL, Shields JA. Prognostic factors in retinoblastoma. J Pediatr Ophthalmol Strab 2000; 37:134-41.

19. Honavar SG, Singh AD, Shields CL, Demirci H, Smith AF, Shields JA. Post-enucleation prophylactic chemotherapy in high- risk retinoblastoma. Arch Ophthalmol 2002; 120:923-31. 145

Resources required Situation HUMAN RESOURCES INVESTIGATION DRUGS AND EQUIPMENT CONSUMABLES 1) Secondary • 1 Ophthalmologist • Ultrasound B- • Surgical set for • Slit-lamp level • 1 OP Nurse scan enucleation • Perkins • 1 IP Nurse • Facility for applanation • 1 Medicosocial general tonometer worker anesthesia • Direct • Topical ophthalmoscope antibiotics, • Indirect topical steroids, ophthalmoscope oral anti- inflammatory drugs, oral antibiotics

2) Tertiary level • 3 Ocular • Ultrasound B- • Surgical set for • Slit-lamp Oncologist or scan enucleation and • Perkins Ophthalmic Plastic • CT-scan orbital applanation Surgeon or Retinal • MRI exenteration tonometer Surgeon • Pathology • Cryotherapy • Direct • 3 OP Nurse Laboratory • Transpupillary ophthalmoscope • 3 IP Nurse Thermotherapy • Indirect • 2 Medicosocial • Plaque ophthalmoscope worker Brachytherapy • Wide-field • EBRT fundus imaging • Facility for • Fundus Chemotherapy fluorescein

• Facility for angiography general anesthesia • Topical antibiotics, topical steroids, oral anti- inflammatory drugs, oral antibiotics 146

Contents Page S.No. Topic No. 1 JALODARA (ASCITIS) 2 2 KUSTHA (SKIN DISORDERS) 2 3 TAMAKA SHWASA 3 4 KASA (COUGH) 4 5 AJIRNA 5 6 AMVATA 5 7 JWARA 6 8 KAMALA 7 9 SANDHIVATA 7 10 GRAHNI 7 11 SHALAKYA TANTRA 8 12 SHALYA TANTRA 9 13 BALA ROGA 11 14 PANDU (NUTRITIONAL ANEMIA) 13 15 ATISAAR (DIARRHOEA) CHIKITSA SIDDHANT 14 16 CONSTIPATION (VIBANDHA) 14 17 POOR APPETITE/ ANOREXIA 16 18 UDAR KRIMI (WORM INFESTATION) 16 1

STANDARD TREATMENT GUIDELINES JALODARA (ASCITIS) General management includes — • Tridoha pacifying management plan • Deepana • Nityameva virechayeta • Treatment of causative disease • Judicious restriction of fluids. • Intake of milk processed with drugs. Specific management plan – • Various mutra • Tikshna • Kshara • Deepaniya • kapha pecifying • Visravana karma KUSTHA (SKIN DISORDERS) • Avoidance of causative factors (nidāna parivarjana) • Samsodhana therapy • Snehapāna in vāta predominant kuṣtha

• Virecana and raktamoksna in pitta predominant kuṣtha • Vamana in kapha predominant kuṣtha • Repeated samsodhana • Samsamana treatment • Treatment of predominant Doṣha and after that secondary Doṣha should be treated 2

• Internal use of medicine • External application of different lepas and kshara. According to involvement of dhatu • Tvakgata – sodhana, lepana • Raktagata – samsodhana, lepana, kasāyapāna, and raktamoksana. • Māṃsagata – sodhana, ālepana, kasāyapāna, raktamoksana and use of āsava, arista and avleha. • Medogata – use of Bhallataka, Shilajatu, Guggulu, Agara, Tuvaraka, Khadira, Asana & Ayaskriti followed by Samsodhana & Raktamokshna. • Pracchānna followed by sringa or alābu application if localized disease.

• Siravedhana if disease involves the deeper levels of the skin. • Snehapāna followed after raktamokshna to avoid vāta vitiation. • Rakataśodhana • Pitta predominant kuṣtha – use of ghrita processed in tikta rasa predominant herbs. • Ingestion of gomūtra in the condition where there is maggots in lesions with associated loss of skin and phalanges. • Use of agads in dry, hard and chronic lesions associated with loss of sensation. TAMAKA SHWASA General managment includes- 1. Nidana parivarjan

2. Kapha –Vataghan, ushna, Vatanuloman medicine & food, (like Shunthi pippali, yavagu) 3. Shamana & vringhana Chikitsa (Best), 4. Samshodhan (by vamana, virechana, and Dhoompana, nasya karma) 5. In Tamaka Shawasa- Virechana karma (by the medicines which have the vata- kaphashamaka properties) 6. Rasayana chikitsa ( like pipali vardhmana kalpa, chayavanaprasha avaleha) 7. Yoga ( like pranayama ) 3

The treatment should be decided on the following 4 criteria: 1. Strength of patient 2. Predominance of Dosha 3. Stage of Disease (Acute / Chronic ) 4. Age and Condition Of Patient If the patient have good strength with predominance of kapha,, acute stage of disease, young age, Samshodhan chikitsa should be given. If the patient have weak strength with predominance of vata, chronic stage of disease, child old, or pregnant women, very ill should be treated with Samshamana and Vringhana

chikitsa.Therefore person affiicted by shwasa roga, whether corrected or not by samshodhan chikitsa, should be treated by Vringhana and shamana chikitsa but never with karshana chikitsa. Specific Conditions – 1. Use of kshara like Apamarga , if the respiratory passage obstructed by kapha. 2. In acute condition, use of nasya karma by Garlic, Onion juice, 3. T/t protocol in Different condition with tamaka shwasa – i. Acute fever &Aama dosha- Langhana, Ruksha swedana or vomiting by salt water.

ii. Aadhamana & Udavarta- use of food mixed with juice of Citrus medica, Amalavetasa, Asafoetida, Vita salt. iii. Cough & Hoarseness of voice – Vamana karma should be used. iv. Dryness of mouth, palate, & throat – pt should be treated with medicated ghee. KASA (COUGH) General management includes – 1. Avoidance of causative factors 2. For dry cough – Snehana and Swedana 3. For wet cough – Vamana karma Treatment according to predominance of Doshas –

1. In vatic kasa - snehana, swedana, anuvasana basti, and snehic virechana. Medication and food mixed with ghee or oil should be given to the patient. 4

2. In pattika kasa- If kapha is associated with pitta vamana should be given, otherwise virechana should be given. 3. In kaphaja kasa – Vamana, Dhoompana, virechana nasya. Food which have ruksha, ushna, and katu properties should be used. 4. In kshataja kasa – it should be treated like the pattika kasa. drugs & food are used which have properties of -madhura, jivaniya and bala and mamsavardhaka. (like ghee, milk & honey) 5. In kshayaja kasa –the line of treatment is to give alternately Deepana, vringhana,&

shodhana of the vitiated channels. AJIRNA • In amajirna vaman karma • In vidagdhajirna langhan , cold water • In vistabdhajirna swedana, saline water • In rasasesajirna day- sleep , langhan , vata varjana • Take parimita food in anakal • Dont take drug to check pain AMVATA • Langhan • Swedan • Tikta ras food • deepan & katu dravya • virachana • snehpana • basti • anuvasan basti of saindhavadi oil • kasarabasti • food & drinks processed with panacakola • sand-pouches rough fometation 5

JWARA Line of management in taruna jwara/nava jwara/sama jwara (up to 6 days) • Langhana • Swedana karma • Tikta rasa samskrit yavagu sevana → Langhana in Taruna jwara is contraindicated in the Kshayaja Jwara, Anilaja Jwara, Krodhaja Jwara, Kamaja Jwara, Shokaja Jwara and Shramaja Jwara. → Vamana is contraindicated in Taruna jwara but if fever is due to Santarpana or if there is predominance of Kapha in Amashaya then mridu Vamana could be done.

→ Yavagu is not given in the patient suffered from Madatyaya, Urdhwaga Raktpitta, in Grishma ritu(summer season) and in the patient who consume alcohol everyday. In these patient Tarpana is given. After 6 days → Pachana is given in Sama Doshas and Shamaniya Kashaya in Nirama doshas on 8th days. → In the patient whom Kapha is less and who is suffered from Pitta pradhan doshas Ghrit is given after 10th days. → If patient is suffered from Daha, Trishna and Constipation then Dugdha (payasa) is given.

→ If fever is not suppressed due to these procedure and patient′s Agni, Mamsa & strength is good then virechana karma is done. → If patient is Kshina(debilited) due to jwara then Vamana & Virechana is contraindicated. In these patient Niruhana is done after taking payasa(milk). → In the patient who is suffered from purana Jwara and whose Agni is good and who is suffered from Rukshata and constipation then Anuvasana is done.

→ If there is heaviness, headache and Jadyata (stupor like condition ) in jirna jwara then Shirovirechana is done. → Abhyanga, pradeha, parisheka and avagahana with cold &hot drugs can be done in jirna jwara. → For Jirna Jwara which only remained in skin, Dhupana is done. For Sannipataja Jwara → Kaphasthananupurvi chikitsa. 6

→ By increasing one dosha & decreasing increased dosha. For Karnamoola Sotha complication of sannipataja jwara → Raktavasechana, Ghrit pana, Pradeha, Nasya and Kavalgraha. For Vishama Jwara → Sadharana karma → In Vata pradhana vishama jwara- Ghrit pana, Anuvasana Vasti, Niruhana, Snigdha and Ushna Anupana. → In Pitta pradhana vishama jwara- Virechana by milk & ghrit (samskarit ghrit) and uses of Tikta & Shita dravyas. In Kapha pradhana vishama jwara- Vamana, Pachana, Rukshana and Ushna dravyas. KAMALA

→ In Kamala snehana is done by Panchagavya ghrit, Mahatikta ghrit or Kalyanaka ghrit etc. → After snehana Mridu Virechana is done with Tikta rasa pradhana dravyas or Gomutra with milk. → In Shakhashrita Kamla Kaphahara drugs is given. → Katu, Tikshna, Ushna & Lavana drugs is used till proper stool colouration by Pitta and after that Samanya treatment of Kamala is done. → Amla & Katu Rasa sadhita chiken, Peacock, Titar Mamsarasa and Yush of reddish &

kulatha is used for eating. Matulunga juice with Honey, Pippali & Maricha should also used. SANDHIVATA (cid:216) Snehan and swedan (Oleation and Fomentaion) both internal and external is done. (cid:216) If there is no relief after these procedures and doshas are situated in Vasti Pradesh then Mridu Virechan is done or in Kshirna(debilitated) patient Vasti Karma is done. (cid:216) In later stage of Sandhivata when doshas are situated in Shirah –pradesh, Navan Nasya and Dhumpana is done. GRAHNI

• Langhna • Pachana • Agni deepana • Krimi roga chikitsa • In paittika grahni virechna followed by tikta aushadhi. SHALAKYA TANTRA Management protocol of Timir (Refractive errors) A. Langhan --> Paachana --> Kaya shuddhi (Snehapana --> Virechana) --> Shirovirechana Nasya --> Tarpana with Vata Kapha shamak ghritas & Shirovasti B. Chakshusya Rasayan sevan C. Trifla sevana Management protocol of Shushkakshipaka (DES) A. Parishek, Pindi, Vidalak

B. Samshodhana --> Paachana --> Nasya, Anjana, Tarpana, Putpaka, Murdha tail C. Rasayan sevan D. Aamvat chikitsa, if associated. Management protocol of Naktandhya, Pitta vidagdha drishti, Doshandhya (Retinitis pigmentosa): A. Deha samshodhana (Snehana --> Virechana) --> Brimhana Chikitsa (Internal --> Pratimarsha nasya --> Anjana, aashchyotana, seka --> pichu, shirodhara --> Tarpana, Putpaka Management protocol of Karna srava (CSOM):

A. Pramarjana --> Prakshalana --> Dhupana --> Karna purana with vrana shodhana -ropana dravyas B. Concurrently Shiro-virechana 8

Management protocol of Pratishyay (Allergic Rhinitis): A. Nidana Parivarjana B. Snehana (Shiro abhyang & Snehapana) --> Swedana (Upanaha in headache & Sankar in sneezing, nasal discharges) --> Niruha vasti --> Snigdha dhumapan --> Snehan nasya as in Ardit vata C. Hot water for drinking D. Pratishyoyokt internal shaman aushadhis. E. Vatanuloman with Haritaki, Hingu etc. SHALYA TANTRA 1. ARSHA Aushadha Sthanik – Snehana Svedana Dhoopana Avagaha Alepa Pratisarana Vasti Parisheka Abhyantar - Deepana Pachana

Anulomana Raktasamgrahana Samnshamana Samshodhana Kshara Karma Agni Karma Shastra Karma 2. Bhagandara Bhagandara Pidka chikitsa Aptarpana, Aalepa, Parisheka, Abhyanga, Swedana, Vimlapana, Upnaha, 9

Pachana, Vishravana, Snehana, Vamana, virechana. Bhagandara chikitsa Shastra Karma – Bhagandara Marg Chedana followed by application of Agni/ Kshara Karma (if required) & Vranopachara Kshara Sootra Chikitsa 3. Parikartika Proper following of Aahara-Vihara Deepana-Pachana yoga Vibandha hara yoga Vedanahara yoga Sthanik use of Snehana, Svedana, Parisheka, Shodhana & Ropana lepa Vranopachara If Aushadha Chikitsa fails to resolve symptoms or recurrence occurs Shastra Karma Kshara Karma Agni Karma

4. Bhagna (Kanda bhagna & Sandhi Moksha) 4 Principles of management of are- Aanchhana Peedana Sankshepa Bandhana Associated Vedana, Vrana & other symptoms are managed accordingly. 5. Jalodar Chikitsa Sanshodhan chikitsa Nitya virechan Gomutra mishrit teekshna kshar ka prayog Deepniya and kaphghna chikitsa Takra ka prayog Karabham payah Shalya karma Sanshaman chikitsa Aushadha prayoga 6. Gulma Chikitsa Nidana Parivarjana Sanshodhan chikitsa Sanshaman chikitsa Shastra Karma (if required) 7. Mootrashteela 10

Sanshaman chikitsa Sanshodhan chikitsa Shastra Karma 8. Ashmari Sanshaman chikitsa Sanshodhan chikitsa Shastra Karma 9. Mootravhasrotorodha Use of Shalaka on regular intervals Shalya Karma 10. Vrana Application of 60 vranopakarma as required. BALA ROGA 1. RESPIRATORY ALLERGIC DISORDRES (KASA-SWASHA) 1ST LINE MANAGEMENT I. Nidan parivarjan II. Symptomatic approach I. Nidan Parivarjan- Factors responsible for allergy should be avoided. For example

dust, smoke, drinking of atisheet jala (freeze water), intake of atisheet padartha- coldrinks icecreams, dry foodstuffs should be avoided. Contact with allergens should be minimised or prohibited. II. Symptomatic treatment Kasa (Cough) Shuska Kasa (Dry cough) Aadra Kasa (wet cough) i. Drugs imparting the lubricating action, i.Drugs which clears the sputum Suppressing the cough Centre, Correcting the by increasing the quantity’ Mucosal degeneration with Snighdha, laghu, breaking and expectoration. 11

properties drugs like Drugs having ruksha,chhedan Yashtimadhu laghu properties can be used Karkatshring a) Vanshalochan ii. Gritha preparations specific to respiratory b) Marich system-e.g. pippalyadi ghrita c) Pippali iii. yoga: Sitpaladi Churna ii.yoga: Talishadi churna Gojivhadi kwatha Management of Shwasa 1. Vatanulomana: Avipattikara churna, Tarunikususmakara churna 2. Ama pachana: Trikatu, Panchakola 3. Symptomatic : o Herbal Drugs: Kasahara and Shwasahara Drugs e.g. - Kanakasaw, Somasaw, Ahiphenasaw

o Rasa kalpa: Abhraka Bhasma, Rasasindoora, Shwasa kuthara ras, Samirpannag rasa 3RD LINE MANAGEMENT- Panchakarma procedure with Apunarbhava chikitsa 1) Panchkarma procedure a. Snehana- Bahya snehan with til taila and saindhava b. Swedan- local swedan with nadisweda c. Mridu virechan or anuloman d. Matra or anuwasan basti e. Nasya- in allergic rhinitis 2) Apunarbhav chikitsa- can be done with the help of Naimitik rasayan (Immunopotentiating Drugs) e.g. Chyawanprash Agastya haritaki Kantkaryavleha

2. PANDU (NUTRITIONAL ANEMIA) CHIKITSA: Treatment in pandu roga can be divided into: • Shodhana (purificatory measures) • Shaman (palliative measures) 1. Shodhana Teekshan vamana and Virechana are advised in Pandu roga. Prior to purificatory procedures a. Internal administration of snehana is to be done as i) Body’s Sneha quality is greatly reduced in Pandu. ii) Alpraktata, Alpamedaskata and Ojokshaya cause prdominence of rukshata in the body. iii) To bring back the shakhashrita dosha to koshta

Eg. Kalyanaka ghrita, panchgavyaghrita b. Swedana has been contraindicated in Pandu c. Shodhana is done for i) Koshta shuddhi ii) To combat the dosha bahulya 2. Shamana: In shamana oushadha, various single and compound preprations can be used which include herbal, mineral and herbomineral preprations. Drakshadi leha, shuddha kant loha bhasma, vyoshadi ghrita etc TREATMENT ACCORDING TO DOSHA a. Vata- Snehapradhana b. Pitta- Tikta and sheet aushadhi c. Kapha- Katu, ruksha and ushna veerya aushadhi

MRIDBHAKHANJANYA PANDU CHIKITSA Strength of the patient has to be assessed before the treatment. • Shodhana: Tikshna shodhan to remove ingested mud. • Shaman: the palliative measures that can be carried out are as follows medicated ghrita eg. Vyoshadi ghrita • Treatment according to the vitiated dosha • Krimighna chikitsa in Udara Krimi 3. Nidan Parivarjan 13

Kshara, amla, lawan, katu rasa, viruddha bhojan, vidahi bhojan, masha, tila, kulatha, nishpaw etc. 3.ATISAAR (DIARRHOEA) CHIKITSA SIDDHANT AMATISAARA PAKWATISARA 1. Langhan 1. Sangrahi Aushadh 2. Deepan 2. Sthambhak Aushadh 3. Pachan Amatisaara 1. Langhan- laghu aahar e.g. peya, vilepi. 2. Deepan- dhanyapanchak, shunthi 3. Pachan- mustak, ativisha, shunthi, dhanyak Pakwatisara 1. Sangrahi- shunthi, jeerak, gajpippali etc 2. Sthambhan- bilwa, kutaj. 4. CONSTIPATION (VIBANDHA)

1ST LINE MANAGEMENT- DIETARY MODIFICATION Pathya Aahara Vihara 14

1).Vataj stanya dushti may be the cause correct faulty feeding in breast feed child in infant so Snighda and Guru aahar exercise- walking, swimming etc should be used correct bowel habit For eg. i) Ghrita with milk ii) Eranda taila with milk 2). Top feeded child Sukhoshna dugdha with Ghrit 3). Older children- Diet should contain whole grain cereals, bran, green & leafy vegetable, Salad (tomato, onion, cabbage) fresh fruits(grapes, papaya, mango) butter and ghee 4). Plenty of water with fruit juices

2nd line of management- medical treatment Following drugs can be used to treat the constipation in children according to condition- (cid:216) Draksha (cid:216) Eranda taila (cid:216) Kutki (cid:216) Aaragwadha (cid:216) Kumari (cid:216) Haritaki (cid:216) Isabgol Following yoga can be used Triphala churna, avipattikar churna, panchasakar churna, gandharva haritaki Abhayarishta etc 3rd line of management- Panchkarma chikitsa 1) Snehana- 15

a. Bahya snehan- dashmula taila b. Abhyantar snehana- Eranda taila, bala taila 2) Swedana- Sthanik swedana over abdomen and kati. 3) Mridu virechana 4) Basti- niruha, anuwasan and matra basti 5) Gudwarti 5. POOR APPETITE/ ANOREXIA A. Krimighna chikitsa: Includes herbal and herbo-mineral compounds mentioned in classics B. Deepana- Pachana: e.g. chitraka, shunthi, mustaka, jeeraka C. Yakrit-uttejak: e.g., Arogyavardhani vati, Bhumyamalaki, Kalmega, Kumari 6. UDAR KRIMI (WORM INFESTATION)

A. Nidana Parivarjana: Masha, tila, kulatha, nishpaw, pishtanna, gud, ksheer, dadhi B. Prakriti vighata: drugs and diet opposite to kapha and purisha e.g. katu, tikta, kashaya, kshara and ushna drugs C. Krimighna chikitsa: includes herbal and herbo-mineral preparation mentioned in classics. D. Apkarshana: Mridu Virechana/ Asthapana basti 16

STANDARD TREATMENT GUIDELINES Dry Eye Disease Screening, Diagnosis, Assessment and Management of Dry Eye Disease in India Full Background document June 2016 Ministry of Health & Family Welfare Government of India

Contents 1.Introduction 3 2.Background 3 3.Scope 6 4. Recommendations 7 1. Diagnosis 8 2. Management 10 3. Provider & Setting 13 4. Counselling Education 13 5. Prevention 14 5.How the STG was Developed 15 Appendix 1: History & Clinical Evaluation of Dry Eyes 26 Appendix 2: Diagnostic Tests in Dry Eye Syndrome 28 Appendix 3 : Classification/ Grading of Dry eye Disease 30 32 Appendix 4 :Categories of Dry Eye Treatments 33 Appendix5 : Treatment Recommendations for Dry Eye Disease by 34 Disease Severity 36

Appendix 6: Recommendations for treatment and referral of disease by level of Care 40 42 Appendix 7: Computer Vision Syndrome- Clinical Features, Prevention and Management Appendix 8: Methods & Key to Ratings ( Adopted from AAO PPPwww.aao.org/ppp. ) Appendix 9: Adapt/Adopt Recommendations References 55

1.Introduction Dry eye disease is defined as a multifactorial disease of the tears and ocular surface resulting in symptoms of visual disturbance, ocular discomfort, tear film instability with potential damage to the ocular surface. It is associated with hyperosmolarity of the tear film and sub acute inflammation of the ocular surface (DEWS Ocul Surf 2007). Any of the structures including the cornea, conjunctiva, the main or accessory lacrimal glands or the meibomian glands may be

affected in dry eye disease. Classification of dry eyes as “aqueous deficient” and “ hyperevaporative” has been useful in clinical practice. A majority of dry eye is due to hyperevaoporative disorders (caused by dysfunction of meibomian glands) and a combination of aqueous deficient and hyperevoporative forms. Less than 10% of clinical dry eye is due to aqueous deficiency. Several diagnostic and therapeutic approaches have since evolved based on this classification.

Dry eye impairs functional vision, especially reading, computer work and driving. Reading speed is significantly reduced with severity of dry eye disease. Tests in driving simulator have revealed significantly reduced reaction times in those with severe dry eye. 60% of patients report reduction in quality of life while 38% also report reduced efficiency at work. Dry eye disease is also significantly associated with anxiety disorders and depression. While the economic burden of dry

eye is not known in the developing economies like India, the annual treatment costs per patient with dry eye in the US are estimated to be USD 783 and the cost to the health care system has been estimated to be around 3.84 million USD per year. 2. Background Around the world, it is learnt that between 5-34% of people have some form of dry eye and prevalence significantly increases with age. The large variation in prevalence is attributed to

variations in study populations, geographical differences and lack of uniformity in methods and definitions of disease. Dry eye impairs functional vision especially during reading ,driving and while using computers and mobile phones. Reading speed, for instance, is significantly reduced and positively correlates with dry eye disease severity. Reaction times are also significantly reduced while driving. 60% of persons with any severity of dry eye report a decline in quality of

life and a third of patients have reduced efficiency at work attributable to dry eye symptoms. Dry eye disease is also significantly associated with anxiety disorders and depression. While the economic burden of dry eye disease is not studied or reported in lesser developed economies like India, annual treatment costs per patient with dry eye in the US have been estimated to be USD 783 and the total cost to the health care system attributable to dry eye disease management is

estimated to be 2.84 Million USD per year. Currently, there is inadequate understanding of dry eye disease even by ophthalmologists in India. Most symptoms pertaining to the eyes, such as pain, irritation, itching and ocular

discomfort as well as blurring of vision, not accountable by physical examination of the eyes, is attributed to dry eye and treated with tear substitutes and lubricants. Artificial tear substitutes are often prescribed indiscriminately by ophthalmic care providers and is also sold over the counter in pharmacies and dispensaries without advice from ophthalmologists. In current medical and ophthalmic practice, dry eyes are diagnosed and treated by primary care ophthalmic

practitioners, ophthalmic assistants and optometrists and specialist ophthalmologists. However, the role and responsibilities of the various healthcare providers and treatment protocols are not adequately defined. In this background, a common national guideline for providing preventive and curative aspects of management of dry eye disease is essential at primary, secondary and tertiary level of health/eye care. This standard treatment guideline has been formulated with the

initiative from the National Health Systems & Resource Centre of the Ministry of Health & Family Welfare of the Government of India to provide a comprehensive, evidence based guidance on care of persons with dry eye disease. This guideline is intended for use by ophthalmic care providers in management of dry eye at primary, secondary and tertiary level, primary health care physicians. 2.1 Definition Dry eye disease is a disorder of the tear film due to reduced tear production or excessive tear

evaporation, which causes damage to the interpalpebral ocular surface. It is a multifactorial disease of the tear film and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to ocular surface. It is accompanied by increased osmolality of tear film and inflammation of the ocular surface. ( DEWS Workshop, 2007)1,20 2.2 Prevalence of Dry Eye Disease

Epidemiological information on dry eye syndrome has been limited by lack of uniformity in its definition and the inability of any single diagnostic test or set of diagnostic tests to confirm or rule out the condition. Dry eye syndrome is a common condition that causes varying degrees of discomfort and disability. While clinic-based studies confirm its frequency (17% of 2127 consecutive new outpatients were diagnosed with dry eye following comprehensive

examination), such studies may not reflect the overall population2 . In a population-based sample of 2520 elderly (65 or older) residents of Salisbury, Maryland, USA, 14.6% were symptomatic, which was defined as reporting one or more dry eye symptoms often or all the time. The combination of being symptomatic and having a low Schirmer test (≤5 mm with anesthesia) or a high rose Bengal score (≥5) was seen in 3.5% of the residents3 . A population-based study of dry

eye conducted in Melbourne, Australia, using different diagnostic criteria reported higher percentages of the 926 participants aged 40 to 97 who had a low Schirmer test (16.3% ≤8 mm)or a high rose Bengal score (10.8% ≥ 4)4 There is no population-based study in relation to dry eye disease in India. However, there are three published reports on prevalence of dry eye among hospital-based population from North and Eastern India and the prevalence varies between 18.4% and 40.8%5. A study from higher

altitudes reported a higher prevalence of 54%6. Since these data are hospital based, they are

likely to overestimate the prevalence of dry eye. 2.3 Natural History of Dry eye disease Dry eye syndrome varies in severity, duration and aetiology9. In a majority of patients, it is not sight threatening and is characterized by intermittent episodes of blurred vision and symptoms of irritation and ocular discomfort that usually worsens at the end of the day. In some persons, aggravating factors such as systemic medications that decrease tear production or

environmental conditions that increase tear evaporation may lead to an acute increase in the severity of dry eye symptoms. Early identification and elimination of such risk factors leads to marked improvement and may even be curative. Dry eye disease may exhibit chronicity, characterized by fluctuating severity of symptoms and / or gradual increase in severity of symptoms with time. Conjunctival squamous metaplasia and punctate epithelial erosions of the

conjunctiva and cornea develop in many persons with clinically significant dry eye, that is often reversible. Persons with severe dry eye rarely develop complications such as ocular surface keratinization, corneal scarring, thinning or neovascularization, infective or sterile corneal ulceration and perforation and severe visual loss and morbidity10 (AAO Basic & Clinical Course Sub Committee).

6 3. Scope Populations Patient Population covered under this guideline on Dry Eye Disease include persons of all ages with signs and symptoms suggestive of dry eye disease of all causes, including irritation, redness, foreign body sensation, grittiness, blurred or fluctuating vision and decreased tear meniscus. Health Care Setting The recommendations on dry eye disease management provided by this guideline covers care of individuals with dye eye syndrome at primary, secondary and tertiary levels of care.

The intended target users/audience of the treatment guidelines on dry eye disease includes primary eye care technicians, optometrists, comprehensive ophthalmologists, ophthalmic private practitioners, sub specialty ophthalmologists, resident and fellow ophthalmologists. Key Clinical issues/ Clinical Management 1. Ocular evaluation to document signs of Dry eye, assess presence & severity of deficient aqueous tear production and/or increased evaporative loss

2. To establish the diagnosis of dry eye through diagnostic tests § Tear Break Up Time (TBUT) § Ocular Surface Dye testing ( Fluorescein & Rose Bengal staining) § Schirmer testing 3. Classification of Dry Eye Disease as Mild / Moderate / Severe 4. Treatment Recommendations of Dry Eye Disease based on disease severity § Environmental/Exogenous § Medical/ Surgical /Other § Guidelines for Referral of persons with unresponsive dry eye disease

5. Treatment Recommendations for Dry Eye Disease at various levels of Eye Care Provider Setting § Primary ( includes primary health care /family physicians, ophthalmic assistants, and optometrists) § Secondary § Tertiary level of eye care 6. Recommendations on Prevention & Follow up of Dry Eye Disease 7. Patient Counseling &Education 8. Preventive aspects of Dry eye disease Major Outcomes 1. Use & accuracy of diagnostic tests for dry eye disease diagnosis and differentiate from other causes of irritation

2. Identify causes, risk factors of dry eye disease 3. Provision of Evidence based treatment guidelines of dry eye for eye care providers at every level of care 4. Patient comfort & relief of symptomatology from dry eye disease 5. Limiting ocular morbidity from dry eye disease& prevention of complications such as visual loss, infection and ocular surface structural damage 6. To educate and involve the patient in management of dry eye disease

7. Improving Health related Quality of life in Persons with Dry Eye Disease

7 Section 4 - Recommendations 6. Diagnosis 7. Management 8. Provider & Setting 9. Counselling & Referral 10. Prevention of Dry eye disease

8 4.1 Diagnosis of Dry Eye Syndrome 4.1.1. Identify characteristics of the causative factors, such as adverse environments , prolonged visual efforts, or ameliorating circumstances, which is helpful in diagnosing dry eye (III; Good: Strong) AAO 2013 guidelines (adopted) Refer Appendix for causative/risk factors for dry eyes 4.1.2. Use supporting clinical observations and tests to confirm diagnosis of dry eye (III; Good; Strong ) AAO 2013 guidelines (adopted)

Refer Appendix for supporting clinical observations and diagnostic tests 4.1.3. Question about patient symptoms and signs, exacerbating conditions, duration of symptoms and ocular history to elicit helpful information (III; Good; Strong ) AAO 2013 guidelines (adopted) Refer Appendix for supporting clinical observations and diagnostic tests 4.1.4. Pay particular attention to the skin, eyelids, adnexa, proptosis, cranial nerve functions,

mouth, skeletal system and hands(III; Good; Strong ) AAO 2013 guidelines (adapted) ( Reference- Kanski& Rowling)11 4.1.5. On slit lamp biomicroscopy evaluation, focus on the tear film, eye lashes, anterior and posterior eyelid margins, puncta, conjunctiva and cornea. Pay particular attention to Meibomian gland dysfunction in evaluation of tear film. (III; Good; Strong ) AAO 2013 guidelines (adapted)( Reference- Kanski& Rowling)11

4.1.6. Test for anti-thyroid and anti-thyroglobulin antibody in dry eye patients suspected of thyroid eye disease. (III; Insufficient; Discretionary)AAO 2013 guidelines (adopted) 4.1.7. order a B-Scan sonogram or other imaging study to assess extra ocular muscle thickness in patients with dry eye who have suspected thyroid eye disease (III; Good; Strong ) AAO 2013 guidelines(adopted) 4.1.8. Recommend/ Perform conjunctival biopsy for dry eye patients who have significant chronic

conjunctivitis with a nodular appearance or cicatrisation ( III; Insufficient; Discretionary)AAO 2013 guidelines (adopted) 4.1.9. For patients with moderate to severe aqueous tear deficiency, establish the diagnosis by using one or more of the following tests: Tear break-up time test, ocular surface dye staining and Schirmer test ( III; Insufficient; Discretionary)AAO 2013 guidelines (adopted) Refer Appendix for diagnostic tests)

9 4.1.10. Perform these tests in this sequence because the Schirmer test can disrupt tear film stability and cause false positive ocular surface dye staining ( III; Insufficient; Discretionary)AAO 2013 guidelines (adopted) 4.1.11. Allow several minutes between the dye testing and the Schirmer test ( III; Insufficient; Discretionary)AAO 2013 guidelines (adopted) 4.1.12. Assess corneal sensation when trigeminal nerve dysfunction is suspected (III ; Moderate ; Discretionary ) AAO 2013 guidelines (adopted)

4.1.13. Consider a laboratory and clinical evaluation for autoimmune disorders for patients with significant dry eye, other signs and symptoms of an autoimmune disorder or a family history of an autoimmune disorder(III; Good; Strong ) AAO 2013 guidelines (adopted) 4.1.14. Consider testing for an underlying Sjogren Syndrome in patients with moderate punctate staining of the cornea and /or conjunctiva as these patients will require a multi- disciplinary approach. AAO 2013 guidelines (adopted)

4.1.15. Evaluate aqueous tear production with the Schirmer test. It gives variable results and do not use as the sole criterion for diagnosing dry eye. (III; Insufficient; Discretionary)AAO 2013 guidelines (adopted)

10 4.2. Management of Dry Eye Treatment of Mild Dry Eye 4.2.1. Place patients who have suggestive symptoms without signs on trial treatments with artificial tears when other potential causes of ocular irritation have been eliminated ( III; Insufficient; Discretionary)AAO 2013 Guidelines (Adopted) 4.2.2. For patients with a clinical diagnosis of mild dry eye, address potentially exacerbating exogenous factors such as anti histamine or diuretic use, cigarette smoking and exposure to

second hand smoke, and environmental factors such as air drafts and low humidity environments (III; Good; Strong )AAO 2013 Guidelines (Adopted) 4.2.3. Suggest measures such as lowering the computer screen to below eye level to decrease lid aperture, scheduling regular breaks, and increasing blink frequency to decrease the discomfort associated with computer and reading activities ( III; Insufficient; Discretionary)AAO 2013 Guidelines (Adopted)

4.2.4. Prescribe emulsions, gels and ointments to treat dry eye symptoms ( III; Insufficient; Discretionary)AAO 2013 Guidelines (Adopted) 4.2.5. Increase use of artificial tears as required, but recommend frequent tear instillation depending on the lifestyle or manual dexterity of the patient ( III; Insufficient; Discretionary)AAO 2013 Guidelines (Adopted) 4.2.6. Prefer Non preserved tear substitutes ; however, you may recommend tears with

preservatives for patients with mild dry eye and otherwise healthy ocular surface ( III; Insufficient; Discretionary)AAO 2013 Guidelines (Adopted) 4.2.7. Prescribe non preserved tears when tear substitutes are frequently and chronically used ( III; Insufficient; Discretionary)AAO 2013 Guidelines (Adopted) 4.2.8. Use Systemic Doxycycline in patients with evidence of Meibomian gland dysfunction12 AAO 2013 guidelines (Adapted )Expert Group Consensus (Reference- Javadi MA &Feizi )

4.2.9. Correct eye lid abnormalities resulting from blepharitis ( II++; Moderate; Discretionary ) AAO 2013 Guidelines (Adopted)

11 4.2.10. Correct eye lid abnormalities resulting from trichiasis ( III; Insufficient; Discretionary)AAO 2013 Guidelines (Adopted) 4.2.11. Correct eyelid abnormalities resulting from lid malposition ( III; Insufficient; Discretionary)AAO 2013 Guidelines (Adopted) Treatment of Moderate Eye Disease 4.2.12. Use low dose topical corticosteroid therapy at infrequent intervals for short period of time ( i.e several weeks) to suppress ocular inflammation

( I-; Moderate; Discretionary ) AAO Guidelines 2013 (Adopted) 4.2.13. Monitor patients prescribed corticosteroids for dry eye for adverse effects such as increased intraocular pressure and cataract formation ( III; Good; Strong ) AAO Guidelines 2013 (Adopted) 4.2.14. Do not routinely recommend omega-3 fatty acid supplements for dry eye treatment since there is no evidence of their efficacy13 ( I-; Insufficient; Discretionary ) AAO Guidelines 2013 ( Adapted ) Expert Group Consensus Reference -Liu A, Ji J

4.2.15. Consider punctual occlusion for patients with aqueous tear deficiency when medical means of aqueous enhancement are ineffective or impractical (I++; Good; Strong ) AAO 2013 Guidelines ( Adopted ) 4.2.16.Punctal plugs are not routinely recommended for dry eye management in India owing to their relatively high cost. Punctal occlusion by thermal cauterization is preferred for patients with aqueous tear deficiency resistant to medical and conservative measures of treatment14

(III; Insufficient; Discretionary )AAO Guidelines 2013 (Adapted ) Expert Group Consensus Reference-Obha&Doghru 4.2.17. Use non invasive therapies like Eye glass side shields and moisture chambers ( III; Good; Strong ) AAO Guidelines 2013 (Adopted) Treatment of Severe Dry Eye 4.2.18. Hydroxy Propyl Celluslose eye drops, emulsions, gels are frequently used in moderate to severe dry eye. Punctal occlusion may be attempted in patients who are unable to use frequent artificial tears15

(III; Insufficient; Discretionary )AAO Guidelines 2013 (Adapted ) Expert Group Consensus Reference- Ervin; Cochrane Database Review

12 4.2.19. Prescribe autologous serum drops to improve ocular irritation symptoms a well as conjunctival and corneal dye staining in patients with Sjogren syndrome and Graft versus host disease (III; Insufficient; Discretionary )AAO Guidelines 2013 (Adopted) 4.2.20. Treat filamentary keratitis with debridement of the filaments or application of topical mucolytic agents, such as acetylcysteine 10 % four times a day (III; Insufficient; Discretionary )AAO Guidelines 2013 (Adopted)

4.2.21.Perform debridement of filaments with a cotton-tip applicator, dry cellulose sponge, or a non -toothed forceps (III; Insufficient; Discretionary )AAO Guidelines 2013 (Adapted) Expert Group Consensus 4.2.22. Avoid treatment with contact lenses in patients with associated neurotrophic keratopathy ( III; Good; Strong ) AAO Guidelines 2013 (Adopted) 4.2.23. Perform thermal cautery16,17 if permanent punctal occlusion is to be accomplished.

( III; Good; Strong ) AAO Guidelines 2013 (Adapted) Expert Group Consensus References- Nelson & Reed, Vrabec&Elsing 4.2.24. Perform a stepwise punctal occlusion so that no more than one punctum is cauterized in each eye at a treatment session (III; Insufficient; Discretionary )AAOGuidelines 2013 ( Adopted) 4.2.25.perform a limited tarsorraphy to decrease tear evaporation in patients with severe dry eye who have not responded to other therapies (III; Insufficient; Discretionary )AAOGuidelines 2013 ( Adopted)

4.2.26. Recommend Scleral Contact lenses in treatment of severe dry eye18 (III; Insufficient; Discretionary )AAOGuidelines 2013 ( Adapted) Expert Group Consensus Reference-Bavinger&Deloss

13 4.3. Provider & Setting 4.3.1. If you are a health care provider other than an ophthalmologist, refer patients with dry eye who have moderate or severe pain, lack of response to therapy, corneal infiltration or ulceration, or visual loss to an ophthalmologist ( III ; Good ; Strong ) AAO Guidelines 2013 ( Adopted ) Refer Appendix for treatment of Dry eye at Primary, secondary & tertiary levels of eye care 4.4. Counseling & Referral

4.4.1. Educate patients with dry eye about the chronic nature of the disease process and provide specific instructions for therapeutic regimens ( III; Good ; Strong ) AAO Guidelines 2013 ( Adopted ) 4.4.2. Periodically reassess the patients’ compliance and understanding of the disease, the risks for associated structural changes and re inform the patient as necessary ( III; Good ; Strong ) AAO Guidelines 2013 ( Adopted )

4.4.3. Caution patients with pre-existing dry eye that keratorefractive surgery, particularly LASIK may worsen their dry eye condition ( III; Good ; Strong ) AAO Guidelines 2013 ( Adopted ) 4.4.4. Treat dry eye, when present, prior to considering keratorefractive surgery ( III; Good ; Strong ) AAO Guidelines 2013 ( Adopted ) 4.4.5. Refer patients with moderate to severe dry eye unresponsive to treatment or when systemic disease is suspected to an ophthalmologist who is experienced in management of these

entities ( III; Good ; Strong ) AAO Guidelines 2013 ( Adopted ) 4.4.6. Refer patients with systemic immune dysfunction or those who require immunosuppressive therapy to an internist or rheumatologist ( III; Good ; Strong ) AAO Guidelines 2013 ( Adopted ) 4.5 Recommendations for Prevention of Dry Eye Disease Suggest the following recommendations to those at risk of dry eye disease: 4.5.1.Avoid excessive movement and windy conditions ( III, Insufficient, Discretionary; AAO 2013 Guidelines ( Adopted)

4.5.2. Avoid hot, dry environments since both heating and air conditioning can worsen dry eye disease ( III, Insufficient, Discretionary; AAO 2013 Guidelines ( Adopted)

14 4.5.3. Use humidifier to keep the air moist. Adding moisture to the air reduces dry eye symptoms ( III, Insufficient, Discretionary; AAO 2013 Guidelines ( Adopted) 4.5.4. Wear wrap around glasses to reduce effect of wind on ocular surface to reduce evaporative dry eye symptoms. III, Insufficient, Discretionary; AAO 2013 Guidelines ( Adopted) 4.5.5. Recommend taking frequent breaks while reading, seeing television and using mobile phone or computer devices. III, Insufficient, Discretionary; AAO 2013

Guidelines ( Adopted) 4.5.6. Position computer screen below eye level to reduce lid aperture and minimize tear evaporation ; III, Insufficient, Discretionary; AAO 2013 Guidelines ( Adopted) 4.5.7. Recommend refraining from smoking and exposure to secondary smoke; III, Good Strong ; AAO 2013 Guidelines (Adopted) 4.5.8. Recommend use of hot compresses and eye massage; III, Insufficient, Discretionary; AAO 2013 Guidelines ( Adopted)

4.5.9. Recommend use of artificial tears and lubricating gels as soon as symptoms of dry eye disease appear; III, Good , Strong ; AAO 2013 Guidelines (Adopted)

15 Section 5: How This STG Was Developed Background : A Task Force was constituted by the National Health Systems ResourcesCentre under the aegis of the Ministry of Health & Family Welfare to guide the development of Standard Treatment Guidelines (STG) in India. The Task Force subsequently approved the draft STG development manual of India (Part 1) for development of adapted guidelines. In addition, it approved a list of 14

topics recommended by a subgroup of the task force appointed to select prioritized topics for STG development. These 14 topics are from 10 clinical specialties for which the first set of STGs will be developed. The topic of Dry Eye management in India is included in this first list and the task of developing STG on Dry eye was delegated to the Clinical Sub Group on Ophthalmology. Overview The STG on Dry Eye management was developed by a team of ophthalmologists specialised in

treatment of Cornea & External eye diseases experienced in management of dry eye syndrome in India. The recommendations in the STG were adopted/adapted from the American Academy of Ophthalmology22 ( 2013) Preferred Practice Pattern on Dry Eye as the principal source guideline, which is available from and full reference provided in the following reference: American Academy of Ophthalmology Cornea/External Disease Panel.Preferred Practice Pattern®

Guidelines. Dry Eye Syndrome. San Francisco, CA: American Academy of Ophthalmology; 201322. Available at: www.aao.org/ppp. The processes and methods used in developing this STG draw on those outlined in the STG development manual of India (Part 1) for development of adapted guidelines and summarized in the Stepwise guide on STG development. The figure below contains a schematic of the process followed and each of the steps are detailed in subsequent sections below.

17 May 2015: NHSRC with technical support from NICE international carried out a training workshop to guide the STG group members and chairs on the methodology to follow in developing adapted STGs suitable for the Indian context. This workshop was conducted on 29th& 30th May, 2015 and two members (R D Ravindran and R Krishnadas, ) of the Ophthalmology Clinical Subgroup of the STG team attended. Subsequently, NHSRC facilitated the STG development process by providing

resources approved by the Ministry of Health & family welfare to the expert group. To assist widespread implementation of the Dry Eye STG, three implementation tools have been developed in addition to the STG document. They include: ● The Quick Reference Guide to help the clinical practitioner (Clinical pathways) ● An information document for the public to create patient awareness about the disease and ● the quality standards developed from key priority recommendations.

Steps followed during the development of the STG on Dry Eye Management are as follows: 1)Dry Eye Treatment STG Subgroup established A multi-disciplinary group consisting of health professionals, subject matter experts in various fields and a patient representative undertook the development of this evidence-based STG on dry eye treatment. Once the Ophthalmology Sub Group co-ordinator in collaboration with the Task Group members constituted and recommended the multi disciplinary expert members, Official

letters of invitation were sent from the NHSRC head office. The names of the Ophthalmology Sub group members in the STG on Dry Eye management, their specialities and organization affiliation are listed here: Taskforce member: Dr. R. D. Ravindran, Chairman, Aravind Eye Care System Coordinator Dr. Krishna Das, Medical Consultant- Glaucoma Services & Director, Human Resources, Aravind Eye Care System Experts 1. Dr. N. V. Prajna, Chief,Cornea Services, Aravind Eye Hospital, Madurai

2. Dr.Parveen Sen, Vitreo Retina Specialist SankaraNethralaya, Chennai, India. 3. Dr.Virender S Sangwan, MS , L V Prasad Eye Institute, Hyderabad 4. Dr.ParthaBiswas B B Eye Foundation, Kolkatta 5. Dr.Revathy, Consultant, Cornea Services, Aravind Eye Hospital, Coimbatore 6. Dr. Vikram, Consultant, Cornea Services, Aravind Eye Hospital, Coimbatore 7. Dr.Ashish, Consultant, Cornea Services, Aravind Eye Hospital, Madurai

18 8. Dr Lukshey Dudeja, ophthalmologist, Cornea Services, Aravind Eye Hospital, Madurai Physician/Private Practitioner/Paramedical personnel and Patient Right Group/NGO: 1. Dr.Sangumani, Physician, Asst Professor of Medicine in Madurai Medical College, Madurai 20 2. Dr. Ramesh Dorairajan, Private Practitioner, Sundar eye Hospital, Chennai 3. Dr.Valluvan, Primary care practitioner, Vriddhachalam, Tamil nadu 4. Mrs. Alees Mary, Staff Tutor, Aravind Eye Hospital, Madurai

5. Mr. Nan Narayanan, Freelance Faculty on soft skills and HR consultant, Madurai Rapporteur: 6. Mr. V. Vijayakumar, Faculty, LAICO, Aravind Eye Care System, Madurai 7. Mr. D. Yesunesan, Faculty Associate, LAICO, Aravind Eye Care System, Madurai A smaller writing group was formed from the above listed multi-disciplinary team along with Rappotaeurssupporting the writing of the STG document/s. The members of the working group were: 1. Dr R Krishnadas ( Ophthalmology Sub Group Co ordinator)

2. Dr R Revathy ( Chief Consultant, Cornea Services, Aravind Eye Hospital, Coimbatore) 3. Dr Vikram (Consultant, Cornea Services, Aravind Eye Hospital, Coimbatore ) 4. Dr Ashish ( Consultant, Cornea Services, Aravind Eye Hospital,Madurai ) 5. Mr. V. Vijayakumar (Faculty, LAICO, Aravind Eye Care System, Madurai 6. Mr. D. Yesunesan ( Faculty Associate, LAICO, Aravind Eye Care System, Madurai All the members of the writing group consisted of chiefly faculty from the Aravind eye hospital,

the institution to which the Sub group facilitator was affiliated, principally to facilitate frequent discussions and face to face meetings which would be logistically easier. The recommendations/guidelines and the entire document on STG of Dry eye management, however was finalized by consensus by repeated discussions with all the Sub group members. The Dry Eye Syndrome STG Sub Group (ophthalmology) members wrote the Dry Eye Syndrome

STG for practice in India. The members of the Sub Group in Ophthalmology elaborately reviewed the available source documents for the treatment guidelines on dry eye management, and evolved the STG by meeting in person once and conducting other reviews by e mail discussion to develop a consensus over the final version of the treatment guidelines. Information for the STG clinical Sub Group members on the details of the processes and methods enumerated and

elaborately delineated in the STG development draft manual and the role of the STG clinical sub group members were shared with all the members to understand their role and responsibilities in evolving the STG on dry eye syndrome. After a brief deliberation to individual members over telephonic conversation on the purpose of the STG, the standard set of slides on the detailed process of STG development provided by the NHSRC were shared with all the members of the Ophthalmology Sub Group.

The draft scope of the Dry eye management STG and the search terms for identifying and compiling the existing relevant guidelines compiled by the facilitator after receiving multiple

19 input from the constituent sub group domain experts (Cornea experts) were shared with all the members and adopted after several rounds of discussion and consensus by e mail. Subsequently a detailed work plan to search and select available guidelines, compare and select recommendations was also formulated by the Sub Group facilitator in consultation with the members of the Sub Group. The STG Subgroup met once face to face in December 2015 in Madurai ( Add minutes of the

meeting, photographs of attendees, list of those who attended, reasons for those who could not attend). The members of the Working Group met weekly before the face to face meeting of the Sub Group in December 2015 since the orientation discussion with the working group members in June 2015. The orientation of the working group members briefed on the rules of operation based on the STG development manual, consistent use of terminology and definitions, with

assistance of the structured power-point presentations provided to the Ophthalmology Sub Group Co Ordinator by the NHSRC / NICE during the Induction & training meeting held in New Delhi on 25-27 May, 2015. The STG development manual and the various structured presentations provided by NHSRC were once again discussed with the members of the sub group These presentations earlier had been shared by e mail prior to formulating the guidelines on dry eye management. 2. Scoping the STG

Dry Eye Management guidelines proposed to be evolved by the Sub Group on Ophthalmology was translated into a scope prior to detailed discussion on the treatment recommendations. Scoping of Dry Eye management was drafted by the Sub group facilitator in consultation with the members and finalized by consensus on discussion by e mail. The purpose of the Scope was to ensure key clinical issues in dry eye management are covered by the STG, set the boundaries of

the development work and provide a clear framework to enable the entire guidelines/recommendations and the methodology employed to evolve STG were within the priorities agreed with NHSRC and to be conducted within the specified, agreed timelines and ensure compilation of the existing guidelines relevant to the scope of the chosen area of the STG. The Scope defines the population that will and will not be covered by the recommended

guidelines on dry eye management, key clinical issues and clinical management that will be included and various types of intervention and management strategies to be included or excluded including clinical evaluation, diagnostic tests, medical and surgical therapies and intervention, patient counselling and education, lifestyle advice and rehabilitation. The Scoping document is also expected to cover the health care setting relevant to the STG as well as the expected

outcomes and any relevant adverse effects of recommendations/ interventions covered in the STG. The Scoping of dry eye guideline, based on this broad framework, was subject to multiple revisions based on the opinion and feedback from the Sub-Group members before it was finalized. The Scope of the STG on Dry eye management, initially drafted by the facilitator with the assistance of the writing group in July 2015,was reviewed, discussed and finally approved by the

STG Sub Group (Ophthalmology) in August 2015. The final version of the Scope on Dry eye management is provided in detail in Section 3 of this document on page 3.

20 Briefly, the Scope of the document on dry eye treatment guidelines includes: 1. The guidelines will cover all persons with signs and symptoms suggestive of dry eye disease at primary, secondary and tertiary levels of eye care. 2. Establishing diagnosis by clinical evaluation and diagnostic tests and treatment recommendations based on severity 3. Recommendations on prevention of dry eye disease, patient counselling 4. Provision of Evidence based treatment guidelines of dry eye for eye care providers at

every level of care 5. Patient comfort & relief of symptomatology from dry eye disease 6. Limiting ocular morbidity from dry eye disease& prevention of complications such as visual loss, infection and ocular surface structural damage The guidelines will not include cost evaluation and cost impact analysis of dry eye treatment, although all recommendations and guidelines have been considered with cost effectiveness of intervention as a major consideration. Recommendations from the Source guidelines which are

expensive and lack sufficient evidence of efficacy have been adapted to suit the clinical care practice and processes widely followed by eye care practitioners in India experienced in management of dry eye syndrome after substantive discussion with the Sub group members and domain experts and evolving a consensus based approach. Details of drugs used in dry eye management, interventions and surgical procedures and the adverse effects of the treatment

approaches to dry eye and any rehabilitative procedures is also not covered in detail. The STG will be reviewed by the Sub Group members once in three years for any major changes in recommendations of dry eye management which will be submitted to NHSRC task force on STG for approval. 3. Search & Select Guidelines The STG Working group search for published evidence based guidelines on dry eye syndrome management. The National Guidelines Clearinghouse (NGC), NICE, WHO websites were accessed

and a google search was also performed to obtain available guidleines, especially since many evidence based guidelines on dry eye management were not listed in the guidline.gov / NGC websites. Some of the available guidelines on dry eye treatment included the 2007 report of the International Dry Eye Workshop, the American Academy of Ophthalmology Preferred Practice Pattern Guidelines on Dry Eye Syndrome22, 2013 (www.aao.org/ppp), and the All India

Ophthalmological Society (AIOS) Preferred Practice Pattern Series (2013) on dry eye syndrome. Some of the additional guidelines considered by the Working group included the American Optometry Association Dry eye guidelines, Canadian Optometry dry eye guidelines, NHS Dry eye treatment guidelines, and the Korean guidelines for diagnosis and management of dry eyes. The AIOS Preferred pattern Series on Dry eye was evolved by the Indian Ophthalmologists and was

completely adapted from the AAO preferred practice pattern on dry eye syndrome. The STG Working group on dry eye management decided to consider the AAO dry eye guidelines as the principle source document since this was the only dry eye management guideline which had graded evidence at least partially acceptable to AGREE 2 method (Appraisal of Guidelines Research and Evaluation). AAO guidelines on dry eye treatment was widely perused by the

21 working group of STG to recommend guidelines for treatment of dry eye in India based on the Adopt/ Adapt method as described in this document subsequently. 4. Compare & Sift Guidelines After sifting through all the available guidelines, the working group selected two guidelines as the primary source guidelines for evolving dry eye treatment guidelines for STG in India: the AAO Preferred Practice Pattern guidelines for dry eye ( 2013) and the AIOS Preferred Practice Series on

Dry Eye Disease (2014) following a review of all the selected guidelines. The selected guidelines were compared in terms of relevance to the topic and key clinical issues listed in the Scoping document of the dry eye, evidence ratings, target population and their applicability and relevance to management of dry eye disease in Indian context. Most recently published guidelines were preferred owing to the necessity to include the most updated, evidence based recommendations.

The selected guidelines were subsequently approved by the STG Sub Group on Ophthalmology as the primary source guidelines for reference to evolve India specific recommendations for management of dry eye for the STG. Before the face to face meeting of the Sub group members, the working group had prepared a draft scope for the STG (step 2), performed background research on available evidence based source guidelines (refer step 3 above ), compared and sifted

the guidelines to select evidence based recommendations developed according to internationally accepted methodology for guideline development with subsequent draft of proposed recommendations (adopted / adapted) from the source guideline. The first draft of guidelines adopted or adapted from the source document were submitted for review and final adoption by the Ophthalmology STG Sub group in September 2015 5. Search & Select Recommendations

Each of the key clinical issue identified in the Scoping document of the STG was revisited and relevant recommendations were searched for in the AAO Dry eye treatment Source Guidelines. All the major recommendations from the AAO Preferred Practice Pattern on dry eye were studied and reviewed by the experts group of the STG sub group with relevance to their application and clinical practice in the Indian context, with specific consideration to the cost, safety, efficacy,

availability, accessibility and practical application of the various recommendations on diagnosis and management of dry eye syndrome. All evidence based recommendations provided in the source document guideline were critically considered by the expert ophthalmologists in the light of their clinical experience of management of dry eye in India, as well as the available expertise, and resources for implementation in clinical practice. While most recommendations from AAO

source guidelines were adopted in the STG on dry eye management in India, some of the recommendations were adapted. The reasons for adaptation and the evidence based support for adapted recommendations have also been provided as references from peer reviewed literature. Each recommendation listed in the draft was circulated to all subgroup members prior to the face to face meeting and subsequently discussed in the Sub group meeting held in Madurai ( provide

22 date and details of the meeting held, with members attended including details of signing of conflict of interest forms) 6. Adopt/ Adapt Recommendations An earnest attempt was made by the Working Group while adopting recommendations from the Source Guidelines to strictly maintain the standards (evidence) used in the original statement of recommendations. A systematic approach was followed to ensure quality and standards of

original recommendations were retained. The STG clinical sub group was required to make a series of judgments on the new STG recommendations formulated by the Working group. These consultations with the Sub Group members was entirely done over e mail communications and the finalized draft of recommendations were evolved over consensus between the experts group. The final draft of recommendations developed after review and consensus within the experts

group was re circulated by e mail to all the Sub Group members for careful consideration, critical review and analysis and any further recommendations. The entire list of draft recommendations agreed over e mail were presented to the Sub Group members in the face to face meeting held in Madurai for final approval and signing of declaration of conflict of Interest. Reasons for each recommendation being adapted were documented to ensure quality assurance. The various

options followed by the Working Group in drafting the STG recommendations included: Adopted Recommendation: this step comprised of transferring a recommendations from the source guideline verbatim to the new STG. In deference to the requirements of the STG task force recommendations, however, the recommendations from the source guideline, even those adopted were transferred to active voice format. Adapted recommendations : this step comprised of editions / additions / deletion or other suitable

modifications in the original source guideline recommendations to ensure their suitability and compatibility or practical application for clinical practice of dry eye management in India. Every attempt has been made by the Working group to ensure when adapting original guidelines, evidence underlying the recommendations is preserved. Additional, evidence based support form peer reviewed literature was actively sought and has been provided to support any adaptations considered in the STG recommendations.

Implementation challenges for eye care providers and patients were considered by the Sub group members when conclusions were made to adopt or adapt recommendations. Factors considered included public/private health care infrastructure available across various levels of eye care, accessibility of the various facilities and resources in the primary, secondary and tertiary level of eye care. Discussions had begun with segregation of recommendations across various levels of eye

care in the community to suit primary, secondary, and tertiary eye care providers. Owing to a consensus in the STG task group that recommendations may be combined to reflect the guidelines to be suitably applied by all levels of health care providers, with clear recommendations to refer the patient to a higher level of care provider if initial line of management tends to be refractory to treatment. The Clinical Sub Group has therefore collated all recommendations as a single list of

23 The working group compiled a list of the proposed recommendations which was reviewed by the STG sub-group. Each proposed recommendation was discussed and debated before a decision was taken on whether it can be adopted or needed adapting to the Indian context. Few recommendations were excluded as they were considered inappropriate in view of the required resources/ cost and/ or feasibility. There was significant debate about use of systemic

azithromycin, omega -3 Essential Fatty Acids, Oral Pilocarrpine, Cevimiline and punctal plugs for management of dry eyes in India. Many of the recommendations on the use of these drugs/ devices provided in the AAO source document have been eliminated from recommendations by the Sub group members by discussion and consensus owing to either their cost, non-availability or lack of sufficient evidence to support their recommendation in the literature. Use of lasers in

punctal occlusion suggested in the original source guideline have also been eliminated to adapt in the STG recommendations, since equally efficacious alternative of thermal cauterization has been supported in the peer reviewed literature. The details of adopted and adapted recommendations and the rationale for adaptation are available in the Annexure names “Adopt/Adapt guidelines”. Ophthalmology Clinical Sub Group Meeting 2-30 – 5.00 PM 19th December, 2015

LAICO Conference room, Aravind Eye Hospital, Madurai The face to face meeting of the Clinical Sub Group Ophthalmology members was held between 2.30- 5.00 PM on 19th December, 2015 at the Conference Room of the Lions Aravind Institute of Community Ophthalmology, Madurai . The initial draft submitted for review by the IHG in October 2015 was presented to the members for discussion and opinion. The following members were present for the discussion: Dr R Krishnadas Dr Venkatesh Prajna Dr Revathi Dr Valluvan

Dr Ramesh Dorairajan Dr Sangumani Dr Ashish Mr NAN Narayanen Mr Vijay Kumar Mr Yesunesan Dr R D Ravindran, who was not available in Madurai and on a visit to Pondicherry, participated in the meeting by Video Conferencing. Dr Parveen Sen and Dr Virendra Sangwan could not be present for the meeting and could not participate in the meeting by Video Conferencing. They had, however, reviewed dthe initial draft submitted to the IHG and had provided their feedback and comments, which had been included.

Dr Partha Biswas could not participate in any of the discussion either by mail or video conferencing owing to his pre occupation with professional and academic commitments. The Minutes of the face to face meeting of the Ophthalmology Sub Group is provided as below:

24 1. Scoping- to include family/general practitioners in the list of healthcare providers who would us the standard treatment guidelines on dry eye management 2. Recommendation 4.1.7 may be eliminated – B Scan is not necessary for management of dry eyes in thyroid eye disease. It may be recommended if required for diagnosis or management of thyroid eye disorder. 3. Modify recommendation 4.1.13 to give priority to perform clinical evaluation to suspect or

diagnose auto immune disease and then consider laboratory evaluation for auto immune diseases. 4. Modify recommendation 4.1.14 as consider a multi disciplinary approach to patients with underlying Sjogren’s syndrome and moderate punctate staining of the cornea / conjunctiva 5. Modify recommendation 4.2.3. Replace moisture chamber spectacles with protective goggles since the former are not available widely for use in India and are more expensive to procure

6. Recommendation 4.2.9- add eye drops to emulsions, gel, ointments to treat dry eyes 7. Recommendation 4.2.13- Systemic doxycycline or azithromycin is used to treat Meibomian gland dysfunction in dry eyes. Use systemic azithromycin cautiously in patients with cardiovascular diseases 8. Recommendation 4.2.27- use of moisture chamber spectacles to be substituted with protective glasses or goggles 9. Modify recommendation 4.4.2 to include – periodically reassess and ensure patients’

compliance and understanding 10. Dr Ramesh Durairajan had suggested some guidelines be provided for practitioners on the use of tear substitutes and therapy of dry eyes. It hsbeen decided to adopt the Northamptonshire Prescribing Advisory Group recommendations on ocular lubricants treatment of dry eye ( NPAG) 11. Consensus on use of the new dry eye drug- Rebapimide a. Most studies on use of rebapimide are in Japanese population patient cohort b. Not known if approved by FDA

c. May be recommended for use in dry eye with mucin deficiency or with chronic inflammation d. Strength of evidence for routine use of Rebapimide in dry eye management still not adequate

25 Review by Internal harmonization Group The initial draft of recommendations of Standard treatment guidelines for management of Dry eye disease in India was submitted to the Internal harmonization Group for review and revision on October 20, 2015. The Internal Harmonization group had critically reviewed the initial draft on Dry eye treatment guidelines and had provided the following recommendations in its communication

dated 16th January, 2016. The Working Group on Ophthalmology Clinical Sub Group substantively worked on the recommendations and suggestions to have all the feedback incorporated in their revised draft and submitted to the broader Experts Group for consensus. The Experts Group, by consultation and discussion by series of e mails, agreed to incorporate all the recommendations of the Internal harmonization Group, except: 1. The recommendation of the IHG on including the Stem cell transplantation as a modality

of treatment of Dry eye disease was not accepted by the Experts Group. All the experts were unanimously of the opinion that limbal stem cell transplantation, currently has little role in management of dry eye disease and there was no evidence based consensus in the published literature to support the role of limbal stem cell transplantation in dry eye management. This recommendation has not been accepted by the Experts Group.

2. The IHG was of the opinion that Autologous serum had no role in management of dry eye disease in India. The Experts Group was of the opinion that autologous serum could be prepared by most laboratories in the teriary eye care centres and Centres of excellence in management of Corneal disease and that autologous serum could be employed in management of moderate to severe dry eye disease, which otherwise is poorly responsive to other conservative methods of therapy.

The final draft of the STG on Dry eye management, with the suggestions of IHG incorporated was submitted for review by the Ministryof Health on 12th May, 2016.

26 Appendix 1: History & Clinical Evaluation of Dry Eyes History Questions about the following aspects of patient history may elicit helpful information on diagnosis, risk factors and management of dry eyes: • Symptoms and signs (e.g., irritation, tearing, burning, stinging, dry or foreign body sensation, mild itching, photophobia, blurry vision, contact lens intolerance, redness, mucous discharge, increased frequency of blinking, eye fatigue and diurnal fluctuation- symptoms that worsen later in the day)

• Exacerbating conditions (e.g., wind, air travel, decreased humidity, prolonged visual efforts associated with decreased blink rate such as reading and computer use) • Duration of symptoms o The ocular history may include details about the following: • Topical medications used, their frequency, and their effect on symptoms (e.g., artificial tears, antihistamines, glaucoma medications, vasoconstrictors, corticosteroids, homeopathic or herbal preparations) • Contact lens wear, schedule, and care

• Allergic conjunctivitis • Ocular surgical history (e.g., prior keratoplasty, cataract surgery, keratorefractive surgery) • Ocular surface disease (e.g., HSV, varicella zoster virus, ocular mucous membrane pemphigoid, Stevens-Johnson syndrome, aniridia, GVHD) • Punctal surgery • Eyelid surgery (e.g., prior ptosis repair, blepharoplasty, entropion/ectropion repair) • Bell palsy o The medical history may take into account the following: • Smoking or exposure to second-hand smoke

• Dermatological diseases (e.g., rosacea, psoriasis) • Technique and frequency of facial washing, including eyelid and eyelash hygiene • Atopy • Menopause • Systemic inflammatory diseases (e.g., Sjögren syndrome, GVHD, rheumatoid arthritis, systemic lupus erythematosus, scleroderma) • Other systemic conditions (e.g., lymphoma, sarcoidosis) • Systemic medications (e.g., antihistamines, diuretics, hormones and hormonal antagonists, antidepressants, cardiac antiarrhythmic drugs, isotretinoin,

diphenoxylate/atropine, beta-adrenergic antagonists, chemotherapy agents, any other drug with anticholinergic effects) • Trauma (e.g., mechanical, chemical, thermal) • Chronic viral infections (e.g., hepatitis C, HIV) • Radiation of orbit • Neurological conditions (e.g., Parkinson’s disease, Bell’s palsy, Riley-Day syndrome, trigeminal neuralgia) • Dry mouth, dental cavities, oral ulcers • Fatigue

27 • Joint pains/muscle aches Examination All patients should have an initial,comprehensive eye evaluation and subsequently at recommended intervals. The initial evaluation of a patient who presents with symptoms suggestive of dry eyeshouldalsoincludea systemic evaluation relevant to dry eye. The purpose of the external examination and the slit-lamp biomicroscopyistobriefly : • Document signs of dry eye • Assess the quality, quantity, and stability of the tear film

• Determine other causes of ocular irritation • The external examination should pay particular attention to the following: • Skin (e.g., scleroderma, facial changes consistent with rosacea, seborrhea) • Eyelids: incomplete closure/malposition, incomplete or infrequent blink, eyelid lag or retraction, erythema of eyelid margins, abnormal deposits or secretions, entropion, ectropion • Adnexa: enlargement of the lacrimal glands • Proptosis

• Cranial nerve function (e.g., cranial nerve V [trigeminal], cranial nerve VII [facial]) • Hands: Joint deformities characteristic of rheumatoid arthritis, Raynaud phenomenon, splinter hemorrhages underneath the nails • The slit-lamp biomicroscopy evaluation should focus on the following: • Tear film: height of the meniscus, debris, increased viscosity, mucous strands, and foam, break-up time and pattern • Eyelashes: trichiasis, distichiasis, madarosis, deposits

• Anterior and posterior eyelid margins: abnormalities of meibomian glands (e.g., orifice metaplasia, reduced expressible meibum, atrophy), character of meibomian gland secretions (e.g., turbid, thickened, foamy, deficient), vascularization crossing the mucocutaneous junction, keratinization, scarring • Puncta: patency and position, presence and position of plugs • Conjunctiva: o Inferior fornix and tarsal conjunctiva (e.g., mucous threads, scarring,

erythema, papillary reaction, follicle enlargement, keratinization, foreshortening, symblepharon) o Bulbar conjunctiva (all four quadrants) (e.g., punctate staining with rose bengal, lissamine green, or fluorescein dyes; hyperemia; localized drying; keratinization, chemosis, chalasis, follicles) • Cornea: localized interpalpebral drying, punctate epithelial erosions assessed with rose bengal, fluorescein or lissamine green dyes, punctate staining with rose bengal or

fluorescein dyes, filaments, epithelial defects, basement membrane irregularities, mucous plaques, keratinization, pannus formation, thinning, infiltrates, ulceration, scarring, neovascularization, evidence of corneal or refractive surgery

28 Appendix 2: Diagnostic Tests in Dry Eye Syndrome This appendix summarizes the currently utilized tests to diagnose tear film and ocular surface disorders. These tests include the tear break-up time test to evaluate tear film stability, ocular surface dye staining to evaluate ocular surface disease and Schirmer test and fluorescein clearance test to evaluate aqueous tear production and clearance. Tear Break Up Time Test

Tear break up time (TBUT) is determined by instilling fluorescein dye in the conjunctival inferior cul-de-sac and subsequently evaluating the pre corneal tear film stability. The test is performed by moistening a fluorescein strip with sterile saline and applying it to the inferior tarsal conjunctiva. Fluorescein – anesthetic combination drops are avoided since the anesthetic may affect the result of the test. After several blinks, the tear film is examined using broad beam of the

slit lamp with a cobalt blue filter. The time lapse between the last blink and appearance of the randomly distributed dark discontinuity in the fluorescein stained tear film is the tear break up time. TBUT is evaluated before instillation of any eye drops and before lids are manipulated. Recurrent tear break up in the same area indicates localized anterior basement membrane disease. Break up times less than 10 seconds are considered abnormal. A rapid tear break up time

is characteristic of aqueous tear deficiency and meibomian gland dysfunction. Ocular Surface Dye Staining Fluorescein, rose bengal, or lissamine green dyes may be used to assess the ocular surface. Fluorescein dye stains areas of the corneal and conjunctival epithelium where there is sufficient disruption of intercellular junctions to allow the dye to permeate into the tissue. Saline- moistened fluorescein strips or 1% to 2% sodium fluorescein solution is used to stain the tear

film. After instilling the dye, the ocular surface is examined through a biomicroscope using a cobalt blue filter. Staining may become more apparent after 1 to 2 minutes. Mild fluorescein staining can be observed in normal eyes and may be more prominent in the morning. Exposure- zone punctate or blotchy fluorescein staining is observed in dry eye, and staining is more easily visualized on the cornea than on the conjunctiva.The dye stains ocular surface cells that lack a

mucous coating as well as debris in the tear film; the Rose bengal staining of the tear film may be performed using a saline-moistened strip or 1% solution. (Patients should be informed that the drop might irritate the eye.) The saline drop used to moisten the strip should remain in contact with the strip for at least a minute to achieve an adequate concentration of rose bengal to stain the ocular surface. Rose bengal staining is more intense on the conjunctiva than on the cornea.

Staining may be easier to observe with a red-free filter.Lissamine green dye has a staining profile similar to that of rose bengal, but it causes less ocular irritation. It is not recommended for evaluating corneal epithelial disease.Diffuse corneal and conjunctival staining is commonly seen in viral keratoconjunctivitis and medicamentosa. Staining of the inferior cornea and bulbar conjunctiva is typically observed in patients with staphylococcal blepharitis, MGD,

lagophthalmos, and exposure, whereas staining of the superior bulbar conjunctiva is typically seen in superior limbic keratoconjunctivitis. A pattern ofexposure zone (interpalpebral) corneal and bulbar conjunctival staining is typically seen with aqueous tear deficiency Schirmer Test The Schirmer test can be performed to evaluate aqueous tear production, but it çives variable results and should not be used as the sole criterion for diagnosing dry eye. It is performed by

29 placing a narrow filter-paper strip in the inferior cul-de-sac. Aqueous tear production is measured by the length in millimeters that the strip wets during the test period, generally 5 minutes. Schirmer testing may be performed with or without the use of topical anesthesia. The Schirmer test with anesthesia, also referred to as a basic secretion test, has been reported to give more variableresults than the Schirmer test done without anesthesia. Results of 10 mm or less for the

Schirmer test with anesthesia are generally considered abnormal. If topical anesthesia is applied, excess fluid should be gently removed from the cul-de-sac prior to insertion of the filter paper. While an isolated abnormal result can be nonspecific, serially consistent low results are highly suggestive of aqueous tear deficiency. Figure 1: Conjunctival & Corneal Staining in Fluorescein Dye Test in Mild to Moderate Dry Eye Disease

30 Appendix 3 - Classification/ Grading of Dry eye Disease Classification/Grading of Dry Eye Disease Specific systems to classify dry eye severity have been developed by DEWS committee in 2007 ( Ref- International DEWS).However, these are not used widely in clinical practice. Dry eye disease is generally classified according to a combination of symptoms and signs. In this PPP, it has been classified as mild, moderate and severe based on both symptoms and signs, but with an emphasis on symptoms over signs21

Due to the nature of dry eye disease, this classification is not precise because of overlapping at each level. • Mild dry eye disease: The patients may have symptoms of irritation, itching, soreness, burning, or occasional blurring of vision. It is often difficult to diagnose dry eye definitively in its mild form because of the inconsistent correlation between reported symptoms and clinical signs as well as the relatively poor specificity and/or sensitivity of clinical tests .Because most dry eye conditions

have a chronic course, repeated observation and reporting of symptoms over time will allow clinical diagnosis of dry eye in most cases. • Moderate dry eye disease: The patients have increased discomfort and frequency of symptoms, and visual effects may become more consistent. • Severe dry eye disease: The patients have increasing frequency of symptoms or constant symptoms, and visual symptoms may be significant and disabling.

Dry eye disease is also loosely classified according to aqueous tear deficiency (ATD) and evaporative tear deficiency (ETD), and both of these conditions may be present in patients with the disease. Table lists characteristic findings for each diagnostic test for each condition. Table : Characteristic Findings for Dry Eye Disease Diagnostic Testing Test Characteristic findings Aqueous tear deficiency Tear break-up time Less than 10 seconds considered abnormal Ocular surface dye staining

Pattern of exposure zone (interpalpebral) corneal and bulbar conjunctival staining - typical Aqueous tear production and clearance (Schirmer test) 5 mm or less for Schirmer test with anesthesia considered abnormal Evaporative Tear Deficiency Tear break-up time Less than 10 seconds considered abnormal Ocular surface dye staining

31 Figure 2: Filamentary keratitis in Moderate Dry Eye Disease Figure 3: Severe DryEye Disease with Corneal Scarring and Vascularization

32 Appendix 4 CATEGORIES OF DRY EYE TREATMENTS( Adopted from AAO Preferred Practice Pattern, Dry Eye Syndrome 2013) Reference : Pflugfelder SC (Chair)19. Management and Therapy Subcommittee of the International Dry Eye Workshop. Management and therapy of dry eye disease: report of the Management and Therapy Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf 2007;5:163-78. Type of Therapy Treatment Environmental/Exogen ous • Education and environmental modifications* (e.g., humidifier)

• Elimination of offending topical or systemic medications Medication Topical medication • Artificial tear substitutes, gels/ointments* • Anti-inflammatory agents (topical cyclosporine and corticosteroids) • Mucolytic agents • Autologous serum tears Systemic medication • Tetracyclines* (for meibomian gland dysfunction, rosacea) • Systemic anti-inflammatory agents • Secretagogues Surgical • Punctal plugs • Permanent punctal occlusion • Tarsorrhaphy* • Repair of eyelid malpositions or exposure*

• Mucous membrane, salivary gland, amniotic membrane transplantation Other • Eyelid therapy (warm compresses and eyelid hygiene)* • Contact lenses • Moisture chamber spectacles* *Particularly of benefit in evaporative tear deficiency

33 Appendix5 : TREATMENT RECOMMENDATIONS FOR DRY EYE SYNDROME BY DISEASE SEVERITY LEVEL (Adopted from AAO Preferred Practice Pattern 2013, Dry Eye Syndrome Mild • Education and environmental modifications • Elimination of offending topical or systemic medications • Aqueous enhancement using artificial tear substitutes, gels/ointments • Eyelid therapy (warm compresses and eyelid scrubs) • Treatment of contributing ocular factors such as blepharitis or meibomianitis • Correction of eyelid abnormalities

Moderate In addition to above treatments: • Anti-inflammatory agents (topical cyclosporine and corticosteroids), • Punctal plugs • Spectacle side shields and moisture chambers Severe In addition to above treatments: • Systemic cholinergic agonists • Systemic anti-inflammatory agents • Mucolytic agents • Autologous serum tears • Contact lenses • Permanent punctal occlusion • Tarsorrhaphy Reference: Pflugfelder. Management and Therapy Subcommittee of the International Dry Eye

Workshop. Management and therapy of dry eye disease: report of the Management and Therapy Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf 2007;5:17419.

34 Appendix 6: Recommendations for treatment and referral of Dry eye disease by level of Care Primary level: at PHC, BPHC and district level by Non-ophthalmologist eye care providers (optometrists, ophthalmic assistants or non- ophthalmologist physicians) • To take proper ocular and medical history to identify the • disease and associated risk factors • To start treatment in case of mild dry eye. • To guide and to counsel the patient • To refer the patient promptly to the secondary/tertiary level in

• any doubt like: • Exacerbation of symptoms • Blurring of vision • No response to artificial tears • Any red eye/lid abnormalities • Positive systemic history, like rheumatoid arthritis Secondary level: at district level by comprehensive ophthalmologist or ophthalmologists of other subspecialties. • To perform common dry eye tests to grade the severity of the • disease • To treat mild to moderate dry eye. • To refer the patient promptly to the tertiary level if any of the • following occurs: • Visual loss

• Moderate or severe pain • Lack of response to the therapy • Corneal infiltration or ulceration Tertiary level: at medical colleges, tertiary eye institutes or by specialist ophthalmologists • To treat and manage patients of dry eye disease at any level. • To find out etiological factors responsible

35 • To treat any complications – in patients with severe dry eye. • To train comprehensive ophthalmologists Referral • _ Referral of a patient with dry eye may be necessary, depending • on the severity of the condition and its responsiveness to • treatment. • _ In moderate to severe cases that are unresponsive to • treatment or when systemic disease is suspected, timely • referral to a specialist Ophthalmologist who is knowledgeable • and experienced in the management of these entities is • recommended.

• _ Referral to medical specialist or rheumatologist can be • considered for patients with systemic immune dysfunction • or for those who require immunosuppressive therapy. For • connective tissue disease such as rheumatoid arthritis

36 Appendix 7: Computer Vision Syndrome- Clinical Features, Prevention and Management Computer Vision Syndrome, alternately described as the Digital eye strain, refers to eye and vision related symptoms as a consequence of prolonged use of computers, mobile phones, tablets and e-readers. Individuals habitually viewing digital screens for extended period of time tend to experience eye discomfort and blurring of vision. The level of discomfort also increases with the amount of digital screen use. The most

common symptoms experienced by persons with computer vision syndrome include eye strain or fatigue, blurred vision, double vision, red eyes, dry and itchy eyes, headache and neck and shoulder pain. The features of computer vision syndrome are principally related to three pathophysiologic causes: ocular surface mechanisms, accommodative mechanisms and extra-ocular factors. 90% of the persons using computers for

more than 3 hours per day have been reported to experience computer vision syndrome in some form. In the developed countries like the UK and the US, 9-12 % of patients reporting to optometrists have been diagnosed to have symptomatic or ocular discomfort attributed to using computers. Table: Computer related Vision Symptoms & Common Ocular Diagnosis Symptom Category Nature of Symptoms Common Ocular Diagnosis Asthenopia Eye strain, eye fatigue, sore, dry Binocular vision or eyes accommodation related

anomalies Ocular Surface related Tearing, irritation, contact lens related problems Visual Blurred vision, Slowness of focus Refractive error, accommodation change, Double vision, Presbyopia insufficiency, binocular vision defects Extra-Ocular Neck pain, backache, shoulder Presbyopic correction, computer pain screen location Source: Blehm et al. Computer Vision Syndrome: A Review. Surv Ophthalmol ; 50(3):253- 262,2005 Clinical Features of Computer Vision Syndrome (CVS)

Asthenopia: Prolonged use of computers or other devices with video display terminals (VDT) has been associated with diminished power of accommodation, removal of near point of convergence, and deviation of phoria for near vision. This observation suggests deficiency of these important visual function could be the cause of eye strain noticed in computer users. High prevalence of exophoria, convergence insufficiency, and

low fusional convergence were observed in persons on prolonged use of computer devices. Changes in accommodative and vergence functions in computer users seem to account for subjective visual fatigue and has been observed to be transient and reversible Ocular Surface related symptoms: Computer users report complaints of eye dryness, burning, grittiness, heaviness or foreign body sensation. Several factors contribute to drying of ocular surface:

1. In computer users, blink rate is decreased, and exposed ocular surface is increased causing desiccation of the eye. These may be aggravated in a dark setting where it is more difficult to read with accelerated desiccation of the eye resulting in fatigue. Most normal individuals blink between 15-22 times per minute. In computer users, the blink rate is drastically reduced to about 5-6 per

37 minute, which contributes to poor tear film quality and stresses on the ocular surface resulting in symptoms of dry eye. The reduced blink rate is also reported to the principle cause for meibomian gland disease in computer vision syndrome. 2. Environmental factors: the cornea and the ocular surface is very sensitive to drying and chemical imbalances from environmental factors. The office atmosphere also includes other aggravating

factors such as dry air, ventilation fans, air-conditioning systems and humidifiers 3. Increased exposure of ocular surface: computer users usually view their monitor screens in a horizontal gaze. This results in wider palpebral fissure and increased surface area exposed to effects of evaporation and aggravation of dry eye disease. 4. Age is an important risk factor in pathogenesis of dry eye disease. Tear production diminishes with

age. Although dry eye in computer vision syndrome can occur in any age or of either sex, post menopausal women appear to be at higher risk 5. Several auto immune diseases including Sjogren syndrome are associated d with dry eyes and individuals with CVS require a thorough systemic medical examination. Several systemic medications including diuretics, anti histamines, psychotropic and anti hypertensive drugs are associated with dry eye symptoms.

6. Persons on contact lens wear are at increased risk of computer vision syndrome and dry eyes. When the ocular surface is dry as in computer users,the lenses dry and adhere to upper lids during each blink without skating along the surface of the eye. This friction effect from dry eye causes greater magnitude of discomfort in contact lens users working on computers for prolonged period of time. 7. Ocular disorders, principally, dysfunction of the glands which produce the tear film contribute

significantly to dry eyes. Anterior blepharitis is one of the most common such ocular disorders, and is inflammation of the eye lids affecting the meibomian glands that secrete the lipid layer of the ocular surface. Lack of adequate lipid layer contributes to rapid evaporation of the water component of the tear film resulting in ocular discomfort. In addition, cosmetics used on eye lids are likely to obstruct the orifices of the oil secreting meibomian glands contributing to evaporative dry eye disease.

Visual Effects of Display Characteristics of Video Display Terminals (VDT) 1. Poor display quality of computer monitors/ VDT significantly contributes to ocular discomfort and visual performance. Visual performance is affected by a number of display parameters, such as character size, structure, style and image contrast and stability. Visual fatigue correlates best with search reaction times and eye movement parameters, all of which were reduced significantly with improved resolution of monitors.

2. Improper lighting conditions can increase ocular fatigue and discomfort. Constant and bright illumination form surrounding source of light create increase reflectivity and glare. Anti glare monitor screen filters may reduce reflections and glare with increasein contrast with improvement in asthenopic and dry eye symptoms in CVS. 3. Monitors with higher refresh rates ( number of times the screen is repainted to produce an image ,

measured in Hz) significantly reduce the flicker rate, which is one of the most important causes of visual fatigue. The widely used LCD monitors, which is the current standard, has significantly improved refresh rates with dramatic improvement in flicker rates contributing to better eye comfort.

38 Proper body positioning for computer use. Some important factors in preventing or reducing the symptoms of CVS have to do with the computer and how it is used. This includes lighting conditions, chair comfort, location of reference materials, position of the monitor, and the use of rest breaks. • Location of computer screen - Most people find it more comfortable to view a computer when the eyes are looking downward. Optimally, the computer screen should be 15 to 20

degrees below eye level (about 4 or 5 inches) as measured from the center of the screen and 20 to 28 inches from the eyes. • Reference materials - These materials should be located above the keyboard and below the monitor. If this is not possible, a document holder can be used beside the monitor. The goal is to position the documents so you do not need to move your head to look from the document to the screen. • Lighting - Position the computer screen to avoid glare, particularly from overhead lighting

or windows. Use blinds or drapes on windows and replace the light bulbs in desk lamps with bulbs of lower wattage. • Anti-glare screens - If there is no way to minimize glare from light sources, consider using a screen glare filter. These filters decrease the amount of light reflected from the screen. • Seating position - Chairs should be comfortably padded and conform to the body. Chair height should be adjusted so your feet rest flat on the floor. If chair has arms, they should

be adjusted to provide arm support while typing. The wrists shouldn't rest on the keyboard when typing.

39 1. Rest breaks - To prevent eyestrain, try to rest your eyes when using the computer for long periods. Rest your eyes for 15 minutes after two hours of continuous computer use. Also, for every 20 minutes of computer viewing, look into the distance for 20 seconds to allow your eyes a chance to refocus. • Blinking - To minimize your chances of developing dry eye when using a computer, make an effort to blink frequently. Blinking keeps the front surface of your eye moist.

Regular eye examinations and proper viewing habits can help to prevent or reduce the development of the symptoms associated with Computer Vision Syndrome. ( Source- Computer Vision Syndrome - Recommendations from the American Optometrists Association : www. aoa.org/patient )

40 Appendix 8 : Methods & Key to Ratings ( Adopted from AAO PPPwww.aao.org/ppp. ) Preferred Practice Pattern® guidelines should be clinically relevant and specific enough to provide useful information to practitioners. Where evidence exists to support a recommendation for care, the recommendation should be given an explicit rating that shows the strength of evidence. To accomplish these aims, methods from the Scottish Intercollegiate Guideline

Network1 (SIGN) and the Grading of Recommendations Assessment, Development and Evaluation2 (GRADE) group are used. GRADE is a systematic approach to grading the strength of the total body of evidence that is available to support recommendations on a specific clinical management issue. Organizations that have adopted GRADE include SIGN, the World Health Organization, the Agency for Healthcare Research and Policy, and the American College of Physicians.3

 All studies used to form a recommendation for care are graded for strength of evidence individually, and that grade is listed with the study citation.  To rate individual studies, a scale based on SIGN1 is used. The definitions and levels of evidence to rate individual studies are as follows: High-quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), I++ or RCTs with a very low risk of bias Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of

I+ bias I- Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias II++ High-quality systematic reviews of case-control or cohort studies High-quality case-control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal Well-conducted case-control or cohort studies with a low risk of confounding or bias II+ and a moderate probability that the relationship is causal

Case-control or cohort studies with a high risk of confounding or bias and a significant II- risk that the relationship is not causal III Nonanalytic studies (e.g., case reports, case series)  Recommendations for care are formed based on the body of the evidence. The body of evidence quality ratings are defined by GRADE2as follows: Further research is very unlikely to change our confidence in the estimate Good quality of Effect Further research is likely to have an important impact on our confidence

Moderate quality in the estimate of effect and may change the estimate Further research is very likely to have an important impact on our Insufficient quality confidence in the estimate of effect and is likely to change the estimate

41 Any estimate of effect is very uncertain Key recommendations for care are defined by GRADE2as follows: Strong Used when the desirable effects of an intervention clearly outweigh the recommendation undesirable effects or clearly do not Discretionary Used when the trade-offs are less certain—either because of low-quality evidence or because evidence suggests that desirable and undesirable recommendation effects are closely balanced

 The Highlighted Findings and Recommendations for Care section lists points determined by the PPP panel to be of particular importance to vision and quality of life outcomes.  All recommendations for care in this PPP were rated using the system described above. To locate ratings for specific recommendations, see Appendix 2 for additional information.  Literature searches to update the PPP were undertaken in June 2012 and January 2013 in

PubMed and the Cochrane Library. Complete details of the literature search are available at www.aao.org/ppp.

42 Appendix (: Methods section, containing information on adopted or adapted recommendations S No Recommendations for Adopted/ Recommendations in the Reasons for Adaptation Care Adapted by STG Adapted original AAO Guidelines Care Process – Diagnosis 1 Identifying Adopt Identifying characteristics of NA characteristics of the the causative factors, such as causative factors, adverse environments, such as adverse prolonged visual efforts, or environments, ameliorating circumstances, is

prolonged visual helpful in diagnosing dry eye efforts, or ameliorating circumstances, is helpful in diagnosing dry eye 2 Supporting clinical Adopt Supporting clinical NA observations and tests are observations and tests are used used to confirm the to confirm the diagnosis diagnosis 3 Questions about patient Adopt Questions about patient NA symptoms and signs, symptoms and signs, exacerbating exacerbating conditions, conditions, duration of duration of symptoms, and

symptoms, and ocular ocular history may elicit history may elicit helpful information helpful information 4 Adapt All patients should have a NA Remove comprehensive adult medical recommend eye evaluation at the ation 4 since recommended intervals it is redundant and it is repetition of recommend ation 5 5 The initial evaluation of a Adopt The initial evaluation of a patient who presents with patient who presents with symptoms suggestive of dry symptoms suggestive of dry

eye should include those eye should include those features of the features of the

43 comprehensive adult comprehensive adult medical medical eye evaluation eye evaluation relevant to dry relevant to dry eye eye 6 The external examination Adapt The external examination Feet and spine may also should pay particular should pay particular attention be relevant places to look attention to the skin, to the skin, eyelids, adnexa, for pathology eyelids, adnexa, proptosis, proptosis, cranial nerve Reference: Clinical cranial nerve function, function, and hands ophthalmology Systemic

mouth and Approach 7th edition. musculoskeltalsystemandha Page124 nds 7 The slit-lamp Adapt The slit-lamp biomicroscopy Meibomian secretions in biomicroscopy evaluation evaluation should focus on the the tear film tells about should focus on the tear tear film, eyelashes, anterior MGD. film, eyelashes, anterior and posterior eyelid margins, Reference: Clinical and posterior eyelid puncta, conjunctiva, and ophthalmology Systemic margins, puncta, cornea Approach 7th edition.

conjunctiva, and cornea. Page125-127 Particular attention to be paid to Meibomian gland dysfunction in evaluation of tear film. 8 Adapt A detailed review of systems Eliminated from STG Eliminated should be performed for any recommendations since patient who has clinically recommendations 6& 7 significant dry eye covers this aspect 9 Adapt A high degree of suspicion is Deleted from Deleted appropriate for patients who recommendations of STG have clinically significant dry since 6-8 reflect evaluation

eye and dry mouth symptoms of systems based on high degree of suspicion Patients who might have thyroid eye disease should be tested for anti-thyroid peroxidase antibody and anti-thyroglobulin antibody 10 Adopt Patients who might have

44 thyroid eye disease should be tested for anti-thyroid peroxidase antibody and anti- thyroglobulin antibody 11 A B-scan sonogram or Adopt A B-scan sonogram or other NA other imaging study should imaging study should be be ordered to assess ordered to assess extraocular extraocular muscle muscle thickness in patients thickness in patients who who have suspected thyroid have suspected thyroid eye eye disease disease 12 Conjunctival biopsy is Adopt Conjunctival biopsy is

appropriate for any patients appropriate for any patients who have significant who have significant chronic chronic conjunctivitis with conjunctivitis with a nodular a nodular appearance or appearance or cicatrization cicatrization 13 Adapt Several studies have failed to correlate tear osmolarity levels Recommendation with clinical signs or patient eliminated since there is symptoms, and it is not clear insufficient evidence to that the test has utility in the correlate tear osmolarity

diagnosis of dry eye levels with clinical signs syndromes and symptoms in patients 14 For patients with moderate Adopt For patients with moderate to NA to severe aqueous tear severe aqueous tear deficiency, deficiency, the diagnosis the diagnosis can be made by can be made by using one using one or more of the or more of the following following tests: tear break-up tests: tear break-up time time test, ocular surface dye test, ocular surface dye staining, and the Schirmer test staining, and the Schirmer test

15 These tests should be Adopt These tests should be NA performed in this sequence performed in this sequence because the Schirmer test because the Schirmer test can can disrupt tear film disrupt tear film stability and stability and cause false- cause false-positive ocular positive ocular surface dye surface dye staining staining

45 16 Several minutes should be Adopt Several minutes should be NA allowed between the dye allowed between the dye testing and the Schirmer testing and the Schirmer test test 17 Corneal sensation should be Adopt Corneal sensation should be Lee, Z CurrieV, Collin assessed when trigeminal assessed when trigeminal JRO. Ophthalmic management of facial nerve dysfunction is nerve dysfunction is suspected nerve palsy [Review] Eye suspectedor exposure 2004; 18:1225–1234. keratitis with bell’spalsy

doi:10.1038/sj.eye.670138 3 18 A laboratory and clinical Adopt A laboratory and clinical evaluation for autoimmune evaluation for autoimmune disorders should be disorders should be considered considered for patients with for patients with significant significant dry eye, other dry eye, other signs and signs and symptoms of an symptoms of an autoimmune autoimmune disorder, or a disorder, or a family history of family history of an an autoimmune disorder autoimmune disorder Care Proc ess – Man agem ent

Because most dry eye Recommendation deleted 19 conditions have a chronic Adapt as this information is course, repeated covered in diagnosis observation and reporting recommendations above, of symptoms over time will allow clinical diagnosis of dry eye in most cases 20 The ophthalmologist should Adopt The ophthalmologist should NA educate the patient about educate the patient about the the natural history and natural history and chronic chronic nature of dry eye nature of dry eye

21 Realistic expectations for Adopt Realistic expectations for NA therapeutic goals should be therapeutic goals should be set

46 set and discussed with the and discussed with the patient patient 22 Particularly effective Adopt Particularly effective NA treatments for evaporative treatments for evaporative tear tear deficiency include deficiency include environmental environmental modifications, modifications, eyelid eyelid therapy for conditions therapy for conditions such such as blepharitis or as blepharitis or meibomianitis, artificial tear meibomianitis, artificial substitutes, moisture chamber

tear substitutes, moisture spectacles, and/or surgery such chamber spectacles, and/or as tarsorrhaphy surgery such as tarsorrhaphy 23 The sequence and Adopt The sequence and combination NA combination of therapies of therapies should be should be determined on determined on the basis of the the basis of the patient’s patient’s needs and needs and preferences and preferences and the treating the treating ophthalmologist’s medical ophthalmologist’s medical judgment judgment

24 Specific therapies may be Adopt Specific therapies may be NA chosen from any category chosen from any category regardless of the level of regardless of the level of disease severity, depending disease severity, depending on on physician experience physician experience and and patient preference patient preference 25 Patients who have Adopt Patients who have suggestive NA suggestive symptoms symptoms without signs without signs should be should be placed on trial

placed on trial treatments treatments with artificial tears with artificial tears when when other potential causes of other potential causes of ocular irritation have been ocular irritation have been eliminated eliminated 26 For patients with a clinical Adopt For patients with a clinical NA diagnosis of mild dry eye, diagnosis of mild dry eye, potentially exacerbating potentially exacerbating exogenous factors such as exogenous factors such as antihistamine or diuretic antihistamine or diuretic use,

use, cigarette smoking and cigarette smoking and exposure to second -hand exposure to second -hand smoke, and environmental smoke, and environmental factors such as air drafts factors such as air drafts and and low-humidity low-humidity environments environments should be should be addressed addressed

47 27 Measures such as lowering Adopt Measures such as lowering the NA the computer screen to computer screen to below eye below eye level to decrease level to decrease lid aperture, lid aperture, scheduling scheduling regular breaks, and regular breaks, and increasing blink frequency increasing blink frequency may decrease the discomfort may decrease the associated with computer and discomfort associated with reading activities computer and reading activities

28 Emulsions, gels, and Adopt Emulsions, gels, and ointments NA ointments can be used can be used 29 The use of artificial tears Adopt The use of artificial tears NA may be increased, but the may be increased, but the practicality of frequent tear practicality of frequent instillation depends on the tear instillation depends on lifestyle or manual the lifestyle or manual dexterity of the patient dexterity of the patient 30 Non-preserved tear Adopt Non-preserved tear NA

substitutes are generally substitutes are generally preferable; however, tears preferable; however, tears with preservatives may be with preservatives may be sufficient for patients with sufficient for patients with mild dry eye and an mild dry eye and an otherwise healthy ocular otherwise healthy ocular surface surface 31 When tear substitutes are Adopt When tear substitutes are NA used frequently and used frequently and chronically, non-preserved chronically, non-preserved

tears are generally tears are generally recommended recommended 32 Adapt Contributing ocular factors NA such as blepharitis or This recommendation is meibomianitis should also already mentioned in be treated recommendation no.32 33 Systemic Doxycycline is Adapted Azithromycin should be Systemic docycycline is used used in patients with used with caution to treat to treat MGD widely by evidence of Meibomian ophthalmologists in India. dry eye in patients who gland dysfunction Systemic Azithromycin is not

have cardiovascular used for treatment of dry eye problems by practitioners in India Javadi M-A, Feizi S. Dry Eye Syndrome. Journal of Ophthalmic & Vision Research. 2011;6(3):192-198. 34 Eyelid abnormalities Adopt Eyelid abnormalities NA

48 resulting from blepharitis resulting from blepharitis should be corrected should be corrected 35 Eyelid abnormalities Adopt Eyelid abnormalities NA resulting from trichiasis resulting from trichiasis should be corrected should be corrected 36 Eyelid abnormalities Adopt Eyelid abnormalities NA resulting from lid resulting from lid malposition should be malposition should be corrected corrected 37 Low-dose topical Adopt Low-dose topical Yes. corticosteroid therapy can corticosteroid therapy can

be used at infrequent be used at infrequent intervals for short periods intervals for short periods of time (i.e., several weeks) of time (i.e., several to suppress ocular weeks) to suppress ocular inflammation inflammation 38 Patients prescribed Adopt Patients prescribed corticosteroids for dry eye corticosteroids for dry eye should be monitored for should be monitored for adverse effects such as adverse effects such as increased intraocular increased intraocular pressure and cataract pressure and cataract

formation formation 39 Use of systemic omega-3 Adapt Use of systemic omega-3 Non proven treatment just fatty acid supplements for fatty acid supplements for adds to the burden. dry eye treatment has been dry eye treatment has been Provide reference to the reported to be potentially reported to be potentially effect that omega 3 fatty beneficial, but there is no beneficial, but there is no acids may not have a evidence of their efficacy. evidence of their efficacy significant role in

They are not recommended management of dry eye for management of dry eye disease disease in India since Liu A, Ji J. Omega-3 Essential evidence of their efficacy Fatty Acids Therapy for Dry and cost effectiveness is Eye Syndrome: A Meta- lacking. Analysis of Randomized Controlled Studies. Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2014;20:1583-1589. doi:10.12659/MSM.891364 40 For patients with aqueous Adopt For patients with aqueous NA

tear deficiency, punctal tear deficiency, punctal occlusion is considered occlusion is considered when the medical means of when the medical means aqueous enhancement are of aqueous enhancement ineffective or impractical are ineffective or impractical 41 Punctal plugs are not Adapt The largest plug that can This whole thing is

49 routinely recommended for be inserted should be used superfluous. Better to go for dry eye management in Adopt to reduce the likelihood of cauterization directly for cost India owing to their Recommend extrusion issues. Punctal Plugs are less relatively high cost. Punctal ation 50 cost effective for use in India occlusion by thermal Delete Rec Thermal cauterization equally cauterization is preferred 51 effective in management of aqueous deficient dry eye for patients with aqueous

disease not responsive to tear deficiency resistant to medical treatment. medical and conservative Reference: measures of treatment Ohba E1, Dogru M, Hosaka E, Yamazaki A, Asaga R, Tatematsu Y, Ogawa Y, Tsubota K, GotoE.Surgical punctal occlusion with a high heat-energy releasing cautery device for severe dry eye with recurrent punctal plug extrusion.Am J Ophthalmol. 2011 Mar;151(3):483-7.e1. doi: 10.1016/j.ajo.2010.08.045. Epub 2011 Jan 12. 42 Adapt Patients who benefit from In our situation, punctual

Adopt having punctal plugs in plugs are costly and place but spontaneously Recommend cumbersone and not a practical lose them may have the ation 50 and solution lost plug(s) replaced or 51 Punctal Plugs are less cost undergo permanent Delete Rec effective for use in India closure of their punctum 52 by a thermal cautery or Thermal cauterization equally alternative means effective in management of aqueous deficient dry eye disease not responsive to medical treatment. Reference: Ohba E1, Dogru M, Hosaka

E, Yamazaki A, Asaga R, Tatematsu Y, Ogawa Y, Tsubota K, Goto E. Surgical punctal occlusion with a high heat-energy releasing cautery device for severe dry eye with recurrent punctal plugextrusion.Am J Ophthalmol. 2011 Mar;151(3):483-7.e1. doi: 10.1016/j.ajo.2010.08.045. Epub 2011 Jan 12. 43 Eyeglass side shields and Adopt Eyeglass side shields and NA moisture chambers are moisture chambers are

50 noninvasive therapies that noninvasive therapies that can be used can be used 44 Hydroxy Propyl Celluslose Adapt Moisture inserts Moisture Inserts are not eye drops, emusions, gels (hydroxypropyl cellulose, commercially available in are frequently used in India Lacrisert, Aton Pharma, moderate to severe dry eye Punctal Occlusion will help Inc., Lawrenceville, NJ) Punctal occlusion may be when there is some tear are occasionally helpful attempted in patients who secretion and there is no ocular

for patients who are are unable to use frequent inflammation artificial tears unable to use frequent artificial tears Reference: Cochrane Review on Punctal occlusion for Dry eye disease Ervin AM, Wojciechowski R, Schien O. Punctal occlusion for dry eye syndrome. Cochrane Database of Systemic Review 2010, Issue 9. An No: CD006775, DOI:10.1002/14651858.CD00 6775.pub2 45 Adapt Pilocarpine and Cevimline is not available for This cevimeline have been use in India

recommend approved by the FDA to Oral pilocarpine is not ation is treat the symptoms of dry recommended for management eliminated mouth in patients with of isolated dry eye in Non from STG Sjögren syndrome Sjogren patients for Dry eye References: syndrome Ervin AM, Wojciechowski R, management Schien O. Punctal occlusion in India for dry eye syndrome. Cochrane Database of Systemic Review 2010, Issue 9. An No: CD006775, DOI:10.1002/14651858.CD00 6775.pub2

46 Autologous serum drops Adopt Autologous serum drops NA have been reported to have been reported to improve ocular irritation improve ocular irritation symptoms as well as symptoms as well as conjunctival and corneal conjunctival and corneal dye staining in patients with dye staining in patients Sjögren syndrome with Sjögren syndrome 47 Autologous serum drops Adopt Autologous serum drops NA have been reported to have been reported to improve ocular irritation improve ocular irritation

symptoms as well as symptoms as well as conjunctival and corneal conjunctival and corneal dye staining in patients with dye staining in patients GVHDGraft-versus-host with GVHD

51 disease (GVHD) 48 Filamentary keratitis can be Adopt Filamentary keratitis can NA treated with debridement of be treated with the filaments or application debridement of the of topical mucolytic agents, filaments or application of such as acetylcysteine 10% topical mucolytic agents, four times a day such as acetylcysteine 10% four times a day 49 Filaments can be debrided Adapt Filaments can be debrided Jewellers’ forceps is expensive

with a cotton-tip applicator with a cotton-tip and not available for use in or dry cellulose sponge. Or applicator, dry cellulose India. Non toothed suture a non-toothed forceps. sponge, or jewelers’ tying forceps are easily forceps available. 50 If the patient has associated Adopt If the patient has NA neurotrophickeratopathy, associated contact lenses should be neurotrophickeratopathy, avoided contact lenses should be avoided 51 Permanent punctal Adapted Permanent punctal Laser is not commonly

occlusion can be occlusion can be employed for punctal cautery in India accomplished by means of accomplished by means of Laser punctal cautery is not thermal cautery thermal or laser cautery cost effective and similar results may be achieved with thermal cautery Benson et al and Vrabec et al found punctum occlusion by argon laser has a high failure rate. The cost associated with laser technique is known to be higher than that of the conventional methods. Nelson CC, Reed S. Argon

laser versus thermal cautery for punctalocclusion.OphthalmicP lastReconstrSurg 1991;7:173– 6.9 Vrabec M, Elsing S, Aitken PA. A prospective randomized comparison of thermal cauter and argon laser for permanent punctal occlusion. Am J Ophthalmol 1993;116:469– 7110. 52 Adapt If occlusion with cautery Performing non- Eliminate is planned, a trial permanentpunctal occlusion is occlusion with not common practice in India recommend nonpermanent implants A stepwise approach to ation 62

52 Consider performed first to screen recommended so that no more Rec No 63 for the potential than one punctum is cauterized development of epiphora in each eye at a treatment session 53 A stepwise approach to Adopt A stepwise approach to NA cautery occlusion is cautery occlusion is generally recommended so generally recommended so that no more than one that no more than one punctum is cauterized in punctum is cauterized in each eye at a treatment each eye at a treatment session session

54 A limited tarsorrhaphy can Adopt A limited tarsorrhaphy can NA be performed to decrease be performed to decrease tear evaporation in patients tear evaporation in patients with severe dry eye who with severe dry eye who have not responded to other have not responded to therapies other therapies Provider & Setting, Counseling & Referral 55 Boston Scleral lenses may Adapted Rigid gas-permeable We don’t use them. Boston be recommended for scleral lenses have been scleral lenses may be useful

treatment of severe dry employed successfully in Bavinger JC1, DeLoss K, Mian eyes. the treatment of severe dry SI.Scleral lens use in dry eye eye for years syndrome. CurrOpinOphthalmol. 2015 Jul;26(4):319-24. doi: 10.1097/ICU.00000000000001 71. 56 Patients with dry eye who Adopt Patients with dry eye who NA are evaluated by non- are evaluated by non- ophthalmologist health care ophthalmologist health providers should be care providers should be referred promptly to the referred promptly to the

ophthalmologist if ophthalmologist if moderate or severe pain, moderate or severe pain, lack of response to therapy, lack of response to corneal infiltration or therapy, corneal ulceration, or vision loss infiltration or ulceration, occurs or vision loss occurs 57 The most important aspects Adopt The most important NA of caring for patients with aspects of caring for dry eye are to educate them patients with dry eye are to about the chronic nature of educate them about the

the disease process and to chronic nature of the provide specific disease process and to instructions for therapeutic provide specific regimens instructions for therapeutic regimens

53 58 It is helpful to periodically Adopt It is helpful to periodically NA reassess the patient’s reassess the patient’s compliance and compliance and understanding of the understanding of the disease, the risks for disease, the risks for associated structural associated structural changes, and to re-inform changes, and to re-inform the patient as necessary the patient as necessary 59 Patients with pre -existing Adopt Patients with pre -existing NA dry eye should be cautioned dry eye should be

that keratorefractive cautioned that surgery, particularly keratorefractive surgery, LASIK, may worsen their particularly LASIK, may dry eye condition worsen their dry eye condition 60 Patients who have dry eye Adopt Patients who have dry eye NA and are considering and are considering keratorefractive surgery keratorefractive surgery should have the dry eye should have the dry eye treated before surgery treated before surgery 61 In moderate to severe cases Adopt In moderate to severe NA

that are unresponsive to cases that are unresponsive treatment or when systemic to treatment or when disease is suspected, timely systemic disease is referral to an suspected, timely referral ophthalmologist who is to an ophthalmologist who knowledgeable and is knowledgeable and experienced in the experienced in the management of these management of these entities is recommended entities is recommended 62 Referral to an internist or Adopt Referral to an internist or NA

rheumatologist can be rheumatologist can be considered for patients with considered for patients systemic immune with systemic immune dysfunction or for those dysfunction or for those who require who require immunosuppressive therapy immunosuppressive therapy 63 Adapt/ Patients with systemic This recommendation can be Eliminated disease such as primary eliminated since guideline 70 Sjögren syndrome, emphasizes referral of persons secondary Sjögren, or with any systemic disease to a

connective tissue disease medical specialist such as rheumatoid Expert Group Consensus arthritis should be managed by an appropriate medical specialist

54 Diagnostic Tests 64 Lissamine green Adopt Lissamine green dye is not NA dye is not recommended for evaluating recommended for corneal epithelial disease evaluating corneal epithelial disease 65 The Schirmer test Adopt The Schirmer test can be NA can be performed performed to evaluate aqueous to evaluate tear production, but it is well aqueous tear recognized that it gives variable production, but it results and should not be used as is well the sole criterion for diagnosing recognized that it

gives variable dry eye: III; Insufficient; results and should not be used as the sole criterion for diagnosing dry eye: III; Insufficient;

55 References: 1. The definition and classification of dry eye disease: report of the Definition and Classification Sub Committee of the International Dry Eye Workshop. Ocul Surf 2007; 5:75- 92 ;2007 Report of the International Dry eye Workshop (DEWS). (Special issue) Ocul Surf 2007; 5: 65-199. 2. Hikichi T, Yoshida A, Fukui Y, et al. Prevalence of dry eye in Japanese eye centers. Graefes Arch Clin Exp Ophthalmol 1995;233:555-8.

3. Schein OD, Munoz B, Tielsch JM, et al. Prevalence of dry eye among the elderly. Am J Ophthalmol 1997;124:723-8. 4. McCarty CA, Bansal AK, Livingston PM, et al. The epidemiology of dry eye in Melbourne, Australia. Ophthalmology 1998;105:1114-9. 5. Sahai A, Malik P. Dry Eye: Prevalence and attributable risk factors in a hospital- based population. Ind J Ophthalmol 2005; 53: 87-91. 6. Gupta N, Prasad I, Jain R, D’Souza P. Estimating the prevalence of dry eye among Indian

patients attending a tertiary ophthalmology clinic. Ann Trop Med Parasitol 2010; 104: 247-55. 7. Basak SK, Pal PP, Basak S, Bandyopadhyay A, Choudhury S, Sar S. Prevalence of Dry Eye Diseases in hospital-based population in West Bengal, Eastern India. J Indian Med Assoc. 2012; 110: 789-94. 8. Gupta N, Prasad I, Himashree G, D’Souza P. Prevalence of dry eye at high altitude: a case controlled comparative study. High Alt Med Biol 2008; 9: 327-34.

9. Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. CLAO J 1995;21:221-32 10. American Academy of Ophthalmology Basic and Clinical Science Course Subcommittee. Basic and Clinical Science Course. External Disease and Cornea: Section 8, 2013-2014. San Francisco, CA: American Academy of Ophthalmology; 2013:47-8. 11. Kanski JJ, Rowling B. Clinical ophthalmology: a systematic approach. 7th ed. Edinburg: Elsevier Saunders; 2011.

12. Javadi M-A, Feizi S. Dry Eye Syndrome. Journal of Ophthalmic & Vision Research. 2011;6(3):192-198. 13. Liu A, Ji J. Omega-3 Essential Fatty Acids Therapy for Dry Eye Syndrome: A Meta-Analysis of Randomized Controlled Studies. Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2014;20:1583-1589. doi:10.12659/MSM.891364 14. Ohba E, Dogru M, Hosaka E, Yamazaki A, Asaga R, Tatematsu Y, Ogawa Y, Tsubota

K, GotoE.Surgical punctal occlusion with a high heat-energy releasing cautery device for

56 severe dry eye with recurrent punctal plug extrusion. Am J Ophthalmol. 2011 Mar;151(3):483-7.e1. doi: 10.1016/j.ajo.2010.08.045. Epub 2011 Jan 12. 15. Ervin AM, Wojciechowski R, Schien O. Punctal occlusion for dry eye syndrome. Cochrane Database of Systemic Review 2010, Issue 9. An No: CD006775, DOI:10.1002/14651858.CD006775.pub2 16. Nelson CC, Reed S. Argon laser versus thermal cautery for punctual occlusion.Ophthalmic Plast Reconstr Surg 1991;7:173–6.

17. Vrabec M, Elsing S, Aitken PA. A prospective randomized comparison of thermal cauter and argon laser for permanent punctal occlusion. Am J Ophthalmol 1993;116:469–7110. 18. Bavinger JC, DeLoss K, MianSI. Scleral lens use in dry eye syndrome. Curr Opin Ophthalmol. 2015 Jul;26(4):319-24. doi: 10.1097/ICU.0000000000000171. 19. Pflugfelder SC. Management and Therapy Subcommittee of the International Dry Eye Workshop. Management and therapy of dry eye disease: report of the Management and

Therapy Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf 2007;5:163-78. 20. International Dry Eye Workshop Subcommittee. The definition and classification of dry eye disease: report of the definition and classification subcommittee of the International Dry Eye Work Shop (DEWS - 2007). Ocul Surf 2007; 5: 75-92 21. Begley CG, Chalmers RL, Abetz L, et al. The relationship between habitual patient-reported symptoms and clinical signs among patients with dry eye of varying severity. Invest

Ophthalmol Vis Sci 2003; 44: 4753-61 22. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice Pattern® Guidelines. Dry Eye Syndrome. San Francisco, CA: American Academy of Ophthalmology; 2013. Available at: www.aao.org/ppp.

Contents Page S.No. Topic No. 1 ANTI RETEROVIRAL THERAPY 2 2 ENCEPHALITIS 29 3 INFECTIOUS DIARRHOEA 33 4 HEPATITIS B 66 5 PRE-OPERATIVE HAEMOSTASIS SCREEN: 87 6 ACTIVATED PARTIAL THROMBOPLASTIN TIME: 93 7 BLEEDING TIME: 95 1

ANTI RETEROVIRAL THERAPY 1. When to suspect/ recognize HIV? a) Introduction: There is no clinical description; the diagnosis is based on lab criteria Laboratory criteria for diagnosis: 1. HIV positive serology (ELISA) 2. Confirmation should be a second ELISA b) Case definition: WHO clinical case definition for AIDS in an adult or adolescents (>12 years of age) is considered to have AIDS if at least 2 of the following major signs are

present in combination with at least 1 of the minor signs listed below, and if these signs are not known to be related to a condition unrelated to HIV infection Major signs (2 signs or more): a.Weight loss >_10% of body weight b.Chronic diarrhoea for >1 month c.Prolonged fever for >1 month (intermittent or constant) Minor signs (1 or more): a. Persistent cough for >1 month b. Generalized pruritic dermatitis c,History of herpes zoster d.Oropharyngeal candidiasis

Incidence of the condition in our country: As per the provisional HIV estimate of 2008-09, there are an estimated 22.7 lakh people living with HIV/AIDS in India. The HIV prevalence rate in the country is percent (2008-09) and most infections occur through heterosexual route of transmission. The absolute number of HIV infections in the country is expected to be close to 2.5 million. Differential Diagnosis:  Flu - the very early HIV infection symptoms are like flu.  Immunodeficiency syndromes

 Epstein -Barr virus  Dementia  Hypogammaglobulinemia  Severe combined immunodeficiency disease  Depression  B-cell deficiency  T-cell deficiency  Non-Hodgkin's Lymphoma  Pelvic Inflammatory Disease  Pyoderma Gangrenosum Prevention and counseling: the primary focus of NACP–III is to halt and reverse the spread of the HIV epidemic in India by 2012. The programme plans to cover 80 percent of HRGs with primary prevention services, including:  Treatment for sexually transmitted infections 2

 Creating an enabling environment with community involvement and participation  Linkages to care and support services Optimal diagnostic criteria, investigations, treatment and referral criteria Situation 1: At secondary hospital/ non-metro situation: Optimal standards of treatment in situations where technology and resources are limited. a) Diagnosis: the diagnosis is based on lab criteria b) Investigations: 1.HIV positive serology (ELISA) 2. Confirmation should be a second ELISA

c) Treatment: after counseling patient is reffered to super speciality centre Situation 2: At super specialty facility in Metro location where higher-end technology is available. a) Clinical Diagnosis: Physical Examination: Record vital signs, body weight, height and body mass index (BMI), temperature, blood pressure, pulse rate, respiratory rate 4

 Baseline screening of CD4 to determine eligibility for starting ART  Baseline laboratory assessment, including CBC, ALT/AST, ALP, urinalysis  For women: Annual PAP smear screening or acetic acid cervical screening at district health care facilities  HBsAg and HCV screening for IDUs/those with transfusion-associated infections or elevated liver enzyme levels  Any other relevant investigations (symptom-driven) and screening for TB at every visit

 Where routinely available, use VL every 6 months to detect viral replication. c) Treatment: 8

Triple NRTI option: It is recommended that the triple nucleoside regimens AZT + 3TC + ABC or AZT + 3TC + TDF should be used for individuals who are unable to tolerate or have contraindications to NNRTIbased regimens, particularly in the following situations: 14

• HIV/TB coinfection; • pregnant women; • chronic viral hepatitis B; • HIV-2 infection. Recommendations: 1. Where available, use viral load (VL) to confirm treatment failure. (Strong recommendation, low quality of evidence) 2. Where routinely available, use VL every 6 months to detect viral replication. (Conditional recommendation, low quality of evidence) 3. A persistent VL of >5000 copies/ml confirms treatment failure. (Conditional recommendation, low quality of evidence)

4. When VL is not available, use immunological criteria to confirm clinical failure. (Strong recommendation, moderate quality of evidence) 15

WHO does what? And Timelines • Doctor: proper monitoring, evaluation and guiding ART • Nurse: proper care support and treatment • Technician: (cid:252) Encourage use of standard reagents/ methodology and trained personnel (cid:252) Monitor laboratory performance and evaluate quality control measures (cid:252) Promote high standards of good laboratory practices (cid:252) Stimulate performance improvement (cid:252) Identify common error Further Reading / References:

1. WHO. Antiretroviral treatment working group treatment white paper. 2010. 2. Siegfried NL, Uthman OA, Rutherford GW. Optimal time for initiation of antiretroviral 17

therapy for asymptomatic, HIV-infected, treatment-naive adults. Cochrane Database of Systematic Reviews 2010. 3. Severe P, Pape J, Fitzgerald D, et al. A randomized clinical trial of early versus standard antiretroviral therapy for HIV-infected patients with a CD4 cell count of 200-350 cells/mm3 (CIPRATH-001). 49th Interscience Conference on Antimicrobial Agents and Chemotherpy, San Fransisco, 2009 4. Sterne JA, May M, Costagliola D, de Wolf F, Phillips AN, Harris R, et al. Timing of initiation

of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV Edathodu J, Ali B, Alrajhi AA. CD4 validation for the World Health Organization classification and clinical staging of HIV/AIDS in a developing country. Int J Infect Dis 2009;13(2):243-6.cohort studies. Lancet 2009;373(9672):1352-63. 5. Department of AIDS Control,Ministry of Health and Family Welfare.Annual report 2009-2010. Abbreviations: 3TC lamivudine ABC abacavir ATV atazanavir

AZT zidovudine (also known as ZDV) d4T stavudine ddI didanosine DRV darunavir EFV efavirenz ETV etravirine FTC emtricitabine HRG high risk group LPV lopinavir LPV/r lopinavir/ritonavir NFV nelfinavir NVP nevirapine RAL raltegravir RBV ribavirin 18

IV catheter related blood stream infections ( CR-BSI) 2. When to suspect/ recognize? Situation 1: Catheter-related blood stream infection (CRBSI): CRI is suspected when there is unexplained fever in a catheterized patient especially if fever can be linked to manipulation of the device, or if there are local inflammatory signs. Situation 2: Catheter-related blood stream infection (CRBSI): Isolation of the same organism from a

semiquantitative or quantitative culture of a catheter segment and from the blood (preferably drawn from a peripheral vein) of a patient with accompanying clinical symptoms of bloodstream infection without any other apparent source of infection. 2. Incidence of the condition in our country: Catheter-related bacteremia is the third most frequent cause of nosocomial bacteremia, with an incidence of 20 to 30%. The emergence of CRB is directly

related to the duration of catheterization and ranges from 0.02 to 0.66 episodes of bacteremia per 100 days, according to the series and the type of catheter used. 3. Differential Diagnosis. Enteric fever Endocarditis Thrombophlebitis Lymphangitis Brucellosis 4. Prevention and counseling; 20

1. Limit duration of IV catheter 2. Dedicated IV line team 3. Aseptic precautions 4. Glycemic control 5. Health education 5. Optimal diagnostic criteria, investigations, treatment and referral criteria Situation 1: At secondary hospital/ non-metro situation: Optimal standards of treatment in situations where technology and resources are limited. a) Clinical Diagnosis: Fever with or without chills and inflammation or purulence around the intravascular device.

b) Investigations: 1. Blood culture: Isolation of pathogenic microorganisms with corresponding clinical features of blood stream infections. 2. Rapid Diagnostic Technique: Gram staining of catheter segments may be helpful for the diagnosis of the local infections. c) Treatment: a- In Patient: It is recommended to treat empirically with vancomycin and change to semisynthetic penicillin if the isolate is susceptible and third generation cephalosporins especially that active against

pseudomonas should also be added. 14 days of treatment is recommeneded. b- Out Patient: 1st generation cephalosporins ( Cefazolin) and Fluoroquinolones 21

d) Referral criteria: 1. Associated complications like thrombosis, endocarditis, osteomyelitis, metastatic seeding. 2. CR-BSI infections could not be ascertained. 3. No improvement after antimicrobial therapy. Situation 2: At super specialty facility in Metro location where higher-end technology is available. a) Clinical Diagnosis: Fever with or without chills and inflammation or purulence around the intravascular device. b) Investigations: Cultures of Samples of IV Catheters:

1. The most widely used laboratory technique for the diagnosis of Catheter related infections is the semi quantitative method in which the catheter segment is rolled across the surface of an agar plate and colony forming units (CFU) are counted after overnight incubation. 2. To obtain the quantitative culture of a catheter, the catheter segment either flushed with and then immersed in broth or placed in broth and vortexed/sonicated; quantitative cultures are done on the

broth recovered from these procedures. The limitation of the quantitative and semi quantitative catheter methods is that they require removal of the catheter to aid in the diagnosis of CR-BSIs. Paired cultures of blood drawn percutaneously and through the IV catheter: An alternative for diagnosis of CR-BSI in patients where catheter removal is undesirable because of limited vascular access. These techniques rely on quantitative culture of paired blood samples, one obtained through

the central catheter and other from peripheral venipuncture site. A colony count from the blood obtained from 22

the catheter that is five to ten folds greater than the colony count from the blood obtained from a peripheral vein has been predictive of CR-BSI. 23

Differential time to positivity for CVC versus Peripheral blood culture: This new method, which correlates well with quantitative blood cultures, makes use of continuous blood culture monitoring for positivity (radiometric method) and compares the differential time to positivity (DTP) for qualitative cultures of blood samples drawn from the catheter and a peripheral vein. Infusate related blood stream infection: Samples are taken from both

infusate and separate percutaneous blood culture for diagnosis of infusate related blood stream infection. b) Treatment: Management of intravascular device associated infection depends on several variables including; the type of infection, local or bacteremic; the organisms involved; the type of device, (peripheral or central catheters, totally implanted devices); and the severity of the illness of the patient. General guidelines: For nontunneled catheters

• Catheter should be removed in patients with CRBSIs if the infection is complicated with septic thrombosis, endocarditis, osteomyelitis. Systemic antibiotic therapy is to be continued for 4-6 weeks. • In patients with uncomplicated CR-BSIs, catheter should be removed and systemic antibiotic therapy should be given for 5-7 days with coagulase negative staphylococcus infection and for 10-14 days in case of staphylococcus aureus and gram-negative bacilli.

• In case of fungal infection, catheter should be removed and antifungal therapy is to be continued for 14 days. For tunneled catheters : • Catheter should be removed if the infection is complicated with tunnel infection, port abscess, septic thrombosis, endocarditis and osteomyelitis. 24

• Catheter can be retained with uncomplicated Staphylococcus aureus and gram-negative bacilli infection under cover of 10-14 days of systemic antimicrobial therapy with antibiotic lock therapy. These devices should be removed if there is clinical deterioration, persisting or relapsing bacteremia. • Salvage therapy for infected tunneled CVCs or IDs is not recommended for routine use in case of fungal infection because salvage rates with systemic fungal therapy and ALT for Candida species have been in the

30% range. Empirical therapy:  It is recommended to treat empirically with vancomycin and change to semisynthetic penicillin if the isolate is susceptible and third generation cephalosporins especially that active against pseudomonas should also be added Specific therapy: 25

Microorganism Preferred antibacterial Out Patient In Patient agents S.aureus ( MSSA) Penicillinase resistant Cloxacillin 25-100 Nafcillin or Oxacilin penicillins mg/kg/day in 4 2gm q4h divided doses S. aureus ( MRSA) Vancomycin or Linezolid 600mg q12h Linezolid, Vancomycin Quinopristine/Dalfopristine 1gm IV q12h S.aureus ( VRSA) Linezolid or Linezolid 600mgq12h Linezolid, Qunopristine/Dalfopristine Quinopristine/ Dalfopristine 7.5 mg/kg q8h

CoNS ( MSSE) Penicillinase resistant Cotrimoxazole 960 Nafcillin or Oxacilin 2 penicillins mg q 12h gm q12h or Cotrimoxazole 960 mg q 12h CoNS ( MRSE) Vancomycin Linezolid 600 mg Vancomycin 1gm q q12h 12h 26

Enterococcus ( Amp Ampicillin+ Gentamicin Ampicillin 2g q4h -6h + Susceptible) Gentamicin 1mg/kg q 8h Enterococcus ( Amp Vancomycin or Vancomycin + Linezolid 600 mg q Vancomycin 1 gm IV 27

resistant) Aminoglycoside 12h q12 h+ Gentamicin 1mg/kg q 8h Enterococcus( Linezolid or Quinopristine+ Linezolid 600 mg q Linezolid 600 mg q 12h Vancomycin resistant) Dalfopristine 12h or Quinopristine+ Dalfopristine 7.5 mg/kg q8h Gram Negative Bacilli Third generation Ciprofloxacin 750 mg Ceftriaxone 1-2g qd ( non ESBL) cephalosporins q12h Candida Amphotericin B or Fluconazole 400-600 Amphotericin B Fluconazole mg qd 0.3mg/kg/d or Fluconazole 400-600 mg qd 28

Further reading: 1. Singhal A K, Mishra S and Bhatnagar S. Recent advances in Management of Intravascular Catheter Related Infections. Indian Journal Of Medical and Paediatric Oncology, Vol. 26 No.1, 2005. 2. Mandell G L, Benett J E, Dolin R. Principles and Practice of infectious diseases. 6th edition. Vol 1. Encephalitis 3. When to suspect/ recognize? : Severe headache, high grade fever, altered consciousness, stiff neck & back

4. a) Introduction: Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningo encephalitis. b) Case definition For both situations of care (mentioned below*) Situation 1 Any person of any age admitted to hospital with encephalopathy (altered consciousness that persisted for longer than 24hr, including lethargy, irritability, or a change in personality and behavior) and with

fever or history of fever (≥38ºC) during the presenting illness; seizures and/or focal neurological findings (with evidence of brain parenchyma involvement); CSF pleocytosis (more than 4 four white blood cells per µl). Situation 2 Any person of any age admitted to hospital with encephalopathy (altered consciousness that persisted for longer than 24hr, including lethargy, irritability, or a change in personality and behavior) and with

fever or history of fever (≥38ºC) during the presenting illness; seizures and/or focal neurological findings (with evidence of brain parenchyma involvement); CSF pleocytosis (more than four white blood cells per µl),electroencephalographic (EEG) findings indicative of encephalitis; and abnormal results of neuroimaging (CT or MRI) suggestive of encephalitis. 29

6. Incidence of the condition in our country: About 20 to 30% of all cases presented with fever 7. Differential Diagnosis: Malaria, Enteric fever, Dengue, Chikungunya, Leptospira, Urinary tract infection, PID, Tuberculosis, Meningitis or Encephalitis . 8. Prevention and counseling: Prompt distinction between causes of acute encephalitis is essential to direct appropriate management. 9. Optimal diagnostic criteria, investigations, treatment and referral criteria

Persistent fever in spite of treatment given for Malaria Enteric fever & tuberculosis, Dengue and Chikungunya Situation 1: At secondary hospital/ non-metro situation: Optimal standards of treatment in situations where technology and resources are limited. a) Diagnosis: Adult patients have acute onset of fever, headache, confusion, sometimes seizures. Pediatric cases present with fever, irritability or loss of appetite. Stiff neck indicates that patient has either meningitis or meningoencephalitis.

b) Investigations: Whole Hemogram, Peripheral smear (Malaria) and other blood parasite Blood culture and widal for enteric fever Sputum examination for Tuberculosis or other infection X-ray chest (Lung infection or patches) c) Treatment: It is usually symptomatic. Keep airway patent.Turn patient to side to avoid aspiration.Seizures can be controlled with diazepam.Acyclovir can be given for herpes simplex virus. In very sick

patients mechanical ventilation may be done. Corticosteroids reduce brain inflammation and swelling. Sedatives are used to reduce irritability or restlessness. Standard Operating procedure a- In Patient: Day & night temperature recording chart b- Out Patient c- Day Care 30

d) Referral criteria: Refer as early as possible Situation 2: At super specialty facility in Metro location where higher-end technology is available. a) Clinical Diagnosis: Neurological examinations usually reveal a drowsy or confused patient. Stiff neck, due to the irritation of the meninges covering the brain, indicates that the patient has either meningitis or meningo-encephalitis Examination of the cerebrospinal fluid obtained by a lumbar puncture procedure usually reveals

increased amounts of protein and white blood cells with normal glucose, though in a significant percentage of patients, the cerebrospinal fluid may be normal. CT scan often is not helpful, as cerebral abscess is uncommon. Cerebral abscess is more common in patients with meningitis than encephalitis. Bleeding is also uncommon except in patients with herpes simplex type 1 encephalitis. Magnetic resonance imaging offers better resolution. In patients with herpes simplex

encephalitis, electroencephalograph may show sharp waves in one or both of the temporal lobes. Lumbar puncture procedure is performed only after the possibility of prominent brain swelling is excluded by a CT scan examination. Diagnosis is often made with detection of antibodies in the cerebrospinal fluid against a specific viral agent (such as herpes simplex virus) or by polymerase chain reaction that amplifies the RNA or DNA of the virus responsible (such as varicella zoster virus).

b) Investigations: test for malaria,blood culture for Salmonella,Widal test,CSF examination,PCR for antigen detection c) Treatment: Establish adequate airway,mechanical ventilation may be needed Administer oxygen, Maintain blood pressure, Avoid fluid overload, Avoid hypoglycemia, Manage seizures, Reduce raised intracranial tension, Do urinary catheterization, Standard Operating procedure 31

a- In Patient b- Out Patient c- Day Care d) Referral criteria 6. WHO does what? And Timelines a- Doctor- ensure patency of airway, manage symptomatically b- Nurse- do suction regularly c- Technician 10. Further Reading / References 1. Granerod et al ,Lancet Infect Dis 2010; 10:835-44 2. Khetsuriani N et al, Clin Infect Dis 2002;35:175-82 Resources required For one patient Procedure (Patient weight 60 KGS)

(Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation Human Resources Investigations Drugs & Equipment Consumables 1 One doctor, one nurse Tests for malaria,typhoid,s erology 2 One doctor, one nurse, Above with one technician Serology and PCR 32

Infectious Diarrhoea Case Definition ACUTE INFECTIOUS DIARRHOEA Clinical Case Description: Acute watery diarrhoea (passage of 3 or more loose or watery stools in the past 24 hours) due to an infectious etiology, often accompanied by symptoms of nausea, vomiting, or abdominal cramps presenting with or without dehydration. “Acute diarrhea” is an episode of diarrhea of <14 days in duration. “Persistent diarrhea” is diarrhea of 14 days in duration. ACUTE INFECTIOUS DYSENTERY Clinical case description:

Acute infective diarrhoea with visible blood in the stool. 11. Incidence of the condition in our country Number of episodes of diarrhoea in each year - About 2 million. Death due to diarrhoea among children < 5 years - 1.87 million. 33

No. of episodes of diarrhoea in a child less than 5 years of age - 2-3. 12. Differential Diagnosis 1. Irritable bowel syndrome, 2. Inflammatory bowel diseases 3. Ischemic bowel disease 4. Partial bowel obstruction 5. Pelvic abscess in the area of the rectosigmoid colon 6. Pernicious anemia 7. Pellagra 8. Malaria 9. Whipple's disease 10. Diabetes mellitus 11. Small bowel scleroderma 12. Small bowel diverticulosis 13. Malabsorption syndrome 13. Prevention and counseling Water, sanitation, and hygiene:

• Safe water • Sanitation: houseflies can transfer bacterial pathogens • Hygiene: hand washing Safe food: • Cooking eliminates most pathogens from foods • Exclusive breastfeeding for infants • Weaning foods are vehicles of enteric infection Micronutrient supplementation: the effectiveness of this depends on the child’s overall immunologic and nutritional state; further research is needed. Vaccines: • Measles immunization can substantially reduce the incidence and severity of diarrheal diseases. Every

infant should be immunized against measles at the recommended age. 34

14. Optimal diagnostic criteria, investigations, treatment and referral criteria Situation 1: At secondary hospital/ non-metro situation: Optimal standards of treatment in situations where technology and resources are limited. Classifications of diarrhea episodes Linking the main symptoms to the causes of acute diarrhea. 35

Evaluation of the acute diarrhea patient. Levels of dehydration in children with acute diarrhea 36

Signs of dehydration in adults: • Pulse rate > 90/ min • Postural hypotension • Supine hypotension and absence of palpable pulse 37

• Dry tongue • Sunken eyeballs • Skin pinch Patient history details and causes of acute diarrhea 38

The incubation period and likely causes of diarrhea. Investigations 1. Fecal leucocyte examination 2. Wet mount for parasitic infection 39

TREATMENT Rehydration Oral rehydration therapy (ORT) is the administration of fluid by mouth to prevent or correct dehydration that is a consequence of diarrhea. ORT is the standard for efficacious and cost-effective management of acute gastroenteritis. Oral rehydration solution (ORS) is the fluid specifically developed for ORT. ORT consists of: • Rehydration — water and electrolytes are administered to replace losses. • Maintenance fluid therapy (along with appropriate nutrition). Contraindication of ORT

with abdominal ileus Nasogastric administration of ORS is an alternative for children who are unable to tolerate ORS via the oral route (with persistent vomiting), Oral rehydration solution(ORS) constituents mmol/L Sodium 75 Chloride 65 Glucose (Anhydrous) 75 Potassium 20 Citrate 10 - - - - - - - - - - - - - - - - - - - - - - - - - - Total osmolarity 245 Supplemental zinc therapy, multivitamins, and minerals Micronutrient supplementation — Supplementation treatment with zinc (20 mg per day until the

diarrhea ceases) Children with persistent diarrhea should receive supplementary multivitamins and minerals each day for 2 weeks at least two recommended daily allowances (RDAs) of folate, vitamin A, zinc, magnesium, and copper. As a guide, one RDA for a child aged 1 year is Folate 50 μg Zinc 20 mg Vitamin A 400 μg Copper 1 mg Magnesium 80 mg 41

Diet The practice of withholding food for > 4 hours is inappropriate. Food should be started 4 hours after starting ORT or intravenous fluid. The notes below apply to adults and children unless age is specified. Give: • An age-appropriate diet — regardless of the fluid used for ORT/maintenance • Infants require more frequent breastfeedings or bottle feedings — special formulas or dilutions unnecessary • Older children should be given appropriately more fluids

• Frequent, small meals throughout the day (six meals/day) • Energy and micronutrient-rich foods (grains, meats, fruits, and vegetables) • Increasing energy intake as tolerated following the diarrheal episode Avoid: • Canned fruit juices — these are hyperosmolar and can aggravate diarrhea. Antimicrobials INDICATIONS - Children with bloody diarrhea (most likely shigellosis) - Suspected cholera with severe dehydration - Serious nonintestinal infections (e.g., pneumonia)

- Diarrhea due to Giardia, Entamoeba histolytica. In adults, the clinical benefit should be weighed against the cost, the risk of adverse reactions, harmful eradication of normal intestinal flora, the induction of Shiga toxin production, and the increase of antimicrobial resistance. Antimicrobials are the drugs of choice for empirical treatment of traveler’s diarrhea and of community- acquired secretory diarrhea when the pathogen is known. 42

Considerations with regard to antimicrobial treatment: • Consider antimicrobial treatment for: — Persistent Shigella, Salmonella, Campylobacter, or parasitic infections. — Infections in the aged, immunocompromised patients, and patients with impaired resistance, sepsis, or with prostheses. — Moderate/severe traveler’s diarrhea or diarrhea with fever and/or with bloody stools — quinolones (co-trimoxazole second choice). • Nitazoxanide is an antiprotozoal and may be appropriate for diarrhea due to

Cryptosporidium. Antimicrobial agents for the treatment of specific causes of diarrhea. SYNDROME PREFERRED ANTIBIOTICS ALTERNATIVE ANTIBIOTICS cholera Doxycycline Azithromycin Ciprofloxacin Adult: 300 mg OD or Tetracycline: 500 mg 4 times a day for 3 days 43

Shigellosis Ciprofloxacin Ceftriaxone Children: Children: 15 mg/kg 2 times a day for 3 days 50 – 100 mg/kg once Adults: 500 mg 2 times a day for 3 days a day IM f 2 to 5 days 44

Amoebiasis Metronidazole Children: 10 mg/kg 3 times a day for 5 days* Adults: 750 mg 3 times a day for 5 days* *10 days for severe disease Giardiasis Metronidazole ** Children: 5 mg/kg 3 times a day for 5 days Adults: 250 mg 3 times a day for 5days Campylobacter Quinolones Azithromycin ** Tinidazole can also be given in a single dose (50 mg/kg orally;maximum dose 2g). Ornidazole can be used in accordance with the manufacturers’ recommendations. • Azithromycin

(cid:216) Adult - 250 mg or 500 mg once daily for 3–5 days. (cid:216) Children - 5 mg to 20 mg per kilogram of body weight per day, once daily for 3–5 days. • Treatment for amebiasis should, ideally, include diloxanide furoate following the metronidazole, to get rid of the cysts that may remain after the metronidazole treatment. • Selection of an antimicrobial should be based on the sensitivity patterns of strains of Vibrio cholerae O1 or O139, or Shigella recently isolated in the area.

• An antimicrobial is recommended for patients older than 2 years with suspected cholera and severe dehydration. • Alternative antimicrobials for treating cholera in children are TMP-SMX (5 mg/kg TMP + 25 mg/kg SMX, b.i.d. for 3 days), furazolidone (1.25 mg/kg, q.i.d. for 3 days), and norfloxacin. The actual selection of an antimicrobial will depend on the known resistance/sensitivity pattern of V. cholerae in the region. CLINICAL PRACTICE Approach in adults with acute diarrhea 45

Principles of appropriate treatment for children with diarrhea and dehydration. Treatment for children based on the degree of dehydration. Minimal or no dehydration. 47

Treatment for children based on the degree of dehydration (Mild to moderate dehydration). Note: if vomiting is persistent, the patient (child or adult) will not take ORS and is likely to need intravenous fluids. Treatment for children based on the degree of dehydration Severe dehydration. Therapeutic approach to acute bloody diarrhea (dysentery) in children 48

Referral criteria : 1. Persistent diarrhea 2. Irritable bowel syndrome 3. Inflammatory bowel disease 4. Malabsorption syndrome 5. Reiter's syndrome (reactive arthritis) 6. Hemolytic-uremic syndrome 7. Child with dysentery who is initially dehydrated, age <1 year or measles in past 6 weeks. 49

Situation 2: At super specialty facility in Metro location where higher-end technology is available. a) Clinical Diagnosis: Classifications of diarrhea episodes Linking the main symptoms to the causes of acute diarrhea. 51

Evaluation of the acute diarrhea patient. Levels of dehydration in children with acute diarrhea 52

Signs of dehydration in adults: • Pulse rate > 90 • Postural hypotension • Supine hypotension and absence of palpable pulse • Dry tongue • Sunken eyeballs • Skin pinch Patient history details and causes of acute diarrhea 53

The incubation period and likely causes of diarrhea. Investigations: 1. Routine stool culture 2. Detection of E. coli enterotoxin 3. Detection of Rota virus antigen(Latex agglutination) 4. RT- PCR and specific antigen detection ELISA for Noro virus. 5. Special staining to detect Cryptosporidium 6. C.difficile toxin detection by rapid immunoassay or Latex agglutination test. 7. Flexible sigmoidoscopy with biopsies and upper endoscopy with duodenal aspirates and biopsies 8. Sigmoidoscopy 9. Colonoscopy

Treatment Rehydration Oral rehydration therapy (ORT) is the administration of fluid by mouth to prevent or correct dehydration that is a consequence of diarrhea. ORT is the standard for efficacious and cost-effective management of acute gastroenteritis. Oral rehydration solution (ORS) is the fluid specifically developed for ORT. ORT consists of: • Rehydration — water and electrolytes are administered to replace losses. • Maintenance fluid therapy (along with appropriate nutrition). Contraindication of ORT

Children with hemodynamic shock with abdominal ileus Nasogastric administration of ORS is an alternative for children who are unable to tolerate ORS via the oral route (with persistent vomiting), Oral rehydration solution(ORS) constituents mmol/L 56

Sodium 75 Chloride 65 Glucose (Anhydrous) 75 Potassium 20 Citrate 10 - - - - - - - - - - - - - - - - - - - - - - - - - - Total osmolarity 245 Supplemental zinc therapy, multivitamins, and minerals Micronutrient supplementation — Supplementation treatment with zinc (20 mg per day until the diarrhea ceases) Children with persistent diarrhea should receive supplementary multivitamins and minerals each day for 2 weeks at least two recommended daily allowances (RDAs) of folate, vitamin A, zinc, magnesium,

and copper. As a guide, one RDA for a child aged 1 year is Folate 50 μg Zinc 20 mg Vitamin A 400 μg Copper 1 mg Magnesium 80 mg Diet The practice of withholding food for > 4 hours is inappropriate. 57

Food should be started 4 hours after starting ORT or intravenous fluid. The notes below apply to adults and children unless age is specified. Give: • An age-appropriate diet — regardless of the fluid used for ORT/maintenance • Infants require more frequent breastfeedings or bottle feedings — special formulas or dilutions unnecessary • Older children should be given appropriately more fluids • Frequent, small meals throughout the day (six meals/day)

• Energy and micronutrient-rich foods (grains, meats, fruits, and vegetables) • Increasing energy intake as tolerated following the diarrheal episode Avoid: • Canned fruit juices — these are hyperosmolar and can aggravate diarrhea. Antimicrobials INDICATIONS - Children with bloody diarrhea (most likely shigellosis) - Suspected cholera with severe dehydration - Serious nonintestinal infections (e.g., pneumonia) - Diarrhea due to Giardia, Entamoeba histolytica and Cryptosporidium

In adults, the clinical benefit should be weighed against the cost, the risk of adverse reactions, harmful eradication of normal intestinal flora, the induction of Shiga toxin production, and the increase of antimicrobial resistance. Antimicrobials are to be considered the drugs of choice for empirical treatment of traveler’s diarrhea and of community-acquired secretory diarrhea when the pathogen is known. Considerations with regard to antimicrobial treatment: 58

• Consider antimicrobial treatment for: — Persistent Shigella, Salmonella, Campylobacter, or parasitic infections. — Infections in the aged, immunocompromised patients, and patients with impaired resistance, sepsis, or with prostheses. — Moderate/severe traveler’s diarrhea or diarrhea with fever and/or with bloody stools — quinolones (co-trimoxazole second choice). • Nitazoxanide is an antiprotozoal and may be appropriate for diarrhea due to Cryptosporidium

Antimicrobial agents for the treatment of specific causes of diarrhea. SYNDROME PREFERRED ANTIBIOTICS ALTERNATIVE ANTIBIOTICS cholera Doxycycline Azithromycin Ciprofloxacin Adult: 300 mg OD or Tetracycline: 500 mg 4 times a day for 3 days Shigellosis Ciprofloxacin Ceftriaxone Children: Children: 15 mg/kg 2 times a day for 3 days 50 – 100 mg/kg once Adults: 500 mg 2 times a day for 3 days a day IM f 2 to 5 days Amoebiasis Metronidazole Children: 10 mg/kg 3 times a day for 5 days* 59

Adults: 750 mg 3 times a day for 5 days* *10 days for severe disease Giardiasis Metronidazole ** Children: 5 mg/kg 3 times a day for 5 days Adults: 250 mg 3 times a day for 5days Campylobacter Quinolones Azithromycin ** Tinidazole can also be given in a single dose (50 mg/kg orally;maximum dose 2g). • Azithromycin (cid:216) Adult - 250 mg or 500 mg once daily for 3–5 days. (cid:216) Children - 5 mg to 20 mg per kilogram of body weight per day, once daily for 3–5 days.

• Treatment for amebiasis should, ideally, include diloxanide furoate following the metronidazole, to get rid of the cysts that may remain after the metronidazole treatment. • Selection of an antimicrobial should be based on the sensitivity patterns of strains of Vibrio cholerae O1 or O139, or Shigella recently isolated in the area. • An antimicrobial is recommended for patients older than 2 years with suspected cholera and severe dehydration.

• Alternative antimicrobials for treating cholera in children are TMP-SMX (5 mg/kg TMP + 25 mg/kg SMX, b.i.d. for 3 days), furazolidone (1.25 mg/kg, q.i.d. for 3 days), and norfloxacin. The actual selection of an antimicrobial will depend on the known resistance/sensitivity pattern of V. cholerae in the region. CLINICAL PRACTICE Approach in adults with acute diarrhea 60

Principles of appropriate treatment for children with diarrhea and dehydration. Treatment for children based on the degree of dehydration. Minimal or no dehydration. Treatment for children based on the degree of dehydration 62

Note: if vomiting is persistent, the patient (child or adult) will not take ORS and is likely to need intravenous fluids. Treatment for children based on the degree of dehydration Severe dehydration. Therapeutic approach to acute bloody diarrhea (dysentery) in children 64

Further Reading / References 1. World Gastroenterology Organisation practice guideline,Acute diarrhea, 2008 2. Harrison’s Principles of Internal Medicine, 17th Edition, Chapter 40 3. Harrison’s Principles of Internal Medicine, 17th Edition, Chapter 122 4. Guerrant RL, Gilder TV, Steiner TS, Thielman NM, Slutsker L, Tauxe RV, Hennessy T, Griffin PM, DuPont H, Sack RB, Tarr P, Neill M, Nachamkin I, Reller LB, Osterholm MT, Bennish ML, Pickering LK: IDSA Practice Guidelines for the Management of Infectious

Diarrhea, Clinical Infectious Diseases 2001; 32:331–50 5. Park K, Park’s text book of preventive and social meducibne, 20th ed, M/s Banarsidas Bhanot, India, 2009 65

Name of the condition: Hepatitis B Introduction Hepatitis B infection is common and potentially fatal problem and is common all over the world, particularly the developing countries where routine vaccination against this disease is not done in the childhood. It can lead to acute and chronic liver disease, fulminant hepatic failure and cirrhosis is liver, which may be complicated by liver cancer in the long-run. Hepatitis B is a preventable disease. If detected early, it can be treated also. Case definition

A clinical case of acute viral hepatitis is an acute illness that includes the discrete onset of symptoms and jaundice or elevated serum aminotransferase levels (>2.5 times the upper limit of normal) A confirmed case of hepatitis B is a suspected case that is laboratory confirmed: HBsAg positive or anti-HBc-IgM positive. Chronic HBV infection is defined as HBsAg positive irrespective of presence or absence of any symptom. Prevalence of hepatitis B in our country

India is in intermediate endemicity zone for hepatitis B. Frequency varies from 4-8% of population studied in various reports. Differential diagnosis Acute hepatitis Acute hepatitis due to other hepatotrophic viral infection such as hepatitis A and hepatitis E may mimic hepatitis B before tests for the later in undertaken. Chronic liver disease Chronic liver disease due to other causes such as that due to alcohol, hepatitis C virus, non-alcoholic

steatohepatitis and auto-immune liver disease. In fact, hepatitis B infection may co-exist with some of the other etiologies. 66

Prevention and counseling 1. Mass vaccination of new-born and children is useful to prevent the infection. Though some authorities advocate selective vaccination of offspring born to infected mother, this strategy is unlikely to control the infection as some of the carrier get the infection later in life. Also, universal vaccination of all new-born is found to be more cost-effective. 2. Vaccination of family members and contacts of infected persons.

3. Vaccination of individuals at high risk to acquire hepatitis B such as those on dialysis, health care workers, intravenous drug addicts, those requiring multiple transfusions of blood and blood products such as hemophiliacs, thalassemics, persons with multiple sexual partners etc. Optimal diagnostic criteria Optimal tests required to decide on management decision includes 1. HBsAg 2. HBeAg 3. Anti-HBe 4. IgM anti-HBc 5. HBV DNA 6. Serum alanine aminotransferase and aspartate aminotransferase Criteria

1. HBsAg +ve, IgM anti-HBc +ve, transaminase raised (>3 times upper limit of normal): Acute hepatitis There is no need for referral unless the patient is in altered state of consciousness, has kidney failure, dehydration or severe vomiting 7. HBsAg +ve, HBeAg +ve or -ve, Anti-HBe –ve or positive, HBV DNA high, Serum alanine aminotransferase and aspartate aminotransferase high: chronic hepatitits, requires referral and treatment. 8. HBsAg +ve, HBeAg -ve, Anti-HBe positive, HBV DNA negative, Serum alanine

aminotransferase and aspartate aminotransferase normal, inactive carrier state, does not require any treatment. 67

Investigation:  HBsAg  HBeAg  Anti-HBe  IgM anti-HBc  HBV DNA  Serum alanine aminotransferase and aspartate aminotransferase Treatment:  Interferon  PEG interferon  Antiviral drugs: Lemivudine, Adefovir, Tenofovir, Entecavir, Telvivudine. Referral criteria  Acute hepatitis Patient with altered state of consciousness, those with kidney failure, dehydration or severe vomiting  Chronic hepatitis Patients with positive HBsAg +ve, HBeAg +ve or -ve, Anti-HBe –ve or positive, HBV DNA

high, serum alanine aminotransferase and aspartate aminotransferase high: requires referral and treatment. Situation 1: At secondary hospital /non-metro situation: Optimal standards of treatment in situations where technology resource is limited  Diagnosis: Test for HBsAg to screen for the infection. Test for serum alanine aminotransferase and aspartate aminotransferase. If facilities are available, tests for HBeAg, anti-HBe, IgM anti- HBc and HBV DNA should also be done.  Investigations: As above

 Treatment: For prevention, subjects at high risk for HBV infection should be vaccinated against HBV infection. 68

Standard Operating procedure a. In patients: One has to get the above investigations done and decide on management as outlined above. In patients with decompensated cirrhosis of liver, management of ascites, liver failure, hepatorenal syndrome and variceal bleeding may be needed. b. Out patients: Screen patients with liver disease and other risk factors for HBV for serum HBsAg test. Those patients found positive to this test, should be further investigated and managed as outlined above.

c. Day care: Screen patients with risk factors for HBV for serum HBsAg test. Those patients found positive to this test, should be further investigated and managed as outlined above. d. Referral criteria  Acute hepatitis: Patient with altered state of consciousness, those with kidney failure, dehydration or severe vomiting • Chronic hepatitis: Patients with positive HBsAg +ve, HBeAg +ve or -ve, Anti-HBe –ve or positive, HBV DNA high, serum alanine aminotransferase and aspartate aminotransferase high:

requires referral and treatment. Situation 2: At super speciality facility in Metro location where higher-end technology is available: a. Clinical diagnosis: For acute hepatitis B: Diagnose complications including fulminant liver failure, acute renal failure using standard criteria and investigations Diagnose chronic liver disease by ascites, pedal edema, jaundice, encephalopathy, varices on upper gastrointestinal endoscopy and findings at ultrasonography. Look for complications such

as hepato-renal syndrome and hepato-pulmonary syndrome. b. Investigations Investigation:  HBsAg  HBeAg  Anti-HBe  IgM anti-HBc  HBV DNA  Serum alanine aminotransferase and aspartate aminotransferase  Ultrasonography  Upper GI endoscopy Treatment: 69

 Interferon  PEG interferon  Antiviral drugs: Lemivudine, Adefovir, Tenofovir, Entecavir, Telvivudine.  Treatment for liver failure  Treatment for hepato-renal syndrome  Terminal liver failure patients may require liver transplantation Standard Operating procedure a. In patients: One has to get the above investigations done and decide on management as outlined above. In patients with decompensated cirrhosis of liver, management of ascites, liver failure,

hepatorenal syndrome and variceal bleeding may be needed. Most of such patients may need liver transplantation. b. Out patients: Screen patients with liver disease and other risk factors for HBV for serum HBsAg test. Those patients found positive to this test, should be further investigated and managed as outlined above. c. Day care: Screen patients with risk factors for HBV for serum HBsAg test. Those patients found positive to this test, should be further investigated and managed as outlined above.

d. Referral criteria: Patients with terminal liver disease would require referral to centers active in liver transplantation Chronic Leukaemias: Myeloid:- The MPN are clonal haematopoietic stem cell disorders chracterized by proliferation of one or moreof the myeloid lineages.( ie granulocytic, erythroid, megakaryocytic and mast cell). They are primary neoplasms of adults. The MPNs are predisposed to a significant risk of thrombohemorrhagic complications.

The prerequisites for WHO classification of myeloid neoplasms relies on the morphologic, cytochemical and immnunophenotypic features of the neoplastic cells to establish the lineage and degree of maturation and to decide whether cellular proliferation is cytologically normal or dysplastic or effective or ineffective. The classification is based on criteria applied to initial specimens obtained prior to any definite

therapy to judge their progression. Cytogeneticc and molecular genetic studies are required at the time of diagnosis not only for recognition of specific genetical entities, but for establishing a baseline against which future studies can be judged to assess disease progression. Classification  The classic MPNs include polycythemia vera (PV), essential thrombocythemia (ET), chronic myeloid leukemia (CML), primary myelofibrosis (PMF), chronic neutrophilic leukemia, chronic 70

eosinophilic leukemia, and mast cell disease.  Atypical MPNs include those chronic myeloid disorders which are currently not classifiable as belonging to either the myelodysplastic syndrome or classical MPN. These include chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical CML, and unclassifiable myelodysplastic syndrome (MDS)/MPN. Diagnosis  CML is characterized by a reciprocal chromosomal translocation between chromosomes 9 and

22 (ie, t(9;22). The diagnosis of chronic myelogenous leukemia requires the presence of BCR- ABL1, while its absence is required for all other MPN.  PV is diagnosed when an otherwise unexplained increased hematocrit/red blood cell mass is accompanied by the presence of a JAK2 mutation along with a decreased erythropoietin level. JAK2 V617F is found in most patients with polycythemia vera, essential thrombocythemia, or primary myelofibrosis and is, therefore, useful as a clonal marker in those settings

 PMF is characterized by a leukoerythroblastic blood picture, splenomegaly, and bone marrow fibrosis that cannot be attributed to another myeloid Chronic myelogenous leukemia(CML): is a myeloproliferative neoplasm that originates in an abnormal pluripotent stem cell. The natural history of CML is bi- or tri phasic.: an initial indolent chronic phase(CP) is followed by an accelarated phase (AP) . a blast phase(BP) or both.

Clinical features: Most patients are diagnosed in CP which usually has an insidious onset. Common findings at presentation include: fatigue, weight loss, anemia and splenomegaly. Transformed phase(AP and BP) are generally accompanied by worsened performance status and symptoms related to anemia, thrombocytopenia and marked splenomegaly. Diagnostic criteria: High total leukocyte count (>10x109/l) Different stages of maturation in the neutrophils with peaks in the myelocyte and segmneted

neutrophils. No leukemic hiatus seen. No significant dysplasia Splenomegaly Thrombocytosis Thrombocytopenia refractory to treatment 20% or more basophils in the peripheral blood <2%- 19% blasts in blood or bone marrow. Cytochemistry: SBB nad MPO positive- all stages of maturation of neutrophils are positive. 71

The neutrophils in CP have markedly decreased neutrophil alkaline phosphtase. In myeloid BP the blasts may have strong, weak or no MPO and with antigens associated with granulocytic, monocytic and megakaryocytic lineage. Lymphoid BP phase shows B or T cell antigens. Genetics: 90- 95% CML have the characteristic t(9;22)(q34;q11.2) reciprocal translocation that results in ph chromosome. BCR ABL 1 fusion gene detection by FISH analysis, RT- PCR or southern blot technique. Prognosis and predictive factors:

Median survival in CML ranged between 2-3 years. Prognosis worsens in transformed phases. CMML Is a neoplasm characterized by features of both myeloproliferative and myelodysplastic syndrome. Diagnostic criteria: persistent monocytosis No philadelphia chromosome. No rearrangement of PDGFRA/PDGFRB. Fewer than 20% blasts Dysplasia in one or more myeloid lineage. Presentation: hepatospenomegaly Lymphadenopathy Total leukocyte count elevated Cytochemistry: NSE positive IPT:

Myelomonocytic markers: CD 33 ,13 14, 68 and 64. Genetics: +8, -7/del(7q) and structural abnormalities of 12p. JMML: Is a clonal hamatopoietic neoplasm of childhood characterized by proliferation of principally of the granulocytic an monocytic lineages. 73

Persistnet monocytosis Blasts<20% No ph chromosome. Plus two or more of the following HbF Immature granlocytes WBC >10X109/L Monosomy 7 GM—CSF hypersensitivity of myeloid progeintors. Presentation; Organomegaly Recurrent infection Signs of bleeding. Cytochemistry;NSE;Positive IPT: no specifc markers Genetics: Monosomy 7 Lymphoid CHRONIC LYMPHOID LEUKEMIAS: CLL / SLL is a disease of advancing age, the mean age at diagnosis is 65 years. it is a neoplasm of lymphoid origin with a an equal male:female ratio.

Clinical presentation: Most patients are asymptomatic but some present with fatigue, autoimmune hemolytic anemia, infections, oraganomegaly( spleen and liver). Diagnostic criteria: Persistent lymphocytosis >3 months. 75

Absolute lymphocyte count of > 10 x109/l. In absence of extramedullary involvement there must be >- 5 x109/l monoclonal lymphocyte with a CLL phenotype. Morphology: small mature lymphoid cells along with smear/ smudge cells and <55% prolymphocytes. Immunophenotype: B cell markers, weak expression of clonality and co express CD5 and CD 23. ZAP- 70. Progression and transformation to High grade lymphomas: CLL may show an transformation to B- PLL though extremely rare. genetics:

IG genes are rearranged with 40-50 % cases unmutated and 50-60% showing somatic hypermutation. B PLL is a neoplasm of B prolymphocytes affecting the peripheral blood, bone marrow and spleen. It is an extremely rare disease most patients being >60 years. Diagnostic criteria: Rising total leukocyte. >55% of prolymphocyte and usually >90%. massive splenomegaly. rapidly rising lymphocyte count usually over 100x109/l. anemia and thrombocytopenia.

IPT: Strongly express Ig M+/-IgD as well B cell antigens (CD 19,20,22,79a and b,FMC 7). genetics: Ig genes are clonally rearranged with unmutated heavy chain in 50% cases. T PLL: TPLL is an aggressive T cell neoplasm characterized by the proliferation of small to medium sized prolymphocytes with a mature post thymic T cell phenotype involving the peripheral blood,bone marrow,lymph node, liver, spleen and skin. it is rare approximately 2% of cases of mature lymphocytic neoplasm with a median age of 65 years.

Generalised lymphadenopathy. Anemia. Thrombocytopenia. Lymphocyte count>100x109/l. Morphology: small to medium sized lymphoid cells with non granular basophilic cytoplasm, cytoplasmic blebs,irregular nucleus with well circumscribed nucleoli . IPT: Peripheral T cell markers: CD 2, 3, 7 and CD 52 positive. Cytogenetics: inversion of chromosome 14 with break points in the long arm at q11 and q32. Abnormalities of chromosome 8, idic(8p11), t(p11-12;q12) and trisomy 8q. Abnnormalities of TP 53 gene seen.

Acute Leukaemias Acute myeloid leukemias: Clinical Diagnostic Features of AML • Adults with AML generally present with a vague history of chronic progressive lethargy; and symptoms of granulocytopenia and thrombocytopenia are common. • As many as 1/3 of patients with AML will be acutely ill at presentation because of a significant skin, soft tissue, or respiratory infection. • Petechiae with or without bleeding may be present. Patients with acute promyelocytic (M3)

leukemia may have severe hemorrhaging secondary to a clotting factor deficiency, which results in an intravascular coagulopathy. • Hyperuricemia is frequent; splenomegaly is present in about 1/3 of patients. • Leukemias with a monocytic component (M4 & M5) may be associated with gingival hypertrophy from leukemia infiltration. Patients with these types of AML are most likely to present with or develop meningeal leukemia, retinal infiltration, leukemia cutis, or other

localized leukemia infiltrations. In the absence of meningeal signs, a lumbar puncture is not indicated. • Chloromas (granulocytic sarcomas, myeloblastomas) are present in about 5% of patients. They may take on a dull green color due to the high peroxidase content in the leukemia cell, may precede other diagnostic evidence, may occur aher diagnosis, or may indicate relapse. They commonly occur in the skin but can be present in other body organs. They are most ohen associated with M4 and M5 leukemias.

• Lymphadenopathy and hepatomegaly are uncommon. Peripheral Blood Features of AML • The peripheral white blood cell count may be increased, decreased, or normal with approximately equal frequency. 78

• Granulocytopenia is very common. Approximately 1/2 of all patients will have granulocyte 79

counts < 1,000/uL. • Thrombocytopenia is frequently observed and platelet counts <20,000/uL are common. • The hematocrit is generally low but severe anemia is uncommon. • Circulating blast cells are absent from the peripheral blood in approximately 15% of AML patients initially, and in 1/2 of patients presenting with leukopenia. Diagnostically Important AML Markers • Morphologic • Auer bodies • "malignant" primary granules • Cytoplasmic organelles • Sudan B • myeloperoxidase • Cytogenetic • t(8;21)

• t(15;17) • -5,-7 • Immunologic • cell surface markers • A variety of morphologic, cytoplasmic, cytochemical, and biochemical features are associated with AML that can aid in diagnosis. • No available marker is either totally specific or sensitive enough to be used in all cases. • Cytogenetic analyses should be performed at diagnosis in all patients with AML. Approximately 65% of patients will have abnormal karyotypes. • Cytogenetic abnormalities may help determine prognosis. Favorable

young age reactivity with CD2(T1) FAB types M2, M3, M4 t(8;21) and t(15;17) inversion of chromosome Prognostic Factors 16 in AML Unfavorable older age aneuoploidy FAB type M7 trisomy 8 hyperleukocytosis deletion of all or part of chromosomes 5 and/or 7 prior treatment abormalities of chromosome 11 at band q23 80 prior heamtologic disorder infection

Acute Leukemias IPT Cytogenetics AML t(8:21) CD13,CD33,CD34,MPO,HLADR CD56,KIT mutation – bad prognosis AML with inv CD34,CD117,CD13,CD33,MPO,CD14,CD11b Good prognosis (16) APML t(15:17) HLD DR(-),CD33(+++) PML RARA fusion gene – good prognosis AML with CD33,CD65,CD4,HLADR(+) MLLT3MLL – t(9:11) Intermediate survival AML with t(6:9) MPO t(6:9) - Poor prognosis AML with inv(3) CD13,CD33,HLADR Poor prognosis Laboratory Factors Correlating With Response to AML Therapy

• The following factors have been found to correlate with achievement of a complete response: • younger age and good performance status • prior bone marrow disorder • Auer rods marrow eosinophilia • rapid clearance of blast cells from the peripheral blood and a low percentage in the bone marrow aspirate ~ days post-treatment 81

• The following factors have had a negative influence on the achievement of a complete response: • older age • co-morbid diseases • specific karyotypic abnormalities • specific cell surface antigens • abnormalities of the erythroid series Prognostic Significance of MDRI Expression in AML • Drug resistance may be due to several mechanisms. These include increased expression of multidrug-resistant (MDR1 or MDR3~ gene, alterations in topoisomerase 11 activity, or enhanced glutathione activity.

• In patients with AML, MDR1 messenger RNA is increased in the minority of de novo cases, but is increased in those with refractory, relapsed, and secondary leukemia. • The MDR1 messenger RNA levels correlate with response to therapy. • Older patients have a higher incidence of MDR1 messenger RNA than younger patients. AML with minimal differentiation: is an AML with no evidence of differentiation. Presentation Anemia Thrombocytopenia Neutropenia Leukocytosis with high blast count.

Cytochemistry:MPO, SBB :Negative. IPT: Early CD 34, 38 and HLADR AML without maturation: Auer rod seen MPO: POSITiVE. IPT: MPO,HLA DR CD 34, 13, 33 and 117. NO SPECIFIC CYTOGENETIC abnormality AML with maturation: High leukocyte count 82

>10% maturation of the myeloids . IPT: as above CD 65, 11b, 15. No cytogenetic abnormality. AML with myelomonocytic: proliferation of both neutrophils and monocytes each comprising of at least 20% of the cells Presentation: anemia thrombocytopenia with an eleveated TLC and a high blast count . IPT: CD 14,4, 11b and 11c and 64 . CYTO: At least 3% blasts- MPO. Dual positive blasts in NSE and MPO. AML with monocytic and monoblastic : Presenting feature: Young individuals Bleeding. Extramedullary lesions

Gingival infiltration CNS >80% or more of the leukemic cells are of monocytic lineage( monocytes, promoncytes and monoblasts) and a minor neutrophilc component.(<20%). This further can be distingusihed based on the relative proportion of monocytes and blasts. No auer rods seen. IPT: MONOCYTIC MARKERS Acute erythroid leukemia: presenting symptom anemia Total count variable with circulating blasts. Cytochemistry: PAS positive IPT: Hb A and glycophorin. Complex karyotype. Acute megakatyoblastic: 84

Hepatosplenomegaly Fibrosis Acute lymphoid luekemias: Acute lymphoid lekemias /lymphoblastic lymphomas is a neoplasm of B or T cell lineage. B cell lineage (Good prognosis): ALL is primarily a disease of children (under 6 years of age). Presentation: Bone marrow failure: anemia, thrombocytopenia with a variable leukocyte count. Organomegaly. Lymphadenopathy Arthralgia. Morphology: peripheral blood and bone marrow involved (>20% blasts)- Cyto: Blasts are MPO and SBB negative PAS:Block positive. IPT:

B CELL MARKERS: CD 19, cytoplasmic CD 79a and cytoplasmic CD 22 GENETICS: Clonal rearrangement of IgH and T cell receptor. FISH analysis detects t(9;22) translocations. T ALL(bad prognosis):is a neoplasm commited to T cell lineage. Presentation: mediastinal involvement.( usually respiratory embarrassment) Lymphadenopathy Hepatosplenomegaly 86

High leukocyte count >20% blasts in PB and BM. Cytochemistry: MPO, SBB negative. Few cases show PAS positivity. IPT: TdT positive CD1a, 2,3,3,5,7 and 8. Cytoplasmic CD 7 and CD3 are specific. Genetics: Clonla rearrangenment of T cell receptor(TCR). CYTOGNETICS; Alpha and Delta TCR loci. Transcription factor HOX11 and MYC. PRE-OPERATIVE HAEMOSTASIS SCREEN: By. Dr. Sukesh C Nair Professor, Head, Div of Laboratory Haematology, Head, Dept of Transfusion Medicine and Immuno-haematology,

Christian Medical College, Vellore, Tamil Nadu - 632004 Introduction: Preoperative screen should comprise the following: 1. Good clinical history especially history of bleeding tendency 2. Platelet count 3. Prothrombin time (PT) 4. Activated partial thromboplastin time (aPTT) 5. Bleeding time Clinical History: A thorough and structured history of bleeding tendency (including previous surgery, family history and trauma) and physical examination are the most important approaches to assess risk of excessive

bleeding during surgery. The British Committee for Standards in Haematology published “Guidelines on the assessment of bleeding risk prior to surgery or invasive procedure” 1 and summarised to say, “The positive predictive value (0.03 – 0.22) and likelihood ratio (0.94 – 5.1) for coagulation tests indicate that they are poor predictors of bleeding. Patients undergoing surgery should have a bleeding history taken. This should include details of previous surgery and trauma, a family history and details 87

of antithrombotic medication. Patients with a negative bleeding history do not require routine 88

coagulation screen prior to surgery”. However, there have been reports to suggest that in an occasional patient excessive bleeding had occurred that would have been prevented if haemostatic screen had been done. The check list for clinical history is given in table 1. Table 1 - History of Bleeding Tendency – Check List Notes: Bleeding score below 3 in males and below 5 in females always allows exclusion of a bleeding disorder.

Ref: A. TOSETTO, G. CASTAMAN and F. RODEGHIERO: Bleeding scores in inherited bleeding disorders: clinical or research tools? Haemophilia (2008), 14, 415–422 Laboratory tests that are to be performed depend on the type of surgery (table 2). GUIDELINES FOR PREOPERATIVE HAEMOSTASIS EVALUATION Level Bleeding History Surgical Procedure Recommended Haemostasis Evaluation I Negative Minor None II Negative Major Platelet Count, APTT, PT 89

III Equivocal Major, involving Platelet count, APTT, PT and haemostatic factor XIII screening assay impatient IV Positive Major or Minor Consult haematologist Platelet count: A platelet count must be performed prior to surgery. Low platelet counts reported on the automated cell counters must be confirmed by microscopic examination of blood film to exclude psuedothrombocytopenia. PT & aPTT Recommendations of Sample collection and processing: 1. Avoid prolonged venous stasis 2. Use a 21g needle for adults.

3. Avoid indwelling catheters or lines. 4. Mix immediately with 0.105-0.109mol/L tri-sodium citrate at 1:9 ratio with Blood.. 5. Discard sample if any delay or difficulty in collection. 6. Discard if marked hemolysis or evidence of clotting 7. Underfilling (<80-90% of target volume) prolongs some screening tests. 8. If hemotocrit is > 55% adjust anticoagulant: blood ratio. More blood to be added to the same volume of anticoagulant. {60/(100-Hct) x standard volume of blood that is added}

9. Sample collection system can affect results by upto 10% 10. For plasma tests centrifuge at 2000g for atleast 10min at room temperature. 11. Test within 4hours. 12. Freezing may affect results depending on temperature and time of storage. 13. Any deep frozen plasma should be thawed rapidly at 37deg C. Prothrombin Time: Principle: Time taken by recalcified citrated plasma to clot after Tissue factor (in the form of tromboplastin) is

added to plasma. Tissue factor reacts with FVIIa to activate the “extrinsic”pathway and thus form a clot. Use of the prothrombin time test: - The PT is sensitive to and thus prolonged in patients with deficiencies of Factors VII, X, V, II and fibrinogen. 90

- It is particularly useful in monitoring anticoagulation in patients on warfarin. Investigation of a prolonged Prothrombin Time: Prolonged prothrombin Time Mixing studies (1/2+1/2 mix of patients plasma and normal pooled plasma) Prolonged (No correction) Correction Specific inhbiotor * Factor Assays *Rarely the lupus anticoagulant can prolong PT, and can also be prolonged in patients with anticoagulant therapy. Procedure: REAGENTS AND MATERIALS:

1. PT Reagent: Reagent needs to be reconstituted as per product insert/instruction sheet, and prewarmed to 37oC. This reagent already contains CaCl . 2 2. Patient plasma, control plasmas as required. (NB: test normal plus abnormal QC plasma whenever a fresh vial of recombiplastin is reconstituted). 3. Waterbath, 12 x 75 test tubes, stop watches, yellow tips, and 100 and 200ul automatic pipettes and light source. METHOD:

1. Add 0.1ml plasma into duplicate small glass tubes placed in a 37oC water bath, and leave 3 min to equilibrate to 37oC. Add 0.2ml prewarmed PT reagent and simultaneously start stop watches. 2. Mix and tilt tubes to nearly horizontal position at one second intervals, otherwise maintaining in 37oC water bath. 3. Depress stop watch mechanism on first appearance of a clot. The time taken for the clot to form (i.e. between addition of PT reagent and the appearance of the clot) is the 'prothrombin time' (PT).

4. Take the mean of the duplicate readings (providing that they don't differ by more than two seconds; otherwise repeat the procedure and check the reagent; replace if necessary). Quality Control Procedures: 91

A normal control (e.g. pooled normal plasma [PNP]) and an abnormal control plasma (eg Accuclot II (sigma) control) should also be included with every batch of patient plasma tested, or every few hours if testing a large number of plasmas throughout the day. Run normal control and abnormal control plasma for 10 days and calculate the mean and +/-2SD. The control values should fall within +/-2SD. Interferences: Do not test plasma from badly haemolysed blood . Badly haemolysed blood may give an

artifactual coagulation results that do not accurately represent the coagulation status of the patient under investigation. Haemolysed blood may suggest a traumatic blood collection and you may need to request a repeat sample. Expression of the Results The results are expressed as a mean of the duplicate reading in seconds, both mean of the patient time and mean of the normal control time, either as raw data or in the form of a rati

(prothrombin ratio). Patients on OAT the results are always interpreted with INR (International Normalized Ratio). Normal Ranges 11 – 16Secs. (Normal values varies depending on the Thromboplastin used the exact technique under visual or automated end point reading is used) ISI INR= Prothrombin Time (PT) of test plasma (sec) Mean Normal Prothrombin Time (MNPT) (sec) ISI = International Sensitivity Index. INR= International normalized ratio.

Ideally, each laboratory should establish its own Mean Normal Prothrombin Time (MNPT). Classically, for the MNPT: this is obtained by testing plasmas from at least 20 normal individual in that laboratory’s PT assay, and taking the mean PT. Selected instrument specific ISI values are usually provided for each batch of Thromboplastin. 92

Activated Partial thromboplastin time: Principle: Time taken by recalcified citrated plasma to clot after Phospholipid (Lacking tissue factor, hence the term “partial” thromboplastin) and particulate matter (such as kaolin, silica & elagic acid) are added to plasma. Abnormalities in the “intrinsic” and “common” pathway will result in prolongation of the APTT. USE OF APTT: This test is abnormal in patients: 1. With deficiencies of factors XII, XI, X, IX, VIII, V, II ad fibrinogen. 2. On heparin therapy; or

3. Who have the lupus anticoagulant. Investigations of prolonged APTT: Prolonged APTT Mixing studies (1/2+1/2 mix of patients plasma and normal pooled plasma) Prolonged (No correction) Correction Specific inhibitor Lupus anticoagulant Factor deficiency against a factor Factor Assays DRVVT test Factor Assay 93

REAGENTS AND MATERIALS: 1. APTT Reagent (SynthAsil) 2. CaCl2 0.025M pre-warmed to 37oC 3. Patient plasma and control plasma as required 4. Glass tubes and stopwatches. 5. Water bath 6. Automated Pipettes/glass pipettes and tips. METHOD: 1. Add 0.1ml of plasma and 0.1ml APTT reagent in a glass tube (12 x 75) and place in a 37oCwater bath. 2. Mix, and leave for 5 minutes to equilibrate to 37 deg C and to provide suitable activation of plasma with contact factor.

3. Add 0.1ml of warmed 0.025M cacl2, and simultaneously start stopwatch. 4. Mix and tilt tubes to nearly horizontal position at one-second intervals, otherwise maintaining in 37 deg C water bath. 5. Depress stopwatch mechanism on first appearance of a clot. The time taken for the clot to form (i.e., between addition of CaCl2 and the appearance of the clot) is the APTT. 6. Always do in duplicates. 7. Take the mean of the duplicate reading (provided that they don’t differ by more than 2 seconds

otherwise repeat procedure and check reagents. Interferences: Do not test plasma from badly haemolysed blood . Badly haemolysed blood may give an artifactual coagulation results that do not accurately represent the coagulation status of the patient under investigation. Haemolysed blood may suggest a traumatic blood collection and you may need to request a repeat sample RESULTS: Report APTT results in seconds for example control 30 sec, patient 36 sec. REFERENCE RANGE:

Each laboratory has to establish their own range. As a rough guide the aPTT of normal plasma should be 25 to 35 sec. 94

Specific assays like FVIII:C and VWF:Ristocetin Co-factor assays needs to be done if the screening tests are normal but History is significant due to high prevalence of Mild bleeding disorders like VWD Type1 and few Type2 and Mild inherited/ acquired Haemophilia A. Caution with :- Alternative methods to perform PT and APTT. Automated and semi-automated methods:- Validation required but if using semi-automated methods all the tests are to be done in Duplicate. BLEEDING TIME: Principle

The bleeding time is the time taken for a standardized skin cut of fixed depth and length to stop bleeding. Prolongation of the bleeding time occurs in patients with thrombocytopenia, von Willebrand’s disease, Glanzmanns thrombasthaenia, Bernard-Soulier disease, storage pool disease and other platelet disorders. Fibrinogen is required and a role for factor V has been suggested. The bleeding time can therefore be prolonged in patients deficient in fibrinogen or factor V. Prolongation also occurs in some

patients with renal disease, dysproteinaemias and vascular disorders. Materials Sphygmomanometer. Cleansing swabs. Template bleeding time device. Filter paper 1 mm thick. Stopwatch. Method - The sphygmomanometer cuff is placed around the upper arm and inflated to 40mm of mercury. This pressure is maintained throughout the test. - The dorsal surface of the forearm is cleaned and the bleeding time device placed firmly against the skin without pressing. The trigger is depressed and the stopwatch started.

- Superficial veins, scars and bruises should be avoided. - At 30 second intervals, blot the flow of blood with filter paper - bring the filter paper close to the incisions without touching the edge of the wound. - Record the time from puncture to cessation of bleeding. Interpretation - The normal range in adults is up to 6 minutes but may vary according to method used. - Note: 95

- At the time of writing there are two commercially available disposable devices for performing the bleeding time both compare very well with each other. Whichever device is used a normal range should be established locally. - The incision should be made in a direction parallel to the length of the arm. Cuts made perpendicular bleed for longer. - It is not necessary to record endpoints if bleeding continues beyond 15 minutes.

- The effect of drugs interfering with platelet function should be considered. For example, drugs containing aspirin can cause prolongation and, where possible, should not be taken for 7 days prior to testing. - There is a possibility of scarring at the site of bleeding time incisions more with the ‘Simplate’ method. This should be brought to the attention of patients prior to performing the incision. Test to be performed before doing Bleeding time: - Platelet count. Advantage:

- Simple test of natural hemostasis - Avoids potential anticoagulation artefacts. Disadvantages: - Poorly reproducible - Poor correlation between the risk of bleeding at surgery and the bleeding time. Hence, some authors do not recommend it as a preoperative screening test in patients without any positive bleeding history. - Insensitive to milder forms of platelet dysfunction. - Interpersonal variations. Suggestions to overcome:- - Have 1-2 technologists only doing BT.

- To do specific PFT if BT is normal and History is significant.* - Devices like PFA-100 too have limitations in relation to sensitivity to detect Mild PFdefects or Milder forms of VWD. Whole blood clotting time (Clotting Time /CT) CT is abnormal when the deficiency of the coagulation factors is gross such as a faction VIII or factor IX of less than 10%. Thus, the test lacks sensitivity. Further, it has poor reproducibility and individuals

with such gross deficiency of clothing factors are symptomatic. The test was deleted from textbooks of practical haematology about 20 years back. References for BT 96

1. Y.L.Chee, J.C. Crawford, H.G. Watson and M.Greaves, 2008, Guidelines on the assessment of bleeding risk prior to surgery or invasive procedures, British Committee for Standards in Haematology, British Journal of Haematology, 140,496-504 2. Ivy AC, Nelson D, Bucher G. The standardization of certain factors in the cutaneous venostasis bleeding time technique. J Lab Clin Med 1941;26:1812-1822. 3. Koster T, Caekebeke – Peerlinck KMJ, Briet E. A randomized and blinded comparison of the

sensitivity and the reproducibility of the Ivy and Simplate II bleeding time techniques. Am J Clin Pathol 1989;92:315–320. 97

QUALITY ASSURANCE IN A CLINICAL LABORATORY Introduction: The laboratory tests are required for several purposes: 1. Arriving at diagnosis, prognostication and monitoring progress 2. Health check 3. Medical check up for employment, insurance and others 4. Disease surveillance for health planning For all these situations, reliability of test results (precision and accuracy) is essential. “Accuracy is the closeness of agreement between the measurement that is obtained and the true value”.

“Precision is the closeness of the agreement when the test is repeated number of times 1”.. Each analytical procedure has inherent probability of error and uncertainty of measurement (UoM). Quality assurance aims at minimising these errors, narrowing the UoM and reducing the turnaround time (TAT). It is important that the procedures are developed, documented, implemented and monitored. Documentation system should be on the lines of ISO 1900. There is a common saying “What is not documented is a rumour”.

Components of quality assurance: Control of pre-examination (pre-analytical) phase Control of examination (analytical) phase Control of post-examination (post-analytical) phase Control of pre-examination phase: 98

Several factors have improved precision and accuracy. These include robust and user-friendly automation and hence precision, accurate calibration with reference materials (calibrators), regular use of controls with each assay and availability of inter-laboratory comparison as national and international ‘External Quality Assessment Schemes’ (EQAS) or ‘Proficiency Testing’ (PT). Consequently in a modern laboratory with established quality

assurance programme, examination errors are few and over 90% errors are attributable to the pre-examination phase2,3. Pre-examination phase includes ‘controllable’ and ‘non-controllable’ variables. The controllable variables relate to patient preparation and sampling (time, proper site and method, labelling to ensure unique identification, transport, storage and preparation). Each one of these is important.

Control of pre-examination phase and patient-related variables, including interference from administration of drugs, (which may grossly affect test results), is discussed in the ‘Specimen Collection Manual’ annex-1 – table 2. Control of Examination Phase (Analytical Phase): This includes use of calibrated equipment, application of standard analytical procedures, appropriate training of staff, internal quality control, external quality assessment and standardization. Calibration of Equipment:

Procure the equipment, which is suitable for the intended use. Give it a unique identification number. It is a good practice to maintain history sheet of the equipment that records the agreement (including AMC Terms) and date of purchase, addresses and contact details of suppliers, down time and repair details. Calibrate equipment, with the frequency defined by the manufacturers and/or by National Accreditation Board for Testing and Calibration Laboratories (NABL) vide the document number 112.

The calibration standard should be traceable to National Physical Laboratory (NPL) or equivalent. Calibration should be performed by a laboratory accredited for ISO Standard 17025 by an accreditation body such as NABL. 99

In case of automated equipment, the suppliers calibrate the system as their engineers are especially trained for maintenance and repair of such equipment. The calibration certificate should contain raw data: just a certificate that the apparatus has been calibrated is not sufficient. Most automated systems in haematology, are calibrated twice a year generally at the time of preventive maintenance. However, the calibration is required whenever the instrument has major repair or there is

change in lot. In biochemistry analysers there is a more frequent need for calibration when the instrument flags a shift in control values. This may occur in days or months. Some biochemistry instruments require daily calibration and in some others the re-calibration occurs automatically. The calibrators are provided by the manufacturers. Some equipment can be calibrated in-house using calibration standards: It is important to develop capability of

in-house calibration of such equipment. The apparatuses that can be calibrated in house include micro- pipettes, glass pipettes4, weighing scales, centrifuges5, spectrophotometers and colorimeters4 (annex 2). A sticker should be placed on the machine showing calibration status (date calibrated and next due date). Calibration status of small equipment such as pipettes can be maintained in a file. Standard analytical procedures:

All analytical procedures should be internationally acceptable – taken from standard books or journals. Any in- house deviation must be validated employing standard statistical methods 5 – Annex 3. Staff Training: Training of the staff before introduction to new procedure is vital to ensure quality of test results. It is important to keep records of training and to check the effectiveness of training Internal Quality Control: 100

Most modern laboratories perform tests using commercially available kits. Practically all these procedures include use of stable controls with each run. The controls are part of the kit or can be purchased from another vender such as Bio-Rad. The controls ensure precision and determine uncertainty of measurement (imprecision). To check precision/imprecision the exact value of the control specimen is not required. However,

if the value has been determined using a standard technique, reference material and a calibrated instrument this can be taken as exact value. Generally, 2 to 3 levels of controls are used. If the laboratory is processing only a small number of samples a single level control may be used per batch. The values of controls can be maintained as a table. It however, is preferable to plot the values as Levy-Jennings (LJ) charts. The mean value

of control is determined and standard deviation (SD) and coefficient of variation (CV %) are calculated. The CV is preferred as it describes the significance of SD irrespective of the measured value. The degree of precision required for most of the analytes has been described6. The LJ chart plots the actual value of the control/s obtained with each batch. The following rules are applied to accept or reject the values (run) of the analyte: Following procedures are used for IQC Control Charts

Replicate testing of patient samples Delta Check Daily means Correlation with other values Clinical correlation Control Charts: The term Control is applied to a stable material that is used with every test run. It can be prepared in-house for some analytes. However, current practice is to purchase the material from commercial sources. Controls should be stable, homogeneous and have the same matrix as that of the specimens to be analysed. These are

procured from the manufacturers of the kits or from alternative vendors. Commercially supplied control specimens (reagents) are assigned a target value (mean and +2 SD). The lab mean may differ from the assigned mean. The lab should determine its own mean and 2 SD values. Coefficient of variation (CV %) is calculated from the SD achieved and it should be within the levels described by (Reference) 101

For complete blood counts (CBC) the control material is artificial and does not have the same matrix as blood specimen. Further, it has a short shelf life 14 – 30 days to 1 month creates problem of determining lab mean of the control. Large laboratories must use 2 or 3 level controls. The values obtained on the controls are plotted on Levy and Jennings Charts to detect deviation from the acceptable precision suggesting a fault with the reagents,

individuals performing the test and/or the machine. Westgard’s multi-rules are applied to take action on the deviations (Reference). However, it may not be necessary to apply all the rules. We suggest the following actions to be taken on violations of the multi-rules. Table: Westgard’s Multirules Sr. # Control Value Interpretation Action to be taken 1 1 value outside 2s Random error If other control values are within 2 s accept Warning sign run. Re-run the previous control to verify

deterioration of material 2 1 value outside 3s Random error If other control values are within 2 s accept Gross error run. If not reject run. Re-run the previous control to verify deterioration of material. Possibilities are deterioration of reagents or fault analyser. Call engineer; get it repaired and recalibrated 2 consecutive Systematic error If other control values are within 2 s accept values exceed 2s Gross error run. If not reject run. Re-run the previous

on either side of control to verify deterioration of material. mean 102

4 1 value exceeds Radom error Repeat test. If value acceptable no further +2s other value Gross error action required. If other control values also exceed -2s outside limit reject run. Recalibrate the machine. 5 4 consecutive Possibly Check values of two other controls if values values exceed 1s systematic error acceptable change the first control on the same side of mean 6 Ten consecutive Systematic error Redraw the chart with your mean as the target control values on or the mean on value

one side of the your machine mean but within 1s differs from the assigned mean s denotes standard deviation The laboratory can choose the rules to be applied. Rule number 6 is generally not applied. Rule number 2 must be used. Any other 2 rules may be added. The laboratory must document which rules are going to be applied. Replicate testing of patient samples: Replicate testing of patient samples is another way of ensuring precision. It does not check accuracy. This

procedure is applicable to very small laboratories where the workload does not justify purchase of ‘controls’. The CV % cannot be determined or monitored from the data derived by this procedure. Initially, analyse 10 samples in duplicate. Determine the differences between the paired results. Calculate the standard deviation (SD) of the differences. Every day perform duplicate tests on 2 to 3 specimens. The difference between the

paired results should not be more than 2SD derived earlier from 10 paired test results. Delta check A homeostatic mechanism sets the values of analytes in an individual, which is considered normal for that individual. In the hospital setting a sudden change in the value of analyte does not occur without change in clinical condition or without therapeutic intervention. For example a significant rise in haemoglobin

concentration over 1 or 2 days may be due to blood transfusion that the patient may have received. Delta check is not applicable in stand-alone laboratories. It however, is an excellent method of internal quality control and should be applied in the hospital setting. Daily means 103

Mean values of an analyte do not significantly change in a laboratory performing over 300 tests of an analyte per day. This is particularly applicable to high volume tests in biochemistry and for Complete Blood Counts (CBC) in haematology. Procedure is as follows. Determine the mean and 2 SD values. If subsequently the mean is outside 2 SD values, investigate especially with another run of ‘Controls’. Correlation with other parameters:

For example in a patient with acute myocardial infarction several cardiac markers will show abnormality. If there is dissociation, check the control data and repeat the tests. The CBC values correlate extremely well with the microscopic examination of blood film. Abnormal CBC values particularly severe thrombocytopenia must be confirmed on examination of blood film. Some individuals develop platelet antibodies against cryptic

antigens, which are exposed when blood sample is taken in EDTA tube. This is an in-vitro phenomenon and causes no morbidity. This leads to formation of platelet clumps, which are counted by the automated systems as leucocytes and platelet counts are erroneously reported very low. This has led to many unnecessary platelet transfusions. Clinical Correlation: The clinical diagnosis depends on the test results given by the laboratory. More often than not the laboratory is

right and the treating doctor must respect the laboratory observations. The same time the laboratory physicians should never dismiss the lack of correlation with clinical profile. If discrepancies are observed the laboratory must review its SOPs and other analytical systems including reagent kits. Inter-laboratory comparison: Internal Quality Control ensures precision and not necessarily accuracy. Accuracy is ensured by proper

technique, good quality reagents, reliable equipment, suitable IQC and most importantly by accurate calibration and concordance with other laboratories through a formal ‘External Quality Assessment Scheme (EQAS) or ‘Proficiency Testing’ (PT). The participation in EQAS is mandatory requirement. Many national and international programmes are available (references). The analysis is provided by the nodal agency that provides the EQAS. The action taken on the EQAS results should be documented. 104

Alternative assessment procedures when no formal EQAS is available: For some analytes no national programme may exist and small laboratories cannot afford participation in international programmes. In such situations the alternative approach is described below. Source: Guidelines approved by the Clinical Laboratory Standards Institute (CLSI) Document HIS – volume 22 GP29-A The document suggests many approaches & the lab to choose from those. The following method is preferred: annex SPLIT-SAMPLE TESTING

• A single biologic sample divided into aliquots, wherein 1 aliquot is tested on a particular assay system (or by a particular analyst) other aliquot(s) are tested on other instrument(s) (or by other analyst[s]) and the results are compared Note: It is often done in different labs. Frequency: At least every 3 months REASONS FOR THIS CHOICE • Other lab(s) to which the sample is sent for ILC may not have the same analytical system with

differences in instrumentation reagents / reference intervals and hence with interpretation problems • The statistical validity of test being done in less than 20 labs is questionable • Hence intra-laboratory split-sample testing is recommended • It is a Mandatory requirement for all analytes where no formal EQAS is available Prerequisites for split-sample testing • Lab must follow IQC apply methods traceable to reference methods

• The comparability between 2 instruments / techniques should be shown through Bland-Altman Plot • Define acceptable differences in 2 values by 2 analysts or 2 instruments and take corrective action if differences are outside those limits Calculations • Calculate difference (d) between each paired resultind the mean of differences • Determine 1 and 2 SD values for the differences • Run is unsatisfactory if d is >2 SD References 105

1. Dacie and Lewis Practical Heamatology 2006 Ed S Mitchell Lewis, Barbara J. Bain, Imelda Bates, 10/e Churchill Livingstone, Philadelphia 2. Lippi G, Guidi GC, Mattiuzzi C and Plebani M (2006); Preanalytical Variability: the dark side of the moon in laboratory testing. Clin Chem Lab Med, 44: 358-365. 3. Bonini Pierangelo, Plebani Mario, Ceriotti Ferruccio and Rubboli Francesca (2002); Error in Laboratory Medicine, 48: 691-698.

4. Burtis Carl A., Ashwood Edward R. and Bruns, David E.: 2006 Tietz Text Book of Clinical Chemistry and Molecular Diagnostics Saunders St. Louis Missouri, USA 5. Ricos C, Baadenhuijsen h, Libeer JC, Htyltoft Peterson P, Stockl D, Eur J Clin Chem Clin Biochem 1996:34:159.65 and Scan J Clin Lab Invest 1988:48:757-64: ANNEX - 1 SPECIMEN COLLECTION MANUAL PURPOSE: To obtain an adequate sample for various laboratory tests

Results of the laboratory depend upon the quality of the specimen received. Poorly collected or transported specimen can result in inaccurate analysis and to improper treatment of the patient. Specimen Collection: Specimens ate of several types such as blood (collected in a plain vial//tube or containing EDTA, oxalate, fluoride, culture media, heparin, serum separator gel), urine, CSF, fluids (pleural, peritoneal), feces, tissue, BAL,

semen, throat swab, pus and tissue, Any of these samples may be required for microbiological examination which very often is collected in a culture bottle. General Principles:  Match the request form with the patient to confirm identity of the patient correctly  Reassure the patient to avoid stress, which can cause a rise or fall in levels of many analytes • Obtain patient’s or guardian’s consent for specified tests where required

• Information required in the request forms includes patient’s data (name, age (DOB), gender, location (address/ phone/ ward or clinic); tests requested; date & time specimen collected, requester’s data (name, address, phone) and pertinent clinical information.  Generate Bar code (when applicable) depicting name, age, sex of the patient and name of the test and fix on the appropriate collection tubes 106

Collection of Blood Specimen:  Site for withdrawal of blood specimen: o Ante-cubital vein: the most preferred site o Dorsum of the hand: Veins on the dorsum of the hand have a tendency to bleed, however, are chosen in an obese subject when it may be difficult to access an ante-cubital vein. o Skin puncture: is used for obtaining a small amount of blood or when it is not possible to obtain venous blood(e.g. in infants <1 yr, in cases of gross obesity)

 When serum or plasma is required for analysis, the specimen volume is 2 to 2.5 times the volume of serum or plasma required for the investigations  Maintain the ratio of anti-coagulant and blood  Seat the patient in a chair or request him to lie down on the couch. Venipuncture is never performed while a patient is standing  Examine both arms. Select best accessible antecubital vein. Apply tourniquet 3-4 inches above the

venipuncture site. Palpate vein to determine its size, depth and direction. Release tourniquet  Wear gloves and reapply tourniquet  Re-palpate the vein  Patient is asked to close his fist  Clean the area with 70% ethyl alcohol or 0.5% chlorhexidine using sterile gauze swab in a circular motion, moving clockwise from inside to out. Allow to air-dry • Keep patient’s arm in a downward position to prevent backflow or reflux

 Use new needle holder for each patient. Thread needle snugly into holder but do not make it over tight. Insert the required collection tube into the tube holder until it makes contact with the backside of the needle. Do not push the collection tube onto the needle  Remove the needle cover and perform venipuncture with bevel pointing up  Push the tube to the end of the holder, puncturing the diaphragm of the stopper. At this point, blood should be visible in tube.  Release tourniquet.

 Pull out collection tube only after the vacuum is exhausted & blood flow has stopped (especially applicable to tubes with additive). Fill tubes in the recommended order of draw. Mix the tubes with additive immediately by gently inverting eight to ten times. Do not shake. Partial mixing may result in formation of clot, which interferes with many tests especially platelet counts and clotting tests • After the last tube is withdrawn, place sterile gauze over the puncture site remove needle from the

arm, press at the site, remove the gauze, check that there is no oozing and stick sterile adhesive such as ‘Bandaid’ or ‘Handyplast’. • Do not recap needle. Dispose the needle in the “sharps container’. • Label the collection tubes with patient’s name, date & time and the identity of the phlebotomist or place the bar code on the tubes as per the practice  Withdrawing blood with a syringe is avoided for safety reasons. The procedure is essentially similar as

for the evacuated tubes except the following::Check that the sterility seal is intact. As there is no vacuum, blood does not flow automatically and plunger of the syringe is gently & slowly drawn back (allowing blood to flow 1~2 mm behind plunger). Continue until the required amount of blood is obtained. Carefully puncture the stopper of the evacuated tube and allow the blood to be sucked into the tube/s. Avoid needle stick injury

ORDER OF DRAW: The following order of draw is recommended when drawing multiple specimens for clinical laboratory testing during a single venepuncture. Its purpose is to avoid possible test result error due to cross contamination from tube additives. 107

Tube Additive Determination Blood Culture Sterile media For microbiological tests container Light blue 3.2 % Sodium citrate Maintain the ratio of blood with that of anticoagulant Gold Clot activator and gel Serum separation (SST) Red Clot activator For serum Green Heparin For plasma Lavender K EDTA For haematology 2 Gray Sodium Fluoride with K For glucose 2 EDTA or Potassium Oxalate Timed specimens: Postprandial glucose - 2 hours after meal

Blood glucose at specified time - to check the effect of insulin therapy Multiple Specimens:  The most common timed procedures are oral glucose challenge and tolerance tests. Draw blood specimen in a fasting state. For GCT, give 50 g glucose orally and collect blood after one hour and for GTT, give 75 g glucose orally and draw samples every half h for 21/2 h or 100 g glucose and take sample every 1 h for 3 h. Collect urine to test for presence of glucose and acetone with every blood sample.

 To test the effect of a certain medication, determination of glucose level is requested on consecutive days, before, during, &/or after the patient has received a medication.  Collection of an acute & convalescent serum to aid in the diagnosis of a viral infection when culturing is not feasible.  Other examples include tests such as stool for occult blood, ova & parasites & blood cultures. Sequential Sampling:

 Diagnosis of many endocrine diseases requires sequential sampling of blood &/or urine. All sequential specimens are from the same patient & are sent to the laboratory in the same order as they are collected.  The specimens are clearly labeled in the chronological sequence (1 of 6, 2 of 6, or time drawn) & with the patient's name & date of collection. Only one test request form accompanies the serial samples, & it is completed with all patient information,

including any medications administered & the number of samples sent. Precautions: • Strictly follow safety precautions e.g. (a) use sterile disposable syringes & needles (b) wear gloves, (c) avoid injuries from sharps (do not capped needles destroy those by mechanical / electric devices), (d) dispose sharps into puncture resistant containers. • Avoid stress to the patient significantly affects analytes values such as blood glucose & total leukocyte count..

• Dispatch samples to the laboratory without delay • Obtaining blood from an indwelling line or catheter is a potential source of error. Because it is a common practice to flush line with heparin, they are flushed free from heparin before any blood is collected for laboratory tests. • If intravenous fluids are being transfused into an arm, the blood sample is collected from opposite arm. If an intravenous infusion is running in both arms, sample is drawn after the

intravenous infusion is turned off for at least two minutes before venipuncture & applying the tourniquet below the intravenous infusion site. Special precautions for collection of blood for clotting tests:  Strictly maintain the ratio of blood to the additive  Puncture must be clean as clotting affects the test results  If the sample has to be transported to another city or there is likely to be delay in processing; prepare platelet-poor plasma at the collection centre

Special considerations for microbiological samples: Blood culture: Routine blood cultures are indicated inpatient suspected to have bacteremia or candidemia. Timing  Blood for cultures is drawn prior to the institution of antibiotics.  If antibiotic/s are given empirically in an emergency blood cultures if required, should be performed as soon as possible before the next scheduled dose. Volume of blood per set  5-10 ml for adults and 2-3 ml of blood for children

 There is a direct relationship between the volume of blood obtained and the yield of a blood culture set. Number of Sets of Blood Cultures • The optimal yield for patients suspected to have bacteremia or candidemia is obtained with two or three sets of blood cultures. • No more than three blood cultures Blood Culture Bottles: Separate blood culture bottles are used for children and adults Site of blood culture  Blood is obtained from peripheral venous sites

 A paired set of culture is recommended when sample is taken from central venous catheters-one from the CVC line and another from the periphery  Blood for culture is not drawn from catheters or the groin when a peripheral (i.e., non-catheterized) site is available. Labeling 109

 The site of each set of blood cultures is labeled, particularly regarding whether a set was drawn from a catheter, the groin, or not. It is of utmost importance in helping to distinguish pathogens from contaminants in those cases in which no peripheral access can be found Preparation of the site for culture  Disinfect a 5 cm area of skin by swabbing concentrically with 70% ethyl alcohol, from the venipuncture site outward. Allow the site to dry

 Remove the plastic cap covering of the blood culture bottle. Disinfect the rubber stopper with 70% alcohol. (Iodine solutions will disintegrate the rubber and should not be used.) NOTE: Needles are not changed between venipuncture and inoculation of the bottles, or between bottles. The risk of needle stick is increased, while the chance of contamination is not significantly lessened Patient Variables Many variables related to patient can affect analyte values

 Basal State: Generally, the specimen to determine concentration of body constituents is collected in the morning around 8.00 AM when the patient is in a basal state {i.e. early in the morning after overnight fasting (about 12-14 h after ingestion of food)}. Reference intervals, most often are derived from the analyses on specimens collected during this period.  Exercise: Moderate exercise can cause an increase in blood glucose, lactic acid, serum proteins and creatine kinase (CK)

 Emotional or Physical Stress: The clinical status of the patient can cause variations in test results.  Circadian rhythm: Levels of many analytes significantly change due to circadian rhythm. For example, growth hormone level peaks in the morning before waking and falls throughout the day. Serum iron level may fall by 30% to 50% from morning until evening. Test Interference: Certain foods & drugs, investigations involving injection/ingestion of dyes etc. may interfere in correct analysis

of analytes. Such interfering items are discontinued for at least 6 to 7 days; if there is a doubt, the clinician is made aware either to avoid the test or to correlate the results with limitations. Bananas contain 5 hydroxy indole acetic acid and may increase its level. Ingestion of green vegetables increase vitamin K level and may decrease the prothrombin time and hence the INR. Administration of dyes and contrast media for investigations interfere with many tests

Table-2 Effect of time of sampling and patient management on analyte values Analyte/Therapy Remarks/Special instructions/Interferences Default rule As a rule blood specimen should be taken early morning while the patient is fasting for 10 h Thiazide administration Produces hyperuricaemia & hyperglycaemia 110

Catecholamines Catcholamine (epinephrine, nor-epinephrine and dopamine) show variable rise in pheochromocytoma, neuroblastoma and carcinoid. Tricyclic antidepressants and phenoxybenzamine, leovdopa and methyl dopa administration can raise levels of catecholamines in blood and 111

urine. If possible these should be withdrawn before these tests Oral contraceptives Mild to marked fall in levels of vitamin B increase in thyroxine-binding 12, globulin (hence rise in thyroxin & unsaturated thyroxin-binding globulin), but with no significant change in unbound (free) thyroxin Serum iron Marked diurnal variation (32 to 50% fall from level at 8.00 a.m. to a level at 2.00 p.m. (Collect fasting sample). Stop iron therapy 6 days before.

Reference intervals differ with regard to gender, age and physiological status (pregnancy, lactation and menstruation. Bleeding time Prolonged after aspirin ingestion Lipid profile Fasting sample Hormonal studies, Specimens are collected at specific times e.g. for Cortisol at 8.00 A.M. & 4.00 P.M. for LH, FSH, Prolactin (because of the episodic, circadian & cyclic variations in secretion of gonadotropin), three sample drawn 20 minute intervals are pooled. Prolactin sample 3 to 4 hours after the

subject has awakened Vitamin B12/ Vitamin D Cover the tube with aluminum foil PTH .Collect in pre-chilled SST evacuated tube & send immediately to lab where it is centrifuged & serum is frozen till it is out sourced 24 hour urine • For safety purposes, instruct the patient to urinate in a clean, collection dry container, then transfer the urine to the collection bottle. The patient should not urinate into the collection bottle. • Avoid alcoholic beverages & vitamins for at least 24 hours before

starting to collect urine, & during the collection period • Do not exceed normal intake of liquids or change dietary habits during the day before & the day of collection unless physician gives specific instructions to do so. • Empty bladder (void) into the toilet on the morning of the collection day. Do not include the first urine specimen of the day. Oral Glucose Tolerance Medications known to affect GTT, diet (give unrestricted for 3 days

Test (OGTT) containing at least 150 g of carbohydrate), bed rest impairs with the test (perform test on ambulatory patients) Effect of Circadian variation Serum iron Level may fall by 50% from 8 am level to 2 pm Cortisone Level may fall by 50% from 8 am level to 4 pm Serum potassium Level may fall from 5.4 mmol/L50% from 8 am level to 4 pm Serum TSH Level may fall by 50% from 2 am- 4 am level to 6 pm- 10pm Serum Phosphate Level are as much as 30% higher at night than during morning 112

Effect of Prolonged Bed Rest Haematocrit Levels can increase by 10% within 4 days Plasma protein Levels may fall by 0.5g/dl Serum Potassium Levels may fall by 0.5mmol/l Effect of Exercise Plasma Lactate Levels may increase by 2-10 folds Plasma rennin activity Plasma rennin activity by 400% after sternous exercise for 10 mins. Serum CK Increased CK activity seen after intramuscular injection of certain drugs Effect of Ingestion of specific foods Caffeine

Serum Cortisol Normal diurnal variation may be suppressed. Serum Gastrin Levels may increase by as much as 5 times. Effect of Smoking Serum growth Levels may increase upto 10 folds within 30 mins of smoking a cigarette hormone Serum Cortisol Levels may increase by 40% within 5 mins of start of smoking TLC Increased by as much as 30% in smokers Vit B12 Levels are notably reduced in smokers Effect of Alcohol Serum triglycerides There is marked hypertriglyceridemia

Serum HDL Increased HDL levels are seen with prolonged moderate ingestion GGT Increased GGT activity ( marker of persistent drinking) MCV Increased MCV Antoconvulsants Reduced serum and red cell folate levels. (Phenytoin) Reduced serum calcium and folate levels. Increased ALP activity. 113

T3 levels are reduced but TSH are normal. Fever Increased blood glucose levels. Plasma cortisol levels are increased. Effect of Shock and Trauma Serum Cortisol Levels may increase by 3-5 fold. Plasma fibrinogen Levels may double in 2-8 days after surgery. Serum CK Increased CK activity seen after trauma and surgery. T3 Levels reduce by 50% after surgery. Collection of Urine Specimen  Urine for routine urinalysis is collected in clean container and for culture in a sterile container. Perform

urinalysis within 2 hours of collection. Specimens held at room temperature for more than 2 hours may show changes in pH and chemical constituents. If the specimen cannot be analyzed within 2 hours, it is refrigerated to prevent bacterial growth  Ensure that the date and time of collection is returned in the request form or on the container. If the sample has been refrigerated it is indicated on the request form  If both urinalysis and culture are requested, 2 separate specimens are collected

• The barcode label should withstand refrigeration and should include the patient’s identification and date and time of specimen collection. The labels are placed on the container, not on the lid. Urine for microbial culture  Urine for microbial culture is collected in sterile screw cap container.  Morning voided urine , mid stream specimen is preferred  The clean catch technique must be followed as mentioned below:

o Urine collection (female): The patient is given instructions to wash her hands with soap and water, rinse and dry. Then cleanse the urethral opening and vaginal vestibule area with soapy water, rinse the area with water dry and hold the labia apart during voiding. Allow a few ml of urine to pass and then collect the midstream portion of urine in a sterile container. o Urine collection (male): The patient is given instructions to wash his hands with soap and water, rinse

and dry. Then cleanse the penis, retract the foreskin (if not circumcised) and wash with soapy water, and then rinse the area well with water and dry. Keeping foreskin retracted, allow a few ml of urine to pass and then collect the midstream portion of urine in a sterile container. o For neonates a suprapubic collected urine is preferred  Foleys catheter tips are not recommended for culture  A minimum of 3 ml urine sample is sent for culture.

 Cultured within 2 hours after collection or refrigerated at 40C and then cultured within 8 hours. Urine: 24h Urine Collection  Take a clean container of 2 litre capacity and add preservative as below: 114

TEST PRESERVATIVE QUANTITY Urinary Urea Boric Acid 10 gms Urinary Phosphorus Boric Acid 10 gms Urinary Uric Acid Sodium Carbonate 05 gms Urinary Calcium 6 N HCL 10 ml. Urinary Magnesium 6 N HCL 24 ml. 17 OH Corticosteroid 6N HCL 25 ml. 17 Ketosteriod 6 N HCL 25 ml. Catecholamines 6 N HCL 25 ml. Metanephrines 6 N HCL 25 ml. Urinary Protein Boric Acid 05 gms Urinary Cortisol 6 N HCL 25 ml. 5 Hydroxyindole Acetic Acid 6 N HCL 25 ml. Vanilmandelic acid 6N HCL 25 ml

Note: No preservative is added for the following tests; Urinary Sodium, Urinary Potassium, Urinary Chloride, Urinary creatinine and Urinary glucose.  To start the collection, the patient is instructed to discard the first morning urine specimen and note the exact time.e.g.7.00 A.M  The subsequent urine samples are collected in the container provided. The collection is continued till the same time next day e.g. up to 7.00A.M. That is the 24 hours urine sample

 The 24 hours urine sample is submitted to the lab within 1.00 hour  Total urine output in 24 hours is measured and recorded on the request form and 20 ml well mixed aliquot from the total volume is sent for the analysis. In case of Creatinine Clearance Test the height, weight, and age of the patient is specified.  Preservative to be added as per the test requirement: Possible interferences: 115

• Stop intake of alcohol and following foods or drugs that may affect analyte values 72 hours prior to the start of collection. Consult the treating physician before stopping any medication. TEST FOODS MEDICATIONS Metanephrines Coffee, tea, soda, chocolate None VMA None Labetolol, methyldopa 5HIAA Bananas, pineapple, plums, Acetaminophen,Aspirin,Mephenesin, tomatoes, walnuts Methocarbamol,Imipramine,Isoniazid, Phenothiazines, Phenacetin, cough syrup containing glyceryl guaiacolate Collection of C.S.F

• The collection of specimen is performed under strict aseptic conditions by the clinician and is sent to the laboratory in sterile screw-capped containers. Usually two specimens are collected from the arachnoids space by inserting a sterile wide bore needle between the 4th and 5th lumber vertebrae. Minimum suggested volume is 1-2 ml for routine, fungal/ mycobacterial cultures respectively. Maximunm sample is sent to microbiology laboratory. The specimen is transported to the lab without any delay.

• CSF is analyzed as early as possible but within 2h of collection • CSF samples for different laboratories are sent in different containers. • If CSF sample is sent in 2 containers for same laboratory, the sample is pooled before analysis. • CSF specimens not refrigerated unless viral studies alone are requested. • CSF always kept at 370C for bacteriological investigation. Collection of Sputum  Sputum is collected in a wide mouthed disposable universal container

 If organism like Corynebacterium diptheriae, cryptosporidium, Bordetella pertussis a suspected, the concerned doctor contacts the laboratory before sending the specimen because it may require special technique to collect the specimen or media for isolation of these agents.  Expectorated sputum: if possible ask the patient to rinse mouth and gargle with water prior to sputum collection. Instruct the patient not to expectorate saliva or postnasal discharge into the container.

Collect specimen resulting from deep cough in sterile screw- cap container.  Induced sputum is sent when the patient is unable to produce sputum on his own.  24 h sputum collections are not recommended for culture. 116

Respiratory Specimens  Tracheostomy and endotracheal aspirations: The clinician aspirates the specimen into a sterile sputum trap. Tracheostomy tube tip or endotracheal tube tip are not recommended for culture, hence are not accepted.  Bronchoscopy specimens: These include bronchoalveolar lavarge, bronchial washing, bronchial brushing and transbronchial biopsy specimens. These samples are collected by the clinicians and sent to the laboratory in sterile containers.

• Throat swabs: Throat samples are not obtained if epiglottis is inflamed, as sampling may cause serious respiratory obstruction. Tongue is gently pressed with a tongue depressor and sterile swab is rotated between the tonsillar pillars and behind the uvula and around the pharynx, tonsillar areas and any inflamed or ulcerated areas for obtaining the specimen. • Post nasal swabs: These are used to sample nasopharyngeal secretion for the diagnosis of

meningococcal carriage. Nasopharyngeal suction when introduced through the mouth, it carries the swab up behind the soft palate into the nasopharynx. Nasal swabs are used for the detection of Staphylococcal infections. • Nasopharyngeal suction: Submitted for the detection of carriers of S. pyogenes, N. meningitidis, C. diptheriae and B. pertussis • Fungal cultures: Recommended volume of the samples is 3-5 ml. Collect 3 early morning specimens by

deep coughing or sputum induction. Lung biopsy or lung aspirates are also used for fungal culture. • Anaerobic cultures:. Sinus aspirates, tympanocentesis fluid, transtrachaeal aspirate and lung aspirates or biopsy specimens are appropriate. • Mycobacterium cultures: Recommended volume of the samples is 5-10 ml. Collect 3 early morning specimens by deep coughing or sputum induction. Lung biopsy or lung aspirates are also used for culture. Collection of Faeces

The universal container for fecal specimen should be wide-mouthed and disposable and should contain a small wooden or metal spatula-shaped stick. Instructions to the patient: “Unscrew the container; hold the stick and pick up a spoonful of faeces. Place it into the universal container. Replace the cap tightly. Deliver the specimen in the laboratory as early as possible. When there is likely to be delay under warm conditions add neutral glycerol saline to the container.

Superficial/ Deep Wounds, Aspirates and Tissue Specimens  Syringe aspirates or biopsy specimens are preferable to swab specimens  Superficial fungal lesions; Clean the surface with alcohol, Scrape periphery (border) of the lesion with a scalpel. Selectively include hair from scalp lesions for examination. Collect debris or material beneath the nail plate when nail is involved. Transport in folded filter paper. If material is very scanty place

directly on a glass slide. Put a drop of KOH solution over it, cover with a cover slip, and send it to the laboratory. Ocular Specimen Collection 117

• Prepared smears (KOH mounts) and inoculated media (obtained from the microbiology laboratory after prior consultation) are sent to the laboratory immediately. • Wet mounts are made for detection of Acanthamoeba sp, or the sample (intraocular fluid) is transported to the laboratory immediately in a capped syringe with bubbles expelled. Genital Tract Specimen Collection  Vaginal swabs: High vaginal swabs are preferred.

 Urethral swab (male): the clinician collects specimens at least 2 h after the patient has urinated. CAPD (continuous ambulatory peritoneal dialysis) Fluid Collection At least 100 ml of fluid is transferred from the bag aseptically and sent to the laboratory in a sterile container. Alternatively whole dialysate bag is sent to the laboratory. Intravascular Devices Tips The clinicians remove the cannula in an aseptic manner after skin disinfection and send 4cm of the

intravascular segment of the catheter in a sterile container. If purulence of the catheter exit site is evident, pus is sent for culture and gram stain. Specimen Collection for Semen Analysis  The sample is collected after a 2- 3 day period of sexual abstinence.  Specimen is collected by masturbation into a sterile plastic container  Specimen is kept as close to body temperature as possible until delivery is made to the laboratory. Extreme heat or cold will ruin the specimen.

 Specimen is delivered to the laboratory within half an hour after collection Anaerobic Culture ACCEPTABLE SPECIMENS UNACCEPTABLE SPECIMENS 118

v Normal sterile body fluids v Saliva, throat swab v Bile, pleural, sinus, joint, v Expectorated sputum, endotracheal aspirates pericardial and peritoneal fluid, v Unprotected BAL blood. v Vaginal/ cervical swab Sample v Surgical specimens from normally v Faeces (except for C. difficile) Collecti sterile sites: v Colostomy or ileo-stomy effluent on and v Abscess contents, deep aspiration v Skin swabs Transp tissue from wounds, sinus. v Superficial wound swabs ort v Suprapubic urine, transtracheal

v Rectal swab Details and culdoscopy aspirates v Urethral swab for v Bone marrow v Voided/ catheterized urine Polyme v Uterine contents, if collected v Semen/ prostatic secretions rase using a protected swab Chain Reaction (PCR), Genotyping and Viral Load Monitoring Specimen type Minimal Optimal quantity Storage and Collection quantity temperature transport (optimal) tubes (optimal) (additives) Mycobacterium Tuberculosis Sputum (3 consecutive days 1 ml As much as Refrigerated Sterile vial

first morning expectorate) practical Pleural/ body fluids other than 1 ml As much as Refrigerated Sterile vial synovial and Ocular fluid/ practical aspirate Synovial/ ocular fluid As much as 0.5 ml Refrigerated Sterile vial practical Endometrial tissue As much as As much as Refrigerated Sterile vial practical practical Urine (first morning single 1 ml 10 – 100ml Refrigerated Sterile vial day/ 3 consecutive days) CSF 0.5 ml 2 ml Refrigerated Sterile vial

Formalin fixed/ paraffin - As much as Room temperature Sterile vial embedded tissue practical 119

Whole blood (tasing) 4 ml 4 ml Refrigerated EDTA/ACD Bone marrow 2 ml Refrigerated EDTA/ACD Menstrual blood, (first day) 1 ml 5 ml Refrigerated Sterile vial HBV/PCR SST serum/ EDTA or ACD 1 ml 3 ml Refrigerated/frozen Sterile vial plasma Paraffin block of liver biopsy - As much as Room temperature Sterile vial possible HCV PCR SST serum/ EDTA or ACD 1 ml 3 ml Refrigerated/frozen Sterile vial Paraffin block of liver biopsy - - - - CMV Amniotic fluid/ CSF 1 ml As much as Refrigerated Sterile vial possible

Bal/ Saliva/ Urine 5 ml As much as Refrigerated Sterile vial possible EDTA plasma/ SST serum 1 ml 2 ml Refrigerated Sterile vial Sample Collection for Mycobacteriological Investigation* Urine 3 consecutive early morning urine whole samples (minimum 40 ml each). Sputum At least 2 consecutive early morning samples Gastric lavage At least 2 consecutive early morning sample to be neutralized (sodium bicarbonate) soon after collection. Endometrial curettage (preferably pre menstrual)

Pus/ tissue/ aspriate and other As for other investigations samples 121

Quantiferon Tb Gold ** Specialized vial (2 vials) for collection of blood is available at sample collection area (OPD) and microbiology lab (IPD). Blood is to be collected till the given mark in each vial.  *All samples are to be refrigerated till processed Transport of specimens Transport of specimens to the laboratory is as important a step as any other to ensure accuracy. The following considerations apply to transport of specimens  Prepare guideline for transport of specimens

 Maintained the identity of the specimen during transport  Avoid mild haemolysis, leakage and deterioration of the specimens  The specimens can be transported manually or through pneumatic chutes. The pneumatic chutes system can cause mild haemolysis which may not be visible on naked eye examination but may be enough to significantly raise plasma haemoglobin concentration and activity of red cell enzymes such as LDH.

 The following specimens are not sent by pneumatic chutes: Histopathology and Cytopathology samples, Open vials/ vials with loose caps, Urine, faeces & Blood culture bottles  If there is delay in sending the samples, unstable constituents significantly fall to give erroneous result. When samples are sent to referral laboratory by courier to another city plasma should be separated and frozen to ensure stability of several analyte (table 2-7 page 54 Tietz Text Book of Clinical Chemistry

and Molecular Diagnostics, Fourth Edition 2006 Saunders, USA)  Blood collected in capillary tubes is placed in a larger tube, which can be labeled with all the information required.  Specimen from patients with the infectious disease should not be labeled as infectious. Every specimen should be treated as potentially infectious  Samples for determination of ammonia, blood gases, acid phosphatase, lactate, pyruvate, gastrin, renin

must be transported at 4o C even if these are sent to the laboratory with in the hospital Histopathology & Cytology Specimen Collection Procedure- • Request prepared and specimens labeled in the Operating Room or other location where the biopsy or surgical procedure was performed. Requisitions include patient identification, source of organ/tissue, name of submitting physician(s), pertinent clinical information, pre- and/or postoperative diagnosis, and date of specimen obtained.

• Specimens are normally submitted in plastic cups (small specimens can be submitted in plastic sputum cups) in 10% buffered formalin, and labeled with the name of the fixative. The required minimum ratio of formalin-to-tissue that permits adequate fixation is 10:1 (i.e., 10 times more formalin than tissue). Specimens are thus submitted in containers at least ten times the volume of the specimen to accompany a sufficient amount of formalin. 122

• In addition, formalin cannot penetrate through very thick, dense tissue regardless of the amount of formalin present, and large tissues whose delivery to the histology section may be delayed is refrigerated and/or cut to allow sufficient penetration of formalin to tissue surfaces. • Specimen containers have a patient label, barcode attached if applicable. Specimen containers are always submitted with a completed histopathology request form. A physician's signature and a short

history are required. A description of the lesion is useful, especially when only a small portion of the lesion is biopsied. Duration of the lesion, age of the patient and clinical differential for the lesion are always appreciated and many times necessary. Specimens arriving with incomplete forms are not accessioned (and not processed) until the forms are completed. The department makes reasonable attempts to contact the responsible physician. We appreciate prompt compliance when we request

additional information. The above instructions are applicable to most submissions to the histopathology department. The exceptions are as follows: • Specimens needing procedures not offered in our department. • Occasionally, physicians will prefer that a specialized outside laboratory perform a specialized diagnostic test on tissues from patients. Before making such arrangements, the clinician notifies the histopathologist. In all such cases, the clinician is responsible for supplying a copy

of the report produced by the outside laboratory. The department making these arrangements must pay for the special services, • Occasionally, the pathologist who receives a specimen may determine that special studies need to be performed at an outside laboratory, in which case the pathologist will make arrangements with the outside laboratory to perform the studies, and will make prior arrangements for funding of the tests.  Frozen Sections: See FROZEN SECTION PROCEDURES (INTRAOPERATIVE CONSULTATIONS).

 Aspirations. Aspirations are always considered cytology specimens, and are only submitted to the cytology laboratory.  Large Specimens. Large specimens (such as amputation stumps) are submitted refrigerated, rather than formalin-fixed. When submitted to histology, requisition form is left on the accession desk. The actual specimen (wrapped and clearly labeled) is placed in the refrigerator. • All specimens are submitted for microscopic examination, except for amputations due to

peripheral vascular disease; degenerative joint disease; bunions; and hernia sacs; and metal or plastic prosthetic devices. Container: • Volume of sample collected should be as minimum as possible. However, the evacuated tubes collect sample according to the size of the tube. Hence, the evacuated tubes should be of minimum volume required • Use proper specimen vials/tubes/containers • Mentioned name of the test on the container • When applicable fix Bar code on the container and the request form

• Record the name of the person collecting the specimen Procedure for sending Histopathology specimens • Specimen can be hand-delivered or sent to the laboratory in a proper fixative (buffered formalin). 123

Specimen should be placed in a white mouth container. The ratio of volume of formalin to the 124

specimen size is normally 1:5 to 1: 10. In case of small endoscopic biopsies and needle biopsies the containers may be smaller with the narrow mouth. A detailed note on the patient’s clinical history and all relevant investigations is detailed in the request form. The specimens for frozen section are sent fresh without delay in saline soaked gauze. Specimens for Immunoflorescence are sent in normal saline. Specimen container must be labeled with the details of the name, age, sex of the patient and

the date of surgery and the doctor identity. • The laboratory matches the details of patient and doctor identity on the specimens with those on the request form. It assigns the specimens a lab reference number (unique identity) and process it further. Cytopathology • Cytopathology specimens comprise gynecology cytology smears received in 95% ethanol fixative, non- gynecology cytology FNAC smears, which are air-dried before put in 95% ethanol fixative and

exfoliative cytology (body fluids, BAL, brushings) smears in 95% ethanol fixative. Note: The specimens collected by the pathologist are generally superior to those collected by others. A request form with details as specified in the previous section should be sent along with the specimen. Specimen Rejection Criteria Each laboratory must defined its specimen rejection criteria and communicate to the same to the users of the laboratory

• Generally specimens are rejected if there are incorrectly labeled, collected in a wrong tube, are leaking, inadequate in volume, outdated or have inadequate clinical information. However some laboratories except specimens, particularly those, which are critical such as tissues or CSF and are vital for diagnosis. The specimens are processed but no report is issued tin the identity of the specimens is established by

the referring physician, clinical details are made available or viability of the specimen is ensured Safe Disposal of Materials Used In Sample Collection • Regulatory requirements must be followed by each laboratory for disposal of waste generated in the lab. Please refer to Bio-Medical Waste Management Rules 1998 of Govt. of India and the state rules if any. Modifications made after the publication of rules must be adhered to. 125

Validation of modified/new method: Perform tests on at least 20 samples with the standard method and the modified method Perform regression analysis and Bland-Altman plot to show agreement. T test may also be done; though not necessary The coefficient of correlation (R2) should be more than 0.97. Perform 20 tests on low and high controls to calculate imprecision; it should not be significantly different from that for the Standard method

Perform linearity check to show the linearity for the modified method is the same as for the standard method NOTE: It is better that the modification should not compromise the principle of the method 126

Annex-2 In-house calibration of equipments in clinical laboratory Source: 1998, WHO/LAB/98.4, World Health Organization, Quality Assurance in Haematology by Dr.S.M. Lewis Calibration of volumetric pipettes 127

Weigh a beaker in calibrated balance using calibrated mass (weight box). Fill the pipette to the calibration mark and deliver it a weighed beaker. Reweigh the beaker. Note the ambient temperature and calculate the volume of the pipette (in mL) by dividing the weight of the water (in mg) by one of the following factors depending on temperature: Temperature(oC) Factor 18 0.9986 19 0.9984 20 0.9982 21 0.9980 22 0.9978 23 0.9976 24 0.9973 25 0.9971 26 0.9968 27 0.9965 28 0.9963 29 0.9960 30 0.9957 m

The calibration must be performed in duplicate for each pipette Calibration of micropipettes: The weighing scale must be calibrated using calibrated mass. Volume of the micropipettes varies from 1 to 500 mL. The procedure described above can be applied. However, 1 mL of water weighs 1 mg the balance should have sensitivity of 0.1 mg to ensure a measurement error less than 2%. As this type of balance is not commonly available, the following modified procedure is recommended. 128

The example given is for a 20 mL micropipette and can be adapted to suit other volumes. 129

Calibrate a 0.2 mL pipette, a 5 mL pipette and a 50 mL volumetric flask by the procedure described above. Mix and lyse (e.g. by adding a few drops of saponin solution), 2-3 mL of EDTA specimen of whole blood. Deliver with a calibrated pipette, 0.2 ml of the specimen in 50 mL haemiglobincyanide reagent in the volumetric flask to reach a dilution in 1/251. Fill the 20 mL pipette to be calibrated, up to the mark with blood and deliver into a test tube containing 5 mL

haemiglobincyanide reagent. (The reagent should be delivered with the previously calibrated 5 mL pipette. The dilutions are carried out in duplicate and the absorbance (A) read at 540 nm on a spectrophotometer. A Absorbance using the previously calibrated (0.2 ml) pipette 1– A – Absorbance using the micropipette (20 mL) 2 Ratio A and A should be 1. If ratio is different use this figure as a division factor to arrive at correct volume of 1 2

the pipette under calibration. Suppose the ratio is 0.95 the volume delivered by 20 mL divided by 0.95 = 21 mL Control of calibration of photometer: To ensure that a photometer is functioning correctly a calibration graph should be prepared when it is first put into use in the laboratory, and thereafter at intervals- usually every six months, but every one to two weeks if there is any doubt about its performance. The following example illustrates the preparation of a calibration

graph for use in haemoglobinometry, but the same principles also apply to other tests. Take a specimen of blood with apparently normal values. Make a concentrated HICN preparation by delivering approximately 0.1 ml blood in approximately 20 ml of haemiglobincyanide reagent (Drabkin’s Reagent). Determine its concentration against a haemiglobinocyanide reference and express it as g/dl or g/L depending on the unit adopted by your laboratory. Make dilutions as follows using calibrated pipettes and measure

absorbance at 540 nm wavelength. Tube Volume of concentrated Volume of Drabkin’s Expected Absorbance preparation (ml) solution (ml) 130

2 4 (Accurately) 1 (Accurately) ‘A’ x 4/5 3 3 (Accurately) 2 (Accurately) ‘A’ x 3/5 4 2 (Accurately) 3 (Accurately) ‘A’ x 2/5 5 1 (Accurately) 4 (Accurately) ‘A’ x 1/5 6 (Blank) Nil 5 ((Approximately) 0 The values can be plotted on linear-linear graph (concentration on the abscissa and absorbance on the ordinate). If accurately performed, the line joining the points passes through zero point and the absorbance of each dilution is very close to the expected value.

If the line of the calibration graph is not linear throughout its length, only the linear portion can be used for deriving measurements. If there is no linearity at all, the instrument requires attention by the manufacturer. Calibration using other standard solutions and / or filters is also described 1 1. Burtis Carl A., Ashwood Edward R. and Bruns, David E.: 2006 Tietz Text Book of Clinical Chemistry and Molecular Diagnostics Saunders St. Louis Missouri, USA Testing for Thrombophilia

Thrombophilia is used to describe disorders of haemostatic system which leads to thrombosis.(1990 BCSH).The term thrombophilic is frequently used by clinicians to describe patients who have developed venous thrombosis either spontaneously or of a severity out of proportion to any recognized stimulus, patients who have recurrent venous thrombotic events and patients who develop venous thrombosis at an early age. Individuals who have a thrombophilic defect identified on

laboratory testing and who have a family history of proven venous thrombosis are at greater risk of thrombosis than individuals who have a thrombophilic defect without family history of venous thrombosis (Lensen et al, 1996).1 Prothrombotic states may be genetic or acquired, it includes 132

Antithrombin deficiency Protein C and Protein S Activated Protein C resistance(APCR) FV Leiden mutation Prothrombin 20210A Dysfibrinogenemia Lupus Anticoagulant Elevated FVIII levels Hyperhomocysteinanemia Conditions associated with acquired thrombophilic laboratory abnormalities3. Acute thrombosis Low protein S Low protein C Low antithrombin Infection Antiphospholipid antibodies Inflammation Elevated factor VIII Low free protein S Elevated Lp(a) Nephrotic syndrome Low protein C Low protein S

Elevated Lp(a) Complex congenital heart disease (single ventricle) Low protein S Low protein C Low antithrombin Asparaginase (acute lymphoblastic leukemia) Low antithrombin Liver disease Low protein S Low protein C Low antithrombin Warfarin therapy Low protein S 133

Heparin therapy Low antithrombin Nutritional deficiency Elevated homocysteine Pregnancy Low protein S The Reason for testing: Identification of risk factors either as single or mutlifactorial helps decide secondary prophylaxis or ? prevention of rethrombosis. When should Thrombophilia testing be performed? Testing done during acute phase of thrombus may result in incorrect results especially in case of inherited deficiency. There is a transient decrease in the levels of AT, protein C and S during acute

thrombosis. Any abnormal results during this phase might be repeated at a later date for confirmation along with devoid of anticoagulation.1,2,3 Molecular testing can be tested and reported without any caution since there is no interference by these test results during acute episode. The acute thrombosis period is not appropriate since activation of coagulation due to the thromboembolic event may induce perturbation of coagulation with false positive or negative results. However at certain circumstances

some test can be performed at the time of the event diagnosis4, LA,aCL,coagulation factors (prolongation of APTT) Protein C,protein S and APCR(skin necrosis) AT (thrombosis at unusual site/young age). Who to test/screen? 1. Evidence of heritable thrombophilia testing is only appropriate in the presence of family history, especially with the history of idiopathic venous thrombosis3,4. 2. All patients with venous thromboembolism, independently of the age of onset (before or

after 45 years), the circumstances of thrombosis (provoked or unprovoked), and the severity of the clinical manifestations. 3. Pateints developing skin necrosis at the initiation of VKA. 135

4. All women with complications of a pregnancy other than venous thromboembolism: 136

- One or more episodes of late fetal loss -Two or more episodes of early fetal loss 5. Women with pre-eclampsia, fetal growth retardation or abruptio placentae are potential candidates. 6. All asymptomatic individuals who are first-degree relatives of a diagnosed carrier of a thrombophilic trait. This should be accompanied by accurate information and counseling. Recommendations regarding thrombophilia testing in children3 Antithrombin deficiency Chromogenic or clotting

Protein C Chromogenic or clotting assay Protein S Immunologic assay of free and total protein S antigen -ELISA Activated Protein C resistance(APCR) Clotting assay 137

Factor V Leiden mutation PCR Elevated factor VIII One-stage clotting assay, chromogenic assay Antiphospholipid antibodies Phospholipid-based clotting assays, (PTT and DRVVT) with confirmatory assay using exogenous phospholipid, ELISA assays for IgG and IgM antibodies directed against cardiolipin and β2 glycoprotein Elevated lipoprotein (a) ELISA Hyperhomocystenemia Fasting homocysteine Laboratory Tests: It includes phenotypic measurement of natural anticoagulant levels and genetic analysis of gain of

function polymorphism1,2,3. Antithrombin deficiency: Antithrombin (previously called antithrombin III) is synthesized by the liver. Its inhibitory effect is not confined to thrombin. It also inhibits the activated proteolytic clotting factors IXa, Xa, XIa, and tissue factor-bound factor VIIa. Heparin also accelerates this effect. There are two major types of AT deficiency,Type I is characterized by a quantitative reduction of qualitatively

(functionally) normal antithrombin protein. Type II deficiency is due to the production of a qualitatively abnormal protein. In both types of antithrombin deficiency, antithrombin activity is reduced to a variable extent. Prevalence: The prevalence of type I antithrombin gene mutations in the general population is around 0.2% (Tait et al, 1994). Family studies suggest that antithrombin deficiency is a more severe disorder

than deficiencies of protein C or protein S with the majority of patients suffering thrombosis before the age of 25 years (Thaler & Lechner, 1981; Hirsh et al, 1989; Demers et al, 1992). The relative risk of venous thromboembolism is around 25-50 fold for individuals with type I antithrombin deficiency (Rosendaal, 1999). Antithrombin assays: Only functional assays of heparin cofactor activity will detect both type I and

type II antithrombin deficiencies. For routine clinical purposes it is recommended that a heparin cofactor activity assay be used in the initial screen. Antigenic – not adequate for diagnosis especially because of the commoner Type II. 138

Functional – two types, progressive inhibitory activity and heparin cofactor activity. The later is ideal as it involves Heparin but has two methodologies involved based on the target enzyme used namely thrombin or Xa. The Xa isolates AT as heparin cofactor II interferes with anti IIa effects. Protein C deficiency: Protein C is a vitamin K-dependent glycoprotein that is synthesized in the liver. Before activation by the thrombin-thrombomodulin complex on the endothelial cell surface, it

circulates as a two-chain zymogen. By degrading activated clotting factors Va and VIIIa, activated protein C (APC) functions as one of the major inhibitors of the coagulation system. Activated protein C also reduces platelet prothrombinase activity by degrading plateletbound factor Va at the receptor for factor Xa. The inhibitory effects of activated protein C are facilitated through the cofactor activity of protein S. It is classified into two types ,type 1(reduction of functional and immunological protein

C),type 2(functional is substantially lower than antigen). Many subtypes in this group based on the functional site affected, either the calcium/phospholipid binding site, proteolytic site or co-factor binding sites. Prevalence: heritable protein C deficiency in the general population is approximately 0.2±0.3% (Miletich et al, 1987; Tait et al, 1995) and in unselected patients with venous thromboembolism is around 3% (Heijboer et al, 1990; Koster et al, 1995a; Mateo et al, 1997). The relative risk of venous

thromboembolism is between 10 and 15 fold for individuals with protein C deficiency (Rosendaal, 1999) Antigenic: not popular as it misses Type II defects. Most functional assays of protein C use the specific activator Protac which is derived from snake venom. The activated protein C formed can be quantified by clotting or chromogenic methods. Both are available in kit form from commercial manufacturers. A standard calibrated against the current

International Standard for protein C must be used. Chromogenic assays are simple to perform and will detect all type I defects and the vast majority of type II defects. Functional: These may be based on measurement of the anticoagulant activity of APC exerted against the natural substrates factor VIIIa and Va, or of the amidolytic activity against small synthetic substrates. Both types of assays require activation of PC. This may in turn be achieved by thrombin-

thrombomodulin complex or snake venom. Thrombin-thrombomodulin activation mimicks in vivo conditions more closely than any other test. These tests are commercially available and may be easily adapted to automation in many coagulometers. However, they are potentially susceptible to artifacts because they may be affected by other conditions, such as APC resistance or high concentrations of factor VIII, and require considerable experience to interpret the results. All of these problems may be

circumvented by use of amidolytic assays with snake venom as the activator. These assays may leave undetected cases of subtle PC dysfunction where the defect is restricted to the active site responsible for inactivation of the natural substrates. 139

Protein S deficiency: Protein S, another vitamin K-dependent protein, is a cofactor for activated protein C. Approximately 65% of the total plasma protein S is complexed with C4b-binding protein (C4bBP) and has no cofactor activity. The remaining 35%, designated free protein S, remains uncomplexed and is the active moiety. The bioavailability of protein S is closely linked to the concentration of C4bBP, which acts as an important regulatory protein in the activated

protein C:protein S inhibitory pathway. Type I- Decrease in levels of Free and Total PS (detected by antigenic assays for both Free and Total PS), Type III- Decrease in levels of Free PS but normal total (probably a phenotypic variant of Type I- same assays), Type II- Qualitative defect (will require functional assays in addition to antigenic levels- but extremely rare). Prevalence: Protein S deficiency in the general population remains unknown. It has been suggested

that the best way to determine protein S deficiency is by measurement of free protein S antigen (Faioni et al, 1997). In the Leiden Thrombophilia Study (Koster et al, 1995a) and in a subsequent population-based case control study reported from Italy (Faioni et al, 1997), low levels of free protein S antigen were found in around 3% of patients with venous thromboembolism and in 2.1% and 1.3% of the controls, respectively, suggesting that low free protein

S levels have a mild effect on the risk of venous thrombosis increasing the risk by only around twofold. Protein S assays: Three main types of assay are available: for functional protein S, and for total immunoreactive protein S and free immunoreactive protein S. Functional: the present day functional assays are not specific and is low for PS in cases of APCR, raised FVIII and LA. Not recommended at all at this stage.

Antigenic: both for total (ELISA, using monoclonal antibody to PS) and free PS. Out of the two the Free PS is a must and is the one STRONGLY RECOMMENDED. For antigenic Free PS the method is ELISA but are based on two main principles: use of a monoclonal antibody that recognizes only the free form of PS or utilization of the natural ligand C4BPb+ as “catcher”. Both are comparable and are also widely available on latex beads, which help automation, and the LIA

are most reliable since it overcomes the high CV of ELISA especially in low PS cases due to fall out of protein during prolonged incubation between steps of ELISA.. Activated Protein C Resistance(APCR) APC resistance is defined as an impaired plasma anticoagulant response to APC added in vitro. APC resistance co-segregated with thrombosis in families with familial venous thromboembolism (Dahlback et al, 1993). These cases have the same point mutation in the gene for clotting factor V (1691G-A), the

factor V Leiden mutation (Bertina et al, 1994). The factor V Leiden is the most common cause of inherited APC resistance, other changes in haemostasis cause acquired APC resistance, e.g. increased plasma levels of factor VIII or the presence of antiphospholipid antibodies. APC resistance tests: The most commonly used test system is the activated partial thromboplastin time (APTT). Samples are tested with and without added APC and the 140

resultant clotting times are expressed as a ratio (Dahlback et al, 1993; De Ronde & Bertina, 1994) ± the so-called APC sensitivity ratio (APC:SR). When testing for APC resistance it is important to avoid platelet contamination and activation. Another test is the APTT-based methods in which test plasma is prediluted with FV-deficient plasma. This modification is highly (close to 100%) sensitive and specific for FV Leiden in both healthy controls and patients with suspected acute

venous thromboembolism. However there is evidence that APCR determined with the original unmodified test correlates with venous thrombosis risk, irrespective of whether or not factor V leiden is present1,7. Factor V Leiden mutation: Detection of the factor V Leiden mutation relies on amplification of the nucleotide region close to the exon- intron boundary in exon 5 of the factor V gene from either genomic DNA or from mRNA followed by a mutation detection step.

Prevalence of the factor V Leiden mutation and risk of thrombosis: In Caucasian populations, factor V Leiden is much more common than any of the other genetic thrombophilias having a reported prevalence of between 2% and 15% (Rees et al, 1995). Prothrombin G20210A mutation: The G to A transition at nucleotide 20210 in the 3’-untransalated region of the prothrombin gene is associated with elevated plasma levels of FII and increased risk for

VT. In the absence of a specific phenotypic test, DNA based procedures are required. Elevated FVIII:C : Role of elevated FVIII:C in VTE have been suggested in literature, the levels of FVIII are persistent, independent of the acute phase reaction and represents as a constitutional risk factor for VTE6. Subjects with plasma FVIII above 150IU/dl had a 4.8 fold higher risk of DVT than those with plasma levels of 100IU/dl.Childrens were six times as likely to have poor outcome when FVIII levels exceeded

cut off value at diagnosis,elevation of FVIII and D dimer at diagnosis was 91% specific and had a positive likelihood ratio of 6.1 for a poor outcome9. LA testing 11: (A) Blood collection 1. Blood collection before the start of any anticoagulant drug or a sufficient period after its discontinuation 2. Fresh venous blood in 0.109 M sodium citrate 9:1 3. Double centrifugation 4. Quickly frozen plasma is required if LA detection is postponed 5. Frozen plasma must be thawed at 37 _C (B) Choice of the test

1. Two tests based on different principles 2. dRVVT should be the first test considered 3. The second test should be a sensitive aPTT (low phospholipids and silica as activator) 4. LA should be considered as positive if one of the two tests gives a positive result 5. For interpretation see Below 141

1. PNP for mixing studies should ideally be prepared in house. Adequate commercial lyophilized or frozen PNP can alternatively be used 2. A 1:1 proportion of patient : PNP shall be used, without preincubation within 30 min. 3. LA can not be conclusively determined if the TT of the test plasma is significantly prolonged 4. For interpretation see Below (D) Confirmatory test 1. Confirmatory test(s) must be performed by increasing the concentration of PL of the screening test(s)

2. Bilayer or hexagonal (II) phase PL should be used to increase the concentration of PL. 3. For interpretation see Below (E) Expression of results 1. Results should be expressed as ratio of patient-to-PNP for all procedures (screening, mixing and confirm) (F) Transmission of results 1. A report with an explanation of the results should be given CUT-OFFs for Interpretation How should this be determined 1. Perform testing on plasmas from healthy donors

2. Take the cut-off as the value above the 99th percentile of the distribution Interpretation 1. Results of screening tests are potentially suggestive of LA when their clotting times are longer than the local cut-off value DDimer: The potential use of D dimer measurements for the diagnosis of DVT is essentially due to its high sensitivity and negative predictive value and this has became so evident after the development of

new commercial assay using a cut-off of 500 mg/mL. However the specificity has been shown to be good since D dimer levels for DVT was much higher in symptomatic than in asymptomatic patients. Repeated D dimer testing especially in the first 3 months after VKA withdrawal for a first episode of unprovoked VTE could identify a subgroup of patients with low risk of recurrence10. A positive D- dimer here was the best predictor of re-thrombosis than any of the risk factors identified. A

continuingly positive D-Dimer after therapy whether on it or after stopping it should prompt serach for any occult malignancy. Regulations for testing: 143

Testing at the time of acute venous thrombosis is not indicated as the utility and implications of testing need to be considered and the patient needs to be counselled before testing. As treatment of acute venous thrombosis is not influenced by test results, testing can be performed later if indicated2. • The prothrombin time (PT) should be measured to detect the effect of oral vitamin K dependent Anticoaqgulants, which will cause a reduction in protein C and S levels.

• Functional assays should be used to determine antithrombin and protein C levels. • Chromogenic assays of protein C activity are less subject to interference than clotting assays and are preferable. • Immunoreactive assays of free protein S antigen are preferable to functional assays. If a protein S activity assay is used in the initial screen, low results should be further investigated with an immunoreactive assay of free protein S.

• If an APC (Activated protein C) resistance assay is performed to detect the F5G1691A , An APC resistance assay is unnecessary if a direct genetic test for F5G1691A is used initially. • Repeat testing for identification of deficiency of antithrombin, protein C and protein S is indicated and a low level should be confirmed on one or more separate samples. Deficiency should not be diagnosed on a single abnormal result.

• Rigorous internal quality assurance and satisfactory participation in accredited external quality assessment schemes are mandatory. • Thrombophilia testing must be supervised by experienced laboratory staff and the clinical significance of the results must be interpreted by an experienced clinician who is aware of all relevant factors that may influence individual test results in each case. References: 1. Guideline,Investigation and Management of Heritable Thrombophilia, Br J Haematol 2001,114,512-528.

2. T.Baglin, Elaine Gray, Mike Greaves et al., Clinical guidelines for testing for heritable thrombophilia. Br J Haematol, 2010,149,209-220. 3. Leslie Raffini , Thrombophilia in Children: Who to Test, How, When, and Why? Hematology 2008,228 – 235. 4. T.Baglin, Management of Thrombophilia: Who to Screen?, Pathophysiol Haemost Thromb 2003/2004:33:401-404. 5. RM.Bertina ,Elevated clotting factor levels and Venous Thrombosis. Pathophysiol Haemost Thromb 2003/2004:33:399-400.

6. O Donnell, Mumford et al., Elevation of FVIII:C in venous thromboembolism is persistent and independent of the acute phase response. Thromb Haemost 2000 Jan ;83(1):10-3. 144

7. Legnani C , Palareti G, Biagi R, Bertina RM, Activated protein C resisitance : a comparison between two clotting assays and their relationship to the presence of the factor V Leiden mutation. Br J Haematol 1996 Jun;93(3):694 – 9. 8. Francesco Dati, Gerd Hafner, Hide Erbes et al., ProC Global : the first functional screening assay for the complete protein C pathway. Clinical Chemistry(1997) 43:9 1719-1723. 9. Neil A. Goldenberg, Knapp – Clevenger et al., Elevated Plasma FVIII and D – Dimer Levels as

Predictors of Poor Outcomes of Thrombosis in children. N Ebgl J Med 2004;351:1081-8. 10. Benilde Cosmi , Cristina Legnani,Alberto Tosetto, et al., Usefulness of repeated D – dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study. Blood.2010;115:481 – 488. 11. Pengo V, Tripodi A , Reber G et al. Update of the guidelines for detection of Lupus anticoagulant. J Thromb Haemost 2009; 7: 1737–1740 145

Introduction: The hemostatic system consists of platelets, coagulation factors, and the endothelial cells lining the blood vessels. The platelets arise from the fragmentation of the cytoplasm megakaryocytes in the bone marrow and circulate in blood as disc-shaped anucleate particles. Thrombocytopenia may be defined as a subnormal number of platelets in the circulating blood. ( which occurs when platelet count is less than 100,000/cumm) and is the most common cause of serious

bleeding encountered clinically. (Note: The normal platelet count in an adult is 1.5 to 4 lakhs/cumm) Pathophysiology: Thrombocytopenia can be further divided into constitutional, increased destruction or decreased production.. • Constitutional disorders of platelets - Mediteranean Macrothrombocytopenia, Bernard soulier syndrome. • Causes of thrombocytopenia related to increased destruction include (1) immune thrombocytopenias (eg, autoimmune, alloimmune, drug-induced) and (2) increased

consumption (eg, DIC, TTP). • Causes of thrombocytopenia related to decreased production include bone marrow depression. Production defects result from those diseases that cause , such as aplastic anemia, infiltration by leukemia or another malignancy, fibrosis or bone marrow failure or granulomatous disorders, or tuberculosis Presentation: Thrombocytopenias from Peripheral Destruction: Immune thrombocytopenic purpura

Immune thrombocytopenia(ITP) is one of the most common autoimmune disorders. It occurs in 2 distinct clinical types, an acute self-limiting form observed almost exclusively in children (5 cases per 100,000 persons), and a chronic form, observed mostly in adults (3-5 cases per 100,000 persons) and rarely in children. ITP is caused by autoantibodies to platelets. ITP occurs commonly in otherwise healthy individuals Acute ITP

Acute ITP is a disease that occurs exclusively in children. It affects both sexes equally and has a peak incidence in children aged 3-5 years. Most patients have a history of an antecedent acute viral 146

The onset is sudden, with symptoms and signs depending on the platelet count. Bleeding is usually mild, unless the platelet count drops below 20,000/µL. With platelet counts from 20,000/µL to 50,000/µL, petechiae and ecchymoses are observed following mild trauma. With platelet counts less than 10,000/µL, generalized petechiae, ecchymoses, and mucosal bleeding occur. With platelet counts less than 2000/µL, widespread ecchymoses, hemorrhagic bullae, and retinal hemorrhage occur.

Physical examination reveals only the presence of petechiae and ecchymoses. The presence of lymphadenopathy or splenomegaly suggests other secondary causes of thrombocytopenia rather than ITP. The peripheral smear shows a decreased number of platelets. Often, the smear shows large young granular platelets, which is a reflection of increased thrombopoietin-induced stimulation of the bone marrow. These platelets reflect the increased megakaryocytic mass in the marrow.

At times, the smear may show eosinophilia and lymphocytosis, possibly reflecting hypersensitivity to the inciting viral antigens. This condition is typically observed in adults aged 20-40 years. It has an insidious onset, and a history of an antecedent infection need not be present. Unlike childhood ITP, chronic ITP is more common in females than in males. As in childhood ITP, the bleeding manifestations depend on the platelet count.

The diagnosis of ITP is established by the exclusion of other causes of thrombocytopenia. The peripheral blood film should be examined to rule out (fragments) or spurious thrombocytopenia resulting from clumping. Bone marrow examination, which is not always necessary, shows increased megakaryocytes. Drug-induced thrombocytopenia Drugs can induce thrombocytopenia by a number of mechanisms. Drug-induced thrombocytopenia

results from the immunologic destruction of platelets. Drugs can induce antibodies to platelets, either acting as a hapten or as an innocent bystander. Also, drugs such as gold salts and interferon can induce an ITP-like disorder. Common drugs associated with thrombocytopenia include quinidine, amiodarone, gold, captopril, sulfonamides, glibenclamide, carbamazepine, ibuprofen, cimetidine, tamoxifen, ranitidine, phenytoin, vancomycin, and piperacillin.

The diagnosis of drug-induced thrombocytopenia is often empirical. A temporal relationship must be present between the administration of the drug and the development of thrombocytopenia, with no other explanations for the thrombocytopenia. Recurrent thrombocytopenia following reexposure to the drug confirms the drug as the cause of thrombocytopenia. Identifying the drug that is causing severe thrombocytopenia in an acutely ill patient who is taking multiple drugs is often challenging.

Heparin causes a unique situation among drug-induced thrombocytopenias in that the antibodies also activate platelets and induce a hypercoagulable state called HITTS. 148

Thrombotic thrombocytopenic purpura TTP is a rare but serious disorder that was initially described as a pentad of thrombocytopenia (with purpura), red blood cell fragmentation, renal failure, neurologic dysfunction, and fever. Relatively recent evidence indicates that this disorder results from the abnormal presence of unusually large multimers of von Willebrand protein. These ultralarge precursors, normally synthesized in the

endothelial cells, are processed by a plasma enzyme to normal-sized multimers. This enzyme is now identified as ADAMTS13, a metalloproteinase synthesized in the liver. TTP is often associated with an episode of flulike illness 2-3 weeks before presentation. Most patients with TTP do not have the classic pentad. The most common presentation is petechiae and neurologic symptoms. Hemolytic uremic syndrome Patients with hemolytic uremic syndrome have vascular lesions indistinguishable from those observed

in patients with TTP, but the renal vasculature endures the most lesions, with minimal neurologic dysfunction. This is a catastrophic illness that predominantly affects children aged 4-12 months, sometimes affects older children, and rarely affects adults. The causative organism is Shigella -like toxins (secreted by Escherichia coli serotype 0157:H7 or Shigella dysenteriae serotype I).. Diarrhea and abdominal cramps are very prominent symptoms. 149

Post transfusion purpura typically occurs 10 days following a transfusion. This syndrome can be induced by a small amount of platelets contaminating a red blood cell transfusion or, occasionally, following fresh frozen plasma (FFP) transfusion. The thrombocytopenia responds to intravenous immunoglobulin (IVIG). Other platelet alloantigens are occasionally implicated in posttransfusion purpura. This alloantibody destroys the transfused platelets and the patient's own platelets, leading to a

severe form of thrombocytopenia that lasts for several weeks and, sometimes, several months. Neonatal alloimmune thrombocytopenia It is the most common cause of severe neonatal thrombocytopenia. Maternal antibodies against the fetal platelet antigens, inherited from the father but absent in the mother, cross the placenta and induce severe thrombocytopenia. Typically, the diagnosis of neonatal alloimmune thrombocytopenia is considered when bleeding

or severe thrombocytopenia occurs in a baby after an otherwise uncomplicated pregnancy. The affected infant may have intracranial hemorrhage, and the disorder is associated with a relatively high mortality rate. The platelet count should be checked immediately after delivery and 24 hours later as it continues to fall. Disorders of platelet function Functional disorders of platelets assocaited with low platelet count are relatively rare, and most

of these disorders are mild and may not be recognized early in life. von Willebrand disease In the type IIB variant, the von Willebrand protein has heightened interaction with platelets, even in the absence of stimulation causing mild to moderate thrombocytopenia. With numerous aggragtes seen in the peripheral blood. A disorder of platelet GP Ib has also been described. In this condition, increased affinity for von

Willebrand protein in the resting stage leads to the deletion of plasma von Willebrand protein. This disease is called pseudo von Willebrand disease or platelet-type von Willebrand disease. 150

Bernard-Soulier syndrome Bernard - Soulier syndrome results from a deficiency of platelet glycoprotein protein Ib, which mediates the initial interaction of platelets to the subendothelial components via the von Willebrand protein. It is a rare but severe bleeding disorder. The platelet count is low, but, characteristically, the platelets are large, often the size of red blood cells, and may be missed because most automatic counters do not count them as platelets.

Storage pool deficicency: Gray platelet syndrome is due to decreased alpha granules in the paletets.which is most often asymptomatic unless it is associated with mixed storage pool deficieny. The platelet count is mildly decreased with few giant platelets. Workup Lab Studies Initial detection/screen:- Cell counter aid in the diagnosis of platelet disorders: Subnormal platelet count and the abnormal platelet morphology can be easily picked up with

the aid of counters, thereby acts as a screening tool in the diagnosis of thrombocytopenia. Platelet data in cell counters From Platelet histogram Platelet count Fitted curve Mean platetlet volume Wiskot aldrich syndrome the MPV will below. BSS/ macrothrombocytopenia: High MPV and fitted line cannot be drawn. TTP: Platelet histogram appears abnormal with high MPV. However In TTP RBCs morphology too interferes with the platelet histogram as fragmnets RBCs are counte as platelets. So a analysis of

RBC histogram and Platelet histogram is a must in these cases. 151

Gray platelets:Marked anisocytosis in the platelets which is depicted in terms of a high PDW with abbnoraml histogram as the agranular platelets may not be picked by the counter. In all cases of thrombocytopenia, the peripheral blood smear must be reviewed to confirm the thrombocytopenia. This review is crucial. Spurious thrombocytopenia due to platelet clumping or platelets adhering to neutrophils (platelet satellitism) can be seen in the smear.

Examination of the peripheral smears in immune thrombocytopenic purpura often shows large young platelets. These platelets reflect the increased megakaryocytic mass in the marrow. These large young platelets appear uniformly hypergranular( metabolically active) are often seen in persons with ITP . Bernard-Soulier syndrome: Peripheral smear of a patient with Bernard-Soulier syndrome showing giant platelets. These platelets are not counted as platelets in most particle counters. The

fitted curve cannot be drawn and PDW is very high. Examination of the smear is essential to exclude TTP and rare instances of acute leukemia. In TTP, a striking degree of red blood cell fragmentation is seen in addition to thrombocytopenia . Examination of the peripheral smear shows red blood cell fragments, schistocytes, basophilic cells, in addition to thrombocytopenia in thrombotic thrombocytopenic purpura. In gray platelet syndrome the platelets appear gray( due to decreased granules) with anisocytosis

of platelets which is depicted in the platelet histogram( ie fitted line cannot be drawn) Imaging Studies • Imaging studies are not necessary to diagnose uncomplicated ITPs. • Rarely, platelet survival studies may be necessary to document decreased platelet survival before splenectomy in a patient with possible bone marrow hypofunction. Typically, the platelet half-life is decreased from the normal 5-7 days. A normal platelet survival curve is not consistent with increased splenic destruction.

• In a patient who has relapsed following splenectomy, an indium-labeled platelet imaging study is sometimes useful for localizing an accessory spleen. Other Tests - Bone marrow examination is not necessary in most cases of platelet disorders. The isolated presence of large platelets in the peripheral blood, in the absence of any other signs of bone marrow dysfunction, is very suggestive of normal marrow activity - Bone marrow examination is necessary in patients whose condition has an atypical

course, have splenomegaly, or will undergo splenectomy, and in patients over age 60 years, as thrombocytopenia may be the initial manifestation of myelodysplastic syndrome. 152

- Bone marrow examination in patients with ITP shows megakaryocytic hyperplasia. Quantifying the megakaryocytes in the bone marrow is technically difficult. Usually, 2-3 megakaryocytes are present in each spicule in typical marrow. Clusters of immature megakaryocytes are often observed in patients with ITP. Prognosis • ITP is generally a benign disorder. Severe ITP with a platelet count of less than 5000/µL is occasionally associated with fatal hemorrhages in the brain or internal organs. Patients

who are elderly, those whose disease is refractory to treatment, those who have a previous history of hemorrhage, and patients with concomitant bleeding disorders (hemophilia and uremia) are at higher risk for serious life-threatening hemorrhage. • TTP is a very serious disorder. With the introduction of plasma exchange therapy, the prognosis is better but mortality rates remain approximately 20%. TTP should be distinguished from ITP before platelet transfusions, because a worsening of clinical

manifestations occurs in patients with TTP who receive platelet transfusions. • Among congenital bleeding disorders involving decrease in platelets BSS, type II von Willebrand disease a are severe diseases associated with lifelong hemorrhages. Most other platelet disorders are mild bleeding disorders. • Patients who have undergone splenectomy should be warned about the low risk of severe sepsis following splenectomy. These patients should be immunized with pneumococcal vaccine before splenectomy.

Special Concerns: • The major causes of thrombocytopenia in pregnant women are immune thrombocytopenia, incidental thrombocytopenia of pregnancy (gestational thrombocytopenia), and hypertensive disorders of pregnancy. • ITP during pregnancy • Gestational thrombocytopenia • This form of thrombocytopenia is defined as mild thrombocytopenia in an otherwise healthy pregnancy. How this can be distinguished from a mild form of ITP is not clear.

• This disorder does not result in infants developing thrombocytopenia. • Hypertensive disorders of pregnancy • These disorders of pregnancy (ie, eclampsia/ preeclampsia syndrome) are associated with increased platelet turnover, even when the platelet count is normal. Controlling hypertension and delivering the fetus lead to restoration of the platelet count. • Occasionally, thrombocytopenia is associated with hemolysis and elevated liver

enzymes (ie, hemolysis, elevated liver enzymes, and low platelet [HELLP] syndrome). This serious disorder often mimics TTP. 153

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1. SCREENING:........................................................................................................................................................5 2. CONFIRMATION OF DIAGNOSIS AND CLASSIFICATION OF HYPERTENSION..........................................................7 3. PATIENT EDUCATION AND ASSESSMENT...............................................................................................................8

4. MANAGEMENT OF HYPERTENSION: THERAPEUTIC RECOMMENDATIONS.........................................................12 Review and respond to possible causes of poor response to BP medications........................................................18 5. FOLLOW UP, MONITORING AND IMPROVING ADHERENCE TO THERAPY...........................................................29 ANNEXURE 1: PATHWAYS : CLASSIFICATION, ASSESSMENT, MANAGEMENT............................................................31

ANNEXURE 2: LIFE STYLE CHANGES RECOMMENDED FOR PATIENTS DIAGNOSED TO HAVE HYPERTENSION AND FOR THOSE AT RISK OF DEVELOPING HYPERTENSION........................................................................................................38 ANNEXURE 3: FORMULARY..........................................................................................................................................47 Standard Treatment Guidelines-Hypertension Page2

1.INTRODUCTION: Hypertension is the number one health related risk factor in India, with the largest contribution to burden of disease and mortality(3, 4). It contributes to an estimated 1.6 million deaths,due to ischemic heart disease and stroke,out of a total of about 10 million deaths annually in India. Fifty seven percent of deaths related to stroke and 24% of deaths related to coronary heart disease are related to hypertension

(7).Hypertension is one of the commonest non-communicable diseases in India, with an overall prevalence of 29.8% among the adult population, and a higher prevalence in urban areas (33.8% vs. 27.6%) according to recent estimates. Awareness of hypertension in India is low while appropriate treatment and control among those with hypertension is even lower: Hypertension is a chronic, persistent, largely asymptomatic disease. A

majority of the patients with hypertension in India are unaware of their condition. This is because of low levels of awareness and the lack of screening for hypertension in adults-either as a systematic programme or as an opportunistic exercise during visits to healthcare providers. The contexts for the screening, diagnosis, evaluation and management of hypertension in India are different from countries where awareness of hypertension in the general population is high and

screening for hypertension is a routine part of primary care, practitioners are trained in delivering lifestyle interventions and medical management of hypertension, and patients are aware of the need and have the means to adhere to therapy. This is why a standard treatment guideline is being developed for the management of hypertension in the Indian context. The guideline has a primary care focus and a public health approach.

A public health approach to hypertension in India would involve the five components stated below: a. Prevention: Promotion of a five point population wide interventions on weight reduction in the obese, increasing exercise levels in the sedentary, decrease in salt, sugar and fat intake, cessation oftobacco use, moderation of alcohol use. Increased intake of fruits and vegetables in addition to decreased salt intake has the potential to lower blood pressure significantly.

b. Screening: Screening for hypertension in all adults will involve opportunistic screening of people > 18 years of age at every point of contact with health professionals or allied health staff. Since healthcare facilities may not be accessed by all potential hypertensives, the guideline also suggests a targeted screening initiative at the community level aimed at detection of hypertension in high risk population. Screening will involve BP measurement

using a standardized procedure and persons will receive advice and/or referral appropriate to the BP level. c. Diagnosis: Diagnosis and evaluation of hypertension will be made at the PHC level which will also serve as the point of follow up for patients diagnosed at higher level facilities. Diagnosis and evaluation of hypertension can also occur at all other levels of care. Assessment will focus on target organ damage related to hypertension, co morbidities like diabetes, and correctable risk factors.

d. Management including lifestyle changes: Ensure availability of representative drugs from a core list of 5 groups of medications – thiazide diuretics, long acting calcium channel blockers, Standard Treatment Guidelines-Hypertension Page3

low cost ACE inhibitors, (low cost Angiotensin Receptor blockers in case patients develop side effects to ACE inhibitors) , and beta-blockers. Lifestyle changes are a vital component of management of hypertension, and may be sufficient for control of mild hypertension. e. Follow-up, MonitoringAdherence: Enable a hypertension registry accessible to all healthcare providers in the local public health system, promote adherence to therapy by simplified regimens, andmonitoring by allied health staff.

Figure1:Clinical pathwayforhypertension care 1. SCREEN FOR HYPERTENSION Screen For HT(UsingOpportunistic & Targetedapproaches) By Physicians AtAll Levels Of Care and byNon-Physicians At Community LevelUsing A Standardized BPMeasurementProcedure 2.CONFIRM DIAGNOSIS OF HYPERTENSION AND CLASSIFY HYPERTENSION Diagnosis to be confirmed by PHYSICIANS, basedon at least 2measurements taken in the clinic or by a healthcare provider on at least 2 visits, which are at least 1-4 weeks apart, (except in the case of

hypertensive urgencies and hypertensive emergencies) 3.EDUCATE PATIENTS. ASSESS LIFESTYLE FACTORS, TARGETORGAN DAMAGE, ASSOCIATED CLINICAL CONDITIONS. Establish rapport with patients.Educate themabout asymptomatic natureof disease which has risk of serious complications which can be prevented by achieving and maintaining target BP by regular therapy. Emphasizeimportance of lifestyle modifications to lower BP and cardiovascular risk.

Assess lifestyle related and other cardiovascular risk factors, target organ damage, associated clinical conditions by using a combination of history, examination and investigations. Assess overall cardiovascular risk.Suspect secondary hypertension in appropriate setting. 4.MANAGE HYPERTENSION ( LIFESTYLE MODIFICATIONS ± DRUG THERAPY)  UseLifestyle Modificationsinallpatients.Initiate Drug therapy with firstline antihypertensives

(calcium channel blockers, ACE Inhibitors (ARBsif indicated), thiazide /thiazide like diuretics in Grade 2 /3 HT and in Grade 1 HTwhen indicated.Titrate drug therapy using optimal doses of one or more classes of drugs to achieve target BPs.  Managecomorbiditieslike diabetes andassociated clinical conditions(heart disease, CVD, CKD)  Manage hypertension appropriately inspecial groups(elderly) andspecial situations(urgencies and emergencies) 

Use othermeasures to reduce cardiovascular risk if indicated(statins, aspirin) 5.FOLLOW UP AND MAINTAIN ADHERENCE. Preferablyfollow upat Primary Care level with a team based approach.  Review BP and advice on adherence.Reassess target organ damage, risk factors periodically.  Review and advice on adherence to life style modification.  Refer in case of hypertension uncontrolled on 3 drugs, suspected secondary hypertension,and in hypertensive emergencies. Standard Treatment Guidelines-Hypertension Page4

KEY RECOMMENDATIONS: 1. SCREENING: 1.1 An ongoing initiative to increase awareness of hypertension as a widely prevalent but asymptomatic disease associated with many adverse outcomes like heart attacks, strokes, heart failure, kidney failure. Early diagnosis and effective control of BP can save people from much morbidity, mortality and disability. 1.2 All adults above the age of 18 years should undergo opportunistic screening by

healthcare providers at all points of care in India, either during the course of their visits to the health facilities, or separately as a screening examination if requested by the person. Targeted screening at the community level of high-risk groups like adults above 50 years of age, persons with diabetes, obese, smokers, those with existing cardiovascular diseases, family history of hypertension, can be undertaken by trained

non-physician staff. a physician or trained non physician staff, using an automated BP instrument or any other validated device, and following a standardized BP measurement procedure,mentioned in table 1 below. TABLE 1-STANDARDIZED BP MEASUREMENT PROCEDURE – STANDARD PROCEDURE FOR BP MEASUREMENT 1.Patient Patient should be in a relaxed state for 5 minutes before measurement of preparation and BP. Patient should not have had caffeine in the past 1 hour or smoked in

position the past 30 minutes. Patient should be seated comfortably with back supported, with arm at heart level, and legs in an uncrossed position. 2.Choice of BP Mercury sphygmomanometer or any other device (including electronic device digital oscillometric devices) which has been validated using a standard protocol, and has been calibrated regularly. 3.Cuff size and The cuff size should be appropriate for the patient. Length of bladder

placement should be 80% of arm circumference and width should be 40% of arm circumference, and a large adult cuff should be used for an obese patient. Patient should not wear any constrictive clothing. Place the midline of the cuff over the pulsations of the brachial artery, at a distance of 2-3 cm above the cubital fossa. 4. Procedure to Palpate the radial pulse and then inflate the cuff to 30 mm beyond the measure systolic disappearance of the radial pulse. Deflate the cuff at 2-3 mm per second

and diastolic and record by auscultation with the stethoscope over the brachial artery, blood pressure( the first and the last sounds as the systolic and diastolic blood pressure applicable in respectively. case of In oscillometric devices, follow the instructions of the manufacturer, the auscultation systolic and diastolic BP will be displayed automatically. based BP If the patient is diabetic or above 65 years measure the BP in supine

measurement) position, and 2 minutes after assuming the standing position to check for postural hypotension. 5.No. of At least 2 readings should be taken at an interval of 1 minute. If the measurements readings differ by more than 5 mm Hg takes a third reading. The lower of and recording the readings should be taken as the representative SBP and DBP. the result Standard Treatment Guidelines-Hypertension Page5

1.3 The diagnosis of hypertension should be done by a physician or trained non physician staff, using an automated BP instrument or any other validated device, and following a standardized BP measurement procedure. 1.4.Thesourcesof error during measurement of blood pressure are given in the table below. TABLE 2 : SOURCES OF ERROR DURING MEASUREMENT OF BLOOD PRESSURE. Source of measurement error(2) Comment(2) Back is not supported Diastolic BP mayincrease by 6 mm

Arm is not at level of heart Dangling the hand unsupported increases BP by 10-12 mm Hg. Legs are crossed Systolic BP increases by 2-8 mm Hg Caffeine in the last 1 hour Transient increase in BP Smoking in the previous30 mins. s Transient increase in BP Cuff size not appropriate May overestimate systolic BP by 10-50 mm in obese persons in whom a smaller cuff has been used Rapid deflation greater than 3 May underestimate systolic BP and overestimate diastolic BP mm/sec

Patient’s anxiety/ conditional This may result in elevated BP readings, which may be normal response to an unusual situation in when recorded by a nurse or when recorded at home. This the presence of a physician “whitecoat hypertension” or “isolated office hypertension” amounted to 32% of hypertensive subjects in population based surveys, and is more prevalent in those with Grade 1 HT. If the facility is available, then ambulatory or home based BP monitoring, can be used to differentiate whitecoat

hypertension from true hypertension. 1.5Patients who are screened for hypertension should be advised lifestyle measures including restriction of salt intake , advice on diet and exercise in case the person is obese, stopping use of tobacco and moderating consumption of alcohol to reduce their blood pressure and to reduce their overall risk of cardiovascular complications. Suggested response toBP readings: TABLE 3: SUGGESTED RESPONSE TO INITIAL BP READINGS

Initial BP reading on screening Advice and Recommendations for Follow up SBP mm Hg DBP mm Hg <<130 <<85 Advise lifestyle modifications esp. smoking, weight reduction if possible : Recheck in 2 years Standard Treatment Guidelines-Hypertension Page6

130-139 85-89 Advise lifestyle modifications: Recheck in 1 year 140-159 90-99 Recheck BP within 1-2 weeks. Advise lifestyle modifications. Refer to nearest health facility within 1 month for diagnosis, assessment. 160-179 100-109 Recheck BP within 1 week. Advise lifestyle modifications. Refer to nearest health facility for confirmation of diagnosis and initiation of treatment. >180 >110 Check for any symptoms/signs of any acute target organ damage (assesssymptoms and signs referred to in the

mnemonic ‘ABCDEFG’1mentioned in pathwayon assessment and managementof hypertensive crisis). In cases of acute target organ damage, treat as hypertensive emergency. Refer to PHC/CHC for evaluation and treatment immediately after confirming elevated readings in this range. Initiate therapy before referral, if seen at PHC. 2.CONFIRMATION OF DIAGNOSIS AND CLASSIFICATION OF HYPERTENSION 2.1Diagnosis of hypertension should be made at primary health centres and facilities above that

level using validated and calibrated BP measurement devices and following thestandardised BP measurement procedure. 2.2Diagnosis of hypertension should be based on at least 2 measurements taken in the clinic or by a healthcare provider on at least 2 visits, which are at least 1-4 weeks apart, except in the case of hypertensive urgencies and hypertensive emergencies, where hypertension is diagnosed during the first visit itself.Ambulatory blood pressure monitoring and home based

BP monitoring is not feasible for diagnosis for most patients with hypertension in Indiaand is therefore not generally recommended. They may be considered where indicated e.g. in patients with suspected white coat hypertension, when the expertise and the facility is available. 2.3Hypertension should be diagnosed when BP is persistently above a systolic of 140 mm and/or diastolic of 90 mm. 2.4.Patients with hypertension shouldbe classified in themannergiven in the table below:

1Abbreviation explained-A: Altered consciousness B: Breathlessness C: Chest pain(Ischemic) D: Deficit (weakness of limbs) or Decreased Urine output E: Edema F: Fundus if feasible which is showing hemorrhages, exudates,papilledema G: Generalised seizures Standard Treatment Guidelines-Hypertension Page7

TABLE 4: CLASSIFICATION OF HYPERTENSION Category SBP(mm Hg) DBP(mm Hg) Optimal <120 and<80 Normal 120–129 and/or 80–84 High Normal 130–139 and/or 85–89 Grade 1 Hypertension 140–159 and/or 90–99 Grade 2 Hypertension 160–179 and/or 100–109 Grade 3 Hypertension ≥180 and/or ≥110 Isolated Systolic ≥140 and < 90 Hypertension Hypertensive urgency >180 and/or >110 Severe asymptomatic hypertension with no evidence of acute target organ damage Hypertensive emergency >180 and /or >110-120

Severe hypertension associated with cardiovascular (e.g. leftventricular failure, cerebral (e.g. hypertensive encephalopathy, stroke),renal (acute renal failure), Grade III-IV retinopathy 3. PATIENT EDUCATION AND ASSESSMENT Standard Treatment Guidelines-Hypertension Page8

Nature of disease- asymptomatic but Need to adopt likely to produce Lifestyle measures serious to reduce BP and complications if cardiovascular risk uncontrolled Lifelong Therapy- Knowledge of (except in some targets of BP cases with Grade 1 control and need HT) is useful in for regular prevention of monitoring adverse events Figure2:Patient Education matrix 3.1Patient education will consist of awareness on: a. Nature of disease: Hypertension is an asymptomatic condition which can lead to disabling and

life-threatening complications like stroke, heart attack and renal failure b. Therapy: Emphasise need for long-term therapy with regularity of drug intake to prevent damage to target organs and prevent adverse events. c. BP control:Educate about the targets for BP control, and encourage patients to monitor efficacy of therapy through regular check-ups which can include home based monitoring of BP. d. Lifestyle measures: It is important to highlight the important role of lifestyle measures in

reducing hypertension and reducing risks of cardiovascular disease. (see annexure for details of lifestyle modifications) 3.2Assessment of patients with hypertension: 3.2.1 Assessment of a patient with hypertension has the following 5 components a. Assessing the lifestyle related and other cardiovascular risk factors in patients with hypertension and the capability each patient’s capacity or willingness to change these factors. Assess lifestylefactors and other cardiovascular risk factors

History: Smoking history Dietary consumption of salt, saturated fats Exercise pattern Alcohol consumption Family history of premature coronary artery disease Examination: Weight &Height and calculation of BMI, abdominal circumference Laboratory evaluation: Blood glucose, Lipids Standard Treatment Guidelines-Hypertension Page9

b. Assessing the target organ damage related to hypertension viz. heart failure, left ventricular hypertrophy, proteinuria, retinopathy. Assess target organ damage: Heart (heart failure), Kidney, and Retina History Breathlessness on effort Swelling on feet Examination Raised Jugular venous pressure, edema, gallops on auscultation (heart failure) Funduscopic evidence of hypertensive retinopathy-hemorrhages, exudates, papilledema Laboratory evaluation ECG: SV1 +RV6 > 3.5 Mv (LVH)

Urine protein, Serum creatinine c. Assessing the presence of associated clinical conditions like diabetes, kidney disease or symptomatic cardiovascular disease with angina, myocardial infarction, cerebrovascular disease (stroke, TIA) or peripheral arterial disease. Assess associated clinical conditions: Myocardial infarction, Stroke, Chronic Kidney disease History: Episode of chest pain at rest (Myocardialinfarction) in past Weakness on one half of body (Stroke) in the past

Examination: Significant pallorin the presence of HT–chronic kidney disease Laboratory: S. Creatinine ECG: Ischemia, infarction, conduction disturbances, arrhythmias (atrial fibrillation) d. Assessing the clues to asecondary cause of hypertension-see table below: Assess clues to presence of secondary hypertension History: Abrupt onset of hypertension below the age of 30 years and above the ageof 60 years (renovascular hypertension) Paroxysms of palpitations, pain(headache), perspiration(

pheochromocytoma)(1) Snoring at night, breathing pauses reported by partner, daytime sleepiness (sleep apnoea) Drug intake: NSAIDs, Steroids, Oral contraceptive pill Examination: mooning of facies, striae: Cushing syndrome Unequal pulses: diminished/absent radial pulses-Takayasu’s arteritis Diminished & delayedfemoral pulsein lower limb: Coarctation of aorta. Tachycardia and postural hypotension (pheochromocytoma) Bruit over renal arteries: renal artery stenosis (renovascular hypertension)

Laboratory investigations: Abnormal urinalysis (proteinuria, haematuria), elevated creatinine.Abnormal kidneys on USG-renal parenchymal disease, renal artery Doppler for renal artery stenosis. Standard Treatment Guidelines-Hypertension Page10

e. Assessment of overall cardiovascular risk of a patient. As seen in the table below the overall cardiovascular risk increases with the grade of HT, number of risk factors, presence of organ damage, diabetes, symptomatic cardiovascular disease or chronic kidney disease. Grade 1 HT Grade 2 HT Grade 3 HT No risk factor Low risk Moderate risk# High§risk 1-2 risk factor* Moderate Moderate to High risk risk high >3 riskfactor* Moderate High High risk to High risk

Target Organ damage, High risk High risk Very high risk DM, CKD stage 3 Symptomatic CVD( Very high Very high risk Very high risk stroke, coronary artery risk disease), diabetes with organ damage, CKD>stage 4 # 20-30% risk of CV event over 10 years § >30% risk of CV event over 10 years*Risk factors(apart from hypertension) : age ( > 55 years in men, 65 years in women), male gender, diabetes mellitus,smoking,obesity(including abdominal obesity), dyslipidemia(High LDL, Low

HDL,High TG), impaired fasting glucose(FPG 100-125 mg/dl), family history of premature coronary artery disease. 3.2.2Pragmatic approach to assessment of hypertensives in India: In the context of the Indian public health system, we suggest an approach which balances the needs of patients and the resources available at various levels and outline a pragmatic approaches to assessment –essentialassessment in all patients with Grade 1 HT,desirableassessmentin those with grade 2 HT or those with diabetes and/or

proteinuria, andcomprehensive assessmentin those with Grade 3 HT, or those with diabetic complications, CKD, heart failure, or with a suspicion of secondary hypertension are suggested. This approach also takes into account the fact that some investigations like ECG for left ventricular hypertrophy have poor sensitivity, while there is insufficient evidence that a routine ophthalmoscopic examination is required for all patients with hypertension. On the other hand, patients with diabetes,

symptomatic cardiovascular disease, smokers, obese, and those with proteinuria, which are all associated with greater cardiovascular risk can be identified even at the level of a primary health centre using a combination of clinical features (history and clinical examination) and investigations. Assessment of lipids is desirable in patients with hypertension, with a higher yield in those who are diabetics, obese

and have cardiovascular disease. Patients can be referred to the community health centre for evaluation of lipids, but the need is not urgent. Essential assessment Should be done in all patients attending primary care facilities,also in patients with Grade 1 hypertension History and physical examination for risk factors (smoking, obesity, diet and exercise patterns, family history of premature CVD), clinical cardiovascular disease (angina, heart failure, stroke)

Fasting capillary blood(FCG) or fasting plasma glucose (FPG).FCG > 126 mg/dl or FPG >126 mg/dl is abnormal and suggestive of diabetes. Abnormal fasting capillary glucose needs to be checked against a fasting plasma glucose obtained in the laboratory Standard Treatment Guidelines-Hypertension Page11

Urinalysis for proteinuria: Presence of proteinuria doubles the risk of morbidity and mortality for a certain BP and is an independent predictor of all-cause mortality in hypertension. Desirable assessment Desirable in patients with Grade 2 hypertension and above, with family history of premature cardiovascular disease, in patients with diabetes and in patients with proteinuria Essential assessment plus Serumcreatinine: Abnormality more often seen in patients with severe hypertension, diabetic nephropathy,

chronic kidney disease or occasionally in patients on ACEinhibitors. Lipids: more often abnormal in patients who are obese, in diabetics, in patients with cardiovascular disease. Commonest abnormality in India is low HDL, increased triglycerides ECG: Low sensitivity for detection of LVH. LVH if present howeverindicates increased cardiovascular risk. LVH with strain strong predictor of heart failure. May yield evidence of ischemic heart disease, conduction system disturbance or arrhythmias.

Comprehensiveevaluation: In patients with Grade 3 hypertension,patients with CKD, heart failure Desirable evaluation plus History and physical examination: exclude signs of secondary hypertension Serum sodium and potassium: hypokalemia clue to secondary hypertension (renovascular, primary hyperaldosteronism) Ultrasound kidney: for evidence of CKD Echocardiography: in case of suspected heart failure (on basis of history, physical examination)

3.3 Screening for diabetes (which is to be available at all health facilities under the free diagnostics initiative) is an integral part of evaluation of hypertension because of the common association of hypertension and diabetes. The care of diabetes should be integrated with management of hypertension. 3.4 All patients should be asked about tobacco use and advised to stop it. 4.MANAGEMENT OF HYPERTENSION: THERAPEUTIC RECOMMENDATIONS

4.1. Overall aim: The overall aim of the management of hypertension is not only reduction of BP to target levels but also to lower the cardiovascular risk of the patient. Management of hypertension should be tailored to the individual and his or her circumstances. Standard Treatment Guidelines-Hypertension Page12

4.2.Lifestyle modifications 4.2.1 Lifestyle measures including adopting a heart-healthy diet with reduced salt and saturated fat intake, stopping use of tobacco products , regular exercise and reduction of body weight in those who are obese, are part of management of all patients with hypertension. 4.2.1.1. These lifestyle measures may be sufficient for treatment of Grade 1 hypertension, may reduce the doses required for control of hypertension, and

will also reduce the cardiovascular risk in all grades of hypertension. 4.2.1.2A trial of lifestyle measures should be monitored for 1-3 months following diagnosis of Grade 1 hypertension. The lower range of durations should be considered in the presence of other risk factors like age, obesity, lipid levels, and smoking status. 4.3 Initiation of drug therapy 4.3.1Drug therapy is indicated in patients with Grade 1 hypertension with • Any sign of target organ damage (LVH on ECG, proteinuria on urinalysis,

hypertensive retinopathy on fundus examination). • Any evidence of coronary artery disease, congestive heart failure, cerebrovascular disease, peripheral arterial disease (clinical cardiovascular disease) • Diabetes • Presence of chronic kidney disease • Patients with 3 or more risk factors2 (including age, gender, smoking, obesity, dyslipidemia, diabetes, impaired fasting glucose, family history of premature coronary artery disease).

4.3.2. Drug therapy in patients with grade I hypertension uncomplicated by any organ damage, without coexisting diabetes mellitus, clinical cardiovascular disease, or multiple cardiovascular risk factors should be initiated after a trial of 1-3 months of lifestyle modifications. 4.3.3. Drug therapy is indicated in all patients with Grade 2 and Grade 3 hypertension and should be combined with lifestyle measures.

2Age > 55 in men, >65 in women; Male gender; smoking; diabetes; obesity including abdominal obesity; impaired fasting glucose ( FBS 100-125 mg/dl); dyslipidaemia (high LDL, high TG, low HDL); family history of premature coronary artery disease Standard Treatment Guidelines-Hypertension Page13

4.3.3.2.Drug therapy is initiated in patients with Grade 2 hypertension on confirmation of the diagnosis on repeat BP measurements in the visits subsequent to the initial visit when Grade 2 HT was first detected. 4.3.3.3.Drug therapy in patients with Grade 3 hypertension is initiated after repeat measurements in the initial visit confirm the severe elevation of the blood pressure. 4.4. Treatment goals for management of hypertension:

4.4.1 The current target for control of BP for patients under 80 years of age should be less than systolic blood pressure less than140 mmand diastolic blood pressure less than 90 mm. 4.4.2 The current target for control of BP for patients 80 years or older should be less than 150 mm systolic and less than 90 mm diastolic. 4.4.3 A recent trial (SPRINT trial) in non-diabetic population at high cardiovascular risk has shown a reduction in cardiovascular mortality in patients in the intensive treatment group

where the goal BP was less than 120 mm systolic and 80 mm diastolic. However this was accompanied by more than 2 fold increased frequency of serious adverse events and increase in serum creatinine. Based on the currently available evidence we do not recommend this lower target generally for physicians and patients in India, except for individual patients and physicians in situations who have agreed upon these targets and where close monitoring for adverse effects is feasible.

4.4.4 Current evidence based on trials of BP targets of <130 mm and < 85 mm diastolic in patients with diabetes have failed to show significant overall benefit on cardiovascular disease outcomes, and have been accompanied by increased frequency of serious adverse events. Therefore we currently recommend the standard BP target of <140 mm systolic and <90 mm in patients with diabetes in India. < 80 years: Systolic BP < 140mm Hg Diastolic BP < 90mm Hg TARGET >80 years: Systolic BP < 150mm Hg

Diastolic BP < 90mm Hg Diabetics: Systolic BP < 140mm Hg Diastolic BP <90mmHg Standard Treatment Guidelines-Hypertension Page14

4.5Key recommendation: Classes of antihypertensive drugs & preferred choices 4.5.1 The primary issue in treatment of hypertension is reduction of cardiovascular risk by effective control of blood pressure. Overall the benefits of antihypertensive treatment are due to lowering of blood pressure rather than choice of therapy. Many patients will require more than one drug for control of hypertension. 4.5.2. All classes of drugs- calcium channel blockers, ACE inhibitors/ARBs, diuretics; beta-blockers

have approximately the same efficacy on lowering of blood pressure, and on outcomes, although beta-blockers have been associated with lesser protection against strokes. All combinations of drugs are not however similarly efficacious, and some are preferred. 4.5.3. The different classes of drugs have differing side effect profiles and requirements for monitoring, which may influence their use and prescription in the health system.

4.5.4 In the absence of any associated clinical conditions (noted below) providing a compelling indication for the use of a particular drug , a long acting calcium channel blocker, a low dose thiazide diuretic, or a low cost ACE inhibitor may be used as the initial antihypertensive drug. 4.5.5. The presence of associated clinical conditions (diabetes, clinical cardiovascular disease, chronic kidney disease) in a patient may provide compelling indication for the use of specific classes of drugs.

4.5.5.1. Preferred drugs for treatment of patients with diabetes and hypertension are ACE inhibitors, especially in those with proteinuria. Calcium channel blockers /low dose diuretics may be used in addition if required to achieve control. 4.5.5.2Preferred drugs for patients with heart failure and hypertension are ACE inhibitors, diuretics (including loop diuretics) and beta-blockers. 4.5.5.3Preferred drugs for patients with coronary artery disease and hypertension are

beta-blockers, ACE Inhibitors or calcium channel blockers. 4.5.6 The specific drugs within these classes recommended on the basis of availability and affordability include amlodipine, (a long acting calcium channel blocker); enalapril or lisinopril, (ACE inhibitor); low dose hydrochlorothiazide, (thiazide) or chlorthalidone (thiazide like diuretic) and if required, losartan, (a low cost angiotensin II receptor blocker).

4.5.7 Angiotensin receptor blockers have a mode of action, efficacy and indications similar to ACE inhibitors, but are currently more expensive than them. They should therefore be used in the place of ACE inhibitors, in case there are side effects with ACE inhibitors like cough, angioedema. Standard Treatment Guidelines-Hypertension Page15

Clinical condition Drug to be preferred as Second drug if needed Third drug if needed to first drugs to achieve BP control achieve BP control Isolated systolic hypertension CCB/Thiazide Diuretic ACE Inhibitor* Thiazide diuretic + ACE ( elderly) Inhibitor*+ CCB Hypertension and diabetes ACE inhibitor* CCB or thiazide diuretic ACE inhibitor* + CCB+ thiazide diuretic Hypertensionand chronic ACE inhibitor*where close CCB or thiazide diuretic ACE inhibitor*

kidney disease(defined as clinical and biochemical (loop diuretic if eGFR is +CCB+ thiazide diuretic albuminuria or an eGFR< 60 monitoring is possible. below 30 ml/min) ml/min/1.73 m2for > 3 Otherwise CCB may be months) preferable Hypertension and previous BB, ACE Inhibitor* CCB or diuretic myocardial infarction Hypertension associated with Thiazide/ loop diuretic+ACE Inhibitor*+BB#+Spironolactone heart failure Hypertension associated with ACE inhibitor* Diuretic or CCB ACE Inhibitor* +CCB+

previous stroke diuretic Table 9: Clinical conditions which may be associated in a patient with hypertension and the drugs to be preferred *Angiotensin receptor blockers (ARBs) may be used for this indication if there is intolerance to ACE inhibitors (cough, angioedema)Abbreviations: ACE inhibitor: angiotensin converting enzyme inhibitor; CCB, calcium channel blocker; BB, beta- blocker.Notes: Examples of representative drugs: ACE inhibitors - Enalapril, Calcium channel blockers-Amlodipine, Thiazide

diuretic- Hydrochlorothiazide, Beta-blocker- Atenolol.# In patients with heart failure the preferred beta-blockers are metoprolol, carvedilol, bisoprolol. § Source: adapted from ref.(21) Table10: Compelling and possiblecontraindicationsto the use of antihypertensive drugs# Drug Compelling contraindication Possible contraindication Diuretics Gout Metabolic syndrome, glucose intolerance, hypokalemia, hypercalcemia Beta-blockers Asthma, AVblock (grade 2 or 3) Metabolic syndrome, glucose

intolerance, chronic obstructive pulmonary disease Calcium channel Tachyarrhythmia, heart failure blockers(dihydropyridines) Calcium channel blockers(non- AV block (Grade 2 or 3),severeleft dihydropyridines) ventricular dysfunction, heart failure ACE inhibitors Pregnancy Women with childbearing potential Hyperkalemia Bilateral renal artery stenosis Angiotensin receptor blockers Pregnancy Women with childbearing potential Hyperkalemia Bilateral renal artery stenosis

Mineralocorticoid receptor Acute or severe renal failure antagonists ( e.g. spironolactone) (eGFR<30 ml/min) Abbreviations: AV, atrioventricular; eGFR, estimated glomerular filtration rate Standard Treatment Guidelines-Hypertension Page16

Source: ref.Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Blood pressure. 2013;22(4):193-278. KEY RECOMMENDATIONS 4.6 The treatment regimen and the use of combinations: 4.6.1 In patients with Grade 1 or Grade 2 hypertension, therapy can be initiated with one drug (CCBs,

ACE inhibitors, thiazide diuretics) in combination with lifestyle modifications(Step 1in table 13). Average initial doses can be 5 mg of amlodipine, 5 mg of enalapril and 12.5 mg of hydrochlorothiazide. 4.6.2 In patients with Grade 3 hypertension, the therapy should be initiated with two drugs, in combination with lifestyle modifications (Step 2 in table 13). The combinations can be calcium channel blocker (amlodipine) + ACE inhibitor (enalapril) or calcium channel blocker (amlodipine) +

thiazide diuretic (hydrochlorothiazide) or ACE inhibitor (enalapril) + thiazide diuretic (hydrochlorothiazide). 4.6.3 The dose of drugs can be increased or a new drug added at approximately 2- to 4-week intervals. This frequency can be faster or slower depending on the clinical circumstances of the patient and the judgment of the practitioner. 4.6.4 The addition of a new drug in patients with Grade 1 or Grade 2 hypertension may be preferable to

maximising the dose of the initial drug. In case a calcium channel blocker (amlodipine) has been used as initial therapy, the add-on drug can be ACE inhibitor (enalapril) or a thiazide diuretic. Similarly if ACE inhibitors have been used as initial therapy, a calcium channel blocker or a diuretic can be used as add on therapy. When amlodipine is used as an add-on therapy, the initial dose used should be 2.5 mg. Similarly if an ACE inhibitor like enalapril is added to a diuretic, the initial

dose used may be 2.5 mg to avoid hypotension. 4.6.5. If the second drug in a usual dose also fails to reduce BP to target levels then the third class of drug previously unutilised should be added (Step3 in table 13). An optimal 3 drug combination in case it is required is a calcium channel blocker with a low dose thiazide diuretic and an ACE inhibitor (e.g. amlodipine+ enalapril+ hydrochlorothiazide). 4.6.6. The preferred 2 drug combinations are combination of calcium channel blockers with ACE

inhibitors, ACE inhibitors with low dose diuretics, and calcium channel blockers with low dose diuretics. 4.6.7. Prescription of a single pill combination of antihypertensive drugs in a defined proportion may be considered if available, after BP has been stabilised with a dose of two drugs given singly in the same proportion. Standard Treatment Guidelines-Hypertension Page17

4.6.8. The practitioner should aim for patients to reach target BP levels with an effective treatment regimen, whether 1, 2, or 3 drugs, within 6 to 8 weeks. 4.6.9. Add-on drugs for control of BP drugs should be added at intervals of 2-4 weeks. 4.6.10.Negative recommendation: ACE Inhibitors should not be combined with Angiotensin receptor blockers. 4.6.11. Avoid prescribing a combination of beta-blockers and diuretics as they can increase the risk of

diabetes mellitus in those at risk, e.g. persons with impaired glucose tolerance or obesity and metabolic syndrome. 4.6.12.If the BP is not controlled despite use of 3 anti-hypertensives, then the hypertension should be termed resistant and the patient should be referred to a specialist at the medical college for further evaluation and management. The management of hypertension is shown in text form in the box below and the doses of the drugs to be used are mentioned in table 12.

Review and respond to possible causes of poor response to BP medications 4.7. Key Recommendations: When a patient does not respond to two drugs given in full doses, the physician should review the underlying issues-related to  BP measurements,  poor adherence to drug and lifestyle modifications, including stoppage of medicines due to belief in other systems of medicine  suboptimal treatment regimens,  presence of associated conditions,

 use of non-antihypertensive drugs which can interfere with the action of anti- hypertensives, and  Consider the possibility of secondary hypertension. Standard Treatment Guidelines-Hypertension Page18

MANAGEMENT OF HYPERTENSION-target BP <140/90 mmHg in those < 80 years, 150/90 in those over 80 years. ALL PATIENTS REQUIRE LIFE-LONG LIFESTYLE MODIFICATION Dietary change to Heart-healthy diet–salt 56 g/day, low-fat diet Regular exercise Maintain weight–target BMI 18.5-22.9 kg/m2 Stop smoking Patients with Grade1 hypertension may require only lifestyle modification, which should be tried for 3 months. GRADE 1HYPERTENSION(SBP 140-159 mm, DBP 90-99mm) with

Inadequate control after 3 months of lifestyle modificationORmore than 3 risk factors: Male,Age: men >55 years, women>65 years,smoking,obesity, including abdominal obesity Dyslipidaemia,impaired fasting glucose, family history of early coronary artery disease Drug therapy–A or C1or D Add second drug-A+C or C+D or A+Dif response not adequate within 2-4 weeks Add third drug–A+C+Dif response not adequate within 2-4 weeks GRADE 2 HYPERTENSION(SBP 160-179, DBP100-109) Drug therapy–A or C or D

Add second drug-A+C or C+D or A+Dif response not adequate within 2-4 weeks Add third drug–A+C+Dif response not adequate within 2-4 weeks GRADE 3 HYPERTENSION(SBP≥180, DBP≥110) Use two drugs-A+C or C+D or A+D Add third drug–A+C+Dif response not adequate within 2-4 weeks ALL GRADES OF HYPERTENSION WITH ASSOCIATED CLINICAL CONDITIONS CAD: coronary artery disease-B+A2, C CHF: congestive heart failure-D+A+B, MRA CKD: chronic kidney disease–A or C or D3 DM: diabetes mellitus–A or C, D

Drugs are added only if they are required to achieve the target BP of <140/90 mm Hg (in patients <80 years old) or <150/90 mm Hg (in patients >80 years of age) Abbreviations:CAD: coronary artery disease,CHF: congestive heart failure,CKD: chronic kidney disease,DBP: diastolic blood pressure,DM: diabetes mellitus,SBP:systolic blood pressure, TOD: target organ damage. Drug classes: A:Angiotensin converting enzyme (ACE) inhibitors, (e.g. enalapril) or Angiotensin II receptor

blockers (ARBs) (e.g. losartan)if intolerance to ACEinhibitors,B:Beta-blockers (e.g. atenolol),C:Calcium channel blockers (e.g. amlodipine),D: thiazidediuretics (e.g. hydrochorothiazide),MRA: mineralocorticoid receptor antagonist (e.g. spironolactone). Drug doses: Doses for initiation of therapy : A : enalapril 5 mg; B: Atenolol 50 mg; C: Amlodipine 5 mg ( 2.5 mg in elderly); D: Hydrochlorthiazide/Chlorthalidone12. 5 mg.

Add-on doses: A : enalapril 5 mg (reduce in elderly or in those on diuretics), C: amlodipine 2.5 mg, D: hydrochlorthiazide 12.5 mg Maximal doses: A : enalapril 20-40mg;B: Atenolol 100 mg C: Amlodipine 10 mg; D: Hydrochlorthiazide: 25 mg Footnotes : 1Calcium channel blockers are antihypertensives of choice in the elderly (> 60 years). 2Patients with CAD and history of myocardial infarction should receive both beta-blockers and ACE inhibitors

3Patients with CKD may require loop diuretics if the glomerular filtration rate is low. Patients on ACE inhibitors will require monitoring of serum creatinine and potassium. Based onreferences:Hypertension: Clinical management of primary hypertension in adults NICE guidelines [CG127]. National Institute for HealthCare Excellence; 2011 Weber MA, Schiffrin EL, White WB, et al.The Journal of Clinical . Hypertension 2014;16(1):14-26. Standard Treatment Guidelines-Hypertension Page19

Table 12: Initial and maximal doses for initiation and titration of therapy for Indian patients with hypertension: (source: adapted from ref (24),(70) and product monographs listed at health Canada www.health-sc.gc.ca) Drug class Low dose in Usual Initial Maximal Doses per certain dose dosage day situations suggested for suggested for Indian Indian patients patients with with hypertension hypertension Calcium channel blockers Dihydropyridines Amlodipine 2.5 mg* 5 mg 10 mg 1

Angiotensin converting enzyme inhibitors Enalapril 2.5 mg§ 5 mg 10-20 mg 1-2 Lisinopril 5 mg 10 mg 1 Angiotensin receptor blockers Losartan 25 mg# 50 mg 100 mg 1-2 Telmisartan 40 mg 80 mg 1 Diuretics Thiazides 1 Hydrochlorothiazide 12.5 mg 25 mg 1 Thiazide-like Chlorthalidone 12.5 mg 25 mg 1 Beta-blockers Atenolol 25 mg 50 mg 100 mg 1 Metoprolol succinate 50 mg 100 mg 2 *Reduce dose of amlodipine to 2.5 mg once a day when it is started in low body weight elderly patients,

and when amlodipine is added to another antihypertensive medication. § Reduce dose to enalapril 2.5 mg when it is used in elderly (>65 years) and when the patient has been on diuretic therapy. # Use dose of 25 mg in patients less than 50 kg (Canadian labelling) Quick Reference Guide-Hypertension Page20

Initiation with 2 drugs or titration of drugs in a patient Use of three Initiation not controlled on a single drug :Step 2 drugs in a with single CCB Diuretic ACE patient not drug (amlodipine) (hydrochlorothiazide) inhibitor controlled Step 1 (enalapril) with 2 drugs Step 3 ACE Enalapril 5 mg+ Enalapril5 mg + Enalapril 10 ACE inhibitor inhibitor Amlodipine 2.5 Hydrochlorothiazide mg (less (Enalapril Enalapril 5 mg , later raise to 12.5mg preferred 5/10mg ) mg 5 mg strategy) + CCB Or Amlodipine

Amlodipine 5 mg + Amlodipine 5/10 mg) CCB Amlodipine 10 Thiazide 12.5 mg 5 mg Amlodipine 5 mg +Enalapril 5 + mg (less preferred mg Thiazide Or strategy) Hydrochlorot Diuretic + CCB Hydrochlorothiazide Hydrochlor hiazide Thiazide (Amlodipine 2.5 25 mg (less preferred othiazide 12.5mg/25 diuretic mg, later 5 mg) strategy) 12.5mg mg) Hydrochloro- Enalapril thiazide 12.5 2.5 mg , mg later 5 mg Table 13: Medication pathway in this guideline evolving from Step 1 (single drug) to Step 2 (two drugs) to Step 3

When a patient is not responding to BP medications, as determined by persistently high BP readings on repeat visits, the physician should pay attention to the following factors: 1. Issues related to BP measurement in the clinic: This may include “white coat effect” because of which the clinic based BP measurements by a doctor may be higher than those obtained at home or by another healthcare provider. Improper size of cuff and improper technique may also give falsely elevated BP readings.

2. Adherence to medications: In a chronic disease, which are asymptomatic, patients often miss doses or even discontinue medications, and the regularity of drug intake should be enquired about from the patient and their relatives. The reasons for non-adherence should also be explored which may include doubts about the diagnosis, belief in lifestyle modifications being sufficient, cost of therapy, or side effects related to medicines. Belief in other systems of medicine may also lead to stoppage of medicines

3. Adherence to lifestyle modifications: Excessive salt intake, excessive alcohol consumption, tobacco use, obesity all can contribute to poor control of hypertension. 4. Suboptimal treatment regimens: This can be the result of low doses, or use of inappropriate combinations. Drug dosages should be optimized. The combinations should be of medicines which are complementary in action. Addition of diuretics in patients not responding to a combination of drugs, usually results in good control.

5. Presence of associated conditions: Presence of sleep apnea, chronic pain can all impair control of BP. 6. Drug interactions: Some commonly used drugs like non-steroidal anti-inflammatory drugs (NSAIDs), oral contraceptives, corticosteroids and anabolic steroids, and common cold remedies which contain sympathomimetics can all result in higher BP. NSAIDs ( including cyclooxygenase-2 inhibitors) can cause salt retention and interfere with the

action of all antihypertensives except calcium channel blockers. Addition of a diuretic may mitigate their effect. 7. Secondary hypertension: The most frequent cause of secondary hypertension is chronic kidney disease, which can be diagnosed on the abnormal urinalysis& blood chemistries, at the level of the CHC. The other causes of secondary hypertension would include endocrine causes (pheochromocytoma, Cushing’s’ syndrome), vascular causes

(renovascular hypertension, contraction of aorta, Takayasu’s arteritis); which will require evaluationby a specialistat a medical college level. Quick Reference Guide-Hypertension Page22

4.8. Therapy of hypertension,comorbidities and associated conditions: A large proportion of patients with hypertension have co-morbidities such as diabetes mellitus,which need to be managed. 4.8.1 Diabetesmellitus: 4.8.1.1 Patients with diabetes mellitus should be initiated on drug treatment when the SBP is greater than 140 mm Hg, and the target for control should be a SBP of less than 140 mm Hg, and a diastolic BP of less than 90 mm Hg.

4.8.1.2 ACE inhibitors are preferred as initial therapy and calcium channel blockers and diuretics may be used as add on therapy. Thiazide diuretics can be associated with glucose intolerance. 4.8.1.3 Drugs which inhibit the renin angiotensin systems- ACE inhibitors and ARBs should be used if the patients have proteinuria (or microalbuminuria). 4.8.2 Heart disease: 4.8.2.1Beta-blockers should be prescribed in patients with hypertension and a recent

myocardial infarction.These patients should also receive an ACE inhibitor. 4.8.2.2 In patients with angina, beta-blockers and calcium channel blockers, should be considered among the antihypertensivedrugs for their effect on symptoms. 4.8.2.3 In patients with heart failure and hypertension, ACE inhibitors, thiazide diuretics, and beta-blockers, and mineralocorticoid receptor antagonists are recommended for reduction in mortality and hospitalization. 4.8.3 Kidneydisease (diabetic or non-diabetic):

4.8.3.1 The target for BP reduction should be a SBP of less than 140 mm Hg, but a SBP of less than 130 mm Hg should be considered for those with overt proteinuria. 4.8.3.2. ACE inhibitors /ARBs are effective in reducing albuminuria and should be used in patients with hypertension and overt proteinuria (or microalbuminuria). Monitoring serum creatinine and potassium in the first week of therapy is advisable after initiation of therapy or any increase in the dose of ACE inhibitors.

4.8.3.4Use of ACE inhibitors and Thiazide or thiazide like diuretics should be used as other antihypertensive agents, and in the presence of volume overload, loop diuretics like frusemide may be used. 4.8.4 Cerebrovascular disease: 4.8.4.1 Prevention of stroke can occur with all classes of antihypertensive drugs if BP is effectively controlled. 4.8.4.2 In patients with a history of stroke or TIA, initiation of drug treatment should be

considered even with Grade 1 hypertension, and a systolic BP of less than 140 mm Hg should be targeted. An ACE inhibitor/ARB is considered an initial drug. 4.8.4.3 In the first 72 hours of an ischemic stroke, do not administer antihypertensive treatment, since excessive lowering of BP can exacerbate the existing ischemia. 4.8.4.4 In patients who are not undergoing thrombolytic therapy for ischemic stroke, extreme values of BP, e.g. systolic BP > 220 mm Hg or diastolic BP > 120 mm Hg should

be treated by agents to reduce mean arterial pressure by about 15% in the first hour and no more than 25% in the first 24 hours and with gradual reduction thereafter. In patients who are candidates for thrombolytic therapy, BP above systolic of 185 mm Hg and diastolic of 110 mm Hg should be treated cautiously and maintained below these levels. 4.8.4.5 In patients with intracerebral haemorrhage, with SBP > 200 mm Hg or MAP3>150 mm Hg, aggressive reduction of blood pressure with intravenous infusion of

antihypertensives is indicated and the patient should be examined every 5 minutes. 4.8.4.6 In patients with intracerebralhaemorrhage , with SBP >180 mm Hg or MAP > 130 mm Hg, modest reduction of BP to 160/90 is indicated using an intermittent or continuous IV infusion with frequent re-examination is indicated. 4.8.4.7 In patients presenting with intracerebral haemorrhage and a SBP of 150-220 mm Hg, BP can probably be lowered to a SBP of 140 mm Hg safely. 4.8.5Hypertension in the elderly:

4.8.5.1Postural hypotension is more common in elderly people. Assess patients for postural hypotension at diagnosis and on follow up by checking BP in sitting and in standing position after 2 minutes. 3MAP = Mean arterial pressure which is calculated as follows MAP =SBP +2(DBP)where SBP is systolic blood pressure and DBP is diastolic blood pressure 3 Quick Reference Guide-Hypertension Page24

4.8.5.2Postural fall of >20 mm in systolic and >10 mm diastolic indicates postural hypotension is a risk factor for falls. 4.8.5.3In a patient with postural hypotension titrate target according to standing BP. 4.8.5.4Start therapy with lower doses of drugs and change doses or add drugs at a slower rate in elderly patients. 4.8.5.5 In elderly patients less than 80 years of age, the blood pressure target for control may be <140 mm systolic and <90 mm diastolic if the patient is fit and the treatment is well

tolerated. 4.8.5.6In elderly patients more than 80 years (the very elderly), the blood pressure target for control is <150 mm systolic and <90 mm diastolic. 4.8.5.7The drug of choice for initiation of therapy in the elderly is a long acting calcium channel blocker, or a low dose thiazide diuretic in the absence of compelling indications. 4.8.5.8 There is a higher likelihood of certain side effects in the elderly- e.g. hyponatremia in the case of thiazides, and hyperkalemia in the case of ACE inhibitors.

4.8.5.9There is a likelihood of drug –drug interactions in the elderly who often receive other drugs; e.g. .NSAIDs for arthritis interferes with action of ACE inhibitors, and diuretics. 4.9 Hypertensive emergencies: 4.9.1 Hypertensive emergencies are those in which severe hypertension (elevations of systolic >180 mm Hg) and/ or diastolic (> 120 mm Hg) is associated with symptoms and signs of acute ongoing organ damage. Such elevations of blood pressure may

be associated with neurologic emergencies (hypertensive encephalopathy, cerebral infarction, and cerebral haemorrhage), cardiac emergencies (acute left ventricular failure, acute coronary syndrome), renal emergencies like acute renal failure, and obstetric emergencies like eclampsia (symptoms and signs of such dysfunction are referred to under the mnemonic of ‘ABCDEFG’in pathway on assessment and management on hypertensive crisis). Eclampsia can occur even at levels of BP less

than 180 mm systolic and/or 120 mm diastolic. 4.9.2 The magnitude and rate of reduction of BP varies according to the organ involvement in the hypertensive emergency. In many hypertensive emergencies including hypertensive encephalopathy reduction of mean arterial pressure of ≤ 25 percent in the first hour, with a gradual reduction to 160 mm systolic and diastolic of 110-120 mm Hg over 2-6 hours, and gradual normalization of blood pressure Quick Reference Guide-Hypertension Page25

over 24-48 hours is recommended. Parenteral agents like IV labetalol, nicardipine may be used initially with a change to oral agents later. 4.9.3 In patients with ischemicstroke as noted earlier, reduction of systolic BP below 220 mm Hg and 120 mm Hg are not treated, unless the patient is being considered for thrombolytic therapy. 4.9.4 Negative recommendation: Oral or sublingual nifedipine may cause excessive, abrupt fall of blood pressure which may result in cardiac, cerebral or renal ischemic

complications. It is not recommended in the treatment of any hypertensive emergency. 4.9.5 In the case of acute left ventricular failure reduction of the elevated BP is indicated with a parenteral loop diuretic like frusemide in addition to vasodilators like nitroglycerine. In patients with acute coronary syndrome with severe hypertension, intravenous nitroglycerine may be used in association with intravenous beta- blockers like esmolol or labetalol.

4.9.6 Patients with a hypertensive emergency should be examined for any clinical clues to the presence of secondary hypertension and be evaluated for the same. 4.10 Hypertensive urgencies: 4.10.1 This refers to situations when severe hypertension (SBP > 180 mm, DBP> 110 mm) is not associated with any signs of acute or ongoing organ damage (cerebral, cardiac, renal, visual), and the patient is relatively asymptomatic except for a mild headache( none of the symptoms,

signs referred to in the mnemonic ‘ABCDEFG’ in pathway on hypertensive crisis). Patients with severe hypertension should be assessed clinically and by laboratory investigations, and target organ damage should be excluded before hypertensive urgency is diagnosed. 4.10.2 Hypertensive urgencies may occur in patients with chronic hypertension in a number of situations. This includes non-adherence to therapy, after sudden withdrawal of beta-blocker or

clonidine therapy, after ingestion of large quantity of salt, or due to anxiety. 4.10.3 There is no benefit from rapid reduction of BP in patients with severe but asymptomatic hypertension and the BP should be reduced over a period of hours and days. 4.10.4 Nursing the patient in a quiet room and relief of anxiety may reduce BP to a certain extent. 4.10.5 Negative recommendation: Do not attempt excessive, rapid and uncontrolled

reduction of blood pressure in hypertensive urgencies, with intravenous drugs or oral or Quick Reference Guide-Hypertension Page26

sublingual nifedipine. This aggressive reduction of BP in a patient with severe asymptomatic hypertension may cause fall of BP below the threshold of autoregulation in vascular beds, and cause serious cerebral and cardiac complications related to ischemia. 4.10.6 Re-institution of therapy or intensification of therapy by increasing the dose of drugs or adding a diuretic may suffice for gradual reduction of blood pressure in a patient who

has developed severe asymptomatic hypertension on the background of chronic hypertension. 4.10.7 If BP reduction over few hours is required in view of imminent cardiovascular events, then oral frusemide, oral clonidine can be used. These can be followed by long term therapy with CCBs, ACE inhibitors or diuretics. Hypertensive emergencies Cardiac conditions Acute left ventricular failure Acute myocardial infarction Renalconditions Acute glomerulonephritis Renovascular hypertension

Cerebrovascular conditions Hypertensive encephalopathy Cerebral infarction Intracerebral hemorrhage Subarachnoid hemorrhage Head injury Accelerated hypertension with exudates and/orpapilledema Obstetric conditions Eclampsia Surgical conditions Postoperative hypertension Severe burns Excess catecholamines Pheochromocytoma Abrupt withdrawal of clonidine, beta-blockers Table14: Conditions presenting as hypertensive emergencies Drug Dose Onset of Adverse effects Comments action

IV Frusemide 20-40 mg in 5-15 min Hypovolemia, May be used in 1-2 min hypokalemia combination with other drugs to maintain their efficacy. Indicated in acute left ventricular failure Quick Reference Guide-Hypertension Page27

IV labetalol 20-80 mg IV 5-10 min Scalp tingling, Can be used in many dizziness, nausea, hypertensive heart block emergencies. Avoid in acute heart failure IV nicardipine 5-15 mg per 5-10 min Tachycardia, Can be used in many hour as IV headache, nausea, hypertensive tachycardia emergencies. Avoid in acute heart failure IV 5-100 µg/min 2-5 min Headache, vomiting, Useful in myocardial nitroglycerine methemoglobinemia, ischemia with tolerance hypertension

Table 15: Selected intravenous drugs useful in management of hypertensive emergencies 4.11 Integration with other interventions to reduce cardiovascular risks 4.11.1 The treatment of hypertension should be integrated with treatment of associated risk factors like lipid lowering therapy and antiplatelet therapy, apart from lifestyle interventions already mentioned. 4.11.2 Antiplatelet therapy with low-dose aspirin (75 mg/day) is recommended in

patients with controlled hypertension who have previous history of cardiovascular event (previous MI, stroke, angina, bypass surgery or coronary angioplasty), because of a favourable benefit –harm ratio. 4.11.3 Low dose aspirin may be considered for those hypertensives who are well controlled and have a high cardiovascular risk (Grade 3 hypertension, 3 or more risk factors, target organ damage). 4.11.4 Negative recommendation: Do not use low-dose aspirin in hypertensive patients

without cardiovascular disease and who are at low-moderate risk as the risk of major bleeds (intracranial and gastrointestinal) outweighs the potential benefit. 4.11.5 The use of low dose aspirin in patients with diabetes without cardiovascular or cerebrovascular disease is not recommended in view of the uncertain risk-benefit ratio. 4.11.6 Prescribe statins for use in hypertensive patients with overt atherosclerotic cardiovascular disease [coronary artery disease including acute coronary

syndromes, history of myocardial infarction, stable angina), cerebrovascular disease (stroke or transient ischemic attack), and peripheral arterial disease], regardless of age. Quick Reference Guide-Hypertension Page28

4.11.7 Prescribe statins in hypertensive patients  aged more than 40 years, with LDL –cholesterol more than 190 mg/dl, where secondary causeshave been ruled out  in hypertensive patients who are diabetic and in the age group of 40-79 years,  in hypertensive patients aged more than 40 years with high cardiovascular risk (3 or more out of list of 11cardiovascular risk factors) 4.11.8 Hypertensive patients who smoke or chew tobacco should be provided advice to stop smoking and chewing tobacco.

5. FOLLOW UP,MONITORING AND IMPROVING ADHERENCE TO THERAPY Key Recommendations: 5.1A simplified regime using long acting drugs which can be used once a day may improve adherence. 5.2The patients should be monitored for efficacy of the regimen, both at the clinic and community level. In patients who are yet to achieve target BP, follow-up visits at 1-2 weeks can be scheduled till target BP is achieved. Thereafter the patient can be seen by a physician

at a frequency determined by the severity of the hypertension, presence of comorbidities, target organ damage. Streamlined methods to collect drugs should be allowed to enable compliance by the patient. 5.3. The patients should be monitored for side effects of drugs. 5.4. The common side effect of calcium channel blockers is peripheral edema, which is dose dependent and may subside with reduction of dose or combination with ACE inhibitor.

5.4.2. The common side effect of ACE inhibitors is dry cough, which may necessitate withdrawal of therapy. There is a risk of hypotension when ACE inhibitors are started on Quick Reference Guide-Hypertension Page29

patients who are on diuretics, or are on very low salt diet. A small rise in serum creatinine can occur on ACE inhibitors, which is reversible. Hyperkalemia can develop with high doses of ACE inhibitors, but also more commonly in patients with renal insufficiency, diabetes, concurrent use of potassium sparing diuretics, and the elderly. 5.5. Consider the use of pill counts, participation of a family member in supervision of drug

intake, periodic counselling and provision of patient information leaflets to improve adherence and control. 5.6Diagnosis and management of hypertension in India, needs to be embedded in the system of primary care. A team approach to management of hypertension needs to be evolved which involves the physicians, allied staff and community based health workers. 5.7Community based health workers can be trained to play a critical role in meeting the

challenge of undetected, untreated and uncontrolled hypertension in India. They can improve detection, promote lifestyle modifications, monitor response and ensure adherence to therapy. They can also help prevent hypertension by advising appropriate lifestyle modifications in those who have a high normal BP ( 130-139 mmHg systolic and 85- 89 mm Hg diastolic) 5.8We strongly recommend creation of a hypertension registry at the PHC & CHC level to

ensure tracking of patients and create a system of recall which can involve the community based health workers. 5.9. Patients with hypertension should be encouraged to consider home blood pressure monitoring using an automated device which has been validated with a clinic based device. 5.10. All patients with hypertension, should undergo an annual review of control of BP, implementation of lifestyle modifications (e.g. maintenance of body weight), target organ

damage (proteinuria), review of treatment including side effects of drugs. 5.11 All patients with high normal BP should also be encouraged to undergo an annual review, and advised appropriate lifestyle modifications e.g. dietary changes, weight maintenance, and abstinence from tobacco Quick Reference Guide-Hypertension Page30

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mmmeeeaaasssuuurrreeemmmeeennnttt ppprrroooccceeeddduuurrreee aaarrreee >>> 111444000 mmmmmm sssyyyssstttooollliiiccc aaannnddd///ooorrr >>>999000 mmmmmm dddiiiaaassstttooollliiiccc (((>>>111555000///999000 mmmmmm iiinnn ttthhhooossseee >>>888000 yyyeeeaaarrrsss))) AAAsssssseeessssss RRRiiissskkk FFFaaaccctttooorrrsss---AAAdddvvviiiccceee ooonnn llliiifffeeessstttyyyllleee mmmooodddiiifffiiicccaaatttiiiooonnnsss---UUUrrrgggeeennnttt rrreeefffeeerrrrrraaalll iiifff BBBPPP >>>111888000 mmmmmm

sssyyyssstttooollliiiccc &&&///ooorrr >>>111111000 mmmmmm dddiiiaaassstttooollliiiccc RReeffeerrrraall ttoo PPHHCC ffoorr ddiiaaggnnoossiiss,, aasssseessssmmeenntt aanndd mmaannaaggeemmeenntt PPaattiieenntt rreeffeerrrreedd bbaacckk ttoo pprriimmaarryy ccaarree RReeggiisstteerr iinn HHTT rreeggiissttrryy tteeaamm ffoorr ffoollllooww uupp aanndd mmoonniittoorriinngg PPPaaattthhhwwwaaayyy 111::: SSScccrrreeeeeennniiinnnggg PPPaaattthhhwwwaaayyy

QQQuuuiiiccckkk RRReeefffeeerrreeennnccceee GGGuuuiiidddeee---HHHyyypppeeerrrttteeennnsssiiiooonnn PPPaaagggeee333111

BP measurement) If the patient is diabetic or above 65 years measure the BP in supine and 2 minutes after assuming the standing position to check for postural hypotension. 5.No. of 1.1.At least 2 readings should be taken at an interval of 1 measurements and minute. If the readings differ by more than 5 mm Hg takes a recording the result third reading. The lower of the two readings should be taken as the representative SBP and DBP. Quick Reference Guide-Hypertension Page32

GGrraaddee 11 HHTT SSBBPP::≥≥ 114400--115599 mmmm HHgg &&//oorr DDBBPP:: ≥≥9900--9999 mmmm HHgg GGrraaddee 22 HHTT SSBBPP:: 116600--117799 mmmm HHgg &&//oorr DDBBPP:: 110000--110099 mmmm HHgg Patient with SBP≥ 140 Hypertensive urgency: mm and/or DBP >90 mm severe asymptomatic GGrraaddee 33 HHTT documented by at least 2 hypertension readings each on 2 visits SSBBPP ::≥≥118800 mmmm HHgg using a standardised BP &&//oorr Hypertensive measurement procedure DDBBPP::≥≥>>111100 mmmm HHgg emergency:severe HT

with acute cardiac /neurologic/renal/retinal dysfunction IIssoollaatteedd SSyyssttoolliicc hhyyppeerrtteennssiioonn:: SSBBPP≥≥≥≥114400 mmmm HHgg ((iiffaaggee<<8800 yyeeaarrss)),,≥≥115500 mmmm HHgg ((iiffaaggee >>8800 yyeeaarrss)) AANNDD DDBBPP << 9900 mmmm HHgg PPPaaattthhhwwwaaayyy 333::: CCClllaaassssssiiifffiiicccaaatttiiiooonnn pppaaattthhhwwwaaayyy QQQuuuiiiccckkk RRReeefffeeerrreeennnccceee GGGuuuiiidddeee---HHHyyypppeeerrrttteeennnsssiiiooonnn PPPaaagggeee333333

History for risk factors, cardiovascular disease Examination for clinical Essential Grade 1 HT cardiovascular disease (angina, evaluation heart failure, stroke) Screening for diabetes, proteinuria History and examination as in Desirable Essential evaluation Grade 2 HT evaluation Screening for diabetes +lipids Patient with Urinalysis,Serum creatinine,ECG hypertension History and examination as in Essential evaluation+ evidence of secondary HT,Ophthalmoscopy: Grade 3 HT or Blood glucose, lipids, serum

patient <40 years Comprehensive creatinine,serum sodium and and >60 years or evaluation potassium,Ultrasoundif suspicion Resistant HT of renal parenchycmal or renovascular disease,ECHO: in case of ? heart failure Pathway 4: Assessment pathway Quick Reference Guide-Hypertension Page34

BBlloooodd pprreessssuurree≥≥114400//9900 mmmm HHgg,,iinn aadduullttss aaggeedd 1188--7799 yyeeaarrss,,oonn mmuullttiippllee ooccccaassiioonnss uussiinngg ssttaannddaarrddiizzeedd pprroocceedduurree ((ffoorr aaggee >> 8800 yyeeaarrss bblloooodd pprreessssuurree >>115500//9900 ))

LLLiiifffeeessstttyyyllleee mmmooodddiiifffiiicccaaatttiiiooonnnsss (((DDDiiieeetttaaarrryyy ccchhhaaannngggeee---sssaaalllttt rrreeessstttrrriiiccctttiiiooonnn,,,lllooowww fffaaattt dddiiieeettt,,, rrreeeddduuuccceee wwweeeiiiggghhhttt,,, SSStttoooppp sssmmmoookkkiiinnnggg))) iiinnn aaallllll

pppaaatttiiieeennntttsss... TTTrrriiiaaalll ooofff llliiifffeeessstttyyyllleee mmmooodddiiifffiiicccaaatttiiiooonnnsss iiinnn uuunnncccooommmpppllliiicccaaattteeeddd GGGrrraaadddeee 111 HHHTTT fffooorrr 333 mmmooonnnttthhhsss bbbeeefffooorrreee iiinnniiitttiiiaaatttiiiooonnn ooofff dddrrruuuggg ttthhheeerrraaapppyyy... GGrraaddee 11 hhyyppeerrtteennssiioonn wwiitthh TTOODD//DDMM//aassssoocciiaatteedd cclliinniiccaall !! GGrraaddee 22 HHTT aanndd GGrraaddee 33 HHTT

ccoonnddiittiioonnss oorr >> 33 rriisskk ffaaccttoorrss Start Drug therapy PPaattiieennttss wwiitthhoouutt ccoommppeelllliinngg Patients with compelling indications iinnddiiccaattiioonnss (Hypertension with associated clinical ((HHyyppeerrtteennssiioonn aalloonnee )) conditions) Grade 1 HT(SBP 140-159, DBP 90-99) GGrraaddee 33 HHTT ((SSBBPP≥≥118800,, Grade 2 HT (SBP 160-179, DBP 100- DM: A /C, D DDBBPP≥≥111100)) 109) # Start with One drug CAD: B + A , C A or C* or D

IncreaseAorCorDto UUSSEE TTWWOO DDRRUUGGSS ((pprreeffeerrrreedd ssttrraatteeggyy)) CCHHFF:: DD++ AA++ BB,, MMRRAA maximal dose (less AA++ CC OORR CC++ DD OORR AA++ DD preferred strategy) § CKD: A, C, D USE 3 drugs A+C +D NNOO rreessppoonnssee ttoo 33 ddrruuggss--RReessiissttaanntt HHTT-- CCoonnssiiddeerr SSppeecciiaalliisstt rreeffeerrrraall PPPaaattthhhwwwaaayyy 555 AAA...::: MMMaaannnaaagggeeemmmeeennnttt pppaaattthhhwwwaaayyy (((aaalllgggooorrriiittthhhmmm fffooorrrmmm)))

DDDrrruuugggsss aaarrreee aaaddddddeeeddd ooonnnlllyyy iiifff ttthhheeeyyy aaarrreeerrreeeqqquuuiiirrreeeddd tttooo aaaccchhhiiieeevvveee ttthhheee tttaaarrrgggeeettt BBBPPP ooofff <<<111444000///999000 mmmmmm HHHggg (((iiinnn pppaaatttiiieeennntttsss <<<888000 yyyeeeaaarrrsss ooolllddd))) ooorrr BBBPPP <<<111555000///999000 mmmmmm HHHggg(((iiinnn pppaaatttiiieeennntttsss >>>888000 yyyeeeaaarrrsss ooofff aaagggeee)))

AAAbbbbbbrrreeevvviiiaaatttiiiooonnnsss::: SSSBBBPPP ::: SSSyyyssstttooollliiiccc bbblllooooooddd ppprrreeessssssuuurrreee,,, DDDBBBPPP::: DDDiiiaaassstttooollliiiccc bbblllooooooddd ppprrreeessssssuuurrreee,,, TTTOOODDD :::tttaaarrrgggeeettt ooorrrgggaaannn dddaaammmaaagggeee,,, DDDMMM::: dddiiiaaabbbeeettteeesss mmmeeelllllliiitttuuusss,,,

CCCAAADDD::: cccooorrrooonnnaaarrryyy aaarrrttteeerrryyy dddiiissseeeaaassseee,,,CCCHHHFFF::: CCCooonnngggeeessstttiiivvveee hhheeeaaarrrttt fffaaaiiillluuurrreee,,, CCCKKKDDD::: CCChhhrrrooonnniiiccc kkkiiidddnnneeeyyy dddiiissseeeaaassseee...DDDrrruuuggg aaabbbbbbrrreeevvviiiaaatttiiiooonnnsss::: AAA:::AAAnnngggiiiooottteeennnsssiiinnn

cccooonnnvvveeerrrtttiiinnnggg eeennnzzzyyymmmeee(((AAACCCEEE))) iiinnnhhhiiibbbiiitttooorrrsss (((eee...ggg... eeennnaaalllaaappprrriiilll))) ooorrrAAAnnngggiiiooottteeennnsssiiinnn IIIIII rrreeeccceeeppptttooorrr bbbllloooccckkkeeerrrsss(((AAARRRBBBsss)))(((eee...ggg... lllooosssaaarrrtttaaannn)))ooonnnlllyyy iiifff iiinnntttooollleeerrraaannnccceee tttooo

aaattteeennnooolllooolll))),,, MMMRRRAAA ::: MMMiiinnneeerrraaalllooocccooorrrtttiiicccoooiiiddd rrreeeccceeeppptttooorrr aaannntttaaagggooonnniiisssttt (((eee...ggg... ssspppiiirrrooonnnooolllaaaccctttooonnneee)))...

FFFooooootttnnnooottteeesss :::!!! OOOttthhheeerrr RRRiiissskkk fffaaaccctttooorrrsss(((aaapppaaarrrttt fffrrrooommmhhhyyypppeeerrrttteeennnsssiiiooonnn))) ::: aaagggeee ((( >>> 555555 yyyeeeaaarrrsss iiinnn mmmeeennn,,, 666555 yyyeeeaaarrrsss iiinnn wwwooommmeeennn))),,, mmmaaallleee gggeeennndddeeerrr,,, dddiiiaaabbbeeettteeesss

mmmeeelllllliiitttuuusss,,,sssmmmoookkkiiinnnggg,,,ooobbbeeesssiiitttyyy(((iiinnncccllluuudddiiinnnggg aaabbbdddooommmiiinnnaaalll ooobbbeeesssiiitttyyy))),,, dddyyysssllliiipppiiidddeeemmmiiiaaa,,, iiimmmpppaaaiiirrreeeddd gggllluuucccooossseee tttooollleeerrraaannnccceee,,, fffaaammmiiilllyyy hhhiiissstttooorrryyy ooofff ppprrreeemmmaaatttuuurrreee cccooorrrooonnnaaarrryyy aaarrrttteeerrryyy dddiiissseeeaaassseee...

*** cccaaalllccciiiuuummm ccchhhaaannnnnneeelll bbbllloooccckkkeeerrrsss aaarrreee aaannntttiiihhhyyypppeeerrrttteeennnsssiiivvveeesss ooofff ccchhhoooiiiccceee iiinnn ttthhheee eeellldddeeerrrlllyyy (((>>> 666000 yyyeeeaaarrrsss)))...### PPPaaatttiiieeennntttsss wwwiiittthhh CCCAAADDD aaannnddd hhhiiissstttooorrryyy ooofff

mmmyyyooocccaaarrrdddiiiaaalll iiinnnfffaaarrrccctttiiiooonnn ssshhhooouuulllddd rrreeeccceeeiiivvveee bbbooottthhh bbbeeetttaaa---bbbllloooccckkkeeerrrsss aaannnddd AAACCCEEE iiinnnhhhiiibbbiiitttooorrrsss...§§§ PPPaaatttiiieeennntttsss wwwiiittthhh CCCKKKDDD mmmaaayyy rrreeeqqquuuiiirrreee lllooooooppp dddiiiuuurrreeetttiiicccsss iiifff ttthhheee

GGGlllooommmeeerrruuulllaaarrr fffiiillltttrrraaatttiiiooonnn rrraaattteeeiiisss lllooowww... TTThhhooossseee pppaaatttiiieeennntttsss wwwhhhooo aaarrreee ssstttaaarrrttteeeddd ooonnn AAACCCEEE iiinnnhhhiiibbbiiitttooorrrssswwwiiillllll rrreeeqqquuuiiirrreee mmmooonnniiitttooorrriiinnnggg ooofff ssseeerrruuummm cccrrreeeaaatttiiinnniiinnneee

aaannnddd pppoootttaaassssssiiiuuummm aaafffttteeerrr iiinnniiitttiiiaaatttiiiooonnn ooofff tttrrreeeaaatttmmmeeennnttt...BBBaaassseeeddd ooonnn rrreeefffeeerrreeennnccceeesss(((222444,,,444999))) QQQuuuiiiccckkk RRReeefffeeerrreeennnccceee GGGuuuiiidddeee---HHHyyypppeeerrrttteeennnsssiiiooonnn PPPaaagggeee333555

nnoonn pphhyyssiicciiaann hheeaalltthh ssttaaffff-- ssccrreeeenn--rreeffeerr ffoorr ddiiaaggnnoossiiss--eedduuccaattee-- aasssseessss--aaddvviissee oonn lliiffeessttyyllee &&aaddhheerreennccee-- mmoonniittoorr--ffoollllooww uupp PPhhyyssiicciiaann aatt PPHHCC//CCHHCC ddiiaaggnnoossee--ccllaassssiiffyy--eedduuccaattee--aasssseessss ((TTOODD,, aassssoocciiaatteedd cclliinniiccaall ccoonnddiittiioonnss)),, aaddvviissee-- rreeggiisstteerr--iinniittiiaattee tthheerraappyy--rreeffeerr iiff

iinnddiiccaatteedd,, ffoollllooww uupp Referrals to District 1. In case of hypertensive emergency after initiation of treatment 2. For evaluation of resistant hypertension. 3. For management of certain associated clinical conditions-Ischemic heart disease PPPaaattthhhwwwaaayyy 666:::PPPaaatttiiieeennnttt ffflllooowww pppaaattthhhwwwaaayyy QQQuuuiiiccckkk RRReeefffeeerrreeennnccceee GGGuuuiiidddeee---HHHyyypppeeerrrttteeennnsssiiiooonnn PPPaaagggeee333666

SBP>180 DBP>110-120 AAsssseessss ffoorr ffoolllloowwiinngg** AA:: AAlltteerreedd ccoonnsscciioouussnneessss BB:: BBrreeaatthhlleessssnneessss CC:: CChheesstt PPaaiinn ((iisscchheemmiicc)) DD:: DDeeffiicciitt ((wweeaakknneessss iinn oonnee oorr mmoorree lliimmbbss)) oorr DDeeccrreeaasseedd uurriinnaarryy oouuttppuutt EE:: EEddeemmaa FF:: FFuunndduuss iiff ffeeaassiibbllee--hheemmoorrrrhhaaggeess,, eexxuuddaatteess,, ppaappiilllleeddeemmaa GG:: GGeenneerraalliisseedd sseeiizzuurreess

AAssyymmppttoommaattiicc :: One or more of symptoms NNoo AA//BB//CC//DD//EE//FF//GG /signs in A-G HHYYPPEERRTTEENNSSIIVVEE HYPERTENSIVE UURRGGEENNCCYY EMERGENCY RReedduuccee BBPP oovveerr hhoouurrss Cardiac Neurologic ttoo ddaayyss.. emergencie emergencies s UUssee oorraall ddrruuggss Renal Accelerated DDOO NNOOTT UUSSEE emergenci Malignant SSUUBBLLIINNGGUUAALL es Hypertension NNIIFFEEDDIIPPIINNEE Surgical Obstetric RReedduuccee BBPP ((oonnllyy rraarreellyy ttoo nnoorrmmaall))

oovveerr mmiinnuutteess ttoo hhoouurrss --aaccccoorrddiinngg ttoo ttyyppee ooff eemmeerrggeennccyy UUssee ppaarreenntteerraall ddrruuggss :: cchhooiiccee ddeeppeennddss uuppoonn ttyyppee ooff eemmeerrggeennccyy DDOO NNOOTT UUSSEE SSUUBBLLIINNGGUUAALL NNIIFFEEDDIIPPIINNEE PPPaaattthhhwwwaaayyy 777::: AAAsssssseeessssssmmmeeennnttt aaannnddd mmmaaannnaaagggeeemmmeeennnttt pppaaattthhhwwwaaayyy iiinnn aaa pppaaatttiiieeennnttt wwwiiittthhh

hhhyyypppeeerrrttteeennnsssiiivvveee cccrrriiisssiiisss (((>>> 111888000 mmmmmm sssyyyssstttooollliiiccc,,, >>>111111000---111222000 mmmmmm dddiiiaaassstttooollliiiccc))) ***AAAlllsssooo iiinnnvvveeessstttiiigggaaattteee aaasss aaapppppprrroooppprrriiiaaattteee::: SSSeeerrruuummm cccrrreeeaaatttiiinnniiinnneee (((iiinnn aaallllll))),,, XXX---rrraaayyy ccchhheeesssttt,,, EEECCCGGG,,, CCCTTT ssscccaaannn iiifff iiinnndddiiicccaaattteeeddd...

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eeemmmeeerrrgggeeennnccciiieeesss::: HHHyyypppeeerrrttteeennnsssiiivvveee eeennnccceeeppphhhaaalllooopppaaattthhhyyy,,, IIIsssccchhheeemmmiiiccc ssstttrrroookkkeee,,, IIInnntttrrraaaccceeerrreeebbbrrraaalll hhhaaaeeemmmooorrrrrrhhhaaagggeee,,, sssuuubbbaaarrraaaccchhhnnnoooiiiddd

hhhaaaeeemmmooorrrrrrhhhaaagggeee,,, HHHeeeaaaddd iiinnnjjjuuurrryyy ;;;RRReeennnaaalll eeemmmeeerrrgggeeennnccciiieeesss::: AAAcccuuuttteee ggglllooommmeeerrruuulllooonnneeeppphhhrrriiitttiiisss###,,, rrreeennnooovvvaaassscccuuulllaaarrr hhhyyypppeeerrrttteeennnsssiiiooonnn;;;

SSSuuurrrgggiiicccaaalll eeemmmeeerrrgggeeennnccciiieeesss::: PPPooosssttt---ooopppeeerrraaatttiiivvveee hhhyyypppeeerrrttteeennnsssiiiooonnn,,, ssseeevvveeerrreee bbbuuurrrnnnsss ;;;OOObbbsssttteeetttrrriiiccc::: EEEccclllaaammmpppsssiiiaaa### ###::: HHHyyypppeeerrrttteeennnsssiiivvveee eeemmmeeerrrgggeeennncccyyy mmmaaayyy oooccccccuuurrr eeevvveeennn aaattt BBBPPP llleeevvveeelllsss lllooowwweeerrr ttthhhaaannn 111888000 mmmmmm sssyyyssstttooollliiiccc aaannnddd 111111000 mmmmmm

dddiiiaaassstttooollliiiccc QQQuuuiiiccckkk RRReeefffeeerrreeennnccceee GGGuuuiiidddeee---HHHyyypppeeerrrttteeennnsssiiiooonnn PPPaaagggeee333777

ANNEXURE 2: LIFE STYLE CHANGES RECOMMENDED FOR PATIENTS DIAGNOSED TO HAVE HYPERTENSION AND FOR THOSE AT RISK OF DEVELOPING HYPERTENSION Background: Lifestyle modifications are an integral part of the management of persons with hypertension, regardless of severity of hypertension. Reduction of BP following lifestyle modifications may suffice for the control of grade I hypertension, while they may aid the control of hypertension

and reduce the dosages of drugs required for control of other grades of hypertension. Lifestyle modifications also help to reduce the overall cardiovascular risk in a person with hypertension. Lifestyle modifications are also an integral part of the prevention of hypertension at both an individual and the population level, and may help prevent progression of high normal BP to hypertensive levels. 1. Physical Activity (adapted from ref. (84)) 

Physical activity includes daily activity like walking and cycling, household work, work related activity, and leisure activity. Moderate intensity physical activity of 30 minutes per day or at least 2.5 hours (150 mins) per week, which can be performed in bouts of 10 minutes or more in 4-7 sessions per week, should be advised to all individuals for its cardio-protective effect . Moderate intensity physical activity includes any activity which can increase the heart rate, make the breathing rapid

and make the body warmer such as brisk walking (at 3-4 mph), stair-climbing, light swimming, walking the treadmill at 3-4 mph, or . 45 minutes (accumulated) exercise per day is recommended for cardiovascular fitness, while 60 minutes (accumulated) per day isrecommended for weight reduction. The specific form of physical activity chosen by or for the patient should be enjoyable and sustainable.  Alternatively persons can indulge in 75 minutes of vigorous physical activity like

running (at 6-8 mph), cycling at 12-14 mph. This kind of activity makes the breathing Quick Reference Guide-Hypertension Page38

very hard, the heartbeat rapid and makes it difficult to carry on a conversation comfortably.  All adults should include physical activities to improve muscle strength at least twice a week.  Regular aerobic exercises can reduce the systolic blood pressure average of 4 mmHg and diastolic BP by an average of 2.5 mmHg.(29)  Epidemiologic evidence suggests that physical activity reduces cardiovascular morbidity and mortality. There is strong evidence that regular physical activity has

an independent cardio protective effect. Physical activity improves cardiorespiratory fitness, lowers SBP and DBP, improves insulin sensitivity and glycemic control, helps reduce and control weight, and lowers markers of inflammation.(53)  Chronically sedentary individuals should not start a program of vigorous activity suddenly, but should gradually increase the duration and intensity of physical activity, starting for example with 10 minutes of moderate activity per session .(85)

This is done to minimise the risk of a sudden cardiac event and musculoskeletal injuries. Any patient experiencing chest discomfort, jaw pain, palpitations, syncope or dyspnea, should undergo evaluation before continuing with exercise. Patients with decompensated heart failure and acute coronary syndromes should not embark on an exercise program. Quick Reference Guide-Hypertension Page39

Source: Ref:(85) Source : ref(85) Quick Reference Guide-Hypertension Page40

2. Weight Reduction:achieve and maintain desirable body weight. All individuals who are overweight or obese should be encouraged to lose weight through a combination of a reduced calorie diet, increased physical activity and behaviour modification. Dietary changes and recommendations for physical activity are mentioned in other sections. Overweight or obesity is assessed by measuring body mass index (BMI), which is calculated

as weight in kg/height in meter2. For Indian population 18.5 to 22.9 BMI is normal, 23 to 24.9 is considered as overweight and BMI of ≥25 kg/m2 is considered as obesity in Indians.4 Apart from BMI which is a measure of general adiposity, it is also important to measure the abdominal adiposity, which is also associated with a higher cardiovascular risk. Abdominal adiposity can be measured by measurement of the waist circumference and the waist-hip

ratio. The waist circumference is measured at the end of several consecutive natural breaths, midpoint between the top of the iliac crest and the lower margin of the last palpable rib in the mid axillary line. Waist circumference should be <90 cm for men and <80 cm for women. Another measure of central obesity is Waist Hip Ratio (WHR), which is the waist circumference divided by the hip circumference. The hip circumference is measured

at the maximum circumference of the buttocks. Normal WHR is <0.85 for women and <0.90 for men. 4Misra A, Chowbey P, Makkar B, et al. Consensus statement for diagnosis of obesity, abdominal obesity and the metabolic syndrome for Asian Indians and recommendations for physical activity, medical and surgical management.JAPI.2009;57(2):163-170. Quick Reference Guide-Hypertension Page41

3. Alcohol Consumption  Reducing alcohol intake can lower the blood pressure substantially. On other hand moderate drinking and binge drinking increases the blood pressure and risk of developing hypertension.  Zero alcohol consumption is recommended for women who are pregnant or planning to have pregnancy and also for those hypertensives who had already suffering from a complication due to hypertension like stroke, heart disease or renal disease.

 Alcohol consumption is measured in terms of units of alcohol (UK) or standard drinks (e.g. Australia, USA). 1 unit of alcohol is 10 ml ethanol (around 8 gms ethanol), while 1 standard drink contains 10 g ethanol (Australia) or 14 g ethanol (USA).  The no. of units consumed per day can be calculated using the drink volume and the Alcohol by (ABV), which is mentioned as a percentage on the container. E.g. Beer may be around 5% ABV, wine is around 12.5%, while whisky and vodka are around 40% ABV.

 The number of units of alcohol = Drink volume x ABV /1000. Therefore 100 ml of whiskywill be 100 x 40/1000= 4 units.  Healthy adults should not regularly drink more than 3-4 units per day in the case of men and 2-3 units in the case of women. If there has been heavy alcohol consumption, there should be no alcohol intake for 48 hours.  Tips on cutting down should be offered to patients and should be employed in an incremental fashion(86) : These include keeping track of alcohol intake ( including

counting and measuring) and keeping intake within recommended limits, setting goals for consumption, drinking slowly and preferably with some food in the stomach. In patients who have decided to quit, avoiding triggers, dealing with urges, and refusing offers of drinks politely are of vital importance. Talking and enlisting the support of spouses, non-drinking friends, and mutual support groups like alcoholics anonymous are also very helpful. Quick Reference Guide-Hypertension Page42

4. Tobacco cessation Non-smokers should be encouraged not to start smoking.(87)All smokers should be encouraged to quit smoking, and should be supported by the health professional in their efforts to do so.(87) Patients who use other forms of tobacco should be motivated to stop doing so.  Smoking cessation may not reduce the blood pressure directly but markedly reduces overall cardiovascular risk. The risk of myocardial infarction is 2–6 times higher and

the risk of stroke is 3 times higher in people who smoke than in non-smokers. Smokers who quit reduce their risk of coronary heart disease.  Brief advice from health professionals is effective in helping persons to quit smoking, increasing quit rates. Even 3–5 minutes taken to encourage smokers to attempt to quit can increase success rates.  The WHO has recommended a 5 As approach to aid in smoking cessation in routine practice- The patient should be asked about smoking status at every opportunity.

Then the patient should be advised about to quit smoking, and assessed about his degree of addiction and readiness to quit. The health professional should assist in formulating a smoking cessation strategy including setting a quit date, counseling and other measures, and finallyarrange a follow up visit.  Pharmacotherapy to stop smoking with nicotine replacement therapy, bupropion, nortryptiline and varenicline are effective and should be offered to motivated

smokers who fail to quit with counseling. The risk of adverse effects is small and is generally outweighed by the significant risk of continuing to smoke. Quick Reference Guide-Hypertension Page43

5. Dietary Recommendations All patients should be encouraged to adopt a heart healthy diet. Fat: All individuals should be strongly encouraged to reduce total fat and saturated fat intake. Total fat intake should be reduced to about 30% of calories, saturated fat to less than 10% of calories, trans-fatty acids ( present in margarine and bakery products )intake should be reduced as much as possible or eliminated and most dietary fat should be

polyunsaturated (up to 10% of calories) or monounsaturated (10–15% of calories). Salt: All individuals should be strongly encouraged to reduce daily salt intake by at least one third and, if possible, to <5g or <90mmol per day. Fruits, vegetables, fibre: All individuals should be encouraged to eat at least 400 g a day of a range of fruits and vegetables as well as whole grains and pulses. 6. Salt Intake All patients should be strongly encouraged to limit their salt intake to < 5 g salt(or 90 mmol)

per day as per WHO recommendations.(87) There is lack of representative data on salt intake in India, although in a study in urban India, the mean intake was found to be 8.5 g salt per day.(88) Reduction of salt intake can be accomplished by not adding additional salt in diet, choosing foods processed without salt, avoiding high-salt processed foods, salty snacks, takeaway foods high in salt and salt added during cooking or at the table.

Preparations which are high in salt and need to be moderated are: Pickles, chutneys, sauces and ketchups, papads, chips and salted biscuits, cheese and salted butter, bakery products and dried salted fish. The above recommendation for dietary salt restriction may have to be individualisedin the case of certain occupational exposures.Acclimation to heat occurs rapidly; thus, within a few days of exposure to hot and humid conditions, individuals lose only small amounts of sodium

through sweat. But in the case of workers performing intense physical activity under conditions of heat stress, may lose significant amounts of fluid and salt in sweat. In a study it Quick Reference Guide-Hypertension Page45

was estimated that a 10 hour shift of working in moderately hot climatic conditions(350C) can result in loss of 10-15 g salt.(89) 7. Stress management  In hypertensive patients in whom stress may be contributing to blood pressure elevation, stress management should be considered as an intervention.  A recent systematic review and meta-analysis of Yoga concluded that there were clinically important effects on cardiovascular disease risk factors and that Yoga could

be considered an ancillary intervention to reduce cardiovascular risk.(90)With regard to its role in hypertension management, another systematic review concluded that there was emerging but low-quality evidence for Yoga as an adjunct to medical therapy, but larger confirmatory studies were required.(91) Quick Reference Guide-Hypertension Page46

ANNEXURE 3: FORMULARY Calcium channel blockers (CCBs) with focus on amlodipine Pharmacology of CCBs: These drugs interfere with the inward movement of calcium ions through the slow channels of cell membranes in the heart and the vascular smooth muscle. They are divided into 2 major classes , the dihydropyridines CCBs which includes amlodipine,nifedipine, felodipine) which do not have a major negative inotropic effect and no

antiarrhythmic activity, and the non-dihydropyridines like verapamil, and diltiazem, which have both significant negative inotropic and anti-arrhythmic activity. Amlodipine: Amlodipine has a very long elimination half- life (35 to 48 hours) and can be given once daily. It has a good safety profile, very few drug interactions, and no adverse effect on glucose, lipid levels. Other agents in this class like cilnidipine, nicardipine, lercanidipine, have no

major advantage over amlodipine whose outcome benefits have been established in large trials. An isomer of amlodipine, S-Amlodipine is also marketed in India, along with the amlodipine in its racemic form. The limited high quality data available suggests that there is no difference in therapeutic efficacy as well as adverse effects between the two forms(92). The S- Amlodipine form is more expensive. The racemic amlodipine is available in various forms –

amlodipine besilate, amlodipine mesilate, and amlodipine maleate, but these are interchangeable. Indications for amlodipine: Used alone or in combination for hypertension, chronic stable angina, coronary artery disease without heart failure or an ejection fraction <40% Dose, titration, and use in combinations Initial dose: 5 mg once daily. In elderly, small patients, and patients with hepatic impairment, the initial dose may be 2.5 mg once daily. The dose of 2.5 mg may also be used when adding

amlodipine to other antihypertensive agents. Dose may be increased at intervals of 7-14 days to achieve BP goals. Doses may be increased up to a maximum of 10 mg once daily. Amlodipine can be used in combination with ACE inhibitors/ARBs, and low dose diuretics for treatment of hypertension. Use in combination with beta-blockers is of benefit in patients with chronic stable angina. Contraindications: Cardiogenic shock, unstable angina, significant aortic stenosis. Worsening angina or increased

risk of myocardial infarction may be seen Quick Reference Guide-Hypertension Page47

Cautions: Drug interactions: Beta-blockers enhance hypotensive effect of amlodipine. Amlodipine increases exposure to simvastatin (dose of simvastatin should not exceed 20 mg per day). Amlodipine also increases exposure to ciclosporin and tacrolimus. Side effects: Generally well tolerated. Side effects are dose related and commoner in women. Pedal edema is the chief side effect, seen in around 10% of people on 10 mg daily, and may be decreased in

patients receiving angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Headache and flushing related to vasodilation may disappear after a few days. Use in Pregnancy and breast feeding Pregnancy Class C. Use if potential benefits outweigh risk. Avoid in lactation. Hepatic impairment: may need dose reduction Renal impairment:No modification of drug dose is required. Quick Reference Guide-Hypertension Page48

Angiotensin converting enzyme inhibitors with focus on enalapril and its use in hypertension Pharmacology: Angiotensin converting enzyme (ACE) inhibitors are drugs which inhibit the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor) and the degradation of bradykinin. They represent a real advance in cardiovascular therapy and have broad spectrum of proven beneficial effects in heart failure, hypertension, renal disease and cardio-protection

after myocardial infarction. They are generally well tolerated with no effect on blood glucose or lipids, with adverse effects which are occasional (e.g. cough), or quite rare (e.g. Angioedema). These adverse effects are not dose related. Some adverse effects are seen when administered in patients with heart failure on high dose diuretics (first dose hypotension), or pre-existing renal parenchymal and vascular disease (rise in creatinine, hyperkalaemia), which may be dose

related.Use of all ACE inhibitors is contraindicated in pregnancy. Indications for enalapril: Hypertension, heart failure (all stages), nephropathy (non-diabetic and diabetic), cardio- protection in early phase acute MI and post-MI LV dysfunction. Dose, titration, and use in combinations:Initial dose in hypertension: 5 mg in one or two divided doses daily. In patients who have received diuretics, those who were elderly, the initial

does may be 2.5 mg5. The dose may be usually increased to 10 mg above which the additional benefit may be minimal6, although the maximum dose mentioned for hypertension is 20 mg per day. Enalapril can be used in combination with low dose diuretics, calcium channel blockers for treatment of hypertension. ACE inhibitors should not be combined with ARBs. Contraindications: Pregnancy is a contraindication for use of ACE inhibitors. Bilateral renal

artery stenosis,History of hypersensitivity (including angioedema). Cautions: Renal function may be assessed before starting therapy. In patients receiving diuretics especially high dose diuretics, there is a risk of first dose hypotension, which may be minimised by using a low dose of enalapril, close medical supervision. Up to 30% increase in serum creatinine may occur on starting ACE inhibitors, which is reversible. Hyperkalemia can occur if

there is renal impairment, or patientis on potassium containing salt substitutes. Side effects: 570. Opie L.H, Gersh B.J, editors. Drugs for the Heart. 8th ed: Saunders; 2013. 670. Ibid. Quick Reference Guide-Hypertension Page49

Generally well tolerated. Cough is the most common side effect; angioedema is rare and may be potentially serious. Breast feeding: Limited information. Do not use enalapril for the first few weeks of life, especially in the case of preterm infants because of risk of neonatal hypotension PregnancyClass D Use in second and third trimesters confers risk of oligohydramnios, and birth malformations. Hepatic impairment: may need dose reduction, and close monitoring.

Renal impairment: mayneed dose reduction when creatinine clearance is less than <30 ml/min (approximate serum creatinine 3 mg/dl), when dose should be 2.5 mg once a day.7 7US FDA full prescribing information for enalapril. Quick Reference Guide-Hypertension Page50

Thiazide diuretics for use in hypertension with special focus on low dose hydrochlorothiazide: They act by increasing sodium excretion. Thiazide diuretics are useful agents in the therapy of hypertension as first line drugs and as add on therapy when initial therapy with calcium channel blockers, ACE inhibitors does not achieve target for BP control. Benefits on cardiovascular outcomes have been proven for hydrochlorothiazide, chlorthalidone and indapamide. They are

long acting agents effective as once a day therapy. In high doses(25 mg and above) thiazides have metabolic side effects like glucose intolerance, worsening of lipids, hypokalaemia, but given in low doses (12.5 mg) they exert near maximal lowering of BP without producing biochemical changes as noted above. Thiazide like agents like chlorthalidone, indapamide are also available, which are longer acting than hydrochlorothiazide, and have beneficial outcomes

on cardiovascular mortality documented in clinical trials. Indications for thiazides: Hypertension, Heart failure Dose, titration, and use in combinations in hypertension Dose in hypertension: 12. 5 mg once daily. Increasing the dose to 25 mg daily may not increase antihypertensive effect but can increase risk of hyperglycemia. Low dose hydrochlorothiazide can be used in combination with calcium channel blockers, and

ACE inhibitors for treatment of hypertension. The combination of thiazide diuretics with beta- blockers is not preferred as it increases the risk of new onset diabetes as well has an adverse effect on lipids. Contraindications: severe hypokalemia, hyponatremia, hypercalcemia. Cautions Thiazides can worsen glycemiccontrol and gout. Side effects: Gastro-intestinal disturbances, orthostatic hypotension, altered plasma lipid concentration, metabolic and electrolyte disturbances (including hypokalaemia,

hyponatraemia, hypomagnesaemia, hypercalcaemia, hyperglycaemia). Occasional thrombocytopenia, impotence. Pregnancy: Not used to treat hypertension in pregnancy. Administration in third trimester carries risk of neonatal thrombocytopenia. Hepatic impairment: Avoid in severe liver disease; hypokalemia may precipitate hepatic encephalopathy Quick Reference Guide-Hypertension Page51

Renal impairment: Avoid if creatinine clearance is less than <30 ml/min (approximate serum creatinine 3 mg/dl), when they may be ineffective. Quick Reference Guide-Hypertension Page52

HYPERTENSIVE URGENCIES AND EMERGENCIES Monitor side effects of drugs HYPERTENSION Drug group Compelling Compelling Usual dose Side effects indications contraindications (reduce in elderly) SBP>180, DBP>110-120 • Calcium channel blockers – peripheral edema. Dose-dependent, may subside with reduction of dose or combination with ACE inhibitor.

Thiazide diuretics Isolated systolic Gout 12.5-25 mg Metabolic – Assess for following and investigate as appropriate: creatinine (all), x-ray chest, ECG, CT scan Screening, diagnosis, assessment, and management Hydrochlorothiazide hypertension hypokalemia, A Altered consciousness • Diuretics – hypokalemia, hyperglycemia. Less frequent at lower doses and when of primary hypertension in adults in india

(in elderly) hyperglycemia, B Breathlessness combined with ACE inhibitors. Thiazide induced hyponatremia commoner in hyperuricemia C Chest pain (ischemic) elderly. Can develop rapidly – altered consciousness or seizures. Low dose D Deficit (weakness in one or more limbs) or decreased urinary output • ACE inhibitors – dry cough. May necessitate withdrawal. Risk of hypotension

minimizes E Edema with ACE inhibitors in patients already on diuretics, or on a very low salt diet. Standard Treatment Guidelines - Ready Reckoner metabolic effects F Fundus if feasible- hemorrhages, exudates, papilledema Hyperkalemia can develop with high doses of ACE inhibitors, more commonly G Generalized seizures in those with renal insufficiency, diabetes, concurrent use of potassium sparing ACE inhibitors Diabetes (especially Pregnancy 5 -20 mg Dry irritating

diuretics, and the elderly. A small reversible rise in serum creatinine can occur. Enalapril with proteinuria or Hyperkalemia (enalapril) cough HYPERTENSIVE URGENCY - none of the above cardiac disease) Bilateral renal Angioedema Use oral drugs History of stroke, MI, artery stenosis Hyperkalemia Reduce BP over hours to days PREVENTION OVERVIEW hypertension with and reversible HYPERTENSIVE EMERGENCY – one or more of the above

heart failure decline in renal Reduce BP (only rarely to normal) over minutes to hours, according to type of emergency Promotion of a five point population-wide intervention CKD where close function in some Use parenteral drugs, choice depends upon type of emergency (see list below) • Weight reduction in the obese Cardiovascular disease is the leading cause of death (including premature death) in India.

biochemical DO NOT USE SUBLINGUAL NIFEDIPINE • Regular exercise in the sedentary Hypertension is the leading risk factor for cardiovascular disease. monitoring possible • Decrease salt, sugar and fat intake Types of hypertensive emergencies Calcium channel Isolated systolic No compelling 5-10 mg Pedal edema at Accelerated Malignant Hypertension • Quit tobacco use Its prevalence is rising and approaches a third of all adults in urban India.

blockers hypertension contraindication. higher doses Cardiac – acute left ventricular failure, myocardial infarction, unstable angina • Moderation of alcohol intake It is symptomatic only when the BP is extremely high or when complications occur. Amlodipine (in elderly) Heart failure, Headache Neurologic – hypertensive encephalopathy, ischemic stroke, intracranial hemorrhage, head injury

Renal – acute glomerulonephritis#, renovascular hypertension Increased intake of fruits and vegetables in addition to decreased salt intake has the CKD where close tachyarrhythmia Tachycardia Surgical – post-operative hypertension, severe burns Uncontrolled hypertension is a ‘silent killer’. It can cause serious complications potential to lower blood pressure significantly. biochemical are possible Obstetric – eclampsia# like stroke (paralysis), heart attack, heart failure, kidney failure and vision loss.

monitoring NOT contraindications # Hypertensive emergency may occur even at BP levels lower SBP 180 and DBP 110 mmHg This prescription for healthy living along with avoidance of tobacco use can also prevent feasible obesity, diabetes, cardiovascular disease and many common types of cancer. Only a quarter of adults in India are aware of their BP status, only a quarter of

Beta-blockers Previous MI Asthma 25-100 mg Fatigue, reduced FOLLOW UP, MONITORING AND IMPROVING ADHERENCE hypertensives are on treatment, and only 10-20% of hypertensives have their Atenolol Heart failure AV block (atenolol) exercise tolerance BP under control. Team approach involving physicians, allied staff and community based health workers. (use metoprolol, Hyperglycemia Prevention, detection, and effective management of hypertension can prevent

bisoprolol, especially when Hypertension registry at PHC and CHC level to ensure tracking of patients. carvedilol) combined with FURTHER READING deaths and serious disability in lakhs of people, and save hundreds of crores in Monitor every 1-2 weeks till target BP achieved. Thereafter frequency determined by diuretics severity of hypertension, co-morbidities, and target organ damage. healthcare costs every year. 1 STG for Screening, Diagnosis, Assessment, Management of Primary Hypertension in Adults in

Angiotensin receptor As in ACE inhibitors Pregnancy 50-100 mg Cough (rare) Annual review of control of BP, implementation of lifestyle modifications, target organ India – Quick Reference Guide. MoHFW, GOI 2016 This standard treatment guideline has been developed for the management of blockers Use if ACE inhibitors Hyperkalemia (losartan) Hyperkalemia damage, review of treatment including side effects of drugs. Contains key recommendations, clinical pathways and a formulary for healthcare providers.

hypertension in the Indian context and has a primary care focus and a Losartan have side effects like Bilateral renal and reversible cough artery stenosis decline in renal People with high normal BP should also be advised appropriate lifestyle modifications and 2 STG for Screening, Diagnosis, Assessment, Management of Primary Hypertension in Adults in public health approach. function in some encouraged to undergo an annual review. India – Full Guideline. MoHFW, GOI 2016

Improve adherence by Contains details of recommendations with evidence base and methodology followed in developing • a simplified regime using long acting drugs once a day the guidelines and implementation issues for healthcare providers and programme managers. Adjunctive therapy • streamlined methods of dispensing drugs and pill counts Low dose aspirin may be given to patients with hypertension and cardiovascular disease, or • supervision by a family member May 2016

well controlled hypertensives with high cardiovascular risk (>3 risk factors). • periodic counselling and patient information leaflets This guideline has been developed by the Medicine Sub-group of the Task Force for the Development Ministry of Health and Family Welfare Statins are indicated in hypertensives with cardiovascular disease, LDL-C >190 mg/dl, of Standard Treatment Guidelines for the National Health Mission of the Ministry of Health and Family

• home blood pressure monitoring using a validated automated device coexisting diabetes, or multiple cardiovascular risk factors. Welfare, Government of India. Government of India

SCREENING – Zero Cost-No Pain-High Gain Procedure EVALUATION ALL PATIENTS REQUIRE LIFE-LONG LIFESTYLE MODIFICATION Dietary change – salt restricted (<5g/day), low-fat diet Opportunistic screening for hypertension should occur at every encounter with the Assess the presence of Reduce weight – target BMI 18.5-22.9 kg/m2 health system including with community based health workers. • other cardiovascular risk factors Regular exercise – moderate intensity, 30 minutes, 5 days a week

• target organ damage (LVH or heart failure, proteinuria, renal failure, retinopathy) Targeted screening for hypertension should be community based and target those at risk STOP SMOKING of developing hypertension – age over 50 years, overweight and obese persons, those • associated clinical conditions (diabetes, ischemic heart disease, cerebrovascular with diabetes, existing cardiovascular disease, those with family history of hypertension disease, CKD) GRADE 1 HYPERTENSION (SBP 140-159, DBP 90-99) with

and smokers. Diabetes OR TOD (proteinuria, LVH, retinopathy) OR associated clinical conditions Essential evaluation OR more than 3 risk factors – male Measuring blood pressure • History – cardiovascular risk factors (diet and exercise patterns, smoking, alcohol men aged >55 years, women aged >65 years consumption, family history of premature CAD) symptoms of target organ 1 Choice of BP device smoking

damage or associated clinical conditions (breathlessness, angina, history of obesity, including abdominal obesity Mercury sphygmomanometer or any other device (including electronic digital transient ischemic attack or stroke) dyslipidemia oscillometric devices) validated using a standard protocol, and calibrated regularly. impaired glucose tolerance • Examination – weight, height, BMI, unequal pulses, raised jugular venous family history of early coronary artery disease

2 Patient preparation and position pulsations, S3 gallop, and pedal edema OR inadequate control after 3 months of lifestyle modification Patient should relax for 5 minutes before measurement. Should not have had • Investigation – fasting capillary/blood sugar, proteinuria caffeine in the past hour or smoked in the past 30 minutes. Should be seated Drug therapy – A or C1 or D

comfortably with back supported, arm at heart level, and legs uncrossed. Desirable evaluation in patients with Grade 2 hypertension, diabetes or proteinuria Add second drug - A+C or C+D or A+D if response not adequate within 2-4 weeks • History, examination – as above 3 Cuff size and placement DIAGNOSIS, CLASSIFICATION • Investigations – as above PLUS serum creatinine, fasting lipid profile, ECG Add third drug – A+C+D if response not adequate within 2-4 weeks

Appropriate cuff size – length of bladder 80% of arm circumference, width 40% of arm circumference. Use a large adult cuff for an obese patient. Patient should not Hypertension is systolic BP 140 mmHg or higher and diastolic BP 90 mmHg or higher. Comprehensive evaluation in patients with Grade 3 hypertension, CKD, heart failure GRADE 2 HYPERTENSION (SBP 160-179, DBP 100-109) wear any constrictive clothing. Place midline of cuff over pulsation of the brachial

• History and examination – as above PLUS fundus examination PLUS examine Drug therapy – A or C or D artery, 2-3 cm above the cubital fossa. TWO readings on at least TWO occasions. for clues for secondary hypertension (moon facies, unequal pulses, postural Add second drug - A+C or C+D or A+D if response not adequate within 2-4 weeks 4 Procedure Valid device and standardised BP measurement procedure. hypotension, renal artery bruit, palpable kidneys)

Add third drug – A+C+D if response not adequate within 2-4 weeks For auscultation based BP measurement, inflate cuff to 30 mm beyond the • Investigations – as above PLUS serum electrolytes, USG abdomen, 2-D Echo Category Systolic BP mmHg Diastolic BP mmHg disappearance of the radial pulse. Deflate cuff at 2-3 mm per second and record GRADE 3 HYPERTENSION (SBP ≥180, DBP ≥110) the first and the last sounds by auscultation over the brachial artery as the systolic Optimal <120 and <80

and diastolic blood pressure respectively. Use two drugs - A+C or C+D or A+D Normal 120 – 129 and/or 80 – 84 MANAGEMENT - target BP <140/90 mmHg, <150/90 in patients over 80. For oscillometric devices follow the manufacturer’s instructions and the BP will be High Normal 130 – 139 and/or 85 – 89 Add third drug – A+C+D if response not adequate within 2-4 weeks displayed automatically. The overall aim is to reduce BP to target levels within 6-8 weeks and to reduce

Grade 1 Hypertension 140 – 159 and/or 90 – 99 ALL GRADES OF HYPERTENSION WITH ASSOCIATED CLINICAL CONDITIONS cardiovascular risk. 5 Number of measurements and recording the result Grade 2 Hypertension 160 – 179 and/or 100-109 CAD: coronary artery disease - B+A2, C At least 2 readings at an interval of 2 minutes. If readings differ by more than PATIENT EDUCATION discuss the following points

5 mmHg take a third reading. The lower of the readings should be taken as the Grade 3 Hypertension ≥180 and/or ≥110 CHF: congestive heart failure - D+A+B, MRA representative SBP and DBP. Isolated Systolic Hypertension ≥ 140 and < 90 Nature of disease – hypertension is asymptomatic but can produce damage to heart, CKD: chronic kidney disease - A, C, D3 brain, and kidney if uncontrolled. DM: diabetes mellitus - A/C, D Recommended action on BP readings (in mmHg) for persons screened by health workers

Hypertensive urgency 1 ≥180 and/or ≥110 Lifestyle measures – can reduce BP, reduce the doses of medicines, and reduce risk of Abbreviations: CAD: coronary artery disease, CHF: congestive heart failure, CKD: chronic kidney disease, DBP: diastolic blood pressure,

SBP ≥180 and/or DBP ≥110 with or without complications REFER IMMEDIATELY to PHC/CHC Hypertensive emergency 2 ≥180 and/or ≥110 damage to the heart. DM: diabetes mellitus, LVH: left ventricular hypertrophy, SBP: systolic blood pressure, TOD: target organ damage. SBP 160-179 and/or DBP 100-109 refer to PHC within 1 week Drug classes: A: Angiotensin converting enzyme (ACE) inhibitors, (e.g. enalapril) or Angiotensin II receptor blockers (ARBs, e.g. losartan)

Therapy – medicines should be taken every day without a break. The patient should only if intolerance to ACE inhibitors, B: beta-blockers (e.g. atenolol), C: calcium channel blockers (e.g. amlodipine), D: thiazide diuretics 1 Severe asymptomatic hypertension with no evidence of acute target organ damage SBP 140-159 and/or DBP 90-99 refer to PHC within 1 month inform the doctor if he notices any side effects. (e.g. hydrochlorothiazide), MRA: mineralocorticoid receptor antagonist (e.g. spironolactone).

2 Severe hypertension associated with ongoing target organ damage – Footnotes: SBP 130-139 and/or DBP 85-89 recheck in 1 year cardiovascular (e.g. left ventricular failure), cerebral (e.g. hypertensive BP targets and monitoring – inform patients about target BP- which is generally < 140 1 Calcium channel blockers are antihypertensives of choice in the elderly (> 60 years).

SBP < 120 and DBP <80 recheck in 2 years encephalopathy or stroke), renal (acute renal failure), Grade III-IV retinopathy mm systolic and <90 mm diastolic. Encourage patient to monitor BP at home, if possible. 2 Patients with CAD and history of myocardial infarction should receive both beta-blockers and ACE inhibitors. 3 Patients with CKD may need loop diuretics if GFR is low. Those on ACE inhibitors need regular monitoring of creatinine and potassium.

Preamble Kala-azar (KA) or Visceral Leishmaniasis (VL) is a parasitic disease with anthroponotic (confined to human only, no animal reservoir) infection in Asian continent. If remain untreated, probability of death of Kala-azar patient within two years of the onset of the disease is high. The disease is endemic in Indian subcontinent in 119 districts in four countries namely Bangladesh, Bhutan, India and Nepal. India alone accounts for about

50% of the global burden of KA. Though KA is one of the most dangerous neglected tropical diseases (NTDs), it is amenable to elimination as a public health problem. Favourable factors for Kala-azar Elimination are: man is the only host, sandfly (Phlebotamus argentipes) is the only vector and rapid diagnostic tests with new and effective drugs are available for use in the programme. The geographical spread of the disease is limited to 54 districts in India and above all there is high political commitment.

Focused activities towards Kala-azar control were intensified in 1990-91, with limited options for prevention and control of the disease. Long treatment schedule with injection Sodium stibogluconate and indoor residual spray (IRS) with DDT 50% were the mainstay of activities. Over a period of time, resistance to the only drug (injection Sodium stibogluconate) led to frequent outbreaks and fatalities. National Health Policy (2002) envisaged KA elimination by 2010 which was revised to

2015. There is a Tripartite Memorandum of Understanding signed by Bangladesh, India and Nepal to eliminate KA from the South-East Asia Region. The criterion of elimination is attainment of annual incidence of KA to less than one per 10,000 population at upazilla level in Bangladesh, sub-district (block PHC) level in India and district in Bhutan and Nepal. Since 2003, KA programme activities have been subsumed under the umbrella of National Vector Borne Disease Control Programme (NVBDCP). All the programme

activities and operational cost, with 100% central assistance, are being implemented. ‘Health Care’ being a State subject, endemic states are implementing programme activities through the State Health system under the National Health Mission. KA elimination activities received impetus with the World Bank supported project (2008- 2013). During the World Bank project, provisions for additional human resource were made at National level. Consultants at State and District level and Kala-azar Technical

Supervisors (KTS) at endemic Block level were provided from World Bank funds. Provisions for mobility were also made therein. After the termination of World Bank project during 2013, same support is being still continued from Central domestic budget. New technology and advances in diagnosis and treatment like availability of easy to use rapid diagnostic test and availability of effective drugs (oral Miltefosine, injectable Liposomal Amphotericin B and combination regimens) has renewed interest in

elimination of KA. Global focus has also been reinvigorated for neglected tropical diseases including Leishmaniasis. The London Declaration in 2012 and World Health Assembly Resolution in 2013 provide opportunities to accelerate the activities towards reducing the impact of neglected tropical diseases and to develop new partnerships. New Central government after taking over the charge took into cognizance the importance of KA

elimination and India’s commitment as reflected in National Health Policy, constituted a ‘Core Group’ at the Ministry of Health Welfare&Familylevel for guidance and oversight of the progress towards elimination. The roadmap document is developed for focused efforts at national, state, district and sub-district level. Presently, resources are available, multiple partners are providing support, easy to use diagnostic tests are available, there is drug donation through WHO inter alia high political

commitment at all levels. Programme is striving for achieving KA elimination by the target date. 2

Executive summary National Roadmap for Kala-azar Elimination (NRKE) has been prepared with clear goal, objectives, strategies, timelines with activities and functions at appropriate level. This document is based on latest global, regional and local evidence available in the prevention, control and management of Kala-azar disease as well as strategies for vector control. NRKE is in line with National Strategic Plan of National Vector Borne

Disease Control Programme for the Twelfth five-year plan period (2012-2017) and at the same time in synchronization with WHO’s Regional Strategic Framework for Kala- azar elimination from South-East Asia Region (2011-2015), recommendations of WHO Expert Committee on Leishmaniasis and WHO Regional Technical Advisory Group, South-East Asia Region. Roadmap provides strategic directions on reducing the delay between onset of disease and diagnosis and treatment by laying down timelines against each activity.

It emphasizes specifically on early case detection and complete management (including follow up mechanisms and monitoring for adverse effects). Recently more drugs are available for treatment. Roadmap highlights plan for the introduction of single dose (10 mg/kg) Liposomal Amphotericin B in the treatment of KA and other conditions like post Kala-azar dermal leishmaniasis. With scanty data currently available on the burden of post Kala-azar dermal leishmaniasis (PKDL), roadmap

lays down surveillance needs to be established and/or strengthened for PKDL as well as for HIV-VL co-infection. Integrated Vector Management (IVM) is the main strategy which provides rational decision-making process for optimum use of resources for vector control. Indoor residual spray operations remain mainstay of vector control. Micro-plan and timely spray activities have been envisaged for reducing longevity of the adult vectors,

elimination of the breeding sites, decrease contact of vector with humans, and reduction in the density of the vector. The population at risk for Kala-azar is among the poorest in the community with limited access to health care due to various socio-economic determinants. Intensive awareness campaigns with the involvement of communities and community health volunteers will address important barriers in utilization of services.

Kala-azar elimination will require effective involvement of health personnel at all levels in the continuum of care, right from the engagement of ASHA at village level to laboratory technicians, medical officers at primary health care to specialists at district hospitals for early identification of a suspected case and then to diagnosis treatment including complications. Effective programme management is one of the most important operational aspects

of success of KA elimination in India along with supervision, monitoring and surveillance components to ensure that success is not only achieved but sustained also. 3

Acronyms ANM Auxiliary Nurse cum Midwife ASHA Accredited Social Health Activist AWW Anganwadi worker BMGF Bill & Melinda Gates Foundation BTAST Bihar Technical Assistance Support Team CARE Care and Relief Everywhere CMHO Chief Medical and Health Officer DDT Dichloro Diphenyl Trichloroethane DFID Department of Foreign Investment and Development DNDi Drugs for Neglected Diseases initiative EDCT Early Diagnosis and Complete Treatment ED Executive Director HIV Human Immunodeficiency Virus

ICMR Indian Council of Medical Research IDSP Integrated Disease Surveillance Programme IEC Information, Education and Communication IRS Indoor Residual Spray ISC Indian subcontinent IVM Integrated Vector Management KA Kala-azar KTS Kala-azar Technical Supervisor LAMB Liposomal amphotericin B LD bodies Leishmania Donovan bodies MD Managing Director MOHFW Ministry of Health and Family Welfare MoU Memorandum of Understanding MSF Medecins Sans Frontieres NCDC National Center for Disease Control

NHM National Health Mission NRKE National Roadmap for Kala-azar Elimination NVBDCP National Vector Borne Disease Control Programme PHC Primary Health Centre PKDL Post Kala-azar Dermal Leishmaniasis RBSK Rogi Bal Suraksha Karyakram RMRI Rajendra Memorial Research Institute RDT Rapid Diagnostic Test RTAG Regional Technical Advisory Group SEAR South-East Asian region SHS State Health Society SPO State Programme Officer VBD Vector Borne Diseases VL Visceral Leishmaniasis WHO World Health Organization 4

Contents Preamble 1 Executive summary 2 Acronyms 3 1. Introduction 6 2. Global Scenario 7 3. India Scenario 8 3.1 Bihar Scenario 8 3.2 Jharkhand Scenario 8 3.3 West Bengal Scenario 9 3.4 Uttar Pradesh Scenario 9 4. National Kala-azar elimination programme 10 4.1 Goal 10 4.2 Target 10 4.3 Objective 10 5. The Elimination strategy 11 5.1 Early diagnosis and complete treatment 11 5.2 Integrated vector management (IVM) 12 5.3 Supervision, monitoring, surveillance and evaluation 12

5.4 Strengthening capacity of human resource in health 13 5.5 Advocacy, communication and social mobilization for behavioral impact and inter-sectoral convergence 13 5.6 Programme management 13 6. Road Map for Kala-azar elimination 14 6.1 Diagnosis and treatment 14 6.2 Active case search 17 6.3 Rolling out of Liposomal Amphotericin B 17 6.4 Criteria for selection of districts and blocks PHCs for Liposomal Amphotericin B roll out 18 6.5 PKDL 19 6.6 Micro-plan 19

6.7 Integrated vector management including indoor residual spraying (IRS) 21 6.8 Release of funds is one of the requisite criteria for Kala-azar elimination 22 5

6.9 Surveillance, monitoring, supervision & evaluation 26 6.10 Human Resources Issues 28 6.11 Capacity building of human resource at all levels 29 6.12 Advocacy, communication and social mobilization 30 6.13 Programme management 30 6.14 Stakeholders in the programme 34 7. Timeline of activities 39 8. Roles and responsibilities of the Centre and State Governments 44 9. Roles and responsibilities of District Collectors/Magistrate 45 9.1 Early diagnosis & complete treatment 45 9.2 Integrated vector control 45

9.3 Environmental measures 46 10. District level activities 47 10.1 Formation of district level Kala-azar elimination (KAE) committee 47 11. Time line for Kala-azar elimination 48 11.1 National level actions 48 11.2 State level actions 50 11.3 District level actions 52 11.4 Block level actions 54 11.5 Village level actions 56 6

National Road Map For Kala-azar Elimination 1. Introduction Kala-azar (KA) also called Visceral Leishmaniasis is a parasitic disease with anthroponotic (confined to human only, no animal reservoir) infection in Asian continent. It is caused by the protozoan Leishmania parasites which are transmitted by the bite of infected female phlebotomine argentipes sand fly. Kala-azar is characterized by irregular bouts of high fever, substantial weight loss, enlargement of

the spleen and liver, and anaemia. If left untreated, the disease can have a fatality rate as high as 100% within two years. Transmission in Indian sub-continent generally occurs in rural areas with a heavy annual rainfall, with a mean humidity above 70%, a temperature range of 15–38 °C, abundant vegetation, subsoil water and alluvial soil. The disease is most common in agricultural villages where houses are frequently constructed with mud walls and

earthen floors, and cattle and other livestock live close to humans. 7

2. The Global Scenario The annual incidence of reported global KA cases is 58,200 of which 42,619 (>70%) is contributed from the Indian Subcontinent (ISC). The revised global and ISC annual incidence estimate of KA is 201,500–378,500 and 160,000–320,000, respectively, of which more than 90% cases occur in six countries, Bangladesh, Brazil, Ethiopia, India, Nepal and Sudan. There are currently no accurate data on the burden of Post Kala-azar Dermal

Leishmaniasis (PKDL). VL–HIV co-infection has also emerged as a serious concern and is reported from 36 countries. There is a strong need to establish surveillance for both the conditions. An estimated 147 million people in 119 districts in 4 countries, namely Bangladesh, Bhutan, India and Nepal, are at risk with an estimated 20,000 new cases each year. India alone accounts for about 50% of the global burden. The proportion of

unreported cases is yet to be established but estimates range from 0.2 to 4 times of the reported cases. 8

3. India Scenario Kala-azar is at present endemic in 54 districts in the country of which 33 districts of Bihar, 4 districts of Jharkhand, 11 districts of West Bengal besides occurrence of sporadic cases in 6 districts of eastern Uttar Pradesh. The state of Bihar alone contributes >70% of total KA reported from the four states. In 2013, the cases have declined by 38% and 33% respectively in comparison with the year 2011. Mortality

has also reduced from 90 deaths in 2011 to 20 in 2013. The same trend is observed during 2014 so far. 3.1 Bihar Scenario Of the 38 districts of Bihar, 33 are affected. The population at risk is 34.65 million, in approximately 12,000 villages spread over 426 blocks. 62% of these blocks have achieved level of elimination. Most of the cases are reported from districts in the northern half, mostly constituting the floodplains of major rivers. 10 districts out of 33 affected by Kala-azar in Bihar

detect 500 or more cases annually and contribute to about 70% cases of the state. These are Araria, East Champaran, Madhepura, Muzaffarpur, Purnia, Saharsa, Samastipur, Saran, Sitamarhi and Vaishali. 3.2 Jharkhand scenario Out of 24 districts 4 districts namely, Dumka, Godda, Pakur and Sahibganj are endemic for Kala-azar. The population at risk is 4.8 million, in approximately 1,507 villages spread over 30 blocks. Only 10% blocks have achieved elimination. 9

3.3 West Bengal Out of 19 districts 11 districts namely, Malda, Murshidabad, Darjeeling, 24- Parganas(N), 24-Parganas(S), Nadia, Hooghly, Burdwan, Dinajpur (N), Dinajpur (S) and Birbhum are endemic for Kala-azar. The population at risk is 4.76 million, in approximately 731 villages spread over 119 blocks. 93% blocks have achieved level of elimination. 3.4 Uttar Pradesh Out of 72 districts, 6 districts in eastern part of the State namely Kushinagar, Balia,

Deoria, Varanasi, Gonda and Gazipur are reporting sporadic cases of Kala-azar. The number of cases reported during 2013 was 11. So far 7 cases have been reported from the State during 2014. The population at risk is 2.35 million. All the blocks have reached level of elimination. 10

4. National Kala-azar elimination programme Kala-azar has been a serious medical and public health problem in India since historical times. Bengal is the oldest known Kala-azar endemic area of the world. After the initial success, Kala-azar resurged in 70s. Concerned with the increasing problem of Kala-azar in the country, the Government of India (GOI) launched a centrally sponsored Kala-azar Control Programme in the endemic states in 1990-91.

The GoI provided drugs, insecticides and technical support and state governments provided costs involved in implementation. The program was implemented through State/District Malaria Control Offices and the primary health care system. The programme brought a significant decline in Kala-azar morbidity, but could not sustain the pace of decline for long. The National Health Policy-2002 set the goal of Kala-azar elimination in India by the

year 2010 which was revised to 2015. Continuing focused activities with high political commitment, India signed a Tripartite Memorandum of Understanding (MoU) with Bangladesh and Nepal to achieve Kala-azar elimination from the South-East Asia Region (SEAR). Elimination is defined as reducing the annual incidence of Kala-azar to less than 1 case per 10,000 population at the sub-district (block PHCs) level in Bangladesh and India and at the district level in Nepal.

Presently all programmatic activities are being implemented through the National Vector Borne Disease Control Programme (NVBDCP) which is an umbrella programme for prevention & control of vector borne diseases and is subsumed under National Health Mission (NHM). 4.1 Goal To improve the health status of vulnerable groups and at-risk population living in Kala-azar endemic areas by the elimination of Kala-azar so that it no longer remains a public health problem. 4.2 Target

To reduce the annual incidence of Kala-azar to less than one per 10,000 populations at block PHC level. 4.3 Objective To reduce the annual incidence of Kala-azar to less than one per 10 000 population at block PHC level by the end of 2015 by:  reducing Kala-azar in the vulnerable, poor and unreached populations in  endemic areas;   reducing case-fatality rates from Kala-azar to negligible level;  reducing cases of PKDL to interrupt transmission of Kala-azar; and 

 preventing the emergence of Kala-azar and HIV/TB co-infections in endemic areas. 11

5 The Elimination strategy The national strategy for elimination of Kala-azar is a multipronged approach which is in line with WHO Regional Strategic Framework for elimination of Kala-azar from the South-East Asia Region (2011-2015) and includes: I. Early diagnosis & complete case management II. Integrated Vector Management and Vector Surveillance III. Supervision, monitoring, surveillance and evaluation V. Advocacy, communication and social mobilization for behavioral impact and inter-sectoral convergence

VI. Programme management 5.1 Early diagnosis and complete case management This is done for eliminating the human reservoir of infection through early case detection. Effective case management includes diagnosing a case early along with complete treatment and monitoring of adverse effects. This strategy will reduce case- fatality and will improve utilization of health services by people suspected to be suffering from the disease.

The starting point of early diagnosis is to follow uniform suspect case definition. - A ‘suspect’ case:history of fever of more than 2 weeks and enlarged spleen and liver not responding to anti malaria in a patient from an endemic area. - All patients with above symptoms should be screened with Rapid Diagnostic Test and if found positive should be treated with an effective drug. - In cases with past history of Kala-azar or in those with high suspicion of Kala-

azar but with negative RDT test result, confirmation of Kala-azar can be done by examination of bone marrow/spleen aspirate for LD bodies at appropriate level (district hospital) equipped with such skills and facilities. Treatment: In 2010, the WHO Expert Committee on Leishmaniasis, and subsequently the Regional Technical Advisory Group (RTAG) of WHO South-East Asia Region (SEAR) recommended Liposomal Amphotericin B (LAMB) in a single dose of 10

mg/kg as the first choice treatment regimen for the Indian Subcontinent (ISC) within the current elimination strategy, given its high efficacy, safety, ease of use and assured compliance. The decision to use Liposomal Amphotericin B for Kala Azar was taken by the Technical Advisory Committee based on the available evidences and approved by Ministry of Health and Family Welfare, Govt. of India. In selected districts, Amphotericin B emulsion has been approved. The combination regimen

(Injection Paromomycin-Miltefosine for 10 days) is also recommended. Miltefosine 28 days regime and Amphotericin B as multiple doses may also be used. Within the Indian National Programme, assuming availability of drugs, appropriate training of health personnel, infrastructure and indication, the following drugs will thus be used in order of preference at all levels: – Single Dose 10mg/kgbw Liposomal Amphotericin B (LAMB) – Combination regimens (e.g. Miltefosine & Paromomycin) – Amphotericin B emulsion 12

– Miltefosine – Amphotericin B deoxycholate in multiple doses Post Kala-azar Dermal Leishmaniasis (PKDL) patients are to be treated with (i) Miltefosine: 100mg orally per day for 12 weeks, for patient weighing >25kgs; 50mg orally per day for 12 weeks for patients weighing <25kgs. All patients receiving Miltefosine lasting longer than 4 weeks should be closely monitored for side effects, or (ii) Liposomal amphotericin B: 5mg/kg per day by infusion two times per week for 3

weeks for a total dose of 30mg/kg, although additional evidence is needed, potassium supplementation is recommended for this regimen given in a patient’s diet (for all patients) or through intravenous infusion (for those with proven severe Hypokalemia). To prevent serious adverse effects caused by Hypokalemia, patients should be monitored for any related signs or symptoms. Hypokalemia should be suspected in all patients with general weakness, nausea, myalgia, muscle weakness

or camp occurring during or after the treatment. (iii) Amphotericin B deoxycholate: 1mg/kg per day by infusion, up to 60-80 doses delivered over 4 months. Case management of special conditions like relapse, HIV-VL co-infection and others will follow NVBDCP operational guidelines of Kala-azar It is to be noted that Miltefosine cannot be given to pregnant and lactating women, nor in young children. In women of child-bearing age Miltefosine should not be

prescribed unless contraception is guaranteed during treatment and for two months after the treatment is completed. In women suffering from PKDL treated with Miltefosine, this period is extended to 5 months following completion of treatment. 5.2 Integrated vector management (IVM) including indoor residual spraying (IRS) Integrated Vector Management (IVM) is a rational decision-making process for the optimal use of resources for vector control. The main objective is to reduce longevity

of the adult vectors, eliminate the breeding sites, decrease contact of vector with humans, and reduce the density of the vector. This approach improves the efficacy, cost-effectiveness, ecological soundness and sustainability of disease-vector control. The five key elements of IVM include capacity building and training, advocacy, collaboration, evidence-based decision-making and integrated approach. IRS is the main stay of vector control for breaking the human-vector-human cycle of transmission.

The current strategy is to do IRS twice a year in all houses (upto six feet height) and complete coverage of cattle sheds in villages which had a Kala-azar case reported in the last 3 years including the current year supplemented with focused IRS in villages reporting KA cases. The spray is usually organized in two rounds, 1st round during February - March when sand fly are fairly active and 2nd round during May – June (months may vary from district-to-district based on entomological data) to limit sand

fly population supplemented with focused IRS in the villages reporting KA cases. 5.3 Supervision, monitoring, surveillance and evaluation Supervision, monitoring and surveillance are essential components to ensure success of the programme. There is a need to strengthen surveillance for KA and PKDL including line listing of cases at village level to identify hot spot areas (villages reporting five or more KA cases in previous or current year) and update areas for

micro planning for spray operations. As per WHO’s Fifth Regional Technical Advisory Meeting of South-East Asia Region, 15-20% of KA patients seek treatment in the private sector. Information from private sector is essential to have better picture of burden of disease and sustain the gains achieved towards elimination. Since the emergence of VL-HIV co-infection and posing threat on the achievements, surveillance of VL-HIV cases is important apart from early and long term follow up of 13

KA and PKDL cases (six and 12 months respectively) as well as information on relapses. Independent evaluation or validation of elimination will pave the pathway towards further reducing KA burden in the community to the lowest level. 5.4 Strengthening capacity of human resource in health Kala-azar elimination will require effective involvement of health personnel at all levels in the continuum of care, right from the early identification of a suspect case to

diagnosis and management, including complications. This can be achieved by orientation of human resource in health appropriate for different levels. There are multiple actors engaged in KA control programme like ASHA at community level, ANM at sub-health centre level, laboratory technicians and supervisory staff in the form of Kala-azar technical supervisors at primary health care centre level, district VBD consultants, PHC and district medical and programme officers. In addition, other

stakeholders like BMGF/CARE has also made provisions for human resource support at the district and block level (district programme manager and link workers at block PHC respectively). Roles and responsibilities at each level need to be defined and followed. 5.5 Advocacy, communication and social mobilization for behavioral impact and Inter-sectoral convergence The population at risk for Kala-azar is among the poorest in the community and often

poorly nourished. Access to care remains an issue in at-risk population and other under privileged sections of communities. Inadequate utilization of health services and lack of faith in public health systems by the affected population are major barriers in achieving elimination. This can be addressed by intensive awareness campaigns with the involvement of communities and community health volunteers. Awareness about the disease, its features, diagnostic and treatment options, prevention, existing

schemes and incentives and other aspects of the disease are not widely known. Therefore there is a need for advocacy, communication and social mobilization through all the existing methods (wall writing, hoardings, banner, pamphlets, radio gingles etc) as per the local context. Opportunities should be explored to spread the messages during weekly market or any other mass gathering (Chath puja, fares, melas etc) Display of messages particularly during campaigns which are community

based and inter-personal communication are considered the best methods for spreading awareness. 5.6 Programme management Programme management is the most important operational component for success of Kala-azar elimination. It involves coordination between centre and state level offices as well as effective coordination and harmonization of activities with different partners in the programme. Day-to-day management of the programme activities like

cold chain maintenance, drug requests, procurement and transportation of drugs, diagnostics and commodities, planning and monitoring need to be strengthened at all levels of implementation. 14

6 Road map for Kala-azar elimination 6.1 Diagnosis and treatment  Need to reduce delays in screening patients with prolonged fever for Kala- azar. Reduction in delay and thus reduction in interruption of transmission can be achieved through different approaches of active case detection apart from voluntary case reporting (passive)   Use of standardized rapid diagnostic kits with maximum sensitivity and specificity suitable to local context.   Patients seeking treatment in private sector. 

 Clear treatment strategy for achieving KA elimination and planning for rolling out single dose Liposomal Amphotericin B is required.   Strengthening cold chain maintenance for drug transportation, storage, distribution and dispensing and ensuring capacity building of health personnel and task shifting in the use of Liposomal Amphotericin B.   Treatment follow-up of KA and PKDL.   Establishing pharmacovigilance as a routine programmatic strategy. 

 Identification of PKDL. Collaboration with leprosy programme for PKDL.   Multidisciplinary strategy for HIV-VL   Monitoring of drug stocks and diagnostics requires strengthening to ensure early flagging of potential stock outs. Components and proposed Timeline Responsibilities No Action (completed by) 1. Reduce delay in screening patients with prolonged fever for Kala-azar. Current average time from onset of fever to diagnosis exceeds one

month. Large proportion of patients first report to private sector (unqualified or qualified providers) for fever where reliable diagnostics are not available a) Fever case screening- Instructions -MoH&FW/ ASHA/ANM to use Integrated approved NVBDCP Disease Surveillance and issued -MD/ED State Programme (IDSP) fever case in Aug’ 2014 Health Society reporting as one of the for approval and indicators for screening fever issuance of cases for KA suspect. instructions to

b) Operationalizing active case districts detection strategies for KA and -States are PKDL. (below mentioned block responsible for wise table 6.2 for active search) implementation c) Pre IRS camp at village level -WHO to assist (twice a year) in villages in planning and identified for IRS (approximately monitoring if 14,500 villages in all the case search on endemic states) the pattern of 15

d) Camp at village level during inter polio IRS operations (twice a year) in the same villages or new villages added during previous camps e) KA fortnight (awareness drive) in all the endemic villages once a year f) House-to-house search in hotspot villages (villages where more than five cases detected in current/previous year) g) As and when KA case is detected (either active or passive), households and neighbouring houses of index case are searched h) House to house approach

during other national campaigns (mass drug administration for Lymphatic Filariasis & Soil Transmitted Helminthiases, leprosy active case search, community need assessment, village health nutrition day etc) Incentive based approach is in place. Requires dissemination in the affected communities [above approaches are sufficient to capture most of the cases] i) Communication strategy to maximize early referral from private clinics j) Develop and disseminate short but effective SOPs for diagnosis

and treatment of Kala-azar in public hospitals k) Conduct regular refresher orientations for doctors and other staff (task shifting) in public facilities to maintain a high degree of suspicion of finding Kala-azar cases. Case detection in children a) Anganwadi workers to prepare Immediate -MoHFW & line list of absentees and other (Aug’ 2014) Department of children (under five) due to Women and prolonged fever, loss of weight, Child malaise, distended abdomen, Development

skin of face, hands, feet and responsible for abdomen implementation b) Under Rashtriya Bal Swasthya Karyakram (RBSK) programme, school drop outs to be actively contacted for medical reasons of drop outs and during school health examination children Kala-azar is included in the list of diseases to search for. 2 Use of standardized diagnostic kits and procedures (algorithms) 1. Standard Operating Procedures Aug’ 2014 -NVBDCP and algorithms for diagnostics -SPO to compile SoPs for KA and PKDL line list of

2. Identification of health personnel persons and capacity building for task identified for task shifting and delegation of shifting and diagnosis under appropriate prepare training circumstances (eg. during plan camps etc) -DFID 3. District hospitals upgraded to consortium to undertake parasitological support training diagnosis for select cases as per -RMRI/MSF operational guidelines responsible for a) Need assessment training b) Identification of a nodal -DFID person & training consortium to

c) Quality Assurance in place support district up gradation 3. Monitoring of drug stocks requires strengthening to ensure early flagging of potential stock outs 1. Include drug stock data in the Sept’ 2014 -States and online HMIS CARE- initial training to data 2. Cold chain maintenance entry monitoring operator/data manager and roll out. -MOI/C PHC responsible for cold chain -DFID Consortium can assist for logistics 17

6.2 Active case search planning in 39 high endemic blocks of Bihar and 22 high endemic blocks of Jharkhand and 2 high endemic blocks of West Bengal (annual incidence of more than 3 per 10,000 population (Dec’2014 -Jan’ 2015) Araria, Forbesganj, Kursa Kanta (Araria), -These 63 high endemic Dandari (Begusarai), Kiratpur, K Sthan blocks constitute more than (Darbhanga), Barauli, Manjha (Gopalganj), 50% of cases Dandkhora, Hasanganj, Pranpur, Sameli, Amdabad, Mansahi (Katihar), Gaihlar, -Same blocks will be

repeated after six months Kishanganj, Gamharia (Madhepura), Bariyarpur (Munger), Bandra, Sahabganj, (May-June 2015) Paroo (Muzaffarpur), K Nagar, Sri nagar, B Kothi, Jalalgarh (Purnea), Simri, Bakhtiarpur, Salkhua, Son Bersa, Sour Bazar, Panchgachia, Mahisi, Patarghat (Saharsa), Samastipur (Samastipur), Parsauni, Bathnaha (Sitamarhi), Goria kothi, Basantpur, Nautan (Siwan), Raghoupur, Mahua (Vaisahli) Jharkhand- Poraiyahat, Meharma, Mahagama, Boarijore, Sundarpahari, Pathargama, Godda

(Godda), Maheshpur, Hiranpur, Littipara, Amrapara, Pakur (Pakur), Dumka, Jama, Shikaripara, Kathikund, Gopikandar, Ramgarh (Dumka), Borio, Barhait, Pathna, Talijhari (Sahibganj) West Bengal- Phansidewa, Kharibari (Darjeeling) 6.3 Rolling out of Liposomal Amphotericin B  Single dose Liposomal Amphotericin B in 10mg/Kgbw introduced as the first line treatment regimen for KA at all health facilities where human resource (trained medical officer and nursing staff) and infrastructure available. 

 Assessment of identified health facilities for cold chain maintenance (equipment, power back up etc)   Upgrading identified health facilities to ensure sustainable cold chain   Cold chain maintenance at all levels- in-country arrival, transportation to state store, district store, block level up to dispensing   Identification and orientation of medical officer(s) for use of Liposomal Amphotericin B (at block level) and task shifting at block level under the

supervision of a trained medical doctor   Orientation of medical officer(s) at referral centre (district level)   Recording and reporting adverse effects, if any 18

 Patient follow up- 6 months for KA   Giving Liposomal Amphotericin B to right patients- (criteria for referral eg. HIV positive, relapses, severe renal disease, anaphylaxis)   Miltefosine will continue to be used till roll out of Liposomal Amphotericin B takes place across health facilities 6.4 Criteria for selection of districts and blocks PHCs for Liposomal Amphotericin B roll out The rapid implementation micro plan for Liposomal Amphotericin B across endemic

districts will be based on block-wise incidence of disease as reported in 2013. Phase 1: August-December 2014  All districts (18) reporting block-level incidence >4/10,000 will have District Hospital upgraded as per above criteria   All blocks (48) with incidence >4/10,000 will have PHC upgraded as per above criteria [Bihar-27, Jharkhand-19, West Bengal-2]   Presently 70% of patients are accessing care either at the district hospital or

sub-district hospital level. It is expected to cover about 30% of reported cases in Bihar, 84% in Jharkhand and 31% of West Bengal by end of 2014 Phase 2: January-April 2015  All remaining districts (10) reporting block-level incidence >2/10,000 will have District Hospital upgraded as per above criteria   All remaining blocks (61) reporting block-level incidence >2/10,000 will have  either the block PHC or a nearby ‘referral’ block PHC upgraded as per above criteria 

 Based on 70% of patients accessing care at the district hospital or sub-district hospital level, 42% of reported cases in Bihar, 11% in Jharkhand and 19% in West Bengal by March 2015   By block level incidence alone, this will cover 90% of reported cases in Bihar by March 2015   Remaining blocks with incidence >1/10,000 will refer patients to referral hospitals or nearby upgraded PHCs in endemic districts, >99% of reported cases in Bihar will be covered. 

 Remaining district hospitals in endemic districts will be orientated and provided with Liposomal Amphotericin B for use. Phase I (August-December 2014) Phase II (January-March 2015) Districts Hospitals (18)- Araria, Districts (10)-West Champaran, Purnia, Siwan, Vaishali, Sitamarhi, Sheohar, Supaul, Patna, Khagaria, Saharsa, Muzaffarpur, Munger, Kishanganj, Madhubani, East Darbhanga, Gopalganj, Katihar, Champaran, Begusarai, Madhepura, Samastipur (Bihar), Blocks (61)- Chehra Kala,

(Jharkhand), Darjeeling (West Bhagwanpur, Vaishali, Lalganj, Bengal) [Bihar-13, Jharkhand-4 and Mahua, Rajapakad, Jandaha, West Bengal-1] Mahnar, Sahdev, Bujurg Deshari, Patepur (Vaishali), Raghopur Blocks (46)- Araria, Kursa Kanta (Supaul), Barahria , Bhagwanpur (Araria), Kiratpur, K Sthan (Siwan), Dumra, Bijapatti, Bathanaha (Darbhanga), Barauli (Gopalganj), (Sitamarhi), Sheohar, Dumri Katsari, Dandkhora, Hasanganj, Pranpur, Piprahi (Sheohar), Baniyapur, Sameli (Katihar), Gamharia

Marhoura, Amnaur, Mashrakh (Madhepura), Bariyarpur (Munger), (Saran), Saharsa, Panch Gachiya, Bandra, Sahabganj (Muzaffarpur), K Mahisi, Patarghat (Saharsa), Purniya Nagar, Sri nagar, B Kothi (Purnea), east, Dagaruwa, kashawa, Jalalgarh , Simri, Bakhtiarpur, Salkhua, Son K.Nagar, Shri Nagar, Banmankhi, Bersa, Sour Bazar (Saharsa), Dhamdhaha, B.Koti, Bhawani Pur Samastipur (Samastipur), Parsauni (Purnea), Kurhani, Marwan, Minapur, (Sitamarhi), Goria kothi, Basantpur, Motipur, Musahari, Paroo, Bochaha

Nautan (Siwan), Raghoupur (Muzzaffarpur), Jhanjharpur (Vaisahli) (Madhubani), Beldaur, Alauli (Khagaria), Manihari, Mansahi Jharkhand- Poraiyahat, Meharma, (Katihar), Manjha, Sidhwali, Mahagama, Boarijore, Sundarpahari Baikunthpur (Gopalganj), Kasariya, (Godda), Maheshpur, Hiranpur, Madhuban (E.Champaran), Dandari Littipara, Amrapara (Pakur), Dumka, (Begusarai), Forbesganj, Bhargama Jama, Shikaripara, Kathikund, (Araria) Gopikandar, Ramgarh (Dumka), Borio, Barhait, Pathna, Talijhari (Sahibganj)

West Bengal- Phansidewa, Kharibari (Darjeeling) 6.5 PKDL All probable cases of PKDL (patient from an endemic area with typical appearance and distribution of papules and nodules, and/or macular hypopigmentation, with or without a history of VL and a positive rapid diagnostic test) identified in the community will be referred to the PHC for RDT testing and if positive referred to district hospital level for confirmation of diagnosis and treatment. Incentivisation will

be conducted as per previously intimated. 6.6 Micro-plan No Particular Proposed action Time line Responsibilities 1 Rapid -Approval from -Aug’2014 By a team- Distt assessment of State/District -Aug’-Sept’2014 VBD officer, health authorities phase I- -Simultaneously Implementation VL - Need assessment district expert from -Assessment hospitals and consortium report to NVBDCP PHCs

2 Up gradation Development and Aug’ 2014 NVBDCP of health SOPs for up gradation as per facilities operational guidelines Approval of SOPs Aug’ 2014 Per NVBDCP plan dated 25 July 2014 Permission from In parallel with State health society national/state assessment, not health authorities later than end of for upgrading Sept’ 2014 3 Actual up District hospital- -End of Dec’ 2014 -Consortium with the gradation -Capacity is for all Phase I support of WHO and created as districts guidance of

identified in the NVBDCP/State operational Health Society guidelines for - End of Dec’ referral centres 2014 for all Phase -Consortium with the Block PHC- I blocks support of WHO and - Capac ity is g uidance of created as NVBDCP/State identified in the Health Society operational guidelines for PHCs 4 Capacity Cascade of training Aug’-Dec’ 2014 Consortium with the building for identified support of WHO and medical officers guidance of and teams NVBDCP Particular Proposed action Time line Responsibilities

HIV-VL -Guidelines and instructions in place Sept’ 2014 -NACO/NVBDCP co- for provider initiated counselling and to develop infection testing (PICT) for all VL patients, protocol for multi- assessment of all HIV patients in KA disciplinary case endemic areas for VL, initiation of management ART (as per WHO VL guidelines guidelines 2010), management and Dec’ 2014 coordination with HIV programme -State AIDS (CD4 count, ART, treatment follow- Control Society up etc), upgradation of district

hospitals and medical colleges -RMRI/MSF to act (similar to RMRI, Vaishali MSF unit) as referral centre for management for training and -Orientation of care givers on management importance of diagnosis of HIV-VL 21

6.7 Integrated vector management including indoor residual spraying (IRS) 6.7.1 Roadmap for indoor residual spray IRS continues to be the mainstay in the battle to eliminate Kala-azar, and close attention must be paid to ensure both, coverage and quality to maximize the likelihood of elimination. Household surveys suggest that only two-thirds of vulnerable homes are currently covered, and that on a number of parameters the quality is less than desirable. The timing of spray across the Kala-azar endemic

states differs from state to state. As per national policy any village reporting Kala-azar in last three years is eligible for IRS for transmission reduction. State Suggested Indoor Residual Spray time line First round Second round Bihar February-March May-June Jharkhand February-March May-June West Bengal February-March May-June Uttar Pradesh February-March May-June Program acknowledges that spray coverage and quality varies over rounds and locations. This depends on factors like:

 Timeliness of release of funds from national, state and district level and submission of SOE/UC   Timing of IRS   Development of micro action plan  oTargeted population  oTargeted houses and rooms  oTargeted cattle-sheds  oRequirement of human resource for spray squads ( one spray squad= five field workers+ one spray supervisor ) oSelection of insecticides and spray pumps  oRequirement of insecticides, spray pumps and related items  oTraining plan 

oMonitoring, supervision (including stakeholders) and evaluation  oPlan for community awareness and mobilization 22

6.8 Release of funds is one of the requisite criteria for Kala-azar elimination. Without a concerted effort to correct all the critical shortcomings, the effect of IRS operations may not rise to levels necessary to achieve and sustain elimination. No Components Proposed Action Timeline Responsibilities (completed by) 1. Timeliness of -proposed action at Centre to - Approval of release of funds all levels (District state- D ec ’ PIP/Admin from centre, state health society to State to sanction-

and district level ensure timely districts- NBVBDCP/NHM and submission of submission of January (funds -MD/ED State SOE/UC SoE/UC, followed released for health society by SPO to ensure both the -DM/DC District compilation and rounds health society submission to State together) -Concerned state health society, programme followed by release officer will of funds) ensure timely submission of SOE/UC from district to state health society unit 2. Timing of IRS Adherence to the Bihar & -ED/SHS

timing of IRS as per Jharkhand: -State SPO national policy February- -District VBD March and officer (DMO) May-June -Block MOI/C West Bengal & Uttar Pradesh: April-May and July-Aug’ 3. Development of micro action plan: Target population- Any village (including hamlets) reporting KA cases in the last three years are eligible for IRS. 100% of the affected village. All rooms up to 6 feet height. Full coverage of cattle sheds a. Micro action plan Block Micro-plan Block level: MOI/C-

prepared and 120 days responsible for examined by district before IRS block plan District level: District Micro-plan District VBD 90 days prepared and officer- before IRS examined by state responsible for district plan State level: State Micro-plan 60 days prepared and before start SPO-responsible examined by of IRS for state plan NVBDCP activities -WHO-supportive supervision in quality of micro action plan 23

-CARE- assistance in development of micro action plan b. Insecticide: DDT -Insecticide State- 90 -letter/instructions 50% -75mt/million requirement days in from NVBDCP population for two calculated advance -SPO (all four rounds (per round -Road permit, states) 37.5mt) and other transportation District- 45 - State Health recommended ensured days in directorate insecticide -Handling, storage, advance responsible for (reported DDT distribution Block- 30 transportation

resistance) -Use of SP in days in (DFID consortium second round in advance is willing to 2014 in district support) Muzaffarpur where -District VBD DDT resistance is officer (first) reported (per TAC -Block MOI/C recommendations) c. Spray Pumps- -Pilot of use of -Development -In second -NVBDCP to hand compressor Partners can round in issue necessary pumps in one support in Sept’ 2014 approvals to state district documentation and - Documentation and submission of report writing report of experience of use

of hand compressor pumps -four months -CARE has and documentation in advance of supplied 1,000 (within 1 month of -SPO to submit first round of stirrup pumps and IRS) procurement plan to IRS another 2,000 State Health -estimates of pump pumps are in Society and -SHS gives requirementand NVBDCP sanction for pipeline. They supplies procurement may consider to three months supply in other before IRS states based on needs (CARE/BMGF) d. Selection of spray Instructions issued -letter from -ED/MD SHS to

team members to districts by SPO state issued give approvals from locations after due approvals to districts -SPO to issue close to targeted from ED/MD SHS. three months letter to districts villages (wherever Letter issued to before spray -CMHO to issue necessary) MOI/C by round instructions to CMHO/District VBD MOI/C officer -Instructions -MOI/C to select from district appropriate teams to block two in consultation months with ANM, ASHA before IRS and VHSC -Selection of team one months in 24

advance e. Training plan -Identification of Aug’ 2014 or -MOI/C to identify prepared trainers three months team members before first -District VBD -Identification of round of IRS officer to compile trainees (new) and block wise plan for re-orientation -SPO to compile -Training plan district wise prepared and communicated e 1.Standardized -Letter from Aug’ 2014 or -RMRI to prepare training curriculum NVBDCP to RMRI three months training curriculum and material and State before first (audio-visual)

prepared round of IRS -Development partners to support e 2.Training -District to identify -Two months -RMRI to train programme district trainers for before first state level trainers -State level ToT training round of IRS - District VBD officers and -Blocks to identify -One month MOI/C to monitor -District level block level trainers before IRS quality of training training -District and block -To be -Development trainers train team finished 10 partners and other

-Block level members days before stakeholders to trainings the IRS identify districts and monitor trainings f. -Pre IRS -ASHA training 10 days in -NVBDCP to awareness and material prepared advance to develop prototype training material search activities three months in IRS for grass root advance of training (minimum level workers. -Funds allocated in two days Funds allocated to PIP before IRS) state -SPO transfers funds to districts -District transfer funds to blocks -MOI/C responsible for training

-Partners (MSF, DNDi, LSHTM and DFID) will support cascade training of front- line workers and raise community awareness. -CARE will provide IEC material 25

g. Supportive -SOPs related to Necessary -NVBDCP to supervision and management of instructions prepare a monitoring during spray operations to and prototype and IRS: be adequately guidelines to send to state refined and be in place -SPO to disseminated. by Sept’ 2014 disseminate to all -First MO of PHC to the districts be notified as nodal -ED/SHS to issue officer for vector- letter to make first borne disease MO PHC as nodal control officer -Other PHC staff to -Use of IQK- be given specific RMRI and

monitoring development responsibilities partners to during rounds support piloting -Development -RMRI/NVBDCP partners to work to be requested to closely with expand program staff to monitoring of support monitoring vector density and --Pilot use of Insecticidal insecticide Quantification Kits sensitivity studies (IQK) and -WHO will subsequent continue to do introduction for independent larger areas. monitoring of IRS h. Micro plan quality: -Identification of 120 days in -Block Mo I/C

Wide variability in targeted villages advance of responsible for completeness and from existing IRS block level list accuracy of IRS records and reports -District VBD microplans -Examine learning officer for district opportunities from polio microplans level -SPO for state level lists -WHO to assist state in learning from polio plans i. Late payment of -Create/Register all Payment -Block MOI/C wages to spray workers bank done for responsible for all workers accounts and previous the payments

activate online round within -District VBD transfers of one month of officer to ensure payments based on spray timely release and IRS completion activities monitoring of reports. payments -Include IRS weekly -WHO to generate reporting in the information as per online MIS by their monitoring squad and by mechanisms worker 26

4. UtilizeHousing‚ -Health Department By December -District VBD scheme for to recommend 2014 line list officer to prepare underprivileged” to clusters of kuccha of high line list make housing houses of eligible burden -District conditions less communities that prepared and Magistrate to conducive for have experienced review and take sandflies high loads of Kala- disseminated necessary actions azar for receiving to relevant -SPO to compile pucca houses under departments line list housing schemes

-List of -Regular villages/hamlets coordination with high patient meetings at state loads to be drawn level up by State VBD Office -Expedite implementation 5. Entomological -Strengthening Dec’ 2014 -Approval from surveillance regional MoH&FW -Entomological entomological March 2015 surveillance is teams -CARE weak. Out of 72 -Creation of vector March 2015 regional teams in surveillance unit at India, only 35 are district level by -DFID consortium functional. There is CARE a need to -Building capacity of

strengthen it entomologist and creation of pool of experts Besides above cited IRS activities, villages reporting KA cases also to be sprayed to eliminate the infected sandfly. 6.9 Surveillance, monitoring, supervision & evaluation 6.9.1 Areas related to surveillance and HMIS With the program in elimination mode, real time data about the exact incidence by location is indispensable, as in the case of polio eradication. Data need to be obtained from different domains and facets:  Data from private sector 

 Strengthening surveillance for KA and PKDL including line listing of KA and PKDL cases at village level   Monitoring progress towards elimination at block level   To accurately identify hot spots and villages which have cases for IRS based on village wise line listing of cases (both KA and PKDL cases)   Strengthening surveillance of VL-HIV cases   Treatment follow up of KA and PKDL and information about relapses 27

No Components Proposed Action Timeline Responsibilities (completed by) 1. Implementation -Plan of action for Aug’ 2014 -SPO and CARE of revised HMIS complete implementation of the -Guidelines -SPO The revised revised HMIS to be to be HMIS has been drawn up (in hard issued in piloted copies and formats) successfully in -Operationalization of Sept’ 2014 -SHS two districts of online HMIS Bihar -To identify a staff at PHC for HMIS related -NVBDCP, SPO The pilot in two entries and issuance of -Oct-Nov’ and CARE

districts indicates instructions, including to 2014 the need for the block and district fixing level computer responsibilities of operators to operate the Dec’ 2014 health staff at online HMIS. PHC for all HMIS -Training/orientation of related tasks identified staff -Complete implementation of revised HMIS across all the states 2. Implementation -Guidelines to be Aug’ 2014 -NVBDCP and of regular Kala- developed and issued partners azar elimination responsible for -National adaptation of Aug’ 2014

activities development M&E Indicators for elimination and IRS (as per WHO/TDR tool kit developed for India, Nepal and Bangladesh) 3. Monitoring from -Six monthly review October -NVBDCP central level meetings at national 2014- Delhi (supported by WHO) level March 2015-Bihar -Six monthly review at -NVBDCP (supported by state level - Bihar WHO) (Nov’2014) - Jharkhand -NVBDCP and (Dec’2014 SPO & May -Monitoring during IRS 2014) -Creation of State and district task force Sept’ 2014 -NVBDCP to form a central

6.10 Human Resources Issues Kala-azar elimination program envisages sufficient human resource to support elimination activities. Currently, Government of India is committed in principle to continuing the additional contractual positions of human resources placed in concerned states. This resource includes Kala-azar Technical Supervisors (@ 6 per affected district), District and State level Vector Borne Disease Control consultants.

Significant concerns persist in terms of vacancies, inadequate remuneration leading to high turnover, inadequate mobility support for field positions, and inadequate ownership and motivation among the health system functionaries for Kala-azar elimination. It is recognized that rapidly rectifying these gaps will be critical to making progress towards elimination. No Components Proposed Action Timeline Responsibilities (completed by) 1. State -Dedicated SPO is required -At the - Principal

Programme for programme earliest Secretary Health Officer implementation 2 District VBD All District VBD Dec’ 2014 -Principal Officer officers/District Malaria Secretary Health officers should be in place 3 VBD Advertising and filling the Sept’ 2014 -State health Consultants vacant positions of VBD society consultants (Seeing the state of high attrition of VBD consultant , waitlist should be kept at least for a year) 4 Kala-azar All endemic blocks should Dec’ 2014 -SHS and SPO

Technical have one KTS or equivalent -Consortium can Supervisors -Advertising and filling the support with this vacant positions of KTS additional human (Seeing the state of high resource attrition of KTS, waitlist should (wherever gaps in be kept at least for a year) the high endemic blocks over and above 6 KTS per district) 5 Other Positions to be filled by the -Principal peripheral state on priority basis Secretary Health positions (malaria inspectors, BHW, BHI, SW etc) 29

6.11 Capacity building of human resource at all levels No Components Proposed Action Timeline Responsibilities (completed by) 1. ASHA cascade Orientation in suspect By ASHA referral, treatment, March 2015 management and follow up unit at block, district and state level Development partners can support 2. KTS 10 days training to Oct 2014 -10 days training new KTS and one day by RMRI re-orientation in M&E -District VBD including IRS officer/consultant supervision, suspect for re-orientation

referral, treatment, to existing KTS and follow up 3. Link worker (CARE) Orientation in M&E Oct 2014 -Training by including IRS CARE and supervision, suspect District VBD referral, treatment, officer/consultant and follow up for programme management 4. District VBD 30 days training to Dec 2014 RMRI and consultant newly recruited and concerned states one day re-orientation in M&E including IRS supervision, suspect referral, treatment, and follow up 5. District VBD officers 3 days orientation Nov- Directorate

and State SPOs training on KA Dec 2014 NVBDCP at elimination and state level programme management 6. District 1 day on KA Nov- Directorate Collector/Magistrate programme Dec 2014 NVBDCP at management in two state level with batches development partners 7. Development Meeting at national Sept’ 2014 Directorate partner’s meeting level NVBDCP with on road-map development partners 30

Regional meeting of Two meetings of one Sept’ 2014 Directorate 8. VBD officers day at Patna and and March NVBDCP, states Kolkata 2015 with development partners 6.12 Advocacy, communication and social mobilization No Components Proposed Action Timeline Responsibilities (completed by) 1. Prototype National programme with Already -Directorate material support from development available NVBDCP partners will develop on the -States to print and prototype material for website disseminate

community sensitization, -Development prevailing schemes and partners and incentives, media consortium can component (radio provide large scale messages and jingles, dissemination of newspaper), wall painting, approved materials. banners, posters, visual, flip charts etc 2. Assessment Through third party Yearly -NVBDCP and of IEC/BCC States material and reach 3. National Through NVBDCP, using Dec’ 2014 Consortium to workshop to existing materials and assist with funding introduce, experts and implementation

standardise under NVBDCP and discuss guidance IEC/BCC strategy 6.13 Programme management Financial and logistic- For any public health programme release of funds is one of the main tools bringing effectiveness in implementation and monitoring of strategies. Government of India provides 100% cash assistance to meet personnel cost of wages, mobility and provides grant in aid for carrying out KA activities and in kind support in the form of supply of diagnostics, drugs and insecticides. On the basis of

approved state’s PIP, GoI releases funds to state in instalments. States in turn releases funds to districts on the basis of district specific action plan. Submission of SoEs and UCs is must for regular release of funds at periodic interval. This is important for carrying out the activities proposed in action plan. The state programme officer is to ensure that SoEs and UCs are submitted to the state health society in time. 31

It is often seen that SOE and UCs are not being submitted by the blocks to the district in time which results in delay in release of funds and inter alia effects the programme implementation. The below mentioned table indicates the timeline on release of funds from national to state and districts. No Issues Proposed Actions Timeline Roles and Responsibilities 1. Submission As per approved FMR code Feb’-Mar’ Concerned nodal of PIP officer of state and SPM, state health society

2. Approval of Discussion at NPCC Jun’-Jul’ National and state PIP/RoP meeting and finalized in NHM members ROP meeting 3. Release of -In two instalments based Jul’-Aug’ & -MoH&FW funds on balance available Dec’-Jan’ -Administrative sanction for Apr’ - MoH&FW carry forward of previous -SHS to districts year’s fund and within 15 days -Instruction from NHM to Apr’ district to blocks use balance fund for VBD No Components/ Proposed Action Timeline Responsibilities Issues (completed by)

1. Creation of KA -Elimination cell should Sept’ 2014 -MoH&FW elimination cell comprise of 4 -Development personnel- one public at NVBDCP partners may health expert, one M&E and at the support at national expert, one vector state and state level specialist and one statistical expert 2. Elimination -SPO is proposed to Sept’ 2014 - MoH&FW and mode: handle up to 5 lakh with SHS co-signature with State The state Programme Manager programme, NHM on the same district VBD pattern of Chief

officers and Medical and Health Block MO I/C Officer (CMHO) and should be District Programme vested with Manager (DPM) as co- signatories at the more powers district level -Similarly District VBD officer should be co signatory with Chief Medical and Health Officer (CMHO) for smooth fund transaction 32

-Guidance to procure drugs and diagnostics from Rogi Kalyan Samiti as and when required - State Health Directorate should be allowed to take decision on inter-state transportation of commodities. 3. Human -To adjust TORs as per Sept’ 2014 -State secretariat resource state specific for regular posts availability of human availability: 30- -SHS for resource 40% posts of contractual the key district position -In case non joining or VBD officers attrition of selected -Partners to

are vacant candidates then consider support -State and selection from district waitlisted candidates contractual -Keeping waitlist valid positions: 20- till one year 30% posts not -Identification of blocks filled due to where additional lengthy human resources are recruitment required from partner process and support high attrition 4. Planning and - Computers with Dec’ 2014 -National Project M&E: accessories at district Coordination - GoI provides VBD and state office Committee

funds to states (including computer (NPCC) for carrying out table, chair etc) either Dec’ 2014 -NHM/ routine M&E from NHM of through SHS/Partners activities, development partners hiring of -Revamp of district -NHM/ vehicles and VBD office under NHM SHS/Partners accelerated fund during -Monthly meeting with IRS operation District Magistrate, and up to block six monthly at state level through level districts 5. Financial: -Financial training of Dec’2014 -Finance division

Financial one day for all financial State Health guidelines assistants of districts Society (or an exist but not and state external finance followed. -At least quarterly expert can be No clarity in review meeting of hired) books of finance nodal persons account, at district level and 33

district biannual at state level financial (to be merged with person is not routine review of KA trained programme) Wide communication gap within programme financial wing and NHM 5. Role of district Constitution of district -One month District Magistrate health KA co-ordination before IRS administration: committee under and at the chairmanship of district completion collector including for any mid- CMHO/CS, district VBD course officer (member correction secretary), Block -Monthly MOI/Cs, District technical

Education Officer, review Block Development meeting by Officers (endemic DM/DC. blocks), ICDS, rural -IRS will be development officer, directly DPRO supervised by district administration 6. Incentives, schemes and provisions: presently GoI provides Rs 50/day to KA patient for loss of wages during 28 days Miltefosine treatment period and Rs 300 to ASHA upon completion of treatment of KA patients Timely -Online bank accounts -GoI to issue letter a. payment of of ASHAs for role of District

incentives and -Regular financial Magistrate provisions for monitoring during KA patients monthly review meetings with District Magistrate d. State specific To continue as schemes and declared by respective provisions states 7. Patient referral and transportation Critically ill Children up to 15 years Immediate - MoH&FW for to be covered under approving the RBSK (all KA services revised incentives free)- KA to be added and provisions in the list of conditions -Block MO I/C -Individuals above responsible for

15years will be transportation and transported by free referral referral system or Rs 34

500 for to and fro transportation-to be met from RKS -All pregnant KA women to be covered under JBSY (all KA services free) 9. Engaging -District wise Sept’ 2014 SPO to issue a private sector identification of private letter to districts health professionals, -District VBD labs and pharmacies officer to providing diagnostic implement and treatment facilities -Formally assess and -NVBDCP and develop strategy that partners integrates the private sector by ensuring high quality awareness and diagnostics are

available, with compulsory reporting, and referal into the public sector for treatment. 6.14 Stakeholders in the programme Presently Kala-azar programme is having assistance and support from national and international partners. These stakeholders are-  Rajendra Memorial Research Institute (RMRI), an ICMR institute   WHO   Regional office of Health & Family Welfare, Patna, Kolkata, and Lucknow   Patna Branch of National Centre for Disease Control (NCDC) 

 State Institute of Health & Family Welfare, Patna, Ranchi, Kolkata and Lucknow   All India Institute of Hygiene and Public Health (AIIH&PH), Kolkata   BMGF/CARE   DFID consortium consisting of o Drugs for Neglected Diseases Initiative (DNDi), o London School of Hygiene and Tropical Medicine (LSHTM), o Médecins sans Frontières (MSF) and o HLSP (with HLSP holding the DFID contract)  DNDi   B-TAST   PATH   World Health Partners (WHP) 35

No Stakeholder(s) Current role/Inputs Future roles and responsibilities 1 RMRI -Training of District VBD Same consultants and KA Technical Supervisors (KTS) in KA and spray workers in IRS -Operationalization of sentinel sites (information on efficacy of treatment regimen) -Pharmacovigilence of available KA drugs and quality assurance of RDK -Susceptibility status of vector and development of insecticide quantification kit (IQK) and data management monitoring system -Policy advice through

primary and operational research -Monitoring & supervision of KA elimination -Management of treatment failures 2. CARE/BMGF -Situational analysis of KA -Entering into MoU for similar disease burden in 8 support in the state of districts of Bihar Jharkhand. In future support to (unpublished) West Bengal may also be extended -Presently supporting the programme through -Another 2000 stirrup pumps to additional human be supplied resource support in Bihar- -Establishing vector District Prog. Manager in

surveillance units in all 33 33 districts, endemic districts of Bihar and Approximately 500 link workers (equivalent to proposed in Jharkhand Kala-azar Treatment -Launching of online HMIS Supervisor (KTS) (Bihar) -Assistance in logistics -GIS mapping of KA cases support eg. 1000 Stirrup 36

pumps, 50,000 RK39 -Monitoring during IRS -Training and establishing HMIS -Monitoring of daily reporting of IRS through mobile application 3. DFID Constituted by DNDi, -Support the programme in consortium MSF and London School scaling up of Liposomal of Hygiene and Tropical Amphotericin B, upgrading Medicine (LSHTM); all facilities have long history of workingin VL control in -Strengthening cold chain and India. logistics -Capacity building of state level health staff, build the pool of

regional entomologists -Support national programme and state programme in M&E activities thorugh provision of dedicated HR -Develop strategy for private sector referral to public sector -Operational research on PKDL, VL-HIV, vector control surveillance -National and international cross border monitoring & surveillance and inter country workshops -Organization of stakeholders meetings -Epidemiological surveillance -Support on IEC/BCC materials, printing and dissemination -Any other support in achieving

ans sustaining VL elimination as requested by the Government of India, NVBDCP and State Health Societies 37

4. WHO -Formulation of policy Same guidelines, norms and standards -Technical support in KA programme implementation at National and State level (through four state coordinators) -Independent monitoring of IRS activities -M&E (through Joint monitoring missions and field visits) -Liposomal Amphotericin B supply 5. DNDi -Research into clinical Same drug trials -Training to Medical Officers and Para-medical staff on newer drugs with the help of RMRI and MSF 6. PATH Proposed to establish

pharmacovigilence through National Pharmacovigilence programme 7 Regional -Support on M&E during Same Branch of IRS NCDC, Patna -Vector surveillance -Operational research 8 AIIH&PH -M&E of KA elimination Same (including IRS) 9 Regional office -Coordination with states Same of MOHFW -Monitoring & supervision 10 WHP - Surveillance and Same diagnosis through sky centres 11 MSF -Curative support to KA, Same 38

PKDL and VL-HIV patients through five PHCs and district hospital unit as pilot project in district Vaishali (since 2007) -Training to MOs and para medical staff -Dissemination of IEC/BCC material -Implementation of combination regimen at PHCs and single dose Liposomal Amphotericin B at districts hospital in seven identified districts with partners 12 B-TAST -Social mobilization with Same community voucher scheme -ASHA training as a composite plan 39

7. Timeline of activities Time Responsibilit Proposed action line ies Aug’ NVBDCP -Operational guideline of KA to be revised and issued 2014 -National roadmap developed and endorsed by core group -Funds approved for KA activities -Roll out plan for Liposomal Amphotericin B prepared and communicated to states -Capacity building including training plan for health personnel in use of Liposomal Amphotericin B prepared and approved -IEC/BCC material prototype developed by NVBDCP

and printing by state /CARE communicated to states -Communication to all the stakeholders about KA elimination roadmap plan -Ppresently SPO does not have financial power therefore delegation of powers to State health directorate and SPO -Draw monitoring plan for second round of IRS in Sept’ 2014 and communicate to state -Incentives and schemes approved and communicated -Use of synthetic pyrethroid in respective states where DDT resistance reported -The uniform use of only RK39 across the state

-National roadmap received and communicated to all the State VBD districts office -Operational guidelines received from centre and communicated to all the districts -Initiate actions based on national and state roadmap of KA elimination -Issue acceptance letter to partners for assessment of cold chain maintenance facilities at PHC -Complete all the activities for second round of IRS in Sept’ 2014; assumed that funds to all the districts released -Initiate action on transportation of synthetic pyrethroid

for use in DDT resistance districts -Completion of a review of the vacant positions and plan for filling up submitted to state health society -Preparation of rationalization of KTS to adequately cover highly endemic blocks, gap analysis and raising additional KTs with development partners Involvement of District Collectors -Preparation of the district wise vacancies, as per the reservation criteria, by the Chief Malaria Office and submission to the ED Office.

-Advertisement and filling of the vacant positions of the KTS’s -Drawing up of a plan of action for the complete implementation of the revised HMIS -Identification of specific staff in all public facilities for 40

specific HMIS related tasks, and issuance of guidelines accordingly CARE -Complete the process for Liposomal Amphotericin B supply -Initiate request for additional supplies -Recruit four state coordinators in NTDs -Plan for independent monitoring of IRS for the second round in Sept’ 2014 -Complete HMIS training -Roll out of HMIS started -Recruitment of district vector surveillance unit initiated -Supply of 50, 000 RK39 completed -Supply of additional 2,000 stirrup pumps completed

DFID -MoU signed with GoI and state of Bihar consortium -Assess health facilities for cold chain maintenance -Submit the report to GoI and state governments -Initiate the upgradation of cold chain and capacity building programme of different level of health functionaries in use of Liposomal Amphotericin B Sept’ NVBDCP - Dissemination of operational guidelines workshop & 2014 reviewed - State and Stakeholder’smeeting for dissemination of national roadmap of KA elimination

- PIP and necessary administrative approvals issued -IRS monitoring plan executed; central team monitoring IRS activities -Approval of use of hand compressor pumps in one district -Monitoring and documentation of hand compressor pumps -Sharing of the report of hand compressor pump and observations on effect of synthetic pyrethroid in one district State VBD -Execution of second round of IRS activities office -Compilation of daily reporting of IRS activities

-Coordination with State health society and districts to support all the logistics and supplies -Draw up plan for PHC upgradation for cold chain and capacity building of health personnel District health -Prototype IEC material received and process for administration printing initiated; actions initiated for local displays of messages etc. -Vacancy advertisement for filling up the remaining posts intitiated All other -Role of district administration defined and stakeholders communicated

-Feedback given to state and necessary local corrective actions taken -IRS monitoring, supervision, trainings, assistance in supplies and logistics continued -Piloting of Insecticide quantification kit in selected districts Oct’ NBBDCP -Review meeting at regional level to assess the progress 2014 of KA elimination -Monitoring of scaling up of Liposomal Amphotericin B -Process of recruitment initiated for filling up of State VBD Office remaining posts -Printing of IEC material initiated

-Planning for first round of IRS 2015 initiated -Letter issued for incentives and schemes and funds disbursed to all the districts -Pre IRS search activities and awareness drives CARE -Vector surveillance units in all endemic districts in place -Monitoring of KA elimination activities- case detection campaigns, surveillance -HMIS operational in all the districts -Scaling up of Liposomal Amphotericin B in progress DFID consortium -Upgrading of health facilities in progress

-Capacity building of medical officers and support staff in progress -Stakeholder’s meeting planned -Printing of IEC material initiated -Development of pool of entomologists intitiated Nov’ State VBD -The Refinement of SOPs related to management of 2014 Office spray operations, and dissemination to all PHCs. -Order of designating the First Medical Officer of PHCs as nodal officers for vector-borne disease control programme to be issued. -Rigorous training for supervisory staff (DMOs, ACMOs,

MIs, VBD consultants) on the areas of supervision and monitoring. -The Issue of order for Pre IRS IEC monitoring to be done by CS/ ACMO/ DMO/MOIC. -The Issue of an order for the mobility allowance (POL & Vehicle hiring expense) given to the DMO to be doubled to Rs 1500 per day, for the duration of the IRS round. -The Issue of order for KTS to be given additional mobility allowance during IRS rounds (@ Rs 2000 extra per month additional) -The Issue of order for Other PHC staff such as BHE,

BCM to be given specific monitoring responsibilities during rounds. -Independent third party monitoring continued. -Micro-action plan compiled from all the districts and examined 42

-Feedback on micro-action plan initiated -Funds released to districts for both the IRS rounds of 2015 Dec’ NVBDCP -Issuance of letter for active case detection campaigns 2014 -Issuance of comprehensive guidelines for VL-HIV case management issued by NVBDCP/NACO -Active case search in high endemic districts- both for State VDB Office KA and PKDL -Strengthening of surveillance system -Training of medical officers, Para-medicals and ASHA in progress -Comprehensive guidelines for VL-HIV case

management received and issued to districts by State Jan’ NVBDCP -Issuance of letter for review meeting, plan of action and 2015 insecticide requirement -Case based tracking of VL-HIV patients discussed and finalized -letter issued to states in this regard -Active case search in high endemic districts- both for KA and PKDL -Strengthening of surveillance system for KA and PKDL -HMIS online started State VDB -Case based tracking of all VL-HIV patients initiated Office -Micro-action plan examined at all levels

-Insecticide procured -Training of medical officers, Para-medicals and ASHA in progress -Comprehensive guidelines for VL-HIV case management received and issued to districts by State Feb’ State VBD -Pre IRS training of spray squads 2015 office -Pre IRS awareness and search activities -Actual IRS spray operations -Concurrent evaluation of IRS -Medical officers training in KA and Liposomal Amphotericin B use -Active case search continued for KA and PKDL -Engagement of ASHA in case referral and follow up

Mar’ NVBDCP -Issuance of letter for review meeting 2015 -Post IRS monitoring meeting and feedback to states -Second stakeholders’ meeting -Active case search in high endemic districts- both for KA and PKDL -Action taken on feedback of IRS monitoring and KA elimination activities State VDB -Strengthening of surveillance system for KA and PKDL Office -Case based tracking of all VL-HIV patients and treatment follow-up of PKDL cases 43

--Training of medical officers, Para-medicals and ASHA in progress -Roll out of Liposomal Amphotericin B is complete in all the high endemic districts April- State VBD -Plan for second round of IRS initiated June Office 2015 -Micro-plan examined and corrective actions taken -ASHA and other health workers trained in IRS and M&E July- NVBDCP -Third party evaluation of status of elimination in all the Aug’ four states 2015 44

8. Roles and responsibilities of the Centre and State Governments Central Government State Government Formulation of policy and Technical Dissemination of GOI guidelines to guidelines districts and periphery for timely and regular implementation of KAE activities. Technical and financial assistance Adequate provision of annual budget from state resources of KAE. Logistic & commodity support Preparation of Road map and contingent plan to achieve national objective of KAE.

Facilitate in infrastructure and capacity Ensuring sanitation, hygiene and healthy building of medical and para-medical environment in an around Kala-azar workers affected villages/blocks. Prototype of IEC/BCC materials. IEC/BCC campaign for increasing awareness and education regarding general sanitation & hygiene, timely treatment, health seeking behavior and full community participation during IRS activities. Supervision and monitoring of Implementation of programme activities

implementation of policy and guidelines in respect of: of GoI for KAE a) Surveillance of Kala-azar cases Others – cross border meetings b) Prompt detection and treatment with drug of choice of Kala-azar cases. c) Enhancing the capacity of CHC, Sub-district and district hospitals for Kala-azar treatment with proposed drug regimen. d) Strengthening of district hospitals and medical colleges for referral back-up support. e) Effective mechanism for supervision and monitoring to ensure implementation of action

plan. f) Timely organization of Kala-azar and PKDL camps search and ensuring their treatment. KAE target is to achieve by 2015, commitment and strong focus from all stakeholders is required to meet these targets. 45

9. Roles and responsibilities of District Collectors/Magistrate 9.1. Early diagnosis & complete treatment Action required from District Administration It would be of great help to the programme, if the personnel from the administration working in the rural set up for collecting revenue and undertaking developmental programs are identified and trained for helping the system in identification of the Kala-azar cases and maintaining a close liaison with ASHAs and other workers for

quick referrals with complete treatment. In the monthly Village Health Nutrition & Sanitation Committee, an awareness programme on kala-azar Elimination for the community be included with a clear message that anybody suspecting a Kala-azar case immediately reports the same to ASHA and other Health personnel. 9.1.1 Strengthening of referral Under the present system PHC is the nearest referral for detection and treatment of the Kala-azar case besides CHCs and District Hospitals. Under this system all the

referral health centers are equipped with manpower, number of Rapid Test Kits as well as the requisite drugs. However, it needs to be ensured that all the above facilities are available at these centers so that the cases referred are do not remain untreated or incompletely treated. Action required from District Administration The adequacy of the manpower, diagnostic test kits and drugs at all the referral centers be ensured through periodic review

by the identified officers. At no point of time the patient should be left untreated /unattended. ASHAs and other health personnel are required to be motivated for sincerely taking of the responsibility of case identification and early referrals as well as complete treatment. 9.2 Integrated vector control Under the programme a dedicated IRS of all the households in the affected blocks system is to be carried out as per NVBDCP guidelines. The 1st round of insecticidal

spray with DDT starts from 15th February. Government of India supplies DDT free of cost and the cost of spray wages is also borne by GoI. It has been observed that the room coverage which should touch more than 90% is not upto the mark due to lack of acceptance by the community. This is primarily due to lack of advance information to the community by the health system prior to scheduled date of spray. As a result of which the community is under prepared for acceptance the spray. It has also been

observed that wherever a satisfactory room coverage (80-90%) is achieved, the incidence of the disease is reduced. Action required from District Administration An aggressive social mobilization campaign aimed at spreading the information on the usefulness of IRS is urgently required for creating awareness amongst the masses which will in turn significantly increase the room coverage for better results. GoI has provisioned funds under IEC to be used by the states. Therefore, a realistic

IEC/BCC action plan has to be developed in consultation with the subject experts available at state /district level so that the desired IEC campaign through IPC, print & electronic media while taking into consideration the media habits of the community, is 46

designed and developed for perfect canvassing. During IRS operation, officers from other department may also be involved for supervision. The hands on training will be provided by District Vector Borne Disease Officer (erstwhile DMO). 9.3 Environmental measures It has been observed that the vector of Kala-azar sandfly usually lives in dark, humid and invalidated hutments with where the soil is moist. This vector also breeds profusely in an around the hutments in moist cow dung hips and in places where

insanitation and unhygienic conditions galore. Simple measures of sanitizing the areas and improving the design of the hutments by cementing the floors and plastering of walls upto 6 feet will go a long way in drastically reducing the vector densities which will in turn have a great epidemiological impact. Action required from District Administration Ministry of Rural Development has released funds for construction of Pucca Houses in Kala azar endemic areas under ‘Indira Awas Yojna‛. The Mushar and Paswan

communities are at a greater risk due to poor housing structure/ condition. It may therefore be ensured that the funds available with district Administration be utilized for constructing pucca houses /renovating the existing hutments to make them pucca thereby reducing significantly the presence of sand flies as well as in helping to interrupt Kala-azar transmission. 47

10. District level activities 10.1 Formation of district level Kala-azar elimination (KAE) committee It would be a great help for all the stakeholders if a District Level Kala-azar Elimination Committee under the Chairmanship of District Magistrate /Collector with District Programme Officer (VBD) as its Member Secretary alongwith other technical members is constituted. The main thrust of this Committee would be to closely monitor the KAE activities in the field and suggest immediate corrective measures.

This Committee should meet at least once in a month to take stock of the situation and sub members of this committee should be advised to visit the field for providing a pragmatic feedback to the Chair person. 48

11. Time line for Kala-azar Elimination 11.1 National level actions • Programme management Components Activities Timeline Responsible Responsible Organization Deptt. Already Policies Formation of Core group done in July MoHFW Policies Revision of guidelines Aug’ 2014 MoHFW MoHFW Policies strategies of Kala-azar Sept’ 2014 MoHFW MoHFW elimination cell at central programme division comprising of public health expert, monitoring and evaluation expert, vector control specialist and

statistician cum data manager Policies Monitoring of stakeholders Aug’ 2014 MoHFW NVBDCP Policies Roll out of revised HMIS to all Dec’ 2014 NVBDCP NVBDCP areas Policies WHO M&E indicators and IRS Aug’ 2014 MoHFW NVBDCP toolkit Review Core group 1st meeting July 2014 MoHFW NVBDCP Review 2nd Core group meeting proposed Sep. MoHFW NVBDCP /October 2014 Policies Upgradation of cold chain March 2015 DFID DFID, NVBDCP • Vector control (indoor residual spray) Components Activities Timeline Responsible Responsible

Organization Deptt. Fund flow Status assessment of SOE and Sept’ 2014 MoHFW NVBDCP requirements Fund flow Release of funds to state Oct’ MoHFW NVBDCP IRS Supervisory visits by assigned Throughout MoHFW NVBDCP & campaign officers to the field the year Partner Training Orientation training for IRS Sept’ 2014 RMRI RMRI Mobilization Dessimination of IEC prototypes Sept’ 2014 NVBDCP & NVBDCP development partners 49

• Monitoring and evaluation Components Activities Timeline Responsible Responsible Organization Deptt. Fund flow Monitoring of fund distribution at Regular NVBDCP national, state, district, block and /state squad level Fund flow Monitoring of submission of Regular SOE/UC state/NVBDCP Cold Chain Cold chain mapping WHO /Partner • Surveillance/treatment Components Activities Timeline Responsible Responsible Organization Deptt. Policies House to house survey Dec’ NVBDCP NVBDCP

(either on polio model or 2014 /development partners other mechanisms) for active case search & PKDL in villages, BCC and advance information about IRS with monitoring support form stakeholders. Case Revision and disseminate Sept’ NVBDCP/Development NVBDCP detection short but effective 2014 partners states SOPs/case management flowchart for diagnosis and treatment of Kala-azar for PHCs and private health facilities in view of new treatment policy Case Coordination with NACO for Sept’ NACO /NVBDCP States

11.2 State level actions • Programme management Components Activities Timeline Responsible Responsible Organization Deptt. Human Filling vacant positions on priority Dec’ State Health SHS Resources 2014 Society Policies Filling of consultants approved by Dec’ State Health SHS; NVBDCP. 2014 Society Development partner Review State Task Force constitution Sept’ State Health PS Health 2014 Department Review STF meeting: 1 month prior and on State Health PS Health

completion of IRS activities. Quarterly Department meetingsforassessingother components. Training Induction/refresher training of District Dec’ NVBDCP RMRI VBD Officer VBD consultants, KTS, 2014 Care link workers Training 1 day sensitization of District Dec’ State Health ED SHS Magistrates at state level 2014 Deptt. • Vector control (indoor residual spray) Components Activities Timeline Responsible Responsib Organization le Deptt. Fund flow Allocation and release of funds to Two State Health SHS

districts months in Society advance to IRS Fund flow Submission of SOEs to national As per State Health SHS level existing Society instructions Supervision Plan for allocation of state nodal Sept’ State Health PS Health officer for contiguous 4-5 districts by 2014 Society state officers for oversight in microplanning and training & supervision Supervision Supervision plan during IRS Sept’ State Health PS Health 2014 Society Mobilization Printing and dissemination of IEC Nov’ 2014 DFID State/DFID

material consortium consortium Development Developme partners nt partners 51

Mobilization Print & electronic media sensitization Nov’ 2014 DFID State/ DFID and use in community mobilization consortium consortium Development Developme partners nt partners Mobilization Print & electronic media sensitization Nov’ 2014 State Health PS Health and use in community mobilization Department IRS Supervisory visits by assigned Before State Health PS Health campaign officers to the field and during Department IRS • Monitoring and evaluation

Components Activities Timeline Responsible Responsible Organization Deptt. Review Feedback to STF on monitoring During State Health PS Health findings IRS Dept. IRS Providing monitoring feedback to STF During State Health PS Health campaign IRS Dept. • Surveillance/treatment Components Activities Timeline Responsible Responsible Organization Deptt. Training Up-gradation of district hospitals to Dec’ RMRI RMRI undertake parasitological diagnosis 2014 MSF MSF

Case Compile and maintain linelist of all Dec’ State Health SPO detection Kala-azar & PKDL cases reported by 2014 Society districts with complete address, treatment details and outcome Case Sharing the linelist of Kala-azar and Dec’ State Health SPO detection PKDL cases with with NVBDCP 2014 Society 52

11.3 District level actions • Programme management Components Activities Timeline Responsible Responsible Organization Deptt. Review DTF meeting: 1 month prior and 1 month District DM on completion of IRS activities. before Health Quarterly meetings for IRS Society assessing other components. Training Training of block and district Immediate State Care/Developm level data operators regarding ent partners coverage, transmission, drug and diagnostic kit data entry • Vector control (indoor residual spray)

Components Activities Timeline Responsible Responsible Organization Deptt. Fund flow Release of funds to blocks District Health DM Continuous Society Fund flow Submission of SOEs to state Monthly District Health DM Society Microplanning Compilation and reviews of As per District Health Dist VBD Officer microplans instructions Department Microplanning Submission of final microplan 90 days District Health Dist VBD Officer to state level with logistic before IRS Department requirement 90 days before IRS

Supervision Allocation of blocks to district 90 days District Health DM officers for oversight in before IRS Society microplanning and training Supervision Supervision plan during IRS 90 days District Health DM before IRS Society Training Supervision of trainings As per District Health Dist VBD Officer plan Department Training Training of trainers (TOT) As per District Health Dist VBD Officer plan Department Mobilization Display of IEC material Pre IRS District Health Dist VBD Officer and during Department

campaigns must, wall writing throughout Mobilization Distribution of IEC material to As per District Health Dist VBD Officer block plan Department Mobilization Using local news networks for As per District Health Dist VBD Officer IEC plan Department Mobilization Assist in display of IEC As per Care Care material plan Mobilization Assist in distribution of IEC As per Care Care material to block plan Mobilization Assist in using local news As per Care Care networks for IEC plan 53

Mobilization Coordination with education As per District Health DM department in DTF for plan Society organization of guru goshtis and rallies prior to IRS campaign IRS campaign Supervisory visits by assigned During District Health DM officers to the field IRS Society IRS campaign Daily compilation of coverage Within a District Health Dist VBD Officer reports and communication to month of Department state level IRS • Monitoring and evaluation Components Activities Timeline Responsible Responsible

Organization Deptt. IRS Providing monitoring feedback Pre and District task District VBD campaign to DTF post IRS force Officer Review Feedback to DTF on monitoring Pre and State Health District VBD findings post IRS Society Officer • Surveillance/treatment Components Activities Timeline Responsible Responsible Organization Deptt. Case detection Refresher on Kala-azar Dec’ 2014 District Health Dist VBD detection and notification Department Officer

Case detection Enlisting important health Dec’ 2014 District Health Dist VBD facilities in private setup Department Officer by KTS/Care link workers Case detection Allocation of government Dec’ 2014 District Health Dist VBD and private health Department Officer facilities to KTS/Care link workers for active case searches and sensitization Case detection Coordination and Nov’ 2014 District Health Dist VBD dissemination of Department/IMA Officer sensitization through letters and meetings by IMA

Pharmacovigilance District hospitals to follow Nov’ 2014 NVBDCP NVBDCP national PATH PATH pharmacovigilance protocol 54

11.4 Block level actions • Vector control (indoor residual spray) Components Activities Timeline Responsible Responsible Organization person Microplanning Selection of villages based on 120 days PHC MOIC cases before IRS Microplanning Updation/preparation of microplan 120 days PHC MOIC as per IRS guideline before IRS Microplanning Submission of microplan to 120 days PHC MOIC district with logistic requirement before IRS 120 days before IRS Microplanning Facilitating microplanning 120 days Care Care

before IRS Fund flow Distribution of allowance to spray As per PHC MOIC workers plan Fund flow Submission of SOEs to district As per PHC MOIC existing instructions IRS campaign Conducting campaigns As per PHC MOIC plan IRS campaign Daily evening briefing of all During PHC MOIC supervisors IRS IRS campaign Daily compilation of coverage During PHC MOIC reports and communication to IRS district Mobilization Distribution IEC material to ASHA Before PHC MOIC in monthly meeting for display IRS prior to IRS

Mobilization ASHA meeting for dissemination As per PHC MOIC of information to beneficiaries plan prior to IRS campaign and search for cases (meeting 20 days prior to campaign, first visit to family by ASHA 15 days prior, second visit 2 days prior) Mobilization Meeting of ANMs 15 days prior to 15 days PHC MOIC campaign for meeting with PRI before IRS and local practitioners Supervision Supervision plan during As per PHC MOIC microplanning, training and IRS plan

Training Training of IRS workers As per PHC MOIC plan Training Submission of training plan to As per PHC MOIC district plan Training Facilitation of trainings at block As per Care Care level plan 55

• Monitoring and evaluation Components Activities Timeline Responsible Responsible Organization Deptt. Microplanning Monitoring the quality and As per District MOIC progress of microplanning plan Training Monitoring of trainings As per WHO/develop plan ment partners MOH&FW/di strict • Surveillance/treatment Components Activities Timeline Responsible Responsible Organization Deptt. Case Active surveillance visits and As per District Health Dist VBD

detection sensitization of government and instructions Department Officer private health facilities by KTS/Care link workers. At least one visit to all assigned health facilities in two months. Case Screening of fever cases from Monthly PHC MOIC detection IDSP weekly linelist Case Sensitization of ASHA/AWW in Monthly PHC MOIC detection their monthly meetings for case detection and reporting by MOIC Case Diagnosis and ensuring Monthly PHC MOIC detection treatment of suspect cases from

any source at designated treatment center Treatment Follow up of HIV-VL cases Regular PHC KTS Treatment Referral of all relapse cases to Regular PHC MOIC district hospital 56

11.5 Village level actions • Vector control (indoor residual spray) Components Activities Timeline Responsible Responsible Organization Deptt. Mobilization First visit to family by ASHA 15 As per PHC MOIC days prior, second visit 2 days plan prior (search of cases/BCC/mobilization) Mobilization Visit by ANM/other health staff to As per PHC MOIC PRI and local practitioners for plan BCC and search for cases IRS IRS spray activities As PHC MOIC campaign planned • Monitoring and evaluation

Components Activities Timeline Responsible Responsible Organization Deptt. Mobilization Monitoring of awareness about As District MOIC IRS and visit of ASHA/ANM/other planned health staff IRS Monitoring of IRS squads and As District MOIC campaign completed villages planned • Surveillance/treatment Components Activities Timeline Responsible Responsible Organization Deptt. Case Quarterly active camp search for As per PHC MOIC detection suspect KA cases & PKDL at the plan village

Case Scanning the village for fever Weekly PHC MPHS detection complex of KA suspect cases and reporting to ANM/ASHA cascade Case Active case search in community Upon PHC KTS/ detection around index case detection Care link of cases worker Treatment Follow up of treated VL and PKDL 6 and 12 PHC KTS/ cases at 6 and 12 months months Care link respectively worker This Road map for kala – azar elimination was prepared with the help from WHO, stakeholders and states. 57

MASSIVE TRANSFUSION PROTOCOL Criteria to activate: 1) Actual /Anticipated 4 units RBC in <4 hours + hemodynamically unstable+/- anticipated ongoing bleeding 2) Severe thoracic,abdominal ,pelvic or multiple long bone trauma Trauma team leader determines if the patient meets the criteria for MTP activation Baselines investigations sent: Full blood count (Hb, hemaocrit and platelets) PT/INR, APTT (if available), (Fibrinogen if available), Creatinine, Calcium, Arterial Blood gases (if available) Activate MTP:

Notify the Blood bank /transfusion laboratory, Haematologist /Blood bank in charge, Surgeon, Operation theatres, Anaesthetists, Radiologist, Concerned nursing staff, ward boys services to ensure collaboration Trauma team requests for the fixed dose ratio of plasma (FFP) :platelets :Red blood cells (1:1:1) i.e., 4 units of each Correct hypothermia/ keep patient warm Surgical measures to stop bleeding Repeat Full blood count, Coagulation profile and Arterial blood gases if available (usually in 30-60min)

Bleeding Controlled YES NO Notify to cease MTP protocol Transfusion guided by the laboratory coagulation results

STANDARD TREATMENT GUIDELINES Management of Alcohol Dependence Full Background document February 2016 Ministry of Health & Family Welfare Government of India 1 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

Table of Contents SCOPE OF THE GUIDELINES ..................................................................................................................... 4 BACKGROUND......................................................................................................................................... 6 PREVALENCE OF ALCOHOL DEPENDENCE IN INDIA ................................................................................. 7

I. WHEN TO SUSPECT/ RECOGNISE? .................................................................................................... 8 Introduction .......................................................................................................................................................... 8 Case definition ...................................................................................................................................................... 9

II. DIAGNOSIS.................................................................................................................................. 10 Alcohol dependence ........................................................................................................................................... 10 Alcohol intoxication and alcohol withdrawal ...................................................................................................... 10

Differential Diagnosis .......................................................................................................................................... 12 III. PREVENTION AND COUNSELING ................................................................................................. 14 IV. DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA ............................ 15

Physical examination ....................................................................................................................................... 18 Mental Status Examination (MSE) ................................................................................................................... 20 INVESTIGATIONS ................................................................................................................................................. 21

TREATMENT ........................................................................................................................................................ 22 Phases of treatment ........................................................................................................................................ 22 Short- term management phase ..................................................................................................................... 22

Management of alcohol withdrawal seizures ................................................................................................. 28 Management of delirium tremens .................................................................................................................. 28 General Nursing Care ...................................................................................................................................... 29

Motivational Enhancement Therapy (MET) .................................................................................................... 29 Long-term management phase ........................................................................................................................... 31 Aims................................................................................................................................................................. 31

REFERRAL CRITERIA ............................................................................................................................................. 37 VI. WHO DOES WHAT AND TIMELINES .................................................................................................. 38 VII. Clinical Pathways for Management of Alcohol Dependence ............................................................ 38

VIII. How these Guidelines were developed .......................................................................................... 40 FURTHER READINGS AND REFERENCES ................................................................................................. 47 2 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

List of Figures and Tables Box 1. Diagnostic criteria for alcohol dependence syndrome as specified in The ICD-10 11 Classification of Mental and Behavioral Disorders (adapted for alcohol) Table 1. Diagnostic criteria for alcohol harmful use (as per ICD 10) 13 Table 2. Screening tools for problem alcohol use 15 Table 3. Chronic medical conditions that are associated with problematic alcohol use 19 (list is not all inclusive)

Table 4. Investigations along with indications in a patient with alcohol dependence (list 21 is not all inclusive) Table 5. Specific investigations along with indications (for higher centers) 22 Table 6. Approximate therapeutic dose equivalent of different benzodiazepines 25 commonly used in management of alcohol withdrawal Table 7. Different regimens for alcohol withdrawal management (detoxification) 27 Table 8. Common side-effect of the medicines used in long term management phase for 34

alcohol dependence Table 9. List of available guidelines on management of alcohol dependence and the 42 guidelines referred to for the purpose of the current guideline. Table 10. Status of the adoption/ adaptation for the various recommendations used in 43 the current guideline 3 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

SCOPE OF THE GUIDELINES The areas that will be addressed by the guideline on alcohol dependence are described in the following sections. Population Groups that will be covered The guideline will cover the individuals with alcohol dependence who require medical management for their alcohol use disorders. This will include those diagnosed with alcohol dependence. It will cover those individuals who require medical services per se for their alcohol use disorder. It will not

cover the groups as specified in the subsequent section. Groups that will not be covered The guideline will not cover the management of the medical conditions associated with alcohol use. The guideline shall also not specifically cover individuals with co-morbid alcohol use disorders, psychiatric disorders and alcohol (methanol) poisoning. Although, the clinicians might find these guidelines useful while planning management for these patients as well. Healthcare setting

The guideline will cover care provided in primary, secondary and tertiary hospital settings. Clinical management • The guideline will provide advice on diagnosis of individuals presenting with alcohol dependence. • The guideline will provide advice on investigations to be carried out while managing a patient with alcohol dependence. • The guideline will provide advice on short-term medical management of individuals with alcohol dependence.

• The guideline will provide advice on long- term medical management of patients with alcohol dependence. • The guideline will provide advice on psycho-social interventions for patients with alcohol dependence. 4 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

• The guideline will provide advice on situations that warrant in-patient care as well as indications for referral. • The guideline will provide advice on patient psycho- education to improve patient and care giver satisfaction. 5 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

BACKGROUND • Excessive use of alcohol is a major public health problem. It causes 5.9% of all deaths globally and is responsible for 5.1% of the DALYs (Disability Adjusted Life Years) (WHO, 2014). Excessive use of alcohol is a component cause of more than 200 disease and injury conditions. Excessive use of alcohol is preceded only by tobacco as the largest modifiable risk factor for morbidity and mortality globally. Alcohol use has been

identified as one of the priority modifiable risk factors to bring down burden due to NCDs. • It has been estimated that around one-fourth to one-third of male population in South Asian countries drink alcohol. Additionally, an increasing trend of alcohol use among women has been observed in these countries. Disease burden per litre consumption of alcohol has been found to be relatively higher among Low and Middle Income countries

(LMIC). It has been recommended that addressing excessive alcohol use shall serve as a low cost effective strategy to reduce the burden of disease in LMIC. 6 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

PREVALENCE OF ALCOHOL DEPENDENCE IN INDIA The National Household Survey of Drug Use was the first systematic effort to document the nation- wide prevalence of (psychoactive) substance use in India. Alcohol was the primary substance used (apart from tobacco) in 21.4% of the subjects (Ray, 2004). Additionally, 17- 26% of alcohol users qualified for ICD- 10 diagnosis of dependence. This corresponded to an average prevalence of about

4%. The alcohol use prevalence varied across different states of the country with a low of 7% (for current use) in Gujarat to a high of 75% (for current use) in Arunachal Pradesh. The National Family Health Survey (NFHS) suggested an increase in alcohol use among males in the NFHS-3 as compared to NFHS-2. The Drug Abuse Monitoring System reported data from the government de-addiction centres across the country. Alcohol was reported as the most commonly used substance

(apart from tobacco) with 43.9% of the treatment seekers reporting its current use.According to the Global Status Report on Alcohol and Health 2011, 25% and 15% of male and female drinkers, respectively were identified as heavy episodic drinkers. Additionally, it has been estimated that unrecorded alcohol consumption is at least two thirds of all alcohol consumption in the Indian subcontinent. There has been limited literature from India that has explored the problems associated with alcohol

use. As per the reports of the industry association sources, 15% to 20% of absenteeism and 40% of accidents at work are due to alcohol consumption. Hospital-based studies from India report alcohol-related problems to account for over a fifth of hospital admissions. It has a disproportionately high association with deliberate self-harm, high-risk sexual behavior, human immunodeficiency virus (HIV) infection, tuberculosis, esophageal cancer, liver disease, and duodenal ulcer. 7

Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

I. WHEN TO SUSPECT/ RECOGNISE? Introduction Alcohol use disorders are a major contributor to global burden of disease. Problematic alcohol use is associated with significant morbidity and mortality. Patients with problematic alcohol use are common in all kinds of medical care settings. Often, those seeking treatment for their medical or surgical conditions in other clinical departments/ specialities may have an underlying

alcohol dependence that may be complicating the medical/ surgical condition. Moreover, many cases of alcohol dependence go undetected for years because of poor motivation on part of the patient as well as failure of the treatment providers to screen for it. At times, individuals with alcohol dependence are brought to the treatment setting after they have come in conflict with law as in case of drunken driving. Alcohol dependence represents a set of biological, psychological and social manifestations. It

represents a maladaptive pattern of alcohol use that leads on to clinically significant impairment or distress or both. One can suspect possibility of alcohol dependence when alcohol use turns problematic. A history of intense, irresistible, compulsive desire to use alcohol (known as craving); a gradual increase in amount of alcohol used over time because of reduction in the effect experienced with previous amount (known as tolerance); and appearance of withdrawal symptoms including

sweating, increased pulse rate, hand tremor, nausea, vomiting, insomnia, psychomotor agitation, anxiety, transient visual, tactile, or auditory hallucinations or illusions on stopping or reducing the amount usually consumed are indicators of psychological and physical dependence on alcohol. An individual with alcohol dependence tends to plan the day around procuring, using and experiencing its effects. History of neglect of other pleasures and responsibilities at school,

home or work and loss of control over the amount or pattern of use are pointers towards possibility of alcohol dependence. Use that persists in spite of being aware of the harms associated with alcohol use is another pointer towards dependence on alcohol. 8 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

Presence of one or more of the aforementioned is an indicator for evaluation for possibility of alcohol dependence. Interpersonal difficulties consequent to alcohol use, difficulties at work place, and emergence of a physical or mental disorder commonly associated with alcohol use also suggest possibility of heavy alcohol use, and should raise the suspicion for possibility of alcohol dependence. Case definition

An individual presenting with history of excessive (regular/ periodic) use of alcohol, especially when associated with medical, psychological, vocational, financial, familial and social problems needs to be assessed for presence of alcohol dependence. Presence of craving, tolerance and/or withdrawal symptoms lends further support to the possibility of alcohol dependence and warrants detailed evaluation for presence of alcohol dependence. 9

II. DIAGNOSIS Alcohol dependence As mentioned in the previous section, alcohol dependence represents a maladaptive pattern of alcohol use that leads on to clinically significant impairment or distress or both. One can suspect possibility of alcohol dependence when alcohol use turns problematic. A history of craving; tolerance; appearance of withdrawal symptoms on stopping or reducing the amount usually consumed are indicators of psychological and physical dependence on alcohol.

An individual with alcohol dependence tends to plan the day around procuring, using and experiencing its effects. History of neglect of other pleasures and responsibilities at school, home or work and loss of control over the amount or pattern of use are pointers towards possibility of alcohol dependence. Use that persists in spite of being aware of the harms associated with alcohol use is another pointer towards dependence on alcohol.

A description of criteria for diagnosis of alcohol dependence syndrome as specified in the WHO’s ICD-10 Classification of Mental and Behavioral Disorders is provided in Box 1. Alcohol intoxication and alcohol withdrawal Presence of clinical features associated with alcohol dependence make the diagnosis of the condition fairly straight forward. These features are unlikely to be confused with any other psychiatric disorder.

However, at times it might be challenging to reach at a diagnosis of alcohol dependence if the adequate information is not available. A patient who is unavailable for interview due to being under intoxication or withdrawal might require a reassessment once the acute medical condition has settled and the patient is in a position to participate in the interview. Even during such conditions of intoxication and withdrawal, presence of clinical features associated with intoxication

(along with alcohol on breath) and withdrawal can help establish the diagnosis of alcohol intoxication and alcohol withdrawal, respectively. Alcohol intoxication is characterized by disinhibition, argumentativeness, aggression, lability of mood, impaired attention, impaired judgment, interference with personal functioning, unsteady gait, difficulty standing, slurred speech, nystagmus, decreased level of consciousness (e.g. stupor, 10 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

coma), flushed face, and conjunctival injection. These clinical features develop following recent use of alcohol at sufficiently high dose levels to be consistent with intoxication. Box 1. Diagnostic criteria for alcohol dependence syndrome as specified in The ICD-10 Classification of Mental and Behavioral Disorders (adapted for alcohol) A cluster of physiological, behavioral, and cognitive phenomena in which the use of

alcohol takes on a much higher priority for a given individual than other behaviors that once had greater value. A central descriptive characteristic of the dependence syndrome is the desire (often strong, sometimes overpowering) to take alcohol. There may be evidence that return to alcohol use after a period of abstinence leads to a more rapid reappearance of other features of the syndrome than occurs with nondependent individuals.

A definite diagnosis of alcohol dependence should usually be made only if three or more of the following have been present together at some time during the previous year: (a)a strong desire or sense of compulsion to take alcohol; (b)difficulties in controlling alcohol-taking behavior in terms of its onset, termination, or levels of use; (c)a physiological withdrawal state when alcohol use has ceased or been reduced, as evidenced by: the characteristic withdrawal syndrome for alcohol; or use of alcohol (or a

closely related) substance with the intention of relieving or avoiding withdrawal symptoms; (d)evidence of tolerance, such that increased doses of alcohol are required in order to achieve effects originally produced by lower doses; (e)progressive neglect of alternative pleasures or interests because of alcohol use, increased amount of time necessary to obtain or take alcohol or to recover from its effects; (f)persisting with alcohol use despite clear evidence of overtly harmful consequences,

such as harm to the liver through excessive drinking, depressive mood states consequent to periods of heavyalcohol use, or alcohol-related impairment of cognitive functioning; efforts should be made to determine that the user was actually, or could be expected to be, aware of the nature and extent of the harm. 11 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

Alcohol withdrawal is characterized by tremors of the outstretched hands, tongue or eyelids, sweating, nausea, retching or vomiting, tachycardia or hypertension, psychomotor agitation, headache, insomnia, malaise or weakness, transient visual, tactile or auditory hallucinations or illusions, and generalized seizures. These features develop on recent cessation or reduction of alcohol after repeated, and usually prolonged and/or high-dose use. At times, patient develops what is known as

‘complicated withdrawal’. It is characterized by presence of seizures or delirium (known as delirium tremens) along with other features associated with alcohol withdrawal. Alcohol intoxication is not a direct indicator of alcohol dependence and can occur independent of it. Similarly, while alcohol withdrawal is one of the clinical features of alcohol dependence, in itself is not sufficient (or necessary) to make a diagnosis of alcohol dependence. However, those presenting

with alcohol intoxication or withdrawal should be assessed for presence of alcohol dependence. Differential Diagnosis • Sedative/ hypnotic/ anxiolytic dependence Features of alcohol intoxication and withdrawal have some overlap with other depressant psychoactive substances such as sedatives/ hypnotics/ anxiolytics. However, history of use of these substances, along with clinical features specifically associated with these can help differentiate dependence on these substances from alcohol dependence.

Sedative/ hypnotic/ anxiolytic intoxication is characterized by slurred speech, incoordination, unsteady gait, nystagmus, impairment in attention or memory, stupor or coma during, or shortly after their use. Sedative/ hypnotic/ anxiolytic withdrawal is characterized by autonomic hyperactivity in form of sweating, increased pulse rate; hand tremor; insomnia; nausea; vomiting; transient visual, tactile, or auditory hallucinations or illusions;

psychomotor agitation; anxiety and grand mal seizures. These features follow cessation of (or reduction in) sedative/ hypnotic/ anxiolytic use that has been heavy and prolonged. • Alcohol abuse and harmful use Harmful use (used in ICD 10) represents a maladaptive patterns of alcohol use that leads to some kind of harm. Harmful use of alcohol refers to a pattern of alcohol use that leads to either physical or psychological harm. On the other hand, alcohol abuse refers to a 12

pattern of alcohol use that leads to failure to fulfill major role obligations; or recurrent use in situations in which it is physically hazardous; or associated with recurrent substance- related legal problems; or continued use despite having persistent or recurrent social or interpersonal problems. The diagnostic criteria for alcohol, harmful use and alcohol abuse have been presented in table 3. Table 1. Diagnostic criteria for alcohol, harmful use (as per ICD 10)

I. Diagnostic criteria for alcohol, harmful use (as per ICD 10) (adapted for alcohol) A pattern of alcohol use that is causing damage to health. The damage may be physical or mental. The diagnosis requires that actual damage should have been caused to the mental orphysical health of the user. Co-morbid conditions • Psychiatric disorders Excessive use of alcohol, particularly in dependent pattern, is associated with different

psychiatric disorders collectively known as alcohol induced disorders. These include dementia, amnestic disorder, psychotic disorder (with delusions or with hallucinations), mood disorder, anxiety disorder, sexual dysfunction, sleep disorder. These need to be differentiated from independent psychiatric disorders. Alcohol induced psychiatric disorders resemble their independent counterparts in terms of clinical features. However, these tend to have temporal

association with pattern of alcohol use, are usually short lasting, and tend to remit with abstinence. However, in clinical practice it might be difficult to differentiate between the two. Consequently, those presenting with any of the psychiatric disorders should be assessed for presence of underlying alcohol dependence as well. 13 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

III. PREVENTION AND COUNSELING Prevention has been recommended as an important public health intervention to address the problem of alcohol dependence. Prevention helps by preventing the onset of alcohol use or problematic alcohol use (in case alcohol use has set in). Some of such strategies include: • Raising awareness and commitment among the general public regarding harmful effects of alcohol use • Health services’ response; • Community action; • Strict action against drunk-driving;

• Regulating availability and marketing of alcohol; • Alcohol pricing policies; • Reducing the negative consequences of drinking and alcohol intoxication; • Reducing the public health impact of illicit alcohol and informally produced alcohol; • Monitoring and surveillance of sell of alcohol Counseling plays a key role in management of alcohol dependence both during the short term as well as long term phase of management. It has been described in greater details in the subsequent sections. 14

IV. DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA ASSESSMENT While assessing an individual for alcohol dependence, it is important to carry out complete clinical assessment. This includesmedical history, physical examination, mental status examination (MSE) and investigations. Assessment is targeted: • To ascertain the diagnosis of alcohol dependence • To establish rapport with the patient • To assess complications associated with alcohol use (including physical and psychological)

• To assess level of motivation • To assess support and resources available • To assess suitable setting for management • To assess need for referral Screening There is a significant time lag between emergence of alcohol dependence and treatment seeking for the same. It is not uncommon for the patient with alcohol dependence tocome in contact with medical facility for some unrelated medical condition. It is important for the clinician to enquire

about alcohol use from every patient. Simple, brief and validated tools can be used to screen those with problem drinking. Those who screen positive on these instruments should then be assessed in greater detail for alcohol dependence. Two such screening instruments include CAGE questionnaire and the Alcohol Use Disorders Identification Test(AUDIT) (Table 4) Table 2. Screening tools for problem alcohol use CAGE questionnaire Items 1. Have you ever felt that you should Cut down on your drinking?

2.Have people Annoyed you by criticizing your drinking? 3.Have you ever felt bad or Guilty about your drinking? 4.Have you ever had a drink first thing in the morning to steady your nerves or get rid of 15 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

a hangover (Eye-opener)? Interpretation# Answering Yes to 2 questions – Strong Indication for alcohol dependence Answering Yes to 3 questions – May be taken as evidence for alcohol dependence The Alcohol Use Disorders Identification Test (AUDIT) Read questions as written. Record answers carefully. Begin the AUDIT by saying “Now I amgoing to ask you some questions about youruse of alcoholic beverages during this past year. “Explain what is meant by “alcoholic beverages”by using local examples of

beer, wine, vodka,etc. Code answers in terms of “standard drinks”.Place the correct answer number in the box atthe right. 1.How often do you have a drink containingalcohol? (0) Never [Skip to Qs 9-10] (1) Monthly or less (2) 2 to 4 times a month (3) 2 to 3 times a week (4) 4 or more times a week 2. How many drinks containing alcohol do youhave on a typical day when you aredrinking? (0) 1 or 2 (1) 3 or 4 (2) 5 or 6 (3) 7, 8, or 9 (4) 10 or more 3.How often do you have six or more drinkson one occasion?

(0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost daily 4. How often during the last year have youfound that you were not able to stop drinking once you had started? (0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost daily 16 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

5. How often during the last year have youfailed to do what was normally expectedfrom you because of drinking? (0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost daily 6. How often during the last year have youneeded a first drink in the morning to getyourself going after a heavy drinking session? (0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost daily 7. How often during the last year have youhad a feeling of guilt or remorse afterdrinking? (0) Never

(1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost daily 8.How often during the last year have youbeen unable to remember what happened the night before because you had beendrinking? (0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost daily 9. Have you or someone else been injured as aresult of your drinking? (0) No (2) Yes, but not in the last year (4) Yes, during the last year 10.Has a relative or friend or a doctor or an-other health worker been concerned

aboutyour drinking or suggested you cut down? (0) No (2) Yes, but not in the last year (4) Yes, during the last year Skip to Questions 9 and 10 if total score forquestions 2 and 3 = 0 17 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

Interpretation- Total scores of 8 or more are recommended asindicators of hazardous and harmful alcohol use,as well as possible alcohol dependence. AUDIT scores in the range of 8-15 represent amedium level of alcohol problems whereasscores of 16 and above represented a high levelof alcohol problems. History Sources of information While assessing an individual for alcohol dependence, the information can be obtained from the

patient, family members, significant others including friends and treatment records. Denial and minimization are commonly observed among individuals with alcohol dependence. It is helpful to corroborate the information from different sources. However, even in case the clinician suspects that the information is being withheld by the patient, it should not become a barrier to the therapeutic process. More information can be expected during the subsequent interviews. Information to be obtained

Apart from socio-demographic details, information should be obtained with regards to pattern of alcohol use, type of alcohol beverage used, duration of use, features of alcohol dependence, alcohol related complications (physical, psychological, familial, social, vocational, financial, legal), past abstinence attempts, and level of motivation. Information should also be obtained for possible high- risk sexual behavior.

Past history of any medical illness, psychiatric disorder, family history and personal history should also be obtained. All this information is important in psychosocial management. Physical examination A thorough general and systemic examination must be carried out for all patients with alcohol dependence. Physical examination can reveal features of alcohol intoxication or withdrawal (described in the previous section).

Additionally, physical examination helps identify presence of physical complications associated with alcohol use. Since patients with alcohol dependence may suffer from other medical 18 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

disorders, physical examination helps identify the associated medical conditions. One needs specifically to look at: • Pulse: Could be low (intoxication) or high (withdrawal) • Blood Pressure could below (intoxication) or high (withdrawal or hypertension as a medical complication) • Pallor: Seen in co-morbid anaemia • Icterus: Indicative of hyperbilirubinemia (hepatic dysfunction) • Generalised oedema: Indicates hypoproteinaemia (due to hepatic dysfunction)

• Abdomen examination: Look for hepatomegaly and signs of portal hypertension (caput medusa) Chronic medical conditions that are associated with problematic alcohol use are listed in table 5. It is recommended to look for presence of clinical features associated with these medical conditions. Table 3. Chronic medical conditions that are associated with problematic alcohol use (list is not all inclusive) (Shield et al, 2013) A. Chronic medical conditions that may be attributed to alcohol

• Alcoholic gastritis • Alcoholic liver disease • Alcoholic fatty liver • Alcoholic hepatitis • Alcoholic fibrosis and sclerosis of liver • Alcoholic cirrhosis of liver • Alcoholic hepatic failure • Alcoholic liver disease, unspecified • Alcohol-induced acute pancreatitis • Alcohol-induced chronic pancreatitis • Alcoholic polyneuropathy • Degeneration of nervous system attributed to alcohol • Amnesic syndrome • Psychotic disorder • Residual and late-onset psychotic disorder

• Other mental and behavioral disorders • Unspecified mental and behavioral disorder 19 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

• Alcoholic myopathy • Alcoholic cardiomyopathy • Fetus and newborn affected by maternal use of alcohol • Fetal alcohol syndrome (dysmorphic) B. Chronic medical conditions for which alcohol consumption is a component cause • Hypertensive heart disease • Ischemic heart disease and ischemic stroke • Alzheimer’s disease and other dementias • Epilepsy • Unipolar depressive disorders • Diabetes • Cancer of various organs Mental Status Examination (MSE)

Mental Status Examination (MSE) includes following assessments. • General appearance and behaviour: Gait incoordination, abusiveness, dressing pattern, smell of alcohol from the body or during conversation • Psychomotor activity: Increased or decreased • Speech: Coherence/relevance • Affect: Irritable, depressed • Thought: Presence of any delusions, ideas of hopelessness, helplessness, worthlessness, suicidal ideation and risk • Perception: Visual/auditory hallucinations

• Orientation: Disorientation to time/place/person in alcohol withdrawal delirium • Attention and concentration, memory, intelligence, abstraction • Judgment- intact/impaired • Insight • Level of motivation. MSE identifies presence of any co-occurring psychiatric disorders, level of motivation and presence of complicated alcohol withdrawal. 20 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

INVESTIGATIONS The diagnosis of alcohol dependence is clinical and is based primarily on the information obtained from history. Findings from the physical examination and MSE can help support the diagnosis. Investigations do not help establish or refute presence of diagnosis of alcohol dependence. However, the investigations are warranted in a case of alcohol dependence for the following reasons- • To assess presence of medical illness (secondary to alcohol use or independent)

• To monitor side effects/ adverse effects associated with medications used for management of alcohol dependence • To rule out possible differential diagnosis of complicated alcohol withdrawal (delirium tremens) The choice of investigations is guided by the information obtained from history and findings during examination. These can include biochemical investigations such as liver function test, neuroimaging such as CT scan, other radiological investigations such as endoscopy. Table 6

summarizes the important investigations indicated in a patient with alcohol use disorder. It is recommended to get a base line haemogram (including haemoglobin, total leucocytes count, differential leukocyte count, peripheral blood smear); random blood sugar; liver function tests (serum bilirubin, SGOT, SGPT); and renal function test (serum creatinine, blood urea) for all patients with alcohol dependence. Table 4. Investigations along with indications in a patient with alcohol dependence (list is

not all inclusive) Investigations Indications Haemoglobin Nutritional deficiency Peripheral blood smear Nutritional deficiency Total Leucocyte Count and Differential Infection (possible cause of delirium) Leucocyte Count Blood glucose Hypoglycaemia (possible cause of delirium) 21 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

Serum electrolyte levels Dyselectrolytemia (possible cause of delirium) Serum bilirubin Hepatic dysfunction SGOT/ SGPT Hepatic dysfunction Table5. Specific investigations along with indications (for higher centres) Investigations Indications Prothrombin time Hepatic dysfunction Serum albumin/ globulin ration Hepatic dysfunction CT scan- Head Head injury (possible cause of delirium) USG abdomen Hepatic damage Upper Gastro-intestinal tract endoscopy Oesophageal varices Fibroscan Cirrhosis of liver TREATMENT

Phases of treatment Treatment of alcohol dependence can be discussed under two distinct, but complimentary phases- the initial short- term management phase (also known as detoxification) and the later long- term management phase. Short- term management phase As mentioned earlier, the short- term management phase is also known as detoxification. Aims Aims of detoxification are as follows- • To manage alcohol withdrawal • To prevent complicated alcohol withdrawal • To manage complicated alcohol withdrawal

• To manage the associated medical (including psychiatric) complications • To establish rapport with the patient • To prepare the patient for the long term management phase 22 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

Setting The treatment for alcohol dependence can be carried out in the out-patient as well as in-patient settings. The choice for the setting can be guided by the patient, clinician as well as treatment facility related variables. Some of the indicators for in-patient management are as follows- • Presence of severe alcohol dependence (drinks over 30 units of alcohol per day or regularly drinks between 15 and 30 units of alcohol per day and have significant psychiatric or physical co-morbidities)

• Presence of or anticipated severe withdrawal • Presence of complicated withdrawal (withdrawal with seizures or delirium) • History of complicated withdrawal (withdrawals with seizures or delirium) • Co-occurring significant physical illness • Co-occurring significant psychiatric disorder • Concurrent abuse/ dependent use of other psychoactive substances including benzodiazepines • Poor psychosocial support • Distance from treatment centre that precludes regular follow up

• Failure of out-patient detoxification in past • Pregnancy • Children and adolescents • Elderly • Personal preference for in-patient treatment Simple alcohol withdrawal Specific assessment for alcohol withdrawal is based on clinical history and examination (physical and mental status) of the patient. 23 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

There is history of recent cessation of alcohol use that has been heavy and prolonged. Additionally, there is presence of clinical features associated with alcohol withdrawal. These include tremor of the outstretched hands, tongue or eyelids, sweating, nausea, retching or vomiting, tachycardia or hypertension, psychomotor agitation, headache, insomnia, malaise or weakness, transient visual, tactile or auditory hallucinations or illusions, and grand mal convulsions.

Alcohol withdrawal typically develops 6 to 8 hours after the cessation of drinking. Tremulousness is usually one of the earliest signs of alcohol withdrawal. The psychotic and perceptual symptoms begin in 8 to 12 hours after cessation of alcohol use. The withdrawal reaches peak intensity on the second or third day, and markedly diminishes by the fourth or fifth day. It is important to rule out other causes of the clinical presentation based on history, examination and relevant investigations.

Complicated alcohol withdrawal At times, patient with alcohol dependence develops what is known as ‘complicated withdrawal’. It is observed among 3-5% of dependent users, and is characterized by presence of seizures or delirium (known as delirium tremens) along with other features associated with alcohol withdrawal. The alcohol withdrawal seizures typically develop 12 to 24 hours after cessation of drinking. These are generalized and tonic-clonic in character. Patients often have more than one seizure 3

to 6 hours after the first seizure. Status epilepticus is relatively rare. Delirium tremens develops between 2- 5 days of cessation of alcohol use, but can appear even up to a week after stopping alcohol use. It is characterized by disturbance of consciousness, reduced ability to focus, to sustain, or to shift attention, a change in cognition (such as memory deficit, disorientation, or language disturbance), and perceptual disturbance. Additionally there

can be disturbance of mood or sleep wake cycle, impairment in recent memory, delusion and 24 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

evening worsening of symptoms, with severe agitation and coarse tremors of limbs and body. Delirium is potentially life threatening if left unattended. It is important to exclude other possible causes of delirium like fluid and electrolyte disturbance, physical conditions like hepatic dysfunction, possibility of head injury, etc. Medications Benzodiazepines share tolerance with alcohol (cross tolerance) and hence can be used for

management of alcohol withdrawal. Several meta-analyses have supported efficacy of benzodiazepines in reducing the severity of withdrawal, prevention of delirium and withdrawal seizures. These are recommended as the first line of treatment of alcohol withdrawal. Long acting benzodiazepines (such as chlordiazepoxide and diazepam) are preferred over short acting benzodiazepine for this purpose. Short acting benzodiazepines (such as oxazepam and

lorazepam) are preferred in liver damage, in elderly and in people with cognitive dysfunction. However, the short acting benzodiazepines have to be administered more frequently to manage withdrawal. The equivalent dose of different benzodiazepines that are commonly used in management of alcohol withdrawal have been provided in table 8. Table 6. Approximate therapeutic dose equivalent of different benzodiazepines commonly used in management of alcohol withdrawal Benzodiazepine Dose equivalent (mg)

Chlordiazepoxide 25 Diazepam 10 Lorazepam 2 Oxazepam 30 #Dosing frequency, duration and dose reduction depends on the regimen used for withdrawal management Treatment regimen Benzodiazepines for management of alcohol withdrawal (detoxification) can be administered using either of the three administration regimens. These include fixed dose schedule, symptom triggered dosing, and front loading schedule (table 7). 25 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

A fixed dose schedule involves starting treatment with a standard dose determined by the recent severity of alcohol dependence and/or typical level of daily alcohol consumption, followed by reducing the dose to zero usually over 7 to 10 days. The starting dose of benzodiazepine is guided by the severity of dependence and expected severity of the withdrawal. The starting dose of benzodiazepine can vary from 15 mg four times a day (q.d.s.) to 50 mg four times a day

(q.d.s.) of chlordiazepoxide dose equivalent (or 10 mg three times a day to 25 mg three times a day of diazepam dose equivalent). The same dose is usually maintained over the next two days. The dose reduction is made at the rate of 20% every day or 25% every alternate day. A symptom triggered dosing approach involves monitoring of the patient on a regular basis and pharmacotherapy is administered according to the patient’s level of withdrawal symptoms

(ranging from 10-20 mg dose equivalent of diazepam per administration). Pharmacotherapy continues as long as the patient is displaying withdrawal symptoms and the administered dose depends on the assessed level of alcohol withdrawal. The severity of the alcohol withdrawal and response to treatment can be assessed objectively using structured rating scales. One of the most commonly used and recommended instrument for this purpose is revised Clinical Institute

Withdrawal Assessment for Alcohol Scale (CIWA-Ar). It includes 10 items which are the common symptoms and signs of alcohol withdrawal- nausea and vomiting, tremor, paroxysmal sweats, anxiety, agitation, tactile disturbances, auditory disturbances, visual disturbance, headache, orientation and clouded sensorium. All items are scored from 0-7 with the exception of the orientation category, scored from 0-4. Scoring is done as 0-9 absent or minimal

withdrawal, 10-19 mild to moderate withdrawal, and severe with score greater than 20. A front-loading regimen involves providing the patient with an initially high dose of medication (30-40 mg dose equivalent of diazepam), and then using either a fixed dose schedule or symptom triggered dosing approach. Usually, very little additional medication is necessary after initial loading in this regimen. Table 7. Different regimens for alcohol withdrawal management (detoxification)

Fixed dose schedule Starting treatment with a standard Reducing the dose to zero dose determined by the recent usually over 7 to 10 days severity of alcohol dependence at the rate of 20% every 26 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

and/or typical level of daily day or 25% every alcohol consumption alternate day Symptom triggered dosing Pharmacotherapy is administered Pharmacotherapy according to the patient’s level of continues as long as the withdrawal symptoms. patient is displaying withdrawal symptoms and the administered dose depends on the assessed level of alcohol withdrawal Front loading schedule An initially high dose of Depends on the regimen medication is adminitered and used. subsequently either a fixed dose

schedule or symptom triggered dosing approach is used There is some evidence to indicate the superiority of symptom-triggered regimens. The use of fixed dosing schedule is recommended for general care in community and symptom triggered dosing is preferred when close observation is possible. Symptom triggered dosing is not recommended in the patients with a past history of withdrawal seizures. Benzodiazepine doses may need to be reduced by about 50% inthe geriatric population, and

in persons with liver impairment. Dose and duration of drug treatment depends on quantity of alcohol daily used/last dose, time elapsed after the last dose of alcohol, severity of alcohol withdrawal symptoms at the initiation of treatment, presence of medical co-morbidities (specifically liver dysfunction) and psychiatric co-morbidities. So, the dose and duration needs to be individualized. Along with benzodiazepines, the alcohol withdrawal management includes general nursing

care in form of maintaining hydration and nutritional status. There is no consensus on adequate dose and duration of thiamine supplementation during management of alcohol withdrawal. In all cases of alcohol detoxification it is recommended to give oral thiamine for minimum of three months. All patients in alcohol withdrawal should receive at least 250 mg thiamine by the parenteral route once a day for the first 3-5 days. Those with suspected 27

Wernicke’s encephalopathy should receive 500 mg/day thiamine for 3-5 days. The symptoms of Wernike’s encephalopathy are confusion, ataxia and nystagmus. Ophthalmoplegia may occur in severe cases. After receiving the parenteral thiamine, the supplementation can then be continued orally. Also, any parenteral administration of glucose during withdrawal management should not be done without addition of thiamine. Management of alcohol withdrawal seizures

Effective management of alcohol withdrawal is preventive against emergence of withdrawal seizures. The alcohol withdrawal seizures can be managed by both short acting (lorazepam- considered to be more effective by some) and long acting (diazepam) benzodiazepines. Benzodiazepines can be given either orally or parenterally. However, diazepam should only be given through intravenous route if administered parenterally because of their erratic absorption by intra-muscular route.

Seizure prophylaxis with lorazepam 2 mg intravenously must be given to all patients with seizures in the current withdrawal period at presentation and also in those with past history of withdrawal seizure. The dose should be tapered down starting at a high dose that should be gradually reduced once the seizures have been controlled. Sufficient benzodiazepines should be given to keep the patient calm and sedated, and manage other alcohol withdrawal symptoms.

Prophylactic use of anticonvulsants such as phenytoin is not recommended except in cases of co-occurring (non- alcohol withdrawal related) seizure disorder and alcohol use. A thorough neurological and general medical evaluation should be done to exclude any other possible cause of seizures among all patients who develop seizures during alcohol withdrawal. Management of delirium tremens Delirium tremens should be managed in inpatient setting. The patient should be kept under

close supervision. Safety of the patient against any physical harm should be ensured. Water and electrolyte balance and nutritional status should be maintained. The benzodiazepines are more effective than antipsychotic medicines in reducing mortality in alcohol withdrawal delirium. These can be administered through parenteral route in sufficient dosages with an aim 28 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

to make the patient clam and sedated. An initial dose of 10 mg diazepam is given intravenously. Further doses of 10 mg can be repeated every 5-20 min interval. The aim is to make the patient calm and sedated. The dose can be increased to 20 mg per bolus for the subsequent boluses if the first two boluses do not calm the patient down. The patient with delirium tremens can have lucid intervals in between. Hence it is important to be vigilant about

reemergence of the clinical features of delirium. Subsequently the patient can be shifted to oral benzodiazepines and the dose can be gradually tapered down. General Nursing Care Nurses should consider patient safety and injury prevention.The patient should be appropriately monitored and emergency airway equipment kept at the bedside, especially for those who require injectable benzodiazepines. • Restraints: The critically ill patient experiencing moderate to severe AWS symptoms

may require both chemical and physical restraints to avoid immediate threat behavior to self and others. Use of bed rails is advisable. • Managing behavioural disturbance: If the patient is confused and disoriented or hallucinating, a supportive and reassuring approach is to be used and patient should not be confronted. • Managing environment. The patient’s room should be kept quiet everyone should move around quietly. Interaction should be minimal and questions limited.

• Nutritional needs. The patient may be malnourished, causing folate, thiamine, or vitamin B12 deficiency. If the patient is unable to eat, tube feedings or total parenteral nutrition (TPN) should be initiated early. If a feeding Ryle’s tube is used it is taped at the nose and cheek area, with the tubing running toward the head and behind the bed. • Involving family: A complete care plan should involve family members in a therapeutic

alliance to provide optimal symptom relief and formulate acceptable behavior objectives for the patient. Motivational Enhancement Therapy (MET) Patients with alcohol dependence can be in different stages of change with regards to their alcohol use. These include pre-contemplation stage (when an individual has not yet 29 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

contemplated bringing in a change), contemplation stage (when an individual is still debating the pros and cons of continuing with alcohol use or quitting it), preparation stage (when an individual has recognized the need to change and is making preparations towards the same), action stage (when an individual, has taken steps towards quitting alcohol use, e.g. seeking treatment) and maintenance stage (when an individual has modified his alcohol use pattern and

maintaining the same). The short-term management phase for alcohol dependence can be used to further enhance the motivation of the patient and strengthen the commitment to change towards an alcohol-free life style. Motivational enhancement therapy (MET) can help achieve this. It utilizes different principles such as expressing empathy through reflective listening, developing discrepancy between clients' goals or values and their current behavior,

avoiding argument and direct confrontation, adjust to client resistance rather than opposing it directly, supporting self-efficacy and optimism. Appropriate motivational strategies for each stage of change could be as follows: Precontemplation: Establish rapport, buildtrust. Raise doubts or concerns in the personabout substance using pattern. Explore themeaning of vents that brought the patient totreatment or the results of previous treatment.Elicit the patient’s perception of the problem.Give factual

information about the risk of sub-stance use. Provide personalized feedback aboutassessment findings. Explore the pros and consof substance use. Examine the discrepanciesbetween the patient and others perception ofthe problem behavior. Express concern andkeep the door open. Contemplation: Normalize ambivalence; helpthe patient tip the decisional balance scale to- wards change by eliciting and weighing prosand cons of substance use and change.

Changeextrinsic and intrinsic motivation. Examine thepatient’s personal values in relation to change.Emphasize the choice of responsibility and self-efficacy. Elicit self-motivational statements ofintent and commitment. Elicit ideas regarding perceived self-efficacy and expectations to-wards treatment. Summarize self-motivational statements. Preparation: Clarify the patient’s own goal andstrategies for change. Offer a menu of

options.With permission, offer advice. Negotiate achange or treatment plan and behavior contract. Counter and lower barriers to change.Help the patient enlist social support. Exploretreatment expectancies and the patient’s role.Elicit what has worked in the past for him 30 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

orothers whom he knows. Assist the patient tonegotiate finances, child care, work or otherbarriers. Have the person publicly announceplans to change. Action: Engage the patient in treatment andreinforce the importance of remaining in recovery. Support a realistic view of changethrough small steps. Acknowledge difficultiesfor the person in early stages of change. Helpin identifying high risk situation and developappropriate coping

strategies to overcomethem. Assist in finding new reinforcers of thechange. Help in assessing whether the personhas strong family and social support. Maintenance: Help in identifying and sample drug free sources of pleasure. Support life stylechange. Affirm person’s resolve and self-efficacy.Assist in practicing the use of new coping strategies to avoid return to drug use. Maintainsupportive contact. Develop a ‘fire-escape’ planif

the patient resumes substance use. Reviewlong term goals (Substance Use Disorder Manual). Long-term management phase While the short-term management phase is an important and essential stage in management of alcohol dependence, it in itself is not sufficient to achieve the long-term abstinence from alcohol. In order to reduce the risk of relapse and improve treatment outcome, it is important to integrate the short-term management phase into the long-term management phase. There is no clear-

cut demarcation between the short-term and long-term management phases, but long-term management phase usually begins, once the initial withdrawal management from alcohol has been achieved and the patient is reasonably comfortable to participate in the long-term management phase. Aims Aims of the long term management phase are as follows- • To consolidate the progress made during the short-term management phase • To maintain abstinence from alcohol • To prevent and delay relapse

• Management of physical and psychological complications associated with alcohol use • Vocational rehabilitation • Addressing other familial, social and legal complications associated with alcohol dependence 31 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

Setting The long-term management phase does not require hospitalization and can be carried out from the outpatient setting. However, in case a patient requires longer hospitalization (e.g. due to management of a medical complication of alcohol use), the long-term management phase can start in the in-patient setting itself. Medications Various medications that can be used in long-term management of alcohol dependence include acamprosate, naltrexone, disulfiram.

Acamprosate: Acamprosate is an anti-craving medication that is used for long-term management of alcohol dependence. It is hypothesized that it acts as a functional glutamatergic NMDA antagonist. It has been found to be more effective than placebo in maintaining abstinence and in preventing relapse in meta-analysis. it is relatively safe in lid to moderate hepatic dysfunction. It is available as 333mg tablets. The usual daily dose of acamprosate ranges from 1332

mg/day (body weight < 50 kg; dosing schedule- Tab. Acamprosate (333 mg) 1-1-2- one tablet each in morning and afternoon and two tablets at bedtime) to 1998 mg/day (body weight> 50 kg; dosing schedule- Tab. Acamprosate (333 mg) 2-2-2, two tablets thrice a day). Disulfiram: Disulfiram is a deterrent medication, used for long-term management of alcohol dependence. It is an irreversible inhibitor that blocks aldehyde dehydrogenase, causing

accumulation of acetaldehyde if alcohol is consumed, resulting in what is known as disulfiram- ethanol reaction (DER). Disulfiram should always be started after a written informed consent of the patient. The patients using disulfiram also need to be informed to avoid all forms of alcohol containing items (including alcoholic beverages, after shave lotions, food items containing vinegar, medications such as metronidazole etc.). 32 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

The usual dose of disulfiram is 250 mg/ day. The first dose of disulfiram should be administered at least 24 hours after the last dose of alcohol. It is advisable to administer the dose under supervision. In case a patient fails to experience DER with 250 mg/day, the dose can be increased to 500 mg/ day, which can further be increased up to 750 mg/ day. However, one should ensure compliance prior to hiking the dose. The DER includes sweating, warmth and flushing, hyperventilation, respiratory difficulty,

respiratory depression, blurred vision, throbbing headache, thirst, nausea, vomiting, chest pain, palpitations, hypotension, tachycardia, cardiovascular collapse, arrhythmia, myocardial infarction (in individuals with preexisting coronary artery disease), acute congestive heart failure (in individuals with preexisting myocardial dysfunction), vertigo, syncope, marked uneasiness, confusion, seizures, unconsciousness, death (rarely, in case of very severe reaction).

Severity of DER depends on the amount of alcohol consumed and individual related variables. There is potential for a reaction with alcohol for up to 2 weeks after stopping disulfiram. The fall in blood pressure should be controlled on a priority basis. If DER is mild, assurance and oral fluids suffice. In patients with moderate or severe DER, intravenous fluids and, in some patients, dopamine infusion is necessary to control the severe hypotension.

Liver function tests (especially SGOT and SGPT levels) should be carried out at base line prior to initiation of disulfiram and then every 2 weeks for the first 2 months of therapy. Subsequently it can be performed once every three months. Naltrexone Naltrexone is another anti-craving agent used for long-term management of alcohol dependence. It is thought to act by preventing the opiate receptor mediated euphoric and

rewarding effects of alcohol by blocking the opioid receptors. Oral naltrexone has been shown to reduce return to heavy drinking. Oral Naltrexone is given at dose of 50mg/ day. 33 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

It is recommended to get baseline liver function tests prior to starting naltrexone. Liver function test should be repeated periodically (monthly for the first three months, and subsequently once every three months) to monitor for emergence of hepatic side effects of the medication. Additionally, naltrexone and acamprosate can be used in combination. Also, disulfiram can also be used in combination with naltrexone and acamprosate.

Table 10 summarizes some of the common side effects and contraindications to use of these medications. Table 8. Common side-effect of the medicines used in long term management phase for alcohol dependence Medicine Common side-effects and Dose Frequency Duration contraindications to use Acamprosate Diarrhea with abdominal pain, nausea, 1332 TDS One year vomiting, pruritus mg/day Contraindications- hypersensitivity (body reaction, pregnancy and breastfeeding, renal insufficiency (serum creatinine weight < 50

more than 120 micromoles per litre), kg) to 1998 severe hepatic failure mg/day FDA pregnancy category C (body weight> 50 kg Disulfiram Drowsiness, fatigue, abdominal pain, 250mg/day OD One year headache, nausea, diarrhea, allergic dermatitis, metallic or garlic like after taste Contraindications (absolute)- hypersensitivity reaction , pregnancy and breast feeding Contraindications (relative)- cardiovascular problems, severe personality disorder, suicidal risk, 34

psychosis FDA pregnancy category C Naltrexone Nausea, headache, abdominal pain, 50 mg/day OD One year reduced appetite and tiredness Contraindications- acute liver failure (caution is suggested when serum aminotransferases are four to five times above normal) FDA pregnancy category C Duration of treatment There is limited consensus on duration of use for medications used in long term phase of management of alcohol dependence. It is advisable to continue these medications for a period

of 9-12 months. These can be continued even longer if deemed appropriate by the clinician and the patient. Risk of relapse, status of rehabilitation of the patient and patient's confidence to live without the support of the medications are some of the factors that can help decide on the duration of treatment. Psychosocial interventions It has been shown that utility of pharmacological therapies can be enhanced when combined with non-pharmacological interventions. It is recommended to offer pharmacological

interventions for alcohol dependence in conjunction with psychosocial interventions. The goal of psychosocial interventions in long term management of alcohol dependence include improved therapeutic adherence, achieving sustained drug free status, encouraging and supporting drug free life style and rehabilitation of the patient. Psycho-social interventions include motivational enhancement therapy (MET), cognitive behavior therapy (CBT), relapse prevention (RP), contingency management (CM) and

family therapy. 35 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

MET has been discussed in the section on short-term management of alcohol management. CBT is based on the social learning theories aimed at improving self-control and social skills. This leads to promotion of a drug free life style. RP is aimed at helping the alcohol dependent individuals to delay lapse and prevent relapse. It involves various steps used to help patients develop greater self-control over alcohol use behaviors.

CM is a behavioral therapy that helps support alcohol free life style by making rewards contingent of alcohol free status. Family therapy help address the issues in the context of family of alcohol dependent individual. These include inter-personal problems, expressed emotions, etc. Additionally, it is important to help the patient with vocational rehabilitation. Timing of psychosocial interventions The psychosocial interventions should be started as early as possible in the management of

alcohol dependence. The relevant psychosocial interventions can be initiated once the patient is physically comfortable and in a position to attend the sessions. This can be done even during the short-term phase of management. Settings for psychosocial interventions The psychosocial interventions can be offered both in inpatient as well as outpatient settings. When a patient receives the short-term management for alcohol dependence in inpatient setting,

psychosocial interventions can start in the inpatient setting and then can be continued on the outpatient basis. Brief interventions (BI) Those who are using alcohol but not in a dependent pattern could also be at increased risk of experiencing harms associated with alcohol use in immediate future or even later. Individuals having harmful or hazardous pattern of alcohol use can benefit from Brief 36 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

Intervention (BI). Such individuals usually do not require medicines and can be helped using short term interventions aimed at changing their behavior by helping them understand how their alcohol use puts them at risk and to reduce or give up their alcohol use. Brief Interventions usually last from 5 minutes of brief advice to 15-30 minutes of brief counseling. While BI help address the problematic or risky substance use, these are not intended to treat people with alcohol dependence.

The consistent features in BI have been summarized by Millerand Sanchez (1993) using the acronym FRAMES: Feedback, Responsibility, Advice, Menu of options, Empathy and Self- efficacy (confidence for change). • The provision of giving personally relevant feedback after assessment such as individual’s drug use and problems and associated personal risks is a key component of brief intervention. • Personal responsibility is emphasized so as to bring about change in behavior.

• Advice about changing the drug taking behavior is given in a non-judgemental manner. • Alternative strategies to cut down or stop their substance use are given. • Empathic counselling and understanding approach to encourage the patient’s confidence so as to promote self- efficacy in their behaviour is used. REFERRAL CRITERIA The following are the indications for referral to a higher centre: • Presence of co-morbid psychiatric condition that cannot be managed at the primary care or secondary care level

• Physical comorbidity of serious nature for which adequate infrastructure and support may not be available (e.g., decompensated cirrhosis with imminent risk of hepatic encephalopathy; actively bleeding peptic ulcer; pancreatitis, uncontrolled seizures, etc.). In such circumstances, liaison should be made for transfer to other specialist departments or to emergency services for stabilization of patient’s physical condition first.

• Presence of a co-morbid substance use disorder for which treatment is not available at primary/secondary hospital setting (e.g. opioid substitution therapy for opioid dependence) • Non-availability of professionals to administer psycho-social interventions 37 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

VI. WHO DOES WHAT AND TIMELINES The roles and responsibilities of various members of treatment team in management of alcohol dependence are as follows- a. Doctor The doctor shall be the overall in-charge of the treatment team. The doctor coordinates and supervises other members of the treatment team. Additionally, he will be responsible for the clinical assessment (history taking, physical examination, MSE), formulation of management

plan, selection of investigations, initiation and continuation of the pharmacological treatment. The doctor shall also make the decision regarding the requirement of referral to a higher center. b. Clinical psychologist/ counsellor The clinical psychologist/ counseloris responsible for psychosocial assessment and interventions. c. Nurse The nurse is responsible for general nursing care, regular observation and monitoring of the

patient, administration of medications, offering feedback to the team regarding the patient based on observations made. d. Medical Social Worker (MSW) The Medical Social Worker (MSW) carries out assessment of the patient on psychosocial issues and helps the patient in vocational rehabilitation. MSW also be establishes contact with the family members/ significant others and contacts the patient in case of treatment drop out. Timeline of various activities/ interventions

A suggested time line for various activities/ interventions in the management of alcohol dependence is shown in figure 1. It can be modified and individualized, based on the requirements of a particular patient based on the clinical judgment of the patient. VII. Clinical Pathways for Management of Alcohol Dependence 38 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

Individual with alcohol use Assess for problematic use Non-dependent use Alcohol dependence Assess for Severity of dependence Severity of withdrawal Presence of complicated withdrawal Severity of withdrawal in past History of complicated withdrawal Comorbid medical/ psychiatric illness Level of social support and supervision Comorbid use of other substances Geographical distance/ time taken to travel Personal preference Severe dependence Mild to moderate Severe withdrawal dependence Presence of complicated

Mild to moderate withdrawal withdrawal Severe withdrawal in past History of complicated withdrawal Absence of complicated Presence of Comorbid medical/ withdrawal psychiatric illness Poor social support and Poor social support and supervision supervision Absence of comorbid use of Presence of comorbid use of other substances other substances Excessive geographical distance/ Personal preference long time taken to travel Personal preference Outpatient withdrawal

Brief Intervention In-patient withdrawal management management 39 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

VIII. How these Guidelines were developed Background A Task Force was constituted in December 2014 to guide the development of Standard Treatment Guidelines (STG) in India for application in the National Health Mission. The Task Force subsequently approved the draft STG development manual of India (Part 1) for development of adapted guidelines. In addition, it approved a list of 14 topics recommended by a subgroup of the task force appointed to select prioritized topics for STG development.

These 14 topics are from 10 clinical specialties for which the first set of STGs will be developed. The topic of Management of Alcohol Dependence was included in this first list and was the dealt with by the Psychiatry clinical subgroup. Formation of STG Group on Psychiatry A multidisciplinary group composed of a mix of primary care practitioners, academicians and practicing psychiatrist was constituted with Dr. Rakesh Chadda as the facilitator of the group. Following were the members of group-

Coordinator Dr Rakesh Chadda Professor of Psychiatry AIIMS, New Delhi drrakeshchadda@gmail.com Experts Prof Rakesh Lal Professor of Psychiatry Deptt of Psychiatry & National Drug Dependence Treatment Centre (NDDTC) AIIMS, New Delhi 110029 rakeshlall@rediffmail.com Prof Debashis Basu Professor of Psychiatry PGIMER, Chandigarh 160012 db_sm2002@yahoo.com Dr Nitin Gupta Associate Professor Department of Psychiatry Govt Medical College & Hospital, Chandigrah nitingupta659@yahoo.co.in Dr Yatan PS Balhara

Asstt. Professor Deptt of Psychiatry & NDDTC AIIMS, New Delhi 110029 40 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

mailto:rakeshlall@rediffmail.comypsbalhara@gmail.com Dr Rachna Bhargava, Asstt. Professor in Clinical Psychology Deptt of Psychiatry & NDDTC AIIMS, New Delhi 110029 rachnabhargava@gmail.com Dr Bichitra Nanda Patra, Asstt Professor Department of Psychiatry, AIIMS, New Delhi 110029 patrab.aiims@gmail.com Dr Sandhya Gupta Lecturer, College of Nursing AIIMS, New Delhi 110029 drsandhyag407@gmail.com The group was constituted 7 August 2015. All the members signed the declaration of

Interest.First face to face Meeting was held on 17 August 2015 attended by Drs Chadda, Lal, Balhara, Rachna,, Bichitra.Scope decided as guidelines on alcohol dependence for use in different settings. Uncomplicated cases can be managed as outpatient and management does not differ across different setting. Complicated cases and those with co morbid problems need specialist input and can be managed only in secondary or tertiary care. First draft got ready on 10th Sept 2015; shared on email amongst the group.

Second Face to Face Meeting was held on 13 Sept 2015.Draft modified as per discussion and submitted on 6 Oct 2015 to the Internal Harmonization Group of STG Taskforce. The draft document was reviewed by Internal Harmonization Groupon 24th of October 2015 consisting of Dr. Sangeeta Sharma (IBHAS), Dr. Anil Gurtoo (LHMC), Dr. Om Sai Ramesh (LHMC), Dr. Babban Jee (ICMR) and Dr. Nikhil Prakash (NHSRC). The comments of internal harmonization group were received on 8th of Novemeber 2015.Third Face to Face

Meeting was called on 13 Nov 2015 Attended by Drs Chadda, Lal, Balhara, Rachna,, Bichitra. The Revised draft was prepared and further discussed meeting on third 3 Dec 2015. Search and Selection of Evidence Based Guidelines In view of the paucity of time available to develop this guideline, a decision was taken by the Task Force for the Development of STGs for the National Health Mission that these STGs would be adopted and/or adapted from existing evidence based guidelines to make them

relevant to our context, resource settings and priorities. A search was conducted for evidence based guidelines which had been framed using evidence based methodology and using international guideline development 41 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

criteria.Following guidelines were selected for Adapting/Adopting recommendations based strength of evidence, currency of guidelines and suitability to Indian context. Table 9. List of available guidelines on management of alcohol dependence and the guidelines referred to for the purpose of the current guideline List of the available guidelines Guidelines consulted for the current Rationale for considering the source guideline guideline

Alcohol use disorders- Diagnosis, Alcohol use disorders- Diagnosis, These guidelines are evidence based, have assessment and management of harmful assessment and management of harmful been created systematically, are some of the drinking and alcohol dependence. NICE drinking and alcohol dependence. NICE most recent documents on this topic, clinical guidelines. National Institute for clinical guidelines. National Institute for represent diverse settings across various

Health and Clinical Excellence, UK, 2011. Health and Clinical Excellence, UK, 2011. countries including India and cover various aspects related to management of alcohol Clinical practice guideline for Clinical practice guideline for dependence. Management of Substance Use Management of Substance Use Disorders (SUD). Department of Disorders (SUD). Department of Veterans Affairs Department of Defense, Veterans Affairs Department of Defense, USA, 2009. USA, 2009.

Clinical Practice Guidelines for the Clinical Practice Guidelines for the assessment and management of substance assessment and management of substance use disorders. Indian Psychiatric Society, use disorders. Indian Psychiatric Society, 2014. 2014. Detoxification and Substance Abuse Detoxification and Substance Abuse Treatment. Treatment Improvement Treatment. Treatment Improvement Protocol (TIP) Series, No. 45. Center for Protocol (TIP) Series, No. 45. Center for

Substance Abuse Treatment. Substance Substance Abuse Treatment. Substance Abuse and Mental Health Services Abuse and Mental Health Services Administration (US); 2006. Administration (US); 2006. Drug and Alcohol Withdrawal Clinical Global strategy to reduce the harmful use of Practice Guidelines – NSW. Mental Health alcohol. World Health Organization, 2010. and Drug & Alcohol Office, NSW Department of Health, Australia, 2007. Global strategy to reduce the harmful use of Guidelines on treatment of alcohol

alcohol. World Health Organization, 2010. problems. Australian Government Department of Health and Ageing, The University of Sydney, Australia, 2009. Guidelines on treatment of alcohol Incorporating Alcohol problems. Australian Government Pharmacotherapies Into Medical Department of Health and Ageing, The Practice. Treatment Improvement University of Sydney, Australia, 2009. Protocol (TIP) Series, No. 49. Center for Substance Abuse Treatment. Substance Abuse and Mental Health Services

Administration (US); 2009. Incorporating Alcohol Pharmacotherapies Manual for Long Term Pharmacotherapy. Into Medical Practice. Treatment NDDTC, AIIMS, New Delhi, 2013. Improvement Protocol (TIP) Series, No. 49. 42 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

Center for Substance Abuse Treatment. Substance Abuse and Mental Health Services Administration (US); 2009. Manual for Long Term Pharmacotherapy. Quick reference guide to the treatment of NDDTC, AIIMS, New Delhi, 2013. alcohol problems. Australian Government Department of Health and Ageing, The University of Sydney, Australia, 2009. mhGAP Intervention Guide for mental, Substance Use Disorders. Manual for neurological and substance use disorders in Physicians. NDDTC, AIIMS, New Delhi,

non-specialized health settings. Mental 2013. Health Gap Action Programme. World Health Organization, 2010. Naltrexone and Alcoholism Treatment. The Maudsley Prescribing Guidelines in Treatment Improvement Protocol (TIP) Psychiatry, 2015. Series, No. 28. Center for Substance Abuse Treatment. Center for Substance Abuse Treatment. Substance Abuse and Mental Health Services Administration (US); 1998. Practice guideline for the Treatment of Patients With Substance Use Disorders,

Second Edition. American Psychiatric Association, USA, 2006. Quick reference guide to the treatment of alcohol problems. Australian Government Department of Health and Ageing, The University of Sydney, Australia, 2009. Substance Use Disorders. Manual for Physicians. NDDTC, AIIMS, New Delhi, 2013. The Maudsley Prescribing Guidelines in Psychiatry, 2015. Adoption/Adaption of Recommendations Recommendations selected from various source guidelines are considered for

adaptations/Adoption.Following is the summary of adaption/adoption of the key recommendations. Table 10. Status of the adoption/ adaptation for the various recommendations used in the current guideline Recommendations in the source guidelines Whether adopted/ adapted Rationale for adaptation The diagnosis of alcohol dependence can be done Adapted While some of the guidelines using ICD-10 diagnostic criteria did not specify the process of reaching at a diagnosis of alcohol dependence, others

recommended use of DSM. Since ICD- 10 is the WHO approved nosological system 43 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

the same has been recommended for diagnosing. The indicators for in-patient management during Adopted the short term phase of management are as follows: -Presence of severe alcohol dependence (drinks over 30 units of alcohol per day or regularly drinks between 15 and 30 units of alcohol per day) -Presence of or anticipated severe withdrawal or complicated withdrawal (withdrawal with seizures or delirium) -Co-occurring significant physical and psychiatric illness -Poor psychosocial support

-Distance from treatment centre that precludes regular follow up -Failure of out-patient detoxification in past -Pregnancy, children and adolescents and elderly Benzodiazepinesare recommended as the first line of Adopted treatment of alcohol withdrawal. Long acting benzodiazepines (such as Adopted chlordiazepoxide and diazepam) are preferred over short acting benzodiazepine for this purpose. Short acting benzodiazepines (such as oxazepam and Adopted lorazepam) are preferred in liver damage, in elderly

people. Benzodiazepines for management of alcohol Adopted withdrawal can be administered using either of the following three administration regimens. -Fixed dose schedule -Symptom triggered dosing -Front loading schedule Along with benzodiazepines, the alcohol withdrawal Adopted management includes general nursing care in form of maintaining hydration and nutritional status. In all cases of alcohol detoxification it is Adopted recommended to give oral thiamine for minimum of three months.

All patients in alcohol withdrawal should receive at Adopted least 250 mg thiamine by the parenteral route once a day for the first 3-5 days. Any parenteral administration of glucose during Adopted withdrawal management should not be done without addition of thiamine. Management of alcohol withdrawal includes general nursing care aimed at: - Keeping the environment quiet - Prevention of injury to the patient and others - Maintaining hydration and nutrition Management of alcohol withdrawal seizure: Adopted

-Effective management of alcohol withdrawal is 44 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

preventive against emergence of withdrawal seizures. -The alcohol withdrawal seizures can be managed by both short acting (lorazepam- considered to be more effective by some) and long acting (diazepam) benzodiazepines. -Benzodiazepines can be given either orally or parenterally. Management of delirium tremens: Adopted -Delirium tremens should be managed in inpatient setting. Safety of the patient against any physical harm should be ensured. -Water and electrolyte balance and nutritional

status should be maintained. -The benzodiazepines are to be administered through parenteral route in sufficient dosages with an aim to make the patient clam and sedated. -An initial dose of 10 mg diazepam is given intravenously. Further doses of 10 mg can be repeated every 5-20 min interval. The dose can be increased to 20 mg per bolus for the subsequent boluses if the first two boluses do not calm the patient down. -Subsequently the patient can be shifted to oral

benzodiazepines and the dose can be gradually tapered down. Long-term management phase: Adopted The aim is to maintain abstinence from alcohol and to prevent and delay relapse. The medications that can be used for this phase Adopted include acamprosate, naltrexone, dislufiram, baclofen. Recommended psycho-social interventions: Adopted -Motivational enhancement therapy -Cognitive behavior therapy -Relapse prevention -Contingency management -Family therapy Referral criteria: Adopted

-Presence of co-morbid psychiatric condition that cannot be managed at the primary care or secondary care level -Physical comorbidity of serious nature for which adequate infrastructure and support may not be available -Presence of a co-morbid substance use disorder for which treatment is not available at primary/secondary hospital setting -Non-availability of professionals to administer psycho-social interventions -A complete care plan should involve family

members to identify treatment options, appropriate supportive care beyond medication and monitoring may help decrease morbidity and mortality rates. Prevention strategies: Adopted -Raising awareness and commitment among the 45 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

general public regarding harmful effects of alcohol use -Health services’ response; -Community action; -Strict action against drunk-driving; -Regulating availability and marketing of alcohol; -Alcohol pricing policies; -Reducing the negative consequences of drinking and alcohol intoxication; -Reducing the public health impact of illicit alcohol and informally produced alcohol; -Monitoring and surveillance of sell of alcohol 46 Management of Alcohol Dependence – Full Background Document Ver. 17-02-16

FURTHER READINGS AND REFERENCES • Alcohol-use Disorders- Diagnosis, assessment and management of Harmful drinking and Alcohol dependence. National Clinical Practice Guideline 115. National Institute for Health & Clinical Excellence, The British Psychological Society and The Royal College of Psychiatrists, 2011. • Clinical Practice Guidelines for the assessment and management of substance use disorders. Eds: Basu D, Dalal P. Indian Psychiatric Society, Hyderabad, 2014.

• Global status report on alcohol and health 2014. World Health organization, Geenva. • Global strategy to reduce the harmful use of alcohol, 2010. World Health Organization, Geneva. • Manual for Long Term Pharmacotherapy. Eds: Dhawan A, Jhanjee S. NDDTC, AIIMS, New Delhi, 2013. • Ray R. The extent, pattern and trends of drug abuse in India: National survey. Ministry of Social Justice and Empowerment, Government of India & United Nations Office on Drugs and Crime, Regional Office for South Asia, 2004.

• Shield KD, Parry C, Rehm J. Focus On: Chronic Diseases and Conditions Related to Alcohol Use. In: Jürgen Rehm and Ralph Hingson (eds) Measuring the Burden— Alcohol’s Evolving Impact on Individuals, Families, and Society. Alcohol Research: Current Reviews 2013, 35, 2, 155. • Substance Use Disorders. Manual for Physicians. Ed: Lal R. NDDTC, AIIMS, New Delhi, 2013. • The Maudsley Prescribing Guidelines in Psychiatry, 12th edition. Eds: Taylor D, Paton C, Kapur S. Wiley-Blackwell Publishing, 2015. 47

STANDARD TREATMENT GUIDELINES Management of Alcohol Dependence Quick Reference Guide February 2016 Ministry of Health & Family Welfare Government of India 1 Management of Alcohol Dependence -–QRG Version 17th Feb 2016

Short- term management phase .................................................................................................................. 5 Simple alcohol withdrawal ........................................................................................................................... 6 Complicated alcohol withdrawal ................................................................................................................ 6

Medications .................................................................................................................................................. 6 Treatment regimen ...................................................................................................................................... 7 I A. Fixed dose schedule: .......................................................................................................................... 7

I B. Symptom triggered dosing: ................................................................................................................ 7 I C. Front loading schedule: ...................................................................................................................... 7 II Thiamine Supplementation: .................................................................................................................. 7

Nursing care ................................................................................................................................................. 8 Motivational Enhancement Therapy (MET) ................................................................................................. 8 Management of alcohol withdrawal seizure: ............................................................................................... 8

Management of delirium tremens ............................................................................................................... 9 Long-term management phase .................................................................................................................... 9 Referral to secondary or tertiary care: ......................................................................................................... 9

Clinical Pathway of Management of Alcohol Dependence ........................................................................ 11 Quality Standards for Management of Alcohol Dependence .................................................................... 12 2 Management of Alcohol Dependence -–QRG Version 17th Feb 2016

Objectives- • The guideline will provide advice on assessment, investigations, short term and long- term medical management of individuals presenting with alcohol dependence. • The guideline will also provide advice on psycho-social interventions for patients with alcohol dependence. Diagnosis The diagnosis of alcohol dependence can be done using ICD-10 diagnostic criteria which are as follows. Table 1. Diagnostic criteria for alcohol dependence syndrome as specified in The ICD-10

Classification of Mental and Behavioral Disorders (adapted for alcohol) A cluster of physiological, behavioral, and cognitive phenomena in which the use of alcohol takes on a much higher priority for a given individual than other behaviors that once had greater value. A central descriptive characteristic of the dependence syndrome is the desire (often strong, sometimes overpowering) to take alcohol. There may be evidence that return to alcohol

use after a period of abstinence leads to a more rapid reappearance of other features of the syndrome than occurs with nondependent individuals. A definite diagnosis of alcohol dependence should usually be made only if three or more of the following have been present together at some time during the previous year: (a)a strong desire or sense of compulsion to take alcohol; (b)difficulties in controlling alcohol-taking behavior in terms of its onset, termination, or levels of use;

(c)a physiological withdrawal state when alcohol use has ceased or been reduced, as evidenced by: the characteristic withdrawal syndrome for alcohol; or use of alcohol (or a closely related) substance with the intention of relieving or avoiding withdrawal symptoms; (d)evidence of tolerance, such that increased doses of alcohol are required in order to achieve effects originally produced by lower doses; (e)progressive neglect of alternative pleasures or interests because of alcohol use, increased

amount of time necessary to obtain or take alcohol or to recover from its effects; (f)persisting with alcohol use despite clear evidence of overtly harmful consequences, such as harm to the liver through excessive drinking, depressive mood states consequent to periods of heavy alcohol use, or alcohol-related impairment of cognitive functioning; efforts should be made to determine that the user was actually, or could be expected to be, aware of the nature and extent of the harm. ASSESSMENT

This includes medical history, physical examination, mental status examination (MSE) and investigations. Assessment is targeted: 3 Management of Alcohol Dependence -–QRG Version 17th Feb 2016

• To ascertain the diagnosis of alcohol dependence • To establish rapport with the patient • To assess complications associated with alcohol use (including physical and psychological) • To assess level of motivation • To assess support and resources available • To assess suitable setting for management • To assess need for referral Screening: As there is a significant time lag between emergence of alcohol dependence and treatment seeking

for the same, it is important for the clinician to enquire about alcohol use from every patient to catch them early. History taking: Following information should be obtained during history taking. • Socio-demographic details • Pattern of alcohol use (Amount, timing, frequency, place, etc) • Type of alcohol beverage used • Duration of use • Features of alcohol dependence (craving, tolerance, withdrawal, physical or psychological symptoms, etc.)

• Alcohol related complications (physical, psychological, familial, social, vocational, financial, legal) • Past abstinence attempts • Level of motivation (coming by self or family or on being referred by another specialist/ employer/ legal agency) • Past history of any medical & psychiatric illness, family history Physical examination: Physical examination should be done to find out -Features of alcohol intoxication: unsteady gait, difficulty standing, slurred speech, nystagmus,

decreased level of consciousness (e.g. stupor, coma), flushed face, and conjunctival injection. -Features of alcohol withdrawal: Tremors, sweating, nausea, vomiting, tachycardia or hypertension, psychomotor agitation and generalized seizures. -Physical complications: associated with alcohol use. Eg. liver enlargement, pedal edema 4 Management of Alcohol Dependence -–QRG Version 17th Feb 2016

Mental Status Examination (MSE): • Assessment of general appearance and behavior, psychomotor activity, speech, affect, thought, perception, orientation, attention and concentration, memory, intelligence, abstraction, judgment, insight and level of motivation. MSE is aimed at identifying the presence of any co-occurring psychiatric disorders and presence of complicated alcohol withdrawal. Investigations: • Haemogram (including hemoglobin, total leucocytes count, differential leukocyte count,

peripheral blood smear) • Random blood sugar • Liver function tests (serum bilirubin, SGOT, SGPT); • Renal function test (serum creatinine, blood urea) TREATMENT Phases of treatment • Initial short- term management phase (also known as detoxification) • Long- term management phase Short- term management phase Treatment for alcohol dependence can be carried out in the out-patient as well as in- patient settings. Some of the indicators for in-patient management are as follows

• Presence of severe alcohol dependence (drinks over 30 units of alcohol per day or regularly drinks between 15 and 30 units of alcohol per day) • Presence of or anticipated severe withdrawal or complicated withdrawal (withdrawal with seizures or delirium) • Co-occurring significant physical and psychiatric illness • Poor psychosocial support • Distance from treatment centre that precludes regular follow up • Failure of out-patient detoxification in past • Pregnancy, children and adolescents and elderly 5

Simple alcohol withdrawal • There is history of recent cessation of alcohol use that has been heavy and prolonged. -Alcohol withdrawal typically develops 6 to 8 hours after the cessation of drinking. -There is presence of clinical features associated with alcohol withdrawal. • These include tremor of the outstretched hands, tongue or eyelids, sweating, nausea, retching or vomiting, tachycardia or hypertension, psychomotor agitation, headache, insomnia, malaise or weakness, transient visual, tactile or

auditory hallucinations or illusions and grand mal convulsions. • These clinical features should be clinically significant means due to these symptoms there is distress and dysfunction to the patient. Complicated alcohol withdrawal • Characterized by presence of seizures or delirium (known as delirium tremens) along with other features associated with alcohol withdrawal. • The alcohol withdrawal seizures typically develop 12 to 24 hours after cessation

of drinking. These are generalized and tonic-clonic in character. • Delirium tremens is characterized by disturbance of consciousness, reduced ability to focus, to sustain, or to shift attention, a change in cognition (such as memory deficit, disorientation, or language disturbance), and perceptual disturbance, severe agitation and coarse tremors of limbs and body. Medications • Benzodiazepines are recommended as the first line of treatment of alcohol withdrawal.

• Long acting benzodiazepines (such as chlordiazepoxide and diazepam) are preferred over short acting benzodiazepine for this purpose. • Short acting benzodiazepines (such as oxazepam and lorazepam) are preferred in liver damage, in elderly people. The equivalent dose of different benzodiazepines that are commonly used in management of alcohol withdrawal are given in table. Table 2 Approximate therapeutic dose equivalent of different benzodiazepines commonly used in management of alcohol withdrawal

Benzodiazepine Dose equivalent (mg) 6 Management of Alcohol Dependence -–QRG Version 17th Feb 2016

Chlordiazepoxide 25 Diazepam 10 Lorazepam 2 Oxazepam 30 Treatment regimen I. Benzodiazepines for management of alcohol withdrawal can be administered using either of the following three administration regimens. I A. Fixed dose schedule: • This involves starting treatment with a standard dose determined by the recent severity of alcohol dependence and/or typical level of daily alcohol consumption, followed by reducing the dose to zero usually over 7 to 10 days.

• The starting dose of benzodiazepine can vary from 15 mg four times a day (q.d.s.) to 50 mg four times a day (q.d.s.) of chlordiazepoxide dose equivalent (or 10 mg three times a day to 25 mg three times a day of diazepam dose equivalent). • The same dose is usually maintained over the next two days. The dose reduction is made at the rate of 20% every day or 25% every alternate day. I B. Symptom triggered dosing: • Benzodiazepine is administered according to the patient’s level of withdrawal

symptoms (ranging from 10-20 mg dose equivalent of diazepam per administration). • Pharmacotherapy continues as long as the patient is displaying withdrawal symptoms and the administered dose depends on the assessed level of alcohol withdrawal. I C. Front loading schedule: • This involves providing the patient with an initially high dose of medication (30-40 mg dose equivalent of diazepam), and then using either a fixed dose schedule or symptom triggered dosing approach. II Thiamine Supplementation:

Along with benzodiazepines, the alcohol withdrawal management includes general nursing care in form of maintaining hydration and nutritional status. • It is recommended to give oral thiamine for minimum of three months. • All patients in alcohol withdrawal should receive at least 250 mg thiamine by the parenteral route once a day for the first 3-5 days. • Any parenteral administration of glucose during withdrawal management should not be done without addition of thiamine. 7

Nursing care • Restraints: The critically ill patient experiencing moderate to severe alcohol withdrawal symptoms may require both chemical and physical restraints to avoid immediate threat behavior to self and others. Use of bed rails is advisable. • Managing behavioural disturbance: If the patient is confused and disoriented or hallucinating, a supportive and reassuring approach is to be used and patient should not be confronted.

• Managing environment. The patient’s room should be kept quiet everyone should move around quietly. Interaction should be minimal and questions limited. • Nutritional needs. The patient may be malnourished, causing folate, thiamine, or vitamin B12 deficiency. If the patient is unable to eat, tube feedings or total parenteral nutrition (TPN) should be initiated early. If a feeding Ryle’s tube is used it is taped at the nose and cheek area, with the tubing running toward the head and behind the bed.

• Involving family: A complete care plan should involve family members in a therapeutic alliance to provide optimal symptom relief and formulate acceptable behavior objectives for the patient. Motivational Enhancement Therapy (MET) It utilizes different principles as follows • Expressing empathy through reflective listening • Developing discrepancy between clients' goals or values and their current behavior • Avoiding argument and direct confrontation

• Adjust to client resistance rather than opposing it directly • Supporting self-efficacy and optimism Management of alcohol withdrawal seizure: • Effective management of alcohol withdrawal is preventive against emergence of withdrawal seizures. • The alcohol withdrawal seizures can be managed by both short acting (lorazepam- considered to be more effective by some) and long acting (diazepam) benzodiazepines. • Benzodiazepines can be given either orally or parenterally. 8

Management of delirium tremens • Delirium tremens should be managed in inpatient setting. Safety of the patient against any physical harm should be ensured. • Water and electrolyte balance and nutritional status should be maintained. • The benzodiazepines are to be administered through parenteral route in sufficient dosages with an aim to make the patient clam and sedated. • An initial dose of 10 mg diazepam is given intravenously. Further doses of 10 mg can

be repeated every 5-20 min interval. The dose can be increased to 20 mg per bolus for the subsequent boluses if the first two boluses do not calm the patient down. • Subsequently the patient can be shifted to oral benzodiazepines and the dose can be gradually tapered down. Long-term management phase • This phase begins after the initial withdrawal management from alcohol has been achieved • The aim is to maintain abstinence from alcohol and to prevent and delay relapse

Medications used in long term management of alcohol dependence are summarized in table 3 Referral to secondary or tertiary care: • Presence of co-morbid psychiatric condition that cannot be managed at the primary care or secondary care level • Complicated withdrawal like delirium or withdrawal seizures • Physical comorbidity of serious nature for which adequate infrastructure and support may not be available • Presence of a co-morbid substance use disorder for which treatment is not available at

primary/secondary hospital setting • Non-availability of professionals to administer psycho-social interventions • A complete care plan should involve family members to identify treatment options, appropriate supportive care beyond medication and monitoring may help decrease morbidity and mortality rates. • Table 3 Medications used in long term management of alcohol dependence Medicine Common side-effects and Dose Frequency Duration contraindications to use 9

Acamprosate Diarrhea with abdominal pain, nausea, 1332 TDS One year vomiting, pruritus Contraindications- mg/day hypersensitivity reaction, pregnancy (body and breastfeeding, renal insufficiency weight < (serum creatinine more than 120 50 kg) to micromoles per litre), severe hepatic 1998 failure mg/day FDA pregnancy category C (body weight> 50 kg Disulfiram Drowsiness, fatigue, abdominal pain, 250mg/day OD One year headache, nausea, diarrhea, allergic dermatitis, metallic or garlic like after taste

Contraindications (absolute)- hypersensitivity reaction , pregnancy and breast feeding Contraindications (relative)- cardiovascular problems, severe personality disorder, suicidal risk, psychosis FDA pregnancy category C Naltrexone Nausea, headache, abdominal pain, 50 mg/day OD One year reduced appetite and tiredness Contraindications- acute liver failure (caution is suggested when serum aminotransferases are four to five times above normal) FDA pregnancy category C 10

Clinical Pathway of Management of Alcohol Dependence Individual with alcohol use Assess for problematic use Non- d e p e n d e n t u s e A l c o h o l d e p e n d ence Assess for Severity of dependence Severity of withdrawal Presence of complicated withdrawal Severity of withdrawal in past Mild to moderate Severe dependence dependence Mild to moderate Severe withdrawal withdrawal Presence of complicated Absence of complicated withdrawal withdrawal Poor social support and

Severe withdrawal in past supervision Absence of comorbid use History of complicated withdrawal of other substances Presence of Comorbid medical/ Personal preference psychiatric illness Brief I n t e r v e ntion In-patient with d r a w a l m anagement Outpati e n t w i t hdrawal management 11 Management of Alcohol Dependence -–QRG Version 17th Feb 2016

Quality Standards for Management of Alcohol Dependence Standard Statement Quality Standard 1 All patients reporting to health facility should be screened for Screening presence of alcohol dependence. Quality Standard 2 All patients reporting current alcohol use and scoring high on the Assessment screening tests or having problems due to alcohol use should be assessed for presence of alcohol dependence and physical complications associated with long term alcohol use .

Quality Standard 3 All patients with alcohol dependence should be assessed for Investigations presence of physical complications using laboratory investigations. Quality Standard 4 All patients with alcohol dependence should be offered short term Short term management (detoxification) in the out-patient, or the inpatient management setting. Quality Standard 5 All patients with alcohol dependence should be offered long term Long term management. management 12

Quality Standard-1 - Screening for alcohol dependence 1. Statement All patients reporting to health facility should be screened for presence of alcohol dependence. 2. Rationale Problematic use of alcohol is a common medical disorder that can go undetected even among those seeking treatment for some unrelated medical disorder. Hence, all patients in contact with health care systems should be screened for presence of alcohol dependence. 3. Quality Measure

3a. Structure Availability of screening instruments (scales) and trained health professionals at the medical facility. 3b. Process Proportion of patients seeking medical care being screened for problematic alcohol use. Numerator- Number of patients screened for problem drinking amongst those seeking care. Denominator- Total number of patients seeking medical care. 3c. Outcome Proportion of patients who are likely to have problematic alcohol use.

Numerator- Number of patients who are likely to have problematic alcohol use. Denominator –Total number of patients screened for problematic alcohol use. 4. What Quality Service Provider –Ensure that all patients seeking medical care are Measure means for screened for problematic alcohol use. each audience Health Administrator- Ensure that adequate screening facility is available at the designated facility. Patient and Community – Patients and caregivers should participate in the screening process.

5. Data Source Out-patient register In-patient register 6. Definitions Health Facility- Any public health care facility (PHC, CHC, District Hospitals, Tertiary care Centers/ Teaching Hospitals) or their equivalent in private sector 13 Management of Alcohol Dependence -–QRG Version 17th Feb 2016

Quality Standard-2 - Assessment for alcohol dependence 1. Statement All patients reporting current alcohol use and scoring high on the screening tests or having problems due to alcohol use should be assessed for presence of alcohol dependence. 2. Rationale Patients with current alcohol use and scoring high on the screening test or having problems due to alcohol use are likely to be dependent on alcohol and consequently require medical intervention. 3. Quality Measure

3a. Structure Availability of trained health professionals at the medical facility. 3b. Process Proportion of patients reporting current alcohol use and scoring high on screening test or having problems due to alcohol use assessed thoroughly for presence of alcohol dependence. Numerator- Total number of patients assessed thoroughly for presence of alcohol dependence. Denominator- Total number of patients reporting current alcohol use and scoring high on screening tests or having problems due to alcohol use.

3c. Outcome Proportion of patients who have alcohol use in dependent pattern. Numerator- Total number of patients who have alcohol use in dependent pattern. Denominator –Total number of patients assessed for alcohol use in dependent pattern. 4. What Quality Service Provider –Ensure that all patients with current alcohol use and Measure means for scoring high on screening tests or having problems due to alcohol use each audience seeking medical care are screened for problematic alcohol use.

Health Administrator- Ensure that trained health professionals are available at the designated facility. Patient and Community – Patients and caregivers should participate in the assessment process. 5. Data Source Out-patient register In-patient register 6. Definitions Health Facility- Any public health care facility (PHC, CHC, District Hospitals, Tertiary care Centers/ Teaching Hospitals) or their equivalent in private sector 14 Management of Alcohol Dependence -–QRG Version 17th Feb 2016

Quality Standard-3 - Investigations for alcohol dependence 1. Statement All patients with alcohol dependence should be assessed for presence of physical complications using laboratory investigations. 2. Rationale Patients with alcohol dependence are likely to experience the physical complications associated with alcohol use. Also it is important to exclude the possible medical causes of delirium observed during alcohol withdrawal. Finally, it is important to monitor for emergence of

side effects associated with medicines used for managing alcohol dependence. Hence it is important to assess these patients with appropriate laboratory investigations. 3. Quality Measure 3a. Structure Availability of laboratory facilities at the medical facility. 3b. Process Proportion of patients advised investigations for presence of physical complications associated with alcohol use, possible medical causes of delirium observed during alcohol withdrawal and monitoring for

emergence of side effects of medicines used for managing alcohol dependence. Numerator- Total number of patients advised investigations. Denominator- Total number of patients being managed for alcohol dependence. 3c. Outcome Proportion of patients with deranged biochemical investigation results. Numerator- Total number of patients who have deranged biochemical investigation results. Denominator –Total number of patients investigated.

4. What Quality Service Provider –Ensure that all patients with alcohol dependence are Measure means for recommended appropriate laboratory investigations. each audience Health Administrator- Ensure that adequate laboratory services are available at the facility. Patient and Community – Patients and caregivers should participate in the investigations. 5. Data Source Out-patient register In-patient register Laboratory register

6. Definitions Health Facility- Any public health care facility (PHC, CHC, District Hospitals, Tertiary care Centers/ Teaching Hospitals) or their equivalent in private sector 15 Management of Alcohol Dependence -–QRG Version 17th Feb 2016

Quality Standard-4 - Short term management of alcohol dependence 1. Statement All patients with alcohol dependence should be offered short term management (detoxification) in the in-patient or the out-patient setting. 2. Rationale Patients with alcohol dependence are likely to experience withdrawals when they quit alcohol use. Hence it is important to offer medical management for alcohol withdrawals. Also it is important to prevent emergence of complicated alcohol withdrawal and manage the same

whenever they emerge. 3. Quality Measure 3a. Structure Availability of short-term management facilities (in patient and out patient) at the medical facility. 3b. Process Proportion of patients offered short-term management for alcohol dependence. Numerator- Total number of patients offered short-term management for alcohol dependence. Denominator- Total number of patients diagnosed with alcohol dependence. 3c. Outcome Proportion of patients who receive short-term management for alcohol dependence.

Numerator- Total number of patients who receive short-term management for alcohol dependence. Denominator- Total number of patients diagnosed with alcohol dependence. 4. What Quality Service Provider –Ensure that all patients with alcohol dependence are Measure means for offered short-term management. each audience Health Administrator- Ensure that adequate short-term management facilities (pharmacological and non pharmacological; from in-patient and out-patient setting) are available at the facility.

Patient and Community – Patients and caregivers should participate in the short-term management. 5. Data Source Out-patient register In-patient register Pharmacy register 6. Definitions Health Facility- Any public health care facility (PHC, CHC, District Hospitals, Tertiary care Centers/ Teaching Hospitals) or their equivalent in private sector 16 Management of Alcohol Dependence -–QRG Version 17th Feb 2016

Quality Standard-5 - Long term management of alcohol dependence 1. Statement All patients with alcohol dependence should be offered long term management. 2. Rationale Patients with alcohol dependence are likely to relapse even after a successful short-term management. Hence it is important to offer long term management to all these patients. 3. Quality Measure 3a. Structure Availability of long-term management facilities at the medical facility.

3b. Process Proportion of patients offered long-term management for alcohol dependence. Numerator- Total number of patients offered long-term management for alcohol dependence. Denominator- Total number of patients diagnosed with alcohol dependence. 3c. Outcome Proportion of patients who receive long-term management for alcohol dependence. Numerator- Total number of patients who receive long-term management for alcohol dependence. Denominator- Total number of patients diagnosed with alcohol dependence.

4. What Quality Service Provider –Ensure that all patients with alcohol dependence are Measure means for offered long-term management. each audience Health Administrator- Ensure that adequate long-term management facilities (pharmacological and non pharmacological) are available at the facility. Patient and Community – Patients and caregivers should participate in the long-term management. 5. Data Source Out-patient register In-patient register Pharmacy register

6. Definitions Health Facility- Any public health care facility (PHC, CHC, District Hospitals, Tertiary care Centers/ Teaching Hospitals) or their equivalent in private sector 17 Management of Alcohol Dependence -–QRG Version 17th Feb 2016

OPTIMAL FEEDING OF LOW BIRTH WEIGHT INFANTS Standard Treatment Guidelines Neonatal Guideline Development Group (Secretariat: Department of Pediatrics, AIIMS)

TABLE OF CONTENTS Executive summary ..................................................................... 1 Introduction ................................................................................ 5 Methodology ............................................................................... 8 Recommendations ...................................................................... 22 Implementation tools .................................................................. 27

Executive summary Low birth weight (LBW) is defined as weight less than 2500g at birth. The World Health Organization estimates that 16% of allneonates—nearly 20 million—are born low birth weight(birth weight less than 2500 g) every year. In India, nearly one- third of live born babies are low birthweight—8 million every year. These neonates are at 11–13times increased risk of dying as compared to normal birthweight babies. Low birth weight neonates may be gestation-wiseimmature (i.e. preterm) or may

have sufferedintrauterine growth restriction (IUGR). The incidence of prematurity is fairlyconstant at 8–16% throughout the world. But the prevalence of IUGR varies widely – in South Asia, IUGR is responsiblefor two-thirds of LBW neonates. LBW infants are at risk of short and long term morbidities. Short term morbidities include hypothermia, hypoglycemia, increased risk of sepsis and feeding difficulties among others. Feeding difficulties in LBW infants are often due to poor feeding

skills because of prematurity per se, altered perfusion of the gut due to high resistance in uterine and umbilical arteries while in utero, and also due to non- availability of own mother’s milk in adequate volume in the initial few days after birth. Providing optimal nutrition not only improves growth but also results in better neurodevelopmental outcome in these infants. Optimal nutrition to LBW infants can be provided by parenteral or enteral means.

While parenteral nutrition is essential when the infant is critically ill, enteral route is preferred over parenteral route once the infant is stabilized because of the cost and inherent risks involved with parenteral nutrition. Enteral feeding should be initiated and advanced as early as possible in LBW infants to optimize nutrition. The objective of this standard treatment guidelines is to improve the quality of care received by LBW infants inhealth facilities of India through improved capacity of

health care providers. These guidelines focus on optimal feeding of clinically stable LBW infants in India. They do not specificallyaddress the feeding of infants with a birth weight less than 1.0 kg (known as extremely LBW, ELBW),who are often clinically unstable and may require parenteral nutrition. Health care providers can adapt the recommendations to their setting and implement to improve short- and long-term outcomes of LBW infants. 1

The Guideline Development Group (GDG)searched the existing guidelines on feeding of low birth weight infants using a broad search strategy. After comparing the available guidelines using the standard approach, the GDG decided to use the WHO optimal feeding of LBW guidelines as the base for the present guidelines and adopt it using the National Neonatology Forum (NNF) guidelines. The WHO guidelines had enlisted 18 priority research questions. The GDG identified

eight additional RQs from the NNF practice guidelines, of which four were considered to be relevant and important for the present guidelines. In addition, the group conducted an electronic survey followed by telephonic discussion among healthcare providers from secondary level facilities to identify additional research questions. The GDG finalized the recommendations by adopting or adapting the original recommendations from the WHO and NNF guidelines:

Recommendations on optimal feeding of low birth weight infants Recommendation Adopted/adapted from What to feed: Choice of milk Low birth weight (LBW) infants, including those with very low Adopted from the WHO birth weight (VLBW), should be fed mother’s own milk. guidelines LBW infants, including those with VLBW, who do not have access Adapted from the WHO to mother's own milk/ whose mother's own milk is guidelines insufficient,should be fed donor human milk.

LBW infants, including those with VLBW, who cannot be fed Adopted from the WHO mother's own milk or donor human milk should be fed standard guidelines infant formula. VLBW infants who cannot be fed mother's own milk or donor human milk should be given preterm infant formula if they fail to gain weight despite adequate feeding with standard infant formula. VLBW infants who are fed mother’s own milk or donor human milk Adopted from the WHO should not routinely be given bovine milk-based human milk guidelines

fortifier. VLBW infants who fail to gain weight despite adequate breastmilk feeding should be given human-milk fortifiers, preferably those that are human milk based. What to feed: Supplements 2

LBW infants (1500-2499 g) should be given vitamin D Adapted from the WHO supplements at a dose of 400 IU per day until 6 months of age. and NNF guidelines VLBW infants (<1500 g) should be given vitamin D supplements at a dose of 800 IU per day until 6 months of age. VLBW infants who are fed mother’s own milk or donor human milk Adapted from the WHO should be given daily calcium (120-140 mg/kg per day) and guidelines phosphorus (60-90 mg/kg per day) supplementation until term

gestation (40 weeks’ postmenstrual age). VLBW infants fed mother’s own milk or donor human milk should Adapted from the WHO be given 2-4 mg/kg per day iron supplementation starting at 2 and NNF guidelines weeks until 6 months of age. Other LBW infants (1500-2499 g) fed mother’s own milk or donor milk should be given 2-3 mg/kg per day iron starting at 6-8 weeks until 6 months of age. Routine zinc supplementation for LBW infants who are fed Adopted from the WHO

mother's own milk or donor human milk is not recommended at guidelines the present time, because there is not enough evidence of benefits to support such a recommendation. When to initiate feeding? LBW infants (birth weight > 1200 g)who are able to breastfeed Adopted from the WHO should be put to the breast as soon as possible after birth when guidelines they are clinically stable. LBW infants with birth weight <1200 g should be given 10 mL/kg Adapted from the WHO

per day of enteral feeds, preferably expressed breast milk, guidelines starting from the first day of life, with the remaining fluid requirement met by intravenous fluids. How to feed? LBW infants who need to be fed by an alternative oral feeding Adopted from the WHO method should be fed by cup (or palladai, which is a cup with a guidelines beak) or spoon. VLBW infants requiring intragastric tube feeding should be given Adopted from the WHO bolus intermittent feeds. guidelines

In VLBW infants who need to be given intragastric tube feeding, Adopted from the WHO the intragastric tube may be placed either by oral or nasal route, guidelines depending upon the preferences of health-care providers. VLBW infants on intragastric tube feeding should be fed 2 hourly. Adapted from the NNF Other LBW infants (1500-2499 g) on intragastric tube feeding guidelines should be fed 3-hourly. LBW infants who are fully or mostly fed by an alternative oral Adopted from the WHO

feeding method should be fed based on infants’ hunger cues, guidelines except when the infant remains asleep beyond 3 hours since the last feed. 3

How much to feed? LBW infants with birth weight >=1200 g should be initiated on Adapted from the NNF 60-80 mL/kg per day of enteral feeds, preferably expressed guidelines breast milk, on the first day of life. In VLBW infants who need to be fed by an alternative oral feeding Adopted from the WHO method or given intragastric tube feeds, feed volumes can be guidelines increased by up to 30 ml/kg per day with careful monitoring for feed intolerance.

LBW infants who need to be fed by an alternative oral feeding Adapted from the NNF method or given intragastric tube feeds, should be fed up to 180- guidelines 200 mL/kg per day after 1-2 weeks of life. Optimal duration of exclusive breastfeeding LBW infants should be exclusively breastfed until 6 months of Adopted from the WHO age. guidelines Miscellaneous issues Non-nutritive sucking (NNS) is recommended in VLBW infants on Adapted from the NNF

intragastric tube feeding to improve transition from gavage to guidelines breast feeding. Growth monitoring LBW infants should be monitored for optimal growth by serial Adapted from the NNF weight and head circumference measurement at least once guidelines weekly in the first weeks of life, using an appropriate growth chart like Fenton’s chart. 4

Introduction Low birth weight (LBW) is defined as weight less than 2500g at birth. The World Health Organization estimates that 16% of allneonates—nearly 20 million—are born low birth weight(birth weight less than 2500 g) every year. The highest burdenof low birth weight (LBW) neonates is in South Asia, wherean estimated 31% neonates are born low birth weightcontributing to nearly one half of the global burden.In India, nearly one-third of live born babies are low birthweight—8 million

every year. These neonates are at 11–13times increased risk of dying as compared to normal birthweight babies and are also predisposed to a variety of adult onsetdiseases. Low birth weight neonates may be gestation-wiseimmature (i.e. preterm) or may have sufferedintrauterine growth restriction (IUGR). The incidence of prematurity is fairlyconstant at 8–16% throughout the world. But the prevalence of IUGR varies widely – in South Asia, IUGR is responsiblefor two-thirds of LBW neonates.LBW

infants are also classified as very low birth weight (VLBW) if their birth weight is less than 1.5 kg, and as extremely low birth weight (ELBW) if their birth weight is less than 1 kg. All these infants have a higher mortality risk than infants who do not have LBW. LBW infants are at risk of short and long term morbidities. Short term morbidities include hypothermia, hypoglycemia, increased risk of sepsis and feeding difficulties

among others. Feeding difficulties in LBW infants are often due to poor feeding skills because of prematurity per se, altered perfusion of the gut due to high resistance in uterine and umbilical arteries while in utero, and also due to non- availability of own mother’s milk in adequate volume in the initial few days after birth. Providing optimal nutrition not only improves growth but also results in better neurodevelopmental outcome in these infants.

Optimal nutrition to LBW infants can be provided by parenteral or enteral means. Even though parenteral nutrition is essential when the infant is critically ill, enteral route is preferred over parenteral once the infant is stabilized because of the cost and inherent risks involved with parenteral nutrition. Enteral feeding should be initiated and advanced as early as possible in LBW infants to optimize nutrition. 5

However, LBW feeding is fraught with controversies resulting in wide variations in clinical practice. Formulating a standard feeding guidelines based on current best evidence would help to streamline enteral feeding practices in LBW infants. Health care providers can adapt the recommendations to their setting and implement to improve short term outcomes of LBW infants. Guideline Development Group (GDG) The following experts were involved in the development of these guidelines: Vinod

Paul (AIIMS, New Delhi), Ashok Deorari (AIIMS, New Delhi), M Jeeva Sankar (AIIMS, New Delhi), Ruchi Nanavati (KEM, Mumbai), Jayashree Mondkar (LTMMC, Sion, Mumbai), Ramesh Agarwal (AIIMS, New Delhi), Nandkishore Kabra (AIIMS, New Delhi), Ashish Jain (MAMC, Delhi), and N Chandrakumar (AIIMS, New Delhi). Team from NHSRC, NICE, (NHSRC team to fill the names and their roles) The guideline development group (GDG) met once in September 2015 to deliberate

on the steps and timelines. A working group comprising three members of the GDG (MJS, NC, and RN) developed the draft guidelines based on the agreed plan. Thisdraft was reviewed electronically and approved by the other GDG members. Declaration of interests All the members of the GDG declare no conflict of interest. Funding source National Health Systems Resource Center (NHSRC), New Delhi Scheduled review We plan to update the STG every 3 years. Scope of the guidelines Target audience

The primary audience for these guidelines is intended to be healthcare workers in primary and secondary level health facilities as well as referral hospitals. The 6

guidelines are also expected to be used by policy-makers, program managers, and health facility managers to set up a system for optimal care of LBW infants. Further, many of the recommendations will be relevant for community health workers providing care to LBW infants at home. The information in these guidelines will be included in several capacity strengthening courses for health workers, such as for Essential Newborn Care and Integrated Management of Newborn and

Childhood Illness (IMNCI), and in community health worker training on caring for the newborn at home. Population of interest The guidelines focus on the feeding of clinically stable LBW infants being cared for in a health facility or at home. Some of the recommendations focus only on very low birth weight infants (VLBW; birth weight less than 1.5 kg). The guidelines do not specifically address the feeding of infants with a birth weight less than 1.0 kg

(extremely low birth weight; ELBW), who are often clinically unstable and may require parenteral nutrition. Further, the guidelines do not provide separate recommendations for the two groups of LBW infants – term small-for-gestational age (SGA) and preterm – because of lack of evidence. Critical outcomes Four outcomes were considered to be critical by the GDG: mortality, severe morbidity, neurodevelopment, and anthropometric status. Mortality and severe

morbidity over the short term (e.g. during initial hospital stay after birth) or long term (e.g. infant mortality) were considered to be critical. Neurodevelopment and anthropometric status were considered critical only if measured at age 6 months or more. Benefits and harms in critical outcomes formed the basis of the recommendations. When information on critical outcomes was not available, other non-critical outcomes were considered. Examples of these other outcomes include

breastfeeding duration or exclusivity, short-term growth, duration of hospital stay, hemoglobin levels and bone mineralization. 7

Methodology Step 1: Search and select guidelines The GDG searched the electronic database MEDLINE via PubMed and the websites www.who.int (World Health Organization), http://www.guideline.gov (National Guideline Clearing House of US), http://www.nice.org.uk (National Institute for Clinical & Care Excellence, UK), www.aap.org (American Academy of Pediatrics), www.cps.ca(Canadian Pediatric Society), and www.nnfi.org (National Neonatology

Forum, India) to search for existing guidelines on feeding of low birth weight infants. The following search strategy “(feeding[All Fields] AND ("infant, low birth weight"[MeSH Terms] OR ("infant"[All Fields] AND "low"[All Fields] AND "birth"[All Fields] AND "weight"[All Fields]) OR "low birth weight infant"[All Fields] OR ("low"[All Fields] AND "birth"[All Fields] AND "weight"[All Fields] AND "infants"[All Fields]) OR "low birth weight infants"[All Fields])) AND Guideline[ptyp]” was used

for searching PubMed. A similar search strategy was used to search the websites of national and international organizations. Two relevant citations – one each by the World Health Organization and Chinese Society of Parenteral and Enteral Nutrition (CSPEN) – were identified. In addition, the GDG identified another guideline – by National Neonatology Forum, India –by hand searching. Another review-cum-guidelines – published recently in 2015 – by

an expert group from McMaster University, Canada was also identified by hand searching. Step 2: Compare and sift guidelines Table 1 depicts the key features of the three guidelines (WHO, CSPEN, and NNF). Of the three guidelines, only one – by the World Health Organization – has been evaluated thoroughly by the National Guideline Clearinghouse of the US (www.guideline.gov). The technical quality and the process of development of the

other two guidelineswere evaluated by two members of the GDG using the AGREE- GRS instrument (http://www.agreetrust.org/). 8

Both the guidelines scored3 to 5 in the 7-point scale for individual items (lowest quality being 1). On the overall guideline assessment, one guideline (CSPEN) scored 2 while the NNF guidelines scored 6 (strongly disagree=1; strongly agree=7 in a 7-point scale). The GDGunanimously decided to use the WHO feeding guidelines as the base for the present guidelines and adopt it using the NNF guidelines, if there was a need to adopt the recommendations to Indian context. 9

Table 1: Comparison of guidelines Guideline Title Guidelines on optimal feeding of low CSPEN guidelines for NNF Clinical Practice Guidelines birth-weight infants in low- and- nutrition support in middle income countries neonates Date Released 2011 2013 2010 Adaptation Not applicable: The guideline was not Not applicable Not applicable adapted from another source. Guideline World Health Organization (WHO) - Chinese Society of National Neonatology Forum, India

Developer(s) International Agency Parenteral and Enteral Nutrition, Chinese Society of Pediatrics Source(s) of Funding These guidelines were developed using ? None National Neonatology Forum, India funding to the Department of Maternal, Newborn, Child and Adolescent Health from the United States Agency for International Development. Financial None of the members of the Guideline None declared any conflict Not clear Disclosures/Conflicts Development Group (GDG) declared any of interest.

of Interest conflicts of interest. Disease/Condition(s) • Low birth weight (LBW) (<2.5 kg) Neonates LBW neonates • Very low birth weight (VLBW) (1.0 to NOT restricted to LBW (one section in the document is on 1.5 kg) neonates ‘Feeding of LBW Infants’) Intended Users Advanced Practice Nurses Not mentioned Not mentioned Allied Health Personnel Dietitians Health Care Providers Health Plans Hospitals Managed Care Organizations Nurses Physician Assistants Physicians Public Health Departments

Guideline To improve the quality of care received To provide proposed To have Neonatal practice Guidelines Objective(s) by low birth weight (LBW) infants in advisable ranges for nutrient which are evidence based relevant to

developing countries through improved intakes in neonates India, acceptable to local needs and capacity of health workers who care for developed by a large group with these infants wider representation Target Population Clinically stable low birth weight (LBW)* All neonates including All neonates infants in low- and middle-income preterm and most sick term countries, including infants born at term neonates (after 37 and before 42 completed weeks of gestation) and preterm (born

up to 37 completed weeks of gestation) *Weighing between 1.0 and 2.5 kg at birth Note: The recommendations do not specifically address the feeding of infants with a birth weight less than 1.0 kg (known as extremely LBW, ELBW), who are often clinically unstable and may require parenteral nutrition. Major Outcomes • Mortality Not clear Not clear Considered • Severe morbidity • Neurodevelopment • Anthropometric status Cost Analysis Yes No No Performed/Reviewed ?

Methods Used to Hand-searches of Published Literature Based on the ‘considered A search of medical literature using Collect/Select the (Primary Sources) review of available scientific specific search terms was made using Evidence Hand-searches of Published Literature reports on the subject, and PubMed, Medline, Cochrane trial (Secondary Sources) on expert consensus for register, Google Scholar and ‘Ovid’. Searches of Electronic Databases which the available scientific Abstracts of the retrieved studies

data are considered were inspected and selected studies inadequate’ were perused in detail and relevant Further details not available data extracted. This search was conducted independently by the three authors in each group and the references were subsequently pooled to widen the 11

reference base. Description of Search Strategy Not mentioned A search of medical literature using Methods Used to A series of systematic reviews were specific search terms was made using Collect/Select the conducted and published by the World PubMed, Medline, Cochrane trial Evidence Health Organization (WHO) as Optimal register, Google Scholar and ‘Ovid’. feeding of low-birth-weight infants: In addition, relevant cross-references

technical review in 2006. The databases were looked at in detail. Abstracts of searched included the Cochrane conference proceedings of National Database of Systematic Reviews of and International meetings (NNF, randomized controlled trials (RCTs), the IAP, PAS, ESPR) and Cochrane Controlled Trials Register, the recommendations of various Cochrane Database of Abstracts of professional bodies were also Reviews of Effectiveness (DARE), the reviewed. A hand search of MD & DM

Cochrane neonatal collaborative review dissertations and non-indexed group specialized register, MEDLINE journals like Journal of Neonatology (1966 to 2005), and EMBASE (1966 to was performed. 2005). The reference lists of relevant articles and a number of key journals were hand searched. Every effort was made to include relevant non-English language articles and abstracts. This approach was complemented by an additional search in August-September 2010 to identify relevant research

papers published between January 2005 and August 2010. The first set of search terms ("all fields" and "MESH terms") was related to the population of interest: low-birth-weight (LBW) infant, preterm infant, premature infant, SGA infant, fetal growth retardation, intrauterine growth retardation, intrauterine growth restriction. The studies identified also needed to have at least one of the search terms in the second set related to issues in feeding of LBW infants. The 12

second set of search terms included: feeding, enteral nutrition, breastfeeding, breast milk, human milk, donor milk, formula, human-milk fortifier, vitamin, micronutrient, vitamin A, vitamin D, calcium, phosphorus, zinc, iron, cup, bottle, spoon, tube, feeding tolerance, trophic feeding, minimal enteral nutrition and gut priming. Methods Used to Weighting According to a Rating Scheme The quality and strength of Literature was assessed for

Assess the Quality (Scheme Given) the supporting literature appropriateness of study design, and Strength of the was graded according to limitations in employed study design, Evidence American Society for and inconsistency across different Parenteral and studies, and applicability to Indian Enteral Nutrition (ASPEN). neonates. Evidence provided by The grade of individual studies was classified as recommendation depends per standard recommendations.

on the scientific quality of Based on evidence guidelines are the studies reported. Meta- provided for practice and research analyses were used to issues. organize information and to draw conclusions about overall treatment effect from multiple studies on a particular subject. Rating Scheme for Quality of the Evidence Level of evidence GRADE recommendations were used the Strength of the A modified GRADE (Grading of I: Large, randomized trials to summarize evidence on therapeutic

Evidence Recommendations Assessment, with clear-cut results; low questions. Development and Evaluation) approach risk of false-positive (alpha) for assessing the quality of evidence was error or false-negative Level Type of study used. The quality of the set of included (beta) error of studies reporting results for an outcome II: Small, randomized trials eviden was graded as: high, moderate, low or with uncertain results; ce

very low. The interpretation of the moderate to high risk of 1a Systematic review of grades in these guidelines is: false-positive (alpha) and/or randomized controlled High: One can be sure that the false-negative (beta) error trials 13

intervention is beneficial, has no effect III: Nonrandomized, 1b Individual randomized or is harmful. The results, including the contemporaneous controls controlled trial (with magnitude of the pooled effect, are IV: Nonrandomized, narrow confidence unlikely to change with new studies. historical controls interval) Moderate: One can be reasonably sure V: Case series, uncontrolled 1c All cases affected before that the intervention is beneficial, has no studies, and expert opinion intervention, some or

effect or is harmful. However, the none affected after magnitude of the pooled effect may Grade of intervention change with new studies. recommendation 2a Systematic review of Low: Although it is likely that the A: Supported by at least two cohort studies intervention is beneficial, has no effect level I investigations 2b Individual cohort study or is harmful, one cannot be sure. The B: Supported by one level I (including low-quality magnitude of the pooled effect is investigation randomized controlled

uncertain and is likely to change with C: Supported by level II trial) new studies. investigations only 2c ‘Outcomes’ research Very low: One cannot be certain about D: Supported by at least 3a Systematic review of the effects of the intervention. two level III investigations case-control studies The criteria used to grade the quality of E: Supported by level IV or 3b Individual case-control evidence are shown in Table I of the level V evidence study original guideline document. 4 Case series (and poor-

quality cohort and case- control studies) Grade Levels of study s of recom m. A Consistent level 1 studies B Consistent level 2 or 3 studies or extrapolations from level 1 studies C Level 4 studies or 14

extrapolations from level 2 or 3 studies D Level 5 evidence or troublingly inconsistent or inconclusive studies of any level Description of the Data Abstraction and Summary Meta-analyses were used to Methods Used to Tables of Individual Studies organize information and to Analyze the Evidence A standardized form was used to extract draw conclusions about information from relevant studies. overall treatment effect Systematically extracted data included: from multiple studies on a

study identifiers, setting, design, particular subject. Further participants, sample size, intervention or details not available. exposure, control or comparison group, outcome measures and results. The following quality characteristics were recorded for randomized controlled trials (RCTs): allocation concealment, blinding of intervention or observers, loss to follow-up, intention to treat analysis, analysis adjusted for cluster randomization (the latter only for cluster-RCTs). The quality characteristics

recorded for observational studies were likelihood of reverse causality, selection bias and measurement bias, loss to follow-up and analysis adjusted for confounding. The studies were stratified according to the type of intervention or exposure, study design, birth weight and gestational age, where possible. Effects were expressed as relative risks (RR) or odds ratios (OR) for categorical data, and as mean differences (MD) or weighted mean differences (WMD) for 15

continuous data where possible. Where results adjusted for potential confounders were available, particularly for observational studies, they were used in preference to unadjusted results. Where results adjusted for potential confounders were not available, unadjusted results were used. All studies reporting on a critical outcome were summarized in a table of individual studies (see the Annexes in the original guideline document). Pooled Effects Pooled effects for developing

recommendations were considered, wherever feasible. If results of three or more RCTs were available for an outcome, and the overall quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was at least "low", observational studies were not considered. However, if there were less than three RCTs for an outcome or the quality of evidence was "very low", the effects from RCTs were pooled with those from available cohort and case- control studies.

Pooled effects from published systematic reviews were used if the meta-analysis was appropriately done, and the reviews were up to date. However, if any relevant published study not included in the systematic review or a methodological problem with the meta- 16

analysis was identified, the results were pooled using the "metan" command in Stata 11.0. For pooling, the author- reported adjusted effect sizes and confidence intervals (CIs) were used as far as possible. Random effects models for meta-analysis were used if there was important inconsistency in effects, and the random effects model was not unduly affected by small studies. Where pooling of results was not possible, the range of effect sizes observed in the individual studies was used in the

development of recommendations. Grading the Quality of Evidence A modified GRADE approach for assessing the quality of evidence was used (see the "Rating Scheme for the Strength of the Evidence" field). One of the difficulties in using GRADE is that the evidence base for an outcome may include studies with varying methodological quality and sample size. Therefore, the weight of the studies in the estimation of the pooled effect was included to make judgments about the

quality of the set of included studies. The criteria used to grade the quality of evidence are shown in Table I in the original guideline document. The following briefly describes how these criteria were used: Study Design The included studies were classified as: 1 RCTs –including RCTs or cluster-RCTs 2 Non-randomized experimental studies 17

3 Observational studies, including cohort studies and case-control studies (studies with other observational designs were not included) If a majority of evidence was from RCTs, indicated by over 50% weight in the pooled effect, a score of 0 was given. A score of -0.5 was given if a majority of evidence was from non-randomized experimental studies, and -1.0 if the evidence was from observational studies. See the original guideline document for the limitations and other details of these methods.

Methods Used to Expert Consensus Not provided Not provided Formulate the Other Recommendations Description of Formulation of Recommendations Not provided Not provided Methods Used to The external guideline panel formulated Formulate the the first version of the recommendations Recommendations based on the technical review published in 2006. This version of guidelines was field tested in health facilities in four countries - Ghana, India, Pakistan and Uganda - in 2008-9.

After the evidence base was updated in 2010 and its quality graded using the modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, the World Health Organization (WHO) staff prepared the second version of recommendations in a format consistent with the new WHO Handbook for Guideline Development (see the "Availability of Companion Documents" 18

field). The Guideline Development Group (GDG) met once to review the evidence synthesized in a technical review. The WHO working group and a consultant developed the draft guidelines based on this evidence. This draft was reviewed electronically by the GDG members and approved by them. The GRADE system for grading recommendations was used. The strength of a recommendation reflects the degree of confidence that the desirable effects of adherence to a recommendation outweigh the

undesirable effects. The decisions were made on the basis of evidence of benefits and harms, quality of evidence, values and preferences of policy-makers, health-care providers and parents, and whether costs are qualitatively justifiable compared to the benefits in low- and middle-income countries. 19

The WHO guidelines were published in year 2011. Because the evidence behind the recommendations was relatively old, the GDG planned to examine the recently published systematic review on feeding of LBW infants to update the evidence and to decide on the need to modify the recommendations. Step 3: Search and select recommendations Before searching and selecting the recommendations, the GDG examined the research questions (RQ) addressed by the WHO and NNF guidelines in the meeting

held in Delhi in late 2015. The group deliberated and enlisted the following steps: 1) Examine the appropriateness and relevance of RQs in WHO feeding guidelines 2) Identify other relevant RQs in NNF Clinical Practice Guidelines to complement those in WHO guidelines 3) Discuss with other stakeholders – particularly healthcare providers from secondary level health facilities – to identify research questions that are relevant to their settings. Examining WHO LBW feeding guidelines

The WHO guidelines had enlisted 18 priority research questions: 1. In LBW infants (P), what is the effect of feeding mother's own milk (I) compared with feeding infant formula (C) on critical outcomes - mortality, severe morbidity, neurodevelopment and anthropometric status (O)? 2. In LBW infants who cannot be fed mother's own milk (P), what is the effect of feeding donor human milk (I) compared with feeding infant formula (C) on critical outcomes (O)?

3. In LBW infants who cannot be fed mother's own milk or donor human milk (P), what is the effect of feeding preterm infant formula (I) compared with feeding standard infant formula (C) on critical outcomes (O)? 4. In LBW infants who cannot be fed mother's own milk or donor human milk (P), what is theeffect of feeding nutrient-enriched infant formula from hospital discharge until 6 months ofage (I) compared with feeding standard infant formula (C) on critical outcomes (O)?

5. In VLBW infants who are fed mother's own milk or donor human milk (P), what is the effectof multi-component fortification of breast milk (I) compared with no fortification of breastmilk (C) on critical outcomes (O)? 6. In VLBW infants who are fed mother's own milk or donor human milk (P), what is the effectof giving 2-4 Recommended Daily Allowance (RDA) of 20

vitamin D supplements (I) comparedwith 1 RDA of vitamin D supplements (C) on critical outcomes (O)? 7. In VLBW infants who are fed mother's own milk or donor human milk (P), what is the effect of calcium and phosphorus supplementation (I) compared with no supplementation (C) oncritical outcomes (O)? 8. In VLBW infants who are fed mother's own milk or donor human milk (P), what is the effectof starting iron supplementation at 2 weeks of age (I)

compared with starting ironsupplementation at 2 months of age (C) on critical outcomes (O)? 9. In VLBW infants who are fed mother's own milk or donor human milk (P), what is the effectof daily oral vitamin A supplementation (I) compared with no supplementation (C) on criticaloutcomes (O)? 10. In LBW infants who are fed mother's own milk or donor human milk (P), what is the effect ofzinc supplementation (I) compared with no supplementation (C) on critical outcomes (O)?

11. In LBW infants who are able to breastfeed (P), what is the effect of initiation of breastfeeding in the first day of life (I) compared with delaying breastfeeding for more than 24 hours (C) on critical outcomes (O)? 12. In VLBW infants born in settings where total parenteral nutrition is not possible (P), what is the effect of starting small amounts of oral feeds (about 10 ml/kg per day) in the first few days of life (I) compared with no enteral feeding (C) on critical outcomes (O)?

13. In LBW infants (P), what is the effect of exclusive breastfeeding for 6 months (I) compared with an exclusive breastfeeding duration of 4 months or less (C) on critical outcomes (O)? 14. In LBW infants who need to be fed by an alternative oral feeding method (P), what is the effect of feeding by a cup or palladai (I) compared with bottle- feeding (C) on critical outcomes (O)? 15. In VLBW infants who need to be given intragastric tube feeding (P), what is

the effect of bolus intermittent feeding (I) compared with continuous feeding (C) on critical outcomes (O)? 16. In VLBW infants who need to be given intragastric feeding (P), what is the effect of orogastric tube feeding (I) compared with nasogastric tube feeding (C) on critical outcomes (O)? 17. In LBW infants who are fully or mostly fed by an alternative oral feeding method (P), what is the effect of feeding based on infants’ hunger cues (I)

compared with strict scheduled feeding (C) on critical outcomes (O)? 18. In VLBW infants who need to be fed by an alternative oral feeding method or given intragastric feeds (P), what is the effect of rapid (>30 ml/kg per day) 21

progression of feeds (I)compared with slow (<20 ml/kg per day) progression (C) on critical outcomes (O)? After reviewing the 18 questions, the GDG decided to retain allbut two RQ (question no. 4 on post-discharge formula and no. 9 on vitamin A supplementation) for the present guidelines. Identifying complementary questions from NNF guidelines The GDG identified eight additional RQs from the NNF practice guidelines. Of these, the following four were considered to be relevant and important:

1. What should be the frequency of feeds for LBW infants - 2-hourly vs. 3- hourly? 2. What should be the volume of feeds in LBW infants? 3. What is the role of non-nutritive sucking? 4. How to monitor growth of LBW infants? Discussion with other stakeholders The GDG conducted an electronic survey followed by telephonic discussion among healthcare providers from secondary level facilities to identify additional research questions. The group did not identify any relevant additional questions. Recommendations

After enlisting the research questions, the GDG finalized the recommendations by adopting or adapting the original recommendations from the WHO and NNF guidelines: • Adopting a recommendation entails transferring the recommendations verbatim to the new guideline. • Adapting a recommendation entails making some changes to the recommendation. This could be a minor edit in order to ensure local compatibility with the country setting, or adding precisions to the wording to clarify the recommendation.

Table 2: Final recommendations New recommendations Adopted/ Recommendations in Reasons for adapted original guidelines adaptation What to feed: Choice of milk 1. Low birth weight (LBW) Adopted from Low-birth-weight (LBW) Nil infants, including those the WHO infants, including those with very lowbirth weight guidelines with very lowbirth weight (VLBW), should be fed (VLBW), should be fed mother’s own milk. mother’s own milk. 2. LBW infants, including Adapted from LBW infants, including The GDG felt it is

those with VLBW, who do the WHO those with VLBW, who not appropriate to not have access to guidelines cannot be fed mother's use the words ‘who mother's own milk/ own milk should be fed cannot be fed whose mother's own milk donor human milk mother’s own milk’. is insufficient, should be (recommendation relevant The words have fed donor human milk for settings where safe been modified to (recommendation relevant and affordable milk- convey the message

for settings where safe and banking facilities are in a more affordable milk-banking available or can be set appropriate manner. facilities are available or can up). be set up). 3. LBW infants, including Adopted from LBW infants, including Nil those with VLBW, who the WHO those with VLBW, who cannot be fedmother's guidelines cannot be fed mother's own milk or donor human own milk or donor human milk should be fed milk should be fed standardinfant formula. standard infant formula (recommendation relevant

VLBW infants who cannot for resource-limited be fed mother's own milk settings). or donorhuman milk VLBW infants who cannot should be given preterm be fed mother's own milk infant formula if they fail or donor human milk togain weight despite should be given preterm adequate feeding with infant formula if they fail standard infantformula. to gain weight despite adequate feeding with standard infant formula. 4. VLBW infants who are fed Adopted from VLBW infants who are fed Nil

mother’s own milk or the WHO mother’s own milk or donor human milk should guidelines donor human milk should not routinely be given not routinely be given bovine milk-based human bovine milk-based human milkfortifier. milk fortifier (recommendation VLBW infants who fail to relevant for resource- gain weight despite limited adequate breastmilk settings). feeding should be given VLBW infants who fail to human-milk fortifiers, gain weight despite 23

preferably those that are adequate breastmilk human milk based. feeding should be given human-milk fortifiers, preferably those that are human milk based. What to feed: Supplements 5. LBW infants(1500-2499 Adapted from VLBW infants should be The WHO guidelines g) should be given the WHO and given vitamin D do not address the vitamin D supplements at NNF guidelines supplements at a dose issue of vitamin D a dose of 400 IU per day ranging from400 IU to supplements in LBW

until 6 months of age. 1000 IU per day until 6 infants with BW of months of age. 1500-2499 g; the VLBW infants (<1500 g) recommendation is should be given vitamin D adapted based on supplements at a dose of the NNF guidelines; 800 IU per day until 6 The ESPGHAN months of age. guidelines recommend 800- 1000 IU for preterm infants; recent evidence also favors a higher dose for preterm VLBW infants. 6. VLBW infants who are fed Adapted from VLBW infants who are fed The WHO guidelines

mother’s own milk or the WHO mother’s own milk or do not specify the donor humanmilk should guidelines donor humanmilk should duration of calcium be given daily calcium be given daily calcium and phosphorus (120-140 mg/kg per day) (120-140 mg/kg per day) supplements. andphosphorus (60-90 andphosphorus (60-90 mg/kg per day) mg/kg per day) supplementation until supplementation during term gestation (40 thefirst months of life. weeks’ postmenstrual age).

7. VLBW infants fed Adapted from VLBW infants fed mother’s The WHO guidelines mother’s own milk or the WHO and own milk or donor human do not address the donor human milk should NNF guidelines milk should be given 2-4 issue of iron be given 2-4 mg/kg per mg/kg per day iron supplements in LBW day iron supplementation supplementation starting infants with birth startingat 2 weeks until 6 at 2 weeks until 6 months weights of 1500- months of age. of age. 2499 g; the recommendation is

Other LBW infants (1500- adapted based on 2499 g) fed mother’s own the NNF guidelines milk or donor milk should be given 2-3 mg/kg per day iron startingat 6-8 weeks until 6 months of age. 24

8. Routine zinc Adopted from Routine zinc Nil supplementation for LBW the WHO supplementation for LBW infants who are guidelines infants who are fed fedmother's own milk or mother's own milk or donor human milk is not donor human milk is not recommended atthe recommended at the present time, because present time, because there is not enough there is not enough evidence ofbenefits to evidence of benefits to support such a support such a recommendation. recommendation. When to initiate feeding?

9. LBW infants (birth weight Adopted from LBW infants who are able Nil > 1200 g) who are able to the WHO to breastfeed should be breastfeed should be put guidelines put to the breast as soon to the breast as soon as as possible after birth possible after birth when when they are clinically they are clinicallystable. stable. 10. LBW infants with birth Adapted from VLBW infants should be Recommendation weight <1200 g should the WHO given 10 ml/kg per day of has been adapted to

be given 10 mL/kg per guidelines enteral feeds,preferably be in sync with NNF day of enteral feeds, expressed breast milk, guidelines – stable preferably expressed starting from the first day infants with BW of breast milk, starting oflife, with the remaining 1200-1499 g can be from the first day of life, fluid requirement met by initiated on full with the remaining fluid intravenousfluids enteral feeds from requirement met by (recommendation relevant day 1 of life. intravenous fluids. for resource-limited

settings). How to feed? 11. LBW infants who need Adopted from LBW infants who need to Nil to be fed by an the WHO be fed by an alternative alternative oral feeding guidelines oral feedingmethod should method should be fed by be fed by cup (or palladai, cup (or palladai, which which is a cup with a is a cup with abeak) or beak) or spoon. spoon. 12. VLBW infants requiring Adopted from VLBW infants requiring Nil intragastric tube feeding the WHO intragastric tube feeding

should be givenbolus guidelines should be given bolus intermittent feeds. intermittent feeds. 13. In VLBW infants who Adopted from In VLBW infants who need Nil need to be given the WHO to be given intragastric intragastric tube guidelines tube feeding,the feeding, the intragastric intragastric tube may be tube may be placed placed either by oral or either by oral or nasal nasal route,depending route,depending upon upon the preferences of 25

the preferences of health-care providers. health-care providers. 14. VLBW infants on Adapted from Frequency of feeding is The NNF guidelines intragastric tube feeding the NNF decided by the gestational recommend 3 hourly should be fed 2-hourly. guidelines age, weight and the feeding for infants clinical condition of the with BW of >1600 Other LBW infants baby (GRADE B). g; for convenience (1500-2499 g) on and to align with intragastric tube feeding other should be fed 3-hourly. recommendations,

the GDG modified it to weight of 1500 g 15. LBW infants who are Adopted from LBW infants who are fully Nil fully or mostly fed by an the WHO or mostly fed by an alternative oral feeding guidelines alternative oral feeding method should be fed method should be fed based on infants’ based on infants’ hunger hunger cues, except cues, except when the when the infant remains infant remains asleep asleep beyond 3 hours beyond 3 hours since the since the last feed last feed (recommendation (recommendation relevant

relevant to settings with to settings with an an adequate number of adequate number of health-care providers) health-care providers) How much to feed? 16. LBW infants with birth Adapted from The volume of feeds The NNF guidelines weight >=1200 g should the NNF should be decided taking have suggested 60- be initiated on 60-80 guidelines into consideration the 80 mL/kg/day in mL/kg per day of gestational age, infants with BW enteral feeds, preferably postnatal age and clinical >=1200 g

expressed breast milk, status. on the first day oflife. 17. In VLBW infants, who Adopted from In VLBW infants who need Nil need to be fed by an the WHO to be fed by an alternative alternative oral feeding guidelines oral feeding method or method or given given intragastric tube intragastric tube feeds, feeds, feed volumes can feed volumes can be be increased by up to 30 increased by up to 30 ml/kg per day with careful ml/kg per day with monitoring for feed careful monitoring for intolerance

feed intolerance. 18. LBW infants who need Adapted from The volume of feeds The GDG adapted to be fed by an the NNF should be decided taking the NNF guidelines’ alternative oral feeding guidelines into consideration the recommendation to method or given gestational age,postnatal make it more clear intragastric tube feeds, age and clinical status. and avoid ambiguity should be fed up to 180- The maximum volume of 200 mL/kg per day after feeds may reach up to 26

1-2 weeks of life. 180-200ml/kg/day (GRADE D). Optimal duration of exclusive breastfeeding 19. LBW infants should be Adopted from LBW infants should be Nil exclusively breastfed the WHO exclusively breastfed until until 6 months of age. guidelines 6 months of age. Miscellaneous issues 20. Non-nutritive sucking Adapted from Non-nutritive sucking The NNF guidelines (NNS) is recommended the NNF accelerates the maturation did not make a clear

in VLBW infants on guidelines of the sucking reflex and recommendation. intragastric tube feeding has beenobserved to The GDG made a to improve transition shorten the transition time recommendation from gavage to breast from gavage to breast after examining the feeding. feeding. NNS helps in evidence. initiation andmaintenance, of successful breast feeding, during hospital stay and after discharge. Growth monitoring 21. LBW infants should be Adapted from All LBW infants should be The GDG adapted

monitored for optimal the NNF checked for weight (daily), the NNF guidelines’ growth by serial weight guidelines head circumference recommendation to and head circumference (weekly)and length make it simple and measurement at least (weekly or fort-nightly) easy to use in even once weekly in the first during their NICU stay. resource restricted weeks of life, using an Serial growth monitoring settings appropriate growth allows earlyidentification chart like Fenton’s of growth faltering.

chart. Fenton’s growth charts can be used for preterm babies. WHO Growth charts (2006) should be used from corrected age of 40 weeks into childhood. Implementation tools The GDG has already developed the quick reference guide for wider dissemination. The guide, along with the standard treatment guidelines, shall be finalized after incorporating the comments of the external consultation/peer review (timeline: 2 months). Concurrently, the group shall develop patient information document and

BIBLIOGRAPHY 1. Bang AT, Reddy HM, Bang RA, Deshmukh MD. Why do neonates die in rural Gadchiroli, India? (Part II): estimating population attributable risks and contribution of multiple morbidities for identifying a strategy to prevent deaths. J Perinatol. 2005 Mar;25 Suppl 1:S35-43 2. Katz J, Lee AC, Kozuki N, Lawn JE, Cousens S, Blencowe H et al. CHERG Small- for-Gestational-Age-Preterm Birth Working Group. Mortality risk in preterm and

small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis. Lancet. 2013 Aug 3;382(9890):417-25. 3. Dickson KE, Simen-Kapeu A, Kinney MV, Huicho L, Vesel L, Lackritz E, de Graft Johnson J, von Xylander S, Rafique N, Sylla M, Mwansambo C, Daelmans B, Lawn JE; Lancet Every Newborn Study Group. Every Newborn: health-systems bottlenecks and strategies to accelerate scale-up in countries. Lancet. 2014;384(9941):438-54. 4. India Newborn Action Plan. Available at

http://www.newbornwhocc.org/INAP_Final.pdf. Accessed on October 24, 2016. 5. Status of India’s Newborn 2014. Available at: http://www.newbornwhocc.org/SOIN_PRINTED%2014-9-2014.pdf. Accessed on October 24, 2016. 6. World Health Organization. Guidelines on optimal feeding of low birth weight infants in low- and middle-income countries. Geneva, Switzerland: World Health Organization; 2011. Available at: http://www.who.int/maternal_child_adolescent/documents/infant_feeding_low_ bw/en/. Accessed October 24, 2016

7. Dutta S, Singh B, Chessell L, Wilson J, Janes M, McDonald K, Shahid S, Gardner VA, Hjartarson A, Purcha M, Watson J, de Boer C, Gaal B, Fusch C. Guidelines for feeding very low birth weight infants. Nutrients. 2015 Jan 8;7(1):423-42 8. Sankar MJ, Agarwal R, Mishra S, et al. Feeding of low birth weight infants. Indian J Pediatr 2008;75(5):459–469. 9. Working Group Of Pediatrics Chinese Society Of Parenteral And Enteral Nutrition, Working Group Of Neonatology Chinese Society Of Pediatrics,

Working Group Of Neonatal Surgery Chinese Society Of Pediatric Surgery. CSPEN guidelines for nutrition support in neonates. Asia Pac J Clin Nutr. 2013;22(4):655-63. 10. Management of Feeding in Low Birth Weight Infants. In: Evidence based clinical practice guidelines. National Neonatology Forum, India 2010. 29

OPTIMAL FEEDING OF LOW BIRTH WEIGHT INFANTS Quick Reference Guide Neonatal Guideline Development Group (Secretariat: Department of Pediatrics, AIIMS)

TABLE OF CONTENTS What to feed: Choice of milk..................................................... 3 What to feed: Supplements ...................................................... 4 How to feed: Initiation of feeds ................................................ 5 How to feed: Progression of feeds ............................................ 6 How much to feed? ................................................................... 7

Appendix .................................................................................. 8 Growth monitoring: Fenton’s growth chart for GIRLS ................................ 8 Growth monitoring: Fenton’s growth chart for BOYS ................................. 9 Steps of spoon/paladai feeding............................................................ 10 Steps of oro-/naso-gastric tube feeding ................................................ 11 2

What to feed: Choice of milk For all LBW infants: Mother's own milk If no access to mother's milk: Donor human milk If no access to both: Infant formula 3

What to feed: Supplements For very low birth weight (<1500 g) infants Nutrients How much? When to start? Till when? Calcium 120-140 mg/kg/day Once infant reaches Term gestation 100 mL/kg/day of (40 weeks’ feeds postmenstrual age) Phosphorus 60-90 mg/kg/day Once infant reaches Term gestation 100 mL/kg/day of (40 weeks’ feeds postmenstrual age) Vitamin D 800 IU/day Once the infant is on 6 months of age* 100 mL/kg/day of feeds Iron 2-4 mg/kg/day 2 weeks of age 6 months of age*

*Supplementation beyond 6 months based on the current national/IAP guidelines For other low birth weight (1500-2499 g) infants Nutrients How much? When to start? Till when? Vitamin D 400 IU/day Once the infant is on 6 months of age* full enteral feeds Iron 2-3 mg/kg/day 6-8 weeks of age 6 months of age* *Supplementation beyond 6 months based on the current national/IAP guidelines 4

How to feed: Initiation of feeds Assessment Action No Is the baby clinically stable? Start intravenous fluids Yes No I s birth weight more than Start intravenous fluids 1200 g? Yes Is the baby able to breastfeed effectively? Yes • When offered breast, the baby Initiate breastfeeding roots, attaches well and suckles effectively • Able to suckle long enough to satisfy needs No Is the baby able to accept feeds by alternative Yes methods? Give oral feeds by • When offered cup/spoon cup/spoon/ paladai*

feeds, the baby opens mouth, takes milk and swallows without coughing/ spluttering • Able to take an adequate quantity to satisfy needs No Start oro-/naso- gastric tube feeds 5

How to feed: Progression of feeds Infants on IV fluids If stable Start trophic feedsat 10-15 ml/kg/da yby oro/naso-gastrictube If tolerating well Gradually increase feeds by 10-15 ml/kg/d ay Taper and stop IV fluids once feeds reach 2/ 3rd of daily requirement Baby on oro-/naso- gastric feeding If tolerating well Try spoon-feeds once or twice a day Also, put baby onto mothers’ breast If accepting well Gradually increase frequency and amount of spoon/paladai feeds Reduce tube feeds Baby on spoon/paladai

feeds Put baby on mother’s breast before each feed If able to breastfeed effectively 6

Steps of spoon/paladai feeding Spoon/paladai feeding 1. Baby should be awake and held sitting semi-upright on caregiver's lap; put a small cloth on front of chest to catch drips of milk 2. Put a measured amount of milk in the spoon/paladai 3. Hold the spoon/paladai so that the pointed tip rests lightly on the baby’s lower lip 4. Tip the spoon/paladai to pour a small amount of milk into the baby’s mouth at a time 5. Feed the baby slowly

6. Make sure that the baby has swallowed the milk already taken before giving any more 7. When the baby has had enough, he or she will close his or her mouth and will not take any more. Do not force-feed the baby. 8. Wash the spoon/paladai with soap and water and then put in boiling water for 20 minutes to sterilize before next feed 10

Steps of oro-/naso-gastric tube feeding Intragastric tube feeding 1. Before starting a feed, check the position of the tube 2. For each feed, take fresh syringe (ideally disposable) and remove the plunger 3. Connect the barrel of the syringe to the end of the gastric tube 4. Pinch the tube and fill the barrel of the syringe with the required volume of milk 5. Hold the tube with one hand, release the pinch and elevate the syringe barrel to 5-10 cm above the level of the baby

6. Let the milk run from the syringe through the gastric tube by gravity; DO NOT force milk through the gastric tube by using the plunger of the syringe 7. It should take about 10-15 minutes for the milk to flow into the baby’s stomach: control the flow by altering the height of the syringe; lowering the syringe slows the milk flow, raising the syringe makes the milk flow faster 8. Observe the infant during the entire gastric tube feed. Do not leave the baby

unattended. STOP the feed if the baby shows any of the following signs:breathing difficulty, change in colour/ looks blue, becomes floppy, and vomits 9. Keep the end of the gastric tube between feeds capped; if the baby is on CPAP, the tube is preferably left open for about half an hour after the feeding 10.Avoid flushing the tube with water or saline after giving feeds 11.Progress to feeding by cup/spoon/paladai when the baby can swallow without

coughing or spitting milk. This could be possible in as little as one or two days, or it may take longer than one week 12.Replace the gastric tube with another clean gastric tube after three days, or earlier in case it is pulled out or becomes blocked. 11

Background Document Detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants October 2016 1

Table of contents S. Topic Page No. No. 1. Introduction 3 2. The purpose and approach of the guideline 5 3. Full Guideline Title 6 4. Key Clinical issues that will be covered in this guideline 6 5. Methodology of Development of Guideline 7 6. Formation of the STG group 7 7. Scoping the STG 7 8. Declaration of interests 8 9. Funding source 8 10. Scheduled review 8 11. Search and selection of evidence based guidelines 8 12. Guideline Comparison 9 13. Adaptation and adoption of recommendations 22 2

and is a common problem in neonates. (1) A significant proportion of these neonates develop pathological jaundice (jaundice requiring treatment) during the first week of life (2). It is also one of the leading causes of hospitalization in the first week of life globally (3-5).The overall incidence of hyperbilirubinemia (>15 mg/dL) has been reported as 3.3% in intramural neonates and 22.1% in extramural neonates (2). Timely and appropriate treatment with phototherapy and/or exchange transfusion is

effective in decreasing excessive bilirubin levels. However, failure of instituting appropriate therapy results in acute bilirubin encephalopathy (ABE) which if not treated immediately, might go on to develop kernicterus and other long term neurological deficits including cerebral palsy, sensorineural hearing loss, intellectual difficulties or gross developmental delays (6-10). It is estimated that nearly 5,00,000 term and late preterm neonates globally are affected by

severe hyperbilirubinemia annually and around one-fourth of them die and 63,000 survive with neurological disability (11). Three-fourth of these affected infants reside in sub-Saharan Africa and South Asia (12). 3

The purpose of the guideline There is a need for a standard guideline for the management of neonatal hyperbilirubinemia in term and late preterm newborn infants in India. The context for the detection, management and prevention of neonatal hyperbilirubinemia in India is different from other countries. The published evidence based guidelines on early detection, management and prevention of neonatal hyperbilirubinemia by various bodies including American Academy of

Pediatrics (13) and National Institute for Health and Clinical Excellence (14) primarily takes care of the need of high income countries. The low and middle-income countries including India are following these guidelines due to dearth of literature and absence of such evidence based guidelines from their own setting. There is an increased incidence of significant hyperbilirubinemia in India due to various risk factors including racial and genetic factors, widespread practice of exclusive breastfeeding,

higher prevalence of G6PD deficiency in some parts of the country, more neonates with low albumin at birth, higher bilirubin levels in summer season due to dehydration, blood group incompatibilities and infections (15, 16). Lack of knowledge among mother and family members about jaundice (17) and poor transport facilities especially in rural areas often results in delay in seeking medical advice. The situation is further compounded by “why worry” attitude among

healthcare professionals especially in the dearth of substantial data documenting bilirubin induced neurological dysfunction (BIND) on arrival to health facility (18). Inadequate knowledge among healthcare professionals, limited facilities for clinical investigations, lack of standardised protocol for management (including absence of monitoring serum bilirubin while under phototherapy) and inconsistent functional status of available phototherapy devices,

often results in inappropriate treatment thus resulting in BIND (19-22). Even the lack of exchange transfusion facilities at majority of the healthcare setting due to non-availability of blood or expertise results in permanent neurological dysfunction which could be easily avoided by doing early exchange transfusion. Though the guidelines published by National Neonatology Forum, India (NNF 2010) (22) have tried to provide a practical framework for managing neonatal hyperbilirubinemia in Indian 4

setting, these guidelines are meant for only tertiary care health facilities. In view of the above stated reasons and opening of Special Care Newborn Units (SCNUs) and private health facilities delivering level II neonatal care in a big way; the current guideline has been developed for the management of neonatal hyperbilirubinemia in late preterm and term infants in the Indian context for health care facilities at all levels. Approach of the guideline

The guidelines have been commissioned to enable a systematic cost-effective approach for the detection, management and evaluation of neonatal hyperbilirubinemia in late preterm and term infants in India. This guideline and its accompanying implementation tools in the form of a quick reference guide, flow charts, and quality standards will serve as a valuable reference material for healthcare providers, patients and administrators. While formulating these

guidelines the main outcome measures taken into consideration have been mortality, incidence of acute bilirubin encephalopathy, incidence of chronic bilirubin encephalopathy, hearing Loss, incidence of exchange transfusion, incidence of severe hyperbilirubinemia, duration of phototherapy and incidence of readmissions required for hyperbilirubinemia • This guideline has a primary care focus and a public health approach. The focus of the

primary care is to improve the early detection and the timely treatment to prevent long term neurological deficits. Increasing awareness among public especially mother and family members at the time of discharge about the need for jaundice evaluation in first week of life in face of early discharges from health facilities in India will improve this dismal situation and result in improving intact survival. • These guidelines will also facilitate effective advocacy and mobilisation of requisite

resources for the optimal care of newborn infants with hyperbilirubinemia at all levels. • The guideline presented covers detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants in primary, secondary and tertiary care setting and includes an algorithmic approach to a newborn with or at risk of hyperbilirubinemia. 5

Full Guideline Title: Detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants Population Groups that will be covered a) Neonates ≥ 35 weeks Groups that will not be covered a) Preterm neonates < 35 weeks b) Neonates with conjugated hyperbilirubinemia Health Care Setting a) Primary care b) Secondary and tertiary care Disease or risk condition At risk or having jaundice Key Clinical issues that will be covered in this guideline A. Screening and Diagnosis

1.1 What should be the screening protocol for detection of jaundice in neonates? 1.2 Which neonates are at a higher risk of hyperbilirubinaemia? 1.3 What is the accuracy of transcutaneous bilirubinometry in recognizing neonatal hyperbilirubinaemia and how should it be done? 1.4 How will you interpret serum bilirubin levels and manage hyperbilirubinaemia? 1.5 What should be optimum discharge and follow-up timing and the assessment policy to

minimize the subsequent risk of severe hyperbilirubinemia and acute bilirubin encephalopathy? 1.6 What should be included in the formal assessment of a neonate with neonatal hyperbilirubinaemia? 1.7 How can we prevent severe hyperbilirubinemia? B. Treatment of hyperbilirubinemia 2.1 Phototherapy 2.2 Exchange transfusion 2.3 Other modalities 2.4 What should be the frequency of long term follow up of neonates with hyperbilirubinemia and what all should be evaluated at follow up?

2.5 Information and support which should be given to parents/care givers of neonates with neonatal hyperbilirubinaemia? 6

Methodology of Development of Guideline A Task Force was constituted in December 2014 to guide the development of Standard Treatment Guidelines (STG) in India for application in the National Health Mission. The Task Force subsequently approved the draft STG development manual of India (Part 1) for development of adapted guidelines. In addition, it approved a list of 14 topics recommended by a subgroup of the task force appointed to select prioritized topics for STG development. These

14 topics are from 10 clinical specialties for which the first set of STGs will be developed. The topic of detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants was dealt by the neonatology sub-group. Formation of the STG group A multidisciplinary group composed of a mix of primary care practitioners, family medicine practitioners, teaching faculty, practicing and academic neonatologists, nurse practitioners,

voluntary sector representatives, and a patient representative was formed by September 2015. The composition of the subgroup is mentioned in the table below. Facilitator: Prof Praveen Kumar Writing Team: Dr Anu Sachdeva, Dr Neeraj Arora, Dr Srinivas Murki, Dr Aparna Chandrasekaran, Dr Shridhar Gopalakrishnan, Dr Deepak Chawla, Dr Mangla Bharti Experts: Prof Vinod K Paul, Prof Ashok K Deorari Primary care Practioner: Nursing Practioner: Ms Meena Joshi Patient participant Scoping the STG

The scope of the STG was discussed at the first clinical subgroup meeting in Delhi in September 2015 7

Declaration of interests All the members of the GDG declare no conflict of interest. Funding source NHSRC… Scheduled review We plan to update the STG every 3 years. Search and selection of evidence based guidelines In view of the paucity of time available to develop this guideline, a decision was taken by the Task Force for the Development of STGs for the National Health Mission that these STGs would be adopted and/or adapted from existing evidence based guidelines to make them relevant to

our context, resource settings and priorities. Search and select guidelines We searched the electronic database MEDLINE via PubMed and the websites www.who.int (World Health Organization), http://www.guideline.gov (National Guideline Clearing House of US), http://www.nice.org.uk (National Institute for Clinical & Care Excellence, UK), www.aap.org (American Academy of Pediatrics), http://www.cps.ca/(Canadian Pediatric Society), and www.nnfi.org (National Neonatology Forum, India) to search for existing

guidelines on detection, management and prevention of hyperbilirubinemia of term and late preterm infants. Step 1 We used the following search strategy: ("jaundice, neonatal"[MeSH Terms] OR ("jaundice"[All Fields] AND "neonatal"[All Fields]) OR "neonatal jaundice"[All Fields] OR ("neonatal"[All Fields] AND "jaundice"[All Fields])) AND guideline [ptyp]which revealed 16 citations of which six were relevant citations. Additional search revealed two additional guidelines. In addition, we

identified another guideline – by National Neonatology Forum, India – by hand searching. Step 2 We evaluated the technical quality and the process of development of these guidelines by the AGREE-GRS instrument (http:// www.agreetrust.org) (Table 1) 8

Table 1: Comparison of existing guidelines on detection, management and prevention of hyperbilirubinemia of term and late preterm infants. Guideline Title Clinical practice ABM Clinical Protocol NNF guidelines (22) Guidelines for Recommendation Neonatal Neonatal Jaundice guideline #22: Guidelines for detection, s on newborn jaundice: (14) Subcommittee on Management management and health (25) prevention, Hyperbilirubinem of Jaundice in the prevention of assessment and

ia Breastfeeding Infant hyperbilirubinemi management Management of Equal a in term and late (26) Hyperbilirubinem to or Greater Than 35 preterm newborn ia in the Newborn Weeks’ Gestation (23) infants (24) Infant 35 or More Weeks of Gestation (AAP)(13) Date Released 2004 2010 2010 2007 Reaffirmed 2013 2012 2010; updated May 2011 2016 Adaptation Not applicable Not applicable Adapted from AAP Adapted from AAP Not applicable: Not applicable Not applicable The guideline was not adapted from another source.

Guideline American The Academy of National Neonatology Canadian World Health Queensland National Institute of Developer(s) Academy of Breastfeeding Medicine Forum, India Pediatric Society Organization - Maternity and Health and care Pediatrics Protocol Committee (fetus and International Neonatal Clinical excellence newborn Agency Guidelines Committee) Program Source(s) of ? None ? None ? None ? None These guidelines Queensland NICE Funding were developed Health, Centre using funding to for Healthcare

the Department Improvement. of Maternal, Newborn, Child and Adolescent Health from the United States Agency for International Development. 9

Guideline Clinical practice ABM Clinical Protocol NNF guidelines Guidelines for Recommend Neonatal Neonatal Title guideline #22: Guidelines for detection, ations on jaundice: Jaundice Subcommittee on Management management newborn prevention, Hyperbilirubinemia of Jaundice in the and prevention health assessment Management of Breastfeeding Infant of and Hyperbilirubinemia Equal hyperbilirubine managemen in the Newborn to or Greater Than 35 mia in term and t Infant 35 or More Weeks’ Gestation late preterm

Weeks of Gestation newborn infants Financial None of the None declared any ? None ? None ? None ? None None Disclosures members of the conflict of interest. /Conflicts Guideline of Interest Development Group (GDG) declared any conflicts of interest. Disease/Co Newborn Infant 35 Breastfeeding Infant All neonates with jaundice Term And Late All neonates All neonates All neonates ndition(s) or MoreWeeks of Equal Preterm with jaundice with jaundice with jaundice Gestation with to or Greater Than 35 Newborn

jaundice Weeks’ Gestation with Infants with jaundice jaundice Intended Hospitals and Not mentioned Not mentioned Not mentioned Not Not Not mentioned Users paediatricians, mentioned mentioned neonatologists, family physicians, physician assistants, and advanced practice nurses who treat newborn infants in the hospital and as outpatients. Guideline To reduce the 1. To provide To have Neonatal practice 1. Can severe 1. What Not 1. Offer

Objective(s incidence of severe guidance in Guidelines which are hyperbiliru health mentioned parents or 10

) hyperbilirubinemia distinguishing evidence based relevant binemia be intervent carers andbilirubin those causes of to India, acceptable to accurately ions informatio encephalopathy jaundice in the local needs and predicted? should n about while minimizing newborn that are developed by a large 2. Who should the neonatal the risks of directly related to group with wider have their newborn jaundice unintended harm breastfeeding representation bilirubin , child that is

such as maternal from those that concentrati receive tailored to anxiety, decreased are not directly on and their breastfeeding, and related to measured, when needs and unnecessary costs breastfeeding. 3. when and should expressed or treatment. 2. To guide by what s/he concern monitoring of method? receive 2. Care for all jaundice and 4. How can it? babies and bilirubin the risk of additional concentration severe care for and management hyperbiliru babies at of these binemia be high risk of

conditions in reduced? hyperbiliru order to 5. When binemia preserve should 3. Measurem breastfeeding severe ent and while protecting hyperbiliru methodolo the infant from binemia be gy of potential risks of treated? bilirubin toxicity from measurem hyperbilirubinemi ent a. 4. Care of a 3. To provide a baby with protocol for prolonged hospital and office jaundice procedures for optimal management of jaundice and hyperbilirubinemi a the breastfed newborn and young infant. 11

Target Newborn Infant 35 Breastfeeding Infant All neonates Term And Late All neonates All neonates All neonates Population or MoreWeeks of Equal Preterm Gestation to or Greater Than 35 Newborn Weeks’ Gestation Infants Major Clear and Not clear Not clear Not clear Not clear Not clear Clear and Outcomes mentioned mentioned Considered Cost Yes Not mentioned Not mentioned Yes Not Not Yes Analysis mentioned mentioned Performed /Reviewed ?

Methods Hand-searches of Not mentioned A search of medical A search was Hand- Not Hand-searches Used to Published literature using specific carried out in searches of mentioned of Published Collect/Sel Literature (Primary search terms was made MEDLINE and Published Literature ect the Sources) using PubMed, Medline, the Cochrane Literature (Primary Evidence Hand-searches of Cochrane trial register, library (Primary Sources) Published Google Scholar and ‘Ovid’. and was last Sources) Hand-searches

Literature Abstracts of the retrieved updated in Hand- of Published (Secondary studies were inspected January 2007. searches of Literature Sources) and selected studies were Search terms in Published (Secondary Searches of perused in detail and MEDLINE were Literature Sources) Electronic relevant data extracted. hyperbilirubine (Secondary Searches of Databases This search was mia and Sources) Electronic conducted independently newborn, and Searches of Databases

by the three authors in the Electronic Hand-searches each group and the clinical queries Databases of Published references were filter of Haynes Hand- Literature subsequently pooled to et al was searches of (Primary widen the reference base. applied using Published Sources) the Literature Hand-searches broad, sensitive (Primary of Published option. Other Sources) Literature searches Hand- (Secondary without the searches of Sources) filter Published Searches of were carried Literature Electronic

publications Sources) addressing Searches of specific issues. Electronic The hierarchy of Databases evidence from the Centre for Evidence- Based Medicine was applied using levels of evidence for both treatment and prognosis. The reference lists of recent publications were also examined – in particular, the evidence- based review by Ip et al and a more extensive review by the same author performed for the Agency for Healthcare Research and Quality of the US Department of Health and Human Services. The

statement of the American Academy of Pediatrics were also examined. Description We searched the Not mentioned A search of medical Same as above Not Not Mentioned and of Medline database literature using specific mentioned in mentioned clear Methods on September 25, search terms was made summary Used to 2001, for using PubMed, Medline, document Collect/Sel publications from Cochrane trial register, retrieved ect the 1966 to the present Google Scholar and ‘Ovid’. Evidence using relevant In addition, relevant

medical subject cross-references were heading terms looked at in detail. (“hyperbilirubinemi Abstracts of conference a”; proceedings of National “hyperbilirubinemia and International , hereditary”; meetings (NNF, IAP,PAS, “bilirubin”; ESPR) and “jaundice, recommendations of neonatal”; and various professional “kernicterus”) and bodies were also text words reviewed. A hand search (“bilirubin,” of MD &DM dissertations “hyperbilirubinemia and non-indexed journals ,” “jaundice,” like Journal of

“kernicterus,” and Neonatology was “neonatal”). The performed. abstracts were limited to human subjects and English-language studies focusing on newborns between birth and 1 month of age. In addition, the same text 14

words used for the Medline search were used to search the PreMedline database. The strategy yielded 4280 Medline and 45 PreMedline abstracts. We consulted domain experts and examined relevant review articles for additional studies. A supplemental search for case reports of kernicterus in reference lists of relevant articles and reviews was performed also. Methods The Steering Not mentioned Literature was assessed Literature was Not Not

Used to Committee on for appropriateness of assessed for mentioned in mentioned Assess the Quality study design, limitations appropriateness the summary Quality and Improvement in employed study design, of study design, document Strength of and Management and inconsistency across limitations in the categorizes different studies, and employed study Evidence evidence quality in applicability to Indian design, and 4 neonates. Evidence inconsistency levels: provided by individual across different

1. Well-designed, studies was classified as studies, and randomized, per standard applicability to controlled trials or recommendations. Based Indian diagnostic studies on evidence guidelines neonates. on relevant are provided for practice Evidence populations and research issues. provided by 15

2. Randomized, individual controlled trials or studies was diagnostic studies classified as per with minor standard limitations; recommendatio overwhelming, ns. Based on consistent evidence evidence from guidelines are observational provided for studies practice and 3. Observational research issues. studies (case- control and cohort design) 4. Expert opinion, case reports, reasoning from first principles Rating The AAP defines Not mentioned GRADE recommendations Grade A modified Not Grade

Scheme for evidence-based were used to summarize recommendatio GRADE mentioned recommendati the recommendations evidence on therapeutic ns (as Oxford (Grading of ons (as Oxford Strength of as follows:1 questions. Centre for Recommend Centre for the • Strong Evidence-Based ations Evidence- Evidence recommendation: Level Type of study Medicine. Assessment, Based the committee of http:// Development Medicine. evide believes www.cebm.net/ and http:// nce

that the benefits of index.aspx?o=1 Evaluation) www.cebm.net 1a Systematic review of the recommended randomized 047 (Version approach for /index.aspx?o= approach controlled trials current at assessing the 1047 (Version 1b Individual clearly exceed the March quality of current at randomized harms of that 28, 2007). evidence was March controlled trial (with approach and that narrow confidence used. The 28, 2007). the quality of the interval) quality of the 1c All cases affected supporting set of

before intervention, evidence is either included some or none excellent or affected after studies impossible to intervention reporting 16

obtain. Clinicians 2a Systematic review of results for an should cohort studies outcome was 2b Individual cohort follow these graded as: study (including low- recommendations high, quality randomized unless a clear and controlled trial) moderate, compelling 2c ‘Outcomes’ research low or very 3a Systematic review of rationale for an low. The case-control studies alternative interpretatio 3b Individual case- approach is control study n of the present. 4 Case series (and grades in • poor-quality cohort these

and case-control Recommendation: guidelines is: studies) the committee High: One believes that the can be sure benefits exceed the that the harms, but the intervention Gra Levels of study quality of evidence des is beneficial, on which this of has no effect recommendation is reco or is harmful. based is mm. The results, not as strong. A Consistent level 1 including the studies Clinicians should magnitude of B Consistent level 2 also generally the pooled or 3 studies or follow effect, are extrapolations

these unlikely to from level 1 recommendations change with studies but should be alert C Level 4 studies or new studies. to extrapolations Moderate: new information from level 2 or 3 One can be and sensitive to studies reasonably patient D Level 5 evidence sure that the preferences. or troublingly intervention inconsistent or In this guideline, is beneficial, inconclusive the term “should” has no effect studies of any implies or is harmful. level a recommendation However, the by the committee. magnitude of

quality of the effect may evidence that exists change with is suspect or well- new studies. performed studies Low: have Although it is shown little clear likely that the advantage to one intervention approach over is beneficial, another. Patient has no effect preference should or is harmful, have a substantial one cannot role in influencing be sure. The clinical decision- magnitude of making the pooled when a policy is effect is described as an uncertain option. and is likely • No to change

recommendation: with new there is a lack of studies. pertinent Very low: evidence and the One cannot anticipated balance be certain of benefits about the and harms is effects of the unclear intervention. The criteria used to grade the quality of evidence are shown in Table I of the original guideline document. Description In this report, 2 Not mentioned Not mentioned Not mentioned Not Not Described in of the statistical analyses mentioned mentioned detail Methods were performed in (https://www. 18

Used to which there were nice.org.uk/arti Analyze sufficient data: the cle/pmg6/chap the NNT and receiver ter/4- Evidence operating Developing- characteristics review- (ROC) curve. questions-and- NNT planning-the- The NNT can be a systematic- clinically review) meaningful metric to assess the benefits of clinical trials.8 It is calculated by taking the inverse of the absolute risk difference. The absolute risk difference is the difference between the event rates between the treatment and

control groups. For example, if the event rate is 15% in the control group and 10% in the treatment group, the absolute risk difference is 5% (an absolute risk reduction of 5%). The NNT then would be 20 (1 divided by 0.05), meaning that 20 patients will need 19

to be treated to see 1 fewer event. In the setting of neonatal hyperbilirubinemia, NNT might be interpreted as the number of newborns needed to be treated (with phototherapy) at 13 to 15 mg/dL to prevent 1 newborn from reaching 20 mg/dL. ROC Curve ROC curves were developed for individual studies in question 4 if multiple thresholds of a diagnostic technology were reported. The areas under the curves (AUCs) were calculated to provide an assessment of the overall accuracy of the tests. Meta-analyses of

Diagnostic Test Performance Meta-analyses were performed to quantify the TcB measurements for 20

which the data were sufficient. We used 3 complementary methods for assessing diagnostic test performance: summary ROC analysis, independently combined sensitivity and specificity values, and meta-analysis of correlation coefficients. Methods Expert Consensus Not mentioned Not mentioned Not mentioned Not Not (https://www. Used to Other mentioned mentioned nice.org.uk/arti Formulate cle/pmg6/chap the ter/4- Recommen Developing- dations review- questions-and- planning-the- systematic- review)

Description Not provided Not mentioned Not mentioned Not mentioned Not Not (https://www. of mentioned mentioned nice.org.uk/arti Methods cle/pmg6/chap Used to ter/9- Formulate Developing- the and-wording- Recommen guideline- dations recommendati ons) 21

Adaptation and adoption of recommendations The Clinical practice guideline ‘Subcommittee on Hyperbilirubinemia’ for Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation was published by American Academy of Pediatrics in 2004. Thereafter the National Neonatology Forum, India published the guidelines in 2010 which were adapted from American Academy of Pediatrics guidelines. The National Collaborating Centre for Women’s and Children’s Health commissioned

by the National Institute for Health and Clinical Excellence published the NICE guidelines for Neonatal jaundice in May 2010. We have adopted and/or adapted from existing evidence based guidelines (Neonatal Jaundice, NICE 2010; updated May 2016, Clinical practice guideline ‘Subcommittee on Hyperbilirubinemia for Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation’, American Academy of Pediatrics, 2004, National Neonatology Forum, India guidelines, 2010)

and tried to make them relevant to our context, resource settings and priorities. 22

S. No. Key recommendation Source guideline(s) Screening and assessment 1. What should be the screening protocol for detection of jaundice in neonates? (14) 1. Healthcare professionals should all look for jaundice (visual Neonatal Jaundice, NICE Adapted. The original inspection) in babies 2010; updated May 2016 recommendation is ‘examine the 2. Assessment of all newborns for jaundice should be done every 12 baby for jaundice at every hours especially in the initial 3 to 5 days. opportunity especially in the

3. Monitoring for development of severe neonatal jaundice may be first 72 hours’. We have given an needed till end of first week of postnatal life. objectivity to the words ‘at every opportunity’ by giving a time frame. This will give clear message to all healthcare professionals and will ensure jaundice evaluation at least q 12 hourly in first 72 hours to avoid missing any case of neonatal jaundice. 2. Which neonates are at a higher risk of hyperbilirubinaemia? (13)

Identify neonates as being more likely to develop significant Clinical practice guideline • Visible jaundice at discharge hyperbilirubinaemia if they have ANY of the following factors: Subcommittee on (Adapted): Just the words have • Gestational age under 38 weeks Hyperbilirubinemia been reframed to make it simple. • A previous sibling with neonatal jaundice requiring Management of The original words are ‘Jaundice phototherapy Hyperbilirubinemia in the observed before discharge’

• Mother's intention to breastfeed exclusively Newborn Infant 35 or • ‘Exclusive breastfeeding, More particularly if nursing is not going • Visible jaundice in the first 24 hours of life. Weeks of Gestation, AAP well and weight loss is excessive.’ • Visible jaundice at discharge 2004 We have given the weight cut- • Setting of blood group incompatibility offs to help healthcare • High prevalence of G6PD deficiency, primipara mother professionals in objectively

• Weight loss at discharge >3% per 24 h of age or >7% defining excessive weight loss. cumulative weight loss • The original recommendation is ‘Blood group incompatibility with positive direct antiglobulin test (DAT)’. In India, direct coomb’s test (DCT)/DAT test facility is not 23

available at primary and secondary level of health care settings and at some of the tertiary care centres. Therefore, if mother’s blood group is O positive or Rh Negative, then infants fall in high risk category unless one has a documented DCT/DAT report being negative. 3. What is the accuracy of transcutaneous bilirubinometry in recognising neonatal hyperbilirubinaemia and how should it be done? 3.1 Clinical examination for jaundice

1. Examine the baby in bright natural light. Alternatively, the Neonatal Jaundice, NICE Adopted baby can be examined in white fluorescent light. Make sure 2010; updated May 2016 there is no yellow/ off white background. 2. Make sure the baby is naked. 3. Examine blanched skin and gums or sclerae 4. Depth of jaundice (degree of yellowness) should be carefully noted as it is an important indicator of level of jaundice and it does not figure out in Kramer’s rule (27)

5. A deep yellow staining (even in absence of yellow soles or palms) is often associated with sever jaundice and therefore TSB should be estimated in such circumstances. 3.2 Transcutaneous and total serum bilirubin Transcutaneous bilirubinometry (TcB) Neonatal Jaundice, NICE Adapted 1. TcB can be used in infants of 35 weeks or more of gestation 2010; updated May 2016 after 24 hr. • Interpret bilirubin levels 2. TcB becomes unreliable once TSB level goes beyond 14 mg/dL. according to the baby's postnatal

3. Hour specific TcB can be used for prediction of subsequent age in hours and manage hyperbilirubinemia. TcB value below 50th centile for age hyperbilirubinaemia according to would rule out the risk of subsequent hyperbilirubinemia with the graphs (adopted from Clinical high probability (high negative predictive value)(28) practice guideline Subcommittee 4. Trends in TcB values by measuring 12 hr apart would have a on Hyperbilirubinemia better predictive value than a single value. Management of

Measurement of Total serum bilirubin (TSB) Hyperbilirubinemia in the 24

1. Indication of TSB measurement: Newborn Infant 35 or More i. Jaundice in first 24 hour Weeks of Gestation, AAP 2004) ii. Beyond 24 hr: if visually assessed jaundice is likely to be more than 14 mg/dL or approaching the phototherapy range or beyond. iii. If you are unsure about visual assessment iv. During phototherapy, for monitoring progress and after phototherapy to check for rebound in select cases (such as those with hemolytic jaundice) 2. Frequency of TSB measurement depends upon the underlying

cause (hemolytic versus non-hemolytic) and severity of jaundice as well as host factors such as age and gestation. In general, in non-hemolytic jaundice in term babies, TSB can be performed every 12 to 24 hr depending upon age of the baby. As opposed to this, a baby with Rh isoimmunisation would require TSB measurement every 6 to 8 hours during initial 24 to 48 hours or so. 4. How will you interpret serum bilirubin levels and manage hyperbilirubinaemia?

Interpret serum bilirubin levels according to the baby's postnatal age Clinical practice guideline Adopted in hours and manage hyperbilirubinaemia as per the guidelines. Subcommittee on 1. American Academy of Pediatrics (AAP) criteria should be used for Hyperbilirubinemia making decision regarding phototherapy or exchange transfusion Management of in these infants. AAP provides two age-specific nomograms- one Hyperbilirubinemia in the

each for phototherapy and exchange transfusion. The nomograms Newborn Infant 35 or have lines for three different risk categories of neonates (Figure 3 More and 4). These lines include one each for lower risk babies (38 wk Weeks of Gestation, AAP or more and no risk factors), medium risk babies (38 wk or more 2004 with risk factors, or 35 wk to 37 wk and without any risk factors) and higher risk (35 wk to 37 wk and with risk factors). 2. TSB value is taken for decision making and direct fraction should

NOT be reduced from it. The babies at lower and higher risk have their cut-offs at approximately 2 mg/dL higher or 2 mg/dL lower than that for medium risk babies, respectively. 3. Risk factors include presence of isoimmune hemolytic anemia, 25

G6PD deficiency, asphyxia, temperature instability, hypothermia, sepsis, significant lethargy, acidosis and hypoalbuminemia.* *Routine estimation of serum albumin is not recommended 5. What should be optimum discharge and follow-up timing and the assessment policy to minimize the subsequent risk of severe hyperbilirubinemia and acute bilirubin encephalopathy? (22) Table 1: Suggested follow-up policy NNF guidelines 2010 Adopted Scenario Age at discharge Follow-up None of risk 24-72 h 48 h after

factors* discharge present >72 h Follow-up optional Any risk 24-48 h 24 h after factor* discharge present After 48 hours 48 h after discharge *History of jaundice needing treatment in previous sibling, setting of blood group incompatibility, visible jaundice at discharge, gestation <38 completed weeks, high prevalence of G6PD deficiency, primipara mother, weight loss at discharge >3% per 24 h of age or >7% cumulative weight loss, **may need a repeat visit depending on physician’s assessment

6. What should be included in the formal assessment of a neonate with neonatal hyperbilirubinaemia? All neonates should undergo a complete clinical examination including Neonatal Jaundice, NICE Adapted; evaluation of intensity of jaundice (27), breast feeding adequacy#, 2010; updated May 2016 1. The approach mentioned in the pallor, splenomegaly, cephalhematoma or other signs of birth trauma, current guideline includes a

and evaluation for lethargy, poor feeding, general activity and tone. complete clinical examination for 1. All pregnant women should be tested for ABO and Rh (D) blood possible risk factors of jaundice types. (14) which have not been mentioned 2. If a mother has not had prenatal blood grouping or is Rh-negative, in the NICE guidelines 2. The words have been simplified a direct anti-body test (or Coombs’ test), blood type, and an Rh (D) so that it is better understood.

type on the infant’s (cord) blood are strongly recommended. (14) The rest content is the same. 3. DO NOT use the albumin/bilirubin ratio when making decisions about the management of hyperbilirubinaemia (14) 26

4. Do not subtract conjugated bilirubin from total serum bilirubin when making decisions about the management of hyperbilirubinaemia. (14) 5. In addition to a full clinical examination by a suitably trained healthcare professional, carry out the following tests in babies with hyperbilirubinaemia (Table 2) as part of an assessment for underlying disease and treatment threshold graphs. Table 2: Tests to be done in babies with hyperbilirubinaemia Indications Assessments

Infant receiving phototherapy Measure TSB; blood type and DCT (if mother is ‘O’ or Rh negative); G6PD status; peripheral smear and reticulocyte count Jaundice present beyond 3 Total and direct (or weeks of age* conjugated) bilirubin level, thyroid profile (T3, T4, TSH), urine for reducing substances (galactosemia), urine r/m, urine c/s Important Note* • Exclude cephalohematoma on examination • Exclude Rh isoimmunisation • Excessive weight loss (more than 10%)

• Breast feeding jaundice due to inadequate breast feeding is common • Presence of direct hyperbilirubinemia (direct bilirubin more than 2 mg/dL at any age) requires specific investigations and care which is beyond the scope of this guideline 7. How can we prevent severe hyperbilirubinemia? (13, 14) 1. All women should be encouraged to breastfeed 8 to 12 times a Neonatal Jaundice, NICE Adopted day 2010; updated May 2016 2. Supplementation is recommended only for dehydrated newborns and Clinical practice

and where weight loss from birth is >10%. Expressed breastmilk is guideline the preferred supplementation. Subcommittee on 27

3. Routine supplementation with intravenous fluids, honey or Hyperbilirubinemia dextrose water for newborns with jaundice is not recommended Management of 4. No interruption of breastfeeding should be done for any jaundice. Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation, AAP 2004 2. Management and treatment 2.1 Phototherapy for the management of hyperbilirubinemia • Phototherapy can be delivered by light - emitting diode (LED) or Neonatal Jaundice, NICE Adopted

fibreoptic or fluorescent lamps or tubes or bulbs.# 2010; updated May 2016 • Do not use sunlight as treatment for hyperbilirubinaemia. Exposing the baby to sunlight does not help in treatment of jaundice and is associated with risk of sunburn and therefore should be avoided. For starting phototherapy • Use serum bilirubin levels ONLY for decision making for starting Clinical practice guideline Adopted phototherapy Subcommittee on

• Intensive phototherapy must be ensured for neonates nearing Hyperbilirubinemia exchange transfusion threshold. Phototherapy can be intensified Management of by adding another light source or increasing the irradiance of the Hyperbilirubinemia in the initial light source used. Newborn Infant 35 or • Phototherapy thresholds presented on seventh day may be used More for rest of the neonatal period Weeks of Gestation, AAP 2004

• It is not necessary to measure spectral irradiance before each use Clinical A d o p t e d of phototherapy; however it is important to perform periodic practice guideline checks of phototherapy units to make sure that an adequate Subcommittee on irradiance is being delivered Hyperbilirubinemia Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation, AAP 28

2004 For stopping phototherapy • There is no standard for discontinuing phototherapy. For infants Clinical practice guideline Adopted who are readmitted after their birth hospitalization (usually for Subcommittee on TSB levels of 18 mg/dL or higher), phototherapy may be Hyperbilirubinemia discontinued when the serum bilirubin level falls below 13 to 14 Management of mg/dL. Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation, AAP 2004 Discharge and follow up after phototherapy

• If phototherapy is used for infants with hemolytic diseases or is NNF Guidelines 2010 Adopted initiated early and discontinued before the infant is 3 to 4 days old, a follow-up bilirubin measurement within 24 hours after discharge is recommended. • For infants who are readmitted with hyperbilirubinemia and then discharged, significant rebound is rare, but a repeat TSB measurement or clinical follow-up 24 hours after discharge is a clinical option.

• Checking serum bilirubin 24 h after discharge to check for rebound is optional Tips for delivering safe and effective phototherapy • Protect the eyes with eye patches/covers Neonatal Jaundice, NICE Adapted with minor language • Keep the baby naked with a small nappy to cover the genitalia 2010; updated May 2016 changes to make the reading simple • Place the baby as close to the lights as the manufacturers’ instructions allow. • Routine position change while the baby is under phototherapy is

not recommended. • Phototherapy does not have to be continuous and can be interrupted for feeding, clinical procedures, and to allow maternal bonding. • Using white cloth or aluminum foil around the light source to reflect light back onto the baby, making sure not to impede the 29

airflow that cools the bulbs is optional • Do not place anything over the top of the phototherapy unit. This may block air vents or light and items may fall on the baby • Encourage frequent breastfeeding. Unless there is evidence of dehydration, supplementing breastfeeding or providing IV fluids is unnecessary • Giving frequent feeding will prevent excessive weight loss and temperature from rising • Visual assessment of jaundice during phototherapy is unreliable

• Ensure all phototherapy equipment is maintained and used according to the manufacturers’ guidelines. Failure of phototherapy • For those infants in the exchange or pre-exchange bilirubin zone, NNF Guidelines 2010 Adopted failure of phototherapy has been defined as an inability to observe a decline in bilirubin of 1-2 mg/dL after 4-6 hours and/or to keep the bilirubin below the exchange transfusion level. • Exchange transfusion is recommended if the TSB rises to these levels despite intensive phototherapy.

• For readmitted infants, if the TSB level is above the exchange level, repeat TSB measurement every 2 to 3 hours and consider exchange if the TSB remains above the levels indicated after intensive phototherapy for 6 hours. However, an exchange transfusion (ET) should be performed at the slightest suspicion of bilirubin encephalopathy irrespective of the bilirubin value. 2.2 Exchange Transfusion • Exchange transfusion should be done by central or peripheral Neonatal Jaundice, NICE Adopted

route aiming replacement of double the baby’s blood volume and 2010; updated May 2016 by skilled personnel in a well-equipped centre. • Immediate EBT is recommended if infant shows signs of ABE or if TSB is ≥25 mg/dL above the recommended age and risk specific cut off TSB • For Rhesus isoimmunization, the best choice would be O (Rh) negative packed cells suspended in AB plasma. O (Rh) negative whole blood or cross-matched baby’s blood group (Rh negative) 30

may also be used. • For ABO isoimmunization, O group (Rh compatible) packed cells suspended in AB plasma or O group whole blood (Rh compatible with baby) should be used. • In other situations baby’s blood group should be used. All blood must be cross matched against maternal plasma. • Blood volume used: 2 x (80-100 ml/kg) x birth weight in kg. 2.3 Other modalities for management of hyperbilirubinemia

• No role of phenobarbitone, tin mesoporphyrin, Agar, Albumin, Neonatal Jaundice, NICE Adapted the recommendation on charcoal, cholestyramine, clofibrate, glycerine, chinese herbs, 2010; updated May 2016 Intravenous immunoglobulin (IVIg) in homeopathy, acupuncture, riboflavin or manna in management of light of a recent systematic review hyperbilirubinemia (29). • Routine use of Intravenous immunoglobulin (IVIg) for Rh haemolytic disease of newborn and ABO disease is not

recommended as evidence from studies with low risk of bias indicates no benefit in Rh haemolytic disease of newborn and studies suggesting benefit in ABO incompatibility had a high risk of bias. (26) 2.4 What information and support should be given to parents/carers of babies with neonatal hyperbilirubinaemia? Offer parents or care givers information about neonatal jaundice but Neonatal Jaundice, NICE Adopted should be tailored to their needs and expressed concerns. This 2010; updated May 2016

information should be provided through verbal discussion backed up by written information whenever possible. (14) Care should be taken to avoid causing unnecessary anxiety to parents or care-givers. Information should include: • factors that influence the development of significant hyperbilirubinaemia • how to check the baby for jaundice • what to do if they suspect jaundice • the importance of recognizing jaundice in the first 24 hours and of seeking urgent medical advice

• the importance of checking the baby’s nappies for dark urine or pale chalky stools 31

• the fact that neonatal jaundice is common, and reassurance that it is usually transient and harmless when treated appropriately • reassurance that breastfeeding should continue Information about treatment including phototherapy • anticipated duration of treatment • reassurance that breastfeeding, nappy-changing and cuddles can usually continue. • Encourage mothers of with jaundice to breastfeed frequently, and to wake the baby for feeds if necessary.

• Provide lactation/feeding support to mothers whose baby is visibly jaundiced. • why phototherapy is being considered • why phototherapy may be needed to treat significant hyperbilirubinaemia • the possible adverse effects of phototherapy • the need for eye protection and routine eye care • reassurance that short breaks for feeding, nappy changing and cuddles will not alter course of jaundice and efficacy of phototherapy • what might happen if phototherapy fails • rebound jaundice

• potential long-term adverse effects of phototherapy Information on exchange transfusion • Offer parents or care givers information on exchange transfusion including: • the baby be admitted to an intensive care bed • why an exchange transfusion is being considered • the possible adverse effects of exchange transfusions • when it will be possible for parents or care givers to see and hold the baby after the exchange transfusion. • when it will be possible for parents or care givers to see and

4. Burke BL, Robbins JM, Bird TM, Hobbs CA, Nesmith C, Tilford JM. Trends in hospitalizations for neonatal jaundice and kernicterus in the United States, 1988–2005. Pediatrics. 2009;123:524–32. 5. Tomashek KM, Crouse CJ, Iyasu S, Johnson CH, Flowers LM. A comparison of morbidity rates attributable to conditions originating in the perinatal period among newborns discharged from United States hospitals, 1989–90 and 1999–2000. Paediatr Perinat Epidemiol. 2006;20:24–34.

6. Mwaniki MK, Atieno M, Lawn JE, Newton CR. Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review. Lancet. 2012;379:445–52. 7. Gladstone M. A review of the incidence and prevalence, types and aetiology of childhood cerebral palsy in resource-poor settings. Ann Trop Paediatr. 2010;30:181–96. 8. Amin SB, Smith T, Wang H. Is neonatal jaundice associated with autism spectrum disorders: a systematic review. J Autism Dev Disord. 2011;41:1455–63.

9. Olusanya BO, Somefun AO. Sensorineural hearing loss in infants with neonatal jaundice in Lagos: a community-based study. Ann Trop Paediatr. 2009;29:119–28. 10. Maulik PK, Darmstadt GL. Childhood disability in low- and middle-income countries: overview of screening, prevention, services, legislation, and epidemiology. Pediatrics. 2007;120Suppl 1:S1–55. 11. Olusanya BO, Ogunlesi TA, Kumar P, Boo NY, Iskander IF, Almeida DF, Vaucher YE, and

Slusher TM. Management of late-preterm and term infants with hyperbilirubinaemia in resource-constrained settings. BMC Pediatr. 2015; 15: 39. 12. Bhutani VK, Zipursky A, Blencowe H, Khanna R, Sgro M, Ebbesen F, et al. Neonatal hyperbilirubinemia and Rhesus disease of the newborn: incidence and impairment estimates for 2010 at regional and global levels. Pediatr Res. 2013;74 Suppl 1:86–100. 13. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of

hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004 Jul; 114(1):297-316. 14. Neonatal Jaundice 2010 Available at https://www.nice.org.uk/guidance/cg98/evidence/full-guideline-245411821. Accessed on 18 May, 2016 15. Narang A, Gathwala G, Kumar P. Neonatal jaundice: an analysis of 551 cases. Indian Pediatr 1997;34:429-32. 16. Olusanya BO, Ogunlesi TA, Slusher TM. Why is kernicterus still a major cause of death

and disability in low and middle-income countries? Arch Dis Child. 2014;99:1117–21. 17. Bhutani VK, Johnson LH. Managing the assessment of neonatal jaundice: importance of timing. Indian J Pediatr. 2000 Oct; 67(10):733-7. 33

18. Bhutani VK, Cline BK, Donaldson KM, Vreman HJ. The need to implement effective phototherapy in resource-constrained settings. Semin Perinatol. 2011;35:192–7. 19. Cline BK, Vreman HJ, Faber K, Lou H, Donaldson KM, Amuabunosi E, et al. Phototherapy device effectiveness in Nigeria: irradiance assessment and potential for improvement. J Trop Pediatr. 2013;59:321–5. 20. Pejaver RK, Vishwanath J. An audit of phototherapy units. Indian J Pediatr. 2000;67:883– 4.

21. Owa JA, Ogunlesi TA. Why we are still doing so many exchange blood transfusion for neonatal jaundice in Nigeria. World J Pediatr. 2009;5:51–5. 22. NNF 2010. Available at http://aimaonline.org/iap-neochap-2013/uploads/acd- corner/nnf_guidelines-2011.pdf. Accessed on 18th May, 2016 23. ABM clinical protocol #22: guidelines formanagement of jaundice in the breast feeding infant equal to or greater than 35 weeks' gestation. Academy of Breast Feeding

Medicine Protocol Committee. Breastfeed Med. 2010 Apr; 5 (2):87-93. 24. KJ Barrington, K Sankaran; Canadian Paediatric Society, Fetus and Newborn Committee Abridged version: Guidelines for detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants. Paediatr Child Health 2007;12(Suppl B):1B-12B 25. Recommendations on Newborn health. Approved by the WHO Guidelines review Committee. http://www.who.int/maternal_child_adolescent/documents/guidelines-

recommendations-newborn-health.pdf. Accessed 18th September 2015 26. Neonatal jaundice: prevention, assessment and management. Queensland Maternity and Neonatal clinical guideline. Accessed 18th September 2015 https://www.health.qld.gov.au/qcg/documents/g_jaundice5-1.pdf. 27. Kramer LI. Advancement of dermal icterus in jaundiced newborn. Am J Dis Child 1969;118: 454-8. 28. Bhutani VK, Stark AR, Lazzeroni LC, Poland R, Gourley GR, Kazmierczak S, Meloy L,

Burgos AE, Hall JY, Stevenson DK; Initial Clinical Testing Evaluation and Risk Assessment for Universal Screening for Hyperbilirubinemia Study Group. Predischarge screening for severe neonatal hyperbilirubinemia identifies infants who need phototherapy. J Pediatr. 2013 Mar;162 (3):477-482 29. Louis D, More K, Oberoi S, Shah PS. Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and meta-analysis.

Arch Dis Child Fetal Neonatal Ed. 2014 Jul; 99(4):F325-31. Epub 2014 Feb 10. 34

STANDARD TREATMENT GUIDELINES FOR ORTHOPAEDICS Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 THE INFECTION OF BONES AND JOINTS 4 2 OSTEOARTICULAR TUBERCULOSIS 7 3 TUBERCULOSIS OF SPINE 13 4 DEGENERATIVE CERVICAL SPODYLOLYSIS 20 5 DISTAL HUMERUS FRACTURES IN ADULTS 23 6 UPPER LIMB FRACTURES FRACTURE OF BOTH BONES FOREARM IN ADULTS 26 7 FRACTURE OF SHAFT OF THE HUMERUS 29 8 RADIAL HEAD FRACTURE 33 9 HAND INJURIES 36 10 LONG LIMB TRAUMA FRACTURE NECK OF FEMUR (INTRA-CAPSULAR) 39 11 TROCHANTERIC FRACTURES (EXTRA-CAPSULAR FRACTURE NECK FEMUR) 49

12 FRACTURE SHAFT OF FEMUR 56 13 FRACTURE OF TIBIA/FIBULA 59 14 PROTOCOL FOR THE MANAGEMENT OF PELVIC FRACTURE 65 15 SPINAL INJURY 77 16 THE NEUROLOGICAL DISORDERS: POLIOMYELITIS AND CEREBRAL PALSY. 101 17 ANKYLOSING SPONDYLITIS 111 BONE TUMOURS, TUMOUROUS CONDITIONS & DEVELOPMENTAL DISORDERS 18 MIMICKING BONE 116 19 GOUTY ARTHRITIS 127 20 OSTEOARTHRITIS 132 21 OSTEOMALACIA 138 22 OSTEOPOROSIS 143 23 RHEUMATOID ARTHRITIS 149 24 RICKETS 156 2

Group Head Coordinates of Development Team Dr. P.K. DAVE, Rockland Hospital, New Delhi Dr. P.S. Maini, Fortis Jessa Ram Hospital, New Delhi Reviewed By Dr. V.K. SHARMA Professor Central Instiute of Orthopaedics Safdarjung Hospital New Delhi 3

THE INFECTION OF BONES AND JOINTS The common infection of bones and joints are mainly due to phylogenic organisms, tuberculosis or rarely brucellosis. 1. When to suspect/recognize A. Introduction The common infection of bones and joints are mainly due to pyogenic organisms. It usually occurs in small children in the metaphysical regions of long bones, usually to a focus of infection elsewhere in the body through hematogenous/ lymphatic. The

offending organisms are staphylococcus commonly: other organisms are less common like streptococcus, Ecoli etc. The bacteria get lodged in the metaphysis where they continue to grow, block small vessels which causes necrosis of bone. Pus focus rapidly which may transverse laterally under the periostenum, form an abscess or may even burst on the surface. This is the tone when treatment should be started aggressively lest it should get converted into chronic osteomyelitus. B. Definition

Osteomyelitus is an acute or chronic inflammatory process. Within bone, bone marrow and surrounding soft tissue that develops. Secondary to infection with bacterial organisms (and rarely fungi). ii) Incidence of the condition in our country It is very common condition in our country iii) Differential diagnosis - Cellulitis - Ewing’s Sarcoma - Osteosarcoma - Arthritis iv) Prevention and counseling – early diagnosis and treatment Can prevent considerable morbidity. 4

v) Optimal diagnoster criteria, investigation, treatment and Referral criteria. Situation 1:- At secondary hospital/Non-Metro situation: limited technology and resources. a. Clinical Diagnosis Signs of acute inflammation High temperature Rapid pulse Extreme degree of pain (Rest/movement) Local tenderness b. Investigation Complete hemogram, culture and sensitivity of aspirated material, ZN staining, Gram’s staining. Simple radiograph Xray Sinogram c. Treatment

- Rest – The limb of the patient to be put on rest - Antibiotic – broad specters antibiotic to be started fi to be Changed according to culture and sensitivity - Out patient – if abscess is present regardless of the stage of disease effective drainage is to be done. - Day Care – Multiple drill holes, rectangular window, thorough Debridement - In patient – Immobilization, saucerisation, IV antibiotic, sequestrectomy - Referral Criteria – No improvement in patients, general condition, deterioration

of patients, conditions and other associated complications Situation 2:- Super specialty facility in metro location where higher end technology is available. a. Clinical Diagnosis – Signs of acute inflammation, high temperature, rapid pulse, extreme degree of pain, Local tenderness b. Investigations:- Complete hemogram, Blood Culture, culture and sensitivity of aspirated material, ZN staining, Gram’s staining. Radiograph Xray Sinogram 5

Bone scan CT Scan ELISA against different antigens of organisms and antibody detection in serum Histopathological study i) FNAC ii) Open Biopsy MRI Radioisotope labeled Leukocyte scanning PET scanning c. Treatment - Rest – The limb of the patient to be put on rest - Antibiotic – broad spectrum antibiotic to be started fi antibiotics to be according to sensitivity - Out patient – if abscess is present regardless of the stage of disease effective drainage is to be done.

- Day Care – Multiple drill holes, rectangular window, thorough debridement - In patient – Immobilization, saucerisation, IV antibiotic, sequestrectomy - Referral Criteria – No improvement in patients, general condition, deterioration of patients, conditions and other associated complications Who does what:- Doctor:- Early diagnosis and treatment The diagnosis and treatment is to be started as early as possible. Delaying the treatment can only increase the severity of the disease. Sometimes patient need to

be referred. Nurse:- Patient care The patient need to be hospitalized in the early stages of the disease to avoid chronicity of the disease for proper patient care. Technician:- Investigation In doubtful cases proper investigation to be done in quick time and in a proper way to avoid contamination of the samples. 6

OSTEOARTICULAR TUBERCULOSIS INTRODUCTION For purposes of description osteoarticular tuberculosis can be discussed under the following heads: • Tuberculosis of joints • Bone tuberculosis • Spine tuberculosis Infection of a joint or bone with Mycobacterium tuberculosis is almost always secondary to a primary focus, in the lymphatic glands or lungs or mesentery, from where it disseminates by hematogenous route. Malnutrition or any debilitating disease, poor environment increase the

incidence of the disease. Patients with immunodeficiency disease or HIV infection are more prone to develop tuberculosis. Involvement of any bone or joint in the body can be affected by tuberculosis. Case definition the lesion in the joint can be: i. Extra-articular ii. Intra-articular: It can originate in the bone (osseous lesion) or in the synovium (synovial disease). Vertebral body involvement with tuberculosis is the most common and is nearly equal to tuberculosis of all other regions put together.

There may be a history of trauma, under the effect of which a small hematoma may form resulting in vascular stasis in that area. The hematoma may become a nidus for the tubercle bacilli to settle down and form a tubercolosis follicle with caseation, epitheloid cells, gaint cells and fibrosis at the periphery. The lesion in the bone is essentially a lytic lesion which is evident radiologically, unlike in pyogenic infection which is characterized by intense sclerotic activity. As the tuberculous lesions

heal, sclerosis takes place. At certain sites like the short long bones and in hand and feet or the clavicle, there is intense sclerotic activity by layer of subperiosteal bone and is characteritic of a tuberculous lesion. The tuberculous pus formed in the medullary canal may travel distally or laterally thus lifting the periosteum, may form an abscess and even burst giving rise to a tuberculous sinus. Multifocal tuberculous is somewhat common and is occasionally. 7

The response to a tuberculous lesion is exudative and may form a cold abscess, which is nothing but a collection of necrotic material caseous tissue and the exudative reaction. These cold abscesses than track through the fascial planes or the neurovascular bundles and may present at a distant site. Since the abscess is away from the area of inflammatory activity, it has no signs of inflammation in the skin overlying the abscess. A superficial abscess may burst and result into a sinus or an ulcer.

Granulation tissue is almost always present in the tuberculous lesion. Ischemic necrosis of bone due to endarteritis and thromboembolic phenomenon in bone lead to formation of sequestra, which in osseous tuberculosis happen to be small. Isolated large sequestrate in osteroarticular tuberculosis are rare. Incidence of condition in our country It is an extremely common condition in our country and is seen in all strata of society. Differential Diagnosis

It can mimic almost any condition seen in bone like chronic osteomyelitis, osteoid osteoma, fibrous dysphasia, malignant/benign tremors. Prevention and Counseling In case of pain, swelling, night cries fever an orthopedics surgeon may be consulted. Referral criteria In case of the symptom like swelling discharging sinuses, paraplegia or the disease not responding to standard anti tubercular drugs the patient may be referred to a higher centre. Situation 2:- Clinical Diagnosis

The tuberculosis of the joints mainly involves big joints. The common differential diagnosis includes pauciarticular juvenile chronic arthritis and septic arthritis. The involvement of joint may be osseous or synovial but if not treated, one would infect the other. Tuberculous synovitis leads to effusion in the joint and synovial membrane becomes edematous. At this stage the joint would look swollen and movements may be present or limited due to muscle spasm. The

radiological picture may show an increased joint space. Later on, the granulation tissue may extend from the periphery on to the articular cartilage or in the subchondral region in the form of a pannus thus eroding it. Once the articular cartilage is eroded there is tremendous muscle spasm and all movements are restricted. Because of the destruction of the articular cartilage the joint space on X-ray looks diminished.

When the lesion is osseous it involves the subchondral bone which also leads to erosion of the cartilage. The lesion may start from the epiphysis in children or may be metaphyseal in origin. When the disease begins to heal, fibrosis occurs across the joint leading to a fibrous ankylosis. At this stage the movements of the joint are restricted and may be painful. There is considerable 8

muscle spasm which may produce a deformity at the joint. Prolonged muscle spasm may lead to subluxation or dislocation of the joint causing further deformity and shortening. If sinus has formed, secondary infection may be superimposed on the tuberculous infection. Fibrous ankylosis may be converted into bony ankylosis either due to complete healing or new bone formation due to superadded pyogenic infection. There are no movements in the joint after

bony ankylosis and it is also painless. Radiologically, in bony ankylosis the trabeculae are seen to be crossing the joint line. CLINICAL FEATURES It is characteristically insidious in onset, and starts as monoarticular or mono-osseous involvement. The child complains of pain in the joint, aggravated by movement, and often wakes ‘up at night because muscle spasm gets reduced and causes pain. It is classically called as “night cries”. Low- grade fever, loss of weight and appetite are some of the symptoms of

generalized toxemia usually seen. Joint movements are painful and elicit muscle spasm on attempted movement. In later stages when the cartilage gets eroded, all movements get restricted. Muscle atrophy around the joint is a predominant feature and occurs early. Sometimes an abscess forms which bursts to form a sinus. It may get secondarily infected and may alter the radiological picture. INVESTIGATIONS i) Blood A low hemoglobin, relative lymphocytosis and raised erythrocyte sedimentation rate

(ESR) are often found in the active stage of the disease. The ESR is often used as a guide in monitoring the progress of the disease during treatment, though some people do not consider it a reliable investigation. ii) Mantoux Test A positive Mantoux test is seen in patients with active tuberculous lesion. A negative test may rarely be seen in severe or disseminated disease or in an immunocompromised patient. iii) Radiographic Examination

It can be diagnostic in view of the typical radiological appearance of the tuberculous lesions. In early stage of the joint disease, capsular markings may become prominent. The earliest sign is widespread osteoporosis around a joint. Lytic lesion and periosteal reaction are seen, although latter is much more prominent in pyogenic infection. In case of joints, small bone erosions occur near the capsular reflection. Joint space

decreases due to cartilage erosion and lytic lesions are seen in the epiphyseal area. The radiological signs of a healing lesion are absence of rarefaction and bony ankylosis. iv) Smear and Culture 9

Tuberculous pus, joint aspirate, granulation tissue, sputum etc. may be examined by smear and culture for tuberculous bacilli. The culture and sensitivity tests for various anti fuberculosis drugs also help in giving appropriate chemotherapy in resistant cases or cases of multi-drug resistant tuberculosis; which are seen quite frequently in today’s clinical practice. FNAC (Fine Needle Aspiration Cytology) Occasionally, even the most modern methods of imaging may not help the clinician to reach to a

final diagnosis, and therefore FNAC or biopsy may be undertaken to obtain tissue diagnosis. FNAC is now available for the cytological diagnosis of vertebral tuberculosis. ‘Biopsy is a safe and a quick diagnostic procedure with high accuracy in the hands of trained cytopathologists. It recommended that it should be practiced in all diagnostic centres of our country, even for suspected vertebral tuberculosis. BIOPSY Biopsy may have to be done in cases where there is doubt about the diagnosis, particularly in

the early stages of the disease. Biopsy from the bone or synovium can provide an early diagnosis for timely starting the treatment and preventing damage to the joint. Biopsy from a cystic lesion in bone or from synovium is more likely to be positive. Investigations should also be done to find out the primary focus of the disease. An X-ray of the chest should always be done. Some other investigations may include: sputum smear

examination and culture, routine urine examination for isolation of tubercie bacilli and an intravenous pyelogram for ruling out pulmonary and genitourinary lesions, respectively. TREATMENT The patient’s response to treatment is variable as anywhere else in the body and is dependent upon the host resistance, severity of infection, and the stage of the disease when the diagnosis is first made and treatment started. Eradication of the disease and preservation of function are

important both in osseous and joint diseases. In case of joints, joint mobility and stability are also the early goals to be achieved. It is possible only if treatment is started early, i.e. when the disease is limited only to synovium. In case the articular cartilage is eroded the joint becomes unsalvageable in terms of function, mobility and stability. In such a situation the aim of treatment is to achieve a sound bony ankylosis which is painless and gives stability, although the

patient will not have movements at that joint. GENERAL MEASURES Good nutrition consisting of a high-calorie and high-protein diet is essential to build up the resistance. General rest and local rest to the specific bone and joint are essential parts of the treatment. Local rest can be provided by means of splints or plaster casts. However, in cases where the articular surface is not involved a judicious blend of rest and mobilization exercises have to be resorted for restoration of function. 10

CHEMOTHERAPY Most of osteoarticular lesions would respond to antituberculous drugs if the therapy is started early. However, in case of persistently draining sinuses which are secondarily infected, suitable broad spectrum antibiotics have to be given. About 15% of patients do not respond to chemotherapy alone if the lesion contains much caseation and sequestra. In such situations excision of the diseased focus not only removes the diseased toxic material but also increases vascularity and

allows the anti-tuberculosis drugs to reach the site of the lesion. A standard drug regimen is given which includes rifampicin, pyrazinamide, ethambutol, isoniazid, and in some cases even streptomycin. The latter is useful because it kills the rapidly multiplying extracellular tubercle bacilli in the lungs for the initial six months. After two clinically and radiologically, pyrazinamide is stopped and isoniazed, rifampicin and ethambutol

are continued for one year. In some cases therapy may be required for 18 months for complete healing of the lesion. In case the infection is suspected to be with multidrug resistant ofloxacin, capreomycin, kanamycin, etc. may have to be given. SURGICAL TREATMENT Surgical treatment is an adjunct to the anti-tuberculosis drug therapy. It cannot be a substitute for the prolonged course of the drug therapy. Surgical treatment has become safe with the

advent of powerful anti-tuberculosis drugs and one is no longer scared of a flare up of the lesion. However, a trail of conservative treatment must be given before surgical treatment is undertaken. The indications for surgery are specific and are as follows:  Doubtful diagnosis requiring excision of the focus or curettage of the lesion.  An abscess or a lesion increasing in spite of adequate chemotherapy.  Synovitis not involving the articular cartilage; synovectomy should be done to prevent

the latter from getting eroded.  Curettage of a lesion in proximity of the articular cartilage to prevent the latter from getting involved.  Spinal tuberculosis with paraplegia: The surgical procedures generally perfomed in children are:  Drainage of an abscess  Excision of a focus  Curettage of the lesion  Synovectomy  Costotransversectomy  Anterolateral decompression 11

The general principle of surgery in tuberculosis demands that the abscess should be completed evacuated. In case of an osseous lesion, all sequestra, granulation tissue and caseous material should be removed till new bleeding bone is encountered, so that the antibiotics may reach the site of lesion better. The cavities so produced should be packed with autogenous bone grafts. Avoid dead spaces to prevent hematoma formation and close the wound primarily with or without suction.

Tuberculosis can involve any bone or joint of the body but in children it has a special predilection for the hip and knee joints commonly, and for ankle and elbow joints rarely. Tuberculosis of spine with or without paraplegia is extremely common. Long bones are rarely involved but the short long bone involvement is somewhat common. Referral Criteria No need to refer anywhere since the patient is already in a tertiary care hospital. Who does What Doctor – Diagnosis, chemo therapy advice and surgery

Nurse – General care like nutrition advise, care of the wounds. Technician – Radiographic examination microbiological examination. 12

NAME OF CONDITION: Tuberculosis of Spine I. WHEN TO SUSPECT/ RECOGNIZE? Introduction: India is classified as a country with a high burden and the least prospects of a favourable time trend of the disease. The average prevalence of all forms of tuberculosis in India is estimated to be 5 per thousand. Skeletal tuberculosis is found in 1 to 3 % of these cases. Spine might be involved in upto 50% of these cases. Neurological complications and progressive deformity are the dreaded

complications of tuberculosis of spine. It is imperative to diagonose this condition early and initiate early medical treatment while recognising and treating patients requiring surgical interventions for optimal outcomes. Case definition: For both situations of care (mentioned below*) II. INCIDENCE OF THE CONDITION IN OUR COUNTRY. The average prevalence of all forms of tuberculosis in India is estimated to be 5 per thousand Skeletal system involvement occurs in 1% to 3% of the patients and up to 50% of

these affected patients have TB of the spine III. DIFFERENTIAL DIAGNOSIS Tumours of spine Traumatic conditions Other infectious afflictions of spine like brucella, pyogenic . IV. PREVENTION AND COUNSELING Prevention would entail measures as for other forms of tuberculosis. Osteoarticular tuberculosis is always secondary, so primary infection should be treated effectively for sufficient time. Once diagnosed, close follow up, regular anti tubercular treatment and aggressive surgical approach may prevent

dreaded complications V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA 13

*Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited Clinical Diagnosis: The presentation depends on the following: Stage of disease Affected site Presence of complications Back pain is the earliest and most common symptom. Any back pain not responding to conservative treatment for more than 6 weeks and/or accompanied by constitutional symptoms should be investigated further

Neurologic abnormalities occur in 50% of cases and can include paraplegia, paresis, impaired sensation, nerve root pain. Patients with cervical spine disease can present with dysphagia or stridor.Symptoms can also include torticollis, hoarseness, and neurologic deficits. The examination should include the following: Assessment of spinal deformity Inspection of skin, with attention to detection of sinuses and subcutaneous mass indicating cold abscess Meticulous neurologic examination a) Investigations:

The erythrocyte sedimentation rate (ESR) is elevated. IgM for mycobacterium tuberculosis can be done.HIV status should be confirmed. Microbiology studies can be used to confirm diagnosis. Aspirates of cold abscees can be obtained to stain for acid-fast bacilli (AFB). The following are radiographic changes characteristic of spinal tuberculosis o Paradiscal involvement with decreased disc space o Increased anterior wedging o Collapse of vertebral body 14

o Enlarged psoas shadow with or without calcification o Fusiform paravertebral shadows suggest abscess formation. b) Treatment: . Goals of management in active tuberculosis Eradication/ Control of Disease Decompression of spinal cord Prevention of progressive deformity and later neurological complications Early mobilization of the patient. • Treatment options Chemotherapy alone (long course is preferred) Surgery with Chemotherapy Antero-Lateral Decompression Antero-Lateral Decompression + post fusion

Antero-Lateral Decompression + strut grafting+post fusion Ant. Decompression + strut grafting+posterior instrumentation Ant. Decompression + strut grafting + instrumentation Standard Operating procedure a. In Patient In patients without deficit,chemotherapy alone is sufficient if the risk of progressive deformity is not there. Inpatient care might be needed initially for patients who are undergoing treatment to ensure rest and monitor response to ATT.

A close watch on development of neurological symptoms is to be kept and at signs of deterioration, the patient may be referred. b. Out Patient Patients on ATT are to be followed closely for progression of deformity and deterioration of neurological deficit c. Day Care Patients needing drainage of cold abscess may be kept in day care. c) Referral criteria: Failure to respond to conservative treatment Deformity/risk of progresion Recurrence of the disease Doubtful diagonosis Severe neurologic symptoms 15

Progressive neurologic symptoms inspite of ATT Unsuccessful nonoperative treatment Instability with spinal deformity, Spinal tumour syndrome. *Situation 2: At Super Specialty Facility in Metro location where higher- end technology is available a) Clinical Diagnosis: As described above in situation 1 b) Investigations: Routine blood investigation,Tb-PCR, In MDR Tb-culture and sensitivity MRI is the most effective imaging study for demonstrating neural compression.

MRI is standard for evaluating disk-space infection and osteomyelitis of the spine and is most effective for demonstrating the extension of disease into soft tissues and the spread of tuberculous debris under the anterior and posterior longitudinal ligaments. CT scanning provides much better bony detail of irregular lytic lesions, sclerosis, disk collapse, and disruption of bone circumference. CT guided biopsy maybe done in case of doubtful diagonoses. c) Treatment: Standard Operating procedure

a. In Patient Tuberculosis spine with no neurological deficit Chemotherapy alone is sufficient if there is no risk of progressive deformity Efforts should be made to identify patients who are at risk of developing kyphosis in active disease. Growing children with dorsal and dorsolumbar caries with more than 3 body involvement or in which there is destruction more than 1.5 times the vertebral body height are at risk of kyphosis. Indications of surgery Failure to respond to conservative treatment

Doubtful diagonosis Tuberculosis spine with neurological deficit Middle path regime In patients with mild deficit trial of chemotherapy can be done, however a close observation is must Indications for surgery for management of tuberculosis with deficit Severe neurologic symptoms Progressive neurologic symptoms Unsuccessful nonoperative treatment Instability with spinal deformity, Spinal tumour syndrome. Operative treatment of tuberculosis spine

§ Anterolateral decompression alone will lead to control of disease and adequate decompression but there might be progression of kyphotic deformity § ALD should ideally be accompanied by posterior fusion and anterior structural graft.By providing structural support and by its osteogenic potential, the graft may prevent progression of kyphosis. § Anterior debridement and arthrodesis by graft only may result in permanent kyphotic deformity as a consequence of fracture of the graft, slippage of the graft

out of its bed, resorption of the graft,or subsidence of the graft into the cancellous vertebral bodies. Anterior grafting procedure should be accompanied by instrumentation either anterior or posterior. § Instrumentation has been shown to be safe in tuberculosis and it helps in stability of graft, early fusion and rapid mobilisation of the patient. § Anterior structural graft that can be used are tricortical iliac crest, fibula, ribs or bone impregnated titanium mesh.

§ Direct anterior approach (transthoracic, retroperitoneal) is a formidable procedure and intensive care facilities should be available. § In a healed disease, severe kyphosis correction is fraught with danger as spinal cord has exhausted its reserve. 17

b. Out Patient Regular follow up of operated patients as well as patients on conservative treatment. At each follow-up detailed neurological examination should be performed and serial x rays should be taken and deformity progression should be noted. Regular biochemical investigations for monitoring ATT c. Day Care For drainage of cold abscesses when needed. d) Referral criteria: Not applicable VI. WHO DOES WHAT? and TIMELINES a. Doctor Clinical diagnoses Investigations Clinical decision making

Surgical procedure Maintenance of record and follow up b. Nurse Councelliung Surgical assistance c. Technician Investigations Helps in surgery Orthosis VII. FURTHER READING / REFERENCES 1. Tuberculosis of skeletal system: SM Tuli 2. MSMoon Tuberculosis of the spine. Controversies and a new challenge: Spine 1997: 1791-1797 3. AK Jain Tuberculosis of the spine: a fresh look at an old disease:J Bone Joint Surg Br. 2010 Jul;92(7):905-13.

4. AK Jain .Treatment of tuberculosis of the spine with neurologic complications. Clin Orthop Relat Res. 2002 May;(398):85-92. 5. Rajasekaran S: The problem of deformity in spinal tuberculosis.Clin Orthop Relat Res. 2002 May;(398):75-84. . 18

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 Orthopedic X rays ATT surgeon Microbiology and Braces biochemistry labs 2 Team of X rays ATT Well equipped surgeons with CT OT inventory OTS with ICU training in MRI Spinal backup. spinal surgery Microbiology with instrumentation

Nurses for OT provision for assistance, advances culture ward work techniques and OPD Biochemistry follow up 19

DEGENERATIVE CERVICAL SPODYLOLYSIS Clinical Diagnoses Degenerative cervical spodylolysis may present as axial neck pain,cervical radiculopathy,cervical myelopathy or a combination of these. Patient complaints should be carefully correlated with physical examination and imaging results for correct diagnosis and appropriate management All differential diagonoses like peripheral neuropathy, motor neuron disease, amyotrophic lateral sclerosis, multiple sclerosis, CVA, syringomyelia, tumors:

intrinsic to spinal cord or extrinsic must be ruled out. Indications and Timing of surgery There is a definite role of conservative management in neck pain and radiculopathy with minor sensory symptoms. Patients with very mild and subtle signs of myelopathy can be managed conservatively but close observation and regular follow up is must. Once moderate signs and symptoms of myelopathy develop patients are less likely to improve on their own and surgical intervention is required.

Manipulation and traction are not recommended in myelopathy because of potential risk of aggravating neurological deficit Indications for surgery in degenerative disease of cervical spine – Cervical spondylotic myelopathy – Radiculopathy with a significant motor deficit – Radicular pain not responding to conservative treatment – Intractable Neck pain due to pseudarthrosis Choice of Surgical approach The decision of which surgical approach is to be used should be based on:

2. Number of vertebral segments involved 3. Cervical alignment 4. Coexisting neck pain 5. Comorbidities 6. Previous surgeries 7. Surgical skill and facilities. Primary focal ventral pathology causing cord compression is best treated by anterior approach. Primary posterior compression related to facet hypertrophy and ligamentum flavum should be tackled by posterior approach In multisegmental pathology(>3 levels) In presence of lordotic spine either posterior approach or anterior approach should

be considered. In presence of kyphotic spine anterior approach is to be considered. Only posterior approach is contraindicated. Supplemental posterior procedure may be needed in multilevel corpectomy Anterior approach Anterior plating improves the rate of fusion, reduces the length and type of postoperative immobilization, reduces the prevalence of graft-related complications, and leads to less postoperative kyphosis, particularly in patients

undergoing two or more levels of anterior cervical discectomy and fusion Autograft is superior to allograft in terms of fusion rates,duration to fuse and graft collapse. Long-term results will be needed before use of structural supports such as metallic cages or synthetic spacers in conjunction with local autograft or allograft can be unequivocally recommended.. Corpectomy may be preferable to multilevel ACDF especially in higher risk patients such as diabetics, smokers and revision cases.

In revision cases when a contralateral anterior approach is contemplated, preoperative laryngoscopy should be done to rule out subclinical vocal cord paresis on the previously treated side. 21

Cervical arthroplasty A promising new technology that may improve patient outcome following anterior cervical decompression. Possible indications are: 1. Monosegmental radiculopathy with mild spondylosis 2. Myelopathy due to single level disc herniation in absence of facet joint or posterior disease. Posterior approach Indicated in multisegmental pathology in a lordotic spine or posterior pathology. Only laminectomy without fusion is contraindicated as it might lead to sequalae

such as segmental instability, kyphosis, swan neck deformity, perineural adhesions etc. Laminoplasty or laminectomy with instrumented posterior fusion is the procedure of choice for cervical spondylotic myelopathy. Significant preoperative neck pain is a relative contraindication to laminoplasty and laminectomy with fusion may be preferred. The keyhole foraminotomy technique can be used for patients with unilateral radicular findings caused by a lateral or foraminal soft cervical disc herniation or

foraminal stenosis CSM is a disease of elderly and associated with significant postoperative morbidity and mortality. Patient and his/her attendants must be counselled regarding postop complications and possible requirement of ventilatory support. 22

DISTAL HUMERUS FRACTURES IN ADULTS 1. INCIDENCE:  3% of all fractures 2. CLASSIFICATION: AO Classification is the easiest to follow and contemplate on management: – Extraarticular – Avulsion Fragment – Simple Fracture – Comminuted – Partly Articular – Lateral Condyle Fracture – Saggital Plane – Medial Condyle Fracture – Sagittal Plane – Fracture in Frontal Plane. – Articular Fracture – Articular Simple Metaphyseal Simple – Articular Simple Metaphyseal Multifragmentary – Articular Multifragmentary

3. Diagnosis: History – Accident / Fall on Hand sustaining injury to Elbow. Pain around elbow joint which increases on movement Examination – Swelling, Deformity, Bruising, Tenderness, Crepitus, Instability. Check for any signs of Compartment Pressure Check for Distal Pulses & Neurological deficits, of Ulnar, Radial and Median Nerves 4. Investigations: X Ray – Elbow AP / Lateral View Traction View Special Tests – CT Scan – To delinate the fracture & plan Surgery especially in Intraarticular fractures

Compartment Pressure Monitoring in suspicious cases Ultrasound Doppler Study – to rule out vascular injury 23

Angiogram – If vascular injury is suspected MRI – rarely needed 5. Treatment: Initial Management – Splint the Limb with elevation & Ice Packs applc’n along with Anti-Oedema measures. Proper Management – a) Conservative – In Medically unfit patients – Cast / Bag of Bones Treatment b) Surgical – External Fixator – in Open Fractures Open Reduction & Internal Fixation (ORIF) - 3.5mm LCDCP - LCP – Anatomical Plates Total Elbow Arthroplasty – In cases with extreme intraarticular comminution 6. Complications:

 Postoperative infection  Nerve injury, especially ulnar nerve palsy  Vascular injury  Elbow stiffness  Hardware prominence  Loss of fixation  Nonunion  Malunion  Heterotrophic bone formation 7. When to Refer : • In cases with Polytrauma (Head / Chest / Abdominal / Pelvic Injuries) – “Life before Limb” • In cases with Vascular Injury – for Vascular repair • In cases with Neurological Injury – for Immediate / Delayed Nerve repair.  Relatively in B and C fractures if the facilities are not available

Comments: The common deficiency (a) The writing style is not consistent. Radial head fracture is given as 33% of elbow region while distal radius as 1/6 of fracture (not known) of what? 24

(b) Imaging – just mentioned AP, Lateral and sometime oblique. Why and for what a particular special x-ray is needed? (c) Complication has been clubbed as most common to least common, early or late in one list. This will not help. (d) When to refer – Generally written type B & C to higher center. Can we make such guidelines in the issue. The outcome of treatment depends on – a) Training of the surgeon. b) Infrastructure – operating theatre & available instrumentation

We need to define what all we should have in primary health center, secondary and tertiary care centre. If we refer all type B & C fracture for all fractures than how the patients in Village, Tehsil, District will be treated as we do not have any networking of referral centers (they are all concentrated in the cities. Summarily the objective of the guidelines should be well stated. Is it to stop small centers in cities to stop operating the particular type of fractures and force them to

refer or to make a national policy for the overall effective management of the orthopaedic patients? 25

UPPER LIMB FRACTURES Fracture of both bones forearm in adults INCIDENCE: 1% of all fractures CLASSIFICATION: AO CLASSIFICATION: TYPE A FRACTURE: simple fracture  A1- simple fracture of ulna and radius is intact  A2- simple fracture of radius and ulna is intact  A3- simple fracture of both radius and ulna TYPE B FRACTURE: wedge fracture  B1- wedge fracture of ulna and radius intact  B2-wedge fracture of radius and ulna intact  B3-wedge fracture of both radius and ulna TYPE C FRACTURE: complex fracture

 C1- ulna complex fracture and radius simple fracture  C2- radius complex fracute and ulna simple fracture  C3- complex fracture of both radius and ulna HISTORY: Fall on an outstretched hand or direct impact. DIAGNOSIS:  Tenderness and swelling of the forearm  Deformity  Abnormal mobility and crepitus at fracture site. INVESTIGATIONS:  Routine radiographs of forearm with elbow and wrist in AP and LATERAL views are helpful in diagnosis and to rule out injuries of joint above and below.

 Other investigations such as BLOOD ROUTINE, CHEST RADIOGRAPHS, ECG and ECHOCARDIOGRAPHY performed for working up the patient for surgery.  Doppler study done in case of suspected vascular injuries.  Thorough neurological examination to rule out any injury to nerves. 26

TREATMENT: Mostly operative NON OPERATIVE (in undisplaced fractures which are stable): If operative treatment is contraindicated because of the patient's poor general condition 1. Closed Reduction and Cast Immobilization 2. Functional Bracing for 6 weeks OPERATIVE: EXTERNAL FIXATORS- In case of open fractures with severe soft tissue damage and in maintaining length in fractures with severe bone loss. Later change into definitive fixation.

INTRAMEDULLARY NAILING- the anatomical reduction cannot be as accurate as can be achieved with plating. Plating of fractures of both bones is ideal either in LCDCP or LCP in osteoporotic fractures. PLATING- Most commonly used and permits accurate reduction of fracture. COMPLICATIONS:  Compartment syndrome  Malunion  Non union  Infection  Radio-ulnar synostosis  Plate removal and refracture  Neurovascular complications FRACTURES THAT NEED TO BE REFERRED TO HIGHER CENTRES:

 Open fractures with severe soft tissue loss  Fractures associated with bone loss and vascular injuries  Polytrauma patients after initial stabilization  Complex fractures Comments: The common deficiency (e) The writing style is not consistent. Radial head fracture is given as 33% of elbow region while distal radius as 1/6 of fracture (not known) of what? (f) Imaging – just mentioned AP, Lateral and sometime oblique. Why and for what a particular special x-ray is needed?

(g) Complication has been clubbed as most common to least common, early or late in one list. This will not help. 27

(h) When to refer – Generally written type B & C to higher center. Can we make such guidelines in the issue. The outcome of treatment depends on – c) Training of the surgeon. d) Infrastructure – operating theatre & available instrumentation We need to define what all we should have in primary health center, secondary and tertiary care centre. If we refer all type B & C fracture for all fractures than how the patients in Village, Tehsil, District will be treated as we do not have any networking of

referral centers (they are all concentrated in the cities. Summarily the objective of the guidelines should be well stated. Is it to stop small centers in cities to stop operating the particular type of fractures and force them to refer or to make a national policy for the overall effective management of the orthopaedic patients? 28

FRACTURE OF SHAFT OF THE HUMERUS INCIDENCE: Fractures of the humeral shaft account for roughly 3% of all fractures. CLASSIFICATION: AO classification Bone = humerus = 1 Segment = diaphysis = 2 Groups = A/B/C where A: Simple fracture B: Wedge fracture C: Complex fracture Subgroups: A1: Simple fracture, spiral A2: Simple fracture, oblique (≥30deg) A3: Simple fracture, transverse (<30deg) B1: Wedge fracture, spiral wedge B2: Wedge fracture, bending wedge B3: Wedge fracture, fragmented wedge

C1: Complex fracture, spiral C2: Complex fracture, segmental C3: Complex fracture, irregular HISTORY: Fall from a height or a direct impact as in vehicular accidents. DIAGNOSIS:  Swelling, pain and bruising are common features.  The arm may appear shortened and deformed if the fracture is significantly displaced.  Inability to extend the wrist (wrist drop) and sensory deficit over the base of the thumb on the dorsal aspect indicates an associated injury of the radial nerve.

 A thorough assessment of the peripheral neurovascular status is essential in all humeral shaft fractures.  Associated injuries to the shoulder and elbow joints are not uncommon.  X-rays (AP and lateral) of the entire humerus including the shoulder and elbow joint should be taken to confirm the diagnosis. 29

 CT is rarely indicated. COMPLICATIONS:  Nerve injury - Radial nerve palsy (upto 10%) is the most important complication.  Vascular injury - Injuries to the brachial artery have been reported in association with humeral shaft fractures. A careful assessment of the peripheral circulation is essential in all humeral fractures.  Non-union - In general, spiral or oblique fractures heal better than the transverse or segmental fracture. Soft tissue interposition, excessive fracture mobility and

infection are important factors responsible for non-union of a humeral shaft fracture.  Joint stiffness - A proper rehabilitation programme is essential to prevent joint stiffness following injury.  Malunion - This may be functionally inconsequential; arm musculature and shoulder, elbow, and trunk range of motion can compensate for angular, rotational, and shortening deformities. INVESTIGATIONS:  AP and lateral radiographs of the humerus should be obtained, including the

shoulder and elbow joints on each view. ,  Traction radiographs may aid in fracture definition in cases of severely displaced or comminuted fracture patterns.  Computed tomography, bone scans, and MRI are rarely indicated except in cases in which pathologic fracture is suspected. MANAGEMENT: CONSERVATIVE:  Most humeral shaft fractures (>90%) will heal with nonsurgical management.  Twenty degrees of anterior angulation, 30 degrees of varus angulation, and up to

3 cm of bayonet apposition are acceptable and will not compromise function or appearance. 30

 Hanging cast: This utilizes dependency traction by the weight of the cast and arm to effect fracture reduction. o Indications include displaced midshaft humeral fractures with shortening, particularly spiral or oblique patterns. Transverse or short oblique fractures represent relative contraindications because of the potential for distraction and healing complications. o The patient must remain upright or semi upright most of the time with the cast in a dependent position for effectiveness.

o It is frequently exchanged for functional bracing 1 to 2 weeks after injury. o More than 90% union is reported OPERATIVE:  Indications for operative treatment are: o Multiple trauma o Inadequate closed reduction or unacceptable malunion o Pathologic fracture o Associated vascular injury o Floating elbow o Segmental fracture o Intraarticular extension o Bilateral humeral fractures o Open fracture o Neurologic loss following penetrating trauma

o Radial nerve palsy after fracture manipulation (controversial) o Nonunion  Open reduction and internal fixation The fracture site is exposed, fragments reduced and fixed with a compression plate (DCP, LCDCP, LCP) and screws, with an anterolateral approach or upper two thirds fracture and posterior approach for lower thirds fracture  Interlocking intramedullary nail An ‘antegrade’ or a ‘retrograde’ nail is introduced into the medullary cavity of

the humerus after closed reduction of the fracture. The nail is then locked 31

proximally and distally to achieve rotational stability. This requires image intensification and is comparable to plating.  External fixation This method of treatment may be used in open or multiple fractures. Percutaneous pins are threaded into the bone and then held together by an external frame. Patients with associated neurovascular injury or in unstable fractures where facilities are not available for ideal internal fixation should be referred to higher centre. Comments: The common deficiency

(i) The writing style is not consistent. Radial head fracture is given as 33% of elbow region while distal radius as 1/6 of fracture (not known) of what? (j) Imaging – just mentioned AP, Lateral and sometime oblique. Why and for what a particular special x-ray is needed? (k) Complication has been clubbed as most common to least common, early or late in one list. This will not help. (l) When to refer – Generally written type B & C to higher center. Can we make such guidelines in the issue.

The outcome of treatment depends on – e) Training of the surgeon. f) Infrastructure – operating theatre & available instrumentation We need to define what all we should have in primary health center, secondary and tertiary care centre. If we refer all type B & C fracture for all fractures than how the patients in Village, Tehsil, District will be treated as we do not have any networking of referral centers (they are all concentrated in the cities.

Summarily the objective of the guidelines should be well stated. Is it to stop small centers in cities to stop operating the particular type of fractures and force them to refer or to make a national policy for the overall effective management of the orthopaedic patients? 32

RADIAL HEAD FRACTURE INTRODUCTION- Radial head fractures account for almost 33% of fractures of the elbow region. Radial head plays an important role in providing smooth movements of forearm (Pronation and Supination) and the elbow joint (flexion and extension at radiocapitullar joint). CLASSIFICATION- Mason`s classification- most widely followed 1- undisplaced or minimally displaced fracture. Displacement < 2mm 2- displaced fracture. Displacement > 2mm 3- communited fracture

4- fracture with dislocation of elbow HISTORY- Fall on an outstretched hand with a valgus strain. DIAGNOSIS- A) CLINICAL FEATURES - -Pain and swelling over elbow region -On examination- tenderness over the radial head with restriction of forearm and elbow movements B) IMAGING TECHNIQUES – X-RAY - AP, LATERAL, OBLIQUE VIEWS. CT – rarely a CT and an MRI may be necessary to study the fragments and the stability of the joint MANAGEMENT- A. (MASON TYPE 1) CONSERVATIVE TREATMENT– MAY BE DONE IF

THERE IS NO RESTRICTION OF RANGE OF MOTION WITH AS ABOVE ELBOW PLASTER SLAB FOR 2 WEEKS. B. SURGERY- 33

1) IN ISOLATED RADIAL HEAD FRACTURES TREATED WITH OPEN REDUCTION & INTERNAL FIXATION WITH SCREWS. (MASON TYPE 2) 2) PROSTHETIC REPLACEMENT- IS USED TO PRVENT PROXIMAL MIGATION OF THE RADIUS. (MASON TYPE 3 & 4 ) EVEN RADIAL EXCISION GIVES FAIRLY GOOD RESULTS. 3) RADIAL HEAD EXCISION-MAY BE USEFUL FOR OLDER PATIENTS WITH COMPLEX ISOLATED FRACTURES. LEVEL OF EXCISION IS PROXIMAL TO ANNULAR LIGAMENT THROUGH LATERAL KOCHER APPROACH. COMPLICATIONS

• Primarily related to improperly placed hardware or loss of fixation. Late excision of the radial head may be necessary after other soft tissues have healed. • Posterior interosseous nerve injury - treat with radial nerve splint. If it doesn’t recover, Jones tendon transfer is to be done. • Elbow stiffness - loss of extension common. No massaging is to be done. • DRUJ instability. • Post traumatic arthritis. • Reflex sympathetic osteodystrophy. • MCL insufficiency & consequent elbow instability.

ESSEX – LOPRESTI LESION • Defined as longitudinal disruption of forearm interosseous ligament, usually combined with radial head fx and/or dislocation plus distal radioulnar joint injury • Difficult to diagnose • Treatment requires restoring stability of both elbow and DRUJ components of injury. • Radial head excision in this injury will result in disabling proximal migration of the radius. 34

WHEN DO YOU REFER IT TO HIGHER CENTRE? 1. Essex Lopresti lesion 2. When the patient comes late 3. In Type 2 fractures when facilities are not available for fixation Comments --- The common deficiency (m) The writing style is not consistent. Radial head fracture is given as 33% of elbow region while distal radius as 1/6 of fracture (not known) of what? (n) Imaging – just mentioned AP, Lateral and sometime oblique. Why and for what a particular special x-ray is needed?

(o) Complication has been clubbed as most common to least common, early or late in one list. This will not help. (p) When to refer – Generally written type B & C to higher center. Can we make such guidelines in the issue. The outcome of treatment depends on – g) Training of the surgeon. h) Infrastructure – operating theatre & available instrumentation We need to define what all we should have in primary health center, secondary and

tertiary care centre. If we refer all type B & C fracture for all fractures than how the patients in Village, Tehsil, District will be treated as we do not have any networking of referral centers (they are all concentrated in the cities. Summarily the objective of the guidelines should be well stated. Is it to stop small centers in cities to stop operating the particular type of fractures and force them to refer or to make a national policy for the overall effective management of the orthopaedic patients?

HAND INJURIES Carpal Injuries Scaphoid Fracture Introduction: Fracture of the carpal scaphoid bone is the most common fracture of the carpus, and frequently diagnosis is delayed. Incidence & classification: Scaphoid fracture accounts for about 50-80% of carpal injuries. It is most common in young men. It is caused by a fall on the outstretched palm, resulting in severe hyperextension and slight radial deviation of the wrist. Herbert’s classification is most commonly used for scaphoid fracture:

A (Acute, Stable): A1 Tubercle A2 Nondisplaced fracture of the waist B (Acute, Unstable): B1 Oblique, distal third B2 Displaced or mobile, waist B3 Proximal pole B4 Fracture Dislocation B5 Comminuted C (Delayed Union) D (Established nonunion): D1 Fibrous D2 Sclerotic Diagnosis & Investigations: Clinical evaluation + X-rays (PA, Lateral, scaphoid view, clenched fist view), MRI, CT, bone scan may be used to diagnose occult scaphoid fractures

Complications: Delayed union, malunion, nonunion, osteonecrosis, CRPS Management: 1. Tuberosity fractures and Nondisplaced distal third fractures: Conservative with scaphoid cast for 6-8 weeks 2. Other Non-displaced fractures: Conservative or Percutaneous fixation 3. Displaced but reducible fractures: Percutaneous fixation 4. Irreducible displaced fractures: ORIF Reasons for referral to higher centre: Lack of expertise, lack of infrastructure, Fracture dislocations

Other carpal injuries: Triquetrum, trapezium, lunate are commonest after scaphoid fracture. Trapezoid, capitate, pisiform and hamate are relatively rare fractures. Specialized views or CT scan may be required for their diagnosis. Undisplaced fractures are treated conservatively; however displaced fractures may require ORIF. Complications can be osteonecrosis, missed dislocations, osteoarthritis, CRPS etc. Hand Fractures: 36

Metacarpal and phalangeal fractures are common, comprising 10% of all fractures. There is a high degree of variation in mechanism of injury accounting for broad spectrum of patterns of fractures in hand. Incidence & classification: Distal phalanx fractures are most common of all hand fractures (45%) followed by metacarpal fractures (30%), proximal phalanx (15%) and middle phalanx (10%). These fractures can be classified in various ways: 1. Location of fracture e.g. head, shaft, base 2. Open vs. closed

3. Displaced vs. Undisplaced 4. Extraarticular vs. Intraarticular 5. Stable vs. Unstable 6. Fracture pattern : transverse, comminuted, spiral, split Diagnosis & Investigations: Clinical evaluation + X-rays (PA, latéral and oblique radiographs). CT may be required to assess the intraarticular fractures. Complications: Delayed union, malunion, nonunion, CRPS, stiffness and loss of motion, infection, post-traumatic osteoarthritis etc. Management: Metacarpal fractures:

Metacarpal head: Undisplaced stable fractures can be treated conservatively with MCP joint immobilized at >70 degrees. Displaced fractures usually require ORIF with k-wires or mini-plates Metacarpal neck: Stable fractures: Conservative Unstable fractures: CRIF or ORIF (K-wires, mini-plates) Metacarpal Shaft: Stable fractures: Conservative Unstable fractures: CRIF or ORIF (K-wires, mini plates) Metacarpal Base: Undisplaced: Conservative Displaced: CRIF or ORIF Proximal and middle phalanx

Intraarticular fractures: ORIF is preferred. For comminuted fractures, ligamentotaxis with external fixators or specialized reconstruction techniques can be used. Extraarticular fractures: Stable fractures: Conservative Unstable fractures: CRIF or ORIF (K-wires, mini plates) Distal Phalanx Intraarticular fracture (Mallet finger) : Extension block pinning for bony mallet finger, Extension splinting for soft mallet finger Extraarticular fractures: Usually treated as soft tissue injury. If displaced widely,

CRIF is recommended. Reasons for referral to higher centre: Lack of expertise, lack of infrastructure, Fracture dislocations Tendon Injuries 37

Extensor Tendon Injuries are usually treated with primary repair Flexor tendon injuries are treated according to zone of injuries: Zone 1: Direct Repair, tenodesis or arthrodesis in some cases Zone 2: Need expertise, primary repair or delayed grafting Zone 3: primary repair Zone 4: primary repair Zone 5: primary repair Complication include stiffness, rupture of the graft or repair site, bowstringing etc. referral should be made in case of lack of expertise or infrastruacture. Comments:

The common deficiency (q) The writing style is not consistent. Radial head fracture is given as 33% of elbow region while distal radius as 1/6 of fracture (not known) of what? (r) Imaging – just mentioned AP, Lateral and sometime oblique. Why and for what a particular special x-ray is needed? (s) Complication has been clubbed as most common to least common, early or late in one list. This will not help. (t) When to refer – Generally written type B & C to higher center. Can we make

such guidelines in the issue. The outcome of treatment depends on – i) Training of the surgeon. j) Infrastructure – operating theatre & available instrumentation We need to define what all we should have in primary health center, secondary and tertiary care centre. If we refer all type B & C fracture for all fractures than how the patients in Village, Tehsil, District will be treated as we do not have any networking of referral centers (they are all concentrated in the cities.

Summarily the objective of the guidelines should be well stated. Is it to stop small centers in cities to stop operating the particular type of fractures and force them to refer or to make a national policy for the overall effective management of the orthopaedic patients? 38

LONG LIMB TRAUMA Fracture Neck of Femur (Intra-capsular) Fracture neck of femur is still the unresolved fracture as evident by the number of procedures available and practiced, thus none is universally applicable and the surgeon has to select one which would be ideal in a given situation. The treatment varies with the age of the patient, the level of the fracture and the displacement of the fragments. Also the duration of the fracture is a major deciding factor. If union of the fracture is not

likely to be achieved then what alternative method should be adopted which will suit the patient, keeping in mind his age, life style, profession and economic status. Majority of our patients are not covered by health insurances, hence all the expenditure has to be born by the patient himself. It is therefore desirable on the part of treating orthopaedic surgeon to choose a method which these patients can afford. Fracture neck femur is commonly seen in old people but in our country quite a good

number of patients are young adults. It is infrequent in children. Fracture neck femur whether intra-capsular or extra-capsular can be diagnosed and differentiated by clinical examination and confirmed by the roentgenograms. Any underlying pathologic condition like metastasis or osteoporosis if present can also be identified on roentgenograms. Fracture neck femur intra-capsular can be divided as per the following classifications: (A) Garden Classification

• Type 1 is a stable fracture with impaction in valgus. • Type 2 is complete fracture but non-displaced. • Type 3 is displaced (often rotated and angulated) with varus displacement but still has some contact between the two fragments. • Type 4 is completely displaced and there is no contact between the fracture fragments. 39

(B) According to the site of fracture • Subcapital • Transcervical • Basicervical 40

Usually caused by trivial fall in the elderly due to presence of osteoporosis, however metastasis from malignancies can also lead to the pathologic fractures. The aim of treatment is to achieve union of the fracture and a durable hip joint afterwards. Principles of management include: a. Osteosynthesis i. Screws, Moore’s Pins etc ii. DHS, Blade Plate iii. Internal Fixation + Fibular Grafting iv. Muscle pedicle Graft + Internal Fixation b. Osteotomy i. Pauwels valgus osteotomy ii. Mcmurray’s osteotomy

c. Arthroplasty i. Hemiarthroplasty ii. Total Hip Replacement iii. Excision Arthroplasty The following points should be considered. 1. Age of the patient: Based on the age the following groups should be made. a. 1-16 years before the closure of the upper femoral epiphysis b. 16-50 years young adults c. 50-60 years middle age group d. Above 60 years (old age) 2. Site of fracture: a. Sub-capital b. Transcervical c. Basicervical 3. Displacement of fragments: a. Undisplaced fractures b. Displaced fractures

4. Duration of fracture: a. 1-21 days – Fresh b. More than 21 days – Neglected fracure Management: Primary health centre level: The doctor on duty should recognise the features of fracture and disloction. Only first aid including the splintage and intravenous drip should be given. In open fractures Tetanus toxoid can be given. There is no need to 41

waste time in preparation of medico-legal formalities. The injured should be referred to the higher centre earliest feasible causing no further harm. Community health centre and Civil hospital level: (Non Metro Hospital) 1. Investigations: X-rays of the pelvis including both hip and knee joint and of other areas if required, General Investigations and specific if required according to the status of the health of the patient. 2. Treatment: FRESH FRACTURE Age 1-16 years when growth plate is intact:

The implant used for internal fixation either should not cross the epiphyseal plate or the implant causing least possible damage should be used. Sub-capital and transcervical fractures should be fixed with multiple Kirschner (K) wires or Moore’s pins after closed reduction in valgus. Basicervical fractures can be fixed either by K wires, Moore’s pins or cancellous/cannulated lag screws. When screws are used they should not cross the preferably epiphyseal plate. Age 16-50 years Sub-capital fractures:

Undisplaced: Internal fixation with 2-3 cancellous/cannulated lag screws Displaced: Closed reduction and fixation with Lag screws. Valgus osteotomy and fixation with double angled blade plate can also be done to convert shearing forces into compression forces. Transcervical fractures: Undisplaced: Internal fixation with 2-3 cancellous/cannulated lag screws Displaced: Closed reduction and fixation with Lag screws. Valgus osteotomy and

fixation with double angled blade plate can also be done to convert shearing forces into compression forces. If closed reduction fails open reduction is done followed by any of the above procedures. 42

Basicervical fractures: Undisplaced: Internal fixation with Dynamic Hip Screw (DHS) Displaced: Closed reduction and fixation with Lag screws or DHS. If closed reduction fails then open reduction and internal fixation (ORIF) with lag screws or DHS. Age 50-60 years: Sub-capital fractures: Undisplaced: Internal fixation with 2-3 cancellous/cannulated lag screws Displaced: Closed reduction and fixation with Lag screws. Valgus osteotomy and

fixation with double angled blade plate can also be done to convert shearing forces into compression forces. Arthroplasty including hemi or excision may be done according to the need and requirement of the patient. If closed reduction fails open reduction and fixation with any of the methods described above may be done or hemi/excision arthroplasty may be offered according to the need and requirement of the patient. Transcervical fractures:

Undisplaced: Internal fixation with 2-3 cancellous/cannulated lag screws Displaced: Closed reduction and fixation with Lag screws. Valgus osteotomy and fixation with double angled blade plate can also be done to convert shearing forces into compression forces. Arthroplasty including hemi or excision may be done according to the need and requirement of the patient. If closed reduction fails open reduction and fixation with any of the methods described above may

be done or hemi/excision arthroplasty may be offered. Basicervical fractures: Undisplaced: Internal fixation with Dynamic Hip Screw (DHS) 43

Displaced: Closed reduction and fixation with Lag screws or DHS. If closed reduction fails then open reduction and internal fixation (ORIF) with lag screws or DHS. Hemi/excision arthroplasty may be offered. Physiologic Age above 60 years: Sub-capital fractures: Undisplaced: Internal fixation with 2-3 cancellous/cannulated lag screws. Arthroplasty including hemi or excision may be done according to the need and requirement of the patient.

Displaced: Arthroplasty including hemi or excision may be done according to the need and requirement of the patient. Transcervical fractures: Undisplaced: Internal fixation with 2-3 cancellous/cannulated lag screws. Arthroplasty including hemi or excision may be done according to the need and requirement of the patient. Displaced: Arthroplasty including hemi or excision may be done according to the need and requirement of the patient. Basicervical fractures:

Undisplaced: Internal fixation with Dynamic Hip Screw (DHS) Displaced: Arthroplasty including hemi or excision may be done according to the need and requirement of the patient. 3. Referral Criteria for Metro hospital a. Polytrauma patient. b. Patient with co-morbid conditions requiring multiple speciality care. c. Patients requiring Joint replacement. d. Non unions / Neglected fractures ie fractures more than 3 weeks duration. e. Pathological fractures. 44

f. Suspected HIV positive cases. g. Fractures associated with any condition requiring higher investigations like CT Scan, MRI etc. Metro hospital level: 1. Investigations: X-rays of the pelvis including both hips and knee and of other areas if required, General Investigations and specific if required according to the presence of any co-morbidity. Special investigations like MRI/CT scan if required. 2. Treatment: All the treatment as in situation 1

Treatment for the referred patients in the form of multispecialty approach. FRACTURE MORE THAN 3 WEEKS DURATION Osteosynthesis in such fractures has a high failure rate. Internal fixation has to be combined with some type of bone graft or osteotomy particularly in young patients in whom it is desirable to preserve the patient’s own femoral head. In patients above the physiologic age of 60 years arthroplasty is the preferred treatment whether unipolar, bipolar, total hip or excision is as per the

affordability and requirement of the lifestyle of the patient and condition of the hip joint (Osteoarthrosis). Age 1-16 years: Mc Murray’s osteotomy and POP one and a half spica may be tried. Abduction osteotomy and internal fixation with angled paediatric blade plate. Care should be taken not to damage the epiphyseal plate. If the gap between the fragments is more than 1 cm free fibula with a screw may be tried but the chances of damage to the epiphyseal plate are very high leading to limb length

discrepancy and deformity of head later on. Age 16-55 years: In this age group patients own hip should be joint should be preserved. Osteosynthesis is carried out aiming at union of fracture and obtaining a durable hip joint. The results of various procedures depend upon the changes which have already taken place at the site of fracture with passage of time. These changes are: a) Fracture surfaces get smoothened out. b) There is progressive absorption of the neck of femur resulting in increase in

the gap between the fragments and decrease in the size of the proximal fragment. 45

c) The head of the femur may start showing signs of avascular necrosis. A good quality X-ray of pelvis including both hip joints in as identical position as possible should be taken. CT scan or MRI of pelvis can be extremely useful in accurately measuring the gap between the fragments and the size of the proximal fragment. Sometimes the absorption of the proximal fragment is more marked in the centre than the periphery giving it the shape of a cup or moon.

This may not be clearly seen on routine. AP view X-ray of the hip and can be better appreciated on CT scan or MRI. Avascular necrosis of the head of the femur may be seen earlier on MRI / CT scan than on plain X-ray of the hip. Based on these changes the fracture can be allocated to one of the following 3 stages. Stage I a) Fracture surfaces are still irregular (Fresh) b) The size of proximal fragment is 2.5 cm or more c) Gap between the fragments is 1 cm or less

d) Head of the femur is viable. There is no sign of avascular necrosis on X-ray picture or MRI or CT Scan. Stage II a) Fracture surfaces are smoothened out b) The size of the proximal fragment is 2.5 cm or more c) The gap between the fragments is more than 1 cm but less than 2.5 cm d) The head of the femur is viable. If either of the feature a or c is present it is allocated to stage II. Stage III a) Fracture surfaces are smoothened out b) The size of the proximal fragment is less than 2.5 cms

c) The gap between the fragments is more than 2.5 cms d) The head of the femur shows signs of avascular necrosis If any of the feature b, c or d is present the fracture is allocated to stage III. Treatment Stage I: In this stage the success rate of various procedures aimed at osteosynthesis is very high. The procedures which are useful are: 1. Closed reduction and internal fixation with one screw and double fibular graft or 2 screws and one fibular graft. If the neck of the femur is narrow then one

screw and one fibular graft may be given. 2. Closed/open reduction Vascularised fibular graft along with screw/k-wire 3. Closed reduction or open reduction and bone muscle pedicle graft based on quadratus femoris or sartorius or tensor fascia femoris can be used. 4. Abduction osteotomy and osteosynthesis with double angled blade plate. This procedure is particularly useful when the fracture is situated more near the base and length of proximal fragment is 3.5 cms or more. 46

5. McMurrays osteotomy with one and half POP hip spica. Stage II: In this stage when the fracture surfaces are smoothened out (as in case of established nonunion) and the gap between the fragments is more than 1 cm various methods of osteosyntehsis which have given good results are 1. Closed reduction and internal fixation with one screw and double fibular graft or 2 screws and 1 fibular graft. 2. Open reduction, freshening of fracture surfaces and internal fixation with 2

screws and one free fibular graft. 3. Closed/open reduction Vascularised fibular graft along with screw/k-wire 4. Open reduction and internal fixation with multiple screws and bone muscle pedicle graft based on quadratus femoris or sartorius or tensor fascia femoris. 5. Other methods of treatment which can be useful (although they will not achieve union of fracture but improve the function of hip) are a. McMurrays osteotomy b. Osteotomy with internal fixation c. Bachelor's or Girdlestone procedure

Stage III: In this stage when the size of the proximal is less 2.5 cms, it cannot give good hold to the implant as well as the graft or there is a gap of more than 2.5 cm between the fragments or femoral head is showing signs of avascular necrosis, chances of union are less. Osteosynthesis is likely to have very high failure rate. The treatment options available are 1. Total hip arthroplasty - - if the patient can afford and his life style permits. It may preferably be non-cemented or may be cemented.

2. Bipolar or hemi arthroplasty 3. McMurray's osteotomy 4. Subtrochantric osteotomy with internal fixation 5. Excision hip Girdlestone's or Bachelor's procedure 6. Patient may be left alone if the patient is poor and cannot afford treatment or is unfit for surgery. He can start walking with the support of a walker or crutches. Later on he can walk with the support of stick or even without than in about 3-4 months time. They are often able to squat or sit in cross legged position (Budha position).

After the age of 55 years 1. Replacement arthroplasty : if the patient can afford or his life style permits. It may be total hip replacement or bipolar or hemi-arthroplasty. 2. Osteosynthesis if the patient wants it and is prepared to wait for 5 - 7 months for independent walking. This should be carried out only in stage I and stage II. 3. Excision hip (Girdlestone procedure or Bachelor's procedure) 4. Osteotomy with internal fixation 5. Leave him alone. 47

There are rough guidelines to help the orthopaedic surgeon to manage fracture neck of femur in different age groups and fracture at different levels of neck for fresh as well as neglected cases. The decision regarding the choice of operative procedure rests with the surgeon depending upon the patient's requirements, his life style, profession and financial position. It also depends upon the training of the Orthopaedic surgeon and facilities available to him. Use of free fibular

graft/vascularised fibula in addition to internal fixation with screws particularly where there is posterior comminution improve the chances of union and may be carried out in such cases. If the reduction of the fracture is less than anatomical but otherwise satisfactory addition of free fibular graft can improve the chances of union. If the patient is suffering from a generalized disease like diabetes mellitus, congestive heart failure, chronic kidney or liver disease, malignancy etc., or is

taking steroids adversely affecting the chances of union of fracture, replacement arthroplasty may be a better option even in younger. 48

Trochanteric fractures (Extra-capsular fracture neck femur) Hip fractures in the elderly are frequent, and their number is increasing fast. The intertrochanteric and the subtrochanteric fractures pose a number of management dilemmas depending on the fractures configuration and status of the bones. A number of different treatment modalities for management of these fractures have been proposed and tried with varying results for both intertrochanteric and subtrochanteric fractures of proximal femur.

Intertrochanteric hip fractures account for approximately half of the hip fractures in the elderly; out of this more than 50% fractures are unstable. Unstable pattern occur more commonly with increased age and with low bone mineral density. The fracture commonly occurs through bone affected by osteoporosis. The presence of osteoporosis in intertrochanteric fractures is important because fixation of the proximal fragment depends entirely on the quality of cancellous bone present, Unstable

intertrochanteric fractures are those in which comminution of posteromedial buttress exceeds a simple lesser trochanteric fragment or those with subtrochanteric extension. The results of unstable fractures are less reliable and have a high rate of failure - 8%- 25%. The goal of treatment of any intertrochanteric fracture in the elderly is to restore mobility safely and efficiently while minimizing the risk of medical complications and

technical failure and to restore the patient to preoperative status. Unstable intertrochanteric fractures are technically much more challenging than stable fractures; a stable reduction of an intertrochanteric fracture requires providing medial and posterior cortical contact between the major proximal and distal fragment to resist varus and posterior displacing forces. Hence Surgeons must understand implant options available and should strive to achieve accurate realignment and proper implant placement.

Subtrochanteric fractures occur 'between lesser trochanter and a point 5 cm distally and are seen as independent entities or as an extension of intertrochanteric fractures. The common problem for these fractures has been malunion, delayed union or non-union. Many newer designs of implants bas been designed for fixation of subtrochanteric fractures. The newer implants were designed to avoid bending, breakage of plates and nails, the loosening of screws and inadequate fixation. After the

failure of A O angled blade plate many implants were designed like dynamic hip compression screw, dynamic condylar screw, modifications of axial compression screw devices like Medoff's device. Most of the hip fractures in the elderly results from simple fall from standing. This is mainly because elderly people are unable to dissipate energy as compared to the young person, and diminished ambulatory speed. Their protective responses are also 49

diminished because of slow reaction time, weakness, disorientation and the side effect of medication. Elderly people also lack shock absorbers such as pad of fat or muscles over the trochanteric region and finally diminished bone strength because of osteopaenia allows fractures to occur with trivial fall. Trochanteric fractures can be classified as: Boyd and Griffin classification 50

Management: Primary health centre level: The doctor on duty should recognise the features of fracture and disloction. Only first aid including the splintage and intravenous drip should be given. In open fractures Tetanus toxoid can be given. There is no need to waste time in preparation of medico- legal formalities. The injured should be referred to the higher centre earliest feasible causing no further harm. Non Metro Hospital (CHC and Civil Hospital level):

1. Investigations: X-rays of the pelvis including both hips and knee joint and of other areas if required, General Investigations and specific if required according to the status of the health of the patient. 2. Treatment: Closed reduction and DHS is the standard modality for most of the Trochanteric fractures. If closed reduction fails open reduction can be done. In unstable Trochanteric fractures Proximal Femoral Nail (PFN), Intramedullary Hip Screw

can also be done depending upon the facilities and the expertise of the operating surgeon. Where there is comminution at the site of entry for the DHS, Dynamic Condylar Screw (DCS) may be used. For subtrochanteric fractures a DCS is the implant of choice after closed or open reduction. Other modalities like PFN, Angled blade plate, Reconstruction nail or Modified Kuntscher’s nail may also be used as per the preference of the surgeon. 3. Referral Criteria for Metro hospital a. Polytrauma patient.

b. Patient with co-morbid conditions requiring multiple speciality care. c. Patients requiring Joint replacement. d. Non unions / Neglected fractures ie fractures more than 3 weeks duration. e. Pathological fractures. f. Suspected HIV positive cases. g. Fractures associated with any condition requiring higher investigations like CT Scan, MRI etc Metro hospital level 1. Investigations: X-rays of the pelvis including both hips and knee and of other

areas if required, General Investigations and specific if required according to the 53

presence of any co-morbidity. Special investigations like MRI/CT scan if required. 2. Treatment: All the treatment as in CHC/Civil hospital level along with multidisciplinary approach as required for other co-morbid conditions of the patient. In very osteoporotic patients cement augmentation along with DHS should be done to decrease chances of cut through. In few selected ones with either osteoarthritis of hip joint or in those patients in whom union is suspected we can go for arthroplasty.

Since lots of co-morbidities are common in geriatric population, a thorough preoperative medical evaluation is necessary. The detailed preoperative work up directly affects the timing of surgery and the operative procedure. Majority of these fractures should be treated operatively for ease of nursing care, rapid mobilisation, decreased mortality, decreased hospitalization and restoration of function. The operative treatment should be considered urgently, but not as an emergency procedure.

The optimal time for surgical intervention appears to be after the patient is evaluated medically and any transient medical ailment corrected i.e. electrolyte and fluid imbalance. However it should not be delayed more than 48-72 hours unless intervention significantly decreases the operative risk. Also most of these patients are osteoporotic and have a high chance of getting fracture in the opposite side, so anti osteoporotic treatment should be started in all of

these patients and so is the early mobilization as osteoporosis will increase if they stay in bed waiting for the union to occur. 54

Resources required for patient and procedure Situation Human Investigations Drugs and consumables Equipment Resources 1 Doctor, Nurse and None None except for first aid No surgical set other paramedics up 2 Doctor, X-rays, Complete Plaster of Paris Theatre set up for Nurse, Haemogram, bandages Surgeries with all Physiotherapist Bleeding time, Anaesthetic drugs Basic equipments and technicians Clotting time, Thromboprophylaxis C-arm image intensifier Complete urine examination for for pre-anaesthetic

check up 3 Doctor, As situation 1 As situation 1 As situation 1, Surgical Physiotherapist, CT Scan, MRI Operating Microscope, Nurse, orthotist, ICU, and major physio- Prosthetist, therapy set up for and technicians rehabilitation 55

FRACTURE SHAFT OF FEMUR Fractures of the shaft of the femur are the result of high-energy trauma and therefore can be both life-threatening injuries and causes of severe permanent disability. Isolated injuries can occur with repetitive stress and may occur in the presence metabolic bone diseases, metastatic disease, or primary bone tumors. The femur is very vascular and fractures can result in significant blood loss into

the thigh. Up to 40% of isolated fractures may require transfusion, as such injuries can result in loss of up to 3 units of blood. This factor is significant, especially in elderly patients who have less cardiac reserve. Most femoral diaphyseal fractures are treated surgically with intramedullary nails or plate fixation. The goal of treatment is reliable anatomic stabilization, allowing mobilization as soon as possible. Surgical stabilization is also important for early

extremity function, allowing both hip and knee motion and strengthening. Injuries and fractures of the femoral shaft may have significant short- and long-term effects on the hip and knee joints if alignment is not restored. The 3 types of femoral shaft fractures are as follows: • Type I - Spiral or transverse (most common) • Type II - Comminuted • Type III - Open Primary health centre level: The doctor on duty should recognise the features of

fracture and disloction. Only first aid including the splintage and intravenous drip should be given. In open fractures Tetanus toxoid can be given. There is no need to waste time in preparation of medico-legal formalities. The injured should be referred to the higher centre earliest feasible causing no further harm. Non-Metro Hospital( CHC and Civil Hospital level): 1. Investigations: X-rays of the part including hip and knee and of other areas if

required, x-ray of pelvis with both hips is must. General Investigations and specific if required according to the status of the health of the patient. 2. Treatment: Conservative management of fractures in children in spica cast or with skeletal traction, Kuntscher’s nail for isthmic fractures, Interlocking Nailing in comminuted fractures, Plating for lower third fractures, Plating of shaft femur fracture in children. Referral Criteria a. Polytrauma patient. 56

b. Patient with co-morbid conditions requiring multiple speciality care. c. Non unions / Neglected fractures. d. Pathological fractures. e. Open fractures requiring Plastic surgery or with Large gaps due to bone loss f. Non unions / Neglected fractures and failed osteosynthesis. g. Fractures associated with neurovascular injuries/Suspected Fat Embolism. h. Suspected HIV positive cases. i. Fractures associated with any condition requiring higher investigations like CT scan, MRI etc.

Metro Hospital -Higher referral centre: 1. Investigations: X-rays of the part and of other areas if required, x-ray of pelvis with both hips is must. General Investigations and specific if required according to the presence of any co-morbidity. Special investigations like MRI/CT scan or angiography if required. 2. Treatment: All the treatment given at situation 1, Closed/Open Interlocking Nailing, DCS/Distal femoral Nail or Plate for Supracondylar/Intercondylar

fractures, External fixator/Enders/solid undreamed Nail for open fractures, Fibular grafting with plating and cancellous bone grafts for non unions, Illizarovs Ring Fixator, Rail road fixator for gap defects, Plastic/Vascular surgeon assistance. 57

Resources required for patient and procedure Situation Human Investigations Drugs and consumables Equipment Resources 1 Doctor, Nurse an None None except for first aid No surgical set other paramedics up 2 Doctor, X-rays, Complete Plaster of Paris Theatre set up for Nurse, Haemogram, bandages Surgeries with all Physiotherapist Bleeding time, Anaesthetic drugs Basic equipments and technicians Clotting time, Thromboprophylaxis C-arm image intensifier Complete urine examination for for pre-anaesthetic

check up 3 Doctor, As situation 1 As situation 1 As situation 1, Surgical Physiotherapist, CT Scan, MRI OperatingMicroscope, Nurse, orthotist, ICU, and major physio- Prosthetist, therapy set up for and technicians rehabilitation 58

FRACTURE OF TIBIA/FIBULA 1. Introduction /description Lower leg fractures include fractures of the tibia and fibula. Of these two bones, the tibia is the main weight bearing bone. Fractures of the tibia generally are associated with fibula fracture, because the force is transmitted along the interosseous membrane to the fibula. The skin and subcutaneous tissue are very thin over the anterior and medial tibia and as a result of this; a significant number of fractures to the lower leg are open. Even in

closed fractures, the thin, soft tissue can become compromised. In contrast, the fibula is well covered by soft tissue. Fractures of the tibia can involve the tibial plateau, tubercle, shaft, and plafond. 2. Incidence: Fractures of the tibia are the most common long bone fractures. The most common fracture of the lower limb occurs at the tibial diaphysis. Isolated mid-shaft or proximal fibula fractures are uncommon. 3. Mode of injury

Tibial plateau fractures occur from axial loading with valgus or varus forces, such as in a fall from a height or collision with the bumper of a car. The lateral tibial plateau is fractured more frequently than the medial plateau. Tibial tubercle fractures usually occur during jumping activities. Mechanisms of injury for tibia-fibula fractures can be divided into 2 categories: 59

• Low-energy injuries such as ground levels falls and athletic injuries and in osteoporotic patients • High-energy injuries such as motor vehicle injuries(esp motor cycle accidents, pedestrians struck by motor vehicles, and gunshot wounds Tibial plafond fractures refer to fractures involving the weight-bearing surface of the distal tibia. This type of injury usually results from high-energy axial loading but may result from lower-energy rotation forces. 4. Clinical presentation:

Patient may complain of severe pain, swelling and bruising down the broken leg, deformity of bones and inability to ambulate with tibia fracture. Tibial plateau fractures often present with a knee effusion. Approximately 20% of tibial plateau fractures are associated with ligamentous injuries. Limb loss may occur as a result of severe soft-tissue trauma, neurovascular compromise, popliteal artery injury, compartment syndrome, or infection such as gangrene or

osteomyelitis. Popliteal artery injury is a particularly serious injury that threatens the limb. 5. MANAGEMENT: Primary health centre level: The doctor on duty should recognise the features of fracture and disloction. Only first aid including the splintage and intravenous drip should be given. In open fractures Tetanus toxoid can be given. There is no need to waste time in preparation of medico- legal formalities. The injured should be referred to the higher centre earliest feasible causing no further harm.

CHC and Civil Hospital level: Trauma patient should be managed by addressing airway, breathing, and circulation. Check and document neurovascular status. Apply sterile dressing to open wounds. Apply gentle traction to reduce gross deformities; splint the extremity. After first aid, pain management and splintage, PRICE therapy (Protection, rest/immobilise the limb, ice therapy, compression and elevation) should be started. Investigations: Perform radiographs of the knee, tibia/fibula, and ankle as indicated

and of other areas if required, General Investigations and specific if required according to the status of the health of the patient. In patients with tibial plateau fractures and tibial plafond fractures, computed tomography can help further evaluate the extent of the fracture. In tibial plateau fractures, radiographs may underestimate the degree of articular depression when compared with computed tomography. This is important because articular depression of greater than 3 mm may be considered for surgery.

Treatment: soft tissue envelope is the most important component in the evaluation and subsequent care of tibial fractures. Compartment syndrome can develop in fractures of the lower leg. Signs of compartment syndrome include crescendo symptoms- (5 P’s) puffiness/oedema, pain out of proportion with passive stretch of involved muscles, paresthesias, and pallor, and a very late finding is pulselessness and paralysis. Increased compartment pressure is present during compartment syndrome; therefore, external

palpation frequently aids in the diagnosis. However, a soft extremity on palpation does not rule out compartment syndrome. Compartment syndrome must be treated promptly with an emergency surgical fasciotomy Open fractures must be diagnosed and treated appropriately. Tetanus vaccination should be updated, and appropriate antibiotics should be given in a timely manner. This should involve antistaphylococcal coverage and consideration of an aminoglycoside for 61

more severe wounds. Adequate wound debridement and wound care. Fractures with tissue at risk for opening should be protected to prevent further morbidity. External fixator should be applied in non comminuited fractures. All simple both bone leg fractures, minimally displaced fractures in children / adults should be managed with closed reduction and above knee cast. In displaced fractures closed reduction and interlock nailing in shaft fractures should be done, Plating should

be done for lower third fractures. Post closed reduction (pop cast) or open reduction and fixation adequate limb elevation is required and patient is encouraged to do passive exercises to avoid edema of limb, deep vein thrombosis and to aid in adequate wound healing. Tibial plateau fracture : Immobilize un-displaced fractures and keep the patient non- weightbearing for 3 months. Tibial tubercle fracture- For un-displaced fractures, immobilize the knee.

Isolated midshaft or proximal fibula fracture- Immobilization in a long leg cast generally is not required. Recommend a few days without weight-bearing activity until swelling resolves, followed by weight-bearing activity as tolerated. In some case, immobilization in above knee cast is done Some of the complications that may arise in treatment are: • A tendency to displace the fragments when swelling subsides, particularly in oblique and spiral fractures

• Cosmetic and sometimes functional disability if the alignment or rotational position of the fragment is imperfect • Conspicuous disfigurement if apposition of the fragments is imperfect • Slow union as a result of severity of the fracture, poor blood supply to one fragment, and sometimes distraction of the bone fragments 62

• Occasional limitation of joint movement in the knee, ankle and foot, usually caused by associated joint, soft tissue, or vascular injury • The common peroneal nerve crosses the fibular neck. This nerve is susceptible to injury from a fibular neck fracture or the pressure of a splint, Referral Criteria for higher centre (Medical College / Tertiary centre) a. Open fractures requiring Plastic surgery or with Large gaps due to bone loss.

b. Comminuted fractures, Fractures requiring Interlocking Nail, proximal intra-articular fractures, distal pilon fractures, open fractures c. Polytrauma patient. d. Patient with co-morbid conditions requiring multiple speciality care. e. Non unions / Neglected fractures and failed osteosynthesis. f. Pathological fractures. g. Fractures associated with neurovascular injuries/Suspected Fat Embolism. h. Suspected HIV positive cases Metro Hospital or Higher centre level

At Medical College / Tertiary centre the goal of management of these include in addition to situation 1. 3. Investigations: computer tomography of concerned joint, colour Doppler studies of limb and CT- angiography if required. 4. Treatment: All Closed/Open (upto 3A as per gustilio Anderson classification) should managed with iterlocking Nailing. All proximal tibial intra-articular fractures esp. depressed fractures should be internally fixed with LCP/LCDCP.

Distal pilon fractures should be operated and internally fixed with plating. Open fractures should be managed by cupious washing of wound, wound debridement and application of External fixator/Enders/nails. In fractures with bone loss various options available are; -tiblisation of fibula and fixation with plating/ k-wires - Illizarovs Ring Fixator and Rail road fixator for gap defects and limb lengthening. -in case of smaller gaps, compression at fracture site and ORIF with

plate/nail with cancellous bone grafts Vascular surgeon assistance (vessel repair or grafting) and plastic surgeon assistance (flap or skin grating) in case of vessel injury and skin or soft tissue loss respectively should be taken. 63

Resources required for patient and procedure Situation Human Investigations Drugs and Equipment Resources consumables 1 Doctor, Nurse and None None except for first aid No surgical set other paramedics up 2 Doctor, X-rays, Complete Plaster of Paris Theatre set up for Nurse, Physiotherap Haemogram, Blee Bandages Surgeries with all and technicians time, Clotting t Tetanus Toxoid Basic equipments Complete u immunoglobulins C-arm image intens examination for Anaesthetic drugs

PROTOCOL FOR THE MANAGEMENT OF PELVIC FRACTURE I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Pelvic fracture are predominantly (10% -20%) present in blunt multiple trauma and represent a significant source of morbidity and mortality. Major forces are required to fracture the normal pelvis. Pelvic ring disruptions, more than any other fracture of the body, can lead to severe complications, including massive bleeding and organ injuries. Exsanguinating hemorrhage is the most

dreaded acute complication of pelvic fracture. In addition, because of its function as a bony basin for different organs, the cauda equina and essential nerves for the lower limbs, serious injuries of those structures significantly increases the total trauma impact of the multiply injured patient with pelvic injury. The unstable untreated pelvis enforces immobility and does not allow appropriate positioning of those patients with chest and brain injuries for their necessary intensive care.

History suggestive of pelvic fracture -motorcycle collision -car vs. pedestrian -fall from more than 15ft height -lateral impact injuries -MVC with vehicle incompatibility (i.e., car/motorcycle, pedestrian/motor vehicle) -Crushing injury (e.g., falling tree, wall) -Gun shot and projectile related b) Case definition: c) For both situations of care (mentioned below*) A patient having injury of the pelvic ring, a break in the continuity of fibro-osseous ring.

For management purpose these injuries are classified into subgroups. 65

Schematic view of the AO-OTA-SICOT alphanumeric classification of pelvic fractures. A: Sites of type 61-A stable injuries. B: type 61-A subcategories by injury sites. C: Sites of type 61-B partially unstable injuries. D: type 61-B subcategories by injury sites and displacement. E: Sites of type 61-C completely unstable injuries. F: type 61-C subcategories by injury sites. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY Accidents in India are definitely on an increase. The exact number of pelvic fractures in

our country is not known. But, indirect estimates point to a very high incidence. As per the data from the National Crime Records Bureau,467537 persons died due to injury and violence in 2009.Injury and violence deaths increased from 246277 in 1998 to 467537 by 2009 (NCRB, 1998 & 2009 a, b ). During the same period the non fatal injuries also increased correspondingly to 1,070,302 in 2009.Injury deaths are only tip of the

iceberg. For every death, it is estimated that nearly 30-50 persons are hospitalized and 50-100 are likely to receive emergency care. The data from the recently completed million death study by the Registrar General of India indicates that injuries contributed for 10 % of deaths and was the leading cause in younger age groups (RGI,2009).Of urban population deaths leading causes were RTI’s (47%),suicides (34%) and assault (10%).Leading causes of injuries were falls

From above figures it can be estimated that the number is quit high. III. DIFFERENTIAL DIAGNOSIS In all cases of trauma, especially in cases with a history suggestive of pelvic injuries should be actively looked for pelvic fracture or dislocation after initial resuscitation (ABC’s). IV. PREVENTION AND COUNSELING Accidents don’t just happen; they are caused. Majority (>90 %) of them are directly or indirectly due to human error, natural (< 10 % ) causes account for very few deaths.

All the causes should be identified by epidemiological methods. Since accidents are multifactorial, they call for an intersectoral approach to both prevention and care of the injured. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: After assessment ABC’s Gross inspection (open wounds, deformities)

-Extensive echymosis and soft tissue swelling -Disruption of the subcutaneous fat along with echymotic skin and potentially deep fascia (Morelle-Levelle lesion) -open wounds around the pelvis Perineal laceration or puncture wound Presacral laceration. Deformities Disturbed relationship of ASIS, iliac crest, Limb length discrepancies Instability Comprehensive neurovascular assessment Urogenital and rectal examination b) Investigations: 68

Chest, pelvic and cervical spine radiograph Focused abdominal ultrasonography for trauma (FAST), Diagnostic peritoneal lavage (DPL) Dependent on specific injuries -- CT of head, ECG, retrograde urethrogram etc CT Pelvis with 3D reconstruction c) Treatment: The primary objective in the initial care of the multiply injured patient is survival with normal cognitive functions. The first hour after admission to the emergency room is most critical in terms of survival and reduction of morbidity.

Multiply injured patients should have immediate evaluation of their vital organ functions, resuscitation, focused and rapid diagnostic procedures, and appropriate surgical treatment, including damage control followed by stabilization of their vital organ functions in the intensive care units (ICU), as per ATLS Protocol (Reference ATLS) Algorithm for management of haemorrhagic shock in pelvic fracture Po lytrauma with pelvic fracture Polytrauma pelvic fracture with UNSTABLE STABLE OR

HAEMODYNAMIC STATUS STABILIZED RULE OUT OTHER CAUSES—thorax, head, limbs FAST /DPL (free FAST/ DPL and CT scan +contrast peritoneal fluid?) (Thoracic, abdominal and pelvic AP) YES NO Arterial causes of haemorrhage? CT if possible LAPROTOMY Angiography -pelvic packing STABLE NO -pelvic clamp +/- Pelvic HAEMODYNAMIC --external fixator clamp/fixator CT scan if not performed before YES 68

STABLE HAEMODYNAMIC STATUS ICU-intensive care unit YES NO Consider surgical bleeding control or ICU repeat angiography FAST—focused abdominal ultrasonography for trauma, DPL—diagnostic peritoneal lavage Standard Operating procedure Pelvic binder / pneumatic antishock garment, Pelvic external fixator / C-clamp Skeletal traction in Type –C injuries a. In Patient ) all patient of pelvic injuries are high energy trauma b. Out Patient ) they need in patient treatment for at least 24 hrs

c. Day Care ) to exclude other serious injuries. d) Referral criteria: Depending upon the resources at the centre patients are referred timely preferably after an attempt at stabilizing the patient .Sometimes only few minutes are there for decision to operate for control of bleeding, (damage control and than referral). Excessive requirement for blood, Polytrauma with additional injuries If adequate OT facilities are not available For arterial bleeding ,angiography requirement 69

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available e) Clinical Diagnosis: Same as situation 1 b) Investigations: Blood gas analysis Chest, pelvic and cervical spine radiograph Focused abdominal ultrasonography for trauma (FAST), Diagnostic peritoneal lavage (DPL) Dependent on specific injuries -- CT of head, ECG, ECHO, retrograde urethrogram etc -- CT pelvis with 3D reconstruction -- CT abdomen -- Angiography f) Treatment: Same as situation 1

Once the patient is stable than the definite management of pelvic fracture is undertaken usually after 5th day and before end of 2nd week. Timing of secondary surgical procedure ---------------------------------------------------------------------Physiologic status surgical intervention timing --------------------------------------------------------------------------------------------------------------- Response to resuscitation -ve life saving surgery D-1 ? “Damage control” +ve delayed primary surgery

Hyperinflammation “second look” only D2-4 Window of opportunity scheduled definitive surgery D5-14 Immunosuppression no surgery! Wk 3 Recovery --------------------------------------------------------------------------------------------------------------- 70

Secondary survey & assessment of pelvic fracture (stability and personality) In Secondary “regeneration “period (i.e., 2-10 days) Once the patient is haemodynamically stabilized detailed assessment of the personality of the fracture and stability should be determined. To asses this Secondary diagnostic procedures are undertaken AP, inlet, outlet and Judet view of pelvis CT scan (with contrast), fluoroscopy and stress view 3D CT, MRI, bone scan, U/S, Angiography

Once this is determined definitive pelvic fracture management is done depending upon the type of injury as described below in flow charts. Pelvic ring disruption Rapid general resuscitation “Damage control” Assessment of “personality” of injury, including stability of the ring Stable (type A or B) Unstable (type –C) Minimal Significant displacement displacement Symptomatic Asses type of injury treatment Lateral compression with Open-book injury with intact posterior impaction, inward rotation,

ligaments Unilateral (B1) or bilateral (B3- upward rotation and 1) external rotation deformity owing to shortening anterior compression or femoral external rotation Close reduction by external rotation Close reduction by “closing the book” Maintain reduction Maintain reduction Bed rest, symptomatic 71 care

Anterior external fixator Ant. Ext. Fixation or orif (Polytrauma) Anterior with symphyseal plates symphysis or Anterior ORIF for locked symphysis, tilt fracture etc. Unstable (type –C) Immediate management (first day) Rapid general resuscitation Application of an external fixator or pelvic clamp plus skeletal traction esp. For patient in shock Early management (the first week) Reassessment of skeletal injury (Esp. views, ct, angiogram if suggestive) Symphysis pubis disrupted Pubic rami fractured

Rami unstable and Rami stable displaced Internal fixation of symphysis plus ext. Frame or preferably internal fixation of posterior lesion Posterior fixation anterior external frame Posterior fixation External fixation anterior Internal fixation remi lesion Closed or open 72

Indications for ORIF of unstable pelvic disruptions (type C) ANTERIOR (symphysis or remi) -to improve pelvic stability in association with laprotomy acutely (no faecal contamination or suprapubic tube) or simplified fracture management (acute or semi acute phase) - Remi fracture associated with lesion of femoral artery or nerve -bone protruding into perineum (tilt # in female) -asso. Ant acetabular fracture that require ORIF POSTERIOR

-Inadequate reduction of posterior SI complex, esp. SI jt dislocation > 1 cm displacement or >30* ext rotation -open fracture with a posterior wound (rarely for perineal wound) -associated posterior acetabular fracture that requires ORIF Standard Operating procedure a. In Patient ) all patient of pelvic injuries are high energy trauma b. Out Patient ) they need in patient treatment for at least 24 hrs c. Day Care ) to exclude other serious injuries.

g) Referral criteria: not applicable for tertiary centre unless some facilities are missing. VI. WHO DOES WHAT? and TIMELINES a. Doctor --Monitors and supervises the treatement and performes any procedures on urgent basis, coordinates with other departments -- Arranges interhospital transfer in time b. Nurse Carry out all the treatment and maintains the formulary (drugs and consumables and equipment) c. Technician Helps in resuscitation, transport , immobilization etc. 73

VII. FURTHER READING / REFERENCES 1. WHO (1984).Tech. Rep. Ser., 703. 2. Global status report on road safety: time for action. Geneva, World Health Organization, 2009 (www.who.int/violence_injury_prevention/road_safety_status/2009). 3. Rockwood and Green’s fractures in adults, 6th and 7th edition; Rober W. Bucholz; Lippincott Williams & Wilkins. 4. Campbell’s operative orthopaedic; 11th edition; S.Terry Canale, James H. Beaty; Mosby Elesvier.

5. Chapman’s orthopaedic surgery; 3rd edition; Michael W. Chapman; Lippincott Williams & Wilkins. 6. Park’s textbook of Preventive and social medicine; 20th edition Park; M/s Banarsidas Bhanot Publishers 2009. 7. www.ncrb.gov.in 8.www.nimhans.kar.nic.in/epidmiology 74

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situati HUMAN RESOURCES INVESTIGATIONS DRUGS & EQUIPMENT on* CONSUMABLES 1 Orthopaedic Routine blood Emergency room with Emergency room surgeon, investigations (cbc, all resuscitation drugs multi-para-monitor, Anesthetist biochemistry and fluids (crystalloids infusion pumps,

Staff nurses -2, including blood gas & colloids),OT gases anaesthesia machine Technician analyzer, serum (O2 ,N2O), strecher, (+/- ventilator) lactate estimation) consumables, pelvic Blood storage ,Rhoent binder, implants, c- refrigerator genogram, CT-scan, clamp/external fixator , Operation room with Ultrasound (Doppler) Et tube ,Ryles Tube, C-arm and compatible Foleys catheter, OT table. syringes i.v.canulla, X-ray machine central line, dressing Ultrasound machine materials for large (Doppler) dressings

Blood storage facility with availability of few units of bloods Orthopaedic Routine blood Emergency room with Emergency room Situati surgeon, investigations (cbc, all resuscitation drugs Monitor, anaesthesia on* Anaesthetist biochemistry and fluids (crystalloids machine (+/- 2 including blood gas & colloids),OT gases ventilator) any other sub analyzer, serum (O2 ,N2O), strecher, Blood storage specialist as required lactate estimation) consumables, pelvic refrigerator with fully

at odd hours(e.g. ,Rhoenghtogram, binder, implants, c- equipped blood bank Gener neurosurgeon/interv Ultrasound machine clamp/external fixator with all facilities al entional (Doppler) Et tube ,Ryles Tube, (components and surge radiologist/vascular CT-scan, Foleys catheter, factors), Ultrasound on surgeon) MRI syringes i.v.canulla, machine (Doppler),ct DSA with facility of central line, dressing scan, MRI facilities Staff nurses –for ER- interventional materials for large , Operation room with 2,OT-2

angiography dressings C-arm and compatible Technician for ER-1, with OT table OT -1 Blood storage facility with availability of few ICU back-up with units of bloods intensive monitoring CT-scan, 75

Cath lab with facility of interventional angiography Rhoenghtogram, Ultrasound machine (Doppler) CT-scan, MRI 76

SPINAL INJURY I. WHEN TO SUSPECT/ RECOGNIZE? d) Introduction: With an estimated annual incidence of 300 per crore population, approximately 40,000 new spine injury cases are added every year in India. 40% of these are complete lesions i.e. tetra or paraplegia. The socio economic impact of spinal injuries is huge with 85% of victims being male in the age group of 15 to 35 years. Management of patients who have sustained spinal cord injury requires careful assessment and management. Inadequate assessment and

management of these injuries may lead to worsening of existing spinal cord injury or the production of a new cord injury. b) Case definition: For both situations of care (mentioned below*) Spinal cord injury (SCI) is an insult to the spinal cord resulting in a change, either temporary or permanent, in its normal motor, sensory, or autonomic function. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY: In the absence of a national spinal cord injury registry in India, the exact incidence is

not known. Approximately 30 cases per million population. Approximately 40% of these will be complete. Majority of the cases are due to road side accidents or fall from height. III. DIFFERENTIAL DIAGNOSIS: 77

All trauma patients should be assumed to have a spinal injury and treated as such till a detailed clinical examination and radiological investigations has been performed. Potential spinal cord injury should be suspected in following situations: a. Altered mental status. b. Evidence of intoxication. c. Associated head injury, extremity fracture d. Focal neurological deficit. e. Spinal pain or tenderness f. Mechanism of injury e.g fall from height, fall on head, whiplash injuries, high energy injuries

IV. PREVENTION AND COUNSELING : All trauma patients should be assumed to have a spinal injury and treated as such, until this can be confidently excluded. Full spinal immobilisation should be employed including a collar, spinal board and blocks. Tape can be used to secure the head to the blocks. This should be done as soon as physically possible and prior to moving the patient to a site of definitive care. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA

*Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: After the ABC have been taken care of, the patient is gently log rolled and whole of the spine is palpated for tenderness or a palpable step-off deformity. Neurogenic 78

shock, incontinence of bowel, bladder and penile erection indicate severe spine injury. A careful and detailed neurological examination is then performed and meticulously documented. 79

Assessment of motor function: Diaphragm C3-5 Shrug shoulders C4 Deltoids/elbow flexion C5 Extend wrist C6 Extension of elbow/ flexion of wrist C7 Abduct fingers C8 Active chest expansion T1-T12 Hip flexion L2 Knee extension L3-4 Ankle dorsiflexion L5-S1 Ankle plantar flexion S1-2 Assessment of sensory function Deltoid area C5 Thumb C6 Middle finger C7 Little finger C8 Nipple T4 Xiphoid T8 Umblicus T10 Symphysis T12 Anterior thigh L2 Anterior knee L3 Antero-lateral ankle L4 Dorsum of great and 2nd toe L5

Lateral side of foot S1 posterior calf S2 perianal sensation S2-5 Frankel’s grades : Spinal Cord Injury is most commonly graded using Frankel’s grades (A to E). A; Complete motor and sensory loss B: Sensation only present below lesion C: Sensations present and motor function is present but useless D: Motor useful but not normal E: No neurological deficit. 80

After the motor and sensory examination, presence of sacral sparing may be noted by voluntary rectal sphincter tone and toe flexor contractions. Presence of sacral sparing indicates a better neurological prognosis. Although spinal shock is over by 24 hours, rarely it may be prolonged. A positive bulbocavernous reflex or a positive anal wink indicates the end of spinal shock. If no motor or sensory function can be documented at this stage, a complete spinal cord injury is present. b) Investigations:

All patients with suspected spinal injury should have radiographic evaluation. 1. Initial screening can be done by conventional antero-posterior and lateral x-rays. The cervical spine radiographs must include the C7-T1 junction to be considered adequate 2. Additional Open-mouth views should be done to evaluate odontoid injury. 3. Whole spine should be evaluated with a patient of spinal injury. d. The patient should be referred for advanced diagnostic modalities only when the patient is stable:

CT Scan: CT scan cervical spine in all cases of head injuries or intoxication at the same time as the brain CT. CT should be done when plain X-Ray is inadequate particularly upper cervical spine injuries and C7-T1 junction. MRI: MRI is essential for evaluating injury to the soft tissues and ligaments, discs, intrinsic cord damage (oedema, hematoma, or contusion) and Para vertebral soft tissues. MRI is particularly useful in scenarios such as central cord syndrome

where plain radiographs will not show any fractures or dislocations. If possible MRI should be done before the cervical traction is applied. In patients with pre- injury morbidities such as Ankylosing Spondylitis, CT and MRI should be done to rule out occult instability even if x-rays are normal. b) Treatment: Standard Operating procedure a. In Patient 81

1. Once the patient with a potential spinal injury reaches the emergency, the patient should be transferred off the backboard onto a firm padded surface while maintaining spinal alignment. A baseline skin assessment can be performed at the time of shifting the patient from spine board to hospital bed. 2. Adequate number of personnel should be employed for logrolling during patient repositioning, turning and transfers. 3. Secure ABC

a. Airway: If intubation is required rapid sequence intubation with manual inline stabilisation should be done. Awake fibreoptic intubation is ideal in a cooperative patient and if facilities are available. b. Prevent and treat hypotension i. Look for other causes of hypotension such as abdominal, chest and pelvic injury ii Look for Neurogenic shock i.e. hypotension with bradycardia in cervical spine and high thoracic injuries. b. Monitor and regulate temperature

4. Perform a baseline neurological assessment on any patient with suspected spinal injury. Determine a neurological level and the completeness of injury (as described above). Perform serial examinations as indicated to detect neurological deterioration or improvement. The neurological examination should be done as per an objective system such as ASIA scoring system and documented properly. Perform serial examinations as indicated e.g. after

each intervention to detect neurological deterioration or improvement 5. Once initial resuscitation is done, complete a comprehensive tertiary trauma survey in the patient with potential or confirmed spinal cord injury. 6. In the patient with acute spinal cord injury, particularly higher cervical injury, assess and document early and frequently any evidence of traumatic brain injury (TBI) in the form of loss of consciousness and posttraumatic amnesia 82

7. Screen for thoracic and intra-abdominal injury in all patients with spinal cord injury. 8. No clinical evidence exists to definitively recommend the use of any neuroprotective pharmacologic agent, including steroids, in the treatment of acute spinal cord injury to improve functional recovery. However high dose methyl-prednislone may be used as per NASCIS III recommendations (Methylprednisolone: Bolus dose of 30 mg/kg of body

weight over 15 minutes, followed by a 45-minute pause, and then a 23-hour continuous infusion of 5.4 mg/kg/hr, If patient presents between 3 and 8 h, give the above steroid infusion for total of 48 h) if the patient presents within 8 hours of injury. The risk of complications such as such as higher infection and sepsis rates, respiratory complications and gastrointestinal hemorrhage should be kept in mind while administering steroids. 9. Genitourinary Tract :

i. Place an indwelling urinary catheter as part of the initial patient assessment unless contraindicated ii. Leave indwelling urinary catheters in place at least until the patient is haemodynamically stable iii. CIC should be taught to patient or the relatives as soon as the patient is stable 10. Gastrointestinal Tract Initiate stress ulcer prophylaxis. Evaluate swallowing function prior to oral feeding in any acute SCI patient 11. Measures to prevent bed sores:

i) Assess areas at risk for skin breakdown frequently. ii) Place the patient on a pressure-reduction mattress or a mattress overlay depending on the patient's condition. iii) Use a pressure-reducing cushion when the patient is mobilized out of bed to a sitting position. iv) Reposition to provide pressure relief or turn at least every 2 hours while maintaining spinal precautions. 83

v) Keep the area under the patient clean and dry and avoid temperature elevation. vi) Assess nutritional status on admission and regularly thereafter. vii) Inspect the skin under pressure garments and splints. viii) Educate the patient and family on the importance of vigilance and early intervention in maintaining skin integrity. b. Out Patient care A secondary hospital is expected to provide outpatient care to the spinal cord

injury patients who may be referred back from specialized centers after definitive treatment. This may be in form of i. physiotherapy for passive mobilisation of all joints and active exercises for muscles ii. Teaching of clean intermittent cathetrisation iii. Counselling of the patient and attendants iv. Care of bed sores c. Day Care Day care might be needed for situations like debridement of bed sores. c) Referral criteria: 1. The patient should be hemodynamically stable and fully resuscitated at the time

of referral 2. All the patients who need surgery (indications discussed in the next section) need to be referred to a specialized tertiary care centre. 3. The decision of need for surgery can only be made by an experienced spinal surgeon either orthopedic or neurosurgeon. In absence of these all patients with proven or suspected spine injury should be referred to a higher center. 4. It is desirable to have a two way communication with higher center while referring a patient.

*Situation 2: At Super Specialty Facility in Metro location where higher- end technology is available 84

h) Clinical Diagnosis: As described above (in situation 1) i) Investigations: Radiographic evaluation of patients with spinal injury. 1. Initial screening can be done by conventional antero-posterior and lateral x- rays. 2. Additional Open-mouth views should be done to evaluate odontoid injury. 3. Special views like swimmer’s view and oblique views can be done to see junctional areas 4. CT scan of the whole spine should be done if in presence of clinical suspicion

but fractures cannot be demonstrated on x rays or if junctional areas are not visualised. 5. MRI should be done to evaluate ligamentous injury, spinal cord injury. In patients with pre-injury morbidities such as AS,DISH, stiff spine CT and MRI should be done to rule out occult instability even if x-rays are normal. 6. Whole spine should be evaluated with a patient of spinal injury. j) Treatment: Standard Operating procedure a. In Patient

1. Once the patient with a potential spinal injury reaches the emergency , the patient should be transferred off the backboard onto a firm padded surface while maintaining spinal alignment. A baseline skin assessment can be performed at the time of shifting the patient from spine board to hospital bed. Adequate number of personnel should be employed for logrolling during patient repositioning, turning and transfers. 2. Secure ABC 85

a. Airway: If intubation is required rapid sequence intubation with manual inline stabilisation should be done. Awake fibreoptic intubation is ideal in a cooperative patient and if facilities are available. b. Prevent and treat hypotension i. Look for other causes of hypotension such as abdominal, chest and pelvic injury ii Look for Neurogenic shock i.e. hypotension with bradycardia in cervical spine and high thoracic injuries. c. Monitor and regulate temperature.

3. Perform a baseline neurological assessment on any patient with suspected spinal injury . Determine a neurological level and the completeness of injury. Perform serial examinations as indicated to detect neurological deterioration or improvement. The neurological examination should be done as per an objective system such as ASIA scoring system and documented properly. Perform serial examinations as indicated e.g. after each intervention

to detect neurological deterioration or improvement. ASIA score is very elaborate, one can follow TLISS/ TCLISS (as recommended by STSG) 4. No clinical evidence exists to definitively recommend the use of any neuroprotective pharmacologic agent, including steroids, in the treatment of acute spinal cord injury to improve functional recovery. However high dose methyl-prednislone may be used as per NASCIS III recommendations (Methylprednisolone: Bolus dose of 30 mg/kg of body weight

over 15 minutes, followed by a 45-minute pause, and then a 23-hour continuous infusion of mg/kg/hr, If patient presents between 3 and 8 h, give the above steroid infusion for total of 48 h) if the patient presents within 8 hours of injury. The risk of complications such as such as higher infection and sepsis rates, respiratory complications and gastrointestinal hemorrhage should be kept in mind while administering steroids, It is basically a treatment option,not standard care.

5. Once initial resuscitation is done, complete a comprehensive tertiary trauma survey in the patient with potential or confirmed spinal cord injury. 86

6. In the patient with acute spinal cord injury, particularly higher cervical injury, assess and document early and frequently any evidence of traumatic brain injury (TBI) in the form of loss of consciousness and posttraumatic amnesia 7. Screen for thoracic and intra-abdominal injury in all patients with spinal cord injury. 8. Perform early stabilization of extraspinal fractures. Perform this surgery as early as possible

to facilitate early rehabilitation and concomitantly with any required spinal stabilization if the patient is medically stable. 9. Surgical treatment a. Perform a closed or open reduction as soon as permissible on patients with bilateral cervical facet dislocation in the setting of an incomplete spinal cord injury b. Consider early spinal stabilization where indicated c. Consider early surgical spinal canal decompression direct or indirect in the setting of a

deteriorating spinal cord injury as a practice option that may improve neurologic recovery, although there is no compelling evidence that it will. The following algorithms may be followed as a guide to help in decision making in operative treatment of spine injuries. These algorithms are meant as a guide and the treatment plan for each patient needs to be individualised i) Upper cervical injuries a) Occipital condyle fractures:

Type III injuries require surgical stabilisation if associated with craniocervical instability Type I : Comminuted Type II : Impaction Type III : Avulsion 87

b) Atlas fractures Surgical stabilisation if: • neurologic symptoms, • instability is more than 5 mm on dynamic radiographs • significant pain is present with the evidence of nonunion. The surgical procedure is stabilization of C1-C2 or occiput-C2 c) Odontoid factures: • Anterior screw fixation in type 2 fractures. This is contraindicated in TAL injury,Comminuted fracture,Anterior oblique fractures ,Nonunion>3 months Osteoporosis ,Barrel chest. Posterior arthrodesis can be done in such cases.

d) Hangman fractures: Type 3 require stabilization. Type I Type II Type II a Type III 88

ii) Subaxial Cervical Spine Injuries Following algorithms might be used to treat subaxial spine injuries Unstable reduced No Anterior Neural Ye No Posterior disruption Ye No Posterior disruption Ye Anterior approach Posterior Anterior approach Anterior approach Consider complimentary posterior 89

Unstable displaced No Reduction with traction Ye No Anterior Neural Ye Follow algorithm Operative reduction Anterior approach anterior or posterior Ye Reduction No Consider complimentary anterior Anterior fusion Posterior reduction with or posterior fixation additional anterior Consider complimentary posterior 90

iii) Surgical treatment of thoracolumbar and lumbar injuries AO classification (annexure ) provides a useful guide in planning the surgical treatment. Type A injuries Complete or Incomplete Neurological deficit with Wedging > 50% No Yes or Kyphosi >25% or Canal Encroachment > 50% Surgery Conservative Anterior Posterior approach Corpectomy Reduction Decompression Stabilisation Structural Decompression by support ligamentotaxis Strut/cage + Posterolateral fusion Strut/cage Insufficient canal clearance

Insufficient ant. support Corpectomy Decompression Structural support Strut/cage 91

1) MRI confirmed PLC injury may need posterior stabilization only Type B Injuries Posterior approach Reduction Stabilisation Posterolateral Fusion if ligamentous (B1) injury Insufficient canal clearance Insufficient ant. Support Corpectomy Decompression Structural support Strut/cage 92

Type C Injuries Posterior approach Reduction Stabilisation Posterolateral Fusion Insufficient canal clearance Insufficient ant. Support Corpectomy Decompression Structural support Strut/cage 93

10. Adjunctive measures: c. Assess areas at risk for skin breakdown frequently. d. Place the patient on a pressure-reduction mattress or a mattress overlay depending on the patient's condition. e. Use a pressure-reducing cushion when the patient is mobilized out of bed to a sitting position. f. Reposition to provide pressure relief or turn at least every 2 hours while maintaining spinal precautions. g. Keep the area under the patient clean and dry and avoid temperature elevation.

h. Assess nutritional status on admission and regularly thereafter. i. Inspect the skin under pressure garments and splints. j. Educate the patient and family on the importance of vigilance and early intervention in maintaining skin integrity. 11. Genitourinary Tract Place an indwelling urinary catheter as part of the initial patient assessment unless contraindicated Leave indwelling urinary catheters in place at least until the patient is haemodynamically stable

CIC should be taught to patient or the relatives as soon as the patient is stable 12. Gastrointestinal Tract § Initiate stress ulcer prophylaxis. § Evaluate swallowing function prior to oral feeding in any acute SCI patient with cervical spinal cord injury, halo fixation, cervical spine surgery, prolonged intubation, tracheostomy. 94

b. Out Patient Out patient care is needed for non surgically treated patients on ambulatory care andSurgically treated patients. This will entail: Prescription of appropriate orthoses Physiotherapy services Counselling: social, psychological,vocational c. Day Care k) Referral criteria: Surgically treated patients may be referred back to secondary hospitals for physiotherapy, and care of back, bladder and bowel. VI. WHO DOES WHAT? and TIMELINES a. Doctor Primary assessment and resuscitation

Clinical diagonosis Ordering and interpretation of investigations Clinical decision making Surgical procedures b. Nurse Primary resuscitation can be performed by a nurse Prevention of bed sores Maintenance of inventory(drugs,consumables etc.) Operating room assistance c. Technician Pre trauma technicians do primary immobilization and do safe transport to hospitals Primary resuscitation can be performed by technicians Appropriate radiological investigations Physiotherapy 95

FURTHER READING / REFERENCES 1. AO Spine manual: Max aebi, J Arlet, J Webb. Thieme publishers 2. Rockwood and Green’s fractures in adults, 6th and 7th edition; Rober W. Bucholz; Lippincott Williams & Wilkins. 3. Campbell’s operative orthopaedic; 11th edition; S.Terry Canale, James H. Beaty; Mosby Elesvier. 4. Chapman’s orthopaedic surgery; 3rd edition; Michael W. Chapman; Lippincott Williams & Wilkins. 5. Sekhon LH, Fehlings MG. Epidemiology, demographics, and pathophysiology of acute

spinal cord injury. Spine 2001;26:S2–12 6. Transfer to definite care. In advanced trauma life support for doctors’ student course manual; 8th edition: Chicago; American college of surgeon: 2008:269-76 7. Trauma practice guidelines of the Eastern Association for the surgery of trauma (EAST). Identifying Cervical spine Injuries following Trauma www.east.org 8. Amar AP, Levy ML. Pathogenesis and pharmacological strategies for mitigating

secondary damage in acute spinal cord injury. Neurosurgery 1999; 44:1027–39. 9. Practice Management Guidelines for the Screening of Thoracolumbar Spine Fracture The Journal of TRAUMA_ Injury, Infection, and Critical Care Volume 63 • Number 3 709- 713 96

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 Orthopaedic Routine blood Emergency room Emergency room surgeon, investigations ( with all resuscitation multi-para- cbc, Anesthetist drugs and fluids monitor, infusion biochemistry including blood gas

Staff nurses -2, analyzer, serum lactate (crystalloids & pumps, estimation) Technician colloids),OT gases anaesthesia Roentgenogram, , (O2 ,N2O), spine machine (+/- CT-scan immobiliser, hard ventilator) Blood storage cervical collars, refrigerator Et tube ,Ryles Tube, , Operation Foleys catheter, room with C-arm syringes i.v.canulla, and compatible central line, with OT table Blood storage facility with availability of few units of bloods 2 Team of Routine blood Emergency room Emergency room

Orthopaedic investigations ( with all resuscitation Monitor, cbc, surgeons with at biochemistry including blood gas drugs and fluids anaesthesia analyzer, serum lactate least one with (crystalloids & machine (+/- estimation) training in spine Roentgenogram, colloids),OT gases ventilator) , surgery, CT-scan, (O2 ,N2O), strecher, Blood storage Anaesthetist MRI consumables, spine refrigerator with boards and cervical fully equipped Staff nurses –for collars, Et tube blood bank with

ER-3,OT-3, ,Ryles Tube, Foleys all facilities wards-4 catheter, syringes (components and Technician for i.v.canulla, central factors), ER-1, OT -1 line, Ultrasound machine Physiotherapists- Air Matresses (Doppler),ct 2 scan, MRI 97

facilities Blood storage , Operation facility with room with C-arm availability of few and compatible units of bloods with OT table ICU back-up with intensive monitoring 98

ANNEXURE 2 AO classification of thoracolumbar fractures n Type A: n Vertebral body compression- injury patterns of the vertebral body n Type B: n Anterior and posterior element injuries with distraction, characterized by transverse disruption either anteriorly or posteriorly n Type C: n Anterior and posterior injuries with rotation, injury patters resulting from axial torque 100

THE NEUROLOGICAL DISORDERS: POLIOMYELITIS AND CEREBRAL PALSY. Standard treatment guidelines for Poliomyelitis 1. Introduction/Definition/Description Poliomyelitis is an acute viral infection caused by polioviruses (three antigenic types I, II, and III). The poliovirus is an enterovirus. All three viruses can cause paralysis; however it occurs most commonly by type I followed by type III and very rarely by type II. 2. Incidence of the condition

Due to intensive pulse polio immunization along with routine immunization has reduced its incidence to negligible and it almost near eradication in our country. But there are still a reasonable number of patients of residual paresis who need some sort of surgical correction either for proper fitting of orthosis or for the proper use of the extremity. 3. Differential diagnosis The cases of cerebral palsy, myopathies and the neuropathies like motor neuron

disease, Gullain-Barre syndrome etc need to be differentiated from poliomyelitis. 4. Clinical features Three types of cases occur: Inapparent infections (95% cases), non-paralytic infections (about 5%) and paralytic cases 0.5% cases. The acute attack can cause death in 2-10% of case. The non-paralytic infection is manifested by fever, sore throat, headache, nausea, vomiting, diarrhea and rigidity of the neck and back lasting for 2-10 days. The

paralytic attack is manifested by acute flaccid paralysis of the muscles of the limb or the trunk and face followed by maximum recovery within 6 months. Broadly and conventionally these are acute attack and the residual paresis and paralysis. 5. Management Primary Health centre level: 101

No surgical treatment is expected at this level. Only referral to higher centre. One should recognize the features of flaccid or lower motor neuron level disorder and its residual effects. CHC and Civil Hospital level: The acute poliomyelitis is managed by pediatricians and the orthopedics management include only the splintage of the extremity in the functional and proper resting position till the phase of convalescence. For residual motor weakness: The goal of the treatment at the non metro

clinic or small hospital is: Evaluation of the motor weakness by muscle power charting by Medical Research Council (MRC) grading system (Grade 0 to5). X-rays of the affected area as per the requirement. Following can be done at this level: Prescription of orthosis/calipers and its fitting; -corrective cast application; -Simple corrective procedures like- tenotomy for the tight tendo-achillis; lengthening of tendon etc -arrangement of

polio corrective surgery camps ( but the team of surgeons from teaching Medical Institute/College should evaluate the cases and supervise the surgeries). -Additionally at the district level hospital the patients can provided the orthosis and walking aids (like sticks, crutches, walkers etc), and wheel chair/tricycles from the district level charitable agencies (Governmental/Non-governmental). -They can be issued the disability certificates for their financial benefits for various

schemes run by the Government. Criteria for referral: The cases who need investigations like nerve conduction studies and electromyographies. Those who need tendon transfers, correction of deformity at multiple joints and in different planes. Any case where the non metro level surgeon is in doubt in decision making of the type of surgery should be referred. Situation 3 102

At the metro or the medical college level hospital the goal of management of these cases include: In addition to the situation 1- If required the elctromyographic studies, nerve conduction studies. Then all surgeries for the correction of deformity -by tendon transfer (dynamic) -the osteotomies/tenodesis, -tendon lengthening, - tenotomies, capsulotomies and arthrodesis as per the indication and after the careful evaluation of the individual. The goal of the treatment is focused on the

independent walking (for lower limb) or the proper use of the upper extremity with/without orthosis. The lower extremity should be with planti-grade foot with no or minimal residual deformity at various joints and the limb should be suitable for fitting of the orthosis/calipers. The upper extremity should be made for the independent usage with/without support. Various common surgical procedures include: Tendo-achillis lengthening-for equinus correction,

Jone’s Teno-suspension- for dropped first metatarsal and sub-luxed 1st metatraso-phalangeal joint, Tibialis posterior tendon transfer- for foot drop, Dorsal bony wedge resection (Japa’s) and Steindler’ release for cavus foot deformity correction, Osteotomy for deformity correction (e.g. supra-condylar osteotomy), Tendon lengthening/tenotomies and capsulotomies-for contracture release, Tripple arthrodesis for talipes equino-varus correction in mature feet etc. 103

All the surgeries should be performed by the experienced surgeon and standard text book on the subject should be available in the operation theatre for the reference. 104

Resources required for patient and procedure Situation Human Investigations Drugs and Equipment consumables Resources 1 Doctor, Nurse and other None None No surgical paramedics intervention except first aid 2 Doctor, X-rays, Complet Plaster bandage Theatre set up for Nurse, Haemogram, PVC splints and Surgeries with all Bleeding time, and technicians Braces, Basic equipments Clotting time, Complete Calipers urine examinati for for pre-anaesth check up 3 Doctor, As situation 1 As situation 1 As situation 1

Physiotherapist, and tricycle, and major physio- Nurse, orthotist, wheel chair etc therapy set up for Prosthetist, rehabilitation and technicians References: 1. WHO. The initiative for global eradication of poliomyelitis- a guide to clinicians. Geneva: WHO; 1994. 2. GOI, Evaluation of Pulse polio Immunization India1996-97.New Delhi: MOH and FW; 1997. 3. Warner WC, Jr. Paralytic disorders. In:Campbell’s Operative Orthopaedics. Eleventh Eds; 2008.pp.1401-98.

4. Turek SL. Orthopaedics-Principles and Their Application. 4th Eds. In: Orthopaedics Neurology. 1998. Pp.464-595. 105

STANDARD TREATMENT GUIDELINES FOR CEREBRAL PALSY 1. Definition: Cerebral palsy is defined as the non-progressive motor impairment (motor neurological deficit) due to the insult to the developing brain; affecting the movements and posture, however, no sensory impairment. The involvement of the brain most commonly occurs between the time of conception and the age 2 years (the time of major motor development). After 8 years of the age,

the development of the immature brain is almost complete; its affection is just like adults. This is very common disorder in the child hood and its incidence is on rise. 2. Types: As per the time of affection of the brain this is categorized as prenatal, perinatal and post natal. Most common is prenatal and only less than 10% cases are affected during the delivery time i.e. perinatal. 3. Management For the management, the complete and proper evaluation of the individual as

whole and the affected part is mandatory. Some times in the situation of spasticity it is difficult to judge the muscle power and the treatment can be worsening rather than improving the functions and there can also be recurrence of the deformity. Therefore, whenever in doubt, the peripheral surgeon can refer the patient to the medical institute or to the metro hospital for the treatment after evaluation. These patients apart from motor power evaluation may require

the gait analysis; MRI of the brain and electromyography. The treatment of the some rare types of cerebral palsy is really difficult and very much demanding even at the level of the medical institute or the metro hospital. At the metro hospital the team approach involving the peaediatrician, the orthopedic surgeon, psychiatrist, physiotherapist and psycho-social workers is required for the better outcome in such patients. Situation 1 106

No surgical intervention is expected at this level. One should refer the patient to the higher centre. CHC/Civil Hospital level: At the non-metro hospital only simple surgeries like tendo-achillis tenotomy and adductor tenotomy for equines and the scissoring gait respectively can be tried and that too if the operating surgeon has the confidence and has reasonable experience. Otherwise it is better to refer the patient. The goal of the treatment at the non metro clinic or small hospital is:

Evaluation of the motor weakness by muscle power charting by Medical Research Council (MRC) grading system (Grade 0 to5). Following can be done at this level: - Prescription of orthosis/calipers and its fitting; -corrective cast application; -Simple corrective procedures like- tenotmy for the tight tendo-achillis; lengthening of tendon and adductor tenotomy etc. 3.4-Arrangement of camps for providing orthosis and walking aids-Additionally at the

district level hospital the patients can be provided the walking aids (like sticks, crutches, walkers etc), and wheel chair from the district level charitable agencies (Governmental/Non-governmental). They can be issued the disability certificates for their financial benefits from various schemes run by the Government. Criteria for referral: The cases that need special investigations like nerve conduction studies, electromyographies and MRI/CT scans. Those who need tendon

transfers, correction of deformity at multiple joints and in different planes; and need care of multiple specialists under one roof. Any case where the non metro level surgeon is in doubt in decision making of the type of surgery should be referred. 3.2Situation 2 At the metro or the medical college level hospital the goal of management of these cases include: In addition to the situation 1- If required the elctromyographic studies, nerve conduction studies, MRI and CT scan of brain as per indication.. 107

The non surgical treatment like botulinum injection can be given to relieve the spasticity. Then all surgeries for the correction of deformity -by tendon transfer -the osteotomies/tenodesis, -tendon lengthening, -tenotomies, capsulotomies and arthrodesis as per the indication and after the careful evaluation of the individual. The goal of the treatment is focused on the independent walking (for lower limb) or the proper use of the upper extremity with/without

orthosis. The lower extremity should be with planti-grade foot with no or minimal residual deformity at various joints and the limb should suitable for fitting of the orthosis/calipers and if feasible for independent walking. The upper extremity should be made suitable for fitting of orthosis and for the use in daily day to day routine like self eating, bathing; cleansing after toilet etc. Various common surgical procedures include: Tendo-achillis lengthening-for equinus correction,

Adductor tenotomy – to correct scissoring gait Split tibialis anterior transfer for inversion foot Tibialis posterior tendon transfer- for foot drop, Egger’s operation/Fractional release of hamstrings (Tendon lengthening/tenotomies and capsulotomies)-for knee contracture release, Tripple arthrodesis for talipes equino-varus correction in mature feet. Flexor pronator release and transfer of flexor carpi ulnaris to the wrist dorsiflexors for contracture of flexor and pronator muscle group.

Sever’s and Fairbank operation and derotation osteotomy of humerus- for internal rotation contracture at shoulder etc All the surgeries should be performed by the experienced surgeon and standard text book on the subject should be available in the operation theatre for the reference. 108

Resources required for patient and procedure Situation Human Investigations Drugs and consumab Equipment Resources 1 Doctor, None None No surgical Nurse, and paramedi intervention except first aid. 2 Doctor, X-rays, Complete Plaster bandages Theatre set up for Nurse, Haemogram, Bleeding PVC splints and Surgeries with all and technicians time, Clotting time, Complet Braces, Basic equipments urine examination for Calipers for pre-anaesthetic check up 3 Doctor, As situation 1 As situation 1 As situation 1

Physiotherapist, and CT scan, MRI and wheel chair, and major physio- Nurse, orthotist facilities tri-cycles etc therapy set up for prosthetist rehabilitation and technicians 109

References: 1. Sawyer JR. Cerebral Palsy. In: Campbell’s Operative Orthopaedics. Eleventh Eds. 2008. pp. 1333-99. 2. Turek SL. Orthopaedics-Principles and Their Application. 4th Eds. In: Orthopaedics Neurology. 1998. pp.464-595. 110

ANKYLOSING SPONDYLITIS I. WHEN TO SUSPECT / RECOGNIZE? a. Introduction: A form of spondyloarthritis, is a chronic, inflammatory arthritis and autoimmune disease. It mainly affects joints in the spine and the sacroiliac joint in the pelvis, and can cause eventual fusion of the spine. b. Case Definition: The typical patient is a young male, aged 20–40, however the condition also presents in females. The condition is known to be hereditary. Symptoms of

the disease first appear, on average, at age 23 years. These first symptoms are typically chronic pain and stiffness in the middle part of the spine or sometimes the entire spine, often with pain referred to one or other buttock or the back of thigh from the sacroiliac joint. II. INCIDENCE OF CONDITION IN OUR COUNTRY Three men are diagnosed with AS for every one woman; the overall prevalence is 0.25%. Many rheumatologists believe the number of women with AS is

underdiagnosed, as most women tend to experience milder symptoms. III. DIFFERENTIAL DIAGNOSIS Differential diagnosis of Ankylosing Spondylitis include 1. Rheumatoid Arthritis 2. Other Spondylo arhtropathies IV. PREVENTION AND COUNSELLING As no direct cause for the disease has been identified the preventive measures could not be established. Patient needs to be counselled regarding the chronic nature of the disease and need for regular treatment, possible complications and possible treatment

options and chances of improvement. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA * SITUATION 1: At Secondary Hospital / Non Metro situation : Optimal standards of Treatment in situations where technology and resources are limited a. Clinical diagnosis: 111

chronic pain and stiffness in the middle part of the spine or sometimes the entire spine, often with pain referred to one or other buttock or the back of thigh from the sacroiliac joint. Post inactivity stiffness and morning stiffness. In 40% of cases, ankylosing spondylitis is associated with an inflammation of the eye (iritis and uveitis), causing redness, eye pain, vision loss, floaters and photophobia. This is thought to be due to the association these two

conditions have with inheritance of HLA-B27. Other common symptoms are generalized fatigue and sometimes nausea. b. Investigations: 1. X Ray 2. CT Scan 3. MRI 4. Complete Blood Picture 5. ESR 6. CRP 7. Liver function test 8. Renal function test 9. HLA B27 c. In a patient complaining of back pain of more than 12 weeks duration: 1. Morning stiffness of > 30 minutes 2. Improvement in back pain with exercise but not with rest. 3. Awakening because of back pain during the second half of the night only .

4. Alternating buttock pain. 5. Peripheral assymetrical large joint involvement. 6. Plain X Ray showing features of sacroilitis. 7. Absence of RA factor. Any 2 out of first four criteria strongly indicate presence of Ankylosing Spondylitis even in the absence of xray and lab investigations. d. Treatment: Standard Operating Procedure i. In Patient : 1. Surgery a. Joint Replacement for hip and knee. ii. Out Patient : 112

1. NSAIDS: First line therapy to relieve symptoms. 2. DMARDs such as cyclosporin, methotrexate, sulfasalazine, and corticosteroids, used to reduce the immune system response through immunosuppression; DMARDs are useful only for peripheral arthritis & not for axial skeleton involvement. iii. Physical Therapy – Patients to be encouraged to undertake active and passive range of motion exercises for all joints to maintain and prevent the progression of loss of mobility. Deep breathing exercises

(Pranayaam) should be promoted to improve chest function. iv. Day Care 1. Injectable medications d. Referral criteria: For further evaluation and management of cases not responding to conventional therapy. * SITUATION 2: At Super Specialty facility in Metro Location where higher end technology is available a. Clinical diagnosis: As in situation 1 b. Investigations: As in situation 1 c. Treatment: Standard Operating Procedure i. In Patient : as in situation 1. Others include

1. Corrective surgeries for spinal deformity ii. Out Patient : As in situation 1. In addition to that 1. TNFα blockers (antagonists) such as etanercept, infliximab, golimumab and adalimumab (also known as biologics), are indicated for the treatment of and are effective immunosuppressants in AS as in other autoimmune diseases. iii. Day Care: As in situation 1 113

d. Referral criteria: VI. WHO DOES WHAT? AND TIMELINES a. Doctor Early diagnosis and appropriate treatment. Counsel the patient for prevention of deformities and dietary advice. b. Nurse counseling the patient. Injectable treatment c. Technician Appropriate bracing manufacturing and application of braces Physiotherapy VII. FURHTER READING / REFERENCES 1. Garrett S, Jenkinson T, Kennedy L, Whitelock H, Gaisford P, Calin A (1994). "A new approach to defining disease status in ankylosing spondylitis: the Bath

Ankylosing Spondylitis Disease Activity Index". J Rheumatol 21 (12): 2286–91 2. Jiménez-Balderas FJ, Mintz G. (1993). "Ankylosing spondylitis: clinical course in women and men". J Rheumatol 20 (12): 2069–72 3. Khan MA. (2002). Ankylosing spondylitis: The facts. Oxford University Press 4. Reveille JD (2006). "Major histocompatibility genes and ankylosing spondylitis". Best Practice & Research Clinical Rheumatology 20 (3): 601–609 114

RESOURCES REQUIRED FOR ONE PATIENT /PROCEDURE (PATIENT WEIGHT 60KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) SITUATION HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 Doctor 1. X Ray a. DMARDs Lab Nurse 2. CT Scan b. NSAIDs equipment Technician 3. MRI c. Steroid Imaging 4. Complete d. Consumables equipment Blood Picture for surgery Exercise 5. ESR equipments 6. CRP Equipments

7. Liver function for Operating test Room 8. Renal function test 9. HLA B27 2 Biologic Agents Spinal (In Addition Fixation to Situation implants 1) 115

BONE TUMOURS, TUMOUROUS CONDITIONS & DEVELOPMENTAL DISORDERS MIMICKING BONE TUMOURS 1) Name of the conditon: Benign Bone Tumours - Ivory Osteoma I. When to suspect / recognize : Introduction: Benign bone tumour arising from osteoblasts, Bony (ivory) hard in consistency, 1 or 2 cm in size, over a flat bone, usually frontal bone asymptomatic unless the deeper extension is pressing on the brain which is very unusual II. Incidence: Not worked out in our country, not very common

III. Differential Diagnosis: None IV. A)Prevention: Nil V. B) Counselling: to report if symptomatic VI. Situation 1. Non-metro Hospital VII. a) Clinical Diagnosis: Hard painless swelling over frontal bone b) Investigation: X-ray VIII. c) Treatment : Usually left alone; can be excised for cosmetic reasons d) referral criteria: If enlarging in size or symptoms of compression on brain Situation 2. Metro location hospital a) Clinical Diagnosis; same as situation1 b) Investigation: X-ray, CT Scan if necessary

c) Treatment: Asymptomatic lesions left alone, Excision of symptomatic ones or for cosmetic reasons Resources Required: Situation 1. Doctor, X-ray machine Situation 2: Doctor (Orthopedic Surgeon / Neuro surgeon), X-ray machine, CT Scanner 2) Name of the condition: Benign Bone tumour – Osteoid Osteoma I. Introduction: Benign bone tumour, vascular and very painful, about 1 cm in size; elicits sclerotic reaction by the parent bone when the lesion is in the

cortical bone; In cancellous bone the lesion is limited by a thin rim of sclerotic bone; in the spine it can cause scoliosis; if the lesion is in the metaphysis which is intraarticular can produce symptoms of arthritis; If the lesion is in the evolving stage it may not be seen routine plain radiography. II. Incidence: Not uncommon; 10% of benign bone tumours III. Differential Diagnosis: usually None in cortical bone, occasionally chronic

osteomyelitis; In the cancellous bone – Brodie’s abscess, arthritis, unusual form of tuberculosis IV. Prevention: Nil V. Situation 1: Non metro hospital: 116

a) clinical diagnosis may be difficult b) Investigation X-ray c) Treatment may be difficult d) referral criteria – suspicion, inability to diagnose Situation 2. Metro hospital a) clinical diagnosis as per description in introduction b) Investigation: X-ray, CT scan, MRI if necessary c0 Treatment: Excision in toto (enbloc in cortical bone); curettage in cancellous bone; In inaccessible locations – radiofrequency / laser ablation under CT guidance; curetted/excised material sent for histopathology

Resources required: Situation 1: Doctor, x-ray machine Situation 2: Orthopedic surgeon, Interventional Radiologist, X-ray machine, CT Scanner, MRI scanner, Radiofrquency ablator / Laser machine. Histopathologist, Facilities for surgery 3) Name of the condition: Benign Bone tumeour – Osteoblastoma I. Introduction: Benign bone tumour arising from osteoblasts II. Incidence: Very rare III. Differential Diagnosis: Other tumourous conditions like Aneurysmal bone cyst, Fibrous dysplasia IV. Prevention: Nil

V. Situation 1. Non metro Hospital a) clinical diagnosis – nothing specific b)Investigation –X-ray c)Referral criteria: If facilities and know-how are not available for curettage and bone grafting Situation 2: a)clinical Diagnisis is difficult. Diagnosis is usually radiological – multi loculated lytic expansile lesion with some new bone formation b) Investigations: Plain X- ray and CT scan c) Treatment: curettage and bone grafting; material sent for histopathology Resources required:

Situation 1: Doctor, X-ray machine Situation 2: Orthopedic surgeon, operating facilities, Histopathologist 3) Name of the condition: Benign Bone tumour Osteochondroma I. Introduction: Benign tumour arising from Chondroblasts of the growth plate; it can be of two types – pedunculated or sessile; the lesions grow as long as the skeleton grows and stop when the growth plates fuse II. Incidence: most common benign tumour from bone; 30 to 50 % of benign bone tumours, 10 to 15 % of all bone tumours 117

III. Differential diagnosis: Chondrosarcoma (secondary), parosteal sarcoma may be mistaken for osteochondroma IV. Prevention: Nil V. Situation 1. a) clinical diagnosis – hard painless swelling in the metaphysis with negligible growth in recent past b) Investigations- X-ray c) Treatment – excision in toto if the lesion is solitary d) referral criteria – recent fast growth, recent onset of pain, nerve palsy distal to tumour or interference with mobility pf neighbouring joint

Situation 2. a)clinical diagnosis – same as above b) Investigations – plain X- ray, CT scan, MRI c)Treatment – differentiation between benign and malignant transformation; if benign excision in toto; If malignant – investigate for lung metastasis followed by wide excision / amputation as the case may be 5) Name of the condition: Benign Bone tumour Enchondroma I. Introduction: Benign bone tumour arising from chondroblasts; usually present in the

small bones of hands and feet and asymptomatic for long time; patient presents usually with a pathological fracture or sometimes pain. II. Incidence: not uncommon; 25 % of all benign tumours, most common primary tumour in the hand III. Differential Diagnosis: Aneurysmal bone cyst, Tubercular dactylitis, Giant cell tumour, clear cell chondrosarcoma & acrometastases. The latter two are extremely rare. IV. Prevention: Nil

V. Situation 1. a) clinical diagnosis: swelling small bones of hands with minimal pain or a pathological fracture b) Investigations: X-ray c) Treatment: may not be possible in non metro scenario d) referral criteria: lytic lesion in small bones where diagnosis & treatment are not possible at non metro level hospital Situation 2. a) clinical diagnosis: same as above b) Investigations: X-ray of the part, X-ray of chest, Needle Biosy, Mantoux test if necessary, Blood for Quanteferon Gold test,

c) Treatment: curettage and auto/allo cancellous bone grafting, if there is a pathological fracture – needs fixation with plate and screws.(small fragment set) 6) Name of the condition: Benign Bone Tumours – Benign Chondroblastoma ) & Chondromyxoid Fibroma I. Introduction: Benign cartilaginous tumours; the former is also called “Codman’s Tumour”. They may show specks of calcification signifying their cartilaginous origin. The latter can be aggressive; ends of bone are

commonly involved especially tibia , proximal humerus and proximal femur II. Incidence: rare tumours; less than 1 % of all primary bone tumours III. Differential Diagnosis: Aneurysmal bone cyst, GCT 118

IV. Prevention: Nil V. Situation 1. a) clinical diagnosis – pain and vague swelling, restricted movemets of the neighbouring joints due to reflex spasm b) Investigation – X-ray c) Treatment –Plaster slab application; further management may not be possible in non-metro scenario d) referral criteria – for precise diagnosis and further management Situation 2. a)clinical diagnosis – same as above b)Investigation X-ray, MRI, wide bore needle biopsy c)Treatment – curettage and bone grafting (auto or allo)

7) Name of condition: Benign Bone tumour – Non-ossifying Fibroma I. Introduction: Benign bone tumour arising from fibroblasts. Usually seen in the metaphyseal region of immature skeleton and most of the times it is asymptomatic. It may be an incidental finding in a x-ray taken for some other purpose or bigger lesions may present as pathological fractures. They have a characteristic radiological appearance of serpigenous margins which have pencil lined sclerotic borders. II. Incidence: not uncommon

III. Differential Diagnosis: none IV. Prevention: nil V. Situation 1. a) clinical dianosis may not be possible b) Investigation – plain x-ray c) Treatment: asymptomatic, small and incidental lesions are left alone and observed. d) Referral criteria: big lesions and pathological fractures Situation 2. a) clinical diagnosis may not be possible. Big lesions are curetted prophylactically to prevent pathological fractures and bone grafted. Once they present

with a pathological fracture – either they are immobilized in plaster cast till the fracture unites and then curetted and bone grafted or the fracture is openly reduced and internally fixed and at the same time the lesion is curetted and bone grafted. 8) Name of condition: Benign tumourous conditions – Simple Bone Cyst, Aneurysmal Bone cyst & Fibrous Dydplasia I. Introduction: These lesions mimic tumours and they look alike. Usually occur in

adolescents. Lytic lesions with clear cut zones of transition. ABC may show fluid levels in MRI; Fibrous dysplasia has ground glass matrix They may present with pain and swelling or with pathological fracture. II. Incidence : not very common III. Differential Diagnosis: GCT, cartilaginous tumours IV. Prevention: Nil V. Situation 1. a) clinical – nothing specific except pan]in ful swelling, not large or may present with pathological fracture. b) Investigation: x-ray

c) referral criteria – Lytic lesion in bone seen on x-ray picture with or without pathological fracture d) Treatment plaster slab and referral to higher centre Situation 2. a) clinical: same as above 119

b) Investigations – X-ray, CT scan / MRI, needle biopsy c) Treatment – curettage and bone grafting; if the patient has a pathological fracture, either the limb is immobilized in plaster cast till the fracture unites and then curettage and bone grafting carried out or the lesion is curetted and bone bone grafted and at the satime the fracture is internally fixed. 9) Name of condition: Benign Tumourous condition – Fibromatosis I. Introduction: A benign very slow growth of in the subcutaneous tissue or

intermuscular connective tissue – does not metastasise but recurrence rate after excision is very high. II. Incidence: rare III. Differential Diagnosis: Other malignant soft tissue tumours like synovial sarcoma or fibrosarcoma. IV. Prevention Nil V. Situation 1. a) clinical: Firm swelling in the soft tissue of long duration, minimally painful b) Investigations – x-ray- may not reveal any information c) Treatment: cannot be treated in small centres – to be referred to higher centres

Situation 2. a) clinical : same as above b) Investigations: plain x-ray, CT scan, MRI, CT chest, Trucut needle biopsy c) Treatment: wide excision with a little surrounding soft tissue to prevent recurrence 10) Name of condition: Benign developmental disorders mimicking bone tumours: SMultiple Osteochondromatosis, Muliple enchondromatosis, Ollier’s disease I. Introduction: Freak outgrowths from the growth plates – multiple osteochondromatosis- which is familial and producing remodeling and growth

abnormalities and ten times more potent for malignancy than its solitary counterpart. Freak inclusions of cartilaginous masses from growth plates into the metaphysic producing streaks of lucency is Ollier’s disease – usually present in one side of the body and produces marked growth anomalies. Proliferation of cartilage in the medullary substance of small bones of hands and feet producing globular swellings is multiple enchondromatosis. This condition is not familial and is also associated with growth

disturbances. II Incidence: The former is quite common whereas the other two are rare; multiple osteochondromatosis is 10 times less common than solitary osteochondroma. III. Differential Diagnosis: usually none; One has to be vizilant to look for a malignant transformation in one of the lesions - the more proximal the lesion is to the axial skeleton more are the chances of malignancy. IV. Prevention: prevent consanguineous marriages

V. Situation 1. a) clinical: multiple hard swellings in the metaphyseal regions of long bones or on the flat bones or multiple globular swellings in the short long bones of hands and feet with growth disturbances. Recent increase in size and onset of pain to be enquired. Mechanical restriction of motion of a neighbouring joint or compression of a nearby nerve are to be looked into b) Investigation – Only plain x-ray is possible d) referral criteria – all cases to be referred to higher centres. 120

Situation 2. a) clinical – same as above b) Investigation : Plain x-ray, CT scan, MRI, wide bore needle biopsy; Caution: Histology cannot be relied upon in diagnosing malignancy in cartilaginous lesions; One has to rely on clinical findings like pain and fast growth to diagnose malignancy. A cartilaginous cap of more than 1 cm thickness as seen in MRI is suggestive of malignancy. c) Treatment: Lesions with complications should be excised.

Lesions very proximal to the axial skeleton should be excised prophylactically 11) Name of condition: Benign Aggressive tumour – Giant Cell Tumour (Osteoclastoma) I, Introduction: .A benign bone tumour arising from undifferentiated connective tissue cells of bone marrow. Occurs in the mature skeleton usually around knee and at wrist. It is an aggressive tumour and the chances of recurrence following curettage are very high. A small percentage might even metastasise to lungs.

II. Incidence: much more common in India, especially South India (4 to 6 times), than the western world. III. Differential Diagnosis: Aneurysmal bone cyst, Benign Fibrous histiocytoma and aggressive chondromyxoid fibroma., Hyperparathyroidism IV. Prevention: Nil V. Situation 1. a) clinical: a globular eccentric swelling in a mature skeleton around the knee bones or lower radius. Other sites are less common. Swelling may start before

pain. The patient may present with a pathological fracture. b) Investigation – x-ray. c) Treatment not possible in non metro hospitals. d) referral criteria- all suspected cases must be referred to higher centre. Situation 2. a) clinical: same as above b) Investigations: Plain x-ray, CT scan, MRI, wide bore needle biopsy c) Treatment: Curettage with h igh speed burr, curettage with usage of adjuvants like phenol or liquid nitrogen (cryosurgery) have been in usage. However,

extended curettage has the least chances of recurrence. Excision in toto is ideal if the bone involved is expendable (like lower ulna, proximal fibula). In instances like lower radius, excision and reconstruction using proximal fibula is practiced. In weight bearing bones like distal femur or proximal tibia, when the the bone is totally destroyed, resection arthrodesis (Enneking procedure) is ideal if the patient belongs lower socioeconomic group. But if the patient belongs to higher strata where the load

demands are less, excision and custom mega prosthesis may be practiced. In fungating cases or after repeated recurrences, an amputation may be the last resort. 12) Name of condition: Malignant bone tumour: Osteosarcoma & its variants I. Introduction: occurs in second decade of life. II. Incidence: most common malignant tumour in the immature skeleton III. Differential Diagnosis: Early lesions are difficult to diagnose unless one has high

index of suspicion. Any pain in the metaphyseal region following a minor injury and disproportionate to the injury or if the pain is slowly increasing day by day after minor injury and especially without fever should lead the clinician to suspect this sinister disease. If it occurs after skeletal maturity, Giant cell tumour also must be thought of. IV. Prevention: Genetic engineering is under trial to prevent the lesion in children who are genetically prone to suffer. 121

V. Situation 1. a) clinical: as described earlier in diff. diag. In late cases pain preceding a spindle shaped swelling in the metaphysic of long bone must give suspicion of osteosarcoma. b) Investigations: plain x-ray c) referral criteria: any suspicion that the swelling is malignant. Situation 2. a) clinical: same as above b) Investigations: plain x-ray, x-ray chest, Serum alkaline phosphatase, MRI of lesion, CT Chest, needle biopsy

c) Treatment: In early cases – chemotherapy for 6 weeks followed by limb sparing surgery (excision of tumour in toto and replacement by custom mega prosthesis), after histological examination of the excised tumour for tumour necrosis, the chemotherapy may be suitably altered. Patient followed at frequent intervals for local recurrence and lung metastases. In cases of late presentation where tumour excision is not feasible a course of chemotherapy is followed by amputation of the limb – chemotherapy is

continued. Where lung metastases are present amputation of the limb is palliative. 13) Name of condition: Malignant bone tumour – Chondrosarcoma I. Introduction: Chondrosarcoma is a malignant bone tumor arising from chondroblasts. The lesion may arise de novo (primary chondrosarcoma) or there may be malignant transformation of an existing benign cartilaginous lesion - osteochondroma / enchondroma (secondary chondrosarcoma). Thus the lesions may be central or

peripheral The lesions are frequently calcified (c-shaped or o-shaped calcifications) II. Incidence: not rare; third most common bone malignancy; 25 % of all sarcomas III. Differential Diagnosis: Non aggressive lesions may be mistaken for benign tumours especially Fibrous Dysplasia. IV. Prevention: Secondary chondrosarcomata may be prevented by proper treatment of primary cartilaginous lesion. V. Situation 1. a) clinical: nothing specific. Recent fast growth and onset of pain in a

primary cartilaginous lesion should make one suspect secondary Chondrosarcoma b) Investigations: x-ray., needle biopsy c) referral criteria – inability to treat at the primary centre Situation 2. a) Clinical: same as above b) Investigations: CT scan of part involved, CT scan Chest, MRI, Isotope bone scan, Needle Biopsy c) Treatment: Chondrosarcomata are resistant to chemo and radiotherapies. Hence excision in toto, short of amputation,

is the only alternative. Secondary and peripheral chondrosarcomata may be amenable for excision. Primary or secondary chondrosarcomata of the limb girdle may be difficult to treat surgically but excision and reconstruction may be tried depending on the situation. Custom made prostheses may be tried for chondrosarcomata of proximal humerus and femur if the lesions are intracompartmental. Inoperable tumours need disarticulation. 14) Name of condition: Malignant bone tumour – Ewing’s sarcoma 122

I. Introduction: A malignant bone tumour where the cell of origin is uncertain; usually occurring in the diaphyses of children. It can also occur in the metaphyseal regions. When the tumour occurs in adults the ilium is more commonly involved. It is a fast growing tumour with a lot of soft tissue swelling. II. Incidence – Rare III. Differential Diagnosis: Osteomyelitis is a major competitor for diagnosis not only clinically but also radiological and histological. Other round cell tumours of bone also

should be thought of. IV. Prevention – Nil V. Situation 1. a) clinical: Painful, spindle shaped swelling in the diaphysis of of a child without trauma should be viewed with suspicion. Fever points a finger at osteomyelitis but acute diaphyseal osteomyelitis is very uncommon. b) Investigations: x-ray, blood counts and ESR. c) Treatment- not possible in non-metro situation d) referral criteria: suspicion of tumour Situation 2. a) clinical: same as above b) Investigations: x-ray, CBP & ESR, MRI of the

part, CT scan of chest, wide bore needle aspiration – material must be sent for histopathology and culture of pyogenic organisms as well. The dictum “culture a tumour and biopsy an infection” holds good here. c) Treatment: Though earlier on Radiotherapy was best suited for Ewing’s sarcoma, present day sheet anchor is Chemotherapy. After an initial course of chemotherapy, wherever feasible, the tumour is resected and reconstruction done (appropriate surgery). For a recurrence of the tumour radiotherapy

is preferred since the recurrence is from cells which are resistant to chemotherapy given earlier. Where resection of the tumour is not possible amputation is performed. 15) Name of condition: Makignant bone tumour Plasmacytoma/Multiple myeloma I. Introduction: It is a malignant tumour of the marrow elements where plaslymacytes multiply cancerously in an elderly individual. The condition must be suspectd when an elderly individual complains of vague pains all over the body and not responding to

usual analgesics II. Incidence: not rare; 10 % of hematological malignancies., 1 % of all forms of cancer. III. Differential Diagnosis: The main contender is osteoporosis with compression fractures; Multiple metastases especially from prostate in males and breast in females should be thought of; Osteomalacia in late adulthood and Fibromyalgia syndrome are also to be differentiated. IV. Prevention: Nil V. Situation 1. a) clinical: a high index of suspicion in the elderly is very important when

the patient complains of generalized body aches of sufficiently long duration not responding to analgesics. Sternal tenderness is an important sign in multiple myeloma. c) Treatment: Once suspected the patient must be referred to a metro level hospital both for conformation of diagnosis and management d) referral criteria: Undiagnosed generalized body aches which are not responding to usual analgesics Situation 2. a) clinical – same as above

b) Investigations: CBP, ESR, S.Calcium, Phosphorus, Alkaline phosphatase, Bone marrow examination (sternal puncture), serum protein electrophoresis 123

c) Treatment: Chemotherapy and cortisones 16) Name of condition: Malignant bone tumour – Metastatic Bone Tumours I. Introduction: Tumours metastatic to bone are usually from Prostate, Female genital organs, Breast, Lungs, Kidney, Thyroid and GIT. Patients usually complain of either localized or generalized pains. Patient may also present with a pathological fracture with no other symptoms. It is important to note that symptoms due to the primary disease

are often lacking and only the secondary deposits cause symptoms. It is also interesting to note that quite often one fails to locate the primary lesion inspite of investigations II. Incidence: Not uncommon III. Differential Diagnosis: Multiple myeloma, osteoporosis, hyperparathyroidism etc IV. Prevention. Nil V. Situation 1. After suspecting a metastatic deposit, after x-ray examination patient has to be referred to a metro level hospital.

Situation 2. a) clinical: Localised or generalized pains in an elderly individual not responding to analgesics must be investigated. They have a pathology unless proved otherwise. A detailed clinical examination of the systems from which a primary is likely to occur should be carried out b) Investigations: CBP, ESR, x-ray chest, CT chest, Serum Ca, P, ALP, PTH, Serum protein electrophoresis, wide bore needle aspiration biopsy of

the lytic lesion detected on x-ray. Other blood investigations to detect cancers of the respective organs (like PSA , Ca 128 etc.) are to be carried out c) Treatment: of the primary depends on the cause. For a pathological fracture (or an impending fracture), curettage of the lesion, filling with bone cement and internal fixation preferably with an intramedullary nail is palliative and gives comfort for the rest of the life. STANDARD TREATMENT GUIDELINES FOR CONGENITAL ORTHOPEDIC ANOMALIES

Of the many congenital anomalies of Orthopedic interest, only two conditions which are common are discussed here – they are CTEV (Congenital Talipes Equino Varus) and (Congenital Dislocation of Hip). Others are to be treated in specialized centres. 1) Name of Condition: CTEV (Congenital Talipes Equino Varus) I. Introduction: The most common congenital anomaly seen in Orthopedics also referred to as CLUB FOOT. The deformity can be unilateral or bilateral. The common

question that needs to be answered by the primary clinician is whether the foot is normal at birth – when dorsiflexed the dorsum of the neonatal foot touches the shin of tibia. If it does not , there is mild equinovarus deformity. In CTEV, the foot has four components of the deformity – plantar flexion at ankle, inversion of foot at subtalar joint, varus of the forefoot at the midtarsal joints and internal torsion of tibia. II. Incidence: most common congenital anomaly in orthopedics

III. Differential Diagnosis: Other conditions which produce the talipes equino varus deformity should be thought of – meningomyelocele (or spina bifida occulta in adolescents as revealed by external tell tale scars like fobrofatty nodule in the lumbar 124

spine, tuft of hair or pigmented skin patch), Cerebral palsy of lower limbs, Arthrogryposis congenita, nerve injuries to lateral popliteal nerve, anterior poliomyelitis. IV. Prevention: Avoiding consanguineous marriages might prevent, at least partly, the incidence of congenital anomalies V. Situation 1. Non metro hospitals. a) clinical – minimal deformity in neonates can be diagnosed as explained in Introduction. Deformities of bigger magnitude are obvious. Clinician has to examine to

find out a cause for the deformity as explained in differential diagnosis. Depending on how much deformity is passively correctible, it can be classified as mild, moderate and severe. The chil must be examined for the presence of other congenital anomalies – orthopedic and non-orthopedic b) Investigations: x-ray in an older child. c) Treatment: the clinician has to familiarize himself with the technique of manipulation and serial plaster casting. Otherwise the patient has to be referred to metro hospitals.

d) Referral criteria – if the clinician does not know the technique of manipulation and plaster cast application; if there is no progress in correction of deformity after 6 to 8 manipulations ; if the child presented for the first time at the age of one year or the complication of rocker bottom foot has developed. Situation 2: metro hospital: a) clinical: same as above b) in a bigger child- x-ray of the part and x-ray of spine, x-ray pelvis to rule out DDH if suspected clinically

c) Treatment: manipulation of foot, preferably by Ponseti technique, even if the child is more than one year age to make the foot supple before surgery. Serial plaster casts appled. If the improvement is not satisfactory by 8 months of age surgery in the form of posteromedial release is suggested followed by serial plaster casts. Once correction is achieved and the child is not yet walking a Denis-Browne splint is prescribed. Corrective

shoes are to be given after the child starts walking. If the heel varus is persisting even at 6 yrs age, Dwyer’s calcaneal osteoteotomy is advised. For persisting round contour of the lateral border of the foot one of the lateral column shortening operations is performed. A supramalleolar osteotomy of tibia is indicated for persisting excessive tibial torsion. If the surgeon is conversant JESS application is a viable alternative. In neglected cases beyond 12 yrs of age a triple arthrodesis may be performed.

2) Name of condition: Developmental Dysplasia of Hip I. Introduction: In teratological conditions, the hip is found dislocated at birth. In other conditions of DDH, the hip is lax and waiting to dislocate if some forces act on it – the dislocatable hip or the hip is found dislocated and can easily be reduced – reducible hip. If the child comes late with a dislocated hip, it cannot be reduced by closed manipulation and needs surgery

II. Incidence: The exact incidence in India is not worked out though the condition is not very rare. III. Differential Diagnosis: Proximal Femoral Focal Deficiency (PFFD), Congenital short femur, sequelae of septic arthritis of hip 125

IV. Prevention: prevention of consanguinous marriages might reduce incidence. V. Situation 1. non-metro hospital a) Clinical: Barlow’s and Ortolani’s signs to diagnose dislocatable or reducible hips. Dislocated hip has a short limb, increased creases on the inner aspect of thighs, femoral head present anteriorly , abduction of hip is restricted and telescopy positive. b) Investigations: X-ray of pelvis – normal view and von Rosen’s view

c) whether the hip is dislocatable or dislocated, closed manipulation performed to reduce the hip and a POP spica applied in human position. d) if the diagnosis is doubtful or hip cannot be reduced by closed manipulation the patient must be referred to higher centre. Situation 2. metro hospitals: a) clinical –same b) investigations: plain x-ray of pelvis for both hips; Ultrasound examination of hip if the child is 6 months or less of age. In failed closed reductions an arthrogram of the hip may

be performed. CT & MRI are very rarely indicated. c) Treatment: in an infant closed manipulation of hip and plaster spica in human position. In a slightly older infant, a preliminary traction might help closed reduction. In an older infant, open reduction may be required followed by plaster spica. If the acetabular coverage is not enough, Salter’s innominate osteotomy is indicated. If the acetabulum is roomy, Pemberton osteotomy may be performed. In a slightly older child,

in addition femoral shortening derotational osteotomy may be beneficial. A shelf operation to augment acetabular coverage may be required. ***************** REFERENCES: 1. Current concepts in Bone and soft tissue tumours; Ed. Ajay Puri and M.G.Agarwal, Paras Medical books Pvt. Ltd., 2007 2. Orthopedic Diseases – Physiology, Pathology and Radiology; Ed. Aegerter and Kirkpatrick 3. Campbells Operative Orthopedics 4. Bone Tumour Management: Richard Coombs & Gary Friedlander; Butterworths

5. Orthopedics in Infancy and Childhood: Ed. Lloyd Roberts 6. Text Book of Orthopedics and Trauma. Ed. G.S.Kulkarni 126

GOUTY ARTHRITIS I. WHEN TO SUSPECT / RECOGNIZE? a. Introduction: Gout characterized by recurrent attacks of acute inflammatory arthritis— a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected (approximately 50% of cases). However, it may also present as tophi, kidney stones, or urate nephropathy. It is caused by elevated levels of uric acid in the blood which crystallize and are deposited in joints, tendons, and surrounding tissues.

b. Case Definition: Affluent males are the usual victims. It very rarely affects pre- menopausal women & such a patient should be viewed with suspicion if a diagnosis of gout is made. Gout can present in a number of ways, although the most usual is a recurrent attack of acute inflammatory arthritis. The metatarsal- phalangeal joint at the base of the big toe is affected most often, accounting for half of cases. Other joints, such as the heels, knees, wrists

and fingers, may also be affected. Joint pain usually begins over 2– 4 hours and during the night. Other symptoms that may occur along with the joint pain include fatigue and a high fever. Long-standing elevated uric acid levels (hyperuricemia) may result in other symptomatology, including hard, painless deposits of uric acid crystals known as tophi. Extensive tophi may lead to chronic arthritis due to bone erosion. Elevated levels of uric acid may also lead to crystals

precipitating in the kidneys, resulting in stone formation and subsequent urate nephropathy. II. INCIDENCE OF CONDITION IN OUR COUNTRY Gout affects around 1–2% of the Western population at some point in their lifetimes, and is becoming more common. A number of factors have been found to influence rates of gout, including age, race, and the season 127

of the year. In men over the age of 30 and women over the age of 50, prevalence is 2% III. DIFFERENTIAL DIAGNOSIS Differential diagnosis of Gout include 3. Septic Arthritis 4. Pseudo Gout 5. Rheumatoid Arthritis IV. PREVENTION AND COUNSELLING Both Dietary and lifestyle changes can decrease uric acid levels. i. reducing intake of food such as meat and seafood, ii. consuming adequate vitamin C, iii. limiting alcohol and fructose consumption iv. avoiding obesity.

v. Coffee, but not tea, consumption is associated with a lower risk of gout. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA * SITUATION 1: At Secondary Hospital / Non Metro situation : Optimal standards of Treatment in situations where technology and resources are limited a. Clinical diagnosis: Usual presentation is acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the

most commonly affected (approximately 50% of cases). However, it may also present as tophi, kidney stones, or urate nephropathy. It is caused by elevated levels of uric acid in the blood which crystallize and are deposited in joints, tendons, and surrounding tissues. Investigations: 1. X Ray 2. Serum Uric Acid Level (Suggestive; to be confirmed by 3 below) 3. MSU crystals in Synovial fluid and tophi (Essential for diagnosis) 128

4. Complete Blood Picture 5. ESR 6. CRP 7. Renal function test a. Treatment: Standard Operating Procedure ii. In Patient : 1. Surgery a. Excision of symptomatic tophi vi. Out Patient : 3. Acute Attack a. NSIADS b. Colchicine c. Steroids 4. Chronic (No role in acute attack) a. Allopurinol b. Febuxostat c. Probenacid 5. Physical Therapy vii. Day Care 1. Injectable medications 2. Intra articular Steroid Injection e. Referral criteria: For further evaluation and management of cases not responding to

conventional therapy. * SITUATION 2: At Super Specialty facility in Metro Location where higher end technology is available e. Clinical diagnosis: As in situation 1 129

f. Investigations: As in situation 1 g. Treatment: Standard Operating Procedure iv. In Patient : as in situation 1. v. Out Patient : As in situation 1. vi. Day Care: As in situation 1 h. Referral criteria: VIII. WHO DOES WHAT? AND TIMELINES a. Doctor Early diagnosis and appropriate treatment. Counsel the patient for prevention and dietary advice. b. Nurse counseling the patient. Injectable treatment c. Technician Appropriate bracing Physiotherapy IX. FURHTER READING / REFERENCES

6. Chen LX, Schumacher HR (October 2008). "Gout: an evidence-based review". J Clin Rheumatol 14 (5 Suppl): S55–62 7. Eggebeen AT (September 2007). "Gout: an update". Am Fam Physician 76 (6): 801–8 8. Fam AG (May 2000). "What is new about crystals other than monosodium urate?". Curr Opin Rheumatol 12 (3): 228–34 9. Schlesinger N (March 2010). "Diagnosing and treating gout: a review to aid primary care physicians". Postgrad Med 122 (2): 157–61 130

RESOURCES REQUIRED FOR ONE PATIENT /PROCEDURE (PATIENT WEIGHT 60KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) SITUATION HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 Doctor 1. X Ray e. NSAIDs Lab Nurse 2. MSU crystals f. Colchicine equipment Technician in Synovial g. Steroid Imaging fluid and tophi h. Uric acid equipment 3. Serum Uric lowering Exercise Acid Level agents equipments

4. Complete i. Consumables Equipments Blood Picture for surgery for Operating 5. ESR Room 6. CRP 7. Renal function test 2 (In Addition to Situation 1) 131

OSTEOARTHRITIS I. WHEN TO SUSPECT / RECOGNIZE? a. Introduction: Osteoarthritis (OA) also known as degenerative arthritis or degenerative joint disease is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. A variety of causes—hereditary, developmental, metabolic, and mechanical—may initiate processes leading to loss of cartilage, When bone surfaces become less well protected by cartilage, bone may be exposed and damaged. As a

result of decreased movement secondary to pain, regional muscles may atrophy, and ligaments may become more lax. b. Case Definition: Osteoarthritis can be classified into either primary or secondary depending on whether or not there is an identifiable underlying cause. Primary osteoarthritis is a chronic degenerative disorder related to aging. A number of studies have shown that there is a greater prevalence of the disease among siblings and especially identical twins, indicating a hereditary

basis. Up to 60% of OA cases are thought to result from genetic factors Secondary Osteoarthritis is caused by other factors such as • Congenital disorders of joints • Diabetes. • Inflammatory diseases (such as Perthes' disease), (Lyme disease), and all chronic forms of arthritis (e.g. costochondritis, gout, and rheumatoid arthritis). In gout, uric acid crystals cause the cartilage to degenerate at a faster pace. • Injury to joints, as a result of an accident • Septic arthritis

• Ligamentous deterioration or instability may be a factor. • Developmental disorder resulting into mal-alignment of extremities. II. INCIDENCE OF CONDITION IN OUR COUNTRY 132

Osteoarthritis affects nearly 27 million people in the United States, accounting for 25% of visits to primary care physicians, and half of all NSAID prescriptions. It is estimated that 80% of the population have radiographic evidence of OA by age 65, although only 60% of those will have symptoms. III. PREVENTION AND COUNSELLING Life style modification , weight control, regular exercise Patient needs to be counselled regarding the nature of the disease and need

for treatment, possible treatment options and chances of improvement. IV. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA * SITUATION 1: At Secondary Hospital / Non Metro situation : Optimal standards of Treatment in situations where technology and resources are limited a. Clinical diagnosis: The main symptom is pain, causing loss of ability and often stiffness. "Pain" is generally described as a sharp ache, or a burning sensation in the associated

muscles and tendons. OA can cause a crackling noise (called "crepitus") when the affected joint is moved. It commonly affects the hands, feet, spine, and the large weight bearing joints, such as the hips and knees, although in theory, any joint in the body can be affected. As OA progresses, the affected joints appear larger, are stiff and painful, and usually feel better with gentle use but worse with excessive or prolonged use. In smaller joints, such as at

the fingers, hard bony enlargements, called Heberden's nodes (on the distal interphalangeal joints) and/or Bouchard's nodes (on the proximal interphalangeal joints), may form, and though they are not necessarily painful, they do limit the movement of the fingers significantly. OA at the toes leads to the formation of bunions, rendering them red or swollen. b. Investigations: 1. X Ray - Particularly standing xrays for knees in which eccentric joint space reduction is the diagnostic crieterion as compared

c. Treatment: Standard Operating Procedure iii. In Patient : 1. Surgery a. Arthroscopy joint debridement b. Joint Replacement ii. Out Patient : 6. Life style modification 7. Physical therapy 8. Analgesics a. Oral b. Topical 9. Steroids a. Systemic b. Intra articular 10. Glucosamine (controversial) iii Day Care 1. Injectable medications 2. Intra articular Steroid injection 3. Intra articular hyaluronic acid injection f. Referral criteria: For further evaluation and management of cases not responding to

conventional therapy. * SITUATION 2: At Super Specialty facility in Metro Location where higher end technology is available i. Clinical diagnosis: As in situation 1 j. Investigations: As in situation 1 . 134

k. Treatment: Standard Operating Procedure vii. In Patient : as in situation 1. viii. Out Patient : As in situation 1. ix. Day Care: As in situation 1 l. Referral criteria: X. WHO DOES WHAT? AND TIMELINES a. Doctor Early diagnosis and appropriate treatment. Counsel the patient for prevention and dietary advice. b. Nurse counseling the patient. Injectable treatment c. Technician Appropriate bracing manufacturing and application of braces Physiotherapy 135

XI. FURHTER READING / REFERENCES 10. Arrich J, Piribauer F, Mad P, Schmid D, Klaushofer K, Müllner M (April 2005). "Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis". CMAJ 172 (8): 1039–43. 11. Brandt KD, Dieppe P, Radin E (January 2009). "Etiopathogenesis of osteoarthritis". Med. Clin. North Am. 93 (1): 1–24 12. Conaghan, Phillip. "Osteoarthritis - National clinical guideline for care and management in adults"

13. Flood J (March 2010). "The role of acetaminophen in the treatment of osteoarthritis". Am J Manag Care 16 Suppl Management: S48–54 14. Fransen M, Crosbie J, and Edmonds J. Physical therapy is effective for patients with osteoarthritis of the knee: a randomized controlled clinical trial. The Journal of Rheumatology January 1, 2001 vol. 28 no. 1 pp156-164 15. Reichenbach S, Sterchi R, Scherer M, et al. (2007). "Meta-analysis: chondroitin for osteoarthritis of the knee or hip". Ann. Intern. Med. 146 (8):

580–90 16. Richette P, Ravaud P, Conrozier T, et al. (March 2009). "Effect of hyaluronic acid in symptomatic hip osteoarthritis: a multicenter, randomized, placebo- controlled trial". Arthritis Rheum. 60 (3): 824–30. 17. Rosenbaum CC, O'Mathúna DP, Chavez M, Shields K (2010). "Antioxidants and antiinflammatory dietary supplements for osteoarthritis and rheumatoid arthritis". Altern Ther Health Med 16 (2): 32–40. 18. Wandel - Effects of glucosamine, chondroitin, or placebo in patients with

osteoarthritis of hip or knee: network meta-analysis -- Wandel et al. 341 -- bmj.com" 136

RESOURCES REQUIRED FOR ONE PATIENT /PROCEDURE (PATIENT WEIGHT 60KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) SITUATION HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 Doctor 1. X Ray j. NSAIDs Lab Nurse 2. Complete Blood k. Steroid equipment Technician Picture l. Consumables Imaging 3. ESR for surgery equipment Exercise equipments Equipments for Operating Room 2 (In Addition to Situation 1) 137

OSTEOMALACIA I. WHEN TO SUSPECT / RECOGNIZE? a. Introduction: Osteomalacia is a generalized bone condition in which there is inadequate mineralization of the bone. Many of the effects of the disease overlap with the more common osteoporosis, but the two diseases are significantly different. There are two main causes of osteomalacia: (1) insufficient calcium absorption from the intestine because of lack of dietary calcium or a deficiency of or resistance to the action of vitamin D; and (2) Phosphate

deficiency caused by increased renal losses b. Case Definition: Osteomalacia is the softening of the bones due to defective bone mineralization secondary to inadequate amounts of available phosphorus and calcium. It may show signs as diffuse body pains, muscle weakness, and fragility of the bones. The most common cause of the disease is a deficiency in vitamin D, which is normally obtained from the diet and/or sunlight exposure II. INCIDENCE OF CONDITION IN OUR COUNTRY

In the US and Europe, more than 40% of the adult population older than age 50 are vitamin D deficient, this being the most prominent cause of osteomalacia. http://bestpractice.bmj.com/best- practice/monograph/517/resources/references.html - ref-4In developing countries vitamin D deficiency leading to clinical rickets is described in 60% of infants. In the Middle East, a high prevalence of rickets and osteomalacia has been described in Muslim women and their infants, perhaps due to increased

clothing coverage of the skin. III. DIFFERENTIAL DIAGNOSIS Differential diagnosis of osteomalacia include Osteoporosis Pagets disease 138

IV. PREVENTION AND COUNSELLING Ensuring adequate sunlight exposure and dietary intake of fortified foods containing vitamin D, calcium, and phosphorus may help avoid osteomalacia It is recommended that maintenance dosing in adults <50 years age should be 400-800 International Units (IU) of vitamin D daily, and that adults ≥50 years age should get 800-1000 IU of vitamin D daily. Adults should also take 1.2 g of elemental calcium in the diet or as a supplement.

V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA * SITUATION 1: At Secondary Hospital / Non Metro situation : Optimal standards of Treatment in situations where technology and resources are limited a. Clinical diagnosis: Osteomalacia in adults starts insidiously as aches and pains in the lumbar (lower back) region and thighs, spreading later to the arms and ribs. The pain is symmetrical, non-radiating and is accompanied by sensitivity in the

involved bones. Proximal muscles are weak, and there is difficulty in climbing up stairs and getting up from a squatting position. Physical signs include deformities like triradiate pelvis and lordosis. The patient has a typical "waddling" gait. However, those physical signs may derive from a previous osteomalacial state, since bones do not regain their original shape after they become deformed. May present as pathological fracture. b. Investigations: Serum Calcium Serum Phosphate Alkaline Phosphatase

Serum urea creatinine 24 Hr urinary calcium X rays of the deformed part c. Treatment: 139

Nutritional osteomalacia responds well to administration of 10,000 IU weekly of vitamin D for four to six weeks. Osteomalacia due to malabsorption may require treatment by injection or daily oral dosing of significant amounts of vitamin D Standard Operating Procedure i. In Patient : For corrective surgery ii. Out Patient : supplementation and bracing iii. Day Care: Injectable form of Vit D d. Referral criteria: For evaluation and management of cases not responding to conventional therapy.

* SITUATION 2: At Super Specialty facility in Metro Location where higher end technology is available m. Clinical diagnosis: As in situation 1 n. Investigations: As in situation 1 . Others are 1,25 – dihydroxy- Vit D level Parathormone level DXA Bone Biopsy with double tetracycline labelling Technitium Bone scan o. Treatment: Standard Operating Procedure i. In Patient : as in situation 1 UV-B radiation 140

Tanning beds and other UV-B radiation devices have been used to treat vitamin D deficiency in the elderly and in malabsorptive disorders. ii. Out Patient : As in situation 1 iii. Day Care: As in situation 1 p. Referral criteria: VI. WHO DOES WHAT? AND TIMELINES a. Doctor Early diagnosis and appropriate treatment. Counsel the patient for prevention and dietary advice. b. Nurse Counselling the patient c. Technician Appropriate bracing manufacturing and application Physiotherapy

VII. FURHTER READING / REFERENCES a. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81:353-373. b. Holick MF. Sunlight, UV-radiation, vitamin D and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2008;624:1-15. c. National Osteoporosis Foundation (NOF): 2010 recommendations http://www.nof.org/prevention/vitaminD.htm (last accessed 18th August 2010) 141

RESOURCES REQUIRED FOR ONE PATIENT /PROCEDURE (PATIENT WEIGHT 60KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) SITUATION HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 Doctor Serum calcium Calcium Lab equipment Nurse Serum phosphorus supplement X Ray Technician Alkaline Phosphorus equipment phosphatase supplement Equipments for Serum urea Vit D supplement Operating creatinine Inj Vit D Room

24 Hr urinary Braces calcium Consumables for X Ray surgery 2 25 hydroxy – Vit D UV B Radiation DXA (In Addition level Bone Scan to Situation 1,25 – dihydroxy- Histopatholoy 1) Vit D level with tissue Parathormone labelling level DXA Bone Biopsy with double tetracycline labelling Technitium Bone scan 142

OSTEOPOROSIS I. WHEN TO SUSPECT / RECOGNIZE? a. Introduction: Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density (BMD) is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered. b. Case Definition: Osteoporosis is defined by the World Health Organization (WHO) as a bone mineral density that is 2.5 standard deviations or more below the mean peak

bone mass (average of young, healthy adults) as measured by DXA; the term "established osteoporosis" includes the presence of a fragility fracture. The disease may be classified as primary type 1, primary type 2, or secondary. The form of osteoporosis most common in women after menopause is referred to as primary type 1 or postmenopausal osteoporosis. Primary type 2 osteoporosis or senile osteoporosis occurs after age 75 and is seen in both

females and males at a ratio of 2:1. Finally, secondary osteoporosis may arise at any age and affects men and women equally. This form of osteoporosis results from chronic predisposing medical problems or disease II. INCIDENCE OF CONDITION IN OUR COUNTRY The exact incidence of osteoporosis in India is not known .However ,according to one study,approximately 6-7 crores of Indian population is suffering from osteopenia / osteoporosis III. DIFFERENTIAL DIAGNOSIS Differential diagnosis of Osteoporosis include

6. Multiple myeloma 7. Osteomalacia 8. Chronic kidney disease 9. Primary hyperparathyroidism 10. Metastatic bone malignancy 11. Vertebral deformities 143

IV. PREVENTION AND COUNSELLING a. Risk factors for Osteoporosis includes following i. Prior fragility fracture ii. Female gender iii. White ancestry iv. Old age v. Low BMI vi. Loss of height vii. Sec amenorrhoea viii. Primary hypogonadism ix. Smoking x. Excessive alcohol use xi. Prolonged immobilizatioin xii. Low calcium intake xiii. Vit D defficiency xiv. Glucocorticoid excess xv. Corticosteroid use xvi. Hyperthyroidism xvii. Heparin use xviii. Anticonvulsant use xix. Weight loss b. Prevention

Change in life style, diet, exercise. Amongst the various risk factors for osteoporosis modifiable risk factors can be modified to prevent development of osteoporosis. Medications to prevent development of osteoporosis. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA * SITUATION 1: At Secondary Hospital / Non Metro situation : Optimal standards of Treatment in situations where technology and resources are limited a. Clinical diagnosis:

Osteoporosis itself doesn’t have any symptom. Symptoms develop once the fragility fracture occurs. Symptoms develop according to the site of fracture. Pain may or may not be there due to osteoporotic fracture. Vertebral compression fracture at times may present with neural symptoms. 144

b. Investigations: 1. Plain X-ray of spine 2. Dual energy X ray absorptiometry (DXA) BMD 3. Renal function test 4. Calcium 5. Albumin 6. Phosphorus 7. Urinary calcium level c. Treatment: Standard Operating Procedure iv. In Patient : 1. Surgery a. Vertebroplasty b. Open surgical spinal stabilization ii. Out Patient : supplementation and bracing 11. Pain control a. Bed rest b. Analgesics c. Brace 12. Antiresorptive agents a. Bisphosphonates b. Estrogen analogs c. Raloxifen d. Calcitonin

13. Bone anabolic agent e. Teriparatide f. Calcium salts g. Sodium fluoride 14. Nutrition h. Calcium i. Vitamin D j. Vitamin K 15. Exercise k. Aerobics l. Weight bearing m. Resistance exercise 16. Orthosis n. Spinal orthoses 17. Long term Osteoporosis prophylaxis iv. Day Care: Injectable medication 145

g. Referral criteria: For further evaluation and management of cases not responding to conventional therapy. * SITUATION 2: At Super Specialty facility in Metro Location where higher end technology is available q. Clinical diagnosis: As in situation 1 r. Investigations: As in situation 1 . Others are 1. QCT (quantitative computer tomography) 2. Quantitative Ultrasound 3. Biochemical markers of bone resorption (increased urinary excretion of C- telopeptides) 4. Vit D level 5. Testosterone level

6. Urinary free cortisol 7. Serum protein electrophoresis s. Treatment: Standard Operating Procedure i. In Patient : as in situation 1. In addition to that 1. Surgery a. Vertebroplasty b. Kyphoplasty ii. Out Patient : As in situation 1. In addition to that 1. Other agents a. RANKL inhibitors b. Strontium ranelate iii. Day Care: As in situation 1 t. Referral criteria: 146

XII. WHO DOES WHAT? AND TIMELINES a. Doctor Early diagnosis and appropriate treatment. Counsel the patient for prevention and dietary advice. b. Nurse counseling the patient c. Technician Appropriate bracing manufacturing and application of braces Physiotherapy XIII. FURHTER READING / REFERENCES 19. Bilezikian JP. Efficacy of bisphosphonates in reducing fracture risk in postmenopausal osteoporosis. Am J Med. 2009;122:S14-21. 20. Consensus development conference: Diagnosis, prophylaxis and treatment of

osteoporosis. Am J Med. 1993;94:646-650 21. Khosla S. Update in male osteoporosis. J Clin Endocrinol Metab. 2010;95:3- 10. 22. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285:785-795. 23. O'Neill S, MacLennan A, Bass S, et al. Guidelines for the management of postmenopausal osteoporosis for GPs. Aust Fam Physician. 2004;33:910-919. 24. Poole KE, Compston JE. Osteoporosis and its management. BMJ.

2006;333:1251-1256. 25. WHO Scientific Group on the Prevention and Management of Osteoporosis. Prevention and management of osteoporosis: report of a WHO scientific group. (WHO technical report series; 921). Geneva, Switzerland: WHO; 2000. 147

RESOURCES REQUIRED FOR ONE PATIENT /PROCEDURE (PATIENT WEIGHT 60KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) SITUATION HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 Doctor 4. Dual energy X m. Bisphosphonates Lab equipment Nurse ray n. Estrogen analogs Imaging Technician absorptiometr o. Raloxifen equipment y (DXA) BMD p. Calcitonin Exercise 5. Renal function q. Teriparatide equipments

test r. Calcium salts Equipments 6. Calcium s. Sodium fluoride for Operating 7. Albumin t. Calcium Room 8. Phosphorus u. Vitamin D 9. Urinary v. Vitamin K calcium level w. Spinal braces x. Consumables for surgery 2 1. QCT RANKL inhibitors Equipments (In Addition (quantitative Strontium ranelate for to Situation computer vertebroplasty 1) tomography) and 2. Quantitative kyphoplasty Ultrasound 3. Biochemical markers of bone resorption (increased urinary excretion of C- telopeptides) 4. Vit D level

5. Testosterone level 6. Urinary free cortisol 7. Serum protein electrophoresi s 148

RHEUMATOID ARTHRITIS I. WHEN TO SUSPECT / RECOGNIZE? a. Introduction: Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium (synovitis) secondary to hyperplasia of synovial cells, excess synovial fluid, and the development of pannus in the synovium. The pathology of the disease

process often leads to the destruction of articular cartilage and ankylosis of the joints. Rheumatoid arthritis can also produce diffuse inflammation in the lungs, pericardium, pleura, and sclera, and also nodular lesions, most common in subcutaneous tissue. Although the cause of rheumatoid arthritis is unknown, autoimmunity plays a pivotal role in both its chronicity and progression, and RA is considered a systemic autoimmune disease. b. Case Definition:

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. It can be a disabling and painful condition, which can lead to substantial loss of function and mobility if not adequately treated. It is a clinical diagnosis made on the basis of symptoms, physical exam, radiographs (X-rays) and labs, although the American College of Rheumatology (ACR) and the European

League Against Rheumatism (EULAR) publish diagnostic guidelines These new classification criteria overruled the "old" ACR criteria of 1987 and are adapted for early RA diagnosis. The "new" classification criteria establish a point value between 0 and 10. Every patient with a point total of 6 or higher is unequivocally classified as an RA patient, provided he has synovitis in at least one joint and given that there is no other diagnosis better

explaining the synovitis. Four areas are covered in the diagnosis: 1. joint involvement, designating the metacarpophalangeal joints, proximal interphalangeal joints, the interphalangeal joint of the thumb, second through third metatarsophalangeal joint and wrist as small joints, and elbows, hip joints and knees as large joints: a. Involvement of 1 large joint gives 0 points b. Involvement of 2-10 large joints gives 1 point 149

c. Involvement of 1-3 small joints (with or without involvement of large joints) gives 2 points d. Involvement of4-10 small joints (with or without involvement of large joints) gives 3 points e. Involvement of more than 10 joints (with involvement of at least 1 small joint) gives 5 points 2. serological parameters – including the rheumatoid factor as well as ACPA – "ACPA" stands for "anti-citrullinated protein antibody": a. Negative RF and negative ACPA gives 0 points

b. Low-positive RF or low-positive ACPA gives 2 points c. High-positive RF or high-positive ACPA gives 3 points 3. acute phase reactants: 1 point for elevated erythrocyte sedimentation rate, ESR, or elevated CRP value (c-reactive protein) 4. duration of arthritis: 1 point for symptoms lasting six weeks or longer II. INCIDENCE OF CONDITION IN OUR COUNTRY About 1% of the world's population is afflicted by rheumatoid arthritis, women three times more often than men. Onset is most frequent between the ages of

40 and 50, but people of any age can be affected. The incidence of RA is in the region of 3 cases per 10,000 population per annum. It is up to three times more common in smokers than non-smokers, particularly in men, heavy smokers, and those who are rheumatoid factor positive. First-degree relatives prevalence rate is 2–3% and disease genetic concordance in monozygotic twins is approximately 15–20%. III. DIFFERENTIAL DIAGNOSIS Differential diagnosis of Rheumatoid Arthritis include

12. Crystal induced arthritis 13. Osteoarthritis 14. SLE 15. Psoriatic Arthritis 16. Lyme Disease 17. Reactive Arthritis IV. PREVENTION AND COUNSELLING As no direct cause for the disease has been identified the preventive measures could not be established. 150

Patient needs to be counselled regarding the chronic nature of the disease and need for regular treatment, possible complications and possible treatment options and chances of improvement. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA * SITUATION 1: At Secondary Hospital / Non Metro situation : Optimal standards of Treatment in situations where technology and resources are limited a. Clinical diagnosis:

Rheumatoid arthritis typically manifests with signs of inflammation, with the affected joints being swollen, warm, painful and stiff, particularly early in the morning on waking or following prolonged inactivity. Increased stiffness early in the morning is often a prominent feature of the disease and typically lasts for more than an hour. For diagnosis and management of other body system involvement by RA Physician needs to be consulted.

Clinical diagnosis can be made as per the guidelines given by ACR & EULAR. b. Investigations: 1. X Ray 2. Complete Blood Picture 3. ESR 4. CRP 5. Liver function test 6. Renal function test 7. Rheumatoid Factor (RA) 8. Anti-citrullinated protein antibodies (ACPAs) or anti-CCP c. Treatment: Standard Operating Procedure v. In Patient : 1. Surgery a. Arthroscopy Synovectomy in early stage b. Joint Replacement in late stages ii. Out Patient : supplementation and bracing

18. Disease modifying anti-rheumatic drugs (DMARDs) a. First Line DMARDs: 151

i. Methotrexate ii. Hydroxychloroquine iii. Sulfasalazine iv. Leflunomide b. Second Line i. Azathioprine ii. cyclosporin (cyclosporine A) iii. D-penicillamine iv. gold salts (Oral & Parenteral) v. minocycline 19. Anti-inflammatory agents and analgesics a. Anti-inflammatory agents include: i. glucocorticoids ii. Non-steroidal anti-inflammatory drug (NSAIDs, most also act as analgesics) b. Analgesics include: i. Paracetamol ii. Opiates iii. Diproqualone iv. Lidocaine topical

20. Bed rest during acute flare ups 21. Physiotherapy iii Day Care 1. Injectable medications 2. Intra articular Steroid injection h. Referral criteria: For further evaluation and management of cases not responding to conventional therapy. 152

* SITUATION 2: At Super Specialty facility in Metro Location where higher end technology is available u. Clinical diagnosis: As in situation 1 v. Investigations: As in situation 1 . Others are 1. Anti-MCV assay (antibodies against mutated citrullinated Vimentin). 2. point-of-care test (POCT) for the early detection of RA has been developed. This assay combines the detection of rheumatoid factor and anti-MCV for diagnosis of rheumatoid arthritis and shows a sensitivity of 72% and specificity of 99.7%

w. Treatment: Standard Operating Procedure iv. In Patient : as in situation 1. v. Out Patient : As in situation 1. In addition to that 1. Biological agents (biologics) include: a. tumor necrosis factor alpha (TNFα) blockers – etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi) b. Interleukin 1 (IL-1) blockers – anakinra (Kineret) c. monoclonal antibodies against B cells – rituximab (Rituxan) d. T cell costimulation blocker – abatacept (Orencia)

e. Interleukin 6 (IL-6) blockers – tocilizumab (an anti- IL-6 receptor antibody) (RoActemra, Actemra) vi. Day Care: As in situation 1 a. Referral criteria: Window of opportunity DMARDs exists within 4 to 6 months of the onset of disease. Early diagnosis & institution of right therapy is thus crucial. VI. WHO DOES WHAT? AND TIMELINES b. Doctor 153

Early diagnosis and appropriate treatment. Counsel the patient for prevention and dietary advice. c. Nurse counseling the patient. Injectable treatment d. Technician Appropriate bracing manufacturing and application of braces Physiotherapy VII. FURHTER READING / REFERENCES 26. Aletaha D, Neogi T, Silman AJ, et al. (September 2010). "2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative

initiative". Ann. Rheum. Dis. 69 (9): 1580–8. doi:10.1136/ard.2010.138461. PMID 20699241. 27. Luime JJ, Colin EM, Hazes JM, Lubberts E. (2009). "Does anti-MCV has additional value as serological marker in the diagnostic and prognostic work- up of patients with rheumatoid arthritis? A systematic review.". Ann Rheum Dis. 2009 Mar 15. [Epub ahead of print] 69 (2): 337–44. doi:10.1136/ard.2008.103283 (inactive 2009-11-06). 28. Majithia V, Geraci SA (2007). "Rheumatoid arthritis: diagnosis and

management". Am. J. Med. 120 (11): 936–9. 29. Renger F, Bang H, Fredenhagen G, Natusch A, Backhaus M, Feist E, Egerer K, Burmester GR. "Anti-MCV Antibody Test for the Diagnosis of Rheumatoid Arthritis Using a POCT-Immunoassay". American College of Rheumatology, 2008 Annual Scientific Meeting, poster presentation. 30. Rheumatoid Arthritis Treatment Options". http://www.treatmentforarthritis.us/rheumatoid.php. Retrieved July 22, 2010.

31. Rheumatology Information: Therapeutics for Rheumatoid Arthritis". Fda.gov. April 17, 2009. http://www.fda.gov/Drugs/ResourcesForYou/HealthProfessionals/ucm10704 6.htm. Retrieved March 3, 2011. 154

RESOURCES REQUIRED FOR ONE PATIENT /PROCEDURE (PATIENT WEIGHT 60KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) SITUATION HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 Doctor 10. X Ray y. DMARDs Lab Nurse 11. Complete Blood z. NSAIDs equipment Technician Picture aa. Steroid Imaging 12. ESR bb. Consumables equipment 13. CRP for surgery Exercise 14. Liver function equipments test Equipments

15. Renal function for Operating test Room 16. Rheumatoid Factor (RA) 17. Anti- citrullinated protein antibodies (ACPAs) or anti- CCP. 2 1. Anti-MCV assay Biologic Agents (In Addition 2. point-of-care test to Situation (POCT) 1) 155

RICKETS I. WHEN TO SUSPECT / RECOGNIZE? a. Introduction: Rickets is a softening of bones in children due to deficiency or impaired metabolism of vitamin D, phosphorus or calcium,http://en.wikipedia.org/wiki/Rickets - cite_note-0 potentially leading to fractures and deformity. Rickets is among the most frequent childhood diseases in many developing countries. The predominant cause is a vitamin D deficiency, but lack of adequate calcium in the diet may also lead to rickets

(cases of severe diarrhea and vomiting may be the cause of the deficiency). Although it can occur in adults, the majority of cases occur in children suffering from severe malnutrition b. Case Definition: The primary cause of rickets is a vitamin D deficiency. Vitamin D is required for proper calcium absorption from the gut. Sunlight, especially ultraviolet light, lets human skin cells convert Vitamin D from an inactive to active state. In the absence of vitamin D, dietary calcium is not properly absorbed,

resulting in hypocalcaemia, leading to skeletal and dental deformities and neuromuscular symptoms Types: • Nutritional Rickets • Vitamin D Resistant Rickets • Vitamin D Dependant Rickets o Type I o Type II • Congenital Rickets II. INCIDENCE OF CONDITION IN OUR COUNTRY In developed countries, rickets is a rare diseasehttp://en.wikipedia.org/wiki/Rickets - cite_note-6 (incidence of less than 1 in 200,000). Children ages 6 months to 24 months are at highest risk, because

their bones are rapidly growing.Mother’s milk gives adequate calcium and vitamin-D so nutritional rickets develops once breast feeding is stopped. Renal or vitamin-D resistant rickets develops in children of 5-8 years of age. 156

III. DIFFERENTIAL DIAGNOSIS Differential diagnosis of reickets include Hypophosphatasia Metaphyseal dysplasia Blounts disease IV. PREVENTION AND COUNSELLING A sufficient amount of ultraviolet B light in sunlight each day and adequate supplies of calcium and phosphorus in the diet can prevent rickets. Recommendations are for 400 international units (IU) of vitamin D a day for infants and children. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA

* SITUATION 1: At Secondary Hospital / Non Metro situation : Optimal standards of Treatment in situations where technology and resources are limited a. Clinical diagnosis: Signs and symptoms of rickets include: • Bone pain or tenderness, dental problems, muscle weakness (rickety myopathy or "floppy baby syndrome" or "slinky baby", increased tendency for fractures • Skeletal deformity o Genu varum, Genu Valgum, Cranial, spinal, and pelvic deformities • Growth disturbance

• Tetany, Craniotabes, Costochondral swelling "rickety rosary", Harrison's groove • Double malleoli sign due to metaphyseal hyperplasia • Widening of wrist raises early suspicion, it is due to metaphysial cartilage hyperplasia. b. Investigations: Alkaline Phosphatase Serum Calcium Serum Phosphorus 157

X rays of the deformed part c. Treatment: The goals of treatment are to relieve symptoms and correct the cause of the condition. Replacing calcium, phosphorus, and vitamin D, Exposure to moderate amounts of sunlight is encouraged. Positioning or bracing may be used to reduce or prevent deformities. Skeletal deformities may require corrective surgery later on. Standard Operating Procedure i. In Patient : For corrective surgery ii. Out Patient : supplementation and bracing

iii. Day Care: Injectable form of Vit D d. Referral criteria: Vitamin D resistant Rickets Hypophosphatemic Rieckets * SITUATION 2: At Super Specialty facility in Metro Location where higher end technology is available x. Clinical diagnosis: As in situation 1 y. Investigations: As in situation 1 . Others are 25 hydroxy – Vit D level 1,25 – dihydroxy- Vit D level 24 hours urinary Ca and Phosphorus levels z. Treatment: Standard Operating Procedure 158

i. In Patient : as in situation 1 and Recombinant Growth hormone therapy for Hypophosphatemic rickets ii. Out Patient : As in situation 1 iii. Day Care: As in situation 1 aa. Referral criteria: VI. WHO DOES WHAT? AND TIMELINES a. Doctor Early diagnosis and appropriate treatment. Counsel the patient for prevention and dietary advice. b. Nurse Counselling the patient c. Technician Appropriate bracing manufacturing and application Physiotherapy VII. FURHTER READING / REFERENCES

a. Gartner LM, Greer FR. Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake. Pediatrics 2003;111:908-910. b. Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest. 2006;116:2062-2072 c. Huiming Y, Chaomin W. Recombinant growth hormone therapy for X-linked hypophosphatemia in children. Cochrane Database Syst Rev. 2005(1):CD004447. d. Pettifor JM. Rickets and vitamin D deficiency in children and adolescents. Endocrinol Metab Clin North Am. 2005;34:537-553,

e. Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008;122:1142-1152. 159

RESOURCES REQUIRED FOR ONE PATIENT /PROCEDURE (PATIENT WEIGHT 60KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) SITUATION HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 Doctor Alkaline Calcium Lab Nurse phosphatise supplement equipment Technician Serum calcium Phosphorus X Ray Serum phosphorus supplement equipment X Ray Vit D supplement Equipments Inj Vit D for Operating Braces Room Consumables for surgery

2 25 hydroxy – Vit D Recombinant (In Addition level Growth Hormone to Situation therapy 1) 1,25 – dihydroxy- Vit D level 24 hours urinary Ca and Phosphorus levels 160

National Treatment Guidelines for Antimicrobial Use in Infectious Diseases Version 1.0 (2016) NATIONAL CENTRE FOR DISEASE CONTROL Directorate General of Health Services Ministry of Health & Family Welfare Government of India

Chapter 2. ................................................................................................................................................................................................................. 9 Syndromic Approach For Empirical Therapy Of Common Infections.......................................................................................................... 9

A. Gastrointestinal & Intra-Abdominal Infections ......................................................................................................................................... 10 B. Central Nervous System Infections ........................................................................................................................................................... 13

C. Cardiovascular Infections .......................................................................................................................................................................... 14 D. Skin & Soft Tissue Infections ................................................................................................................................................................... 15

E. Respiratory Tract Infections ...................................................................................................................................................................... 16 F. Urinary Tract Infections ............................................................................................................................................................................. 17

G. Obstetrics And Gynaecological Infections ................................................................................................................................................ 18 H. Bones And Joint Infections ....................................................................................................................................................................... 22

K. Infections in Burn and Plastic Surgery ...................................................................................................................................................... 26 L. Fungal Infections ...................................................................................................................................................................................... 27

M. Febrile Neutropenia .................................................................................................................................................................................. 27 N. Post-Cardiovascular Surgery Infections .................................................................................................................................................... 29

R. Post Solid Organ Transplant ...................................................................................................................................................................... 40 S. Surgical Antimicrobial Prophylaxis ........................................................................................................................................................... 41

Chapter 3 ................................................................................................................................................................................................................ 42 Treatment Of Muti-Drug Resistant Bacterial Pathogens .............................................................................................................................. 42

1. Methicillin- Resistant S. aureus (MRSA) .................................................................................................................................................. 42 2. Vancomycin Resistant Enterococcus (VRE) ........................................................................................................................................... 42

3. Extended Spectrum Βeta-Lactamases (ESBL) Producing Enterobacteriaceae. .......................................................................................... 42 4. Carbapenem- Resistant Enterobacteriaceae (CRE) .................................................................................................................................... 42

Chapter 4 ................................................................................................................................................................................................................ 44 Guidelines For Optimizing Use Of Key Antimicrobials ................................................................................................................................ 44

A. Antimicrobial Prescribing: Good Practice ................................................................................................................................................ 44 B. Reserve Antimicrobials ............................................................................................................................................................................ 45

E. Alert Antibiotics And Their Indications .................................................................................................................................................... 46 Chapter 5 ................................................................................................................................................................................................................ 49

Preventive Strategies For Healthcare Associated Infections ......................................................................................................................... 49 A. Healthcare Associated Infections .............................................................................................................................................................. 49

B. Reducing the risk of Health care associated infections.............................................................................................................................. 49 Chapter 6 ................................................................................................................................................................................................................ 50

B. Need For Surveillance To Track Antimicrobial Use And Resistance ....................................................................................................... 50 C. Standardized Methodology And Outcome Measures ................................................................................................................................ 50

D. Situation In Developing Countries ............................................................................................................................................................ 51 High-end Antibiotic Monitoring Sheet .......................................................................................................................................................... 52

Dosage Guide For Commonly Used Antimicrobial Agents ........................................................................................................................... 53 Chapter 8 ................................................................................................................................................................................................................ 57

Link To National Programme Current Guidelines For Treatment Of Specific Infections......................................................................... 57 Chapter 9 ................................................................................................................................................................................................................ 59

Case Definitions And Diagnosis For Common Infections .................................................................................................................................. 59 DIARRHEA ................................................................................................................................................................................................... 59

Chapter 1 INTRODUCTION Infections caused by microorganisms have threatened human life since time immemorial. During the pre-antibiotic era, these have been a major concern for the high morbidity and mortality in humans. Some of the virulent organisms with the potential to spread infection from one infected person to another at a very rapid rate may cause worldwide pandemics, epidemics or

outbreaks. With the discovery of the first antibiotic, "the magic bullet" Penicillin in the year 1943, patients could be effectively cured of many life-threatening infections. This gave a huge relief to the medical practitioners. Next three decades saw the development and discovery of a wide variety of antimicrobial agents. Subsequently, the pace of discovery of newer molecules declined from 1970 to 1987. It has reached a “discovery void” level from 1987 onwards up till now. This is the post-antibiotic

era in which the medical practitioners have to treat and manage all types of infections with equal or greater efficiency. Spontaneous natural development of antimicrobial resistance in the microorganisms in nature is a slow process. However, the frequent and inappropriate use of a newly discovered antimicrobial drug leads to the development of altered mechanisms in the pathophysiology of the concerned microbes as a survival strategy. Such antibiotic selection pressure kills the susceptible

microbes and helps in selective replication of drug resistant bacteria. These resistant bacteria already existed in the population along with the susceptible ones or susceptible bacteria acquired resistance during antimicrobial treatment. Ultimately, such resistant bacteria multiply abundantly and entirely replace the susceptible bacterial population. This results in treatment failure

or ineffective management of such infected patients. Antimicrobial resistance has been observed and reported with practically all the newly discovered antimicrobial molecules till date. Antimicrobial resistance makes the treatment of patients difficult, costly and sometimes impossible. Emergence of antimicrobial resistance in pathogens has become a matter of great public health concern. Antimicrobial

resistance is well recognised as a global threat to human health. Infections caused by antimicrobial-resistant micro-organisms in hospitals are associated with increased morbidity, mortality and healthcare costs. Resistance has emerged even to newer and more potent antimicrobial agents like carbapenems. Selection and spread of resistant microorganisms in the presence of antimicrobials is facilitated by:  Irrational use of drugs  Self-medication  Misuse of drugs

Antimicrobial resistance is closely linked to inappropriate antimicrobial use. It is estimated that 50% or more of hospital antimicrobial use is inappropriate. There is a need for increased education and awareness about antimicrobial resistance among the public and health-care professionals. One needs to develop and improve the surveillance system for antimicrobial resistance and infectious diseases in general, particularly through improved linkage of data. Nothing will work unless we

improve diagnostic testing to ensure more tailored interventions and respond to the opportunities afforded by advances in genomic technologies and point of care testing. Since ‘post antibiotic era’ is reported to be “discovery void”; antimicrobial resistance is considered to be the most serious health threats especially for the common infections like sepsis, diarrhea, pneumonia, urinary tract infection, gonorrhea,

malaria, tuberculosis, HIV, influenza. Presently, carbapenem resistance is reported worldwide in more than 50% of strains of Klebsiella pneumoniae causing health care associated infections like pneumonia, blood stream infections, infections in the newborn and intensive care units. More than 50% of Escherichia coli strains causing urinary tract infections are reported worldwide to be resistant to fluoroquinolones. Similarly, patients suffering from gonorrhea are reported to be resistant to the

last resort of antibiotics - third generation cephalosporins. High mortality (64%) was seen among patients infected with Methicillin resistant Staphylococcus aureus (MRSA). Over all, the antimicrobial resistance is associated with higher mortality rate, longer hospital stay, delayed recuperation and long term disability. Similar observations on the emergence of antimicrobial resistance in gram-negative and gram-positive bacteria are reported

also from India. The resistance range varies widely depending on the type of health care setting and the geographical location, availability of antimicrobials in hospitals and over the counter, prescribing habits of treating clinicians coming from different streams of medicine like allopathy, homeopathy, ayurvedic or quacks. The drug resistance has been reported to develop in a microbial population to an antibiotic molecule following its improper and irrational use. To combat the problem of ineffective

management of infections and their complications caused by drug resistant microorganisms, it is imperative to report such problems and generate national data at all levels of healthcare settings thus leading to a better tracking and monitoring system in the country. The published reports in the country reveal an increasing trend of drug resistance in common diseases of public health importance i.e. Cholera: showing high level of resistance to commonly used antimicrobials e.g. Furazolidone (60-80%),

Cotriamoxazole (60-80%) and Nalidixic Acid (80-90%), Enteric fever: Chloramphenicol, Ampicillin, Cotriamoxazole (30- 50%), Fluoroquinolones (up to 30%), Meningococcal infections: Cotriamoxazole, Ciprofloxacin and Tetracycline (50-100%), Gonococcal infections: Penicillin (50-80%), Ciprofloxacin (20-80%). Resistance is also seen in Meningococcal infections, malaria, leprosy, kala-azar, TB, & HIV. Recently, NDM-1 positive bacteria have also been reported. Factors responsible for

emergence of antimicrobial resistance could be widespread use and availability of practically all the antimicrobials over the counter for human, animal and industrial consumption. There are definite policies/guidelines for appropriate use of antimicrobials at national level in specific national health programmes (e.g. RNTCP, National AIDS Control Programme, National Malaria Control Programme etc.). etc

For other pathogens of public health importance like enteric fever, diarrhoeal disease, respiratory infections etc., the individual hospitals are following their own antimicrobial policies and hospital infection control guidelines. Reliable Indian data on antimicrobial resistance (AMR)for important pathogens of public health importance is an essential pre- 7

requisite for developing/modifying appropriate guidelines for use of antimicrobials. Currently, there is no accepted national database of antimicrobial resistance in different pathogens except for those where there is a specific national health programme. Despite many microbiology laboratories (in both public as well as private sector) performing routine antibiotic susceptibility testing (AST) of at least bacterial pathogens, the data is neither analysed regularly nor disseminated for use by

clinicians / public health experts / programme managers. Quality control and data sharing by these laboratories are other important issues that need attention. Recently, Ministry of health has launched ‘National programme for AMR Containment’ in 2012-2017, and one of the key activities initiated under the programme is AMR surveillance with a network of ten laboratories across the country. Currently,

the National programme for Containment of AMR is generating AMR data for common bacterial pathogens from various surveillance network sites across the country. The data generated from these surveillance sites shall be useful to understand the magnitude and trend of drug resistance and identify the emergence of resistance, and will enable to accordingly update the treatment guidelines. Furthermore, need for antibiotics can be reduced by spreading the knowledge of infection control measures and adopting and

implementing the hospital infection control practices, formation of active hospital infection control teams in each hospital working round the clock and monitoring and containing the spread of infections. The importance of hand hygiene cannot be more emphasized in helping to control the spread of infections from one patient to another. Access to clean water also helps in the containment of waterborne diseases and outbreaks and infections. Lastly, preventing the acquisition of an infection by

vaccination for different microbial infections will also help in reducing the need for prescription of antibiotics. Implementation of an antibiotic stewardship program - a multidisciplinary program in the country will help to find out the lacunae and improve upon the rational use of antibiotic with appropriate interventions and strategies. To contain the further development of antimicrobial resistance with no new drug on the horizon and bring the existing levels of

reported resistance in the country, it is imperative to have standardized national treatment guidelines for the practitioners so that they rationally use the currently available antimicrobial agents effectively for a long duration and manage their patients more effectively. How to use these guidelines? These guidelines list the recommended treatments for common infectious diseases that are based on scientific evidence,

literature review and are consistent with the already existing international guidelines and formulated with the collective opinion of a wide group of recognised national experts. The topics covered in this document include empiric treatment choices for different syndromes, infections of specific body sites, and in certain special settings; antimicrobial choices for multi-drug resistant bacterial pathogens; optimizing and monitoring use of antimicrobials; preventive strategies for healthcare associated

infections, case definitions and diagnosis of common infections. It is emphasized that antimicrobials should be prescribed only when they are necessary in treatment following a clear diagnosis. Not all patients need antibiotics; non−drug treatment may be suitable and this has been emphasized in these guidelines. In all cases, the benefit of administering the medicine should be considered in relation to the risk involved. This is particularly

important during pregnancy where the risk to both mother and foetus must be considered. The content of these treatment guidelines will undergo a process of continuous review. Comments or suggestions for improvement are welcome. These suggestions may be sent to: amrsurveillance@gmail.com DISCLAIMER: This publication provides only suggestive guidelines and the opinions expressed herein reflect those of the contributors. The

protocols described herein are general and may not apply to a specific patient. They should NOT supplant clinical judgment, factors like hemodynamics of specific patients, availability of antimicrobials and local antibiogram of healthcare setting. 8

Chapter 2. SYNDROMIC APPROACH FOR EMPIRICAL THERAPY OF COMMON INFECTIONS Empirical or presumptive anti-infective therapy is based on a clinical diagnosis combined with evidence from the literature and from the educated experience of the probable pathogens causing the infection. To optimize an accurate microbiological diagnosis, clinicians should ensure that diagnostic specimens are properly obtained and promptly submitted to the

microbiology laboratory, preferably before the institution of antimicrobial therapy. All attempts should be made to establish diagnosis of the patients based on the facilities available to the treating doctor and affordability of the patients. Definitive therapy depends on the microbiologic diagnosis by isolation or other direct evidence of pathogen. According to WHO, presumptive treatment is a one-time treatment given for a presumed infection in a person, or group of people, at high risk of infection.

Presumptive treatment is prescribed typically while waiting for the culture report or in situations where the facilities for doing these tests is not available, is difficult or not cost effective or is impractical. However in certain situations the empirical therapy prescribed as prophylaxis also (e.g surgical prophylaxis, high prevalence, repeated risk of exposure). The syndromic approach is based on the presence of consistent groups of symptoms and easily recognized signs caused by a

single pathogen or a mixture of pathogens. Before starting presumptive therapy ensure the following 1. Send and follow up on standard investigations for all suspected infections for correct and accurate diagnosis and prognosis. 2. Antibiotics SHOULD be started only after after sending appropriate cultures if facilities are available. Similary any change in antibiotic MUST be guided by sensitivity profile.

3. Assess the factors affecting activity of antimicrobilas such as renal excretion, interactions and allergy before prescribing antibiotics. 4. Review of antibiotic therapy MUST be done daily and the therapy escalated or deescalated accordinglyespacially after the culture reports are available. Empirical Therapy si justified in patients with life threatening infections, in ICU settings and while awaiting results of culture.

The timing of initial therapy should be guided by the patient’s condition and urgency of the situation. In critically ill patients e.g. patients in septic shock or bacterial meningitis therapy should be initiated immediately after or concurrently with collection of diagnostic specimens. In other conditions wehere patient is stable, antimicrobial therapy should be deliberately withheld until appropriate specimens have been collected and submitted to the microbiology laboratory e.g when treating a

patient of osteomyelitis or sub-acute endocarditis. Premature usage of antimicrobial in such cases can preclude opportunity to establish a microbiological diagnosis, which is critical in the management of these patients. Merits and limitations of empiric vs definitive antimicrobial therapy should be very clear to the treating doctor prescribing antimicrobials.As the laboratory results pertaining to microbiological tests do not become available for 24 to 72 hours, initial

therapy for infection is often empiric and guided by the clinical presentation. Therefore, a common approach is to use broad- spectrum antimicrobial agents as initial empiric therapy with the intent to cover multiple possible pathogens commonly associated with the specific clinical syndrome. However, once laboratory results of microbiology tests are available with identification of pathogen alongwith antimicrobial susceptibility data, every attempt should be made to narrow the antibiotic

spectrum. This is a critically helpful and integral component of antimicrobial therapy because it can reduce cost and toxicity and significantly delay the emergence of antimicrobial resistance in the community. Antimicrobial agents with a narrower spectrum should be directed at the most likely pathogens for the duration of therapy for infections such as community-acquired pneumonia, urinary tract infections, soft tissue infections etc. in anOPD setting because specific microbiological tests are not

routinely performed or available or affordable. Due considerations housld be given to the bactericidal vs bacteriostatic nature of the antimicrobial agents. Bactericidal drugs, which cause death and disruption of the bacterial cell, include drugs that primarily act on the cell wall (e.g., β-lactams), cell membrane (e.g., daptomycin), or bacterial DNA (e.g., fluoroquinolones). Bacteriostatic agents (e.g. sulfonamides and

macrolides) inhibit bacterial replication without killing the organismact by inhibiting metabolic pathways or protein synthesis in bacteria. However, some antimicrobials are bactericidal against certain organisms may act as bacteriostatic against others and vice versa. Unfortunately such distinction is not significant in vivo. Bactericidal agents are preferred in the case of serious infections to achieve rapid cure (e.g in cases of meningitis and endocarditis).

There are few conditions where combination antimicrobial therapy is contemplated. These include conditions where synergism of antimicrobials established or cases of infection withspecific microbes, where monotherapy is not generally recommended (e.g., treatment of endocarditis caused by Enterococcus species with a combination of penicillin and gentamicin). It also includes critically ill patients who may require empiric therapy before microbiological etiology and/or

antimicrobial susceptibility can be determined (e.g. suspected healthcare-care associated infections with Acinetobacter baumannii or Pseudomonas aeruginosa). Other conditions where combination therapy may be required include cases where 9

there is a need to extend the antimicrobial spectrum beyond a use of a single agent is the treatment of polymicrobial infections. Also, it may be used where treatment is initiated for pan-resistant organisms and to prevent emergence of resistance. Host factors like age, physiological state of the patient (e.g. pregnancy and lactation), organ function (e.g. renal or hepatic function), genetic variation (e.g. G6PD deficiency), allergy or intolerance must be kept in mid while prescribing antimicrobial

therapy. Due consideration should be give to the efficacy of an antimicrobial agent at the site of infection (e.g. first- and second-generation cephalosporins and macrolides do not cross the blood-brain barrier and are not recommended for central nervous system infections. Fluoroquinolones achieve high concentrations in the prostate and are preferred oral agents for the treatment of prostatitis).

The contents of this chapter include the commonst infections encountered in healthcare practice. The first section gives treatment guidelines for the adult patients while the second part gives same for the pediatric and neonatal infections. The table below describes the infective syndromes, likely causative agnets and the empirical antibiotic therapy advocated aginst them. How to use this table:

The table is divided into sections as indicated below. Each section has 5 rows. Row 1 lists the clinical condition. Row 2 lists the most likely agents responsible for this condition, row 3 lists the first line antibiotics while row 4 lists the alternative antibiotic. The alternate antibiotic may be prescribed in cases when the first line antibiotics cannot be used due to hypersensitivity or patient’s clinical parameters or non-availability of first line drugs. The table is divided into following

subsections: Presumptive therapy for adult patients suspected of infection A.Gastrointestinal & Intra-Abdominal Infections B. Central Nervous System Infections C. Cardiovascular Infections D. Skin & Soft Tissue Infections E. Respiratory Tract Infections F. Urinary Tract Infections G. Obstetrics And Gynaecological Infections H. Bones And Joint Infections I. Eye Infections J. Ear Infections K .Infections in Burn and Plastic Surgery L. Fungal Infections M. Febrile Neutropenia

N. Post-Cardiovascular Surgery Infections O. Pediatric Infections P. Neonatal Infections R. Post Solid Organ Transplant S. Surgical Antimicrobial Prophylaxis A. GASTROINTESTINAL & INTRA-ABDOMINAL INFECTIONS Condition Likely Causative Empiric Alternative Comments Organisms (presumptive) antibiotics/Second Line antibiotics/First Line Acute Viral, None None Rehydration Gastroenteritis Entero-toxigenic & (oral/IV) essential Entero-pathogenic E. coli Food poisoning S. aureus, B. cereus, C. botulinum

Cholera V.cholerae Doxycycline 300mg Azithromycin 1gm Oral stat Rehydration Oral stat or (oral/IV) Ciprofloxacin 500mg BD is essential Azithromycin Oral in for 3 days children (20mg/kg) Antibiotics are and pregnant women adjunctive therapy. (1g) Bacterial dysentery Shigella sp., Ceftriaxone 2gm IV Azithromycin 1g OD x For Campylobacter Campylobacter, OD for 5 days or oral 3days the drug of choice Non- typhoidal cefixime 10-15 is azithromycin. salmonellosis mg/kg/day x 5 days

producing E. coli not recommended. use associated with development of hemolytic uremic syndrome. Amoebic dysentery E. histolytica Metronidazole 400mg Tinidazole 2gm Oral OD Add diloxanide Oral TDS for 7-10 for 3 days furoate 500 mg days TDS for 10d Giardiasis Giardia lamblia Metronidazole 250- Tinidazole 2 gm oral x 500mg oral 1 dose TID x 7-10 d Enteric fever S.Typhi, Outpatients: Majority of strains S.Paratyphi A Cefixime 20mg/kg/day Cotrimoxazole 960 mg BD arenalidixic acid

for 14 days or for 2 weeks resistant. Azithromycin 500 mg BD for 7 days. Ceftriaxone to be Inpatients: Ceftriaxone changed to oral 2 g IV BDfor 2 weeks cefixime when +/-Azithromycin 500 patient is afebrile to mg BD for 7 days finish total duration of 14days. Biliary tract infections Enterobacteriaceae Ceftriaxone 2gm IV Imipenem 500mg IV Surgical or (cholangitis, (E.coli, Klebsiella OD or 6hourly endoscopic cholecystitis) sp.) Piperacillin- or intervention to be

Tazobactam 4.5gm IV Meropenem 1gm IV considered if there 8 hourly 8hourly is biliary or obstruction. Cefoperazoe- For 7-10 days High prevalence of Sulbactam 3gm IV ESBL producing 12hourly E.coli, Klebsiella sp.strains. De- For 7-10 days escalate therapy once antibiotic susceptibility is known. Hospital acquired C. difficile Metronidazole 400 mg Severe disease:start diarrhea oral TDSfor 10 days Vancomycin 250 mg oral 6h empirically.

Spontaneous bacterial Enterobacteriaceae Cefotaxime 1-2 gm IV Imipenem 500 mg IV Descalate to Peritonitis (E.coli, Klebsiella TDS 6hourly or Ertapenem 1 gm IV sp.) or Meropenem 1gm IV OD for 5-7 days Piperacillin- 8hourly once the patient Tazobactam 4.5gm IV improves 8 hourly or Cefoperazone- Sulbactam 3gm IV 12h Secondary peritonitis, Enterobacteriaceae Piperacillin- Imipenem 1g IV 8hourly Source control is Intra-abdominal (E.coli, Klebsiella Tazobactam 4.5gm IV or important to reduce

abscess/ GI perforation sp.), Bacteroides 8 hourly Meropenem 1gm IV bacterial load. (colonic or 8hourly If excellent source perforation), Cefoperazone- or control – for 5-7 Anaerobes Sulbactam 3gm IV Doripenem 500 mg TDS days; other wise 2- 12hourly in severe or 3 weeks suggested. infections Ertapenem 1 gm IV OD In very sickpatients, if required, addition of cover for yeast (fluconazole iv 800 mg loading dose day 1, followed by 400 mg 11

2nd day onwards) & and for Enterococcus (vancomycin /teicoplanin) may be contemplated Pancreatitis No antibiotics Mild- moderate Post necrotizing Entrobacteriaceae, Piperacillin- Imipenem-Cilastatin 500mg Duration of pancreatitis: infected Enterococci, S. Tazobactam 4.5 gm IV IV 6hourly treatment is based pseudocyst; pancreatic aureus, 8 hourly empirically or on source control abscess S. epidermidis, or Meropenem 1gm IV and clinical anaerobes, Candida Cefoperazone- 8hourly improvement

sp. Sulbactam 3gm IV 8 or hourly in severe Doripenem 500mg IV 8h infections In very sick patients, if required, addition of cover for yeast (fluconazole iv 800 mg loading dose day 1, followed by 400 mg 2nd day onwards) & and for Enterococcus (vancomycin /teicoplanin) may be contemplated For 7-10 days Diverticulitis Gram-Negative Amoxycillin- Ciprofloxacin + Mild- Bacteria Clavulanate 625mg Metronidazole for 7 days OPD treatment Anaerobes TDS for 7 days

Diverticulitis moderate Gram- Negative Ceftriaxone 2gm IV BL-BLI agents Bacteria OD +metronidazole have very good Anaerobes 500 mg IV TDS or anaerobic cover, so Piperacillin- no need to add Tazobactam 4.5 gm IV metronidazole. 8 hourly empirically or Cefoperazoe- Sulbactam 3gm IV 8 hourly Diverticulitis Gram- Negative Meropenem 1gm IV Duration based on Severe Bacteria 8hrly or Imipenem improvement Anaerobes Cilastatin 500mg IV 6 hourly

Liver Abscess Polymicrobial Amoxycillin- Piperacillin-Tazobactam IV Ultrasound guided clavulanate/ 3rd drainage indicated generation inlarge abscesses, cephalosporin signsof imminent + rupture andno Metronidazole 500mg response to I.V.TID / 800mg oral medicaltreatment. TID for 2 weeks 12

B. CENTRAL NERVOUS SYSTEM INFECTIONS Condition Likely Causative Empiric antibiotics Alternative Comments Organisms (presumptive antibiotics) antibiotics Acute bacterial S. pneumoniae, Ceftriaxone Chloramphenicol if Antibiotics should be Meningitis H.influenzae, 2 g IV 12hourly/ Cefotaxime patient is allergic to started as soon as the Neisseria 2 g IV 4-6hourly penicillin possibility of bacterial meningititidis meningitis becomes evident, ideally within 10-14 days treatment 30 minutes. Do not

wait for CT scan or LP results. No need to add vancomycin as primary agent, as ceftriaxone resistant Pneumococcus is not common in India. Listeria is also rare in India and so ampicillin is also not indicated Adjust therapy once pathogen and susceptibilities are known. Meningitis-Post- Staphylococcus Meropenem 2gm IV 8 May need intra neurosurgeryor epidermidis, hourly ventricular therapy in Penetratinghead Staphylococcus AND severe cases trauma aureus, Vancomycin 15mg/kg IV 8 Propionibacterium hourly

acnes, Pseudomonas aeruginosa, For 14 days. Acinetobacter baumanii Meningitis with basilar S.pneumoniae, Ceftriaxone 2gm IV 12 Dexamethasone skull fractures H. influenzae hourly 0.15mg/kg IV 6 For 14 days hourlyfor 2-4days (1st dose with or before first antibiotic dose) Brain abscess, Streptococci, Ceftriaxone Meropenem 2gm IV Exclude TB, Nocardia, Subdural empyema Bacteroides, 2 gm IV 12hourly 8hourly Aspergillus, Mucor Enterobacteria-ceae, or S.aureus Cefotaxime If abscess <2.5cm &

2 gm IV 4-6hourly patient neurologically stable, await response AND to antibiotics. Otherwise, consider Metronidazole 1 gm IV aspiration/surgical 12hourly drainageand modify antibiotics as per Duration of treatment to be sensitivity of decided by clinical & aspirated/drained radiological response, secretions. minimum two months required. 13

C. CARDIOVASCULAR INFECTIONS Condition Likely causative Empiric Alternative Comments Organism antibiotics antibiotics (presumptive antibiotics) Infective Endocarditis: Viridans Streptococci, Penicillin G Vancomycin If patient is stable, ideally waitblood other Streptococci, 20MU IV 15mg/kg IV 12 cultures. Native valve (awaiting Enterococci divided doses, 4 hourly cultures) Indolent hourly (maximum 1g 12 Antibiotic choice as per sensitivity or hourly)//teicplani results.

Ampicillin 2gm n 12mg/kg IV 12 Guidance from Infectious disease iv 4h hourly x 3 doses specialist or clinical microbiologist is followed by 6 - recommended AND 12 mg once daily IV depending Gentamicin upon severity + 1mg/kg im or iv Gentamicin 8h 1mg/kg IM or IV 8 hourly Duration: 4-6 weeks Duration: 4-6 weeks or Daptomycin 6mg/kg IV once a day Duration: 4-6 weeks Infective Endocarditis: S.aureus Vancomycin 25- Daptomycin Modify antibiotics based on culture

Native valve (awaiting (MSSA or MRSA) 30 mg/kg 6mg/kg IV once results and complete 4-6 weeks of cultures) Risk for gram- loading followed a day antibiotics In Severe Sepsis negative bacilli by 15-20 mg/kg AND IV 12 hourly Meropenem 1gm (maximum 1gm IV q8h 12 hourly)/teicoplan Duration: 4-6 in 12mg/kg IV weeks 12 hourly x 3 doses followed by 6 -12 mg once daily IV depending upon severity AND Meropenem 1gm IV 8h Duration: 4-6 weeks 14

Infective Endocarditis: Vancomycin Daptomycin can Antibiotic choice as per sensitivity. Prosthetic Valve 15mg/kg IV 12 be used in place Guidance from Infectious disease awaiting Cultures hourly of Vancomycin/ specialist or microbiologist is Teicoplanin for (maximum 1gm recommended. patients 12 unresponsive to hourly)/teicoplan or intolerant of in 12mg/kg IV Vancomycin/Tei 12 hourly x 3 coplanin or with doses followed Vancomycin/Gly by 6 -12 mg once copeptide- daily IV resistant isolates depending upon

severity + Gentamicin 1mg/kg q12h IV D. SKIN & SOFT TISSUE INFECTIONS Condition Likely Causative Empiric Alternative Comments Organisms antibiotics antibiotics (presumptive antibiotics) Cellulitis Streptococcus Amoxicillin- Clindamycin Treat for 5-7 days. pyogenes(common), Clavulanate 600-900mg IV S.aureus 1.2gm IV TDS TDS/625 mg oral TDS or Ceftriaxone 2gm IV OD Furunculosis S.aureus Amoxicillin- Clindamycin Get pus cultures before starting Clavulanate 600-900mg IV antibiotics 1.2gm IV/Oral TDS 625 TDS or

Ceftriaxone 2gm IV OD Duration – 5-7 days Necrotizing Streptococcus Piperacillin- Imipenem 1g Early surgical intervention crucial fasciitis pyogenes, S. aureus, Tazobactam IV8hourly anaerobes, 4.5gm IV or Enterobacteriaceae 6hourly Meropenem 1gm (polymicrobial) or Cefoperazone- IV 8hourly Sulbactam 3gm AND IV 12hourly Clindamycin 600-900mg IV AND TDS/linezolid 600 mg IV Clindamycin BD/daptomycin 600-900mg IV 8 6mg/kg/day hourly Duration depends on the progress 15

E. RESPIRATORY TRACT INFECTIONS Condition Likely Causative Empiric Alternative Comments Organisms antibiotics antibiotics (presumptive antibiotics) Community S. pneumoniae, Mild to moderate Piperacillin- If MRSA is a concern, add acquired H.influenzae, cases Tazobactam 4.5gm Linezolid 600mg IV/Oral BD Legionella, Amoxycillin- IV 6 hourly Pneumonia E.coli, Klebsiella sp., 500mg-1 g TDS or If atypical pneumonia S.aureus oral. Imipenem 1g IV suspected, Doxycycline If IV indicated, 6hourly 100mg bd

amoxycillin- or or clavulanate 1.2 g Cefoperazone- Azithromycin 500 mg oral/IV IV TDS or Sulbactam 3gm IV OD Ceftriaxone 2g IV 12 hourly OD For Severe cases Amoxycillin- clavulanate 1.2 g IV TDS OrCeftriaxone 2g IV OD Duration 5-8 days Lung abscess, S. pneumoniae, Piperacillin- ADD Clindamycin 3-4 weeks treatment required Empyema E.coli, Tazobactam 4.5gm 600-900mg IV Klebsiella sp., IV 6hourly 8hourly Pseudomonas or aeruginosa, Cefoperazone- S.aureus, anaerobes Sulbactam 3gm IV 12 hourly

Acute pharyngitis Viral None required As most cases are viral no antimicrobial therapy required Group A ß-hemolytic Oral Penicillin v In case of penicillin Antibiotics are recommended Streptococci 500mg BD allergy: to reduce transmission rates (GABHS), or Azithromycin and prevention of long term Group C, G Amoxicillin 500 mg 500mg OD for 5 sequaelae such as rheumatic Streptococcus, Oral TDS for 10 days fever days or Benzathine penicillin 12 lac units IM stat

Ludwig’s angina Polymicrobial Clindamycin 600 Piperacillin- Duration based on Vincent’s angina (Cover oral anaerobes) mg IV 8 hourly Tazobactam 4.5gm improvement or IV 6 hourly Amoxicillin- Clavulanate 1.2gm IV Acute bacterial Viral, Amoxicillin- Moxifloxacin rhinosinusitis S. pneumoniae, clavulanate 1gm 400mg OD for 5- H.influenzae, oral BD for 7 days 7days M. catarrhalis Acute bronchitis Viral Antibiotics not - - required Acute bacterial S. pneumoniae Amoxicillin- Azithromycin 500

exacerbation of H. influenzae clavulanate 1gm mg oral OD × 3 M. catarrhalis oral BD for 7 days days COPD 16

F. URINARY TRACT INFECTIONS Asymptomatic bacteriuria NOT to be treated except pregnant women and immunocompromised patients. All cases of dysuria may not be UTI. Refer to Obstetrics and gynaecology infections for treatment of asymptomatic bacteriuira in pregnant women. Condition Likely Causative Empiric antibiotics Alternative Comments Organisms (presumptive antibiotics antibiotics) Acute E.coli, Staphylococcus Nitrofurantoin 100 Cefuroxime 250 Get urine cultures before

uncomplicated saphrophyticus(in mg BD for 7 days mg BD for 3-5 antibiotics & modify therapy Cystitis sexually or Cotrimoxazole days based on sensitivities. activeyoungwomen), 960mg BD for 3-5 Klebsiella pneumoniae days or Ciprofloxacin 500 mg BD for 3-5 days Acute E.coli, Amikacin 1 g OD Piperacillin- Urine culture and uncomplicated Staphylococcus IM/IV Tazobactam 4.5g susceptibilities need to be Pyelonephritis saphrophyticus (in or IV 6 hourly collected before starting

sexually active young Gentamicin 7 or antimicrobial treatment to women), mg/kg/day OD Cefoperazone- guide treatment. Klebsiella pneumoniae, Sulbactam 3g IV Proteus mirabilis (Monitor renal 12 hourly function closely and or rationalise according Ertapenem 1 g IV to culture report) OD Complete total duration of 14 days Complicated Escherichia coli, Piperacillin- Imipenem 1g IV 8 Get urine cultures before Pyelonephritis Klebsiella pneumonia, Tazobactam 4.5gm hourly antibiotics & switch to a

Proteus mirabilis, IV 6 hourly or narrow spectrum agent based Pseudomonas or Meropenem 1gm on sensitivities. Treat for 10- aeruginosa, Amikacin 1 g OD IV 8 hourly 14 days. Enterococcus sp. IV or De-escalate to Ertapenem 1 Frequently multi-drug Cefoperazone- gm IV OD, if resistant organisms are Sulbactam 3gm IV Imipenem/meropenem present 12 hourly initiated. Monitor renal function if aminoglycoside is used. Doxycline 100 mg In severe cases,

Acute prostatitis Enterobacteriaceae BD Piperacillin- Get urine and prostatic (E.coli, Klebsiella sp.) or Tazobactam massagecultures before Co-trimoxazole 960 4.5gm IV 6 antibiotics & switch to narrow mg BD. hourly spectrum agent based on or sensitivities and then treat Cefoperazone- total for 3-4 weeks. sulbactam 3gm IV Use Ciprofloxacin (if 12 hourly sensitive) or Ertapenem 1 gm IV OD or Imipenem 1g IV 8 hourly or Meropenem 1gm IV 8 hourly 17

G. OBSTETRICS AND GYNAECOLOGICAL INFECTIONS  Fluoroquinolones are contraindicated in 1st trimester.  Cotrimoxazole is contraindicated in 1st trimester.  Doxycycline is not recommended in nursing mothers. If need to administer doxycycline discontinuation of nursing may be contemplated. Infections Likely organism Primary treatment Alternate Remarks (presumptive treatment antibiotics) Asymptomatic Nitrofurantoin 100 Oral Screen in 1st trimester.

Bacteriuria mg Oral, BD for 7 cephalosporins, Can cause pylonephritis > 1,00,000 cfu/ ml of days TMP-SMX or TMP in upto 25% of all bacteria of same or Amoxicillin 500 alone pregnant women. species in 2 urine mg Oral BD 30 % Chance of cultures obtained 2-7 x 7-10 days . recurrence after days apart. empirical therapy 1. Few Treat as per direct effects, uterine sensitivity result for 7 hypo perfusion due to days. maternal anemia dehydration, may cause fetal cerebral hypo perfusion. 2. LBW,

prematurity,premature labour, hypertension, preeclampsia, maternal anemia, and amnionitis. Need to document pyuria (Pus cells > 10/HPF) Group B Group B Streptococci IV Penicillin G 5 Cefazolin 2 gm IV P revalance very low so streptococcal million units. (Loading Dose) and the prophylaxis may be Disease, Prophylaxis (Loading dose) then then 1 gm TID r e q u i r e d o n l y o n c u l t u r e and Treatment 2.5 -3 million units documented report IV QID until Associated with high

delivery. Clindamycin 900 risk of pre-term or mg IV TID or labour,still birth,neonatal Ampicillin 2 gm IV v a n c o m y cin IV or sepsis ( Loading dose) then teicoplanin for 1 gm QID until penicillin allergy delivery Chorioamnionitis Group B streptococcus, Gram negative bacilli, Clindamycin/ Preterm Birth, 9-11% chlamydiae, ureaplasma and anaerobes, usually vancomycin/ death rate in preterm Polymicrobial teicoplanin and infant’s unfavourable cefoperazone- neurologic outcome, sulbactum lesser risk to term

infants. If patient is not in sepsis then IV Ampicillin Bacteroides, Prevotella bivius, Ampicillin 500 Ceftriaxone 2g IV Septic abortion Group B, Group A mg QID + OD Streptococcus, Metronidazole Enterobactereaceae, C. 500mg IV TDS if trachomatis, Clostridium patient has not perfringens. taken any prior antibiotic (start antibiotic after sending cultures) If patient has been 18

partially treated with antibiotics, send blood cultures and start Piperacillin- Tazobactam or Cefoperazone- sulbactam till the sensitivity report is available. Endomyometritis Bacteroides, Prevotella bivius, Same as above. and Septic Pelvic Group B, Group A Vein Phlebitis Streptococcus, Enterobactereaceae, C. trachomatis, Clostridium perfringens Obstetric Sepsis Group A beta-haemolytic If patient is in during pregnancy Streptococcus, shock and blood E.coli, anaerobes. culture reports are

pending, then start Piperacillin- Tazobactam or Cefoperazone- sulbactam till the sensitivity report is available and modify as per the report. If patient has only fever, with no features of severe sepsis start amoxicillin clavulanate oral 625TDS/IV 1.2 gm TDS Or Ceftriaxone 2gm IV OD+ Metronidazole 500mg IV TDS +/-gentamicin 7mg/kg/day OD if admission needed. MRSA cover may be required if suspected or colonized (Vancomycin/ Teicoplanin) Obstetric Sepsis S. pyogenes, S a m e as above Sources of sepsis

following pregnancy E. coli, outside Genital tract S. aureus Mastitis S. pneumoniae, UTI Meticillin-resistant Pneumonia S. aureus (MRSA), Skin and soft tissue C. septicum & (IV site, surgical Morganella morganii. site, drain site etc.) Syphillis Refer to STD program guidelines Tuberculosis in Similar to NON Please refer RNTCP guideline Very small chance of pregnancy PREGNANT transmission of infection population with WHO has advocated that, all the first line drugs are to fetus. 19

some exceptions safe in pregnancy and can be used except (see comment and streptomycin. SM causes significant ototoxicity to chapter 8) the fetus (Pyrazinamide not recommended by US FDA) 1. Mother and baby should stay together and the baby should continue to breastfeed. Late diagnosis can 2. Pyridoxine supplementation is recommended for predispose to LBW, all pregnant or breastfeeding women taking prematurity. isoniazid as well as to neonate who are being breast fed by mothers taking INH.

VIRAL INFECTIONS (NO ANTIBIOTICS TO BE GIVEN) Influenza In 1. Tendency for severe Direct fetal infection pregnancy Oseltamivir 75 mg Oral Nebulization with including premature labor rare (seasonal And BD for 5 days Zanamvir respules (2) &delivery. H1N1) 5 mg each, BD for 5 days 2. Treatment should Preterm delivery and The best begin within 48 hrs of pregnancy loss. preventive onset of symptoms. strategy is administration of 3. Higher doses single dose of commonly used in non

killed vaccine. pregnant population (150 mg) are not recommended in pregnancy due to safety concerns. 4. Chemoprophylaxis can be used in significant exposures. 5. Live (nasal Vaccine) is contraindicated in pregnancy. Varicella >20 wks of gestation, VZIG should be offered to susceptible women < 10 Chickenpox during presenting within 24 days of the exposure. VZIG has no role in treatment pregnancy does not hours of the onset of the once the rash appears. justify termination rash, without prior prenatal

The dose of VZIG is 125 units / 10kg not exceeding diagnosis as only. Aciclovir 800mg Oral 5 625 units, IM. times a day A minority of fetuses IV acyclovir infected develop fetal recommended for the varicella syndrome. treatment of severe complications, > 24 hrs from the onset of rash, antivirals are not found to be useful. PARASITIC INFECTIONS Acute <18 weeks gestation at diagnosis Toxoplasmosis in pregnancy Spiramycin 1 gm Oral qid until 16-18 weeks/Pyrimathamine + sulphadizine. Alternate every two weeks–

If PCR Positive - >18 weeks gestation and documented fetal infection by positive amniotic fluid PCR. Pyremethamine 50 mg Oral BD x 2 days then 50 mg OD + Sulphadiazine 75 mg/kg Oral x 1 dose then 50mg/kg bd + Folinic Acid (10-20 mg Oral daily) for minimum of 4 weeks or for duration of pregnancy. Malaria In As per national program pregnancy GENITAL TRACT INFECTIONS Candidiasis Candida species Fluconazole oral 150 mg single dose Non-pregnant- If For milder cases- recurrent candidiasis,

Intravaginal agents as creams or suppositories (4 or more clotrimazole, miconazole, nystatin. episodes/year) 6 Intravaginal azoles, single dose to 7-14 days. months suppressive treatment with fluconazole 150 mg oral once a week or clotrimazole vaginal suppositories 500 mg once a week. Bacterial Polymicrobial Metronidazole500mg Oral BD x 7 days T reat the partner. vaginosis Or metronidazole vaginal gel 1 HS x 5 days Or Tinidazole 2 g orally ODx 3 days Or 2% Clindamycin Vaginal cream 5 gm HS x 5 days

Trichimoniasis Trichomonas vaginalis Metronidazole 2 gm single dose or 500 mg Oral BD X 7 days or Treat sexual partner with metronidazole 2 Tinidazole 2 gm Oral single doseFor treatment failure gm single dose – retreat with Metronidazole 500 mg Oral BD X 7 Days, if 2nd failure Metronidazole 2 gm Oral OD X 3- 5 days Cervicitis Ceftriaxone 250 mg IM Single dose + Azithromycin 1 /Urethritis Polymicrobial gm single dose OR Doxycycline 100mg BD x 7 day Mucopurulent gonoccocal

Pelvic S. aureus, Outpatient treatment Drainage of tubo- Inflammatory Enterobacteriacae, Ceftriaxone 250 mg IM/IV single dose plus +/- ovarian abscess Disease gonococci, gardenella Metronidazole 500 mg BD x 14 days Plus Doxycycline wherever indicated (Salpingitis & 100 mg BD x 14 Days Evaluate and treat sex tubo-ovarian Inpatient Treatment Clindamycin +ceftriaxone till partner abscess) patient admitted then change to OPD treatment Mastitis S. aureus Amoxycillin clavulunate/Cephalexin 500 mg QID/ OR

without abscess Ceftriaxone 2 gm OD OR MRSA- based on sensitivities Add Clindamycin 300 QID or Vancomycin I gm IV 12 hourly /teicoplanin 12mg/kg IV 12 hourly x 3 doses followed by 6 once daily IV Mastitis with Drainage with antibiotic cover for abscess MRSA Clindamycin 300 QID or Vancomycin 15mg/kg IV 12 hourly (maximum 1gm 12 hourly)/teicoplanin 12mg/kg IV 12 hourly x 3 doses followed by 6 mg once daily IV 21

H. BONES AND JOINT INFECTIONS Condition Likely causative Empiric antibiotics Alternative Comments Organisms antibiotics Acute S.aureus, Ceftriaxone 2g IV OD Piperacillin- Treat based on culture of osteomyelitis OR Streptococcus tazobactam blood/synovial fluid/bone Septic arthritis pyogenes Followed by Oral therapy by 4.5gm IV q 6h or biopsy Enterobacteriaceae Cloxacillin 500mg q 8h Cefoperazone- Or sulbactam 3gm Orthopedic Consultation Cephalexin 500mg q 6h IV q 12h is essential for surgical

AND debridement Clindamycin 600- 900mg IV TDS Duration: 4-6 weeks (From initiation or last major debridement) Chronic No empiric therapy Definitive Osteomyelitis treatmentguided by OR bone/synovial biopsy Chronic synovitis culture. Treat for 6 weeks minimum Investigate for TB, Nocardia, fungi. Extensive surgical debridement. Total duration of treatment depends on the joint and the organism. Choose antibiotic based on sensitivity. Prosthetic joint Coagulase negative Ceftriaxone 2g IV OD. Add 4 weeks

infection staphylococci, Vancomycin1gm IV BD or Staphylococcus Teicoplanin 800mg x 3 aureus,Streptococci doses followed by 400mg Gram-negative bacilli, Once daily Enterococcus, Anaerobes 22

I. EYE INFECTIONS Eyelid infections Likely organisms First line/ Suggested Alternate regimen Remarks Regimen Blephritis Unclear Lid margin care with baby S.aureus, shampoo & warm compresses S.epidermidis 24 hourly. Artificial tears if associated with dry eye. External Hordeolum S. aureus Hot pack Internal Horedeolum MSSA/ Oral Cloxacillin 250-500 mg Blephritis S. epidermidis qid or Oral Cephalexin 500mg QID Lid margin care with baby shampoo & warm MRSA Oral Trimethoprim compresses 24 hourly.

sulphamethoxazole960 mg Artificial tears if BD or associated with dry eye. Linezolid 600mg BD Cunjuctival infections No antibiotics required treat Highly contagious. Viral conjunctivitis for symptoms If pain & (pink eye) photophobia the suggestive of keratitis. Bacterial S.aureus, Ophthalmologic solution: Uncommon causes- conjunctivitis S.pneumoniae, Gatifloxacin 0.3%, Chlamydia H.influenzae levofloxacin 0.5%, trachomatis Moxifloxacin 0.5% 1-2 drops N.gonorrhoeae q2h while awake during 1st 2

days, then q4-8h upto 7 days Corneal infections Herpes Simplex Trifluridine ophthalmic soln Ganciclovir 0.15% Flurescine staining keratitis H.simplex type 1drop 2 hourly, up to ophthalmic gel for shows topical 1&2 9times/day until re-epithilised. acute herpitic keratitis. dendritic then 1 drop 4 hourly upto 5 figures.30-50% times/day for total duration of recur within 2yr. 21days Varicella Zoster Varicella–zoster Famciclovir 500mg BD Or Acyclovir 800mg 5

ophthalmicus virus TID OR Valacyclovir 1gm times/d x 10days . oral TID X 10days Acute bacterial S.aureus, Moxifloxacin topical(0.5%):1 Gatifloxacin 0.3% Moxifloxacin. keratitis (No S.pneumoniae, drop 1 hourly for first ophthalmic Solution Preferable. comorbidities) S.pyogenes, 48hr,then reduce as per 1drop 1 hourly for 1st Treatment may fail Haemophilus spp response 48hrs then reduce as against MRSA. per response Acute Bacterial P.aeruginosa Tobramycin or Gentamicin Ciprofloxacin

(Contact lens users) 14mg/ml + Piperacilin or ophthalmic 0.3% or Ticarcillin eye drops (6- Levofloxacin 23

12mg/mL) q15-60 min around ophthalmic 0.5% the clock 24-72hr,then slowly reduce frequency Fungal keratitis Aspergillus, Natamycin (5%) 1drop 1-2 Amphotericin B Empirical therapy Fusarium, hourly for several days,then 3- (0.15%) 1 drop q1-2 is not Candida and others 4 hourly for several days hourly for several days recommended. depending on response depending on the response - Protozoan Acanthamoeba spp. Optimal regimen uncertain Uncommon.Traum (soft contact lense Suggested –(Chlorhexidine a & soft contact

users) 0.02% or lenses are risk Polyhexamethylenebiguanide factors 0.02%) + (Propamidineisethionate 0.1%or Hexamidine 0.1%) eye drops 1drop every 1 hourly hourly during day time, taper according to clinical response Orbital infections Orbital cellulitis S.pneumoniae, Cloxacillin 2 gm IV q4h+ If If MRSA is H.influenzae, Ceftriaxone 2 gm IV q24 Pencillin/Cephalospori suspected substitute M.catarrhalis, hourly+ Metronidazole 1gm n allergy: cloxacillin with S.aureus, IV 12h Vancomycin 1gm iv Vancomycin

Anaerobes, q12h + levofloxacin Group A 750 mg IV once daily + Streptococcus, Metronidazole iv 1gm Occasionally Gram 24h Negative bacilli post trauma. . Endophthalmits Post-ocular surgery S.epidermidis Immediate Adjuvant systemic Bacterial S. aureus, Streptococci, ophthalmological antibiotics enterococci, Gram- negative consultation. ( doubtful value in bacilli Immediate vitrectomy+ post cataract intravitreal antibiotics surgery (Inj Vancomycin + Inj endophthalmitis)Inj ceftazidime) Vancomycin+ Inj Meropenem

Hematogenous S.pneumoniae, N.meningitidis, I n t r a v i t r e a l a n t i biotics S. aureus, Inj Vancomycin + Inj Group B streptococcus, c e f t a z i d ime K. pneumoniae + Systemic antibiotics Inj Meropenem 1gm iv q8h /Inj Ceftriaxone 2gm iv q24h + Inj Vancomycin 1g iv q12h Intavitreal amphotericin B Liposomal Duration of Endophthalmitis Candida sp, 0.005-0.01 mg in 0.1 ml Amphotericin B 3- treatment 4-6 Mycotic (Fungal) Aspergillus sp. Systemic therapy: 5mg/kg weeks or longer

Amphotericin B 0.7-1mg/kg + Or depending upon Flucytosine 25mg/kg qid Voriconazole clinical response. Patients with 24

chorioretinitis and ocular involvement other than endophthalmitis often respond to systemically administered antifungals J. EAR INFECTIONS Ear infection Likely Etiology/ Suggested Regimen Alternate Remarks Malignant otitis externa P. aeruginosa (in Piperacilin+Tazobactam Ceftazidime Debridement usually >90% cases) 4.5gm IV 6h Or required. Rule out Imipenem/Meropenem osteomyelitis; Do CT or Ciprofloxacin MRI, If bone involved , treat for 4-6 wks. S. pneumoniae Treat children <2 years

Acute otitis media H. influenzae Amoxicillin+clavulanate Ceftriaxone If >2 years, afebrile and Morexella 90/6.4mg /kg/day bid or 50mg/kg I/M no ear pain- consider catarrahalis cefpodoxim /cefuroxime for 3 days analgesics and defer axetil 250mg BD antibiotics Duration of treatment If age <2 years: 10 days If age >2 years : 5-7 days Mastoiditis Acute S.pneumoniae S.aureus Cefotaxime 1-2 gm iv 4-8 Modify as per culture H.infiuenzae hourly Unusual causes- P.aeruginosa Ceftriaxone 2 gm iv OD Nocardia, TB,

Actinomyces. Chronic Polymicrobial Piperacillin- tazobactam 4.5g IV 8h Meropenem 1 gm iv 8h Acute Pharyngitis/tonsillitis Exudative/Diffuse Mostly viral Penicillin allergic, Erythema Group A, C, G Penicillin V oral x10 days or Clindamycin 300-450 Streptococcus, Benzathine Penicillin 1.2 mg orally 6-8 hourly x 5 Infectious MU IM x 1 dose or Cefdinir days. Azithromycin mononucleosis, or cefpodoxime x 5 days clarithromycin are alternatives. Membranous pharyngitis C.diptheriae, Erythromycin 500 mg IV

QID or Penicillin G 50,000 units/kg IV 12 hourly. Diptheria antitoxin: Horse serum. <48 hrs:20,000-40,000 units, Nasopharyngeal membranes:40,000-60,000 units >3 days & bull neck : 80,000-1,20,000 units Levofloxacin Epiglotitis(Supraglotis) Children: Cefotaxime 50 mg/kg IV 8 10 mg/kg IV H.influenzae , hourly or ceftriaxone 50 24 hourly + S.pyogenes, mg/kg IV 24 hourly clindamycin S.pneumoniae, 7.5 mg/kg IV 6 S.aureus. hourly. 25

Adult: Group A Streptococcus , H.influenzae Laryngitis(hoarseness) Viral (90%) No antibiotic indicated K. INFECTIONS IN BURNS PATIENTS Condition Likely Causative Empiric antibiotics Alternative Comments Organism antibiotics For burns wound that is Prophylactic parenteral clinically or antibiotics in burns are microbiologically not NOT indicated infected Topical antibiotics to be given after debridement For burns wound that are Strep pyogenes, i. Burn wound sepsis Antibiotic choices are

clinically or Enterobacter sp., P i percillin-tazobactam Carbapenem dependent on the microbiologically infected S. aureus, or +/- antibiogram of the S. epidermidis, Cefoperazone-sulbactam Vancomycin/ individual institution. Pseudomonas, or Teicoplanin fungi (rare) With or without: Surgical debridement as  Vancomycin necessary. //Teicoplanin Amphotericin B is toxic (if there is suspicion for to all burn patient as MRSA) renal system compromised, hence  Antifunal Therapy – Caspofungin may be

When extensive burns used. and patient not responding to antibiotics o If hemodynamically stable: fluconazole o If hemodynamically unstable: Echinocandin Burn wound cellulitis Cefazolin or Clindamycin or Vancomycin if there is suspicion for MRSA With and without (for burns involving the lower extremity or feet or burns in patients with diabetes) Pipercillin-tazobactam or cefoperazone-sulbactam Prophylaxis in Plastic Surgery

Surgical prophylaxsis: Inj Cefuroxime 1.5 g/ Cefazolin IV just before incision single dose. 26

L .FUNGAL INFECTIONS Routine antifungal prophylactic therapy in critically ill patients is NOT recommended. Fungal therapy is usually started based on positive cultures or systemic evidence of fungal infection. It is advised to take paired cultures if fungal infection is suspected. Evidence includes persistent sepsis / SIRS despite broad spectrum antibiotic (exclude sepsis, abscess, drug fever, DVT etc). Treat according to identification and antifungal sensitivity of Candida isolate.

Fluconazole IV/oral 800 mg OD first day (12mg/kg) and then 400 mg OD (6mg/kg from second day) if fluconazole naïve or sensitive Or 2nd line Liposomal Amphotericin B (for Candida krusei and C.glabrata as inherently resistant to Fluconazole.) or Caspofungin (As Caspofungin is inherently inactive against Zygomycetes, Cryptococcus, Fusarium and Trichosporon Spp) Liposomal Amphotericin B IV 3mg/kg OD or Caspofungin dose: IV 70mg on Day 1 (loading),

50mg OD (<80kg) or 70mg OD (if >80kg) thereafter.Moderate to severe hepatic dysfunction: reduce the subsequent daily dose to 35mg OD. Check for drug interactions. To be decided by Microbiologist/ID physician based on patient’s hepatic / renal functions/Severity of infection /drug interactions e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine, cyclosporin, dexamethasone, tacrolimus etc. M. FEBRILE NEUTROPENIA Febrile Neutropenia- definition

 Neutropenia-ANC<500/mm3 and expected to fall below 500/mm3 in 48hrs  Fever -single oral temperature of 38.3oC (1010 F) on one occasion or 38oC (100.40 F) on at least 2 occasions (1 hour apart)  Neutropenic patients may not have usual signs of infection. Redness, tenderness and fever may be the only signs. Protocol:  Critical examination of areas usually harboring infections, including but not limited to, oral cavity, axillary region, scalp, groin, perineal region.

 Send blood Cultures 2 sets (each bottle 10ml x 4 bottles)  Other relevant investigations: urea, creatinine, ALT, urine culture, Chest Xray, separate culture from central line, etc. Patient-Haemodynamically stable  Blood culture 2 sets  Start IV Ceftazidime  No need to add glycopeptide in the initial regimen (except in specific situations, given below) Patient-Haemodynamically unstable  Start BL-BLI agent (Cefoperazone-Sulbactam/piperacillin-tazobactam) OR Carbapenem (meropenem/imipenem/doripenem)

 No need to add glycopeptide in the initial regimen (except in specific situations, given below) Reassess after 48 hours: If blood cultures are negative, haemodynamically stable but still febrile  Reculture blood  Add amikacin for 3 days  Add colistin (instead of amikacin) if indicated (see below) If blood cultures are negative, haemodynamically unstable but still febrile  Inj Colistin (+/-Carbapenem) + glycopeptide + Echinocandin/L-Ampho B Blood culture growing Gram negative bacilli

 Patient afebrile - continue the empirical antibiotic till antibiotic sensitivity is available.  Rationalise as per susceptibility profiles When to add glycopeptides? 1. Haemodynamic instability, or other evidence of severe sepsis, septic shock or pneumonia 2. Colonisation with MRSA or penicillin-resistant S. pneumonia 27

3. Suspicion of serious catheter-related infectione.g. chills or rigours with infusion through catheter and cellulitis around the catheter exit site 4. Skin or soft-tissue infection at any site 5. Positive blood culture for gram-positive bacteria, before final identification and susceptibility testing is available 6. Severe mucositis When to add empirical colistin in febrile neutropenic patients? 1. Heamodynamic instability. 2. Colonisation with carbapenem resistant gram-negative bacteria.

3. Previous infection with carbapenem resistant gram-negative bacteria. 4. GNB in blood, sensivity pending, persistent fever with haemodynamic instability. Empirical Antifungal Therapy  No response to broad spectrum antibiotics (3-5 days)-add L-Ampho B / echinocandin  When a patient is located at a remote area and may not have access to emergency healthcare services, febrile neutropenia can be lifethreatening. Under such circumstances, availability of broad-spectrum oral antibiotics with the

patient can help them gain time to reach emergency healthcare service. Useful tips  Febrile after 72 hrs-CT chest and consider empirical antifungal.  If fever persists on empirical antibiotics, send two sets blood cultures/day for 2 days  Send further cultures if clinical deteriaration  Unexplained persistent fever in otherwise stable patient doesn’t require change in empirical antibiotic regimen. Continue the regimen till ANC is >500 cells/mm3

 If glycopeptide started as a part of empirical regimen, STOP after 48 hrs, if no evidenc of Gram positive infection  Antibiotic treatment should be given for at least seven days with an apparently effective antibiotic, with at least four days without fever.  Once Neutrophil count has recovered, with no culture positivity and heamodynamically stable; antibiotics can be stopped and patient observed, even if remains febrile. Evaluate for fungal infection, if at risk. Antibiotic Prophylaxis

Though quinolone prophylaxis is recommended by International guidleines, it is not useful in Indian scenario due to high resistance. Antiviral prophylaxis  For HSV IgG positive patients undergoing allo-HSCT or leukemia induction needs acyclovir prophylaxis  All patients being treated for cancer need to receive annual influenza vaccination with an inactivated vaccine.  Neutropenic patients presenting with influenza like illness should receive empirical treatment with neuraminidase inhibitor.

Antifungal prophylaxis a) Induction chemotherapy of Acute Leukemia: Posoconazole b) Post allo BMT Pre engraftment: Voriconazole/echinocandin Post engraftment: Posoconazole 28

N. POST-CARDIOVASCULAR SURGERY INFECTIONS Surveillance regarding the Infections following CTVS should be done in each institute 1. Antibiotic Prophylaxis to be guided by the institutional prevalence of MRSA infection and in patients at increased risk for MRSA colonization 2. Nasal screening before CTV surgery is recommended to rule out MRSA colonization S. Surgery Antibiotic Prophylaxis Comments no. 1st line 2nd line Special Antibiotic/Combination

1. C ABG Cefazolin Cefuroxime - Vancomycin /Teicoplanin to be used in case of high prevalence of MRSA infections only Using only Vancomycin/Teicoplanin is NOT recommended due to lack of coverage of GNB Vancomycin infusion to be given over 1 hour & to be started 2 hrs before the surgical incision Teicoplanin dosing to start with 800 mg x 3 doses and then 6 mg/kg to complete prophylxis Duration of Prophylaxis: Continued till 48 hours after the surgery

Empirical Treatment after appropriate specimen for stain & cultures have been collected S. Infection/ Likely Antibiotics Comments no. Syndrome Causative 1st line 2nd line Special Antibiotic/ agents Combination 1 Sternotomy site Not known BL-BLI Daptomycin/ Consider de- infection (Piperacillin- Linezolid with escalation to 1) Removal of tazobactam, carbapenem TMP/SMX , the foreign Cefoperazone- doxy/minocycline, body (steel sulbactam, cefipime- cloxacillin, cefazolin, wires) should

tazobactam) with or If these are sensitive be considered without amikacin. With Vancomycin/ teicoplanin 2 Infection of Not known BL-BLI Carbapenem Consider de- vascular (Piperacillin- escalation as per the catheters tazobactam, (Empirical isolate, Cefoperazone- anti-MRSA susceptibility, sulbactam, cefipime- drug if the MICs, adverse tazobactam) with or incidence of effects, drug allergy without amikacin MRSA CRBSI withVancomycin/ is high) teicoplanin 3 Pneumonia Not known BL-BLI Carbapenem Consider de-

(Piperacillin- escalation as per the tazobactam, isolate, Cefoperazone- susceptibility, sulbactam) with or MICs, adverse without amikacin effects, drug allergy 4 Mediastinitis Not known BL-BLI Carbapenem Consider de- (Piperacillin- with or escalation as per the tazobactam, without isolate, 29

Cefoperazone- Amikacin susceptibility, sulbactam) with or MICs, adverse without amikacin effects, drug allergy With Vancomycin/ teicoplanin 5 Urinary tract Not known BL-BLI Carbapenem Consider de- infection (Piperacillin- with or escalation as per the tazobactam, without isolate, Cefoperazone- Amikacin susceptibility, sulbactam with or MICs, adverse without amikacin effects, drug allergy Definitive Treatment after appropriate specimen for stain & cultures have been collected

S. Infection/ Likely Antibiotics Comments No. Syndrome Causative 1st line 2nd line Special Antibiotic/ agents Combination 1 Sternotomy site Coagulase Vancomycin, Daptomycin Consider de-escalation 1) Consider infection Negative Teicoplanin Linezolid to Cotrimoxazole or MICs, risk of Staphylococc Cloxacillin or nephrotoxicity i Cefazolin , bone penetration Consider de-escalation for choosing to TMP/SMX or the antibiotic doxy/minocycline 2) Removal of

MRSA Vancomycin, Daptomycin If these are sensitive the foreign Teicoplanin, Linezolid body (steel wires) should Consider de-escalation be considered to Ampicillin/ Ampi- 3) Longer sulbactam duration of Enterococcus Vancomycin, duration – 6- Teicoplanin, Consider de-escalation 12 months to oral agent if may be possible after 2-6 required GNB weeks of antibiotic (Enterobacteri- BL-BLI Carbapenem therapy -acae, (Piperacillin- (Meropenem, Pseudomonas, tazobactam, Imipenem) Acinetobacter) Cefoperazone-

sulbactam, with or without amikacin De-escalation to For Candida L-AmB/AmB-d for Fluconazole 800 mg osteomyelitis, Candida 3 weeks followed by loading followed by longer duration of Fluconazole 200 mg BD treatment (12 (If susceptible) months) is recommended 30

O. PEDIATRIC INFECTIONS Specific Conditions For Infant below 2 months age (more than 2kg): Antibiotic Each dose Frequency Route Duration <7 days >7days Inj. Cefotaxime + Inj. 50 mg/kg/dose 12 hrly 8 hrly IV 2-3 weeks Gentamicin 5 mg/kg/dose 24 hrly 24 hrly IV 2nd line therapy: Meropenem+ 20 mg/kg/dose 12 hly 8hly IV 2-3 weeks Vancomycin 15 mg/kg/dose 12 hly 8hly  Treat bacterial meningitis due to Gram-negative bacilli or Staphyloccocus sp for at least 21 days. For 2 months and above –

Inj Ceftriaxone (100mg/kg/day-2 divided dosage) for 10 -14 days 2nd line therapy: Meropenem (120 mg/kg/day in 3 div doses) + Vancomycin (60mg /kg/day in 4 div doses) for 10-14 days  In case Ceftriaxone is not available, Inj Cefotaxime (200mg/kg/d, 3-4 divided doses) is given for the same duration.  However if strong clinical suspicion for Staphylococcus infection in the form of skin boils, arthritis or flowing

external wounds – Inj. Vancomycin can be added. In such situations the regimen is given for minimum period of 3 weeks.  With confirmed meningococcal disease, treat with intravenous Ceftriaxone for 7 days  H influenzae type b meningitis is treated with intravenous Ceftriaxone for 10 days  S pneumoniae meningitis is treated with intravenous Ceftriaxone for 14 days  Bacterial meningitis due to Staphyloccocus sp is treated for at least 21 days.

Chemoprophylaxis for Meningococcal Disease Contacts (including non-vaccinated Hospital Staff): To be effective in preventing secondary cases, chemoprophylaxis must be initiated as soon as possible (i.e. not later than 48 hours after diagnosis of the case). Mass chemoprophylaxis not needed. Drug Dose (Adults) Dose (Children) Route Duration Rifampicin 600mg/12hr 10mg/kg/12hr Oral Two Days Ciprofloxacin 500mg - Oral Single Dose Ceftriaxone 250mg <15yr – 125mg IM Single Dose

Azithromycin 500mg 10mg/kg Oral Single Dose 1) LOWER RESPIRATORY TRACT INFECTION – Community acquired Pneumonia is categorized in to 2 types –Severe pneumonia (those with respiratory distress) and pneumonia (those with fast breathing only, treated on OPD basis). (a) For Severe Pneumonia (Children with respiratory distress requiring indoor care)-  Under 2 months of age: o Inj Cefotaxime / Ceftriaxone and Gentamicin for 10 days  Over 2 months of age:

o Inj. Ampicillin (50mg/kg/dose 6h) + Gentamicin (7.5mg/kg/day OD i.m or i.v) is used. Inj Ampicillin can be switched to Oral Amoxycillin (45mg/kg/day TDS) once child is stable and able to take oral feeds. Total treatment duration is 7-10 days. o In case of no response in 2 days the patient is assessed for complications like empyema, or infection at any other site. In the absence of any complication, a 3rd generation Cephalosporin (Cefotaxime

50mg/kg/dose 6h or Ceftriaxone 75- 100mg/kg/day in two divided doses, IV ) is used and can be 31

switched to oral Cefopodoxime (10mg/kg/day BD) once the child is able to take orally. Total treatment duration is 7-10 days. o In case the patient has severe sepsis/ septic shock, Inj. Piperacillin + Tazobactam (90mg/kg/dose 6h) + MRSA cover with IV Vancomycin (15mg/kg/dose 6h) is recommended. Whenever Staphyloccus aureus is suspected in children (see Text Box), the various drug options are: It is important to have high index of suspicion for staphylococcal infection as the initial

choice of antibiotic does not cover this less common but a more severe infection adequately. Staphylococcal pneumonia is suspected if any child with pneumonia has:  Rapid progression of the disease, or  Pneumatocele, or Pneumothorax, or Effusion on chest X-ray, or  Large skin boils or abscess or infected scabies or  Post-measles pneumonia, which is not responding within 48 hours to the initial therapy. To cover for staphylococcal infection, Cloxacillin or other antistaphyloccal drug

should be added to the initial regimen as discussed in the text.  In severe pneumonia, use Inj.Cloxacillin or Inj Clindamycin may be added to the initial regime. OR  Oral or IV Co- Amoxyclavulanic acid can be used.  In very severe necrotizing pneumonia or for a patient in septic shock, MRSA cover should be added with IV Vancomycin Vancomycin 25-30 mg IV loading followed by 15-20 mg/kg 8-12 Hourly /)/ Teicoplanin 12 mg/kg x3 doses followed by 6 mg/kg once a day or Linezolid (10mg/kg/dose 8h).

 The total duration for treatment for uncomplicated Staphylococcal pneumonia is 3-4 weeks. (b) For pneumonia (OPD)  Oral Amoxicillin (45mg/kg/day TDS) for a period of 5 days is recommended as the first choice. In case of non availability, one may use oral Co-trimoxazole (8mg/kg/day of TMP component BD). Routine use of macrolide antibiotics for all cases of pneumonia is not advocated. Recent data suggests that (i) the routine

addition of macrolides to children with CAP does not improve outcome (ii) selective use of macrolides would reduce their indiscriminate use and reduce antibiotic resistance. Classically the mycoplasma pneumonia presents in an atypical fashion but literature suggests that it can sometimes be difficult to distinguish mycoplasma pneumonia from a pyogenic pneumonia. Macrolide antibiotics should be considered in following clinical scenarios where the likelihood of mycoplasma pneumonia is high:

a. Children with a subacute presentation with prolonged low grade fever, persistent cough, chest signs out of proportion to the radiographic abnormality (usually showing perihilar streaky infiltrates). b. Children with CAP (acute pneumonia like presentation with radiological evidence of patchy or lobar consolidation) who also have or develop extrapulmonary manifestations like myocarditis, hemolytic anemias, glomeruonephritis, aseptic arthritis, CNS problems (aseptic meningitis, encephalitis, ataxia), etc.

c. Non response to first line antibiotics in children who are immunized with Hib/PCV and have no suppurative complications of CAP. In the first two conditions macrolide antibiotics can be used along with the first line therapy for CAP. EMPYEMA • Proper drainage : Forms the main core of treatment.  Antimicrobial Therapy:  Anti- Staphylococcal penicillin (Cloxacillin 100-200 mg/kg/day) along with 3rd generation cephalosporin like Ceftriaxone may be used as first line drug.

 In seriously ill patients with disseminated staphylococcal disease and septic shock to cover for MRSA, Vancomycin is recommended. Vancomycin is less effective than the first line drugs for the commoner Methicillin sensitive strains of Staphylococcus aureus.  Children may continue to be febrile for 5-7 days after starting antibiotic therapy in the case of S. pneumoniae and H. influenzae and for 10-14 days in the case of Staphylococcus aureus. The clinical response to therapy should be

assessed with parameters such decrease in fever, normalization of lab parameters such as CBC count, CRP, decrease in drain volume, clearing in chest x-ray, improvement in the overall condition of the patient.  The decline in toxicity and fever are good signs of likely response. In case of complete non response after 96 hours of treatment, high spiking fever and persistent drainage, second line treatment may be instituted.

Vancomycin should be substituted instead of the first line cloxacillin or co-amoxyclav.  All children with non response should be evaluated for presence of pus pockets in the pleural cavity by an ultrasound chest. Here the key lies in better drainage rather than in a change of antibiotics. Extraneous causes of fever should also be evaluated. VENTILATOR ASSOCIATED PNEUMONIA: Treat as per the sensitivity pattern of your ICU. General Suggestion: Potential Pathogens Combination antibiotic therapy

Pseudomonas aeruginosa Beta Lactam + beta lactamase inhibitor (Piperacillin – Tazobactam) Plus Or Either Klebsiella pneumonae (ESBL) Aminoglycoside (Amikacin, Gentamicin, or Tobramycin) Or Acinetobacter species OR Antipseudomonal fluroquinolone (Cipro/ Levofloxacin) Methicillin – resistant Vancomycin or Linezolid Staphylococcus aureus (MRSA) Second line Therapy  Meropenem – 60 mg/kg/day I/V every 8 hrly AND Vancomycin - 40 mg/kg/day I/V every 6 - 8 hrly Third line Therapy

 Colistin base IV., 2.5 – 5 mg/kg/day I/V every 6 – 12 hrly (1mg= 30000 IU) AND Vancomycin - 40 mg/kg/day I/V every 6 - 8 hrly UPPER RESPIRATORY TRACT INFECTIONS As these are mostly viral in origin, antibiotics are not needed barring following situations. (a) Bacterial Pharyngotonsillitis (Group A Streptococcus) – Any of the following Antibiotic Children (<30kg) (days) Children (>30kg) (days) (route) Penicillin V (Oral) 250 mg BID x 10 days 500 mg BID x 10 days

Amoxycillin (Oral) 40 mg/kg/day x 10 days 250 mg TID, can be given BID Benzathine Pencillin G (IM) 6 Lakh units (Single Dose) 12 Lakh units (Single Dose) While Penicillin is the drug of choice Amoxycillin is good alternative and used widely. If the patient is Pencillin allergic, the alternative drugs are Antibiotic (route) Dose and duration Erythromycin (oral) 40-50 mg/kg/day BID or TID x 10 days Azithromycin (oral) 12 mg/kg OD x 5 days

First Generation Cephalosporin (oral) (10 days) (if only, Cefaclor (20-40 mg/kg/d in 3 divided doses) / it is non Type 1 allergy to penicillin) Cephalexin (50 mg/kg/d in 3 divided doses) (b) Faucial diphtheria  Inj.Crystalline Penicillin (100,000-150,000 Units/kg/day I.V 6h) for 10 days in recommended. Alternativey, Inj.Procaine Penicillin 25,000-50,000 U/kg/day BD maximum of 12 lakh units i.m. can be used.

 In case of penicillin allergy, Erythromycin (40-50mg/kg/day TDS/QID for 14 days or Azithromycin 10mg/kg/day OD for 5 days can be given. 33

(c) Acute otitis media (AOM) –  Oral Amoxicillin (45mg/kg/day TDS/50-60mg/kg/day in two divided doses) for 7 to 10 days is recommended.  For severe cases (Severe Otalgia and/ or Temp >390C), Co-Amoxycillin Clavulanate (45 mg/kg/day po BD) or Inj.Ceftriaxone 75 mg/kg/day OD can be used.  In case of penicillin allergy, Cefidinir (14 mg/kg/d in 2 divided doses) can be used  Total duration of treatment is recommended for 7 to 10 days. (d) Mastoiditis And Other Acute Ear Infection

 Inj. Amoxicillin-clavulanate OR 3rd Gen Cephalosporin (Ceftriaxone/ cefotaxime). (e) CSOM  Routinely systemic antibiotic is not recommended until there is exacerbation and these are referred to ENT (f) Acute Sinusitis with URI-  Oral Amoxycillin (45 mg/kg/day TDS) for 7-10 days is recommended. For severe cases, Amoxycillin Clavulanate (45 mg/kg/day oral BD) or Inj.Ceftriaxone 75 mg/kg/day OD can be used. (g) Ludwig’s Angina  1st line : Clindamycin IV 8 hourly or Amoxicillin-Clavulanate IV

 2nd line : Piperacillin-Tazobactam IV 6 hourly (h) Pertussis  Erythromycin for 14 days, Azithromycin for 5 days, Clarithromycin for 7 days and have similar efficacy but differ in terms of cost, duration of therapy, side effects, tolerability, likelihood of drug interaction. Considering all factors, Azithromycin in a dose of 10 mg/kg once a day for 5 days in infants less than 6 months and 10 mg/kg on day 1 and

then 5 mg/kg day on 2 to 5 days is the cheapest, shortest best tolerated and most convenient option and can be safely given to infants less than 1 month (unlike all other macrolides). GASTRO-INTESTINAL DISEASES (1) Dysentery (a) For inpatients- Inj Ceftriaxone (100mg/kg) for 5-7 days. (b) For OPD cases  Cefixime (8mg/kg/day BD) Or Azithromycin 10-20 mg/ kg (ceiling dose of 1 gm) for 5 days.  In case of non response after 2 antibiotics, investigate for appropriate therapy.

Fluoroquinolones are not preferred due to high level of resistance in many parts of the country. (2) Cholera  Single dose oral azithromycin 10 mg/ kg (ceiling dose of 1 gm) or Doxycycline (50mg for less than 3 years and 100 mg for those above). (3) Enteric Fever (a) For OPD cases-  Oral Cefixime 20 mg/kg/day (max dose of 1200) for 14 days or azithromycin 10-20 mg/kg (ceiling dose of 1 gm) for 7-10 days. Antibiotic therapy should be continued till one week post-fever defervescence. (b) For inpatients

 Inj Ceftriaxone 100 mg/ kg/day and shift to oral cefixime once fever resolves. Antibiotic therapy should be continued till one week post-fever defervescence.  Second line: a) Ofloxacin 15mg/kg/d in two divided doses for 10-14 days. Antibiotic therapy should be continued till one week post-fever defervescence. b) Chloramphenicol (50- 75mg/kg/day PO) x 14 days c) TMP-SMX (8 mg/kg/day of TMP PO) x 14 days 34

(4) Peritonitis For primary peritonitis in nephrotic syndrome: Inj. Ampicillin + Aminoglycoside OR inj. cefotaxime for primary peritonitis in a cirrhotic, inj. cefotaxime. (5) Liver Abscess 1st Line 2nd Line Amoxycillin-clavulanate/ 3rd Piperacillin- Ultrasound guided drainage generation cephalosporin Tazobactam IV indicated in large abscesses, + signs of imminent rupture and Aminoglycoside no response to medical treatment. Metronidazole (30-50 mg/kg/d in 3 divided doses for

10-14 days) is added if Amoebic abscess suspected Total duration of therapy is 4-6 weeks URINARY TRACT INFECTION (UTI) a) Uncomplicated UTI (age> 2 months with lower UTI, without any urinary tract obstruction) – Oral Cotrimoxazole (8-10mg of TMP component) /kg/day oral BD OR Cefixime (8-10 mg/kg/day BD) to be given for 7-10 days OR Co Amoxycillin+Clavulanic Acid (30-50 mg of Amoxicillin) for 7-10 days. b) Complicated / Severe UTI (Febrile UTI, Systemic toxicity, renal angle tenderness or with any urinary

structural abnormality) and all UTI in children less than 2 months should be treated with parenteral antibiotics. Inj. Cefotaxime (150-200mg/kg/day 8h OR Inj. Ceftriaxone (100mg/kg/day OD OR Inj. Amikacin 15mg/kg OD To be given for 10-14 days c) In Immunocompromised host/ severe systemic sepsis or as second line for complicated UTI- Inj. Piperacillin Tazobactum 90mg/kg/dose IV 6h) or Inj. Meropenem (20-40mg/kg/dose 8h) To be given for 10-14 days FEBRILE NEUTROPENIA 1st Line 2nd Line 3rd Line

Ceftazidime (150 mg/kg/day in Piperacillin + Tazobactam (200- Meropenem (60 mg/kg/day in 3 div 3div doses)+ Amikacin (15- 300 mg/kg/day IV in 3-4 div doses) + Amphotericin B (1 20mg/kg/day in 2 or 3 div doses) doses)+ Vancomycin (40 mg/kg/day IV for 2 weeks) or mg/kg/day IV in 4 divided doses) liposomal Amphotericin B 1-5 mg kg/day, usually 3 mg/kg/day  Patients without an identified etiology who become afebrile within first 3-5 days of therapy and are clinically well

with ANC of > 200 cells/cmm can be shifted to oral antibiotics (Cefixime or Co- Amoxy- Clavulanic acid) and therapy should be continued for minimum 7 days.  However, if fever persists or ANC remains <200 parenteral therapy should be continued with 2nd line antibiotics  In clinically stable patients without an identified etiology but with persistent neutropenia, therapy can be stopped after 2 weeks. 35

Presumptive therapy for initial antimicrobial coverage in critically ill children with severe sepsis and septic shock Antibiotics should be administered within 1 hour of the identification of severe sepsis and septic shock, if possible, after obtaining appropriate cultures. The initial empiric antibiotic therapy should include one or more drugs that have activity against the likely pathogens and that penetrate the presumed source of sepsis. Initially, broad antibiotic coverage is

recommended. Following are the general rules which can help for decision making: I. All children with septic shock should receive coverage for methicillin-resistant Staphylococcus aureus (MRSA) initially at recognition of the event. II. Coverage for enteric organisms should be added whenever clinical features suggest genitourinary and/or gastrointestinal sources (eg, perforated appendicitis or bacterial overgrowth in a child with short gut syndrome).

III. Treatment for Pseudomonas species should be included for children who are immunosuppressed or at risk for infection like those with cystic fibrosis). IV. When treating empirically, antibiotics which can be given by rapid intravenous bolus (eg, beta-lactam agents or cephalosporins) should be administered first followed by infusions of antibiotics, such as vancomycin, that must be delivered more slowly.

V. Ongoing antimicrobial therapy should be modified based upon culture results, including antimicrobial susceptibility and the patient's clinical course. Suggested initial empiric antimicrobial regimens based upon patient age, immunocompetence, and previous antibiotic administration include: 1. Children >28 days of age who are normal immunocompetent patient: a) Ceftriaxone/Cefotaxime plus Vancomycin //Teicoplanin

c) Consider adding an aminoglycoside (eg, gentamicin/amikacin) if possibility of genito- urinary source is likely d) Consider adding piperacillin-tazobactam / clindamycin / metronidazole if possibility of gastro-intestinal source 2. Children >28 days who are immunosuppressed or at risk for infection with Pseudomonas species: a) Ceftazidime or Cefepime plus Vancomycin/Teicoplanin b) add an aminoglycoside or carbapenem in settings where bacterial organisms with extended-spectrum beta-lactamase

(ESBL) resistance are prevalent. c) addition of a carbapenem is favored over an aminoglycoside if the patient has received any broad-spectrum antibiotics like 3rd generation cephalosporin, aminoglycoside or fluoroquinolone within two weeks. 3. Children who cannot receive penicillin or who have recently received broad-spectrum antibiotics: a) Vancomycin/Teicoplanin plus Meropenem* * Alternatives to Meropenam i) Aztreonam OR ii) Ciprofloxacin plus Clindamycin

4. Patients at increased risk of fungal infection (immunocompromised with persistent fever on broad spectrum antibiotics) or with an identified fungal source. Add the following antifungals to the antimicrobial regimen a) Liposomal Amphotericin B or b) an echinocandin (eg, caspofungin, micafungin) 5. Patients with risk factors for rickettsial infection (eg, travel to or reside in an endemic region): Add a tetracyclin antibiotic (eg, doxycycline) to the antimicrobial regimen

The empiric drug choice should be in accordance with the ongoing epidemic and endemic infections eg, H1N1, methicillin- resistant S. aureus, chloroquine-resistant malaria, penicillin-resistant pneumococci. Control of the Infection Source The source of the infection should be located and treated early and aggressively. Conditions requiring debridement or drainage include necrotizing pneumonia, necrotizing fasciitis, gangrenous myonecrosis, empyema, and abscesses. Perforated viscus

requires repair and peritoneal washout. If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after other vascular access has been established. Duration of antibiotic therapy for sepsis It will depend on the foci of infection, immune status of the patient and response to the antibiotics. If there are no complications the duration of therapy is 7-10 days. Longer courses may be appropriate in patients who have a slow clinical

response, undrainable foci of infection, bacteremia with S. aureus; some fungal and viral infections or immunologic 36

deficiencies, including neutropenia Use of procalcitonin levels or similar biomarkers may assist the clinician in the discontinuation of empiric antibiotics in patients. Management of Central line/long line catheter-Related Infections - 1. Empirical coverage if suspecting gram-negative bacilli Choice should be based on local antimicrobial susceptibility and the severity of disease a fourth-generation cephalosporin, carbapenem, or b-lactam/b-lactamase combination, with or without an aminoglycoside).

2. Empirical antimicrobial therapy if suspecting MRSA a. for health care settings with an elevated prevalence of MRSA- Vancomycin is recommended b. for institutions in which the most of MRSA isolates have vancomycin minimum inhibitory concentration (MIC) values 12 mg/mL- Daptomycin, should be used. c. Linezolid should not be used for empirical therapy. 3. Empirical combination antibiotic coverage for MDR gram-negative bacilli, such as Pseudomonas aeruginosa, should be used when CRBSI is suspected in

a. Neutropenic patients b. severely ill patients with sepsis c. patients known to be colonized with such pathogens, until the culture and susceptibility data are available and de- escalation of the antibiotic regimen can be done. 4. Empirical therapy for suspected CRBSI involving femoral catheters in critically ill patients should include coverage for gram-positive pathogens, gram-negative bacilli and Candida species. 5. Empirical therapy if catheter-related candidemia is suspected *- a. Echinocandin or

b. Fluconazole can be used in patients without azole exposure in the previous 3 months in health care settings where the risk of Candida krusei or Candida glabratainfection is very low. *It should be suspected in septic patients with any of the following risk factors: total parenteral nutrition, prolonged use of broad-spectrum antibiotics, hematologic malignancy, receipt of bone marrow or solid-organ transplant, femoral catheterization, or colonization due to Candida species at multiple sites.

6. Antibiotic lock therapy should be used for catheter salvage; however, if antibiotic lock therapy cannot be used, systemic antibiotics should be administered through the colonized catheter. Duration of antimicrobial therapy: A. Uncomplicated Short term central venous or arterial catheter related blood stream infection a. Coagulase negative staph: i) treat for 5-7 days, if the catheter is removed ii) treat for 10-14 days, if the catheter is retained 1. Remove the catheter

b. Staph aureus :- treat for more than 14 days c. Enterococcus :- treat for 7-14 days 2.Treat with systemic d. Gram negative bacilli :- treat for 7-14 days antibiotics e. Candida sp. :- treat for 14 days after the first negative blood culture, B. Complicated Short term central venous or arterial catheter related blood stream infection Four to 6 weeks of antibiotic therapy should be administered to patients with persistent fungemia or bacteremia after catheter removal (i.e., occurring more than 72

hours after catheter removal), and to patients who are found to have infective endocarditis or suppurative thrombophlebitis, and to pediatric patients with osteomyelitis. BRAIN ABSCESS Inj Ceftriaxone + Vancomycin OR Inj Teicoplanin + Metronidazole, Drain pus, rationalize antibiotics according to culture and sensitivity and continue for 3 to 4 week. 37

OSTEOMYELITIS – Co-Amoxy clavulunic + Gentamicin SEPTIC ARTHRITIS 1 st line Inj Co-Amoxy clavulunic + Gentamicin 2nd line Inj Ceftriaxone//cefotaxime +/- Vancomycin TETANUS – Inj Crystalline Penicillin (2 lac IU /kg/ d /12 hourly) or Inj Metronidazole (mg/kg/d). ACUTE ENDOCARDITIS – Inj Crystalline Penicillin/ampicillin + Gentamicin for 3-4 weeks is given which is tailored depending upon culture & sensitivity report. MALARIA - As per National Malaria Control Program guidelines. See chapter 8.

TUBERCULOSIS IN CHILDREN Refer to RNTCP guidelines ACUTE RHEUMATIC FEVER (ARF) Antibiotic Dose Route Frequency Duration Primary prophylaxis for rheumatic fever (Treatment of group A streptococcal tonsillo-pharyngitis) The primary goal of treating an ARF attack is to eradicate streptococcal organisms and bacterial antigens from the pharyngeal region. The antibiotic therapy is very effective if started within 9 days after onset of symptoms to prevent rheumatic fever specially carditis.

Benzathine Penicillin G* weight ≥ 27 kg :- 1.2 million units Deep Only once Single dose [After sensitivity testing] weight < 27 kg :- 0.6 million units intramuscular Single dose According to weight of the injection child Alternative antibiotics Azithromycin 12.5 mg/kg/day divided Oral OD 5 days Amoxicillin 25–50mg/kg/day divided Oral TDS 10 days Adult dose 750-1500 mg/day Cephalexin 15-20 mg/kg/dose Oral BD 10 days Erythromycin 250 mg #OR Oral QID 10 days 40 mg/kg/day divided

Penicillin-V 250 mg Oral QID 10 days Adult dose 500mg Secondary prophylaxis for rheumatic fever It involves continuous administration of antibiotics in patients with a previous attack of RF and/or rheumatic heart disease. It is mandatory for all patients who have had an attack of RF, whether or not they have residual rheumatic valvular heart disease. Benzathine Penicillin G Same as above same same Every 3-4 weeks Penicillin V Same same BD See below Sulfadiazine weight >27 kg:- 0.5 g oral OD See below

(patients allergic to penicillin) weight ≥27 kg:- 1 g Erythromycin Same same BD See below (patients allergic to penicillin & sufadiazine) *Contraindicated in penicillin allergy # maximum dose-500mg; contraindicated in liver disorders; can be given in patients with penicillin allergy; do not use if high rates of group A streptococal macrolide resistance prevalent. Duration for secondary prophylaxis: It depends on the presence of carditis during the acute episode. 38

1. NO carditis: continue for 5 years after last attack or 18 years of age [whichever is longer] 2. Carditis present (healed carditis or mild mitral regurgitation): continue for 10 yearsafter last attack or 25 years of age [whichever is longer] 3. Carditis present (established heart disease or following valve surgery or ballon mitral valvotomy): continue lifelong 4. Expert consultation should be sought if want to discontinue after 40 years of age instead of life-long prophylaxis as

recurrence beyond this age is minimal. PAEDIATRIC SURGICAL CASES Clean Surgery Clean Surgery likely to be Contaminated/dirty Surgery or contaminated Peritonitis Surgeries like Uncomplicated For GI surgeries All surgeries under this group Hernia, cyst excision, hydrocoele Inj Ceftriaxone 50 – 75 mg/kg/day, Inj Ceftriaxone 50 – 75 mg/kg/day, I.V - No Pre-operative prophylaxis I.V or I/M 12 hly doses or I/M 12hrly doses needed AND AND Metronidazole 20 – 30 mg/kg/day Metronidazole 20 – 30 mg/kg/day I/V

every 8 hrly I/V every 8 hrly AND Given for 48hrs only. Gentamicin 7.5mg/kg/d 24hrly IV or IM Urinary tract surgeries For all other surgeries under 2nd Line this group: Inj Ceftriaxone 50 – 75 mg/kg/day I.V or I/M 12hrly doses Piperacillin + Tazobactam (200-300 Inj Ceftriaxone 50 – 75 mg/kg/day mg/kg/day IV in 3-4 div doses) + I.V or I/M single dose half an Do not continue beyond 48hrs of Vancomycin (40 mg/kg/day IV in 4 hour before surgery surgery divided doses)

Cellulitis/ Abscesses Cloxacillin (50- Clindamycin (20- Treat for 5-7 days. 100 mg/kg/d) in 40mg/Kg/d in 6-8 3-4 divided hly doses) doses OR Co- Amoxy- Clav OR Cefazolin (50 mg/Kg/d in 6-8 h doses) P. NEONATAL INFECTIONS a. SEPTICEMIA OR PNEUMONIA 1. In asymptomatic babies at high risk of sepsis eg. presence of foul smelling liquor or two or more risk factors listed below warrants the initiation of antibiotic therapy. Risk factors for Early onset sepsis are :

(a) Maternal fever (Temperature > 380C) before delivery or during labor (b) Membranes ruptured for more than 24 hours before delivery. (c) More than three vaginal examinations during labor. (d) Low birth weight (<2500 gms) or preterm babies. (e) Prolonged and difficult delivery with instrumentation. 39

(f) Perinatal asphyxia. (Apgar < 4 at 1 min of age) (g) Meconium stained liquor. 2. A sepsis screen should be done in such infants. If two sepsis screens (NNF protocols) done at 12 hours interval or a single sepsis screen is negative and infant remains asymptomatic at 48 -72 hours, the antibiotics may be discontinued. Antibiotic Each dose Frequency Route Duration(Days) < 7 days > 7 days Inj. Ampicillin 50 mg/kg/dose 12 hrly 8hrly IV 7-10 And Inj. Gentamicin 5-7.5 mg/kg/dose 24 hrly 24hrly IV 7-10

o In cases with severe sepsis (Sclerema/ Shock / suspicion of meningitis) Inj Cefotaxime 200 mg/kg/day IV in 4 div doses) + Amikacin (15mg/kg/d) is recommended o If sepsis is suspected to be health care associated or if there is no response in 48-72 hours of initial therapy or if there is documented resistance then change to injection Piperacillin- Tazobactam (200-300 mg/kg/day IV in 3-4 div doses) and Amikacin. o Vancomycin can be added to the regime if staphylococcus is suspected. b. NEONATAL MENINGITIS

Antibiotic Dose Frequency Route Duration < 7 days > 7 days (Weeks) First Inj. Ampicillin and 100 mg/kg/dose 12 hrly 8 hrly IV 3 Line Inj. Gentamicin 5-7.5 mg/kg/d 5 mg/kg/d 7.5 mg/kg/d IV 3 24 hrly 24hrly Second Inj. Cefotaxime 50 mg/kg/dose 12 hrly 8 hrly IV 3 Line and Inj. Gentamicin 5-7.5 mg/kg/d 5 mg/kg/d 7.5 mg/kg/d IV 3 24 hrly 24hrly Q. POST SOLID ORGAN TRANSPLANT Post-operative infections following solid organ transplant (kidney, liver, heart, lung)

Condition Likely causative Empiric antibiotics Alternative Comments Organisms antibiotics Post-op fever with Usually not due to None Look for hematoma, DVT, hemodynamic stability infection transfusion related fever Surgical site infection S. aureus, Entero- Treat based on culture and bacteriaceae, sensitivities Pseudomonas spp. VAP/HAP Entero-bacteriaceae, Piperacillin- Imipenem 1g IV Modify based on culture of Pseudomonas spp., tazobactam 4.5g IV q8h or lower respiratory tract

Acinetobacter spp. q6h or Cefoperazone- meropenem1g IV secretions. sulbactam 3g IVq8h q8h 40

Vancomycin loading Daptomycin 6 Draw 2-3 blood culture sets S. aureus, Entero- of 25-30 mg /kg in mg/kg IV od with at least one from CLABSI bacteriaceae, patients of septic +Meropenem 1g peripheral sites before starting Pseudomonas spp., shock followed by IVq8h antibiotics and modify based Acinetobacter spp. 15mg/kg IV 12 hourly on culture. Candida spp. (maximum 1gm 12 hourly)/teicoplanin Removal of catheter must be 12mg/kg IV 12 hourly contemplated. x 3 doses followed by 6 -12 mg once daily

IV depending upon severity + Piperacillin- tazobactam 4.5g IV q6h or Cefoperazone- sulbactam 3g IVq8h For 2 weeks duration CAUTI Entero-bacteriaceae, Piperacillin- Imipenem 1g IV Do blood and urine cultures Enterococci tazobactam 4.5g IV q8h or before starting antibiotics and Candida spp. q6h or Cefoperazone- Meropenem 1g IV modify based on culture. sulbactam 3g IVq8h q8h Removal of catheter must be contemplated. R. SURGICAL ANTIMICROBIAL PROPHYLAXIS

 To be administered within 1 hr before the surgical incision.  Single dose is recommended. Consider for second intra-operative dosein prolong surgery based on the choice of antibiotic used for prophylaxis.  Prophylaxis should not be given beyond surgery duration (except for cardiothoracic surgery, up to 48 hours permissible)  Choice of the prophylaxis should be based on the local antibiogram. SURGERY MEDICATION Breast Inj.Cefazolin 2gm or Inj.Cefuroxime 1.5gm IV stat

Gastroduodenal & biliary Inj.Cefaperazone- Sulbactam 2gm IV stat & BD for 24hrs(maximum) ERCP Inj.Piperacillin-Tazobactum 4.5gm or Inj.Cefaperazone- Sulbactam 2gm IV stat Cardiothoracic Inj.Cefuroxime 1.5gm IV stat & BD for 48hrs Colonic surgery Inj.Cefaperazone- Sulbactam 2gm IV stat & BD for 24hrs(maximum) Abdominal surgery (hernia) Inj.Cefazolin 2gm or Inj.Cefuroxime 1.5gm IV stat Head & Neck/ ENT Inj.Cefazolin 2gm IV stat Neurosurgery Inj.Cefazolin 2gm or Inj.Cefuroxime 1.5gm IV stat

Obstetrics& Gynecology Inj.Cefuroxime 1.5gm IV stat Inj.Cefuroxime 1.5gm IV stat & BD for 24 hrs(maximum) Orthopaedic or Inj.Cefazolin 2gm IV stat Open reduction of closed fracture with internal fixation- Inj.Cefuroxime 1.5gm IV stat and q 12h or Inj.Cefazolin 2gm IV stat and q 12h for 24 hrs Trauma Inj.Cefuroxime 1.5gm IV stat and q 12h (for 24 hrs) or Inj.Ceftriaxone 2gm IV OD Urologic procedures Antibiotics only to patients with documented bacteriuria

Trans- rectal prostatic surgery Inj.Cefaperazone- Sulbactam 2gm IV stat 41

Chapter 3 Treatment of Muti-Drug Resistant Bacterial Pathogens 1. Methicillin- Resistant S. aureus (MRSA) a. These organisms are considered resistant to all penicillins, cephalosporins and macrolides. b. Though MRSAstrains may be reported as susceptible to Fluoroquinolones, aminogycogides, chloramphenicol and doxycycline in-vitro, these drugs are NOT to be used alone or as initial treatment for serious MRSA infections. c. Rifampicin use should be avoided in diseases other than Mycobacterial diseases.

d. The drug of choice for treatment of infections due to MRSA is the glycopeptides i.e Vancomycin and Teicoplanin. e. Linezolid can be used to treat skin and soft tissue infections caused by MRSA. f. Mupirocin local application (intranasally bid x 5 days) for eradicating nasal carriage. g. Daptomycin: Daptomycin is an intravenous antibiotic approved to be used for the treatment of complicated skin infections and Staphylococcus aureus bacteraemia. Daptomycin should NOT be used for treatment of pneumonia due

to its inactivation by surfactant. 2. Vancomycin Resistant Enterococcus (VRE) Enterococci are a therapeutic challenge because of their intrinsic resistance to many antibiotics. The acquisition of resistance to vancomycin by enterococci has seriously affected the treatment and infection control of these organisms. The treatment for VRE should be based on infection severity and in-vitro susceptibility of the strain to other antibiotics.

 Linezolid: Linezolid is the only drug specifically approved for the treatment of VRE-blood stream infections. Linezolid may be particularly useful in patients who require oral or outpatient therapy (when intravenous therapy is undesirable), who are intolerant to glycopeptides, or who have impaired renal function. Linezolid is a bacteriostatic agent; furthermore, linezolid toxicity when administered for prolonged courses may limit its use in VRE endocarditis.

 Ampicillin: Isolates that remain relatively susceptible to penicillin or ampicillin may be treated with high doses of these agents.  Daptomycin: Not approved for treatment of VRE infection. Not approved for treatment of endocarditis. Limited clinical information for VRE, but bactericidal activity makes consideration of this agent as sole therapy in serious infections. However, emergence of resistance during therapy has been reported.

 Doxycycline: Not a first line therapy. For susceptible isolates, not for bacteremia or endocarditis. It should not be used as monotherapy.  Nitrofurantoin:Uncomplicated UTIs have been treated successfully with nitrofurantoin.  Fosfomycin: For urinary tract infections (cystitis) with isolates susceptible to fosfomycin.  Chloramphenicol: For chloramphenicol-susceptible isolates of E faecium and E. faecalis. Not a first-line therapy and it should not be used as monotherapy.

 Gentamicin or streptomycin: To be used in combination with ampicillin for the treatment of enterococcal endocarditis caused by organisms susceptible in vitro to either agent; streptomycin is used when gentamicin cannot be used because of resistance.  Tigecycline: Tigecycline has in vitro activity against a broad spectrum of Gram-positive and -negative bacteria, anaerobes as well as multidrug-resistant pathogens such as MRSA and VRE. However, there is not much clinical

dataregarding its use for treatment of VRE infections. 3. Extended Spectrum Βeta-Lactamases (ESBL) Producing Enterobacteriaceae. a. ESBLs are plasmid mediated β-lactamases that confer resistance to broad spectrum β- lactum antibiotics including third and fourth generation cepahlosporins, azetronam, and extended spectrum penicillins. These plasmids often encode mutations which confere resistance to other broad spectrum agents including aminoglycosides, co-trimoxazole

and fluoroquinolones, resulting in organism resistant to most broad spectrum antibiotics. b. A major problem with ESBLs is their capacity to cause therapeutic failure with cephalosporins and azetreonam when host organism appears to be susceptible to these agents in laboratory tests. Hence, CLSI recommends that laboratories should report ESBL producing isolates as resistant to all penicillins, cephalosporins (including cefepime and cefpirome), and azetreonam irrespective of in-vitro test results.

c. The emergence of ESBL producing enterobacteriaceae is related to indiscriminate use of third generation cephalosporins. d. The carbapenems (Ertapenem, Meropenem and Imipenem) are currently considered the drug of choice for serious infections caused by these pathogens. Piperacillin–Tazobactam and Cefoperazone- Sulbactam may be considered options in mild infections and when ESBL producers are demonstrably susceptible in -vitro. 4. Carbapenem- Resistant Enterobacteriaceae (CRE) a) Mechanism of resistance :

i. Combinations of ESBL or AmpC and porin loss: Porin loss is often unstable and may impose afitness cost, meaning that these strains rarely spread. Ertapenem is particularly affected. ii. Acquired carbapenemases b) Treatment : i. Most carbapenemase producers are extremely drug resistant: being resistant to β-lactam antibiotics, aminogycosides, and β-lactam–βlactam inhibitor combinations. ii. Polymyxins, tigecycline & fosfomycin are the agents with most frequent in vitro activity, but all have limitations.

Dosage will vary with the patient and infection site, but should be on the principle of ‘highest safe’ rather than ‘minimum potentially effective; durations should be as standard for the infection type. iii. Colistin - Case reports of successful use in a range of infections due to carbapenemase producers. iv. Tigecycline:Active in-vitro vs. most carbapenem-resistant E. coli. Licensed for complicated skin and soft-tissue

Infections and complicated intraabdominal infections. Case reports of success in various infections with carbapenemase producers. Low blood concentrations; off-label use should be cautious for blood stream infections, unsuitable in urinary infections as only 22% excreted in urine. Excess deaths in some trials, especially ventilator associated pneumonia (not a licensed indication). v. Others: a few isolates are susceptible to other antibiotics including e.g. chloramphenicol, ciprofloxacin and

cotrimoxazole. Most producers, however, are resistant to these drugs. Recommended measures to control spread of Multi-drug resistant organisms (MDRO) : i. Improved laboratory detection and reporting of MDRO ii. Enhanced infection surveillance and control in ICUs iii. Prevent spread by barrier precautions : Gowns and gloves iv. Hand Washing v. Restricted use of 3rd generation cephalosporins 43

Chapter 4 Guidelines For Optimizing Use Of Key Antimicrobials A. Antimicrobial Prescribing: Good Practice 1. Send for the appropriate investigations in all suspected infections as recommended. These are the minimum required for diagnosis, prognosis and follow up of these infections. 2. All attempts shall be made to send microbiological samples prior to initiating antimicrobial therapy. Rapid tests, such as Gram stain, can help determine therapeutic choices when decision on empiric therapy is required.

3. Differentiation between contamination, colonization and infection is important to prevent overuse of antimicrobials. Use hospital guidelines based on local antibiograms when choosing antimicrobial therapy whenever possible. If alternatives to those recommended as used, reasons in the case records should be documented. 4. Prescribing antibiotics just in case an infection is present is rarely justified. Where patients are in hospital close observation is usually a better option till the diagnosis is made.

5. Choice of antibiotics: This depends on antibiotic susceptibility of the causative organism. There are some infections, which can be treated by one of several drugs. The choice can be based on Toxicity, Efficacy, Rapidity of action, Pharmacokinetics and Cost. Use the most effective, least toxic and least expensive antibiotic for the precise duration of time needed to cure or prevent infection. Pathogens specific guidance in hospital policy is encouraged.Before prescribing consider the following:

a. Which organism is likely to cause the disease? b. What is the clinical diagnosis and what other steps should be taken to reach diagnostic precision? c. Which antimicrobial agents are available and active against the presumed cause of the illness? Is their range of antimicrobial activity appropriate and what information is available about the likelihood of drug resistance? d. Check for factors, which will affect choice of drug and dose, e.g., renal function, interactions, allergy, pregnancy and lactation.

e. Check that the appropriate dose is prescribed. If uncertain, contact Infectious Diseases Physician or clinical microbiologist. Alternatively, check in the formulary. f. What is the duration of treatment? g. Is treatment working? 6. Clinical Diagnosis: The antibiotic treatment chosen must be based on presumptive diagnosis made on some assumption regarding the nature of disease. The treating doctor may not have difficulty in choosing the appropriate antibiotic to treat a

disease caused by a single microorganisms e.g scarlet fever, typhoid, anthrax, as microbiological diagnosis is implicit in clinical diagnosis. However, diseases such as pneumonia, meningitis and urinary tract infection can be caused by spectrum of bacterial species and doctor may be wrong if he has to guess which antimicrobial agent to use. In such instances one should seek a bacteriological diagnosis.

7. Empiric Therapy – If the causative agent is not known and where delay in initiating therapy would be life threatening or risk serious morbidity, antimicrobial therapy based on a clinically defined infection is justified and the following points should be taken into consideration : a. Do not rush to treat. b. Collect the necessary specimens before commencing therapy. c. Cover all possible microbial causes. d. Try to attain synergy. e. Consider possible interaction with other drugs.

f. Accuracy of diagnosis should be reviewed regularly and treatment altered/stopped when microbiological results become available. g. Use less costly drugs where possible. 8. The need for antimicrobial therapy should be reviewed on a daily basis. For most infections 5 – 7 days of antimicrobial therapy is sufficient (simple UTI can be adequately treated with 3 days of antibiotic). 9. All IV antibiotics may only be given for 48 – 72 hours without review and consideration of oral alternatives. New

microbiological or other information (e.g. fever defervescence for at least 24h, marked clinical improvement; low CRP) should at this stage often permit a switch to oral antibiotic(s), or switch to an IV narrow spectrum alternative, or cessation of antibiotics (no infection present). 10. Once culture reports are available, the physician should step down to the narrowest spectrum, most efficacious and most

cost effective option. If there is no step down availed, the reason shall be documented and is subjected to clinical audit. 11. Some guiding principles for de-escalation /Escalation: a. If ESBL +ve: drug choice is monotherapy with carbepenems. Preferably choose group I carbepenem. Piperacillin –Tazobactum and Cefoperazone –Sulbactam can be used if in-vitro sensitive and for mild infections. b. Vancomycin should be used only for confirmed MRSA infections and not in MSSA infections.

c. In case of Pan drug resistant Pseudomonas /Acinetobacter spp. combination therapy using colistin along with beta-lactams (using PK/PD principles) should be discussed with microbiologist / physician. 12. . Treatment with antibiotic combinations: In order to avoid antagonism between drugs and undesirable side effects of several antibiotics it is advisable to use a single drug where ever possible. There are situations however, when the use of antibiotic combination is desirable. The situations are: 44

a. A temporary expedient during the investigation of an obscure illness. b. To prevent the development of bacterial resistance in long term therapy e.g treatment of tuberculosis. c. To achieve synergistic effect, e.g. in treating infective endocarditis. d. Mixed infection, when one drug is not effective against the pathogen. e. To permit a reduction of the dose of potentially toxic drug. The choice of the drug should be that they act synergistically. The following combinations are synergistic

1. Aminoglycoside and beta–lactam antibiotic. 2. Beta –lactam antibiotic and beta–lactamase inhibitor. 3. Beta –lactam antibiotic and Glycopeptide (vancomycin/teicoplanin) 4. Sulphamethoxazole and Trimethoprim. 14. Is Treatment working?: Where treatment is apparently failing, advice from an ID physician/clinical microbiologist should normally be sought rather than blindly changing to an alternative choice of antimicrobial agent.

Antimicrobial drug therapy cannot be considered in isolation and other aspects of therapy must be taken into account in judging the effect of treatment. Even an appropriate antibiotic may be ineffective unless pus is drained, septic shock treated and hypoxia and anemia corrected. There are several conditions in which chemotherapy alone cannot eliminate an infection. Obstructive lesions can cause infection to recur, unless they can be dealt with surgically. Also, chemotherapy

cannot obviate the necessity for draining an abscess or removing sequestra or calculi. Failure of treatment can also be due to a super-added infection, e.g. phlebitis, development of resistance during therapy or poor tissue penetration. 13. Laboratory control of the effects of treatment: Whether treatment has been successful or not is best judged by clinical criteria, but it is useful to know whether the infecting organism has been eliminated. Reapeated cultures are, therefore sometimes indicated.

B. Reserve Antimicrobials These reserve antimicrobials will be made available following a recommendation from the Microbiology Department as per culture report or if included in an antimicrobial policy for a clinical specialty that has been agreed with antibiotic management team. They are held in reserve to maintain their effectiveness in treating certain difficult infections by reducing the spread of

microbial resistance and to encourage cost effective prescribing. Before a reserve antibiotic is issued to the ward, the pharmacist is instructed to ascertain the indication and if this falls outside the approved policy, to request that the prescriber consult the ID Physician/clinical microbiologist. The following criteria has been proposed to protect the Carbapenems and Linezolid from overuse – 1. Severe sepsis as defined by more than one organ failure of new onset and/or elevated serum lactate.

2. Clinical failure of other classes of antibiotics over 48 hours in terms of worsening inflammatory markers, unresolving fever and new/worsening hemodynamic instability. 3. Underlying severe immuno-suppression – Neutropeniea, immuno-suppressive therapy, Diabetic Ketoacidosis (DKA) etc. 4. The organism is susceptible to only carbapenems / linezolid, as per culture report. The following criteria has been proposed for initiating Colistin –

1. Pan-resistant organism as per culture report with evidence of invasive disease – fever/ leucocytosis/elevated procalcitonin (PCT) or culture from a sterile site. 2. Clinical failure of all other classes of antibiotics over 72 hours. The following criteria has been proposed for initiating Rifampicin – 1. Empiric or proven TB as a part of ATT (4 drug regimen) Rifampicin should not be prescribed in our country for any treatment other than for Mycobacteria and for

chemoprophylaxis of meningoccal meningitis in clinically indicated population Rifampicin should not be prescribed alone as an anti-bacterial. The following criteria has been proposed for initiating Aminoglycosides – I. The focus of infection is not lung or an anaerobic abscess. II. Only as a part of initial empiric regimen of a combination therapy – shall step down to single drug after culture report. III. Other safer drug options have been ruled out in a culture report. C. Hypersensitivity

All patients should be asked about drug allergies. This is the responsibility of the doctor caring the patient. If a patient reports a drug allergy clarify whether this is an allergy or drug intolerance. In some cases there will be an overlap between drug allergy and drug intolerance.  Clinical features suggestive of drug allergy: One or more symptoms developed during or following drug administration including difficulty breathing, swelling,

itching, rash, and anaphylaxis, swelling of the lips, loss of consciousness, seizures or congestion involving mucous membranes of eyes, nose and mouth. 45

 Clinical features suggestive of drug intolerance: One or more symptoms developed during or following drug administration including gastrointestinal symptoms e.g. nausea, vomiting, diarrhoea, abdominal pain and feeling faint. If patients are unable to give an allergy history, the doctor caring in the patient should take reasonable steps to contact someone who can provide a reliable allergy history. It is the prime responsibility of the prescribing doctor to ensure that:

i. The allergy box on the patient’s drug chart is completed, when a new prescription chart is written or transcribed. If no allergy - specify "No known allergy". The box should be signed and dated. If allergy history cannot be obtained, then specify "history not available." Under no circumstances should the allergy box be left blank. A pharmacist or nurse may complete the allergy box if the allergy status is documented in the clerking in notes.

ii. The allergy box is completed before prescribing a new drug, except in exceptional circumstances. If patients have a suspected drug allergy then the drug and suspected reaction. Should be documented in the clerking-in notes and the drug chart. D. Alert Antimicrobials To Prevent and Control the Emergence and Spread of Antimicrobial-Resistant Micro-organisms in Hospitals” one major strategic goal is to “define guidelines for use of key antibiotics”, (“Alert” antibiotics) targeted in these guidelines are

ciprofloxacin, ceftazidime, cefotaxime, ceftriaxone, vancomycin (or teicoplanin), imipenem, levofloxacin, meropenem, moxifloxacin,piperacillin-tazobactam, linezolid (oral/IV), voriconazole, caspofungin, valganciclovir, ertapenem and newer preparations of amphotericin. Collectively, these are among the drugs most frequently prescribed irrationally which is largely responsible for the current

escalation of antibiotic costs. They also account for a significant proportion of serious antibiotic toxicity including Clostridium difficilediarrhoea and CNS toxicity/seizures as well as the emergence of major antimicrobial resistance. Safer, cheaper and equally effective alternatives are often available which allow such agents to be kept in reserve for occasions when there are clear cut microbiological indications. It is critical, therefore, that these Alert antibiotics be prescribed only on the

recommendation of senior medical staff or after discussion with the on-call Clinical Microbiologist or ID physician. E. Alert Antibiotics And Their Indications 1. CIPROFLOXACIN, INTRAVENOUS Oral ciprofloxacin is well absorbed and this is therefore the preferred route of administration. Intravenous therapy is only indicated in the following situations:  When the patient is unable to swallow or the oral route is otherwise compromised.

 In serious sepsis (e.g. nosocomial pneumonia in ITU) when the recommended dose is 400mg 8 hourly. Common indications for ciprofloxacin in the Antibiotic Policy, either alone or in combination, are as follows:  second line therapy in exacerbation of chronic bronchitis  pyelonephritis  acute inflammatory infective diarrhoeas  serious infected diabetic ulcers infected burn wounds with coliforms or Pseudomonas infection present

 treatment of documented or presumed gram-ve bacilli resistant to penicillins or cephalosporins or when the patient is allergic (history of anaphylactic reaction or rash) to these agents  selected haematology patients requiring prophylaxis  severe acute pelvic inflammatory disease 2. CEFTAZIDIME Limited use only. Main indication is documented or suspected Pseudomonas aeruginosainfection. Other indications currently listed in the Antibiotic Policy are as follows:

 Second line agent in neutropenic patients with septicaemia or pneumonia  Empiric therapy of CAPD associated peritonitis (not children), 1g IV stat then 125mg/litre in each bag  Empiric therapy of post operative, post traumatic or shunt associated meningitis  Empiric therapy of infective exacerbation of cystic fibrosis 3. PIPERACILLIN - TAZOBACTAM Currently listed in the antibiotic policy for the following:  Pneumonia or septicaemia in neutropenic patients (+ Gentamicin)

 As a single agent (or in combination with Gentamicin) for treatment of sepsis which has not responded to first line treatment or if it is not appropriate for gentamicin to be added to first-line therapy. 4. CEFTRIAXONE IV Ceftriaxone is currently listed in the antibiotic policy for the following:  Epiglottitis,  Brain abscess, 46

 Bacterial meningitis,  Pyelonephritis in children,  Empiric therapy of septicaemia in children,  In ascites for treatment of sub-acute bacterial peritonitis,  Skin and soft tissue infections managed via out-patients or the home IV antibiotic programme,  Acute septic monoarthritis if penicillin allergic,  Spontaneous bacterial peritonitis. 5. APPROPRIATE USE OF CARBEPENEMS  Very high rates (60-75%) of resistance to 3rd and 4th generation cephalosporins {due to extended spectrum beta-

lactamases (ESBL) production} observed in E. coli and Klebsiella species..  This pattern of resistance although seen primarily among nosocomially acquired infections, is also seen isolates of E coli and Klebsiella species isolated from community acquired infections.  These strains of bacteria are frequently resistant to other major classes of antibiotics (fluoroquinolones, β-lactam + β- lactamase inhibitor(BL + BLI) combinations and aminoglycosides)

 Carbapenems (imipenem, meropenem and ertapenem), beta-lactam antibiotics with exceptionally broad spectrum of activity, are the only class of antimicrobials which remain effective against ESBL-producing isolates of E coli and Klebsiella species  Imipenem is susceptible to degradation by the enzyme dehydropeptidase-1 (DHP-1) located in renal tubules and requires coadministrationwith a DHP-1 inhibitor cilastatin. Meropenem and ertapenem are administered without a DHP-1 inhibitor.

Indications for carbapenem use: 1. Infections [e.g., bacteremia, pyelonephritis, intra-abdominal infections (peritonitis, cholangitis, abscesses), nosocomial pneumonia etc.] confirmed (by appropriate culture and susceptibility studies) to be caused by Gram-negative bacteria (E coli, Klebsiella spp., Enterobacter spp., Pseudomonas aeruginosa, other non-fermenting Gram-negative bacilli) resistant to other classes of antimicrobials and susceptible only to carbapenemsin-vitro

2. Initial empiric treatment for severe, life-threatening infections (associated with multi-organ dysfunction, septic shock) caused by Gram-negative bacteria.  Febrile neutropenia  Ventilator associated / nosocomial pneumonia  Pyelonephritis / complicated urinary tract infections  Complicated intra-abdominal infections Once the culture and susceptibility reports are available, choose the most appropriate antibiotic based on spectrum of activity, toxicity and cost (‘de-escalation’).

Indications for Ertapenem use: Ertapenem has excellent in-vitro and in-vivo activity against ESBL producing Enterobacteriaceae, but lacks activity against Pseudomonas aeruginosa, and is therefore not considered appropriate for the treatment of conditions like febrile neutropenia and serious nosocomial infections. Ertapenem does not select Carbapenem-resistant Pseudomonas aeruginosa (at least in the

short-term). Its use should be restricted to severe Gram-negative or polymicrobial community acquired infections confirmed to be caused by susceptible bacterial pathogens. Hence, this drug may be recommended as the initial choice for ESBL producing strains of E coli and Klebsiella spp.. Indication of Meropenem and Imipenem Meropenem and Imipenem regarded as third line agents and are reserved for:  serious infections due to multiple resistant strains (e.g. ESBL)

 empiric use in the seriously ill patient in either ITU or Haematology  the treatment of infective exacerbations in Cystic fibrosis (CF)  severe acute narcotising pancreatitis  Outside these clinical settings it should only be used after consultation with a Clinical Microbiologist or ID physician. Unlike imipenem , meropenem has not been associated with CNS toxicity. Also, it is administered by convenient IV bolus

injection. Clinicians must be aware that mechanism of resistance to meropenem and imipenem are different and hence in-vitro test for one carbapenem cannot be used to interpret the other. Dose Imipenem*: 500 mg i.v. Q6H Meropenem: 1 gmi.v.Q8H Ertapenem: 1gm i.v. /i.m.Q 24H *Note Anti-infective sub-committeerecommends use at a more frequent dosing interval. They believe that optimum plasma concentrations are more reliably maintained with 6-hourly dosing. 47

6. LINEZOLID (IV AND ORAL FORMS) Linezolid should only be prescribed after consulting an ID specialist or clinical microbiologist and a mandatory order form completed.  Restricted indications including infections due to proven glycopeptide-insensitive Staphylococcus aureus or vancomycin-resistant enterococcus (currently uncommon).  To enable IV/oral switch from IV vancomycin (used for MRSA or MRSE) to oral linezolid (when patient’s discharge

is possible and continuation treatment using combination rifampicin /trimethoprim is inappropriate.  May be an option in surgical site infections (e.g. large bowel surgery, vascular surgery, etc).  Poor IV access and a glycopeptide is indicated.  Use in out-patient home parenteral antibiotic therapy for skin and soft tissue infections as an alternative to IV teicoplanin.  Rare cases of proven hypersensitivity/allergy to the glycopeptides. 7. VANCOMYCIN

Vancomycin is the drug of choice for in-patient treatment of the following infections.  Serious (e.g. bacteraemia, osteomyelitis) coagulase negative staphylococcal and MRSA infections and penicillin resistant enterococcal infections  Empiric therapy in febrile neutropenic patients not responding to first line therapy  Continuous ambulatory peritoneal dialysis (CAPD) associated peritonitis  Prosthetic valve endocarditis 8. TEICOPLANIN

Teicoplanin is a suitable alternative to vancomycin for all indications for Vancomycin except meningitis:  patients receiving out-patient/home parenteral therapy with glycopeptidesafter loading dosages  inability to tolerate vancomycin  oncology/haematology patients  Rare cases of vancomycin resistant and teicoplanin sensitive strains. 48

Chapter 5 Preventive Strategies for Healthcare Associated Infections A. Healthcare Associated Infections Health Care Associated Infections or HCAI are a worldwide phenomenon. HCAI have been defined variously at different times and by different organizations. Current definitions incorporate infections which were neither incubating nor did they manifest or present, during the period of admission in patients admitted in the hospital but were present on or after the 3rd

calendar day of admission, (the day of hospital admission being calendar day 1). B. Reducing the risk of Health care associated infections B1. Development of an effective Infection Prevention and Control Program Infection Prevention and Control Programs are directed towards patient safety and health care professionals’ safety. Reducing the preventable part of health care associated infections (HCAI) is central to any Infection Control program.

An effective Infection Prevention and Control Program would have the following components: 1. Infection Control Committee with its defined role and constituents 2. Infection Control Core Team for day to day working with defined roles 3. Infection Control Manual with policies, guidelines, recommendations and working protocols including activities and practices under the program with Hand hygiene and Standard Precautions being the mainstay

4. Annual Plan for each healthcare setup with prioritization based on risk matrix for that unit and review 5. Should incorporate Antimicrobial Stewardship programs B2. Hand-hygieneand Standard Precautions’ Health care workers and professionals anywhere and at all levels should be well oriented to concepts of hand hygiene. Practicing ‘Standard Precautions’, prevents direct contact with all body fluids (including blood), secretions, excretions, non- intact skin (including rashes), and mucous membranes.

Hand hygiene in the form of tap, sink and appropriate antiseptic/ rubs for washing or hand-rub or surgical scrub should be facilitated. Atleast hand rubs should be available in all patient care areas including patient’s bed side or easily available within vicinity. Indications for hand washing and hand antisepsis should be made known amongst all engaged in providing patient care. Protocols and procedures of any area should always include hand hygiene as applicable and these should be mandatory step.

B3. Antimicrobial Stewardship Program Antimicrobial Stewardship Program shall form another main focus of the Infection Prevention and Control Program. This shall include all components of antimicrobial stewardship so as to stress upon advocacy of safe use of antimicrobials, which shall be strengthened, with periodic review of antimicrobial guidelines and implementation locally in each of the health care setups. B4. Educational Programs and Strategies

Appropriate educational material should be made available to all. These shall be based upon recent evidences and part of relevant national and international guidelines and appropriately indigenized for effective implementation. This would be augmented by periodic CME or educational interactive programs and awareness drives. Local Health care setup should provide antimicrobial susceptibility patterns, appropriate usage of antimicrobials and have updates on antimicrobials communicated to

all relevant personnel in patient care, locally and periodically. Specific infectious diseases and their prevention and control awareness should be made available as and when required to relevant staff locally and may be extended to community if so desired by the health departments of that district/city/area. B5. NotificationAll relevant information as required by law on communicable diseases would be notified as appropriate to

relevant authority. Incase of specific reports from public health agencies requiring action on their recommendations, appropriate action should be taken. B6. Prophylaxis including Immunization Staff should be immunized against diseases, which have risk of transmission through exposure from patients and to limit transmission of diseases from healthcare workers to patients. Immunisation in high-risk group may be required for influenza,

meningococcal infections among exposure prone healthcare workers in outbreak situations, hepatitis B vaccination for all staff, varicella vaccine to high-risk group etc. Among the diseases that have potential of being transmitted from healthcare workers to patients typhoid vaccine should be included among the food handling staff. Immunise all health care workers and others involved in handling of bio-medical waste for protection against diseases including Hepatitis B and Tetanus that are likely to

be transmitted by handling of bio-medical waste. All the under trainee staff including medical and nursing students should be immunized for potential occupational risk exposures (e.g. hepatitis B vaccination to the students). 49

Chapter 6 Monitoring Antimicrobial Use A. Background World Health Organization’s 2014 report on global surveillance of antimicrobial resistance reveals that antibiotic resistance is no longer a prediction for the future; it is happening right now, across the world, and is putting at risk the ability to treat common infections in the community and hospitals. It is an increasingly serious threat to global public health that requires action across all government sectors and society.

There are high proportions of antimicrobial resistance (AMR) amongst bacteria that cause common infections (e.g. urinary tract infections, pneumonia, bloodstream infections) throughout the world. Resistant microorganisms (including bacteria, fungi, viruses and parasites) are able to survive attack by antimicrobial drugs, such as antibacterial drugs (e.g., antibiotics), antifungals, antivirals, and antimalarials, so that standard treatments become ineffective and infections persist, increasing

the risk of spread to others. The evolution of resistant strains is a natural phenomenon the use and misuse of antimicrobial drugs accelerates the emergence of drug-resistant strains. The evolving public health threat of AMR is driven by both appropriate and inappropriate use of antimicrobial agents. Overuse plays an important role in the emergence of AMR. Paradoxically, underuse through inappropriate choice, inadequate dosing, poor adherence to treatment, and substandard antimicrobials,

also plays an important role in the emergence and spread of AMR. Hence, there is need to monitor the use of antimicrobials at all levels of health care, study the antimicrobial use practices in various infections and behavior of stakeholders for antibiotic use and resistance. B. Need For Surveillance To Track Antimicrobial Use And Resistance Increasing levels of antimicrobial resistance correlate with inappropriate antibiotic use as shown at the population and

individual level. Therefore, our goal should be to use antimicrobials rationally and for that we need to know how antimicrobials are being used. Monitoring of antimicrobial use is a crucial component to identify targets for improving antimicrobial use and to further correlate with antimicrobial resistance surveillance programmes. World Health Organization (WHO) highlights the establishment of effective, epidemiologically sound surveillance of antimicrobial use and AMR among

common pathogens in the community, hospitals and other health-care facilities as one of the key public health priorities. Surveillance systems are required to understand trends in antibiotic use and AMR, as well as the long-term temporal associations between these two in different areas. Tracking antimicrobial use, and the emergence and spread of resistant strains of bacteria provides information, insights, and tools needed to guide policy and to evaluate measures taken to promote

appropriate antimicrobial use at all levels, from local to global. Data could also stimulate a sense of urgency to act. Improving antibiotic use is the key feature in efforts to contain AMR. Strategies for interventions to reduce antibiotic use have to be prioritized and customized based on local realties. Data from surveillance could help in identifying priorities and processes and in documenting a baseline for monitoring effects of interventions. C. Standardized Methodology And Outcome Measures

The use of a standardised methodology allows meaningful comparisons over time and between different facilities or countries. Expression of antibiotic consumption should be in international accepted formats. Therefore, we need to have a methodology and a common unit of measurement in each country in order to assure the comparability of the data. The Anatomical Therapeutic Chemical (ATC) classification and the Defined daily Dose (DDD) as a measuring unit have

become the gold standard for international drug utilization research. ATC/DDD methodology of classification is a tool for drug utilization research in order to improve quality of drug use. It is an international language for grouping of drugs and measuring consumption of drug use. The WHO recommends this methodology of classification as their international standard for drug utilization studies. This methodology is widely used in drug catalogues, drug safety assessment and drug utilization

and pharmacoepidemiology. The ATC/DDD system is a tool for exchanging and comparing data on drug use at international, national or local levels. When monitoring antimicrobial consumption in pediatric setting, tota antibiotic events C1. The ATC Classification The ATC system was initiated in the 1970s by the Norwegian Medicinal Depot, and is now coordinated by the World health Organization (WHO) Collaborating Centre for Drug Statistics methodology, established in Oslo in 1982. The centre revises the

ATC codes as necessary and maintains an online database and published index. Drugs are divided into different groups according to the organ or system on which they act and/or their therapeutic and chemical characteristics. Each drug is assigned at least one ATC code, which are classified into groups at five different levels. Table 1 below shows an illustration using amoxicillin as an example. Table1: Classification of amoxicillin of the Anatomical Therapeutic Chemical (ATC) classification system

ATC ATC Category Description Classification J General anti-infectives for systemic use 1st level, anatomical main group 50

J01 Antibacterials for systemic use 2nd level, therapeutic main group J01C Beta-lactam antibacterials, penicillins 3rd level, therapeutic/pharmacological subgroup J01C A Penicillins with extended spectrum 4thlevel,chemical/therapeutic/pharmacological subgroup J01C A04 Amoxicillin 5th level, subgroup for chemical substance C2. Defined Daily Dose To facilitate the ability to compare consumption information across time and geography, a technical unit of measurement was

created for use in conjunction with the ATC classification. It is referred as the Defined Daily Dose (DDD) and assigned to each drug at the 5th level (chemical substance) classification. It is defined by the ATC as the assumed average maintenance dose per day for a drug used for its main indication in adults. For antibiotics, the main indication is moderate to severe infections. The WHO Collaborating Centre using established principles assigns ATC and DDDs. Different DDDs may be

assigned for different drug formulation (ie, parenteral versus oral). Table 2 provides some examples of DDDs for antibiotics. Table 2: Examples of Defined Daily Doses ATC Classification ATC Dru gs Defined Daily Dose J01C A04 Amoxicillin 1 g (oral or parenteral) J01M A06 Norfloxacin 0.8 g (oral) J01M A02 Ciprofloxacin 1 g (oral) 0.5 g (parenteral) J01F F01 Clindamycin 1.2 g(oral) 1.8 g (parenteral) J01C A12 Piperacillin 1.4 g (parenteral) ATC – Anatomical Therapeutic Chemical

DDDs are useful for measuring and comparing volumes of drug use. DDDs should not be considered as the “correct” dose but as an international compromise on review of available documentation. C3. How to use the ATC/DDD classification to quantify the antibiotic consumption? 1. For OPD from administrative prescription claims data, If data are available at the individual claim level and the antibiotic is identified or mentioned, it is a fairly straightforward process to apply the ATC classification and convert

into a number of DDDs. For example, if the prescription indicates that the particular patient was dispensed 14 ciprofloxacin 500 tablets from a particular pharmacy. The number of DDDs is calculated by multiplying the quantity by the DDD conversion factor. In this example, the strength of one tablet is 500 mg and the ATC/DDD is 1 g for ciprofloxacin. Each 500 mg tablet is equivalent to 0.5 DDD. Multiplication of the quantity dispensed (14 tablets) by a

conversion factor of 0.5 equals to total of 7 DDDs dispensed from this prescription. Data can then be collated, expressed and evaluated based on any other prescriptions record and then merged. 2. Hospital pharmacy data: Most hospital pharmacies have the ability to express their drug dispensing information in monthly collation of numbers of drugs dispenses by type of drug. ATC/DDD system can be applied in a similar

fashion to the above out-patient prescription example. The usual divisions within a hospital are wards or various departments. Consumption data can be collated for each department separately from the pharmacy records. C4. Expressing consumption information Most commonly, units for antibiotic consumption include DDD per 1000 inhabitant-days for out-patient data and DDD per 100 bed-days in hospitals.

Because the ATC/DDD system is continuously being modified, it is essential that the version (year) of ATC classification in use is clearly identified. The most recent classification is usually used. However, one must be aware of changes in the classification or DDD assignment when comparing with earlier information. D. Situation In Developing Countries There are wide variations between regions and countries, in their capacity to carry out surveillance system. In resource-poor

countries with comparatively weak health systems, there are constraints related to infrastructure, trained personnel, networking and coordination. Currently it is not possible in resource-poor countries to quantify the effects of AMR on the individual or the community, because of lack of availability of good quality data in sufficient quantities. Therefore, developing validated, reproducible and sustainable surveillance methodologies to quantify AMR and antibiotic use in the community, and to inform

the development of interventions and evaluate their impact is a priority. The methods for obtaining data are often problematic, especially with regards to data on antimicrobial use. About 80% of antibiotics are used in the community and the rest are used in hospitals. There is a lack of community-based databases on AMR and antibiotic use in developing countries. Moreover, antibiotics can be obtained easily from private retail pharmacies

without prescription and pharmacists also advise and dispense antibiotics to patients. Therefore, developing a methodology, which is reproducible and sustainable, is needed to measure antimicrobial use in the community for developing country. 51

High-end Antibiotic Monitoring Sheet Surgical Prophylaxis Monitoring Sheet 52

Chapter 7 Dosage Guide For Commonly Used Antimicrobial Agents ANTIBIOTICS ADVERSE REACTION ROUTE PAEDIATRIC ADULT DOSE DOSE Amikacin Nephrotoxicity, Ototoxicity Intravenous 15-22.5 mg/Kg/day 15mg/Kg/day q 8-12 in 2-3 doses hours, max doses 1.5mg/Kg Amoxycillin Fever, rash, diarrhea, abdominal cramps, Oral 20-50mg/Kg/day, 3-4 250-500mg q 8 hourly AST ALT elevation. doses Amoxycillin- Rash, diarrhea, abdominal, AST ALT Oral, 40mg/kg/day 375mg 8hourly

clavunate elevation (amoxicillin) in 2 625-1000mg 12 hourly (co-amoxyclav) doses 90mg/kg/day if penicillin resistant S. Intravenous pneumoniaesuspected in otitis media 100mg/kg/day Ampicillin Hypersensitivity reaction, nausea, Intravenous 100-400 mg/kg/day 500 mg-1gm q 6 hourly diarrhea, exfoliative dermatitis, seizures, or in 4 doses (IV) precipitates infectious mononucleosis Oral rash, interstitial nephritis. Azithromycin Leukopenia, transient elevation of liver Oral 10 mg/kg/day once 500mg daily

enzymes, renal toxicity. daily Enteric fever 20 mg/kg/day once daily Azetronam Rash, Diarrhoea , vomiting, AST, ALT Intravenous 30 - 120mg/kg/day 1-2g q 8 hourly, Max elevation Q 6-8 hourly dose 8gm in 24 hours In cystic fibrosis max dose 200 mg/kg/day Benzathine Hypersensitivity and Jarisch Herxheimer Intramuscular 1,200,000 units( >30 1.2-2.4 million penicillin reaction, haemolytic anemia, seizures Kg) units/dose with high doses in renal failure 600,000 units ( <30 Kg)

Cefadroxil Rash eosinophilla Oral 30 mg/kg/day in 2 500mg bid or 1 g bid doses Cefazolin Leukopenia, eosinophilia, rash, transient Intravenous 100 mg/kg/day 3-4 0.52gm q 6-8 hourly elevation of liver enzymes renal toxicity divided doses Cefepime Same as third generation cephalosporins. Intravenous 1-4gm/day 2-3 doses Adjust dose in renal failure. Cefixime Diarrhoea, Leukopenia, renal toxicity, Oral 15mg/kg/day in 2 400mg/day in 1-2 transient elevation of liver enzymes. divided doses, divided doses.

20mg/kg/day in 2 divided doses for enteric fever. Cefotaxime Arrythmia, transient elevation of liver Intravenous 100mg/kg/day in 3-4 1-2gm 6-8 hourly enzymes, renal toxicity. divided doses, 200mg/kg/day in 4 divided doses for meningitis Ceftazidime Hypersensitivity reaction, dizziness, rash, Intravenous 75-100mg/kg/day in 1-2g q 8-12 hourly (IV) diarrhea, colitis, exfoliative dermatitis, 3 divided doses thrombocytopenia Intramuscular 100mg/kg/day in meningitis (IV)

Ceftriaxone Gall bladder sludging , transient elevation Intravenous 50-100 mg/kg/day in 1-2gm q 12-24 hourly of liver enzymes, renal toxicity 2 divided doses Meningitis 100mg/kg/day in 2 divided doses Cefuroxime Leukopenia, eosinophilia, allergic Intravenous 75-100mg/kg/day in 750mg- 1.5g q 8 hourly reaction, transient elevation of liver 3 divided doses enzymes , renal toxicity 53

ANTIBIOTICS ADVERSE REACTION ROUTE PAEDIATRIC ADULT DOSE DOSE Cefuroxime Leukopenia, eosinophilia, allergic Oral 20-30mg/kg/day in 2 250-500md bid reaction, transient elevation of liver divided doses enzymes , renal toxicity Cephalexin Transient neutropenia, AST and ALT Oral 30-40mg/kg/day in 3 250-500mg q 8 hourly elevation, arthralgia, rash, eosinophilia. divided doses Chloramphenicol Bone marrow suppression, aplastic Oral 75-100mg/kg/day in 50mg/kg/day in 4

anaemia, grey baby syndrome, hemolysis 4 divided doses divided doses in G6PD deficiency Intravenous Avoid in infants less than 3 months Ciprofloxacin Nausea, vomiting, abdominal discomfort, Oral 20-30mg/kg/day in 2 250-750mg q 12 hourly arthralgia, photosensitivity transient divided doses elevation of liver enzymes Intravenous Clarithromycin Transient elevation of liver enzymes, Intravenous 15mg/kg/day in 2 250-500mg bid renal toxicity, nausea, abdominal cramps divided doses Oral

Clindamycin Diarrhea, nausea, pseudomembranous Oral 40-60mg/kg/day in 3- 150-300 mg q 6-8 colitis, skin rash, Erythema multiforme , 4 divided doses hourly (oral, iv) raised ALT AST, thrombocytopenia, Intravenous Severe infections 300- leucopenia 600 mg 8 hourly IV Cloxacillin Dose related neutropenia, elevated AST, Oral 50-100mg/kg/day in 250-500mg/kg/day in ALT, Cholecystitis interstitial nephritis. Intravenous 3-4 divided doses. 3-4 divided doses 100-200mg/kg/day 1-2 gram q 6 hourly divides q 6 hourly

Cotrimoxazole Megaloblastic anaemia, distrurbance, Oral 5-10mg/kg/day in 2 160mg (Trimethoprim) rash, erythema mutliforme major/minor divided doses (5-0 bid mg trimethoprim) 20mg/kg/day in 4 divided doses in Pneumocystis jirovecii pneumonia Ertapenem Diarrhoea, nausea, vomiting, headache, Intravenous 3-12 years: 13 years and above hallucination, seizures, arrhythmia, 15mg/kg/day twice 1gm IV infusion/ IM pseudomembranous colitis, dose Intramuscular daily. (not to exceed once daily in 3-5 ml of

reduction in renal failure 1gm/day) lidocain CI if hypersensitivity to lidocaine/β lactam Erythromycin Arrhythmia Jaundice Oral 40on 4 divided doses 250-500mg q 6 hourly Furazolidine Avoid alcohol, tyramine containing food, Oral 100mg 3-4 times a 100mg 3-4 times a day Mao inhibitors, Nausea headache, day 5mg/kg in 3-4 dizziness, fall in BP, urticarial, safety in divides doses (not pregnancy unknown below one year)

Gentamicin Nephrotoxicity ototoxicity and optic Intravenous 5-7.5 mg/kg/day in 2- 1.3-6 mg/kg/day in 3 neuritis Intramuscular 3 divided doses divided doses Imipenemcilastin Nausea, diarrhea, rash Oral Intravenous 500mg once daily Linezolid Peripheral and optic neuropathy, Oral 10mg/kg/dose 6-8 400-600 mg q 12 thrombocytopenia, hypertension, Intravenous hourly (oral, IV) hourly myelosuppression, colitis. Meropenem Hypotension, transient elevation of liver Intravenous 7.5 mg/kg/day/dose 1.5-3gm/day in 3

enzymes, renal modification in renal Oral (IV) divided doses in divided doses 6gm/day failure meningitis in meningitis Metronidazole Nausea, metallic taste, disulfuran like Intravenous 7.5 mg/kg/day dose 3 500-700 q 8 hourly reaction with alcohol, peripheral Oral times/day neuropathy 30-50mg/kg/day in 3 divided doses for liver abscess Nalidixic acid Hepatotoxicity, myalgia, leukopenia, Oral 8 mg/kg/day in 2 1gm 4 times/day vertigo, rash, dizziness, pseudotumor divided doses

ANTIBIOTICS ADVERSE REACTION ROUTE PAEDIATRIC ADULT DOSE DOSE Nitofurantoin Discoloration of urine, vertigo, rash, Oral 8 mg/kg/day in 2 50-100 mg q 6 hourly methemoglobinemia, cholestatic jaundice, divided doses (5-7mg/kg/day in 4 hepatocellular damage and neuropathy. divided doses max dose Avoid at term and labour. 400mg) Norfloxacin Sam as quinolones Oral 20-30 mg/kg/day in 2 200-400 mg twice daily divided doses Ofloxacin Leukopenia, transient of liver enzymes, Oral 20 mg/kg/day in 2 200-400 q 12 hourly

renal toxicity. May precipitate divided doses psychosis/seizures,photosensitivity. Intravenous Penicillin G Hypersensitivity reaction like anaphylaxis Oral 50,000units/kg/ rare. nonfatal reactions are like serum dose 6 hourly (Oral) sickness, rash contact dermatitis seen in 1 in 1000 adults. Jarisch Herxheimer Intravenous 200,000-400,000 2-24 million units day reaction, haemolytic anaemia with high units/kg/day in 4 in divided doses q 4-6 doses divided doses (IV) hours (IV)

Penicillin V Rash, haemolytic anaemia interstitial Oral 20-50 mg/kg/day in 4 250-500 mg every 6-8 nephritis, seizure with high doses. divided doses hourly. Piperacillin – Leukopenia, transient elevation of liver Intravenous 200-400mg/kg/day in 4.5 gm q 8hourly Tazobactum enzymes, renal toxicity. 3-4 divided doses Teicoplanin Hypersensitivity reactions, rash, less Intravenous 10mg/kg/day /dose 400mg once daily (6- nephrotoxic as compares to Vancomycin every 12 hours for 3 30mg/kg/day) Intramuscular doses the

10mg/kg/day once daily Tigecycline Nausea, vomiting, allergic reactions, Intravenous Above 10 years 100mg followed by photosensitivity, pseudo tumor cerebri, 50mg every 12 hurly pancreatitis. infusion over 30-60 No dose adjustment to renal failure minutes. Vancomycin Red man syndrome, oto-toxicity, Intravenous 40-60 mg/kg/day in 0.5gm q 6 hourly or nephrotoxicity 3-4 divided doses 1gm q 12 hourly . Drug doses in Pediatric Age group Drug name Dose Frequency Maximum Comments dose Cefepime 50 mg/kg q 12 h

Infants >14 days of age and Children >40 kg in weight Ceftazidime 100–15 Divided q 8 h 6 g Infants and children <12 years mg/kg/d Cefotaxime 2 g Infants and children Divided q6-8 h a) < 50 kg 100–200 q 8 h b) >12 years and >50 kg mg/kg/d 1–2 g Ceftriaxone 50-75 mg/kg/d Divided q 12 h 2 g Infants and children Vancomycin 40 mg/kg/d Divided q 6-8 2 g Infants and children h Linezolid Infants and children <12 years 10 mg/kg q 8 h Children >12 years of age and adolescents 10 mg/kg q 12 h

Piperacillin 100-300 q 8 h 4 g mg/kg/d Ciprofloxacin 20–30 mg/kg/d divided every 800 mg 12 h Levofloxacin 500 mg Children 6 months to 5 years of age 10 mg/kg q12 h Children >5 years of age 10 mg/kg q 24 h 55

Amikacin 15–22.5 q 24 h Infants and children mg/kg/d Gentamicin 5-7.5 mg/kg/d q 24 h If normal renal function Meropenem 20 mg/kg q 8 h 1 g Infants ≥3 months of age and children Imepenem-cilastin 100 mg/kg/d Divided q 6 h 4 g Infants < 3 months of age 60-100 Divided q 6 h Infants > 3 months of age and children mg/kg/d Fluconazole 12 mg/kg/d q 24 h Anidulafungin 1.5 mg/kg/day Limited experience Children 2– 17 years of age Micafungin 1–4 mg/kg/day 150 mg Limited experience Children >2 years of age

Caspofungin loading dose of 70 mg; may Children 3months-17 years 70 mg/m2/day increase to 70 on day 1 mg/m2/day if followed by clinical 50 mg/m2/day response thereafter is inadequate. Clindamycin 10 mg/kg/dose q 6-8 h 900 mg Q 8 56

Chapter 8 Link To National Programme Current Guidelines For Treatment Of Specific Infections (HIV, RTI& STI, Tuberculosis, Malaria, Dengue, Kala azar, Leptospirosis, Leprosy, Japanese Encphalitis, Filariasis) National AIDS control programme (NACP): In 1986, following the detection of the first AIDS case in the country, the National AIDS Committee was constituted in the Ministry of Health and Family Welfare. In 1992 India’s first National AIDS Control Programme (1992-1999)

was launched, and National AIDS Control Organisation (NACO) was constituted to implement the programme. During NACP-II (1999-2006), the free ART (Antiretroviral therapy) programme was rolled out on April 1, 2004 in eight government hospitals in six high prevalence states has since been scaled up to 400 ART centres where in a total of around 16,00,000 patients have been registered in HIV care and nearly 6,00,000 patients are currently on ART. The

national programme provides free First line, alternate First line and Second line antiretroviral drugs to adults and children as per their eligibility. NACO makes available with updated related infections antimicrobial therapy guidelines on regular basis. Following links can be refered for further details: NACO Guidelines for Antiretroviral therapy for HIV-infected Adults and Adolescents 2013 http://www.naco.gov.in/upload/Policies%20&%20Guidelines/Antiretroviral%20Therapy%20Guidelines%20for

%20HIV-Infected%20Adults%20and%20Adolescents.pdf National Guidelines on Second-line and Alternative First-line ART For Adults and Adolescents 2013 http://www.naco.gov.in/upload/Policies%20&%20Guidelines/National%20Guidelines%20on%20Second- line%20and%20Alternative%20First- line%20ART%20For%20Adults%20and%20Adolescents%20May%202013.pdf Guidelines for Prevention and Management of Common Opportunistic Infections/Malignancies among HIV- Infected Adult and Adolescent 2007

http://naco.gov.in/upload/Policies%20&%20Guidelines/7- Guidelines%20for%20Prevention%20and%20Management%20of%20common%20opportunistic%20infections. pdf National Guidelines on Prevention, Management and Control of Reproductive Tract Infections and Sexually Transmitted Infections 2014 http://www.naco.gov.in/upload/2014%20mslns/National%20RTI%20STI%20technical%20guidelines%20Sep20 14.pdf Revised National Tuberculosis Control Programme (RNTCP) DOTS-PLUS:

The Revised National TB Control Programme (RNTCP), an application of the WHO recommended Directly Observed Treatment, Short Course (DOTS) strategy was launched in 1992 with the objective of detecting at least 70% of new sputum positive TB patients and curing at least 85% of such patients. However the emergence of resistance to drugs used to treat tuberculosis, and particularly multidrug-resistant TB

(MDR-TB), has become a significant public health problem in a many countries. In India, the available information from the several studies conducted in the past suggests that the rate of MDR-TB is relatively low in India. Yet this translates into a large absolute number of cases. Specific measures are being taken within the Revised National Tuberculosis Control Programme (RNTCP) to address the MDR-TB problem through appropriate management of

patients and strategies to prevent the propagation and dissemination of MDR-TB. Revised National Tuberculosis Control Programme (RNTCP) DOTS-PLUS Guidelines 2010– http://health.bih.nic.in/Docs/Guidelines/Guidelines-DOTS-Plus.pdf National Vector Borne Disease Control Programme (NVBDCP): NVBDCP Is an umbrella programme for prevention and control of vector borne diseases viz. Malaria, Japanese Encephalitis (JE), Dengue, Chikungunya, Kala-azar and Lymphatic Filariasis. Out of these six diseases, two diseases 57

namely Kala-azar and Lymphatic Filariasis have been targeted for elimination by 2015. Malaria, Filaria, Japanese Encephalitis, Dengue and Chikungunya are transmitted by mosquitoes whereas Kala-azar is transmitted by sand-flies. The transmission of vector borne diseases depends on prevalence of infective vectors and human vector contact, which is further influenced by various factors such as climate, sleeping habits of human, density and biting of vectors etc.

Following links can be referred for further details: Dengue Clinical Management Guidelines 2014 http://nvbdcp.gov.in/Doc/Dengue-National- Guidelines-2014.pdf Diagnosis and Treatment of Malaria Guidelines 2013 http://nvbdcp.gov.in/Doc/Diagnosis-Treatment-Malaria-2013.pdf Operational Guidelineson Kala-Azar (Visceral Leishmaniasis) Elimination in India 2015 http://nvbdcp.gov.in/Doc/opertional-guideline-KA-2015.pdf National Guidelines Diagnosis, Case Management Prevention and Control of Leptospirosis 2015

http://www.ncdc.gov.in/writereaddata/mainlinkfile/File558.pdf Operational Guidelines on Disability Prevention & Medical Rehabilitation under National Leprosy Eradication Program 2012 http://nlep.nic.in/pdf/Guidelines%20for%20Primary,%20Secondary%20and%20TLC%20(Atul%20Shah%2 0247.2012.pdf Guidelines on clinical management of acute encephalitis syndrome including Japanese encephalitis 2009 http://nvbdcp.gov.in/Doc/Revised%20guidelines%20on%20AES_JE.pdf

Guidelines on Filariasis Control in India & Its Elimination http://nvbdcp.gov.in/doc/guidelines-filariasis-elimination-india.pdf 58

Chapter 9 Case Definitions and Diagnosis for Common Infections DIARRHEA “Diarrhea” is an alteration in a normal bowel movement characterized by an increase in the water content, volume, or frequency of stools. A decrease in consistency (i.e., soft or liquid) and an increase in frequency of bowel movements to ⩾3 stools per day have often been used as a definition for epidemiological investigations.

“Infectious diarrhea” is diarrhea due to an infectious etiology, often accompanied by symptoms of nausea, vomiting, or abdominal cramps. “Acute diarrhea” is an episode of diarrhea of <14 days in duration. “Persistent diarrhea” is diarrhea of >14 days in duration. If diarrhoea present WITH vomiting, low grade fever with no mucus in stools think of viral infection. If diarrhoea present WITH vomiting, abdominal cramps, blood and mucus in stools WITH fever, think of bacterial infection.

If diarrhoea present WITH blood and mucus in stool WITH no fever, think of amoebiasis. If profuse diarrhoea present (rice water stools) WITH vomiting, think of cholera. If diarrhoea present WITH excessive vomiting (especially if in more than one member of the household or group) think of food poisoning. ENTERIC FEVER Acute non-complicated disease: Acute typhoid fever is characterized by prolonged fever, altered bowel function (constipation

in adults, diarrhea in children), headache, malaise and anorexia. Bronchitic cough and exanthem (rose spots on chest , abdomen, and trunk) may be seen in the early disease. Complicated disease: Severe disease can have abdominal pain, occult blood in stools, malena, perforation peritonitis, myocarditis, pneumonitis and enteric encephalopathy. Case definition Confirmed case of typhoid fever

A patient with fever (38°C and above) that has lasted for at least three days, with a laboratory-confirmed positive culture (blood, bone marrow, bowel fluid) of S. typhi. Probable case of typhoid fever A patient with fever (38°C and above) that has lasted for at least three days, with a positive serodiagnosis or antigen detection test but without S. typhi isolation. SPONTANEOUS BACTERIAL PERITONITIS

The diagnosis of spontaneous bacterial peritonitis (SBP) is made in transudative ascitis with increased absolute polymorphonuclear leukocyte (PMN) count (i.e., ≥250 cells/mm3 [0.25 x 109/L]) and without an evident intra-abdominal, surgically treatable source of infection. An abdominal paracentesis must be performed and ascitic fluid must be analyzed before a confident diagnosis of ascitic fluid infection can be made. ACUTE PANCREATITIS

Acute inflammation of pancreas, usually caused by alcohol or gallstone migrating through the common bile duct. Less commonly caused by trauma, infections like mumps, ascariasis and drugs like diuretic, azathioprine, etc. Routine use of prophylactic antibiotics in patients with severe AP is not recommended. The use of antibiotics in patients with sterile necrosis to prevent the development of infected necrosis is not recommended.

Infected necrosis should be considered in patients with pancreatic or extrapancreatic necrosis who deteriorate or fail to improve after 7 – 10 days of hospitalization. In these patients, either (i) initial CT-guided fi ne-needle aspiration (FNA) for Gram stain and culture to guide use of appropriate antibiotics or (ii) empiric use of antibiotics after obtaining necessary cultures for infectious agents, without CT FNA, should be given. 59

In patients with infected necrosis, antibiotics known to penetrate pancreatic necrosis, such as carbapenems, quinolones, and metronidazole, may be useful in delaying or sometimes totally avoiding intervention, thus decreasing morbidity and mortality. ACUTE BACTERIAL MENINGITIS Acute bacterial meningitis (ABM) is a potentially life-threatening neurological emergency. Patients generally presents with short history of high-grade fever with prominent headache, neck stiffness, photophobia,

nausea, vomiting and altered mental status (lethargy to coma). Infants, elderly, and immunocompromised patients may show only mild behavioural changes with low-grade fever and little clinical evidence of meningeal inflammation. Patients with ABM should be rapidly hospitalized and assessed for consideration of lumbar puncture (LP) if clinically safe. Ideally, patients should have fast-track brain imaging before LP, but initiation of antibiotic therapy should not be delayed

beyond 3 h after first contact of patient with health service. CSF examination reveals elevated pressure (200-500 mm H O) and protein (100- 500 mg/dl, normal 15-45 mg/dl), decreased 2 glucose (<40% of serum glucose) and marked pleocytosis (100-10,000 white blood cells/μl, (normal <5) with 60% or greater polymorphonuclear leucocytes. Pyogenic meningitis should be differentiated from tubercular meningitis, which has relatively longer history of low to high

grade of fever, constitutional symptoms, and CSF shows lymphocytic predominance, normal to mildly reduced sugar and raised proteins. BRAIN ABSCESS Brain abscess is defined as a focal suppurative infection within the brain parenchyma, typically surrounded by a well- vascularized capsule. The most important investigation to diagnose brain abscesses is cranial imaging, either cranial tomography (CT) or magnetic resonance imaging (MRI).

Headache is the most common presenting symptom of brain abscess. Fever is generally present but its absence does not rule out the diagnosis. Mostly patients have a focal neurologic deficit such as hemiparesis, apahasia, visual field defects depending on the location of abscess. INFECTIVE ENDOCARDITIS Bacterial endocarditis is a life-threatening infectious disease. Clinical manifestations of bacterial endocarditis include fever,

toxaemia, clubbing, splenomegaly, anaemia, microscopic haematuria, a new onset or changing murmur, evidence of immune phenomena such as roth spots, osler nodes. The diagnosis of bacterial endocarditis is based on Modified Duke s criteria which involves clinical, laboratory and echocardiographic findings. Definite IE Pathological criteria  Microorganisms demonstrated by culture or on histological examination of a vegetation, vegetation that has embolized, or an intracardiac abscess specimen; or

 Pathological lesions; vegetation or intracardiac abscess confirmed by histological examination showing active endocarditis Clinical criteria  2 major criteria; or  1 major criterion and 3 minor criteria; or  5 minor criteria Possible IE  1 major criterion and 1 minor criterion; or  3 minor criteria Rejected IE  Firm alternate diagnosis; or  Resolution of symptoms suggesting IE with antibiotic therapy for ≤4 days; or

 No pathological evidence of IE at surgery or autopsy, with antibiotic therapy for ≤4 days; or  Does not meet criteria for possible IE, as above Modified Duke s criteria for diagnosis of endocarditis Major Criteria 1. Blood cultures positive a. Typical microorganisms consistent with IE from 2 separate blood cultures 60

 Viridans streptococci, Streptococcus gallolyticus (Streptococcus bovis), HACEK group, Staphylococcus aureus; or  Community-acquired enterococci, in the absence of a primary focus; or b. Microorganisms consistent with IE from persistently positive blood culture  ≥2 positive blood cultures of blood samples drawn >12 h apart; or  All of 3 or a majority of ≥4 separate cultures of blood (with first and last samples drawn ≥1 h apart); or

c. Single positive blood culture for Coxiella burnetii or phase I IgG antibody titre >1:800 2. Imaging positive for IE a. Echocardiogram positive for IE  Vegetation;  Abscess pseudoaneurysm, intracardiac fistula  Valvular perforation or aneurysm;  New partial dehiscence of prosthetic valve b. Abnormal activity around the site of prosthetic valve implantation detected by “F-FDG PET/CT (only if the prosthesis was implanted for >3 months) or radiolabelled leucocytes SPECT/CT

c. Definite paravalvular lesions by cardiac CT Minor Criteria 1. Predisposition such as predisposing heart condition, or injection drug use 2. Fever defined as temperature >38°C 3. Vascular phenomena (including those detected by imaging only): major arterial emboli, septic pulmonary infarcts, infectious (mycotic) aneurysm, intracranial haemorrhage, conjunctival haemorrhages, and Janeway’s lesions 4. Immunological phenomena: glomerulonephritis. Osler’s nodes, Roth’s spots, and rheumatoid factor

5. Microbiological evidence: positive blood culture but does not meet a major criterion as noted above or serological evidence of active infection with organism consistent with IE CELLULITIS Cellulitis is an acute spreading infection that involves subcutaneous tissue, most commonly caused by group a streptococcus and staph aureus. Trauma and underlying skin lesion can lead to the development of cellulitis. Cellulitis may also develop due to the spread of adjacent infections like osteomyelitis.

Clinical findings: Clinically rapidly intensifying pain and redness is a common presentation. Fever and lymphadenopathy may be present. The borders in cellulitis are not well demarcated. Though group A streptococci and staphylococcus are the most common organisms rarely organisms like H influenza, pneumococcus may also cause cellulitis. FURUNCULOSIS Furunculosis is a deep infection of the hair follicle leading to abscess formation with accumulation of pus and necrotic tissue.

Furuncles appear as red, swollen, and tender nodules on hair-bearing parts of the body, and the most common infectious agent is Staphylococcus aureus, but other bacteria may also be causative. Furunculosis often tends to be recurrent and may spread among family members. A carbuncle is a coalescence of several inflamed follicles into a single inflammatory mass with purulent drainage from multiple follicles. URINARY TRACT INFECTIONS

The term UTI encompasses a variety of clinical entities viz asymptomatic bacteriuria (ASB), cystitis, prostatitis and pyelonephritis. Uncomplicated UTI refers to acute cystitis or pyelonephritis in non pregnant outpatient women without anatomic abnormalities or instrumentation of urinary tract. Complicated UTI includes all other types of UTI. Cystitis: The typical symptoms of cystitis are dysuria, urinary frequency, and urgency. Other symptoms are nocturia, hematuria, suprapubic discomfort, and hesitancy.

Pyelonephritis : severe pyelonephritis present as high fever, rigors, nausea, vomiting, flank or loin pain.symptoms are acute in onset and symptoms of cystitis may not be present. Fever is the main distinguishing feature between cystitis and pyelonephritis. Prostatitis: Acute bacterial prostatitis presents as dysuria, frequency and pain in pelvis or perineal area. Fever and chills are usually present and symptoms of bladder outlet obstruction are common. PNEUMONIA

Pneumonia is an inflammation in alveolar tissue, most often caused by a microbial agent. The community acquired pneumonia is most commonly caused by Streptococcus pneumoniae (typical) and less frequently by Mycoplasma pneumoniae, H. influenzae, Chlamydia pneumoniae, Staphylococcus aureus or Legionella pneumoniae (atypical). Haemophilus influenzae infection is seen mostly in patients with chronic bronchitis. Nosocomial pneumonia is likely to be caused by Gram-negative bacilli or Staphylococcus aureus. 61

Sudden onset of fever, productive cough, chest pain, shortness of breath and (in some cases) pleuritic chest pain; systemic symptoms like headache, bodyache and delirium are more severe with atypical pneumonia. For assessment of the severity of pneumonia “CURB- 65” severity score can be used- Confusion, Urea >7 mmol/l, Respiratory rate ≥30/min, low Blood pressure (diastolic blood pressure (DBP) ≤ 60 mm Hg or systolic BP ≤ 90 mm Hg) and Age ≥65 years

Patients with scores 0 and 1 are at low risk of mortality (1.5%) might be suitable for management as hospital outpatients. Patients with a score of 2 are at intermediate risk of mortality (9%) and should be considered for hospital supervised treatment. Patients with a score of >2 are at high risk of mortality (>19%) and requires ICU care. 62

ABBREVIATIONS AIDS Acute Immuno Deficiency Syndrome GBS- Guillain Barre syndrome ALT- Alanine Amino Transferase GI-Gastro-Intestinal AM-CL- Amoxicillin/clavulanate HIV-Human Immunodeficiency Virus AMR – Antimicrobial Resistance HSV- Herpes Simplex virus ANC- Antenetal Care ICU-Intensive Care Unit AOM- Acute otitis media ID- Infectious disease ART- Anti retroviral treatment IU- International unit AST- Anti microbial susceptibility test IUD- Intra Uterine Device ATT- Anti Tubercular Treatment IV-Intra Venous

BAL- Broncho Alveolar lavage LBW-Low Birth Weight BCG- Bacillus Calmette Guerin MDR-Multi Drug Resistant BD- Bis in Die (12 hourly) MIC- Minimum Inhibitory Concentration BL-BLI- Beta lactam-beta-lactam inhibitor MRSA- Methicillin Resistant Staphylococus aureus BMT- Bone Marrow Transplantation MSSA- Methicillin Sensitive Staphylococcus aureus BP- Blood Pressure NICU- Neonatal Intensive Care Unit CABG- Coronary Artery Bypass graft OD- Once a day

CAPD- Continuous Ambulatory Peritoneal Dialysis OPD-Outdoor Patient Department CI- Confidence Interval OT-Operation Theatre CLSI- Clinical and Laboratory Standards Institute PANDAS- Pediatric Autoimmune Neuropsychiatric CME- Continuing medical education Disorders Associated with Streptococcal Infections CMV- Cyto Megalo Virus PCR- Polymerase chain reaction CNS-Central Nervous System PICU-Pediatric Intensive Care Unit CRBSI-Catheter Related Bloodstream Infection PJI-Periprosthetic Joint Infection

CRP- C reactive protein RNTCP-Revised National Tuberculosis Control Programme CRS-Congenital Rubella Syndrome RTI- Reproductive tract infection CSF- Cerebro Spinal Fluid SOP- Standard operating procedure CSSD- Central Stores and Supply Department STI-Sexually Transmitted Infection CTVS- Cardio Thoracic and Vascular Surgery TB-Tuberculosis CVS- Cardiovascular System TDS - Ter die sumendum (8 hourly) DS- Double Strength TMP-SMX- Trimethoprim sulphamethoxazole

DT-Dispersible Tablet TMP-SMX-DS- Trimethoprim sulphamethoxazole double DVT- Deep Venous Thrombosis strength E.T.O-Ethylene Oxide Sterizilation URI-Upper Respiratory Infection ECG- Echo Cardio Gram UTI-Urinary Tract Infection ECHO- Echo Cardio Graphy VAP-Ventilator Associated Pneumonia EGA-Estimated Gestational Age HAP-Hospital Acquired Pneumonia ENT-Ear Nose Throat VDRL-Venereal Disease Research Laboratory ESBL-Extended-Spectrum Beta- Lactamase VRE-Vancomycin Associated Enterococci

ESRD- End Stage Renal Disease VZIG- Varicella Zoster immunoglobulin FDA- Food and Drug Authority WBC-White Blood Cell FQ- Fluoroquinolone WHO-World Health Organization G6PD- Glucose 6- phosphate dehydrogenase 63

LIST OF EXPERTS Authors- Dr..S. Venkatesh, Director, National Centre for Disease Control, New Delhi. Dr..L.S. Chauhan, Ex-Director, National Centre for Disease Control, New Delhi. Dr. A. K. Gadpayle, Director PGIMER and Medical Superintendent Dr. RML Hospital, New Delhi Dr. T. S. Jain, President, Hospital Infection Control Society, India Dr. Chand Wattal, Senior Consultant, Clinical Microbiology, Sir Ganga Ram Hospital, New Delhi

Dr. S. Aneja, Director Professor, Paediatrics, Kalawati Saran Children Hospital & Lady Hardinge Medical College, New Delhi Dr. Abdul Ghafur, Consultant Infectious Diseases & Clinical Microbiology, Apollo Hospital, Chennai Dr. Manju Puri, Professor &Head Gynecology and Obstetrics, Lady Hardinge Medical College and Smt Sucheta Kriplani Hospital, Delhi Dr. Ajit Sinha, Head Surgery, Safadarjang Hospital, New Delhi

Dr. Varinder Singh, Professor Paediatrics, Kalawati Saran Children Hospital & Lady Hardinge Medical College, New Delhi Dr. Usha Baveja, Senior Consultant, Microbiology, Medanta-The Medicity, Gurgaon, Haryana Dr. Renu Dutta, Director Professor, Microbiology, Lady Hardinge Medical College, New Delhi Dr. Rajni Gaind, Consultant and Professor, Head Microbiology,VMMC & Safdarjang Hospital, New Delhi

Dr. Raman Sardana, Head & Chairman, Hospital Infection Control & Microbiology, Indraprastha Apollo Hospitals, Sarita Vihar, NewDelhi. Dr. Vikas Manchanda, Assistant Professor, Microbiology, Maulana Azad Medical College, New Delhi Dr. Anita Kotwani, Ex-Associate Professor, Pharmacology, Vallabhbhai Patel Chest Institute, Delhi Dr. Charoo Hans, Head Microbiology, PGIMER and associated Dr. RML Hospital, New Delhi

Dr. Sudha Chandelia, Assistant Professor, Pediatrics & Division of Critical care, PGIMER and associated Dr. RML Hospital, New Delhi Dr. Piyush Jain, Assistant Professor, Medicine, PGIMER and associated Dr. RML Hospital, New Delhi Dr. Shashi Khare, Ex-Additional Director, Microbiology, National Centre for Disease Control, New Delhi. Dr. Sarika Jain, Assistant Director, Microbiology, National Centre for Disease Control, New Delhi. Contributors/Reviewers-

Dr K. K. Aggarwal, Hon’ble Secretary General, Indian Medical Association, Delhi Dr Jagdish Chandra, Director Professor & Head Paediatrics, Kalawati Saran Children Hospital & Lady Hardinge Medical College, Delhi Dr.Anupam Prakash, Associate Professor, Medicine, Lady Hardinge Medical College & associated Smt Sucheta Kriplani Hospital, Delhi Dr. Ravinder Kaur, Director Professor & Head Microbiology, Lady Hardinge Medical College, New Delhi

Dr. Sonal Saxena, Professor Microbiology, Lady Hardinge Medical College, New Delhi Dr. Anil Garg, C.M.O. (SAG) Medicine, Deen Dayal Upadhayaya Hospital, New Delhi Dr. Harish Gandhi, C.M.O. (SAG) Ophthalmology, Deen Dayal Upadhayaya Hospital, New Delhi Dr. K. K. Kumra, C.M.O. (SAG) Orthopedics, Deen Dayal Upadhayaya Hospital, New Delhi Dr. Manisha Jhawar, President Elect, Surat Ob & Gyn Society, Surat, Gujarat

Dr. Anurag Aggarwal, Assistant Professor, Pediatrics, Maulana Azad Medical College and associated Lok Nayak Hospital, New Delhi Dr. Narender Saini, Former Hon’ble Secretary General, Indian Medical Association, Delhi Dr. Rakesk Kumar. Mahajan, Professor & Consultant, Microbiology, PGIMER and associated Dr. RML Hospital, New Delhi Dr. Kamini Walia, Sr. Scientist, Indian Council of Medical Research, Ansari Nagar, New Delhi

Dr. Padmini Srikantiah, Senior Medical Epidemiologist, Centers for Disease Control and Prevention, Delhi Dr. S. Roy Choudhury, Professor & Head, Kalawati Saran Children Hospital & Lady Hardinge Medical College, New Delhi Dr. Sunil Gupta, Additional Director and Head, Microbiology, National Centre for Disease Control, New Delhi. 64

STANDARD TREATMENT GUIDELINES MEDICINE (NON RESPIRATORY INFECTIOUS MEDICAL CONDITIONS) Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 ENDOCERVICITIS (MUCOPURULENT CERVICITIS OR MPC) 4 2 EPIDIDYMITIS 10 3 GENITAL (INCLUDING ANAL/ PERIANAL) ULCER DISEASE [GUD] 18 4 GENITAL WARTS 28 5 PELVIC INFLAMMATORY DISEASE (PID) 35 6 URETHRITIS (URETHRAL DISCHARGE) IN MALES 47 7 ABNORMAL VAGINAL DISCHARGE (ABNORMAL) 58 2

Group Head Coordinator of Development Team Dr. M.K. Daga Department of Medicine Maulana Azad Medical College New Delhi 3

NAME OF CONDITION: Endocervicitis (mucopurulent cervicitis or MPC) I. WHEN TO SUSPECT/ RECOGNIZE? Case definition An inflammation of the cervical mucosa characterized by two major diagnostic signs.  Purulent or mucopurulent endocervical exudate (mucopurulent cervicitis)  Sustained endocervical bleeding easily induced by gentle passage of a cotton swab through the cervical os. Either or both signs might be present. Introduction: Symptoms  Asymptomatic in majority  Abnormal vaginal discharge in some

 Post coital and intermenstrual vaginal bleed Causative organisms:  C. trachomatis  N. gonorrhoeae  Mycoplasma genitalium II. INCIDENCE OF THE CONDITION IN OUR COUNTRY No institutional data available in the Indian scenario. III. DIFFERENTIAL DIAGNOSIS  Cervical ectopy (seen in adolescents)  Ectropion (patulous parous cervix)  Ectocervicitis caused by HSV, T. vaginalis, CMV, C. albicans  Endocervical inflammation associated with oral contraceptive use IV. PREVENTION AND COUNSELING

General measures as applicable to all patients with suspected STIs 4

 Educate and counsel patient and sex partner(s) regarding RTIs/STIs, genital cancers, safer sex practices and importance of taking complete treatment.  Treat partner(s) for the suspected organisms.  Advise sexual abstinence during the course of treatment to minimize transmission.  Promote the use of barrier contraception like condoms, educate about correct and consistent use.  Refer for voluntary counseling and testing for HIV, Syphilis and Hepatitis B.  Consider immunization against Hepatitis B.

 Schedule return visit after 7 days to ensure treatment compliance as well as to see reports of tests done.  If symptoms persist, assess whether it is due to treatment failure or reinfection and advise prompt referral. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited Clinical Diagnosis: Based on

 History of abnormal vaginal discharge, urinary burning or frequency, dysmenorrhoea, menorrhagia, irregular menstrual cycles.  Speculum examination showing signs of cervical infection like yellowish discharge, redness with swelling, easy bleeding on probing cervix, cervical erosion to be assessed.  Swab test: yellow colour of endocervical discharge visualized on a white swab  Bimanual pelvic examination: fornicial or cervical motion tenderness suggests PID 5

Investigations:  Gram's stain of endocervical mucus: to document cervicitis and look for presence of GNID  Cervical Cytopathology: PAP smear can demonstrate characteristic cellularity. Treatment: Provide presumptive therapy for cervicitis (not to await the results of diagnostic tests) Treatment for cervical infection (chlamydia and gonorrhea)  Tab cefixime 400 mg orally, single dose Plus  Tab Azithromnycin 1 gram, 1 hour before lunch. (If vomiting within 1 hour, give antiemetic and repeat)

Alternative regimes  Inj Ceftriaxone 250 mg im stat Plus  Tab Doxycycline 100 mg orally twice a day for 7 days If Vaginitis also present  treat for both vaginitis and cervicitis (refer to guidelines)  Trichomoniasis and BV should be treated if detected Other measures to be advised  Instruct client to avoid douching  Advise sexual abstinence during the course of treatment Follow-Up  Followup after one week  Repeat testing of all women with chlamydia regardless of whether their sex partners

were treated as there is high risk of reinfection Specific guidelines for partner management  Treatment as for urethritis (refer to relevant guidelines)  Provide condoms, educate about correct and consistent use 6

 Schedule return visit after 7 days Special situations  Pregnancy, diabetes, HIV may also be influencing factors and should be considered in recurrent infections Management in pregnant women  Per speculum examination  In women with persistent symptoms attributable to cervicitis, refer to gynaecologist HIV Infection  same treatment regimen as those who are HIV negative Recurrent and Persistent Cervicitis  Reevaluate for possible reexposure to an STD as they have a high rate of reinfection

within 6 months after treatment.  Exclude BV  Sex partners to be evaluated and treated  Repeat alternative course of therapy  Revaluate to determine whether cervicitis has resolved Referral criteria:  Gynecologic referral to rule out other causes in case of persistent, unresponsive or recurrent cervicitis. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical Diagnosis: Same as above 7

b) Investigations: Same as above In addition  Colposcopy  Cervical biopsy  Microbial etiology of cervicitis to be delineated (indicated in patients with recurrent or persistent cervicitis) as per relevance in a given clinical situation, any of the following tests may be done. o isolation of C. Trachomatis o culture for N. Gonorrhoeae o HSV culture: viral isolation o Isolation of T. Vaginalis o immunologic detection of microbial antigens o use of nucleic acid probes

o DNA amplification / detection methods.  NAAT should be used for diagnosing C. trachomatis and N. gonorrhoeae in women with cervicitis Treatment:  For reasons that are unclear, cervicitis can persist despite repeated courses of antimicrobial therapy.  Most persistent cases not caused by relapse or reinfection with C. trachomatis or N. gonorrhoeae  Other factors like persistent abnormality of vaginal flora, douching, exposure to other

types of chemical irritants or idiopathic inflammation in the zone of ectopy to be evaluated 8

VI. FURTHER READING / REFERENCES 1. Oh MK, Cloud GA, Fleenor M, Sturdevant MS, Nesmith JD, Feinstein RA. Risk for gonococcal and chlamydial cervicitis in adolescent females: incidence and recurrence in a prospective cohort study. J Adolesc Health. 1996 Apr;18(4):270-5. 2. Morbidity and Mortality weekly report. December 17, 2010 / Vol. 59 / No. RR-12. Sexually Transmitted Diseases Treatment Guidelines, 2010 3. National guidelines on prevention, management and control of reproductive tract

infections including sexually transmitted infections. Ministry of Health and Family welfare, Governemnt of India, August, 2007. 4. Holmes KK, Stamm WE, Sobel JD. Lower genital tract infection syndromes in women. In Sexually Transmitted Diseases Eds: Holmes KK, Sparling PF, Stamm WE, Piot P, Wasserheit JN, Corey L, Cohen MS, Watts DH, Nelson RA. 4th Edition, 2008 McGraw-Hill, p 987-1016. 9

NAME OF CONDITION: Epididymitis I. WHEN TO SUSPECT/ RECOGNIZE? Case definition: Epididymitis is inflammation of epididymis resulting in pain, swelling and tenderness of the scrotal sac. Many cases are related to genitourinary tract infections, especially sexually transmitted infections and bacterial urinary tract infections. The process causes scrotal pain and swelling that is characteristically unilateral and relatively acute in onset. It can be of two types

1. Acute epididymitis: pain, swelling, and inflammation of the epididymis lasting <6 weeks. In most cases of acute epididymitis, the testis is also involved in the process (epididymo- orchitis). 2. Chronic epididymitis is characterized by a ≥6 week history of discomfort, pain or swelling in the epididymis. Generally seen in conditions with granulomatous reaction e.g tuberculosis (most common granulomatous disease affecting the epididymis).

Tuberculous epididymitis should be suspected in all patients whose clinical status worsens despite appropriate antibiotic treatment. Causes of acute epididymitis 1. Among sexually active men (<35 years) • Most frequently- C. trachomatis or N. gonorrhoeae. • Sexually transmitted enteric organisms e.g., Escherichia coli and Pseudomonas spp. Sexually transmitted acute epididymitis usually is accompanied by urethritis, which frequently is asymptomatic. 2. In men aged >35 years

 Sexually transmitted epididymitis is uncommon  Bacteriuria secondary to obstructive urinary disease (e.g., benign prostatic hyperplasia)  Association with urinary tract instrumentation, surgery, systemic disease and immunosuppression. Sequelae o Abscess formation 10

o Infarction of the testicle o Gangrene of the testicle o Subfertility or Infertility o Chronic epididymalgia or epididymitis II. INCIDENCE OF THE CONDITION IN OUR COUNTRY Epididymitis is common, and it carries much morbidity in terms of suffering and loss of time from work. Researchers have reported that the incidence of epididymitis may range from one to four per 1000 men per year3,4. No institutional data available in India. III. DIFFERENTIAL DIAGNOSIS (non RTIs/STIs)

 Testicular torsion: surgical emergency, occurs more frequently in adolescents and in men without evidence of inflammation or infection.  Infections: Filariasis, Coliforms or pseudomonas infection, Mumps virus infection, fungal infection  Non infectious causes: Trauma, Hernia, Hydrocoele, Testicular tumor, testicular infarction IV. PREVENTION AND COUNSELING General measures as applicable to all patients with suspected STIs

 Educate and counsel patient and sex partner(s) regarding RTIs/STIs, genital cancers, safer sex practices and importance of taking complete treatment.  Treat partner(s) for the suspected organisms.  Advise sexual abstinence during the course of treatment to minimize transmission.  Promote the use of barrier contraception like condoms, educate about correct and consistent use.  Refer for voluntary counseling and testing for HIV, Syphilis and Hepatitis B.  Consider immunization against Hepatitis B. 11

 Schedule return visit after 7 days to ensure treatment compliance as well as to see reports of tests done.  If symptoms persist, assess whether it is due to treatment failure or reinfection and advise prompt referral. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited Clinical Diagnosis:

In a male suffering from urethritis, the onset of scrotal tenderness and swelling suggests the diagnosis of epididymitis. Clinical diagnosis is based on  Examination o erythema or asymmetry in scrotal size o scrotal swelling, minimal or more apparent o penile size, oedema or phimosis should be examined o Meatal erthema, discharge (thick, creamy or mucopurulent). o Milking the penis (urethra) may produce discharge at the meatus. o Shaft of penis with papules, nodules, ulcers or other skin lesions.

 Palpation o Of inguinal region for tender lymphnodes. o Of spermatic cords to rule out tenderness, asymmetry, and thickening o Of scrotum to assess for asymmetry, tenderness and consistency of testes and epididymis.  Transillumination: to rule out hydrocoele.  Hernia to be assessed for. 12

Clinical features  Unilateral testicular pain and tenderness  Hydrocele and palpable swelling of the epididymis  Inflammation and swelling usually begins in the tail of the epididymis and spreads to involve the rest of the epididymis and testicle.  Spermatic cord tender and swollen. Investigations: To assess for a) urethritis and urinary-tract infection b) to rule out the various differentials These include • Gram stain of urethral secretions demonstrating ≥5 WBC per oil immersion field. If

normal, then epidiymitis as a cause of scrotal pain is highly unlikely.  Positive leukocyte esterase test on first-void urine • Microscopic examination of first-void urine sediment demonstrating ≥10 WBC per high power field.  Urine culture: In asymptomatic patients colony counts of >1 X 10(5) cfu/ml of urine is significant. In cases with acute dysuria and frequency colony count of 1 X 10(2) cfu/ml bacteria is the most useful criterion. Also aids in identification of gram species.

 Testing for other STDs as the setting suggests.  Ultrasound: Primarily used for ruling out torsion of the spermatic cord. Otherwise, minimal utility in a clinical presentation consistent with epididymitis. Reserved for patients with scrotal pain who cannot be diagnosed accurately by physical examination, history, and objective laboratory findings. Treatment: Standard Operating procedure  Empiric therapy is indicated before laboratory test results are available. 13

 Treat for C. trachomatis and N. gonorrhoeae  Goals of treatment are o microbiologic cure of infection, o improvement of signs and symptoms, o prevention of transmission to others o decrease in potential complications (e.g., infertility or chronic pain). Adjunct therapy  Bed rest with scrotal elevation with T bandage  Analgesics are recommended until fever and local inflammation have subsided.  Treat for both gonococcal and chlamydial infections. Recommended regime

 Tab Cefixime 400 mg orally BD for 7 days OR  Inj. Ceftriaxone 250 mg IM in a single dose PLUS  Cap. Doxycycline 100mg orally, twice daily for 14 days  Additional therapy to include a fluoroquinolone o if infection not found to be caused by gonorrhea or o if enteric organisms are more likely (e.g., MSM who report insertive anal intercourse). o Or if significant gram negative bacteriuria is present. In these cases o T. Levofloxacin 500 mg orally once daily for 10 days OR

o T. Ofloxacin 300 mg orally twice a day for 10 days  If gonococcal infection is confirmed (or is highly likely), patient to be hospitalised and parenteral cephalosporin (Ceftriaxone) to be started as it is a complicated gonococcal infection. A longer duration of treatment may be needed. (Refer to guidelines on urethral discharge) 14

Syndrome specific guidelines for partner management  Patients to be instructed to refer sex partners for evaluation and treatment if their contact with the index patient was within the 60 days preceding onset of their own symptoms.  Instructed to abstain from sexual intercourse until they and their sex partners have been adequately treated (i.e., until therapy is completed and patient and partners no longer have symptoms).  Partner needs to be treated depending on the clinical findings

Management protocol in case the partner is pregnant  Depending on the clinical findings in the pregnant partner (whether vaginal discharge or endocervical discharge or PID is present) the drug regimens should be used.  Doxycycline is contraindicated in pregnancy  Erythromycin base/Amoxicillin can be used in pregnancy (Erythromycin estolate is contraindicated in pregnancy due to hepatotoxicity), Erythromycin base or erythromycin ethyl succinate should be given) In patient care

Hospitalization to be considered  When severe pain suggests other diagnoses (e.g., torsion, testicular infarction, or abscess)  When patients are unable or unlikely to comply with an antimicrobial regimen  High fever is uncommon in epididymitis and indicates a complicated infection; these patients should be admitted for further evaluation  Parenteral therapy to be started in view of complicated gonococcal infection. Follow-Up

 Instructed to return if symptoms fail to improve within 48 hours of the initiation of treatment. Requires re-evaluation of the diagnosis and therapy.  After completion of antibiotic therapy: Swelling and tenderness that persist after completion should be evaluated comprehensively to assess for tumor, abscess, infarction, testicular cancer, TB, and fungal epididymitis. 15

Special Considerations HIV Infection  Same treatment regimen as those who are HIV negative.  Other etiologic agents implicated in acute epididymitis with HIV infection include CMV, salmonella, toxoplasmosis, Ureaplasma urealyticum, Corynebacterium sp., Mycoplasma sp., and Mima polymorpha.  Fungi and mycobacteria are also more likely to cause acute epididymitis in this setting. Referral criteria:  If the diagnosis is questionable, then immediate referral to urologist to preserve testicular viability.

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available c) Clinical Diagnosis: Same as above d) Investigations: Same as above PLUS  Culture for gonococcus  Nucleic acid hybridization tests and NAATs: aid in quick detection of both N. gonorrhoeae and C. trachomatis. Done on urethral swab specimens (NAAT can be performed on urine as well). Because of their higher sensitivity, amplification tests are preferred for the detection of C. trachomatis.

 Radionuclide scanning of the scrotum (most accurate radiologic method of diagnosis, but it is not routinely available). e) Treatment: Same as above f) Referral criteria: Same as above 16

AND Surgical management (if required)  Surgical drainage of testicular abscesses, Orchiectomy, Epididymectomy might be indicated in an older group of patients BUT ONLY after unsuccessful conservative treatment.  Surgical therapy (generally orchiectomy) may be necessary for complications of severe epididymoorchitis, such as testicular infarction, abscess formation, development of a pyocele of the scrotum (infected hydrocele). VI. FURTHER READING / REFERENCES

1. Tracy CR, Steers WD, Costabile R. Diagnosis and management of epididymitis. Urol Clin North Am 2008;35:101–8. 2. Nickel JC, Siemens DR, Nickel KR, et al. The patient with chronic epididymitis: characterization of an enigmatic syndrome. J Urol 2002;167:1701–4. 3. Gasparich JP, Mason JT, Greene HL, et al. Amiodarone-associated epididymitis: drug- related epididymitis in the absence of infection. J Urol 1985; 133: 971-972.

4. Drotman DP. Epidemiology and treatment of epididymitis. Rev Infect Dis 1982; 4: S788- S792. 5. Morbidity and Mortality weekly report. December 17, 2010 / Vol. 59 / No. RR-12. Sexually Transmitted Diseases Treatment Guidelines, 2010 6. National guidelines on prevention, management and control of reproductive tract infections including sexually transmitted infections. Ministry of Health and Family welfare, Governemnt of India, August, 2007.

7. Geisler WM, Krieger JN. Epididymitis. In Sexually Transmitted Diseases Eds: Holmes KK, Sparling PF, Stamm WE, Piot P, Wasserheit JN, Corey L, Cohen MS, Watts DH, Nelson RA. 4th Edition, 2008 McGraw-Hill, p1128-1145. 17

NAME OF CONDITION: GENITAL (INCLUDING ANAL/ PERIANAL) ULCER DISEASE [GUD] I. WHEN TO SUSPECT/ RECOGNIZE? a. Case definition: Any ulcer present in the genital, anal or perianal area needs to be reviewed to rule out the possibility of sexually transmitted infections, although non-sexually transmitted causes may also be responsible. b. Introduction: The causes of sexually transmitted ulcers are: • Genital herpes • Syphilis • Chancroid • Lymphogranuloma Venereum • Donovanosis

GUD especially with HSV, syphilis, and chancroid have been associated with an increased risk for HIV transmission, II. INCIDENCE OF THE CONDITION IN OUR COUNTRY: Institutional data on prevalence and incidence not available. The frequency of each cause differs by geographic area and population. Genital herpes is the most prevalent of these. More than one etiologic agent can be present in an ulcer. The clinical diagnosis of GUD is undermined

when HIV infection is present. Diagnosis based on clinical impression may not always be correct. The etiology of GUD according to M-PCR was reported to be HSV in 26%, chancroid in 23%, primary syphilis in 10%, and multiple infections in 7% cases1. Also, HIV seroprevalence is significantly higher in patients with HSV compared with other etiologies presumably because of HIV-induced immunosuppression and consequent HSV reactivation. All this calls for syndromic

management of genital ulcers especially in the setting of HIV. 18

III. DIFFERENTIAL DIAGNOSIS Non sexually transmitted genital ulcers include: • Yeast • Trauma • Carcinoma • Aphthae and Behcet’s • Fixed drug eruption • Psoriasis IV. PREVENTION AND COUNSELING General measures as applicable to all patients with suspected STIs  Educate and counsel patient and sex partner(s) regarding RTIs/STIs, genital cancers, safer sex practices and importance of taking complete treatment.  Treat partner(s) for the suspected organisms.

 Advise sexual abstinence during the course of treatment to minimize transmission.  Promote the use of barrier contraception like condoms, educate about correct and consistent use.  Refer for voluntary counseling and testing for HIV, Syphilis and Hepatitis B.  Consider immunization against Hepatitis B.  Schedule return visit after 7 days to ensure treatment compliance as well as to see reports of tests done.  If symptoms persist, assess whether it is due to treatment failure or reinfection and

advise prompt referral. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited 19

a) Clinical Diagnosis: • Clinical examination of the genital area to confirm the presence of ulcers. • Ulcers to be examined for location, number (single, multiple), superficial (erosions) or deep, edge (undermined/punched out), margins regular/irregular) and floor (presence of exudates, slough/granulation tissue). Palpation of ulcers for tenderness, induration of the floor and edges or bleeding on maneuvering. • Palpation of inguinal region for lymph nodes in terms of tenderness, increased warmth,

superficial or deep, discrete or matted, free mobility or fixity to deeper structures, consistency (firm or soft) and fluctuance. b) Investigations: Standard tests for all patients with genital ulcer - Testing for HIV: on all persons with genital, anal, or perianal ulcers who are not known to have HIV infection - Serologic tests for syphilis - Smear from the base of ulcer, Gram stained (for chancroid) and Giemsa stained (for herpes and donovanosis)

- Biopsy at times- for unusual causes or those that do not respond to initial therapy. - Type-specific serologic tests for HSV: useful to identify pregnant women at risk for HSV infection and to guide counseling regarding the risk for acquiring genital herpes during pregnancy. To be offered to uninfected women whose sex partner has HSV infection. c) Treatment: • Treat patients before test results are available • Empirically treat for the diagnosis considered most likely on the basis of clinical

presentation and epidemiologic circumstances (including travel history) as even after extensive investigations, at least 25% of patients will have no laboratory-confirmed diagnosis. 20

Standard Operating procedure On the basis of clinical examination and investigations, decide whether the ulcers are herpetic or non-herpetic • If vesicles or multiple painful ulcers are present Treat for herpes • Tab. Acyclovir 400mg orally, three times a day for 7-10 d OR • Tab Acyclovir 200mg five times a day for 7-10 d OR • Tab Famciclovir 250mg three times a day for 7-10 d OR • Tab Valacyclovir 1 g twice a day for 7-10 d - Initiation of therapy within 1 day of lesion onset or during the prodrome

- Patient to be provided with a supply of drug or a prescription with instructions to initiate treatment immediately when symptoms begin. - Suppressive therapy in select cases • If vesicles are not seen and only ulcer is seen Treat for syphilis and chancroid and counsel on herpes genitalis To cover syphilis • Inj Benzathine penicillin 2.4 million IU IM after test dose in two divided doses (with emergency tray ready)

• In individuals allergic or intolerant to penicillin Tab Doxycycline 100mg orally, twice daily for 14 days Plus To cover chancroid • Tab Azithromycin 1g orally single dose OR • Inj. Ceftriaxone 250 mg IM single dose OR 21

• Tab. Ciprofloxacin 500mg orally, twice a day for three days Treatment should be extended beyond 7 days if ulcers have not reepithelialised Suppressive Therapy for Recurrent Genital Herpes • Reduces the frequency of genital herpes recurrence by 70%–80%, improves quality of life. • Also effective in patients with less frequent recurrences. • Safety and efficacy documented with acyclovir for as long as 6 years and with valacyclovir or famciclovir for 1 year.

• The frequency of recurrent outbreaks diminishes with time. Also, the patient’s psy- chological adjustment to the disease might change. Therefore, during suppressive treatment (e.g., once a year), re-discuss the need to continue therapy. • Acyclovir treatment late in pregnancy reduces the frequency of cesarean sections among women who have recurrent genital herpes by diminishing the frequency of recurrences at term. • Drugs recommended: for as long as required - Tab Acyclovir 400mg BD

- Famiciclovir 250 mg orally twice a day - Valacyclovir 500 mg orally once a day - Valacyclovir 1g orally once a day Counselling of persons with genital HSV infection: - Educate concerning the natural history, potential for recurrent episodes, asymptomatic viral shedding, and risk of sexual transmission. - Advise that suppressive therapy is available for preventing symptomatic recurrent episodes - Episodic therapy to shorten the duration of episodes. - Encourage to inform current and future partners. 22

- Remain abstinent from sexual activity with uninfected partners when lesions or prodromal symptoms are present. - Male latex condoms, used consistently and correctly, might reduce the risk of transmission - Sex partners to be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of the asymptomatic partners recommended to determine whether they are already HSV seropositive or are at risk for acquiring HSV.

- The risk for neonatal HSV infection should be explained to all persons, males and females. Increased risk if infection acquired for the first time near delivery. - Pregnant women and women of childbearing age with genital herpes encouraged to inform their health care providers during pregnancy and those who will care for their newborn infant about their infection (risk of neonatal herpes is high). - Pregnant women who are not known to be infected with HSV-2 should be advised to

abstain from intercourse with men who have genital herpes during the third trimester of pregnancy. - Asymptomatic persons diagnosed with serologic evidence of HSV-2 should receive the same counseling messages as persons with symptomatic infection. Syndrome specific guidelines for partner management • Treat all partners who are in contact with client in last 3 months • Partners should be treated for syphilis and chancroid • Advise sexual abstinence during the course of treatment

• Provide condoms, educate about correct and consistent use • Refer for voluntary counseling and testing for HIV, Syphilis and Hepatitis B • Schedule return visit after 7 days Management of HIV infected patients • To be monitored closely. More likely to experience treatment failure and heal slowly • Might require repeated or longer courses of therapy 23

• Treatment failures can occur with any regimen. • Ceftriaxone and Azithromycin based regimens used only if follow-up can be ensured. Management of Pregnant Women • Quinolones (like ofloxacin, ciprofloxacin), doxycycline, sulfonamides are contraindicated in pregnant women. • Pregnant women with positive RPR- consider infected unless adequate treatment is documented in records and sequential serologic antibody titres have declined.

• Pregnant women with primary, secondary, or latent syphilis: Two doses of Inj Benzathine penicillin 2.4 million IU IM after test dose (with emergency tray ready) at 1 week interval. • Pregnant women who are allergic to penicillin: o Tab. Erythromycin 500mg orally four times a day for 15 days (Erythromycin estolate contraindicated in pregnancy) o Neonate to be treated for syphilis after delivery. • All pregnant women should be asked history of genital herpes and examined carefully for herpetic lesions.

o Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally. o Women with genital herpetic lesions at the onset of labour- delivered by caesarean section to prevent neonatal herpes. o Acyclovir may be administered orally to pregnant women with first episode genital herpes or severe recurrent herpes. Considered a safe drug Neonatal Herpes • Infants exposed to HSV during birth should be followed carefully in consultation with a pediatric infectious disease specialist.

• Intravenous acyclovir considered for infants born to women who acquired HSV near term (as the risk for neonatal herpes is high for these infants). • Intravenous acyclovir promptly started for infants who have neonatal herpes. 24

• The recommended regimen for infants treated for known or suspected neonatal herpes is acyclovir 20 mg/kg IV every 8 hours for 21 days for disseminated and CNS disease or for 14 days for disease limited to the skin and mucous membranes. d) Referral criteria: Refer to higher centre • Cases of genital ulcer not responding to the above treatment protocols. • Neonatal herpes if adequate monitoring and expertise not available

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available g) Clinical Diagnosis: Same as above. h) Investigations: Same as above In addition Specific tests for evaluation of genital, anal, or perianal ulcers which may be available in this situation and which may be required for specific diagnosis in difficult cases 1) Darkfield microscopy (from ulcer fluid or lymph node aspirate) to look for motile

treponemes. If available, should be done for all suspected patients with syphilis. 2) Culture for Haemophilus ducreyi: not widely available; even when used, sensitivity is <80% 3) Multiplex PCR: to detect various possible causes in a genital ulcer 4) Surveillance cultures of mucosal surfaces (for HSV) might be considered for neonates possibly exposed to maternal herpes. 5) Donovanosis: visualization of dark-staining Donovan bodies on tissue crush preparation or biopsy. 25

i) Treatment: Same as above In Addition Severe HSV disease • Intravenous (IV) acyclovir therapy: for patients with severe HSV disease or complications that necessitate hospitalization (e.g., disseminated infection, pneumonitis, or hepatitis) or CNS complications (e.g., meningoencephalitis). • Recommended regime o Inj Acyclovir 20 mg/kg IV every 8 hours for 2–7 days or until clinical improvement is observed, followed by oral antiviral therapy to complete at least 10 days of total therapy.

• Dose adjustment for impaired renal function. j) Referral criteria: Non- Responsive ulcers (to recommended treatment protocol) Causes of no improvement after 7 days follow up • incorrect diagnosis • coinfection with another STD • HIV infection • Non-compliance • Resistance to antimicrobial used Other factors to be accounted for • Large size of ulcer • Slower healing in uncircumcised men • Presence of fluctuant lymphadenopathy- may need drainage

• Donovanosis: typically slow healing. Recommended treatment is Tab Doxycycline 100 mg bd for at least three weeks or till lesions is healed. 26

VI. FURTHER READING / REFERENCES 1. Risbud A, Chan-Tack K, Gadkari D, Gangakhedkar RR, Shepherd ME, Bollinger R, et al. The aetiology of genital ulcer disease by multiplex polymerase chain reaction and relationship to HIV infection among patients attending sexually transmitted disease clinics in Pune, India. Sex Transm Dis 1999; 26(1): 63-65. (s). 2. Morbidity and Mortality weekly report. December 17, 2010 / Vol. 59 / No. RR-12. Sexually Transmitted Diseases Treatment Guidelines, 2010

3. National guidelines on prevention, management and control of reproductive tract infections including sexually transmitted infections. Ministry of Health and Family welfare, Governemnt of India, August, 2007. 4. Ballard RC. Genital ulcer adenopathy syndrome. In Sexually Transmitted Diseases Eds: Holmes KK, Sparling PF, Stamm WE, Piot P, Wasserheit JN, Corey L, Cohen MS, Watts DH, Nelson RA. 4th Edition, 2008 McGraw-Hill, p 1200-1208. 27

NAME OF CONDITION: GENITAL WARTS I. WHEN TO SUSPECT/ RECOGNIZE? Introduction: Genital warts are single or multiple soft, painless, flat, papular, or pedunculated growths which appear around the anus, vulvovaginal area, penis, urethra and perineum. May also appear as keratinized papules. Common sites are • Women: around the introitus • Men: under the foreskin, on the shaft • Both: On the anogenital epithelium, within the anogenital tract. Causative organism:

• Caused by Human Papilloma virus (HPV) Type 6 or 11 (90% cases) • HPV types 16, 18, 31, 33, and 35 found occasionally and associated with high-grade intraepithelial neoplasia. Symptoms: • Usually asymptomatic • Depending on the size and anatomic location, can be painful or pruritic. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY Epidemiological studies show genital warts to be the most common sexually transmitted diseases. The population-based incidence of genital warts is estimated to be 106-160 cases

per 100,000 population in the west, with the highest incidence rates in young adults aged 15-25 years. Genital warts affect approximately 30 million individuals worldwide. The case load in India is estimated to be above 3 million (only extrapolated data, no well defined population based statistics available). III. DIFFERENTIAL DIAGNOSIS • Condyloma lata (syphilis) • Molluscum contagiosum • Bowenoid papulosis • Lichen planus and nitidus • Pearly penile papules 28

• Seborrhoeic keratoses • Fordyce’s spots IV. PREVENTION AND COUNSELING General measures as applicable to all patients with suspected STIs • Educate and counsel patient and sex partner(s) regarding RTIs/STIs, genital cancers, safer sex practices and importance of taking complete treatment. • Treat partner(s) for the suspected organisms. • Advise sexual abstinence during the course of treatment to minimize transmission. • Promote the use of barrier contraception like condoms, educate about correct and

consistent use. • Refer for voluntary counseling and testing for HIV, Syphilis and Hepatitis B. • Consider immunization against Hepatitis B. • Schedule return visit after 7 days to ensure treatment compliance as well as to see reports of tests done. • If symptoms persist, assess whether it is due to treatment failure or reinfection and advise prompt referral. Key counseling messages to be conveyed to all patients diagnosed with HPV infection:

• Genital HPV infection is very common and can also be spread by oral- sexual contact. • It usually has no signs or symptoms. • Mostly, clears spontaneously. Some infections do progress to genital precancers, and cancers. • The types of HPV causing genital warts are different from the ones causing anogenital cancers. • Treatments are available for the conditions caused by HPV but not for the virus itself. • Warts do not affect a woman’s fertility or ability to carry a pregnancy to term.

• Correct and consistent male condom use lowers the chances of giving or getting genital HPV does not protect fully. • To lower the chances of getting infection, limit the number of partners. HPV vaccines 29

Two types which offer protection against the HPV types 16 and 18 that cause 70% of cervical cancers. o Cervarix: bivalent vaccine against Type 16 and 18 (0.5 ml IM at 0,1 and 6 mths) o Gardasil: quadrivalent vaccine which also protects against the types 6 and 11. Three doses (0.5 ml IM at 0,2 and 6 months) Most effective when all three doses have been administered before any sexual contact. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA

*Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited Clinical Diagnosis: • Presumptive Diagnosis based on clinical examination (inspection) • History of exposure followed by signs and symptoms is contributory towards diagnosis. On examination, genital warts can be • Single or multiple • Soft or verrucous • Asymptomatic, may be painful occasionally Investigations:

• Aceto-white test: Application of 3%–5% acetic acid, which causes HPV-infected genital mucosa to turn white in color. • Biopsy: might be indicated if o the diagnosis is uncertain o the lesions do not respond to standard therapy o the disease worsens during therapy o the lesion is atypical o the patient has comprised immunity 30

o the warts are pigmented, indurated, fixed, bleeding, or ulcerated. o The lesion shows a high risk of atypia • HPV DNA testing: Not recommended on a routine basis as test results would not alter clinical management of the condition. Treatment: • Should be guided by the preference of the patient, available resources, and the experience of the health-care provider. • No definitive evidence that any of the available treatments are superior to any other

• No single treatment is ideal for all patients or all warts. • Spontaneous resolution of lesions may also occur. Recommended regimens: (NACO recommended) I. Penile and Perianal warts (external warts) 20% Podophyllin in compound tincture of benzoin II. Cervical warts o Podophyllin is contraindicated. o Biopsy of warts to rule out malignant change. o Cryo cauterization is the treatment of choice. o Cervical cytology should be periodically done in the sexual partner(s) of men with genital warts.

• The treatment modality should be changed if a patient has not improved substantially after a complete course of treatment or if side effects are severe. Alternate Regimens for External Genital Warts Self applied • Imiquimod 5% cream Provider administered • Cryotherapy: repeat application every 1-2 weeks • Trichhloroaceitic acid: weekly applications • Surgical removal: scissor excision, curettage, electrosurgery, radiosurgery 31

Alternate Regimens for Cervical Warts • Management of exophytic cervical warts should include consultation with a specialist Special situations 1. Vaginal Warts • Cryo-cuaterisation • TCA or BCA 80%–90% applied to warts. 2. Urethral Meatus Warts • Cryotherapy with liquid nitrogen • Podophyllin 10%–25% in compound tincture of benzoin. • Imiquimod use 3. Anal Warts • Cryotherapy with liquid nitrogen • TCA or BCA 80%–90% applied to warts. • Surgical removal

• Intra-anal warts should be managed in consultation with a surgical specialist for digital examination, standard anoscopy, or high-resolution anoscopy. Alternative Regimens • intralesional interferon • photodynamic therapy • topical cidofovir. Special Considerations Pregnancy • Imiquimod, podophyllin not to be used • genital warts can proliferate and become friable • Removal of warts during pregnancy can be considered, though resolution might be incomplete or poor until pregnancy is complete.

• Cesarean delivery for women with genital warts is indicated if o pelvic outlet is obstructed 32

o Vaginal delivery would result in excessive bleeding. o HPV types 6 and 11 can rarely cause respiratory papillomatosis in infants and children. Whether cesarean section can prevent this is unclear, hence this is not an absolute indication for caesarean delivery HIV Infection • more likely to develop genital warts • Lesions are more recalcitrant to treatment • Same treatment regimes to be followed, however, might not respond as well and might have more frequent recurrences after treatment

• Squamous cell carcinomas arising in or resembling genital warts are more frequent, hence biopsy for confirmation of diagnosis in suspicious cases. • Screening for anal intraepithelial neoplasia by cytology recommended in HIV-infected MSM. Squamous Cell Carcinoma in Situ • referred to a specialist for treatment • Ablative modalities usually are effective • Careful follow-up is essential Referral to specialists: Cervical Intraepithelial neoplasia Invasive cervical squamous cell carcinoma

Penile Intraepithelial Neoplasia Anal intraepithelial neoplasia or carcinoma *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available k) Clinical Diagnosis: Same as above l) Investigations: 33

Same as above m) Treatment: Same as above VI. FURTHER READING / REFERENCES 1. Garland SM, Steben M, Sings HL et al. Natural history of genital warts: analysis of the placebo arm of 2 randomized phase III trials of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine. J Infect Dis 2009;199:805–14. 2. Morbidity and Mortality weekly report. December 17, 2010 / Vol. 59 / No. RR-12. Sexually Transmitted Diseases Treatment Guidelines, 2010

3. National guidelines on prevention, management and control of reproductive tract infections including sexually transmitted infections. Ministry of Health and Family welfare, Governemnt of India, August, 2007. 4. Weiner RL, Koutsky LA. Genital Human papilloma virus infection. In Sexually Transmitted Diseases Eds: Holmes KK, Sparling PF, Stamm WE, Piot P, Wasserheit JN, Corey L, Cohen MS, Watts DH, Nelson RA. 4th Edition, 2008 McGraw-Hill, p490-508. 34

NAME OF CONDITION: Pelvic Inflammatory disease (PID) I. WHEN TO SUSPECT/ RECOGNIZE? a) Case definition: Pelvic inflammatory disease (PID) comprises a spectrum of upper genital tract inflammatory disorders among women, which includes any combination of endometritis, salpingitis, tuboovarian abscess, and pelvic peritonitis1. 1. Includes infections of the upper genital tract by microorganisms ascending from the cervix or vagina 2. Excludes blood-borne infections such as tuberculosis.

3. Also infections following delivery or induced abortion are also categorized separately as puerperal or postabortion infection. b) Introduction: Various causative organisms include 1. Sexually transmitted organisms, especially N. gonorrhoeae and C. trachomatis, 2. Microorganisms that comprise the vaginal flora (e.g., anaerobes, G. vaginalis, Haemophilus influenzae, enteric Gram-negative rods, and Streptococcus agalactiae)2.

3. Others like: Cytomegalovirus (CMV), M. hominis, U. urealyticum, and M. genitalium associated in some cases. Often more than one species from vaginal flora isolated (“polymicrobial” PID). No microorganisms are recovered from 20-30% of patients. A large number of unculturable species which are normal residents of the genital tract may have role to play. Clinical features: The presentation may be Acute or Chronic. Important clinical signs and symptoms include

• Vaginal/cervical discharge, congestion or ulcers • Menstrual irregularities like heavy irregular vaginal bleeding, dysmenorrhoea, 35

• Dyspareunia, Dysuria or tenesmus • Temperature> 39 degree C • Lower abdominal tenderness or guarding • Uterine/adnexal tenderness, cervical movement tenderness, • Presence of a pelvic mass PID can present with a vast array of clinical manifestations • Salpingitis is the most important feature of PID. • Infection and inflammation of the endometrium, blood vessels and lymphatics without visually recognized salpingitis. • None of the symptoms, clinical signs, or laboratory results are pathognomonic for PID.

About two-thirds of cases of PID are probably unrecognized.4 • Chronic PID is an even more poorly defined entity used for patients with chronic pain or infertility, caused by pelvic adhesions and other abnormalities from a prior episode Sequelae Sequelae are common. • Tubal infertility due to tubal and peritubal damage • Ectopic Pregnancy • Chronic pain and other gynecological morbidity II. INCIDENCE OF THE CONDITION IN OUR COUNTRY

The exact incidence of PID is unknown, because the disease cannot be diagnosed reliably from clinical symptoms and signs. Direct visualization of the fallopian tubes by laparoscopy is the best single diagnostic test, but it is invasive, lacks sensitivity, and is not used routinely in clinical practice. PID is the most common gynaecological reason for admission to hospital in the USA. In resource-poor countries it accounts for 17% to 40% of gynaecological admissions in sub-Saharan

Africa, 15% to 37% in Southeast Asia, and 3% to 10% in India (3). 36

III. DIFFERENTIAL DIAGNOSIS • In mild cases o Rule out various causes of vaginal discharge. • In severe cases o Rule out causes of acute abdomen, including ectopic pregnancy and acute appendicitis. o Other gynecological differentials include rupture, bleeding, or torsion of an ovarian cyst, pelvic endometriosis. o Mesenteric lymphadenitis, regional ileitis, enteritis, and other manifestations of inflammatory bowel disease. o Urinary tract infection and colic from renal or ureteral stones.

IV. PREVENTION AND COUNSELING General measures as applicable to all patients with suspected STIs • Educate and counsel patient and sex partner(s) regarding RTIs/STIs, genital cancers, safer sex practices and importance of taking complete treatment. • Treat partner(s) for the suspected organisms. • Advise sexual abstinence during the course of treatment to minimize transmission. • Promote the use of barrier contraception like condoms, educate about correct and consistent use.

• Refer for voluntary counseling and testing for HIV, Syphilis and Hepatitis B. • Consider immunization against Hepatitis B. • Schedule return visit after 7 days to ensure treatment compliance as well as to see reports of tests done. • If symptoms persist, assess whether it is due to treatment failure or reinfection and advise prompt referral. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA 37

*Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: The clinical diagnosis of acute PID is imprecise. I. The PPV of a clinical diagnosis depends on the epidemiologic characteristics of the population. It is higher among sexually active young women (particularly adolescents), patients attending STD clinics, and those who live in other settings where the rates of

gonorrhea or chlamydia are high. II. Many episodes of PID go unrecognized. Health-care providers should maintain a low threshold for the diagnosis of PID. Clinical evaluation is aimed at A. RULING OUT THE NUMEROUS DIFFERENTIALS B. ASSESSING FOR SEVERITY OF DISEASE A. RULING OUT THE NUMEROUS DIFFERENTIALS A simple stepwise algorithm for a patient presenting with abdominal signs and symptoms and vaginal discharges uggestive of Acute PID 1. Pregnancy test:

• If positive points towards Ectopic Pregnancy or other pregnancy complications. • If negative: then do wet mount or Gram stain of cervical/vaginal secretions. 2. In a Sexually active patient: presence of yellow cervical mucopus or the wet mount revealing WBC’s outnumbering the number of epithelial cells makes PID a probable diagnosis 3. USG and explorative laparoscopy to exclude appendicitis or ruptured abscess. No symptom or sign is pathognomonic of PID. All symptoms have a low positive and negative

B. ASSESSING FOR SEVERITY OF DISEASE 1. SUBCLINICAL DISEASE (ATYPICAL PID, “SILENT” PID) 2. MILD AND MODERATELY SEVERE PID 3. SEVERE PID Recommendations for diagnosing PID Empiric treatment for PID should be initiated in sexually active young women and other women at risk for STDs, • if there is pelvic or lower abdominal pain (with no other apparent cause) AND • if one or more of the following minimum criteria are present on pelvic examination: a. cervical motion tenderness OR b. uterine tenderness OR

c. adnexal tenderness. Additional criteria to enhance the specificity of the minimum criteria and support a diagnosis 1. CLINICAL • oral temperature >101° F (>38.3° C); • abnormal cervical or vaginal mucopurulent discharge (MPC) • cervical friability 2. LABORATORY • presence of abundant numbers of WBC on saline microscopy of vaginal fluid; • elevated erythrocyte sedimentation rate; • elevated C-reactive protein • laboratory documentation of cervical infection with N. gonorrhoeae or C. trachomatis.

Most specific criteria for diagnosing PID include: (NOT ROUTINELY RESORTED TO) • endometrial biopsy with histopathologic evidence of endometritis • transvaginal sonography or magnetic resonance imaging techniques showing thickened, fluid-filled tubes with or without free pelvic fluid or tubo-ovarian complex 39

• Doppler studies suggesting pelvic infection (e.g., tubal hyperemia) • Laparoscopic abnormalities consistent with PID. C. Investigations: LABORATORY TESTS • Vaginal smear demonstrating o increase in the inflammatory cells o presnec of gnid (Gram’s stain) o organism for BV or trichomoniasis • Raised ESR (>15 mm/h) • CRP: The mean CRP is 47 mg/L (range 32-63) for mild tubal abnormalities and 83 mg/L (range 65-103) for severe tubal disease. • Peripheral WBC count (>10,000 mm3)

• Laparoscopy: Gives a more accurate diagnosis of salpingitis and more complete bacte- riologic diagnosis. It has been the gold standard to diagnose PID. Criteria used to define salpingitis observed through the laparoscope include tubal erythema, swelling, and exudate. However, not practical and not justified for majority of cases when symptoms are mild or vague. • Endometrial biopsy: for the outpatient diagnosis of subclinical or silent PID.

• Pregnancy test for all potentially fertile women with acute abdominal/pelvic pain irrespective of contraception use. • Ultrasound examination: useful noninvasive test to diagnose and follow the course of severe PID. • Transvaginal ultrasound • Transvaginal power Doppler sonography • Testing for N. gonorrhoeae and C. trachomatis: for a more specific diagnosis • Microscopy and culture of urine • Culdocentesis (USG guided): Its use has become less common to diagnose PID. 40

D. Treatment: • Antimicrobial therapy is required to treat infection present in PID. • Early antibiotic treatment in the first 3 days reduces tubal infertility. • Choice of antimicrobial is empiric as collection and microbial testing of fallopian-tube specimens is not practical and reports take time in the majority of cases • Antimicrobial regimen must cover at least the most frequently expected microbes i.e N. gonorrhoeae, C. trachomatis, and common aerobic and anaerobic isolates.

• At least two drugs are recommended for syndromic treatment of PID • Treatment should be initiated as soon as the presumptive diagnosis has been made because prevention of long-term sequelae is dependent on early administration of appropriate antibiotics. Treatment Outpatient treatment In mild or moderate PID • Tab. Cefixime 400 mg orally BD for 7 days PLUS • Tab. Metronidazole 400mg orally, twice daily for 14 days PLUS • Tab Doxycycline, 100mg orally, twice a day for 2 weeks Adjunctive treatment

• Tab. Ibuprofen 400mg orally, three times a day for 3-5 days • Tab. Ranitidine 150mg orally, twice daily to prevent gastritis • Remove intra uterine device, if present, under antibiotic cover of 24-48 hours • Advise abstinence during the course of treatment and educate on correct and consistent use of condoms Follow up • Observe for 3 days, if no improvement i.e. o Fever persists 41

o No reduction in abdominal tenderness o No reduction in cervical movement, adnexal and uterine tenderness o If symptoms worsen Refer for inpatient treatment • Repeat testing of all women who have been diagnosed with chlamydia or gonorrhea is recommended 3–6 months after treatment, regardless of whether their sex partners were treated Syndrome specific guidelines for partner management • Treat all partners in past 2 months • Treat male partners for urethral discharge (Refer Guidelines)

• Advise sexual abstinence during the course of treatment • Provide condoms, educate on correct and consistent use • Refer for voluntary counseling and testing for HIV, Syphilis and Hepatitis B • Inform about the complications if left untreated and sequelae • Schedule return visit after 3 days, 7 days and 14 days to ensure compliance Prevention • Screening and treating sexually active women for chlamydia • Whether the incidence of PID can be reduced by identifying and treating women with BV is unclear

Inpatient Treatment Guidelines for the hospitalization of patients • If no response; poor response to treatment; or worsening within 48-72 hrs • Severe PID or signs of prostration, signs of peritonitis, septicaemia, nausea and vomiting, or high fever • Surgical emergencies (e.g., appendicitis) cannot be excluded; • Patient is pregnant; • Patient unable to follow or tolerate an outpatient oral regimen 42

• Tubo-ovarian abscess. Recommended Parenteral Treatment Inj. Cefotetan 2 g IV every 12 hourly (better coverage against anaerobes) OR Inj. Cefoxitin 2 g IV every 6 hour (better coverage against anaerobes) PLUS Tab. Doxycycline 100 mg orally or IV every 12 hours (Preferably orally because of pain associated with intravenous infusion) 1. Clinical experience to guide decisions regarding transition to oral therapy 2. Usually can be shifted within 24–48 hours of clinical improvement

3. Oral therapy with doxycycline (100 mg twice a day) should continue to complete 14 days of therapy. Alternative Regimes 1. Other second- or third-generation cephalosporins (e.g., ceftizoxime, cefotaxime, and ceftriaxone) WITH Doxycycline. Effective therapy for PID but are less active than cefotetan or cefoxitin against anaerobic bacteria. 2. Inj. Clindamycin 900 mg IV every 8 hours WITH Inj. Gentamicin loading dose IV or IM (2 mg/kg of body weight), followed by a maintenance dose (1.5 mg/kg) every 8 hours

Then Shift to Ongoing oral therapy with Tab. doxycycline 100 mg orally twice a day OR Tab Clindamycin 450 mg orally four times a day to complete a total of 14 days of therapy 3. Inj. Azithromycin for 1 week (500 mg IV for 1 or 2 doses followed by 250 mg orally for 5– 6 days) WITH 12-day course of metronidazole. 4. Inj. Ceftriaxone 250 mg IM in a single dose WITH Tab. Doxycycline 100 mg orally twice a day for 14 days WITH or WITHOUT Metronidazole 500 mg orally twice a day for 14 day

5. Inj. Cefoxitin 2 g IM in a single dose and Probenecid, 1 g orally administered concurrently in a single dose WITH Tab Doxycycline 100 mg orally twice a day for 14 days WITH or WITHOUT Tab Metronidazole 500 mg twice a day for 14 day • If the culture for gonorrhea is positive, treatment should be based on results of antimicrobial susceptibility. Special Considerations Pregnancy • High risk for maternal morbidity and preterm delivery

• Suspected PID should be hospitalized, treated with parenteral antibiotics. • Doxycycline is contraindicated in pregnancy. • Metronidazole is not recommended during the first three months. However, not to be withheld for a severely acute PID, which represents an emergency. HIV Infection • Standard parenteral and oral antibiotic regimens • Microbes like M. hominis, candida, streptococcus apart from HPV infections and related cytologic abnormalities may be associated. Intrauterine Contraceptive Devices

• Risk for PID confined to the first 3 weeks after insertion • Insufficient evidence to recommend removal of IUDs in women with acute PID. • Caution to be exercised if the IUD remains in place, close clinical follow-up is mandatory. Referral criteria: • The diagnosis is uncertain • Surgical emergencies e.g. appendicitis or ectopic pregnancy cannot be excluded • A pelvic abscess is suspected 44

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available Clinical Diagnosis: Same as above Investigations: Same as above Plus 1. Cervical secretion or urine can be tested with NAAT (for N. gonorrhoeae or C. trachomatis): a positive test for either strongly increases the probability of PID. 2. Newer diagnostic techniques, such as PCR and antigen detection assays Treatment: Same as above PLUS For Tubo-Ovarian Abscess

• At least 24 hours of direct inpatient observation is recommended. • Initial parenteral therapy with Inj. Ampicillin/Sulbactam 3 g IV every 6 hour WITH Tab Doxycycline 100 mg orally or IV every 12 hour OR • Ampicillin/sulbactam plus doxycycline is effective against C. trachomatis, N. gonorrhoeae, and anaerobes in women with tubo-ovarian abscess. • Clindamycin should be continued for oral therapy rather than doxycycline, because clindamycin provides more effective anaerobic coverage.

c. Day Care VI. FURTHER READING / REFERENCES 1. Wiesenfeld HC, Sweet RL, Ness RB, et al. Comparison of acute and subclinical pelvic inflammatory disease. Sex Transm Dis 2005;32:400–5. 2. Ness RB, Kip KE, Hillier SL, et al. A cluster analysis of bacterial vaginosis-associated microflora and pelvic inflammatory disease. Am J Epidemiol 2005;162:585–90. 3. http://bestpractice.bmj.com/best-practice/evidence/background/1606.html 4. Morbidity and Mortality weekly report. December 17, 2010 / Vol. 59 / No. RR-12.

Sexually Transmitted Diseases Treatment Guidelines, 2010 5. National guidelines on prevention, management and control of reproductive tract infections including sexually transmitted infections. Ministry of Health and Family welfare, Governemnt of India, August, 2007. 6. Paavonen J, Westrõm L, Eschenbach D. Pelvic inflammatory disease. In Sexually Transmitted Diseases Eds: Holmes KK, Sparling PF, Stamm WE, Piot P, Wasserheit JN, Corey L, Cohen MS, Watts DH, Nelson RA. 4th Edition, 2008 McGraw-Hill, p 1018-

NAME OF CONDITION: Urethritis (Urethral discharge) in males I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Urethritis, manifested by urethral discharge, dysuria, or itching at the end of the urethra, is the response of the urethra to inflammation of any etiology. It is generally due to infection of the urethral mucosa with organisms (predominantly sexually transmitted, few cases non- sexually transmitted). Symptoms, if present, include discharge of mucopurulent or purulent

material, dysuria, or urethral pruritus. Asymptomatic infections are also common. b) Case definition: The characteristic physical finding is urethral discharge, and the pathognomonic confirmatory laboratory finding is an increased number of polymorphonuclear leukocytes (PMNL) on Gram stain of a urethral smear or in the sediment of the first-voided urine. c) Causative organisms: Urethritis can be • Gonococcal, or gonorrhea, when Neisseria gonorrhoeae is detected

within the PMNL (may frequently be accompanied by chlamydial infections). Gonorrhoea is the second most commonly reported STI. • Nongonococcal if N. gonorrhoeae cannot be detected in the PMNL. The term nongonococcal urethritis (NGU) has many causes and in most cases no pathogen can be detected. These include o Chlamydia trachomatis o Mycoplasma genitaliu o T. vaginalis o HSV o Adenovirus o Ureaplasma urealyticum o Enteric bacteria

NGU occurring soon after curative therapy for urethral gonorrhea is called Postgonococcal Urethritis (PGU). 47

II. INCIDENCE OF THE CONDITION IN OUR COUNTRY: Among the cases of urethritis presenting to STD clinics, the incidence of gonococcal urethritis is close to 65% and that of Non gonococcal Urethritis (NGU) is 35%. The common organisms causing NGU were chlamydia (28%) ureaplasma (11%) and mycoplasma (11%)[Ref 1]. III. DIFFERENTIAL DIAGNOSIS: Other causes of urethritis or urethral discharge which may not be sexually transmitted include

• Bacterial urethritis occurring in association with urinary tract infection, bacterial prostatitis, urethral stricture, phimosis, and secondary to catheterization or other instrumentation of the urethra. • Urethritis with congenital abnormalities, chemical irritation, and tumors. • Allergic etiology • Stevens-Johnson syndrome may produce urethritis Complications: • NGU among males infected with C. trachomatis include epididymitis and Reiter’s syndrome. • GU- The following complications may arise

Complicated Gonococcal infection: Involves infection of urinary tract above the anterior urethra o posterior ureththritis, periurethral abscess o infection of Cowper’s/ Tyson’s glands o urethral stricture o prostatitis, epididymo-orchitis o corneal perforation, blindness o DGI (arthritis-dermatitis syndrome) Disseminated Gonococcal Infection (DGI) • Petechial or pustular acral skin lesions, asymmetrical arthralgia, tenosynovitis, or septic arthritis.

b) Complicated occasionally by perihepatitis and rarely by endocarditis or meningitis. c) Some strains of N. gonorrhoeae that cause DGI can cause minimal genital inflammation. IV. PREVENTION AND COUNSELING: General measures as applicable to all patients with suspected STIs • Educate and counsel patient and sex partner(s) regarding RTIs/STIs, genital cancers, safer sex practices and importance of taking complete treatment. • Treat partner(s) for the suspected organisms. 48

• Advise sexual abstinence during the course of treatment to minimize transmission. • Promote the use of barrier contraception like condoms, educate about correct and consistent use. • Refer for voluntary counseling and testing for HIV, Syphilis and Hepatitis B. • Consider immunization against Hepatitis B. • Schedule return visit after 7 days to ensure treatment compliance as well as to see reports of tests done. • If symptoms persist, assess whether it is due to treatment failure or reinfection and

advise prompt referral. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited Clinical Diagnosis: Based on clinical examination of the amount, character and color of discharge. • Urethral discharge should first be objectively documented. • If not visible on initial examination, an attempt should be made to strip or milk the

urethra from proximal to distal to elicit the discharge. • If discharge still not detected, the patient should be examined the next morning, after not voiding overnight, to enhance the likelihood of reaching a firm diagnosis. The quantity of discharge categorized as - profuse (spontaneously flowing from the urethra), - scant (apparent only after stripping the urethra), - intermediate (between profuse and scant). The color or character to be noted.

- A yellowish color (most common) or greenish color (seen only occasionally) can be described as “purulent.” - A grey or white discharge often mixed with clear fluid should be labeled “mucoid” or “mixed.” - The third category is “clear.” The presence or absence of meatitis, penile edema and enlarged inguinal lymph node should be determined. 49

Investigations: I. To validate the inflammatory nature of urethral discharge and to differentiate between GU and NGU. • Gram stain of urethral secretions demonstrating ≥5 WBC per oil immersion field. • Positive leukocyte esterase test on first-void urine • Microscopic examination of first-void urine sediment demonstrating ≥10 WBC per high-power field. Gram stain, preferred rapid diagnostic test for evaluating urethritis • Highly sensitive and specific in males

• Nongonoccocal urethritis (NGU): microscopy indicates inflammation without GNID. • GU- High specificity (>99%) and sensitivity (>95%) for infection with N. gonorrhoeae in symptomatic men. II. For complicated GU or DGI • Haematological and Biochemical tests (to rule out systemic involvement) • Echocardiography Treatment: Standard Operating procedure As dual infection is common and cannot be ruled out with reasonable certainty, the

treatment for urethral discharge should adequately cover therapy for both, gonorrhea and chlamydial infections (Ref 5). • Treatment should be initiated as soon as possible after diagnosis. • Single-dose regimens advantageous: improve compliance, can be directly observed. • Treatment is mostly on an outpatient basis. Only cases with complicated gonococcal infections or disseminated gonococcal infections would require inpatient care. A. Outpatient care

Recommended regimen for uncomplicated gonorrhea + chlamydia Uncomplicated infections (disease limited to the anogenital region (anterior urethra or rectum). - Tab. Cefixime 400 mg orally, single dose Plus 50

- Tab Azithromycin 1 gram orally single dose under supervision • Advise the patient to follow up after 7 days of start of therapy • To minimize transmission, abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7-day regimen • To minimize reinfection, abstain from sexual intercourse until all sex partners are treated. • All partners in the past 60 days before the initial diagnosis and any interim partners should be referred for evaluation and appropriate treatment.

Alternative drugs • Ceftriaxone (single injection of 250 mg) • Preferred in cases with oral sexual exposure (efficacy in treating pharyngeal infection) • As of April 2007, quinolones no longer recommended for the treatment of gonorrhea and associated conditions, such as PID (Ref 6). Follow up After seven days - To see reports of tests done for HIV, syphilis and Hepatitis B - If symptoms persist, to assess whether it is due to treatment failure or reinfection - For prompt referral if required

- Test of cure is not recommended unless therapeutic noncompliance or reinfection is suspected. When symptoms persist or recur after adequate treatment for gonorrhea and chlamydia or If discharge or only dysuria persists after 7 days • Reassess compliance and re-exposure: Retreatment with the initial regimen if not ensured • Treatment completed but persistent symptoms and no objective signs of urethritis: only urinary alkalinisers, no extension of antimicrobial therapy.

• Persistent urethritis (objectively assessed): treat with T. doxycycline (100 mg bd for 7 days) • Persistent urethritis (objectively assessed) after treatment with Doxycycline: might be caused by o doxycycline-resistant U. urealyticum or M. genitalium- treat with flouroquinolone (Ofloxacin) or macrolides (erythromycin). o T. vaginalis 51

o Prostatic infection • Investigate these cases with culture or NAAT (PCR or TMA) on a urethral swab, first void urine or semen. • Recommended regime while awaiting the results. Recommended Regimens • Metronidazole 2 g orally in a single dose OR • Tinidazole 2 g orally in a single dose PLUS • Azithromycin 1 g orally in a single dose (if not used for initial episode) • Index patient and partner(s), should be treated for Trichomonas vaginalis with Tab.

Secnidazole 2gm orally, single dose (to treat for T. vaginalis) Persistence of chronic prostatitis/chronic pelvic pain syndrome o Persistent pain (perineal, penile, or pelvic), discomfort, irritative voiding symptoms, pain during or after ejaculation, or new-onset premature ejaculation lasting for >3 months. o A four-glass test to localize pathogens to the prostate. o Referral to urologist should be considered. Providers should be alert to the possibility of in male patients experiencing

Alternative treatments for NGU • Erythromycin base 500 mg orally four times a day for 7 days OR • Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days OR • Levofloxacin 500 mg orally once daily for 7 days OR • Ofloxacin 300 mg orally twice a day for 7 days Syndrome specific guidelines for partner management • Partner management recommended for all males regardless of any specific etiology as substantial number of female partners are affected.

• All sex partners within the preceding 60 days should be referred for evaluation, testing, and empiric treatment • Treat female partners on same lines after ruling out pregnancy and history of allergies 52

Management of pregnant partner - Pregnant partners of male clients with urethral discharge should be examined by doing a per speculum as well as per vaginal examination - Should be treated for gonococcal as well as chlamydial infections (Refer guidelines for cervicitis). - Cephalosporins to cover gonococcal infection are safe and effective in pregnancy - Recommended treatment regime o Tab. Cefixime 400mg orally, single dose OR o Ceftriaxone 125mg by intramuscular injection PLUS

o Tab. Erythromycin 500mg orally four times a day for seven days OR o Cap Amoxicillin 500mg orally, three times a day for seven days to cover chlamydial infection Special Considerations HIV Infection • Urethritis might facilitate HIV transmission. • Same treatment regimen to be followed. B. In Patient care Required for • few cases of complicated gonococcal urethritis needing intravenous cephalosporins • disseminated gonococcal infection Treatment

For complicated urethritis or Disseminated Gonococcal infection d) Hospitalization is recommended for initial therapy of DGI, especially for patients who might not comply, in whom diagnosis is uncertain, for those who have purulent synovial effusions or other complications. e) Examination for clinical evidence of endocarditis and meningitis should be performed. f) Persons treated for DGI should be treated presumptively for concurrent C. trachomatis infection. 53

Complicated / Disseminated infection o Initial therapy: (Step1) - Ceftriaxone 1 g IM or IV 24 hourly - Cefotaxime 1 g IV 8 hourly o Continue for seven days, may switch 24–48 hours after symptoms improve to (Step 2) - Cefixime 400 mg twice daily Ophthalmia neonatorum o Ceftriaxone 25–50 mg/kg (1gm) IV or IM as a single dose o Cefotaxime 100 mg/kg IM as a single dose o Frequent conjunctival irrigation with saline. • Regimen to be continued for 24–48 hours after improvement begins

• Switched to cefixime 400 mg orally twice daily to complete at least 1 week of antimicrobial therapy. Management of Sex Partners • Partners are frequently asymptomatic • All partners to be treated as per urethritis guidelines Gonococcal Meningitis and Endocarditis Recommended Regimen Ceftriaxone 1–2 g IV every 12 hours Referral to a higher centre required for cultures, inpatient treatment and monitoring Referral criteria: Refer to higher centre

• If the symptoms still persists after treatment step 1 and 2 and adequate partner treatment. *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available Clinical Diagnosis 54

As in Situation 1 Investigations: Steps as being followed in Situation 1 above In addition Other tests depending on availability: (not widely available) • Culture for gonococcus and chlamydiae • Nucleic acid hybridization tests and NAATs for detection of genitourinary infection with N. gonorrhoeae Treatment: Same as above for uncomplicated infection of urethra. VI. WHO DOES WHAT? and TIMELINES a. Doctors:  Dermatologist - History including detailed sexual history - Examination

- Collection of specimen/s, preparation of smears - Prescription of drugs according to requirement - Follow up - Counseling - Determining the need for hospitalization - Managing patients in intensive care units  Intensivist: - Monitoring patient with complications or disseminated disease.  Microbiologist: - Reporting of smears and cultures b. Nurse: - Assisting in examination - Collection of blood samples - Nursing care of patient in intensive care unit c. Technician: - Laboratory processing of specimens

d. Counselor: - Counseling the patient about safe sex practices - Voluntary testing of HIV - Promotion of barrier methods - Encouraging partner notification and adequate treatment VII. FURTHER READING / REFERENCES 1. Gupta CM, Sanghi S, Sayal SK, Das AL, Prasad GK. Clinical and bacteriological study of urethral discharge. Indian J Dermatol Venereol Leprol 2001;67:185-7 2. Morbidity and Mortality weekly report. December 17, 2010 / Vol. 59 / No. RR-

12. Sexually Transmitted Diseases Treatment Guidelines, 2010 3. National guidelines on prevention, management and control of reproductive tract infections including sexually transmitted infections. Ministry of Health and Family welfare, Governemnt of India, August, 2007. 4. Martin DH. Urethritis in males. In Sexually Transmitted Diseases Eds: Holmes KK, Sparling PF, Stamm WE, Piot P, Wasserheit JN, Corey L, Cohen MS, Watts DH, Nelson RA. 4th Edition, 2008 McGraw-Hill, p1108-1126.

5. Lyss SB, Kamb ML, Peterman TA, et al. Chlamydia trachomatis among patients infected with and treated for Neisseria gonorrhoeae in sexually transmitted disease clinics in the United States. Ann Intern Med 2003;139:178–85. 6. CDC. Update to CDC’s sexually transmitted diseases treatment guidelines, 2006: fluoroquinolones no longer recommended for treatment of gonococcal infections. MMWR 2007;56:332–6. 56

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 1 Dermatologist Urethral smear for Tab. Cefixime 400 Slides 1Microbiologist Gram’s stain mg orally, single Disposable 1 Nurse First voided urine for dose urethral swabs 1 Technician leukocyte esterase Plus Gloves

1 Counselor First voided urine for Tab Azithromycin 1 Staining material preparation of urinary gram orally single Microscope sediment, staining dose under and examination supervision 2 1 Dermatologist As for situation 1 As per situation 1 As per situation 1 1Microbiologist plus plus plus 1 Intensivist Culture for Injectable Paraphernalia for 1 Nurse gonococcus and Ceftriaxone or intensive care 1 Technician chlamydiae (if Cefotaxime 1 Counselor available) Specific NAAT 57

NAME OF CONDITION: abnormal Vaginal discharge (abnormal) I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Vaginal discharge is a fluid produced by glands in the vaginal wall and cervix that drains from the opening of the vagina. The amount and appearance of normal vaginal discharge varies throughout the menstrual cycle. An increased quantity of discharge from the vaginal orifice accompanied by discomfort, pain, itching or malodor for which the patient seeks treatment

characterizes abnormal vaginal discharge. A large number of cases may also be asymptomatic or may have only minimal symptoms. b) Causative organisms The three diseases most frequently associated with vaginal discharge are 1. Bacterial Vaginosis: It is the most prevalent cause of vaginal discharge or malodor, however most women with BV were asymptomatic1. 2. Trichomoniasis: 3. Vulvo-vaginal candidiasis: a. Uncomplicated VVC which includes cases with sporadic or infrequent

vulvovaginal candidiasis, mild-to-moderate symptoms, likely to be due to C. albicans or in non-immunocompromised women. b. Complicated VVC which includes cases with recurrent vulvovaginal candidiasis, severe symptoms, non-albicans candidiasis or in women with uncontrolled diabetes, debilitation, or immunosuppression. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY Most women will have a vaginal infection, characterized by discharge, itching, or odor, during

their lifetime. The exact population prevalence or incidence is not clearly delineated as majority of patients do not seek any treatment. Many patients use over the counter medications as well as alternative medicines and never report to STD clinics. III. DIFFERENTIAL DIAGNOSIS While assessing a patient with vaginal discharge, one needs to rule out 58

1. Cervicitis 2. Pelvic inflammatory disease 3. Gynecological causes like fistulas, prolapse etc 4. Obstetric causes 5. Mechanical, chemical, allergic, or other noninfectious irritation of the vulva IV. PREVENTION AND COUNSELING General measures as applicable to all patients with suspected STIs • Educate and counsel patient and sex partner(s) regarding RTIs/STIs, genital cancers, safer sex practices and importance of taking complete treatment. • Treat partner(s) for the suspected organisms.

advise prompt referral. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited Clinical Diagnosis: A careful history, examination, and laboratory testing are warranted to determine the etiology 59

HISTORY should include Information on sexual behavior and practices, menstrual cycles, vaginal hygiene practices (such as douching), and other medications. EXAMINATION to assess colour, odour, amount (profuse or scanty), character (curdy or thin) of the discharge, associated vulvar abrasions or erosions, urethral meatal discharge and presence or absence of foreign body or IUD thread Speculum examination can reveal o White, homogenous discharge, uniformly adherent to vaginal walls with redness

of the vaginal walls suggests BV o White, curdlike discharge seen in candidiasis o Greenish, frothy discharge seen in trichomoniasis. May also cause strawberry appearance of the cervix. Investigations: • Vaginal discharge pH • Potassium hydroxide (KOH) test • Wet mount • Gram stain (considered the gold standard laboratory method for diagnosing BV) • Culture for yeast- For women with negative wet mounts who are symptomatic.

Identifying Candida by culture in the absence of symptoms or signs is not an indication for treatment Treatment: • Treatment is recommended for symptomatic women to relieve vaginal signs/ symptoms • Other potential benefits are reduction in the risk of cervicitis causing organisms, HIV and other viral STDs. If there is Vaginitis (TV+BV+Candida) • Tab. Secnidazole 2gm orally, single dose (Tab. Metoclopropramide taken 30 minutes before to prevent gastric intolerance) OR

• Tab Fluconazole 150mg orally single dose OR • Clotrimazole 500mg vaginal pessaries once If Cervicitis • refer to relevant guidelines If vaginitis and cervicitis both • treat for both Also • Schedule return visit after 7 days • Instruct client to avoid douching • Pregnancy, diabetes, HIV may also be influencing factors (to be considered in recurrent infections) Management of Sex Partners • Routine treatment of sex partners is not recommended in cases with VVC or BV.

• Treat current partner only if no improvement after initial treatment • If partner is symptomatic, treat patient and partner using above protocols • Advise sexual abstinence during the course of treatment • Provide condoms, educate about correct and consistent us • Partners of patients with T. vaginalis should be treated with either tinidazole in a single dose of 2 g orally or metronidazole twice a day at 500 mg orally for 7 days.

• For patients with VVC a minority of male sex partners might have balanitis and benefit from treatment with topical antifungal agents Alternative regimes For TV or BV (ANY ONE) • Metronidazole 2 g orally in a single dose • Metronidazole 500 mg orally twice a day for 7 days • Tinidazole 2 g orally once daily for 3 days • Tinidazole 1 g orally once daily for 5 days 61

• Clindamycin 300 mg orally twice daily for 7 days For VVC (ANY ONE) • Miconazole 2% cream 5 g intravaginally for 7 days • Clotrimazole 1% cream 5 g intravaginally for 7–14 days Special Considerations Complicated VVC A. Recurrent Vulvovaginal Candidiasis (RVVC): characterized by four or more episodes of symptomatic VVC in 1 year. Mostly there are no apparent predisposing or underlying conditions. For management • Investigations: Obtain vaginal cultures

• Treatment: To maintain clinical and mycologic control Initial therapy- longer duration of recommended therapy to attempt mycologic remission o 7–14 days of topical therapy o 100-mg, 150-mg, or 200-mg oral dose of fluconazole every third day for a total of 3 doses [day 1, 4, and 7] Maintenance Regime o Oral fluconazole 100-mg, 150-mg, or 200-mg dose weekly for 6 months o susceptibility testing is not recommended B. Severe VVC: Characterised by extensive vulvar erythema, edema, excoriation, and

fissure formation. Patients treated with short courses of topical or oral therapy are associated with lower clinical response rates in. • Treatment with o 7–14 days of topical azole OR 62

o 150 mg of fluconazole in two sequential doses (second dose 72 hours after initial dose) C. Nonalbicans VVC: Optimal treatment options remain unknown. • Treatment options o longer duration of therapy with a non fluconazole azole drug (oral or topical) as first-line therapy. o If recurrence occurs, 600 mg of boric acid in a gelatin capsule administered vaginally once daily for 2 weeks. D. Compromised Host: Includes women with underlying debilitating conditions who do not respond as well • Treatment

o Correct modifiable conditions o Prolonged (i.e., 7–14 days) conventional antimycotic treatment Pregnancy Recommended Regimens for Pregnant Women In first trimester of pregnancy • Local treatment with Clotrimazole vaginal pessary/cream only for candidiasis. • Oral Flucanozole is contraindicated in pregnancy. • Metronidazole pessaries or cream intravaginally if trichomoniasis or BV is suspected. In second and third trimester

• oral metronidazole can be given (500 mg orally twice a day for 7 days OR 250 mg orally three times a day for 7 days) OR • Tab. Secnidazole 2gm orally, single dose OR • Tab. Tinidazole 500mg orally, twice daily for 5 days 63

HIV Infection • HIV-positive women- screening for trichomoniasis at entry into care with subsequent screening at least annually is recommended based • Rescreening 3 months after completion of therapy should be considered among HIV- positive women with trichomoniasis • Multidose treatment regimen to be considered in HIV-infected women, single doses not effective • Therapy for VVC in HIV-infected women remains same • Long-term prophylactic therapy with fluconazole (200 mg weekly) recommended for

recurrent VVC with HIV. • Occurrence of RVVC should not be considered an indication for HIV testing Referral criteria: Treatment failure (after excluding reinfection and resistance) *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available n) Clinical Diagnosis: Same as above o) Investigations: Same as above In addition, following tests can be done if available • For TV a. Culture for T. vaginalis- sensitive and highly specific commercially available

method of diagnosis. b. NAAT c. Nucleic acid probe test to evaluates for T. vaginalis, G. vaginalis, and C. albicans. • For BV 64

a. DNA probe-based test for high concentrations of G. vaginalis b. PCR- used in research settings for detection of a variety of organisms associated with BV. Clinical utility is uncertain. c. Culture of G. vaginalis not recommended as a diagnostic tool • For other causes a. PCR assay for detection of gonorrhea and chlamydial infection, also tests for T. vaginalis p) Treatment: Same as above VI. FURTHER READING / REFERENCES 7. Koumans EH, Sternberg M, Bruce C, et al. The prevalence of bacterial

vaginosis in the United States, 2001–2004: associations with symptoms, sexual behaviors, and reproductive health. Sex Transm Dis 2007;34:864–9. 8. Morbidity and Mortality weekly report. December 17, 2010 / Vol. 59 / No. RR- 12. Sexually Transmitted Diseases Treatment Guidelines, 2010 9. National guidelines on prevention, management and control of reproductive tract infections including sexually transmitted infections. Ministry of Health and Family welfare, Governemnt of India, August, 2007.

10. Holmes KK, Stamm WE, Sobel JD. Lower genital tract infection syndromes in women. In Sexually Transmitted Diseases Eds: Holmes KK, Sparling PF, Stamm WE, Piot P, Wasserheit JN, Corey L, Cohen MS, Watts DH, Nelson RA. 4th Edition, 2008 McGraw-Hill, p 987-1016. 65

STANDARD TREATMENT GUIDELINES PEDIATRICS & PEDIATRIC SURGERY Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 PROTOCOL FOR DENGUE FEVER IN CHILDREN 4 2 EMPYEMA THORACIS 17 3 INGUINAL HERNIA IN CHILDREN 36 4 NEONATAL CHOLESTASIS 45 5 Urinary tract infection and vesico ureteric reflux 62 6 NEONATAL JAUNDICE: UNCONJUGATED HYPERBILIRUBINEMIA 69 7 NEONATAL INTESTINAL OBSTRUCTION 87 8 PROTOCOL FOR NEONATAL SEIZURES 97 9 UNDESCENDED TESTIS IN CHILDREN 114 2

Group Head Coordinator of Development Team Dr Ashley J D'cruz Narayana Hurdayalaya Bangalore 3

PROTOCOL FOR DENGUE FEVER IN CHILDREN Dr.Supraja Chandrashekar and Dr.Rajiv Aggarwal Department of Pediatrics, Narayana Hrudayalaya, Bangalore. Dengue Fever 1 Introduction Dengue has a wide spectrum of clinical presentations, often with unpredictable clinical evolution and outcome. Reported case fatality rates are approximately 1%, but in India, Indonesia and Myanmar, focal outbreaks away from the urban areas have reported case- fatality rates of 3-5%. 2 Classification and Case definition

The Newer WHO Classification of Dengue is practical from the management perspective and involves 2 categories- Dengue and Severe Dengue [including both the previously classified categories Dengue Shock Syndrome and Dengue Haemorrhagic fever]1 Case definition of Dengue fever (DF) (1,2): Dengue fever is an acute febrile illness with one or more of the following:- Headache, retrorbital pain, myalgia, arthralgia, rash, hemorrhagic manifestations, and leukopenia and lab confirmation by ELISA.

Case Definition of Severe Dengue Severe dengue should be considered if the patient is from an area of dengue risk presenting with fever of 2–7 days plus any of the following features: • There is evidence of plasma leakage, such as: 4

– high or progressively rising haematocrit; – pleural effusions or ascites; – circulatory compromise or shock (tachycardia, cold and clammy extremities, capillary refill time greater than three seconds, weak or undetectable pulse, narrow pulse pressure or, in late shock, unrecordable blood pressure). • There is significant bleeding. • There is an altered level of consciousness (lethargy or restlessness, coma, convulsions). • There is severe gastrointestinal involvement (persistent vomiting, increasing or

intense abdominal pain, jaundice). • There is severe organ impairment (acute liver failure, acute renal failure, encephalopathy or encephalitis, ARDS or other unusual manifestations. ) Warning Signs in Dengue Fever * • Abdominal pain or tenderness • Persistent vomiting • Clinical fluid accumulation • Mucosal bleed • Lethargy, restlessness • Liver enlargement >2 cm • Laboratory: increase in HCT concurrent with rapid decrease in platelet count *(requiring strict observation and medical intervention)

3 Differential diagnosis Conditions that mimic the febrile phase of dengue infection • Influenza, • Measles, • Chikungunya, • Infectious • Mononucleosis , • HIV Seroconversion Illness • Rubella, • Scarlet Fever, • Meningococcal infection, • Drug reaction • Enteric infections • Meningo/encephalitis • Febrile seizures Conditions that mimic the critical phase of dengue infection • Acute gastroenteritis, 5

• Malaria, • Leptospirosis, • Typhoid, • Typhus, • Viral hepatitis, • Acute HIV, seroconversion illness, • Bacterial sepsis, septic shock • Malignancies Acute leukaemia and other malignancies 4 Investigations Situation 1 Diagnostic Methods Test Advantage Disadvantage Antigen Detection • Easy to perform • Not as sensitive as above [NS-1] • Early detection IgM assay • Less expensive • May miss secondary infection due • Easy to perform to undetectable IgM • Useful in outbreaks • Useful only after 5 days

• Cross reactivity Supportive Tests • Complete Blood Count-Hemoglobin, haematocrit, White Cell Count, Platelet count. • Blood grouping and Cross Matching. • Peripheral smear: Indicates the type of anemia and confirms leukopenia The presence of giant platelets and clumps is indicative of good platelet function • Serum electrolytes, Urea, Creatinine, Random Blood Sugar • Liver and renal function tests. • Chest X Ray 5 Treatment Situation 1 6

Out Patient Management Simple Dengue Fever with no warning signs, adequate oral intake and clinically well. Home Care Advice • Adequate rest • Adequate fluid intake - Milk, fruit juice, electrolyte solution (ORS) and barley/rice water. • Paracetamol [ Acetylsalicylic acid, Mefenemic acid, ibuprofen or other non- steroidal anti-inflammatory agents (NSAIDs) and steroids to be avoided.] • Tepid sponging • To look for mosquito breeding places in and around the home and eliminate them

• Antibiotics are not necessary. To observe for the following Danger signs and report immediately for hospital admission • Bleeding: - red spots or patches on the skin - bleeding from nose or gums - vomiting blood - black-coloured stools - heavy menstruation/vaginal bleeding • Frequent vomiting • Severe abdominal pain • Drowsiness, mental confusion or seizures • Pale, cold or clammy hands and feet • Difficulty in breathing Out -patient laboratory monitoring- as indicated • Haematocrit • White cell count

• Platelet count Admission Criteria to Secondary Centre • Child having high fever, poor oral intake, or any danger signs as enumerated above. • If platelet count < 100,000 /cu.mm or rapidly decreasing trend. • If haematocrit is rising trend. 7

• Special Social Circumstances (living far from a health facility without reliable means of transport). Admission Criteria to Tertiary Centre directly from OPD • If signs of severe dengue or warning signs. • If < 50,000/cu.mm to refer to Tertiary facility • If Dengue fever is present with other co-morbidities Management • Encourage oral fluids. If not tolerated, start intravenous isotonic fluid therapy with or without dextrose at maintenance. Give only isotonic

solutions.[ see annexure 1] Start with 5 ml/kg/hour for 1–2 hours, then reduce by 2ml/kg/hour every 2 hours till 2ml/kg/hr provided there is clinical improvement and haematocrit is appropriately improving. IV fluids are usually required for 1-2 days. • Reassess the clinical status and repeat the haematocrit after 2 hours. If the haematocrit remains the same, continue with the same rate for another 2–4 hours and reassess. If the vital signs/haematocrit is worsening increase the

fluid rate and refer immediately. • Switch to oral as soon as tolerated, total fluid therapy usually 24-48 hrs, titrated to adequate urine output. Tests for Monitoring: Frequent recording of vital signs and investigation are essential for evaluating the results of treatment. • Temperature, Pulse, blood pressure and respiration should be recorded every hour (or more often) until stable subsequently 2 hourly. • An hourly fluid balance sheet should be kept, recording the type of

fluid and the rate and volume of its administration in order to evaluate the adequacy of fluid replacement. • Chest X-ray, ultrasound abdomen, electrolytes 12-24 hrly as when clinically indicated 8

Referral Criteria • All patients with Warning signs and signs of Severe dengue. • Patients not clinically responding to therapy in situation. • Patients with serious co-morbid conditions • Platelet counts < 50,000/cu.mm with a decreasing trend. Situation 2 Diagnostic Tests As in situation 1 in addition the following tests may be useful - Test Advantage Disadvantage PCR • Sensitive • Expensive • Rapid turn around IgM/IgG ratio • Can differentiate between • No standardisation primariy and secondary dengue

Supportive Tests As in Situation1 and in addition- • Blood gases. • Coagulation studies • Ultrasound • CT scan • ECHO Admission Criteria  Same as in Situation 1 in addition  All patients fulfilling referral criteria form secondary care centres presenting directly or referred. 9

Pre requisites for management • Paediatric Intensive care facilities should be available. Management: • Obtain a reference haematocrit before fluid therapy. Give only isotonic solutions. Start with 5–7 ml/kg/hour for 1–2 hours, then reduce to 3–5 ml/kg/hr for 2–4 hours, and then reduce to 2–3 ml/kg/hr or less according to the clinical response. • Reassess the clinical status and repeat the haematocrit. If the haematocrit remains the same or rises only minimally, continue with the same rate (2–3

ml/kg/hr) for another 2–4 hours. If the vital signs are worsening and haematocrit is rising rapidly, increase the rate to 5–10 ml/kg/hour for 1–2 hours. Reassess the clinical status, repeat the haematocrit and review fluid infusion rates accordingly. • Give the minimum intravenous fluid volume required to maintain good perfusion and urine output of about 0.5 ml/kg/hr. Intravenous fluids are usually needed for only 24–48 hours. Reduce intravenous fluids gradually

when the rate of plasma leakage decreases towards the end of the critical phase. This is indicated by urine output and/or oral fluid intake that is/are adequate, or haematocrit decreasing below the baseline value in a stable patient. • Patients with warning signs should be monitored by health care providers until the period of risk is over. • Supportive Management- antipyretics, empirical antibiotics as clinically indicated. Monitoring as follows-

• A detailed fluid balance should be maintained. Parameters that should be monitored include hourly vital signs and peripheral perfusion. (Until the patient is out of the critical phase), urine output (hourly). • Arterial blood pressure monitoring and central venous pressure monitoring ideal for all children in shock who are fluid unresponsive. Arterial blood gas monitoring as clinically indicated. Infusion pump will help in precise regulation of fluid input.

• Haematocrit (before and after fluid replacement/change, Hourly to 2nd hourly haematocrit for first 6 hours , decreasing frequency as patient improves ), Platelet counts 12 hourly blood glucose, and other organ functions (such as renal profile, liver profile, coagulation profile, as indicated). • Chest x-ray –Effusions, pulmonary edema 10

• Echocardiogram for assessment of left ventricular function, dimensions and • regional wall dyskinesia • ECG to exclude arrhythmia; Treatment of Shock- See flow chart 1 Treatment of haemorrhagic complications • A drop in haematocrit with no clinical improvement despite adequate fluid administration indicates significant internal bleeding. Internal bleeding is difficult to recognize in the presence of haemo-concentration. First correct the

component of shock according to standard guidelines with early use of packed cell transfusion. Component transfusion is indicated in cases with significant clinical bleeding. • The results of hematological tests (PT, APTT) may be studied to document the severity of DIC Transfusion of cryoprecipitate and or fresh frozen plasma should be considered in cases of DIC with bleeds. • Indications for platelet transfusion • Shock, acidosis with rapidly declining platelets ( greatest risk of DIC)

• Significant mucosal bleeds (harbinger of intracranial hemorrhage) • Platelet count < 20,000 cu mm in the acute phase • Need for invasive procedures such as central lines maintain platelet count > 50,000 cu mm • A low platelet count is less significant after recovery from shock and may not need to be transfused. Treatment of Fluid overload Fluid overload with large pleural effusions and ascites is a common cause of acute respiratory distress and failure in severe dengue. Other causes of respiratory

distress include acute pulmonary oedema, severe metabolic acidosis from severe shock, and Acute Respiratory Distress Syndrome (ARDS) Prevention of fluid overload 11

• When the following signs are present, resuscitation intravenous fluids should be discontinued or reduced to the minimum rate necessary to maintain euglycaemia: – signs of cessation of plasma leakage; – stable blood pressure, pulse and peripheral perfusion; – haematocrit decreases in the presence of a good pulse volume; – afebrile for more than 24–48 days (without the use of antipyretics); – resolving bowel/abdominal symptoms; – improving urine output.

• Aim for a minimum acceptable urine output [ 0.5ml/kg/hr] to titrate fluids. • Maintain intravascular volume by using colloids and maintaining oncotic pressure. The action plan for the treatment of fluid overload is as follows: § Oxygen therapy/ventilation if indicated should be given immediately. § Stopping intravenous fluid therapy during the recovery phase will allow fluid in the pleural and peritoneal cavities to return to the intravascular compartment resulting ion dieresis. § Diuretics as given below

If the patient has stable haemodynamic status and is out of the critical phase (more than 24–48 hours of defervescence) • Stop intravenous fluids but continue close monitoring. • If necessary, give oral or intravenous furosemide 0.1–0.5 mg/kg/dose once or twice daily, or a continuous infusion of furosemide 0.1 mg/kg/hour. Monitor serum potassium and correct the ensuing hypokalaemia. If the patient has stable haemodynamic status but is still within the critical

phase, reduce the intravenous fluid accordingly. • Avoid diuretics during the plasma leakage phase. • Patients who remain in shock with low or normal haematocrit levels but show signs of fluid overload may have occult haemorrhage. Further infusion of large volumes of intravenous fluids will lead only to a poor outcome. If the patient remains in shock and the haematocrit is elevated, repeated small boluses of a colloid solution may help. Other Complications of Dengue • Hypo/Hyperglycemia

• Electrolyte abnormalities • Nosocomial/Co-infection • Metabolic Acidosis Should be managed under standard ICU protocols 12

Supportive Care and Adjuvant Therapy This may include: • Renal replacement therapy, with a preference to continuous veno-venous haemodialysis (CVVH), or peritoneal dialysis if the former unavailable; • Vasopressor and inotropic therapies as temporary measures to prevent life- threatening hypotension in dengue shock and during induction for intubation, while correction of intravascular volume is being vigorously carried out; • Further treatment of organ impairment, such as severe hepatic involvement or

encephalopathy or encephalitis; cardiac abnormalities, such as conduction abnormalities, may occur. Criteria for discharge: • Absence of fever for at least 24 hrs. • Return of appetite. • Clinical improvement. • Good urine output. • Stable haematocrit. • 2 days after recovery from shock. • No respiratory distress from pleural effusion and ascitis. 6 Annexure Immediate replacement of plasma loss/ Issotonic solutions: (1,2) This should be done with any of the following solutions; • Normal saline.

• Ringer’s lactate • In severe/refractory shock, colloids such as Plasma , plasma substitutes (6% hetastarch/dextran/ / 5% albumin /) may be preferred • Fresh whole blood or packed red blood cells may be needed for persistent shock despite restoration of fluid volume and a fall in haematocrit, suggesting the possibility of occult blood loss. § Rapidly administered dextrose containing solution when used for resuscitation may result in hyperglycemia and osmotic diuresis, delaying correction of hypovolaemia.

Secondly, dextrose is rapidly metabolized resulting in a hypotonic solution that is inappropriate for shock correction. 13

Recognition of Shock The following clinical signs should indicate the presence of shock Tachycardia , Low pulse volume Capillary Refill time > 2 sec Narrow pulse pressure Blood pressure less than the 3rd centile for age Cold clammy peripheries Altered sensorium Poor urine output [ <0.5ml/kg/hr consistently ] Tachypnoea Metabolic acidosis Choice of Vasoactive agents/ post resuscitation fluid removal (8) • Shock with low BP for age: Dopamine 10mcg/kg/min OR Noradrenaline /adrenaline 0.1-0.2mcg/kg/min

• Shock with normal BP for age: Dobutamine 5-10mcg/kg/min • Shock with diastolic dysfunction on echo: Milrinone 0.25-0.75mcg/kg/min (no loading dose) • Predominant pulmonary edema, haemodynamics stable : Nitroglycerine 1- 3mcg/kg/min, furosemide infusion 3- 5mg/kg/day, titrate to urine output of 3-5 ml/kg/hr. Cease infusion and infuse fluid if hypoperfusion occurs. • Pulmonary edema, fluid overload, haemodynamics unstable: Ventilation vital

(high risk of mortality), can consider peritoneal dialysis if 24 hour experienced nursing and medical staff available in PICU Good Clinical Practice • Serial haematocrit measurement (if not bleeding), and urine output provide the most objective guides to fluid replacement and prevention of fluid overload. • In shock –fluid resuscitate with 10-20ml/Kg of isotonic fluids over 30-60 minutes. Consider in severe shock • Aim for ≈ 20% fall in haematocrit and adjust fluid rate downwards to avoid overload

• Aim for minimal acceptable urine output (0.5-1ml/kg/hr). • A urine output > 3 ml /kg /hour indicates Hypervolaemia.. • Fluid replacements are dynamic hence require continuous reassessments. • No dextrose containing fluid should be used for fluid resuscitation, • Separate maintenance fluids are usually not required. Glucose/potassium may need to be given separately. Start enteral feeds early. • All invasive procedures must be performed by most experienced person. If

possible, aim for platelets > 50,000/cu mm prior to central line insertion. 14

• Profuse bleeds may necessitate transfusion of platelets and FFP regardless of lab values: conversely, low platelet counts in the recovering, stable patient may not be an indication for transfusions. Flow Chart 1-Volume replacement flow chart for a patient with Severe Dengue and a >20% increase in haematocrit. [No Shock](1) 5 % Fluid Deficit Initiate intravenous therapy (deficit + maintenance)* 5-7 ml/kg/hr No Improvement Improvement • Haematocrit, Pulse Rate Haematocrit Falls Rises, Pulse pressure < 20

Pulse rate and BP stable • Insert Urinary Catheter Urine Output Rises Decrease IVF Increase fluid to Vitals/Haematocrit to 5ml/Kg/Hr 10 mL/Kg/Hr Worsens Improvement No Improvement, Improvement evaluate for bleeds Decrease IVF to 3ml/kg/hr Increase IVF to 15-20ml/kg/hr for 1 hour then reassess Further improvement Deterioration of vitals and urine Stop IV Fluids See Flowchart 2 *- Ideally, infuse replacement and deficit fluid as normal saline/Ringers Lactate (isotonic, non-dextrose

containing fluid) and maintenance fluid as ½ DNS with potassium as needed. 14

Flow Chart 2: Management of Severe Dengue with Shock High flow oxygen, normal saline /colloids 10-20ml/kg* as rapid boluses x 2 Monitor hourly vitals , urine output with an indwelling catheter. Obtain baseline haematocrit, correct hypoglycaemia, hypocalcaemia, Improvement No improvement, re-check hematocrit, Evaluate for source of blood loss Decrease IVF Colloid or plasma substitutes 10-20ml/kg, Repeat as necessary (if HCT falls or is “normal” with signs of shock,

Transfuse PRBC 10ml/kg or whole blood 20ml/kg.) Further improvement No improvement Insert CVP with great caution Can discontinue OR fluids over 24-36 Proceed to inotrope / vasopressor (see appendix) CVP normal or high with shock CVP low /HCT fall <20% Discharge Inotropes/ vasopressors (see box below)* Fluids till CVP/HCT target Echo for LV systolic and diastolic function, Assess chamber filling Respiratory distress, Echo as above Consider assisted ventilation

Hemodynamics improved Hemodynamics unstable Initiate vasodilators when BP stable Low dose diuretics Assisted ventilation, continue fluids infusion 15

References 1. Dengue guidelines for diagnosis, treatment, prevention and control. A joint publication of the World Health Organization (WHO) and the Special Programme for Research and Training in Tropical Diseases (TDR). New Edition 2009 2. Manual of Pediatric emergencies and Critical Care. Dr Suchitra Ranjit. Paras Publications. Second Edition, 2010 16

EMPYEMA THORACIS Dr.Rajendra Saoji, Consultant Pediatric Surgeon, Nagpur INTRODUCTION : Empyema thoracis is a disease of historical importance with modern menace. It results into significant morbidity ; affects precious growing period of a child, parental working days & possible negligence of other family members & also incurs formidable burden on scarce resources if treated improperly or inadequately. Traditionally empyema is being

managed empirically. However, with the widespread availability of radioimaging techniques , fibrinolytic agents, safe & effective surgical procedures ( open or thoracoscopy ) the recent data is leading to more focused management guidelines though optimal management is still controversial (22). CASE DEFINITION : ‘Empyema’ is a term derived from the Greek verb ‘empyein’ ( to suppurate ) & literally refers to frank pus in the pleural space. It could be localised or free collection of purulent

material in pleural space as a result of combination of inoculation of bacteria & culture medium of pleural fluid. It is an advanced parapneumonic effusion. Pleural space infection is a continuum but classically has been divided into three stages : Stage 1 or Exudative or Acute phase ( lasts upto 3 days ) : The inflammatory process associated with the underlying pneumonia leads to accumulation of clear fluid with no or low PMN invasion ,ph >7.3, normal glucose & LDH levels : termed as ‘ simple ‘

parapneumonic effusion . Stage 2 or Fibrinopurulent or Transitional phase ( 3 to 21 days ): There is deposition of fibrin in the pleural space leading to septations & formation of loculations.There is increase in white cell count , ph < 7.3, glucose < 40mgs.,LDH >3 times the normal. This is termed as ‘complicated ‘ parapnumonic effusion. Eventually when it becomes overt or frank pus which is termed as an ‘ empyema’.The presence of septations (fibrinous strands 17

in pleural fluid )doesn’t necessarily mean fluid doesn’t flow freely, although separate loculations will not communicate with each other. Stage 3 or Organisational or Chronic phase (> 3 wks . duration ): Fibroblasts infiltrate the pleural space & thin intrapleural membranes are reorganised to become thick & non elastic – the ‘peel’ or ‘rind’. These solid fibrous or leather like peels may prevent lung re- expansion ( “trapped lung” ), impair lung function & create a persistent pleural space with

potential for infection.At this stage spontaneous healing may occur or a chronic empyema may develop. Further complications which may occur are : bronchopleural fistula , lung abscess, pneumatocele formation, empyema necessitans : perforation through chest wall, fibrothorax etc… Video-assisted thoracoscopic surgery (VATS ) is a key hole or minimal access surgical approach. It achieves debridement of fibrinous pyogenic material, breakdown of

loculations, and drainage of pus from the pleural cavity under direct vision. It leaves three small scars. Mini-thoracotomy achieves debridement and evacuation in a similar manner to VATS but it is an open procedure leaving a small linear scar along the rib line. Decortication involves an open posterolateral thoracotomy and excision of the thick fibrous pleural rind with evacuation of pyogenic material. It is a longer and more complicated procedure leaving a larger linear scar along the rib line.

INCIDENCE OF CONDITION : Empyema thoracis constitutes 5-10 % cases seen by a paediatrician in our country(23). The reported rate of empyema thoracis complicating community acquired pneumonia is said to be 27% in children(21). The prevalence of small parapneumonic effusions is difficult to estimate (and often undetected )& they are unlikely to be reported in case series. However cases non secondary to infection viz.. heart disease, malignancy,

connective tissue disorders, trauma etc. are largely dependent on the referral base & case mix in the particular hospital (5,6,7,8). 18

DIFFERENTIAL DIAGNOSIS: Empyema secondary to bacterial infection eg.. staph./streptococci,Mycobacteria, Anarobes etc.. Neoplasm Massive consolidation Chylous collection Haemothorax Lung abscess PREVENTION & COUNSELING : Though complete prevention of empyema may not be possible due to factors such as variance in microbial virulence & host’s immunological idiosyncracies etc.. but following measures will be very beneficial……… * Adequate management of pneumonia ie early recognition, proper selection ,

duration& mode of delivery of antibiotics according to regional sensitivity pattern & prompt referral facilities to higher centers. *Prevention of pneumonia : Ensuring widespread vaccination program for predisposing conditions such as measles,Hib,Pneumococcal, chickenpox etc. because significant fall in incidence of empyema has been reported in vaccinated as compared to non vaccinated zones (21). Since Staph aureus is the most common organism responsible in our country improving

hygienic conditions especially during hot & humid conditions of the year ie April to August will bring down in general incidence & severity of staph infections. Improvement in nutritional status as PEM is known predisposing factor for all infective illnesses & their complications. Improvement in dental/oral hygiene as it is a welknown predisposing factor for development of aspiration pneumonia. Patients with immunodeficient conditions, tuberculosis, musculoskeletal/neurological

illnesses, CHD, Diabetes, Renal disease etc..must remain under high index of suspicion as classical clinical presentation may be absent in such situations. 19

SITUATION 1 : At Secondary hospital / Non metro situation : Optimal standards of Treatment in Situations where technology& resources are limited. Clinical Diagnosis* Acute , recurrent or chronic presentations are common. If a child with pneumonia remains pyrexial or unwell 48 hrs. after the start of the treatment possibility of parapneumonic effusion or empyema should be suspected. Constitutional signs / symptoms viz.. lassitude, poor appetite, pallor, intermittent fever,

easy fatigability, sick look with dull percussion note & decreased breath sounds on auscultation in the setting of partially treated pneumonia, PUO, Disseminated infections e g.. Pyoderma / otitis media /arthritis/Osteomylitis / Serosal infections etc.. Febrile response may be blunted in immunocompromised patients. *Physical findings & presentation may vary depending on type organism & duration of illness. *Inflammation of pleural space may present with abdominal pain &vomiting. INVESTIGATIONS :

1) Chest X-ray : Posteroanterior ( PA ) view 2) Ultrasound chest :Sensitive for confirmation of pleural fluid , for guided diagnostic tapping & insertion of chest drainage tube. 3) Pleural fluid exam: Colour, Odour, Gram staining, AFB, Bacterial culture, cytology. Biochemistry: Ph, Sugar, LDH, Proteins. 4 ) Blood & sputum culture : if feasible TREATMENT : Conservative Management : Antibiotics ± Intercostal Dranaige Tube (ICD)

If effusion is simple & small in quantity : can be managed with antibiotics alone .But very close observation is necessary for development of enlarging size &/or compromise of respiratory function when prompt ICD placement is necessary. Repeated thoracentesis has no role. 20

If effusion is complicated or frank pus : Antibiotics + ICD Surgical management : Only if adequately trained personnel & blood banking facilities are available then limited thoracotomy in a situation where there is no satisfactory response (persistent fever, incomplete lung expansion ,loculations on ultrasound etc..)ie.. in stage 2 or fibrinopurulent phase. Standard operating procedure ( SOP ) All the patients of parapneumonic effusion or empyema should be admitted in hospital

i e.. no out patient or day care management to be done. Pediatric surgeon or General surgeon familiar with basic thoracic surgery along with paediatrician or respiratory physician should manage these cases. They should be monitored closely & carefully by frequent clinical assessment & room air saturation by pulse oximeter whenever child is in resp. distress. Diagnostic imaging, microbiology, pleural fluid analysis should be carried out promptly.

Conservative management to be started swiftly & supported by antipyretics, analgesia, oxygen , if necessary. Empirical antitubercular therapy should be avoided as far as possible. Antibiotics : Intravenous antibiotics for 10 to 14 days for community acquired pneumonia covering Gram positive cocci & anaerobes to be started empirically pending preferably c & s report. Broad spectrum coverage should be started for hospital acquired pneumonia as

well as empyema following surgery, trauma & aspiration. Oral antibiotics should be continued at discharge for 1-4 wks. or longer depending on disease state. Chest drainage tube(ICD) insertion: Chest drains should be inserted by adequately trained personnel to reduce the risk of complications. 21

Preferably procedure should be done in operation room or isolated / treatment room on ward. However , if need arises it can be done as a bed side procedure as well. A suitable assistant and trained nurse must be available. Routine measurement of the platelet count and clotting studies are only recommended in patients with known risk factors. Where possible, any coagulopathy or platelet defect should be corrected before chest drain insertion.

Ultrasound should be used to guide thoracocentesis or drain placement. If general anaesthesia is not being used, intravenous sedation should only be given by those trained in the use of conscious sedation, airway management and resuscitation of children, using full monitoring equipment. . Local anaesthesia, 2% xylocaine Or .25% bupivacaine, can also be used . Large bore surgical drains should be inserted at the optimum site suggested by

ultrasound, but preferentially placed in the mid axillary line through the ‘‘safety triangle’’. Substantial force should never be used to insert a drain. Trocar usage preferably should be avoided & should it be needed ,due to circumstances, great care is mandatory to have a guard or control on it while inserting. Chest tube should be secured well with non absorbable suture & appropriate dressing. A chest radiograph should be performed after insertion of a chest drain.All chest tubes

should be connected to a unidirectional flow drainage system (such as an underwater seal bottle) which must be kept below the level of the patient’s chest at all times. A bubbling chest drain should never be clamped. A clamped drain should be immediately unclamped and medical advice sought if a patient complains of breathlessness or chest pain. The drain should be clamped for 1 hour once 10 ml/kg are initially removed. Patients with chest drains should be managed on wards by staff trained in chest drain

When there is a sudden cessation of fluid draining, the drain must be checked for obstruction (blockage or kinking) by flushing. The drain should be removed once there is clinical resolution. A drain that cannot be unblocked should be removed and replaced by new catheter if significant pleural fluid remains. Surgical management : Proper planning & ensuring availability of all the trained & experienced personnel ie ..surgeon, anaesthesiologist ,OT technician & nursing staff and also smooth supply of

oxygen,blood ,medicines etc..is very important . Limited thoracotomy with or without rib resection by 5-7cms total incision on either side of chest tube ,if already in situ. To ensure complete lung expansion at the end of the procedure with minimal air leak. If necrotic lung tissue is present then excision of the segment is to be done. Send debrided tissue or ‘gubbin ‘ for histopathological examination. ICD removal after complete lung expansion ,minimal or no drainage ,afebrile state & no air leak

X ray chest to be done before ICD tube removal Good analgesia ( oral &/or suppositories ) & early ambulation to hasten the recovery should be practiced regularly. Antibiotics for 1-2wks. after the discharge are usually sufficient except in situation of complications. Follow- up : Till complete resolution of disease process & near complete lung expansion on x- ray chest. Evaluation of underlying condition, if any. Referral criteria If no satisfactory response to conservative management by 5-7 days.

Suspecting underlying immunodeficiency condition or empyema associated with non pneumonic pathologies which also require specialist’s attention. Development of complications eg Persistent air leak. Non availability of trained personnel at given time. Situation 2 At Super Speciality Facility in Metro location where higher end technology is available Clinical diagnosis* If a child with pneumonia remains pyrexial or unwell 48 hrs. after the start of the

treatment possibility of parapneumonic effusion or empyema should be suspected. Constitutional s/s viz.. lassitude, poor appetite, pallor, intermittent fever, easy fatigability, sick look with dull percussion note & decreased breath sounds on auscultation in the setting of partially treated pneumonia, PUO, Disseminated infections e g.. Pyoderma / otitis media /arthritis/Osteomylitis / Serosal infections etc.. Patients inadequately treated or responded to previous therapy.

Complications of an empyema eg.. BPF, lung abscess, empyema necessitans etc. Patients with underlying conditions such as liver abscess, pancreatitis ,trauma , surgical or endoscopic procedure done etc with respiratory signs & symptoms. Response may be blunted ‘absent fever’ in immunocompromised patients. *Acute , recurrent or chronic presentations are common. *Physical findings & presentation may vary depending on type of organism & duration of illness.

*Inflammation of pleural space may present with abdominal pain &vomiting Investigations Diagnostic imaging 24

Posteroanterior or anteroposterior radiographs should be taken; there is no role for a routine lateral radiograph. Ultrasound may be used to confirm the presence of a pleural fluid collection, septations, to guide thoracocentesis or drain placement. Chest CT scans should not be performed routinely. It should be done once surgery is contemplated to know pleural peel thickness, loculations & their details such as number,position,size etc.; parenchymal pathology,guide for port placement if VATS is

being planned . Diagnostic microbiology Blood cultures should be performed in all patients with parapneumonic effusion. When available, sputum should be sent for bacterial culture. Diagnostic analysis of pleural fluid Pleural fluid must be sent for microbiological analysis including Gram stain and bacterial culture. Aspirated pleural fluid should be sent for differential cell count. Tuberculosis and malignancy must be excluded in the presence of pleural lymphocytosis.

If there is any indication the effusion is not secondary to infection, consider an initial small volume diagnostic tap for cytological analysis, avoiding general anaesthesia/sedation whenever possible. Biochemical analysis of pleural fluid : Ph, LDH, sugar, & proteins Diagnostic bronchoscopy There is no indication for bronchoscopy and it is not routinely recommended. Considered only when bronchoalveolar lavage is necessary or suspected foreign body or assessing

bronchial mucosal status for safe closure of br. stump when major pulmonary resection is also planned alongwith decortication . 25

Treatment Conservative management (antibiotics ± simple drainage) Effusions which are enlarging and/or compromising respiratory function should not be managed by antibiotics alone. Give consideration to early active treatment as conservative treatment results in prolonged duration of illness and hospital stay. If a child has significant pleural infection, a drain should be inserted at the outset and repeated taps are not recommended. Antibiotics

All cases should be treated with intravenous antibiotics and must include cover for Gram positive cocci eg..Staph Aureous, Streptococci & Anarobes. Broader spectrum cover is required for hospital acquired infections, as well as those secondary to surgery, trauma, and aspiration. Where possible, antibiotic choice should be guided by microbiology results. Oral antibiotics should be given at discharge for 1–4 weeks, but longer if there is residual disease. Chest drains

Chest drains should be inserted by adequately trained personnel to reduce the risk of complications. A suitable assistant and trained nurse must be available. Routine measurement of the platelet count and clotting studies are only recommended in patients with known risk factors. Where possible, any coagulopathy or platelet defect should be corrected before chest drain insertion. Ultrasound should be used to guide thoracocentesis or drain placement, when available.

If general anaesthesia is not being used, intravenous sedation should only be given by those trained in the use of conscious sedation, airway management and resuscitation of children, using full monitoring equipment. 26

Large bore surgical drains should be inserted at the optimum site suggested by ultrasound. The usual site for ICD insertion should be in the mid axillary line in the 5th intercostal space which is in the ‘safe triangle.’ Substantial force should never be used to insert a drain. Trocar usage preferably should be avoided & should it be needed ,due to circumstances, great care is mandatory to have a guard or control on it while inserting. Chest radiograph should be performed after insertion of a chest drain.

All chest tubes should be connected to a unidirectional flow drainage system (such as an underwater seal bottle) which must be kept below the level of the patient’s chest at all times. Appropriately trained nursing staff must supervise the use of chest drain suction. A bubbling chest drain should never be clamped. A clamped drain should be immediately unclamped and medical advice sought if a patient complains of breathlessness or chest pain.

Patients with chest drains should be managed on specialist wards by staff trained in chest drain management. When there is a sudden cessation of fluid draining, the drain must be checked for obstruction (blockage or kinking) by milking / flushing. If it can not be unblocked in presence of significant pleural infection then it should be reinserted. The drain should be removed once there is clinical resolution & / or lung expansion on x- ray. Intrapleural fibrinolytics

Intrapleural fibrinolytics are said to shorten hospital stay and may be used for any stage 2 empyema . There is no evidence that any of the three fibrinolytics ( Streptokinase, Urokinase, Alteplase ) are more effective than the others, but only urokinase has been studied in a randomised controlled trial . Urokinase should be given twice daily for 3 days (6 doses in total) using 40 000 units in 40 ml 0.9% saline for children weighing 10 kg or above, and 10 000 units in 10 ml 0.9%

Surgery Patients should be considered for surgical treatment if they have persisting sepsis in association with a persistent pleural collection, despite chest tube drainage and antibiotics. Failure of chest tube drainage, antibiotics, and fibrinolytics would necessiiate surgical intervention.However, a pediatric surgeon should be involved early in the management of empyema thoracis. If requisite skill & facilities are available then VATS debridement is preferable over

open surgical procedure in stage 2 & select stage 3 empyema cases. Organised empyema in a symptomatic child may require formal thoracotomy and decortication. Other management Antipyretics should be given. Analgesia is important to keep the child comfortable, particularly in the presence of a chest drain. Early mobilisation , chest physiotherapy and exercise is recommended. Secondary scoliosis noted on the chest radiograph is common but transient; no specific

treatment is required but resolution must be confirmed. Standard operating procedure ( SOP ) All the patients of parapneumonic effusion or empyema should be admitted in hospital i e.. no out patient or day care management to be done. Pediatric surgeon or a surgeon well trained in pediatric thoracic surgery along with paediatrician or respiratory physician should manage these cases. CECT( Contrast Enhanced Cat Scan ) should be done if surgery is contemplated.

There are no evidence based criteria to guide the decision on when a child should proceed to surgery, and consequently there is little consensus on the role of medical versus surgical management (1) 28

Intrapleural fibrinolytics Intrapleural fibrinolytics shorten hospital stay and are recommended for any complicated parapneumonic effusion (thick fluid with loculations) or empyema (overt pus). There is no evidence that any of the three fibrinolytics(streptokinase,urokinase &tPA ) are more effective than the others, but only urokinase has been studied in a randomised controlled trial in children so is recommended(10 to 16) Surgery:

The decision to involve a pediatric surgeon early in the decision making process should be encouraged and referral should not automatically mean surgery is inevitable .(1) Available procedures are: VATS, Mini thoracotomy & Decortication. A chest drain(s) is left after each procedure for further drainage of fluid/pus. A persistent radiological abnormality in a symptom-free well child is not an indication for surgery. Role of surgical management in complex empyema

(A) Organised empyema with a thick fibrous peel Organised empyema in a symptomatic child may require formal thoracotomy and decortication. The surgical management of an organised empyema, in which a thick fibrous peel is restricting lung expansion and causing chronic sepsis with fever, requires a formal thoracotomy with excision of the pleural rinds (decortication) to achieve proper lung re- expansion. However, if the child is asymptomatic, surgery is not necessarily indicated.(18 )

(C) Bronchopleural fistula and pyopneumothorax Different approaches have been advocated for a bronchopleural fistula related to an empyema. Most fistulae are peripheral and the majority resolve with continued chest drainage and antibiotics provided the lung shows satisfactory lung expansion. However, at times they are slow and difficult to resolve, and it has been said that conservative management and open thoracostomies result in protracted recovery and

morbidity. A more radical approach is partial decortication and muscle flap surgery to bring a blood supply to the necrotic area and help with healing the fistula. This can either be done as a staged procedure or a more aggressive one stage approach (19, 20) 29

Follow up Children should be followed up after discharge until they have recovered completely and their chest radiograph has returned to near normal. Underlying diagnosis—for example, immunodeficiency –may need to be considered in selected situations. open chest tube care in select patients till tube is in situ For monitoring of ATT Referral to tertiary speciality centre Non availability of skilled & experienced personnel or infrastructure necessary for

management of complex situations eg. BPF, major lung resections or Thoracoscopic procedure or need of PICU facilities etc.. When respiratory paediatrician is needed to be involved early in the care of patients requiring chest tube drainage for a pleural infection & in critically ill child. Who does what ? & Time lines : Doctor : Pediatric Surgeon : Does all the interventional procedures & involved in decision making regarding overall management with paediatrician.

Pediatrician (Respiratory ) : Along with surgeon involved in conservative management & post operative care & preop. preparation General Surgeon : Does interventions In situation 1 only & in situation 2 maybe involved in assisting pediatric surgeon. Anaesthesiologist : Anaesthesia & pain management Junior doctor : Assisting in surgery, ICD care ,dressings & day to day ward management b ) OT Technician : Helping anaesthesiologist & surgeon in OT & if required on ward bedside interventions. 30

C ) Nursing Staff : Care & organisation of instrument trolly, medications & ICD care, suction etc. & day to day nursing care. Time line : Radiological clearance takes few wks. to many months. If an empyema fails to respond in 3-5 days of conservative treatment then surgical intervention should be considered to reduce morbidity. Dwelling time for fibrinolytics is 1-4 hours. There is no specific / precise time period for spontaneous closure or need for surgical intervention in BPF patients.

Antibiotics are needed for 4-8 wks. ( Intravenous 2-3 wks. & oral 1-4wks.) ATT is required for 6-9 mths duration. 31

REFERENCES 1 BTS guidelines for the management of pleural infection in children I M Balfour-Lynn, E abrahamson, G Cohen, et al.Thorax 2005 60: i1-i21 2 British Thoracic Society Standards of Care Committee. BTS guidelines for the management of pleural disease. Thorax 2003;58(Suppl II):ii1–59. [I+] 3 Playfor SD, Smyth AR, Stewart RJ. Increase in incidence of childhood empyema. Thorax 1997;52:932. 4 Freij BJ, Kusmiesz H, Nelson JD, et al. Parapneumonic effusions and empyema in

hospitalized children: a retrospective review. Pediatr Infect Dis1984;3:578–91. 5 Chonmaitree T, Powell KR. Parapneumonic pleural effusion and empyema in children. Review of a 19-year experience, 1962–1980. Clin Pediatr 1983;22:414–9. [III] 6 Wolfe WG, Spock A, Bradford WD. Pleural fluid in infants and children. Am Rev Respir Dis 1968;98:1027–32. [III] 7 Alkrinawi S, Chernick V. Pleural infection in children. Semin Respir Infect 1996;11:148–54. [III]

8 Thomson AH, Hull J, Kumar MR, et al. Randomised trial of intrapleural urokinase in the treatment of childhood empyema. Thorax 2002;57:343–7. 9 Tiryaki T, Abbasoglu L, Bulut M. Management of thoracic empyema in childhood. A study of 160 cases. Pediatr Surg Int 1995;10:534-6 10 Barbato A, Panizzolo C, Monciotti C, et al. Use of urokinase in childhood pleural empyema. Pediatr Pulmonol 2003;35:50–5. 11 Kilic N, Celebi S, Gurpinar A, et al. Management of thoracic empyema in

children. Pediatr Surg Int 2002;18:21–3. 12 Kornecki A, Sivan Y. Treatment of loculated pleural effusion with intrapleural urokinase in children. J Pediatr Surg 1997;32:1473–5. 13 Krishnan S, Amin N, Dozor AJ, et al. Urokinase in the management of 32

uncomplicated parapneumonic effusions in children. Chest 1997;112:1579–83. 14 Rosen H, Nadkarni V, Theroux M, et al. Intrapleural streptokinase as adjunctive treatment for persistent empyema in pediatric patients. Chest 1993;103:1190–3. 15 Stringel G, Hartman AR. Intrapleural instillation of urokinase in the treatment of loculated pleural effusions in children. J Pediatr Surg 1994;29:1539–40. 16 Wells RG, Havens PL. Intrapleural fibrinolysis for parapneumonic effusion

and empyema in children. Radiology 2003;228:370–8. [III] 17 Bouros D, Schiza S, Patsourakis G, et al. Intrapleural streptokinase versus urokinase in the treatment of complicated parapneumonic effusions: a prospective, double-blind study. Am J Respir Crit Care Med 1997;155:291–5. 18 Fraga JC, Kim P. Surgical treatment of parapneumonic plearl effusion and its complications. J Pediatr 2002;78(Suppl 2):161–73. 19 Asp K, Pasila M, Sulama M. Treatment of pyopneumothorax in infants and

children. Acta Chir Scand 1964;128:715. 20 Puskas JD, Mathisen DJ, Grillo HC, et al. Treatment strategies for bronchopleural fistula. J Thorac Cardiovasc Surg 1995;109:989–95. 21 A K Baranwal, M Singh, R K Marwaha, L Kumar Empyema thoracis: a 10-year comparative review of hospitalised children from south Asia . Arch Dis Child 2003;88:1009–1014 22 Sonnappa S, Cohen G, Owens CM, van Doorn C, Cairns J, Stanojevic S, Elliott MJ,

Jaffe´ A. Comparison of urokinase and video-assisted thoracoscopic surgery for treatment of childhood empyema. Am J Respir Crit Care Med 2006;174:221–227 23 DKGupta,Shilpa Sharma.Management of empyema-Role of a surgeon J Indian assoc pediatr surg July-Sept2005/vol10/issue 3.. 33

24 Robert L. Gates, Mark Hogan, Samuel Weinstein, and Marjorie J. Arca Drainage, Fibrinolytics, or Surgery: A Comparison of Treatment Options in Pediatric Empyema Journal of Pediatric Surgery, Vol 39, No 11 (November), 2004: pp 1638-1642 Resources required for one patient / procedure Situation 1 Human resources : Surgeon 1, Pediatrician1, nursing staff1, OT technician 1, Anaesthesiologist Investigations : Chest radiograph Ultrasound scan of chest Full blood count

C-reactive protein (some regard this as a useful marker of progress) .Blood culture (including anaerobic bottle) & Sputum culture (if available) Drugs & Cosumables : Antibiotics ,Analgesics,antipyretics,Oxygen,IVFluids,sedatives,atropine/pyrolate,ketamine, propafol,local anaesthetics,muscle relaxants,antiemetics, PPI/H2 blockers,Emergency medicationsetc…,Betadine, Savolon, spirit, Normal saline Syringes & needles,IVsets,oxygen mask,IVCannulae,Sticking plaster,Cotton, gauze pieces,

pads,suture material,ICD tubes, Under water seal drainage bags etc…Gloves (surgical),Gowns, Eye towel Equipments : EQUIPMENT FOR CHEST DRAIN INSERTION Sterile gloves and gown Skin antiseptic solution, e.g. povidone iodine (Betadine) or chlorhexidine in alcohol Sterile gauze swabs 34

A selection of syringes (2 ml and 5 ml) and needles (21–25gauge) Local anaesthetic, e.g. 0.25% bupivacaine (Marcaine) , 2% xylocaine Scalpel and blade Suture (e.g. 2/0 or 3/0 silk) Guide wire with dilators for Seldinger technique Chest tube: 10–12 FG appropriate for most children (8–14 FG should be available) Connecting tubing Closed drainage system (including sterile water if underwater seal being used) Sterile universal containers and anaerobic blood culture bottle for pleural fluid

Large transparent adhesive dressings Equipment for percutaneous long line and bottles for blood tests. Limited Thoracotomy Equipments : Basic Thoracotomy set General Anaesthesia machine, Tracheal intubation set organised well in operation room with other basic facilities eg. Good negative suction source, satisfactory illumination, patient warming gadgets etc.. Situation 2 Human resources : Well trained pediatric surgeon, Respiratory pediatrician &

Anaesthesiologist mandatory ,Assistent Surgeon, Resident doctors & specialised nursing staff round the clock, Anaesthesia technician. Investigations : As in situation 1 + Albumin, Creatinine, blood group ,Blood gases, Specialised infective, immunodeficiency etc…workup facilities + Contrast Enhanced CT Scan + investigations facilities for associated problems & complications from the disease process. Equipments : Basic + High end open surgery & Thoracoscopy set in well planned & equipped OT.

INGUINAL HERNIA IN CHILDREN Dr.Sanjay Rao Dr.Vinay C Dr. Zameer K Consultant Pediatric Surgeons, Narayana Hrudayalaya, Bangalore a) WHEN TO SUSPECT/ RECOGNIZE? Inguinal hernia is suspected in any child with a swelling in the inguinoscrotal region. a. Introduction: Inguinal hernia repair is one of the most common pediatric operations performed. Most hernias that present at birth or in childhood are indirect inguinal hernias. All pediatric

inguinal hernias require operative treatment to prevent the development of complications, such as inguinal hernia incarceration or strangulation. b. Case definition: Inguinal hernia is a type of ventral hernia that occurs when an intra-abdominal structures, such as bowel or omentum, protrude through the open processus vaginalis through the inguinal canal. b) INCIDENCE OF THE CONDITION IN OUR COUNTRY Although the exact incidence of indirect inguinal hernia in infants and children is unknown, the

reported incidence ranges from 1-5%. Sixty percent of hernias occur on the right side. Premature infants are at increased risk for inguinal hernia, with incidence rates of 2% in females and 7-30% in males. 36

Inguinal hernias are much more common in males than in females. The male-to-female ratio is estimated to be 4-8:1. Premature infants are at an increased risk for inguinal hernia, with the incidence ranging from 7- 30%. Moreover, the associated risk of incarceration is more than 60% in this population. c) DIFFERENTIAL DIAGNOSIS Congenital Hydrocoele Inguinal adenitis Femoral adenitis Psoas abscess Saphenous varix Retractile testis Varicocele Testicular tumor Undescended testis d) PREVENTION AND COUNSELING :

A high index of suspicion is required-especially in the high risk population of premature babies. If a child has developed a unilateral hernia, there is a potential risk of developing a hernia on the opposite side-this risk is higher in premature babies and infant girls. These families need to be counseled about signs and symptoms of these recurrences. e) OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA 37

Diagnostic criteria: diagnosis is clinical. 1. History of a soft swelling in inguinal region. Gets larger when child cries, may disappear completely when the child is quietly lying down. 2. Examination: Soft, reducible mass in the inguinal area is diagnostic. Even in the absence of the mass at examination, a strong history is adequate for diagnosis. Investigations: No imaging studies are required. General tests towards anaesthesia fitness may be required ( haemoglobin, urine analysis). Referral Criteria:

A strong clinical history and physical findings of inguinal hernia are indications for referral for surgery. HISTORY The child with an inguinal hernia presents with a bulge at the internal or external ring or within the scrotum. The parents typically provide the history of a visible swelling or bulge, commonly intermittent, in the inguinoscrotal region in boys and inguinolabial region in girls. Usually, a simple inguinal hernia in an infant is painless.

The bulge commonly occurs after crying or straining and often resolves during the night while the baby is sleeping. 38

If the family provides a history of a painful bulge in the inguinal region, one must suspect the presence of an incarcerated inguinal hernia. Patients with an incarcerated hernia generally present with a tender firm mass in the inguinal canal or scrotum. The child may be fussy, unwilling to feed, and inconsolably crying. The skin overlying the bulge may be edematous, erythematous, and discolored. 39

EXAMINATION Physical examination of a child with an inguinal hernia typically reveals a palpable smooth mass originating from the external ring lateral to the pubic tubercle. The mass may only be noticeable after coughing or performing a Valsalva maneuver and it should be reduced easily. Occasionally, the examining physician may feel the loops of intestine within the hernia sac. In girls, feeling the ovary in the hernia sac is not unusual; it is not infrequently confused with a

lymph node in the groin region. In boys, palpation of both testicles is important to rule out an undescended or retractile testicle. Hernia and hydrocele: Transillumination has been advocated as a means of distinguishing between the presence of a sac filled with fluid in the scrotum (hydrocele) and the presence of bowel in the scrotal sac. However, in cases of inguinal hernia incarceration, transillumination may not be beneficial because any viscera that are distended and fluid-filled in the scrotum of a

young infant may also transilluminate. INVESTIGATIONS No laboratory studies are needed in the assessment of a patient with a suspected inguinal hernia and/or hydrocele. Ultrasonography: Its routine use is unnecessary. It is indicated when presentation and examination suggest a diagnosis other than hernia or hydrocele. An enlarged inguinal lymph node can mimic an incarcerated inguinal hernia. Laparoscopy: Diagnostic laparoscopy may rarely be required for determining the presence of an

inguinal hernia. It is used only in the following: a) assessment of contralateral hernia when one is being operated upon, and b) recurrent hernia after previous surgery. TREATMENT Congenital hernias are treated surgically with herniotomy. Surgical treatment can be either open or laparoscopic. Inguinal hernias do not spontaneously heal and must be surgically repaired because of the ever-present risk of incarceration. Repair is usually planned as an elective procedure as soon as possible after diagnosis. 40

If hernia is irreducible, ie cannot be easily pushed back into the abdomen, child needs to be admitted and a manual reduction tried by an experienced pediatric surgeon. If successful, the operation is performed after 24-48 hours to allow local oedema to settle down. If reduction is unsuccessful, or if there is clinical evidence of inflammation (as evidenced by pain, redness, edema of skin on hernia) emergency exploration and hernia repair is necessary.

Hydroceles without hernia in neonates: This is the only exception in which surgical treatment may be delayed. Repair of hydroceles in neonates without the presence of hernia is typically delayed for 12 months because the connection with the peritoneal cavity (via the processus vaginalis) may be very small and may have already closed or be in the process of closing. If the hydorcoele persists after this observation period, operative repair is indicated and appropriate.

Postpone the operation in the event of upper respiratory tract infection,otitis media, or significant rash in the groin. FOLLOW UP No specific limitations are indicated once the diagnosis of an inguinal hernia has been established; however, following operative repair, avoidance of major physical activity for 1 week is recommended. After that time, the patient is allowed to participate in physical activities (eg, sports, swimming, running).

Children younger than 5 years are likely to recover extremely quickly from surgery; they are typically capable of returning to their normal level of activities within 24-48 hours of surgery. *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a. Clinical Diagnosis: Similar generic diagnostic criteria apply. A typical history and physical finding are adequate for diagnosis. 41

b. Investigations: a. Investigations are not required other than for anaesthetic purposes. b. Rarely, ultrasonography and diagnostic laparoscopy may be indicated c. Treatment: a. Inguinal hernia: Treatment is surgery -herniotomy operation that aims at ligating the patent processus vaginalis at the internal ring after reduction of contents into the abdomen b. Congenital hydrocoele: Treatment is deferred until the 2nd birthday as there is a

80% chance of spontaneous closure. Surgery is indicated if hydrocoele persists beyond the 2nd year and if it is rapidly growing is size. c. All hernia and hydrocoele repairs in infants and children MUST be performed by a qualified pediatric surgeon. Standard Operating procedure a. In Patient : inpatient care is indicated if: I. h/o incarceration or obstructions II. neonate awaiting hernia repair b. Out Patient i. Outpatient care is adequate for diagnosis and follow up in most children

ii. Clinical evaluation usually sufficient to diagnose c. Day Care i. most hernia operations in children are done as day care procedures d. Referral criteria: A child with a hernia needs referral to a higher centre if: 1. neonatal age and anaesthesia facilities are inadequate 2. ex-premature baby who had prolonged ventilation 3. recurrent inguinal hernia 4. inguinal hernia with complications (incarceration, obstruction) 5. associated major morbidity-such as cardiac anomalies, lung disease, renal

disease, ascites *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available 42

a. Clinical Diagnosis: a. Same as in situation1 b. Investigations: a. Same as in situation1 b. additional tests for comorbid conditions such as pulmonary and cardiac anomalies c. Treatment: a. principles of treatment are same as above Standard Operating procedure a. In Patient i. criteria same as above ii. all babies under 1 year of age need inpatient care after surgery-as there is an increased risk of apnoea in this subgroup. iii. All children with comorbid problems-cardiac, respiratory or

others, need inpatient care after surgery b Out Patient i. criteria same as above c. Day Care ii. criteria same as above iii. Children who are above 1 year of age and in good health with no associated comorbid problems can be treated as day care procedures d. Referral criteria: No further referrals f) WHO DOES WHAT? and TIMELINES a. Doctor makes a clinical diagnosis, counsels the family and plans surgery- a pediatric surgeon performs the surgery

b. Nurse: assists surgeon in care of child during pre, intra and post operative course of the baby c. Technician: assists medical and nursing teams in care of child during intra and post-operative periods. 43

g) FURTHER READING / REFERENCES 1. Brandt ML. Pediatric hernias. Surg Clin North Am. Feb 2008;88(1):27-43, vii-viii. 2. Skinner MA, Grosfeld JL. Inguinal and umbilical hernia repair in infants and children. Surg Clin North Am. Jun 1993;73(3):439-49. 3. Deeba S, Purkayastha S, Paraskevas P, et al. Laparoscopic approach to incarcerated and strangulated inguinal hernias. JSLS. Jul-Sep 2009;13(3):327-31. RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS)

(Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation Human Resources Drugs & Consumables Equipment 1 • Pediatric • I.V. Glucose/ Fluids • Radiant Warmer Surgeon • I.V. cannula • Saturation • Pediatrician • I.V. Set monitor • Pediatric Nurse • anesthetic drugs, disposables • Basic Lab • Lab. Technician • antibiotic prophylaxis • Child friendly OT 2 • Pediatric • I.V. Glucose/ Fluids • ICU

surgeon • I.V. cannula • Pediatric O.T. • Pediatrician • I.V. Set • Pediatric • anesthetic drugs, disposables anaesthesist • antibiotic prophylaxis • Pediatric Nurse 44

NEONATAL CHOLESTASIS Prepared by: 1. Dr.Sanjay Rao MS,MCh (Paediatric Surgery) Consultant Pediatric Surgeon, Narayana Hrudayalaya, Bangalore 2. Dr.Rajiv Aggarwal, MD Consultant Pediatrician and Neonatologist Narayana Hrudayalaya, Bangalore Assisted by: 1. Dr.Vinay C 2. Dr. Zameer K Both from Department of Pediatric Surgery Narayana Hrudayalaya,Bangalore I. WHEN TO SUSPECT/ RECOGNIZE? Introduction: Neonatal cholestatis is a pathological condition in the newborn where in bile flow from

the liver is reduced. Neonatal Cholestasis Syndrome (NCS) includes a wide spectrum of clinical conditions ranging from congenital malformations of the hepatobiliary tree, infections, inborn errors of metabolism to some of the recently identified clinical conditions with or without genetic predilection. Most of these disorders have linkage with insults during antenatal, natal and postnatal periods. 45

NCS has largely remained ignored in our country. Case definition: Neonatal cholestasis refers to conjugated hyperbilirubinemia >1.5 – 2 mg% and/or direct component of more than 20% of total bilirubin in a newborn/ infant with passage of high coloured urine with or without clay stools. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY NCS constitutes 30% of referrals with hepatobiliary disorders in India. The average age of presentation to a specialized center is 3.5 months (range birth to 15 months) with a

consequent delay of 3 months in referral (medical and surgical centers). Based on consensus conference by paediatric gastroenterology, out of 1008 cases analysed in our country • Hepatocellular causes: 53 %( neonatal hepatitis-47%, metabolic-4%, others-2%) • Obstructive causes: 38 %( billiary atresia-34%, Choledochal cyst-4%) • Ductal paucity: 3% • Idiopathic: 6% In neonatal hepatitis- • Idiopathic giant cell hepatitis: 64%, • TORCH: 22% • Sepsis: 8% • Others: 6% III. DIFFERENTIAL DIAGNOSIS 46

A. CAUSES OF EXTRA HEPATIC OBSTRUCTION § Biliary Atresia § Choledochal Cyst § Spontaneous perforation of bile ducts § Biliary stenosis § Inspissation of bile ducts § Mass/peritoneal bands B. HEPATOCELLULAR 1. INFECTIVE • Sepsis • TORCH • Malaria • UTI • Hepatitis • Other Viral infections • HIV 2. METABOLIC • Galactossemia • Hereditary Fructosemia • Tyrosinemia • Alfa 1 AT deficiency • Bile acid disorders • Fatty Acid Oxidation defects • Cystic fibrosis • Storage disorders • Neonatal hemochromatosis

• TPN • Shock • Hypoperfusion • Downs • Congenital heart / valvular abn 4. IDIOPATHIC C. PAUCITY OF INTRAHEPATIC DUCTS § Syndromic - Alagille's syndrome, Byler's, Aagene's § Non - Syndromic - a 1AT deficiency, Idiopathic, Familial IV. PREVENTION AND COUNSELING A high index of suspicion is necessary. Mothers must be informed about the need to seek medical attention if jaundice persists beyond two weeks of birth and / or baby passes

pale stools and high coloured urine. If the previous sibling has had liver disease antenatal counselling and referral for further evaluation may be necessary. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA a. Diagnostic criteria: 1. Clinical: Neonate with jaundice persistent beyond 2 weeks, dark colour urine and/or pale stool 2. Screening Biochemistry: Serum bilirubin direct and indirect Any child that meets with the clinical and /or biochemical criteria needs

Typical presentation: • Newborn with jaundice/ high colored urine with or without clay colour stools beyond two weeks of age. • Typically a child with biliary atresia is usually a term baby with normal weight, accepting feeds well. • Pigmented stools do not rule out Biliary atresia, upto 30% of biliary atresia stools are yellow in the early weeks. Clinical examinations: Clinical evaluation- 1. Sick baby: Sepsis/UTI/Congenital infections/metabolic disorders.

2. Dysmorphism : Downs syndrome/ alagilles syndrome. 3. Examination of eye and fundus must be done- • Cataract in Galactosemia • Chorioretinitis in TORCH • Posterior embryotoxins in alagilles syndrome • Cherry red spot in Lipid storage disorders 4. Chronic Cholestatis – Pruritis/ irritability/xanthomas 5. Failure to thrive. *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited 49

e. Clinical Diagnosis: 2. Jaundiced child 3. Dark urine 4. Pale stool 5. Hepatomegaly ± splenomegaly f. Investigations: • Hematology: CBC • Urine routine & microscopy • Biochemistry: a. LFT b. RFT c. PT/INR d. RBS • Imaging: USG Abdomen g. Treatment: Standard Operating procedure 4. Resuscitation if required, 5. Correction of Hypoglycemia 6. Administration of Vitamin K (0.3mg/kg parenteral) 7. Initiation of antibiotics: if there is clinical or laboratory evidence of infection or sepsis

a. In Patient : Child needs admission if 1. there is clinical evidence of dehydration 2. clinical ± laboratory evidence of hypoglycemia sepsis or coagulopathy. 3. failure to thrive b. Out Patient : Baby who is clinically well, feeding well and has no evidence of hypoglycemia or coagulopathy can be investigated as an outpatient 50

c. Day Care : No role of day care admission. h. Referral criteria: ( All workup at this level must be completed by 48 hours) 1. Any child with neonatal cholestasis syndrome who is > 2 weeks of age 2. Clinically unwell, poor feeding, poor weight gain 3. Evidence of coagulopathy, hypoglycemia or sepsis *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available Clinical Diagnosis: Investigations: Urgent Investigations § Blood counts § LFT § PT § Electrolytes

§ Blood culture § Urine culture, Urine microscopy § Urine reducing substances § GRBS § Ascitic tap (if ascites) Standard LFT are usually abnormal with modestly raised levels of AST, ALT, and alkaline phosphatase. GGT is raised in all cases of cholestasis except in one of the bile acid synthetic defects. Serum albumin does not fall till late. None of the biochemical tests are of deciding value and at best reflect the degree of damage to liver. Tests directed towards infective and metabolic causes : 51

Blood Tests • TORCH, VDRL, Hepatitis B/C, HIV • T4, TSH • Serum cortisol • α l AT levels and phenotype • Galactose 1 Phosphate Uridyl transferase (to r/o galactosemia) • Urinary succinyl acetone (to r/o tyrosinemia) • Cholesterol, triglycerides • S. iron and ferritin levels (to r/o neonatal hemachromatosis) Radiology Role of USG USG can exclude choledochal cyst, any focal lesions, dilated CBD, anomalies of viscera or portal hypertension. Role of Hida Scan

Hepatobiliary scintigraphy, after a 5 day priming with phenobarbitone,is useful. Excretion of the radio-tracer into the gut rules out biliary atresia. However, the converse is not true and absence of gut excretion of radiotracer requires further evaluation. Role of Liver Biopsy Liver biopsy is useful in the charecterisation of NCS in some cases. Coagulopathy and ascitis are contraindications for percutaneous liver biopsy. 52

TREATMENT On suspicion of cholestatic liver disease, vitamin-K is started along with supplementation of other fat soluble vitamins (A,D,E,) Treatable Causes Medical § Sepsis § UTI § Congenital infections § Hepatitis § Galactosemia § Heriditary fructose intolerance § Hypothyroidism § Hypopitaris m § Tyrosinaemia Surgical 3. Biliary Atresia 4. Choledochal cyst 5. Spontaneous perforation of bile ducts 6. Inspissation of bile ducts SUPPORTIVE CARE Nutrition  Energy - 125% RDA

 Protein intake -2-3 gm/kg/day in infants (0.5gm/kg/day in hepatic encephalopathy) 53

 Vitamin A should be supplemented in a dose of 50,000 IU intramuscularly at diagnosis and then 10,000 IU monthly till cholestasis resolves. Avoid hyper- vitaminosis as it can enhance fibrosis.  Vitamin D should be supplemented in a dose of 30,000 IU intramuscular at diag-nosis and then monthly till cholestasis resolves. If the child has rickets give a dose of 60,000 IU.  Oral Vitamin E, supplementation (50-200 mg/day) is required to avoid neuro-muscular

degeneration, retinal pigmentation and hemolytic anemia.  Provide Vitamin K 5 mg/day intramuscular/intravenous for first 3 days and then 5 mg weekly. Perform prothombin time (PT) monthly. Administer injectable vitamin K if PT is prolonged.  Water soluble vitamins and trace elements (2-5) times RDA) Pruritis For control of pruritis following agents have been tried :- 1. Phenobarbitone-5mg/kg/day 2. Rifampicin- 1Omg/kg/day 3. Ursodeoxycholic acid-10-20 mg/kg/day 4. Cholestyramine-4- 8gm/kg/day

5. Terfenadine l-3mg/kg/day 6. Carbamazepine Liver Transplantation This may remain the only option for infants with decompensated liver disease (ascites and /or encephalopathy) or failed portoenterostomy. 54

Standard Operating procedure  In Patient only: May require ICU monitoring  Referral criteria: Referral criteria for a specialist centre: Any case of neonatal cholestasis as defined by above parameters with deranged liver function tests to be referred to tertiary centre for further management. Child needs to be referred to a specialist pediatric liver unit if, 1. Evidence of progressive liver failure 2. Evidence of complications such as portal hypertension, SBP, Respiratory distress, pathological

fractures. 3. Failure of Kasai operation Evidence of liver cirrhosis in biopsy Jaundice not cleared by 2 months after surgery 4. Considerations for liver transplant Situation 2: Referred cases from secondary centres or any newborn with evidence of cholestatis with deranged liver function tests. 56

Investigation: Medical causes Surgical causes As in situation 1 & Additional investigations USG Abdomen: Day 5 : Prepare patient for HIDA (Priming Blood culture with gardenal 3-5 mg/kg) Urine culture Urine reducing substances Prothrombin time T3/T4/TSH TORCH/VDRL Hep B/C, HIV Metabolic work up 57

Subsequent investigation (if initial workup negative) • α 1 antitrypsin levels & phenotype  Galactose 1- P uridyl transferase  Urinary succinyl acetone  Cholesterol, Triglycerides  Serum ferritin, iron  Radiology  Rare investigation- Bone marrow aspiration/skin biopsy/muscle biopsy/ serum lactate / pyruvate / ammonia, very long chain fatty acid, urinary organic acids, urinary bile acids, auto immune screen / sweat chloride test. Treatment:  Aims of treatment

 Within 7 days of hospitalisation treatment is mandatory. • Kasai’s Portoenterostomy preferably within 60 days of life. Medical: Neonatal hepatitis: 2. Bacterial Sepsis/ UTI : antibiotics 3. Malaria : antimalarial 4. Toxoplasmosis & syphilis : specific antibiotics 5. CMV : ganciclovir 6. Herpes : acyclovir 7. Metabolic: 8. Galactosemia : stop lactose milk 9. Fructosemia : withdrawal of fructose containing item 10. Hypothyroidism : Thyroxine Chronic cholestatis:  Basically improve nutritional status 58

 Provide energy (125%RDA)  Proteins intake 2-3 gm/kg  MCT diet  Fat Soluble vitamins (A/D/E/K)  Pruritis control: Phenobarbitone / Rifampicin/ UDCA/ Cholestyramine/ Terfenadine/ Carbamazepine Surgical Biliary atresia Kasai Portoenterostomy Choledochal cyst Laparatomy Failed Kasai Liver Transplantation End stage liver disease PFIC VI. WHO DOES WHAT? and TIMELINES • Doctor : • Close and continuous and crucial monitoring of the child • Planning of tests and treatment • • Nurse

§ Counseling and support to child and family § Assisting to treatment • Technician VII. FURTHER READING / REFERENCES 1. S.K.Yachha: Consensus Reoprt on Neonatal Cholestasis Syndrome, Indian Pediatircs 2000;37:845-85 2. Neelam Mohan: Neonatal Cholestasis, openmed.nic.in/1827/01/neelam.pdf 3. Chardot C, CartonM, Spire-bendelae N etal.Is Kasais. Operation still indicated in children older than 3 months. Diagnosed with billiary atresia Pediatr2001; 138:224-28 59

4. ChhabraM, PoddarU, Thapa BR, SinghK, Spectrum of Cholestatis of infancy. Indian J gastroenterology 1996; 15: suppl1 A73 5. KaderHH, Balisteri WF.In: Rd Behrmann, RM Kliegman, HB jenson, (Eds): cholestatis from nelson text of pediatrics.saunders company. (17edition) 2003; 1314-19. 6. 4.Kotb MA,Sheba M, El koofy N,etal.Evaluation of Triangular cord sign in the diagnosis of billiary atresia.2001;108:416-20. 7. Lai MW, Chang MH.Hsu SC, Cheng TS, kao CL, Lee CY.Differential diagnosis of

extrahepatic billiary atresia from neonatal hepatitis: a prospective study Pediatr Gastroenterology Nutr 1994; 18:121-217 8. McEvoy CF, SuehyFJ.Billiary tract disease in children.Ped clin north Am1996; 43:75-98 9. Paltiel HJ.Imaging of neonatal cholestatis.semin Ultrasound CT and MRI 1994; 15:290- 305 60

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situatio Human Investigations Drugs & Equipment n resources consumables 1 Pediatrician Vitamin K Radiant Warmer Pediatric Nurse Antibiotics Saturation monitor Radiologist I.V. Glucose/ Fluids Basic Lab. Lab. Technician I.V. canula USG I.v. set 2 Pediatrician with Higher antibiotics NICU liver intensivists

Pediatric O.T. Pediatric surgeon Pathologist for Pediatric biopsy anaesthesists Radiologists Radiologists Nuclear medicine Gastroenterologis ts Nuclear medicine 61

Urinary tract infection and vesico ureteric reflux e. When to suspect and recognise h) Introduction Urinary tract infection (UTI) is a common condition affecting children and vesico ureteric reflux (VUR) is one common cause of recurrent UTI. UTI in the presence of infection results in kidney damage and one of the common causes of chronic renal failure in adult hood . UTI and VUR need prompt recognition to reduce morbidity and mortality in children. ( B) Case definition.

Vesico ureteric reflux may be primary due to short intramural course of ureters or it may be secondary to posterior urethral valves, Ureteroceles. Neurogenic bladder or it may be a part of duplex system of the kidney. II . Incidence of the condition in our country The exact incidence in our country is not known But from published data it is the risk of developing UTI before the age of 14 years is approximately 1% in boys and 3-5% in girls

The incidence varies with age. During the first year of life, the male to female ratio is 3- 5:1. Beyond 1-2 years, there is female preponderance with male to female ratio of 1:10. The incidence of VUR in children with UTI is approximately 30 to 50 % in the siblings of the index case shows an incidence of 20 to 30 %. III . Differential diagnosis of VUR I. Obstructive Mega ureters, II. Ureteroceles, III. Uretral valves, 62

IV. PUJ obstructions V. Ureteric stenosis, VI. Neurogenic bladder, VII. Posterior urethral valves with reflux VIII. Stones in the bladder and ureter. IV. Prevention and counselling VUR is congenital disease either primary or secondary to congenital outlet obstructions. As such prevention is not possible. Presence of pelviureteric dilatation on antenatal scans needs evaluation soon after birth. However UTI secondary to VUR can be prevented by prophylactic antibiotic therapy,

Periodical cultures and recognising infective episodes and treating them aggressively. Mothers must be counselled on the need for long term chemo prophylaxis and have the urine culture done every febrile episode of the child with VUR. Early recognition can prevent damage and scarring to the kidney , As regards the parents can be counselled that Grade I to III is likely to disappear spontaneously in most cases within a period of two to three years. However

spontaneous disappearance Gr IV and Gr V is likely to be less but can be given a chance of Chemo prophylaxis and observation for a period of two to three years. Break through infections and fresh scars and structural abnormalities will be an indication for surgical intervention. V. Optimal diagnostic criteria , investigations treatment and referral criteria. Situation 1. At secondary hospital / Non metro situation – optimal standards of treatment in situations where technology and resources are limited.

A. Clinical diagnosis High degree of suspicion of VUR in all UTI patients. Febrile episodes with anorexia , vomiting and shivering 63

Recurrent fever/ PUO Recurrent vomiting Failure to thrive. Voiding dysfunction and dysuria b. Investigations Urine Routine and microscopy Urine culture and sensitivity (MSSU) Blood urea and serum creatinine Ultra sonogram Micturiting cysto urethrogram if expertise is available C. Treatment: If the urine culture is positive c. Day care: No role for day-care d. Out patient : UTI treated with appropriate oral antibiotics e. Inpatient: UTI treated by appropriate antibiotics intravenously : Sick child

Based on culture and sensitivity report child needs admission . Appropriate antibiotics are chosen and administered for a period of 7 to 10 days intravenously. It should be followed by oral chemo prophylaxis till the reflux subsides with periodical monitoring of the urine culture especially during febrile episodes. In metro hospitals for the VUR no surgical intervention is done . Ultrasonogram done shows some structural abnormalities , should be investigated further

with Intravenous urogram and sent to higher centres for intervention. Referral criteria 11. All cases of UTI who have not been evaluated with MCU should be referred to higher centre for further evaluation and plan of management. 64

12. All patients with VUR should be referred to higher centres for Radionuclide studies to see the differential renal function and asses the renal damage. Lower grades of reflux with recurrent UTI and evidence of development of new scars and anatomical abnormalities need to be referred to higher centres for management. ( B) All cases of Gr IV and Gr V VUR should be referred to centres doing major paediatric surgical work as they do not undergo spontaneous resolution and require

surgical or endoscopic management. . Situation 2 At super specialty at metro location where higher end technology is available Investigations. Routine urine examination and culture and sensitivity Blood urea creatinine Ultrasonogram DMSA scan IVU in selected cases to exclude upper urinary tract lesions Bladder function Urodynamics studied in selected cases Other investigations such as Plasma rennin activity and Genetic studies may be required in some cases. Absolute indications for surgery

i. Anatomic abnormalities of the bladder and VU junction j. Unresolving VU reflux k. Progressive renal injury l. Break through Pyelonephritis inspite of appropriate antibiotic prophylaxis m. Failure of renal and somatic growth 65

n. Non compliance in medical management of the drug regime Treatment Primary treatment Treatment of UTI with appropriate drug with appropriate dosage and period of time. Spontaneous resolution for most of the minor VUR and to a small extent Major VUR It happens over period of time which is usually 3 years. Children need long term chemoprophylaxis & surveillance ( BP monitoring ), Somatic growth monitoring , renal function tests , urine analysis and Periodical cultures

Periodical assessment of renal condition with Ultra sonogram and Nuclear scans and MCU Surgical treatment: Type of surgery Open surgery :- Reimplantation of ureters Average stay 7 to 10 days Has a success rate of 98 % Child may need readmission for removal of stents if used for splinting the reimplanted ureters Alternative management There is a role for alternate procedures in select patients like 1.Circumcision 2. Endoscopic injection therapy 3 Diversion procedures like Ureterostomy and vesicostomy.

Long term management will include surveillance of the child and addressing bladder dysfunction if present. Referals Even in Metro cities there are several levels of care. Surgical and endoscopic procedures should be done in institutions with proper cystoscopes for different age groups including 66

the neonates. C arm facilities and monitors to see the endoscopic procedures are necessary. Anaesthetist trained in paediatric anaesthesia is essential. Who does what and timelines • Doctor. • Paediatric chief surgeon........ Main surgery • Assistant surgeon... Assists the surgeon • Scrub nurse • Theatre technician • X- Ray technician to monitor C Arm • Ward staff Further Reading and references Consensus statement of management of Urinary tract infections

Indian Paediatric nephrology group Ind Paeditrics 2001:38:106-1155 Progress in Paediatric urology Edited bY Minu bajpai. Volume 6 Vesico ureteric reflux SITUATION HUMAN RESOURCE INVESTGATIONS DRUGS AND EQUIPMENT CONSUMABLES 1 Pediatrician, Nurse., Urinanalysis urine Oral antibiotics Ultrasound ultrasonologist lab culture ultrasound machine basic technician blood counts laboratory serum creatinine 2 Pediatric surgeon In addition to (1) Oral antibiotics IV In addition to (1)

pediatric fluoroscopy, antibiotics advanced nephrologist/pediatricia nuclear medicine material for IV laboratory, n ultrasonologist, urodynamics access , material fluoroscopy faclity radiologist, nuclear for radiological nuclear medicine medicine specialist , tests. Material for facility, 67

urodynamics expert nuclear medicine urodynamics tests, operation theatre 68

Neonatal Jaundice-Unconjugated hyperbilirubinemia Prepared by: 1.Dr.Swarna Rekha Bhat, Professor of Pediatrics, St.John’s Medical College and Hospital Bangalore. ` 2. Dr. Chandrakala, Department of Pediatrics, St.John’s Medical College and Hospital Bangalore 69

NEONATAL JAUNDICE : UNCONJUGATED HYPERBILIRUBINEMIA 7. When to suspect / Recognize? f. Introduction: Neonatal jaundice is one of the most common neonatal problems. The most common cause of neonatal jaundice is physiologic jaundice. Although most newborns with jaundice are otherwise healthy, they need to be monitored because bilirubin is potentially toxic to central nervous system, causing bilirubin induced neuronal damage (BIND). Chronic BIND is also known as kernicterus. Kernictrus leads to permanent

neurodevelopmental handicap. Physiologic jaundice is benign and self limiting, but pathologic jaundice can cause severe hyperbilirubinemia , which if not treated appropriately can result in kernicterus g. Case definition : For both situation of care ( mentioned below) Neonatal jaundice : indicates presence of visible jaundice. Jaundice is visible in a neonate at bilirubin levels of 5 mg/dl Neonatal hyperbilirubinemia : bilirubin > 15 mg/dl

Significant hyperbilirubinemia : jaundice requiring treatment (bilirubin > 17 mg/dl ) Severe hyperbilirubinemia : bilirubin > 20 mg / dl Extreme hyperbilirubinemia : bilirubin > 25 mg / dl Acute bilirubin encephalopathy : used to describe acute CNS manifestation of bilirubin toxicity. Chronic bilirubin encephalopathy (Kernictrus ): Chronic and permanent clinical sequelae of bilirubin toxicity Bilirubin induced neurological dysfunction (BIND): changes associated with acute bilirubin encephalopathy

TERM infants : o. Onset on day 2-3 of life p. Reaches peak of 12mg/dl on day 4-5 q. Subsides over 7-10 days Preterm : f. Onset on day 2 of life g. Reaches peak of 15mg/dl on day 6-8 h. Subsides over 10-14 days of life There is no clear consensus on what is bilirubin cut off for physiological jaundice. However levels greater than 17 mg% are unlikely to be due to physiologic jaundice Pathological jaundice : 8. Onset of jaundice before 24 hours of life 9. Rise in bilirubin of > 0.5 mg/dl/hour

10. Any level of bilirubin that requires phototherapy 11. Signs of underlying illness in an infant with jaundice ( vomiting, lethargy, poor feeding, excessive weight loss, apnoea, tachypnoea, temperature instability ) 12. Jaundice persisting more than 14 days in a preterm and term infant 13.Direct bilirubin of more than 2mg/dl or more than 15 % of total serum bilirubin. 8. INCIDENCE OF THE CONDITION IN OUR COUNTRY : 65 -70 % of all neonates have clinical jaundice . Incidence is higher

among preterm neonates as compared to term neonates. Incidence of neonatal hyper bilirubinemia is 4.3- 6.5 % of all live births ( NNPD 2005 ) 71

9. Differential diagnosis : 1. The most important aspect is to differentiate neonates with self limiting physiologic jaundice from those having neonatal jaundice due to underlying problems ( pathologic jaundice ), as the latter group can develop severe hyperbilirubinemia which can result in neuronal damage 2. Neonatal unconjugated hyperbilirubinemia should always be differentiated from neonatal cholestasis. One should suspect neonatal cholestasis if any neonate with jaundice has pale

coloured stools and high coloured urine Causes of indirect hyperbilirubinemia • Fetomaternal blood group incompatibility – ABO / Rh • Hemolytic jaundice • Drug induced – Vitamin K, antimalarials, Oxytocin • Collection of blood in the extravascular space ( cephalhematoma ) • Polycythemia • Metabolic and endocrine conditions Galactosemia, Criggler Najjar syndrome, Hypothyroidism, hypopituitarism, Tyrosinosis • Prematurity • Infant of diabetic mother • Sepsis 14. PREVENTION & COUNSELLING : Primary prevention :

1. Screening for isoimmunisation: All pregnant women should be tested for ABO/ Rh (D) typing 72

All neonates born to O blood group and Rh negative mothers should have a cord blood sample taken for blood grouping, typing and Coombs test ( DCT ) 2. Preventing hyperbilirubinemia : Having hospital policies for detection for jaundice in newborn i) Protocols for assessment of jaundice at 12 hrly interval j) Identifying the babies at risk of developing hyperbilirubinemia k) Ensuring successful breast feeding ***Babies at risk for developing hyperbilirubinemia are; Major:

IX. Predischarge TSB ( total serum bilirubin ) in high risk zone X. Jaundice within first 24 hours XI. Blood group incompatibility with positive DCT XII. All preterm babies XIII. Previous sibling received photo therapy XIV. Cephalhematoma or significant bruising XV. Exclusive breast feeding , if nursing is not going on well and weight loss is excessive (greater >10%) Minor: XVI. Predischarge TSB in the high intermediate risk zone XVII. Gestational age 37-38 weeks

XIX. Maternal age >25 yrs XX. Male gender Counselling parents : a. It is essential to make sure that the parents are informed about newborn jaundice. b. Early discharge (<48 hours) is one of the reasons for missing neonates with hyperbilirubinemia ( as breast feeding is not yet established and jaundice usually peaks at about 3 to 5 days ) c. It is preferable to keep the mother and baby pair in the hospital at least for a period of 48 hours even for normal deliveries

d. Those with major risk factors*** should definitely not be discharged early (preferably observed for 72 hours) e. If for any reason early discharge is planned, a pre- discharge bilirubin should be done and treatment planned as per the bilirubin nomogram ( appendix 1) and frequent follow up is essential 15. Optimal diagnostic criteria: Investigations, treatment and referral criteria Situation 1: At secondary hospital / Non Metro situation: Optimal standards of treatment in situation where technology

and resources are limited A ) Clinical criteria: Identify any risk factors in mother and baby Clinical assessment using Kramer’s criteria 74

Non invasive measurememt of jaundice if available – transcutaneous bilirubinometer • Lab measurement of bilirubin : Total serum bilirubin (TSB) and Direct bilirubin (daily) More frequent bilirubin assessment ( 8-12 hrly) if hemolytic jaundice is suspected Blood grouping/typing (ABO/Rh ) of all mothers and neonates born to mothers with Rh negative and O positive mothers Coomb’s test if mother is Rh negative or O positive Complete hemogram including Peripheral smear , Reticulocyte count

if hemolytic jaundice is suspected or neonate requires phototherapy Jaundice present beyond 2 weeks or sick infants need further evaluation C) Treatment: No role of outpatient or day care treatment If a neonate is referred from outside, neonate needs to be assessed for level of jaundice and assessment of risk factors needs to be done*** The following will need to be admitted and bilirubin estimation should be done • Any term neonate having clinical jaundice till lower abdomen and beyond

• Any preterm neonate having jaundice • Any neonate having jaundice in the first 24 hrs • Any neonate having jaundice beyond 2 weeks or has pale coloured stools 75

INPATIENT TREATMENT 1. AAP guide lines for management of hyperbilirubinemia in baby >_35 weeks (Appendix 2) The bilirubin level is estimated and plotted on the chart based on age of the baby. Decision is taken depending on which part of the graph the value falls § In addition to providing phototherapy for those who require the following policy needs to be practiced for all intramural neonates § Promote & support successful breast feeding § Establish nursery protocols for identification and

evaluation of hyperbilirubinemia § Assess all neonates for presence of risk factors § Only visual estimation of degree of jaundice can lead to errors in darkly pigmented infants, therefore frequent bilirubin estimations will have to be done § Perform systemic assessment on all infants prior to discharge for the risk of hyperbilirubinemia § Do a serum bilirubin for infants discharged before 48 hours § Interpret all babies bilirubin levels according to infant age, in hour specific nomogram

§ Provide appropriate follow up based on the time of discharge and risk assessment. § Treat newborn when indicated with phototherapy/ exchange transfusion 76

Phototherapy Indications for phototherapy in neonates above 35 weeks is based on the chart provided ( appendix 2) Indications in preterm babies In preterm neonates < 35 weeks there are no charts Guidelines for phototherapy in thus group is as follows < 1000gms ? prophylactic phototherapy 1000 to 1500 gms 7 to 9 mg% 1500 – 2000gms 10 to 12 mg% 2000 – 2500gms 13 – 15 mg% Duration of phototherapy : to be given till the bilirubin value reaches

safe level as per chart. It is advisable to keep the neonate in hospital for a period of 12 to 24 hrs or repeat a bilirubin value 12 to 24 hrs after stopping phototherapy as rebound hyperbilirubinemia can occur, particularly in neonates with hemolytic jaundice Types of light: Single or double surface phototherapy . A combination of special blue (TL20) lights and white lights Do not use white lights covered with blue paper as they are ineffective IT IS IMPORTANT TO CHANGE LIGHTS AFTER EVERY 1000 HOURS OF USE

EXCHANGE TRANSFUSION CAN BE DONE AT A SECONDARY LEVEL ONLY IF EXPERTISE IS AVAILABLE If expertise is not available early referral of high risk neonates is recommended • Referral criteria: Early referral • Presence of major risk factors (Rh/ABO) 77

• Onset of jaundice within 24 hours • Rapid rise of bilirubin in spite of phototherapy • TSB is nearing Exchange transfusion range • Associated other morbidity Situation 2 Tertiary centre a) Clinical diagnosis : Same as Explained c) Investigation : Non invasive mode of detection of jaundic Transcutaneous bilirubinometry These instruments gives fairly accurate estimates of TSB in term/near term, values within 2-3mg/dl They have been considered as a predischarge screening tool to identify at risk infants

Lab investigation : As above Additional investigations • G6PD • T3 T4 TSH • Bilirubin monitoring 6-8 hourly in neonates with hemolytic jaundice or 12 to 24 hrly in other neonates Treatment : 78

Phototherapy : started when the bilirubin value crosses the percentile charts. Appendix 2 The lights which can be used for the treatment are: Special blue light ( TL 20) - (acceptable range for flux should be 8-10 microwatts/cm2 /nm and for intensive photo therapy ; >30 microwatts/cm2 /nm Fiberoptic ( bili blanket) LED ( light emitting diode) Exchange transfusion Is indicated if bilirubin rises beyond recommended levels as per chart Appendix 3

It is indicated at earlier levels in preterm neonates and neonates with immune hemolysis Guideline for preterms < 1000gms 10 to 12 mg % 1000 to 1500 gms 12 to 15 mg% 1500 – 2000gms 15 to 18 mg% 2000 – 2500gms 18 to 20 mg% Rh or ABO immune hemolysis Bilirubin values of 10 mg% within 24 hrs of age 15 mg% between 24 to 48 hours of age In all other situations - as per chart ( appendix 3 ) Other pharmacological treatment ; 79

• Intravenous immunoglobulin( IVIG) – is useful as it inhibits hemolysis, may decrease the need for ET but does not eliminate it completely. IVIG can be used in neonates either Rh or ABO isoimmunization ( dose ) • Tin mesoporphyrin – at 6 micro mol/kg more effective than special blue light . Human studies have shown that a single IM dose of 6 microM/kg eliminates the need of phototherapy in the postnatal period. (Not yet available) 2 ) Standard operational procedure Inpatient : • Phototherapy

• Exchange transfusion : whole blood crossed matched against mothers group ,matched to baby blood group .volume decided by the weight of the baby. It is an invasive procedure requires cannulation of the umbilical vein/any other peripheral vein. Out patient : Sampling blood for investigations,cross matching , no prccedure on outpatient basis Referral criteria : No referral from tertiary centre 13. WHO DOES WHAT ? and TIMELINES Doctor : Identification of the babies with risk factors

To follow up the cord blood group as early as possible after birth,initiate treatment early if required especially if there is O/ Rh negative history 80

Daily assessment for jaundice clinically if required investigation Decision regarding Photo therapy / exchange transfusion Perform Exchange transfusion Nurse : To assess clinically for jaundice when checking 6 -8 hrly vitals To inform doctors and to do trans cutaneous bili check or send blood for bilirubin Assessment of clinical status , hydration, side effects while the baby on the photo therapy. Technician : To find the bilirubin value as soon receiving the sample in a risk baby

and immediate information if abnormal Information on the abnormal blood group ,DCT report to concerned people 7) Further reading/ references: 6. Guha’s Neonatology principles and practice 3rd edition 2005 7. Neonatal pathology and management of the newborn by Avery , 6th edition 8. Neonatal perinatal medicine- Avroy A Fanaroff 9. Fanaroff and Martin’s Neonatal- Perinatal medicine- Diseases of the fetus ans infant- 8th edition 81

Methods of giving Phototherapy Baby fulfills the criteria for phototherapy (cid:216) To make sure that the lights are in usable condition (been used not more than 1000 hrs or > 3 months whichever is earlier) (cid:216) If double light phototherapy is given , infant lies on a fiberoptic blanket with conventional phototherapy overhead or a double surface phototherapy can be given (cid:216) To place the light as close to the baby as possible, if double light

phototherapy not given, position of the baby to be changed frequently (cid:216) If an incubator is used there should be a 5-8 cm space between it and the lamp cover to prevent over heating (cid:216) The most effective lights for phototherapy are those with output 425- 475 nm (cid:216) The baby should be naked with eyes and genitalia covered (cid:216) Temperature should be monitored and maintained (cid:216) Infant should be weighed daily

(cid:216) To monitor the hydration status of the baby and adjust the fluid/ feeds accordingly (cid:216) Frequent breast feeding, additional oral fluids only if significant weight loss is present ( > 10% wt loss ) (cid:216) Skin colour is not a guide to hyperbilirubinemia in infants on phototherapy ,hence bilirubin should be monitored every 12 hrs (cid:216) Once satisfactory decline in bilirubin has occurred, infants can be removed from phototherapy for feeding Exchange transfusion

(cid:216) To make sure the baby fulfills the criteria for exchange transfusion (cid:216) Choice of blood:  Fresh, less than 7 days old, irradiated ( if possible ), whole blood  In Rh hemolytic disease, blood is prepared before delivery, type O Rh negative crossed matched against mother. If the blood is obtained after delivery to be crossed against baby OR ABO group of baby and Rh negative blood  ABO incompatibility: O Rh negative or Rh compatible with the baby

and mother, crossed matched against mother and infant and have low 85

titer of anti A or anti B antibodies Usually type O cells are used with AB plasma to ensure that no anti A or anti B antibodies (cid:216) Volume for Exchange transfusion involves double volume of the infants blood that is 80 ml/ kg x 2 = 160 ml/kg ( in preterm neonates blood volume = 100 ml/kg) (cid:216) Technique : Procedure done under servocontrolled warmer and cardiac and blood pressure monitoring,  Equipment and personnel for resuscitation should be readily available

an assistant to record volumes of blood, observe and check the vitals  Infants arm and legs are properly restrained  Blood warmed to 37 degree centigrade • Sterile technique used during the whole procedure, Umbilical vein cannulated , position of the catheter to be checked by X –ray  Procedure done using 3 way valve assembly, most often push pull technique used • The total time taken for the procedure to be not more than 1-1 ½ hrs, Photo therapy to be continued after the procedure

 CVP should be measured before and after the procedure  During the procedure care to be taken to monitor the baby for vitals  The amount of blood per aliquot depends on weight of the baby which is as follows  <1000 gms - 3ml  1000- 1500 gms - 5 ml  1500-2000 gms -10 ml  2000-3500 gms - 15 ml  >3500 gms -20 ml Standard Treatment Guidelines Group Pediatrics and Pediatric Surgery Date: 28.02.2011 86

NEONATAL INTESTINAL OBSTRUCTION Dr.Ramesh Santhanakrishnan, Professor and Head, Department of Pediatric Surgery, Indira Gandhi Institute of Child Health, Bangalore. XXI. WHEN TO SUSPECT/ RECOGNIZE? a. Introduction: Neonatal Intestinal Obstruction (NIO) is a common condition affecting neonates and requires prompt recognition and appropriate specialist treatment to save these babies and to reduce avoidable morbidity & mortality b. Case definition:

Intestinal Obstruction in a new born child caused by intrinsic or extrinsic factors involving the stomach / duodenum / jejunum / ileum / any part of the colon. XXII. INCIDENCE OF THE CONDITION IN OUR COUNTRY i. The Exact incidence of the condition in our population is difficult to ascertain. However it may be approximately assessed to be 14 per 1,000 live births DIFFERENTIAL DIAGNOSIS a. Gastric Outlet Obstruction - Pyloric / Antral web / Hypertrophic Pyloric Stenosis b. Malrotation c. Duodenal Atresia

d. Jejuno-ileal Atresia e. Meconium Ileus f. Colonic Atresia g. Hirschprung’s Disease h. Meconium Plug Syndrome i. Necrotising Enterocolitis (NEC) 87

j. Medical conditions mimicking Neonatal intestinal obstruction like Neonatal Sepsis with ileus, Hypothyroidism etc. k. Other rare conditions like intestinal duplications, intra- abdominal cysts, congenital bands etc.  PREVENTION AND COUNSELING • As this is often a congenital disease, prevention is impossible. • However, the obstetricians at all levels need to have a high index of suspicion about the possibility of a GI obstruction when polyhydramnios is detected on antenatal scans

• When a fetus is suspected to have NIO, the counseling can be done to have a discussion with the obstetrician, the pediatrician & the pediatric surgeon and to plan the delivery to be done at a place where neonatal surgery is safely feasible 16. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited

• Clinical Diagnosis: Any child with any of the following criteria should be suspected to have NIO 10. Bilious Vomiting (green colour) 11. Abdominal distention 12. Visible peristalsis 13. Not passed meconium beyond 48 hours after birth (72 hours in preterm babies) 14. Passing abnormal stool (pellets / mucus / mucus plug) 15. Feed intolerance 16. Upper or Lower Gastrointestinal Bleeding. 88

Persistent Non-bilious vomiting  Investigations: a. Plain X-Ray Abdomen (preferably erect) b. Air contrast X-Ray - A naso-gastric tube is inserted prior to shifting the baby for the X-Ray. About 20 cc of Room air is insufflated through the naso-gastric tube and the X-Ray is taken. (This is to highlight the stomach, duodenum and the proximal jejunum and to rule out obstruction at this level.). Make sure the insufflated air is aspirated out immediately after

the X-Ray is taken and the NG tube is left for drainage c. Ultrasonography, if indicated. § Treatment: Standard Operating procedure 10. Day Care - No role for treatment on day care basis 11. Out Patient - No role for treatment on out-patient basis 12. In Patient - • Gastric Deompression • Place a No. 8 infant feeding tube through the nasogastric route. In very small babies, oro- gastric tube can be utilised if the nostrils are small. The baby should be kept nil orally.

• Ensure that the tube is correctly placed in the stomach and that it is patent. • Gently aspirate the tube hourly and connect to continuos drainage. • Maintain accurate chart to monitor the colour and volume of the aspirates i. Temperature Maintenance § Keep the child warm using an incubator / warmer and keeping the room ambient temperature high. A room warmer can be used in winter seasons • Intravenous Fluids to maintain Hydration / glucose levels. § The choice of IV fluids in the first 48 hours

§ After 48 hours of birth, the IV fluid of choice would be Isolyte P to be run @ 100 - 120 ml / kg / day (the rate will vary as per the gestation of the baby and other factors as determined by the pediatrician). § The fluid should be infused using ‘Burette’ / ‘Pediatric Drip Chamber set’ in order to avoid over or under infusion. Microdrip sets with ‘dosiflow’ regulators may be used if these are not available. § I.V. Antibiotics. Broad spectrum antibiotics to cover

gram positive, gram negative and anerobic bacteria should be used. Some of the suggested combinations are: 1. Ampicilin / Gentamicin / Metronidazole 2. Cefotaxime / Amikacin / Metronidazole 3. Co-Amoxiclav / Amikacin / Metronidazole 4. The choice of the antibiotic will vary on a lot of factors and can be suitably chosen by the treating clinician . ii. Preferable Investigations 1. Serum glucose / Electrolytes 2. BUN / Serum Creatinine 3. Hemoglobin & Blood Counts 4. Blood culture

6. 7. 8. b) Referral criteria: a. Ideally, all cases of neonatal intestinal obstruction should be transferred to hospitals with level 2 / 3 Neonatal intensive care facilities. b. However, in situations where a qualified pediatric surgeon is available, these children can be handled provided the hospital has the following facilities i. Neonatal nursery with the availability of full-time trained neonatal / pediatric nurses ii. Round the clock availability of Pediatrician

iii. Warming system for the baby - Radiant warmer/ Incubator etc/ iv. Operation Theatre well equipped with Monitors for ECG / Pulse Oximetry / Baby warming systems and other facilities for operating on a small baby v. A Well Trained Anesthesiologist with adequate exposure to neonatal anesthesia vi. Facilities for post-operative monitoring of the baby - warmer, multi-system monitor, resuscitation equipment etc. c. Mode of transportation & Precautions during transfer”

i. Keep the child warm using clean blankets/ thermocol boxes, cotton padding etc, Keep the NGT open & connect to continuous drainage. Strictly Avoid oral / NGT feeds ii. Maintain the patency of IV line by flushing it before transportation and run fluids at the pre-determined rate if the travel is expected to last more than a few hours iii. It is preferable to have a trained paramedical / medical supervision during transportation . The person should preferably be trained in basic neonatal care / neonatal

resuscitation methods, handling medical equipment like those required for airway maintenance / suction etc. iv. 91

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical Diagnosis: Same as earlier b) Investigations: a. Blood: i. CBC / CRP / Blood Culture ii. S. Electrolytes / BUN / Creatinine iii. Arterial Blood Gas iv. Blood Grouping & Rh typing / v. Serum Bilirubin vi. Other blood tests as deemed necessary by the neonatologist. b. Imaging: (Depending on the working diagnosis) i. Plain X-Ray of Abdomen in all cases

ii. Air contrast X-Ray - if upper GI obstruction is suspected. iii. Upper G.I. barium study - if upper GI obstruction is suspected. iv. Contrast (Gastrograffin preferably) Enema - if lower GI obstruction is suspected. v. Ultrasonography of Abdomen / Pelvis vi. CT scanning / MRI - in rare instances c. Additional Screening for Associated anomalies may be required in select cases i. 2-D Echocardiography ii. Renal Ultrasonography iii. Chromosomal & Metabolic screening iv. Any other as indicated c) Treatment: 92

Standard Operating procedure a. Out Patient - no role b. Day Care - No role c. In Patient: i. Initial resuscitation / Stabilisation ii. IV Fluids / Antibiotics as indicated earlier iii. Pre-operative Preparation - This will by and large depend on the condition of the baby and if any pre- existing morbidity is present and will be handled by the neonatologist. iv. Operative plan - This will depend on the diagnosis made about the level of obstruction. The possibilities include

1. Simple laparotomy + Ladd’s procedure / release of bands / Pyloromyotomy etc. 2. Laparotomy + Resection anastomosis 3. Laparotomy + Resection + Ileostomy / colostomy 4. Laparotomy + pull-thorough 5. One stage pull-through for Hirschprung’s Disease 6. Laparotomy + Other procedures as per variations in the operative findings. i. Post-operative Care - This will again have to be tailored to suit the child’s condition and requirements. The probable supportive measures will include:

1. IV Fluids with possible transfusion of blood products like Packed Cells / Plasma / etc. 2. IV Antibiotics- as suggested earlier and as dictated by various factors influencing the decision making process. 3. Inotropic Support - Dopamine / Dobutamine / Noradrenaline 4. Ventilatory Support 5. Parenteral Nutrition 6. Advanced Support like peritoneal dialysis 7. Vascular access ii. Some children may also require Additional Surgery like: 1. Re-look laparotomy 2. Definitive surgery 93

3. Explorations for complications like anastomotic leak, adhesive obstruction / dehiscence 4. Ilesotomy / colostomy closure iii. Other events during hospitalisation complicating the clinical course during hospitalisation = like renal failure, nutritional support, colostomy / ileostomy care etc. iv. Maternal support during hospitalisation including rooming in while feeding is initiated d) Referral criteria: a. Even within the metro cities, as there are several levels of

hospital care available, we recommend that new born babies with surgical problem should be handled by only those hospitals with reasonably good neonatal care (level 2 & 3) facilities with the availability of qualified Pediatric Surgeon and an experienced pediatric anesthetist. b. However, depending on the nature of the disease and the general condition of the baby, decision may be taken to handle the baby in centres with less than optimal facilities in Metro

cities if there is a genuinely good cause to believe that good surgical and post-operative care can be extended to the child without much detriment to the baby c. In any situation, after the initial resuscitation, if the general condition of the baby is poor or if there is a possible necessity of ventilatory support or specialised treatment, it will be necessary to shift the baby to a higher centre where such facilities are available, ensuring safe transportation of the baby 17. WHO DOES WHAT? and TIMELINES

a. Doctor i. Pediatrician: 1. Initial assessment and day to day care of the baby, 2. Early involvement of a pediatric surgeon and regular co-ordination with him/ her 3. taking appropriate decisions & involving the various specialists as indicated ii. Resident / Registrar 94

1. Periodic assessment of the patient and regular reporting to the specialists 2. Carry out the orders of the Pediatrician / Pediatric Surgeon in charge of the patient 3.To ensure that all the orders are properly carried out by the nursing and other paramendical personnel 4.Blood sampling and vascular access iii. Pediatric Surgeon 1. Prompt assessment of the baby on referral and to formulate an appropriate plan of action 2. Co-ordinating with the anesthetist and the

other Operation Theatre personnel for the proposed surgery 3. Performing the appropriate surgery and to make reasonable efforts for a smooth post- operative recovery. 4. Post-operative care & Daily assessment with regard to the post-operative recovery 5.Vascular access 6.Take decisions with regard to the daily progress and further interventions as and when indicated iv. Anesthetist 1. Suitable pre-operative preparation 2.Appropriate anesthetic care and smooth post- operative recovery

3.Co-ordination with the other clinicians involved in the care of the child v. Neonatologist 1. Initial assessment and day to day care of the baby, 2. Early involvement of a pediatric surgeon and regular co-ordination with him/ her 3. Taking appropriate decisions & involving the various specialists as indicated 4. Other specialist interventions AS AND WHEN NEEDED like : a. Vascular access b. Umbilical Venous / Arterial cannulation c. Peritoneal dialysis d. Enteral / Parenteral nutrition 95

a. Nurse i. Nursing care of the baby ii. Following all the instructions of the attending doctors iii. Close co-ordination with all the departments iv. Maintaining the records of the children upto date a. Emergency Room i. Ward ii. Neonatal Intensive Care Unit iii. Operation Theatre iv. Post-operative Recovery a. Technician 96

PROTOCOL FOR NEONATAL SEIZURES Drafted by: Dr Ramesh Agarwal MD, DM (Neonatology) Assistant Professor Newborn Health Knowledge Centre (NHKC) WHO Collaborating Centre for Newborn Training and Research ICMR Centre for Advanced Research Division of Neonatology, Department of Pediatrics New Private Ward-1st Floor All India Institute of Medical Sciences Ansari Nagar New Delhi, India- 110029 Tel: 91-11-2658 9644 Fax: 91-11-2658 8663, 2658 8641

Email: agarwalrameshdr@hotmail.com, ra010869@gmail.com, aranag@rediffmail.com 97

Neonatal Seizures (Seizure protocol adapted from: Sankar JM, Agarwal R, Deorari A, Paul VK. AIIMS Protocol on management of neonatal seizures. Available at: http://www.newbornwhocc.org/pdf/Seizures_2010_270810.pdf) a) WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Neonatal seizures (NS) are the most frequent and distinctive clinical manifestation of neurological dysfunction in the newborn infant. Infants with NS are at high risk of neonatal death or neurological impairment and epilepsy

disorders in later life. Though, mortality due to NS has decreased over the years from 40% to about 20%, the prevalence of long-term neurodevelopment sequelae has largely remained unchanged at around 30%.2 Improper and inadequate management of seizures could be one of the major reasons behind this phenomenon. b) Case definition and classification: A seizure is defined clinically as a paroxysmal alteration in neurologic function, i.e. motor, behavior and/or autonomic function.

Four types of NS have been identified- subtle, clonic, tonic and myoclonic. Myoclonic seizures carry the worst prognosis in terms of neuro- developmental outcome and seizure recurrence. Focal clonic seizures have the best prognosis. 98

In secondary level hospital At tertiary care centers A clinical definition should be used for The diagnosis essentially is clinical. recognition and classification of NS However sophisticated investigations such as EEG may be employed for confirmation and further classification. b) INCIDENCE OF THE CONDITION IN OUR COUNTRY The incidence of NS is 2.8 per 1000 in infants with birth weights of more than 2500 g; it is higher in preterm low birth weight neonates – as high as 57.5 per

1000 in very low birth weight infants. c) DIFFERENTIAL DIAGNOSIS The most common causes of seizures as per the recently published studies from the country are hypoxic ischemic encephalopathy, metabolic disturbances (hypoglycemia and hypocalcemia), and meningitis. HIE secondary to perinatal asphyxia is the commonest cause of NS. Most seizures due to HIE (about 50-65%) start within the first 12 hrs of life while the rest manifest by 24-48 hours of age. Common metabolic causes of seizures

include hypoglycemia, hypocalcemia, and hypomagnesemia. Meningitis should be excluded in all neonates with seizures. Meningoencephalitis secondary to intrauterine infections (TORCH group, syphilis) may also present as seizures in the neonatal period. Seizures due to subarachnoid, intraparenchymal or subdural hemorrhage occur more often in term neonates, while seizures secondary to intraventricular hemorrhage (IVH) occur in preterm infants. Cerebral dysgenesis and neuronal migration disorders are rare 99

causes of seizures in the neonatal period. a) PREVENTION AND COUNSELING Good obstetric and neonatal care would go a long way in prevention of neonatal seizures. Screening and management of polycythemia and hypoglycemia can prevent seizure occurrence due to these reasons. Avoiding animal mlk feeding by exclusive breastfeeding may reduce seizures due to late onset hypocalcemia. b) OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA Approach and diagnosis

In secondary level hospital At tertiary care centers • Clinical evaluation • Clinical evaluation • Measurement of blood glucose, • Measurement of blood glucose, calcium, hematocrit calcium, hematocrit • Lumbar puncture • Lumbar puncture • Neuroimaging (USG brian for preterm; CT/MRI for term baby • EEG Detailed approach to an infant with neonatal seizures1, 4-6 1. History Seizure history: A complete description of the seizure should be obtained from the

parents/attendant. History of associated eye movements, restraint of episode by passive flexion of the affected limb, change in color of skin (mottling or cyanosis), autonomic phenomena, and whether the infant was conscious or sleeping at the time of seizure should be elicited. The day of life on which the seizures occurred may provide an important clue to its diagnosis. While seizures occurring on day 0-3 might be related to 100

perinatal asphyxia, intracranial hemorrhage, and metabolic causes, those occurring on day 4-7 may be due to sepsis, meningitis, metabolic causes, and developmental defects. Antenatal history: History suggestive of intrauterine infection, maternal diabetes, and narcotic addiction should be elicited in the antenatal history. A history of sudden increase in fetal movements may be suggestive of intrauterine convulsions. Perinatal history: Perinatal asphyxia is the commonest cause of neonatal seizures and a

detailed history including history of fetal distress, decreased fetal movements, instrumental delivery, need for resuscitation in the labor room, Apgar scores, and abnormal cord pH (<7) and base deficit (>10 mEq/L) should be obtained. Use of a pudendal block for mid-cavity forceps may be associated with accidental injection of the local anesthetic into the fetal scalp. Family history: History of consanguinity in parents, family history of seizures or mental

retardation and early fetal/neonatal deaths would be suggestive of inborn errors of metabolism. History of seizures in either parent or sib(s) in the neonatal period may suggest benign familial neonatal convulsions (BFNC). 2. Examination Vital signs: Heart rate, respiration, blood pressure, capillary refill time and temperature should be recorded in all infants. General examination: Gestation, birth-weight, and weight for age should be recorded as

they may provide important clues to the etiology – for example, seizures in a term ‘well baby’ may be due to subarachnoid hemorrhage while seizures in a large for date baby may be secondary to hypoglycemia. The neonate should also be examined for the presence of any obvious malformations or dysmorphic features. CNS examination: Presence of a bulging anterior fontanel may be suggestive of 101

meningitis or intracranial hemorrhage. A detailed neurological examination should include assessment of consciousness (alert/drowsy/comatose), tone (hypotonia or hypertonia), and fundus examination for chorioretinitis. Systemic examination: Presence of hepatosplenomegaly or an abnormal urine odor may be suggestive of IEM. The skin should be examined for the presence of any neuro- cutaneous markers. Presence of hypopigmented macules or ash-leaf spot would be suggestive of tuberous sclerosis.

3. Investigations In secondary level hospitals At tertiary care centers • blood sugar measurement • blood sugar, calcium and electrolyte • sepsis work up and LP measurement • rule out polycythemia • sepsis work up and LP • rule out polycythemia • neuroimaging • metabolic work up • EEG Essential investigations: Investigations that should be considered in all neonates with seizures include blood sugar, serum electrolytes (Na, Ca, Mg), cerebrospinal fluid (CSF)

examination, cranial ultrasound (US), and electroencephalography (EEG). CSF examination should be done in all cases as seizures may be the first sign of meningitis. It should not be omitted even if another etiology such as hypoglycemia is present because meningitis can often coexist. CSF study may be withheld temporarily if severe cardio- respiratory compromise is present or even omitted in infants with severe birth asphyxia (documented abnormal cord pH/base excess and onset within 12-24 hrs). An arterial

blood gas (ABG) may have to be performed if IEM is strongly suspected. 102

One should carry out all these investigations even if one or more investigations are positive, as multiple etiologies may coexist, e.g. sepsis, meningitis and hypoglycemia. Imaging: Neurosonography is an excellent tool for detection of intraventricular and parenchymal hemorrhage but is unable to detect SAH and subdural hemorrhage. It should be done in all infants with seizures. CT scan should be done in all infants where an

etiology is not available after the first line of investigations. It can be diagnostic in subarachnoid hemorrhage and developmental malformations. Magnetic resonance imaging (MRI) is indicated only if investigations do not reveal any etiology and seizures are resistant to usual anti-epileptic therapy. It can be diagnostic in cerebral dysgenesis, lissencephaly, and other neuronal migration disorders. Electroencephalogram (EEG): EEG has both diagnostic and prognostic role in seizures.

It should be done in all neonates who need anticonvulsant therapy. Ictal EEG may be useful for the diagnosis of suspected seizures and also for diagnosis of seizures in muscle- relaxed infants. It should be done as soon as the neonate is stable enough to be transported for EEG, preferably within first week. EEG should be performed for at least one hour.9 Inter-ictal EEG is useful for long-term prognosis of neonates with seizures. A

background abnormality in both term and preterm neonates indicates a high risk for neurological sequelae. These changes include burst-suppression pattern, low voltage invariant pattern and electro-cerebral inactivity. Management In secondary level hospitals At tertiary care centers • Stabilize the baby • Stabilize the baby • Correct hypoglycemia or • Correct hypoglycemia or hypocalcemia, if present hypocalcemia, if present • Anti-epileptic drug therapy (AED): • Anti-epileptic drug therapy (AED): 103

phenobarbitone is the first choice phenobarbitone is the first choice • Refer if intractable seizures, or baby • Use additional drugs to control requires ventilation seizures • Management of concurrent illnesses Detailed approach to an infant with neonatal seizures1, 4-6 1. Initial medical management: The first step in successful management of seizures is to nurse the baby in thermoneutral environment and to ensure airway, breathing, and circulation (TABC). Oxygen should be

started, IV access should be secured, and blood should be collected for glucose and other investigations. A brief relevant history should be obtained and quick clinical examination should be performed. All this should not require more than 2-5 minutes. 2. Correction of hypoglycemia and hypocalcemia: If glucostix shows hypoglycemia or if there is no facility to test blood sugar immediately, 2 ml/kg of 10% dextrose should be given as a bolus injection followed by a continuous infusion of 6-8 mg/kg/min.

If hypoglycemia has been treated or excluded as a cause of convulsions, the neonate should receive 2 ml/kg of 10% calcium gluconate IV over 10 minutes under strict cardiac monitoring. If ionized calcium levels are suggestive of hypocalcemia, the newborn should receive calcium gluconate at 8 ml/kg/d for 3 days. If seizures continue despite correction of hypocalcemia, 0.25 ml/kg of 50% magnesium sulfate should be given intramuscularly (IM). 104

3. Anti-epileptic drug therapy (AED)1 Anti-epileptic drugs (AED) should be considered in the presence of even a single clinical seizure since clinical observations tend to grossly underestimate electrical seizures (diagnosed by EEG) and facilities for continuous EEG monitoring are not universally available. If aEEG is being used, eliminating all electrical seizure activity should be the goal of AED therapy.1 AED should be given if seizures persist even after correction of

hypoglycemia/ hypocalcemia (Figure 1). Phenobarbitone (Pb) It is the drug of choice in neonatal seizures. The dose is 20 mg/kg/IV slowly over 20 minutes (not faster than 1 mg/kg/min). If seizures persist after completion of this loading dose, additional doses of phenobarbitone 10 mg/kg may be used every 20-30 minutes until a total dose of 40 mg/kg has been given. The maintenance dose of Pb is 3-5 mg/kg/day in 1-2 divided doses, started 12 hours after the loading dose. Phenytoin

Phenytoin is indicated if the maximal dose of phenobarbitone (40 mg/kg) fails to resolve seizures or earlier, if adverse effects like respiratory depression, hypotension or bradycardia ensue with phenobarbitone. The dose is 20 mg/kg IV at a rate of not more than 1 mg/kg/min under cardiac monitoring. Phenytoin should be diluted in normal saline as it is incompatible with dextrose solution. A repeat dose of 10 mg/kg may be tried in

refractory seizures. The maintenance dose is 3-5 mg/kg/d (maximum of 8 mg/kg/d) in 2-4 divided doses. Oral suspension has very erratic absorption from gut in neonates, so it should be avoided. Thus only IV route is preferred in neonates and it should preferably be discontinued before discharge. 105

Benzodiazepines This group of drugs may be required in up to 15-20% of neonatal seizures. The commonly used benzodiazepines are lorazepam and midazolam. Diazepam is generally avoided in neonates due to its short duration of action, narrow therapeutic index, and because of the presence of sodium benzoate as a preservative. Lorazepam is preferred over diazepam as it has a longer duration of action and results in less adverse effects

(sedation and cardiovascular effects). Midazolam is faster acting than lorazepam and may be administered as an infusion. It causes less respiratory depression and sedation than lorazepam. However, when used as continuous infusion, the infant has to be monitored for respiratory depression, apnea, and bradycardia (equipment for resuscitation and assisted ventilation should be available at the bedside of all neonates given multiple doses of AED). The doses of these drugs are given below:

Lorazepam: 0.05 mg/kg IV bolus over 2-5 minutes; may be repeated Midazolam: 0.15 mg/kg IV bolus followed by infusion of 0.1 to 0.4 mg/kg/hour. According to Volpe, the expected response of neonatal clinical seizures to anticonvulsants is 40% to the initial 20-mg/kg loading dose of phenobarbitone, 70% to a total of 40 mg/kg of Pb, 85% to a 20-mg/kg of phenytoin, and 95% to 100% to 0.05 to 0.1 mg/kg lorazepam.1 Antiepileptic drugs for seizures refractory to above treatment

In exceptional circumstances when the seizures are refractory to the first-line AEDs, the following second-line drugs might be tried. 106

Maintenance anti-epileptic therapy Principles of AED used in older children and adults are applicable to neonates also. Monotherapy is the most appropriate strategy to control seizures. Attempts should be made to stop all anti-epileptic drugs and wean the baby to only phenobarbitone at 3-5 mg/kg/day. If seizures are uncontrolled or if clinical toxicity appears, a second AED may be added. The choice may vary from phenytoin, carbamezepine, and valproic acid. When to discontinue AED

This is highly individualized and no specific guidelines are available. We follow an adaptation of the protocol recommended by Volpe.1 We usually try to discontinue all medication at discharge if clinical examination is normal, irrespective of etiology and EEG. If neurological examination is persistently abnormal at discharge, AED is continued and the baby is reassessed at one month. If the baby is normal on examination and seizure

free at 1 month, phenobarbitone is discontinued over 2 weeks. If neurological assessment is not normal, an EEG is obtained. If EEG is not overtly paroxysmal, phenobarbitone is tapered and stopped. If EEG is overtly abnormal, the infant is reassessed in the same manner at 3 months and then 3 monthly till 1 year of age (Figure 2). The goal is to discontinue phenobarbitone as early as possible. 107

1. Volpe JJ. Neurology of the newborn. 5th ed. Philadelphia: Saunders Elsevier, 2008. Chapter 5, Neonatal Seizures;p.203-44. Tekgul H, Gauvreau K, Soul J, Murphy L, Robertson R, Stewart J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics References 2. 2006;117:1270-80. 3. Mizrahi EM, Kellaway P. Characterization and classification. In Diagnosis and management of neonatal seizures. Lippincott-Raven, 1998; pp 15-35

4. Painter MJ, Scher MS, Stein MD, Armatti S, Wang Z, Gardner JC et al. Phenobarbitone compared with phenytoin for treatment of neonatal seizures. N Engl J Med 1999;341:485-9 5. Rennie JM. Neonatal seizures. Eur J Pediatr 1997;156:83-7 6. Nirupama Laroia. Controversies in diagnosis and management of neonatal seizures. Indian Pediatr 2000;37:367-72 7. Iype M, Prasad M, Nair PM, Geetha S, Kailas L. The newborn with seizures -- a follow-up study. Indian Pediatr 2008;45:749-52

8. Kumar A, Gupta A, Talukdar B. Clinico-etiological and EEG profile of neonatal seizures. Indian J Pediatr 2007;74:33-7. 9. Wical BS. Neonatal seizures and electrographic analysis: evaluation and outcomes. Pediatr Neurol 1994;10:271-5 108

Figure 1 Acute management of neonatal seizures Neonate with seizures • Identify and characterize the seizure • Secure airway and optimize breathing, circulation, and temperature • Start oxygen if seizures are continuous • Secure IV access and take samples for baseline investigations including sugar, calcium, magnesium, sodium, potassium, arterial blood gas, hematocrit, sepsis screen 109

Seizures persist Administer phenobarbitone 20mg/kg IV stat Seizures continue Repeat phenobarbitone in 10 mg/kg/dose aliquots until 40 mg/kg dose is reached Seizures continue Administer phenytoin 20 mg/kg IV slowly over 20 minutes under cardiac monitoring Seizures continue Repeat phenytoin 10 mg/kg/dose Seizures continue Consider Lorazepam / midazolam bolus and midazolam infusion if needed; 110

Figure 2 Weaning of anticonvulsant therapy Newborn on anticonvulsant therapy Wean all antiepileptic drugs except phenobarbitone once seizure controlled Perform neurological examination prior to discharge Normal Abnormal Stop phenobarbitone Continue prior to discharge phenobarbitone for 1 month 112

Repeat neurological examination at 1 month Normal examination Abnormal examination Evaluate EEG Taper drugs Normal EEG Abnormal EEG over 2 weeks Taper drugs Continue drug; over 2 weeks reassess at 3 months *Intractable seizures may need lifelong therapy; consider switching over to other drugs (phenytoin or carbamazepine) 113

UNDESCENDED TESTIS IN CHILDREN Dr.Sanjay Rao Consultant Pediatric Surgeon, Narayana Hrudayalaya, Bangalore Assisted by: 1. Dr.Vinay C 2. Dr. Zameer K Department of Pediatric Surgery, Narayana Hrudayalaya, Bangalore l) WHEN TO SUSPECT/ RECOGNIZE? . h. Introduction : Diagnosis and management of the undescended testicle is required by 1 year of age as per current recommendation. i. Case definition: Cryptorchidism is the absence of one or both testes from the scrotum. It is the most

common birth defect involving the male genitalia. INCIDENCE OF THE CONDITION IN OUR COUNTRY The incidence of cryptorchidism is 1% to 4% in full-term newborns and in up to 45% of preterm male babies.However, a large number of these will descend spontaneously by 6 months of age. m) DIFFERENTIAL DIAGNOSIS 114

j. Retractile testis k. Ectopic testis l. Disorders of sexual differentiation ( if associated with hypospadias) n) PREVENTION AND COUNSELING If a newborn boy has been found to have an undescended testis, the family needs to be counseled about the need for review at 6 months and the possibility of surgery. In case of pain and swelling in the groin, there is a possibility of torsion and emergency intervention is necessary. o) OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA

History and Physical Examination It is important to note if the testes were ever palpable in the scrotum at the time of birth or within the first year of life. Classification is based on testicular location, either along the normal line of descent (abdomen, inguinal canal, external ring, pre-scrotal, upper scrotal) or in an ectopic position (usually in the superficial inguinal pouch or perineal) It is important to document associated findings such as hernia, hydrocele, penile size, and meatal position.

Check the size, location, and texture of the contralateral descended testis. Assess testicular mobility, size, consistency, and spermatic cord tension. The key to distinguishing a retractile from an undescended testis is success of delivery and stability of the testis within the scrotum. The retractile testis will remain intrascrotal after 115

overstretching of the cremaster muscle, whereas a low cryptorchid testis will return to its undescended position after being released. If there is any question, a follow-up examination is indicated. Imaging and Laboratory Tests Routinely no imaging studies are needed. Ultrasound (US), computed tomography (CT) scans and magnetic resonance imaging (MRI) imaging studies are optional in select cases. Basic investigations (such as hemoglobin and urinalysis) will be required for anesthetic workup. TREATMENT

Surgery Surgery is planned between the 6th to the 12th month of age by a trained pediatric surgeon. Palpable testis Standard open inguinal orchidopexy is done. Nonpalpable testis Exploration for a non-palpable testis is usually performed with laparoscopy. Once the testes is located by laparoscopy, it may be brought down into the scrotum in a single or two stage procedure. 116

UNDESCENDED TESTIS DOUBTFUL INTERSEX IMPALPABLE ANOMALY PALPABLE TESTICLE TESTICLE (associated OPEN INGUINAL OPEN / ORCHIOPEXY LAPAROSCOPIC ORCHIOPEXY Evaluate for DSD as per (SINGLE / TWO 117

FOLLOW UP Children are usually followed up as per the following time table: 10. 1 week after surgery 11. 3 months after surgery 12. Annually thereafter till puberty 13. Testicular self examination is taught to the boy at puberty *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited r. Clinical Diagnosis: • based on history and physical examination • it is adequate in majority of instances s. Investigations:

a. tests for anesthesia- Hemoglobin, urinanalysis t. Treatment: • Surgery under general anesthesia • Planned at 6-12months of age • If palpable testis- standard open orchidopexy • If non-palpable testis-laparoscopic assisted orchidopexy-either as single stage or two-stage 118

Standard Operating procedure a. In Patient: Child needs inpatient care if there are other co-morbidities that increase anesthesia risk b. Out Patient: Children are evaluated and worked up as outpatients, followup too is done in the outpatient department c. Day Care: Most orchidopexy operations are done as day case procedures. Children require inpatient admission if pain control is inadequate post operatively and if there are co-morbid conditions that require monitoring in the post op period.

u. Referral criteria: Child with undescended testis referred to higher centre if: 1. adequate anaesthesia facilities unavailable locally 2.intersex anomaly is suspected- as when there is: 1. severe hypospadias with unilateral non palpable testis 2. bilateral nonpalpable testis with or without hypospadias 3.child dysmorphic and a syndrome suspected *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available • Clinical Diagnosis: as above • Investigations:

a. for location of testis- not routinely required b. for intersex anomalies; i. Karyotyping, ii. Ultrasonography of abdomen and pelvis iii. genitography iv. genitoscopy v.laparoscopy 119

vi. hormonal assessment c. for syndromes: i. genetics consultation ii. karytyping iii. developmental assessment • Treatment: as above • If intersex – as per DSD protocol • Standard Operating procedure a. In Patient b. Out Patient c. Day Care • Referral criteria: No further referral needed p) WHO DOES WHAT? and TIMELINES q) a. Doctor makes a clinical diagnosis, counsels the family and plans surgery- a pediatric surgeon performs the surgery

b. Nurse: assists surgeon in care of child during pre, intra and post operative course of the baby c. Technician: assists medical and nursing teams in care of child during intra and post-operative periods. r) FURTHER READING / REFERENCES 18. Cendron M, Huff DS, Keating MA, et al. Anatomical, morphological and volumetric analysis: a review of 759 cases of testicular maldescent. J Urol 1993;149:570. 120

19. Moul JW, Belman AB. A review of surgical treatment of undescended testes with emphasis on anatomical position. J Urol 1988;140:125. 20. Cisek LJ, Peters CA, Atala A, et al. Current findings in diagnostic laparoscopic evaluation of the nonpalpable testis. J Urol 1998;160:1145. 21. Kirsch AJ, Escala J, Duckett JW, et al. Surgical management of the nonpalpable testis: the Children’s Hospital of Philadelphia experience. J Urol 1998;159:1340.

22. Patil KK, Green JS, Duffy PG. Laparoscopy for impalpable testes. BJU Int 2005;95:704. 23. Radmayr C, Oswald J, Schwentner C, et al. Longterm outcome of laparoscopically managed nonpalpable testes. J Urol 2003;170:2409. 24. Hegarty PK, Mushtaq I, Sebire NJ. Natural history of testicular regression syndrome and consequences for clinical management. J Pediatr Urol 2007;3:206. 25. Mesrobian HG, Chassaignac JM, Laud PW. The presence or absence of an

impalpable testis can be predicted from clinical observations alone. BJU Int 2002;90:97. 26. Cox MJ, Coplen DE, Austin PF. The incidence of disorders of sexual differentiation and chromosomal abnormalities of cryptorchidism and hypospadias stratified by meatal location. J Urol 2008; 180:2649. 27. Kaefer M, Diamond D, Hendren WH, et al. The incidence of intersexuality in children with cryptorchidism and hypospadias: stratification based on gonadal palpability and meatal position. J Urol 1999;162:1003.

28. Hrebinko RL, Bellinger MF. The limited role of imaging techniques in managing children with undescended testes. J Urol 1993;150:458. 121

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation Human Investigatio Drugs & Consumables Equipment Resources ns 1 • Pediatric • I.V. Glucose/ 14. Radiant Surgeon Fluids Warmer • Pediatricia • I.V. cannula 15. Saturation n • I.V. Set monitor • Pediatric • anesthetic drugs, 16. Basic Lab Nurse disposables 17. Child friendly • Lab. • antibiotic

Technician prophylaxis OT 2 • Pediat • I.V. 18. ICU ric Glucose/ 19. Pediatric surgeo Fluids O.T. n • I.V. cannula • Pediat • I.V. Set rician • anesthetic • Pediat drugs, ric disposables anaest • antibiotic hesist prophylaxis • Pediat ric Nurse 122

Diagnosis and Treatment of Malaria 2013 Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-1

Diagnosis and Treatment of Malaria in India For malaria control, the main thrust of the National Vector Borne Diseases Control programme (NVBDCP) is on early diagnosis and prompt, complete and effective treatment. Malaria diagnosis is carried out by microscopic examination of blood films collected by active and passive agencies. Health agencies and volunteers treating fever cases in inaccessible areas are being provided with Rapid Diagnostic Test (RDT) kits (Pf specific so

far and now Bivalent RDT) for diagnosis of Malaria cases so as to provide full radical treatment to the confirmed cases. It is stressed that all fever cases should be suspected of malaria after ruling out other common causes and should be investigated for confirmation of malaria by Microscopy or Rapid Diagnostic Kit (RDK) so as to ensure treatment with full therapeutic dose with appropriate drug to all confirmed cases. Presumptive treatment of

malaria with a single dose of chloroquine has been stopped. In all cases of suspected malaria which cannot be immediately confirmed by tests, full treatment with chloroquine for 3 days should be given. The malaria case management is very important for preventive serious cases and death due to malaria. So, the private healthcare providers should also follow the common National Guidelines for treatment of malaria as per the Drug Policy 2010. The aims of the Malaria case management are:

 To provide prompt and complete treatment to all suspected/ confirmed cases of malaria  To prevent progression of mild cases of malaria in to severe or complicated from of malaria  To prevent deaths from severe and complicated malaria  To prevent transmission of malaria  To minimize risk of spread of drug resistant parasites by use of effective drugs in appropriate dosage by everyone. Diagnosis and Treatment for Malaria Diagnosis &Treatment

All fever cases diagnosed as malaria by either RDT or microscopy should be promptly given effective treatment. The medicine chosen will depend upon whether the patient has vivax Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-2

malaria or falciparum malaria as diagnosed by the blood test. The flow charts in different settings for diagnosis and drug selection for the treatment of malaria are as under: Where microscopy result is available within 24 hours Suspected malaria case Take slide and send for microscopic examination Result ? Positive for Positive for Positive for Negative P. vivax P. falciparum Mixed infecion No anti- Treat with: In NorthEastern In NorthEastern states: malarial

CQ 3 days + states: Age-specific Treat with: Age-specific treatment PQ 0.25 mg ACT-AL for 3 days + ACT-AL for 3 days + per kg body PQ Single dose on Primaquine 0.25 mg per Treat as per weight daily for second day kg body weight daily for clinical 14 days 14 days. diagnosis In other states: Treat with: ACT-SP In other states: for 3 days + PQ SP-ACT 3 days + Single dose on Primaquine 0.25 mg per second day kg body weight daily for 14 days. Or daily for 14 days

ACT-AL - Artemisinin-based Combination T herapy- Artemether - Lumefantrine ACT-SP- Artemisinin-based Combination Therapy (Artesunate+Sulfadoxine-Pyrimethamine) CQ - Chloroquine PQ - Primaquine Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-3

Where microscopy result is not available within 24 hours and Monovalent RDT is used Suspected malaria case Where TfR >=1%, and Pf % In other areas, if patient not > 30% in any of last 3 years at high risk of Pf* Wait for slide result. Give CQ Do RDT for detection of 25mg/kg over 3 days only if Malaria & high suspicion of malaria Prepare slide Positive for RDT Negative: Wait P. falciparum for slide result. Positive for Positive for Give CQ 25mg/kg P. vivax P. falciparum In NorthEastern over 3 days, if high

states: Age-specific suspicion of malaria CQ if not In NorthEastern ACT-AL for 3 days already states: Age-specific + PQ Single dose given + ACT-AL for 3 days + on second day PQ 0.25 PQ Single dose on If confirmed as Pv mg/kg single second day In other states: CQ if not already dose for 14 Treat with: ACT-SP given days In other states: Treat for 3 days + PQ PQ 0.25 mg/kg/day with: ACT-SP for 3 days Single dose on over 14 days + PQ Single dose on second day second day TfR= Test falciparum rate

Note: if a patient has severe symptoms at any stage, then immediately refer to a nearest PHC or other health facility with indoor patient management or a registered medical doctor. Note: PQ is contra-indicated in pregnancy and in children under 1 year (Infant). ACT-AL - Artemisinin-based Combination Therapy- Artemether - Lumefantrine ACT-SP- Artemisinin-based Combination Therapy (Artesunate+Sulfadoxine-Pyrimethamine) CQ - Chloroquine PQ - Primaquine

Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-4

Where microscopy result is not available within 24 hours and Bivalent RDT is used Suspected malaria case Do blood test with RDT Positive for Positive for Positive for Negative P. vivax P. falciparum Mixed infecion Discard Discard slide Discard slide No anti-malarial slide treatment In NorthEastern In NorthEastern states: Treat with: states: Age-specific Treat with: Age-specific ACT- CQ 3 days ACT-AL for 3 days + AL for 3 days + Primaquine + PQ 14 PQ Single dose on 0.25 mg per kg body weight

days second day daily for 14 days. In other states: Treat In other states: with: ACT-SP for 3 SP-ACT 3 days + Primaquine days + PQ Single dose 0.25 mg per kg body weight on second day daily for 14 days. Note: 1) However, if malaria is strongly suspected, prepare & send slide for microscopy 2) If a patient has severe symptoms at any stage, then immediately refer to a nearest PHC or other health facility with indoor patient management or a registered medical doctor.

3) PQ is contra-indicated in pregnancy and in children under 1 year (Infant). ACT-AL - Artemisinin-based Combination Therapy- Artemether - Lumefantrine ACT-SP- Artemisinin-based Combination Therapy (Artesunate+Sulfadoxine-Pyrimethamine) CQ - Chloroquine PQ - Primaquine Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-5

Treatment of Vivax Malaria Diagnosis of vivax malaria may be made by the use of RDT (Bivalent) or microscopic examination of the blood smear. On confirmation following treatment is to be given: Drug schedule for treatment of P vivax malaria: 1. Chloroquine: 25 mg/kg body weight divided over three days i.e. 10 mg/kg on day 1, 10 mg/kg on day 2 and 5 mg/kg on day 3. 2. Primaquine*: 0.25 mg/kg body weight daily for 14 days. Primaquine is contraindicated in infants, pregnant women and individuals with

G PD deficiency. 6 14 day regimen of Primaquine should be given under supervision. Dosage Chart for Treatment of Vivax Malaria Day 1 Day 2 Day 3 Day 4 to 14 CQ CQ CQ Age PQ PQ PQ (150 (150 (150 PQ (2.5 (2.5 (2.5 mg mg mg (2.5 mg) mg) mg) mg) base) base) base) Less than 1 yr ½ 0 ½ 0 ¼ 0 0 1-4 years 1 1 1 1 ½ 1 1 5-8 years 2 2 2 2 1 2 2 9-14 years 3 4 3 4 1½ 4 4 15 yrs or more* 4 6 4 6 2 6 6 Pregnancy 4 0 4 0 2 0 0 Note: CQ 250mg tablet is having 150 mg base Treatment of Falciparum Malaria

Diagnosis of falciparum malaria may be made by the use of RDT (Monovalent or Bivalent) or microscopic examination of the blood smear. It is imperative to start the treatment for falciparum malaria immediately on diagnosis. The treatment for falciparum malaria is as follows: Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-6

In North-Eastern States (NE States): 1. ACT-AL Co-formulated tablet of ARTEMETHER( 20 mg) - LUMEFANTRINE (120 mg) (Not recommended during the first trimester of pregnancy and for children weighing < 5 kg) Recommended regimen by weight and age group The packing size for different age groups based on Kg bodyweight. 5–14 kg 15–24 kg 25–34 kg Co-formulated ( > 5 > 34 kg (≥ 3 to 8 (≥ 9 to14 tablet ACT-AL months to (> 14 years) years) years) < 3 years) 20 mg/ 40 mg /240 60 mg /360 80 mg /480

Total Dose of 120 mg mg mg mg ACT-AL twice daily twice daily twice daily twice daily for 3 days for 3 days for 3 days for 3 days Pack size No. of tablets 6 12 18 24 in the Packing 1 Tablet 2 Tablets 3 Tablets 4 Tablets Give twice daily twice daily Twice daily Twice daily for 3 days for 3 days for 3 days for 3 days Colour of the Yellow Green Red White pack 2. Primaquine*: 0.75 mg/kg body weight on day 2 In other States: 1. Artemisinin based Combination Therapy (ACT-SP)*

Artesunate (AS), available as 50 mg tablets are given for three days, and Sulfadoxine- Pyrimethamine (S-P) tablets, containing 500 mg Sulfadoxine and 25 mg pyrimethamine are given for one day, as shown in the dosage chart below. All tablets for a day should be taken together, swallowed with water. In addition, Primaquine (PQ Large) tablets should be given on the second day. Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-7

Dose schedule for Treatment of uncomplicated P.falciparum cases: 1. Artemisinin based Combination Therapy (ACT-SP)* Artesunate 4 mg/kg body weight daily for 3 days Plus Sulfadoxine (25 mg/kg body weight) – Pyrimethamine (1.25 mg/kg body weight) on first day. * ACT is not to be given in 1st trimester of pregnancy. 2. Primaquine*: 0.75 mg/kg body weight on day 2. With the introduction of different coloured Blister Packs for different age groups,

treatment by the field level staff has been made easy. The colour code for different age groups for Packing of Tablet ACT+SP has been given as follows: Dosage Chart for Treatment of falciparum Malaria with ACT-SP Age Group 1st day 2nd day 3rd day (Years) AS SP AS PQ AS 1 0-1 1 1 1 (250 +12.5 Nil Pink Blister (25 mg) (25 mg) (25 mg) mg) 1-4 1 1 1 1 1 Yellow (500+25 (7.5 mg (50 mg) (50 mg) (50 mg) Blister mg each) base) 5-8 1 2 1 1 1 Green (750+37.5 (7.5 mg (100 mg) (100 mg) (100 mg)

Blister mg each) base each) 2 4 9-14 1 1 1 (500+25 (7.5 mg Red Blister (150 mg) (150mg) (150 mg) mg each) base each) 15 & Above 2 6 1 1 1 White (750+37.5 (7.5 mg (200 mg) (200 mg) (200 mg) Blister mg each) base each) Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-8

Treatment of uncomplicated P.falciparum cases in pregnancy: 1st Trimester : Quinine salt 10mg/kg 3 times daily for 7 days. Quinine may induce hypoglycemia; pregnant women should not start taking quinine on an empty stomach and should eat regularly, while on quinine treatment. 2nd and 3rd trimester: Area-specific ACT as per dosage schedule given above. i.e. ACT-AL in North Eastern States ACT-SP in Other States Primaquine (PQ) prevents transmission of falciparum malaria to others by its ability to kill

gametocytes. PQ tablets should be taken after a meal; not on an empty stomach. Children less than the age of one year and pregnant women should not be given Primaquine. As pregnant women having falciparum malaria require different medicines, they should be directed to go to the nearest PHC or hospital immediately, without delay. Treatment of mixed infections (P.vivax + P.falciparum) cases: All mixed infections should be treated with full course of ACT and Primaquine 0.25 mg per

kg body weight daily for 14 days. In North-Eastern States: Treat with: Age-specific ACT-AL for 3 days + Primaquine 0.25 mg per kg body weight daily for 14 days. In Other States: SP-ACT 3 days + Primaquine 0.25 mg per kg body wt. daily for 14 days. Dosage Chart for Treatment of mixed (vivax and falciparum) Malaria with ACT-SP Age Days Day 1 Day 2 Day 3 4-14 PQ PQ PQ PQ AS tablet SP AS tablet AS tablet (2.5 (2.5 (2.5 (2.5 (50 mg) tablet (50 mg) (50 mg) mg) mg) mg) mg) Less than 1 yr ½ ½ 0 ½ 0 ½ 0 0

1-4 years 1 1 1 1 1 1 1 1 5-8 years 2 1 ½ 2 2 2 2 2 2 9-14 years 3 2 4 3 4 3 4 4 15 yrs or more 4 3 6 4 6 4 6 6 Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-9

Teatment of P. ovale and P. malariae: In India these species are very rarely found in few places. P. ovale should be treated as P. vivax and P. malariae should be treated as P. falciparum. Treatment of mixed infections: All cases of mixed infection are to be treated as Pf as per the drug policy applicable in the area plus primaquine for 14 days Use of paracetamol Paracetamol tablets are available as part of the ASHA kit also in the health facilities.

Paracetamol usually brings down fever from any cause within half an hour. However, paracetamol does not cure the disease that is causing the fever. So, its effect does not last long. The fever remains low for about 4-6 hours, and then the fever can rise again. Paracetamol can be safely given at any age and even during pregnancy, in the dose shown in the dosage chart. In this dose, it can be given 3-4 times a day if needed. If the fever is not

very high, and the patient is able to tolerate the fever, there is no need to give paracetamol. Dosage chart for use of Paracetamol Age No. of Tablets of Paracetamol (500 mg tablets) Less than 1 yr ¼ 1-4 years ½ 5-8 years ¾ 9-14 years 1 15 yrs or more 1 or 2 Initiation of treatment and advice to the patient/caretaker Once a suspected case is diagnosed positive by RDT or microscopy, treatment is started. The first dose is always taken in the presence of the health volunteer/worker. The blister

pack with remaining tablets is given to the patient/caretaker to take home with clear instructions. Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-10

Caution: If the patient is a child under 5 years or pregnant, ask the patient to wait for 15 minutes after taking the first dose. If it is vomited within this period, let the patient rest for 15 minutes, then give the first dose again i.e. open a new blister-pack and discard what remains of the old. If the patient vomits the first dose again, it is considered a case of severe malaria, refer the patient immediate to the nearest Block PHC/ CHC/ Hospital. Explain to the patient/caretaker

 That if the treatment is not completed as prescribed, the disease may manifest again with more serious features and more difficult to treat.  To come back immediately, if there is no improvement after 24 hours, if the situation gets worse or the fever comes back.  That regular use of a mosquito net (preferably insecticide treated net) is the best way to prevent malaria. Resistance to anti-malarial drugs. Resistance can be defined as either the ability of a parasite strain to survive and/or multiply

despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended, but within the limits of tolerance of the patient. In the last two decades, an increasing proportion of Plasmodium falciparum infections is proving to be resistant to chloroquine in India. Drug resistance is declared in a study area, when the proportion of treatment failures exceeds 10% of all falciparum infections. In these

areas the decision has been taken to treat all Pf cases with the drug ACT instead of chloroquine, Why does malaria parasite become resistant to anti-malarials? Drug resistance is a complex phenomenon, where by genetic mutation, a parasite acquires the ability to resist, partly or fully, the effects of one or more anti-malarial drugs. When the resistant parasites are exposed to the drug, they multiply selectively If parasites are resistant to the drug being used, the patient may not respond to treatment.

One of the commonest reasons for the development of drug resistance is that the parasites are exposed to insufficient amount of the drug due to  Low prescription dosage  Lesser amount of drug dispensed  Incomplete treatment taken by the patient  Drug vomited out Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-11

 Low absorption due to any reason, for example, diarrhoea. In such cases, most of the sensitive parasites are killed by even these small doses, but resistant parasites survive, multiply and spread to other people by mosquitoes. The new patient then gets infection from the resistant malaria parasites and does not respond to the drug at all, or responds only partly. Meanwhile, the earlier patient may appear cured because most of the parasites were killed by the drug, and the symptoms abated.

Why is it difficult for parasites to develop resistance to ACT? ACT contains three drugs: artesunate, sulphadoxine and pyrimethamine. Each drug acts on a different part of the parasite, in a different manner. It is very, very rare for three simultaneous genetic mutations to occur by chance to produce resistance to such diverse drugs. Resistance can be produced in multiple steps, one drug at a time, but this is expected to take many more years. At present, we do not expect resistance to develop to

ACT. If resistance develops, it is expected to first develop against sulphadoxine or pyrimethamine, since they have been in use for a longer time. If this begins to happen, some other, newer drug will be used as a companion drug for artesunate, to which resistance has so far not been reported in most malarious areas of the world. How can one suspect drug resistance in the field? What can one do when faced with treatment failure?

As mentioned above, when a patient fails to respond to treatment (symptoms fail to disappear, or they re-appear), one should think of the possibility of drug resistance. However, there may be many other causes of persistent symptoms:  the diagnosis might be wrong (the patient had a positive test, but the symptoms were due to some other cause)  the drug might not have been taken as expected (insufficient dosage was prescribed or swallowed), or may have been vomited out

 the drug was not absorbed in the gut (because of diarrhea, or other reasons), the drug may be of poor quality (past its date of expiry, or poorly stored, or of poor quality when supplied) Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-12

 the patient’s body might handle the drug abnormally (there are genetic differences in the metabolism of some rare individuals, which may cause the drug to be altered or eliminated quickly)  the patient might have had a fresh reinfection, or in the case of vivax malaria, there might have been a relapse of the malaria. In the absence of any of these conditions, if a patient has completed full treatment and is still having symptoms after 72 hours, treatment failure may be suspected.

The course of action when a patient has persistent symptoms is:  Ask the patient and the family a series of questions to help rule out some of the causes listed above (Did the patient get the drug from an authentic, designated provider? Did the patient get the right amount of the drug? Was all of it swallowed as prescribed? Was the drug vomited out? How many days has it been since drug treatment was begun (if it is not yet 72 hours, one can wait)? Can you see the

packing to check the expiry date? Are there symptoms of other obvious causes of fever? If the symptoms had disappeared and then reappeared, how long was the interval (if more than 15 days, it could be a fresh infection)?)  If it appears that the drug was not adequately taken or retained, a fresh course may be given at home unless the patient has symptoms of severe malaria. Take a fresh blood smear (take two, for checking in different laboratories, if need be), and ask the

nearest health care provider to keep an eye on the patient.  Refer any patient who has symptoms despite taking and retaining a full course of treatment, or who has developed symptoms of severe malaria. Severe and complicated malaria A case of uncomplicated malaria usually presents with fever, rigors, headache, bodyache, fatigue, anorexia and nausea. Serious complications can arise in P.falciparum infection and rarely in P vivax. They may

sometimes develop suddenly over a span of time as short as 12 -24 hours and may lead to death, if not treated promptly and adequately. Severe malaria is clinically characterized by confusion or drowsiness with extreme weakness (prostration). In addition, the following may develop: Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-13

 cerebral malaria with generalized convulsions  pulmonary oedema  severe anaemia  renal failure  hypoglycaemia  metabolic acidosis  circulatory collapse/shock  spontaneous bleeding and laboratory evidence of DIC  macroscopic haemoglobinuria  hyperthermia  hyperparasitaemia In children, febrile convulsions, repeated vomiting and dehydration are common if the temperature is high due to any cause. Therefore, these symptoms are not necessarily

indicative of severe malaria. However, children with such symptoms should be managed as severe malaria in routine program situations, and a diagnosis of malaria should be confirmed at the earliest. In pregnancy, malaria, especially P.falciparum is a serious disease because with each bout of malaria, there is a reduction in haemoglobin and profound anaemia may develop rapidly. They are also at high risk of abortions or intrauterine growth retardation because

sequestration of parasites in placenta restricts oxygen and nutrients flow to the fetus. The management of severe malaria is possible in health facilities which are equipped with the following:  Parenteral Antimalarials , antibiotics, anticonvulsants, antipyretics  Intravenous infusion equipment and fluids  Special nursing for patients in coma  Facilities for blood transfusion  Well equipped laboratory  Oxygen respirator Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-14

Often these items are not available at the PHC level. Under such circumstances, the Medical Officer, PHC and paramedical staff should be able to administer emergency treatment and refer the case without delay to other institutions where such facilities are available. A list of all health care facilities in the district where emergency care for severe malaria is available should be kept in PHCs and with Community Workers like ASHA. MO-PHC will

maintain liaison with all these institutions. For timely referral of severe cases, transportation arrangements should be made with the use of untied funds available under NRHM. The role of peripheral workers The community comes in contact with ASHA and MPW (M&F) as a routine. They depend on these persons for advice and treatment of different diseases, malaria being one of them. Therefore, while training these workers the need to recognize a serious case of malaria

should be emphasized. These workers should be conversant with the signs and symptoms of malaria and those which are likely to indicate serious complications. Severe malaria may be suspected, if the patient does not get relief from symptoms of malaria within 24 hours, and/or headache/fever continues to increase. Such patients should be referred immediately to the nearest PHC/CHC/Hospital. Criteria for immediate referral to Primary Health Centre: a) Persistence of fever after 24 hours of initial treatment.

b) Continuous vomiting and inability to retain oral drugs. c) Headache continues to increase d) Severe dehydration – dry, parched skin, sunken face e) Too weak to walk in the absence of any other obvious reason f) Change in sensorium e.g. confusion, drowsiness, blurring of vision, photophobia, disorientation g) Convulsions or muscle twitchings h) Bleeding and clotting disorders i) Suspicion of severe anaemia j) Jaundice k) Hypothermia

Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-15

Requirements for management of complications: The management of severe malaria requires immediate administration of life saving drugs. Therefore essential requirements for management of severe malaria are as follows:  A person trained in nursing serious/ comatose cases  Antimalarials which can be given parenterally: Artesunate, arte-ether, arte-mether or quinine  Supportive treatment: Antipyretics, anticonvulsants, diuretics, antibiotics, Saline/dextrose for intravenous transfusion

 Intravenous infusion equipment  Facilities for blood transfusion  Well equipped laboratory: Blood smear examination & parasite count with result within one hour, Routine examination of urine, haemoglobin, blood glucose  Oxygen respirator, Oxygen If these items are not available, the patient must be referred without delay to a facility, where such facilities are avialable. The DVBDCO/ DMO should list all facilities in the district where

emergency care for severe malaria is available and this list should be available in PHCs and with all Community Workers like ASHA. MO-PHC should develop links with these institutions. For timely referral of severe cases, transportation is provided from untied funds available under NRHM from Rogi Kalyan samity (RKS). Treatment of severe malaria cases Severe malaria is an emergency and treatment should be given as per severity and

associated complications which can be best decided by the treating physicians. Before admitting or referring patients, the attending doctor or health worker, whoever is able to do it, should do RDT and take blood smear; give a parenteral dose of artemisinin derivative or quinine in suspected cerebral malaria cases and send case sheet, details of treatment history and blood slide with patient. The guidelines for specific antimalarial therapy is as follows:

Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-16

Parenteral artemisinin derivatives or quinine should be used irrespective of chloroquine resistance status of the area with one of the following options: Chemotherapy of severe and complicated malaria Initial parenteral treatment for at least 48 Follow-up treatment, when patient can take hours: oral medication following parenteral CHOOSE ONE of following four options treatment  Quinine: 20mg quinine salt/kg body weight Quinine 10 mg/kg three times a day on admission (IV infusion or divided IM with:

injection) followed by maintenance dose of doxycycline 100 mg once a day or 10 mg/kg 8 hourly; infusion rate should not exceed 5 mg/kg per hour. Loading dose of clindamycin in pregnant women and children 20mg/kg should not be given, if the patient under 8 years of age, has already received quinine. - to complete 7 days of treatment.  Artesunate: 2.4 mg/kg i.v. or i.m. given on admission (time=0), then at 12 h and 24 h, then Full oral course of Area-specific ACT: once a day.

 In NorthEastern states: Age-specific ACT-  or AL for 3 days + PQ Single dose on second day  Artemether: 3.2 mg/kg bw i.m. given on admission then 1.6 mg/kg per day.  In other states: Treat with: ACT-SP for 3 days + PQ Single dose on second day  or  Arteether: 150 mg daily i.m for 3 days in adults only (not recommended for children). Note: The parenteral treatment in severe malaria cases should be given for minimum of 24 hours once started

(irrespective of the patient’s ability to tolerate oral medication earlier than 24 hours). After parenteral artemisinin therapy, patients will receive a full course of Area-specific oral ACT for 3 days. Those patients who received parenteral Quinine therapy should receive oral Quinine 10 mg/kg body weight three times a day for 7 days (including the days when parenteral Quinine was administered) plus Doxycycline 3 mg/kg body weight once a day or

Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-17

Clindamycin 10 mg/kg body weight 12-hourly for 7 days (Doxycycline is contraindicated in pregnant women and children under 8 years of age) or area-specific ACT as described. Note:  Pregnant women with severe malaria in any trimester can be treated with artemisinin derivatives, which, in contrast to quinine, do not risk aggravating hypoglycaemia.  The parenteral treatment should be given for minimum of 48 hours  Once the patient can take oral therapy, give:

 Quinine 10 mg/kg three times a day with doxycycline 100 mg once a day or clindamycin in pregnant women and children under 8 years of age, to complete 7 days of treatment, in patients started on parenteral quinine.  Full course of ACT to patients started on artemisinin derivatives.  Use of mefloquine should be avoided in cerebral malaria due to neuropsychiatric complications associated with it. Some don’ts in severe malaria case management

Do not use corticosteroids, give intravenous mannitol, use heparin as anticoagulant, administer adrenaline or overhydrate. In recent years, increased attention has been drawn to severe malaria caused by P.vivax, especially in Indonesia and Papua New Guinea, where this parasite has become chloroquine-resistant. Some cases have been found in India, and there is reason to fear that this problem will become more common in the coming years. Historically, P.vivax has been

an important cause of death in India and in Europe, and this parasite can no longer be considered as “benign”. Chemoprophylaxis Chemoprophylaxis should be administered only in selective grips in high P.falciparum endemic areas. Use of personal protection measures including Insecticide Treated bed Nets (ITN) / Long Lasting Insecticidal Nets (LLIN) should be encouraged for pregnant women and Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-18

other vulnerable population including travelers for longer stay. However, for longer stay of Military and Para-Military forces in high Pf endemic areas, the practice of chemoprophylaxis should be followed wherever appropriate e.g troops on night patrol duty and decisions of their Medical Administrative Authority should be followed. Short term chemoprophylaxis (up to 6 weeks) Doxycycline : 100 mg once daily for adults and 1.5 mg/kg once daily for

children(contraindicated in children below 8 years). The drug should be started 2 days before travel and continued for 4 weeks after leaving the malarious area. Note : It is not recommended for pregnant women and children less than 8 years Chemoprophylaxis for longer stay (more than 6 weeks) Mefloqiune: 250 mg weekly for adults and should be administered two weeks before, during and four weeks after exposure. Note : Mefloquine is contraindicated in individuals with history of convulsions,

neuropsychiatric problems and cardiac conditions. Therefore, necessary precautions should be taken and all should undergo before prescription of the drug. Use of chemoprophylaxis is limited to following situations: Short term travelers/tourists (less than 6 weeks) from non-malarious areas to malarious areas. Drug of choice is Doxycycline 100 mg daily in adults and 1.5 mg/kg bwt in children above 8 years; beginning 2 days before travel – 4 weeks after leaving a malarious area.

Doxycycline is contraindicated in children under 8 years and pregnant women, in whom personal protection should be used In long term travelers where appropriate e.g. military & paramilitary troops on night patrol duty etc. in malarious areas, the decision of respective medical administrative authority is to be followed. Drug of choice in such cases is Mefloquine 250 mg weeky for adults and 5 mg/kg for children once a week; beginning 2 weeks before to 4 weeks after exposure.

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References: 1. National Drug Policy for Malaria 2010, NVBDCP, MoH&FW, Govt. of India, 2010. 2. Operation Manual for Malaria Control for District level Officers. NVBDCP, 2008. 3. Website of National Vector Borne Disease Control Programme http://www.nvbdcp.gov.in/malaria-new.html 4. World Health Organization (2006). WHO Guidelines for the Treatment of Malaria. Geneva World Health Organization Dte. of National Vector Borne Disease Control Programme (NVBDCP) | Page-20

Protect yourself from Leptospirosis Early reporng to health facility can prevent illness and deaths Leptospirosis is caused by bacteria which is found in urine of rodents, cattle, pigs etc Programme for Prevention and Control of Leptospirosis Do not bathe, wash face or hands in dirty water National Guidelines Do not enter or work in dirty water without rubber boots/gloves Diagnosis, Case Management If you have walked through dirty/ood water bare foot, Prevention and Control of Leptospirosis

thoroughly wash the feet with soap and water Contact the health facility immediately if you have fever with headache, eye suffusion, calf muscle pain, chest pain Do not litter food grains and left over food Keep your surroundings clean and clutter free to avoid rodent infestation Take medicines as advised by your doctor NATIONAL CENTRE FOR DISEASE CONTROL NATIONAL CENTRE FOR DISEASE CONTROL (Directorate General of Health Services) (Directorate General of Health Services)

Programme for Prevention and Control of Leptospirosis National Guidelines Diagnosis, Case Management Prevention and Control of Leptospirosis

Contents 1. Introduction 5 2. Epidemiology 6 2.1 Causative Agent 6 2.2 Risk factor & determinants 6 2.3 Mode of transmission 7 2.4 Age & Sex distribution 7 2.5 Seasonal variation 7 2.6 High Risk groups 7 3. Clinical Presentation 8 3.1 Clinical types 8 3.2 Differential diagnosis 11 3.3 Recommended Case denitions 12 4. Laboratory diagnosis 13 4.1 Criteria for diagnosis 13 4.2 Collection and transportation of samples 13 4.3 Protocol for Laboratory Investigation 14 4.4 Referral Laboratories 15

5. Leptospirosis Case Management 17 5.1 Treatment at PHCs 17 5.2 Treatment at CHCs/ District Hospital 18 5.3 Treatment at Medical College/ tertiary level 20 6. Prevention & Control 6.1 Personal Protection 21 6.2 Health education 21 6.3 Chemoprophylaxis 21 6.4 Rodent control 21 6.5 Mapping of water bodies for establishing a proper drainage system 22 6.6 Health impact assessment of developmental projects 22 6.7 Vaccination of animal 22 Annexures 23 List of Contributors 32

1. Introduction India with an 8,129 km long coastline and with endowment of plenty of natural resources has one of the major important coastal, agro-ecosystem that supports livelihood of several million people and contributes substantially to the national economy. Due to the rapid ecological changes in the region during the past decade many new zoonotic diseases have emerged and resulted in epidemics leading to signicant morbidity and mortality in humans. Leptospirosis is one among them.

The change in the distribution and incidence rate of leptospirosis has occurred proportionately to the alterations in the eco-system. Reclamation of wastelands, aforestations, irrigation, changes in crops and agricultural technology have been important factors. The areas which would have remained free of this infection have converted into potentially endemic zones either by the changes brought out by man or the nature. The outbreaks of leptospirosis have been reported from coastal

districts of Gujarat, Maharashtra, Kerala, Tamil Nadu, Andhra Pradesh, Karnataka, Andamans & Nicobar, Dadar & Nagar Havelli, Daman & Diu & Puducherry from time to time. In addition, the cases have been reported from Goa and Odisha The high burden of disease has been reported from Andaman & Nicobar, Gujarat (4 districts affected) Kerala (14 districts affected), Maharashtra (4 districts and Mumbai city affected ), Karnataka (9 districts affected) and Tamil Nadu (2 districts and Chennai city affected).

4 National guidelines for leptospirosis National guidelines for leptospirosis 5

2. Epidemiology alkaline pH provides favorable environment for survival of leptospires for months. 2.2.4 Soil temperature The soil of endemic areas in general has lower base saturation and the mean annual soil temperature at the depth of 50 cm is 22˚C or more and the difference between mean summer (June-August) and mean winter (December-February) temperature is 2.1 Causative Agent less than 5˚C. This favors the survival of leptospires for long durations.

Leptospirosis is primarily a disease of animals, occasionally infect humans. It is caused by pathogenic spirochete of the genus leptospira that traditionally consist of two species, Leptospira interrogans and Leptospira biexa. The former includes all 2.3 Mode of transmission pathogenic serovars and the later includes the saprophytic strains. Leptospira strains Infection is acquired through contact of abraded skin and/or mucus membrane with

have been divided into 26 serogroups, of which 2 belong to saprophytic leptospires. the environment contaminated with urine of rodents, carrier or diseased animals. Each serogroup consists of several strains designated as seorovars. Nearly 300 host Direct transmission of leptospirosis is rare. adopted leptospiral serovars are naturally carried by more than a dozen species of rodents, wild and domestic animals. The moderate to highly conducive abundantly

available variety of hosts, results in successful perpetuation of this organism. The 2.4 Age and sex distribution leptospira serovars predominantly present in India are L.andamana, L.pomona, L.grippotyphosa, L.hebdomadis, L.semoranga, L.javanica, L.autumnalis, Gender difference in susceptibility is not apparent under conditions where both men L.canicola. and women are at equal risk. Males suffer more frequently from leptospirosis than females because of greater occupational exposure to infected animals and

contaminated environment. Leptospiral infections occur more frequently in persons 2.2 Risk Factors & Determinants 20-45 years of age group. Leptospirosis rarely occurs in young children and infants, possibly, because of minimal exposure. The conditions that are favorable for maintenance and the transmission of the leptospirosis are as follows: 2.5 Seasonal variation 2.2.1 Reservoir and carrier hosts Leptospirosis is usually a seasonal disease that starts at the onset of the rainy season

Leptospirosis has a very wide range of natural rodent and non-rodent reservoir hosts and declines as the rains recede. Sporadic cases may occur throughout the year. In which include rabbits etc. The domestic animals such as cattle, buffalo, goat, sheep India the disease has been found more commonly associated during post-monsoon and pigs carry the microorganisms and therefore act as carriers of the leptospires. period. In natural disasters such as oods it may assume epidemic potential

Together the rodents and the cattle excrete large number of organisms in their urine and thus are responsible for the contamination of soil as well as large and small water bodies. 2.6 High risk groups Agricultural workers such as rice eld planters, sugar cane and pineapple eld 2.2.2 Drainage, congestion and water logging harvesters, labourers engaged in canal cleaning operations and livestock handlers are subjected to exposure with leptospires.

Heavy concentrated rainfall leaves a lot of surplus water. Developmental activities like canal network, roads and railway lines obstruct natural drainage of rain water causing its accumulation for longer periods. The water logged areas force the rodent Other occupational high risk groups are – population to abandon their burrows and contaminate the stagnant water by their Fishermen, sewer workers and all those persons who are liable to work in rodent

urine. The farmers and agricultural labourers working in the water logged infested environment. Lorry drivers as they may use contaminated water to wash contaminated elds acquire the infection. their vehicles and masons, who may come in contact with the organisms while preparing the cement and sand mixture for construction work with contaminated 2.2.3 Soil salinization water. Soil salinity and water logging are inter-linked problems. The salinity of the soil and

6 National guidelines for leptospirosis National guidelines for leptospirosis 7

3. Clinical presentation 3.1.1 Anicteric leptospirosis It is the milder form of the disease. Patients present with-  Fever - Patients have remittent fever with chills. It may be moderate to severe.  Myalgia - It is characteristic nding in leptospirosis. Calf, abdominal & lumbosacral muscles are very painful & severely tender. This symptom is very Incubation Period:Average 5-14 days with a range 2-30 days. useful in differentiating leptospirosis from other diseases causing fever. This is

Case Fatality Rate: 0-15% associated with increase in serum Creatinine Phosphokinase (C.P.K.) which helps in differentiating leptospirosis from other illnesses.  Conjunctival suffusion - There is reddish coloration of conjunctiva which is a very predominant sign in leptospirosis. It is usually bilateral and is most marked on palpebral conjunctiva. It may be associated with unilateral or bilateral conjunctival hemorrhage.

Clinical types of leptospirosis  Headache - Usually intense, sometimes throbbing, commonly in frontal region. It is often not relieved by analgesics  Renal manifestations - Some form of renal involvement is invariable in leptospirosis. It usually occurs as asymptomatic urinary abnormality in the form of mild proteinuria with few casts and cells in the urine. Severe renal Anicteric leptospirosis Icteric leptospirosis involvement in the form of acute renal failure, (which occurs in icteric

It is the milder form of the disease. It is the severe form of the disease. leptospirosis) is rare Patients have fever, myalgia but do It is characterized by jaundice and is not have jaundice. usually associated with involvement of  Pulmonary manifestations –Cough and chest pain are primary manifestations Almost 90% of patients have this other organs. and in few cases haemoptysis may occur. Severe involvement leading to type of illness. respiratory failure does not occur in anicteric leptospirosis.

About 5-10% of patients have these  Hemorrhage - Hemorrhagic tendencies are also present in some cases type of manifestations Note: All the clinical features either decrease or disappear within two to three days Severe leptospirosis and then they reappear and may progress to severe disease Haemorrhage Acute renal failure Acute respiratory failure In endemic area all cases of fever with myalgia and conjunctival suffusion should be Multiorgan failure considered as suspected cases of leptospirosis.

3.1.2 Icteric leptospirosis This is the more severe form of leptospirosis. As the name suggests, patients present with jaundice. Others features are- 3.1 Clinical types :  Fever – Same as in anicteric leptospirosis but may be more severe and prolonged. The clinical spectrum of leptospirosis is very wide, with mild anicteric presentation at one end to severe leptospirosis with severe jaundice and multiple organ  Myalgia – Calf muscle tenderness becomes more evident. Severe myalgia may

involvement on the other. Many infections may go unnoticed because of lack of force the patient to stop walking and may even be mistaken as paraplegia. signicant clinical illness. Various clinical presentations of leptospirosis are as Muscle pain may occur due to myositits, myonecrosis or bleeding into the follows- muscles. 8 National guidelines for leptospirosis National guidelines for leptospirosis 9

 Headache- 50 % of the patients present with diffuse headache which is seldom pulmonary alveolar hemorrhage and renal complications. severe.  Conjunctival suffusion – Many patients will have reddish yellow discoloration, Cardiovascular system involvement: Patients present with one or more of the caused by icterus and congested block vessels or sub conjunctival hemorrhage. following features:

 Acute renal failure manifests as oliguria/anuria and/or proteinuria Shock: Patient develop severe hypotension, cold clammy extremities, and tachycardia. Echocardiography reveals normal systolic function of left ventricle  Nausea, vomiting, diarrhea, abdominal pain hence hypotension is due to either dehydration or peripheral vasodilatation.  Hypotension and circulatory collapse. Arrhythmias: Patient presents with palpitations, syncope and irregular pulse.

3.1.3 Severe leptospirosis Common arrhythmias seen are supraventricular tachyarrhythmia and various degrees of A.V. blocks. Ventricular tachy-arrhythmias are infrequent. Segment The more severe form of disease with severe liver and kidney involvement is known depression and T wave inversion may be present in some patients. as Weil's disease.Salient features of the organ involvements are described below. Central nervous system: CNS involvement in leptospirosis commonly present as

Hepatic: Jaundice is the most important clinical feature. It may be mild to severe. It meningitis. Headache may be the only manifestation or irritability, restlessness, starts after 4 to 7 days of illness. Hepatic encephalopathy or death due to hepatic seizures and coma can occur. Encephalitis, focal decits, spasticity, paralysis, failure is rare. Hepatomegaly & tenderness in right hypochondrium are usually nystagmus, peripheral neuropathies, nerve palsies, radiculitis, myelitisall have been detected.

reported. Renal:Renal involvement is almost invariably present in Leptospirosis. It presents Skin:Macular, maculopapular erythematous skin eruptions are seen in the face, as acute tubular necrosis (ATN) andinterstitial nephritis. Hematuria with complaints trunks and / or extremities in many patients with occasional cases of purpura. It may of Cola colored urine and RBC casts in urine microscopy is common. In severe be noted that bleeding manifestations in leptospirosis are not directly related to the

cases patients have acute renal failure and present with: level of thrombocytopenia. They resolve in two to three days without any specic  decreased urine output (oliguria or even anuria) intervention.  edemaon face and feet. Leptospirosis in Pregnancy: Leptospirosis during pregnancy has a bad prognosis  featuresof uremia like breathlessness, convulsion, delirium and altered and fetal loss had been reported to be high in the rst trimester and near term level of consciousness in very severe cases.

mothers. The renal dysfunction worsens during the rst week to the end of 2nd week, after All patients with severe, multiple organ involvement should be referred to tertiary which it starts improving and complete recovery occurs by the end of the 4th week if care centre the patients is maintained on renal support. Severe acute failure cases will need dialysis to tide over the acute phase .There is usually no residual renal dysfunction.

Pulmonary :In mild illness patient presents with only cough, chest pain and blood 3.2 Differential diagnosis tinged sputum. In severe cases patients have cough, hemoptysis, rapidly increasing breathlessness which may lead to respiratory failure and death. On examination, Falciparum malaria, Dengue fever, Dengue hemorrhagic fever, Scrub typhus,

these patients have increased respiratory rate with crepitation in the basal region, Typhoid and Viral hepatitis closely resemble leptospirosis and are prevalent in areas which rapidly spread upwards to middle and upper lobes.X-ray shows basal and mid reporting leptospirosis. Other conditions to be differentiated include viral zone opacity in severe cases. It may be normal in mild cases. pneumonia, viral hepatitis, alcoholic hepatitis, acute encephalitis syndrome and

pyelonephritis. Possibility of coinfections should be kept in mind. SGOT (AST) and Hemorrhagic pneumonitis with interstitial and intra alveolar hemorrhage SGPT (ALT) are either normal or mildly elevated usually in hundreds only (in IU/L) surrounded by focal capillary injury are common pathologic changes. Death can in leptospirosis. This helps to differentiate leptospirosis from viral hepatitis where occur within hours to two days due to pulmonary hemorrhage and severe respiratory

SGPT is markedly elevated and also from alcoholic hepatitis where SGOT is distress. There are wide variations in pulmonary presentation. It is the commonest markedly elevated. High level of Creatinine Phosphokinase (CPK) is suggestive of cause of death due to Leptospirosis.Case fatality rate in leptospirosis is 0-15% and leptospirosis. It is normal in viral hepatitis and alcoholic hepatitis and hence helps to more than ninety percent (90%) of deaths due to leptospirosis occur due to

10 National guidelines for leptospirosis National guidelines for leptospirosis 11

4. differentiate from leptospirosis. Laboratory Diagnosis 3.3 Recommended case denition The recommended case denition for the management of cases of leptospirosisis as follows- 4.1 Criteria for diagnosis Suspected: Acute febrile illness with headache, myalgia and prostration associated with a history of exposure to infected animals or an environment contaminated with Presumptive diagnosis

animal urine with one or more of the following  A positive result in IgM based immune- assays, slide agglutination test or  Calf muscle tenderness latex agglutination test or immunochromatographic test.  Conjunctival suffusion  A Microscopic Agglutination Test (MAT)titre of 100/200/400 or above in single sample based on endemicity.  Anuria or oliguria and/or proteinuria  Demonstration of leptospires directly or by staining methods  Jaundice  Hemorrhagic manifestations (intestines, lung)

Confirmatory diagnosis  Meningeal irritation  Isolation of leptospires from clinical specimen  Nausea, Vomiting, Abdominal pain, Diarrhoea.  Four fold or greater rise in the MAT titer between acute and convalescent phase serum specimens run in parallel. Probable: Suspected case with positive presumptive laboratory diagnosis.  Positive by any two different type of rapid test.  Sero-conversion. Confirmed: Suspect/Probable case with conrmatory laboratory test.  PCR test.

(Note: The classication of suspected, probable and conrmed does not in any way explain the severity and that has to be assessed based on the severity and rapidity of organ involvement.) 4.2 Collection and Transportation of samples 4.2.1 Blood sample While collecting blood and separating serum proper procedures should be followed to avoid lysis or contamination. The important steps are-  Use sterile syringe and needle  Syringe, needle and vial must be dry  Collect 5 ml blood

 Transfer from syringe to sterile vial after removing needle  Allow the blood to clot at room temperature. Do not shake  Separate serum by dislodging retracted clot with a sterile Pasteur pipette.  If facilities for serum separation are not available then refrigerate at 4 to 80 C. Samples should not be frozen  Transfer the liquid portion to sterile centrifuge tube. Centrifuge at 3000 rpm for 5 minutes.  Transfer supernatant (serum) to sterile plastic disposable leak proof screw

12 National guidelines for leptospirosis National guidelines for leptospirosis 13

capped vials. Add 5 µl of 1% solution of Sodium azide, if available, per 1 ml The diagnostic tests to be carried out at different health facilities areas follows- of serum sample. (a) At Primary Health Centers  Store and transport at 4 to 80 C in vaccine carriers/ice box. If transportation in the cold chain is not possible then use quickest mode of transportation.  Immuno-chromatographic technique.  Slide agglutination test. 4.2.2 CSF sample (b) At Selected CHCs andat District level laboratories

 CSF should be collected in a sterile container by lumbar puncture under aseptic conditions before the institution of antibiotics.  TLC and DLC - Total WBC count slightly elevated with neutrophilia  Preferably CSF should be collected in three different vials, one for cell  ESR : Increased erythrocyte sedimentation rate ( about 60mm) count, one for biochemical examination and one for culture.  Platelet Count - Thrombocytopenia  CSF should be transported immediately to laboratory without delay.

 BUN and Serum Creatinine: Increased BUN and serum Creatinine  Liver Function Tests: Alkaline phosphatase, SGOT and SGPT - 4.2.3 Urine sample moderately elevated  Serum Electrolytes: Sodium potassium – normal or slightly reduced  Urine should be collected in sterile widemouth container  Urine routine and microscopic examination : proteinuria, hematuria and  Carefully clean the peri-urethral area with soap and plenty of water. casts

 Discard rst voided sample and subsequent midstream urine is collected in  Serum bilirubin :Increase in serum bilirubin levels. sterile widemouth container.  Serum Creatinine Phosphokinase (CPK):Marked elevation in serum Creatinine phosphokinase (CPK)  Transport the sample immediately to avoid multiplication of contaminants  Rapid diagnostic tests Each sample should be properly labeled mentioning name, date of collection, and  ELISA

accompanied with a duly lled proforma with relevant clinical details should be included. If delay is expected, specimen should be kept cool preferably at 4 to 80 C (c) At State level hospitals/ reference laboratories (serology and molecular tests)and ambient temperature (culture) and sent to laboratory as early as possible.  All tests at CHC and district laboratories  Isolation 4.3 Protocol for laboratory investigations  ELISA  PCR  MAT 4.4 Referral Laboratories

 Regional Medical Research Center (ICMR), Port Blair (A&N), Tel: 03192- 251158/251159  National Centre for Disease Control, 22-Sham Nath Marg, Delhi, Tel: 011- 23971272/23971060/ 23912901  National Institute of Epidemiology, Chennai,Tel: 044-26820517, 044- 26821600  GovernmentMedical College, Surat,Tel: 0261-2244175, 0261-2208373  BJ Medical College, Ahmedabad, Tel: 079-22680074  Madurai Medical College, Madurai,Tel: 0452-2533235 (Details of Laboratory investigations are at Annexure I)

14 National guidelines for leptospirosis National guidelines for leptospirosis 15

5. Leptospirosis – Case management  National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), Bengaluru, Karnataka .Tel:080 2309 3110  Bacteriology & Mycology Division, IVRI, Izatnagar, UP, 243122 Tel: 0581- 2301865  DRDE, Gwalior (MP) Tel: 0751-2340730; 0751-2341550  Tamil Nadu Vetrinary& Animal Science University, Chennai, Tel: 044- 5.1 Treatment at PHC (in leptospirosis endemic areas) 25362787; 044-2530 4000 STEP -1: How to clinically suspect Leptospirosis ?

 Refer to case denition  Guidelines for fever case management at eld level are annexed at Annexure-2 STEP-2: How to treat clinically suspected Leptospirosis ? Adults:Doxycycline 100 mg twice a day for seven days.Pregnant & lactating mothers should be given capsule ampicillin 500 mg every 6 hourly. Children< 8 years: Amoxycillin/ Ampicillin 30-50 mg/kg/day in divided doses for 7 days. STEP-3: Laboratory screening of all suspected leptospirosis cases by rapid immunodiagnostic test :

 Certain rapid tests are available for diagnosis of leptospirosis. They do not require expertise or any expensive instruments. However, they require conrmation by ELISA. STEP-4: Treatment at PHC for mild disease and rapid immunodiagnostic test positive cases Adults: Doxycycline 100 mg twice a day for seven days.Pregnant & lactating mothers should be given capsule ampicillin 500 mg every 6 hourly. Children< 8 years: Amoxycillin/ Ampicillin 30-50 mg/kg/day in divided doses for 7 days.

Guidelines for fever case management at PHC level are annexed at Annexure 3 STEP-5: How to treat patients with negative ELISA and negative rapid immunodiagnostic test and clinically stable? Adults: Doxycycline 100 mg twice a day for seven days. Pregnant & lactating mothers should be given capsule ampicillin 500 mg every 6 hourly. Children< 8 years: Amoxycillin/ Ampicillin 30-50 mg/kg/day in divided doses for 7 days. 16 National guidelines for leptospirosis National guidelines for leptospirosis 17

STEP -6: When to shift patients to higher centre? STEP-4: Treatment at CHC for mild disease and rapid immunodiagnostic positive cases All suspected leptospirosis cases whether positive or negative with rapid immunodiagnostic test having feature of organ dysfunction as follows should be Adults: Doxycycline 100 mg twice a day for seven days. Pregnant & lactating IMMEDIATELY shifted to higher centre. mothers should be given capsule ampicillin 500 mg every 6 hourly.  Hypotension

Children<8 years: Amoxycillin/ Ampicillin 30-50 mg/kg/day in divided doses for 7  Decreased urine output (<400ml per day) days.  Jaundice (serum bilirubin >3.0 mg%)  Haemoptysis or breathlessness STEP-5: How to treat patients with negative ELISA and negative rapid  Bleeding tendency immunodiagnostic test and clinically stable cases ?  Irregular pulse  Altered level of consciousness Adults: Doxycycline 100 mg twice a day for seven days. Pregnant & lactating

mothers should be given capsule ampicillin 500 mg every 6 hourly. While shifting patients to higher centre, individual patient's record should be furnished in the following order- Children< 8 years: Amoxycillin/ Ampicillin 30-50 mg/kg/day in divided doses for 7 days.  Age, Sex  Occupation STEP-6: When to shift patients to higher centre?  Clinical symptoms  Date of onset of clinical symptoms All suspected leptospirosis cases whether positive or negative with rapid

 Serological result immunodiagnostic test having feature of organ dysfunction as follows should be  Hospitalization details-treatment given and outcome IMMEDIATELY shifted to higher centre. Guidelines for fever case management at higher centers are annexed at Annexure-4 Renal :  Decreased urine output (< 400 ml per day) 5.2 Treatment at CHC/District Hospital  High blood urea (> 60 mg. % )  High S. Creatinine (> 2.5 mg% )

STEP -I : How to clinically suspect Leptospirosis ?  Clinical features of uremia,breathlessness,convulsion,delirium,and / or altered level of consciousness Refer to case denition Hepatic :  Jaundice STEP-2 : How to treat clinically suspected Leptospirosis ?  High S. Bilirubin(>3.0m.g. %) Adults: Doxycycline 100 mg twice a day for seven days. Pregnant & lactating Pulmonary : mothers should be given capsule ampicillin 500 mg every 6 hourly.  Breathlessness

Children< 8 years: Amoxycillin/ Ampicillin 30-50 mg/kg/day in divided doses for 7  Haemoptysis days.  Increased respiratory rate  X- ray chest showing opacities STEP-3: Laboratory screening of all suspected leptospirosis cases by rapid Blood : immunodiagnostic test :  Bleeding tendency Certain rapid tests are available for diagnosis of leptospirosis. They do not require  Low platelet count expertise or any expensive instruments. However, they require conrmation by ELISA.

18 National guidelines for leptospirosis National guidelines for leptospirosis 19

6. Prevention and Control Neurological :  Altered level of consciousness While shifting patients to the higher centres, relevant clinical prole along with the treatment given should be furnished 6.1 Personal protection 5.3 Treatment at medical college/tertiary level health care Hygienic methods such as avoidance of direct and indirect human contact with facility animal urine are recommended as preventive measures. Workers in ooded elds

should be cautioned against direct contact with contaminated water or mud and Treatment should be started as early as possible. Any case of fever in should be advised to use rubber shoes and gloves. In case of any cuts or abrasion on leptospiraendemic areas during monsoon and post-monsoon season should be the lower extremities of the body, the worker should apply an antiseptic ointment administered antibiotics as follows- e.g. betadine, before entering the eld and after exit.

Adults: Doxycycline 100 mg twice a day for seven days 6.2 Health education Inj. Crystalline penicillin 20 lacs IU IV every 6 hourly after sensitivity test. The main preventive measure for leptospirosis is to create awareness about the (For the individuals who are sensitive to penicillin group of drugs following disease and its prevention. This has to be conceptualized through intensive alternative regimes maybe used) educational campaign, IEC templates/software for audio visual, print, press,

outdoor outreach modes, new and emerging electronic media. Ceftriaxone 1 gm IV x 6 hourly for 7 days OR Cefotaxime 1 gm IV x 6 hourly for 7 days 6.3 Chemoprophylaxis OR Erythromycin 500 mg IV x 6 hourly for 7 days During the peak transmission season Doxycycline 200 mg, once a week, may be given to agricultural workers (eg. paddy eld workers, canal cleaning workers in

Pregnant & lactating mothers should be given capsule ampicillin 500 mg every 6 endemic areas) from where clustering of cases has been reported. The hourly. chemoprophylaxis should be for six weeks and never to be extended for more than eight weeks. Children< 8 years: Amoxycillin/ Ampicillin 30-50 mg/kg/day should be given in divided doses for 7 days 6.4 Rodent control Inj. Crystalline penicillin should be given 2–4 lacs IU/kg/ day for 7 days.

It is established beyond doubt that rodents are the major reservoirs of bacterium (For individuals who are sensitive to penicillin group of drugs following alternative Leptospira interogans. Four species of rodents Rattusrattus(House rat), Rattus regimes may be used) norvegicus(Norway rat), Bandicotabengalensis (Lesser bandicoot) and Bandicotaindica(Larger bandicoot) are so far found to be reservoirs for this Ceftriaxone 50-75 IV mg/kg/day for 7 days

bacterium in India. Hence controlling these reservoir species with proper strategy OR planning and management planning will reduce the incidence of the disease in the Cefotaxime50-100 IV mg/kg/day for 7 days affected areas. The strategic planning should cover the following: OR 1. Identifying the reservoir species of affected area Erythromycin 30-50mg/kg/day in divided dose for 7 days 2. Delineating areas for anti rodent activities

In disease progression multiple organs such as kidney, liver, lungs , CVS and CNS 3. Completion of activities in pre monsoon months. may be involved. The management of organ involvement does not differ then that of 4. Adopting appropriate technology for anti rodent operations. This includes non-leptospirosis causes. correct inputs and appropriate application technology. 5. Capacity building 6. Creating awareness in general community and community participation.

20 National guidelines for leptospirosis National guidelines for leptospirosis 21

6.5 Mapping of water bodies for establishing a proper Annexure 1 drainage system Protocols for Laboratory investigations The mapping of water bodies and human activities in water logged areas should be carried out. This will help to identify the high risk population. Farmers may be educated to drain out the urine from the cattle shed into a pit, instead of letting it ow 1. Isolation of Leptospires

and mix with water bodies (rivers, ponds etc.) Isolation of leptospires from clinical specimens is the strongest evidence for conrmatory diagnosis. Isolation and identication is the method of choice to identify circulating serovars in a particular geographical region. 6.6 Health impact assessment of developmental projects Health impact assessment should be made mandatory for all developmental projects a) Blood culture

along with environmental assessment Ideal time : Within 10 days of the onset of the disease.Sample should be collected before antibiotics are started 6.7 Vaccination of animals Media : EMJH, Fletcher's and Stuart's (commercially available or obtain from the Leptospiral vaccines confer a limited duration of immunity. Boosters are needed designated regional/ district laboratory) every one to two years. Vaccination should however be very selective and used only Procedure :

in endemic situations having high incidence of leptospirosis. The vaccine must  Swab the area with the spirit contain the dominant local serovars. While this prevents illness, it does not  Draw the blood using sterile syringe and needle by vein puncture necessarily protect from infection and renal shedding.  Take 2 tubes containing 5 ml EMJH medium and inoculate two drops of blood in the rst tube and four drops in the second tube.  Incubate at 300C for 4-6 weeks.

 Examine the culture using dark eld illumination initially on 1st, 3rd and 5th days followed by at 7-10 days interval upto 6 weeks.  Selective culture media containing 5FU 50-1000 µg/ml can be used to avoid contamination.  Sub culture should be made within 48 hrs to minimize the inhibitory effect of the selective agents on Leptospires. Growth of the fastidious isolates is encouraged by adding to the medium 0.1% -0.15% agarose & 0.4%-1% of rabbit serum or fetal calf serum. b) Urine culture :

Time: 10-30 days after the onset of the disease Media: EMJH, Fletcher's and Stuart's Procedure :  Collect fresh midstream sample. The sample should be tested within 2 hours of collection.  Dilute the urine as follows: using sterile test tubes and sterile phosphate buffer (pH 7.2). o Add 0.4 ml of urine to 3.6 ml of PBS (1in 10) o Add 3 ml of (urine) to 3 ml of PBS (1 in 20) o Add 2 ml of (urine) to 2 ml of PBS (1 in 40) o Add 1 ml of (urine) to 1 ml of PBS (1 in 80)

22 National guidelines for leptospirosis National guidelines for leptospirosis 23

 Take 5 ml of medium in 4 separate tubes and add 0.5 ml each of a, b, c, d proteins or cell fragments may mimic leptospires. Even experienced personnel may solutions of PBS in 4 different medium tubes. be confused with these artifacts as in majority of the clinical samples leptospires  Label the tubes mentioning the dilution may not exhibit typical motility due to reactive antibodies or due to mechanical  Incubate at 300C injury during the process of specimen for examination. Critical evaluation of this

 Examine the culture using dark eld illumination at intervals of 7-10 days technique as a diagnostic tool has shown that the test has low sensitivity (40.2%) and upto 6 weeks. specicity (61.5%). Therefore DFM is not recommended as a sole diagnostic tool  The above procedure should be repeated 2 or 3 times with urine samples for the diagnosis of leptospirosis. collected at different times/days to increase the probability of isolation.

 Urine can be ltered (through 0.22 µm lter) and/or inoculated into Specimens : The specimens should be taken aseptically and sent to laboratory selective culture media to avoid contamination. without delay, they must not be frozen. Oxalate, citrate or heparin may be used as  Urine may have acidic pH in many cases. Therefore urine should be anticoagulant for blood or pleural uid. collected in tubes containing equal amount of PBS with pH 7.2. Procedure (Blood)

c) CSF Culture  Centrifuge 5 ml of blood (treated with an anticoagulant) at 1000 g for 15 min. Time : Within 5 - 10 days of the onset of the disease  Add approximately 10 µl of plasma on a thin microscopic slide and apply Medium : EMJH, Fletcher's and Stuart's cover slip. Procedure :  Examine under dark eld microscope with low power and high power (x  Inoculate 0.5 ml of CSF into 5 ml of culture media 200 and x 400).  Follow the same procedure as blood culture

 If no leptospires are seen, centrifuge plasma at 3000-4000 g for 20 min. Advantages of isolating leptospires from clinical specimens:  Carefully remove the supernatant and examine a drop of sediment  Denite proof of infection microscopically as above.  Circulating serovars can be identied  Local isolates can be used as antigen in MAT Procedure (Urine)  Local isolates can be used in vaccine development.  Centrifuge a portion of freshly voided urine at 3000 g for 10 min.

Limitations :  Examine a drop of deposit by DFM (x 200 and x 400).  Fastidious organism requires special medium for isolation Limitations :  Leptospires grow slowly. Isolation of leptospires from clinical  Low sensitivity and specicity. specimens takes several days to several weeks.  Serum proteins and brin strands in blood resembles leptospires.  The technique is laborious, time consuming and is not possible in small  The concentration of organism is frequently too low in the specimens.

laboratories  Requires technical expertise.  Contamination of culture media by other micro-organisms or by saprophytic leptospires is common in routine practice B. Silver Impregnation techniques  The successful isolation rate is less due to prior use of antibiotic, Various silver impregnation techniques are used for the staining of leptospires in imperfectly cleaned glass ware or wrong incubation temperature and body uids and tissues. pH. Fontana Staining 2 . Demonstration of Leptospires Requirements

A. Dark Field Microscopy  Fixative- Acetic acid 1ml+Formalin (40% HCHO) 2 ml+ Distilled water Demonstration of leptospires by using Dark Field Microscopy appears to be a 100 ml simple and rapid procedure. Though the organism is present in the blood during  Mordant- Phenol 1 gm+ tannic acid 5 gm+ Distilled water 100ml acute stage of the disease, the concentration is too low to allow detection by direct  Ammoniated silver nitrate (to make fresh): Add 10 % ammonia to 0.5%

microscopy. The leptospiral shedding in urine is intermittent. Moreover serum solution of silver nitrate in distilled water until the precipitate formed just 24 National guidelines for leptospirosis National guidelines for leptospirosis 25

dissolves. Now add more silver nitrate solution drop by drop until the  Add 50 µl leptospira cultures to all wells. precipitate returns and does not re-dissolve.  Mix thoroughly on a micro shaker. Procedure  Incubate for 2 - 4 hour at 30 0C  Treat the lm three times, 30 seconds each time, with xative. Reading of the test results: The serum antigen mixtures are examined under a dark

 Wash off the xative with absolute alcohol and allow the alcohol to act for 3 eld microscope for agglutination. For observation, one drop mixture is transferred min. with a platinum loop or pipette from a well to a microscopic slide and examined  Drain off the excess alcohol and carefully burn off the remainder until the under dark eld microscope with 20x objective without cover slip. Compare with a lm is dry control suspension of leptospires diluted 1 in two in PBS without serum.

 Pour on the mordant, heated till steam rises, and allow it to act for 30 sec. Agglutination is measured indirectly by establishing the reduction of Leptospiral  Wash well in distilled water and again dry the slide. density with 50% in comparison with the density of free leptospires in control.  Treat with ammoniated silver nitrate, heated till steam rises, for 30 sec, till Advantages : the lm becomes brown in colour.  It is serovar/ serogroup specic test. Some clue about the infecting serovar

 Wash well in distilled water, dry and mount in Canada Balsam. can be obtained  Once infected the person stays MAT positive for several years so the test is It is essential that the specimen be mounted in balsam under a cover slip useful for epidemiological purpose. before examination, as some immersion oils cause the lm to fade at once. The Limitations : spirochetes are stained brownish black on a brownish-yellow background.  14-21 strains have to be maintained in cultures which are often very

difcult. 3. Detection of specic antibodies of leptospires  Procedure is complex and time consuming. a) Detection of serovar specific antibodies :  It is not possible to distinguish between IgM indicative of current infection Microscopic Agglutination Test ( MAT): MAT is the gold standard test for detection and IgG indicative of past infection. of serovar/ serogroup specic antibodies. One of the critical issues of MAT is the cut  Finding agglutination antibodies in single serum sample does not

off or a signicant titer for diagnosis, when the test is done on a single sample. A necessarily prove current leptospirosis. An antibody titer may be due to battery of antigens covering the range of serovars that are expected or likely to be residual antibodies of a past infection. Therefore the interpretation of a circulating in a particular geographical area, where the patient becomes infected, single titer is not easy so a second serum sample is required for

should be used. demonstrating a rising titer which has a diagnostic signicance. Preparation of Antigens : b) Detection of genus specific antibodies  The stock for collection of leptospires is best maintained in screw capped 1. ELISA test tube containing 5-6 ml of liquid media. ELISA is one of the techniques commonly used for the diagnosis. The test can detect

 Fresh subculture are made by inoculating 0.5 ml from each strain/ serovar specic antibodies earlier than MAT. The advantage of the test is that it can into tubes differentiate between recent and past infection by detecting the type of antibodies  A loop full of culture should be examined by dark eld microscopy to (IgM or IgG) present in the clinical specimen. In this test, broadly, reactive antigen is

conrm the presence of viable leptospires and the absence of contaminant. used. The antigen antibody reaction is visualized or measured by  The inoculated cultures are incubated at 30º C and checked for the presence spectrophotometer/ ELISA reader using a conjugate (enzyme conjugated to anti- of growth after 5-7 days. IgM or IgG) and a colour reagent. Procedure : (Kits are commercially available. Procedure of the test should be as per the

 Fill all 96 wells of microtitre plate with 50µl PBS manufacturers' instructions.)  Add another 140 µl PBS to the wells of column 2  Add 10 µl of serum to the wells of column 2 (now dilution becomes 1:20), Advantages mix and discard 100 µl.  Single antigenic preparation can be used.  Dilute by pipetting 50 µl from one well to the next, discard the nal 50 µl.  Allows rapid processing of large number of samples.Limitations :

26 National guidelines for leptospirosis National guidelines for leptospirosis 27

Annexure 2  Infecting serovar cannot be assessed. Community Surveillance by Paramedics/ Volunteers/Field workers 2. Rapid Diagnostic Test  Latex based Agglutination Test Acute febrile illness with headache, myalgia and prostration associated with  . Immunochromatography a history of exposure to infected animals or an environment contaminated The tests should be performed as per manufacturer's instructions. with animal urine with one or more of the following:

Calf muscle tenderness/Conjuctival suffusion/Anuria or oliguria and/or 4. Molecular Methods: proteinuria/Jaundice/Hemorrhagic manifestations (intestines, lung)/Meningeal Polymerase Chain Reaction (PCR): irritation/Nausea, Vomiting, Abdominal pain, Diarrhoea. PCR method involves in vitro amplication of genus-specic target, DNA sequence, if present, in clinical samples. A pair of short DNA fragments, known as

primers is used for specic amplication of DNA fragments from the pathogen in Suspected leptospirosis blood, urine or CSF. Positive diagnosis results from the amplication of the target sequence whereas negative samples fail to produce amplied DNA in PCR. PCR can be used to detect leptospiral infection in both animals and human beings, especially during the rst few days of the disease when antibodies are not fully No Yes detectable in serological tests. The primers used for the PCR are G1 5' – CTG AAT

CGC TGT ATA AAA GT-3' & G2 5'-GGA AAA CAA ATG GTC GGA AG-3' and B Look for other causes Ask/ Look for 64I5'-CTG AAT TCT CAT CTC AAC TC-3' & B64II5'-GCA GAA ATC AGA TGG of fever Severe myalgia ACG AT-3'. Oliguria/Anuria Jaundice Advantages : Blood in cough Gives relatively quick results in the early stage of the disease when antibodies have Breathlessness not yet developed in detectable levels Confusion Cold extremities Limitations :- Sophisticated equipment and trained manpower is required. Absent Present

Note : 1. The sero-diagnostic tests being used for Leptospirosis has shown cross- reactivity with hepatitis E and A. Thus, caution is necessary in the interpretation Refer to CHC/ Refer to PHC of serological data. District hospital 2. The health facilities undertaking sero-diagnosis should send 5% of their sera samples to the designated laboratory for cross-verication to ensure correct diagnosis Note: Field Worker shall daily report (A) Number of persons surveyed (B) Number

of fever cases (C) Fever cases referred and (D) Any death following fever 28 National guidelines for leptospirosis National guidelines for leptospirosis 29

Annexure 3 Annexure 4 Guidelines for fever case management at PHC level for Medical ofcers Guidelines for Suspected/ Probable case management at Higher Centre (CHC/ District Hospital/ Medical College) Acute febrile illness with headache, myalgia and prostration associated with a history of exposure to infected animals or an environment contaminated with Suspected/Probable case animal urine with one or more of the following: Calf muscle tenderness/Conjuctival suffusion/Anuria or oliguria and/or

proteinuria/Jaundice/Hemorrhagic Doxycycline 100 mg BD for 7 days manifestations (intestines, lung)/Meningeal irritation/Nausea, Vomiting, Abdominal pain, Diarrhoea. Perform rapid diagnostic test Perform biochemical test Yes Ask/ Look for Severe myalgia Suspected case Oliguria/Anuria Jaundice Prepare slide for Blood in cough malarial parasite Rapid diagnostic test Breathlessness Doxycycline 100 mg Confusion BD for 7 days Cold extremities Positive Negative Probable case

Ensure complete course Rapid diagnostic test Positive/ Negative Rapid diagnostic test Positive/Negative And And of doxycycline 100 mg Ask/Look for Organ involvement present No organ involvement present BD for 7 days Severe myalgia oliguria, anuria, jaundice blood in cough/vomitus/ stool Complete seven day course Inj. Crystalline Ensure complete course penicillin after negative test dose of doxycycline breathlessness Treat the patient according to organ involvement 100 mg BD

confusion Report to Chief district medical ofcer for line cold extrmities listing (LL) number for 7days irregular pulse General condition worsening Organ involvement Bleeding tendency Confusion Breathlessness Present Absent Any one of above Report to Chief district medical Ensure complete course of ofcer for line listing (LL) number doxycycline100 mg BD Refer to higher centre for 7 days Refer to higher centre Note: Note:

3. Amoxycillin/ Ampicillin 30-50 mg/kg/day should be given in divided doses 6hourly for 7 days. 3.Amoxycillin/ Ampicillin of 30-50 mg/kg/day should be given in divided doses 6hourly for 7 days. 30 National guidelines for leptospirosis National guidelines for leptospirosis 31

Contributors Dr. S Venkatesh, Director, National Centre for Disease Control, 22-Sham Nath Marg, Delhi. Dr. Gyanendra Gongal, Nodal Point Zoonosis, WHO Regional Ofce for South-East Asia, Indraprastha Estate, New Delhi-110002, India. Dr. Dinkar Rawal, Deputy Director Epidemic, Division of Epidemiology & Communicable Disease, Commissonerate of Health Services, Gandhinagar, Gujarat Dr. Manju Rahi, Scientist E & Deputy Director General, Division of

Communicable Diseases, Indian Council of Medical Research, Ansari Nagar, New Delhi Dr. D K Singh, Principal Scientist, Veterinary Public Health Division, Indian Veterinary Research Institute (IVRI), Izzatnagar, Bareilly, Uttar Pradesh- 243122 Dr. R G Bambal, Deputy Commisioner (LH), Department of Animal Husbandry, Dairying and Fisheries, Ministry of Agriculture , KrishiBhawan, New Delhi Dr. Veena Mittal, Additional Director & Head, Zoonosis Division, National

Centre for Disease Control, 22-Sham Nath Marg, Delhi Dr. Dipesh Bhattacharya, Additional Director, Zoonosis Division, National Centre for Disease Control, 22-Sham Nath Marg, Delhi Dr. Mala Chhabra, Joint Director, Zoonosis Division, National Centre for Disease Control, 22-Sham Nath Marg, Delhi Dr. UVS Rana, Ex-Joint Director, Zoonosis Division, National Centre for Disease Control, 22-Sham Nath Marg, Delhi Dr. Monil Singhai, Assistant Director, Zoonosis Division, National Centre for

Disease Control, 22-Sham Nath Marg, Delhi Dr. Simmi Tiwari, Assistant Director, Zoonosis Division, National Centre for Disease Control, 22-Sham Nath Marg, Delhi 32 National guidelines for leptospirosis

© World Health Organization 2014 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.

The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. This publication contains the collective views of a national and international group of experts and does not necessarily represent the decisions or the policies of the World

Health Organization. This publication can be reprinted for wider dissemination of standards for TB care under due acknowledgment to Central TB Division, Ministry of Health & Family Welfare, Government of India and World Health Organization, Country Office for India.

Table of contents Acknowledgements.…………………………………….………….................... 1 Workshop participants……………………………………................……...….. 2 Development process……………………………………….................…...….. 9 Introduction…………………………………………………..................…...…... 11 STCI summary………………………………………………….....................…. 13 Standard 1 Testing and screening for Pulmonary TB………......................… 24 Standard 2 Diagnostic technology……………………………......................… 27

Standard 3 Testing for extra-pulmonary TB…………………......................… 30 Standard 4 Diagnosis of HIV co-infection in TB patients and diagnosis of DR-TB.. 32 Standard 5 Probable TB……………………………………….......................…. 35 Standard 6 Paediatric TB...…………………………………..........................… 36 Standard 7 Treatment with first-line regimen………………..................…....... 38 Standard 8 Monitoring treatment response……………………........................ 43

Standard 9 Drug Resistant TB management…..……………........................... 45 Standard 10 Addressing TB with HIV infection and other comorbid conditions..... 51 Standard 11 Treatment adherence……………………………........................... 54 Standard 12 Public health responsibility......………………….......................… 56 Standard 13 Notification of TB cases… …………………….........................… 58 Standard 14 Maintain records for all TB patients……...………..............…...... 60

Standard 15 Contact investigation…………………………….......................… 61 Standard 16 Isoniazid Prophylactic therapy.…………….......................…...... 63 Standard 17 Airborne infection control……………………….................…....... 64 Standard 18 Quality assurance systems……………………............................ 65 Standard 19 Panchayati Raj Institutions..………………….................…......… 66 Standard 20 Health education………………………………….......................... 67

Standard 21 Death audit among TB patients.........………............................. 68 Introduction to Standards for Social Inclusion for TB…...........….................... 69 Standard 22 Information on TB prevention and care seeking.......................... 70 Standard 23 Free and quality services………...……………….......................... 71 Standard 24 Respect, confidentialty and sensitivity………….......................... 72 Standard 25 Care and support through social welfare programmes.............. 73

Standard 26 Addressing counseling and other needs .................................... 74 ii

Acknowledgements Development of the Standards for TB Care in India (STCI) is the culmination of a series of discussions involving various stakeholders and review of literature. Central TB Division, Ministry of Health & Family Welfare, Government of India and WHO Country Office for India took the lead in the process. The national TB institutions in India namely National Institute of TB and Respiratory Diseases (NITRD) New Delhi, National Institute for

Research in Tuberculosis (NIRT) Chennai and National TB Institute (NTI) Bangalore contributed significantly in the development process. USAID has provided funding support to this initiative through WHO Country Office for India. We acknowledge the contribution of all participants of the workshop and also those experts who reviewed the report and made comments for its betterment. Programme managers of Revised National Tuberculosis Control Programme (RNTCP) at central, state and district level have contributed

substantially to finalize this document. Special appreciation is due for the medical consultants of WHO-RNTCP technical assistance network for their contribution in literature search and in providing necessary technical and operational support for the development of STCI. WCO-India communications team has provided crucial support in editing this document and we thank them for this. The writing group comprised of (alphabetically) Dr A Sreenivas, Dr K Rade,

Dr KS Sachdeva, Dr M Ghedia, Dr M Parmar, Dr R Ramachandran and Dr Shepherd J. The draft guidelines have been reviewed and valuable comments have been provided by a group of experts comprising of: (alphabetically) Dr A Mohan , Dr A Joshi, Dr B John, Dr C Rodrigues, Dr GR Sethi, Dr N Kulshrestha, Dr N Wilson, Dr O George, Dr P Dewan, Dr RN Solanki , Dr R Sarin, Dr RV Ashokan, Dr S Gutta , Dr S Sahu, Dr S Swaminathan, Dr S Vijayan and Dr V Singh. These contributions are gratefully acknowledged. 1

Workshop participants S.No Name Designation and Affiliations 1 Dr Jagdish Prasad Director General Health Services, MoHFW, GoI,New Delhi 2 Dr Nata Menabde WHO Representative to India, New Delhi 3 Dr Ashok Kumar Deputy Director General -TB, CTD, DGHS, MoHFW, GoI, New Delhi 4 Dr R S Gupta Deputy Director General, NACO, MoHFW,GoI, New Delhi 5 Dr Neeraj Kulshreshtha ADDG-TB, Central TB Division, DGHS, MoHFW, GoI, New Delhi 6 Dr K.S. Sachdeva ADDG-TB, Central TB Division, DGHS, MoHFW, GoI, New Delhi

7 Dr Devesh Gupta ADDG-TB, Central TB Division, DGHS, MoHFW, GoI, New Delhi 8 Dr S Sahu Team Leader, Stop TB Partnership Secretariat, WHO, Geneva 9 Dr Rohit Sarin Director, National Institute of Tuberculosis and Respiratory Disease , New Delhi 10 Dr Prahlad Kumar Director, National Tuberculosis Institute, Bangalore 11 Dr Soumya Swaminathan Director, National Institute for Research in Tuberculosis, Chennai 12 Dr E Reddy Assistant Drug Controller, DCGI, New Delhi

13 Dr Ira Ray Former Additional Director General, Dte. GHS, MoHFW, GoI, New Delhi 14 Dr Rajendra Prasad Director, Patel Chest Institute, New Delhi 15 Dr S K Sharma Professor & Head, Department of Medicine, AIIMS,New Delhi 16 Dr Digambar Behera Professor, Department of Pulmonary Medicine, PGIMER, Chandigarh 2

17 Dr Rupak Singla HOD TB & Pulmonary Med. Department, National Institute of Tuberculosis and Respiratory Disease, New Delhi 18 Dr Sreenivas A Nair NPO-TB, WHO Country Office For India, New Delhi 19 Dr Ranjani Ramachandran NPO-Laboratories, WHO Country Office India, New Delhi 20 Dr Malik Parmar NPO-DR-TB, WHO Country Office India, New Delhi 21 Mr E Thanaraj NPO-TB Drugs, WHO Country Office India, New Delhi 22 Dr J N Bandvalikar Vice-Chairman, TB Association of India, New Delhi

23 Dr AB Taly Professor of Neurology NIMHANS, Bangalore 24 Dr A C Phukan Chair of Zonal Task Force for Medical Colleges, North East, Shillong 25 Dr A Muruganathan President, Association of Physicians of India, New Delhi 26 Dr A S Puri Professor, Gastroenterology, G B Pant Hospital, New Delhi 27 Dr Ajay Gambhir President, IAP, New Delhi 28 Dr Alladi Mohan Professor & Head, Medicine, SVIMS, Tirupati, Andhra Pradesh 29 Dr Ameeta Joshi Professor, Microbiology Department. Sir JJ Hospital, Mumbai

30 Dr AmitaAthavale Professor & Head, Department of Chest Medicine, KEM Hospital, Mumbai 31 Dr Anil S Director, STDC Bangalore, Karnataka 32 Dr Anil. J. Purty Professor, Department of Community Medicine, Pondicherry Institute of Medical Sciences, Pondicherry 33 Dr Anita Arora Principal Consultant, Microbiology Department. Fortis, New Delhi 34 Dr Anna Stratis Medical Officer, World Health Partners 35 Mr A Senkathir CDSO, HQ, FDA, Bhawan, New Delhi 3

36 Ms Aditi Ananthanarayanan CCM Member and Activist, TB & HIV, New Delhi 37 Mr Alok Chaturvedi Senior GM Macleods Pharmaceutics 38 Dr Anjali Nayyar Senior Vice President, Global Health Strategies 39 Mr Ashish Mungantiwar Senior. Vice President, Medical Services & Head, Macleods Pharmaceuticals Ltd., Mumbai 40 Dr Ashok Rajput Consultant & Head of Pulmonary Medicine, Research & ReferralHospital, (Dte. AFMS), New Delhi 41 Dr BB Rewari NPO, NACO, New Delhi 42 Dr Bobby John President, Global Health Advocates,

New Delhi 43 Dr Brij Bhusan Agarwal Surgeon, Ganga Ram Hospital, New Delhi 44 Dr Balasangameshwara Senior. Project Manager & Technical Officer Foundation For Innovative New Diagnostics 45 Dr C.S.Pandav President, Indian Public Health Association, New Delhi 46 Dr C N Paramsivan Project Head, FIND India, New Delhi 47 Dr Camilla Rodrigues Consultant, Microbiology Department, Hinduja Hospital, Mumbai 48 Dr D R Rai Hon. Secretary General, IMA, New Delhi

49 Dr Debajyoti Bhattacharyya MD(Med)Pulmonary Medicine, Armed Forces Medical College, Pune 50 Dr GC Khilnanai President, National College of Chest Physicians,New Delhi 51 Dr Giridhar Gyani Secretary General Quality Council of India, New Delhi 52 Ms Geeta Bamzai Faculty, Indian Institute of Mass Communication, New Delhi 53 Dr GR Sethi Professor Department of Paediatrics, Maulana Azad Medical College, New Delhi 54 Dr GR Khatri World Lung Foundation, New Delhi

55 Mr Harkesh Dabas Programme Officer, Clinton Health Access Initiative, New Delhi 4

56 Dr J. Arivoli Director, STDC Chennai, Tamil Nadu 57 Mr Jagannath Shinde President, All India Association of Chemist and Druggist, Mumbai 58 Dr Karishma Saran Programme Associate Global Health Strategies 59 Dr KC Sen Director-Medical, CISF, New Delhi 60 Dr Lalit Nath Senior Advisor, Voluntary Health Association of India, New Delhi 61 Ms Manjot Kaur Programme Officer, Clinton Health Access Initiative,New Delhi 62 Dr Minni Khetarpal Mumbai TB Officer, Mumbai

63 Dr M S Jawahar Deputy Director (Sr. Gr) NIRT, Chennai 64 Dr N. Appa Rao Chairman, National Leaders Forum, IMA, Hyderabad 65 Dr N.Meenakshi Director, ITM, Chennai 66 Dr Nadeem Khan Director, STDC Nagpur, Maharashtra 67 Ms Neera Agnimitra Delhi School of Social Work, New Delhi 68 Dr Neerja Arora National Coordinator, CBCI CARD, Delhi 69 Mr Niteesh Srivastava Senior General Manager, Macleods Pharmaceutics 70 Dr Nandakumar KV DTO Mallapuram, Kerala

71 Dr Nandini Sharma Director, Professor & Head, Department of Community Medicine, MAMC, New Delhi 72 Dr Narayan Mishra Former President, CPAI, Prof & HOD Pulmonary Medicine, Orissa 73 Dr Oommen George Technical Specialist (TB), Abt Associates 74 Dr Peter Small Senior Programme Officer, Bill & Melinda Gates Foundation, India 75 Sister Prabha Executive Director, CBCI CARD, New Delhi 76 Dr Pradeep Mishra Secretary SEAR Pharm forum, 77 Dr Rajesh N Solanki Professor & Head, TB & Chest Dept., BJMC, Ahmedabad

78 Ms Ramya Ananthakrishnan Executive Director, REACH, Chennai 79 Dr Ranjan K Das Consultant Eminent Private Pulmonologist, CMRI, West Bengal 5

80 Dr Ravindra H R Reddy Deputy Director, India TB Project, PATH, Hyderabad 81 Dr Ravindra K Dewan Thoracic Surgeon, LRS Institute of TB & Respiratory Diseases, Delhi 82 Dr Rahul Thakur FIND India 83 Dr Rajesh Chawala Senior Consultant, Department of Respiratory Medicine, Apollo Hosp, Delhi 84 Dr Reuben Swamickan Project Management specialist (TB), USAID, New Delhi 85 Dr RV Asokan National Coordinator IMPACT, IMA GFAM RNTCP PPM project, Kerala 86 Dr S. Subramanyam Family Physician, IMA, Bangalore

87 Dr Sandeep Mishra National Programme Manager, VHAI 88 Dr Sanjay Kapur Team leader, Health Office, USAID, New Delhi 89 Dr Satish Kaipilyawar Deputy Director, India TB Project, PATH 90 Dr Shalabh Malik Head, Microbiology Department, Dr Lal Path Labs, Delhi 91 Dr Somdutta Patra Prof & Head, Dept. of Community Medicine, UCMS, Delhi 92 Dr Sonia Malik Sr. Consultant & Director Infertility Specialist, Paras Hosp & South End Infertility Centre, Delhi 93 Dr Subhakar Kandi Professor Pulmonary& Medicine OSMANIA

Hyderabad 94 Dr Sudhir K Jain Joint Director, Centre for Epidemiology, NCDC, Delhi 95 Mr Sumedh M Gaikwad Director Medical Services, Themis Medicare Limited, Mumbai 96 Dr Sunita Mittal Professor & Head Dep. of Obstetrics & Gynaecology, All India Institute of Medical Sciences, New Delhi 97 Dr Suresh Gutta National coordinator, IMA GFATM RNTCP PPM project, Hyderabad 6

98 Dr S N Rai Consultant RNTCP, CTD Central TB Division,DGHS GOI Nirman Bhawan New Delhi 99 Dr Sameer Kumta Programme Officer Gates Foundation 100 Dr Shashi Khare Consultant & Head Division of Microbiology, National Centre for Disease Control, Delhi 101 Dr Shibu Vijayan Global Health Advocate India 102 Dr Sugata Mukhopadhyay Technical Consultant World Vision India 103 Ms T. Mercy Annapoorni Director, Blossom affected community representative, Rainbow TB Foundation, Virudhunagar

104 Mr Tejaswi Sharma General Manager, Global TB & API B u s i n e s s , S a n d o z - N o v a r t i s Pharmaceuticals, Mumbai 105 Dr Urvashi B Singh Associate Professor, Dept. of Microbiology, AIIMS, Delhi 106 Dr Usha Baweja Sr. Consultant, Medanta The Medicity Hospital, Gurgaon 107 Dr Usha Gupta Executive Vice President, Delhi Society for Promotion of RUD, Delhi 108 Dr V K Arora Vice Chancellor, Santosh Medical University, Ghaziabad 109 Dr Varinder Singh Professor, Dept. of Paediatrics, LHMC, New Delhi

110 Dr Vijay Edwards Director, Health & HIV, World Vision India 111 Dr Vinay K Dube DTO Hoshangabad, Madhya Pradesh 112 Dr Vineet Chadha Sr. Epidemiologist, NTI, Bangalore 113 Dr Y N Dholakia Hon. Secretary, Maharashtra State Anti-TB Association, Mumbai 114 Dr Zile Singh Professor and Head, Department of Community Medicine,Pondicherry Institute of Medical Sciences, Pondicherry 115 Dr V.P Myneedu Microbiologist (SAG) & HOD, National Institute of Tuberculosis and Respiratory Diseases, New Delhi 7

116 Dr B.N. Sharath WHO-RNTCP National Consultant - TB-HIV, Central TB Division, New Delhi 117 Dr Avinash Kanchar WHO-RNTCP National Consultant and Program Officer HIV/TB NACO, New Delhi 118 Dr Kiran Rade WHO-RNTCP National Consultant - Epidemiologist, Central TB Division, New Delhi 119 Dr Avi Bansal WHO-RNTCP National Consultant - Public Health, Central TB Division, New Delhi 120 Dr Mayank Ghedia WHO-RNTCP National Consultant - Laboratories, Central TB Division, New Delhi

121 Mr Arindam Moitra WHO-RNTCP National Consultant - PPM, Central TB Division, New Delhi 122 Ms Smrity Kumar WHO-RNTCP National Consultant - DPC, Central TB Division, New Delhi 123 Dr Mohan PS Kohli PPM Consultant, Central TB Division, New Delhi 124 Dr Shibu Balakrishnan WHO-RNTCP Medical Consultant, Kerala 125 Dr Rajeev Vishnoi WHO-RNTCP Medical Consultant, Agra, UttarPradesh 126 Dr Shamim Manan WHO-RNTCP Medical Consultant -RNTCP, New Delhi 127 Dr Shivani Chandra WHO-RNTCP Medical Consultant -RNTCP,

New Delhi 128 Dr Meeta Mahar Technical Officer DR TB, Central TB Division, New Delhi 129 Dr ShikhaDhawan Technical Officer, Laboratories, Central TB Division, New Delhi 8

Development process The first edition of the Standards for TB Care in India was conceived by a wider community of clinicians, public health specialists, community workers and patient advocates both within and outside of the Government of India as a necessary step in requiring and monitoring a widely accepted standard of TB care for the people of India. International guidelines and standards for TB care which existed such as International Standards for TB Care 2006 and

2009 editions, American Thoracic Society Standards, European Standards 2011, WHO Guideline for Treatment of TB 2010 and WHO Guidelines for PMDT 2011 were used as a foundation for developing India's standards. However with its unique challenges, approximately one third of the world's TB burden, and long history of dealing with a TB problem that appears to be resilient to the best efforts, it was felt that India should have its own standards

that could be used as a benchmark by all providers managing TB patients within India. It is hoped that a set of standards recognized as appropriate for the specific challenges of India will spur observance to these standards by all care providers of India when managing a TB patient. The standards developed and described here are the result of a long process that culminated in a three day national workshop organized by Central TB Division at New Delhi in December 2012 with technical assistance from WHO

Country Office for India. The objective of the workshop was to develop the Standards for Tuberculosis Care in India that will be applicable to providers in public, private and other settings across India. About 120 experts from national and international level including various public health administrators, programme managers, representatives from various professional associations (Indian Medical Association, Association of Physicians of India,

College of Physicians Association of India, Indian Association of Paediatricians, Federation of Obstetricians and gynecologists congress of India, Family Physician Association of India etc.), academicians and specialists from public and private sectors (pulmonologists, physicians, surgeons, paediatricians, gynaecologists, orthopaedic surgeons, microbiologists, public health specialist etc.), donors, technical and implementation partners, pharmaceutical companies, pharmacists 9

association, consultants, management experts, social science experts and civil society representatives participated at the workshop and actively worked to develop the evidence based Standards for Tuberculosis Care in India. The methodology consisted of panel discussions and group work and the approach was to find appropriate answers to the following questions: • What should be the standard tools and strategies for early and complete detection?

• What should be the standards of treatment in terms of drugs and regimens for best patient outcome? • What should be the public health standards including regulations, strategies and systems for public health impact? • What should be standards for patient support systems, both in public and private sectors and for community engagement for social inclusion? As part of the development process, noted experts in the field of TB in India modified the international standards, following detailed review of India-

specific and India-relevant evidence. As an output of the workshop, 26 standards developed and the India-relevant evidence debated, and listed for each of the standards in this document. This includes a new set of standards for social inclusion that goes beyond the areas covered in the International Standards for TB Care (ISTC) 2009. After the statement of each standard a brief summary of the international and national evidence are described along

with the references to the literature. The standards thus evolved, are intended to be used to enhance quality and mutually acceptable engagement with the private and other sectors in India to enhance TB care. This is thus, an important tool for achieving the goal of universal access to quality TB care . 10

Introduction India, the world's second most populous country, accounts for a quarter of the world's annual incidence of TB. Every year around two million people develop TB in India and 300,000 die of TB. Over 15 million patients have been treated and three million additional lives have been saved by the Revised National TB Control Programme (RNTCP) over the last decade. Cure rates have consistently been above 85% and the TB Millennium Development Goals are

reachable. However, despite a comprehensive national TB control program guiding states for implementation of TB diagnosis and treatment there is still a long way to go. The decline in TB incidence has been slow, mortality remains unacceptably high and the emergence of drug-resistant TB has become a major public health concern. There are many challenges for TB control in India. Prompt, accurate diagnosis and effective treatment of TB are not only essential for good patient

care, but they are also the key elements in the public health response to tuberculosis and the cornerstone of any initiative for tuberculosis control. The private sector holds a factual predominance of health care service delivery in India. There is very little information about the TB patient from the private sector available to the programme and little is known about their quality of treatment, including treatment outcomes. Engaging the private sector

effectively is the single most important intervention required for India to achieve the overall goal of universal access to quality TB care. The vision of India's national TB control programme is that the people suffering from TB receive the highest standards of care and support from healthcare providers of their choice. It is spelt out in the National Strategic Plan (2012-17) to extend the umbrella of quality TB care and control to include

those provided by the private sector (i). The need for quality and standards for TB care is made particularly acute where a largely unregulated and unmonitored private sector accounts for almost half of the TB care delivered in India with gross challenges as far as quality of diagnosis and treatment is concerned. Thus, it was felt essential to develop and disseminate the standards of TB care that is particularly relevant in Indian context, acceptable

to the medical fraternity in both the public and private sector in India. 11

Also, the availability of new diagnostic tools and strategies for early TB diagnosis, emerging evidences on existing regimens and newer regimens, and the need for better patient support strategies including addressing social inclusiveness necessitated the development of Standards for TB Care in India. To paraphrase the ISTC, the standards in this document differ from existing guidelines in that the standards present what should be done whereas

guidelines describe how the action is to be accomplished. There are comprehensive national guidelines from the Central TB Division, GoI [www.tbcindia.nic.in] that are regularly reviewed and updated. These standards represent the first what is expected from the Indian healthcare system. It is expected that the standards discussed in this document are clear and usable and will be accessible to all TB providers as an easy reference. Reference:

1. National Strategic Plan (2012-17) for Tuberculosis – Directorate of Health Services, Central TB Division, Ministry of Health & Family Welfare (MoHFW), Government of India, New Delhi. www.tbcindia.nic.in 12

STCI summary Standard 1: Testing and screening for Pulmonary TB 1.1 Testing: • Any person with symptoms and signs suggestive of TB including cough >2 weeks, fever >2 weeks, significant weight loss, haemoptysis etc. and any abnormality in chest radiograph must be evaluated for TB. • Children with persistent fever and/or cough >2 weeks, loss of weight / no weight gain, and/or contact with pulmonary TB cases must be evaluated for TB. 1.2 Screening:

• People living with HIV (PLHIV), malnourished, diabetics, cancer patients, patients on immunosuppressant or maintenance steroid therapy, should be regularly screened for signs and symptoms suggestive of TB. • Enhanced case finding should be undertaken in high risk populations such as health care workers, prisoners, slum dwellers, and certain occupational groups such as miners. Standard 2: Diagnostic technology 2.1 Microbiological confirmation on sputum:

• All patients (adults, adolescents, and children who are capable of producing sputum) with presumptive pulmonary TB should undergo quality-assured sputum test for rapid diagnosis of TB (with at least two samples, including one early morning sample for sputum smeer for AFB) for microbiological confirmation. 2.2 Chest X-ray as screening tool: • Where available, chest X-ray should be used as a screening tool to increase the sensitivity of the diagnostic algorithm. 13

2.3 Serological tests: • Serological tests are banned and not recommended for diagnosing tuberculosis. 2.4 Tuberculin Skin Test (TST) & Interferon Gamma Release Assay (IGRA) • TST and IGRA are not recommended for the diagnosis of active tuberculosis. Standardised TST may be used as a complimentary test in children. 2.5 CB-NAAT (cartridge-based nucleic-acid amplification test) is the preferred first diagnostic test in children and PLHIV. 2.6 Validation of newer diagnostic tests:

• Effective mechanism should be developed to validate newer diagnostic tests. Standard 3: Testing for extra-pulmonary TB • For all patients (adults, adolescents and children) with presumptive extra-pulmonary TB, appropriate specimens from the presumed sites of involvement must be obtained for microscopy/culture and drug sensitivity testing (DST)/CB-NAAT/molecular test/histo-pathological examination. Standard 4: Diagnosis of HIV co-infection in TB patients and Drug Resistant TB (DR-TB)

4.1 Diagnosis of HIV in TB patients: • All diagnosed TB patients should be offered HIV counselling and testing. 4.2 Diagnosis of multi-drug resistant TB (MDR-TB): • Prompt and appropriate evaluation should be undertaken for patients with presumptive MDR-TB or Rifampicin (R) resistance in TB patients who have failed treatment with first line drugs, paediatric non- responders, TB patients who are contacts of MDR-TB (or R resistance), TB patients who are found positive on any follow-up

sputum smear examination during treatment with first line drugs, diagnosed TB patients with prior history of anti-TB treatment, TB patients with HIV co-infection and all presumptive TB cases among PLHIV. All such patients must be tested for drug resistance with available technology, a rapid molecular DST (as the first choice) or liquid / solid culture-DST (at least for R and if possible for Isoniazid (H); Ofloxacin (O) and Kanamycin (K), if R-resistant/MDR).

• Wherever available DST should be offered to all diagnosed tuberculosis patients prior to start of treatment. 14

4.3 Diagnosis of Extensively Drug Resistant TB (XDR-TB): • On detection of Rifampicin resistance alone or along with isoniazid resistance, patient must be offered sputum test for second line DST using RNTCP approved phenotypic or genotypic methods, wherever available. Standard 5: Probable TB • Presumptive TB patients without microbiological confirmation (smear microscopy, culture and molecular diagnosis), but with strong clinical and other evidence (e.g. X-ray, Fine Needle Aspiration Cytology

(FNAC, histopathology) may be diagnosed as “Probable TB” and should be treated. • For patients with presumptive TB found to be negative on rapid molecular test, an attempt should be made to obtain culture on an appropriate specimen. Standard 6: Paediatric TB 6.1 Diagnosis of paediatric TB patients: • In all children with presumptive intra-thoracic TB, microbiological confirmation should be sought through examination of respiratory specimens (e.g. sputum by expectoration, gastric aspirate, gastric

lavage, induced sputum, broncho-alveolar lavage or other appropriate specimens) with quality assured diagnostic test, preferably CB-NAAT, smear microscopy or culture. 6.2 Diagnosis of probable paediatric TB patients: • In the event of negative or unavailable microbiological results, a diagnosis of probable TB in children should be based on the presence of abnormalities consistent with TB on radiography, a history of exposure to pulmonary tuberculosis case, evidence of TB infection

(positive TST) and clinical findings suggestive of TB. 6.3 Diagnosis of extra-pulmonary paediatric TB patients: • For children with presumptive extra-pulmonary TB, appropriate specimens from the presumed sites of involvement should be obtained for rapid molecular test, microscopy, culture and DST, and histo-pathological examination. 15

Standard 7: Treatment with first-line regimen 7.1 Treatment of New TB patients: • All new patients should receive an internationally accepted first-line treatment regimen for new patients. The initial phase should consist of two months of Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), and Ethambutol (E). The continuation phase should consist of three drugs (Isoniazid, Rifampicin and Ethambutol) given for at least four months. 7.2 Extension of continuation phase:

• The duration of continuation phase may be extended by three to six months in special situations like bone & joint TB, spinal TB with neurological involvement and neuro-tuberculosis. 7.3 Drug dosages: • The patients should be given dosages of the drugs depending upon body weight in weight bands 7.4 Bio-availability of drugs: • The bioavailability of the drug should be ensured for every batch, especially if fixed dose combinations. (FDCs) are used, by procuring and prescribing from a quality-assured source.

7.5 Dosage frequency: • All patients should be given daily regimen under direct observation. However, the country programme may consider daily or intermittent regimen for treatment of TB depending on the available resources and operational considerations as both are effective provided all doses are directly observed. • All paediatric and HIV infected TB patients should be given daily regimen under direct observation. 7.6 Drug formulations:

• Fixed dose combinations (FDCs) of four drugs (Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol), and three drugs (Isoniazid, Rifampicin and Ethambutol) and two drugs (Isoniazid and Rifampicin) are recommended. 7.7 Previously treated TB patients: • After MDR-TB (or R resistance) is ruled out by a quality assured test, TB patients returning after lost to follow up or relapse from their first treatment course or new TB patients failing with first treatment course

may receive the retreatment regimen containing first-line drugs: 2HREZS/1HREZ/5HRE 16

Standard 8: Monitoring treatment response 8.1 Follow up sputum microscopy: • Response to therapy in patients with pulmonary tuberculosis, new as well as retreatment cases, should be monitored by follow-up sputum microscopy (one specimen) at the time of completion of the intensive phase of treatment and at the end of treatment. 8.2 Extension of intensive phase: • The extension of the intensive phase is not recommended. 8.3 Offer DST in follow up sputum positive cases:

• If the sputum smear is positive in follow-up at any time during treatment, a rapid molecular DST (as the first choice) or culture-DST (at least for R and if possible for Isoniazid (H); Ofloxacin (O) and Kanamycin (K), if R-resistant/MDR) should be performed as laboratory facilities become available. 8.4 Response to treatment in extra-pulmonary TB: • In patients with extra-pulmonary tuberculosis, the treatment response is best assessed clinically. The help of radiological and

other relevant investigations may also be taken. 8.5 Response to treatment in children: • In children, who are unable to produce sputum the response to treatment may be assessed clinically. The help of radiological and other relevant investigations may also be taken. 8.6 Long-term follow up: • After completion of treatment the patients should be followed up with clinical and/or sputum examination at the end of six months and 12 months. Standard 9: Drug Resistant TB management

9.1 Treatment of M/XDR-TB (or R resistant TB): • Patients with tuberculosis caused by drug-resistant organisms (especially M/XDR or only R resistance or with O or K resistance), microbiologically confirmed by quality assured test, should be treated with specialized regimens containing quality assured second-line anti-tuberculosis drugs. 9.2 Model of care for drug resistant TB: • Patients with MDR-TB should be treated using mainly ambulatory

care rather than models of care based principally on hospitalization. If required, a short period of initial hospitalisation is recommended. 17

9.3 Regimen for MDR / R-Resistant TB cases: • The regimen chosen for MDR-TB may be standardized and/or based on microbiologically confirmed drug susceptibility patterns. At least four drugs (second line) to which the organisms are susceptible, or presumed susceptible, should be used. Most importantly the regimen should include at least a later-generation Fluoroquinolone (such as high dose Levofloxacin) and a parenteral agent (such as Kanamycin or Amikacin), and may include Pyrazinamide, Ethambutol,

Ethionamide (or Prothionamide), and either Cycloserine or PAS (P- aminosalicylic acid) if Cycloserine cannot be used. 9.4 Regimen for MDR patients with Ofloxacin and/or Kanamycin resistance detected early: • Treatment regimen may be suitably modified in case of Ofloxacin and/or Kanamycin resistance at the initiation of MDR-TB treatment or during early intensive phase, preferably not later than four to six weeks. 9.5 Surgery in MDR/XDR TB patients:

• All patients of MDR/XDR-TB should be evaluated for surgery at the initiation of treatment and/or during follow up. 9.6 Treatment Duration in MDR TB patients: • Till newer effective drugs are available with proven efficacy with shorter duration of MDR-TB treatment; total treatment should be given for at least 24 months in patients newly diagnosed with MDR- TB (i.e. not previously treated for MDR-TB) with recommended intensive phase of treatment being six to nine months. The total

duration may be modified according to the patient's response to therapy. 9.7 Specialist consultation in M/XDR TB patients: • Consultation with a specialist experienced in treatment of patients with MDR/XDR tuberculosis should be obtained, whenever possible. 9.8 Ensuring adherence in M/XDR TB patients: • Patient support systems, including direct observation of treatment, are required to ensure adherence. It should be ensured that the patient consumes all the doses of the drugs.

9.9 Single sample follow-up culture in M/XDR TB patients: • The use of sputum culture (1 sample) is recommended for monitoring of patients with MDR-TB during treatment. 18

9.10 Second line DST during treatment of MDR TB: • During the course of MDR TB treatment, if the sputum culture is found to be positive at 6 months or later, the most recent culture isolate should be subjected to DST for second-line drugs (at least O and K) to decide on further course of action. DST to other drugs namely Moxifloxacin, Amikacin and Capreomycin may also be done if laboratory facilities are available to guide treatment. 9.11 Regimen for MDR patients with Ofloxacin and/or Kanamycin resistance

detected later: • The patients with MDR-TB found to be resistant to at least Ofloxacin and/or Kanamycin during the later stage of MDR TB treatment must be treated with a suitable regimen for XDR TB using second line drugs including Group 5 drugs such as Amoxicillin Clavulanate, Clarithromycin, Clofazimine, Linezolid, Thioacetazone, Imipenem to which the organisms are known or presumed to be susceptible. 9.12 New drugs: • New drugs need to be considered for inclusion in regimens whenever

scientific evidence for their efficacy and safety becomes available as per the national policy for newer antimicrobials. Appropriate regulatory mechanisms for distribution control needs to be ensured. Standard 10: Addressing TB with HIV infection and other comorbid conditions 10.1 Treatment of HIV infected TB patients: • TB patients living with HIV should receive the same duration of TB treatment with daily regimen as HIV negative TB patients.

10.2 Anti-retroviral & Co-trimoxazole prophylactic therapy in HIV infected TB patients: • Antiretroviral therapy must be offered to all patients with HIV and TB as well as drug-resistant TB requiring second-line anti-tuberculosis drugs, irrespective of CD4 cell-count, as early as possible (within the first eight weeks) following initiation of anti-tuberculosis treatment. Appropriate arrangements for access to antiretroviral drugs should be made for patients. However, initiation of treatment for tuberculosis

should not be delayed. Patients with TB and HIV infection should also receive Co-trimoxazole as prophylaxis for other infections. 19

10.3 Isoniazid preventive therapy in HIV patients without active TB: • People living with HIV should be screened for TB using four symptom complex (current cough or, fever or weight loss or night sweats) at HIV care settings and those with any of these symptoms should be evaluated for ruling out active TB. All asymptomatic patients in whom active TB is ruled out, Isoniazid Preventive Therapy (IPT) should be offered for six months or longer. Standard 11: Treatment adherence

11.1 Patient centered approach for adherence: • Both to assess and foster adherence, a patient-centered approach to administration of drug treatment, based on the patient's needs and mutual respect between the patient and the provider, should be developed for all patients. 11.2 Measures for treatment adherence: • Supervision and support should be individualized and should draw on the full range of recommended interventions and available support

services, including patient counselling and education. A central element of the patient centred strategy is the use of measures to assess and promote adherence to the treatment regimen and to address poor adherence when it occurs. These measures should be tailored to the individual patient's circumstances based on details of the patient's clinical and social history and be mutually acceptable to the patient and the provider. 11.3 Trained treatment supporter for treatment adherence:

• Such measures may include identification and training of a treatment supporter (for tuberculosis and, if appropriate, for HIV, Diabetes Mellitus etc.) who is acceptable, accessible and accountable to the patient and to the health system. 11.4 Use of Information Communication Technology (ICT) to promote treatment literacy and adherence: • Optimal use of ICT should be done to promote treatment literacy and adherence Standard 12: Public health responsibility

• Any practitioner treating a patient for tuberculosis is assuming an important public health responsibility to prevent on-going transmission of the infection and the development of drug resistance. • To fulfil this responsibility the practitioner must not only prescribe an appropriate regimen, but when necessary, also utilize local public health services / community health services, and other agencies including 20

NGOs to assess the adherence of the patient and to address poor adherence when it occurs. Standard 13: Notification of TB cases • All health establishments must report all TB cases and their treatment outcomes to public health authorities (District Nodal Officer for Notification). • Proper feedback need to be ensured to all healthcare providers who refer cases to public health system on the outcome of the patients which they had referred. Standard 14: Maintain records for all TB patients

• A written record of all medications given, bacteriologic response, adverse reactions and clinical outcome should be maintained for all patients. Standard 15: Contact investigation • All providers of care for patients with tuberculosis should ensure all household contacts and other persons who are in close contact with TB patients are screened for TB • In case of pediatric TB patients, reverse contact tracing for search of any active TB case in the household of the child must be undertaken.

Standard 16: Isoniazid Prophylactic therapy • Children <6 years of age who are close contacts of a TB patient, after excluding active TB, should be treated with isoniazid for a minimum period of 6 months and should be closely monitored for TB symptoms. Standard 17: Airborne infection control • Airborne infection control should be an integral part of all health care facility infection control strategy. Standard 18: Quality assurance (QA) systems 18a QA for diagnostic tests:

• All health care providers should ensure that all diagnostic tests used for diagnosis of TB are quality assured. 18b QA for anti-TB drugs: • Quality assurance system should ensure that all anti-TB drugs used in the country are subjected to stringent quality assurance mechanisms at all levels. 21

Standard 19: Panchayati Raj Institutions • Panchayati Raj Institutions and elected representatives have an important role to share the public health responsibility for TB control with the healthcare providers, patients and the community. Standard 20: Health education • Every TB symptomatic should be properly counselled by the healthcare provider. • TB patients and their family members should get proper counselling and health education at every contact with healthcare system

Standard 21: Death audit among TB patients • Death among TB patients should be audited by a competent authority. Standard 22: Information on TB prevention and care seeking • All individuals especially women, children, elderly, differently abled, other vulnerable groups and those at increased risk should receive information related to TB prevention and care seeking. Standard 23: Free and quality services • All patients, especially those in vulnerable population groups, accessing

a provider where TB services are available should be offered free or affordable quality assured diagnostic and treatment services which should be provided at locations and times so as to minimize workday or school disruptions and maximize access. Standard 24: Respect, confidentiality and sensitivity • All people seeking or receiving care for TB should be received with dignity and managed with promptness, confidentiality and gender sensitivity. Ensure that infection control procedures do not stigmatise

TB patients. Standard 25: Care and support through social welfare programmes • Patient support system should endeavour to derive synergies between various social welfare support systems to mitigate out of pocket expenses such as transport and wage loss incurred by people affected by TB for the purpose of diagnosis and treatment. 22

Standard 26: Addressing counselling and other needs • Persons affected by TB should be counselled at every opportunity, to address information gaps and to enable informed decision making. Counselling should address issues such as treatment adherence, adverse drug reactions, prognosis and physical, financial, psycho-social and nutritional needs. 23

Standard 1 Testing and screening for Pulmonary TB 1.1 Testing: • Any person with symptoms and signs suggestive of TB including cough >2 weeks, fever >2 weeks, significant weight loss, haemoptysis etc. and any abnormality in chest radiograph must be evaluated for TB. • Children with persistent fever and/or cough >2 weeks, loss of weight / no weight gain, and/ or h/o contact with pulmonary TB cases must be evaluated for TB. 1.2 Screening: • People living with HIV (PLHIV), malnourished, diabetics, cancer

patients, patients on immunosuppressant or maintenance steroid therapy, should be regularly screened for signs and symptoms suggestive of TB. • Enhanced case finding should be undertaken in high risk populations such as healthcare workers, prisoners, slum dwellers, and certain occupational groups such as miners. The most common symptom of pulmonary TB is prolonged cough that lasts longer than the cough with most other acute lung infections. However cough

is a common symptom and most coughing patients do not have TB (1). Many countries have attempted to distinguish likely TB cases from other lung infections by specifying a chronic cough lasting two to three weeks (2,3). The evidence from India suggests that cough lasting > 2 weeks is a more sensitive indicator for TB than >3 weeks cough and is thus recommended here (4,5,7,8). A high level of clinical suspicion for TB is necessary as many TB

patients will not have a cough, particularly if they are infected with HIV or are 24

otherwise immunosuppressed. Children can present a diagnostic challenge and a high level of suspicion for TB must accompany the approach to any child with prolonged illness not otherwise explained, especially if there is a history of contact with a pulmonary TB case (5). Enhanced case finding means maintaining a high index of suspicion for TB in all encounters, with proactive exclusion of TB using the appropriate combination of clinical queries, radiographic or microbiologic testing. For

PLHIV, the WHO has developed a four-symptom screen that has proven highly sensitive for active TB (3,6). Recent evidence from surveys in southern India has pointed to the significant comorbidities of TB and type 2 diabetes (10, 11) and consequently diabetics are included in the high risk categories for regular screening (12). Any other immunosuppressed patients are also at considerably heightened risk and should be enquired about symptoms of TB

at every healthcare encounter. In addition, slum dwellers are a large and recognized portion of Indian urban society where the transmission of infection is high. A recent estimate of the ARTI in Delhi was 2.3-3% (9), indicating that screening for active TB may be cost-effective and sensible. Occupational groups such as miners have been reported to have high risk of tuberculosis and they could be specially targeted for active case finding. An additional

group with high risk for TB is certain indigenous populations in the tribal areas of India. References: 1. International Standards for TB Care, Second Edition (2009) Tuberculosis Coalition for Technical Assistance, The Hague, 2009. 2. Treatment of Tuberculosis: guidelines 4th Ed. (2009) World Health Organization, Geneva 3. Systematic Screening for Active Tuberculosis: Principles and Recommendations (2013) World Health Organization, Geneva 4. Revised Guidelines for Diagnosis of Pulmonary TB (2009) Revised

National TB Control Programme, Delhi 5. National Guidelines on Diagnosis and Treatment of Paediatric Tuberculosis (2012) Revised National TB Control Programme, Delhi 6. Cain, KP et al; An Algorithm for TB Screening and Diagnosis in People with HIV (2010) New England Journal of Medicine 362, 707 7. Santha T et al, Comparison of cough of 2 weeks and 3 weeks to improve detection of smear-positive tuberculosis cases among out-patients in India, IJTLD, 2005, 9(1), 61-68 25

8. Thomas A et al., Increased yield of smear positive pulmonary TB case by screening patients with >2weeks cough compared to >3 weeks cough and adequacy of 2 sputum smear examinations for diagnosis, IJTLD 2008, 55: 77-83 9. Sarin R, Behera D et al, Annual Risk of Tuberculosis Infection (ARTI) in the slum population covered under RNTCP by LRS Institute, National OR Committee for RNTCP, meeting, 2012. (under publication) 10. Viswanathan V. et al, Prevalence of Diabetes and Pre-Diabetes and

Associated Risk Factors among Tuberculosis Patients in India, PLOS ONE. 2012 7(7); e41367 11. Balakrishnan S. et al, High Diabetes Prevalence among Tuberculosis Cases in Kerala, India, PLOS ONE, 2012. 10 (7); e46502 12. Baker et al. The impact of diabetes on tuberculosis treatment outcomes- A systematic review: BMC Medicine 2011. 9 (81);1741-7015 26

Standard 2 Diagnostic technology 2.1 Microbiological confirmation on sputum: • All patients (adults, adolescents, and children who are capable of producing sputum) with presumptive pulmonary TB should undergo a quality-assured sputum test for rapid microbiological diagnosis of TB 2.2 Chest X-ray as screening tool: • Where available, chest X-ray should be used as a screening tool to increase the sensitivity of the diagnostic algorithm 2.3 Serological tests:

• Serological tests are banned and not recommended for diagnosing tuberculosis. 2.4 Tuberculin Skin Test (TST) & Interferon Gamma Release Assay (IGRA): • TST and IGRA are not recommended for the diagnosis of active tuberculosis. Standardized TST may be used as a complimentary test in children. 2.5 Cartridge-Based Nucleic-acid Amplification Test (CB NAAT) is the preferred first diagnostic test in children and PLHIV 2.6 Validation of newer diagnostic tests:

• Effective mechanism should be developed to validate newer diagnostic tests. One of the first responsibilities of the TB programme is to endeavour to make a bacteriological diagnosis of TB if at all possible. Currently, only sputum tests are sufficient and recommended under the programme for the microbiologic testing of 27

TB (1). The Government of India recently issued government orders banning the manufacture, importation, distribution and use of serological tests for diagnosing TB (2). In addition Tuberculin Skin Test (TST) and Interferon-Gamma Release Assays (IGRA) are not recommended for diagnosis of TB, although in certain cases TST may be useful as an additional test for the diagnosis of children(3). Chest radiograph is an unquestionably sensitive test for the detection

of pulmonary disease in adults and children, and is recommended as a screening tool for TB. Due to the non-specific nature of radiographic testing for TB, any abnormal chest radiograph should prompt further bacteriologic and clinical assessment for TB (4). As sputum tests are the key to TB diagnosis, attention to collection of a good sputum sample is paramount; a number of studies have looked at this, including studies in India. A consensus is that two samples are almost as

good as three samples and a morning sample is better than a spot sample for detection of mycobacteria (5,6,7). Acceptable methods for bacteriologic testing of sputum include sputum smear microscopy (both conventional and fluorescent), culture (on solid or liquid media), commercial line probe assay (LPA), or CB NAAT. The most commonly-used method for bacteriologic diagnosis of TB for the last 70 years, sputum smear microscopy, has had enormous value in TB diagnosis,

but has limited sensitivity, particularly in children where microscopy is less than 50% sensitive. Sputum culture remains a highly sensitive, specific, and under-utilized method for TB diagnosis, but requires weeks to yield results and hence alone does not help clinicians for early diagnosis. Nucleic acid amplification testing (NAAT) offers enormous potential for accurate rapid diagnosis, but only commercial kits have been validated and are trustworthy for replicable results(8).

While both “in-house” manual NAAT is widely available, their lack of reproducibility and quality assurance concerns means that such in-house assays cannot be recommended(9). Commercial semi-automated NAAT have been developed in India, these are yet to be validated, hence are not recommended. With the advent of CB-NAAT the sensitivity and specificity of rapid TB diagnosis from sputum has increased to approximately levels seen in solid-media sputum culture, particularly valuable for the assessment of

A list of RNTCP approved diagnostics tests are given in the guidelines for TB notification accessible at www.tbcindia.nic.in. References 1. Technical and Operational Guidelines for Tuberculosis. 2005. www.tbcindia.nic.in/pdf 2. TB India 2013. Pg 53. www.tbcindia.nic.in/annual reports/pdf 3. New Paediatric TB guidelines. www.tbcindia.nic.in/documents/pdf 4. Koppaka R, Bock N. How reliable is chest radiography? In: Frieden TR, ed. Toman's tuberculosis. Case detection, treatment and monitoring, 2nd Edition.

Geneva: World Health Organization, 2004: 51-60. 5. Van Deun A, Salim AH, Cooreman E, et al. Optimal tuberculosis case detection by direct sputum smear microscopy: how much better is more? Int J Tuberc Lung Dis 2002; 6(3): 222–30. 6. Sarin R, Mukerjee S, Singla N, Sharma PP. Diagnosis of tuberculosis under RNTCP: examination of two or three sputum specimens. Indian J Tuberc 2001(48):13–16. 7. TB diagnostics and laboratory strengthening - WHO policy. www.stoptb/wg/gli/resources

8. WHO policy statement: automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF assay. WHO/HTM/TB/2011.4 9. Pai M. The accuracy and reliability of nucleic acid amplification tests in the diagnosis of tuberculosis. Natl Med J India 2004;17(5):233–6. 29

Standard 3 Testing for extra-pulmonary TB 3.1 Testing for extra-pulmonary TB • For all patients (adults, adolescents and children) with presumptive extra-pulmonary TB, appropriate specimens from the presumed sites of involvement must be obtained for microscopy/culture/ CB- NAAT/molecular test/histopathology examination and drug sensitivity testing (DST). Even as pulmonary TB presents significant diagnostic challenges, extra- pulmonary TB diagnosis can be more challenging. Signs and symptoms are

not specific and yield of mycobacteria are generally low from most tissue and fluid sources (1,2,3). Extra-pulmonary TB is comparatively common in PLHIV (approximately 30% of cases) and in these hosts the non-specificity of symptoms and low yield of mycobacteria present an even greater challenge. The basic principle of seeking bacteriologic diagnosis at every opportunity where TB is suspected applies to extra pulmonary TB as well. The use of un-

validated non-commercial 'in-house' NAAT on tissue specimens is not recommended; histopathology examination, smear microscopy, culture and validated commercial NAAT are the only acceptable options. Recently the use of CB-NAAT for specimens other than sputum was explored in many studies; although the test is not as sensitive on most of these samples compared with its sensitivity on sputum nevertheless it performs well and in all cases better than smear microscopy (4,5). 30

References: 1. Wares F et al.; Extrapulmonary Tuberculosis: Management and Control (2011) Revised National TB Control Program, Delhi 2. International Standards for TB Care, Second Edition (2009) Tuberculosis Coalition for Technical Assistance, The Hague, 2009 3. National Guidelines on Diagnosis and Treatment of Paediatric Tuberculosis (2012) Revised National TB Control Programme, Delhi. www.tbcindia.nic.in 4. Rapid Molecular Detection of Extra pulmonary Tuberculosis by the Automated

GeneXpert MTB/RIF System. Journal Clin Micro. 2011; 4:1202–1205 5. Gerardo A-U, Azcona JM, Midde M, Naik P.K, Reddy S and Reddy Ret al. Hindawi Publishing Corporation Tuberculosis Research and Treatment, Volume 2012, Article ID 932862 31

Standard 4 Diagnosis of HIV co-infection in TB patients and diagnosis of Drug Resistant TB (DR-TB) 4.1 Diagnosis of HIV in TB patients: • All diagnosed TB patients should be offered HIV counselling and testing. 4.2 Diagnosis of Multi-Drug Resistant TB (MDR-TB): • Prompt and appropriate evaluation should be undertaken for patients with presumptive MDR-TB or Rifampicin (R) resistance in TB patients who have failed treatment with first line drugs, paediatric non-

responders, TB patients who are contacts of MDR-TB (or R resistance), TB patients who are found positive on any follow-up sputum smear examination during treatment with first line drugs, diagnosed TB patients with prior history of anti-TB treatment, TB patients with HIV co-infection and all presumptive TB cases among PLHIV. All such patients must be tested for drug resistance with available technology, a rapid molecular DST (as the first choice) or

liquid / solid culture-DST (at least for R and H; and at least for Ofloxacin (O) and Kanamycin (K), if MDR). Wherever available DST should be considered and offered to all diagnosed tuberculosis patients prior to star of treatment. 32

4.3 Diagnosis of Extensively Drug Resistant TB (XDR-TB): • On detection of Rifampicin and isoniazid resistance, patient must be offered sputum test for second line DST using quality assured phenotypic or genotypic methods, wherever available. TB is a very clear clinical sign of possible HIV infection, and all TB patients deserve to have HIV ruled out through voluntary counselling and testing. India is considered a low HIV endemic area with high rates of TB, and the country-

wide average HIV prevalence in TB patients is around 5%. In any given case of TB, at any age, HIV infection is possible. Early detection of HIV offers the opportunity for potentially life-saving additional interventions. Thus it is recommended that all patients with active TB be tested for HIV (1). If HIV infection is detected then, TB treatment and anti-retroviral therapy is as described in Standard 10. Drug resistant TB is a growing problem worldwide including in India. Current

surveillance data estimates a prevalence of MDR-TB of 2-3% in new, untreated TB patients and more than 15% in previously treated TB cases (2). The Programmatic Management of Drug Resistant TB (PMDT) has recently been expanded in order to treat DR-TB in the RNTCP and extend standards and monitoring of DR-TB treatment to the private sector. The laboratory support for this programme is in development and a growing network of accredited, quality-assured drug sensitivity testing labs will support the goal

of universal DST for all TB patients. In order to provide timely information to the clinical team treating the patient and reduce primary transmission of DR- TB, rapid testing for rifampicin resistance is recommended (3). The emergence of extensively-drug resistant TB (XDR-TB) underlines the importance of developing a laboratory infrastructure to support DST for second-line drugs. The most important tests are for resistance to the Fluoroquinolones (Ofloxacin) and the injectable agent (Kanamycin), which

forms the backbone of MDR-TB treatment and resistance to these drugs defines XDR-TB. (4). It is recommended that, as facilities allow, all MDR-TB isolates are further tested for Ofloxacin and Kanamycin resistance. 33

References: 1. WHO policy on collaborative TB/HIV activities guidelines for national programmes and other stakeholders. Updated version of a document originally published in 2004 as Interim policy on collaborative TB/HIV activities (WHO/HTM/TB/2004.330; WHO/HTM/HIV/2004.1) WHO/HTM/TB/2012.1 and 012.1 WHO/HIV/2012 2. Ramachandran R, Nalini S, Chandrasekar V, Dave PV, Sanghvi AS, Wares F, Paramasivan CN, Narayanan PR, Sahu S, Parmar M, Chadha S, Dewan

P, Chauhan LS. Surveillance of drug-resistant tuberculosis in the state of Gujarat, India. Int J Tuberc Lung Dis. 2009. 13(9):1154-60 3. Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update. WHO/HTM/TB/2011.6 4. Gandhi NR, Nunn P, Dheda K, Schaaf HS, Zignol M, van Soolingen D, Jensen P, Bayona J. Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis. Lancet. 2010. 375(9728):1830-43 34

Standard 5 Probable TB 5.1 Probable TB • Patients with symptoms suggestive of TB without microbiological confirmation (sputum smear microscopy, culture and molecular diagnosis), but with strong clinical and other evidence (e.g. X-ray, Fine Needle Aspiration Cytology (FNAC), histopathology) may be diagnosed as “Probable TB”. (1) Despite the advent of new tests for TB diagnosis with greater sensitivity than smear microscopy of appropriate sputum samples, about 20-30% of TB

patients will not have microbiologic confirmation. This figure may be much higher in children and patients with extra-pulmonary TB or PLHIV. Although it is recommended that any sample from a suspected TB patient that is initially negative by a rapid diagnostic test be cultured for TB growth and confirmed diagnosis, there will be a group of patients that have TB but without microbiologic confirmation. These are included in the Government of India TB

case notification as “patients diagnosed clinically as a case of TB, without microbiologic confirmation, and initiated on anti-TB drugs” (2). References: 1. WHO Case Definitions 2011 Update. http://www.stoptb.org/wg/gli/assets/documents 2. TB Notification, GO No. Z-28015/2/2012-TB, dated 7th May 2012, Ministry of Health, Government of India 35

Standard 6 Paediatric TB 6.1 Diagnosis of paediatric TB patients: • In all children with presumptive intra-thoracic TB, microbiological confirmation should be sought through examination of respiratory specimens (e.g. sputum by expectoration, gastric aspirate, gastric lavage, induced sputum, broncho-alveolar lavage or other appropriate specimens) with a quality assured diagnostic test, preferably CB-NAAT, smear microscopy or culture. 6.2 Diagnosis of probable paediatric TB patients:

• In the event of negative or unavailable microbiological results, a diagnosis of probable TB in children should be based on the presence of abnormalities consistent with TB on radiography, a history of exposure to pulmonary TB case, evidence of TB infection (positive TST) and clinical findings suggestive of TB. 6.3 Diagnosis of extra-pulmonary paediatric TB patients: • For children with presumptive extra-pulmonary TB, appropriate specimens from the presumed sites of involvement should be

obtained for rapid molecular test, microscopy, culture and DST, and histo-pathological examination. Diagnosis of TB in children is particularly challenging as in small children it can be difficult to collect samples and the paucibacillary nature of TB in children reduces the sensitivity of testing. Regardless, there should be every effort to obtain bacteriologic diagnosis. Standardised TST may be used as a complimentary test in children, in combination with microbiological

investigations, history of contact, radiology, and symptoms. The guidelines of 36

the Indian Academy of Paediatrics (IAP) and paediatric TB guidelines of the RNTCP recommend obtaining specimens for mycobacteriology, the use of standardised TST with a cut-off of 10mm induration in non- immunosuppressed children, and specialist consultation. Serodiagnostic tests and IGRA have no role in paediatric TB diagnosis. References: 1. Emily C. Pearce, A Systematic Review of Clinical Diagnostic Systems Used in the Diagnosis of Tuberculosis in Children, Hindawi Publishing Corporation AIDS

Research and Treatment Volume 2012, Article ID 401896, 11 pages doi: 10.1155/2012/401896) 2. National Guidelines on diagnosis and treatment of Paediatric Tuberculosis, In consultation with Indian Academy Paediatrics during January- February 2012 3. New Paediatric TB guidelines. www.tbcindia.nic.in/documents/pdf 37

Standard 7 Treatment with first-line regimen 7.1 Treatment of New TB patients: • All new patients should receive an internationally accepted first-line treatment regimen for new patients. The initial phase should consist of two months of Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), and Ethambutol (E). The continuation phase should consist of three drugs (Isoniazid, Rifampicin and Ethambutol) given for at least four months. 7.2 Extension of continuation phase:

• The duration of continuation phase may be extended by three to six months in special situations like Bone & Joint TB, Spinal TB with neurological involvement and neuro-tuberculosis. 7.3 Drug dosages: • The patients should be given dosages of the drugs depending upon body weight in weight bands. 7.4 Bio-availability of drugs: • The bioavailability of the drug should be ensured for every batch, especially if fixed dose combinations (FDCs) are used, by procuring and prescribing from a quality-assured source.

7.5 Dosage frequency: • All patients should be given daily regimen under direct observation. However, the country programme may consider daily or intermittent regimen for treatment of TB depending on the available resources and operational considerations as both are effective provided all doses are directly observed. 38

• All paediatric TB patients and HIV associated TB patients should be given daily regimen under direct observation. 7.6 Drug formulations: • Fixed dose combinations (FDCs) of four drugs (Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol), three drugs (Isoniazid, Rifampicin and Ethambutol) and two drugs (Isoniazid and Rifampicin) are recommended. 7.7 Previously treated TB patients: • After MDR-TB (or R resistance) is ruled out by a Quality Assured test,

TB patients returning after lost to follow up, relapsing from their first treatment course or new TB patients failing with first treatment course may receive the retreatment regimen containing first-line drugs: 2HREZS/1HREZ/5HRE Treatment of drug-susceptible pulmonary TB with RHZE for two months followed by four months of RH or RHE has been highly effective in clinical trials (1). More than 95% of patients are cured using this regimen (1, 2, 3). The

results are so impressive and repeatable that the lower rates of cure in national TB programs highlight the operational challenges of delivering a daily regimen over an extended period of time (4,5). The concept of daily, directly observed therapy, incorporating a full six months of R has been adopted by the majority of countries worldwide as a major part of Stop TB Strategy (5). India implemented the Revised National TB Control Program (RNTCP) in

1996 as a national government run system that used a thrice weekly regimen administered by DOT (6). Cure rates in India have been comparable with countries using daily dosing, TB mortality has dropped significantly, and the prevalence of TB has declined slightly over the last two decades (6). Nevertheless, high relapse rate of 11-13% has been reported in patients treated by DOT in the RNTCP in India from several different locations over the

last several years (21, 23, 24). In places where the background of H resistance is high and/or HIV co-infection is common and in patients with cavitary disease the daily regimen is preferred because the intermittent dosing schedules result in higher rates of treatment failure and relapse (7, 8, 9). In India, H resistance is 11% in untreated TB patients and 37% in previously treated cases and the prevalence of HIV co-infection is 5% (6). In

countries where H resistance is prevalent a full six months course of 39

Rifampicin is recommended with a third drug, Ethambutol, added to the four months continuation phase (2, 3, 18, 19). Recent data indicates that this is also safe in paediatric patients (20). The extension of the continuation phase for extra-pulmonary TB to 9 or 12 months is based on expert opinion rather than evidence. The recommendation for “category 2” treatment for previously treated cases with the addition of streptomycin to the intensive phase is currently under

review and it is safe to say that a drug sensitivity test, if available, is a better guide to retreating TB than a “category 2” regimen (13, 14, 15, 16, 17, 18, 19, 21, 22, 23). The addition of a single drug to a failing regimen violates one of the tenets of TB therapy so close follow up of patients on a retreatment regimen is especially important (14). Fixed dose combinations (FDCs) are desirable as they simplify drug procurement and logistics, the delivery of DOT and may increase adherence

(10). It is important that the provider prescribe only quality-assured pills of fixed drug combinations in RNTCP and WHO recommended dosing (2,3,10). Individual drug dosing should be reserved for patients with toxicities or contraindications to one or more components of the FDC (10). The RNTCP guidelines outline dosing based on weight bands. Suggested weight bands for adults are: 30-39kg, 40-54kg, 55-70kg and >70kg. Recommended weight

bands for paediatric patients are: 6-8kg, 9-12kg, 13-16kg, 17-20Kg, 21-24kg and 25-30kg. The expert group acknowledged that the intermittent regimen used under the programme over the past decade is equally effective under direct observation as compared to the daily regimen, and choosing daily regimen does not undermine the successes of the programme (11,12). However, based on the above evidences and in the interest of having uniformity of care across all

healthcare sectors to achieve the future vision of the programme for universal access to quality TB care and prevention of further drug resistance to TB; the choice for daily regimen was required. It was recommended that the programme to undertake an operational research to assess the feasibility of implementing daily therapy using FDCs under direct observation under programmatic settings. 40

References 1. Menzies D, Benedetti A, Paydar A, Martin I, Royce S, et al. (2009) - Effect of Duration and Intermittency of Rifampin on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis. PLoS Med 2009. 6(9): e1000146. doi:10.1371 2. World Health Organisation. Treatment of Tuberculosis Guidelines. 4th edition. Geneva: World Health Organisation; 2010. 3. International Standards for TB Care, Second Edition (2009) Tuberculosis Coalition for Technical Assistance, The Hague 2009.

4. World Health Organization, Global Tuberculosis Report 2012; Geneva 2012 5. World Health Organization, Stop TB Strategy, 2013; Geneva 2013 6. Revised National TB Control Programme, 2013; tbcindia.nic.in 7. Kwok Chiu Chang et al.Dosing Schedules of 6-Month Regimens and Relapse for Pulmonary TB.Amer Journal of RespirCrit Care Medicine. 2006; 174: 1153-1158. 8. Chang KC et al. Treatment of tuberculosis and optimal dosing schedules – Downloaded from thorax.bmj.com on June 29, 2011 – Published by group.bmj.com

9. ChangKCetal. – A Nested Case-Control Study on Treatment – related Risk Factors for Early Relapse of Tuberculosis. Amer Journal of RespirCrit Care Medicine. 2004; 170: 1124-1130. 10. MonederoI. et al. Evidence for promoting fixed-dose combination drugs in tuberculosis treatment and control: a review. Int J Tuberc Lung Dis. 2011;15(4):433–439. 11. Alvarez TA et al.Prevalence of drug-resistant Mycobacterium tuberculosis in patients under intermittent or daily treatment. J Bras Pneumol. 2009;35(6):555-560.

12. Wells AW et al. Implications of the current tuberculosis treatment landscape for future regimen change. IntJTubercLungDis. 2011; 15(6):746–753. 13. Ramachandran R, S Nalini, V. Chandrasekar, P. V. Dave, A. S. Sanghvi, F. Wares, C. N. Paramasivan, P. R. Narayanan, Sahu S, Parmar M, Chadha S, Dewan P, L. S. Chauhan.Surveillance of drug-resistant tuberculosis in the state of Gujarat, India - Int J Tuberc Lung Dis. 13(9):1154–1160.

14. Bhargava A, Pai M, et al. - Mismanagement of tuberculosis in India: Causes, consequences, and the way forward - Hypothesis 2011, 9(1): e7. 15. Mahmoudi A, Iseman MD. Pitfalls in the Care of Patients with Tuberculosis. JAMA 1993 July 7, 1993; 270:65 16. Bhargava A, Jain Y. The Revised National Tuberculosis Control Programme in India: Time for Revision of Treatment regimens and rapid up–scaling of DOTS–Plus initiative. National Medical Journal of India 2008;21(4):187–91 41

17. Espinal MA. Time to abandon the standard retreatment regimen with first–line drugs for failures of standard treatment.Int J Tuberc Lung Dis 2003;7:607–8. 18. Patricio E et al. – Treatment of Isoniazid-Resistant Tuberculosis in South- eastern Texas – Chest 2001; 119; 1730-1736 19. Menzies D et al.Standardized Treatment of Active Tuberculosis in Patients with Previous Treatment and /or with Mono-resistance to Isoniazid: A Systematic Review and Meta-analysis – PLoS Med 6(9): e1000150.doi: 10.1371.

20. Donald PR, Maher D, Maritz JS, Qazi S. Ethambutol dosage for the treatment of children: literature review and recommendations 2006; 10;1318-1330. 21. GS Azhar – DOTS for TB relapse in India: A Systematic Review. Lung India. 2012. 29(2). 22. Poncea M, et al. (2009) - Additional evidence to support the phasing-out of treatment category II regimen for pulmonary tuberculosis in Peru - Transactions of the Royal Society of Tropical Medicine and Hygiene 106 (2012) 508– 510

23. Thomas A et al. Predictors of relapse among pulmonary tuberculosis patients treated in a DOTS programme in a DOTS programme in South India. International Journal of Tuberculosis and Lung Diseases 2005;9(5):556-561 24. Dave P, Rade K, Modi B, SolankiR,Patel P, Shah A, Vadera B. Assessment of Long-term Outcome among New Smear Positive Pulmonary TBPatients Treated with Intermittent Regimen under RNTCP – A Retrospective Cohort Study. Natl J Community Med 2013; 4(2):189-194. 42

Standard 8 Monitoring treatment response 8.1 Follow-up sputum microscopy: • Response to therapy in patients with pulmonary tuberculosis, new as well as retreatment cases, should be monitored by follow-up sputum microscopy/culture (one specimen) at the time of completion of the intensive phase of treatment and at the end of treatment. 8.2 Extension of intensive phase: • The extension of the intensive phase is not recommended. 8.3 Offer DST in follow up sputum positive cases:

• If the sputum smear is positive in follow-up at any time during treatment, a rapid molecular DST (as the first choice) or culture-DST (at least for R and if possible for Isoniazid (H); Ofloxacin (O) and Kanamycin (K), if R-resistant/MDR) should be performed as laboratory facilities become available. 8.4 Response to treatment in extra-pulmonary TB: • In patients with extra-pulmonary tuberculosis, the treatment response is best assessed clinically. The help of radiological and other relevant

investigations may also be taken. 8.5 Response to treatment in children: • In children, who are unable to produce sputum, the response to treatment may be assessed clinically. The help of radiological and other relevant investigations may also be taken. 43

8.6 Long- term follow up: • After completion of treatment the patients should be followed up with clinical and/or sputum examination at the end of six and 12 months. International standards recommend that a sputum sample should be collected at the end of the intensive phase (two months) and at the end of treatment (six months) to monitor the success of therapy (1,2). Recent evidence from India shows that collecting more than one sample added little

to the detection of failure of treatment and therefore only one sample at two months is recommended for initial treatment monitoring (3,4,6). If the sample is positive for TB then it is recommended that a DST be done to guide further selection of therapy, either by a molecular probe for drug resistant loci or phenotypic DST in liquid culture. Consensus summarised by the WHO found little benefit for extending the intensive phase to three months if the two

months smear was positive (2). It is, however, necessary to re-address adherence issues and/or other comorbid conditions that may have affected proper completion of the two months intensive phase (1). Follow up of extra-pulmonary and smear negative TB is challenging and best done by regular clinical review. Chest X-ray has shown limited accuracy (5). References: 1. International Standards of TB Care (2009) 2. WHO Guidelines of Treatment of TB (2010) Geneva

3. Kundu D, MV Kumar A, Satyanarayana S, Dewan PK, Achuthan Nair S, et al. (2012) Can Follow-Up Examination of Tuberculosis Patients Be Simplified? A Study in Chhattisgarh, India. PLoS ONE 7(12): e51038. doi:10.1371/journal.pone.0051038 4. Toshniwal M, MV Kumar A, Satyanarayana S, Dewan PK, Achuthan Nair S, et al. (2012) – IUATLD – Abstract Book – UNION World Conference for Lung Health, November 2012 – Kuala Lumpur, Malaysia 5. Horne et al., Lancet Infectious Diseases 2010 Gandhi MP, Kumar AMV,

Toshniwal MN, Reddy RHR, Oeltmann JE, et al. (2012) Sputum Smear Microscopy at Two Months into Continuation- Phase: Should It Be Done in All Patients with Sputum Smear-Positive Tuberculosis? PLoS ONE 7(6): e39296. doi: 10.1371/journal.pone.0039296 44

Standard 9 Drug Resistant TB management 9.1 Treatment of M/XDR-TB(or R resistant TB): • Patients with TB caused by drug-resistant organisms (especially M/XDR or only R resistance or with O or K resistance), microbiologically confirmed by an accredited laboratory, should be treated with specialized regimens containing quality assured second-line anti- tuberculosis drugs. 9.2 Model of care for drug resistant TB: • Patients with DR-TB should be treated using mainly ambulatory care

rather than models of care based principally on hospitalization. If required, a short period of initial hospitalisation is recommended. 9.3 Regimen for MDR - TB (or R resistant cases): • The regimen chosen for MDR-TB may be standardized and/or based on microbiologically confirmed drug susceptibility patterns. At least four drugs (second line) to which the organisms are known or presumed to be susceptible, should be used. Most importantly the regimen should include at least Pyrazinamide, Ethambutol, a later-

generation Fluoroquinolone (such as high dose Levofloxacin) and a parenteral agent (such as Kanamycin or Amikacin), Ethionamide (or Prothionamide), and either Cycloserine or PAS (P-aminosalicylic acid), if Cycloserine cannot be used. 9.4 Regimen for MDR-TB patients with O and/or K resistance detected early: • Treatment regimen may be suitably modified in case of Ofloxacin and/or Kanamycin resistance at the initiation of MDR-TB treatment or during early intensive phase, preferably not later than four to six

9.5 Surgery in M/XDR-TB patients: • All patients of M/XDR-TB should be evaluated for surgery at the initiation of treatment and/or during follow up. 9.6 Treatment duration in MDR-TB patients: • Till newer effective drugs are available with proven efficacy with shorter duration of MDR-TB treatment; total treatment should be given for at least 24 months in patients newly diagnosed with MDR- TB (i.e. not previously treated for MDR-TB) with recommended

intensive phase of treatment being six to nine months. The total duration may be modified according to the patient's response to therapy. 9.7 Specialist consultation in M/XDR-TB patients: • Consultation with a specialist experienced in treatment of patients with M/XDR-TB should be obtained, whenever possible. 9.8 Ensuring adherence in M/XDR-TB patients: • Patient support systems, including direct observation of treatment, are required to ensure adherence. It should be ensured that the

patient consumes all the doses of the drugs. 9.9 Single sample follow up culture in M/XDR-TB patients: • The use of sputum culture (1 sample) is recommended for monitoring of patients with M/XDR-TB during treatment. 9.10Second line DST during treatment of MDR-TB: • During the course of MDR-TB treatment, if the sputum culture is found to be positive at 6 months or later, the most recent culture isolate should be subjected to DST with second-line drugs (at least Ofloxacin

and Kanamycin) to decide on further course of action. DST to other additional drugs may also be done if laboratory facilities are available to guide treatment. 9.11Regimen for MDR-TB patients with Ofloxacin and/or Kanamycin resistance detected later: 46

• The patients with MDR-TB found to be resistant to at least Ofloxacin and/or Kanamycin during the later stage of MDR-TB treatment must be treated with a suitable regimen for XDR-TB using second line drugs including Group 5 drugs such as Amoxicillin-Clavulanate, Clarithromycin, Clofazimine, Linezolid, Thioacetazone, Imipenem to which the organisms are known or presumed to be susceptible. 9.12 New drugs: • The new drugs e.g. Bedaquiline, Delaminid may be considered

whenever scientific evidence for their efficacy and safety becomes available as per the national policy for newer antimicrobials. Appropriate regulatory mechanisms for distribution control needs to be ensured. The treatment of drug resistant TB is much more complex and challenging than the treatment of drug susceptible TB and requires drugs with greater toxicities for longer periods of time with relatively less encouraging outcomes. Unfortunately the evidence for drug regimen recommendations for drug-

resistant TB are based on observational studies and expert opinion and no large scale randomized controlled clinical trial data has been generated across the globe. Newer agents and newer regimens are becoming available and it is hoped the level of evidence for treatment choices increases in the next few years. The new drugs e.g. Bedaquiline, however, may be considered whenever scientific evidence for their efficacy and safety is available as per the national

policy for newer antimicrobials. Appropriate regulatory mechanisms for distribution control need to be ensured. This is of utmost importance to safeguard the new drugs from the risk of unregulated irrational use and emergence of resistance to these precious drugs. Laboratory based microbiological confirmation of drug resistance is an important pre-requisite for deciding on an appropriate treatment regimen under consultation with a specialist experienced in management of M/XDR

TB, wherever possible. Patients with tuberculosis caused by drug-resistant organisms (especially M/XDR or only Rifampicin resistance or with Ofloxacin or Kanamycin resistance), microbiologically confirmed by an accredited laboratory, should be treated with specialized regimens containing quality 47

assured second-line anti-tuberculosis drugs. For all practical purposes, Rifampicin resistance should be considered as a surrogate of MDR-TB and treated with the same regimen for MDR-TB. While all efforts should be made for microbiological confirmation, in exceptional circumstances (e.g. paediatric and extra-pulmonary cases) the MDR treatment may be considered in absence of the microbiological confirmation. Clear guiding principles need to

be laid down by the national programme to define the eligibility of patients under such exceptional circumstances for treatment with second line anti-TB drugs in absence of microbiological confirmation. The basic principles of drug-resistant TB treatment include using at least four second line drugs that the organism has demonstrated susceptibility to through DST or that guided by the current epidemiology of drug-resistance in the relevant population. In the treatment of patients with MDR-TB, four

second-line anti-TB drugs likely to be effective (including a parenteral agent), as well as Pyrazinamide and Ethambutol should be included in the intensive phase (1, 2), the duration of that should be at least for six to nine months. Consider extending treatment at least 18 months beyond the last evidence of mycobacteria in a culture from the patient. Thus, the total duration of treatment should be at least 24 months up to a maximum of 27 months in

patients newly diagnosed with MDR-TB (i.e. not previously treated for MDR- TB). The total duration of treatment may be modified according to the patient's response to therapy. In the treatment of patients with MDR-TB, regimens should thus include at least Pyrazinamide, a Fluoroquinolone, a parenteral agent, Ethionamide (or Prothionamide), and either Cycloserine or PAS (P-aminosalicylic acid) if Cycloserine cannot be used. (1, 2). Treatment regimen may be suitably

modified in case of Ofloxacin and/or Kanamycin resistance detected early at the initiation of MDR-TB treatment or during early intensive phase, preferably not later than four to six weeks. However, for patients on MDR-TB regimen that are found to be resistant to at least Ofloxacin and/or Kanamycin during the later stage of MDR-TB treatment; they must be treated with a suitable regimen for XDR-TB using second line drugs including Group 5 drugs to which the organisms are known or presumed to be susceptible.

Ambulatory care is the preferred choice for management of DR-TB patients rather than models of care based principally on hospitalization as there are 48

convincing evidences that improving access to treatment for DR-TB through decentralization of care to centers near the patient's residence reduced the risk of default (2,3). However, if required, a short period of initial hospitalisation is recommended (2). Patient support systems, including direct observation of treatment, are required to ensure adherence. It should be ensured that the patient consumes all the doses of the drugs as missed

doses for more than a week increases the odds of further augmentation of drug resistance and adversely affects treatment outcomes. Monitoring of treatment should be done by collecting a single monthly sample of sputum for culture from month three to month seven and then quarterly until the end of therapy. It has been observed in an operational research conducted under the RNTCP that there is no meaningful advantage in using two specimens and a

single specimen policy could be safely implemented with negligible clinical effect on MDR-TB patients and favourable resource implications for RNTCP(4). Prompt identification of early failures of MDR-TB regimen and timely actions for initiating second line DST in culture isolates of such patients is alluded to in Standard 4. However, if the sputum culture is found to be positive at six months or later and the patient has no clinical or radiological

deterioration, a repeat DST may be done to confirm sensitivity status. Last but not the least, it must be emphasized that treatment of drug resistant TB can be complicated by drug toxicities, drug to drug interactions and emerging DST patterns and enlisting the help of an expert in DR-TB should be sought sooner rather than later through more than 100 established DR TB centers across the country. References: 1. Guidelines for the programmatic management of drug-resistant tuberculosis

(2011 update), World Health Organization, WHO/HTM/TB/2011.6. www.who.int/publications 2. Guidelines on Programmatic Management of Drug Resistant TB (PMDT) in India, Revised National Tuberculosis Control Programme, Central TB Division, Directorate General of Health Services,Ministry of Health & Family Welfare, Nirman Bhavan, New Delhi, www.tbcindia.nic.in/documents 3. M. T. Gler,* L. J. Podewils,† N. Munez,* M. Galipot,* M. I. D. Quelapio,* T.E.

Tupasi* et al. (2012) - Impact of patient and program factors on default during treatment of multidrug-resistant tuberculosis-INT J TUBERC LUNG DIS 16(7):955–960 © 2012 The Union http://dx.doi.org/10.5588/ijtld.11.0502- 7 May 2012 49

4. Nagaraja SB, Kumar AMV, Sachdeva KS, Ramachandran R, Satyanarayana S, Parmar M et al. (2012) Is One Sputum Specimen as Good as Two during Follow- Up Cultures for Monitoring Multi Drug Resistant Tuberculosis Patients in India? PLoS ONE 7(9): e45554. doi:10.1371/journal.pone.0045554 50

Standard 10 Addressing TB with HIV infection and other comorbid conditions 10.1 Treatment of HIV infected TB patients: • TB patients living with HIV infection should receive the same duration of TB treatment with daily regimen as HIV-negative TB patients. 10.2 Anti-retroviral therapy and co-trimoxazole prophylactic therapy in HIV infected TB patients: • Anti-retroviral therapy must be offered to all patients with HIV and TB as well as drug-resistant TB who require second-line anti-TB drugs,

irrespective of CD4 cell-count, as early as possible (within the first eight weeks) following initiation of anti-TB treatment. Appropriate arrangements for access to anti-retroviral drugs should be made for patients. However, initiation of treatment for TB should not be delayed. Patients with TB and HIV infection should also receive Co- trimoxazole as prophylaxis for other infections. 10.3 Isoniazid preventive therapy in HIV patients without active TB:

• People living with HIV (PLHIV) should be screened for TB using four symptom complexes (current cough or fever or weight loss or night sweats) at HIV care settings and those with any of these symptoms should be evaluated for ruling out active TB. All asymptomatic patients in whom active TB is ruled out, Isoniazid Preventive Therapy (IPT) should be offered to them for six months or longer. PLHIV are more susceptible to TB infection, more likely to develop active TB

disease after infection and more likely to suffer from severe TB and disseminated, extra-pulmonary TB. In general, the treatment for TB in PLHIV is the same as treatment for patients without HIV and treatment outcomes are successful although the mortality rate of PLHIV is higher, more so with DR-TB 51

comorbidity than the HIV uninfected (1).With growing evidences it is globally recommended, that HIV infected TB patients should be treated with daily regimen (2,3,4,5). Intermittent regimen has been proven to lead to higher risk for relapse and development of acquired Rifampicin resistance if intermittent dosing of Rifampicin was started during the intensive phase of treatment in HIV-infected patients treated with Rifampicin-based regimens. (2,3,4,5)

Anti-retroviral therapy must be offered to all patients with HIV and TB as well as drug-resistant TB who require second-line anti-TB drugs, irrespective of CD4 cell-count, as early as possible (within the first eight weeks) following initiation of anti-TB treatment(2,3,5). A number of recent studies have investigated the optimal timing of TB and HIV treatment to reduce mortality and it seems clear that as soon as possible after initiating treatment for active

TB in a PLHIV they should be started on antiretroviral therapy (2, 5). ART reduces the risk of TB relapse and acquired drug resistance to rifampicin in HIV infected TB patients (2,3,5). Further, in settings with high Fluoroquinolone resistance and extensive prior second-line treatment, encouraging results are being achieved in an ambulatory MDR-TB programme in a slum setting in India. Rapid scale up of both Antiretroviral Therapy (ART) and second-line treatment for MDR-TB are needed to ensure

survival of co-infected patients and mitigate this growing epidemic (6). Considerations such as the ability to tolerate a large pill burden, drug interactions and toxicities all have to be balanced with the life-saving treatment of both TB and HIV simultaneously. Appropriate arrangements for access to anti-retroviral drugs should be made for patients. However, initiation of treatment for TB should not be delayed. Patients with TB and HIV infection should also receive co-trimoxazole as

prophylaxis for other infections (3). In PLHIV that do not appear acutely ill and do not have one or more of the WHO recommended four symptom screens for active TB are very unlikely to be suffering from active TB and may safely be given Isoniazid Preventative Therapy (IPT) for at least six months as part of a comprehensive package of HIV care(7). IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to

those on ART, those who have previously been treated for TB and pregnant women (7). Recent studies have demonstrated the profound protective effect of IPT although those that derive the most benefit are TST positive. In addition, evidence from India, along with other countries, points to a prolonged course of IPT being more protective than the standard six month course. 52

References: 1. S. Tripathy, A. Anand, V. Inamdar et. al - Clinical response of newly diagnosed HIV seropositive &seronegative pulmonary tuberculosis patients with the RNTCP Short Course regimen in Pune, India - Indian J Med Res 133, May 2011, pp 521-528 2. Faiz Ahmad Khan, Jessica Minion, Abdullah Al-Motairi, Andrea Benedetti, Anthony D. Harries, and Dick Menzies - An Updated Systematic Review and Meta-analysis on the Treatment of Active Tuberculosis in Patients With HIV

Infection - 1154 CID 2012:55 (15 October) HIV/AIDS 3. WHO Guidelines for Treatment of Tuberculosis –2010 update 4. Jiehui Li et.al. Relapse and Acquired Rifampicin Resistance in HIV-Infected Patients with Tuberculosis Treated with Rifampicin – or Rifabutin-Based Regimens in New York City, 1997-2000 – Clinical Infectious Diseases 2005; 41:83-91 5. PayamNahid et.al. – Treatment outcomes of patients with HIV and Tuberculosis - American Journal of Respiratory Critical Care Medicine – Vol 175 pp 1199-1206, 2007

6. Isaakidis P, Cox HS, Varghese B, Montaldo C, Da Silva E, et al. (2011) Ambulatory Multi-Drug Resistant Tuberculosis Treatment Outcomes in a Cohort of HIV-Infected Patients in a Slum Setting in Mumbai, India. PLoS ONE 6(12): e28066. doi:10.1371/journal.pone.0028066 7. DelphineSculier and HaileyesusGetahun.Scaling up TB screening and Isoniazid preventive therapy among children and adults living with HIV: new WHO guidelines. Africa Health, November 2011, page 18-23 53

Standard 11 Treatment adherence 11.1 Patient-centered approach for adherence: • To assess and foster adherence, a patient-centered approach to administration of drug treatment, based on the patient's needs and mutual respect between the patient and the provider, should be developed for all patients. 11.2 Measures for treatment adherence: • Supervision and support should be individualized and should draw on the full range of recommended interventions and available support

services, including patient counselling and education. A central element of the patient centered strategy is the use of measures to assess and promote adherence to the treatment regimen and to address poor adherence when it occurs. These measures should be tailored to the individual patient's circumstances based on details of the patient's clinical and social history and be mutually acceptable to the patient and the provider. 11.3 Trained treatment supporter for treatment adherence:

• Such measures may include identification and training of a treatment supporter (for tuberculosis and, if appropriate, for HIV, Diabetes Mellitus etc.) who is acceptable, accessible and accountable to the patient and to the health system. 11.4 Use of ICT to promote treatment literacy and adherence: • Optimal use of ICT should be done to promote treatment literacy and adherence Treatment adherence is a critical determinant of treatment outcomes,

prognosis and further emergence of DR-TB in patients experiencing irregular and incomplete treatment. The DOTS Strategy has been the backbone of most country's TB programmes for the last decade. In certain places, strict 54

healthcare worker DOTS has been cost-effective and sustainable and resulted in control of limited TB epidemics. However, accumulating evidence has pointed to the effectiveness of a wide variety of approaches including community and family-centered DOTS, which is more achievable for most developing healthcare systems and produce comparable outcomes to healthcare worker supervised DOTS(1). However, treatment adherence goes beyond the realm of DOTS to a larger

concept of treatment support system developed with mutual trust and respect between the patient, family, providers, treatment supporters and the health system at large to promptly identify and address all possible factors that could lead to treatment interruptions. This includes not only medical factors such as promptly addressing co-morbidities, adverse drug reactions and emergencies but also spans out to addressing various social, vocational,

nutritional, economic, psychological stress experienced by the patient throughout the course of treatment. Periodic regular and effective supervision by the public health supervisors at various levels and close monitoring of the progress made by the patient on treatment by the treating provider are critical components to ensure high standards of care. Capacity building and engaging with local community based organizations, self-help groups and

patient support groups could prove to be effective interventions to promote treatment adherence (2, 3). India is enabled with highly functional ICT systems and a population that is technology-literate. Through the use of SMS reminders and call center linkages between patients, providers and pharmacists, it is hoped that adherence to treatment will reach the necessary levels to reduce the prevalence of TB throughout India. References: 1. International Standards of TB Care

2. Volmink J, Garner P - Directly observed therapy for treating tuberculosis (Review) - The Cochrane Library - 2009, Issue 1, http://www.thecochranelibrary.com 3. Munro SA, Lewin SA, Smith H, Engel ME, Fretheim A, et al. (2007) Patient adherence to Tuberculosis treatment: A systematic review of qualitative research. PLoS Med 4(7): e238. doi:10.1371/journal.pmed. 55

Standard 12 Public health responsibility 12.1 Any practitioner treating a patient for tuberculosis is assuming an important public health responsibility to prevent on-going transmission of the infection and the development of drug resistance. 12.2 To fulfil this responsibility, the practitioner must not only prescribe an appropriate regimen, but when necessary, also utilize local public health services / community health services, and other agencies

including NGOs to assess the adherence of the patient and to address poor adherence when it occurs. (1) India continues to have high TB incidence and the mortality due to TB is still unacceptably high. The challenges of TB control in India are magnified by the existence of parallel systems for TB diagnosis and treatment – the public and private. Each system takes care of approximately half the TB cases (2) and methods and standards vary greatly depending on whether public or private

care is accessed and furthermore what type of private care is sought, from super-speciality tertiary institutions to non-qualified providers (3). In part publishing, these standards of care attempts to standardise care so that certain responsibilities of the provider, whether public or private, are clear. In addition Standard 13, the notification of TB cases from both public and private providers, is expected to improve surveillance and quality of the care

delivered and a subsequent reduction in the burden of TB in India. 56

References: 1. International Standards of TB Care 2. Satyanarayana S, Nair SA, Chadha SS, Shivashankar R, Sharma G, et al. (2011) From Where Are Tuberculosis Patients Accessing Treatment in India? Results from a Cross-Sectional Community Based Survey of 30 Districts. PLoS ONE 6(9): e24160. doi:10.1371/journal.pone.0024160 3. AnuragBhargava et al., Mismanagement of Tuberculosis in India: Causes, Consequences, and the Wayforward. Hypothesis 2011, 9(1): e7. 57

Standard 13 Notification of TB cases 13.1 All health establishments must report all TB cases and their treatment outcomes to public health authorities (District Nodal Officer for Notification). 13.2 Proper feedback need to be ensured to all healthcare providers who refer cases to public health system on the outcome of the patients which they had referred. TB is a notifiable disease in India as per the government order dated 7 May, 2012 and requires that all healthcare providers who have diagnosed a case of

TB through microbiological testing or clinically diagnosed and/or started treatment for TB must report to the District Nodal Officer for Notification(1). Notification is a basic public health activity common to diseases of public health importance. With notification, public health authorities can identify TB patients and offer necessary public health care, supervise and support for the quality of treatment, and monitor disease trends. Ensuring notification of all

TB cases is the most important step for a comprehensive TB surveillance system, which is required for effective TB control in the country. Cases are defined as anyone who has a microbiological (smear or culture) or approved molecular test proven disease or anyone who has a clinical syndrome consistent with active TB and is started on TB treatment. The requirement for reporting applies equally to government-run facilities and to private facilities.

In both settings, it is the primary TB care provider or laboratory diagnostician's responsibility to ensure that the required notification is completed (2). RNTCP has an electronic TB notification system (NIKSHAY) wherein all providers can register and notify cases -http://nikshay.gov.in 58

References: (1) Notification of TB in India http://www.tbcindia.nic.in/pdfs/TB%20Notification%20Govt%20%20Or der%20dated%2007%2005%202012.pdf (2) Guidance tool for TB notification http://tbcindia.nic.in/pdfs/Guidance%20tool%20for%20TB%20notificati on%20in%20India%20-%20FINAL.pdf 59

Standard 14 Maintain records for all TB patients 14.1 A written record of all medications given, bacteriologic response, adverse reactions and clinical outcome should be maintained for all patients. Patient-level recording of details of diagnosis, treatment and outcome are the foundations of any effective public health surveillance system. Use of appropriate technology such as Nikshay should improve the quality and accessibility to a primary provider initiated record that is linked at every level

from a primary clinic to the State Department of Health. In turn, it is the duty of the programme to monitor outcomes, both at primary level and aggregated into larger units, on a regular basis and reports the information that allow timely actions to improve services as needed. The Government of India through a gazette notification has made all anti-TB drugs under schedule H1. These drugs should not be dispensed without a valid prescription from a qualified practitioner. A copy of the prescription

should be maintained and details of the patient to be recorded by the chemist and should be made available for verification by the responsible public health authorities. 60

Standard 15 Contact investigation 15.1 All care providers to patients with TB should ensure all household contacts and other persons who are in close contact with TB patients are screened for TB as per defined Diagnostic Standards. 15.2 In case of paediatric TB patients, reverse contact tracing for search of any active TB case in the household of the child must be undertaken. The highest priority contacts for active screening are: o Persons with symptoms suggestive of tuberculosis

o Children aged <six years o Contacts with known or suspected immune-compromised patient, particularly HIV infection o Contacts with Diabetes Mellitus o Contacts with other higher risks including pregnancy, smokers and alcoholics etc. o Contacts of patients with DR-TB. In case of contact with a DR-TB index case, close clinical monitoring should be provided, as there is no evidence that treatment of latent infection with available drugs is presently effective

A contact investigation should focus on those in close contact with the index case, most importantly family members and other members of the household who may have prolonged exposure. Among this group of contacts past studies have found 4.5% to have TB (1, 2). A recent study in India found 8.7% of household contacts were diagnosed with TB (3). Particular attention should be paid to contacts with the highest susceptibility to TB infection and

subsequent active disease, namely small children and immunosuppressed people. References: 61

1) Recommendations for investigating contacts of persons with infectious tuberculosis in low and middle income countries. www.who.int/tb/publications/2012/en/index.html 2) Fox GJ, Barry SE, Britton WJ, Marks GB. Contact investigation of tuberculosis, a systematic review and meta-analysis. European Respiratory Journal, 2012 3) Evaluation of TB case finding through systematic contact investigation, Chhattisgarh, India – Presented at the 43rd UNION World Lung Conference, Nov 2012, Kuala Lumpur, Malaysia 62

Standard 16 Isoniazid Prophylactic therapy 16.1 Children <6 years of age who are close contacts of a TB patient, after excluding active TB, should be treated with isoniazid for a minimum period of six months and should be closely monitored for TB symptoms. Because children are more susceptible to TB infection, more likely to develop active TB disease soon after infection, and more likely to develop severe forms of disseminated TB, it is widely recommended (The Union, WHO) that

close contacts of index cases under the age of 6 who do not have active TB should receive IPT. Close contacts of index cases with proven or suspected DR-TB should be monitored closely for signs and symptoms of active TB as isoniazid may not be prophylactic in these cases. 63

Standard 17 Airborne infection control • Airborne infection control should be an integral part of all health care facility infection control strategy. Each healthcare facility caring for patients who have, or are suspected of having, TB should develop and implement an appropriate airborne infection control plan as per the national guidelines. Administrative, environmental and personal protective measures should be implemented in all health care facilities

as per national airborne infection control guidelines. Protection of health care workers from airborne infection should be ensured through adequate preventive measures including training, personal protection measures in high risk situations and periodic screening at least once a year. TB is an airborne bacillus spread through inhalation of droplets. Therefore, in addition to general infection control procedures recommended for all health

care facilities such as regular hand-washing, attention must be paid to limiting risk from airborne transmission. Airborne infection control measures are generally grouped into three main categories; environmental, administrative and managerial. Environmental controls require safe infrastructure and involve designing buildings and systems that promote safe air exchange e.g. HVAC systems, air flow management and UV light sterilization of areas. These tend to

be expensive and installation is disruptive. Managerial controls refer to management plans that promote and enable safe practices in every facility and as such every healthcare facility, whether public or private, should have clear plans for an airborne infection control strategy that are implemented and monitored for completeness. Administrative controls are the most cost- effective and should be within the reach of every facility. They include screening

and timely diagnosis of TB in all clients of the facility, respectful and non- stigmatizing removal of people with active TB from the general circulation of clients for rapid assessment and care, and use of personal protective equipment by active TB patients and staff to protect both staff and other patients. Such guidelines for Indian facilities are available at www.tbcindia.nic.in 64

Standard 18 Quality assurance systems 18.1 Quality assurance for diagnostic tests: • All healthcare providers should ensure that all diagnostic tests used for diagnosis of TB are quality assured. 18.2 Quality assurance for anti-TB drugs: • Quality assurance system should ensure that all anti-TB drugs used in the country are subjected to stringent quality assurance mechanisms at all levels (from manufacturer to patients). Providers should ensure that all anti-TB drugs prescribed come from a Quality

assured source. India has banned the use of commercial serology tests for diagnosis of TB. However, any diagnostic test used for diagnosing TB should have a quality assurance system in place. India's national TB programme (RNTCP) have established a good external quality assurance system for TB diagnostics, and is available to both public and private laboratories. The same principle applies to the use of drugs; the drugs should be from a quality assured source and should be under a standard Quality

Standard 19 Panchayati Raj Institutions 19.1 Panchayati Raj Institutions (PRIs) and elected representatives have an important role to share the public health responsibility for TB control with the healthcare providers, patients and the community. Health being an important responsibility of the PRIs in India, there are many opportunities for greater involvement of the PRIs for TB control. Because the diagnosis and treatment of TB is complicated and takes long, and

mistreatment of TB and emergence of drug-resistant TB affects everybody in the community, the Panchayat should be involved in all aspects of TB control. PRIs can facilitate good communication between facilities, public or private, that diagnose and treat TB and the communities, which they serve thus greatly helping in mobilizing community support for TB control. PRIs can help TB patient to link to other social welfare schemes, can help in nutritional and rehabilitation support etc. 66

Standard 20 Health education 20.1 Every TB symptomatic should be properly counselled by the healthcare providers 20.2 TB patients and their family members should get proper counselling and health education at every contact with healthcare system Proper health education to the patient and family is very important for TB care. There should be systems for education and counselling as an integral part of TB treatment. Every visit of the patient to the healthcare provider and visit of

the health worker to the patient's home should be utilised for health education. 67

Standard 21 Death audit among TB patients 21.1 Every death among TB patients should be audited by a competent authority. Investigation into the cause of death is an important standard which needs to be followed to study the conditions that led to the death in order to initiate actions to prevent development of such conditions to other TB patients. Every TB death should be notified to the concerned authority. Competent authority at the district level should do the death audit of every TB death and

provide a report to the programme to take necessary steps for preventing avoidable deaths. 68

Introduction to Standards for Social Inclusion for TB The principles for introducing Standards for Social Inclusion in TB Care are: • To ensure all individuals presenting to the healthcare facility are treated with dignity, irrespective of their health and socio-economic status. • To ensure universal delivery of quality assured TB diagnostic and treatment services across public and private sector. • To ensure visibility and accessibility of the TB service programme to all,

irrespective of socio-economic status. • To find and treat women, children and the elderly within hard to reach populations (Marginalized communities in rural and urban populations). • To eliminate out of pocket expenditure including those incurred on covering travel costs and bridging the nutrition gap. • To address loss of income when work day is lost due to TB. • To ensure no one is left without a plan of action to address their presenting complaint if it is not because of TB.

The Patients Charter (accompanying the ISTC) is the key operational guideline in engaging with patients in all TB care settings. 69

Standard 22 Information on TB prevention and care seeking 22.1 All individuals especially women, children, elderly, differently abled, other vulnerable groups and those at increased risk should receive information related to TB prevention and care seeking. 70

Standard 23 Free and quality services 23.1 All patients, especially those in vulnerable population groups, should be offered free or affordable quality assured diagnostic and treatment services, which should be provided at locations and times so as to minimize workday or school disruptions and maximize access. 71

Standard 24 Respect, confidentiality and sensitivity 24.1 All people seeking or receiving care for TB should be received with dignity and managed with promptness, confidentiality and gender sensitivity. Public health responsibilities including notification, contact tracing, chemoprophylaxis, fast tracking, outcome monitoring etc. should be sensitive to respect and confidentiality of patients. 72

Standard 25 Care and support through social welfare programmes 25.1 Healthcare providers should endeavour to derive synergies between various social welfare support systems such as RSBY, nutritional support programmes, national rural employment guarantee scheme etc. to mitigate out of pocket expenses such as transport and wage loss incurred by people affected by TB. 73

Standard 26 Addressing counseling and other needs 26.1 Persons affected by TB and their family members should be counselled at every opportunity, to address information gaps and to enable informed decision-making. Counseling should also address issues such as healthcare, physical, financial, psycho-social and nutritional needs. 74

532, A - Wing, Nirman Bhawan Maulana Azad Road, New Delhi 110 011 www.searo.who.int/india

STANDARD TREATMENT GUIDELINES Major Trauma Ministry of Health & Family Welfare Government of India

Table of Contents Sections Contents Pg no. I Introduction 3-4 II Scope 5-6 III Recommendations 7-22 1.0 Prehospital 7-8 2.0 Airway and Chest trauma 8-10 3.0 Haemorrhage and Shock Management 10-13 4.0 Head Injury 13-14 5.0 Spinal Trauma 14-17 6.0 Pelvic trauma 17-18 7.0 Complex fracture management 18-19 8.0 Pain Management 19 9.0 Providing Support and Information in Major Trauma 19-22 Providing information about patients to the next level hospital/casualty IV Background and How this STG was developed 23-30

V Review 30-31 VI Way Forward for India 32-33 VII References 34-35 Annexure 1 Adopt/Adapt Tables 36-79 Annexure 2 Abbreviations 80 Standard Treatment Guidelines-Major Trauma 1

Annexure 3 Definitions 81 Annexure 4 Tables and Figures 82 Annexure 5 Doses 83 Standard Treatment Guidelines-Major Trauma 2

I. Introduction Between 1990 and 2013, non-communicable diseases like injuries have become the main causes of mortality and morbidity across the world [1]. Every year 5 million people die due to injuries accounting for 1/10th of world's deaths, larger than fatalities due to HIV/AIDS, TB and malaria combined [2]. Over 90% of these deaths occur in low-and-middle-income-countries (LMICs) and if the injury death rates in these countries could be reduced, to that of high-income-countries,

nearly 2 million lives could be saved every year [3][4]. Consequently, there has been increased attention in the international sphere of the need to reduce mortality due to injuries. The Sustainable Development Goals (SDGs) have set the target of halving the current rates of mortality due injuries by 2030 [5]. This requires a continuum of interventions ranging from improving pre-hospital services, streamlined in-hospital care protocols and trained personnel [6].

Out of all trauma deaths, 30-50% has been estimated to occur in hospital, highlighting the need for strengthened hospital trauma care [7]. However, most LMICs do not have in place such capacities to deal with trauma care [8]. Trauma Scenario in India India, the second-most populous country in the world, is in rapid epidemiological transition, with an increasing burden of noncommunicable diseases like injury [1]. With its large population and

inadequate health care system, it shares a major chunk of the trauma burden. It accounts for nearly 20% of the global injury mortality making it a key health priority with substantial scope of improvement [9]. Injuries and trauma are rapidly increasing becoming the top causes mortality and morbidity in the country necessitating critical attention in policy and practice [1] [10] [11]. More than half of these deaths can be prevented by improving trauma services, developing

guidelines and investing resources [12] [13]. Why this STG is needed While there is some acknowledgment among policy makers in India of the significant health challenge posed by trauma, the current trauma care system is largely deficient in terms of guidelines and resources to meet the growing burden of injury and trauma in the country [14][15][16]. The increasing burden of injuries would consequently result in more pressure on

the healthcare system to provide adequate and quality trauma care services. Therefore, it is imperative that the healthcare system develops guidelines and protocols to better equip it to respond to this challenge. A key step is developing standard treatment guidelines for trauma which are suitable for the Indian setting by adapting and contextualizing existing guidelines already being used in other settings. This Standard Treatment Guideline on Major Trauma aims to begin this process by developing

guidelines on major trauma in the Indian health setting. This document does not seek to exhaustively cover every aspect of major trauma and would need to be periodically updated. It Standard Treatment Guidelines-Major Trauma 3

would be focusing primarily on major trauma among the adult population covering broad issues such as management of airway, breathing, hemorrhage, pain and other broad areas of trauma without going into definitive care. Recognizing the role played by patient carers in the healthcare system in India, it will include key information to support and guide patients and their carers. Moreover, the resource availability both equipments and personnel is different in different

settings. This document acknowledges that it cannot solve all the challenges of providing trauma care in every health facility given the differences in resources available in different facilities. But it is a tool for medical professionals to enhance the effectiveness and the quality of the services that they can provide and thereby make improvements in the management of major trauma in their own facilities with the resources that they have. Thus, the STG aims to contribute in better

planning and provisioning of trauma care services to be made available in the Indian context. Standard Treatment Guidelines-Major Trauma 4

II. Scope of STG Major Trauma Management A) Population Adult Population more than 18 years of age B) Health settings Primary, secondary and tertiary health care settings C) Key issues that will be covered 1. Prehospital care Briefly describing the management of airway, breathing, circulation, spine and fractures in pre- hospital settings. 2. In-Hospital care 1) Airway management with cervical spine protection ● Definitive airway control 2) Breathing and ventilation

● Recognition of chest trauma(clinical assessment) and management of life saving chest trauma and pneumothorax. ● Imaging assessment of chest trauma (including choice and timing of imaging modality and imaging parameters) such as, X-ray, FAST, CT 3) Circulation with haemorrhage control ● Assessment and management of haemorrhage and shock ● Control of external haemorrhage, non compressible haemorrhage ● Control of haemorrhage o use of major haemorrhage protocols o damage-control surgery ● Management of shock

o i.v. access o hypotensive versus normotensive resuscitation o type of fluid replacement o Intravenous fluid therapy o haemostatic agents ● Monitoring o blood tests o frequency of monitoring ● Management of specific complications in hospital relating to anticoagulation reversal. Standard Treatment Guidelines-Major Trauma 5

4) Head Injury management ● Early management 5) Spine trauma management 6) Major Fracture management ● Stabilization of Major fractures (Pelvic, long bone) ● Assessment of Vascular complications related to fractures 7) Assessment and management of pain relief 8) Skills to be present within the multidisciplinary team 9) Documentation of clinical assessments and management for people with major trauma 10) Information and support needs of patients and their families and carers when appropriate.

D) Clinical issues that will not be covered a) Prevention of major trauma. b) Any management after definitive life saving or limb saving intervention. c) Major trauma resulting from burns. d) Head injury (for disability relating to neurological assessment) e) Details of Pre-hospital management of trauma (extrication, whom to transfer, where to transfer) f) Trauma Rehabilitation E) Main outcomes a) Mortality. b) Morbidity c) Health related quality outcomes.

d) Time to operating theatre, time to CT scan, time to definitive control of haemorrhage (surrogate outcome of quality of care). Standard Treatment Guidelines-Major Trauma 6

III Recommendations “Since the management of Trauma is situation based and treatment may undergo change accordingly, the guidelines are therefore recommendatory only" 1. Pre-Hospital 1.1. Airway management 1.1.1 Consider using a supraglottic device* if the patient's airway reflexes are absent. Use basic airway manoeuvres like inserting a Guedel’s airway** and bag and mask ventilation if required or if supraglottic device placement is not possible.

*supraglottic device - Laryngeal mask airway, proseal, i-gel etc. **Guedels airway = Oropharyngeal airway/oral airway 1.2 Chest Trauma 1.2.1 Use clinical assessment to diagnose pneumothorax for the purpose of triage or intervention 1.2.2 In patients with an open pneumothorax: Cover the open pneumothorax with a three sided occlusive dressing and Observe for the development of a tension pneumothorax 1.3 Haemorrhage 1.3.1 Use simple dressings (sterile gauze pads) with direct pressure to control external

haemorrhage. 1.3.2 In patients with major limb trauma use a tourniquet* if direct pressure has failed to control life threatening haemorrhage. (*Tourniquet can be a bandage roll, rubber tubing , crepe bandage etc.) 1.3.3 If active bleeding is suspected from a pelvic fracture after blunt high-energy trauma: Apply a pelvic binder 1.3.4 Use intravenous tranexamic acid as soon as possible in patients with major trauma and active or suspected active bleeding.

(*Dose of Tranexamic acid - 1 gm i.v. over 10 min followed by 1 gm I.v. over 8 hrs) 1.3.5 Do not use intravenous tranexamic acid more than 3 hours after injury in patients with major trauma 1.3.6 For circulatory access in patients with major trauma in pre-hospital settings: Use peripheral intravenous access. 1.3.7 In pre-hospital settings, titrate volume resuscitation to maintain a palpable central pulse(carotid or femoral).

1.3.8 In pre-hospital settings only use crystalloids (Ringer’s lactate or Normal saline) to replace fluid volume in patients with active bleeding 1.3.9 Minimise ongoing heat loss in patients with major trauma. *Blankets can be used for reducing heat loss Standard Treatment Guidelines-Major Trauma 7

1.4 Pain Management 1.4.1 Assess pain regularly in patients with major trauma using a pain assessment scale 1.4.2 For patients with major trauma, use intravenous morphine/strong opioids as the first line analgesic and adjust the dose as needed to achieve adequate pain relief *To be administered after medical consult 1.5 Spine Trauma 1.5.1 Carry out full in-line* spinal immobilisation *By placing two blocks on either side of the head. Intravenous fluid bottles can also be used to prevent movement.

1.6 Fractures 1.6.1 Do not irrigate open fractures of the long bones, hindfoot or midfoot in pre-hospital settings 1.6.2 Consider a saline soaked dressing covered with an occlusive layer for open fractures in pre- hospital settings. 1.6.3 In the pre-hospital setting, consider the following for people with suspected long bone fractures of the legs: A rigid or malleable splint or adjacent leg as a splint if the suspected fracture is above the knee 2. In-Hospital Care 2.0 Airway and Chest trauma Management

2.1 Airway Assessment 2.1.1 A clinical examination of the thorax and respiratory function must be carried out. 2.1.2 The examination should include as a minimum the measurement of the respiratory rate and auscultation of the lungs. The examination should be repeated. 2.1.3 The following can be helpful: inspection (bilaterally unequal in respiratory excursion, unilateral bulging, paradoxical respiration), palpation (pain, crepitations, subcutaneous

emphysema, instability) and percussion (hyperresonant percussion) of the thorax together with pulse oxymetry and, in ventilated patients, monitoring ventilation pressure(if available). 2.2 Securing Airway 2.2.1 Manual in-line stabilization should be carried out for endotracheal intubation with the cervical spine immobilization device temporarily removed. 2.2.2 A difficult airway must be anticipated when endotracheally intubating a trauma patient.

2.2.3 The multiply injured patient must be preoxygenated before anesthesia. 2.2.4 Use drug-assisted rapid sequence induction (RSI) of anaesthesia and intubation as the definitive method of securing the airway in patients with major trauma who cannot maintain their airway and/or ventilation. 2.2.5 If RSI fails, use basic airway manoeuvres and adjuncts and/or a supraglottic device until a surgical airway or assisted tracheal placement is performed. Standard Treatment Guidelines-Major Trauma 8

2.2.6 If difficult anesthetization and/or endotracheal intubation are expected, an anesthesiologist must carry out or supervise this procedure in-hospital provided this does not cause delay in an emergency life-saving measure. Suitable measures must be in place to ensure that an anesthesiologist is normally on site in time 2.2.7 After more than 3 intubation attempts, alternative methods must be considered for ventilation and securing an airway.

2.2.8 Alternative methods for securing an airway must be provided when anesthetizing and endotracheally intubating a multiply injured patient. *Alternatives like emergency cricothyroidotomy or surgical airway 2.2.9 Etomidate should be avoided as an induction agent due to the associated side effects on adrenal function . *Ketamine can be used as a safe alternative as an induction agent. Dose- 1-2 mg/kg, time to effect of 45-60 seconds.

2.2.10 ECG, blood pressure measurement, pulse oxymetry and capnography(if available) must be used to monitor the patient for anesthesia induction, endotracheal intubation and emergency anesthesia. 2.2.11 Normoventilation must be carried out in endotracheally intubated and anesthetized trauma patients. 2.2.12 Ventilation must be monitored and controlled by frequent arterial blood gas analyses(if available) in the hospital.

If ABG analysis not available, then keep a check clinically by observing the chest rise & four point auscultation of the chest. 2.2.13 In mandible and maxillofacial injuries, primary securing of the airways and hemostasis in the oral and maxillofacial region must be carried out. 2.3 Chest Trauma Diagnosis and Management 2.3.1 A suspected diagnosis of pneumothorax and/or hemothorax must be made if breath sounds are weaker or absent on one side (after checking correct placement of the tube). Absence of such

auscultation findings largely rules out a larger pneumothorax, especially if the patient is normopneic and has no chest pain. 2.3.2 A suspected diagnosis of tension pneumothorax should be made if auscultation of the lung reveals no breath sounds unilaterally (after checking correct placement of the tube) and, in addition, typical symptoms are present, particularly severe respiratory disorder or upper inflow congestion combined with arterial hypotension.

2.3.3 Clinically suspected tension pneumothorax must be decompressed* immediately. *Chest decompression mainly refers to tube thoracostomy/ Chest drain placement. 2.3.4 Use open thoracostomy instead of needle decompression if the expertise is available, followed by a chest drain via the thoracostomy in patients who are breathing spontaneously. *Open method of chest drain insertion to be preferred over trocar method. Needle decompression should not be attempted unless absolutely indicated.

2.3.5 Observe patients after chest decompression for signs of recurrence of the tension pneumothorax. Standard Treatment Guidelines-Major Trauma 9

2.3.6 In patients with an open pneumothorax: cover the open pneumothorax with a simple occlusive dressing and observe for the development of a tension pneumothorax. 2.3.7 Pneumothorax diagnosed on the basis of an auscultation finding in a patient on positive pressure ventilation should be decompressed. 2.3.8 Pneumothorax diagnosed on the basis of an auscultation finding in patients not on ventilation should usually be managed by close clinical observation.

2.3.9 Pneumothorax should be treated with a chest drain provided the indication exists. 2.3.10 If there are perforating chest injuries, embedded foreign bodies should only be removed during surgery under controlled conditions after opening up the chest. 2.3.11 A penetrating chest injury, which is the cause of hemodynamic instability in the patient, must undergo an immediate exploratory thoracotomy. 2.3.12 A thoracotomy can be performed if there is an initial blood loss of > 1,500 ml from the

chest drain or if there is persistent blood loss of > 250 ml/h over more than 4 hours. 2.4 Imaging in Chest Trauma 2.4.1 Imaging for chest trauma in patients with suspected chest trauma should be performed urgently, and the images should be interpreted immediately by a healthcare professional with training and skills in this area. 2.4.2 Consider immediate chest X-ray and/or eFAST (extended focused assessment with sonography for trauma) as part of the primary survey to assess chest trauma with severe

respiratory compromise. 2.4.3 Consider immediate CT for those with suspected chest trauma without severe respiratory compromise who are responding to resuscitation or whose haemodynamic status is normal. 3.0 Haemorrhage and Shock 3.1 Dressings and tourniquets in hospital settings 3.1.1 Use simple dressings* with direct pressure to control external haemorrhage. *sterile gauze pads 3.1.2 In patients with major limb trauma use a tourniquet* if direct pressure has failed to control life-threatening haemorrhage.

*a bandage,a strip of cloth,a band of rubber,etc.,that checks bleeding or blood flow by compressing the blood vessels 3.2 Haemostatic agents in hospital settings 3.2.1 Use intravenous tranexamic acid as soon as possible in patients with major trauma and active or suspected active bleeding. Dosage as German guidelines Tranexamic acid initially 1 g i.v. as saturation over 10 minutes + 1 g over 8 hours (CRASH 2 Trials) * Or 2 g (15–30 mg/kg)

3.2.2. Do not use intravenous tranexamic acid more than 3 hours after injury in patients with major trauma. Standard Treatment Guidelines-Major Trauma 10

3.3 Anticoagulant reversal in hospital settings 3.3.1 Rapidly reverse anticoagulation in patients who have major trauma with haemorrhage. 3.3.2 FFP (10-15ml/kg body weight)is recommended when there is bleeding associated with clotting factors deficiency and if no alternative processed products or specific factor concentrates are available. If immediate reversal of warfarin effect is required. Intravenous vitamin K 5mg should be concurrently given for sustained reversal of warfarin effect

*Management of bleeding following major trauma: an updated European guideline Rolf Rossaint et al. 3.3.3 Consult a physician immediately for advice on adults (18 or over) who have active bleeding and need reversal of any anticoagulant agent other than a vitamin K antagonist. 3.3.4 Do not reverse anticoagulation in patients who do not have active or suspected bleeding. 3.4 Trauma induced coagulopathy 3.4.1 Trauma-induced coagulopathy is an autonomous clinical picture with clear influences on

survival. For this reason, coagulation diagnostic tests* and therapy must be started immediately in the emergency room. *Coagulation diagnostic tests - Platelets, PT/INR, APTT and Fibrinogen (if available) 3.5 Activating major haemorrhage protocols in hospital settings 3.5.1 Use physiological criteria that include the patient's haemodynamic status and their response to immediate volume resuscitation to activate the major haemorrhage protocol.

3.5.2 Do not rely on a haemorrhagic risk tool* applied at a single time point to determine the need for major haemorrhage protocol activation. *For example: ABC score, TASH score, PWH score, McLaughlin score, Emergency transfusion score, Shock Index etc These measure variables at a single point in time. 3.6 Circulatory access in hospital settings 3.6.1 For circulatory access in patients with major trauma in hospital settings: use peripheral

intravenous access (14 or 16 gauge intravenous cannula) or if peripheral intravenous access fails, a venous cutdown should be done. 3.7 Volume resuscitation in hospital settings 3.7.1 For patients with active bleeding use a restrictive*/balanced approach to volume resuscitation until definitive early control of bleeding has been achieved, *Restrictive resuscitation - in order to keep the circulation at a low stable level (Systolic BP: 90 mmHg or palpable

central pulse) and not exacerbate the bleeding. (from the german guidelines) 3.7.2 In hospital settings, titrate volume resuscitation to maintain a palpable central pulse (carotid or femoral). 3.7.3 For patients who have haemorrhagic shock and a traumatic brain injury: if haemorrhagic shock is the dominant condition, continue restrictive volume resuscitation or if traumatic brain injury is the dominant condition, use a less restrictive volume resuscitation approach to maintain cerebral perfusion.

3.7.4 Damage Control resuscitation: ● In patients who are actively bleeding, the goal can be set at mean arterial pressure ~ 65 mmHg and systolic arterial pressure ~ 90 mmHg until surgical hemostasis. ● Suitable measures should be taken and treatment given to avoid hypothermia. ● Acidemia should be avoided and treated by suitable treatment. 3.8 Fluid replacement in hospital settings 3.8.1 In hospital settings, only use crystalloids* to replace fluid volume in patients with active

bleeding if blood components are not available. * preferably Normal saline,Ringers lactate. Glucose containing fluid should be avoided in (a head injury) patients, during initial resuscitation. 3.8.2 Human albumin must not be used in hospital volume replacement. 3.8.3 Colloidal solutions can be used in hypotensive trauma patients, if available and preference should be given to HES 130/0.4. 3.9 Haemorrhage protocols in hospital settings

3.9.1 Hospital should have specific major haemorrhage protocols for adults. 3.9.2. For patients with active bleeding, start with a fixed-ratio protocol (1:1:1 FFP: platelets: RBC) for blood components and change to a protocol guided by laboratory coagulation results at the earliest opportunity. In patients with Grade 3 and 4 hemorrhagic shock with imminent threat to life and if components are not available then whole blood can be given to stabilize the patient before transferring to a higher centre[MK5] .

3.9.3 In an actively bleeding patient, the indication for transfusion can be made at hemoglobin levels below 10 g/dL, and the hematocrit value maintained at 30%. 3.9.4 In critically ill trauma patients, transfusion strategy to be employed ● Hb concentration <7 g/dL, RBC transfusion is likely to be appropriate; however, transfusion may not be required in well-compensated patients or where other specific therapy is available.

● Hb concentration of 7–9 g/dL, RBC transfusion is not associated with reduced mortality. The decision to transfuse patients (with a single unit followed by reassessment) should be based on the need to relieve clinical signs and symptoms of anaemia. ● Hb concentration >9 g/dL, RBC transfusion is generally unnecessary. 3.9.5 Red blood cell (RBC) transfusion should not be dictated by a haemoglobin (Hb) concentration alone, but should also be based on assessment of the patient's clinical status

3.9.6 Replacement of fibrinogen should be carried out, if test provisions are available, at levels < 1.5 g/l (150 mg/dl). 3.10 Haemorrhage imaging in hospital settings 3.10.1 Imaging for haemorrhage in patients with suspected haemorrhage should be performed urgently, using FAST, and a CT if required, and the images should be interpreted immediately by a healthcare professional with training and skills in this area. Standard Treatment Guidelines-Major Trauma 12

3.10.2 Limit diagnostic imaging (such as chest and pelvis X-rays or FAST [focused assessment with sonography for trauma]) to the minimum needed to direct intervention in patients with suspected haemorrhage and haemodynamic instability who are not responding to volume resuscitation. 3.10.3 Be aware that a negative FAST does not exclude intraperitoneal or retroperitoneal haemorrhage. *To repeat a FAST examination if clinical index of suspicion for intraperitoneal hemorrhage.

3.10.4 Consider immediate CT for patients with suspected haemorrhage only if they are responding to resuscitation or if their haemodynamic status is normal. 3.11 Damage control surgery 3.11.1 Use damage control surgery in patients with haemodynamic instability who are not responding to volume resuscitation. 3.12 Resuscitation ( Criteria for Cardiac arrest after trauma) 3.12.1 In the case of definitive cardiac arrest or uncertainties in detecting a pulse or other clinical

signs that make cardiac arrest likely, resuscitation must be started immediately 3.12.2 During resuscitation, trauma-specific reversible causes of cardiac arrest ., airway obstruction, esophageal intubation, hypovolemia, tension pneumothorax or pericardial tamponade) should be diagnosed and treated. 3.12.3 If resuscitation is unsuccessful after eliminating possible causes of cardiac arrest, cardiopulmonary resuscitation must be stopped. 3.13 Role of Emergency Thoracotomy

3.13.1 If expertise is available, emergency thoracotomy should be performed in the case of penetrating injuries, particularly if the onset of cardiac arrest is recent and vital signs are initially present. 4.0 Head Injury initial management 4.1.1State of consciousness with pupil function and Glasgow Coma Scale (bilateral motor function) must be recorded and documented at repeated intervals. 4.1.2 The goals are normoxia*, normocapnia**, and normotension***. A fall in arterial oxygen

saturation below 90% must be avoided. *Normoxia - sPO2>90% **Normocapnia - paCO2 = 35 -40 mmHg{4.7kPa} ***Normotension - SBP ≥90 mmHg 4.1.3 Intubation with adequate ventilation (with capnometry and blood gas analysis if available) must be carried out in unconscious patients (reference value GCS ≤ 8). Standard Treatment Guidelines-Major Trauma 13

4.1.4 A Cranial Computed Tomography scan must be performed in the case of polytrauma after stabilization with suspected traumatic brain injury. 4.1.5 A (monitoring) CT scan must be performed in the case of neurologic deterioration. 4.1.6 Glucocorticoids must not be administered in the treatment of TBI. 4.1.7 If severely elevated intracranial pressure is suspected, particularly with signs of transtentorial herniation (pupil widening, decerebrate rigidity, extensor reaction to painful

stimulus, progressive clouded consciousness), the following treatments can be given: ● Hyperventilation where ABG analysis is available* ● Mannitol** * 20 breaths per minute to maintain paCO2 at 30-35 mm of Hg **20% solution at 0.5-2 gm/kg over 30 to 60 minutes 5.0 Spinal Injury Management 5.1 Assessment for spinal injury 5.1.1 On arrival at the hospital, use a prioritising sequence to assess people with suspected trauma, for example ABCDE: ● Airway with in-line spinal immobilisation ● Breathing

● Circulation ● Disability (neurological) ● Exposure and environment. 5.1.2 At all stages of the assessment: ● protect the person's cervical spine with manual in-line spinal immobilisation, particularly during any airway intervention and ● avoid moving the remainder of the spine. 5.1.3 History and thorough clinical examination for spinal injury including the functions associated with it must be carried out. 5.1.4. The spine is suspected to be stable, unless any of the following 5 criteria are present,

• impaired consciousness ● neurologic deficit ● spinal pain or myogelosis ● intoxication ● trauma in the extremities *myogelosis (area of hard or stiff muscle) 5.1.5 The presence of a spinal injury must be assumed in unconscious patients until evidence to the contrary is found. 5.1.6 Carry out full in-line spinal immobilisation if any of the factors in recommendation 4.1.4 are present or if this assessment cannot be done. Standard Treatment Guidelines-Major Trauma 14

5.2Assessment of Cervical Spine 5.2.1 Assess whether the person is at high, low or no risk for cervical spine injury using the Canadian C-spine rule as follows: ➔ the person is at high risk if they have at least one of the following high-risk factors: ● age 65 years or older ● dangerous mechanism of injury (fall from a height of greater than 1 metre or 5 steps, axial load to the head – for example diving, high-speed motor vehicle collision, rollover motor accident, ejection from a motor vehicle, accident

involving motorised recreational vehicles, bicycle collision, horse riding accidents) ● paraesthesia in the upper or lower limbs ➔ the person is at low risk if they have at least one of the following low-risk factors: ● involved in a minor rear-end motor vehicle collision ● comfortable in a sitting position ● ambulatory at any time since the injury ● no midline cervical spine tenderness ● delayed onset of neck pain ➔ the person remains at low risk if they are:

● unable to actively rotate their neck 45 degrees to the left and right (the range of the neck can only be assessed safely if the person is at low risk and there are no high-risk factors).t ➔ the person has no risk if they: ● have one of the above low-risk factors and, ● are able to actively rotate their neck 45 degrees to the left and right. 5.3 Assessment of Thoracic or Lumbosacral Spine 5.3.1 Assess the person with suspected thoracic or lumbosacral spine injury using these factors:

● age 65 years or older and reported pain in the thoracic or lumbosacral spine ● dangerous mechanism of injury (fall from a height of greater than 3 metres, axial load to the head or base of the spine – for example falls landing on feet or buttocks, high-speed motor vehicle collision, rollover motor accident, lap belt restraint only, ejection from a motor vehicle, accident involving motorised recreational vehicles, bicycle collision, horse riding accidents)

● pre-existing spinal pathology, or known or at risk of osteoporosis – for example steroid use ● suspected spinal fracture in another region of the spine ● abnormal neurological symptoms (paraesthesia or weakness or numbness) ● on examination: ➢ abnormal neurological signs (motor or sensory deficit) ➢ new deformity or bony midline tenderness (on palpation) ➢ bony midline tenderness (on percussion) Standard Treatment Guidelines-Major Trauma 15

➢ midline or spinal pain (on coughing) ● on mobilisation (sit, stand, step, assess walking): pain or abnormal neurological symptoms (stop if this occurs). 5.4 When to carry out in-line spinal immobilisation 5.4.1 Carry out or maintain full in-line spinal immobilisation if: ● a high-risk factor for cervical spine injury is identified and indicated by the Canadian C- spine rule ● a low-risk factor for cervical spine injury is identified and indicated by the Canadian C-

spine rule and the person is unable to actively rotate their neck 45 degrees left and right ● indicated by one or more of the factors listed in recommendation 5.3.1 5.4.2 Do not carry out or maintain full in-line spinal immobilisation in people if: ● they have low-risk factors for cervical spine injury and, are pain free and are able to actively rotate their neck 45 degrees left and right ● they do not have any of the factors listed in recommendation 5.3.1

5.5 How to carry out full in-line spinal immobilisation 5.5.1 The spinal immobilisation devices need to be adjusted In uncooperative, agitated or distressed people, think about letting them find a position where they are comfortable with manual in-line spinal immobilisation. 5.5.2 When carrying out full in-line spinal immobilisation in adults, manually stabilise the head with the spine in-line using the following stepwise approach: ● Fit an appropriately sized semi-rigid collar unless contraindicated by:

➔ a compromised airway ➔ known spinal deformities, such as ankylosing spondylitis (in these cases keep the spine in the person's current position). ● Reassess the airway after applying the collar. ● Place and secure the person on a stretcher. 5.6 When to carry out or maintain full in-line spinal immobilisation and request imaging 5.6.1 Carry out or maintain full in-line spinal immobilisation and request imaging if: ● a high-risk factor for cervical spine injury is identified and indicated by the Canadian C-

spine rule or ● a low-risk factor for cervical spine injury is identified and indicated by the Canadian C- spine rule and the person is unable to actively rotate their neck 45 degrees left and right or ● indicated by one or more of the factors listed in recommendation 4.3.1 5.6.2 Do not carry out or maintain full in-line spinal immobilisation or request imaging for people if: Standard Treatment Guidelines-Major Trauma 16

● they have low-risk factors for cervical spine injury as identified and indicated by the Canadian C-spine rule, are pain free and are able to actively rotate their neck 45 degrees left and right ● they do not have any of the factors listed in recommendation 4.3.1 5.7 Diagnostic imaging 5.7.1 Imaging for spinal injury should be performed urgently, and the images should be interpreted immediately by a healthcare professional with training and skills in this area after stabilisation.

5.7.2 Perform CT in adults if; ● imaging for cervical spine injury is indicated by the Canadian C-spine rule (see recommendation 4.6.1) or ● there is a strong suspicion of thoracic or lumbosacral spine injury associated with abnormal neurological signs or symptoms. C spine xray should be considered if CT is not available with caution of high false negative rate. 5.7.3 If, after CT, there is a neurological abnormality which could be attributable to spinal cord injury, advice MRI.

5.8 Lumbosacral Spine Imaging 5.8.1 Perform an X-ray as the first-line investigation for people with suspected spinal column injury without abnormal neurological signs or symptoms in the thoracic or lumbosacral regions (T1–L3). 5.8.2 Perform CT if the X-ray is abnormal or there are clinical signs or symptoms of a spinal column injury. 5.8.3 If a new spinal column fracture is confirmed, image the rest of the spinal column.

5.8.4 After circulatory stabilization and before transfer from the emergency room, a spinal injury should be cleared by clinical examination or imaging . (if available). 5.9 Medications 5.9.1 Do not use the following medications, aimed at providing neuroprotection and prevention of secondary deterioration, in the acute stage after acute traumatic spinal cord injury: ● Methylprednisolone ● Nimodipine ● Naloxone. 5.9.2 Do not use medications in the acute stage after traumatic spinal cord injury to prevent

neuropathic pain from developing in the chronic stage. 6.0 Pelvic Fracture Management 6.1 Using a pelvic binder 6.1.1. An acute life-threatening pelvic injury must be excluded when the patient is admitted to the hospital. Standard Treatment Guidelines-Major Trauma 17

6.1.2 The stability of the patient’s pelvis must be clinically examined. 6.1.3 If active bleeding is suspected from a pelvic fracture following blunt high‑energy trauma, apply a pelvic binder. 6.2 Pelvic imaging 6.2.1 During the diagnostic study a pelvic survey radiograph should be taken and/or computed tomography (CT) be performed once patient is stabilized*. *unstable patients do portable X-Ray if available 6.2.2 Use CT (if available, otherwise X-ray) for first-line imaging with suspected high‑energy

pelvic fractures once patient is stabilized 6.2.3 Unstable patients with suspected active bleeding from pelvic fracture, use: ● pelvic packing to stabilize the patient. 6.3 Removing a pelvic binder 6.3.1 For people with suspected pelvic fractures and pelvic binders, remove the binder as soon as possible if: ● there is no pelvic fracture, or ● a pelvic fracture is identified as mechanically stable, or ● the binder is not controlling the mechanical stability of the fracture, or

● there is no further bleeding or coagulation is normal. Remove all pelvic binders within 24 hours of application. 6.4 Log rolling 6.4.1 Do not log roll people with suspected pelvic fractures before pelvic imaging unless: ● an occult penetrating injury is suspected in a person with haemodynamic instability ● log rolling is needed to clear the airway (for example, suction is ineffective in a person who is vomiting). ● When log rolling, pay particular attention to haemodynamic stability.

7.0 Management of open fractures and complications 7.1 Open fractures 7.1.1 Do not irrigate open fractures of the long bones, hindfoot or midfoot in the emergency department before debridement. 7.1.2 Consider a saline-soaked dressing covered with an occlusive layer (if not already applied) for open fractures in the emergency department before debridement. 7.1.3 In the emergency department, administer prophylactic intravenous antibiotics immediately to people with open fractures if not already given.

7.1.4 Do not base the decision whether to perform limb salvage or amputation on an injury severity tool score. 7.1.5 Perform emergency amputation when: ● A limb is the source of uncontrollable life-threatening bleeding, or Standard Treatment Guidelines-Major Trauma 18

● A limb is salvageable but attempted preservation would pose an unacceptable risk to the person's life, or ● A limb is deemed unsalvageable after orthoplastic assessment 7.1.6 Perform debridement: ● Immediately for highly contaminated open fractures ● Within 24 hours of injury for all other open fractures management 7.2 Vascular injury 7.2.1 Use hard signs (lack of palpable pulse, continued blood loss, or expanding haematoma) to diagnose vascular injury.

7.2.2 Do not rely on capillary return or Doppler signal to exclude vascular injury. 7.2.3 Perform immediate surgical exploration if hard signs of vascular injury persist after any necessary restoration of limb alignment and joint reduction. Do not delay revascularisation for angiography in people with complex fractures 7.3 Compartment syndrome 7.3.1 In people with fractures of the tibia, maintain awareness of compartment syndrome for 48

hours after injury or fixation by regularly assessing and recording clinical symptoms and signs in hospital 8.0 Pain management in Major trauma 8.1.1 Assess pain regularly in patients with major trauma using a pain assessment scale suitable for patients cognitive function. 8.1.2 For patients with major trauma, use intravenous morphine/opiods as the first-line analgesic and adjust the dose as needed to achieve adequate pain relief. Dose of Morphine – 2.5-5 mg/kg q 4h

Pentazocine Dosing: Adult IV: 30 mg every 3-4 hours. Butorphanol:IV: Initial: 1 mg, may repeat every 3-4 hours as needed. Buprenorhine:Slow IV: Initial: 0.3 mg every 6 to 8 hours as needed; 8.1.3 Consider ketamine in analgesic doses as a second-line agent. *Dose of Ketamine 1-4.5 mg/kg (medscape) 8.2 Efficacy of Analgesic Modalities in blunt thoracic trauma 8.2.1 Epidural analgesia is the preferred mode of analgesia delivery in severe thoracic trauma.

9.0 Providing support and Information to patients & relatives Providing information about patients to the next level hospital/casualty 9.1 Providing support 9.1.1 When communicating with patients, family members and carers ● manage expectations and avoid misinformation ● answer questions and provide information honestly, within the limits of your knowledge Standard Treatment Guidelines-Major Trauma 19

● do not speculate and avoid being overly optimistic or pessimistic when discussing information on further investigations, diagnosis or prognosis ● ask if there are any other questions. 9.1.2 The trauma team structure should include a clear point of contact for providing information to patients, their family members and carers. 9.2 Providing information 9.2.1 Explain to patients, family members and carers what is happening and why it is happening. Provide: ● information on known injuries

● details of immediate investigations and treatment, and if possible include time schedules. 9.2.2 Offer people with fractures the opportunity to see images of their injury, taken before and after treatment. 9.2.3 Provide people with fractures on the following when the management plan is agreed or changed: ● expected outcomes of treatment, including time to returning to usual activities and the likelihood of permanent effects on quality of life (such as pain, loss of function and psychological effects)

● amputation, if this is a possibility ● activities they can do to help themselves ● home care options, if needed ● rehabilitation, including whom to contact and how (this should include information on the importance of active patient participation for achieving goals and the expectations of rehabilitation) ● mobilisation and weight‑bearing, including upper limb load bearing for arm fractures. 9.2.4 Document all key communications with patients, family members and carers about the management plan.

9.2.5 Ensure that all health and social care practitioners have access to information previously given to people with fractures to enable consistent information to be provided. 9.3 Providing information about transfer from an emergency department 9.3.1 For patients who are being transferred from an emergency department to another centre, provide verbal and written information that includes: ● the reason for the transfer

● the location of the receiving centre and the patient's destination within the receiving centre ● the name and contact details of the person responsible for the patient's care at the receiving centre (if possible) ● the name and contact details of the person who was responsible for the patient's care at the initial hospital. 9.4 Recording information in before transferring to definitive care settings Standard Treatment Guidelines-Major Trauma 20

9.4.1 Record the following in people with major trauma in hospital settings: ● ABCDE (airway with in-line spinal immobilisation, breathing, circulation, disability [neurological], exposure and environment) ● History and Examination. 9.4.2 If possible, record information on whether the assessments show that the person's condition is improving or deteriorating. 9.4.3 Record pre-alert information using a structured system and include all of the following: ● the patient's age and sex ● time of incident

● mechanism of injury ● injuries suspected ● signs, including vital signs and Glasgow Coma Scale ● treatment so far ● estimated time of arrival at emergency department ● special requirements ● the ambulance call sign, name of the person taking the call and time of call ● 9.5 Training and skills 9.5.1 Ensure that each healthcare professional within the trauma service has the training and skills to deliver, safely and effectively, the interventions they are required to give as per this guideline.

Training in the form of ATLS, NTMC, EMTC etc 9.6 Receiving information in hospital settings 9.6.1 Casualty Medical Officer/Trauma team leader in the emergency department should receive the pre-alert information, and determine the level of trauma team response according to agreed and written local guidelines. 9.6.2 The trauma team leader should be easily identifiable to receive the handover and the trauma team ready to receive the information.

9.6.3 The pre- hospital documentation, including the recorded pre-alert information, should be quickly available to the trauma team and placed in the patient's hospital notes. 9.7 Sharing information in hospital settings 9.7.1 Follow a structured process when handing over care within the emergency department (including shift changes) and to other departments. Ensure that the handover is documented. 9.7.2 Ensure that all patient documentation, including images and reports, goes with the patient

when they are transferred to other departments or centres. 9.7.3 Produce a written summary, which gives the diagnosis, management plan and expected outcome and: ● is aimed at and sent to the patient's referring physician/surgeon/primary or secondary care hospital within 24 hours of admission Standard Treatment Guidelines-Major Trauma 21

● includes a summary written in plain English/local language that is understandable by patients, family members and carers ● is readily available in the patient's records. Standard Treatment Guidelines-Major Trauma 22

IV. Background A Task Force was constituted in December 2014 to guide the development of Standard Treatment Guidelines (STG) in India. The Task Force subsequently approved the draft STG development manual of India (Part 1) for development of adapted guidelines. This taskforce essentially decides the clinical subgroup topics as per the public health needs of the country. Each Clinical subgroup is headed by a facilitator which forms the guideline choosing his writing

team and expert group for that particular topic. A meeting was held on 12th May 2016 at National Health System Resource Centre (NHSRC) and management for Major trauma guideline was finalized for the surgery clinical subgroup. Methods of STG Development in India The NHSRC with technical support from National Institute for Health and Care Excellence (NICE), United Kingdom (UK), carried out a training workshop in May 2015 to guide the STG

group members and chairs on the methodology to follow in developing adapted STGs suitable for the Indian context. This workshop was conducted on 29th& 30th May, 2015 and two members (NR, MK) of the surgery clinical subgroup team attended. Subsequently, NHSRC facilitated the STG development process by providing resources approved by the Ministry of Health & family welfare to the expert group. The processes and methods used in developing this STG were drawn on those outlined in the

STG development manual of India (Part 1) for development of adapted guidelines and summarized in the Stepwise guide on STG development. The figure below contains a schematic of the process followed and each of the steps is detailed in subsequent sections below for the formation of Major trauma management guideline. Standard Treatment Guidelines-Major Trauma 23

How this STG was developed 1. Establish the STG group and conduct STG Meetings The STG on Major trauma management was developed by a team of experts, subject matter experts, patient representative undertook the development of this STG on Major trauma management. Official letters of invite were sent from NHSRC head office. One of the members who were invited could not attend the meetings and so was subsequently dropped and new

experts were invited. The following are the names of the group members, their roles in the development of the STG on Major trauma, along with their specialties and organization are listed below, Major Trauma Group Members Roles Name Title Specialist Area Facilitator Prof. Nobhojit Roy Professor & Head, Surgeon, Public Department of Surgery, Health Specialist BARC Hospital (HBNI University), Mumbai Standard Treatment Guidelines-Major Trauma 24

Expert Dr. Manjul President, IATSIC ( Orthopedic Joshipura International Association for Surgeon Trauma and Surgical Intensive Care ) Director of Academy of Traumatology, India Private Dr. Sudheer Consultant, Division of Neurosurgeon Practitioner Ambekar Skullbase and Cerebrovascular Surgery, Department of Neurological Surgery, Jaslok Hospital and Research Centre, Mumbai Physician Kapildev Soni Assistant Professor in Critical Anesthetist and Expert & Intensive care, JPN Apex Critical Care

Trauma Centre, AIIMS, New Specialist Delhi Paramedic Dr. Ganesh Auti Training Manager and Instructor, Life Supporters Pre Hospital Institute of Health Sciences, Emergency Mumbai specialist Rehabilitation Dr. Swagatika Prosthetics & Orthotics Unit Orthotist Expert Mishra and laboratory, Mahatma Gandhi Mission (MGM) Hospital Primary Care Dr. Aditi Kashikar MGIMS, Wardha General Practitioner Practitioner Patient Siddharth David Tata Institute of Social Public Health Representative Sciences Researcher

NGO/Patient 1.Dr. Raman 1 and 2.Jan Swasthya Sahyog, 1.Pediatric Rights Group Kataria Ganiyari Village, Bilaspur Surgeon 2. Dr. Sushil Patil District, Chhattisgarh 2.Hospital 3.Dr. Nandakumar 3. Ashwini, Gudalur, Tamil Administrator Menon Nadu 3. Secondary Care Surgeon Standard Treatment Guidelines-Major Trauma 25

Writing Team 1. Dr. Monty 1. Assistant Professor General and Khajanchi (Lead) Surgery, Dept. of Surgery, Trauma Surgeons 2. Dr. Bhakti Seth GSMC and KEM Sarang Hospital, Mumbai. 3. Dr.Vineet 2. Assistant Professor Surgery Kumar Dept. of Surgery, Raigad 4. Dr. Deepa KV Hospital and Research Centre, Karjat. 3. Assistant Professor Surgery, Dept of Surgery, LTMMC and LTMG Hospital, Mumbai. 4. School of Habitat, Tata Institute of Social Sciences, Mumbai. Expert Advisor

1. Dr. Nitin Gadgil - Additional Professor, Department of Pathology, LTMMC and LTMG Hospital, Mumbai. 2. Dr. B. Suprabhat S - Assistant Professor, Radiology Terna-Sahyadri Hospital (MUHS University). 3. Francoise Cluzeau – National Institute for Health and Care Excellence, United Kingdom. The STG Subgroup met once face-to-face and all meetings (including the smaller weekly ones were quorate (50%=8 members). The working group met every Friday evening, over a period of

three months. Some of the members joined the small group meetings via video-conference. In the induction and orientation session held on 29th July, 2016 the facilitator (Chair) welcomed all the members of the subgroup, and set up the rules of operation based on the STG development manual, on the consistent use of terminology and definitions, using the structured powerpoint presentation provided by NHSRC/NICE. Also, the individual members in the writing team kept in touch via e-mails and Whatsapp.

Discussions over the electronic media: The documents were shared with all the members by utilizing technology like Google Docs, draw.io and personal e-mails wherever required. Any changes made in the document were shared with all the group members. In the event of any areas of uncertainty requiring a discussion, Standard Treatment Guidelines-Major Trauma 26

opinion was sought over electronic media and all issues were addressed after developing mutual consensus. A group was also created on Whatsapp to enable organization of meetings and discussion of issues. In the initial meetings the recommendations were drafted, and in the subsequent meetings, the recommendations were edited. Details of the meetings are attached below, and supplementary attachments provided of each meeting. (Press ctrl+click) Meeting Nos. and Date Minutes Confirmed

1. 29th July 2016 STG-MT_1_290716 Yes 2. 05th August, 2016 STG-MT_2_050816 Yes 3. 25th August, 2016 STG-MT_3_250816 Yes 4. 2nd September, 2016 STG-MT_4_020916 Yes 5. 10th September, 2016 STG-MT_5_100916 Yes 6. 17th September, 2016 STG-MT_6_170916 Yes 7. 30th September, 2016 STG-MT_7_300916 Yes 8. 7th October, 2016 STG-MT_8_071016 Yes 9. 14th October, 2016 STG-MT_9_141016 No 10. 21st October, 2016 STG-MT_10_211016 Yes 2. Scope of the STG

To develop the scope of this STG we followed the principle of what the scope will include and exclude. It also identifies only the key aspects of care that “must” be included, set the “boundaries” of the development work and provide a clear “framework” to enable work to stay within the agreed priorities, inform the development of the clinical questions and search strategy, inform “professionals” and the “public” about expected content of the guideline, keep the STG to

a “reasonable size” to ensure that its development can be carried out within the “allocated period”. Based on these principles, the scope of the STG underwent multiple revisions. In the 29th July, 2016 and 05th of August, 2016 meeting, the first draft of scope of the diabetic foot guideline was discussed. The scope was subsequently reviewed and approved by the STG sub group face to face meeting on 17th September, 2016. It was decided in this meeting and in Standard Treatment Guidelines-Major Trauma 27

subsequent emails with the expert and facilitator to include some aspects of pre-hospital care, and also to include basics of fracture management till the point of stabilization. It was decided that this guideline will not include cost-effectiveness analysis and cost impact analysis. The costing task force instituted by the Ministry of Health & Family Welfare may carry out a cost impact analysis of the STG subsequent to its finalization. The final version of the Scope is above (pgs 5& 6)

3. Selection and Comparison of Guidelines Before the first face-to-face meeting of the STG sub-group, the working group searched guidelines.gov, NICE, World Health Organization and Google for guidelines based on the scope defined. In addition, the selected guidelines were compared in terms of relevance to the topic and key clinical issues listed in the scope, evidence ratings, target population and also their applicability or relevance to the Indian context. Currency of the selected guideline was censured

by including only guidelines published/ updated in the last 5-8 years. After sifting through all the available guidelines, the group selected four guidelines as the primary source guidelines (Guidelines no. 1-4). The selected four guidelines were subsequently approved as source guidelines by the full STG sub group on Major trauma. Some these guidelines were not included in the guidleines.gov site or in the NICE site and these were selected if their evidence was graded

as per the AGREE II method (Appraisal of Guidelines Research and Evaluation). These guidelines were – Guideline on Treatment of Patients with Severe and Multiple Injuries, German Trauma Society. In addition to the four source guidelines there were 3 other guidelines selected by the group from whom a few recommendations could be adopted/adapted which fitted the scope of this guideline. The following guidelines were selected,

1) National Clinical Guideline Centre. Major trauma assessment and initial management. London (UK): National Institute for Health and Care Excellence(NICE); 2016 Feb 17.22p.(NICE guideline; no.39) 2) National Clinical Guideline Centre. Spinal Injury assessment and initial management. London (UK): National Institute for Health and Care Excellence(NICE); 2016 Feb 17.23p.(NICE guideline;no.41) 3) National Clinical Guideline Centre. Fractures (Complex): assessment and management.

London (UK): National Institute for Health and Care Excellence(NICE); 2016 Feb 17.18p.(NICE guideline;no.37) 4) S3- Guidelines on treatment of patients with severe and multiple injuries. English version of the German guideline S3- Leitlinie Polytrauma/ Schwerverletzten- Behandlung (AWMF- Registry No. 012/019) Standard Treatment Guidelines-Major Trauma 28

5) Singapore: Singapore Ministry of Health. Clinical blood transfusion. Singapore: Singapore Ministry of Health; 2011 Feb. 90 p. 6) National Blood Authority. Patient blood management guidelines: module 4 - critical care. Canberra ACT (Australia): National Blood Authority; 2012. 78 p. 7) Management of pulmonary contusion and flail chest, Journal of Trauma and Acute Care Surgery,2012 The following guidelines were not selected and reasons mentioned as below, Guidelines available Rationale

Practice Management Guidelines for Identification Recent guidelines on similar topic of Cervical Spine Injuries Following Trauma: were available and their Update From the Eastern Association for the recommendations were more Surgery of Trauma Practice Management relevant to Indian context Guidelines Committee WHO Essential trauma care The evidence was not graded as per the Agree II method. Also were outdated Guidelines for a Structured Approach The evidence was not graded as per

to the Provision of optimal trauma care the Agree II method. Royal Australasian College of Surgeons New Zealand Trauma Committee 5) Search & select recommendations The working group created a draft table with proposed recommendations (adopted/ adapted) selected from the selected source guideline. Each key clinical issue defined in the scope of the STG was reviewed and relevant recommendations were searched for in each of the 4 selected

guidelines. None of the 4 guidelines individually covered the whole STG scope, so recommendations from all 4 guidelines were used, found best to the Indian setting (for example available expertise and resources for implementing them in practice) and keeping in mind the scope of the guidelines. Each recommendation listed in the draft was circulated 3 days before the meeting and at first the working group discussed these recommendations at length (in meeting 3,

4 and 5). A systematic approach was followed to ensure high quality of the process. The group either adopted/adapted a recommendation and if adapted reasons for the same were mentioned and documented. Implementation challenges were considered when decisions were made to Standard Treatment Guidelines-Major Trauma 29

adopt or adapt recommendations. Factors considered included public/ private health infrastructure available and affordability and primary, secondary and tertiary care. a) Adopted recommendation - this entailed transferring a recommendation verbatim to the new STG. b) Adapted recommendation – This ranged from a minor edit in order to ensure local compatibility with India, or adding precisions to the wording to clarify the recommendation. It is

important that when adapting a recommendation the evidence underpinning the recommendation remains intact. The draft recommendations were discussed with the full sub-group (meeting 6) on 17th September, 2016 from 0930 am to 0400 pm in BARC Hospital Conference Room, Anushakti Nagar, Mumbai. All group members declared and signed conflict of interest forms, before the meeting. (Minutes attached). There were further changes made during this meeting in the

recommendations after full length discussions. All the changes were documented and minuted. Few recommendations were excluded as they were considered inappropriate in view of the required resources/cost and/or feasibility. The working group met after this meeting in person and over video conferencing to discuss the 2nd draft of this guideline (meeting 7, 8, 9 &10). The working group in these meetings also developed the Patient Information Document, The

Quick Reference Guide (Flowcharts). These Recommendations were further emailed to the other members of the group and their comments were discussed again in meeting 10 and changes made accordingly. The details of adopted and adapted recommendations and the rationale for adaptation are available in the Annexure I named “Adopt/Adapt guidelines”. V Review Review I: Peer review received on 16th January 2017, from NHSRC internal peer-review committee and Prof. R.S. Mohil

The STG team members over email resolved these comments. All these comments were in track changes mode in the Microsoft word document. The suggestions have been carried out and appropriate changes made in the relevant places in the documents. To view the comments and replies press the link below, https://drive.google.com/file/d/0B3VNCDm-CyuAcUV6UjYyNlB0SHc/view?usp=sharing Standard Treatment Guidelines-Major Trauma 30

Review II: A meeting was held on 13th January 2017 at 2.30 P.M. in Room no. 441-A wing, Nirman Bhawan, under the Chairmanship of Dr. Anil Manaktala, DDG (P) to discuss the draft Standard Treatment Guidelines of Major Trauma. The minutes of this meeting and the comments are as in the below link, https://drive.google.com/open?id=0B3VNCDm-CyuAY3RMOENrZUo2TWs STG team members met over video conference and discussed these comments and prepared the

rebuttal. The minutes of this comments and the rebuttal can be found in the below link, Minute - https://drive.google.com/open?id=0B3VNCDm-CyuAWFFfVE44YXZkLW8 Rebuttal - https://drive.google.com/open?id=0B3VNCDm-CyuALUltREFyVWswNms Standard Treatment Guidelines-Major Trauma 31

VI Way Forward for India It is hoped that this document can lead to the development of further standard treatment guidelines for specific areas of trauma management for the Indian context. It seeks to improve the quality of trauma care services, intends to advocate for changes in health policy and decisions towards better outcomes for trauma. Trauma can occur to anybody, anywhere and therefore, it is imperative for a nation as large as

ours to holistically work with the government and non-government organizations including all sectors of the society to bring awareness and management skills to every individual to handle a situation in a calm and accurate way. In view of the increasing burden of trauma in India and the rising cost of management of these patients, we would need to look into decreasing this burden and cost by a systematic management approach in each of the following parts:

1. Prevention if done properly, it would lead to more effectiveness with less expenditure. ● Implementation of rules during driving motored vehicles along with swiftness of penalty for disobeying it is must, like: ○ helmets even for bicyclists and a separate area for them ○ seat belts compulsory ○ speed limits and breaking signals to be taken seriously ○ driver education on basic first aid must be done in driving tests, etc) ● Proper checks and policing on alcohol and drug abuse in vehicle drivers.

● Road quality to be improved, especially in prone areas, like improving lighting, filling potholes. ● Access improved for health care facilities, especially in the rural areas of India ● Implementation of safety rules along with regular drills and checks in large organizations like factories, mines, schools, offices, hospitals, railway stations, etc ● Safety measures to prevent burns, falls, electrocution and prevention of railway

accidents (simply closing the doors of local trains should be made compulsory). ● Identification of risks, research and injury surveillance projects to be undertaken regularly. ● Violence minimization in high risk groups like adolescents, alcoholics and drug abusers by awareness sessions to prevent them from entering into abusive relations with society and enabling them to make informed decisions ● Children, aged, mentally and physically challenged, and pregnant women are

more prone to injury and hence, infrastructure should be made with them in mind. ● Awareness programmes to be increased using all forms of media to reach maximum population 2. Pre-hospital care - ● Training of paramedical staff to give life saving safe treatment en-route to hospital. Standard Treatment Guidelines-Major Trauma 32

● Training and awareness sessions for the general public, including schools and colleges, to be propagated on First Aid and CPR could save a lot of lives in the golden hour. ● Enabling better ambulance facilities to manage emergencies by ○ Proper and functional equipment of oxygen cylinders ○ Trained personnel to apply pelvic and spine stabilizers ○ Essential emergency drug provision and training to use them 3. In-Hospital - ● System changes to make sure each of the necessary process measures (time to CT,

Time to Operation/intervention) is carried out in time ● Trauma team - Comprising minimum of a surgeon, anesthetist, trauma nurse, blood bank officer and an administrator. In addition to this, the super specialty team should be a part of the trauma team wherever available. ● Training - Ensure compulsory training provided by the Government/hospital, in recognised national or international courses in advance trauma management for all personnel working in emergency department.

● Forming local and National Trauma registry 4. Trauma rehabilitation - is an integral part in getting a seriously injured patient back to productivity and decreasing morbidity. Standard Treatment Guidelines-Major Trauma 33

VII References 1. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national disability- adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990–2013: quantifying the epidemiological transition. Lancet. 2015; 386(1009):2145-2191. 2. World Health Organization. Injuries and Prevention: The Facts. Geneva: World Health Organization; 2014.

3. Chandran A, Hyder AA, Peek-Asa C. The global burden of unintentional injuries and an agenda for progress. Epidemiol Rev. 2010;32:110-20. 4. Mock C, Joshipura M, Arreola-Risa C, Quansah R. An estimate of the number of lives that could be saved through improvements in trauma care globally. World J Surg. 2012;36(5):959-63. 5. United Nations. Open Working Group proposal for Sustainable Development Goals Geneva: United Nations; 2015

6. Gruen RL, Gabbe BJ, Stelfox HT, Cameron PA. Indicators of the quality of trauma care and the performance of trauma systems. Br J Surg. 2012; 99(1):97-104. 7. Ker K, Kiriya J, Perel P, Edwards P, Shakur H, Roberts I. Avoidable mortality from giving tranexamic acid to bleeding trauma patients: an estimation based on WHO mortality data, a systematic literature review and data from the CRASH-2 trial. BMC Emerg Med [Internet]. 2012;12(1):3. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/22380715\nhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC331455 8/pdf/1471-227X-12-3.pdf 8. Purvachandra P & Hyder AA. The Burden of Traumatic Brain Injury in Asia: A Call for Research. Pak J Neurol Sci 2009; 4(1):27-32 9. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death 1990-2013: a systematic analysis

for the Global Burden of Disease Study 2013. Lancet. 2015; 385(9963):117-71. 10. Joshipura MK, Shah HS, Patel PR, Divatia PA, Desai PM. Trauma care systems in India. Injury. 2003; 34(9):686-92. 11. Joshipura M. Guidelines for essential trauma care: progress in India. World J Surg. 2006; 30(6):930- 3. 12. Jagnoor J, Suraweera W, Keay L, Ivers RQ, Thakur J, Jha P, et al. Unintentional injury mortality in India, 2005: nationally representative mortality survey of 1.1 million homes. BMC Public Health. 2012;

12:487. 13. World Health Organization. Global Status Report of Road Safety. Geneva: World Health Organization; 2015. Standard Treatment Guidelines-Major Trauma 34

14. Joshipura MK. Trauma care in India: current scenario. World J Surg.2008; 32: 1613–1617. 15. Roy N, Murlidhar V, Chowdhury R, Patil SB, Supe PA, et al. Where there are no emergency medical services-prehospital care for the injured in Mumbai, India. Prehosp Disaster Med 2010; 25: 145–151. 16. Oestern HJ, Garg B, Kotwal P. Trauma Care in India and Germany. Clinical Orthopaedics and Related Research. 2013; 471(9):2869-77. Standard Treatment Guidelines-Major Trauma 35

Annexure 1 Adopt/ Adapt Tables 1.0 Prehospital Trauma Care MoHFW Guideline Adopt/ Original Recommendation and Remarks Adapt Source guideline 1.1 Airway management 1.1.1 Consider using a Adapt If RSI cannot be performed at the Use of Guedel’s supraglottic device if the patient's scene: Consider using a airway with bag airway reflexes are absent. Use supraglottic device if the patient's and mask basic airway manoeuvres like airway reflexes are absent. Use ventilation and

inserting a Guedel’s airway** basic airway manoeuvres and oxygen and bag and mask ventilation if adjuncts if the patient's airway supplementation required or supraglottic device reflexes are present or may be a better placement is not possible. supraglottic device placement is modality of not possible prehospital transfer *supraglottic device - Laryngeal NICE Guideline [NG39] than RSI and mask airway, proseal, i-gel etc. intubation in the **Guedels airway = Oropharyngeal Indian scenario airway/oral airway

due to lack of trained personnel in the ambulances. Needs further discussion about use of LMAs and other supraglottic devices DGHS comments were to change the language in the second part of the recommendation. 1.2 Chest Trauma 1.2.1 Use clinical assessment to Adopt Use clinical assessment to diagnose pneumothorax for the diagnose pneumothorax for the purpose of triage or intervention purpose of triage or intervention NICE Guideline [NG39]

1.2.2 In patients with an open Adapt In patients with an open DGHS reviewers Standard Treatment Guidelines-Major Trauma 36

pneumothorax: Cover the open pneumothorax: Cover the open comments were to pneumothorax with a three sided pneumothorax with a simple change it to occlusive dressing and Observe occlusive dressing and Observe “simple” to “three for the development of a tension for the development of a tension sided” which the pneumothorax pneumothorax STG team NICE Guideline [NG39] members also felt will be more specific 1.3 Haemorrhage 1.3.1 Use simple dressings Adapt Use simple dressings with direct

(sterile gauze pads) with direct pressure to control external pressure to control external haemorrhage. haemorrhage. NICE Guideline [NG39] 1.3.2 In patients with major limb Adopt In patients with major limb trauma use a tourniquet if direct trauma use a tourniquet if direct pressure has failed to control life pressure has failed to control life threatening haemorrhage. threatening haemorrhage (*Tourniquet can be a bandage NICE Guideline [NG39] roll, rubber tubing , crepe bandage etc.)

1.3.3 If active bleeding is Adapt If active bleeding is suspected suspected from a pelvic fracture from a pelvic fracture after blunt after blunt high-energy trauma: high-energy trauma: Apply a Apply a pelvic binder purpose-made pelvic binder or Consider an improvised pelvic binder, but only if a purpose- made binder does not fit NICE Guideline [NG39] 1.3.4 Use intravenous tranexamic Adopt Use intravenous tranexamic acid acid as soon as possible in as soon as possible in patients

patients with major trauma and with major trauma and active or active or suspected active suspected active bleeding. bleeding. NICE Guideline [NG39] *Dose of Tranexamic acid - 1 gm administered IV over 10 min followed by 1 gm over 8 hrs IV 1.3.5 Do not use intravenous Adapt Do not use intravenous tranexamic acid more than 3 tranexamic acid more than 3 hours after injury in patients with hours after injury in patients with Standard Treatment Guidelines-Major Trauma 37

major trauma major trauma unless there is evidence of hyperfibrinolysis NICE Guideline [NG39] 1.3.6 For circulatory access in Adapt For circulatory access in patients patients with major trauma in pre- with major trauma in pre-hospital hospital settings: Use peripheral settings: Use peripheral intravenous access. intravenous access or If peripheral intravenous access fails, consider intra-osseous access NICE Guideline [NG39] 1.3.7 In pre-hospital settings, Adopt In pre-hospital settings, titrate

titrate volume resuscitation to volume resuscitation to maintain maintain a palpable central a palpable central pulse(carotid or pulse(carotid or femoral). femoral). NICE Guideline [NG39] 1.3.8 In pre-hospital settings only Adapt In pre-hospital settings only use use crystalloids (Ringer’s lactate crystalloids to replace fluid or Normal saline) to replace fluid volume in patients with active volume in patients with active bleeding if blood components are bleeding not available NICE Guideline [NG39]

1.3.9 Minimise ongoing heat Adopt Minimise ongoing heat loss in loss* in patients with major patients with major trauma trauma. NICE Guideline [NG39] *Blankets can be used for reducing heat loss 1.4 Pain management 1.4.1 Assess pain regularly in Adapt Assess pain regularly in patients patients with major trauma using with major trauma using a pain a pain assessment scale assessment scale suitable for the patient's age, developmental stage and cognitive function NICE Guideline [NG39]

1.4.2 For patients with major Adapt For patients with major trauma, Morphine is not trauma, use intravenous use intravenous morphine as the available easily so morphine/strong opioids as the first-line analgesic and adjust te alternative to first line analgesic and adjust the dose as needed to achieve morphine strong dose as needed to acheive adequate pain relief. opioids were also adequate pain relief included. NSAIDs *To be administered after Standard Treatment Guidelines-Major Trauma 38

medical consult were also considered as analgesics to be included but to raise the standard of care for pain management we have not included and may dilute the stress on morphine/opioids in trauma 1.5 Spine Trauma 1.5.1 Carry out full in-line spinal Adapt Carry out full in-line spinal immobilisation immobilisation if any of the *By placing two blocks on either above factors in the side of the head. Intravenous fluid recommendation above are bottles can also be used to prevent present or if this assessment

movement. cannot be done NICE Guideline [NG37] 1.6 Fractures: Complex 1.6.1 Do not irrigate open Adopt Do not irrigate open fractures of fractures of the long bones, the long bones, hindfoot or hindfoot or midfoot in pre- midfoot in pre-hospital settings. hospital settings NICE Guideline [NG37] 1.6.2 Consider a saline soaked Adopt Consider a saline soaked dressing dressing covered with an covered with an occlusive layer occlusive layer for open fractures for open fractures in pre-hospital

in pre-hospital settings. settings. NICE Guideline [NG37] 1.6.3 In the pre-hospital setting, Adapt In the pre-hospital setting, consider the following for people consider the following for people with suspected long bone with suspected long bone fractures of the legs: fractures of the legs: A rigid or malleable splint or A traction splint or adjacent leg adjacent leg as a splint if the as a splint if the suspected suspected fracture is above the fracture is above the knee knee A vacuum splint for all other

suspected long bone fractures Standard Treatment Guidelines-Major Trauma 39

NICE Guideline [NG37] *Tourniquet can be a bandage roll, rubber tubing, crepe bandage etc 2.0. Airway and Chest Trauma Management MoHFW Guideline Adopt/ Original Recommendation and Reasons for Adapt Source Guideline Adaptation 2.1 Airway Assessment 2.1.1 A clinical examination of Adopt A clinical examination of the the thorax and respiratory thorax and respiratory function function must be carried out. must be carried out. German Trauma Society Guideline

2.1.2 The examination should Adopt The examination should include include as a minimum the as a minimum the measurement measurement of the respiratory of the respiratory rate and rate and auscultation of the auscultation of the lungs. The lungs. The examination should examination should be repeated be repeated. German Trauma Society Guideline 2.1.3. The following can be Adapt The following can be helpful: Ventilation helpful: inspection (bilaterally inspection (bilaterally unequal in pressure

unequal in respiratory excursion, respiratory excursion, unilateral monitoring if unilateral bulging, paradoxical bulging, paradoxical respiration), available as it is respiration), palpation (pain, palpation (pain, crepitations, not available in crepitations, subcutaneous subcutaneous emphysema, many centres. emphysema, instability) and instability) and percussion percussion (hyperresonant (hyperresonant percussion) of the percussion) of the thorax thorax together with pulse

together with pulse oxymetry oxymetry and, in ventilated and, in ventilated patients, patients, monitoring ventilation monitoring ventilation pressure pressure(if available). German Trauma Society Guideline 2.2 Securing Airway 2.2.1 Manual in-line stabilization Adopt Manual in-line stabilization should be carried out for should be carried out for endotracheal intubation with the endotracheal intubation with the cervical spine immobilization cervical spine immobilization

device temporarily removed. device temporarily removed German Trauma Society Standard Treatment Guidelines-Major Trauma 40

Guideline 2.2.2 A difficult airway must be Adopt A difficult airway must be anticipated when endotracheally anticipated when endotracheally intubating a trauma patient. intubating a trauma patient. NICE Guideline [NG39] 2.2.3 The multiply injured Adopt The multiply injured patient must patient must be preoxygenated be preoxygenated before before anesthesia. anaesthesia. German Trauma Society Guideline 2.2.4 Use drug-assisted rapid Adopt Use drug-assisted rapid sequence

sequence induction (RSI) of induction (RSI) of anaesthesia anaesthesia and intubation and intubation as the definitive method of as the definitive method of securing the airway in patients securing the airway in patients with major trauma with major trauma who cannot maintain their airway who cannot maintain their airway and/or ventilation. and/or ventilation. NICE guideline [NG39] 2.2.5 If RSI fails, use basic Adopt If RSI fails, use basic airway

airway manoeuvres and adjuncts manoeuvres and adjuncts and/or and/or a supraglottic device until a supraglottic device until a a surgical airway or assisted surgical airway or assisted tracheal placement is performed. tracheal placement is performed. NICE guideline [NG39] 2.2.6 If difficult anesthetization Adopt If difficult anesthetization and/or and/or endotracheal intubation endotracheal intubation are are expected, an anesthesiologist expected, an anesthesiologist

must carry out or supervise this must carry out or supervise this procedure in-hospital provided procedure in-hospital provided this does not cause delay in an this does not cause delay in an emergency life-saving measure. emergency life-saving measure. Suitable measures must be Suitable measures must be in place to ensure that an in place to ensure that an anesthesiologist is normally on anesthesiologist is normally on site in time site in time NICE guideline [NG39]

2.2.7 After more than 3 Adopt After more than 3 intubation intubation attempts, alternative attempts, alternative methods methods must be considered for must be considered for ventilation and securing an ventilation and securing an airway. airway. German trauma Society Guideline Standard Treatment Guidelines-Major Trauma 41

2.2.8 Alternative methods for Adopt Alternative methods for securing securing an airway must be an airway must be provided provided when anesthetizing and when anesthetizing and endotracheally intubating a endotracheally intubating a multiply injured patient. multiply injured patient *Alternatives like emergency NICE Guideline [NG39] cricothyroidotomy or surgical airway 2.2.9 Etomidate should be Adopt Etomidate should be avoided as Ketamine is

avoided as an induction agent an induction agent due to the usually a good due to the associated side effects associated side effects on adrenal alternative here. on adrenal function . function. *Ketamine can be used as a safe German Trauma Society alternative as an induction agent. Guideline Dose- 1-2 mg/kg, time to effect of 45-60 seconds. 2.2.10 ECG, blood pressure Adapt ECG, blood pressure Capnography, if measurement, pulse oxymetry measurement, pulse oxymetry available as many

and capnography(if available) and capnography must be used to secondary and must be used to monitor the monitor the patient for anesthesia tertiary centres patient for anesthesia induction, induction, endotracheal will not have the endotracheal intubation and intubation and emergency equipment needed emergency anesthesia. anesthesia for capnography German Trauma Society in emergency Guideline available and with blood pressure and pulse oxymeter a reasonable intubation can be carried out. (experts

discussion) 2.2.11 Normoventilation must be Adopt Normoventilation must be carried out in endotracheally carried out in endotracheally intubated and anesthetized intubated and anesthetized trauma patients. trauma patients German Trauma Society Guideline 2.2.12 Ventilation must be Adapt Ventilation must be monitored If available then monitored and controlled by and controlled by frequent do, if not, then frequent arterial blood gas arterial blood gas analyses in the check Clinically

analyses(if available) in the hospital by: hospital. German Trauma Society Chest rise If ABG analysis not available, Guideline By four point then keep a check clinically by auscultation of the Standard Treatment Guidelines-Major Trauma 42

observing the chest rise & four chest. point auscultation of the chest. 2.12.3 In mandible and Adopt 2.12.3 In mandible and maxillofacial injuries, primary maxillofacial injuries, primary securing of the airways and securing of the airways and hemostasis in the oral and hemostasis in the oral and maxillofacial region must be maxillofacial region must be carried out. carried out.[German Trauma Society Guidelines 2.3 Chest Trauma Diagnosis and Management

2.3.1 A suspected diagnosis of Adopt A suspected diagnosis of pneumothorax and/or pneumothorax and/or hemothorax must be made if hemothorax must be made if breath sounds are weaker or breath sounds are weaker or absent on one side (after absent on one side (after checking correct placement of checking correct placement of the tube). Absence of such the tube). Absence of such auscultation findings largely auscultation findings largely rules out a larger pneumothorax, rules out a larger pneumothorax,

especially if the patient is especially if the patient is normopneic and has no chest normopneic and has no chest pain. pain German Trauma Society Guideline 2.3.2 A suspected diagnosis of Adopt A suspected diagnosis of tension tension pneumothorax should be pneumothorax should be made if made if auscultation of the lung auscultation of the lung reveals reveals no breath sounds no breath sounds unilaterally unilaterally (after checking (after checking correct placement

correct placement of the tube) of the tube) and, in addition, and, in addition, typical typical symptoms are present, symptoms are present, particularly severe respiratory particularly severe respiratory disorder or upper inflow disorder or upper inflow congestion combined with congestion combined with arterial hypotension arterial hypotension. German Trauma Society Guideline 2.3.3 Clinically suspected tension Adopt Clinically suspected tension pneumothorax must be pneumothorax must be

decompressed* immediately. decompressed immediately. German Trauma Society *Chest decompression mainly Guideline refers to tube thoracostomy/ Chest drain placement. Standard Treatment Guidelines-Major Trauma 43

2.3.4 Use open thoracostomy Adopt Use open thoracostomy instead Needle instead of needle decompression of needle decompression if the decompression for if the expertise is available, expertise is available, followed the hospitals with followed by a chest drain via the by a chest drain via the less resources. thoracostomy in patients who are thoracostomy in patients who are breathing spontaneously. breathing spontaneously. *Open method of chest drain NICE Guideline [NG39] insertion to be preferred over

trocar method Needle decompression should not be attempted unless absolutely indicated. 2.3.5 Observe patients after chest Adopt Observe patients after chest decompression for signs of decompression for signs of recurrence of the tension recurrence of the tension pneumothorax. pneumothorax. NICE Guideline [NG39] 2.3.6 In patients with an open Adopt In patients with an open pneumothorax: pneumothorax: cover the open pneumothorax cover the open pneumothorax

with a simple occlusive dressing with a simple occlusive dressing and observe for the development and observe for the development of a tension pneumothorax of a tension pneumothorax NICE Guideline [NG39] 2.3.7 Pneumothorax diagnosed Adopt Pneumothorax diagnosed on the on the basis of an auscultation basis of an auscultation finding finding in a patient on positive in a patient on positive pressure pressure ventilation should be ventilation should be decompressed. decompressed German Trauma Society Guideline

2.3.8 Pneumothorax diagnosed Adopt Pneumothorax diagnosed on the on the basis of an auscultation basis of an auscultation finding finding in patients not on in patients not on ventilation ventilation should usually be should usually be managed by managed by close clinical close clinical observation observation. German Trauma Society Guideline 2.3.9 Pneumothorax should be Adopt Pneumothorax should be treated treated with a chest drain with a chest drain provided the

provided the indication exists. indication exists. German Trauma Society Guideline 2.3.10 If there are perforating Adopt If there are perforating chest chest injuries, embedded foreign injuries, embedded foreign Standard Treatment Guidelines-Major Trauma 44

bodies should only be removed bodies should only be removed during surgery under controlled during surgery under controlled conditions after opening up the conditions after opening up the chest. chest German Trauma Society Guideline 2.3.11 A penetrating chest injury, Adopt A penetrating chest injury, which which is the cause of is the cause of hemodynamic hemodynamic instability in the instability in the patient, must patient, must undergo an undergo an immediate

immediate exploratory exploratory thoracotomy thoracotomy. German Trauma Society Guideline 2.3.12 A thoracotomy can be Adopt A thoracotomy can be performed performed if there is an initial if there is an initial blood loss of blood loss of > 1,500 ml from the > 1,500 ml from the chest drain chest drain or if there is or if there is persistent blood loss persistent blood loss of > 250 of > 250 ml/h over more than 4 ml/h over more than 4 hours. hours. German Trauma Society Guideline

2.4 Imaging in Chest Trauma 2.4.1 Imaging for chest trauma in Adopt Imaging for chest trauma in patients with suspected chest patients with suspected chest trauma should be performed trauma should be performed urgently, and the images should urgently, and the images should be interpreted immediately by a be interpreted immediately by a healthcare professional with healthcare professional with training and skills in this area. training and skills in this area NICE Guideline [NG39]

2.4.2 Consider immediate chest Adapt Consider immediate chest X-ray As this document X-ray and/or eFAST (extended and/or eFAST (extended focused focuses only in focused assessment with assessment with sonography for adults more than sonography for trauma) as part of trauma) as part of the primary 18 years of age. the primary survey to assess survey to assess chest trauma in chest trauma with severe adults (16 or over) with severe respiratory compromise. respiratory compromise NICE Guideline [NG39]

2.4.3 Consider immediate CT for Adapt Consider immediate CT for As this document those with suspected chest adults (16 or over) with focuses only in trauma without severe respiratory suspected chest trauma without adults more than compromise who are severe respiratory compromise 18 years of age. responding to resuscitation or who are responding to Standard Treatment Guidelines-Major Trauma 45

whose haemodynamic status is resuscitation or whose normal. haemodynamic status is normal NICE Guideline [NG39] * Needle decompression when indicated (shock with distended neck veins, reduced breath sounds, deviated trachea) should be done in the 2nd intercostal space * Chest tube to be inserted in the 5th intercostal space. *Triangle of safety is the recommended site for chest tube insertion. Boundaries are- Anterior- Lateral border of pectoralis major. Lateral- Lateral border of latissimus dorsi

Inferior- 6th rib or line of 5th intercostal space 3.0 : Hemorrhage and Shock Original Guidelines Taken from: 1. NICE: Major trauma (NG39) © NICE 2016 2. German: S3 – Guideline on Treatment of Patients with Severe and Multiple Injuries English Version of the German Guideline S3 – LeitliniePolytrauma/Schwerverletzten-Behandlung (AWMF-Registry No. 012/019) 3.Singapore: Singapore Ministry of Health. Clinical blood transfusion. Singapore: Singapore Ministry of Health; 2011 Feb. 90 p. 4. NBA:

The National Blood Authority’s (Australia)Patient Blood Management Guideline: Module 1 – Critical Bleeding/Massive Transfusion 5. National Blood Authority. Patient blood management guidelines: module 4 - critical care. Canberra ACT (Australia): National Blood Authority; 2012. 78 p. MoHFW Guideline Adopt/ Original Recommendation and Reasons for Adapt Source Guideline Adaptation Standard Treatment Guidelines-Major Trauma 46

3.1 Dressings and tourniquets in hospital settings 3.1.1 Use simple dressings* with Adopt Use simple dressings with direct The term simple direct pressure to control external pressure to control external dressings was haemorrhage. haemorrhage. further elaborated as sterile gauze *sterile gauze pads NICE Guideline [NG39] pads.# [1] #(World Health Organization. Guidelines for essential trauma care/Injuries and Violence Prevention Department, World Health Organization and the International Association for

the Surgery of Trauma and Surgical Intensive Care (IATSIC), International Society of Surgery) 3.1.2 In patients with major limb Adopt 1.5.2 In patients with major limb The term trauma use a tourniquet* if direct trauma use a tourniquet if direct tourniquet was pressure has failed to control life- pressure has failed to control life- further elaborated threatening haemorrhage. threatening haemorrhage on for understanding of *(a bandage,a strip of cloth,a NICE Guideline [NG39] the all

band of rubber,etc.,that checks (Webster’s bleeding or blood flow by dictionary) compressing the blood vessels) 3.2 Haemostatic agents in hospital settings 3.2.1 Use intravenous tranexamic Adopt Use intravenous tranexamic acid The dosage of acid as soon as possible in as soon as possible in patients intravenous patients with major trauma and with major trauma and active or tranexamic acid active or suspected active suspected active bleeding. was added as per Standard Treatment Guidelines-Major Trauma 47

bleeding. NICE Guideline [NG39] the German guidelines which Dosage as German Trauma inturn was taken Society Guideline: from the CRASH Tranexamic acid initially 2 trials 1 g as saturation over 10 minutes + 1 g over 8 hours (CRASH 2 Trials) * Or 2 g (15– 30 mg/kg BW) 3.2.2 Do not use intravenous Adopt Do not use intravenous Hyperfibrinolysis tranexamic acid more than 3 tranexamic acid more than 3 tests are not hours after injury in patients with hours after injury in patients with routinely available

major trauma. major trauma unless there is in the Indian evidence of hyperfibrinolysis. Setting NICE Guideline [NG39] 3.3 Anticoagulant reversal in hospital settings 3.3.1 Rapidly reverse Adopt Rapidly reverse anticoagulation anticoagulation in patients who in patients who have major have major trauma with trauma with haemorrhage. haemorrhage. NICE Guideline [NG39] 3.3.2 FFP (10-15ml/kg body Adapt FFP recommended : As specific factor

weight) is recommended when Bleeding associated with clotting concentrates are there is bleeding associated with factors deficiency if no not easily clotting factors deficiency and if alternative processed products or available and are no alternative processed products specific factor concentrates are expensive,this is or specific factor concentrates available. not feasible in the are available. If immediate reversal of warfarin Indian Setting.The

If immediate reversal of warfarin effect is required. Intravenous alternative could effect is required. Intravenous vitamin K should be concurrently therefore be Fresh vitamin K *(5mg) should be given for sustained reversal of frozen plasma . concurrently given for sustained warfarin effect reversal of warfarin effect Singapore Ministry of Health. (*Management of bleeding Clinical blood transfusion following major trauma: an Guideline updated European guideline Rolf Rossaint et al.)

3.3.3 Consult a physician Adapt Consult a haematologist At the district immediately for advice on adults immediately for advice on adults hospital access to who have active bleeding and (16 or over) who have active a physician is a need reversal of any bleeding and need reversal of any more practical anticoagulant agent other than a anticoagulant agent other than a approach as vitamin K antagonist. vitamin K antagonist. hematologist may not be available in NICE Guideline [NG39] this setting. Also

adults age group is defined as 18 years and more. 3.3.4 Do not reverse Adopt Do not reverse anticoagulation in anticoagulation in patients who patients who do not have active do not have active or suspected or suspected bleeding. bleeding. NICE Guideline [NG39] 3.4 Trauma induced coagulopathy 3.4.1 Trauma-induced Adopt Trauma-induced coagulopathy is The coagulation coagulopathy is an autonomous an autonomous clinical picture diagnostic tests

clinical picture with clear with clear influences on survival. were further influences on survival. For this For this reason, coagulation defined to avoid reason, coagulation diagnostic diagnostic tests and therapy must confusion. tests* and therapy must be be started immediately in the started immediately in the emergency room. emergency room. German Trauma Society Guideline Coagulation diagnostic tests - Platelets,PT/INR,APTT and Fibrinogen (if available)

3.5 Activating major haemorrhage protocols in hospital settings 3.5.1 Use physiological criteria Adopt Use physiological criteria that that include the patient's include the patient's haemodynamic status and their haemodynamic status and their response to immediate volume response to immediate volume resuscitation to activate the resuscitation to activate the major haemorrhage protocol. major haemorrhage protocol. NICE Guideline [NG39] Standard Treatment Guidelines-Major Trauma 49

3.5.2 Do not rely on a Adopt Do not rely on a haemorrhagic haemorrhagic risk tool* applied risk tool applied at a single time at a single time point to point to determine the need for determine the need for major major haemorrhage protocol haemorrhage protocol activation. activation. (*For example- ABC score, NICE Guideline [NG39] TASH score, PWH score, McLaughlin score, Emergency transfusion score, Shock Index etc These measure variables at a single point in time.)

3.6 Circulatory access in hospital settings 3.6.1 For circulatory access in Adapt For circulatory access in patients Intraosseous patients with major trauma in with major trauma in hospital access is not hospital settings: use peripheral settings: use peripheral considered as the intravenous access (14 or 16 intravenous access or if guidelines are gauge intravenous cannula) or if peripheral intravenous access dealing with adult peripheral intravenous access fails, consider intra-osseous population alone

fails, a venous cutdown should access while central access is for now.Expert be done. being achieved. group was of the NICE Guideline [NG39] opinion that central access needs training and skill and it is not the best route for fluid resuscitation.Ther efore central access is not be advised ,rather a venous cutdown if peripherla intravenous access fails is a more feasible and safe option 3.7 Volume resuscitation in hospital settings Standard Treatment Guidelines-Major Trauma 50

3.7.1 For patients with active Adapt For patients with active bleeding The guideline was bleeding use a use a restrictive approach to combined with the restrictive/balanced approach to volume resuscitation until german guideline volume resuscitation until definitive early control of for a more detailed definitive early control of bleeding has been achieved. explanation of the bleeding has been achieved. approach. After NICE Guideline [NG39] DGHS comments *Further explanation of the STG tem

restrictive resuscitation - in members added order to keep the circulation at a the term low stable level and not “balanced” as it exacerbate the bleeding. (Systolic may be better BP: 90 mmHg or palpable central understood in the pulse) and not exacerbate the Indian trauma bleeding. (from the german centres guidelines) 3.7.2 In hospital settings, titrate Adapt In pre-hospital settings, titrate Rephrased to in volume resuscitation to maintain volume resuscitation to maintain hospital settings.

a palpable central pulse (carotid a palpable central pulse (carotid or femoral). or femoral). NICE Guideline [NG39] 3.7.3 For patients who have Adopt For patients who have haemorrhagic shock and a haemorrhagic shock and a traumatic brain injury: if traumatic brain injury: if haemorrhagic shock is the haemorrhagic shock is the dominant condition, continue dominant condition, continue restrictive volume resuscitation restrictive volume resuscitation

or if traumatic brain injury is the or if traumatic brain injury is the dominant condition, use a less dominant condition, use a less restrictive volume resuscitation restrictive volume resuscitation approach to maintain cerebral approach to maintain cerebral perfusion. perfusion. NICE Guideline [NG39] 3.7.4 Damage Control Adapt Damage Control resuscitation: As per the expert resuscitation- In patients who are actively group consensus it ● In patients who are bleeding, the goal can be set at was decided to

actively bleeding, the permissive hypotension (mean keep the goals goal can be set at mean arterial pressure ~ 65 mmHg, alone and do away Standard Treatment Guidelines-Major Trauma 51

arterial pressure ~ 65 systolic arterial pressure ~ 90 with the term mmHg and systolic mmHg) until surgical permissive arterial pressure ~ 90 hemostasis. This strategy is hypotension to mmHg until surgical contraindicated in injuries of the avoid confusion in hemostasis. central nervous system. the interpretation ● Suitable measures should Suitable measures should be of the term.Also be taken and treatment taken and treatment given to that this strategy is

given to avoid avoid the patient cooling down. contraindicated in hypothermia Acidemia should be avoided and injuries of the ● Acidemia should be treated by suitable shock central nervous avoided and treated by treatment. system was suitable treatment. decided to be German Trauma Society omitted as the Guideline earlier recommendation already mentions about the management in traumatic Brain injury.The other two recommendations have been merged from the German Trauma Society as they were a part of the damage

control resuscitation. After the DGHS reviewers comments specific words like “hypothermia” was used and the word “shock” was removed from the “suitable shock treatment” 3.8 Fluid replacement in hospital settings Standard Treatment Guidelines-Major Trauma 52

3.8.1 In hospital settings, only Adapt In pre-hospital settings only use Rephrased to use crystalloids* to replace fluid crystalloids to replace fluid include hospital volume in patients with active volume in patients with active settings alone and bleeding if blood components are bleeding if blood components are also the specific not available. not available. type of NICE Guideline [NG39] crystalloids to be * preferably Normal used.The expert saline,Ringers lactate. Glucose group felt that this

containing fluid should be was important to avoided in (a head injury) mainly discourage patients, during initial the use of 5% resuscitation. Dextrose as a resuscitation fluid. 3.8.2 Human albumin must not Adapt Human albumin must not be used Rephrased to be used in hospital volume in prehospital volume include hospital replacement. replacement. settings. (German) German Trauma Society Guideline 3.8.3 Colloidal solutions can be Adapt If colloidal solutions are used in If it’s available,

used in hypotensive trauma hypotensive trauma patients, then should be patients, if available and preference should be given to used.The expert preference should be given to HES 130/0.4. group felt that this HES 130/0.4. German Trauma Society may not be Guideline available in all the settings ,therefore this wording was added. 3.9 Haemorrhage protocols in hospital settings 3.9.1 Hospitals should have Hospital trusts should have Link to the specific major haemorrhage Adapt specific major haemorrhage massive

protocols for adults. protocols for adults (16 or over) transfusion and children (under 16s). protocol.(Appendi NICE Guideline [NG39] x) The age was corrected to include adults 18 years and above. Standard Treatment Guidelines-Major Trauma 53

3.9.2 For patients with active Adapt For patients with active bleeding, The Fixed ratio bleeding, start with a fixed-ratio start with a fixed-ratio protocol protocol was protocol (1:1:1 FFP: platelets: for blood components and further defined to RBC) for blood components and change to a protocol guided by be 1:1:1 of change to a protocol guided by laboratory coagulation results at FFp:Platelets:Red laboratory coagulation results at the earliest opportunity. blood cells as per

the earliest opportunity. NICE Guideline [NG39] the PROPPR and PROMMTT trial. (*In patients with Grade 3 and 4 hemorrhagic shock with The Expert group imminent threat to life and if consensus was components are not available that in a low then whole blood can be given to resource setting, stabilize the patient before blood components transferring to a higher centre.) will not be readily available and in such a case if a patient presents with grade III or IV hemorrhagic shock and with imminent threat to

life then whole blood can be given to stabilize the patient before transferring to a higher centre. 3.9.3 In an actively bleeding Adapt In an actively bleeding patient, Deleted Values patient, the indication for the indication for transfusion can which are not transfusion can be made at be made at hemoglobin levels routinely used in hemoglobin levels below 10 g/dl below 10 g/dl or 6.2 mmol/l, and India and the hematocrit value the hematocrit value maintained maintained at 30%. at 30%. German Trauma Society

Guideline 3.9.4 In critically ill trauma Adapt In critically ill patients, a The scope of the patients, transfusion strategy to restrictive transfusion strategy original guideline be employed should be employed . includes critically ● Hb concentration <7 g/dL, ● Hb concentration <70 g/L, ill trauma patients RBC transfusion is likely to be RBC transfusion is likely to be so this word as Standard Treatment Guidelines-Major Trauma 54

appropriate; however, transfusion appropriate; however, transfusion added. Also the may not be required in well- may not be required in well- term restrictive compensated patients or where compensated patients or where was avoided to other specific therapy is other specific therapy is prevent available. available. confusions. ● Hb concentration of 7–9 g/dL, ● Hb concentration of 70–90 g/L, Also units are RBC transfusion is not RBC transfusion is not changed to

associated with reduced associated with reduced commonly used mortality. The decision to mortality. The decision to units in India transfuse patients (with a single transfuse patients (with a single unit followed by reassessment) unit followed by reassessment) should be based on the need to should be based on the need to relieve clinical signs and relieve clinical signs and symptoms of anaemia. symptoms of anaemia. ● Hb concentration >9 g/dL, ● Hb concentration >90 g/L,

RBC transfusion is generally RBC transfusion is generally unnecessary. unnecessary. National Blood Authority Guideline-module 4 3.9.5 Red blood cell (RBC) Adopt Red blood cell (RBC) transfusion transfusion should not be should not be dictated by a dictated by a haemoglobin (Hb) haemoglobin (Hb) concentration concentration alone, but should alone, but should also be based also be based on assessment of on assessment of the patient's the patient's clinical status clinical status NBA Guideline - module 4

3.9.6 Replacement of fibrinogen Replacement of fibrinogen Rephrased to if should be carried out, if test should be carried out if levels are test provisions are provisions are available, at levels Adapt at < 1.5 g/l (150 mg/dl). available as it may < 1.5 g/l (150 mg/dl). German Trauma Society not be available in Guideline the district hospitals. 3.10 Haemorrhage imaging in hospital settings 3.10.1 Imaging for haemorrhage Adapt Imaging for haemorrhage in Rephrased to

in patients with suspected patients with suspected specify the haemorrhage should be haemorrhage should be imaging performed urgently, using FAST, performed urgently, and the modalities to be Standard Treatment Guidelines-Major Trauma 55

and a CT if required, and the images should be interpreted used and the images should be interpreted immediately by a healthcare sequence in which immediately by a healthcare professional with training and they may be used . professional with training and skills in this area. skills in this area. NICE Guideline [NG39] *if FAST is not available at the treating centre, then Diagnostic FAST and DPL to Peritoneal Lavage can be be used before performed to detect occult CT[3].* intraabdominal bleeding.

*Cha JY, Kashuk JL, Sarin EL, et al. Diagnostic peritoneal lavage remains a valuable adjunct to modern imaging techniques. J Trauma. 2009 Aug. 67(2):330-4; discussion 334-6. 3.10.2 Limit diagnostic imaging Adopt Limit diagnostic imaging (such (such as chest and pelvis X-rays as chest and pelvis X-rays or or FAST [focused assessment FAST [focused assessment with with sonography for trauma]) to sonography for trauma]) to the the minimum needed to direct minimum needed to direct

intervention in patients with intervention in patients with suspected haemorrhage and suspected haemorrhage and haemodynamic instability who haemodynamic instability who are not responding to volume are not responding to volume resuscitation. resuscitation. NICE guideline [NG39] 3.10.3 Be aware that a negative Be aware that a negative FAST FAST does not exclude Adopt does not exclude intraperitoneal intraperitoneal or retroperitoneal or retroperitoneal haemorrhage. haemorrhage. NICE Guideline [NG39]

*To repeat a FAST examination if clinical index of suspicion for intraperitoneal hemorrhage. Standard Treatment Guidelines-Major Trauma 56

3.10.4 Consider immediate CT Adopt Consider immediate CT for for patients with suspected patients with suspected haemorrhage only if they are haemorrhage if they are responding to resuscitation or if responding to resuscitation or if their haemodynamic status is their haemodynamic status is normal. normal. NICE Guideline [NG39] 3.11 Damage control surgery 3.11.1 Use damage control Adopt Use damage control surgery in surgery in patients with patients with haemodynamic

haemodynamic instability who instability who are not are not responding to volume responding to volume resuscitation. resuscitation. NICE Guideline [NG39] 3.12 Resuscitation ( Criteria for Cardiac arrest after trauma) 3.12.1 In the case of definitive Adopt A In the case of definitive cardiac arrest, uncertainties in cardiac arrest, uncertainties in detecting a pulse or other clinical detecting a pulse or other clinical signs that make cardiac arrest signs that make cardiac arrest

likely, resuscitation must be likely, resuscitation must be started immediately started immediately. German Trauma Society Guideline 3.12.2 During resuscitation, Adopt During resuscitation, trauma- trauma-specific reversible causes specific reversible causes of of cardiac arrest ., airway cardiac arrest ., airway obstruction, esophageal obstruction, esophageal intubation, hypovolemia, tension intubation, hypovolemia, tension pneumothorax or pericardial pneumothorax or pericardial

tamponade) should be diagnosed tamponade) should be diagnosed and treated. and treated. German Trauma Society Guideline 3.12.3 If resuscitation is Adopt If resuscitation is unsuccessful unsuccessful after eliminating after eliminating possible possible causes of cardiac arrest, trauma-specific causes of cardiac Standard Treatment Guidelines-Major Trauma 57

cardiopulmonary resuscitation arrest, cardiopulmonary must be stopped. resuscitation must be stopped. German Trauma Society Guideline 3.13 Role of Emergency Thoracotomy 3.13.1 If expertise is available, Adapt Emergency thoracotomy should Rephrased to say emergency thoracotomy should be performed in the case of that it can be done be performed in the case of penetrating injuries, particularly if the expertise is penetrating injuries, particularly if the onset of cardiac arrest is available at the

if the onset of cardiac arrest is recent and vital signs are initially treating centre. recent and vital signs are initially present. present. German Trauma Society Guideline 4.0 Head Injury MoHFW Recommendation Adapt/A Original Recommendation and Remarks dopt Source Guideline 4.1.1 State of consciousness with Adopt State of consciousness with pupil pupil function and Glasgow function and Glasgow Coma Coma Scale (bilateral motor Scale (bilateral motor function)

function) must be recorded and must be recorded and documented at repeated intervals. documented at repeated intervals. NICE Guideline [NG39] 4.1.2 The goals are normoxia*, Adopt The goals are normoxia, normocapnia**, and normocapnia, and normotension. normotension***. A fall in A fall in arterial oxygen arterial oxygen saturation below saturation below 90% must be 90% must be avoided. avoided. NICE Guideline [NG39] 4.1.3 Intubation with Adapt Intubation with Not all hospitals

adequate ventilation adequate ventilation across may have the facility of (with capnometry and (with capnometry and capnography or blood gas analysis if blood gas analysis) ABG analysis, available) must be must be carried out in Standard Treatment Guidelines-Major Trauma 58

carried out in unconscious patients hence intubation is unconscious patients (reference value GCS ≤ to be supplemented with (reference value GCS ≤ 8). them if available. 8). NICE Guideline [NG39] 4.1.4 A Cranial Computed Adapt A CCT scan must be performed It is not advisable Tomography of Brain scan must in the case of polytrauma with to send an be performed in the case of suspected traumatic brain injury. unstable patient polytrauma after stabilization for CT scan in our

with suspected traumatic brain scenario. Hence injury. the patients can be sent after stabilization only. CCT is changed to CT Brain as it is the term used in India 4.1.5 A (monitoring) CT scan Adopt A (monitoring) CT scan must be must be performed in the case of performed in the case of neurologic deterioration. neurologic deterioration. NICE Guideline [NG39] 4.1.6 Glucocorticoids must not Adopt Glucocorticoids must not be be administered in the treatment administered in the treatment of of TBI. TBI.

NICE Guideline [NG39] 4.1.7 If severely elevated Adapt If severely elevated intracranial Hypertonic saline intracranial pressure is suspected, pressure is suspected, is expensive and particularly with signs of particularly with signs of not available transtentorial herniation (pupil transtentorial herniation (pupil universally. widening, decerebrate rigidity, widening, decerebrate rigidity, Hyperventilation extensor reaction to painful extensor reaction to painful is advisable if

stimulus, progressive clouded stimulus, progressive clouded ABG analysis is consciousness), the following consciousness), the following available to treatments can be given : treatments can be given: maintain paCO2 at - Hyperventilation where ABG - Hyperventilation 30-35 mm of Hg. analysis is available# - Mannitol Mannitol is to be - Mannitol## - Hypertonic saline solution used in isolated head injury in NICE Guideline [NG39] normotensive patients. Standard Treatment Guidelines-Major Trauma 59

*normoxia - spO2 > 90% **Normocapnia - paCO2 = 35-40 mmHg{4.7kPa} ***Normotension - SBP ≥ 90 mmHg # 20 breaths per minute to maintain paCO2 at 30-35 mm of Hg ## 20% solution at 0.5-2 gm/kg over 30 to 60 minutes 5.0 Spinal Trauma MoHFW Recommendation Adapt/A Original Recommendation & Remarks dopt Source Guideline 5.1 Assessment for spinal injury 5.1.1 On arrival at the hospital, Adapt On arrival at the scene of the This is true in the use a prioritising sequence to incident, use a prioritising pre-hospital

assess people with suspected sequence to assess people with settings to look for trauma, for example ABCDE: suspected trauma, for example catastrophic ● airway with in-line spinal <C>ABCDE: haemorrhage not immobilisation ● catastrophic haemorrhage in hospital as per ● breathing ● airway with in-line spinal experts group ● circulation immobilisation discussion. ● disability (neurological) ● breathing ● exposure and environment. ● circulation ● disability (neurological) ● exposure and environment.

NICE Guidelines [NG41]. 5.1.2 At all stages of the Adopt At all stages of the assessment: assessment: ● protect the person's cervical ● protect the person's cervical spine with manual in-line spinal spine with manual in-line spinal immobilisation, particularly immobilisation, particularly during any airway intervention during any airway intervention and and ● avoid moving the remainder of ● avoid moving the remainder of the spine. the spine. NICE Guidelines [NG41]

5.1.3 History and thorough Adapt The medical history has high The following clinical examination for spinal importance and should be taken. three injury including the functions GoR B recommendations associated with it must be carried German Trauma Society can be made into out. Guideline one. Standard Treatment Guidelines-Major Trauma 60

Adapt The clinical examination for spinal injuries has a high importance in the emergency room and should be carried out. (GoR B) German Trauma Society Guideline Adapt A thorough physical examination including the spine and the functions associated with it must be carried out. (GoR A) German Trauma Society Guideline 5.1.4. The spine is suspected to Adapt If the following 5 criteria are Internal be stable, unless any of the absent, it can be assumed that no Harmonization

unstable spinal injury is present: group in the following 5 criteria are present, • impaired consciousness review felt there • impaired consciousness • neurologic deficit were too many • neurologic deficit • spinal pain or negatives, so made • spinal pain or myogelosis changes in the myogelosis wording too make • intoxication • intoxication it simpler to read. • trauma in the extremities • trauma in the extremities GoR A German Trauma Society *myogelosis (area of hard or stiff Guideline muscle)

5.1.5 The presence of a spinal Adopt The presence of a spinal injury injury must be assumed in must be assumed in unconscious unconscious patients until patients until evidence to the contrary is found. evidence to the contrary is found. (GoR A) German Trauma Society Guideline 5.1.6 Carry out full in-line spinal Adopt Carry out full in-line spinal immobilisation if any of the immobilisation if any of the factors in recommendation 4.1.4 factors in recommendation 1.1.3

are present or if this assessment are present or if this assessment cannot be done. cannot be done. NICE Guidelines [NG41] 5.2Assessment of Cervical Spine 5.2.1 Assess whether the person Adopt Assess whether the person is at is at high, low or no risk for high, low or no risk for cervical Standard Treatment Guidelines-Major Trauma 61

cervical spine injury using the spine injury using the Canadian Canadian C-spine rule as C-spine rule as follows: follows: ● the person is at high risk if ● the person is at high risk if they they have at least one of the have at least one of the following following high-risk factors: high-risk factors: o age 65 years or older o age 65 years or older o dangerous mechanism o dangerous mechanism of injury (fall from a of injury (fall from a height of greater than 1

height of greater than 1 metre or 5 steps, axial metre or 5 steps, axial load to the head – for load to the head – for example diving, high- example diving, high- speed motor vehicle speed motor vehicle collision, rollover motor collision, rollover motor accident, ejection from a accident, ejection from a motor vehicle, accident motor vehicle, accident involving motorised involving motorised recreational vehicles, recreational vehicles, bicycle collision, horse bicycle collision, horse riding accidents)

riding accidents) o paraesthesia in the o paraesthesia in the upper or lower limbs upper or lower limbs ● the person is at low risk if they ● the person is at low risk if they have at least one of the following have at least one of the following low-risk factors: low-risk factors: o involved in a minor o involved in a minor rear-end motor vehicle rear-end motor vehicle collision collision o comfortable in a o comfortable in a sitting sitting position position o ambulatory at any

o ambulatory at any time time since the injury since the injury o no midline cervical o no midline cervical spine tenderness spine tenderness o delayed onset of neck o delayed onset of neck pain pain ● the person remains at low risk ● the person remains at low risk if they are: if they are: o unable to actively o unable to actively rotate their neck 45 rotate their neck 45 degrees to the left and degrees to the left and right (the range of the right (the range of the neck can only be

neck can only be assessed safely if the assessed safely if the person is at low risk and person is at low risk and there are no high-risk there are no high-risk factors). factors). ● the person has no risk if they: ● the person has no risk if they: o have one of the above o have one of the above low-risk factors and Standard Treatment Guidelines-Major Trauma 62

low-risk factors and o are able to actively o are able to actively rotate their neck 45 rotate their neck 45 degrees to the left and degrees to the left and right. right. NICE Guideline [NG41] 5.3 Assessment of Thoracic or Lumbosacral Spine 5.3.1 Assess the person with Adopt Assess the person with suspected suspected thoracic or thoracic or lumbosacral spine lumbosacral spine injury using injury using these factors: these factors: ● age 65 years or older and

● age 65 years or older and reported pain in the thoracic or reported pain in the thoracic or lumbosacral spine lumbosacral spine ● dangerous mechanism of injury ● dangerous mechanism of injury (fall from a height of greater than (fall from a height of greater than 3 metres, axial load to the head 3 metres, axial load to the head or base of the spine – for or base of the spine – for example falls landing on feet or example falls landing on feet or buttocks, high-speed motor

buttocks, high-speed motor vehicle collision, rollover motor vehicle collision, rollover motor accident, lap belt restraint only, accident, lap belt restraint only, ejection from a motor vehicle, ejection from a motor vehicle, accident involving motorised accident involving motorised recreational vehicles, bicycle recreational vehicles, bicycle collision, horse riding accidents) collision, horse riding accidents) ● pre-existing spinal pathology, ● pre-existing spinal pathology, or known or at risk of

or known or at risk of osteoporosis – for example osteoporosis – for example steroid use steroid use ● suspected spinal fracture in ● suspected spinal fracture in another region of the spine another region of the spine ● abnormal neurological ● abnormal neurological symptoms (paraesthesia or symptoms (paraesthesia or weakness or numbness) weakness or numbness) ● on examination: ● on examination: o abnormal neurological o abnormal neurological signs (motor or sensory signs (motor or sensory deficit)

deficit) o new deformity or bony o new deformity or bony midline tenderness (on midline tenderness (on palpation) palpation) o bony midline o bony midline tenderness (on tenderness (on percussion) percussion) o midline or spinal pain ● midline or spinal pain (on coughing) (on coughing)on ● on mobilisation (sit, mobilisation (sit, stand, stand, step, assess step, assess walking): walking): pain or Standard Treatment Guidelines-Major Trauma 63

pain or abnormal abnormal neurological neurological symptoms symptoms (stop if this (stop if this occurs). occurs). NICE Guidelines [NG41] 5.4 When To carry out in-line spinal immobilisation 5.4.1 Carry out or maintain full Adopt Carry out or maintain full in-line in-line spinal immobilisation if: spinal immobilisation if: ● a high-risk factor for cervical ● a high-risk factor for cervical spine injury is identified and spine injury is identified and

indicated by the Canadian C- indicated by the Canadian C- spine rule spine rule ● a low-risk factor for cervical ● a low-risk factor for cervical spine injury is identified and spine injury is identified and indicated by the Canadian C- indicated by the Canadian C- spine rule and the person is spine rule and the person is unable to actively rotate their unable to actively rotate their neck 45 degrees left and right neck 45 degrees left and right ● indicated by one or more of ● indicated by one or more of

the factors listed in the factors listed in recommendation 4.3.1 recommendation 1.1.7. NICE Guidelines [NG41] 5.4.2 Do not carry out or Adopt Do not carry out or maintain full maintain full in-line spinal NICE in-line spinal immobilisation in immobilisation in people if: Guidelin people if: ● they have low-risk factors for es ● they have low-risk factors for cervical spine injury and, are [NG41]. cervical spine injury as identified pain free and are able to actively and indicated by the Canadian C-

rotate their neck 45 degrees left spine rule, are pain free and are and right able to actively rotate their neck ● they do not have any of the 45 degrees left and right factors listed in recommendation ● they do not have any of the 5.3.1 factors listed in recommendation 1.1.7. NICE Guidelines [NG41] 5.5 How to carry out full in-line spinal immobilisation 5.5.1 The spinal immobilisation Adapt The use of spinal immobilisation The first part of devices need to be adjusted In devices may be difficult (for the

uncooperative, agitated or example in people with short or recommendation distressed people, think about wide necks, or people with a pre- was deleted as the letting them find a position existing deformity) and could be expert group where they are comfortable with counterproductive (for example members felt it manual in-line spinal increasing pain, worsening would add immobilisation. neurological signs and confusion symptoms). In uncooperative, agitated or distressed people, including children, think about

letting them find a position where they are comfortable with manual in-line spinal immobilisation. NICE Guidelines [NG41] 5.5.2 When carrying out full in- Adapt When carrying out full in-line Modified as per line spinal immobilisation in spinal immobilisation in adults, the Indian settings adults, manually stabilise the manually stabilise the head with head with the spine in-line using the spine in-line using the the following stepwise approach: following stepwise approach:

● Fit an appropriately sized ● Fit an appropriately sized semi-rigid collar unless semi-rigid collar unless contraindicated by: contraindicated by: o a compromised airway o a compromised airway o known spinal o known spinal deformities, such as deformities, such as ankylosing spondylitis ankylosing spondylitis (in these cases keep the (in these cases keep the spine in the person's spine in the person's current position). current position). ● Reassess the airway after ● Reassess the airway after

applying the collar. applying the collar. ● Place and secure the person on ● Place and secure the person on a stretcher. a scoop stretcher. ● Secure the person with head blocks and tape, ideally in a vacuum mattress. NICE Guidelines [NG41] 5.6 When to carry out or maintain full in-line spinal immobilisation and request imaging 5.6.1 Carry out or maintain full Adopt Carry out or maintain full in-line in-line spinal immobilisation and spinal immobilisation and request imaging if: request imaging if:

● a high-risk factor for cervical ● a high-risk factor for cervical spine injury is identified and spine injury is identified and indicated by the Canadian C- indicated by the Canadian C- spine rule or spine rule or ● a low-risk factor for cervical ● a low-risk factor for cervical spine injury is identified and spine injury is identified and indicated by the Canadian C- indicated by the Canadian C- spine rule and the person is spine rule and the person is

unable to actively rotate their unable to actively rotate their neck 45 degrees left and right or neck 45 degrees left and right or ● indicated by one or more of ● indicated by one or more of the factors listed in the factors listed in recommendation 5.3.1 recommendation 1.1.7. NICE Guidelines [NG41]. Standard Treatment Guidelines-Major Trauma 65

5.6.2 Do not carry out or Adopt Do not carry out or maintain full maintain full in-line spinal in-line spinal immobilisation or immobilisation or request request imaging for people if: imaging for people if: ● they have low-risk factors for ● they have low-risk factors for cervical spine injury as identified cervical spine injury as identified and indicated by the Canadian C- and indicated by the Canadian C- spine rule, are pain free and are

spine rule, are pain free and are able to actively rotate their neck able to actively rotate their neck 45 degrees left and right 45 degrees left and right ● they do not have any of the ● they do not have any of the factors listed in recommendation factors listed in recommendation NICE Guidelines [NG41]. 5.3.1 5.7 Diagnostic imaging 5.7.1 Imaging for spinal injury Adapt Imaging for spinal injury should After stabilisation should be performed urgently, be performed urgently, and the was added to

and the images should be images should be interpreted emphasize that no interpreted immediately by a immediately by a healthcare patients be sent for healthcare professional with professional with training and imaging if training and skills in this area skills in this area. unstable. after stabilisation. NICE Guidelines [NG41]. 5.7.2 Perform CT in adults if; Adapt Perform CT in adults (16 or Xray role in ● imaging for cervical spine over) if: Cervical spine.

injury is indicated by the ● imaging for cervical spine District Hospital Canadian C-spine rule (see injury is indicated by the with or Ct scan recommendation 5.6.1) or Canadian C-spine rule (see available. ● there is a strong suspicion of recommendation 1.4.7) or thoracic or lumbosacral spine ● there is a strong suspicion of KS: Don't injury associated with abnormal thoracic or lumbosacral spine advocate X-Ray neurological signs or symptoms. injury associated with abnormal because it has high

C spine xray should be neurological signs or symptoms. false negative and considered if CT is not available NICE Guidelines [NG41]. would cause more with caution of high false morbidity. negative rate. NK: Lateral C- spine X-ray if true positive then it would be good. 5.7.3 If, after CT, there is a Adapt If, after CT, there is a Expert group feels neurological abnormality which neurological abnormality which we would advice could be attributable to spinal could be attributable to spinal MRI as for this

cord injury, advice MRI if cord injury, perform MRI. reasons patient available. NICE Guideline [NG41] should not be transferred 5.8 Lumbosacral Spine Imaging Standard Treatment Guidelines-Major Trauma 66

5.8.1 Perform an X-ray as the Adopt Perform an X-ray as the first-line first-line investigation for people investigation for people with with suspected spinal column suspected spinal column injury injury without abnormal without abnormal neurological neurological signs or symptoms signs or symptoms in the thoracic in the thoracic or lumbosacral or lumbosacral regions (T1–L3). regions (T1–L3). NICE Guideline [NG41] 5.8.2 Perform CT if the X-ray is Adopt Perform CT if the X-ray is

abnormal or there are clinical abnormal or there are clinical signs or symptoms of a spinal signs or symptoms of a spinal column injury. column injury. NICE Guideline [NG41] 5.8.3 If a new spinal column Adopt If a new spinal column fracture is fracture is confirmed, image the confirmed, image the rest of the rest of the spinal column. spinal column. NICE Guideline [NG41] 5.8.4 After circulatory Adapt After circulatory stabilization Changes made as

stabilization and before transfer and before transfer to the per the Indian from the emergency room, a intensive care unit, a spinal settings. Imaging spinal injury should be cleared injury should be cleared by diagnostic tests by clinical examination or imaging diagnostic tests. (GoR were difficult to imaging . (if available). B) understand so was German Trauma Society changed as per the Guideline expert group members 5.9 Medications 5.9.1 Do not use the following Adopt Do not use the following

medications, aimed at providing medications, aimed at providing neuroprotection and prevention neuroprotection and prevention of secondary deterioration, in the of secondary deterioration, in the acute stage after acute traumatic acute stage after acute traumatic spinal cord injury: spinal cord injury: ● methylprednisolone ● methylprednisolone ● nimodipine ● nimodipine ● naloxone. ● naloxone. NICE Guideline [NG41] 5.9.2 Do not use medications in Adopt Do not use medications in the

the acute stage after traumatic acute stage after traumatic spinal spinal cord injury to prevent cord injury to prevent neuropathic pain from neuropathic pain from developing in the chronic stage. developing in the chronic stage. NICE Guidelines [NG41] Standard Treatment Guidelines-Major Trauma 67

6.0 Pelvic Fracture Management: MoHFW Recommendation Adapt/A Original Recommendation & Remarks dopt Source Guideline 6.1 Using a pelvic binder 6.1.1. An acute life-threatening Adopt An acute life-threatening pelvic pelvic injury must be excluded injury must be excluded when when the patient is admitted to the patient is admitted to the the hospital. hospital. (GoR A) Guideline German Trauma Society 6.1.2 The stability of the Adopt The stability of the patient’s

patient’s pelvis must be clinically pelvis must be clinically examined. examined. (GoR A) Guideline German Trauma Society 6.1.3 If active bleeding is Adapt 1.1.1 If active bleeding is Changes made as suspected from a pelvic fracture suspected from a pelvic fracture per the availability following blunt high‑energy following blunt high‑energy in the Indian trauma, apply a pelvic binder. trauma: settings. ● apply a pelvic binder, or ● consider an improvised pelvic binder but only if a

purpose‑made binder does not fit. NICE Guidelines [NG38]. 6.2 Pelvic imaging 6.2.1 During the diagnostic study Adapt During the diagnostic study a Emphasizing on a pelvic survey radiograph pelvic survey radiograph should the fact that should be taken and/or computed be taken and/or computed unstable patient tomography (CT) be performed tomography (CT) be performed. should not be sent once patient is stabilized*. (GoR A) for diagnostic (*unstable patients do portable German Trauma Society imaging.

X-Ray if available) Guideline 6.2.2 Use CT (if available, Adapt Use CT for first-line imaging in Emphasizing on otherwise x-ray) for first-line adults (16 or over) with the fact that imaging with suspected suspected high‑energy pelvic unstable patient Standard Treatment Guidelines-Major Trauma 68

high‑energy pelvic fractures fractures should not be sent once patient is stabilized* NICE Guidelines [NG38]. for diagnostic imaging The expert group felt that in the Indian settings the CT may not be available everywhere. 6.2.3 Unstable patients with Adapt For first‑line invasive treatment Interventional suspected active bleeding from of active arterial pelvic bleeding, radiology is not pelvic fracture, use: use: available in most

● pelvic packing to stabilize the ● interventional radiology if centres across patient. emergency laparotomy is not India and so the needed for abdominal injuries expert group ● pelvic packing if emergency members felt that laparotomy is needed for it is best to do abdominal injuries. open packing in NICE Guidelines [NG38]. these patients. 6.3 Removing a pelvic binder 6.3.1 For people with suspected Adopt For people with suspected pelvic pelvic fractures and pelvic fractures and pelvic binders,

binders, remove the binder as remove the binder as soon as soon as possible if: possible if: ● there is no pelvic fracture, or ● there is no pelvic fracture, or ● a pelvic fracture is identified as ● a pelvic fracture is identified as mechanically stable, or mechanically stable, or ● the binder is not controlling the ● the binder is not controlling the mechanical stability of the mechanical stability of the fracture, or fracture, or ● there is no further bleeding or ● there is no further bleeding or

coagulation is normal. coagulation is normal. ● Remove all pelvic binders ● Remove all pelvic binders within 24 hours of application. within 24 hours of application. NICE Guidelines [NG38] 6.4 Log rolling 6.4.1 Do not log roll people with Adopt Do not log roll people with suspected pelvic fractures before suspected pelvic fractures before pelvic imaging unless: pelvic imaging unless: ● an occult penetrating injury is ● an occult penetrating injury is Standard Treatment Guidelines-Major Trauma 69

suspected in a person with suspected in a person with haemodynamic instability haemodynamic instability ● log rolling is needed to clear ● log rolling is needed to clear the airway (for example, suction the airway (for example, suction is ineffective in a person who is is ineffective in a person who is vomiting). vomiting). ● When log rolling, pay ● When log rolling, pay particular attention to particular attention to haemodynamic stability. haemodynamic stability. NICE Guidelines [NG38].

*Stabilization, by consensus, we mean, Vital signs i.e. heart rate, blood pressure and pulse oxygen saturation is near normal limits for two consecutive readings 15 minutes apart. An unconscious, semiconscious patients airway needs to be secured even if he is hemodynamically stable before shifting for further imaging. 7.0 Orthopaedic trauma MoHFW Guideline Adopt/ Original Recommendation and Remarks Adapt Source Guideline 7.1 Open fractures 7.1.1 Do not irrigate open Adopt Do not irrigate open fractures of

fractures of the long bones, the long bones, hindfoot or hindfoot or midfoot in the midfoot in the emergency emergency department before department before debridement. debridement. NICE guideline [NG. 37] 7.1.2 Consider a saline-soaked Adopt Consider a saline-soaked dressing covered with an dressing covered with an occlusive layer (if not already occlusive layer (if not already applied) for open fractures in the applied) for open fractures in the emergency department before emergency department before

debridement. Debridement. NICE guideline [NG. 37] 7.1.3 In the emergency Adopt In the emergency department, department, administer administer prophylactic prophylactic intravenous intravenous antibiotics antibiotics immediately to people immediately to people with open with open fractures if not already fractures if not already given. given. NICE guideline [NG. 37] Standard Treatment Guidelines-Major Trauma 70

7.1.4 Do not base the decision Adopt Do not base the decision whether whether to perform limb salvage to perform limb salvage or or amputation on an injury amputation on an injury severity severity tool score. tool score. NICE guideline [NG. 37] 7.1.5 Perform emergency Adopt Perform emergency amputation amputation when: when: ● A limb is the source of ● A limb is the source of uncontrollable life-threatening uncontrollable life-threatening bleeding, or bleeding, or

● A limb is salvageable but ● A limb is salvageable but attempted preservation would attempted preservation would pose an unacceptable risk to the pose an unacceptable risk to the person's life, or person's life, or ● A limb is deemed ● A limb is deemed unsalvageable after orthoplastic unsalvageable after orthoplastic assessment assessment NICE guideline [NG. 37] 7.1.6 Perform debridement: Adapt Perform debridement: Points deleted ● Immediately for highly ● Immediately for highly were too specific

contaminated open fractures contaminated open fractures for open fractures ● Within 24 hours of injury for ● Within 12 hours of injury for so were deleted all other open fractures high-energy open fractures after expert groups (likely Gustilo–Anderson consensus classification type IIIA or type IIIB) that are not highly contaminated ● Within 24 hours of injury for all other open fractures NICE guideline [NG. 37] 7.2 Vascular injury 7.2.1. Use hard signs (lack of Adopt Use hard signs (lack of palpable

palpable pulse, continued blood pulse, continued blood loss, or loss, or expanding haematoma) expanding haematoma) to to diagnose vascular injury. diagnose vascular injury. NICE guideline [NG. 37] 7.2.2 Do not rely on capillary Adopt Do not rely on capillary return or return or Doppler signal to Doppler signal to exclude exclude vascular injury. vascular injury. NICE guideline [NG. 37] Standard Treatment Guidelines-Major Trauma 71

7.2.3 Perform immediate surgical Adopt Perform immediate surgical exploration if hard signs of exploration if hard signs of vascular injury persist after any vascular injury persist after any necessary restoration of limb necessary restoration of limb alignment and joint reduction. alignment and joint reduction. NICE guideline [NG. 37] 7.2.4 Do not delay Adopt Do not delay revascularisation revascularisation for angiography for angiography in people with in people with complex fractures complex fractures.

NICE guideline [NG. 37] 7.3 Compartment syndrome 7.3.1 In people with fractures of Adapt In people with fractures of the Few points deleted the tibia, maintain awareness of tibia, maintain awareness of as they are not compartment syndrome for 48 compartment syndrome for 48 feasible in the hours after injury or fixation by hours after injury or fixation by:- Indian settings regularly assessing and recording clinical symptoms and signs in ● Regularly assessing and hospital recording clinical symptoms and

signs in hospital ● Considering continuous compartment pressure monitoring in hospital when clinical symptoms and signs cannot be readily identified (for example, because the person is unconscious or has a nerve block) ● Advising people how to self- monitor for symptoms of compartment syndrome, when they leave hospital NICE guideline [NG. 37] 8.0 Pain Management in Major trauma MoHFW Recommendations Adopt/ Original recommendation Reasons for Adapt & Source guideline adaptation

8.1 Pain management in Major trauma 8.1.1 Assess pain regularly in Adapt Assess pain regularly in patients Removed patients with major trauma using with major trauma using a pain developmental a pain assessment assessment stage and age as scale suitable for patients scale suitable for the patient's we are dealing cognitive function. age, developmental stage and with only adults in cognitive function. this guideline NICE Guidelines [NG39].

8.1.2 For patients with major Adapt For patients with major trauma, Expert group feels trauma, use intravenous use intravenous morphine as the to add opioids like morphine/opioids as the first-line first-line Buprenorphine, analgesic and adjust the dose as analgesic and adjust the dose as Pentazocine and needed to achieve adequate pain needed to achieve adequate pain other opioids as relief. relief. not all hospitals NICE Guidelines [NG39]. have Morphine license.

8.1.3 Consider ketamine in Adopt 5. Consider ketamine in analgesic doses as a second-line analgesic doses as a second-line agent. agent. NICE Guidelines [NG39]. 8.2 Efficacy of Analgesic Modalities in blunt thoracic trauma 8.2.1 Epidural analgesia is the Adapt The use of optimal analgesia and Expert group feels preferred mode of analgesia aggressive chest physiotherapy it is important to delivery in severe thoracic should be applied to minimize mention analgesia

trauma. the likelihood of respiratory for severe thoracic failure and ensuing ventilatory trauma as pain is a support. Epidural catheter is the neglected entity in preferred mode of analgesia our injured group delivery in severe FC injury. of patients. Though this is a specific Management of pulmonary management we contusion and flail chest: an would like to Eastern Association for the mention in the Surgery of Trauma practice guideline for pain management guideline. management in severe thoracic trauma

9.0 Providing support and Information to patients & relatives Providing information about patients to the next level hospital/casualty Indian Recommendation Adapt/A Original Recommendation & Remarks dopt Source Guideline 9.1 Providing support 9.1.1 When communicating with Adopt When communicating with patients, family members and patients, family members and carers carers: ● manage expectations and avoid ● manage expectations and avoid misinformation misinformation

● answer questions and provide ● answer questions and provide information honestly, within the information honestly, within the limits of your knowledge limits of your knowledge ● do not speculate and avoid ● do not speculate and avoid being overly optimistic or being overly optimistic or pessimistic when discussing pessimistic when discussing information on further information on further investigations, diagnosis or investigations, diagnosis or prognosis prognosis

● ask if there are any other ● ask if there are any other questions. questions. NICE Guideline [NG39] 9.1.2 The trauma team structure Adopt The trauma team structure should should include a clear point of include a clear point of contact contact for providing information for providing information to to patients, their family members patients, their family members and carers. and carers. NICE Guideline [NG39] 9.2 Providing information 9.2.1 Explain to patients, family Adopt Explain to patients, family

members and carers what is members and carers, what is happening and why it is happening and why it is happening. Provide: happening. Provide: ● information on known injuries ● information on known injuries ● details of immediate ● details of immediate investigations and treatment, and investigations and treatment, and if possible include time if possible include time schedules. schedules. Standard Treatment Guidelines-Major Trauma 74

NICE Guideline [NG39] 9.2.2 Offer people with fractures Adopt Offer people with fractures the the opportunity to see images of opportunity to see images of their their injury, taken before and injury, taken before and after after treatment. treatment. NICE Guideline [NG39] 9.2.3 Provide people with Adapt Provide people with fractures fractures on the following when with both verbal and written the management plan is agreed or information on the following changed: when the management plan is

● expected outcomes of agreed or changed: treatment, including time to ● expected outcomes of returning to usual activities and treatment, including time to the likelihood of permanent returning to usual activities and effects on quality of life (such as the likelihood of permanent pain, loss of function and effects on quality of life (such as psychological effects) pain, loss of function and ● amputation, if this is a psychological effects) possibility ● amputation, if this is a

● activities they can do to help possibility themselves ● activities they can do to help ● home care options, if needed themselves ● rehabilitation, including whom ● home care options, if needed to contact and how (this should ● rehabilitation, including whom include information on the to contact and how (this should importance of active patient include information on the participation for achieving goals importance of active patient and the expectations of participation for achieving goals

rehabilitation) and the expectations of ● mobilisation and rehabilitation) weight‑bearing, including upper ● mobilisation and limb load bearing for arm weight‑bearing, including upper fractures. limb load bearing for arm fractures. NICE Guideline [NG39] 9.2.4 Document all key Adopt Document all key communications with patients, communications with patients, family members and carers about family members and carers about the management plan. the management plan. NICE Guideline [NG39]

9.2.5 Ensure that all health and Adopt Ensure that all health and social social care practitioners have care practitioners have access to access to information previously information previously given to given to people with fractures to people with fractures to enable enable consistent information to consistent information to be be provided. provided. NICE Guideline [NG39] 9.3 Providing information about transfer from an emergency department

9.3.1 For patients who are being Adapt For patients who are being Expert group transferred from an emergency transferred from an emergency feels it is difficult department to another centre, department to another centre, to give always the provide verbal and written provide verbal and written name and contact information that includes: information that includes: details of the ● the reason for the transfer ● the reason for the transfer person in the

● the location of the receiving ● the location of the receiving receiving centre. centre and the patient's centre and the patient's destination within the receiving destination within the receiving centre centre ● the name and contact details of ● the name and contact details of the person responsible for the the person responsible for the patient's care at the receiving patient's care at the receiving centre (if possible) centre ● the name and contact details of ● the name and contact details of

the person who was responsible the person who was responsible for the patient's care at the initial for the patient's care at the initial hospital. hospital. NICE Guideline [NG39] 9.4 Recording information in before transferring to definitive care settings 9.4.1 Record the following in Adapt Record the following in people We needed to people with major trauma in with suspected spinal injury in include this point hospital settings before pre-hospital settings: for inter hospital

transferring to a higher centre: ● <C>ABCDE (catastrophic transfer. Also the ● ABCDE (airway with in-line haemorrhage, airway with in-line expert groups spinal immobilisation, breathing, spinal immobilisation, breathing, feels it will be circulation, disability circulation, disability difficult to define [neurological], exposure and [neurological], exposure and catastrophic environment) environment) hemorrhage so NICE Guidelines [NG39] have excluded this point.

9.4.2 If possible, record Adopt 1.9.2 If possible, record Standard Treatment Guidelines-Major Trauma 76

information on whether the information on whether the assessments show that the assessments show that the person's condition is improving person's condition is improving or deteriorating. or deteriorating. NICE Guidelines [NG39] 9.4.3 Record pre-alert Adapt 1.9.3 Record pre-alert Ambulance call information using a structured information using a structured sign, name of the system and include all of the system and include all of the person and time of following: following: call of the person

● the patient's age and sex ● the patient's age and sex was not felt ● time of incident ● time of incident important to be by ● mechanism of injury ● mechanism of injury the expert group. ● injuries suspected ● injuries suspected ● signs, including vital signs and ● signs, including vital signs and Glasgow Coma Scale Glasgow Coma Scale ● treatment so far ● treatment so far ● estimated time of arrival at ● estimated time of arrival at emergency department emergency department

● special requirements ● special requirements ● the ambulance call sign, name ● the ambulance call sign, name of the person taking the call and of the person taking the call and time of call time of call. NICE Guidelines [NG39] 9.5 Training and skills 9.5.1 Ensure that each healthcare Adapt Ensure that each healthcare Changed as per professional within the trauma professional within the trauma needed in this service has the training and skills service has the training and skills guideline for the

to deliver, safely and effectively, to deliver, safely and effectively, Indian settings the interventions they are the interventions they are Training in the required to give as per this required to give, in line with the form of ATLS, guideline. NICE guidelines on non-complex NTMC, EMTC fractures, complex fractures, etc. major trauma, major trauma services and spinal injury assessment. NICE Guidelines [NG39] 9.6 Receiving information in hospital settings

9.6.1 Casualty Medical Adapt A senior nurse or trauma team Changes are made Officer/Trauma team leader in leader in the emergency as per the Indian Standard Treatment Guidelines-Major Trauma 77

the emergency department department should receive the Settings should receive the pre-alert pre-alert information, and information, and determine the determine the level of trauma level of trauma team response team response according to according to agreed and written agreed and written local local guidelines. guidelines. NICE Guideline [NG39] 9.6.2 The trauma team leader Adopt The trauma team leader should should be easily identifiable to be easily identifiable to receive

receive the handover and the the handover and the trauma trauma team ready to receive the team ready to receive the information. information. NICE Guideline [NG39] 9.6.3 The pre- hospital Adopt The pre- hospital documentation, documentation, including the including the recorded pre-alert recorded pre-alert information, information, should be quickly should be quickly available to the available to the trauma team and trauma team and placed in the placed in the patient's hospital

patient's hospital notes. notes. NICE Guideline [NG39] 9.7 Sharing information in hospital settings 9.7.1 Follow a structured process Adopt Follow a structured process when when handing over care within handing over care within the the emergency department emergency department (including shift changes) and to (including shift changes) and to other departments. Ensure that other departments. Ensure that the handover is documented. the handover is documented. NICE Guideline [NG39]

9.7.2 Ensure that all patient Adopt Ensure that all patient documentation, including images documentation, including images and reports, goes with the patient and reports, goes with the patient when they are transferred to when they are transferred to other departments or centres. other departments or centres. NICE Guideline [NG39] 9.7.3 Produce a written Adapt Produce a written summary, Changes made as summary, which gives the which gives the diagnosis, per the feasibility

diagnosis, management plan and management plan and expected in the Indian expected outcome and: outcome and: settings ● is aimed at and sent to the ● is aimed at and sent to the Standard Treatment Guidelines-Major Trauma 78

patient's referring patient's GP within 24 hours of physician/surgeon/primary or admission secondary care hospital within 24 ● includes a summary written in hours of admission plain English that is ● includes a summary written in understandable by patients, plain English/local language that family members and carers is understandable by patients, ● is readily available in the family members and carers patient's records. ● is readily available in the patient's records. NICE Guideline [NG39]

Annexure II: Abbreviations 1. ABG Arterial Blood Gas 2. APTT Activated Partial Thromboplastin Time 3. CT Computed Tomography 4. FAST Focussed assessment with sonography for trauma 5. FFP Fresh Frozen Plasma 6. Hb Hemoglobin 7. HES Hydroxyethyl starch 8. i.v. Intravenous 9. INR International Normalized ratio 10. MAP Mean Arterial Pressure 11. mmHg Millimeters of Mercury 12. PaCO Partial Pressure of Carbon dioxide 2 13. PT Prothrombin Time 14. RBC Red Blood Cell 15. SBP Systolic Blood Pressure

16. SpO Oxygen Saturation of blood 2 17. STG Standard Treatment Guideline Standard Treatment Guidelines-Major Trauma 80

Annexure III: Definitions 1. Chest decompression mainly refers to tube thoracostomy/ Chest drain placement. 2. Hemorrhagic Risk Tools ABC score, TASH score, PWH score, McLaughlin score, Emergency transfusion score, Shock Index etc. These measure variables at a single point in time. 3. Myogelosis An area of hard or stiff muscle 4. Normocapnia PaCO = 35 mm Hg {4.7kPa} 2 5. Normotension SBP > 90 mm Hg 6. Normoxia SpO > 90% 2 7. Restrictive resuscitation Fluid infusion in order to keep the

circulation at a low stable level (Systolic BP: 90 mmHg or palpable central pulse) and not exacerbate the bleeding. (from the german guidelines) 8. Simple dressings sterile gauze pads 9. Supraglottic device Laryngeal mask airway, proseal, i-gel etc. 10. Tourniquet can be a bandage roll, rubber tubing, crepe bandage, that checks bleeding or blood flow by compressing the blood vessels. Standard Treatment Guidelines-Major Trauma 81

Annexure IV: Tables Grades of Haemorrhage Diagrams and Important Information 1. Where to Insert Chest Tube? Triangle of safety is the recommended site for chest tube insertion. Boundaries are- Anterior- Lateral border of pectoralis major. Lateral- Lateral border of latissimus dorsi. Inferior- 6th rib or line of 5th intercostal space. Standard Treatment Guidelines-Major Trauma 82

Annexure V: Doses 1. Buprenorphine Initial: 0.3 mg i.v. every 6 to 8 hours as needed(slow) 2. Butorphanol Initial: 1 mg i.v. may repeat every 3-4 hours as needed 3. FFP(Fresh Frozen Plasma) 10-15ml/kg body weight 4. Ketamine 1-2 mg/kg i.v or 5-6mg/kg im after ruling out raised intracranial pressure 5. Mannitol 20% solution at 0.5-2 gm/kg over 30 to 60 minutes 6. Morphine 0.1-0.2 mg/kg q 4-6h i.v 7. Pentazocine 15-30 mg i.v. every 3-4 hours 8. Tranexamic acid Dosage as German guidelines-

Tranexamic acid initially 1 g as saturation over 10 minutes + 1 g over 8 hours (CRASH 2 Trials) * or 2 g (15–30 mg/kg BW) 9. Vitamin K i.v. 5mg bolus Standard Treatment Guidelines-Major Trauma 83

STANDARD TREATMENT GUIDELINES UROLOGY Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 HAEMATURIA 4 2 URINARY AND MALE GENITAL TRACT INFECTIONS 9 3 UROLITHIASIS AND URETERIC COLIC 19 4 Benign Hyperplasia Of Prostate (BPH) 46 5 RENAL CELL CARCINOMA (RCC) 50 6 BLADDER CANCER 58 7 PROSTATE CANCER 73 8 Testicular Swelling – Testicular Torsion 90 2

Group Head Coordinator of Development Team Prof. Rajesh Ahlawat Chairman, Department of Urology & Kidney Transplant, Medanta Medicity Reviewed By: Dr Anup Kumar Gupta Head of Department Department of Urology VMMC and Safdarjang Hospital, New Delhi 3

HAEMATURIA Introduction:- Hematuria is the presence of red-blood cells (RBC) in urine. • It may be categorized as gross (visible to naked eye) or microscopic (detected in urine microscopy). The recommended definition of microscopic hematuria is three or more red blood cells per high-power field on microscopic evaluation of urinary sediment from two of three properly collected urinalysis specimens. • It may arise from any part of the urinary tract, from glomerulus to meatal tip and may

be characterized as initial, terminal or total, which points to the approximate site of origin (distal to external sphincter, proximal urethra-bladder neck, and bladder and upper tracts, respectively). • Severity of hematuria bears no relation with the etiology, therefore, its presence must be considered serious unless proven otherwise. Prevalence:- The prevalence of asymptomatic microscopic hematuria varies from 0.19 percent to as high as 21 percent any varies widely with different age groups.

Differential diagnosis Hematuria is a manifestation of a myriad of varied clinical diagnoses ranging from exercise-induced to cancer-related. The differential diagnosis can be classified on the basis of site of origin as shown below: Origin Etiologies Glomerular Acute glomerulonephritis, lupus nephritis, benign familial hematuria, Berger’s disease, Goodpasture’s disease, exercise hematuria. Renal Polycystic kidney disease, Medullary sponge kidney, papillary necrosis, renal infarct, lymphoma, multiple

myeloma, amyloidosis, inflammation and infections, vascular malformation Urologic Neoplasia, calculi, benign Prostatic hyperplasia, urethral stricture, endometriosis, diverticulitis, infection, foreign body, GUTB Adjacent organ Abdominal aortic aneurysm, appendicitis, infiltrating malignancy Hematologic Congenital and acquired coagulopathy, therapeutic anticoagulation, sickle-cell disease and trait, sickle-cell thalassaemia, sickle-cell Hemoglobin-C disease Fictitious Vaginal bleed

Diagnosis and evaluation: Once a patient presents with history of hematuria, first step is detailed history and clinical examination. 1. History should include nature of hematuria whether intermittent / continuous, total / initial / terminal, or episodic. 2. Associated symptoms 3. passage of stones, tissues, clots; shape of clots (tubular, small). 4. Lower urinary tract symptoms (poor stream, frequency, urgency, nocturia, incontinence, dysuria, etc.

5. Pain, location (flank, groin, suprapubic, other), nature and other characteristics. 6. History of fever, facial puffiness, pedal edema. 7. Medications (e.g. oral contraceptives, analgesics, anticoagulants, others) 8. Co-morbidity like tuberculosis, diabetes mellitus, hypertension, 9. Coagulation disorders and family history of renal disease. 10. General physical examination and a focused examination pertaining to genitourinary system.

Next step is to perform a urine microscopy to confirm presence of RBCs and to rule out other causes of red brown colour in urine; Dipstick tests commonly available will be positive in presence of RBCs, hemoglobin or myoglobin, therefore not specific for hematuria. Therefore, a positive dipstick must be followed by a microscopy. Urine analysis: • Ideally the sample is collected in the lab. rather than brought from home (a urine

sample not freshly voided or collected from drainage bag is unreliable for analysis). • For male and female adults, clean catch mid-stream urine sample should be evaluated. In female the technique is similar but requires more attention as chances of contamination are much higher. • In children the method is similar for those who can be made to follow the instructions. Otherwise, after cleansing, a sterile plastic bag is placed over penis /

vulva. In case the specimen is not satisfactory, suprapubic aspiration may be done (easy in small children because intra-abdominal location of bladder). 5

One aliquot of the sample is subjected to routine examination (color, transparency, specific gravity, chemical analysis for pH, protein, etc.). Ten milliliters of the second aliquot of urine is centrifuged at 2000rpm for 5min, and supernatant is discarded. The sediment is re-suspended, a drop of which is examined under microscope for cells, crystals and casts. RBCs are easily visible in X400 power. Microhematuria is diagnosed in presence of more

than 3 RBCs per high power field in adults and 5 or more in children and in trauma cases. The morphology of RBC as well as presence of RBC clumps and casts should be seen. Phase contrast microscopy is the best way to detect dysmorphic RBCs. Dysmorphic RBCs are suggestive of a renal or glomerular source of hematuria. Hematuria must be interpreted as part of complete urine analysis, as presence of other anomalies e.g. proteins, casts, crystals and pus cells, etc. may suggest towards diagnosis.

After confirmation of erythrocytouria, the next logical step is to differentiate between: • Glomerular hematuria (presence of dysmorphic RBC, and RBC casts and clumps and usually associated with proteinuria). • Nonglomerular hematuria - an ultrasonography of abdomen is the next step to detect any anatomical abnormality in the urinary tract (e.g. stones, renal cysts, renal mass, bladder tumor, prostatomegaly, hydronephrosis, etc.).

• For those with history suggestive of infection and associated pyuria, a urine culture and sensitivity should be done to rule out infection, • Complete blood count, renal functions, blood sugar and coagulogram (if appropriate), must be done to rule out other causes and as a part of workup for surgery if an abnormality is detected on ultrasonography. In absence of features of glomerular hematuria, urinary tract infection and USG evidence

of renal mass, most patients would require cystourethroscopy. Certain investigations are suggested, before proceeding for the same- 1. Urine cytology for malignancy 2. Urine for AFB 3. Intravenous urography / CT urography. Management: After complete evaluation approximately overall, 1/3rd will have origin in kidney and the rest in middle and lower urinary tract. a. Further management needed in, b. 25% with urinary tract infection c. 20% will be diagnosed as malignancy (bladder cancer, kidney cancer),

f. 20% are diagnosed as benign essential hematuria (of obscure origin) and these require careful follow up. Treatment is guided by the underlying cause of hematuria. As general practitioners are the frequently the first contact clinicians, they should perform the initial workup (urine analysis, urine culture, ultrasonography) and based on the presentation and these investigation. Uncomplicated UTIs may be managed at the community level. Others should be referred to appropriate specialist (nephrologists,

urologist). Those with glomerular cause of hematuria (fever , facial puffiness, pedal edema, hypertension and presence of dysmorphic RBCs on microscopy) require a nephrology referral for further diagnosis and management. Those patients diagnosed with a malignancy/renal stone as the cause, need appropriate urology referral to a higher center for further evaluation and management. Resources required 1. Facility for routine and microscopy of the urine. 2. Ultrasonography. 3. Microbiological services.

4. Radiological services (preferably with facility of computed tomography). Suggested reading: • Adler SG, Fairley K: the patient with hematuria, proteinuria or both, and abnormal findings on urine microscopy. In: Schrier RW (ed) Manual of Nephrology, fifth edition, Philadelphia: Lippincott Williams and Wilkins, 2000, pp: 114-131. • Dinlenc C, Siroky MB: Hematuria and other urine abnormalities. In: Siroky MB, Edelstein RA, Krane RJ (eds), Manual of Urology: diagnosis and therapy, second

edition, Philadelphia: Lippincott, Williams and Wilkins, 1999, pp: 95-105. • In: Walsh PC, Retik AB, Vaughan ED, Wein AJ (eds), Campbell’s Urology, 8th ed, vol 1, Philadelphia: Saunders, 2002, pp: • Grossfeld GD, Wolf JS, Litwin MS, Hricak H, Shuler CL, Agerter DC, Carroll P. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy recommendations. Part I: definition, detection, prevalence, and etiology. Urology 2001;57(4)

• Messing EM, Young TB, Hunt VB, Roecker EB, Vaillancourt AM, Hisgen WJ, et al. Home screening for hematuria: results of a multiclinic study. J Urol 1992;148(2 pt 1):289-92. 7

Suggested algorithm of evaluation of surgical hematuria: USG • Normal No obvious • Simple cyst cause with Stone hydronephrosis Renal mass persistent • IVU/ CTU • Urine AFB • Urine cytology • cystoscopy Bladder tumor IVU/CTU Triphasic CECT Yes/no • RGU Lateralizing • Ureterorenoscopy hematuria Operate • Wash cytology Pathology detected in upper urinary tract Yes/no Angiography for vascular malformation in the urinary tract IVU-intravenous pyelography CTU- CT urography RGU- retrograde urography Yes/no

URINARY AND MALE GENITAL TRACT INFECTIONS Introduction Infections of the urinary tract pose a serious health problem, also because of their frequent occurrence. Clinical and experimental evidence support that the ascent of micro-organisms within the urethra is the most commom pathway leading to urinary tract infections, especially for organisms of enteric origin (I.e Escherichia coli and other Enterobacteriaeae). This is a logical

explanation for the greater frequency of UTIs in women than in men and the increased risk of infection following bladder catherisation or instrumentation. Classification of Urinary and Male Genital Tract Infections For practical clinical reasons, urinary tract infections (UTIs) and male genital tract infections are classified according to entities with predominating clinical symptoms: (I) uncomplicated lower UTI (cystitis); (2) uncomplicated pyelonephritis; (3) complicated UTI with or without

pyelonephritis; (4) Urosepsis; (5) urethritis; and (6) prostatitis, epididymitis, orchitis. Definitions the definitions of bacteriuria and pyuria are as follows: Significant bacteriuria in adults: • > 103 uropathogens/ml of midstream urine in acute uncomplicated cysitis in female; • > 104 uropathogens/ml of midstream urine in acute uncomplicated pyelonephritis in female; • > 104 uropathogens/ml of midstream urine of women or 104 uropathogens/ml of

midstream urine in men (or in catheter, urine specimen in women) with complicated UTI. In a suprapubic bladder puncture specimen any count of bacteria is relevant. Asymptomatic bacteriuria (ABU) ABU is defined as two positive urine cultures taken more that 24h apart with 105 uropathogens/ml of the same bacterial strain. Pyuria The requirement for pyuria is 10 white blood cells per high power field in the resuspended sediment of a centrifuged aliquot of urine or per mm3 in unspun urine. For the routine, a

dipstick method can also be used, including leukocyte esterase test, or nitrite reaction. 9

Table 1. Classification of prostatitis according to NIDDK/NIH I Acute bacterial prostatitis (ABP) II Chronic bacterial prostatitis (CBP) III Chronic pelvic pain syndrome (CPPS) A Inflammatory CPPS: WBC in EPS/voided bladder urine-3 (VB3) or semen B Noninflammatory CPPS: no WBC/EPS/VB3/semen IV Asymptomatic inflammatory prostatitis Diagnosis Disease history, physical examination and urine analysis by dipstick including white and red

blood cells as well as nitrate reaction is recommended for routine diagnosis. In case of suspicion of pyelonephritis, evaluation of the upper urinary tract may be necessary to rule out upper urinary tract obstruction or stone disease. Table 2. Recommendations for antimicrabial therapy in urology Diagnosis Most Frequent Initial, empiric antimicrobial Therapy duration pathogens therapy Cystitis, acute, E.coli Trimethoprim/ sulfamethoxazole 3 days Uncomplicated Klebsiella Fluroquinolonea 3 days

Proteus Alternatives: Staphylococcus Fosfomycin 1 day Nitrofurantoin 7 days Pyelonephritis, acute, E.coli Fluroquinolone 7-10 days uncomplicated Proteus Cephalosporin Gr. 2b/3a Klebsiella Alternatives Other Enterobacteria Aminopenicillin / BLI Staphylococcus Aminoglycoside UTI with complicating E.coli Fluoroquinolone 3-5 days after defervescence or control/ examination of complicating factor 10

Factors Enterococcus Aminopenicillin / BLI Nosocomial UTI Staphylococcus Celphalosporin Gr. 2 Pyelonephritis, acute, Klebsiella Celphosporin Gr. 3 a Complicated Proteus Aminoglycosides Enterobacter In case of failure of initial therapy within 1-3 days or in clinically severe cases: Other Enterobacteria Anti-Pseudomonas active: Pseudomonas Fluroquinolone, if not used initially Acylaminopenicillin/BLI (Candida) Cephalosporin Gr. 3B Carbapenem + Aminoglycoside In case of Candida Fluconazole Amphotericin B

Prostatitis, acute, E.coli Fluroquinolonea Acute : 2 weeks chronic Epididymitis,acute Other Enterobacteria Alternative in acute bacterial prostatitis Pseudomonas Cephalosporin Gr. 2 Chronic : 4-6 weeks or longer Enterococcus Cephalosporin Gr. 3a/b Staphylococcus In case of Chlamydia or Ureaplasma: Chlamydia Doxycyline Ureaplasma Macrolide Urosepsis E.coli Cephalosporin Gr. 3a/b 3-5 days after defervescence or control/ elimination of complicating factor Other Enterobacteria Fluorquinolonea

After urological Anti-Pseudomonas active interventions - Multiresistant Acylaminopenicillin/BLI 11

pathogens: Proteus Carbapenem Serratia Aminoglycosides Enterobacter Pseudomonas a Fluroquinolone with mainly renal excretion; BLI= B- lactamase inhibitor. B 1st,2nd and 3rd generation respectively (3a - without; 3b - with anti-Pseudomonas activity) Treatment Treatment of UTI is dependent on a variety of factors. An overview of most frequent pathogens, antimicrobial agents and duration of treatment in various conditions is given in table 2. Patients

with recurrent UTI may be recommended prophylactic treatment. The following regimens have a documented effect in preventing recurrent UTI in women (table 3). Table 3. Antimicrobial regimens for prevention of acute uncomplicated urinary infection in women Agent Dose Standard regimens (taken at bedtime) Trimethoprim / sulfamethoxazole 40/200mg/day or 3 times weekly Trimethoprim 100mg/days Nitrofurantoin 50mg/day Others Cephalexin 125 or 250 mg/day Norfloxacin 200 mg/day Ciprofloxacin 125 mg/day

Special situations: • UTI in pregnancy. Asymptomatic bacteriuria is treated with a 7 day course based on sensitivity testing. For recurrent symptomatic infections, either cephalexin 125-250 mg/day or nitrofurantoin 50 mg/day may be used. • UTI in postmenopausal women. In women with recurrent infection intravaginal estriol is recommended. If this does not work, in addition antibiotic prophylaxis is indicated. 12

• UTI in children. Treatment perioud should be extended to 7-10 days. Tetracyclines and fluroquinolones should not be used due to effects on teeth and cartilage. • Acute uncomplicated UTI in young men. The treatment should last at least 7 days. • UTI in diabetes mellitus and renal insufficiency. After treatment, a prophylactic regimen may be recommended afterwards. • Complicated UTI due to urological disorders. The underlying disorded must be managed

if permanent cure is to be expected. In order to avoid inducing resistant strains, treatment should be guided by urine culture whenever possible. • Sepsis syndrome in Urology (urosepsis). Patient with UTI may develop sepsis. Early signs of systemic inflammatory response (fever or hypothermia, tachycardia, tachypnea, hypotension,oliguria, leukopenia) should be recognized as the first signs of possible multiorgan failure. In conjunction with appropriate antibiotic therapy,

life supporting therapy in collaboration with an intensive care specialist may be necessary. Any obstruction in the urinary tract needs to be drained. Follow-up of patients with UTI for follow-up after uncomplicated UTI and pyelonephritis in women, a urinanalysis by dipstick is enough for routine use. In women who will have recurrence within 2 weeks, repeated urinary culture with antimicrobial testing and evaluation of the urinary tract is recommended.

In the elderly, newly developed recurrent UTI may warrant a full evaluation of the urinary tract. In men with UTI, a urologic evaluation should be done when the patient is in adolescence, in cases with recurrent infection and in all causes with pyelonephritis. Also patients with prostatitis, epididymitis and orchitis should follow these recommendations. In children, investigations are indicated after two episodes of UTI in girls and one episode in

boys. Recommended investigations are ultrasonography of the urinary tract supplemented by voiding cystourethrography. Urethritis Symptomatic urethritis is characterized by dysuria and purulent discharge Diagnosis The Gram stain of secretion or urethral smear showing more than 5 leukocytes per high power field (HPF) (1,000) and eventually gonococci located intracellularly as Gram-negative diplococci indicate a pyogenic urethritis. A positive leukocyte 13

esterase test or more than 10 leukocytes per high-power field (400) in the first voiding urine specimen are diagnostic. Therapy The following guidelines for therapy comply with the recommendations of the Centre for Disease Control and Prevention (1998). For the treatment of gonorrhea the following antimicrobials can be recommended: Cefixime 400 mg orally Ciprofloxacin 500 mg orally As a single dose as a single dose Cefriaxone 250 mg i.m. Ofloxacin 400 mg orally as As a single dose single dose

(i.m. with local anaesthetic) As gonorrhea is frequently accompanied by chalamydial infection, an antichlamydial active therapy should be added. The following treatment has been successfully applied in C. trachomatis infections : First choice Second choice Azithromycin Erythromycin 1 g (=4 caps.@250 mg) orally 500 mg orally 4 times daily for 7 days as single dose Doxycycline Ofloxacin 10 mg 2 times daily orally for 7 days 200 mg orally for 7 days

if therapy fails, one should consider infections by T. vaginalis and / or Mycoplasma, which can be treated with a combination of metronidazole (2 g orally as single dose) and erythromycin (4 times daily 500 orally for 7 days). Prostatitis, Epididymitis and Orchitis Prostatitis Treatment g. Acute bacterial prostatitis can be a serious infection and parenteral administration of high doses of bactericidal antibiotic such as aminoglycosides and a penicillin derivative

or a 3rd generation cephalosporin are required until defervescence and normalization of infection parameters. In less severe cases a fluoroquinolone may be given orally for at least 10 days. h. In chronic bacterial prostatitis and chronic inflammatory pelvic pain syndrome, a fluoroquinolone or trimethorpim should be given orally for 2 weeks after the initial 14

diagnosis. Then the patient should be reassessed and antibiotics only continued if pretreatment cultures were positive or if the patient reports positive effect of the treatment. A total treatment period of 4-6 weeks is recommended. Epididymitis, Orchitis The majority of cases of epididymitis are due to common urinary pathogens. Bladder outlet obstruction and urogenital malformations are risk factors for this type of infection. Treatment

Prior to antimicrobial therapy a urethral swab and midstream urine should be obtained for microbiological investigation. Fluoroquinolones, preferably those which react well against C. trachomatis (e.g. ofloxacin, levofloxacin) should be first choice drugs because of their broad antibacterial spectra and their Table 4. Recommendations for perioperative antibacterial prophylaxis in urology Procedure Most common Antibiotic(s) of choice Alternative Remarks pathogens (s) antibiotic(s)

Open Enterobacteria Aminopenicillin + BLI In high-risk patients: In all patients operations Enterococci Cephalosporin 20+ Cephalosporin3 urinary tract Anaerobes Metronidazole Acylaminopenicillin + including bowel Wound infection: BLI segments Staphylococci Urinary tract Enterbacteria Fluoroquinolone in high-risk patients: in patients with without bowel Enterococci Cephalosporin 20 Cephalosporin3 increased risk of segments Wound infection: Aminopenicilin +BLI Acylaminopenicillin + infection staphylococci BLI

Implant / Staphylococci in all patients prosthesis: Staphylococci Cephalosporin 10/20 in secondary operations penis, sphincter Cephalosporin 10/20 & in patients with Reconstructive increased risk of genital infection operation Other in patients with interventions Staphylococci Cephalosporin 10/20 increased risk of outside of the infection 15

urinary tract Endoscopic – In patients with instrumental Fluoroquinolone Cotrimozazole increased risk of operations Enterobacteria Aminopenicillin + BLI Aminoglycoside infection Urethra, Staphylococci Cephalosporin 20 prostate, Enterococci Fosfomycin bladder, ureter, Trometamol kidney, incl. percutaneous litholapaxy and ESWL Diagnostic Aminoglycoside In all patients intervention Enterobacteria Fluoroquinolonea Cotrimozazole Transrectal Enterococci Aminopenicllin + BLI

biopsy of the Anaerobes Cephalosorin 20+ prostate (with Streptococci Metronidazole thick needle) Enterobacteria Fluoroquinolonea Perineal biopsy Enterococci Aminopenicillin + BLI Cotrimoxazole In patients of the prostate, Staphylococci Cephalosporin 20 with increased risk of urethrocystosc infection opy, ureterorenosco py, percutaneous pyeloscopy, laparoscopic procedures BLI = B- Lactamase inhibitor, ESWL- extracorporeal shock-wave lithotripsy. 10,20,30 = 1st, 2nd, 3rd generation respectively.

11. Fluroquinolone with sufficient renal excretion Favorable penetration into the tissues of the urogenital tract. In case C. trachomatis has been detected as etiologic agent, treatment could also be continued with doxycycline 200 mg/day for a total treatment period of at least 2 weeks. Macrolides may be alternative agents. In case of C .trachomatis infection, the sexual partner should be treated as well. Antibiotics and α Blockers in combination 16

Urodynamic studies have shown increase urethral closing pressure in patients with chronic prostatitis. A combination treatment of α blockers and antibiotics is reported to have a higher cure rate than antibiotics alone in inflammatory CPPS. This is a treatment option favored by many urologists. In general, surgery should be avoided in the treatment of prostatitis patients except for drainage of prostatic abscesses. Perioperative Antibacterial Prophylaxis in Urological Surgery

The main aim of antimicrobial prophylaxis in urology is to prevent symptomatic / febrile genitourinary infections, such as acute pyelonephritis, prostatitis, edpididymitis and urosepsis as well as serious wound infections. Antibiotic prophylaxis is recommended only for a maximum of 24 hours after surgery in most situations. More rampant use leads to antibiotic resistance and places an additional economic burden. Prophylaxis does not substitute for poor surgical asepsis. 17

Suggested reading: • Warren JW, Abrutyn E, Hebel JR, Johnson JR, Schaeffer AJ, Stamm WE. Guidelines. for antimicrobial treatment of uncomplicated acutebacterial cystitis and acute pyelonephritis in women. Infectious Diseases Society of America (IDSA). Clin Infect Dis 1999; 29: 745–58. • Huang ES, Stafford RS. National patterns in the treatment of urinary tract infections in women by ambulatory care physicians. Archives of internal medicine 2002; 162: 41–7.

• O’Connor PJ, Solberg LI, Christianson J, Amundson G, Mosser G. Mechanism of action and impact of a cystitis clinical practice guideline on outcomes and costs of care in an HMO. The Joint Commission journal on quality improvement 1996; 22: 673–82. • Stamm WE. Evaluating guidelines. Clin Infect Dis 2007; 44: 775–6. • Mavromanolakis E, Maraki S, Samonis G, Tselentis Y. Effect of norfloxacin, trimethoprim- sulfamethoxazole and nitroffurantoin on fecal flora of women with recurrent urinary

tract infections. J Chemother 1997; 9: 203–7. • Sullivan A, Edlund C, Nord C. Effect of antimicrobial agents on the ecological balance of human microflora. Lancet Infect Dis 2001; 1: 101–14 • Grabe M, Bishop MC, Bjerklund-Johansen TE, et al. Guidelines on urological infections. In EAU Guidelines edition presented at the 25th EAU Annual Congress, Barcelona 2010. ISBN 978-90-79754-70-0. • Arredondo-Garcia JL, Figueroa-Damian R, Rosas A, Jauregui A, Corral M, Costa A, et al.

Comparison of short-term treatment regimen of ciprofloxacin versus long-term treatment regimens of trimethoprim/sulfamethoxazole or norfloxacin for uncomplicated lower urinary tract infections: a randomized, multicentre, open-label, prospective study. J Antimicrob Chemother 2004; 54: 840–3. 18

STANDARD TREATEMTN GUIDELINES UROLITHIASIS AND URETERIC COLIC When to suspect /recognize Introduction:- American urological association (AUA) has been the frontrunner in formulating guidelines for Urolithiasis since 1991. Since then, editions of guidelines have been published with the 2005 guidelines on staghorn calculus being the latest (1) The European association of urology(EAU) has published similar guidelines since 2000. The latest updates have been published in 2010(2).

The significant differences in the socioeconomic and disease pattern (mode of presentation, stone bulk, health care delivery facilities) for urolithiasis in India make it imperative to formulate our own guidelines. We have reviewed the literature for drafting the guidelines. The recommendations drawn are largely based on the AUA/EAU guidelines with modifications recommended where appropriate. Indian references have been cited, particularly so, if they are prospective randomized studies

and/or metanalysis. Recommendations have been given when adequate literature support is available. The referral criteria are noted when appropriate. Case definition The index patients are defined as follows:- Ureteral stones 19

A non pregnant adult patient with unilateral ureteral calculi (no renal stones) and normal functioning contralateral kidney, the body habitus, anatomy and medical condition should not preclude the application of any of the available treatment options (2) Staghorn calculi A staghorn calculi is defined as a stone with central body and at least one calyceal branch. A partial staghorn calculus fills part of the collecting system. A complete staghorn fills all the calyces and the renal pelvis.

Index patient (staghorn calculi):- Adult with a staghorn stone (non Cystine, non uric acid) who has two functioning kidneys (functioning both kidneys) or a solitary kidney with normal function. The patients overall medical condition, body habitus and anatomy should permit any of the available intervention (1). Non staghorn calculi Any pelvic and /or calyceal calculi which do not fit in the definition of staghorn calculi (2). Incidence in our country

Although a few studies have been reported for a small group of subjects in screening camps. The true incidence of urolithiasis in India is still not known. It is commonly seen in western states, hypothetically, attributable to high salinity of water .The presentation of a patient with urolithiasis differs in India. Large stone bulk on presentation is commonly seen in India. 20

What should be the optimal? Renal stones Investigations:- Imaging is absolutely imperative if, the patient has a solitary kidney or a history of fever. If the diagnosis of stone is in doubt then imaging is mandatory. (2) Execratory urography has been the gold standard in the work up for urolithiasis. Non contrast computerized tomography(NCCT) scan is quick and safe, contrast free alternative to excretory urography. Randomized studies

have shown that non contrast helical CT has similar or superior results to excretory urography in acute flank pain(3) Contrast media should not be given or should be avoided when there is a elevated creatinine level, pregnancy or lactation(4)(5) Additional information can be gained by contrast enhanced CT scan(CTU), however at the moment there is no level 1 evidence to suggest that CTU is superior to IVU in the work up of urolithisis. .(6). X-ray KUB and ultrasound is

used by few clinicians as a measure of preoperative investigations, however this cannot be considered as a standard. These investigations help to plan access and predict the possible success rates. Recommendation:-Excretory urography is the gold standard in work up for urolithiasis and is mandatory in solitary kidney, history of fever and when the diagnosis is in doubt. NCCT is the investigation of choice in acute flank pain due to stone. Analysis of stone composition

Stone analysis is desirable in recurrent stone formers. The preferred analytical procedures are:- (2) 1) X ray crystallography. 2) Infrared spectroscopy. 21

The other methods of stone analysis are:- 1) Radiographic characteristics of the stone. 2) Microscopic examination of the urinary sediments to detect crystals. 3) Urine Ph (alkaline in infection stones and acidic in uric acid stones. 4) Urine culture. Special investigations which are ordered on case to case merit are renal scintigraphy, antegrade, retrograde contrast study. Indications for intervention The indication for stone removal depends on the size, site and shape of the calculus. The

likelihood of spontaneous passage, presence of obstruction should be assessed. The indications for intervention are:- 1) When the stone diameter is more than 7 mm (because of low rate of spontaneous passage). 2) When adequate pain relief is not achieved. 3) When there is stone obstruction associated with infection. 4) Pyonephrosis. 5) Obstruction in single kidney. 6) Bilateral obstruction. Recommendation:-For1, 2 stone removal with or without prior decompression(depending on

the clinical situation) is recommended ,in situation ,3,4,5,6 emergency deobstruction of the collecting system is recommended. The choice of decompression can be with ureteric stents, percutaneous nephrostomy depending on surgeon preference, expertise and the level of obstruction (7) (8) (9) (10) Treatment (including standard operating procedure) 22

I) Extracorporeal shock wave lithotripsy(ESWL) The success of lithotripsy depends on the body habitus, location of the stone, efficacy of the lithotripter, stone bulk. The contraindications for ESWL for renal stones include pregnancy, bleeding disorders, uncontrolled urinary tract infections, morbid obesity, aortic aneurysms close to F1(2) i) Role of stents Routine use of stents is not recommended for ESWL for renal stones. (11) ii) Location of stones

The stone clearance is lower for stones in the lower calyx as compared to anywhere else in the kidney. Various studies have attempted to show the correlation of geometry of the lower calyx to predict the clearance of stone in this location. However the calyceal stone burden is the most important factor in predicting the clearance. Although there is no critical size, 20 mm should be considered the upper limit for stones in the lower calyx to be recommended for ESWL. The EAU guidelines recommend ESWL as the

treatment of choice for renal stones less than 20mm2(300mm2) (2). A multicentre trial has compared ESWL and Flexible ureteroscopy for lower calyceal stones. It failed to show any difference in the clearance rates (12) iii) Total stone burden It is recommended that stones smaller than 20mm2 to be treated with ESWL , while for larger stones more than 20mm2(300mm2), PCNL should be considered the treatment of choice.(2) iv) Composition and hardness of stone

The composition of the stone is an important factor for predicting the success rates of renal calculi. Specific stone compositions have different clearance rates because of the varying 23

fragility of stones. Cystine stones are harder to fragment, hence cystine stones larger than 15mm should not be treated with ESWL.PCNL would be a good option in these patients(2) The measurement of stone density with NCCT helps in predicting success rates of ESWL. Stones with greater than 1000 Hounsfield units (HU) show poor results with ESWL.(13)(14) v) ESWL-procedural standard operating protocol Simultaneous fluoroscopy and ultrasound monitoring is desirable.(2) The acoustic coupling

between shock head and the skin should be optimal. Ultrasound gel is the best available gel. The ultrasound gel should be applied straight from the container rather than by hand.(15)(16). Level 4 evidence is available to suggest that proper analgesia results in limited movement and respiratory excursions. Better fragmentation can be achieved with starting the fragmentation at lower energy setting and then ramping up the power(17) . the manufacturers

recommendation regarding the number of shocks and frequency should be followed.The optimal shock wave frequency is 1.0 Hz(18) It is important to limit the number of shocks and the power, due to concerns regarding damage to the kidney. In case of infected stones, antibiotics should be given according to urine culture sensitivity, the same should be continued after surgery for 4 days (2) Clinical experience suggests that stones in

the ureter rather than the kidney should be treated with shorter intervals between sessions. vi) Complications The complications which are likely to be encountered and which should be counseled to the patient prior to surgery are:- 5. Pain 6. Hydronephrosis 7. Fever 8. Urosepsis 24

Recommendations:- It is recommended that stones smaller than 20mm2 to be treated with ESWL. Routine use of stents is not recommended for ESWL for renal stones.The contraindications for ESWL for renal stones include pregnancy, bleeding disorders, uncontrolled urinary tract infections, morbid obesity, aortic aneurysms close to F1. Antibiotics should be given according to urine culture sensitivity, the same should be continued after surgery for 4 days. The physicians should refer to

the manufacturer recommendation regarding the decision of number, frequency and power of shocks. II) Percutaneous Nephrolithotomy Technically most of the renal stones can be managed with a percutaneous nephrolithotomy. However the usual indications for PCNL are larger than 20mm2, staghorn, partial staghorn calculi and stones in patients with chronic kidney disease. Standard operating protocol General anaesthesia is preferable, although studies have demonstrated the utility of regional

anaesthesia (19) PCNL has been performed traditionally in a prone position however it can technically also be performed in supine position, the advantage of this (supine position) approach is that the retrograde access is easier in supine position, anesthetist has a better control over the airway and simultaneous ureteric and renal stones can be managed without changing the position.(20)(21) The access to the collecting system can be gained either ultrasound

guided or fluoroscopy guided depending on the availability of instruments and expertise. The advantage of ultrasound guided access is the potential to avoid major visceral injuries.(22) The access site should be the posterior calyx. The tract should be the shortest possible tract from 25

the skin to the desired calyx traversing the papilla. Depending on the stone configuration a calyx should be selected (Supracostal, infracostal or subcostal) so that maximum stone bulk can be cleared minimum number of tracts. (23) Renal tract dilatation either balloon, amplatz or metallic dilators are a matter of surgeon preference and availability (2). In lower polar stones ESWL, PCNL and flexible ureterorenoscopy are competing procedures with different success

rates and complications (12)(24).In complicated cases or when secondary intervention is required a nephrostomy tube which serves the dual purpose of tamponade and a conduit for second look is placed. In uncomplicated cases, tubeless percutaneous nephrolithotomy with or without application of tissue sealants is a safe alternative (25) (26) i) Complications The patients should be counseled regarding the complications which are likely to be

encountered such as life threatening bleeding with a possible need for angioembolisation or even nephrectomy. It may be associated with infective complications leading to urosepsis. The patients should be counseled regarding the possibility of residual calculi and the consequences thereof. The procedure becomes challenging in complex stones, although the complications are not specific to them. Such cases should be identified and managed by experienced surgeons. Recommendations

Technically, most of the renal stones can be managed with a percutaneous nephrolithotomy. However the uasual indications for PCNL are larger than 20mm2, staghorn, partial staghorn calculi and stones in patients with chronic kidney disease. The access to the collecting system 26

can be gained either ultrasound guided or fluoroscopy guided depending on the availability of instruments and expertise. Renal tract dilatation either balloon, amplatz or metallic dilators are a matter of surgeon preference and availability. In complicated cases or when secondary intervention is required a nephrostomy tube which serves the dual purpose of tamponade and a conduit for second look is placed. In uncomplicated cases, tubeless percutaneous

nephrolithotomy with or without application of tissue sealants is a safe alternative. III) Flexible ureterorenoscopy Flexible ureteroscopy offers a good treatment option for calculi less than 20mm in size. Due to improved technology and development in accessories and optics the role of flexible ureteroscopy is likely to be expanded in the future. The procedure wherein flexible ureteroscopy is used in the kidney is called as retrograde intrarenal surgery (RIRS). Flexible URS is not

recommended as a first line of treatment for renal calculi. It has been demonstrated as a effective way of treating stones which are refractory to ESWL. It has also been seen useful when simultaneously used with PCNL, in this way it reduces the number of tracts during the procedure It is recommended that sterile urine should be documented prior to intervention. (27)(28) Standard technique for flexible ureteroscopy • Fluoroscopy equipment is advisable in all cases

• Preoperative imaging helps to determine the size and location of the stone. • The use of safety wire is recommended (0.035 floppy tip) . • The ureteroscope can be introduced over a guide wire (back loaded) or they may be advanced through a ureteral access sheath. • Stone extraction blindly without endoscopic vision should not be done 27

• Small stones can be extracted with baskets of forceps. • Intracorporeal lithotripsy can be performed with holmium laser. The other alternatives are ballistic, ultrasonic or electrohydraulic lithotripsy. (2). The holmium Yag laser is the preferred modality for flexible ureteroscopy (29) • The stenting after an uncomplicated flexible ureteroscopy is optional. The indications for stenting after completion of URS are ureteral stricture, ureteral injury, solitary

kidney, renal insufficiency, large stone burden residual stones. Accessories and instrumentation A 365 micron laser fiber is suited for ureteral stones. The 200 micron fiber preserves tip deflection. Holmium laser is the preferred energy source for flexible ureteroscopy. Nitinol baskets preserve tip deflection, in addition the tipless design reduces the mucosal injury, hence they are more suited for flexible ureteroscopy.(30)

Access sheaths have been used by various workers. The size of the available access sheaths ranges from 9-16Fr, they have a hydrophilic coating. Generally they are introduced over a wire. The advantages of access sheath are reducing the operating time particularly in large stone burden. Another theoretical advantage is, it helps in maintaining a low pressure in the pelvicalyceal system.(31) Recommendations:- Flexible ureteroscopy offers a good treatment option for calculi less than 20mm in size.

Flexible URS is not recommended as a first line of treatment for renal calculi. It has been demonstrated as a effective way of treating stones which are refractory to ESWL. Stenting after a uncomplicated ureteroscopy is optional.It is mandatory that sterile urine should be documented prior to intervention. 28

Staghorn calculi:- A retrospective study with 200 patients has shown that renal deterioration occurs in 28% of patients with staghorn calculi treated conservatively. This emphasizes the fact that staghorn stones should be aggressively managed surgically(32) PCNL should be the recommended modality as clearance rates are greater than 3 times that of ESWL.(33) The following are the treatment options in staghorn calculi:- 1) Percutaneous nephrolithotomy should be the first treatment utilized for most patients.

(level2) 2) ESWL should not be used as the preferred treatment modality for staghorn stones. 3) Open surgery should be recommended only if the stones are not expected to be removed in a reasonable number of stages. 4) Nephrectomy should be considered in non functioning kidneys. (1) Recommendations:- PCNL is the first choice for staghorn calculi. Open surgery is desirable in the situation when expertise is not available wherein the stone can be cleared in reasonable number of stages and

tracts. Nephrectomy should be considered for non functioning kidneys. Management of ureteric calculi and ureteric colic The most common cause for ureteric colic is ureteric calculus. The priority in these patients should be relief of pain. The subsequent management of patients with ureteric colic would be determined by the level of obstruction and the stone size. i) Agents recommended for relieving pain 29

It is recommended that pain should be relieved with diclofenac whenever possible. A alternative drug might be used if pain persists. Further more it has been shown that the resistive index significantly reduces if diclofenac is administered.. Level 4 evidence suggests that hydromorphine might be helpful, however there is a significant risk of vomiting (34) (35) (36) Diclofenac can affect renal function in patients with already reduced function. There is

however no effect if the kidneys are functioning normally. (37) ii) Agents for preventing episodes of renal colic Diclofenac sodium is recommended for the purpose. Studies indicate that the incidence of recurrent renal colic decreases with administration of diclofenac sodium. (38) When the pain is unremitting the treating urologist should think of alternative measures such as drainage by stenting or percutaneous nephrostomy or even removal of the stone. iii) Medical expulsive therapy (MET)

The beneficial effect of these drugs is attributed to ureteral smooth muscle relaxation mediated through inhibition of calcium channel pumps or alpha receptor blockade. The prerequisite for this approach is that the patient should be comfortable this approach. And there should not be any immediate indication for stone removal.. Studies indicate that alpha blockers facilitate ureteral passage ,while nifedipine provides marginal benefit. Alpha blockers are recommended for MET(2) Ureteric calculi

Guidelines for Index patients • Patients with bacteriuria should be treated with appropriate antibiotics • Blind basketing without visualization endoscopically should not be performed. 30

• Patients with newly diagnosed stones less than 6 mm and well controlled symptoms, should be advised MET • Patients who opt for Medical expulsion therapy should have well controlled pain, no evidence of sepsis, and adequate functional reserve, such patients should be periodically observed for stone position and assessment of hydronephrosis. • Stone removal is recommended in persistent obstruction, failure of stone progression. or increasing or unremitting colic.

• Patient should be informed about the available treatment options. • Both ESWL/ flexible URS are the preferred treatment options for upper ureteric calculi less than 1cm in size. For larger stones Antegrade ESWL/PCNL/laproscopic removal are recommended depending on expertise and instruments available • URS is the preferred modality for distal and midureteric calculus. Recommendations:- Alpha blockers are recommended for MET. It is recommended that pain should be relieved

with diclofenac whenever possible. Patients with newly diagnosed stones less than 6 mm and well controlled symptoms, should be advised MET .Patients who opt for Medical expulsion therapy should have well controlled pain, no evidence of sepsis, and adequate functional reserve, such patients should be periodically observed for stone position and assessment of hydronephrosis. Both ESWL/ flexible URS are the preferred treatment options

for upper ureteric calculi less than 1cm in size. For larger stones antegrade ESWL/PCNL/laproscopic removal are recommended depending on clinical situation expertise and instruments available. URS is the preferred modality for distal and midureteric calculus 31

Treatment of calculi in special situations Calyceal diverticular stones Once symptomatic all these stones require treatment. ESWL, PCNL, laparoscopy and observation remain the treatment options which can be offered to the patient. As the drainage of the calyx in concern is at times questionable ESWL has rather poor results. Sometimes the combination this treatment modality is recommended (39). Anomalous kidneys These group of patients include those patients with stones in ectopic, horseshoe or kidneys with

fusion anomalies. The approach to managing these stones should be individualized. The factors to be taken into consideration are the stone bulk, the location of the stone, the vascular and the anatomy of the pelvicalyceal system. Ultrasound helps in gaining access in ectopic kidney apart from being a diagnostic tool. CT is pivotal in deciding the management and choosing the method of treatment in anomalous kidney..

CT will also give the attenuation values and be a deciding factor in deciding ESWL or flexible ureteroscopy. Flexible ureteroscopy will be useful tool in stones small burden stones in size with the availability of smaller flexible ureteroscopes, and access sheaths. However the surgeon should consider complete “on table” clearance in these patients as the drainage is likely to be impaired. USG guided approach for ectopic kidneys should be done by surgeons well versed

with it. Laparoscopic assisted PCNL has shown good clearance rates with minimal morbidity and less likely hood of ancillary procedures. Although adequate fragmentation can be achieved with ESWL, the drainage of fragments might be impaired due to the anatomical abnormalities. The choice of ESWL as a treatment option should be done prudently.(40) Pediatric urolithisis 32

Although the treatment modalities used are same in children as in adults. Specific points should be noted in children. The indications for ESWL are similar to those in adults. Stones in Children with a diameter of less than 20mm are ideal cases. The success rates decreases as stone burden increases. Larger stones should be treated with PCNL (2). They are as follows:- 1) Children have a tendency to pass larger fragments. 2) Ultrasound should be the modality for localization of stone when ESWL is the

modality chosen. 3) Smaller instruments should be used for endourologic manipulations(2) Role of open surgery in the current era In a developing country such as India, the cost factor plays a major role, which is mostly borne by the patient or a health care delivery mechanism, A study from India by Sinha et al , which although is a retrospective data and has a small sample size suggests that PCNL is less costly and as effective as open surgery. However randomized level 1 evidence by Al Kohlany et al

comparing open surgery with PCNL suggests that PCNL offers equivalent clearance as open pyelolithotomy, with less morbidity, short hospital stay.and less renal damage. The trade off in a Indian clinical scenario will be to offer the best cost effective alternative available.(41)(42)(43) Nephrolithiassis –metabolic work up See recommendation in section on- Nephrolithiassis –metabolic work up . Who does what/ and timeline Doctor 33

The treating doctor ideally should be an Urologist or a surgeon trained in Urology. He is responsible for the initial workup of the patient and subsequent management of the patient. He is responsible for counseling the patient regarding the success rates, complications and possible outcome of any given procedure. All possible treatment options in a given clinical situation should be discussed with the patient. The patient on discharge should be given instructions for

follow up and measures (dietary and pharmacologic) to prevent stone recurrence. Nursing and technical staff:-The nursing staff should be trained in the aspect of maintenance and use of endourologic equipment, considering the fragility and cost of these equipments. The responsibility of sterilization of these equipment lies with these personnel .The technical/nursing staff prepares the trolley and assists the surgeon during the procedure. Referral criteria:-

The criterion for referral remains, lack of appropriate infrastructure and expertise at primary level. The indications for referral to tertiary care centre in managing stones disease are:- !)Complex calculi ( multiple stones , staghorn calculi, stones with CKD, stones with obstructive uropathy) where in the opinion of the treating physician , the patient needs nephrolurological care and advanced surgical and medical care from a infrastructure standpoint

2) Special situations such as pediatric urolithiasis, stones in ectopic kidney. Annexure 1 Indications and selection of modality for treating calculi in a index patient It depends on the stone size location, stone composition and BMI of the patient The following are the guidelines to be followed 34

1) Stone less than 1cm in the kidney -ESWL 2) Stone more than 1cm and less than 2cm in the kidney , -Flexi URS/ESWL/PCNL 3) Any stone more than 2cm in the kidney-PCNL 4) All staghorn and partial staghorn-PCNL 5Non progressive more than 6mm stone in the mid and lower ureter-semirigid URS. 6) Stones less than 1cm in upper ureter-ESWL 7) stones larger than 1cm in upper ureter-PCNL/ESWL/Flexi URS Further reading • Preminger GM,Assimos DG,Lingeman JE et al Nephrolithaiis guideline panel chapter 1

AUA guideline on management of staghorn calculi : Diagnosis and treatment recommendation J Urol 2005;173:1991-2000. • EAU guidelines on Urolithiasis Turk, T Knoll, A Petrik, K Sarica, C Seitz, M Straub, O Traxer 2010 • Worster A, Preyra I , Weaver B, Haines T The accuracy of non contrast helical computed tomography versus intravenous pyelography in the diagnosis of suspected acute urolithiasis A metanalysis Ann emerg Med 2002 ;40(3):280-6

• Morcos SK, Thomsen HS, Webb JA. Contrast media safety committee of the European society of urogenital radiology prevention of generalized reactions to contrast media ; A consensus report and guidelines Eur Radiol 2001;11(9):1720-8 • Thomsen HS, Morcos SK, Contrast media and the kidney: European society of urogenital radiology (ESUR) guidelines Br J Radiol 2003; 76(908):513-8. • P Aga ,R Bansal Is intravenous urogram no longer an imaging of choice for percutaneous

7) Andersson L, Sylven M Small renal calyceal calculi as a cause of pain J Urol 1983; 130(4):752-3. 8) Coury TA, Sonda LP, Lingeman JE, Kahnoski RJ, Treatment of painful calyceal Stones urology 1988; 32(2); 119-23. 9) Hubner W, Porpaczy P Treatment of calyceal calculi Br J Urol 1990;6691) :9-11 10) Brandt B, Ostri P, Lange P, K Kristenssen J. Painful calyceal calculi. The treatment of small non obstructing calyceal calculi in patients with symptoms. Scand J urol Nephrol 1993;27910:75-6.

11) Suleiman MN, Buchholz NP, Clark PB. The role of ureteral stent placement in the Prevention of steinstrasse J Endourol 1999;13(3):151-5. 12) Perale MS, Lingeman JE, Leveille R, Kuo R, Preminger GM,Nadler RB,Macaluso J, Monga M, Kumar U, Dushinski J, Albala DM, Wolf JS,Assimos D,Fabrizio M, Munch LC, Nakada SY, Auge B,Hoeny J,Ogan K,Pattaras J, McDougall EM, Averch TD, Turk T, Pietrow P, Watkins S Prospective Randomized trial comparing shock wave lithotripsy and ureteroscopy for lower

pole calyceal calculi 1cm or less J urol 2005; 173(6);2005-9. 13) Shah K,Kurien A,Mishra S,GanpuleA,Muthu V,SabnisRB DesaiM predicting effectiveness of extracorporeal shockwave lithotripsy by stone attenuation value Endourol 2010;24(7);1169-73 14) El Nahas AR, El Assmy AM, Manour O, Sheir KZ. A prospective multivariate analysis of factors predicting stone disintegration by extracorporeal shock wave lithotripsy: The value of high resolution non contrast computed tomography Eur Urol 2007; 51(6):1688-93.

15) Pishchalnikov YA, Neucks JS, VonDeHarr RJ, Pishchalnikova IV, Williams JS 36

Jr, McAteer JA. Air pockets trapped during routine coupling in dry head lithotripsy can significantly decrease the delivery of shock wave energy. J Urol 2006; 176(6 pt 1):2706-10. 16) Neucks JS, Pishchalnikov YA,Zancanaro AJ,VonDer haar JN,Williams JC Jr, McAteer JA. Improved acoustic coupling for shock wave lithotripsy Urol Res 2008; 36(1):61-6. 17) Semins MJ,Trock BJ, Matalaga BR the effect of shock wave rate on the Outcome of shock wave lithotripsy: A metanalysis J Urol 2008 ;179(1):194-7.

18) Connors BA Evan AP, Blomgren PM,handa RK,Willis LR, Gao S Effect of initial shock wave voltage on shock wave lithotripsy-induced lesion size during step wise voltage ramping BJU Int 2009;103(1):104-7. • Mehrabi S, Karimzadeh Shiraji K ).Results and complications of spinal anesthesia in percutaneous Nephrolithotomy Urol J 2010;7(1):22-5 20) Scoffone CM,cracco CM,Cossu M, Grande S, Poggio M,Scarpa RM Endoscopic combined intrarenal surgery in Gladakao –modified supine

Valdivia position: A new standard for percutaneous nephrolithotomy?Eur Urol 2008;54(6):1393-403. 21) De Sio M, Autorino R Quatro , Calabo F,Damiano R,Giuglioano F,Mordente, S,D’Armiento M Modified supine versus prone position in Percutaneous nephrolithomy for renal stones treatable with single percutaneous renal access. A prospective randomized trial Eur Urol 2008; 54(1):196-202. 22) Basiri A ,Ziaee AM, Kianian HR,Mehrabi S, Karami H, Moghadam SM. ultrasonographic versus fluoroscopic access for percutaneous

nephrolithotomy: A randomized clinical trial J Endourol 2008;22(2):281-4. 23) Desai M, Jain P,Ganpule A,Sabnis R,Patel S, Shrivastav P Developments In technique and technology: Effect on the results of percutaneous nephrolithomy for staghorn calculi 2009;542-548. 24) Albala DM, Assimos DG,Clayman RV,Denstedt JD, Grasso M,Gueteriz AJ,Kahn RI,Leveillie RJ, Lingeman JE,Macaluso JN Jr,Munch LC,Nakada SY,Newman RC,Pearle MS,Preminger GM,Teichman J, Woods JR.Lower

pole I A prospective randomized trial of extracorporeal shock wave lithotripsy and percutaneous nephrolithotomy for lower pole nephrolithiassis-initial results J Urol 2001;166(6):2072-80. 25) Desai MR,Kukreja RA,Desai MM,Mhaskar SS, wani KA,Patel SH,Bapat SD A prospective randomized comparison of type of nephrostomy Drainage following percutaneous nephrolithotomy:large bore versus small bore versus tubeless J urol 2004;172(20:565-7 26) Agarwal MS,Agarwal M,Gupta A,bansal s,Yadav A,Goyal J. A

randomized comparison of tubeless and standard percutaneous nephrolithotomy. J Endourol 2008; 22(3)439-42. 27) Knopf HJ, Graff HJ,Schulze H . Perioperative antibiotic prophylaxis in ureteroscopic stone removal Eur Urol 2003; 44(1):115-8. 28) Grabe M. Perioperative antibiotic prophylaxis in urology Curr Opin Urol 2001; 1191:81-5. 29) Michel MS, Knoll T,Ptaaschnyk T, Kohrmann KU, Alken P. Flexible ureterorenoscopy for the treatment of lower pole calyx stones; influence of

different lithotripsy probes and stone extraction tools on scope deflection 38

and irrigation flow. Eur Urol 2002; 41(3):312-6. 30) Teichman JM, rao RD,rogenes VJ,harris JM. Ureteroscopic management Of ureteral calculi:Electrohydraulic versus holmium Yag lithotripsy J Urol 1997;158(4):1357-61. 31) Rehman J, Monga M, landaman J,Lee DI,Felfela T, Conradie MC,srinivas R,Sundaram CP,ClaymanRV,Characterisation of intarpelvic pressures during ureteropyeloscopy with ureteral access sheaths Urology 2003;61(4):713-8. 32) Tiechman JM, long RD, Hulbert JC Long term renal fate and prognosis

after staghorn calculus management Jurol 153:1403, 1995) . 33) Mertyk S, Gofrit ON,gafni O,Pode D, Shapiro A Verstandig A et al Complete staghorn calculi;randomized prospective comparison between extracorporeal shock wave lithotripsy monotherapy and combined with percutaneous nephrolithotomy J Urol 157:780,1997. 34) Lundatm So,wahlander LA,Kral LG Treatment of ureteric colic by prostaglandin synthetase inhibition with diclofenac sodium Curr Ther Res 1980;28::355-8.

35) Walden M,lahteinen J, Elvander E Analgesic effect and tolerance of ketoprofen and diclofenac in acute ureteral colic Sacnd J Urol Nephrol 1993;27(3):323-5 36) Shokeir A Abdulmaaboud M, Farage Y, Mutabagani H Resistive index in renal colic :The effect of non steroidal anti-inflammatory drugs BJUI Int 1999;84(3):249-51. 37) Lee A, Cooper MG, Craig JC, Knight JF, Keneally JP Effects of non 39

steroidal anti inflammatory drugs on post operative renal function in adults with normal renal function Cochrane Database Syst Rev 2007,18(2):CD 002765) 38) Laerum E, Ommudsen OE,Gronseth JE, Chrsiationasen A, fagertun HE.oral diclofenac in prophylactic treatment of recurrent renal colic. A double blind comparison with placebo Eur Urol 1995; 28(2):108-11. 39) Gross AJ,Hermann TR.Management of stones in calyceal diverticulum.Curr opin urol 2007;17(2):136-40.

40) Ganpule AP, Desai MR Urolithiasis in kidneys with abnormal lie, rotation or form Curr Opin Urol 2011;21(2):145-53. • M Sinha et al A cost comparison of open versus percutaneous approaches to the management of large staghorn calculi Indian J Urol 2008:24:28-34 • Goel MC et al Management of staghorn calculi : analysis of combination therapy and open surgery Urol Int 1999;63:228-33 • Al Kohlany et al Treatment of complete staghorn stones: A prospective

randomized Comparison of open surgery versus percutaneous nephrolithotomy J urol 2005;175:469-73 Annexure 1 Resources required for one patient/procedure (units) Human resources ESWL i. Urologist-1 j. Technician-1 40

k. Anesthetist-1 PCNL 12. Urologist-1 13. Surgical assistant-1 14. Technician/Nurse-2 15. Anesthetist-1 Flexible ureteroscopy 1) Urologist-1 a) Surgical assistant-1 3) Technician/Nurse-2 4) Anesthetist-1 Investigations:- As detailed in previous section Drugs and consumables List of consumables for PCNL Normal saline 1000ml-(n=4) 5% Dextrose 1000ml-(n=2) Normal saline -3000ml-(n=3) Iv set – (n=1) 41

Injection Fortwin – (n=1) Injection Metoclopromide-(n=4) Injection Tramadol 50 mg –(n=4) Injection ranitidine-50 mg-(n=4) Foley catheter 16 fr-(n=1) Urobag-(n=2) Irrigation set-(n=1) Phosphate enema-(n=1) Injection glycopylorrate-(n=1) Antibiotic according to clinical situation List of consumables for ureteroscopy Normal saline 1000ml-(n=4) 5% Dextrose 1000ml-(n=4) Normal saline -3000ml-(n=3) Iv set – (n=1) Injection Fortwin – (n=1) Injection Metoclopromide-(n=4) Injection Tramadol 50 mg –(n=4)

Injection ranitidine-50 mg-(n=4) Foley cathter 16 fr-(n=1) Urobag-(n=1) Irrigation set-(n=1) Phosphate enema-(n=1) Injection glycopylorrate-(n=1) 42

Antibiotic according to clinical situation Equipment Trolley preparation for PCNL Tray with cover-2 Legging-2 Towel clips-5 Towel -2 Surgeon gown -3 Gloves -3 Hole towel-2 Artery forcep-2 Needle holder-1 Number 11 knife-1 Sponge holder -1 Scissor-1 Knife holder-1 Thread-1 20cc syringe-2 10 cc synringe-1 Bowl-1 Xylocaine jelly-2 Cystoscope sheath (19 Fr/20 Fr) Telecope-30 degree Light cable with cord 1 in number 43

Open end ureteric cathter-1 in number Nephroscope -24-26 Fr (depending on availability) Suction pipe-1 Stone holding forcep-1 Spanner -1 Ultrasound probe (optional) Puncture needle-1 Metal rod/Telescopic metal dilators (till 24 Fr)-1 J tip guide wire/ glidewire-1 Teflon dilator with Upto 14 Fr-1 Ampatz dilator set-1 Amplatz sheath (size depends on surgeon preference) Nephrostomy catheter (Nelaton preferable) Trolley preparation for URS Trolley with cover-1 Legging-2 Hole towel-1 Gown with napkin-1 Gloves-3

Ureteric cathter-1 Ureteric dilator set-1 Irrigation tube-1 Cystoscope sheath with bridge-1 Telescope-30 degree-1 Guide wire 0.035/glide wire-1 each Ureteroscope (depends on surgeon preference)-1 45

Benign Hyperplasia Of Prostate (BPH) Prof. Nitin S. Kekre, Professor and Head Dr. Arabind Panda, Associate Professor Department of Urology CMC Medical College, Vellore General comments: Clinical guideline are supposed to be reflections of the best currently available evidence. They have 2 parts – a. A systematic review of the best available evidence and the strength of that evidence. I. The methodology of systematic review is important. This should be clearly

stated. All relevant studies should be studied. If Indian studies are available, then they should be included. The evidence should then be ranked using a standard system e.g. levels of evidence - Oxford Centre for Evidence-based Medicine [1]. If necessary relevant focused questions can be framed in order to exactly define the purview of the exercise. b. Recommendations for practice based on that evidence. These should be graded according to the level of available evidence.

This standard treatment guideline on BPH does not state the methodology used to arrive at the recommendations. The levels of evidence are not mentioned. There is no grading of the recommendations. The document is without any references to back up the claims. The authors should be clearly mentioned in the published version ( we understand this is not desirable in a document for peer review). A conflict of interest declarations should be included in the final document.

Use of the term benign hyperplasia of the prostate (BPH) – BPH is a histological diagnosis. It symptoms come under the umbrella of lower urinary tract symptoms. While BPH occurs in the vast majority of elderly men, it can be difficult or impossible to directly attribute the symptoms of the patient to BPH. Introduction Line 17 – 20 : ”However, a significant proportion, particularly in rural areas tend to disregard symptoms till complications develop and this segment requires a more

proactive and individualized approach.” – There is no evidence that the rural population disregard symptoms more than the urban people. The lack of access to effective health care in rural areas will make a proactive and individualized approach difficult. It is important for guidelines to be applicable to the entire populations of the country. Evaluation of BPH 1. Symptom assessment – Need to state the complete term International Prostatic Symptom Score before using the abbreviation IPSS.

Mandatory diagnostic tests 2. PSA measurement – Need to state the complete term. There is no evidence that prostate specific antigen measurement has any role in the routine management 46

of BPH. The role of PSA screening for prostate cancer is controversial. Metaanalysis of the recent evidence showed screening to have no significant impact on either overall mortality or death from prostate cancer with significant overdiagnosis and overtreatment and is unlikely to save lives. It cannot be recommended in India. A patient anxious about prostate cancer should be explained about the benefits and risks of PSA screening and about the available

evidence. He should be then in a position to make an informed choice. 3. Abdominal ultrasound evaluation –Upper tract imaging is not required for routine evaluation of BPH. The estimation of prostate size by abdominal ultrasound is also unreliable. Ultrasound evaluation should be restricted to the bladder and post void residual urine as an optional test. 4. Uroflowmetry – This is not mandatory even in developed countries. The equipment is specialized, expensive (Indian makes cost Rs. 50000/- approx.,

foreign equipment – 1.5 – 2.5 lacs/ - approx.) and require regular maintenance and calibration. It cannot be mandatory and should be an optional test. Optional diagnostic tests 2. Blood urea – Blood urea estimation is superfluous when creatinine is being measured. It is not as accurate indicator of renal function as creatinine. Unnecessary. 3. Urine Cytology – Urinary cytology is a specialized test with low sensitivity. In absence of microscopic haematuria, it is unlikely to be useful.

6. Urethrography – An uroflowmerty is a non invasive test which can indicate a possible urethral stricture. An urethrography is invasive and will require prior urine culture sensitivity before its performance. Uroflowmetry and ultrasound abdomen can be added as optional tests. Treatment options 2. a. “Dose titration is not essential for Alfuzosin and Tamsulosin ” should read - Dose titration is not required for extended release Alfuzosin and Tamsulosin.

“Hypotensive episodes are least seen with use of Alfuzosin” – The vasodilatory effects of Alfuzosina nd Tamsulosin are similar. There are no statistical differences between the two in this regard [4]. b. 5 Alpha reductase inhibitors: “Reduction of blood loss during TURP is evident only after long term use of 5 ARI’s.” - The evidence is very weak and not enough for a recommendation[5,6,7,8]. c. Combination therapy: “Concominant use of Alpha adrenergic blockers and 5Alpha

reductase inhibitors is appropriate therapy for patients with LUTS due to BPH, particularly if response has been insufficient with either drug.” - Combination 47

therapy is necessary in those who are at risk of progression (moderate to severe LUTS, enlarged prostates, and reduced Qmax) . Response is not a criterion for combination therapy [9]. 3. Indications for surgery “Patients presenting with chronic low pressure require catheterization and urodynamic evaluation” – Catheterization is not required unless the patient has acute on chronic retention, overflow incontinence or obstructive uropathy with raised creatinine. 4. Minimally invasive procedures

TUNA and intraprostatic stents – Cannot be recommended based on current evidence. 5. Surgical (endoscopic and open) procedures • “Open prostatectomy is still an acceptable procedure for glands exceeding 100 gms in wt.” – Any gland over 60 gms can be managed with open prostatectomy if TURP is not available. f) “Follow-up with IPSS, DRE & PSA recommended every 3 to 6 months initially and annually thereafter.” – Three monthly follow up is not required after surgery. PSA is certainly not needed.

Conclusions: Very poorly written clinical practice guideline. It is unfit for use in its present form. Needs extensive revision. References: • Center for evidence based medicine, Oxford, UK http://www.cebm.net/index.aspx?o=1025. Accessed on 1st April, 2012. • Ilic D, O'Connor D, Green S, Wilt TJ. Screening for prostate cancer: an updated Cochrane systematic review.BJU Int. 2011 Mar;107(6):882-91. • Djulbegovic M, Beyth RJ, Neuberger MM, Stoffs TL, Vieweg J, Djulbegovic B et

al. Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials. BMJ. 2010; 341:c4543 • Nickel JC, Sander S, Moon TD. A meta-analysis of the vascular-related safety profile and efficacyof a-adrenergic blockers for symptoms related to benign prostatic hyperplasia. Int J Clin Pract 2008 Oct;62(10):1547-59. • Hahn R, Fagerstrom T, Tammela T et al: Blood loss and postoperative complications associated with transurethral resection of the prostate after

• Boccon-Gibod L, Valton M, Ibrahim H et al: Effect of dutasteride on reduction of intraoperative bleeding related to transurethral resection of the prostate. Prog Urol 2005; 15: 1085. • Sandfeldt L, Bailey D, Hahn R: Blood loss during transurethral resection of the prostate after 3 months of treatment with finasteride. Urology 2001; 58: 972. • Donohue J, Sharma H, Abraham R et al: Transurethral prostate resection and bleeding: a randomized, placebo controlled trial of role of finasteride for decreasing

operative blood loss. J Urol 2002; 168: 2024. • Desgrandchamps F. Who will benefit from combination therapy? The role of 5 alpha reductase inhibitors and alpha blockade: a reflection from MTOPS. Curr Opin Urol 14:17–20. 49

RENAL CELL CARCINOMA (RCC) Renal cell carcinoma (RCC), which accounts for 2% to 3% of all adult malignant neoplasms, is the most lethal of the urologic cancers. The mortality rate of RCC is as much as twice that of bladder cancer1,2. There is no epidemiological data available from Indian subcontinent. However, the disease is fairly prevalent in our country. In 2010, an estimated 58,240 Americans were diagnosed with renal malignancies and

13,040 deaths were estimated3. In 2008, there were an estimated 88,400 new cases and 39,300 kidney cancer–related deaths from RCC in Europe4. Surgical excision remains the only curative treatment as this tumor is remarkably resistant to radiotherapy and chemotherapy. Presentation – • Incidental: detected on imaging (CT / ultrasound) performed for other indication • Symptomatic: local / metastatic / paraneoplastic • Flank pain, hematuria, mass

• Weight loss, fever, night sweats, recent onset hypertension, anemia / polycythemia • Cervical lymphadenopathy / non-reducing varicocoele / pathological fracture • others Workup – Any mass lesion detected on ultrasound needs further imaging. b) CT / MRI abdomen & pelvis/ MR Urography – both without and with contrast (if renal functions permissible). MRI specifically indicated if disease is infiltrating adjacent organs or IVC thrombus (triphasic multiplanar CT or high resolution

c) Blood investigations – Hemogram, kidney functions, alkaline phosphatase (ALP), calcium, albumin, lactate dehydrogenase (LDH) d) Chest X-ray – in all cases. Further imaging (CT scan) required only if clinically indicated or primary tumor locally advanced or lymph-nodes enlarged e) Bone scan – only if clinically indicated (bone pain, raised ALP) or primary tumor locally advanced or lymph-nodes enlarged. f) PET CT – not routinely recommended in the workup for RCC. Has good specificity

but low sensitivity in the evaluation of metastatic disease. Currently, it may be considered in case of equivocal findings on conventional imaging, where detection of metastatic disease will influence management decision. g) Biopsy / FNAC – not required in most cases. Acceptable in the following indications: h) Considering inflammatory mass / lymphoma / metastasis, vague Radiology, multiple masses, associated significant lymphadenopathy

i) Considering non-surgical therapy (e.g. cryotherapy, systemic therapy in case of metastatic disease) / active surveillance (small renal masses) / watchful waiting Staging (American Joint Committee on Cancer, TNM staging system for renal cancer, 7th ed, 2010) – Primary tumor Tx Primary tumor cannot be assessed T0 No evidence of primary tumor T1a Tumor dia ≤ 4 cm confined to kidney T1b Tumor dia > 4-7cm confined to kidney T2a Tumor dia > 7-≤10cm confined to kidney T2b Tumor dia > 10cm confined to kidney 51

T3a Tumor grossly extends into renal vein or its muscle-containing branches; tumor invading perirenal or sinus fat T3b Tumor grossly extends into vena cava below diaphragm T3c Tumor grossly extends into vena cava above diaphragm or invades its wall T4 Tumor invades beyond Gerota’s fascia (including contiguous spread into ipsilateral adrenal) Regional lymph nodes Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in single regional lymph node (s) Distant metastasis

M0 No distant metastasis M1 Distant metastasis Stage Grouping Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T1-2 N1 M0 T3 N0-1 M0 Stage IV T4 Any N M0 Any T Any N M1 Stage wise treatment – In addition to clinical stage, patient’s performance status (ECOG5) should be taken into consideration before deciding the treatment options. Stage I Preferred – nephron-sparing surgery if technically feasible Optional – radical nephrectomy* Others 52

9. Active surveillance 10. Ablative therapies (cryotherapy, radiofrequency ablation, microwave thermotherapy, high frequency focussed ultrasound, etc.) Adrenalectomy / lymphadenectomy: not indicated, unless grossly involved intraoperatively (staging changed) * In patients with early stage RCC radical nephrectomy is justified when NSS is technically not feasible / the patient understands the other option (NSS) and opts for RN. Stage II Preferred – radical nephrectomy

Optional (imperative setting**) – nephron-sparing surgery Adrenalectomy / lymphadenectomy: not indicated ** Imperative indications of NSS: solitary kidney, compromised function or reserve of contralateral kidney (chronic renal insufficiency, severe diabetes mellitus, severe hypertension), bilateral synchronous tumors, familial RCC Stage III Preferred – radical nephrectomy, with tumor thrombectomy (if present) Lymphadenectomy – may be performed for better staging. LND in patients with high-

risk disease improves stage assessment and may prolong survival6,7. A mere sampling of the renal hilar lymph nodes is insufficient for pathologic staging. For right sided tumor, paracaval and interaortocaval lymph nodes and for left sided tumor para-aortic and interaortocaval lymph nodes should be removed from the crus of the diaphragm to the common iliac artery. If disease is confirmed within the interaortocaval nodes, a complete retroperitoneal LND is recommended to define the full extent of metastatic

lymph node involvement8. Adrenalectomy: not required unless direct invasion or tumor nodule (stage changed) Stage IV 16. Nephrectomy with adjacent organ excision 17. Metastasectomy (if solitary metastasis) 53

18. Adrenalectomy 19. Cyto-reductive nephrectomy Patients of stage IV disease are candidates for adjuvant systemic therapy (vide infra). Socio-economic and facility issues – Advanced – • staging tools • surgical facility • follow up facility • socio-economic support may not be available everywhere. Centers which intend to treat RCC must be equipped with facility for histopathology / CECT / Blood transfusion. If above facilities not available / locally advanced disease / patient wants NSS → ref. to

higher center. Follow up protocol after definitive local treatment – Risk grouping (UCLA integrated staging system)9: T stage 1 2 3 4 Furhman grade 1-2 3-4 1-4 1 2-4 1-4 ECOG PS 0 ≥ 1 Any ≥ 1 Any 0 ≥ 1 0 ≥ 1 Any Risk group Low Intermediate high Follow up protocol based on the above risk grouping10 – 6m 12m 18m 24m 30m 36m 42m 48m 54m 60m 6y 7y 8y 9y 10y Hx/Ex/labs L - √ - √ - √ - √ - √ - - - - - I √ √ √ √ √ √ - √ - √ √ √ √ √ √ H √ √ √ √ √ √ - √ - √ √ √ √ √ √ 54

CT chest* L - √ - √ - √ - √ - √ - - - - - I √ √ √ √ √ √ - √ - √ √ √ √ √ √ H √ √ √ √ √ √ - √ - √ √ √ √ √ √ CT abdomen L - - - √ - - - √ - - - - - - - I - √ - √ - - - √ - - √ √ √ H √ √ √ √ - √ - √ - √ √ √ √ * CT chest can be replaced with CxR after initial 3 years. L – low risk; I – intermediate risk; H – high risk group. Systemic therapy – Indications: l. Metastatic RCC with resectable disease (cytoreductive nephrectomy and metastatectomy should be done whenever feasible)

m. Non-resectable Locally advanced / metastatic RCC Agents– Name • Sunitinib • Sorafenib • Pazopanib • Bevacizumab + IFN-α • Tamsirolimus • Everolimus • IFN-α • High dose IL-2 Targeted therapy in the form of tyrosine kinase inhibitors (1-4) and m-TOR inhibitors (5- 6) have become first line systemic treatment for management of metastatic RCC. A substantial improvement in progression-free survival and overall survival has been 55

achieved in large randomized controlled trials, when compared to Interferon-α. These agents have also been found to be effective in non-clear cell RCC, which are typically resistant to cytokines and interferons. Sarcomatoid variant is associated with poor prognosis, and a modest response with doxorubicin & gemcitabine is observed. Limitations – • high cost and limited availability • significant side-effects • efficacy Note : Targetted therapy for metastatic RCC/ locally advanced RCC should be decided by

References: • Landis et al., 1999. Landis SH, Murray T, Bolden S, Wingo PA: Cancer statistics: 1999. CA Cancer J Clin 1999; 49:8-31. • Pantuck et al., 2001b. Pantuck AJ, Zisman A, Belldegrun AS: The changing natural history of renal cell carcinoma. J Urol 2001; 166:1611-1623. • Jemal A, Siegel R, Xu J, Ward E. Cancer Statistics 2010. CA Can J Clin 2010; 60: 277-300. • Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010; 46: 765–81.

• Oken MM, Creech RH, Tormey DC et al. Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655. • Pantuck AJ, Zisman A, Dorey F, et al. Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol 2003; 169: 2076–83. • Vasselli JR, Yang JC, Linehan WM, et al. Lack of retroperitoneal lymphadenopathy predicts survival of patients with metastatic renal cell carcinoma. J Urol 2001; 166: 68–72.

• Crispel PL, Breau RH, Allmer C, et al. Lymph Node Dissection at the Time of Radical Nephrectomy for High-Risk Clear Cell Renal Cell Carcinoma: Indications and Recommendations for Surgical Templates. Eur Urol 2011; 59: 18-23. • Zisman A, Pantuck AJ, Wieder J, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol. 2002; 20: 4559-4566.

• Chin AI, Lam JS, Figlin RA, Belldegrun AS. Surveillance strategies for renal cell carcinoma patients following nephrectomy. Rev Urol 2006; 8: 1-7. 57

BLADDER CANCER I. WHEN TO SUSPECT / RECOGNIZE? a) Introduction / b) Case definition: Bladder carcinoma is the most common malignancy of the urinary tract and is the 9th most common cancer diagnosis worldwide. At the initial diagnosis of bladder cancer, 70% of cases are diagnosed as non-muscle-invasive bladder cancer (NMIBC) and approximately 30% as muscle-invasive disease. [1, 2] Non-muscle-invasive bladder cancer: Bladder cancer that does not involve the muscularis propria.

Invasive bladder cancer: Bladder cancer that histologically invades the muscularis propria. • Risk factors [3,4,5,6] – Tobacco consumption – Occupational exposure to chemicals – Radiation therapy – Chronic urinary tract infection – Bladder schistosomiasis – Chemotherapy – Cyclophosphamide • Active and passive tobacco smoking continues to be the main risk factor, while exposure-related incidence is decreasing. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY: Exact incidence is unknown. The

recent trends indicate increasing incidence of bladder cancer. This may be partially attributed due to better detection and improved health care. Expected to be of same incidence as the western world. III DIFFERENTIAL DIAGNOSIS: 20. Chronic cystitis 21. Tuberculous cystitis 22. Bladder calculi 23. Interstitial cystitis 24. Radiation cystitis 25. Eosinophilic cystitis IV. PREVENTION AND COUNSELING: 11. Mass education about bladder cancer and its relationship with tobacco use 12. Anti-tobacco campaign

13. Careful history about smoking, occupational exposure to risk factors and storage LUTS 14. Detailed evaluation of all patients with gross hematuria and elderly patients (>40 years) with microscopic hematuria and associated risk factors like smoking 15. All patients with hematuria should undergo full urological evaluation 58

16. Prompt referral of men with advanced bladder cancer to higher centers for further evaluation V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA Diagnostic criteria: 1. History of gross painless hematuria 2. History of severe storage LUTS – may be due to CIS 3. Recurrent cystitis in elderly 4. Positive cytology 5. Cystoscopic examination and imaging studies showing tumour(s) in the bladder. Diagnosis –The diagnosis mainly depends on the cystoscopic examination of the

bladder, biopsy, and urine cytology. The initial therapy for bladder tumours is complete macroscopic transurethral resection of bladder tumours (TURBT) including a part of underlying muscle [7]. Cold cup biopsies should be discouraged. A second TURBT should be considered [8]: 1. If there is suspicion that the initial resection was incomplete 2. When multiple or large tumours are present 3. When pathologist reported no muscle in the specimen 4. When a high grade tumour (pT1G3) was detected.

The management algorithm is based on the diagnosis of invasion of muscularis propria or not. Routine bladder mapping biopsies are not indicated except in 1. Patients with positive urine cytology with normal looking mucosa in cystoscopy 2. Biopsy of the apical prostatic urethra when there is a bladder neck tumour or when abnormalities of prostatic urethra are visible. Carcinoma in situ (CIS) is diagnosed based on the histology of bladder mucosal biopsies.

Fluorescent cystoscopy is recommended in these cases [9]. Investigations: 4. Urine cytology: Cytology is useful when a high-grade malignancy or CIS is present. It is used to predict high grade tumour before TUR. However, urinary cytology often is negative in the presence of low-grade cancer. 5. Ultrasonography (USG): Transabdominal USG permits characterization of renal masses, detection of hydronephrosis and visualization of intraluminal masses in

the bladder. It can be as accurate as IVU for diagnosis of upper urinary tract obstruction [10]. The USG is thus a useful tool for investigation in patients with haematuria to detect obstruction; it cannot however exclude the presence of upper tract tumours. 59

6. Pelvic examination (Bimanual examination) under anaesthesia: Helpful in assessment of local staging in muscle invasive bladder cancer and advanced cases. Not of much value in superficial bladder cancers. Should be done along with TURBT.[11] 7. Cystoscopy & TURBT: Cystoscopy should describe all macroscopic features of the tumour (site, size, number and appearance) and mucosal abnormalities. A bladder diagram is recommended. The gold standard in establishing the diagnosis of bladder tumour is TURBT.

8. Intravenous Urography (IVU): Intravenous urography (IVU) is used to detect filling defects in the calyces, renal pelvis and ureters, and hydronephrosis. Acceptable for staging of muscle invasive bladder cancer when CT Urography is not readily available [12]. 9. CT Urography (CTU): CTU is mainly recommended for histologically proven muscle invasive bladder cancers for staging. It is not useful for making a diagnosis of muscle invasive bladder cancer. Pre TURBT CTU is indicated in select

group of patients in whom it would significantly alter the management. Especially in muscle invasive tumours of the bladder and in upper tract tumours, CT urography gives more information than IVU does (including status of lymph nodes and neighbouring organs) [12]. 10. MRI – abdomen and pelvis/ MR Urography: Optimal investigation for staging in muscle invasive bladder cancer Recommended only when there is definite contraindication for CT urography or IVU like contrast allergy and renal failure.

11. Serum alkaline phosphatase – if elevated indicates metastatic bone disease. 12. Bone scan –Indicated in patients with raised alkaline phosphatase and with bone pain. 13. CT scan of chest is recommended for optimal staging in muscle invasive bladder cancer; if not available chest X-ray is acceptable. Staging of bladder cancer: Based on Tumour Node Metastasis (TNM) classification of carcinoma bladder (2010) [13]. • T - primary tumour • TX Primary tumour cannot be assessed

• T0 No evidence of primary tumour • Ta Non-invasive papillary carcinoma • Tis Carcinoma in situ. ‘flat tumour’ • T1 Tumour invades subepithelial connective tissue • T2 Tumour invades muscle • T2a Tumour invades superficial muscle (inner half) • T2b Tumour invades deep muscle (outer half) • T3 Tumour invades perivesical tissue • T3a Macroscopically • T3b Microscopically (extravesical mass) 60

• T4 Tumour invades any of the following: Prostate, uterus, vagina, pelvic wall, abdominal wall • T4a Tumour invades prostate, uterus or vagina • T4b Tumour invades pelvic wall or abdominal wall • N - regional lymph nodes • NX Regional lymph nodes cannot be assessed • N0 No regional lymph node metastasis • N1 Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac or presacral) • N2 Metastasis in a multiple lymph nodes in the true pelvis (hypogastric,

obturator, external iliac or presacral) • N3 Metastasis in a common iliac lymph node(s) • M - distant metastasis • MX Distant metastasis cannot be assessed • M0 No distant metastasis • M1 Distant metastasis Characteristics of Stages Ta, T1, and Tis Stage Ta tumours are confined to the urothelium, have a papillary configuration of their exophytic part, and do not penetrate from the urothelium into the lamina propria or detrusor muscle. Stage T1 tumours originate from the urothelium but penetrate the basement

membrane which separates the urothelium from the deeper layers. T1 tumours invade into the lamina propria, but are not so deep that they reach the detrusor muscle. Carcinoma in situ (Tis) is a high-grade (anaplastic) carcinoma confined to the urothelium, but with a flat non-papillary configuration. Unlike a papillary tumour, Tis appears as reddened and velvety mucosa and is slightly elevated but sometimes not visible. Tis can be local or diffuse. Three types of Tis are distinguishable;

• Primary Tis (no previous or concurrent papillary tumours); • Secondary Tis (with a history of papillary tumours); • Concurrent Tis (in the presence of papillary tumours). Characteristics of grade [14]: 1973 WHO Classification Apart from their architecture, the individual cells show different degrees of anaplasia: Grade 1: well differentiated tumour Grade 2: moderately differentiated tumour Grade 3: poorly differentiated tumour 2004 WHO Classification

A new classification system was initially proposed by the WHO/ISUP in 1998 and updated by the WHO in 2004. For non-invasive urothelial neoplasias, the categories are: • Flat lesions • Hyperplasia (flat lesion without atypia or papillary) 61

• Reactive atypia (flat lesion with atypia) • Atypia of unknown significance • Urothelial dysplasia • Urothelial carcinoma in situ (CIS) • Papillary lesions • Urothelial papilloma (a completely benign lesion) • Papillary urothelial neoplasm of low malignant potential • (PUNLMP) • Low-grade papillary urothelial carcinoma • High-grade papillary urothelial carcinoma The 2004 WHO grading system defines Tis as a non-papillary, i.e. a flat, lesion in which

the surface epithelium contains cells that are cytologically malignant. Papillary tumours are classified as either papillary urothelial neoplasms of low malignant potential (PUNLMP) or as urothelial carcinomas, with the latter being subdivided into two grades: low grade and high grade. The intermediate group (G2) has been eliminated; this group was the subject of controversy in the 1973 WHO classification. Use of the 2004 WHO

classification is advocated, as this should result in less diagnostic variability among pathologists. Predicting recurrence and progression of tumours [15,16]: TaT1 tumours The pattern of recurrence and progression depends on the following clinical and pathological factors: 1. Number of tumours 2. Tumour size 3. Prior recurrence rate 4. T-category 5. Pesence of concurrent CIS 6. Tumour grade. CIS No prognostic factors are well established. Retrospective studies suggest the following:

1. Concurrent CIS with T1 tumours have worser prognosis than primary CIS and secondary CIS [17, 18] 2. Responders to BCG have better prognosis than those non-responders. [19] Treatment: Treatment strategy varies according to the stage and grade of bladder cancer. Non-muscle invasive bladder cancer (superficial bladder cancer) NMIBC: The standard initial therapy for Ta and T1 papillary bladder tumours is complete TURBT. Tumours less than 1cm in size can be resected enbloc. Larger tumours should be

resected in fractions, which include the exophytic part, the underlying bladder wall and the edges of resection area. Complete and correct TUR is essential to achieve a good prognosis [20]. 62

Prognostic Factors and Adjuvant Treatment TaT1 papillary tumours Recommendations for Low Risk Tumours Patients with a single, small, low grade Ta tumour without CIS, who are at low risk for both recurrence and progression, should receive: 1. A complete TUR. 2. An immediate single post-operative instillation with a chemotherapeutic agent (drug optional – Mitomycin C preferred). [21] 3. No further treatment is recommended prior to recurrence. Recommendations for High Risk Tumours

Patients with TaT1 high grade tumours with or without CIS and those with CIS alone are at high risk of progression. Treatment should consist of: 1. Complete TUR of papillary tumours followed by an immediate post-operative instillation with a chemotherapeutic agent (drug optional – Mitomycin C preferred).[21] 2. A second TUR after 4–6 weeks.[9] 3. Adjuvant intravesical immunotherapy with BCG (full dose or reduced dose in case of

side effects). Maintenance therapy for at least 1 year (monthly once) is necessary [22,23] although the optimal maintenance scheme has not yet been determined. 4. Immediate cystectomy may be offered to patients at highest risk of tumour of progression (Patients with multiple tumours, large tumours (> 3 cm), and highly recurrent tumours (> 1 recurrence/year), stage T1 tumours with high grade tumours, and CIS). 5. In patients with BCG failure, cystectomy is recommended. [24]

Recommendations for Intermediate Risk Tumours In the remaining intermediate risk patients, adjuvant intravesical therapy is necessary but no consensus exists regarding the optimal drug and the most appropriate scheme. BCG is more effective than chemotherapy in both reducing recurrence and progression. The major issue in the management of intermediate risk tumours is to prevent recurrence and progression, of which recurrence is clinically the most frequent. Treatment should include:

1. Complete TUR followed by an immediate postoperative instillation with a chemotherapeutic agent (drug optional). 2. A second TUR after 4–6 weeks when the initial resection was incomplete. 3i. Adjuvant intravesical chemotherapy (drug optional), schedule: optional although the duration of treatment should not exceed 1 year. (Or) 3ii. Adjuvant intravesical immunotherapy with BCG (full dose or reduced dose in case of side effects). Maintenance therapy for at least 1 year (monthly once) is necessary

although the optimal maintenance schedule has not yet been determined. Carcinoma in situ CIS have a high risk of progression to muscle invasive disease which exceeds 50% in some studies. BCG intravesical immunotherapy (induction and maintenance) is superior to intravesical chemotherapy in increasing the complete response rate and the overall percent of patients remaining tumour free. Moreover, BCG reduces the risk of 63

progression as compared to either intravesical chemotherapy or a different immunotherapy [25]. Early radical cystectomy at the time of diagnosis provides excellent disease-free survival, but over-treatment occurs in up to 50% of patients. Recommendations for the treatment of CIS 1. In concurrent CIS, the initial strategy (TUR, early intravesical instillation, a second TUR) is based on the features of the papillary tumour. 2. Intravesical BCG immunotherapy including at least 1 year maintenance.

3. After the 6 week induction course, a second course of 6 weekly BCG instillations or maintenance cycles consisting of 3 weekly instillations may be considered in non- responders since about 40-60% of these patients will respond to additional treatment with BCG. [23] 4. In BCG non-responders at 6 months, radical cystectomy is recommended. [26]. Muscle invasive bladder cancer: Neo-adjuvant chemotherapy: Neo-adjuvant cisplatin-containing combination chemotherapy improves overall survival

by 5-7% at 5 years [27]. It should be considered irrespective of the type of definitive treatment. Neo-adjuvant chemotherapy is not recommended in patients with performance status (PS) > 2 and impaired renal function [28]. Radical Surgery and Urinary Diversion Cystectomy is the preferred curative treatment for localized muscle invasive bladder cancer [29]. Radical cystectomy includes removal of regional lymph nodes, the extent of which has

not been sufficiently defined [30]. A delay in cystectomy increases the risk of progression and cancer-specific death [31]. No pre-operative radiotherapy should be administered. Radical cystectomy in both sexes must not include the removal of the entire urethra in all cases, which may then serve as outlet for an orthotopic bladder substitution. If no bladder substitution is attached, the urethra must be checked regularly. Terminal ileum and colon are the intestinal segments of choice for urinary

diversion. The type of urinary diversion does not affect oncological outcome. Contraindications for orthotopic bladder substitution [32]: 1. Positive margins at the level of urethral dissection 2. Positive margins anywhere on the bladder specimen (in both sexes), if the primary tumour is located at the bladder neck or in the urethra (in women), or if tumour extensively infiltrates the prostate. Pre-operative bowel preparation is not mandatory.

Before cystectomy, the patient should be counselled adequately regarding all possible alternatives, and the final decision should be based on a consensus between patient and surgeon. For patients with inoperable locally advanced tumours (T4b), primary radical cystectomy is a palliative option and not recommended as a curative treatment. 64

Neoadjuvant Radiotherapy in Muscle-Invasive Bladder Cancer [33] Pre-operative radiotherapy does not increase the survival for operable muscle invasive bladder cancer. Bladder-Sparing Treatments Radical TURBT Radical TURBT is not recommended except in a rare situation when patient not willing for open surgery or unfit for radical cystectomy [34]. External beam radiotherapy [35, 36] External beam radiotherapy alone should only be considered as a therapeutic option

when the patient is unfit for cystectomy or a multimodality bladder-preserving approach Radiotherapy can also be used to stop bleeding from the tumour when local control cannot be achieved by transurethral manipulation because of extensive local tumour growth. Chemotherapy [37,38] Although cisplatin-based chemotherapy, as primary therapy for locally advanced tumours in highly selected patients, has led to complete and partial local responses, the long-term success rate is low.

Multimodality treatment [39,40] There are comparable long-term survival rates in cases of multimodality treatment success. Delay in surgical therapy can compromise survival rates. Adjuvant Chemotherapy [41] Adjuvant chemotherapy is advised within clinical trials, but not for routine use. Metastatic Disease [42 -47] Urothelial carcinoma is a chemosensitive tumour. Performance status (PS) and the presence or absence of visceral metastases are independent prognostic factors for survival.

These factors are at least as important as the type of chemotherapy administered. Cisplatin-containing combination chemotherapy is able to achieve a median survival of up to 14 months, with long-term disease-free survival reported in about 15% of patients with nodal disease and good PS. Single-agent chemotherapy provides low response rates of usually short duration. Post-chemotherapy surgery after a partial or complete response may contribute to long-term disease-free survival. Prognostic factors should

guide the treatment selection. NOTE : All chemotherapeutic drugs/ targeted therapy should be decided and administered in consultation with a Urologist. First-line treatment for “fit” patients: Use cisplatin-containing combination chemotherapy with GC, MVAC, preferably with GCSF, or HD-MVAC with GCSF. Carboplatin and non-platinum combination chemotherapy is not recommended. 65

First-line treatment in patients ineligible (‘unfit”) for cisplatin: Use carboplatin combination chemotherapy or single agents. For cisplatin-ineligible patients (‘unfit’) with either PS 2 or impaired renal function, or with poor prognostic factors, first-line treatment is carboplatin-containing combination chemotherapy, preferably with gemcitabine/carboplatin. Second-line treatment: In patients progressing after platinum-based combination chemotherapy for metastatic

disease vinflunine should be offered, which has the highest level of evidence to date, or clinical trials of other treatments. Follow-up for non-muscle invasive bladder tumours [48, 49] Patients with non-muscle invasive bladder tumours need to be regularly followed up because of the risk of recurrence and progression; however, the frequency and duration of cystoscopies should reflect the individual patient’s degree of risk.

The result of the first cystoscopy after TUR at 3 months is a very important prognostic factor for recurrence and for progression. The first cystoscopy should thus always be performed at 3 months after TUR in all patients with non-muscle invasive bladder tumour. Recommendations for follow-up cystoscopy Patients with tumours at low risk of recurrence and progression should have a cystoscopy at 3 months. If negative, the following cystoscopy is advised at 9 months and consequently yearly for 5 years.

Patients with tumours at high risk of progression should have a cystoscopy and urinary cytology at 3 months. If negative, the following cystoscopies and cytologies should be repeated every 3 months for a period of 2 years, every 4 months in the third year, every 6 months thereafter until 5 years, and yearly thereafter. A yearly evaluation of the upper tract by IVU or retrograde pyelogram is recommended. Patients with intermediate-risk of progression (about one-third of all patients) should

have an in-between follow-up scheme using cystoscopy and cytology, adapted according to personal and subjective factors. Patients with Tis should be followed up for life due to the high risk of recurrence and progression, both within the bladder and extravesically. Urine cytology together with cystoscopy (and bladder biopsies in cytology positive cases) is essential for monitoring of treatment efficacy. The follow-up schedule is the same as for patients with high-risk tumours.

Follow up for muscle invasive bladder cancer [50] Follow-up is based on the stage of initial tumour after cystectomy. At every visit, the following should be performed: 66

History, Physical examination, Serum chemistries and chest radiograph annually for pT1 disease; semiannual evaluation for patients with pT2 disease; and quarterly evaluation for patients with pT3 disease. For the last group, semiannual CT scan is recommended. Bone scan only when indicated or symptomatic. IVU can be done for upper tract surveillance when CT scan is not readily available. After 5 years of follow-up, stop oncological surveillance and continue with functional surveillance. Referral criteria:

• Patients with gross painless hematuria with association with high risk factors • Patients with severe storage LUTS with or without palpable pelvic mass suggestive of bladder cancer • Those with advanced bladder cancer and metastases *Situation 1: At Secondary Hospital / Non-Metro Situation: Optimal Standards Of Treatment In Situations Where Technology And Resources Are Limited. a) Clinical diagnosis: Careful evaluation of patients with gross painless hematuria, Pelvic

examination for bladder masses, not useful in non-muscle invasive bladder cancers. b) Investigations: Urine microscopy for hematuria, urine cytology for malignant urothelial cells. Ultrasound of abdomen and pelvis - to localize the cause of hematuria like renal and bladder tumours. Cystoscopy in all cases of gross hematuria and those with bothersome severe storage LUTS and positive microscopic hematuria. c) Treatment: According to the stage of the disease. Standard operating procedure: j) Inpatient:

k) Outpatient: l) Daycare: Referral criteria: Patients with gross painless hematuria known to have bladder tumour Positive urine dipstick or microscopic hematuria Positive urine cytology *Situation 2: At super specialty facility in metro location where higher end technology is available. a) Clinical diagnosis: Evaluation of gross hematuria, positive microscopic hematuria and positive urine cytology. Pelvic examination – to look for bladder masses. 67

b) Investigations: All the possible investigations mentioned. c) Treatment: According to the stage of the disease and the treatment options selected by the patient after counseling. Standard operating procedure a) Inpatient b) Outpatient c) Daycare Referral Criteria: For diagnosis and staging – CT Urography, molecular urinary markers. Evaluation of metastatic disease – bone scan if required. VI. WHO DOES WHAT? AND TIMELINES n. Doctor – clinical diagnosis, treatment, follow-up

o. Nurse – counseling, preoperative preparation, essential post-operative care, stoma care and follow-up p. Technician – Investigations and preoperative preparation. VII. FURTHER READING / REFERENCES. 68

References: 1. Ploeg M, Aben KK, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol 2009; 27:289-293. 2. Vaidya A, Soloway MS, Hawke C, Tiguert R, Civantos F. De novo muscle invasive bladder cancer: is there a change in trend? J Urol 2001 Jan;165(1):47-50. 3. Gandini S, Botteri E, Iodice S, et al. Tobacco smoking and cancer: a meta-analysis. Int J Cancer 2008 Jan;122(1):155-64. 4. Kogevinas M, t’Mannetje A, Cordier S, et al. Occupation and bladder cancer among

men in Western Europe. Cancer Causes and Control 2003 Dec;14(10):907-14. 5. Chrouser K, Leibovich B, Bergstralh E, et al. Bladder cancer risk following primary and adjuvant external beam radiation for prostate cancer. J Urol 2006 Jul;174(1):107-10. 6. Gouda I, Mokhtar N, Bilal D, et al. Bilharziasis and bladder cancer: a time trend analysis of 9843 patients. J Egypt Natl Canc Inst 2007 Jun;19(2):158-62. 7. Mariappan P, Zachou A, Grigor KM. Detrusor muscle in the first, apparently complete

transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience. Eur Urol 2010 May;57(5):843-9. 8. Kulkarni GS, Hakenberg OW, Gschwend JE, et al. An updated critical analysis of the treatment strategy for newly diagnosed high-grade T1 (previously T1G3) bladder cancer. Eur Urol 2010 Jan;57(1):60-70. 9., Hungerhuber E, Stepp H, Kriegmair M, Stief Ch, Hofstetter A, Hartmann A, Knuechel

R, Karl A, Tritschler S, Zaak D. Seven years´ experience with 5-aminolevulinic acid in detection of transitional cell carcinoma of the bladder. Urology 2007 Feb;69(2):260-4. 10. Goessl C, Knispel HH, Millar K, et al. Is routine excretory urography necessary at first diagnosis of bladder cancer? J Urol 1997 Feb;157(2):480-1. 11. Fossa SD, Ous S, Berner A. Clinical significance of the ‘palpable mass’ in patients with muscle infiltrating bladder cancer undergoing cystectomy after pre-operative

radiotherapy. Br J Urol 1991 Jan; 67(1):54-60. 12. Nolte-Ernsting C, Cowan N. Understanding multislice CT urography techniques: many roads lead to Rome. Eur Radiol 2006 Dec;16(12):2670-86. 13. Sobin LH, Gospodariwicz M, Wittekind C (eds). TNM classification of malignant tumors. UICC International Union Against Cancer. 7th edn. Wiley-Blackwell, 2009 Dec; pp. 262-265. 14. Epstein JI, Amin MB, Reuter VR, et al. The World Health Organization/International

Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Am J Surg Pathol 1998 Dec;22(12):1435-48. 15. Millan-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J, et al. Primary superficial bladder cancer risk groups according to progression, mortality and recurrence. J Urol 2000 Sep;164(3 Pt 1):680-4. 16. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and

progression in individual patients with stage TaT1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006 Mar;49(3):466-5. 69

17. Griffiths TRL, Charlton M, Neal DE, et al. Treatment of carcinoma in situ with intravesical bacillus Calmette-Guerin without maintenance. J Urol 2002 Jun;167(6):2408- 12. 18. Takenaka A, Yamada Y, Miyake H, et al. Clinical outcomes of bacillus Calmette- Guérin instillation therapy for carcinoma in situ of urinary bladder. Int J Urol 2008 Apr;15(4):309-13. 19. Van Gils-Gielen RJ, Witjes WP, Caris CT, et al. Risk factors in carcinoma in situ of the urinary bladder. Urology 1995 Apr;45(4):581-6.

20. Brausi M, Collette L, Kurth K, et al; EORTC Genito-Urinary Tract Cancer Collaborative Group. Variability in the recurrence Rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur Urol 2002 May;41(5):523-31. 21. Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta

T1 bladder cancer: a meta-analysis of published results of randomized clinical trials. J Urol 2004 Jun;171(6 Pt 1):2186-90. 22. Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta- analysis of the published results of randomized clinical trials. J Urol 2002 Nov;168(5):1964-70. 23. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin

immunotherapy for recurrent Ta, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000 Apr;163(4):1124-9. 24. Herr HW, Dalbagni G. Defining bacillus Calmette-Guerin refractory superficial bladder tumours. J Urol 2003 May;169(5):1706-8. 25. Sylvester RJ, van der Meijden APM, Witjes JA, et al. Bacillus Calmette-Guerin versus chemotherapy in the intravesical treatment of patients with carcinoma in situ of the

bladder: a meta-analysis of the published results of randomized clinical trials. J Urol 2005 Jul;174(1):86-92. 26. Shariat SF, Palapattu GS, Amiel GE, et al. Characteristics and outcomes of patients with carcinoma in situ only at radical cystectomy. Urology 2006 Sep;68(3):538-42. 27. Sherif A HL, Rintala E, Mestad O, et al. Nordic Urothelial Cancer Group. Downstaging and pathoanatomical outcome following neoadjuvant cisplatinum based combination

chemotherapy for muscle-invasive bladder carcinoma: An analysis of selected patients from two combined randomised prospective Nordic trials. Urology 2006;68(Suppl 1):137, MP-1307. 28. Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 2003 Jun;361(9373):1927-34. 29. World Health Organization (WHO) Consensus Conference in Bladder Cancer,

Hautmann RE, Abol-Enein H, Hafez K, Haro I, Mansson W, Mills RD, Montie JD, 70

Sagalowsky AI, Stein JP, Stenzl A,Studer UE, Volkmer BG. Urinary diversion. Urology 2007 Jan;69(1 Suppl):17-49. 30. Leissner J, Hohenfellner R, Thuroff JW, et al. Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder; significance for staging and prognosis. BJU Int 2000 May;85(7): 817-23. 31. Chang SS, Hassan JM, Cookson MS, et al. Delaying radical cystectomy for muscle invasive bladder cancer results in worse pathological stage. J Urol 2003 Oct;170(4 Pt 1):1085-7.

32. Hautmann RE, Volkmer BG, Schumacher MC, et al. Long-term results of standard procedures in urology: the ileal neobladder. World J Urol 2006 Aug;24(3):305-14. 33. Widmark A, Flodgren P, Damber JE, et al. A systematic overview of radiation therapy effects in urinary bladder cancer. Acta Oncol 2003;42(5-6):567-81. 34. Whitmore WF Jr, Batata MA, Ghoneim MA, et al. Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J Urol 1977 Jul:118(1 Pt 2):184-7.

35. Gospodarowicz MK, Hawkins NV, Rawlings GA, et al. Radical radiotherapy for muscle invasive transitional cell carcinoma of the bladder: failure analysis. J Urol 1989 Dec;142(6):1448-53; discussion 1453-4. 36. Gospodarowicz MK, Quilty PM, Scalliet P, et al. The place of radiation therapy as definitive treatment of bladder cancer. Int J Urol 1995 Jun;2(Suppl 2):41-8. 37. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus

cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003 Aug 28;349(9):859-66. 38. Kachnic LA, Kaufman DS, Heney NM, et al. Bladder preservation by combined modality therapy for invasive bladder cancer. J Clin Oncol 1997 Mar;15(3):1022-9. 39. Shipley WU, Kaufman DS, Heney NM, et al. An update of selective bladder preservation by combined modality therapy for invasive bladder cancer. Eur Urol 1998;33 Suppl 4:32-4.

40. Sánchez-Ortiz RF, Huang WC, Mick R, et al. An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma. J Urol 2003 Jan;169(1):110-5. 41. Lehmann J, Retz M, Wiemers C, et al; AUO-AB 05/95. Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter,phase III trial (AUO-AB

05/95). J Clin Oncol 2005 Aug;23(22):4963-74. 42. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1992 Jul;10(7):1066-73. 43. Logothetis CJ, Dexeus FH, Finn L, et al. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin

Oncol 1990 Jun;8(6):1050-5. 44. Sternberg CN, de Mulder P, Schornagel JH, et al; EORTC Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus 71

classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 2006 Jan;42(1):50-4. 45. Bellmunt J, Ribas A, Eres N, et al. Carboplatinbased versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer 1997 Nov;80(10):1966-72. 46. Nogué-Aliguer M, Carles J, Arrivi A, et al; Spanish Cooperative Group. Gemcitabine and carboplatin in advanced transitional cell carcinoma of the urinary tract: an alternative therapy. Cancer 2003 May;97(9):2180-6.

47. De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer “unfit” for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol 2009 Nov 20;27(33):5634-9. 48. Holmang S, Johansson SL. Stage Ta-T1 bladder cancer: the relationship between findings at first followup cystoscopy and subsequent recurrence and progression. J Urol 2002 Apr;167(4):1634-7.

49. Mariappan P, Smith G. A surveillance schedule for G1Ta bladder cancer allowing efficient use of check cystoscopy and safe discharge at 5 years based on a 25-year prospective database. J Urol 2005 Apr;173(4):1008-11. 50. Slaton JW, Swanson DA, Grossman HB, Dinney CP. A stage specific approach to tumour surveillance after radical cystectomy for transitional cell carcinoma of the bladder. J Urol. 1999 Sep;162(3 Pt 1):710-4. RESOURCES REQUIRED FOR ONE PATIENT /PROCEDURE (PATIENT WEIGHT 60 KGS)

(Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 2 72

PROSTATE CANCER I. WHEN TO SUSPECT / RECOGNIZE? • Introduction and Case definition: Cancer of the prostate (PCa) is now recognized as one of the most important medical problems facing the male population.[1]Prostate cancer is the 2nd most common cause of cancer death in men. Affects 4% of men in undeveloped countries & 15% of men in developed countries [2] • Risk factors • Increasing age • Ethnical origin • Heredity • Risk is doubled when one first line relative has prostate cancer. Risk is 5 – 11 fold

when two or more first line relatives has PCa[3] II. INCIDENCE OF THE CONDITION IN OUR COUNTRY: Exact incidence is unknown. Expected to be of same incidence as the western world. III DIFFERENTIAL DIAGNOSIS: m) Benign prostatic hyperplasia n) Granulomatous Prostatitis o) Transitional cell carcinoma of prostate p) Chronic prostatitis q) Prostatic calculi IV. PREVENTION AND COUNSELING: d) Mass education about prostate cancer e) Opportunistic screening for prostate cancer with serum PSA

f) Counseling about serum PSA and its implications g) Chemoprevention of prostate cancer h) Recognizing bladder outflow obstruction and other complications in men due to prostate cancer i) Thorough examination in elderly men who are at risk j) Prompt referral of men with suspicion of prostate cancer to higher centres for further evaluation V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA Diagnostic criteria: Screening & Early detection of prostate cancer 73

Population or mass screening is defined as the examination of asymptomatic men (at risk). It usually takes place as part of a trial or study and is initiated by the screener. In contrast, early detection or opportunistic screening comprises individual case findings, which are initiated by the person being screened (patient) and/or his physician. The primary endpoint of both types of screening has two aspects: 1. Reduction in mortality from PCa. 2. Quality-of-life adjusted gain in life years (QUALYs).

Screening for prostate cancer has conflicting results. Based on the results of two large, randomised trials [4,5], it is accepted that at present widespread mass screening for PCa is not appropriate. Rather, early detection (opportunistic screening) should be offered to the well-informed man. Hence • Early PSA testing should be a shared decision between patient and physician • PSA testing & DRE – offered to men >40 years of age & expected life expectancy of atleast 10 years

Diagnosis –The main diagnostic tools to obtain evidence of PCa include digitial rectal examination (DRE), serum concentration of PSA and transrectal ultrasonography (TRUS). Investigations: 1. DRE: Most prostate cancers are located in the peripheral zone of the prostate and may be detected by DRE when the volume is about 0.2 mL or larger. A suspect DRE is an absolute indication for prostate biopsy. In about 18% of all patients, PCa is detected by a suspect DRE alone, irrespective of the PSA level [6]

2. Serum PSA(Prostate-specific antigen) is organ-specific but not cancer-specific. Thus, serum levels may be elevated in the presence of benign prostatic hypertrophy (BPH), prostatitis and other non-malignant conditions. The level of PSA as an independent variable is a better predictor of cancer than suspicious findings on DRE or TRUS [7]. The level of PSA is a continuous parameter: the higher the value, the more likely is the existence of PCa. This means there is no

universally accepted cut-off or upper limit.[8] As yet, there is no long-term data to help determine the optimal PSA threshold value for detecting non-palpable, but clinically significant, PCa. Modifications to improve the specificity of PSA in early detection of Ca.P a. PSA density b. PSA density of transition zone c. Age specific PSA d. PSA molecular forms – PCA3 e. Free / Total PSA ratio (at PSA 4-10ng/ml) <0.10 – 56% biopsy positive f. PSA doubling time (PSADT) g. PSA velocity

h. When in doubt, repeat PSA under standardised conditions 3. Transrectal ultrasound of prostate (TRUS) guided biopsy of prostate. Gray-scale TRUS does not detect areas of PCa with adequate reliability. It is therefore not useful to replace systematic biopsies with targeted biopsies of suspect areas. 74

However, additional biopsies of suspect areas may be useful. Transrectal ultrasonography (TRUS) guided biopsy under antibiotic cover with periprostatic nerve block– minimum 10 core laterally and posteriorly directed biopsy is recommended (>12 not significantly more conclusive). [9]The indications for a repeat biopsy (including TZ biopsy) [10] are: a. Rising and/or persistent PSA, suspicious DRE; b. Atypical small acinar proliferation (ASAP). c. Extensive High-grade prostatic intraepithelial neoplasia (PIN)

Complications of biopsy – infection, sepsis < 1%, clot retention, acute urinary retention, bleeding from rectum, hematuria, hemospermia (the last 3 are mostly self limiting). d. Pathology of prostate cancer: i. The Gleason score is the sum of the most dominant and second most dominant (in terms of volume) Gleason grade. ii. A diagnosis of Gleason score 4 or lower should not be given on prostate biopsies iii. Gleason score system is the single strongest prognostic

factor for clinical behaviour and treatment response. 4. TRUS is also useful for staging of prostate cancer, however remains inadequate. [11] 5. MRI – abdomen and pelvis/ MR Urography [12] (risk stratification) a. Local staging (T-staging) b. MRI demonstrates higher accuracy for the assessment of uni- or bilobar disease (T2), Extracapsular extension (ECE) and Seminal vesicle invasion (SVI) (T3), as well as the invasion of adjacent structures (T4).

c. Lymph node status (N-staging) is only important when potentially curative treatment is planned. 6. Pelvic lymph node dissection remains the only reliable staging method in clinically localized PCa. [13] 7. Bone scan - Skeletal metastasis (M-staging) is best assessed by bone scan. This may not be indicated in asymptomatic patients if the serum PSA level is less than 20 ng/mL (risk stratification) in the presence of well or moderately differentiated tumours.[14]

8. Serum alkaline phosphatase – if elevated, indicates metastatic bone disease. 9. Transurethral resection of prostate- In those men who come with bladder outflow obstruction in an unsuspected fashion and biopsy report may reveal carcinoma of prostate. Staging of prostate cancer: Based on Tumour Node Metastasis (TNM) classification of carcinoma prostate [15]. • T - primary tumour • TX Primary tumour cannot be assessed • T0 No evidence of primary tumour 75

• T1 Clinically inapparenttumour not palpable or visible by imaging • T1a Tumour incidental histological finding in 5% or less of tissue resected • T1b Tumour incidental histological finding in more than 5% of tissue resected • T1c Tumour identified by needle biopsy (e.g. because of elevated prostate-specific antigen [PSA] level) • T2 Tumour confined within the prostate1 • T2a Tumour involves one half of one lobe or less • T2b Tumour involves more than half of one lobe, but not both lobes

• T2c Tumour involves both lobes • T3 Tumour extends through the prostatic capsule • T3a Extracapsular extension (unilateral or bilateral) including microscopic bladder neck involvement. • T3b Tumour invades seminal vesicle(s) • T4 Tumour is fixed or invades adjacent structures other than seminal vesicles: external sphincter, rectum, levator muscles, and/or pelvic wall • N - regional lymph nodes • NX Regional lymph nodes cannot be assessed • N0 No regional lymph node metastasis

• N1 Regional lymph node metastasis • M - distant metastasis • MX Distant metastasis cannot be assessed • M0 No distant metastasis • M1 Distant metastasis • M1a Non-regional lymph node(s) • M1b Bone(s) • M1c Other site(s) • Group I T1a-c N0 M0 PSA < 10 Gleason < 6 • T2a N0 M0 PSA < 10 Gleason < 6 • Group IIA T1a-c N0 M0 PSA < 20 Gleason 7 • T1a-c N0 M0 PSA > 10 < 20 Gleason < 6 • T2a, b N0 M0 PSA < 20 Gleason < 7 • Group IIb T2c N0 M0 Any PSA Any Gleason • T1-2 N0 M0 PSA > 20 Any Gleason

• T1-2 N0 M0 Any PSA Gleason > 8 • Group III T3a, b N0 M0 Any PSA Any Gleason • Group IV T4 N0 M0 Any PSA Any Gleason • Any T N1 M0 Any PSA Any Gleason • Any T Any N M0 Any PSA Any Gleason – (Note: When either PSA or Gleason is not available, grouping should be determined by cT category and whichever of either PSA of Gleason is available. When neither is available prognostic grouping is not possible, use stage grouping) 76

Treatment: Treatment of prostate cancer depends on the stage of the disease and prognostic information available. • Deferred treatment (Watchful waiting & Active surveillance) [16- 20] Make difference between active survillience and watchful waiting Indications: • In presumed localisedPCa (Nx-N0, M0): – Stage T1a: well and moderately differentiated tumours. In younger patients with a life expectancy of > 10 years, re-evaluation with PSA, TRUS and biopsies of the prostatic remnant is recommended

– Stage T1b-T2b: well & moderately differentiated tumours. In asymptomatic patients with a life expectancy of < 10 years – Inclusion criteria for active surveillance with the lowest risk of cancer progression are: • PSA < 10 ng/ml, biopsy Gleason score < 6, < 2 positive biopsies, < 50% cancer per biopsy, cT1c-2a • In presumed localisedPCa (Nx-N0, M0): – Stage T1b-T2b patients who are well informed and have well- differentiated (or Gleason 2-4) PCa and a life expectancy of 10-15 years.

– All patients not willing to accept side-effects of active treatment. – Well-informed, asymptomatic patients with high PSA levels for whom cure is unlikely. • In locally advanced disease (stage T3-T4): – Asymptomatic patients with well- or moderately differentiated cancer, PCa and a short life expectancy – PSA < 50 ng/mL and PSA doubling time > 12 months • In metastatic disease (M1): – A very rare patient without any symptoms and the possibility of close follow-up

The criteria for active surveillance have not reached a consensus stage yet. Every institution has different parameters and that should be mentioned. Active surveillance is not the same as watchful waiting. 2. Radical Prostatectomy [21,22]period between biopsy and surgery • Indications – In patients with low and intermediate risk localisedPCa (cT1a-T2b and Gleason score 2-7 and PSA < 20) and a life expectancy > 10 years • Optional – Selected patients with low-volume high-risk localisedPCa (cT3a or

Gleason score 8-10 or PSA >20) – Highly selected patients with very high-risk localisedPCa (cT3b-T4 N0 or any T N1) in the context of multimodality treatment 77

• Recommendations – Short-term (3 months) neoadjuvant therapy with gonadotrophin releasing-hormone analogues is not recommended in the treatment of stage T1-T2 disease – Nerve-sparing surgery may be attempted( offered) in pre-operatively potent patients with low risk for extracapsular disease (T1c, Gleason score < 7 and PSA < 10 ng/mL or see Partin tables / nomograms) – Unilateral nerve-sparing procedures are an option in stage T2a disease – Recommendation for Lymphadenectomy

– Extended PLND is recommended for all patients who have a greater than 2% chance of having lymph node disease. (NCCN guidelines) 3. Definitive radiation therapy [23-28] • In localised prostate cancer T1c-T2c N0 M0, 3D-CRT with or without IMRT is recommended even for young patients who refuse surgical intervention. There is fairly strong evidence that low-, intermediate- and high-risk patients benefit from dose escalation • For patients in the high-risk group, short-term ADT prior to and during

radiotherapy results in increased overall survival, but three years of adjuvant ADT are better according to the results of EORTC 22961 • Transperineal interstitial brachytherapy with permanent implants is an option for • Patients with cT1-T2a, Gleason score < 7 (or 3 + 4), PSA < 10 ng/mL, prostate volume < 50 mL, without a previous TURP and with a good IPSS • Immediate post-operative external irradiation after RP for • Patients with pathological tumour stage T3 N0 M0 improves overall

survival, biochemical and clinical disease-free survival with the highest impact in cases of positive margins (R1) • An alternative option is to give radiation at the time of biochemical failure, but before PSA rises above 0.5 ng/mL • In locally advanced prostate cancer T3-4 N0 M0, overall survival is improved by concomitant and adjuvant hormonal therapy for a total duration of 3 years, with external beam irradiation for patients with a WHO 0-2 performance status.

• For a subset of patients with T2c-T3 N0-x and a Gleason score of 2-6, short-term ADT before and during radiotherapy may favourably influence overall survival • In very high-risk prostate cancer, c-pN1 M0 with no severe co-morbidity, pelvic external irradiation and immediate long-term adjuvant hormonal treatment improve overall survival, disease-specific failure, metastatic failure and biochemical control 4. Experimental local treatment of prostate cancer[29-32]under invstigations • Cyrosurgery: 78

– Patients with low-risk PCa (PSA < 10 ng/mL, < T2a, Gleason score < 6) or intermediate-risk PCa (PSA > 10 ng/mL, or Gleason score > 7, or stage > 2b) represent potential candidates for CSAP. – Prostate size should be < 40 mL at the time of therapy. – Long-term results are lacking, while 5-year biochemical progression free rates are inferior to those achieved by RP in low risk patients. Patients must be informed accordingly. • Cryosurgery - a possible alternative treatment for PCa in patients who are unfit

for surgery or with a life expectancy < 10 years. • All other minimally invasive treatment options – such as HIFU microwave and electrosurgery – are still experimental or investigational. • Focal therapy of PCa is still in its infancy and cannot be recommended as a therapeutic alternative outside clinical trials r) Hormonal therapy[33-4] Bone densitometry and bisphosphonates 17. In advanced PCa, androgen deprivation therapy (ADT) 18. delays progression,

19. prevents potentially catastrophic complications, and 20. palliates symptoms effectively, but does not prolong survival. 21. In advanced PCa, all forms of castration used as monotherapy (e.g. orchiectomy, LHRH and DES) have equivalent efficacy. 22. Non-steroidal anti-androgen monotherapy (e.g. bicalutamide) is an alternative to castration in patients with locally advanced disease. 23. In metastatic PCa, the addition of a non-steroidal anti-androgen to castration

(CAB) results in a small advantage in OS over castration alone, but is associated with increased adverse events, reduced QoL, and high costs. 24. Intermittent ADT should no longer be regarded as experimental, even though long-term data from prospective clinical trials are still awaited. ‘Minimal’ ADT should, however, continue to be seen as experimental. 25. In advanced PCa, immediate ADT (given at diagnosis) significantly reduces

disease progression, as well as the complication rate due to progression itself, compared with deferred ADT (delivered at symptomatic progression). However, the survival benefit is at best marginal and not related to cancer-specific survival. 26. Bilateral orchiectomy might be the most cost-effective form of ADT, especially if initiated after the occurrence of symptoms from metastatic disease. Follow-up [47-50] After treatment with curative intent

14. In asymptomatic patients, a disease-specific history & a serum PSA measurement supplemented by DRE - recommended tests for routine follow-up. These should be performed at 3, 6 & 12 months after treatment, then every 6 months until 3 years, and then annually. 15. After radical prostatectomy, a serum PSA level of more than 0.2 ng/mL can be associated with residual or recurrent disease. 79

16. After radiation therapy, a rising PSA level over 2 ng/mL above the nadir PSA, rather than a specific threshold value, is the most reliable sign of persistent or recurrent disease. 17. Both a palpable nodule and a rising serum PSA level can be signs of local disease recurrence 18. Detection of local recurrence by TRUS and biopsy is only recommended if it will affect the treatment plan. 19. In most cases TRUS and biopsy are not necessary before second-line therapy.

20. Metastasis may be detected by pelvic CT/MRI or bone scan. In asymptomatic patients, these examinations may be omitted if the serum PSA level < 120 ng/mL. 21. Routine bone scans & other imaging studies are not recommended in asymptomatic patients. If a patient has bone pain, a bone scan should be considered irrespective of the serum PSA level. After hormonal therapy [51-53] • Patients should first be evaluated at three & six months after the initiation of

treatment. (one month and 3 months after initiating treatment) • As a minimum, • serum PSA measurement • digital rectal examination (DRE), • serum testosterone and careful evaluation of symptoms in order to assess the treatment response and the side-effects of the treatments given. • Follow-up should be tailored for the individual patient, according to symptoms, prognostic factors and the treatment given. • In patients with stage M0 disease with a good treatment response, follow-up is

scheduled every six months, and should include as a minimum a disease-specific history, DRE and serum PSA determination • In patients with stage M1 disease with a good treatment response, follow-up is scheduled for every three to six months. • As a minimum, this should include a disease-specific history, DRE and serum PSA determination, and is frequently supplemented with haemoglobin, serum creatinine and alkaline phosphatase measurements.

• Patients (especially if M1b status) should be advised on the clinical signs that could suggest spinal cord compression • When disease progression occurs, or if the patient does not respond to the treatment given, the follow-up needs to be individualised • Routine imaging of stable patients is not recommended Treatment of biochemical failure after treatment with curative intent [54- 61] Presumed local failure after radical prostatectomy

• Patients with presumed local failure only may be candidates for salvage radiotherapy. At least 64 Gy given and preferably before PSA has risen above 0.5 ng/mL. • Other patients are best offered a period of watchful waiting (active monitoring), with possible hormonal therapy later on 80

• Presumed local failure after radiotherapy • Selected patients may be candidates for salvage radical prostatectomy and patients should be informed about the higher risk of complications, such as incontinence and erectile dysfunction. • Salvage prostatectomy should only be performed in experienced centres. Other patients are best offered a period of watchful waiting (active monitoring), with possible hormonal therapy later on • Presumed distant failure

• There is some evidence that early hormonal therapy may be of benefit in +/- local failure, delaying progression, and possibly achieving a survival benefit in comparison with delayed therapy. • Local therapy is not recommended except for palliative reasons Castration refractory prostate cancer (CRPC or HRPC)- • Definition: – Serum castration levels of testosterone (testosterone < 50 ng/dL or < 1.7 nmol/L) – Three consecutive rises of PSA, 1 week apart, resulting in two 50%

increases over the nadir, with a PSA > 2 ng/mL – Anti-androgen withdrawal for at least 4 weeks* – PSA progression, despite consecutive hormonal manipula(cid:1)ons† • * Either anti-androgen withdrawal or one secondary hormonal manipulation should have been done in order to fulfil the criteria for CRPC. • † Progression of osseous lesions: progression or appearance of two or more lesions on bone scan or soft tissue lesions using RECIST (Response Evaluation Criteria in Solid Tumours) and with

nodes > 2 cm in diameter. CRPC- Recommendation of treatment after hormonal treatment • It is recommended to stop anti-androgen therapy once PSA progression is documented • Four to six weeks after discontinuation of flutamide or bicalutamide, an eventual anti-androgen withdrawal effect is apparent • No clear-cut recommendation can be made for the most effective drug for secondary hormonal manipulations. Secondary hormonal manipulations possibilities

• Abiraterone and Cabazitaxel have shown to prolong survival in CRPC after docetaxel chemotherapy. Sipuleucel T is prostate vaccine which is used and has been approved in the west for CRPC which is minimally symptomatic or asymptomatic. Not yet available in India. Recommendation of cytotoxic therapy 26. Ideally, patients with CRPC should be counselled, managed and treated in a multidisciplinary team 81

27. In non-metastatic CRPC, cytotoxic therapy should only be considered in clinical trials 28. In patients with a PSA rise only, two consecutive increases of PSA serum levels above a previous reference level should be documented 29. Prior to treatment, PSA serum levels should be > 2 ng/mL to assure correct interpretation of therapeutic efficacy 30. Potential benefits of cytotoxic therapy and expected side-effects should be discussed with each individual patient

31. In patients with metastatic CRPC, and who are candidates for cytotoxic therapy, docetaxel at 75 mg/m2 every 3 weeks has shown a significant survival benefit 32. In patients with symptomatic osseous metastases due to CRPC, either docetaxel or mitoxantrone with prednisone or hydrocortisone are viable therapeutic options 33. Second-line docetaxel should be considered in previously responding patients to docetaxel. 34. Otherwise, treatment is tailored to the individual patient

35. Cabazitaxel should be considered as effective second-line treatment following docetaxel 36. Chemotherapeutic drugs/ targeted therapy for cancer prostate patients should be decided and administered under supervision of a Urologist. Recommendation of palliative management • Patients with symptomatic and extensive osseous metastases cannot benefit from medical treatment with regard to prolongation of life • Management of these patients has to be directed at improvement of QoL and mainly pain reduction

• Effective medical management with the highest efficacy and a low frequency of side-effects is the major goal of therapy • Bisphosphonates may be offered to patients with skeletal masses (mainly zoledronic acid has been studied) to prevent osseous complications. However, the benefits must be balanced against the toxicity of these agents, in particular jaw necrosis must be avoided • Palliative treatments such as radionuclides, external beam radiotherapy,

adequate use of analgesics should be considered early in the management of painful osseous metastases • Spinal surgery or decompressive radiotherapy are emergency surgeries which have to be considered in patients with neurological symptoms might be an emergency Denosumab is more efficacious in preventing skeletal related events than Zoledronic acid with no need to adjust dose for mild to moderate renal dysfunction Referral criteria for Urologist :

• Men who come with LUTS with DRE showing hard nodular prostate • Localized prostate cancer • Men with advanced prostate cancer / metastases 82

*Situation 1: At Secondary Hospital / Non-Metro Situation: Optimal Standards Of Treatment In Situations Where Technology And Resources Are Limited. a) Clinical diagnosis:Hard, nodular, asymmetric prostatic enlargement in digital rectal examination. b) Investigations: Ultrasound of abdomen and pelvis (preferably by trans rectal ultrasound) – to assess the size and echotexture of prostate and to assess the tumour factors. c) Treatment:According to the stageof the disease. Standard operating procedure:

Inpatient: Outpatient Daycare: Referral criteria: Men who come with LUTS with DRE showing hard nodular prostate Localized prostate cancer Men with advanced prostate cancer / metastases *Situation 2: At super speciality facitlity in metro location where higher end technology is available. a) Clinical diagnosis; DRE and look for metastatic lesions. b) Investigations: All the possible investigations mentioned. c) Treatment:According to the stage of the disease and the treatment options selected

by the patient after counseling. Standard operating procedure a) Inpatient b) Outpatient c) Daycare 83

Referral Criteria: For diagnosis and staging – TRUS guided biopsy of prostate (depending on centers of excellence) Evaluation of metastatic disease – bone scan Extensive metastatic disease requiring advanced speciality care like radiopharmaceuticals, spine decompression surgery and neurosurgery. VI. WHO DOES WHAT? AND TIMELINES q. Doctor – clinical diagnosis, treatment r. Nurse – counseling, Preoperative preparation, essential post-operative care.

s. Technician – Investigations like serum PSA, bone scan and for administering treatment like radiopahramaceuticals. VII. FURTHER READING / REFERENCES. References: 1. Boyle P, Ferlay J. Cancer incidence and mortality in Europe 2004. Ann Oncol 2005 Mar;16(3):481-8. 2. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin 2008 Mar;58(2):71-96. 3. Steinberg GD, Carter BS, Beaty TH, Childs B, Walsh PC. Family history and the risk of

prostate cancer. Prostate 1990;17(4):337-47. 4. Andriole GL, Crawford ED, Grubb RL 3rd, Buys SS, Chia D, Church TR, et al; PLCO Project Team. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009 Mar 26;360(13):1310-9. 5. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al; ERSPC Investigators. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009 Mar 26;360(13):1320-8.

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J Urol 1994 May;151(5):1283-90. 8. Stamey TA, Freiha FS, McNeal J, Redwine EA, Whittemore AS, Schmid H-P. Localized prostate cancer. Relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer 1993 Feb;71(3 Suppl):933-8. 9. Donovan J, Hamdy F, Neal D, Peters T, Oliver S, Brindle L, et al; ProtecT Study Group. Prostate Testing for Cancer and Treatment (ProtecT) feasibility study. Health Technol Assess 2003:7(14):1-88.

10. Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol 2006 Mar:175(3 Pt 1):820-834. 84

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29. Beerlage HP, Thüroff S, Madersbacher S, Zlotta AR, Aus G, de Reijke TM, de la Rosette JJ. Current status of minimally invasive treatment options for localized prostate carcinoma. EurUrol 2000 Jan;37(1):2-13. 30. Aus G. Current status of HIFU and cryotherapy in prostate cancer–a review. EurUrol 2006 Nov;50(5):927-34. 31. Blana A, Walter B, Rogenhofer S, Wieland W. High-intensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience. Urology 2004 Feb;63(2)297-300.

32. Ahmed HU, Pendse D, Illing R, Allen C, van der Meulen JH, Emberton M. Will focal therapy become standard of care for men with localized prostate cancer? Nat ClinPractOncol 2007 Nov;4(11):632-42. 33. McLeod DG. Hormonal therapy: historical perspective to future directions. Urology 2003 Feb;61(2Suppl 1):3-7. 34. Walsh PC. Physiologic basis for hormonal therapy in carcinoma of the prostate. UrolClin North Am 1975 Feb;2(1):125-40.

35. Oefelein MG, Feng A, Scolieri MJ, Ricchiutti D, Resnick MI. Reassessment of the definition of castrate levels of testosterone: implications for clinical decision making. Urology 2000 Dec;56(6):1021-4. 36. Desmond AD, Arnold AJ, Hastie KJ. Subcapsular orchiectomy under local anaesthesia. Technique, results and implications. Br J Urol 1988 Feb;61(2):143-5. 37. Byar DP. Proceedings: the Veterans Administration Co-operative Urological Research

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40. Anderson J. The role of antiandrogenmonotherapy in the treatment of prostate cancer. BJU Int 2003 Mar;91(5):455-61. 86

41. Moffat LE. Comparison of Zoladex, diethylstilboestrol and cyproterone acetate treatment in advanced prostate cancer. EurUrol 1990;18(Suppl 3):26-7. 42. Moul JW. Twenty years of controversy surrounding combined androgen blockade for advanced prostate cancer. Cancer 2009 Aug;115(15):3376-8. 43. Samson DJ, Seidenfeld J, Schmitt B, Hasselblad V, Albertsen PC, Bennett CL, Wilt TJ, Aronson N. Systematic review and meta-analysis of monotherapy compared with

combined androgen blockade for patients with advanced prostate carcinoma. Cancer 2002 Jul;95(2):361-76 44. Ornstein DK, Rao GS, Johnson B, Charlton ET, Andriole GL. Combined finasteride and flutamide therapy in men with advanced prostate cancer. Urology 1996 Dec;48(6):901- 5. 45. Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, di’SantAgnese PA, Trump D; Eastern Cooperative Oncology Group study EST 3886. Immediate versus

deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 2006 Jun;7(6):472-9. 46. Abrahamsson PA. Potential benefits of intermittent androgen suppression therapy in the treatment of prostate cancer: a systematic review of the literature. EurUrol 2010 Jan;57(1):49-59. 47. Han M, Partin AW, Pound CR, Epstein JI, Walsh PC. Long-term biochemical disease-

free and cancerspecific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. UrolClin North Am 2001 Aug;28(3)555-65. 48. Rosser CJ, Chichakli R, Levy LB, Kuban DA, Smith LG, Pisters LL. Biochemical disease- free survival in men younger than 60 years with prostate cancer treated with external beam radiation. J Urol 2002 Aug;168(2):536-41. 49. Moul JW. Prostate specific antigen only progression of prostate cancer. J Urol 2000 Jun;163(6):1632-42.

50. American Society for Therapeutic Radiology and Oncology Consensus Panel. Consensus statement: guidelines for PSA following radiation therapy. Int J RadiatOncolBiolPhys 1997 Mar;37(5):1035-41. 51. Petros JA, Andriole GL. Serum PSA after antiandrogen therapy. UrolClin North Am 1993 Nov;20(4):749-56. 52. Kwak C, Jeong SJ, Park MS, Lee E, Lee SE. Prognostic significance of the nadir prostate specific antigen level after hormone therapy for prostate cancer. J Urol 2002 Sep;168(3):995-1000.

53. Tsai HK, D’Amico AV, Sadetsky N, Chen MH, Carroll PR. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 2007;99:1516-24. 54. Grossfeld GD, Stier DM, Flanders SC, Henning JM, Schonfeld W, Warolin K, Carroll PR. Use of second treatment following definitive local therapy for prostate cancer: data from the CaPSURE database. J Urol 1998 Oct;1609(4):1398-404. 55. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural

history of progression after PSA elevation following radical prostatectomy. JAMA 1999 May;281(17):1591-7. 87

56. Gomez P, Manoharan M, Kim SS, Soloway MS. Radionuclide bone scintigraphy in patients with biochemical recurrence after radical prostatectomy: when is it indicated? BJU Int 2004 Aug;94(3):299-302. 57. Connolly JA, Shinohara K, Presti JC Jr, Carroll PR. Local recurrence after radical prostatectomy: characteristics in size, location, and relationship to prostate-specific antigen and surgical margins. Urology 1996 Feb;47(2):225-31.

58. Heidenreich A, Semrau R, Thüer D, Pfister D. Radical salvage prostatectomy: Treatment of local recurrence of prostate cancer after radiotherapy. Urologe A 2008 Nov;47(11):1441-6. 59. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 2009 Mar;181:956-62.

60. Carroll P. Rising PSA after a radical treatment. EurUrol 2001;40(Suppl 2):9-16. 61. Trock BJ, Han M, Freedland SJ, Humphreys EB, DeWeese TL, Partin AW et al. Prostate cancerspecific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA 2008 Jun;299:2760-9. 62. Isaacs JT, Coffey DS. Adaptation vs selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation therapy as studied in the Dunning R-

3327-H adenocarcinoma. Cancer Res 1981 Dec;41(12 Pt 1):5070-5. 63. Attard G, Cooper CS, de Bono JS. Steroid hormone receptors in prostate cancer: a hard habit to break? Cancer Cell 2009 Dec 8;16(6):458-62. 64. Schröder FH. Progress in understanding androgen-independent prostate cancer (AIPC): a review of potential endocrine-mediated mechanisms. EurUrol 2008 Jun;53(6):1129-37. 65. Mohler JL, Gregory CW, Ford OH 3rd, Kim D, Weaver CM, Petrusz P, Wilson EM,

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67. Waselenko JK, Dawson NA. Management of progressive metastatic prostate cancer. Oncology (Huntingt) 1997 Oct;11(10):1551-60; discussion 1560-3, 1567-8. 68. Kelly WK, Scher HI, Mazurmdar M, Vlamis V, Schwartz M, Fossa SD. Prostate-specific antigen as a measure of disease outcome in metastatic hormone-refractory prostate cancer. J ClinOncol 1993 Apr;11(4):607-15. 69. Smith DC, Dunn RL, Strawderman MS, Pienta KJ. Change in serum prostate-specific

antigen as a marker of response to cytotoxic therapy for hormone-refractory prostate cancer. J ClinOncol 1998 May;16(5):1835-43. 70. Heidenreich A, Hofmann R, Engelmann UH. The use of bisphosphonates for the palliative treatment of painful bone metastasis due to hormone refractory prostate cancer. J Urol 2001 Jan;165(1):136-40. 88

71. Ryan CJ, Small EJ. Role of secondary hormonal therapy in the management of recurrent disease. Urology 2003 Dec;62(Suppl 1):87-94. 72. Kelly WK, Scher HI. Prostate specific antigen decline after antiandrogen withdrawal syndrome. J Urol1993 Mar;149(3):607-9. 73. McLeod DG. Antiandrogenic drugs. Cancer 1993 Feb;71(3 Suppl):1046-9. 74. Fowler JE Jr, Pandey P, Seaver LE, Feliz TP. Prostate specific antigen after gonadal androgen withdrawal deferred flutamide treatment. J Urol 1995 Aug;154(2 Pt 1):448-53.

75. Smith DC, Redman BG, Flaherty LE, Li L, Strawderman M, Pienta KJ. A phase II trial of oral diethylbestrol as a second line hormonal agent in advanced prostate cancer. Urology 1998 Aug;52(2):257-60. 76. Danila DC, de Bono J, Ryan CJ, Denmeade S, Smith M, Taplin M, Bubley G, Molina A, Haqq C, Scher HI. Phase II multicenter study of abiraterone acetate (AA) plus prednisone therapy in docetaxel-treated castration-resistant prostate cancer (CRPC) patients (pts):

Impact of prior ketoconazole (keto). J ClinOncol 27:15s, 2009 (suppl; abstr 5048) 77. Fosså SD, Jacobsen AB, Ginman C, Jacobsen IN, Overn S, Iversen JR, Urnes T, Dahl AA, Veenstra M, Sandstad B. Weekly docetaxel and prednisolone versus prednisolone alone in androgen-independent prostate cancer: a randomized phase II study. EurUrol 2007 Dec;52(6):1691-8. 78. 110. Ryan CW, Stadler WM, Vogelzang NJ. Docetaxel and exisulind in hormone- refractory prostate cancer. SeminOncol 2001 Aug;28(4 Suppl 15):56-61.

79. Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, Armitage GR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J ClinOncol 1996 Jun;14(6):1756-64. 80. Laplanche A, Beuzeboc P, Lumbroso J, Massard C, Plantade A, Escudier B, Di Palma M, Bouzy J, Haddad V, Fizazi K. A phase II trial of docetaxel and samarium in patients

with bone metastases from castration-refractory prostate cancer (CRPC). Abstract. J ClinOncol Jun 2007;25(18S): 5122. 81. George R, Jeba J, Ramkumar G, Chacko AG, Leng M, Tharyan P. Interventions for the treatment of metastatic extradural spinal cord compression in adults. Cochrane Database Syst Rev 2008 Oct:8;(4):CD006716. 82. Heidenreich A, Hofmann R, Engelmann UH The use of bisphosphonate for the palliative treatment of painful bone metastasis due to hormone refractory prostate

cancer. J Urol 2001 Jan;165(1):136-40. RESOURCES REQUIRED FOR ONE PATIENT /PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 2 89

Testicular Swelling – Testicular Torsion Prof. Nitin S. Kekre, Professor and Head Dr. Arabind Panda, Associate Professor Department of Urology CMC Medical College, Vellore General comments: Clinical guideline are supposed to be reflections of the best currently available evidence. They have 2 parts – c. A systematic review of the best available evidence and the strength of that evidence. I. The methodology of systematic review is important. This should be clearly

stated. All relevant studies should be studied. If Indian studies are available, then they should be included. The evidence should then be ranked using a standard system e.g. levels of evidence - Oxford Centre for Evidence-based Medicine [1]. If necessary relevant focused questions can be framed in order to exactly define the purview of the exercise. d. Recommendations for practice based on that evidence. These should be graded according to the level of available evidence.

The standard treatment guidelines for testicular torsion fail to mention if it is based on based on current literature following a systematic review. If the literature on testicular torsion lacks well designed studies that are amenable to a structured analysis, this should be mentioned. The evidence for the statements made here should be mentioned. There is no grading of the recommendations. If due to lack of sufficient high quality evidence this

document will largely be a consensus document, this should be mentioned. Review V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA Diagnostic criteria: 7. Blue dot sign – testicular appendix torsion – Unlikely to be seen in dark skin. This should be mentioned. Investigation The diagnosis of testicular torsion is mainly clinical as mentioned. In case of a strong suspicion of torsion testes, waiting for a USG ( with or without Doppler) can result in

significant delay and loss of viability. If at all a USG is to be included in the guideline, it should be accompanied by a rider that - in case of a strong suspicion of torsion testes the USG cannot be performed within 30 minutes, scrotal exploration is recommended. It should be emphasized that by no means should be time between presentation to the surgeon and exploration in strongly suspected cases exceed 1 hour. 90

Treatment It is not necessary to lay down the steps of surgery. Guidelines are not cookbooks. It is enough to recommend scrotal exploration and fixation of the contralateral testes. While fixation of the testes with in a subdartos pouch is a good technique, it is by no means the only technique. Concluding remarks With the above alterations, it will be suitable for publication. References: • Center for evidence based medicine, Oxford, UK http://www.cebm.net/index.aspx?o=1025. Accessed on 1st April, 2012. 91

NATIONAL PROGRAMME FOR PREVENTION AND CONTROL OF FLUOROSIS (NPPCF) REVISED GUIDELINES (2014) DIRECTORATE GENERAL OF HEALTH SERVICES MINISTRY OF HEALTH & FAMILY WELFARE GOVERNMENT OF INDIA

Foreword Fluorosis, a public health problem is caused by excess intake of fluoride through drinking water/food products/industrial pollutants over a long period. The duration for the clinical manifestation to appear varies depending on various factors like age, nutritional status, quantity of fluoride ingested, efficiency of kidney to excrete fluoride, etc. It results in major health disorders like dental fluorosis, skeletal fluorosis and non-skeletal fluorosis.

There is no treatment for severe cases of skeletal fluorosis, only efforts can be made towards reducing the disability which has occurred. However, the disease is easily preventable if diagnosed early and steps are taken to prevent intake of excess fluorosis through provision of safe drinking water, promote nutrition and avoid foods with high fluoride content. At present more than 14 thousand habitations are affected with fluoride levels higher than

the permissible limit with population at risk being 117.7 lakhs. With an aim to prevent and control Fluorosis cases in the country, Government of India initiated the National Programme for Prevention and Control of Fluorosis (NPPCF) as a new health initiative during 11th Five Year Plan in 2008-09 in a phased manner. 100 districts of 17 States were covered during 11th Plan and additional 95 new districts are being taken up in a phased manner during the 12th Plan.

Under the programme, assistance to States for strengthening manpower in endemic districts, purchase of equipment for lab including an Ion meter, training at various levels, health education and publicity, treatment including reconstructive surgery and rehabilitation and am hopeful that people in the affected districts will be benefitted considerably. I am glad that Nutrition & IDD cell is updating the guidelines for the National Programme for

Prevention and Control of Fluorosis which now includes details of qualifications, job responsibilities of contractual staff under NPPCF, specifications for ion meters, monitoring, dietary counselling etc among other things. I am sure these Guidelines will be extremely helpful in effective implementation of the NPPCF. Dr. Jagdish Prasad Director General of Health Services Ministry of Health & Family Welfare Page | 1

Preface The National Programme for Prevention and Control of Fluorosis (NPPCF) addresses a long felt need to take early measures for preventing onset of fluorosis in areas with high fluoride content in ground water. The Guidelines for National Programme for Prevention and Control of Fluorosis (NPPCF) were formulated in 2009, following a one day workshop held in Chennai. During the first meeting of the Technical Advisory Committee of NPPCF, held on 21st March 2014

under the Chairmanship of Dr. S.Y. Kothari, Special DG (PH), it was decided that guidelines be revised giving details of various components. After several discussions and circulation, the Guidelines have since been updated with no change in the objectives and strategy of the programme. We received valuable suggestions from some of the members of the Technical Advisory Committee but I would take this opportunity to specially thank Dr. A.K. Susheela, Executive Director, Fluorosis

Research & Rural Development Foundation, Delhi who has very diligently and sincerely worked on the several drafts of the Guidelines. I would also like to thank Ms. Kumkum Marwah, Research Officer (N) in Directorate General of Health Services for the effort and contribution to this document. Dr. Devesh Gupta Additional Director General of Health Services Page | 2

C O N T E N T S 1. Introduction 5 2. Goal and Objectives 6 3. Strategy 6 4. Expected Outcome 8 5. Programme Framework & Phasing during the 11th Five Year Plan 8 6. Activities 9 7. Infrastructure 12 8. Survey of Fluorosis in a Community 13 9. Capacity Building for various categories 16 10. Comprehensive Detection and Management of Fluorosis afflicted individuals 18 11. Information, Education and communication (IEC) for Prevention and Control of Fluorosis 20 12. Monitoring 22 13. Annexures

Annex 1 The list of districts covered upto 2014- 2015 . Annex 2 The qualifications and duties for the District Consultant, Laboratory Technician and Field Investigator Annex 3. The remuneration for the contractual staff Annex 4a Tool for assessing Dental Fluorosis Page | 3

Annex 4b Tool for assessing Joint Pain Annex 5a Precoded Proforma for survey of Dental Fluorosis (DF) and Bone deformities in School children Annex 5b Proforma for Class summary Annex 5c Proforma for School summary Annex 5d Proforma for Block summary Annex 5e Proforma for District summary Annex 6a Precoded Proforma for household survey (baseline data) Annex 6b Village summary of household survey Annex 6c Block summary of household survey Annex 6d District summary of household survey

Annex 7 Specification for ion meters Annex 8 Food items with high Fluoride (to avoid) and Recommended Foods Annex 9 Dietary Guidelines Annex 10 Format for Quarterly and six monthly Progress Report Page | 4

NATIONAL PROGRAMME FOR PREVENTION AND CONTROL OF FLUOROSIS Revised Guidelines (2014) 1. Introduction Fluorosis, a public health problem is caused by excess intake of fluoride through drinking water/food products/industrial emission over a long period. It results in major health disorders like dental fluorosis, skeletal fluorosis and non-skeletal fluorosis. The late stages of skeletal and dental fluorosis effects being permanent and irreversible in

nature are detrimental to the health of an individual and the community, which in turn has adverse effects on growth, development & economy of the country. The desirable limit of fluoride as per Bureau of Indian Standards (BIS) is 1ppm ( 1 mg per litre). Fluoride may be kept as low as possible as high fluoride is injurious to health . High levels of Fluoride were reported in 230 districts of 20 States (after bifurcation of

Andhra Pradesh in 2014) . The population at risk as per population in habitations with high fluoride is 11.7 million as on 1.4.2014 ( data from MDWS). It affects men, women and children of all age groups. In the endemic States, the geological crust is heavily loaded with fluoride bearing minerals and this fluoride leaches out into the drinking water. The drinking water fluoride so far detected in the country ranges from 0.2 to 48 mg/ litre. However, the

information on fluoride content in agricultural crops and other ready to consume food items and industrial emissions from various industries with high fluoride content is a matter of concern. Several of the ready to serve foods, beverages, snacks, etc. have high content of black rock salt (CaF2) or ‘kala namak’ which has 157ppm fluoride. There is a need to avoid fluoride from these sources for improving the health and preventing fluorosis. This can be achieved only through awareness programmes.

As the damage/change in skeletal system and teeth due to prolonged exposure to high fluoride levels is irreversible, the focus of management of fluorosis is on prevention, health promotion, deformity correction and rehabilitation. In order to address the problem of fluorosis in the country, Govt. of India started 100% centrally approved “National Programme for Prevention and Control of Fluorosis (NPPCF)” as a new health initiative during 11th Five Year Plan in a

phased manner. During the 11th Plan 100 districts from 17 States were identified for programme implementation. During the 12th Five Year Plan period it is proposed to add another 95 districts for prevention and control of fluorosis. Further, in the 12th Plan the programme has been brought under the NCD Flexi-pool of National Health Mission (NHM). The ratio of sharing of funds between Centre and State accordingly would be 75:25 and in case of North Eastern States would be 90:10 . Page | 5

2. Goal and Objectives The NPPCF aims to prevent and control Fluorosis disease in the country. (1) The Objectives of the National Programme for Prevention & Control of Fluorosis are as follows:To collect, assess and use the baseline survey data of fluorosis of Ministry of Drinking Water Supply for starting the project; (2) Comprehensive management of fluorosis in the selected areas; (3) Capacity building for prevention, diagnosis and management of fluorosis cases. 3. Strategy

Following is the strategy under the NPPCF A. Capacity building (Human Resource ) at different level of health care delivery system for early detection, management and rehabilitation of fluorosis cases. A.1 Training: Various types of training, advocacy and sensitization for various categories of health professionals /personnel at different levels of health care facilities such as Health workers, ASHA, Anganwadi Workers, Policy Makers, PRI’s, VHSC & Teachers will be undertaken at district level.

There will be Trainers Training for State Nodal Officer, District Nodal Officers, District Consultants at Head Quarter of any endemic State/any recognized Reference Laboratory by National experts. Besides, Laboratory monitoring/techniques (estimation of fluoride in urine) Training for Laboratory Technicians at any recognized National Reference Laboratory will be undertaken . A.2 Manpower Support: In order to implement the activities under the Programme manpower support at National

level and district level, one National Consultant and one DEO at Central level and one District Consultant, one Lab Technician and three Field Investigators (for six months ) on contractual basis in the district are provided. B. Surveillance of fluorosis in the community including school children Survey will be conducted by the district contractual staff in association with district health officials as per surveillance guidelines for assessment and diagnosis of fluorosis cases

including dental fluorosis in children in the age group of 6-11 years, skeletal and non- skeletal fluorosis at community level. After availability of baseline data Resurvey after three months of intervention activities Page | 6

C. Establishment of diagnostic facilities in the district/ medical hospitals: It is proposed to strengthen the laboratory diagnostic facilities in district/ hospitals/ medical college for early detection and confirmation of fluorosis cases. D. Management of fluorosis cases including treatment, surgery, rehabilitation: D.1 Early Detection The identified cases shall be confirmed by (i)physical examination i.e dental changes, pain

and stiffness of peripheral joints, skeletal deformities (ii) laboratory tests i.e. urine,and drinking water analysis for fluoride level and where possible (iii) radiological examination i.e. X-ray of forearm, X-ray of most affected part D .2 Prompt Intervention : The prompt intervention is planned in the following manner D.2.1 Health Education is very important aspect of management. Creating awareness about fluorosis disease, drinking water (safe/unsafe), diet editing and diet counselling

through interpersonal communication, group discussions, media, posters, wall paintings etc. Fluorosis is mainly caused due to excess intake of fluoride through drinking water/food products/industrial pollutants over a long period. Fluorosis is not diagnosed as fluorosis even by several of the medical professionals. This is because there is not much awareness of the problem from the health point of view. There is need to create awareness and skills

among the medical as well as paramedical health workers to detect the disease in the community. D.2.2 Provision of safe drinking water, water harvesting (rain water), other measures in collaboration with Public Health Engineering Department. D.2.3 Referral effective linkages would be developed from village level to district with the help of functionaries and personnel from grass root level (AWW, ASHA, PRIs etc.) PHC/CHC level Medical Officers, Health personnel School teachers and District level Officers.

D. 2.4 Medical Management Efforts are aimed to reduce the fluorosis induced disability and to improve quality of life of affected patients. Medical treatment is mainly supplementation of Vitamins C & D, Calcium, antioxidants and treatment of malnutrition. Treatment of deformity includes physiotherapy, corrective plasters, orthoses (appropriate appliances). Some cases of skeletal fluorosis may need surgery to rehabilitate them.

 All patients identified for deformity treatment and surgery will be referred to district hospital. Page | 7

 Those who need surgery will be given the appropriate treatment at the District hospital  Complicated cases that cannot be adequately handled at the District hospital will be further referred to the Medical College for expert treatment. 4. Expected Outcome The expected outcome of the National Programme for Prevention & Control of Fluorosis in the districts will be:- a) Number of fluorosis cases managed and rehabilitated in the programme districts

b) Capacity for laboratory testing for fluoride in water, urine to be developed. c) Trained health sector manpower in Government set up for measuring fluoride in urine and water d) Improve information base for the community and all concerned in the programme districts. 5. Programme Framework & Phasing The programme commenced implementation in100 endemic districts in 17 States/UTs in a phased manner during the 11th Five Year Plan. 2008-09 6 districts were selected from

each of the 6 zones of the country based on information collected from Ministry of Drinking Water and Sanitation. The activities included baseline survey, diagnosis of Fluorosis afflicted areas, capacity building by setting up/strengthening laboratory for fluoride estimation, training of medical and laboratory manpower, early detection and rapid management and awareness generations through Informative Education Communications (IEC) .

The districts taken up during 2008-09 were : a) Southern zone - Nellore (Andhra Pradesh) and Dharampuri, (Tamil Nadu) ; b) Western zone – Jamnagar, (Gujarat); c) Northern zone – Nagaur, (Rajasthan) ; d) Eastern zone – Nayagarh, (Odisha) ; e) Central zone – Ujjain, (Madhya Pradesh). Year wise addition of districts has been as follows: Year No. of districts 2008-2009 6 2009-2010 14 2010-2011 40 2011-2012 31 2012-2013 9 2013-2014 5 2014-2015 6 The list of districts covered upto 2014- 2015 is at Annex 1.

6. Activities Activities required to initiate the NPPCF 1. Procurement of Ion Meter and other items for Fluoride testing. 2. Training of Laboratory Technicians for 5 days in a reputed institution, where fluoride testing is a regular activity. 3. Training of Consultants on all aspects of Fluorosis – 2 days Programme activities 1. Community Diagnosis of Fluorosis village/block/cluster wise. 2. Facility mapping from prevention, health promotion, diagnostic facilities,

reconstructive surgery and medical rehabilitation point of view – village/block/district wise. 3. Gap analysis in facilities and organization of physical and financial support for bridging the gaps, as per strategies listed above. 4. Behavioral changes through appropriate IEC strategy . 5. All members having Fluorosis should be introduced to interventions and monitored to improve health. 3 months later, health complaints and UFL to be re-assessed. 6. Referrals for severe cases and their follow up

The Activities Proposed at 5 levels are tabulated below:- S. No. Activities Level 1. Community 1. The consultant along with field personnel will assess the entire endemic village and identify the persons suffering from (Village) any form of fluorosis, so as to reach to provisional field based diagnosis. 2. Awareness-cum-Training Programme for Medical Officers of PHC/CHC and District Hospitals about general symptoms of fluorosis and preventive management.Also for paramedical

workers, ICDS workers, PRI functionaries, teachers in the community 3. Line listing of water sources, identify and colour code safe Page | 9

sources to be introduced through the PHED. Intervention activities to be introduced for fluorosis prevention. Rehabilitative intervention, reconstructive surgery and Referral system for what is not possible locally 4. Behavioural changes to be introduced through appropriate IEC approach. 5. Inter-sectoral cooperation for interventions for Prevention and Control of Fluorosiswith special emphasis on identification and colour code of safe sources.

6. Selected interventions for prevention and health promotion to be introduced, behavioural changes, supply of safe drinking water. Monitoring and impact assessment are required. 7. Prevalence of fluorosis in a District to be recorded. Management of Non-skeletal Fluorosis would be achieved in a short span of time by introducing interventions. 2. Community 1. Similar activities to be introduced for CHC level staff and Health block level functionaries. Centres

(CHCs)/ 2. Training Programme for Clinical examination and FRU management of fluorosis cases – Medical officers, Health personnel of CHCs. 3. Training-cum-Awareness Programme for BDC, ICDS staff and Block level functionaries about different components of the Programme for proper supervision and implementation. 4. Diagnostic tests of urine fluoride level and skeletal fluorosis level assessment if facilities are available. 5. Monitoring the of village/PHC level activities 6. Referrals .

3. District 1. Similar activities as the CHC level to be introduced at District level. 2. Develop Fluorosis mapping of the district using water fluoride estimation data and dental fluorosis survey in school children 3. Detailed training Programme for Medical Officers & Health Personnel for comprehensive management of fluorosis cases to be drawn up and implemented. 4. Training-cum-Awareness Programme for DDC, ICDS and education personnel on various components of the programme . Page | 10

5. Diagnostic support for dental, skeletal and non-skeletal fluorosis to be established in a District. 6. Basic medical, surgical and rehabilitative activities for cases diagnosed by district level specialists. 7. Monitoring. 8. Referral of difficult cases to near by Medical College Hospital. 9. The CMO of the district will be the Nodal Officer for NPPCF. 4. State 1. Programme Planning, execution of programme activities, monitoring, mid-term evaluation and reporting to the Centre

(GOI) through the State Nodal officer. 2. Receipt and disbursement of allocation. 3. Utilization certificate processing and physical progress to be submitted to the Centre (GOI) as per proforma. 4. Assisting Central Team in follow-up activities. 5. The SNO to regularly monitor the progress in the districts 5. Centre 1. Programme Development, Programme Planning & implementation through States/UTs. 2. Fund management and release to the States/UTs 3. Supervision, Monitoring and impact assessment.

Time Schedule of the Activities S. Activity for New Districts Duration for recruitment/procurement No. 1. Appointment of District Level Consultant, Lab Technician 2 months and Field Investigators (3 for 6 months) 2. Procurement of laboratory equipment – Ion Meter etc l 4 months 3. Training of Medical Officers / Doctors at district level, 4 months CHCs and PHCs 4. Community level assessment and diagnosis of fluorosis 6 months after cases appointment

5. Comprehensive management of fluorosis cases identified After six months of among the community launching of the programme 7. Infrastructure Under the programme there are no regular posts that have been sanctioned either at the Central level or the district level. Coordination of the programme at the Central level is to be done by Adviser Nutrition/ Incharge of Nutrition and IDD in the Directorate General of Health Services, at the State level by the State Nodal officer and at the District level by the

District Nodal officer. The contractual staff under the programme is as follows: National Level National Consultant (1) DEO (1) District Level District Consultant (1) Lab Technician (1) Field Investigator ( 3 for six months) The qualifications and the duties required for the Consultants ( National and District level), Laboratory Technicians and Field Investigators are at Annex 2. The remuneration for the contractual staff may be seen at Annex 3. Page | 12

8. Survey of Fluorosis in a Community The magnitude of fluorosis problem in an endemic area needs to be assessed based on appropriate surveillance tools including case definitions, adequate and proper sampling, and survey methodology for taking preventive measures, health promotion activities, deformity correction and rehabilitation of cases. Under the National Programme for Prevention and Control of Fluorosis, the district

laboratory is established/ strengthened for confirmation of fluorosis cases, the district cell under district Nodal Officer is created, staffed with Consultant, Lab Technician and Field Assistants and funds are provided for mobility, support for undertaking community based activities. The survey would also generate the database for impact assessment of the programme. The case definition, sampling procedure and survey methodology are as under: A. Case Definition 1. Suspect Case:-

 Dental Fluorosis ( in children ): Any case with a history of residing in an endemic area along with one or both of the followings:  Chalky white teeth / white spots on the white enamel surface  Transverse yellow, brown / black bands or spots on the enamel surface (Discoloration away from the gums and bilaterally symmetrical)  Skeletal Fluorosis Any case with a history of residing in an area with Fluoride above 1.0 mg/l along with one or more of the followings health complaints.

 Severe pain and stiffness in neck, back bone (lumbar region), shoulder, knee and hip region. Pain may commence either in 1 or 2 or more joints. Patient has restricted mobility of cervical and /or lumbar spine and has to turn the whole body towards that side to see  Knock knee/ Bow leg (In children, adolescents )  Inability to squat ( advanced stage of Skeletal Fluorosis )  Ugly gait and posture ( advanced stage of Skeletal Fluorosis )  Non-Skeletal Fluorosis

Any case with a history of residing in an endemic area along with one or more of the following health complaints. Gastro-intestinal problems: Consistent abdominal pain, intermittent  diarrhea/Constipation, bloated feeling, nausea, loss of appetite. Page | 13

 Neurological manifestations: Nervousness & depression, tingling sensation in fingers and toes, excessive thirst and tendency to urinate frequently (Polydipsia and polyuria)  Muscular manifestations: Muscle weakness & stiffness, pain in the muscle and loss of muscle power, unable to walk or work. [ Fluorosis endemic area refers to a habitation/village/ town having fluoride level more than 1.5 ppm in drinking water . It is also possible that the drinking water

fluoride may be safe with Fluoride <1.5 mg/l; but have all health complaints of Fluorosis. Fluoride entry to the body may be due to food / beverages / snacks / street food with Black Rock Salt consumption which has 157ppm F ].  It is important to identify Non-Skeletal Fluorosis as it is the earliest signs of Fluoride toxicity. 2. Confirmation of a Case: Any suspected case can be confirmed after retrieval of a clinical history, by the following tests:

 Any suspected case with high level of fluoride in urine (>1mg/L).  Any suspected case with interosseous membrane calcification in the forearm confirmed by X-ray Radiograph.  Any suspected case, if kidney ailment is prevailing, serum fluoride need to be tested, besides urine fluoride. B. Sampling procedure The information on fluorosis endemic areas along with fluoride level in the drinking water sources is to be obtained from Public Health Engineering Department (PHED) of the respective endemic states.

The survey for fluorosis would be conducted by the officials of district programme cell in the fluorosis endemic areas through stratified sampling procedure Urine analysis for fluoride is to be undertaken for suspected cases, both in the schools and the community 1. Based on the level of fluoride content, the villages can be identified in the following 3 categories: Strata Fluoride Level I upto 1.0 – 3.0 ppm II 3.1 – 5.0 ppm III > 5.0 ppm

2. For prevalence of fluorosis cases, 10% villages of each strata will be selected randomly. If number of villages is up to 20, then all the villages will be surveyed. If number of villages is more than 20, then 10% of villages from each strata (at least 20 villages in total) will be surveyed. Page | 14

3. All the children in the age group of 6 to 11 years from the primary school (3rd to 5th standard) in villages of a block will be surveyed for prevalence of dental fluorosis. 4. Survey for skeletal and non-skeletal fluorosis cases would also be carried out in at least 20 households of each of the randomly selected villages of the district where dental fluorosis is prevalent in school children. C. Survey Methodology Two types of surveys are expected to be carried out _ the school and the community

survey. The tools for assessing Dental Fluorosis is provided at Annex 4a and tool for assessing the Joint pain, ie., the physical tests, is provided at Annex4b. . The school survey is for Dental Fluorosis (DF) in School children. The base line data for DF and visible Bone Deformities (BD) in School children is assessed class by class. Precoded proforma for baseline data collection for DF and BD survey is provided in Annex 5a Thereafter, a class summary is developed as per the format in Annex5b; All class

summaries in a School would lead to a School summary - Annex 5c. Similarly, there would be a Block and District summaries – Annex 5d and 5e respectively. In the community survey, the base line data of all the members of the selected households is collected as per Annex 6a. Thereafter a village summary has to be developed. Details in Annex 6b. Similarly, when all household surveys in a Block and a District are completed, Block and District level summaries are brought out as per Annex 6c and 6d respectively.

Analysis of urine sample Urinary analysis is carried out using an Ion meter. The specifications for the Ion meter are at Annex 7 Sample Collection (Urine and Water) : 1. 30ml of spot urine sample of the suspected cases will be collected in a plastic screw capped bottles (not glass bottles). 2. Put 1 - 2 drops of toluene (AR grade) on urine samples to make a complete layer. 3. Each sample should be properly labeled with number and relevant details.

4. Similarly 30 ml water sample will also be collected from the source and not from any container in the kitchen. Page | 15

Transportation of samples:  Urine samples should be sent to district laboratory as early as possible; store in a refrigerator.  Water Samples can be kept at room temperature at district laboratory if not being analyzed immediately; urine should be stored in refrigerator.  Analysis to be done using ION METER only. Date of testing and method used for testing to be specified in the report.  Report should be sent to State Nodal officer on the pre-designed Proforma. When

one village is completed, the data sheet to be shared with Additional DDG, DGHS, New Delhi. 9. Capacity Building Capacity building is taken up at the Central as well as the district levels. The training of doctors including State, District programme officers and the Consultants as Training of Trainers (TOT) as well as training of Laboratory technicians is organized centrally. The health workers, community based health link workers

(ASHA & AWW), sensitization of policy makers, PRIs, VHSC and school teachers in the programme is a key step for its successful implementation is taken up at the district level. Page | 16

Training Schedules Venue Trainers Trainees Method of Training contents Duration training Medical officers 2 days District HQs / National 20-25 Presentation, Clinical identification of including State State HQs/ le v e l e x p e r t s discussion & cases of dental, non- and District National demonstration skeletal and skeletal programme Institution fluorosis, fluoride toxicity, officers, diagnostic tests, Consultants radiological findings, fluorosis surveillance strategy, training, comprehensive

management of fluorosis cases, IEC to change the behaviour of the community Issues which may confront doctors ( non responding to orally administered drugs) Lab. 5 days Recognised Faculty of 20 Lecture-cum- Handling of Ion meter and Technician laboratory the Lab/Org. demonstration: Ion selective electrode, Internal and standardization of External Quality technique, collection, Control storage, preservation and Procedures; transportation of urine accuracy of testing samples. Use of variable

and reproducible pipettes. Estimation of results. fluoride in Urine blood and water and interpretation of results. Paramedics One day District HQ. Faculty from 25-30 Lecture and Clinical identifications of District Discussion, power cases of non-skeletal, Hospital, point presentation Dental and Skeletal who has fluorosis in field undergone areas/community. training on Radiological findings, Fluorosis Comprehensive management of cases, Nutritional interventions and IEC.

ASHAs and Half day PHCs of District 30-35 Lecture and Details about fluorosis, ANMs Workers endemic Nodal discussion in local demonstration of fluorosis village/CHCs Officer/Distri language, using cases (Dental/skeletal), ct Powerpoint prevention and control, Consultant/ presentation IEC and nutritional CMO district interventions monitoring. Hospital who have undergone training on Fluorosis. Policy makers Half day District HQ. State Nodal 25-30 Lecture-cum- Details about the burden

(PHE, Dept of sensitisati Officer/Cons demonstration of fluorosis in the country, child dev., on ultant/ powerpoint morbidity, clinical feature school health, District presentation and interventions. education etc) trainers Advocacy PRI & ½ Day District HQ Faculty from Block level Lecture and Consequences, VHSNC & State/District workers discussion, importance of prevention, Teachers Hospitals/ powerpoint nutritional interventions, District presentation IEC trainers Page | 17

10. Comprehensive Detection and Management of Fluorosis afflicted individuals The following guidelines were accepted for implementation of the National Programme on Fluorosis on the recommendation of the Expert Group which met in June 2009:- A. Early Detection of fluorosis B. Prompt Intervention A. Early Detection:- It includes History retrieval, physical and radiological examination (if X-rays are available). During physical testing the cases are to be identified as suspected cases to

be confirmed later by testing urine fluoride level and drinking water fluoride. The symptoms of the suspected cases are as follows:- a) Dental changes – chalky white tooth with mottled appearance b) Pain & stiffness of major joints ( not the joints in toes and fingers ) c) Deformities of lower limb in children. d) Most importantly history of complaints – with focus on Non-skeletal Fluorosis The confirmation of the cases shall be undertaken by following methods: a) Physical tests

b) Radiological examination (if X-rays available ). i. X-ray of forearm (AP view) ii. X-ray of most affected part (AP and lateral views) c) Laboratory tests i. Urine analysis for fluoride level ii. Serum analysis for fluoride level (Not for community approach) iii. Analysis of drinking water for fluoride level B. Practice of Interventions for recovery The practice of Interventions is to be planned in the following manner: i. Preventive measures – This involves Diet Editing and Diet Counseling –

( Diet Editing = Removal of fluoride consumption. Diet Counseling = Promotion of nutrients through diet ). Testing urine fluoride level after 3 months. ii. Treatment – Fluorosis disease has no treatment. Medicines like, Calcium, Vit. C & D may be prescribed; but dietary intervention is the best. iii. Rehabilitation, if required, to be addressed. Page | 18

i) Health Education is very important aspect of the total management. It is to be undertaken in the following way:  Creating disease awareness among the community, State Health Dept., Doctors in all avenues  Creating awareness about source of water (safe/unsafe) by: IEC, media, posters, wall paintings, etc. ii) Preventive Measures: a) Providing defluoridated safe drinking water / if available; OR shift to safe ground water sources existing. ( through correct testing of Fluoride by the Consultant /

Technician of NPPCF). b) Changing dietary habits o avoid use of fluoride rich foods, Black rock salt o avoid use of fluoride rich Dental products / drugs o use of food rich in calcium, vitamin ‘C’, anti-oxidants, etc. c) Water harvesting (rain water), so that safe ground water not depleted. d) health education with focus on fluoride toxicity and the need to avoid fluoride consumption. iii) Treatment: Though the cure for fluorosis has not been documented, some efforts can be aimed

at: Reducing the fluorosis induced disability and improving quality of life of affected persons The treatment has two components: a) Supplementation with Vitamin ‘C’; Vitamin ‘D’; Antioxidants; Calcium; and correction of malnutrition. Even better is to ensure nutrient rich vegetables and fruits, dairy products etc b) Treatment of deformity (i) It may be Rickets; Urine and Drinking water Fluoride tested; reduce fluoride to normal range – 0.1 – 1.0 g/l

(ii) Surgical management: The surgery is indicated in selected cases for decompression of spine in case of compressive myelopathy and pathological fractures. Otherwise refer to tertiary care hospital for above management. The problem of early stages decompression, the Orthopaedic Surgeon or Neuro- Surgeon to decide based on the cases. Page | 19

(iii) Rehabilitation: Apart from treatment of deformity there is provision of providing free mobility aids like crutches, wheel chairs, tricycle etc., as prescribed by specialists for the affected persons. (iv) Physiotherapy Corrective plasters are to be given in a child aged 3 years having Genu Valgum where inter malleolar distance is > 3 inches. The corrective plaster (Plaster of Paris) is to be given repeatedly at 3-4 weeks interval and meanwhile the child is to be given medical

treatment. Every child will require approximately 5-6 corrective plasters which shall be followed by appropriate lower limb orthoses / appliances. The same method can be applied for Genu Varum where intercondylar distance is to be measured before & after completion of treatment. Orthoses: Correction of knee deformities can only be maintained by appropriate appliances like Mermaid Splint, KAFO (Conventional/ Metallic / Plastic). Some cases

may require special orthopaedic shoes for correction & maintenance. The appliances may be required for few years till child is growing. The selected districts are expected to provide these facilities. 11. Information, Education and communication (IEC) for Prevention and Control of Fluorosis The IEC Plan covering awareness generation and to bring behavioural changes at the community level in affected districts are very important in order to prevent and control

fluorosis in the community. For this, there is a need to educate community about adverse health effects of drinking water with high level of fluoride (above 1 ppm). To educate the community about the safe drinking water sources in their habitation and rain water harvesting measures to be adopted at the Panchayat Raj Level, are essential interventions. Besides water contamination with fluoride, community should be sensitized to avoid all

food items contaminated with Black Rock salt ( Vrat ka namak – a high source of fluoride). The district level media team would be entrusted with the job of advocating with the various functionaries of the district including community level workers namely, ASHA, ANM, School teachers, Panchayat Members, etc. The details are tabulated below:- Page | 20

National & State Level a) Website of Ministry of Health & F.W., b) Press release in National/State Papers regarding the Programme, c) Co-ordinate with Ministry of Rural Development to provide alternate source of water and list the sources on internet. District level activities Media/Agency Method Frequency Content 1. Local news papers a) Press Release At initiation of the Aims & Objectives of the b) Questions & Prog. & repeat after Prog. Services provided, Answers six months symptoms, preventive measures

2. Local T.V. a) Video spot – Alternate days Causes of Fluorosis 30seconds(before one of Treatment facilities Safe the most popular drinking water sources programme in the areas) b) Interviews with experts Twice in a year Questions & Answers 3. Local Radio a) Audio spots Once a day Cases of Fluorosis Treatment facilities Safe b) Question & Answer Thrice in a year drinking water sources Session 4. Hospitals/Dispensary/ a) Posters (local language) Repeat every year Treatment facilities, Dietary

interventions, Safe drinking CHCs/PHCs water 5. Directorate of Field a) Group discussion, Twice in a month Treatment facilities Safe Publicity, Song & b) Nukkad Natak drinking water sources c) Songs Drama Division d) Seminars, etc. e) Films 6. Health Personnel ANM, a) Discussion & inter personal Every day Treatment facilities Safe ASHA, Mahila Mandal communications drinking water sources Representatives 7. Schools/Home Science a) Posters One in a year Safe drinking water sources,

Colleges in the area b) Discussion with teachers Avoid unsafe sources c) Film show 8. Doctors both Private & a) Seminar at district level One day, once in a Identification of Fluorosis Govt. Hospitals year to cover all cases, their referral and concerns comprehensive management 9 Public Health a) Awareness meeting at One day, once in a Need to have safe sources Engineering Department district level month to cover all of water; Harmful effects of personnel concerned districts Fluorosis

Slogans for Prevention and Control of Fluorosis a) Peele dant, haddi jam yeh hay pani mey fluoride ka kam. b) Doodh, dahi, hari sabzi khao, fluorosis se mukti pao. c) Peeney ke pani mey fluoride hay jahan fluorosis hay vahan. d) Peeney ke pani ki janch karo, apenko fluorosis se bachao. Page | 21

Diet Counselling Diet Counselling is a very important aspect in prevention. Besides bringing in change towards drinking of safe water it is also important that foods with high fluoride levels are avoided. The list of foods to be avoided as well as recommended foods are at Annex 8. Reinforcement of balanced diet with plenty of fruits and vegetables to provide the vitamins and minerals is a must. It is observed that in persons with good nutrition status the

adverse effects of higher fluoride are much lower. People also need to be aware that besides water it is also important to avoid foods with high fluoride content. The Dietary Guidelines may be seen at Annex 9. 12. Monitoring Regular monitoring by the District Nodal Officer and the State Nodal Officer is required. The monthly report of all activities undertaken along with the expenditure incurred at the district level should be sent by the District Nodal Officer to the State Nodal officer and

should reach the State by 10th of each month. . The quarterly report is also to be sent by the District Nodal Officer which is to be examined by the State Nodal officer and forwarded to the Central Fluorosis cell and should reach by 15th of the subsequent month after the quarter as per the same format at Annex 10 . Information at Serial Number 1 and 2 may not be provided for the quarterly reports but in case of any change in status of District Consultant or Lab Technician, the same may be informed.

The six monthly report as per the format at Annex 10 along with the cumulative progress , should be sent to the Centre by 15th of October and 15th April every year by the State Nodal officer. Utilisation certificates and the Statement of expenditure to be forwarded to the centre every six months. Page | 22

Annex 1 Year wise selected districts under National Programme for Prevention and Control of Fluorosis: Year State Districts 2008-09 Andhra Pradesh 1. Nellore Gujarat 2. Jamnagar Rajasthan 3. Nagaur Madhya Pradesh 4. Ujjain Orissa 5. Nayagarh Tamil Nadu 6. Dharmapuri 2009-10 Assam 7. Neygaon Bihar 8. Nawada Chhattisgarh 9. Durg Andhra Pradesh 10. Nalgonda Jharkhand 11. Palamau Karnataka 12. Mysore, 13. Bellary Kerala 14. Pallakad Maharashtra 15. Chanderpur 16. Nanded Punjab 17. Sangrur

Uttar Pradesh 18. Unnao, 19 RaeBarelli West Bengal 20. Bankura 2010-11 Andhra Pradesh 21. Karimnagar, 22. Prakasam Assam 23. K.Long, 24. Kamrup Uttar Pradesh 25. Pratagarh, 26. Firozabad Karnataka 27. Chikkaballapur, 28. Kopel, 29. Davangere, 30. Tumkur Madhya Pradesh 31. Dhar, 32. Seoni, 33. Chindwara, 34. Mandla Punjab 35. Firozpur Haryana 36. Mahendragarh, 37. Mewat Bihar 38. Banka, 39. Aurangabad, 40. Bhagalpur, 41. Gaya, 42. Jammui, 43. Nalanda, 44. Shekhpura Jharkhand 45. Garhwa, 46. Chatra

Orissa 47. Angual, 48. Naupada Gujarat 49.Sabarkantha Rajasthan 50. Ajmer, 51. Rajsamand, 52. Bhilwara, 53. Tonk, 54. Jodhpur Maharashtra 55. Latur, 56. Washim, 57. Yavatmal W. Bengal 58. Birbhum, 59. Purlia, 60. D.Dinajpur 2011-12 Andhra Pradesh 61. Guntur, 62. Mehboob Ngr. Bihar 63. Kaimur, 64. Munger Jharkhand 65. Hazaribagh Kerala 66. Alppuzha Maharashtra 67. Beed Uttar Pd. 68. Mathura W. Bengal 69 Maldha Karnataka 70. Bangalkot , 71. Bangalore(U), 72. Bijapur, 73. Raichur, 74. Chitra Durga, 75. Gadag,

76. Gulbarga, 77. Hassan, 78. Kolar, 79. Mandia 80. Ramnagaram 81.Shimoga Page | 23

Rajasthan 82. Bikaner, 83. Churu, 84. Dausa, 85. Dungarpur, 86. Jaipur, 87. Jaisalmer, 88. Jalore, 89. Pali, 90. Sikar, 91. Udaipur Madhya Pradesh 92. Betul, 93. Jhabua, 94. Raigarh, 95. Sehore, 96. Alirajpur, 97. Dindori, 98. Khargoan, 99. Raisen 100. Shajapur 2013-14 Rajasthan 101. Banswara, 102. Sawai Madhopur Chhattisgarh 103. Kanker Gujarat 104. Vadodra J&K 105. Doda 2014-15 Rajasthan 106. Karauli, 107. Chittaurahgarh, 108. Ganganagar 109. Jhalawar, 110. Jhunjhunu Gujarat 111. Banas kantha Page | 24

Annex 2 Qualifications for District Consultant Qualifications for the District Consultant and Laboratory Technician have been communicated vide letters No. G.20011/3/2011-Nut&IDD Cell dated 11th May 2012, 17th September 2012 and 15th July 2013. Overall, the qualifications are as below: District Consultant (Fluorosis) 1. Essential Qualification (a) For Medical Person: Post Graduate Degree (MD) in Community Medicine/ Public Health/ Biochemistry/ Microbiology/ Pathology/ Community Resource

Management/ Environment Health or equivalent. OR (b) For Non Medical Person : Doctorate Degree (PhD) in Biochemistry/ Nutrition/ Microbiology/ Molecular Biology/ Life Sciences/ Public Health/ Community Resource or equivalent 2. Desirable At least 3 years experience after Post Graduate medical qualification/Doctorate qualification for non medical in research/ teaching/ laboratory services/ programme implementation etc. Note : In case of non-availability of medical person with MD Qualification or Non

Medical person with PhD qualification, the essential qualification can be relaxed for medical person as MBBS/ BDA or for Non Medical person as M.Sc in the subjects specified above. The desirable experience in such cases where relaxed qualifications are being considered would be 6 years in research/ teaching/ laboratory services/ programme implementation etc. Laboratory Technician 1 post Qualification as per State Government recruitment. Field investigators ( for six month only) 3 posts

10+2 with science at least 50% aggregate marks. Preference will be given to candidates with 60% & above marks. Page | 25

Job Responsibilities District Consultant (Fluorosis) o To conduct Survey for assessment of magnitude of fluorosis in the district o To collect the information of fluoride levels in water from PHED dept & mapping the endemic villages of the districts. To establish the laboratory for fluoride estimation of water, urine and serum o To assist in training programmes for various categories of personnel o Monitoring and maintenance of data base

o To coordinate for IEC and BCC activities for generating awareness and behavioral changes about Fluorosis in endemic districts o Coordination with DHS/State Nodal Officers, Public Health Engineering Department (PHED) and other stakeholders o Preparation of reports and regular reporting of data o Line listing of fluoride affected villages, Lab facilities available in district for fluoride testing, persons who can benefit with medical intervention in

consultation with M.O, and Centres/ hospitals for corrective surgeries Lab Technician:  To collect water and urine samples from schools and villages for analysis of fluoride level.  Analysis of the samples  To submit laboratory reports to District Consultant/ District Nodal Officer regularly  To assist in preparation of reports  Assist in training and IEC activities Field Investigators:  To assist in conducting survey for dental fluorosis in school children and skeletal and

non-skeletal fluorosis in villages.  Assist in collection of water and urine samples  Compilation of survey data and reports Page | 26

Annex 3 Remuneration of Contractual Staff : Contractual staff Remuneration the 12th Plan Earlier provisions National Level National Consultant Rs. 60,000/-pm. Rs. 50,000/- p.m DEO (Central level) Rs. 15,000/- Rs. 6,500 District Level District Consultant Rs. 45,000/-pm Rs. 35,000/-pm Lab.Technician Rs. 11,000/-pm Rs. 10,000/-pm Field Investigators Rs. 11,000/-pm Rs. 10,000/-pm (3 for six months) Page | 27

Annexure IV(a) DENTAL FLUOROSIS 1 2 White, Yellow spots on the teeth. Spots Chalky white appearance of teeth with away from the gums and seen as pits (arrow). horizontal streaks and in pairs (arrow). 3 4 Teeth Teeth showing brown or black showing yellow or brown horizontal spots (arrow) lines (arrow) ½ DENTAL FLUOROSIS & DIRTY DENTAL CARIES TEETH Cavities between 2 teeth or under the Upper teeth showing Dental gums. Different disease than Dental Fluorosis & Lower showing Dirty Fluorosis.

Annexure IV(b) Annexure IV(b) How to test pain in major joints (possibly Skeletal Fluorosis) Page | 29

Annexure – 5a SCREENING FOR DENTAL FLUOROSIS (DF) & BONE DEFORMITIES (BD) IN SCHOOL CHILDREN NAME OF THE SCHOOL & ADDRESS: _____________________________________________________________________________________________ CLASS: SECTION: STRENGTH OF STUDENTS : STUDENTS PRESENT ON THE DAY OF SURVEY: TOTAL STUDENTS WITH DF: TOTAL STUDENTS WITH BD: N S O . . NAME OF THE STUDENTS SEX (M/F) A (Y G R E S. ) H (T E IC A K L siso roulf latn F eD I T F H Y E C S O ) MPL T R O H S A E R U T A T S INTS

W O B S G E L K C O N K E E N K N V F S W H R I T A A L IT U O M I L L H D M A E S E D G O W F N F E R F T H , & O E T M B H R D E E THE E L P M A S E N IR D E D IV O R P )N /Y ( F U L R U IN O E R S ID A E M C P O LE N T ( E m N g T / l I ) N 1 D U • 2 • 3 • 4 • 5 • 6 • 7 • 8 • 9 • 10 • NAME OF THE CLASS TEACHER: ______________________________________ SIGNATURE: _____________________ DATE: NAME OF THE Prog official & ________________________________________ SIGNATURE: _____________________ DATE:

designation: * School Code No., Name of the student, Class, Section, should be written on the plastic bottle during urine samples collection ** Use extra sheet(s), if the number of students afflicted with DF in one class is more than 10.

Annexure – 5b CLASS SUMMARY SURVEY OF DENTAL FLUOROSIS (DF) & BONE DEFORMITIES (BD) IN SCHOOL CHILDREN Date of Survey: ______________ Code no. of the school: Name of the __________________________ Name of the ________________ school: GP/Municipality: Name of the block: _________________________ Village name /Ward no. ___________________ 1. Total nos. of students in the class: 1a. Nos. of boys: 1b. Nos. of girls: 2. Total nos. of students examined for 2a. Nos. of boys: 2b. Nos. of girls: DF/BD

3. Total nos. of students examined for BD 3a. Nos. of boys: 3b. Nos. of girls: 4. Total nos. of students afflicted with BD 4a. Nos. of boys: 4b. Nos. of girls: 5. Total nos. of students afflicted with DF & 5a. Nos. of boys: 5b. Nos. of BD: girls: 6. Total nos. of villages from where the students afflicted with DF & BD hails from: Name of the Prog. Official: __________________________________________________________________________________________________________ Signature: Date:

Annexure – 5c SCHOOL SUMMARY (SUMMARY OF CLASSES (3to 5) IN A SCHOOL) SURVEY OF DENTAL FLUOROSIS (DF) & BONE DEFORMITIES (BD) IN SCHOOL CHILDREN 1. Total nos. of students in class 3 to 5 1a. Nos. of boys: 1b. Nos. of girls: the school: 2. Total nos. of students examined for DF 2a. Nos. of boys: 2b. Nos. of girls: 3. Total nos. of students afflicted with DF 3a. Nos. of boys: 3b. Nos. of girls: 4. Percentage of students afflicted with 4a. % of boys: 4b. % of girls: DF:

5. Total nos. of students afflicted with 5a. Nos. of boys: 5b. Nos. of girls: BD 6. Percentage of students afflicted with 6a. % of boys: 6b. % of girls: BD: 7. Total nos. of students afflicted with DF & Percentage of students BD: 8. Total nos. of villages from where the students afflicted with DF & BD hails from: (a) Nature of source(s): HP TW OW RW RO PWS Any other: _________ (b) F ‾ content in water source in (i) • mg/l (ii) • mg/l school:

Name of the Coordinator, who summarized the data: ____________________________________________________________________________ Signature: Date:

Annexure -5d BLOCK SUMMARY (SUMMARY OF SCHOOLS Surveyed IN A BLOCK) SURVEY OF DENTAL FLUOROSIS (DF) & BONE DEFORMITIES (BD) IN SCHOOL CHILDREN 1.a Total nos. of schools in the block: 1b Total nos. of schools surveyed in the block: 2. Total nos. of students in the block: 2a. Nos. of boys: 2b. Nos. of girls: 3. Total nos. of students examined for DF 3a. Nos. of boys: 3b. Nos. of girls: 4. Total nos. of students afflicted with DF 4a. Nos. of boys: 4b. Nos. of girls:

5. Percentage of students afflicted with 5a. % of boys: 5b. % of girls: DF: 6. Total nos. of students afflicted with BD 6a. Nos. of boys: 6b. Nos. of girls: 7. Percentage of students afflicted with 7a. % of boys: 7b. % of girls: BD: 8. Total nos. of students afflicted with DF & 8a. Percentage of students BD: 9. Total nos. of villages from where the students afflicted with DF & BD hail from: Name of the coordinator:

Annexure – 5e DISTRICT SUMMARY (Summary of schools surveyed in all blocks) SURVEY OF DENTAL FLUOROSIS (DF) & BONE DEFORMITIES (BD) IN SCHOOL CHILDREN 1. Total nos. of schools surveyed in district: 2. Total nos. of students in all the blocks: 2a. Nos. of boys: 2b. Nos. of girls: 3. Total nos. of students examined for DF 3a. Nos. of boys: 3b. Nos. of girls: 4. Total nos. of students afflicted with DF 4a. Nos. of boys: 4b. Nos. of girls:

5. Percentage of students afflicted with DF: 5a. % of boys: 5b. % of girls: 6. Total nos. of students afflicted with BD 6a. Nos. of boys: 6b. Nos. of girls: 7. Percentage of students afflicted with BD: 7a. % of boys: 78b. % of girls: 8. Total nos. of students afflicted with DF & BD: 8a. Percentage of students 9. Total nos. of villages from where the students afflicted with DF & BD hails from: Name of the coordinator:

Annexure – VI a (page 1of 2) PROFORMA FOR HOUSEHOLD LEVEL BASELINE SURVEY x`g Lrj dh lpw uk gsrq izi= Proforma No. Name of the village: ___________________________ Name of the Block: _______________________ izk:i la[;k xkao dk uke CYkkWd dk uke (Tick ) 1. Name of the head of the family: _________________________________________________ 2. Are you aware / heard of fluoride poisoning / Fluorosis disease? Y gkW

Ikfjokj ds eqf[k;k dk uke D;k vkius a ¶yksjkbM fo"kfDrdj.k ;k ¶ykjs kfs ll chekjh ds ckjs es a lquk gSA N ugha (Tick ) (Tick ) 3a. Source of drinking water: Private Public 3b. Type of source(s): HP TW OW RW PSW Pond Any other (Specify): ___________ ihus ds ikuh dk L=ksr f u t h ljdkjh L=ksr dk izzdkj gS.MiEi uydwi [kqyk dqvk o"kkZ ty uy dk ikuh Rkkykc vU; ¼Li"V dj½s Øekad 4 ls 8 rd ds ckDl] ist u- 2 dh izfof"B ds i'pkr HkjsaA Fill the following box (S. No. 4 to 8) after filling the Page 2:

4a. Total no. of family members: 4b. Male 4c. Female: ifjokj ds lnL;ks a dh dqy l[a ;k iq:"k efgyk (Tick ) 5a. No. of pregnant woman in the family: 5b. No. of lactating mother in the family: 5c. Any abortion (A) / stillbirth (S) in the family (last 1 Year): Y gkW ifjokj es a xHkZorh efgykvkas dh la[;k ifjokj es a Lruiku djkus okyh efgykvks a dh l[a ;k dkbs Z xHkZikr@ejs gq;s cPp s dk tUe ifjokj esa a ¼fiNys ,d o"kZ es½a N ugha a 6. No. of children affected with DF:

nkra ¶ykjs kfsll ls xzflr cPpks a dh la[;k 7. No. of family members affected with early warning signs: ifjsokj eas [krjukd fLFkfr ds iwoZ y{k.kka s ls xzflr lnL;ks a dh la[;k 8. No. of family members affected with Skeletal Fluorosis: ifjokj es a dadkyh; ¶yksjksfll ls izHkkfor lnL;kas dh la[;k Name of the Field Investigator who did the survey: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ S i g n a t u r e : Date: losZ{k.k djus okys dk;Z{k=s vUos"kd dk uke gLrk{kj fnukda

Name of the Supervisor: __________________________________________________ Signature: Date: i;Zo{s kd dk uke gLrk{kj fnukda NOTE: Guideline for filling-up the Proforma : For Example  Block Name is DEGANA = DG (1st & 3rd Letters of Block Name)  Village Name is RAMPURA = RAM (First 3 letters of Village Name) D G R A M 1 8 1 0 0  Field Investigator ID No. = 18  Household Number = 100 ● HP – Hand Pump; TW – Tube Well; OW – Open Well; RW – Rain Water; PSW – Pipe Supply Water

ukVs izk:i Hkjus ds fy, fn’kkfuns’Z k % mnkgj.kkFkZ  CykWd dk uke Msxkuk = Mhth ¼ CykWd ds uke ds izFke ,oa r`rh; 'kCn½  xkao dk uke jkeiqjk = jke ¼ xkao ds uke ds izFke rhu 'kCn½  dk;Z{ks= vUos"kd vkbZMh la[;k = 18  ifjokj la[;k = 100

Annexure – VI a (page 2of 2) INFORMATION ON MEMBERS OF A HOUSEHOLD Ikfjokj ds lnL;ks a dh lwpuk S. Early warning signs (9) Skeletal Changes (6) Consumption of fluoride containing No. food items (Habits) (9) Ø-l a [krjukd fLFkfr ds iwoZ y{k.k dadkyh; ifjoruZ ¶yksjkbM ;Dq r [kk| inkFkks Z dk los u ¼vknrs½a Shade the circle if complaints are YES Shade the circle if not possible Shade the circle if consuming the above items to do

;fn f’kdk;r gka gS rks xksys dks Hkjs ;fn lHako ugh gks rks xksys dks Hkjs ;fn uhps fy[kh [kk| inkFkks Z dk los u dj jgs gS rks xksys dk Hkjs 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 1 2 3 4 5 6 7 8 9

N U a kk m e e ½kZ"o ¼ q; kv )s r a e Y ( e g A e @ qi x ya f )F /M ( x e S u ki u r L@ h r o x Zk H )L ( g n ita tc a L / )P ( tn a n g e r P kp Pc e Ut r `e @ r ki kZH x )S ( h tr ib llitS / )A ( n o itr o b A l l f ksj ; ks R y Un ¶ s is o r o u lF la tn e D ½l Sx ¼ Zn V n ase si n o ita m r o f s a G / h c n a i m n i o a t P s ht ¼ ku x y k [ k kw u H a e s u a N / e tite p p A fo s s o L ½ku ky p e f t Cd n o ita p its n o C r Ln )tn e ttim r e tn I( a e o h r r a iD Zn n jl f e h c a d a e H o ku x y l k; I jkc & jkc n o ita n ir u d n a ts r i c h x t s E e s ku kv c kk’si kF@ hjks V t o e k d d n k a e w n e d m e e r i r t t x / s s E e s e s ksM Zn kst n ase s tn io j r o ja m n i n ia P kr i Y kr D j e c n a r a e p p a c im e n A ku wN ksd hr kN ls hM skB n h ih c c h h c t u iw o s T e t sB qx v ds jSi jdw d q> o t e h t h c u o t & d r a w r o f g n id n e s B e ku Nw ksd j d ky SQ sx kv ksd kaskFkg h c u o t d n a s y a w e d is s m r a e h t h c te r tS ku wN sN hi sd jl f d a e h fo k c a b e h t s t p iS u – ku B Sc & ku B m @ kr su x y ia v p ase k la w o t e lb a n U / g n ilp p ir C hu kk’sji kd us V wk?¼ kr x ai v ase kasp Pc n e r d lih c n i y tim r o fe D w o B ,e e n k k c o n K ( ]ku Nw j g se kc l su i V kv wk ? )e ru ta ts tro h S ,n o ita d ra te r la tn e M ,g e l es k d u l l y k f d d u u k o e f f ] u i k h u e Sk d c ] hjki lq ½kd V qx ¼qd kc Er o c c g a a n i h r b i a w k o p t e T u u h G S f C o / / ku kc p x ks; zi kd d e u ky kd tla S k c o R ) k k c a a m lB a N fo a l e a s K U ( hd qc ahu @ ; kp h y ; k k d p k c a lb g n n ik o n m a ir e e D t /l )k lim tu o h tiw ( x sk; zi kd h tiw d e lk n ir p s s k c a n S / s n e e k m a N r D ;q d e u ky kd l D uS L@ u hd e u S k k c c o t a l B R a l k c o R k c a lB h tiw d e d d a s k n ir d y n A ; si r D ;q d e u ky kd tla S kZFkn i k c c ip a l s B e h d t a iw m y d d e a d e d s R e a ky kl e r D ;q d e u ky kd tla S k c o R r D ;q d e u ky kd g iD s t c e i l d b e a v T r u e y v s A i e t d p ki d n ka; fso y qZ; f k ks v x tla S k c o R k c a lB g n in ia tn o c r D q; j k d k y p e k k d v u tla S k c o R k c a lB h tiw d lk e c c s i a P e l u t ae r an r D q; M b kjksy ¶ e ts a p h to o t d e ta d ir o u lF

1 2 3 4 5 6 7 8 9 10 • There are 9 health complaints • There are 6 skeletal problems • There are 9 fluoride containing food habits • Total no. of circles are 10 x 9 = 90 • Total no. of circles are 10x6=60 • Total no. of circles are 10 x 9 = 90 • If 50 circles are shaded among the 10 members, then • If 36 circles are shaded among the • If 45 circles are shaded among the 10 members, then

• Provision is made for 10 members in a household the % prevalence of early warning signs in the 10 members then the % of the % of consuming the fluoride containing food items household is = 50 / 90 x 100 = 55.5 % prevalence of skeletal problems in in the household is = 45 / 90 x 100= 50 % the houshold is = 36/60 X 100 = 60 %  9 LokLF; f’kdk;r  6 dadkyh; leL;k gS  9 ¶yksjkbM ;qDr [kk| inkFkZ gS  dqy xksys dh la[;k 10 X 9 = 90  dqy xksys dh la[;k 10 x 6 = 60  dqy xksys dh la[;k 10 x 9 = 90

,d ?kj ds 10 lnL;k s izko/kku  ;fn 10 lnL;ks es a 50 xksys Hkjs gS rks [krjukd fLFkfr ds iwoZ  ;fn 10 lnL;ksa es a 36 xksys Hkjs gS rks ?kj  ;fn 10 lnL;ksa es a 45 xksys Hkjs gS rks ifjokj es a ¶yksjkbM ;qDr y{k.k dh O;kidrk = 50 x 100 = 55.50% es a dadkyh; leL;k dh O;kidrk = 36 x [kk| inkFkk sZ dk los u djus dh O;kidrk 90 100 = 60% = 45 x 100 = 50% 60 90

Annexure –VI b Village Summary (Summary of all members of all households in a village) xzke dh ladfyr lpw uk ¼ifjokj ds lHkh lnL;kas dh lda fyr lpw uk½ Name of the village: _____________________________________________ Name of the block: ________________________________________ xkao dk uke CykWd dk uke 1. Total no. of households surveyed in the village: 2. % of household members is aware / heard of Fluorosis disease? • %

xkao es a losZ{k.k fd;s x; s dqy ?kjkas dh l[a ;k % Ikfjokj ds lnL;kas us ¶yksjksfll chekjh ls voxr gS \ 2a. Total no. of members in all households in the village: 2b. Male: 2c. Female: xkoa eas lHkh ?kjks a eas lnL;ks a dh dqy l[a ;k iq:"k efgyk 3. No. of Private / Public water sources in the village: (a) Private (b) Public xkao essa futh@ljdkjh ikuh ds L=ksrk s dh la[;k futh ljdkjh 4. The Type & No. of water sources: (i) HP (ii) TW (iii) OW (iv) RW (v) PSW

Ikkuh ds L=ksrkas ds izzdkj vkSj l[a ;k gS.MiEi uydwi [kqyk dqvk o"kkZ ty uy dk ikuh (vi) Pond rkykc (vii) Any other vU; dksbZ Total No. sources dqy L=ksr (i + ii + iii + iv + v + vi + vii) 5. No. of pregnant women in the village (during survey period): xkao es a xHkZorh efgykvks a dh la[;k ¼ loZs{k.k ds nkSjku½ 6. No. of lactating mothers in the village (during survey period): xkoa es a Lruiku djkus okyh ekrkvkas dh la[;k ¼ losZ{k.k ds nkSjku½

7. No. of abortions / still births taken place in the village (last 1 year): xkoa es a xHkZikr@e`rtUe cPpks a dh dqy l[a ;k ¼fiNys 1 o"kZ es½a 8a. Total no. of children affected with DF: 8b. Prevalence (%) of DF in children: . % nUR; ¶ykjs kfsll ls izHkkfor cPpkas dh dqy l[a ;k cPpks a es a nUR; ¶ykjs kfsll dh O;kidrk (%) 9a. No. of persons affected with early warning signs: 9b. Prevalence (%) of early warning signs: . %

[krjukd fLFkfr ds iwo Z y{k.kks a ls xzflr lnL;kas dh la[;k [krjukd fLFkfr ds iwoZ y{k.k dh O;kidrk (%) 10a. No. of persons affected with Skeletal Fluorosis: 10b. Prevalence (%) of Skeletal Fluorosis: . % dadkyh; ¶yksjksfll ls xzflr lnL;kas dh la[;k dadkyh; ¶ykjs kfsll dh O;kidrk (%) 11a. No. of persons consuming fluoride containing food items: 11b. Percentage of population consuming . % ¶yksjkbM ;qDr [kk| inkFkksZ dk los u djus okys lnL;ks a dh la[;k fluoride containing food items:

¶ykjs kbM ;qDr [kk| inkFkZ lsou djus okys lnL;kas dh O;kidrk (%) Name of the Supervisor: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ S i g n a t u r e : Date: i;Zo{s kd dk uke gLrk{kj fnukad ● HP – Hand Pump; TW – Tube Well; OW – Open Well; RW – Rain Water Harvesting; PSW – Piped Water Supply ● gS.MiEi uydwi [kqyk dqvk o"kkZty uy dk ikuh

Annexure – VI c Block Summary (Summary of all members of all households in all villages in a block) [k.M dh ladfyr lwpuk Name of the Block: _______________________________________________ Name of the district: __________________________________________ CykWd dk uke ftys dk uke 1. Total no. of households surveyed in the block: CykWd es a losZ{k.k fd;s x;s dqy ?kjkas dh l[a ;k 2a. Total members in all households in the block: 2b. Male: 2c. Female:

CykWd essa lHkh ?kjks a es a lnL;ks a dh dqy l[a ;k iq:"k efgyk 3. No. of Private / Public water sources in the block (a) Private (b) Public CykWd es a futh@ljdkjh ikuh ds L=ksrks dh la[;k futh ljdkjh 4. The type & No. of water sources: (i) HP (ii) TW (iii) OW (iv) RW (v) PSW Ikkuh ds L=ksrkas ds izzdkj vkSj l[a ;k gS.MiEi uydwi [kqyk dqvk o"kkZ ty uy dk ikuh (vi) Pond rkykc (vii) Any other vU; dksbZ Total No. sources dqy L=ksr (i + ii + iii + iv + v + vi + vii)

5. No. of pregnant women in the block (during survey period): CykWd es a xHkZorh efgykvkas dh l[a ;k ¼ losZ{k.k ds nkSjku½ 6. No. of lactating mothers in the block (during survey period): CykWd es a Lruiku djkus okyh ekrkvks a dh la[;k ¼ losZ{k.k ds nkSjku½ 7. No. of abortions / still births taken place in the block (last 1 year): CykWd es a xHkZikr@e`rtUe cPpks a dh dqy l[a ;k ¼fiNys 1 o"kZ es½a

8a. Total no. of children affected with Dental Fluorosis: 8b. Prevalence (%) of Dental Fluorosis among the children: . % nUR; ¶ykjs kfsll ls izHkkfor cPpkas dh dqy l[a ;k cPpks a es a nUR; ¶ykjs kfsll dk O;kidrk (%) 9a. No. of persons affected with Early warning signs: 9b. Prevalence (%) of Early warning signs: . % [krjukd fLFkfr ds iwo Z y{k.kks a ls xzflr lnL;kas dh la[;k [krjukd fLFkfr ds iwoZ y{k.k dh O;kidrk (%)

10a. No. of persons affected with Skeletal Fluorosis: 10b. Prevalence (%) of Skeletal Fluorosis: . % dadkyh; ¶ykjs kfsll ls xzflr lnL;kas dh la[;k dadkyh; ¶ykjs kfsll dh O;kidrk (%) 11a. No. of persons consuming fluoride containing food items: 11b. Percentage of population consuming . % ¶yksjkbM ;qDr [kk| inkFkksZ dk los u djus okys lnL;ks a dh la[;k fluoride containing food items: ¶ykjs kbM ;qDr [kk| inkFkZ lsou djus okys lnL;kas dh O;kidrk (%)

Name of the Supervisor: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Date: i;Zo{s kd dk uke fnukad

Annexure – VI d District Summary (Summary of all blocks) ftys dh ladfyr lpw uk Name of the District: ___________________________________ ftys dk uke 1. Total no. of households surveyed in all the blocks in the district: ftys ds iw.kZ CykWd es a losZ{k.k fd;s x;s dqy ?kjkas dh la[;k 2a. Total population of the district: 2b. Male: 2c. Female: fty s es a dqy tula[;k iq:"k efgyk 3. No. of Private and Public water sources in the district: (a) Private (b) Public

ftys es a futh o ljdkjh Ikkuh ds L=kSrk s dh la[;k futh ljdkjh 4. The Type & No. of water sources: (i) HP (ii) TW (iii) OW (iv) RW (v) PSW Ikkuh ds L=ksrkas ds izzdkj vkSj l[a ;k gS.MiEi uydwi [kqyk dqvk o"kkZ ty uy dk ikuh (vi) Pond rkykc (vii) Any other vU; dksbZ Total No. sources dqy L=krs (i + ii + iii + iv + v + vi + vii) 5. No. of pregnant women in the district (during survey period): ftys es a xHkZorh efgykvkas dh l[a ;k ¼ losZ{k.k ds nkSjku½

6. No. of lactating mothers in the district (during survey period): ftys es a Lruiku djkus okyh ekrkvks a dh la[;k ¼ losZ{k.k ds nkSjku½ 7. No. of abortions / still births taken place in the district (last 1 year): ftys es a xHkZikr@e`rtUe cPpks a dh dqy l[a ;k ¼fiNys 1 o"kZ es½a 8a. Total no. of children affected with DF: 8b. Prevalence (%) of DF among the children: . % nUR; ¶ykjs kfsll ls izHkkfor cPpkas dh dqy l[a ;k cPpks a es a nUR; ¶ykjs kfsll dk O;kidrk (%)

9a. No. of persons affected with early warning signs: 9b. Prevalence (%) of early warning signs: . % [krjukd fLFkfr ds iwoZ y{k.kka s ls xzflr lnL;kas dh la[;k [krjukd fLFkfr ds iwoZ y{k.k dh O;kidrk (%) 10a. No. of persons affected with Skeletal Fluorosis: 10b. Prevalence (%) of Skeletal Fluorosis: . % dadkyh; ¶ykjs kfsll ls xzflr lnL;kas dh la[;k dadkyh; ¶ykjs kfsll dh O;kidrk (%) 11a. No. of persons consuming fluoride containing food items: 11b. Percentage of population consuming . %

¶yksjkbM ;qDr [kk| inkFkksZ dk los u djus okys lnL;ks a dh la[;k fluoride containing food items: ¶ykjs kbM ;qDr [kk| inkFkZ lsou djus okys lnL;kas dh O;kidrk (%) Name of the Supervisor: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Date: i;Zo{s kd dk uke fnukda

Annex 7 Technical Specification for Fluoride Ion meter FLUORIDE ION METER FOR MEASUREMENT OF FLUORIDE IN DRINKING WATER, URINE & SERUM Technical Features  Large colour graphic LCD display which can show parameter (s) together or each parameter individually.  Display should provide additional information of showing reading with connections, time, date, sample ID, User ID, Calibration information, temperature, etc.  Up to 5 point calibration.  Meter should have Auto Read continuous display facility.

 ISE measurement should have Auto Blank, Linear Point to Point & Non linear point to point.  Low Concentration Range Stability.  At leaset 1500 point Data logging with time and date.  USB and RS232 for transfer of data to PC  Software upgradation facility of equipment through Internet. Technical Specifications ISE Range : 0 to 100 ppm Resolution : Up to 3 significant digits Units : mg/L, ppm, ppb. Power : Universal AC Power Adapter, 90 – 260 VAC, 50 - 60 Hz ACCESSORIES TO BE SUPPLIED WITH EQUIPMENT

1. Fluoride Combination, Epoxy Body Electrode - 2Nos. 2. Fluoride Calibration Standard, 1.0 ppm & 100 ppm, 400 ml each - 1 No. 3. TISAB III, at least 400 ml - 2Nos. 4. TISAB II, at least 3 Liters - 1 No. 5. Electrode filling solution, 5 x 60 ml in one packet - 1No. 6. Electrode holding Stand - 1No.  The Supplier should provide 3 year warranty for the equipment & 2 year AMC  Supplier should provide list of users of the equipment in Health Sector during the last five years.

Annex 8. Foods with high Fluoride ( to avoid) and Recommended Foods Recommended Foods Food Items contains high F¯ (proteins, carbohydrates, essential, micronutrients DO NOT EAT and antioxidants to eat on a daily basis) Black tea (with or without lemon) Black rock salt in salad/raita/fruits/baked or steamed corn Balanced Diet Black rock salt containing food and snacks e.g Samosa Calcium: Milk, Yogurt (Dahi), Paneer, , Chole Bhature Green leafy vegetables ( specially amaranth,

Golgappe/ Pani Poori fenugreek and drumstick leaves) til seeds, Bhel poori/ Papdi Chat ragi etc. Namkins/ Bhujia/ Dalmoth Jaljeera/ Nimboo pani added with Iron:, All Green leafy vegetables, cereals black rock salt and millets especially bajra and ragi, pulses Vitamin C: Amla, Lemon, Guava, orange, Achar with black rock salt lime, grapes, Tomato, Pineapple etc. Sprouted dals Readymade masala packet with black salt e.g. /Garam masala/chat Other Antioxidants present in: All Fruits +

masala/ Rajma Masala/ Chole Vegetables. Masala, Pav Bhaji Masala etc. Hajmola/ Churan/Imli and other Magnesium: Nuts, cereals, pulses , green leafy digestive tablets laced with black vegetables , Lotus stem, mango etc. rock salt Canned Fruit Juices/ Fruit juice Zinc: Pulses, Legumes, mushrooms, pumpkin with masala salt/ preserved food etc. items Chips/Kurkure and other salty packaged snacks (Packet would reveal the ingredients)

Annex 9. DIETARY GUIDELINES Right nutritional behavior and dietary choices are needed to achieve dietary goals. The following 15 dietary guidelines provide a broad framework for appropriate action: 1. Eat variety of foods to ensure a balanced diet. 2. Ensure provision of extra food and healthcare to pregnant and lactating women. 3. Promote exclusive breastfeeding for six months and encourage breastfeeding till two years or as long as one can.

4. Feed home based semi solid foods to the infant after six months. 5. . 6. Ensure adequate and appropriate diets for children and adolescents, both in health and sickness. 7. Eat plenty of vegetables and fruits. 8. Ensure moderate use of edible oils and animal foods and very less use of ghee/ butter/ vanaspati. 9. Avoid overeating to prevent overweight and obesity. 10. Exercise regularly and be physically active to maintain ideal body weight. 11. Restrict salt intake to minimum.

12. Ensure the use of safe and clean foods. 13. Adopt right pre-cooking processes and appropriate cooking methods. 14. Drink plenty of water and take beverages in moderation. 15. Minimize the use of processed foods rich in salt, sugar and fats. 16. Include micronutrient-rich foods in the diets of elderly people to enable them to be fit and active. Source: Dietary Guidelines for Indians, National Institute of Nutrition, 2011

Annex 10 District Status report regarding National Programme For Prevention and Control of Fluorosis. 1. District Profile 1.1 Total No. of Blocks 1.2 Total no. of villages 1.3 Affected villages (with high fluoride in water (MDW&S) 1.4 Total Habitations 1.5 Affected Habitations (High fluoride water (MDW&S) 2. District Fluorosis Cell 2.1 Staff engaged Name Trained at NIN Contact No. out of GOI funds .......................... ................. ....................... ............

(a) District Consultant Yes/No (b) Lab. Technician Yes/No (c) Field Investigators - (for six months) 2.2 Establishment of Lab with procurement of ion meter Yes/No 3.Surveys Upto Last Current Year & Cumulative (since year Qrtly Report initiation of Prog.) (mention the ( Mention from years) April (year) to (month & year ie the number of months the report covers) 3.1 No of Villages Surveyed for fluorosis 3.2 School Survey No. of schools covered No. of children surveyed

No. of Children with suspected dental fluorosis. No of urinary tests carried out in school children with suspected d.fl. No. of children with confirmed d.fl. Percentage children with confirmed d.fl. 3.3 Community Survey No. of households surveyed No. of persons examined No of suspected cases of dental fluorosis No. of urinary tests of suspected d.fl. carried out No of confirmed cases of d.fl. Percentage of confirmed d.fl. No. of suspected cases of skeletal fluorosis (sk.fl.)

( with or without dental fluorosis) No. of urinary tests of suspected sk. fl. carried out No. of confirmed cases of sk.fl. Percentage of skeletal fluorosis. 3. Water Analysis

No. of villages No of samples tested Samples found above 1ppm 4. Urinary Analysis Total samples analysed No. above prescribed limit Percentage samples above limit. 6 IEC activities 6.1 Articles/press release in local newspaper/ mag 6.2 Video spots/interview with expert on local TV 6.3 Audio spots/Q&A session on local radio/ Community Radio 6.4 Locations where posters are put up 6.5 Pamphlets/booklets distributed 6.6 Seminars 6.7 Nukkad nataks 6.8 Songs/Dances 6.9 Any other :

7. Training at the District level 7.1 No.of medical officers trained 7.2 No. of Paramedicals trained 7.3 No. of Health workers trained 7.4 No. of ASHA/AWW trained 7.5 Personnel in schools/WCD Dept/PHE etc trained 7.6 PRIs/ VHSNC members/ Teachers trained 8. Medical Management of Fluorosis. 8.1 Supplementation (No of persons ) ( specifying the vitamins & minerals) 8.2 Physiotherapy/ orthoses ( No) 8.3 Surgical intervention (specify type) 8.4 No. provided with mobility aids 9. Provision of safe water

9.1 No. of water sources declared unfit 9.2 No of safe water sources made available by PHED 10. Coordination with PHED 10.1 No of meetings held with PHED 10.2 Specific measures taken by PHED in affected areas covered under the programme 11. Line listing completed for 11.1 Fluoride affected villages Yes/No 11.2 Lab facilities available in district for fluoride testing Yes/No 11.3 Persons who can benefit with medical intervention Yes/No 11.4 Centres/hospitals for corrective surgeries Yes/No

GUIDELINES FOR THE MANAGEMENT OF GASTROENTEROLOGICAL DISEASES Ministry of Health & Family Welfare Govt. of India 1

Contents Page S.No. Topic No. 1 APPROACH TO DYSPHAGIA 4 2 ACHALASIA CARDIA 13 3 ACUTE LIVER FAILURE 19 4 LIVER CANCER OR HEPATOCELLULAR CARCINOMA (HCC) 23 5 3.5 INFLAMMATORY BOWEL DISEASE 32 6 3.6 LOWER GASTROINTESTINAL BLEED 45 7 3.7 INTESTINAL OBSTRUCTION 51 8 3.8 PANCREATIC CARCINOMA 62 2

APPROACH TO DYSPHAGIA Dr Ashok Chacko Department of Gastroenterology Christian Medical College I. When to suspect/recognize? a. Introduction: Dysphagia is an important symptom of esophageal or orpharyngeal disorder. It usually indicates the presence of an underlying disease process and, therefore, requires prompt evaluation. b. Case definition: Dysphagia is defined as difficulty or inability to transfer food from the oral cavity to the stomach. II. Incidence of Dysphagia 1,2

Dysphagia has been shown to be present in 20% of patients seen at primary care level and 15% of elderly patients in the community. Many of the elderly patients do not seek medical advice. Incidence data from India are lacking. III. Differential Diagnosis 3,4 Dysphagia is sub classified into two types depending on the location of the lesion. Inability or difficulty in transferring food from oral cavity to upper esophagus is referred to as oropharyngeal

dysphagia. Inability or difficulty in transferring food from upper esophageal region to stomach is termed as esophageal dysphagia. A careful history is vital in identifying the type and underlying cause of dysphagia. Difficulty in initiating a swallow suggests oropharyngeal dysphagia. This may be accompanied by sensation of food getting stuck above suprasternal notch, choking sensation, nasal regurgitation of food,

aspiration, dysarthria and dysphonia. When swallow is initiated but a few seconds later the patient feels food is getting stuck in esophagus (below suprasternal notch), esophageal dysphagia is likely. Dysphagia may occur due to structural lesions in the pathway of food bolus transit (Mechanical dysphagia) or neuromuscular dysfunction (Motor dysphagia). Difficulty in swallowing liquids and solids from the onset of dysphagia suggests motor dysphagia while difficulty in swallowing solids

alone at the onset of illness indicates mechanical dysphagia. A short duration of progressive symptoms with significant weight loss is suggestive of malignancy. Presence of pain during swallowing (odynophagia) may occur in infective lesions (Candida, CMV, etc,) or acute ulcerating lesions (pill esophagitis). History of gastroesophageal reflux symptoms, systemic illness (Stroke, 4

Parkinson’s disease, myasthenia gravis, muscular dystrophy, scleroderma, AIDS, etc.), drug/corrosive ingestion, exposure to radiation and surgeries in past may provide further clues to the diagnosis. Clinical examination for thyromegaly, cervical lymph nodes, oral cavity lesions and central nervous system function may be helpful. Hence, a careful history usually enables a physician to narrow down the list of differentials. Table 1 shows the differential diagnosis of dysphagia.

Table 1: Differential diagnosis in a patient with dysphagia Oropharyngeal Esophageal Mechanical Mechanical • Oropharyngeal malignancy • Esophageal tumours • Upper esophageal web • Corrosive stricture • Zenker’s diverticulum • Peptic stricture • Cervical osteophytes • Post radiation stricture • Thyromegaly • Anastomotic stricture • Retropharyngeal abscess • Food bolus impaction • Oropharyngeal infection • Foreign body impaction • Esophageal webs and rings • Diverticula • Mediastinal mass lesion

• Vascular compression Motor Motor • Cerebrovascular accident • Achalasia Cardia • Myasthenia Gravis • Nutcracker esophagus • Parkinson’s disease • Diffuse esophageal spasm • Intracranial Tumour • Hypertensive lower esophageal • Polymyositis or Dermatomyositis sphincter • Muscular Dystrophy • Scleroderma • Rabies • Tetanus • Cricopharyngeal achalasia IV. Prevention and Counselling As dysphagia is a symptom resulting from various disease entities rather than a single

disease, preventive measures are feasible in only certain situations. Diseases resulting from specific inciting agents may be prevented if awareness is improved among the general population. 1. Esophageal cancers have been associated with alcohol consumption, obesity and smoking and counselling about avoiding these risk factors might be useful. 4

2. Appropriate labelling of corrosive substances and keeping them away from the reach of children may prevent corrosive injuries of esophagus. 3. Swallowing pills in upright position with plenty of fluid may prevent pill esophagitis. 4. Prompt therapy of gastroesophageal reflux disease with proton pump inhibitors may heal esophageal ulcers and prevent development of peptic stricture. 5. Adequate chewing of food reduces the chance of food bolus impaction.

6. Counselling patients that dysphagia is an alarm symptom which requires prompt medical attention may help in early diagnosis and management of malignancy of esophagus. V. Optimal diagnostic criteria, Investigations, Treatment and Referral Criteria5-8 Situation 1: At Secondary Hospital/Non-Metro situation a. Clinical diagnosis: Dysphagia is a symptom and hence a history of difficulty/inability to initiate or complete a swallow is sufficient to confirm its presence. Further probing about the duration,

nature (solids alone or for both solids and liquids), course (progressive or intermittent) of the symptom as well as associated symptoms (see section on differential diagnosis) helps to reduce the number of possible etiologies and plan appropriate focussed investigations. b. Investigations: • Prior to investigations for oropharyngeal/esophageal lesions, systemic illnesses causing dysphagia (stroke, Parkinson’s disease, Myasthenia gravis, etc.) should be considered and appropriately evaluated.

• For structural oropharyngeal dysphagia, a nasopharyngeal endoscopy is appropriate. Specimen from lesions should be obtained for histopathology and/or microbiological evaluation. For motor oropharyngeal dysphagia, video-fluoroscopic swallowing study is the best modality. • In patients with structural esophageal dysphagia, upper gastrointestinal endoscopy is appropriate as it enables better characterisation of lesion and collection of

specimen for histopathology and/or microbiological evaluation. In suspected esophageal motility disorder, barium swallow study may be the appropriate initial test. For further characterisation of the motility disorder, patient may be referred to a higher center for esophageal manometry. 5

c. Treatment: Oropharyngeal dysphagia: 1. Treatment of neuromuscular causes is difficult but in conditions like myasthenia gravis and Parkinson’s disease medical therapy may be useful. 2. Adequate nutrition is crucial. Thick fluids or soft solids are better tolerated. 3. If risk of aspiration is high, feeding through nasogastric tube may be considered or surgical gastrostomy/jejunostomy may be performed for feeding. 4. For infective lesions, antibiotics may be used.

5. Malignant lesions require a multidisciplinary approach at a higher center. Esophageal dysphagia: 1. Both structural and motor lesions require therapeutic endoscopic procedures or surgery and, hence, are better managed at a higher center. 2. Calcium channel blockers provide some relief in achalasia cardia or diffuse esophageal spasm. 3. Proton pump inhibitors may be given for peptic strictures. 4. Soft foods should be recommended in case of esophageal webs and rings. Standard Operating Procedure

Out Patient: Patients without systemic illness and with adequate hydration and good sensorium can be managed as outpatients. In Patient: Patients with severe systemic illness, dehydration and impaired level of consciousness should be managed as inpatients. Day Care: Patients with dehydration can be managed on a day care basis and discharged after proper hydration and intervention if they can subsequently adequately nourish themselves at home. Referral criteria:

1. Oropharyngeal dysphagia: Non-availability of video fluoroscopy or gastrointestinal endoscopy facilities or for management of malignant lesions 2. Esophageal dysphagia: For further evaluation and management after barium swallow study 6

3. Patients with systemic illnesses requiring specialised care Situation 2: At super speciality facility in Metro Location where higher-end technology is available a. Clinical diagnosis: Same as in situation 1. b. Investigations: 1. Prior to investigations for oropharyngeal/esophageal lesions, systemic illnesses causing dysphagia (stroke, Parkinson’s disease, Myasthenia gravis, etc.) should be considered and appropriately evaluated. Consultation with a neurologist and imaging of brain as well as

electrophysiological study of nerve/muscles may be warranted. 2. Structural oropharyngeal dysphagia: (i) Consultation with an ENT specialist for nasopharyngeal endoscopy is appropriate. Specimen from lesions should be obtained for histopathology and/or microbiological evaluation. (ii) If no lesion is found, a computed tomography of the lower head and neck region would be required. 3. Motor oropharyngeal dysphagia: (i) Video-fluoroscopic swallowing study is the best modality.

(ii) Manometric study may be undertaken to assess for upper esophageal sphincter dysfunction and cricopharyngeal achalasia. 4. Structural esophageal dysphagia: (i) Upper gastrointestinal endoscopy is appropriate as it enables better characterisation of lesion and collection of specimen for histopathology and/or microbiological evaluation. (ii) If a peptic stricture is suspected, a 24 hour esophageal ph study would confirm the presence of gastroesophageal reflux.

(iii) If the esophageal mucosa is normal during endoscopy, extrinsic compressive lesions should be suspected and computed tomography of mediastinum or endoscopic ultrasonography from esophagus is required to locate these lesions. 5. Esophageal motility disorder: (i) Barium swallow study may be the appropriate initial test. 7

(ii) For further characterisation of the motility disorder, esophageal manometry should be performed. Figure 1 shows the approach to a patient with dysphagia. c. Treatment: Oropharyngeal dysphagia: 1. Treatment of neuromuscular causes is difficult but in conditions like myasthenia gravis and Parkinson’s disease medical therapy may be useful. 2. Adequate nutrition is crucial. Thick fluids or soft solids are better tolerated.

3. If risk of aspiration is high, feeding through nasogastric tube may be considered or percutaneous endoscopic gastrostomy may be performed. If percutaneous endoscopic gastrostomy is not feasible, surgical gastrostomy/jejunostomy may be performed for feeding. 4. For infective lesions, antibiotics may be used. For malignant lesions a multidisciplinary approach involving the surgeon, radiotherapist and oncologist is required. Esophageal dysphagia: Treatment depends on the disease. 1. Achalasia Cardia:

a) For surgically low risk patients, graded pneumatic dilatation should be performed. b) If two sessions of pneumatic dilatation does not provide adequate symptom relief, surgical (laparoscopic or open) myotomy of lower esophageal sphincter should be performed. Direct referral of patients for surgery is also an option. c) For high risk surgical patients, botulinum toxin injection in the LES region may provide short term symptom relief. 2. Strictures (Corrosive, Radiation, Peptic and Anastomotic):

a) Endoscopic dilatation (bougie dilators) is the preferred initial treatment if feasible. Repeated dilatations may be required. 8

b) For long, tight strictures or those with frequent recurrence of symptoms after endoscopic dilatation, surgery may be considered. For short strictures dilatation using CRE (Controlled Radial Expansion) under endoscopic vision is effective. For Anastomotic strictures, dilatation using CRE balloons is beneficial. c) Anti-reflux therapy with proton pump inhibitors reduces the need for further dilatation in peptic strictures. 3. Esophageal tumours:

a) Benign tumours causing dysphagia should be surgically resected. b) If lesion is small and does not extend beyond submucosa (assessed using endoscopic ultrasonography), endoscopic mucosal resection/endoscopic submucosal dissection are less invasive options. c) For operable malignant tumours, chemoradiation followed by surgery is the treatment of choice. d) Most malignant lesions of esophagus are inoperable at diagnosis and hence palliation is the only

option. Palliative options include – i) placement of a nasogastric feeding tube over a guide wire (placed during endoscopy), ii) esophageal stenting using self expandable metal stent (SEMS), iii) radiation therapy and iv) surgical gastrostomy/jejunostomy for feeding. 4. Esophageal webs and rings: Esophageal webs and rings should be managed with endoscopic dilatation. 5. Other conditions: a) Nitrates or calcium channel blockers can be used for diffuse esophageal spasm.

b)Systemic illness like scleroderma requires appropriate medical therapy. Standard Operating Procedure Same as in situation 1. Referral criteria: While a super speciality center is expected to have all the diagnostic and therapeutic facilities, patients may be referred if required equipments/expertise are not available. 9

VI. Who does what and timelines? a. Doctor: 1. Within one hour of patient’s arrival at the hospital Initial resuscitation if patient is sick, dehydrated, etc,. History and clinical examination Need for hospitalisation After the patient is stabilised Planning further diagnostic tests Explaining the condition to patients and relatives and obtaining informed consent for procedures Definitive treatment of the patient Referral to other specialists in the same hospital or to other centers b. Nurse:

1. On patient’s arrival at the hospital - Measure blood pressure, pulse rate, breathing rate and level of consciousness and inquire about the chief complaint. The doctor should be accordingly informed. 2. Obtain intravenous access, collect blood samples for investigations and carry out treatment orders for patients requiring emergency care. 3. Assist the doctor in performing procedures, surgery, etc. c. Technician 1. Set up and maintenance of equipments required for emergency or elective care

2. Assist the doctor during endoscopic or surgical procedures 3. Keep a ready stock of instruments/accessories required for emergency or elective procedures 10

Dysphagia* Symptoms occur at the onset of swallow# Yes No Esophageal Dysphagia (Occurs few Oropharyngeal Dysphagia seconds after initiating swallow) Dysphagia to both solids and liquids at Dysphagia to both solids and liquids at the onset of symptom onset of symptom Yes No Yes No Motor Dysphagia Mechanical Motor Dysphagia Mechanical Dysphagia Dysphagia Assess for Assess for systemic, Character, systemic, Character, neurological Weight loss neurological Weight loss illnesses illnesses Video Nasopharyngeal

fluoroscopy endoscopy Video UGI Endoscopy fluoroscopy Manometry CT pharynx/neck CT /Endoscopic Manometry ultrasound of Neurological medisatinum evaluation Neurological evaluation *Patients with absolute dysphagia (unable to swallow at all) should be stabilised prior to evaluation of the cause #Key points in history – character (solid/liquid food), duration, course (progressive/intermittent), weight loss, pain during swallowing, medications/corrosive ingestion, radiation, systemic illness

CT – Computed Tomography; UGI – Upper Gastrointestinal Figure 1: Approach to a patient with dysphagia 11

VII. Further reading/References: 1. Kawashima K, Motohashi Y, Fujishima I. Prevalence of dysphagia among community-dwelling elderly individuals as estimated using a questionnaire for dysphagia screening. Dysphagia. 2004 Fall;19(4):266-71 2. Thad Wilkins, Ralph A. Gillies, Andria M. Thomas, et al. The Prevalence of Dysphagia in Primary Care Patients: A HamesNet Research Network Study The Journal of the American Board of Family Medicine2007; 20 (2): 144-150

3. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 9th edition, Elsevier. 4. Trate, DM, Parkman, HP, et al. Dysphagia. Evaluation, diagnosis, and treatment. Prim Care 1996; 23:417 5. Varadarajulu S, Eloubeidi MA, Patel RS, et al. The yield and the predictors of esophageal pathology when upper endoscopy is used for the initial evaluation of dysphagia. Gastrointest Endosc 2005; 61:804 6. Kumar S. Swallowing and dysphagia in neurological disorders. Rev Neurol Dis. 2010;7(1):19-27.

7. Garcia JM, Chambers E 4th. Am J Nurs. Managing dysphagia through diet modifications. 2010 Nov;110(11):26-33 8. Sreedharan A, Harris K, Crellin A, et al. Interventions for dysphagia in oesophageal cancer Cochrane Database Syst Rev. 2009 Oct 7;(4):CD005048. 12

ACHALASIA CARDIA Dr Ashok Chacko Department of Gastroenterology Christian Medical College I. When to suspect/recognize? a. Introduction 1: Esophageal dysphagia involves difficulty in transferring food from the upper esophageal region to the stomach. It is subdivided into mechanical dysphagia (caused by structural lesions in the path of food bolus transit) or motor dysphagia (caused by neuromuscular dysfunction).

Mechanical dysphagia is generally progressive in nature with dysphagia to solids being noticed at first followed in time by dysphagia to liquids. On the other hand, in motor dysphagia, there is simultaneous dysphagia to both solids and liquids from the onset. Among the various causes of motor dysphagia, achalasia cardia remains the most recognised. Besides dysphagia, clinical features of achalasia include regurgitation, chest pain, hiccups, halitosis, weight loss, aspiration pneumonia

and heartburn. The exact pathophysiology of this entity is unknown although increasing evidence suggests that loss of ganglion cells within the myenteric plexus supplying the smooth muscles of the esophagus (including the lower esophageal sphincter) to be responsible. b. Case definition1: Achalasia (a Greek term meaning "failure to relax") is a disease of unknown etiology characterised by loss of peristalsis in the distal esophagus and a failure of lower esophageal sphincter (LES) relaxation.

II. Incidence2-4: In the West, the incidence of achalasia cardia is reported to be approximately 1/100,000 population per year with prevalence being 7.1 to 13.4/100,000 population per year. There is hardly any data on the incidence and prevalence of the disease in India. A recent retrospective study from Lucknow conducted in a tertiary care centre reported that achalasia cardia constituted 77% of the patients who presented with motor dysphagia. This disease affects people of both

genders equally and presents between 25 to 50 years age. III. Differential Diagnosis1: Other motor disorders: Diffuse esophageal spasm Nutcracker esophagus Hypertensive LES Diseases with distinct etiology but with functional consequences mimicking achalasia: Pseudoachalasia (associated with malignancies and infiltrative diseases) Chagas disease Post surgical (following fundoplication and bariatric surgery) 13

IV. Prevention and Counselling5: There are no particular preventive measures for achalasia cardia. Long standing dilatation of esophagus can result in development of squamous cell carcinoma of the esophagus although there are no recommendations for surveillance. V. Optimal diagnostic criteria, Investigations, Treatment and Referral Criteria Situation 1: At Secondary Hospital/Non-Metro situation a. Clinical diagnosis1,6: Presence of insidious onset, gradually progressing dysphagia to both solids

and liquids with varying combinations of regurgitation, chest pain, hiccups, halitosis, weight loss, heart burn and aspiration pneumonia may suggest achalasia cardia. The patient may give history of adopting certain manoeuvres like lifting the head or throwing the shoulders back to facilitate esophageal emptying. b. Investigations1,6: • Chest X ray: Mediastinal widening with presence of air fluid level and absence of gastric bubble maybe seen. • Barium swallow:

i) Dilated esophagus with a characteristic “bird beak” deformity in the lower esophagus ii) Massively dilated esophagus may produce a “sigmoid” esophagus • Upper GI Endoscopy: Typical findings include i) Dilated esophagus with food or fluid residue ii) Esophageal mucosa that is generally normal may show inflammation caused by retained food, pills or Candidiasis iii) Contracted LES that can be negotiated with a gentle push of the endoscope.

Endoscopy is essential to rule out neoplasms in the cardia and the fundus. c. Treatment1,7: Treatment of achalasia cardia maybe pharmacological, endoscopic or surgical. • Surgical therapy is generally not performed in secondary hospitals. • Endoscopic therapy can be attempted only if endoscopes, appropriate accessories, fluoroscopy and preferably, a surgical backup are available. 14

• Pharmacological therapy includes sublingual nitrates and calcium channel blockers given immediately before meals. These have the advantage of being non-invasive but they are not as effective as the other therapeutic options. Side effects and tachyphylaxis limit their use. Generally these are given to patients who cannot tolerate or are unwilling for invasive therapies. Standard Operating Procedure If adequate facilities of investigation and invasive therapy are available, patients in secondary

hospitals are generally managed as outpatients. If endoscopic therapy is possible, this can be done as a day care procedure. Referral criteria: - Non-availability of endoscopy, endoscopic accessories, manometry, fluoroscopy and surgery - Patients with systemic illness requiring specialised care Situation 2: At super speciality facility in Metro Location where higher-end technology is available a. Clinical diagnosis: Same as in situation 1.

b. Investigations1,6-8: In addition to those discussed in situation 1, other investigations that can be performed include conventional manometry and high resolution manometry of the esophagus. - Characteristic findings on conventional manometry include failure of the LES to relax, elevated basal LES pressure and aperistalsis of the esophageal body. - High resolution manometry (HRM) of the esophagus is an advanced form of manometry. Based on HRM, achalasia is classifed into 3 subtypes:

Type 1(Classic) achalasia, where swallowing results in no significant change in esophageal pressurization. Type II achalasia, where swallowing results in simultaneous pressurization that spans the entire length of the esophagus. Type III (spastic) achalasia, where swallowing results in abnormal, lumen-obliterating contractions (spasms). Responses to all types of achalasia treatment (both endoscopic and surgical) were best in type II patients and worst in type III patients.

- It is preferable to quantify the basal LES pressure by manometry prior to endotherapy or surgery to assess the efficacy of the same on follow up especially in the event of recurrence of symptoms. 15

c. Treatment1,9,10: Pharmacological treatment would be same as in situation 1. The other forms of therapy are broadly divided into endoscopic or surgical. 1) Endoscopic therapy: a. Pneumatic dilatation: Forceful stretching of the LES is accomplished using a Rigiflex pneumatic balloon dilator in a graded fashion under fluoroscopy. Although this is quite effective and can be done as a day care procedure, there is a 3-5% risk for perforation which

can warrant additional surgery. If two sessions of pneumatic dilatation are unsuccessful, surgery should be performed. b. Botulinum injection: Botulinum toxin A is injected into the LES so as to reduce its pressure. Its effect may not be as durable as that following pneumatic dilatation. Minor side effects of this procedure include rash and transient chest pain. It is ideal for high risk surgical patients in providing short term relief. 2) Surgery:

a. Open Heller’s myotomy (either transabdominal or transthoracic) b. Minimally invasive (either laparoscopic or thoracoscopic) Surgical therapy is more effective and long lasting than endotherapy. Reflux esophagitis can be a problem after surgery but can be ameliorated by performing an antireflux procedure (fundoplication). Overall mortality from Heller’s myotomy is less than 2%. Current evidence suggests that a laparoscopic approach is associated with similar efficacy, reduced morbidity, and

shorter hospital stay when compared with surgical myotomy via other approaches. Direct referral for laparoscopic surgery can be considered for a low risk patient rather than pneumatic dilatation. Standard Operating Procedure Out Patient: Patients who do not have major comorbidities can be managed as outpatients. Post procedure patients can also be followed up. In Patient: This would be required for those with major comorbidities that need stabilisation, for

postoperative care and for monitoring those with anticipated complications following endotherapy. This may also be required for those who have copious food residue on initial endoscopy for clearing the contents (using a Ryle’s tube) before the next endoscopy. Day Care: This would be required for patients who are dehydrated for stabilisation following which they can nourish themselves at home. Endotherapy can also be performed as a day care procedure. 16

Referral criteria: A superspecialty center is expected to have the required diagnostic and therapeutic facilities for management of achalasia. However, a patient maybe referred if required equipment or expertise is unavailable. VI. Who does what and timelines? a. Doctor: If patient is sick (within 1 hour of arrival to hospital) Initial resuscitation and assess if patient is dehydrated, has pneumonia, etc and requires admission. If patient is otherwise well History and clinical examination

Planning diagnostic tests Discussion of condition and management options with patients and responsible well wishers and relatives and obtaining informed consent Definitive treatment Referral to other specialists in the same hospital or to a higher center b. Nurse: Measure vital signs and assess level of consciousness Inquire chief complaints and inform the doctor accordingly Obtain intravenous access for blood investigations Carry out treatment orders as directed by the doctor

Assist the doctor in performing therapeutic procedures c. Technician: Maintain equipment required for emergency or elective care Assist the doctor and the nurse during therapeutic procedures 17

VII. Further reading/References: 1. Sleisenger and Fortran's Gastroenterological and Liver Disease. 9th edition (Saunders Elsevier, 2010) 2. Howard, PJ, Maher, L, Pryde, A, et al. Five year prospective study of the incidence, clinical features, and diagnosis of achalasia in Edinburgh. Gut 1992; 33:1011. 3. Mayberry JF: Epidemiology and demographics of achalasia. Gastrointest Endosc Clin North Am 2001; 11:235-48. 4. Misra A, Chourasia D, Ghoshal UC. Manometric and symptomatic spectrum of motor

dysphagia in a tertiary referral center in northern India. Indian J Gastroenterol. 2010 Jan;29(1):12-6 5. Sandler RS, Nyren O, Ekbom A, et al: The risk of esophageal cancer in patients with achalasia. A population-based study. JAMA 1995; 274:1359-62 6. Spechler SJ. Clinical manifestations and diagnosis of achalasia. Uptodate. [Internet] 2010 [cited 2011 April 19]. Available from: http://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of- achalasia

7. Hirano, I, Tatum, RP, Shi, G, et al. Manometric heterogeneity in patients with idiopathic achalasia. Gastroenterology 2001; 120:789. 8. Pandolfino, JE, Kwiatek, MA, Nealis, T, et al. Achalasia: a new clinically relevant classification by high-resolution manometry. Gastroenterology 2008; 135:1526. 9. Spechler SJ. Overview of the treatment of achalasia. Uptodate. [Internet] 2010 [cited 2011 April 19]. Available from: http://www.uptodate.com/contents/ overview-of- the-treatment-of-achalasia

10. Rosati R, Fumagalli U, Bona S, et al: Evaluating results of laparoscopic surgery for esophageal achalasia. Surg Endosc 1998; 12:270-3. 18

ACUTE LIVER FAILURE Dr. Avinsh Kumar Seth, MD, DM Head, Department of Gastroenterology BL Kapur Hospital, New Delhi 1. WHEN TO SUSPECT /RECOGNIZE? a. Introduction: Acute liver failure is a syndrome of varying aetiology resulting in rapid loss of hepatic metabolic and immuological functions, manifesting as altered mentation and coagulopathy and in many cases progressive multi-organ failure, in a previously normal individual. The

condition is associated with high mortality and is a frequent indication for liver transplantation. b. Case definition: Various terminologies and definitions have been used. Fulminant Hepatic Failure: Potentially reversible disorder that is the result of severe liver injury with onset of encephalopathy within eight weeks of symptoms and in the absence of pre-existing liver disease. Acute Liver Failure: Evidence of coagulopathy (INR>1.5) and any degree of mental alteration

(encephalopathy) occurring within 26 weeks of onset of illness in a patient without preexisting liver disease. Note: Diagnosis of hepatic encephalopathy is clinical; West Haven grading of encephalopathy is followed:- Grade I: Changes in behaviour with minimal change in level of consciousness Grade II: Disorientation, drowsiness, asterixis, inappropriate behaviour Grade III: Marked confusion, incoherent speech, ssleeping but arousable Grade IV: Comatose, unresponsive, decorticate or decerebrate posturing

2. INCIDENCE OF THE CONDITION IN OUR COUNTRY No systemic studies till date to define the incidence of acute liver failure in our country. 3. DIFFERENTIAL DIAGNOSIS of causes of ALF: Country HAV HBV HEV PCM Non-PCM Unknown India 2% 15% 44% 0% 1% 31% USA 4% 7% - 39% 13% 18% UK 2% 5% 1% 57% 11% 17% 19

Legend to above table: HAV= Hepatitis A virus ; HBV = Hepatitis B virus; HEV = Hepatitis E virus; PCM= Paracetamol 4. PREVENTION AND COUNSELING The prevention of ALF due to viral hepatitis entails prevention of hepatitis and avoiding use of hepato-toxic drugs after onset of hepatitis, including paracetamol. Immunization against hepatitis B is recommended for all. In India over 95% adults are exposed to HAV. Vaccine for HAV is available and may be used in children. Use of potable water is recommended for

prevention of HAV and HEV. 5. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS,TREATMENT & REFERRAL CRITERIA a. Situation 1: At secondary hospital / non-metro situation i. Clinical Diagnosis: Patients presenting with acute hepatitis should be monitored for altered sensorium or asterixis. Liver span (normal 12-15 cm) should be examined daily. Spleen tip may be palpable in 20% patients with acute hepatitis due to reticulo-endothelial cell hyperplasia. Evidence of

chronic liver disease in the form of spider naevi, gynecomastia, palmar erythema, splenomegaly or ascites goes against the diagnosis of ALF. ii. Investigations: For severity and aetiology of liver failure and to exclude acute on chronic liver failure and chronic liver disease. CBC, LFT, INR, Creatinine, Electrolytes, Sugar, USG upper abdomen, HbsAg. iii. General Measures: 1. Patients with altered mentation should be admitted to ICU. 2. Avoid stimulation, avoid sedation.

3. Nurse with head end elevation to 30® 4. Consider intubation if grade III/IV encephalopathy. 5. Fluid and electrolyte maintenance. Any fluid may be used. 6. Enteral nutrition preferred till grade 1 /2 encephalopathy. Protein intake 1G/Kg. 7. Inj PPI (proton pump inhibitor) IV once daily to prevent stress induced erosive gastritis / ulcers. iv. Specific Measures 1. Inj Vitamin K 10 mg IV single dose. 2. Inj Mannitol bolus 0.5-1g/Kg if signs of cerebral edema: systolic

hypertension, bradycardia, irregular respiration or unequal pupils or posturing. Use mannitol only if plasma Osmolality is < 320 mosmol/L. 3. Antibiotics. Surveillance blood culture followed by prophylactic antimicrobials. Suggested protocol : Piperacillin + Tazobactam, Teicoplanin, Metronidazole and Fluconazole. Modify as per prevalence of local flora / sensitivity pattern. 4. Inj N-acetyl cysteine 150mg/Kg over 1 hour, 12.5mg/Kg/hour over next 4 hours and then 6.25mg/Kg/hour over 67 hours. Start early in

course of illness i.e., for patients with grade 1 or 2 hepatic encephalopathy. 5. Treatment directed at aetiology: a. Acetaminophen: N-Acetyl Cystine b. HSV: Acyclovir: Skin lesions in 50% only c. Amanita phalloides: Penicillin G 1 million units/kg/day d. HELLP/AFLP: Terminate pregnancy e. HBV: Tenofovir. Concerns of lactic acidosis with Entecavir v. Avoid 1. Fresh frozen plasma (FFP) as it interferes with assessment for liver transplantation. Use only if invasive procedure planned.

2. Platelet transfusion with platelets >10,000/cmm unless invasive procedure planned 3. Protein restriction to <1G/Kg 4. Branched chain amino acids 5. Lactulose 6. Inj L-Ornithine L-Aspartate 7. Prophylactic anticonvulsants 8. Hypothermia vi. Referral Criteria 1. Diagnosis not clear: ALF Vs ACLF / CLD 2. Aetiology not clear 3. Worsening clinical condition 4. Transfer to tertiary care facility may be considered early in the course of illness (Grade 2 encephalopathy).

b. Situation 2: At super-speciality facility in metro location i. Clinical Diagnosis: same as level 1 ii. Investigations: Same as level 1. In addition:- IgM-anti HBc if HbsAg positive, IgM-antiHEV. If viral markers negative then ANA, SMA, serum ceruloplasmin, examination for KF rings. In ICU setting: ABG, arterial ammonia. iii. Treatment: Same as at level 1. In addition:- 3% saline infusion @ 30 ml/hour till serum Na 145 mEq/L, then maintain 10-

15 ml/hour (aim serum Na 145-155 mEq/L). Monitor serum sodium 12 hourly. iv. Referral criteria for liver transplantation The approach to liver transplantation for ALF has to be clear and mathematical. The following questions to be answered:- 21

Step 1. Is liver transplantation indicated? Apply modified King’s College Hospital (KCH) criteria:- Prothrombin time >100s or INR >6.5 Or, any 3 of the following:- Age < 10 years or > 40 years Jaundice-Hepatic Encephalopathy interval > 7 days S bilirubin > 17.5 mg /dl Prothrombin time >50s or INR > 3.5 NonA-NonE Hepatitis If answer to step 1 is yes, proceed to step 2. If answer to step1 is no, keep looking for indication for liver transplantation as

the negative predictive value of KCH criteria is low. Give due consider ation to MELD score (>30) and arterial ammonia (>124). Step 2: If answer to step 1 is yes, is there a contraindication to transplantation? Contraindications include sepsis and posturing due to severe cerebral edema. Get in touch with the nearest liver transplant centre for advise before deciding aginst transplantation. Step 3: If answer to step 2 is no, can the family afford liver transplantation?

Step 4: If answer to step 3 is yes, is there a suitable donor? Test blood group of patient and willing near relatives aged 18 to 50 years. If ABO compatible donor is available, counsel on success and risk of liver transplantation and donor surgery. Step 5: Transfer patient and ABO compatible willing near relative to transplant centre. Consult the nearest liver transplant centre for precautions during the process of transfer. 6. FURTHER READING / REFERENCES

i. Polson J, Lee WM. AASLD Position paper: The mangement of Acute Liver Failure. Hepatology 2005;41:1179-97. ii. Bernal A, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet 2010;376:190-201 22

LIVER CANCER OR HEPATOCELLULAR CARCINOMA (HCC) Dr. Kaushal Madan Senior Gastroenterologist Medanta Medicity I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Liver cancer or primary liver cancer or hepatocellular carcinoma (HCC) is, as the name suggests, a primary malignant tumor arising from the liver cells or hepatocytes. It usually arises on a background of cirrhosis, but it may even arise in non-cirrhotic livers. The etiology

of cirrhosis may be hepatitis B, hepatitis C, alcohol or even non-alcoholic steatohepatitis. Liver cancer has been reported as the 5th most common cancer and the third most common cause of cancer related mortality in the world literature. b) Case definition: For both situations of care (mentioned below*) Secondary care centers: Any space occupying lesion (SOL) or a nodule in the liver detected either on ultrasonography, CT scan or MRI, in a patient who has underlying

cirrhosis, should be considered as an HCC unless proved otherwise. The presence of high AFP >400ng/ml confirms the diagnosis of the SOL/nodule being HCC. However, normal AFP levels do not exclude the presence of HCC. Appearance of a new SOL in liver even in patients, who do not have underlying cirrhosis, should be investigated with HCC being the first differential diagnosis. Tertiary care centers: 1. In a patient who has cirrhosis any SOL, more than 2 cm, if it shows enhancement in

the arterial phase and washout in the delayed phase, on at least one dynamic imaging (either a triple phase contrast CT scan of abdomen or dynamic contrast enhanced MRI of the abdomen), should be labeled as HCC unless proved otherwise, irrespective of alpha feto protein (AFP) levels. 2. In a patient who has cirrhosis, and the SOL is between 1-2 cm, then the typical contrast enhancement and washout pattern needs to be demonstrated on at least two imaging modalities to make a diagnosis of HCC

3. Patients who have SOL in the liver but do not have cirrhosis, or those who have atypical enhancement characteristics on dynamic imaging, the diagnosis of HCC can be confirmed by characteristic microscopic features on a biopsy of the lesion or fine needle aspiration cytology of the lesion. 23

Where ever possible efforts should be made to make a non-invasive diagnosis of HCC, that is, without putting any needle in to the tumor II. INCIDENCE OF THE CONDITION IN OUR COUNTRY In our country, the reported incidence of HCC is 1.2 /100,000 females per year and 2.7/100,000 males per year and a prevalence of 1.9% of all cancers, based on population cancer registry data. In a prospective study in patient with cirrhosis, the reported incidence is 1.6 per 100 person years of follow up.

III. DIFFERENTIAL DIAGNOSIS Differential diagnosis include all other causes of mass /SOL in the liver. These can be either benign or malignant Benign liver masses Malignant liver masses Hemangioma Metastases from other malignant tumors (secondaries) Focal nodular hyperplasia Cholangiocarcinoma Hepatocellular adenoma Complex liver cysts These lesions can be differentiated from HCC by means of characteristic imaging findings of these lesions as well as the clinical setting of presentation.

IV. PREVENTION AND COUNSELING The most important risk factors for the development of liver cancer are hepatitis B infection, hepatitis C infection, alcoholic cirrhosis, non-alcoholic steatohepatitis related cirrhosis, and other causes of cirrhosis. Therefore the most important preventive measures would be to prevent development of these diseases. The following measures can me considered to be preventive strategies for HCC: 1. Vaccination against hepatitis B

2. Universal screening of donated blood for hepatitis B and C and discarding of infected units 3. Preventive strategies for diabetes and obesity 4. Strategies to prevent alcoholism At present there is no recommended chemopreventive strategy, once a patient becomes cirrhotic. 24

V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a. Clinical Diagnosis: All patients with cirrhosis of liver who develop recent worsening of their clinical status should be suspected of having developed liver cancer and should be appropriately investigated. It should be suspected when:

1. A patient who has stable cirrhosis develops new ascites 2. A cirrhotic patient develops a difficult to control ascites. 3. A stable cirrhotic develops severe constitutional symptoms, such as weight loss or anorexia. 4. Any patient, especially one who has cirrhosis, develops prolonged fever of unknown origin (FUO) 5. A patient of cirrhosis develops pain in the upper abdomen. b. Investigations: The initial investigations should include:

1. Abdominal ultrosonography which can pick up features of cirrhosis and presence of any SOL in the liver. 2. Alpha feto protein (AFP) levels: Levels of more than 10 ng /ml should raise the suspicion of HCC and should be investigated further. c. Treatment: Standard Operating procedure Comprehensive treatment of Liver cancer involves: 1. Treatment of the tumor 2. Treatment of cirrhosis 3. Treatment of complications of cirrhosis 4. Treatment of the virus if the cause is hepatitis B or C.

Treatment of the tumor is based on the stage of the tumor. The most commonly used staging and treatment plan followed is based on the BCLC (Barcelona clinic liver cancer) staging system. This system incorporates, not only the size and number of tumors, but also, 25

the residual liver function, the functional status of the liver and presence or absence of extrahepatic spread. The BCLC staging system is given below: Scheme of BCLC staging for liver cancer (PST: Performance status score; CTP: Child Turcott Pugh class) d. In Patient In the secondary care set up, the patient should be managed for complications of cirrhosis, such as GI bleeding, ascites, hepatic encephalopathy. e. Out Patient Only in cases requiring symptomatic treatment Referral criteria:

Patients requiring curative or palliative therapies for HCC [ such as liver transplantation, liver resection, radiofrequency ablation, percutaneous ethanol injection, trans-arterial chemoembolization, trans arterial radioembolization, and biological therapy (tyrosine kinase inhibitors or monoclonal antibodies)], should all be referred to a hepatologist or gastroenterologists with interest in managing HCC at a tertiary care center

Even patients requiring advanced treatment for complications of cirrhosis, should be referred to tertiary care centers. 26

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical Diagnosis: All patients with cirrhosis of liver who develop recent worsening of their clinical status should be suspected of having developed liver cancer and should be appropriately investigated. It should be suspected when: 1. A patient who has stable cirrhosis develops new ascites 2. A cirrhotic patient develops a difficult to control ascites.

3. A stable cirrhotic develops severe constitutional symptoms, such as weight loss or anorexia. 4. Any patient, especially one who has cirrhosis, develops prolonged fever of unknown origin (FUO) 5. A patient of cirrhosis develops pain in the upper abdomen. b) Investigations: The initial investigations should include: 1. Abdominal ultrosonography which can pick up features of cirrhosis and presence of any SOL in the liver. 2. Alpha feto protein (AFP) levels: Levels of more than 10 ng /ml should raise the

suspicion of HCC and should be investigated further. The further investigations required are: 3. Triple phase contrast enhanced CT Scan of abdomen 4. Dynamic contrast enhanced MRI of the abdomen 5. Contrast enhanced ultrasonography 6. PET CT scan of the abdomen 7. Bone scan 8. Biopsy or FNAC of the tumor with immunohistochemical staining 9. Other tumor markers such as PIVKA-II and AFP-L3 27

The investigations from number 3-9 may all be required or may be required selectively for confirming the diagnosis, determining the stage of the disease, determining extrahepatic spread and suitability for treatment. c) Treatment: As has been mentioned earlier, treatment depends on the BCLC stage of the disease Standard Operating procedure a. In-Patient Curative forms of therapy for liver cancer include: 1. Liver resection (surgical removal of a part of the liver involved by the tumor)

2. Percutaneous ablative therapies [burning the tumor with either radiofrequency current (radiofrequency ablation) or with injection of 100% alcohol or with injection of 50% acetic acid] or 3. Liver transplantation. Palliative therapies include: 1. Transarterial chemoembolization, 2. Transarterial radio-embolization 3. Systemic chemotherapy. 4. Continuous intra-arterial chemotherapy through implatable port. As mentioned earlier, BCLC staging system guides therapy as follows:

Patients with very early HCC (stage 0)and early HCC (stage A): Can be offered all forms of curative therapy: 1. Liver transplantation 2. Liver resection 3. Percutaneous ablative therapies (radio frequency ablation, percutaneous ethanol injection or percutaneous acetic acid injection therapy) Patients with intermediate HCC (stage B): 28

Can be offered therapy with: 1. Transarterial chemoembolization (TACE). 2. Oral chemotherapy with biological such as sorafenib 3. Liver transplantation can be offered to patients with single large tumor or even multiple tumors, but only at experienced centres. (these would be patients outside Milan’s criteria [single tumor < 5 cm or up to 3 tumors with diameter < 3 cm]) Patients with (stage C): Can be offered 1. Systemic chemotherapy with Sorafenib 2. Radioembolization with yttrium 99 theraspheres

Patients with end-stage disease (stage D): Can be offered 1. Oral chemotherapy with Sorafenib 2. Symptomatic therapy b. Out Patient Patients being given symptomatic therapy or oral chemotherapy can be managed in the out patient setting. Follow up after curative therapies would also be done in the out patient setting. Following percutaneous ablative therapies, patients need to undergo regular FU with a dynamic contrast imaging (either a CT or MRI scan), liver function profiles and tumor markers at regular

intervals or as indicated. d) Referral criteria: Patients fit for undergoing liver transplantation should be referred to a hepatologist at a liver transplant center VI. WHO DOES WHAT? and TIMELINES a. Doctor 1. Diagnosis and treatment(medical, radiological and surgical) of cases b. Nurse 1. Nursing care to patients undergoing treatement at in-patients. 2. Endoscopy nurse c. Technician 1. Endoscopy technician 2. Interventional radiology technician 29

3. Liver surgery technician 4. Lab technician, biochemistry/hematology lab 5. Blood bank technician VII. FURTHER READING / REFERENCES 1. J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 42: 1208-1236. 2. Paul SB, Sreenivas B, gulati MS, Madaqn K, Gupta AK, Mukhopadhaya S, Panda SK, Acharya SK. Incidence of hepatocellular carcinoma among Indian patients with cirrhosis of liver. An experience from a tertiary care center in northern India. Indain J Gastroenterol 2007; 26: 274-8.

3. Paul SB, Chalamalasetty SB, Vishnubhatla S, Madan K, Gamnagatti SR, batra Y, Gupta SD, Panda SK, Acharya SK. Clinical profile, etiology and therapeutic outcomes in 324 hepatocellular carcinoma patients in a tertiary care center in India. Oncology 2009; 77: 162- 71. 30

RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 Specialist MD or CBC, LFT, RFT, INR, IV set, IV cannulas, Ryles tube, DM doctor, AFP, Blood cultures, Syringes, Sengstaken urine cultures, Nurse, Diuretics (aldactone, blackmore tube, ultrasound furosemide, torsemide),

Technician Ultrasound lactulose, pantoprazole machine, ECG oral and iv, machine somatostatin, terlipressin, tenofovir, entecavir, telbivudine, b complex, calcium, oral iron, UDCA, vitamin E, insulin, oral hypoglycemic drugs 2 DM Endoscopy, All drugs and Endoscopy gastroenterologist consumables required in equipments, Multislice CT or hepatologist, liver surgeries and liver Multislice CT scanner, MRI, Interventional transplant surgeries, scanner, MRI Ultrasound, PET

radiologist, GI/liver interventional radiology scanner, PET scanner, bone transplant surgeon, set up, sorafenib, scanner, bone scan…….in addition biochemist, ………in addition to what scanner, Contrast to what is required hematologist, is required in situation 1 ultrasound machine in situation 1 microbiologist, and the contrast (sonovue/sonazoid) Resident doctors in Wards, ICUs, OTs, all specialities Interventional radiology set up and Nurses, technicians all equipment required in such set ups……in addition to

INFLAMMATORY BOWEL DISEASE Dr Vineet Ahuja Deptt of Gastroenterology, All India Institute of Medical Sciences, New Delhi I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: Inflammatory bowel disease (IBD) represents a group of idiopathic chronic inflammatory intestinal conditions. The two main disease categories included are Crohn’s disease (CD) and ulcerative colitis (UC), with both overlapping and distinct clinical and pathological

features. In addition the spectrum also comprises two categories ; IBD unclassified and indeterminate colitis. The pathogenesis of IBD is still under investigation. The most simplified view is that intestinal injury results due to aberrant immune response to commensal bacteria in a background of genetic predisposition. b) Case definition: o Ulcerative colitis: Ulcerative colitis is a chronic disorder of unknown etiology in which a part or the

whole of the mucosa of the colon becomes diffusely inflamed and ulcerated. Rectum is involved in a vast majority of the cases. o Crohn’s Disease: A chronic granulomatous disease which can affect any part of GI tract in a discontinuous, asymmetric manner. Unlike Ulcerative colitis which is a mucosal disease, Crohn’s disease is a transmural disease. o IBD unclassified: Categorization is not possible after clinical, radiological, endoscopic and histological features o Indeterminate colitis:

Categorization is not possible even after evaluation of resected specimen. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY The epidemiological studies from this region are being made available it is clear that the incidence and prevalence rates of IBD in Asia–Pacific region are low compared with Europe and North America. They are however, increasing rapidly. 32

There are substantial variations in the incidence and prevalence rates of IBD in various ethnic groups in Asia. The highest incidence rates are recorded from India, Japan and the Middle East and there exists a genetic predisposition of South Asians (Indians, Pakistanis and Bangladeshis) to ulcerative colitis (UC). In a study done in 2001 from Ludhiana in Punjab, the crude prevalence rate was 44.3/105. The incidence was calculated after a second visit to the same area one year later. The

crude incidence rate was 6.02/105. The incidence rate of UC in India is higher than in Asian countries like Japan (1.95/105) and Korea (1.23/105). There is no population-based study on Crohn’s disease (CD) in India, however, the accepted perception is that the incidence of CD is rapidly rising in India. The peak age of incidence of CD is the third decade of life, with a decreasing incidence rate with age. The incidence rate in UC is quite stable between the third and seventh decades.

III. DIFFERENTIAL DIAGNOSIS The main differential diagnosis of Ulcerative colitis and Crohn’s disease are : Ulcerative colitis Crohn’s disease Acute self limiting colitis Intestinal Tuberculosis Amoebic colitis Acute self limiting colitis Crohn’s Disease Amoebic colitis HIV enteropathy Ulcerative colitis Behcet’s disease NSAID enteropathy HIV enteropathy IV. PREVENTION AND COUNSELING IBD is an autoimmune disease, and environmental factors which can trigger an episode

have not been identified, hence primary prevention strategy is not possible. There is a family history in 5% of IBD patients. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited 33

There is no gold standard test available to make a diagnosis of IBD. A diagnosis of ulcerative colitis or Crohn’s disease is made on the basis of compatible clinical history, examination, imaging, endoscopy and histology findings. a) Clinical Diagnosis: History The most important features are the chronic duration of symptoms and the frequent remissions and relapses which characterize IBD and help in distinguishing from other infectious diseases affecting the large and small bowel. Ulcerative colitis

1. Diarrhea : Large bowel diarrhea which is daytime or nocturnal 2. LGI bleed : Blood may be mixed with stool and at times separate from the stools 3. Rectal symptoms: tenesmus, urgency , frequency of stools 4. Abdominal pain and fever in case of severe disease 5. Symptoms are limited to large bowel Crohn’s disease(CD) Symptoms depend upon the site of involvement. In CD , any part of bowel from esophagus to anal canal may be involved . Small Intestinal involvement / Ileocolonic involvement :

1. Abdominal Pain 2. Symptoms suggestive of recurrent partial intestinal obstruction may be present 3. Chronic diarrhea 4. Fever, anorexia, weight loss Large bowel involvement : 1. Chronic diarrhea 2. Hematochezia 3. Peri anal disease 4. Fever, weight loss 5. Abdominal pain Upper GI involvement 1. Dysphagia, odynophagia 2. Epigastric pain 3. Symptoms suggestive of gastric outlet obstruction 34

Extraintestinal manifestations (EIM) :Arthritis is the most common EIM and is observed in 15-20% of cases. Other extraintestinal complications include ankylosing spondylitis, pyodermagangrenosum, erythema nodosum, iritis, uveitis, episcleritis, and primary sclerosing cholangitis. Complications include : 1. Hemorrhage: profuse bleeding from ulcers in UC. Bleeding is less common in CD. Massive bleeding in CD is more often seen from ileal ulceration than colitis.

2. Strictures, bowel perforation and Intra-abdominal abscesses in CD. 3. Fistulas and perianal disease in CD 4. Colorectal cancer: Significantly increased risk of colon cancer in UC after 8 years of diagnosis; the risk is lower in CD as compared to UC. b) Investigations: Primary and secondary care settings : • Stool for ova and cysts • Haemogram and Serum albumin • Sigmoidoscopy (if available) • Barium enema for ulcerative colitis

• In India, at present, a suspected case of Crohn’s disease should always be referred to a tertiary care hospital before initiating therapy. This is so as to rule out intestinal tuberculosis which closely mimics Crohn’s disease. Referral Hospitals: • Stool examination: i ) Parasites ii)Clostridium difficile(should be considered even in absence of antecedent antibiotics). • Blood tests : i) Haemoglobin , ESR , serum albumin , Human immunodeficiency virus (HIV)

ii) Perinuclear antineutrophil cytoplasmic antibody (p-ANCA) and anti- Saccharomyces cerevisiae antibodies (ASCA): need not be done iii) Celiac serology • Monteux skin test • Chest X ray • Sigmoidoscopy / Colonoscopy An endoscopic examination is necessary a) to establish the diagnosis b) to assess severity of disease c) to take targeted mucosal biopsies . In cases with severe activity , a full length colonoscopy is not indicated as there is a high risk of perforation.

Ulcerative colitis: An ileocolonoscopy is indicated to establish the extent of disease 35

Crohn’s Disease: Endoscopic procedures required include : 1) ileocolonoscopy 2) UGI endoscopy ( especially in pediatric cases) 3)Capsule endoscopy/ double balloon enteroscopy if small bowel involvement suspected. • Histology Multiple mucosal biopsies should be taken from inflamed areas. Features suggestive of ulcerative colitis include crypt architectural destruction, crypt abscesses, goblet cell depletion, paneth cell metaplasia, basal plasmocytosis. In Crohn’s disease non caseating

granulomas may be seen in 30% of cases • Imaging 1. Abdominal X ray: In severe UC or CD where perforation or toxic mega colon is suspected. In CD, if intestinal obstruction is suspected. 2. Contrast enhanced computed tomography ( Enteroclysis/Enterography) : In cases with CD i) to evaluate small intestinal involvement ii) to differentiate from intestinal tuberculosis 3. Barium meal follow through: If facilities for CT (enteroclysis) are not present.

• These investigations not only help in diagnosing the disease but also help in determining the extent and severity of the disease . The tables below show the classification for extent and severity of UC and CD. Table 1: Disease extent in Ulcerative colitis: Extent Disease Description E1 Ulcerative proctitis Involvement limited to rectum E2 Left sided UC Involvement distal to the splenic flexure (distal colitis) E3 Extensive UC Involvement extends proximal to the splenic flexure (Pancolitis) 36

Table 2: Disease activity in ulcerative colitis (adapted from World Gastroenterology Organisation Global Guidelines June 2009) Table 3 : Disease activity in Crohn’s Disease (ACG classification) 37

Table 4 : Montreal Classification of Crohn’s disease phenotype In addition , these investigations also help in 1) differentiating Ulcerative colitis from Crohn’s disease 2) Intestinal tuberculosis from Crohn’s disease as shown in the tables below 38

Table 5 : Features for differentiating between ulcerative colitis (UC) and Crohn’s disease (CD) (adapted from World Gastroenterology Organisation Global Guidelines June 2009) 39

Table 6 : Distinguishing between tuberculosis and Crohn’s disease ( adapted from World Gastroenterology Organisation global Guidelines June 2009) 40

IBD management should be based on: UC vs. CD (although this is less important for early aspects of treatment) Disease location and phenotype Severity The goals of treatment are to: • Maintain steroid-free remissions (decreasing the frequency and severity of recurrences and reliance on steroids) • Prevent complications hospitalization and surgery Treatment include two phases • Induction of remission • Maintenance of remission

The figure below shows the drugs which are useful in induction and maintenance phase Ulcerative colitis : Disease extent: Proctitis and Proctosigmoiditis • Inducing Remission Proctitis : 5ASA suppositories ; Optimal dose : 1gm/day Proctosigmoiditis : 5ASA enemas : 2-4 gm/ 41

If no response within 4 week Use of topical glucocorticoids If still no response : Use of hydrocortisone rectal drip: 200mg/200ml/1-2 hrs • Maintaining remission Oral 5 ASA in a dose of 1600-2400 mg daily may be used with or without topical therapy If disease extent is left sided colitis/pancolitis, then the treatment may be planned as in the table below: A. For Induction of remission depending upon the severity of disease

B. For maintenance of remission : Use of 5 ASA alone or 5ASA and azathioprine in patients who require frequent steroids Management guidelines in Crohn’s Disease ( as in the table below) Inflammatory CD Mild to moderate Induction regime Remission : ( B1 phenotype) SSZ : left colon Azathioprine Budesonide : ileocolon Methotrexate Moderate with systemic Induction regime Remission : 42

Symptoms Prednisolone Azathioprine Severe IV Hydrocortisone Methotrexate Small bowel extensive disease Introduction of Infliximab Corticosteroid dependent Remission : Corticosteroid refractory IFX + 2 courses of steroids/year Azathioprine Risk factors for Top Down rx Not Methotrexate group Fistulizing Perianal : Simple vs Antibiotics, azathioprine Disease complex Infliximab , Surgery (B3 phenotype) Non perianal Surgery Stricturing Steroids/balloon Disease dilatation/surgery/? Infliximab (B2 phenotype)

ii) Referral criteria: Criteria for surgery referral : • Toxic megacolon • Perforation peritonitis • Severe bleed • Refractory to medical therapy • Stricturing Crohn’s disease Standard Operating procedure a. In Patient : Patients with severe disease not responding to oral steroids b. Out Patient : Patients with mild to moderate disease or patients in remission on follow up c. Day Care : Any patient requiring infliximab maintenance infusion 43

VI. WHO DOES WHAT? and TIMELINES a. Doctor: Diagnose and strategise therapy b. Nurse : Assist in administering drugs c. Technician : Assist in endoscopy and imaging investigations VII. FURTHER READING / REFERENCES 1. Inflammatory bowel disease: a global perspective. World Gastroenterology Organisation Global Guidelines. June 2009 2. Hanauer SB. Medical management of Crohn's disease: treatment algorithms 2009. Dig Dis. 2009;27(4):536-41.

3. Van Assche G, Vermeire S, Rutgeerts P. Management of acute severe ulcerative colitis. Gut. 2011 Jan;60(1):130-3. 4. Mowat C, Cole A, Windsor A,et al ; on behalf of the IBD 5. Section of the British Society of Gastroenterology. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2011 May;60(5):571-607. RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment.

Quantity to also be specified) Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 2 44

LOWER GASTROINTESTINAL BLEED Dr Vineet Ahuja Deptt of Gastroenterology, All India Institute of Medical Sciences, New Delhi I. WHEN TO SUSPECT/ RECOGNIZE? c) Introduction: Lower GI bleeding is a common GI problem. It may present as acute lower GI bleed or may present as occult GI bleed leading to chronic GI blood loss. It may also present as a challenging problem in the form of obscure GI bleed. d) Case definition: Any bleeding beyond ligament of Treitz is called as lower GI bleed. Mid GI bleed is any bleed

between ampulla of Vater and ileocaecal valve. The source of bleed is colonic in 80-90% of the cases and small intestinal in 1-10% of the cases II. INCIDENCE OF THE CONDITION IN OUR COUNTRY It is less common than Upper GI bleed. Men are affected more commonly than women. An increased incidence is seen with increase in age. The incidence in Western countries is 20-30/10,000. Incidence data are not available for India. III. DIFFERENTIAL DIAGNOSIS

LGI bleed may present with a constellation of clinical symptoms like anaemia, haematochezia, maelena, maroon coloured blood in the stools with or without constitutional features. The common causes of LGI bleed in the Indian context include anorectal causes (haemorrhoids, anal fissures), acute self limiting colitis ( Shigella, E. coli), amoebiasis , enteric fever, colonic tuberculosis , inflammatory bowel disease ( ulcerative colitis and Crohn’s disease), solitary rectal ulcer syndrome , colon cancer,

polyposis coli, radiation colitis, diverticular disease, NSAID induced bleed, Meckel’s diverticulum and ischaemic colitis . IV. PREVENTION AND COUNSELING 45

Acute self limiting colitis and parasitic diseases are often food or water borne diseases and maintaining high levels of hygiene may prevent these diseases. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited Clinical Diagnosis: History should include following points, which may aid in clinical diagnosis:

a) Age: Elderly are more predisposed to cancer colon, diverticular disease and ischaemic colitis. Pediatric age group is predisposed to bleed from rectal polyp or Meckel’s diverticulum. b) History of fever : suggests infectious disease as a cause c) H/o of altered bowel habits for a long duration suggests inflammatory bowel disease or intestinal tuberculosis d) H/o constipation with bleed suggests haemorrhoidal bleed or solitary rectal ulcer syndrome

e) Constitutional symptoms – anorexia, pain abdomen, weight loss f) History suggestive of partial intestinal or colonic obstruction g) H/o of drugs – NSAIDS, anticoagulants h) H/o of radiation, mainly to pelvic region in past i) Past H/o of similar or less threatening LGI Bleed j) Past H/o of endoscopic intervention e.g. polypectomy Assess for a) Type of blood per rectum - red, maroon or malaenic which depends upon source and rapidity of blood loss

b) Whether blood is mixed with stools, separate from stool or only blood is seen. Blood if separate from the stools suggests haemorrhoidal bleed or solitary rectal ulcer syndrome. Investigations: • Assess for signs of blood volume loss-Pulse rate, BP • Assess for aetiology of bleed a) Skin telengiectesia, Lymph nodes, abdominal tenderness, abdominal lump b) Digital rectal examination – to look for anorectal causes and stool colour c) Proctoscopy to rule out haemorrhoids and evaluate rectal mucosa

• Assessment of other organ systems mainly cardiovascular and pulmonary Treatment: Standard Operating procedure 46

• Resuscitation and assessment go hand in hand • Two large bore i.v.cannula or a central venous line if acute LGI bleed • Start crystalloids and plasma expanders, arrange packed RBC • Send samples for CBC, electrolytes, urea, coagulation profile and sample for grouping and cross match • Ryle’s tube (RT) placement and check for RT aspirate a. InPatient: Patients should be admitted if presenting with LGI bleed b. OutPatient: If a patient presents with occult GI bleed and anaemia the management

may be outpatient based if the anaemia is not very severe c. DayCare: In occult GI bleed, the patient may be given blood transfusions to treat for symptoms resulting from anaemia and thereafter referred to a tertiary centre for further investigations k) Referral criteria: • Continuous active bleed • Hemodynamic compromise either hypotension or orthostatic hypotension • Transfusion requirement of >2 packed RBCs to maintain haemodynamic stability • Presence with comorbid illness who require monitoring

• Obscure GI bleed where the cause of bleed needs to be ascertained *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available a) Clinical Diagnosis: Same as mentioned before b) Investigations: Active LGI bleed: • UGI endoscopy • Colonoscopy • Angiography • Radio nuclide scan • Exploratory Laparotomy with intra-operative endoscopy Occult/Obscure GI bleed: • Stool for occult blood • Stool for parasites • UGI endoscopy • Colonoscopy

• Computed tomography (Enteroclysis) • Radionuclide scan • Exploratory laparotomy with intra-operative endoscopy c) Treatment: • Endoscopic therapy :10% to 15% of patients undergoing urgent colonoscopy receive endoscopic therapy 1. Injection therapy (epinephrine or saline) 2. Heater probe therapy 3. Argon plasma coagulation 4. Haemoclips • Radiology techniques 1. Vasopressin infusion 2. Selective embolisation: Definitive means of controlling hemorrhage – stops bleeding 67-100% – Re-bleed 15%-40%

– High incidence of bowel ischemia 3. Super selective embolisation Target artery - the vasa recta; also within the marginal arteries and the distal intestinal arcades A number of primary embolic agents a. Microcoils b. Gelatin sponge particles c. Poly vinyl sponge particles • Surgery 1. Bleeding refractory to other therapies 2. Requirement of more than 8 units of blood over 24 hours 3. Hemodynamic instability 4. Re-bleeding after non-operative treatment, esp if localized

5. Segmentectomy if site of bleed is known 6. Right hemicolectomy if bleed from unknown d) Referral centre: Outcomes at a tertiary referral centre 48

• Mortality at 3 yr follow up 19% • Most patients stop bleeding spontaneously • Rebleed occurs in 10% to 40% of patients • Between 5% and 50% of patients with persistent bleeding require surgical hemostasis The figure below shows the algorithm of management of acute LGI bleed (Abbreviations in the figure : UGIE : upper gastrointestinal endoscopy; CT : computed tomography; DBE : double balloon enteroscopy) VI. WHO DOES WHAT? and TIMELINES a. Doctor b. Nurse c. Technician 49

VII. FURTHER READING / REFERENCES 1: Lee J, Costantini TW, Coimbra R. Acute lower GI bleeding for the acute care surgeon: current diagnosis and management. Scand J Surg. 2009;98(3):135-42. Review. PubMed PMID: 19919917. 2: Singh V, Alexander JA. The evaluation and management of obscure and occult gastrointestinal bleeding. Abdom Imaging. 2009 May-Jun;34(3):311-9. Review. PubMed PMID: 18581161. 3: Strate LL, Naumann CR. The role of colonoscopy and radiological procedures in the

management of acute lower intestinal bleeding. ClinGastroenterolHepatol. 2010 Apr; 8(4):333-43.Review. PubMed PMID: 20036757 RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 2 50

INTESTINAL OBSTRUCTION Govind K Makharia Additional Professor, Department of Gastroenterology and Human Nutrition, AIIMS, New Delhi DrSujoy Pal Associate Professor, Department of Gastrointestinal Surgery, AIIMS, New Delhi WHEN TO SUSPECT/ RECOGNIZE? Introduction Intestinal obstruction is an important gastrointestinal emergency and a common cause of hospitalization. Most of the patients with intestinal obstruction report to surgeons or surgical care

units. Some of them however report to physicians or medical emergency units. . Intestinal obstruction carries a high risk of mortality and morbidity if surgical therapy is inappropriately delayed because of misdiagnosis. Case definition Acute intestinal obstruction occurs when there is an interruption in the forward flow of intestinal contents. This interruption can occur at any point along the length of the gastrointestinal tract. The

clinical presentation varies depending on the severity, duration, site and type of intestinal obstruction..The classical clinical tetrad of presentation is colicky abdominal pain, nausea and vomiting, abdominal distention, and progressive obstipation. There are two types of intestinal obstruction-mechanical and adynamic. Mechanical intestinal obstruction Site of obstruction: The obstructive pathology may lie in the proximal small intestinal or distal intestine including the colon. 51

Grade and severity of the obstructing lesion: The intestinal obstruction could be either complete or incomplete (partial). While in the partial intestinal obstruction, the gas or liquid stool can pass through the point of narrowing, in complete intestinal obstruction, the obstruction is complete and there is no passage of gas or the liquid stool beyond the point of the obstruction. Partial obstruction is further classified as high grade or low grade according to the severity of the narrowing. In general,

surgical intervention is often required for complete intestinal obstruction; partial intestinal obstruction can be treated using conservative measures.The mechanical intestinal obstruction could remain uncomplicated or may get complicated by vascular compromise, intestinal perforation and septicemia. Adynamic intestinal obstruction There are two types of adynamic intestinal obstruction - paralytic ileus and acute intestinal pseudo- obstruction.

It is important to classify intestinal obstruction into above mentioned catagories asthe treatment of intestinal obstruction will vary according to the site, severity and cause of the intestinal obstruction. Therefore, following questions should be addressed while dealing with a patient with intestinal obstruction: 1. Differentiation between complete mechanical obstruction, partial mechanical obstructionor adynamic obstruction

2. The site of obstruction: Small bowel obstruction (proximal or distal) vs. large bowel obstruction (colon/rectal) Patho-physiology In simple intestinal obstruction, the intestine is occluded at one point. Fluid and chyme accumulate proximal to the site of intestinal obstruction. This leads to impairment in intestinal water and electrolyte absorption and enhanced intestinal secretion resulting in volume depletion. Stasis of

intestinal contents predisposes to bacterial overgrowth (predominantly anaerobes) in the segment proximal to obstruction. The bacterial overgrowth leads to bacterial fermentation and increased production ofgas. Accumulation of liquid and gas in the intestine leads to intestinal dilatation which induces localinflammation and neuro-endocrine reflexes that initially increase enteric propulsiveactivity to attempt to overcome the obstruction. Intestinal motilitygradually decreases as

intestinal muscle becomes fatigued.Intestinal dilatation graduallycompromises vascular perfusion because of increasing intraluminalpressure and intramural tension. Forward arterial flow is severely 52

compromisedwhen the intraluminal pressure reaches the diastolic pressure,and ceases when the intraluminal pressure reaches the systolic pressure. Venousobstruction causes increased intraluminal fluid transudation and intramuraledema. Almost 80% of blood flow to the intestine goes to the mucosa, therefore intestinal mucosa is highly sensitive to ischemia as it is perfused by end arteries and has a high rate of metabolic activity.

In closed-loop obstruction, anintestinal segment is occluded at two points.Common forms of closed loops include an incarcerated hernia, in whicha loop of the intestine is compressed at both ends within a hernial sac, and volvulus,in which a loop of intestine is mechanically compressed at both ends because of a twist in the supporting mesentery. If the ileocecal valve is competent, anobstructive lesionin the coloncauses a closed loopdue to a pathologic mechanical obstruction at

the distal end and a physiologic occlusion at theileocecal valve proximally. If the ileocecal valve is incompetent, the obstructive lesionin the colon produces a simpleobstruction as the colon is decompressed by way of the small intestine. Aclosed loop of intestine rapidly dilates because of the lack of a proximaland a distal outlet for the accumulated gas and liquid. The mucosa consequently develops ischemia rapidly. Extrinsic compression that strangulatesmesenteric vessels (e.g. at a point

of volvulus or at the neck of a hernialsack) exacerbates the ischemia and rapidly produces intestinalgangrene or necrosis and perforation. INCIDENCE OF THE CONDITION IN OUR COUNTRY The most common (75%) cause of small intestinal obstruction is post-operative adhesions The rate of adhesive small intestinal obstruction development is highest in the first few postoperative years following the index surgery, particularly after colorectal surgery, but the risk remains life-long. The

risk of recurrent intestinal obstruction from adhesions after 10 years of the index surgery varies widely from 15 to 50%. Although, post-operative intestinal obstruction recovers mostly with conservative management, 25 to 66% of them may require exploratory laparotomy and adhesinolysis. Although hernia was the second most important cause of intestinal obstruction, there has been a marked decline of intestinal obstruction due to hernia from 40% in the 1960s to 15%,

presumably due to an increased rate of elective hernia repair. Other causes of intestinal obstruction include intestinal tuberculosis, bands, and volvulus. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, Clinical features of intestinal obstruction: The clinical presentation varies depending on the severity, duration, andtype of intestinal obstruction. The classical clinicaltetrad is colicky abdominal pain, nausea and vomiting, abdominal distensionand progressive obstipation. 53

Differentiation between proximal vs distal intestinal obstruction Proximal intestinal obstruction typically produces epigastricpain that occurs every 3 to 4 minutes, with frequent bilious vomiting. Distalintestinal obstruction typically produces peri-umbilical pain that occurs every 15 to 20 minutes, with infrequent feculent emesis.Abdominal distension is more marked in the distal obstruction as there is a large length of the intestine proximal to the obstructive

lesion, which can accumulate volumes of fluid and gas. Closed-loop obstruction often presents with pain outof proportion to the abdominal signs because of concurrent mesentericischemia. Inspection occasionally reveals visible peristalsis. Air-filled intestinal loops produce abdominal tympany. Palpation reveals mild generalized abdominal tenderness. Peritoneal signs, such as rebound tenderness and guarding, are typically absent, unless intestinal necrosis or perforation supervenes.

Intestinal sounds are initially high-pitched (tinkling) and hyperactive, with audible rushes or borborygmi corresponding to paroxysms of abdominal pain, but become progressively hypoactive and softer, and then disappear because of intestinal fatigue. Patients with obstructive lesion in the rectum may give a history of spurious diarrhoea, altered bowel habit and progressive constipation before presenting with large bowel obstruction. Features that suggest complications

The development of rigors, high fever, or systemic toxicity suggests thatthe obstruction may be complicated by intestinal necrosis or perforation.Intussusception typically presents in infants with episodic abdominal pain,currant jelly stools, and bilious vomiting.Physical examination reveals an acutely ill, restless, and febrilepatient. Signs of intravascular volume depletion include tachycardia, orthostatichypotension, dry mucous membranes, and poor skin turgor. Jaundicesuggests possible

gallstone ileus or malignant obstruction. Features that suggest aetiology of intestinal obstruction A good systemic and abdominal examination can provide important clues to the aetiology of the intestinal obstruction. A history of previous abdominal surgery especially intestinal surgery can point towards the most common cause of intestinal obstruction i.e. postoperative adhesive intestinal obstruction. Other causes of intestinal obstruction such as abdominal scars, clinically obvious

external incarcerated hernia (femoral, inguinal, umbilical, or incisional), per-rectal examination (fecal impaction, or a rectal mass), and digital examination of the stoma to rule out stomal obstruction in patients with colostomy or ileostomy.Presence of hepatomegaly, splenomegaly, a palpableabdominal mass, or periumbilical (Sister Mary Joseph nodule), inguinal, and right 54

supraclavicular (Virchow node) lymphadenopathy may suggest presence of a malignant obstructive lesion in the intestine with systemic dissemination. Evaluation at the time of acute obstruction Plain upright abdominal radiograph Plain upright abdominal X-ray film should be done for initial confirmation of intestinal obstruction in patients presenting with clinical signs and symptoms of intestinal obstruction. It can confirm

intestinal obstruction in approximately 60%and its positive predictive value approaches 80% in patients with high-grade intestinal obstruction.Presence of multiple air fluid levels (> 3) in the erect film is an important sign pointing towards the diagnosis of intestinal obstruction. At times when the patient is too sick a decubitus film also may help in detecting the presence of air fluid levels. Large air fluid levels occurring more or less at the same level on the radiograph are suggestive of paralytic

ileus whereas air fluid levels at different levels are more likely in a dynamic obstruction. Additionally, the abdominal film can show dilation of intestinal loops (dilation >3 cm), and a transition zone between dilated and non dilatedintestinal segment. The pattern of dilation can suggest the site of intestinal obstruction. While the supine abdominal film in patients with small intestinal obstruction shows dilatation of multiple loops of small intestine, with a paucity of air in the large intestine, the

large intestinal obstruction shows dilatation of the colon, with decompressed small intestine in the setting of a competent ileocecal valve. It is important to assess the diameter of the distended caecum in such cases as dilatation beyond 10 cm indicates impending caecal rupture. Air-filled loops of small intestine are distinguished from those of large intestine by their more central abdominal location, by their narrower calibre even when dilated, and by the presence of valvulaeconniventes

that extend across the entire luminal diameter as opposed to the colonic haustral folds that extend only partially across the luminal diameter. Presence of free air under the diaphragms immediately confirms intestinal perforation.Although this finding diminishes in significance if it is found on an X- ray done in the early postoperative period following an abdominal surgery. Limitation of abdominal radiograph: Plain abdominal film can appear normal in early obstruction

and in high gut obstruction (jejunal or duodenal obstruction) and thus may be misleading. Next step: An abdominal CT scan,non contrast and contrast enhanced (both oral and intravenous contrast; water-soluble contrast preferred) is appropriate for further evaluation of patients with suspected intestinal obstruction in whom clinical examination and radiography do not yield a definitive diagnosis. CT is very useful in a patient suspected to have intestinal obstruction and it can show all

that necessary information about the intestinal obstruction. The presence of a discrete transition point helps guide operative planning. CT findings in patients with intestinal obstruction include dilated loops of intestine proximal to the site of obstruction, with distally decompressed intestine. In addition, CT can identify emergent causes of intestinal obstruction, such as volvulus or intestinal strangulation.Although CT is highly

sensitive and specific for high-grade obstruction, its value diminishes in patients with partial obstruc- 55

tion. In these patients, oral contrast material may be seen traversing the length of the intestine to the rectum, with no discrete area of transition. A C-loop of distended intestinal with radial mesenteric vessels with medial conversion is highly suspicious for intestinal volvulus. Thickened intestinal walls and poor flow of contrast material into a section of intestinal suggests ischemia, whereas pneumatosisintestinalis, free intra-peritoneal air,

and mesenteric fat stranding suggest necrosis and perforation. The CT can also identify intussusceptions easily by picking up the intussusceptum in the intussuscepiens, as the mesenteric fat and vasculature can be identified within the lumen of the intestine or a ‘double target sign’ can be seen on cross-sectional imaging. The American College of Radiology recommends non-contrast CT as the initial imaging modality of choice.However, because most causes of small intestinal obstruction will have systemic

manifestations or fail to resolvenecessitating operative interventionthe additional diagnostic value of CT compared with radiography is limited. Radiation exposure is also significant. Therefore, in most patients, CT should be ordered when the diagnosis is in doubt, when there is no surgical history or hernias to explain the etiology, or when there is a high index of suspicion for complete or high-grade obstruction.The CT signs of strangulation include:a thickened intestinal wall because of intestinal

wall edema, inflammation, or intramural hemorrhage; mural thumb-printing from intramural hemorrhage or edema; pneumatosisintestinalis from intramural gas produced by bacteria; absence of enhancement with intravenous contrast because of vascular hypoperfusion;hazy or streaky mesentery or ‘‘dirty’’ fat from inflammatory infiltration, portal venous gas, target sign, and ascites. Evaluation after resolution of an episode of intestinal obstruction with conservative management

After the acute intestinal obstruction has resolved, the cause of intestinal obstruction should be investigated and treated appropriately (medical or surgical) depending upon the diagnosis. The basic principal of investigation is to find out site, cause, extent and etiology of the intestinal obstructive disease. • Small intestinalevaluation: Barium meal follow through (BMFT), Enteroclysis or CT enteroclysis • Large intestinal evaluation: Preferably colonoscopy and if not available barium enema

• Histological examination of the biopsies for pathological diagnosis • Microbiological tests such as PCR and culture for tuberculosis in appropriate clinical setting Evaluation after control of an episode of intestinal obstruction with surgery Often, in patients with refractory adhesive intestinal obstruction, all that is required at laparotomy is adhesiolysis to separate the adhesions and relieve the obstruction. In such cases there is no need for

any excision of intestine unless there is a strangulated gangrenous segment of intestine. Whenever 56

resection is warranted, the resected specimen should be evaluated both histologically and microbiologically to determine the etiology. In some patients, inflammatory lesions such as tuberculosis or Crohn’s disease, malignant lesions such as adenocarcinomas/gastrointestinal stromal tumors or lymphomas, a specific treatment will be required for the management of the disease postresection. TREATMENT & REFERRAL CRITERIA General measures

The principles in management of acute intestinal obstruction include correction of abnormalities in the fluid and electrolyte imbalances, gastric decompression, and bowel rest, prevention of infection, analgesics, and specific treatment for cause of obstruction. • Monitoring of clinical and hemodynamic status Pulse, Blood pressure Respiratory rate Abdominal girth Intestinal sound Abdominal tenderness • Fluid and electrolyte balance Intravenous fluid: Isotonic crystalloids

Arterial blood gas: Correction of acid base abnormalities Correction of electrolyte imbalance, especially hypokalemia Measurement of urine output • Symptomatic treatment • Oral administration of water-soluble contrast agent (Urograffin)(see below)* Analgesics such as intravenous anti-cholinergics or NSAIDS • Anti-emetics: Metoclopromide, ondansetron • Antibiotics: Antibiotics are used to treat intestinal overgrowth of bacteria and translocation

across the intestinal wall. The presence of fever and leukocytosis should prompt inclusion of antibiotics in the initial treatment regimen. Antibiotics should have coverage against gram-negative organisms and anaerobes, and the choice of a specific agent should be determined by local susceptibility and availability. 57

• Nutritional support: o If intestinal obstruction is prolonged (for example ,in patients with post operative state)and the patients cannot be fed enterally, they should be given total parenteral nutrition. Generally speaking, a previously healthy adult can tolerate 5-7 days of fasting or bowel rest without any significant clinical debility. Beyond this period appropriate parenteral nutritional support is advisable. Outcome following conservative management

Conservative management is successful in 40 to 70 percent of clinically stable patients, with a higher success rate in those with partial intestinal obstruction.Although conservative management is associated with shorter initial hospitalization, there is also a higher rate of eventual recurrence. With conservative management, resolution generally occurs within 24 to 48 hours. Beyond this time frame, the risk of complications, including vascular compromise, increases. If intestinal obstruction is

not resolved with conservative management, surgical evaluation is required. Patients who develop adhesive intestinal obstructionof the small intestinein the postoperative period(both early and late)constitute a special group of patients in whom a new form of conservative intervention is indicated as outlined below.After the baseline abdominal radiographs have documented intestinal obstruction, the next step is to administer 100 ml of urograffin(water-

soluble contrast agent) diluted in 400 ml of saline or drinking water orally or through the nasogastric tubewhich has already been inserted as part of the conservative management of intestinal obstruction. Thereafter, abdominal radiographs are obtained at 8-12 h intervals till 24 hours of ingestion of urograffin.The appearance of contrast in the colon within 8-24 h after its administration predicts resolution of small intestinal obstruction with a sensitivity of 96% and specificity of 98%.

Water soluble contrast agent administration is effective in reducing the need for re-operation and shortening the hospital stay compared with conventional ‘drip-and-suck’ regimen. This simple therapeutic maneuver also has a diagnostic valueand can delineate the level of obstruction in those patients in whom the contrast fails to reach the large intestine in the stipulated time frame. In those patients in whom water soluble contrast agent does not reach colon, the probability of need for

surgery is higher. While administration of water soluble contrast agent can occasionally be repeated, one should keep a close vigil on abdominal signs and clinical status of the patient. This modality can also be used in other patients with intestinal tuberculosis or Crohn’s disease who are likely to have a partialsmall intestinal obstruction. Indications for surgery Although there are clinical features which allow a clinician to decide about the time of surgery and

also predict or suggest resolution of intestinal obstruction with conservative management in the index patient, such a prediction is challenging at occasions. As such, presence of fever, tachycardia, leukocytosis, or anion-gap acidosis, in the setting of abdominal imaging consistent with obstruction constitutes a low threshold for laparotomy. Peritonitis remains an absolute indication for exploration today as it did decades ago.There are clinical scenarios that are considered somewhat

exempt from an “early” operative approach in the absence of peritonitis. These include small bowel 58

obstruction in the early postoperative period (unless following laparoscopic surgery), tuberculosis, Crohn’s disease, or carcinomatosis. Postoperative small bowel obstruction occurs within 4–6 weeks of abdominal surgery with an estimated incidence of 1–4%. Caused by filmy adhesions in most open cases, up to 90% of these obstructions resolve (dissolve or reform) with non-operative management within 7–14 days of the index operation. The exception to this watchful waiting approach is

postoperative obstruction following laparoscopic surgery which warrants an early surgical approach more often than not. The cause of obstruction will depend on the underlying operation, but it is likely that (amongst other causes) intestine is incarcerated within a peritoneal defect caused by trocar placement. Clinical situations such as, volvulus, obstructed hernia, large bowel obstruction with gross cecal dilatation and instances where a closed loop obstruction is suspected should have a

low threshold for surgical intervention. Patients with an intestinal obstruction that resolves after reduction of a hernia should be scheduled for elective hernia repair, whereas immediate surgery is required in patients with an irreducible or strangulated hernia. Stable patients with a history of abdominal malignancy or high suspicion for malignancy should be thoroughly evaluated for optimal surgical planning. Abdominal malignancy can

be treated with primary resection and reconstruction or palliative diversion, or placement of venting and feeding tubes. There is emerging evidence to suggest that patients with colonic/rectal obstruction due to malignancies are best treated by emergency surgical diversion/or resection (wherever feasible) rather than colonoscopic stenting. Patients with post operative adhesive obstruction Treatment of stable patients with intestinal obstruction and a history of abdominal surgery present a

challenge. Conservative management of a high-grade obstruction should be attempted initially, using nasogastric suction and decompression, aggressive intravenous rehydration, and antibiotics. Most show improvement in 48 hours. If not, then a therapeutic trial with water soluble contrast agent (as described above) is warranted in the absence of peritoneal signs. Monitoring Bad signs Tachycardia Hemodynamic status Tachypnea Increase in abdominal girth Vitals Persistent obstruction GI bleed Abdominal girth

Worsening of vitals Persistence of absence of bowel sound Appearance of rebound tenderness Fever 59

Specific measures The cause of the intestinal obstruction should be treated appropriately. *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: As above b) Investigations: Haemogram, electrolytes, sugar, urea levels, chest and abdominal X rays c) Treatment: Standard Operating procedure a. Inpatient: All patients suspected or confirmed to have intestinal obstruction should

be admitted and treated appropriately as described above. b. Outpatient: Not applicable c. Day Care: not applicable d) Referral criteria: Non availability of a surgeon,basic facilities as outlined above A sick patient Failed conservative management Complete obstruction Complicated obstruction Perforation Obstruction secondary to suspected malignancy Obstruction in the setting of IBD *Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available

a) Clinical Diagnosis:As above b) Investigations:Hemogram, electrolytes, RFT, LFT, Blood gases, Serum lactate levels, X-ray: chest/abdomen, CT scan, endoscopic facilities 60

c) Treatment: Standard Operating procedure a. Inpatient: as outlined above b. Outpatient Not recommended;provide follow up and counseling after discharge c. Day Care: Not recommended in the acute setting; d) Referral criteria:None WHO DOES WHAT? and TIMELINES a. Doctor b. Nurse c. Technician RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified)

Situation HUMAN INVESTIGATIONS DRUGS & EQUIPMENT RESOURCES CONSUMABLES 1 2 2 - 2 2 3 1 - 3 61

PANCREATIC CARCINOMA Dr Vikram Bhatia, MD, DM Consultant Gastroenterologist Institute of Liver and Biliary Disease, Delhi I. WHEN TO SUSPECT/ RECOGNIZE? a) Introduction: The most common histological type of pancreatic cancer is ductal adenocarcinoma, which accounts for over 90% of all tumors. Most pancreatic cancers are advanced at the time of diagnosis.The overall 5-year survival rate is 4%. Because the 5-year survival of this condition is

so poor, incidence and mortality rates are virtually identical. At the time of diagnosis, approximately 80% of all pancreatic cancers are advanced. The 5-year survival of operated patients approaches 40% when performed at specialized medical institutions. Pancreatic cancer is rare before the age of 45 years and 80% of cases occur in the 60–80 year age group. b) Case definition: For both situations of care (mentioned below*)

The three main symptoms of pancreatic cancer are pain, loss of weight, and jaundice. However, signs and symptoms are non-specific. Cases of pancreatic cancer are defined by image guided biopsy, surgical resection or intra-operative biopsy, or suggestive imaging features with a progressive and compatible clinical course on follow up. II. INCIDENCE OF THE CONDITION IN OUR COUNTRY The incidence of pancreatic cancer in India hastraditionally been thought to be low (0.5-2.4 per

100,000 men and 0.2-1.8 per 100,000 women). However, this is likely to be a reflection of under-recognition and under-reporting. The incidence of pancreatic cancer is higher in the urban male populations of western and northern parts of India. Time trends show that the incidence is increasing for both carcinoma of the pancreas and also peri-ampullary tumors. The annual pancreatic cancer load of India in 2001 was approximately 14,230 patients: the

estimated current figure is approximately 17,000 and is likely to increase in the near future. 62

III. DIFFERENTIAL DIAGNOSIS 1) Chronic pancreatitis, including autoimmune pancreatitis. 2) Acute pancreatitis, including focal pancreatitis / pseudo-tumoral pancreatitis / groove pancreatitis. 3) Metastasis to the pancreas from renal cell carcinoma, melanoma, breast cancer, colon cancer e.t.c IV. PREVENTION AND COUNSELING No simple screening test is available for the general population. The strongest etiological association of pancreatic cancer is with cigarette smoking. Hence health

education to reduce tobacco consumption should lower the risk of developing pancreatic carcinoma. Other high-risk groups include patients with chronic pancreatitis, adult onset diabetes of less than two years’ duration, hereditary pancreatitis, familial pancreatic cancers, and certain familial cancer syndromes. However, there are no screening or preventive guidelines for these higher risk groups. V. OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA INVESTIGATIONS,

The goals of investigations are: (a) Establishing the diagnosis, and (b) Assessing the tumor resectability The following investigations can be used as indicated: 1) Abdominal ultrasound. 2) Computerized tomography (CT) scan. 63

3) Magnetic resonance (MR), including magnetic resonance cholangiopancreatography (MRCP). 4) Positron emission tomography (PET) - CT scan 5) Endosonography (EUS). 6) Laparoscopy with laparoscopic ultrasonography Endoscopic retrograde cholangiopancreatography (ERCP) is now seldom used for the primary diagnosis. However, it can be used to obtain intra-ductal tissue for diagnosis, when biliary drainage is planned. TREATMENT (a) Curative treatment

Pancreaticoduodenectomy (with or without pylorus preservation) is the most appropriate resectional procedure for tumors of the pancreatic head. Left sided resection (with splenectomy) is appropriate for localized carcinomas of the body and tail of the pancreas. Involvement of the splenic vein or artery is not in itself a contraindication to such resection. (b) Neoadjuvant treatment Neoadjuvant treatment is indicated for tumors considered borderline resectable. This category includes the following:

(1) No distant metastases. (2) Venous involvement of the SMV/portal vein demonstrating tumor abutment with or without impingement and narrowing of the lumen, encasement of the SMV/portal vein but without encasement of the nearby arteries, or short segment venous occlusion resulting from either tumor thrombus or encasement but with suitable vessel proximal and distal to the area of vessel involvement, allowing for safe resection and reconstruction.

(3) Gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis. (4) Tumor abutment of the SMA not to exceed greater than 180 degrees of the circumference of the vessel wall. 64

Gemcitabine or gemcitabine-based combination therapy may be considered as initial therapy prior to 5-FU-based chemoradiation. (c) Palliative treatment Palliative treatment is indicated for unresectable tumors, which are defined by the following criteria, according to the tumor location: Pancreatic head tumors: 1) Distant metastases 2) Greater than 180 degrees SMA encasement, any celiac abutment 3) Unreconstructible SMV/portal occlusion 4) Aortic invasion or encasement Pancreatic body tumors:

1) Distant metastases 2) SMA or celiac encasement greater than 180 degrees 3) Unreconstructible SMV/portal occlusion 4) Aortic invasion Pancreatic tail tumors: 1) Distant metastases 2) SMA or celiac encasement greater than 180 degrees All tumors with metastases to lymph nodes beyond the field of resection should be considered unresectable. 1. Surgical palliation Surgery for palliative purpose is now rarely indicated. It may have some role in resource-

limited setting. It may also be indicated if the patient is found to be unresectable during laparotomy. Duodenal and biliary bypass should be used during palliative surgery. The biliary bypass should be constructed with the bile duct in preference to the gall bladder. 2. Medical palliation 65

Patients should have access to palliative care specialists. Pain relief should be achieved using a progressive analgesic ladder. Patients with pancreatic head tumors, who require relief of jaundice will need biliary stenting. Endoscopic stent placement is preferable to trans-hepatic stenting. Both plastic and self-expanding metal stents (SEMS) are effective in achieving biliary drainage but SEMS are preferable for patients with longer life expectancy (more than 6 months). Currently, the

choice between these stents depends on clinical factors, local availability, and local expertise. Plastic stents have been traditionally placed to relieve jaundice before surgery. However, covered SEMS can also be placed without compromising the surgery and afford a faster relief of jaundice. Gastric outlet obstruction can be palliated with enteral SEMS. Treatment of associated depression. Pancreatic enzyme replacement for pancreatic insufficiency.

Low molecular weight heparin for prophylaxis of thromboembolic disease. Gemcitabine is considered the standard front line chemotherapy for patients with metastatic disease. Gemcitabine combinations have shown a favorable impact on time to progression or survival for patients with good performance status. *Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited a) Clinical Diagnosis: b) Investigations: 66

1) Liver function tests. 2) CA 19.9 levels (CA 19-9 may be elevated in cases of benign biliary obstruction and does not represent an appropriate baseline until the patient is decompressed. In addition, CA19-9 may be undetectable in Lewis-a negative individuals). 3) Chest imaging. 4) Abdominal ultrasound. 5) CT or MRI scanning. c) Treatment: 1) Nutritional build up and early referral for potentially resectable patients. 2) Symptom palliation for unresectable patients. Standard Operating procedure

a. In Patient b. Out Patient c. Day Care d) Referral criteria: 1) Suspected carcinoma pancreas, where the diagnosis cannot be established with the existing resources. 2) Potentially resectable patients for further staging. 3) Potentially resectable patients for pancreaticoduodenectomy surgery to a high volume center. 4) Unresectable patients, with specialized palliation needs, like celiac plexus neurolysis, patient controlled analgesia, stenting for relief of biliary obstruction e.t.c.

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available 67

a) Clinical Diagnosis: b) Investigations: In addition to above: 1) PET-CT scan 2) Endoscopic ultrasound. 3) Laparoscopy and laparoscopic ultrasound. 4) Guided biopsy techniques for patients considered not suitable for surgical resection. If biopsy is required in a resectable lesion, then EUS-directed FNA biopsy is preferable to a CT- guided FNA because of lower risk of peritoneal seeding with the former. Biopsy proof of

malignancy is not required before surgical resection and a non-diagnostic biopsy should not delay surgical resection when the clinical suspicion for pancreatic cancer is high. c) Treatment: In addition to above, super-specialty facilities should also have: 1) Facilities for assessment of resectability. 2) Increased therapeutic resources, including oncologic treatment. 3) Adequate surgical expertise for pancreatic resections. 4) Specialized services in histopathology, intensive care, and palliative care.

5) Facilities for the organization and conduct of local, national, and international trials. Standard Operating procedure a. In Patient b. Out Patient c. Day Care 68

VI. WHO DOES WHAT? and TIMELINES a. Doctor Clinical evaluation, decides investigations, interprets the investigations, and generates a treatment plan. b. Nurse Ensures adequacy of palliative care, and carries out the treatment plan. c. Technician Carries out the investigations planned. VII. FURTHER READING / REFERENCES 1. NCCN guidelines: http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf( accessed on 20.03.11).

2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277- 300. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20610543. 3. Cascinu S, Falconi M, Valentini V, Jelic S. Pancreatic cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21 Suppl 5 (): v55-8. 4. Tempero M, Arnoletti JP, Ben-Josef E, Bhargava P, Casper ES, Kim P, Malafa MP, Nakakura EK, Shibata S, Talamonti M, Wang H, Willett C. Pancreatic adenocarcinoma.

Clinical Practice Guidelines in Oncology. J NatlComprCancNetw 2007; 5 (10): 998-1033. 5. Guidelines for the management of patients with pancreatic cancer periampullary and ampullary carcinomas. Gut 2005; 54 Suppl 5 (): v1-16. RESOURCES REQUIRED FOR ONE PATIENT / PROCEDURE (PATIENT WEIGHT 60 KGS) (Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified) Situation HUMAN INVESTIGATIONS DRUGS &EQUIPMENT RESOURCES CONSUMABLES 1 2 69

STANDARD TREATMENT GUIDELINES The Diabetic foot Prevention and management in India Quick Reference Guide (Draft) January 2016 Ministry of Health & Family Welfare Government of India The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

TABLE OF CONTENTS- 1. INTRODUCTION – ................................................................................................................... 3 2. CASE DEFINITION – ................................................................................................................. 3 3. INCIDENCE OF DIABETIC FOOT IN INDIA ................................................................................. 3

4. RECOMMENDATIONS ............................................................................................................. 4 Clinical Pathway 1- Overview of Foot care in Diabetes .................................................................. 4 Clinical Pathway 2 - Prevention of Diabetic Foot ........................................................................... 5

4. 1: PREVENTION ............................................................................................................................... 6 4.2 ASSESSMENT, CLASSIFICATION AND REFERRAL ....................................................................................... 8 Clinical Pathway 2.1 – Assessment of Patients ............................................................................ 11

Clinical Pathway 3 - Overview of Management of Diabetic Foot ................................................ 12 4.3: DIABETIC FOOT INFECTIONS ...................................................................................................... 13 4.4: WOUND CARE ........................................................................................................................... 15

Clinical Pathway 3.1 - Care of Acute Wound ............................................................................... 16 Clinical Pathway 3.2 - Care of Chronic Wound ............................................................................ 17 4.5 : FOOTWEAR ............................................................................................................................... 18

4.6 TREATMENT OF DIABETIC FOOT WITH OSTEOMYELITIS ........................................................................ 19 4.7. CHARCOT’S FOOT .......................................................................................................................... 20 Clinical Pathway 3.3 - Management of Charcot’s Foot ................................................................ 21 4.8: SURGICAL INTERVENTIONS AND REVASCULARIZATION ............................................................ 22

1. Introduction – India is set to become the diabetes capital of the world with a projected 109 million individuals with diabetes by 2035. India ranks second (after China) with more than 66.8 million diabetics in 3 the age group of 20-70. The prevalence of Diabetes in India is 8.6% and, as of 2013, more than 4 1 million Indians die each year due to diabetes related causes. 5 Diabetic foot care is one of the most ignored aspects of diabetes care in India. 24 Due to social,

religious, and economic compulsions, many people walk barefoot. Poverty and lack of education lead to usage of inappropriate footwear and late presentation of foot lesions. Many non-medically qualified persons are interfering in the treatment of diseases, including diabetes. Patients also try home remedies before visiting their physicians. It estimated that 90% of diabetic patients in India 24 do not see a specialist in their lifetime. Problem is further worsened by a delay in accessing 25

healthcare due to patient approaching informal care providers and alternative medicine prescribers. There is a lack of a good evidence-based standard guideline on Diabetic foot are in India. Currently, diabetic feet are treated by individual practitioners. Physicians, General surgeons, orthopaedic surgeons, primary care physicians, endocrinologists and podiatrists all look after the diabetic feet. But neither their roles, responsibilities nor the protocols are clearly defined in the

public domain. Moreover, in the Indian context, due to the pronounced variability in the health care system, a common national guidance for providing curative as well as preventive methods to curb the growth of diabetic foot in the future is essential. Hence, it is a public health imperative to create an integrated framework for comprehensive management of diabetic foot. 2. Case Definition – Diabetic foot as defined by the World Health Organization is, “The foot of a diabetic patient

that has the potential risk of pathologic consequences, including infection, ulceration, and/or destruction of deep tissues associated with neurologic abnormalities, various degrees of peripheral vascular disease, and/or metabolic complications of diabetes in the lower limb”. 3. Incidence of Diabetic foot in India Diabetic Foot (DF) is one of the most common complications for admissions imposing tremendous medical and financial burden on our healthcare system. The lifetime risk of a person 6 7

with diabetes having a foot ulcer could be as high as 25% and is the commonest reason for 8 hospitalization of diabetic patients (about 30%) and absorbs about 20% of the total health-care costs, more than all other diabetic complications. The prevalence of foot ulcers in diabetics 9, 10 attending a centre managing diabetic foot (both indoor and outdoor setup) in India is 3%. Foot 11, 12 ulcers among outpatient and inpatient diabetics attending hospitals in rural India was found to be 10.4%. 13

Peripheral vascular disease (PVD) occurs in about 3.2% diabetics below 50 years of age and rises to 55% in those above 80 years of age. 15% of those with diabetes for a decade suffer from 14 diabetic foot, where as it increases to almost 50% by another decade. 15 Approximately, 85% of non-traumatic lower limb amputations are seen in patients with prior history of diabetic foot ulcer. Each year, more than 1 million people with diabetes lose at least 16,17

a part of their leg due to diabetic foot. It shows that every 20 seconds a limb is lost in the world somewhere. In India, though recent population based data is not available, it is estimated that 18 approximately 45,000 legs are amputated every year in India. The vast majority (75%) of these are probably preventable because the amputation often results from an infected neuropathic foot. More than half of all foot ulcers become infected, requiring hospitalization, while 20% of 19

infections result in amputation. After a major amputation, 50% of people will have the other 20 limb amputated within two years’ time. People with a history of diabetic foot ulcer have a 40% greater 10-year death rate than people with diabetes alone 4. Recommendations Clinical Pathway 1- Overview of Foot care in Diabetes FOOT CARE in Diabetes (Pathway no. 1) REDUCE the risk of Diabetic Foot problem (Go to pathway no. 2) MANAGE the Diabetic Foot problem (Go to pathway no. 3)

Clinical Pathway 2 - Prevention of Diabetic Foot REDUCE the risk of Diabetic Foot problem (Pathway no. 2) Educate the patient regarding DF care (Go to the Patient Information Document) Assessing the Risk (Go to the Recommendation no. 4.2.1) Frequency of follow up (Go to the Recommendation no. 4.1.1) Managing the Risk (Go to the Recommendation nos. 4.1.2 to 4.1.10 and also 4.5.1 to 4.5.8) MANAGE the Diabetic Foot problem (Go to pathway no. 3) The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

4. 1: PREVENTION Overview: 1. Identification of the at-risk foot 2. Regular inspection and examination of the at-risk foot 3. Education of patient, family and healthcare providers 4. Routine wearing of appropriate footwear 5. Treatment of pre-ulcerative signs 4.1.1 Prevention of Diabetic foot problems 4.1.1 To identify a person with diabetes at risk for foot ulceration, examine the feet annually / six monthly / quarterly / monthly (depending on patient’s risk category) to seek

evidence for signs or symptoms of peripheral neuropathy and peripheral artery disease. Risk Classification System and preventive screening frequency Category Characteristic Frequency 0 No peripheral neuropathy Once a year 1 Peripheral neuropathy Once every six months 2 Peripheral neuropathy with peripheral artery disease Once every 3-6 and/or a foot deformity months 3 Peripheral neuropathy and a history of foot ulcer or Once every 1-3 lower-extremity amputation months source : The IWGDF guidelines 2015

4.1.2 In a person with diabetes who has peripheral neuropathy, screen for: a history of foot ulceration or lower-extremity amputation; peripheral artery disease; foot deformity; pre- ulcerative signs on the foot; poor foot hygiene; and ill-fitting or inadequate footwear. 4.1.3 Treat any pre-ulcerative sign on the foot of a patient with diabetes. This includes: removing callus; protecting blisters and draining when necessary; treating ingrown or

thickened toe nails; treating haemorrhage when necessary; and prescribing antifungal treatment for fungal infections. 4.1.4 To protect their feet, instruct an at-risk patient with diabetes not to walk barefoot, in socks, or in thin-soled standard slippers, whether at home or when outside. 4.1.5 Instruct an at-risk patient with diabetes to: daily inspect their feet and the inside of their shoes; daily wash their feet (with careful drying particularly between the toes); avoid

using chemical agents or plasters to remove callus or corns; use emollients to lubricate dry skin; and cut toe nails straight across. 4.1.6 Instruct an at-risk patient with diabetes to wear properly fitting footwear to prevent a first foot ulcer, either plantar or non-plantar, or a recurrent non-plantar foot ulcer. When a foot deformity or a pre-ulcerative sign is present, consider prescribing therapeutic shoes, custom-made insoles, or toe orthosis.

4.1.7 Instruct a high-risk patient with diabetes to monitor foot skin temperature at home to prevent a first or recurrent plantar foot ulcer. This aims at identifying the early signs of The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

inflammation, followed by action taken by the patient and care provider to resolve the cause of inflammation. 4.1.8 To prevent a first foot ulcer in an at-risk patient with diabetes, provide education aimed at improving foot care knowledge and behaviour, as well as encouraging the patient to adhere to this foot care advice. 4.1.9 To prevent a recurrent plantar foot ulcer in an at-risk patient with diabetes, prescribe therapeutic footwear that has a demonstrated plantar pressure relieving effect during

walking and encourage the patient to wear this footwear. 4.1.10 To prevent a recurrent foot ulcer in an at-risk patient with diabetes, provide integrated foot care, which includes professional foot treatment, adequate footwear and education. This should be repeated or re-evaluated once every one to three months as necessary. The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

4.2 Assessment, Classification and Referral 4.2.1 Assessing the risk of developing a diabetic foot problem 4.2.1a Evaluate a diabetic patient presenting with a foot wound at 3 levels: the patient as a whole, the affected foot or limb, and the infected wound. 4.2.1b Assess the affected limb and foot for arterial ischemia , venous insufficiency, presence of protective sensation, and biomechanical problems. Explanatory note: Biomechanical problems means anatomical and physiological

disturbances of the foot, i.e., structural changes which happen in the bones, joints and muscles of the foot of diabetics and the changes in the blood circulation and nerve sensation of the foot of diabetics. 4.2.2. Classification of Diabetic foot 4.2.2a Assess the severity of any diabetic foot infection using the Infectious Diseases Society of America/ International Working Group on the Diabetic Foot Classification system.

Table 1. Infectious Diseases Society of America and International Working Group on the Diabetic Foot Classifications of Diabetic Foot Infection Clinical Manifestation of Infection PEDIS IDSA Grade Infection Uninfected: 1 Uninfected No symptoms or signs of infection Infected: 2 Mild At least two of the following items are present: • Local swelling or induration • Erythema >0.5cm around the wound • Local tenderness or pain • Local warmth • Purulent discharge (thick, opaque to white or sanguineous secretion)

Exclude other causes of an inflammatory response of the skin (eg, trauma, gout, acute Charcot neuro-osteoarthropathy, fracture, thrombosis, venous stasis). Local infection involving only the skin and the subcutaneous tissue (without involvement of deeper tissues and without systemic signs as described below). An erythema, must be </=2 cm around the ulcer. Local infection (as described above) with erythema > 2 cm, or 3 Moderate involving structures deeper than skin and subcutaneous tissues

(eg, abscess, osteomyelitis, septic arthritis, fasciitis), and No systemic inflammatory response signs (as described below) The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

Local infection (as described above) with the signs of SIRS, as 3 Severea manifested by ≥2 of the following: • Temperature >38°C or <36°C • Heart rate >90 beats/min • Respiratory rate >20 breaths/min or PaCO2 <32 mm Hg • White blood cell count >12,000 or <4000 cells/µL or ≥10% immature (band) forms Abbreviations: IDSA, Infectious Diseases Society of America; PaCO2, partial pressure of arterial carbon dioxide; PEDIS, perfusion, extent/size, depth/tissue loss, infection, and sensation; SIRS,

systemic inflammatory response syndrome. 4.2.2b Do not use the Wagner classification system to assess the severity of a diabetic foot ulcer. 4.2.3 Referral for Diabetic foot problems 4.2.3a Initially hospitalize all patients with a severe infection, selected patients with a moderate infection with complicating features (eg, severe peripheral arterial disease [PAD] or lack of home support), and any patient unable to comply with the required outpatient

treatment regimen for psychological or social reasons. Also hospitalize patients who do not meet any of these criteria, but are failing to improve with outpatient therapy. (Also refer to Table-3 and 4 below, for explanatory notes.) Table 3: Characteristics suggesting a more serious diabetic foot infection source : from The IWGDF guidelines 2015 Table 4: Factors indicating that hospitalization may be necessary The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

source : from The IWGDF guidelines 2015 4.2.3b Prior to being discharged, make sure that a patient with a DFI (Diabetic Foot Infection) is clinically stable; has had any urgently needed surgery performed; has achieved acceptable glycemic control; is able to manage (on his/her own or with help) at the designated discharge location; and has a well defined plan that includes an appropriate antibiotic regimen to which he/she will adhere, an off-loading scheme (if needed), specific

wound care instructions, and appropriate outpatient follow-up. The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

Clinical Pathway 2.1 – Assessment of Patients Clinical Assessment at three levels Patient as a whole Affected limb Wound/Ulcer Duration of DM No wound Charcot’s Foot Glycaemic Control (HbA1c) Anti-DM medications Other co-morbidities Refer to higher centre (HTN, IHD, CKD, etc) Control of HTN Management of IHD (Aspirin / Clopidogrel / Statin) Smoking cessation No Cellulitis Cellulitis present Past history of Ulceration / Infection / Amputation / Charcot’s foot Look for Oral Antibiotics Mild Bed Rest

Scaling in OPD Corns / Calluses Follow up Footwear modification Topical Antifungal Web space Moderate Refer to fungal infection higher Adequate Severe centre trimming In-growing toe-nails Protective Footwear Gross Deformities Corrective Surgery Skin changes Suspect PAD Absent sweating Absent pedal pulses Refer to ABI < 0.9 higher centre 10-gm Monofilament test Suspect Neuropathy Ipswich touch test The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

Clinical Pathway 3 - Overview of Management of Diabetic Foot MANAGEMENT of the Diabetic Foot problem (Pathway no. 3) When to Refer ? (Go to the Recommendation nos. 4.2.3 and 4.7.2) Inform the patient his/her clinical condition and what all investigations and treatment are needed DF infection/ Ulcer / Vasculopathy Charcot’s Foot Osteomyelitis (4.8.14) (4.7.1) (4.2.2, 4.3.1, 4.3.2) Investigations Investigations Investigations (4.3.3, 4.3.4, (4.8.9 to 4.8.13, (4.7.3 to 4.7.5) 4.6.1 to 4.6.4) 4.8.15, 4.8.16)

Treatment Treatment Treatment (4.3.5, (4.8.12, 4.8.13, (4.7.6 to 4.7.10) 4.4.1 to 4.4.11, 4.8.17 to 4.8.24) 4.5.1 to 4.5.8, 4.6.5 to 4.6.7, 4.8.1 to 4.8.8 4.8.12 to 4.8.13, 4.8.21 to 4.8.24) The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

4.3: DIABETIC FOOT INFECTIONS 4.3.1 Consider the possibility of infection occurring in any foot wound in a patient with diabetes. Evidence of infection generally includes classic signs of inflammation (redness, warmth, swelling, tenderness, or pain) or purulent secretions, but may also include additional or secondary signs (e.g., nonpurulent secretions, friable or discolored granulation tissue, undermining of wound edges, foul odor).

4.3.2 Be aware of factors that increase the risk for diabetic foot infections (DFI) and especially consider infection when these factors are present; these include a wound for which the probe-to-bone (PTB) test is positive; an ulceration present for >30 days; a history of recurrent foot ulcers; a traumatic foot wound; the presence of peripheral vascular disease in the affected limb; a previous lower extremity amputation; loss of protective

sensation; the presence of renal insufficiency; or a history of walking barefoot. 4.3.3 Take plain radiographs of the affected foot of all patient presenting with a new Diabetic Foot Infection to look for bony abnormalities (deformity, destruction) as well as for soft tissue gas and radio-opaque foreign bodies. 4.3.4 When and how to obtain culture from Diabetic foot patients? 4.3.4a For clinically uninfected wounds, do not collect a specimen for culture.

4.3.4b Send a specimen for culture that is from deep tissue, obtained by biopsy or curettage and after the wound has been cleansed and debrided. Avoid swab specimens, especially of inadequately debrided wounds, as they provide less accurate results. Explanatory note: Wash the wound with saline and the surrounding skin with antiseptic solution before taking culture to avoid contamination of the specimen obtained for culture.

4.3.4c Do not obtain repeat cultures unless the patient is not clinically responding to treatment. Explanatory note - Expert consensus says that if the signs of inflammation do not subside even after 72 hours of starting treatment, then it should be considered that patient is not responding. 4.3.4d For infected wounds, clinicians should send appropriately obtained specimens for culture prior to starting empiric antibiotic therapy, if possible. Cultures may be unnecessary

for a mild infection in a patient who has not recently received antibiotic therapy. 4.3.5. Selection of Antibiotic and when should it be modified? 4.3.5a Do not treat clinically uninfected wounds with antibiotic therapy. 4.3.5b Prescribe antibiotic therapy for all infected wounds but caution that this is often insufficient unless combined with appropriate wound care. 4.3.5c Base the route of therapy largely on infection severity. Prefer parenteral therapy for

all severe, and some moderate, DFls, at least initially with a switch to oral agents when the patient is systemically well and culture results are available. Clinicians can probably use highly bioavailable oral antibiotics alone in most mild, and in many moderate, infections and topical therapy for selected mild superficial infections. The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

4.3.5d Select an empiric antibiotic regimen on the basis of the severity of the infection and the likely etiologic agent(s). a. For mild to moderate infections in patients who have not recently received antibiotic treatment, therapy just targeting aerobic gram-positive cocci (GPC) is sufficient b. For most severe infections, start broad-spectrum empiric antibiotic therapy, pending culture results and antibiotic susceptibility data.

c. Empiric therapy directed at P. aeruginosa is usually unnecessary except for patients with risk factors* for true infection with this organism. d. Consider providing empiric therapy directed against MRSA in a patient with a prior history of MRSA infection; when the local prevalence** of MRSA colonization or infection is high; or if the infection is clinically severe. Explanatory notes: * Risk factors for true infection with Pseudomonas aeruginosa include

Immunocompromised status, Chronic Kidney Disease, warm climate and frequent exposure of foot to water. **The local prevalence of MRSA (i.e., percentage of all S. aureus clinical isolates in that locale that are methicillin resistant) is high enough (perhaps 50% for a mild and 30% for a moderate soft tissue infection) that there is a reasonable probability of MRSA infection. 4.3.5e Give an initial antibiotic course for a soft tissue infection of about 1–2 weeks for mild

infections and 2–3 weeks for moderate to severe infections. 4.3.5f Continue antibiotic therapy until, but not beyond, resolution of findings of infection, but not through complete healing of the wound. 4.3.5g Administer parenteral therapy initially for most severe infections and some moderate infections, with a switch to oral therapy when the infection is responding. The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

4.4: WOUND CARE 4.4.1 Clean ulcers regularly with clean water or saline*, debride them when possible in order to remove debris from the wound surface and dress them with a sterile, inert dressing in order to control excessive exudate and maintain a warm, moist environment in order to promote healing**. Explanatory note: *Clean water is boiled cooled water (distilled water) ** Do not use H2O2, EUSOL, etc 4.4.2 Select dressings principally on the basis of exudate control, comfort and cost.

4.4.3 Do not use antimicrobial dressings with the goal of improving wound healing or preventing secondary infection. 4.4.4 Do not offer the following to treat diabetic foot ulcers, unless as part of a clinical trial: · Electrical stimulation therapy, autologous platelet-rich plasma gel, regenerative wound matrices and dalteparin. · Growth factors (granulocyte colony-stimulating factor [G-CSF], platelet-derived growth factor [PDGF], epidermal growth factor [EGF] and transforming growth factor beta [TGF-β]).

· Hyperbaric oxygen therapy. 4.4.5 Consider dermal or skin substitutes as an adjunct to standard care when treating diabetic foot ulcers, only when healing has not progressed and on the advice of the multidisciplinary foot care service. 4.4.6 Consider negative pressure wound therapy after surgical debridement for diabetic foot ulcers, on the advice of the multidisciplinary foot care service. 4.4.7 Do not select agents reported to improve wound healing by altering the biology of the

wound, including growth factors, bioengineered skin products and gases, in preference to accepted standards of good quality care. 4.4.8 Do not select agents reported to have an impact on wound healing through alteration of the physical environment, including through the use of electricity, magnetism, ultrasound and shockwaves, in preference to accepted standards of good quality care. 4.4.9 Do not select systemic treatments reported to improve wound healing, including

drugs and herbal therapies, in preference to accepted standards of good quality care. 4.4.10 Redistribution of pressure off the wound to the entire weight-bearing surface of the foot (“off-loading”). While particularly important for plantar wounds, this is also necessary to relieve pressure caused by dressings, footwear, or ambulation to any surface of the wound. 4.4.11 When deciding about wound dressings and offloading when treating diabetic foot

ulcers, take into account the clinical assessment of the wound and the person’s preference, and use devices and dressings with the lowest acquisition cost appropriate to the clinical circumstances. The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

Clinical Pathway 3.1 - Care of Acute Wound Wound / Ulcer Acute Chronic Not Infected Infected Separate Flowchart Simple dressings only Off-loading No antibiotics Rule out Osteomyelitis (PTB test, X-ray) Take adequate specimen for culture Assess patient’s clinical condition Patient stable Patient unstable Wet Gangrene No Sepsis Sepsis present Oral Antibiotics Hospitalization AMPUTATION Wound Care / Dressings i.v. antibiotics Glycaemic control Debridement Follow-up Wound care / Dressings

Improvement No Improvement Continue same No threat to life Threat to life present Protective Footwear after ulcer heals Periodic Evaluation Evaluate further for Osteomyelitis, to prevent recurrence PAD, Neuropathy, Charcot’s foot The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

Clinical Pathway 3.2 - Care of Chronic Wound Chronic Wound / Ulcer (non-healing for > 6 weeks) Assess Vascularity Check for LOPS Assess for Osteomyelitis Gross Deformities (Loss of Protective Sensation) Inability to feel the Therapeutic Footwear Palpate pedal pulses 10-gm monofilament Calculate ABI No relief Arterial Colour Doppler Neuropathy present Corrective surgery Off-loading PAD present Protective Footwear Patient moribund Patient Fit for Surgery PTB test Inconclusive

Microangiopathy Large vessel disease X-ray High Suspicion MR Angio / CT Angio DSA Confirmed Osteomyelitis MRI Medical Plan for management Revasularisation Hospitalization i.v. antibiotics for 4-6 weeks Debridement & Dressings Off-loading Protective Footwear after cure The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

4.5 : FOOTWEAR 4.5.1 To heal a neuropathic plantar forefoot ulcer without ischemia or uncontrolled infection in a patient with diabetes, offload with a non-removable knee-high device with an appropriate foot-device interface. Non-removable (cast) walker: Same as removable (cast) boot/walker but then with a layer(s) of fibreglass cast material circumferentially wrapped around it rendering it irremovable (also known as "instant total contact cast")

4.5.2 When a non-removable knee-high device is contraindicated or not tolerated by the patient, consider offloading with a removable knee-high walker with an appropriate foot- device interface to heal a neuropathic plantar forefoot ulcer in a patient with diabetes, but only when the patient can be expected to be adherent to wearing the device. Removable (cast) boot/walker: Prefabricated removable knee-high boot with a rocker or

roller outsole configuration, padded interior, and an insertable and adjustable insole which may be total contact. 4.5.3 When a knee-high device is contraindicated or cannot be tolerated by the patient, consider offloading with a forefoot offloading shoe, cast shoe, or custom-made temporary shoe to heal a neuropathic plantar forefoot ulcer in a patient with diabetes, but only and when the patient can be expected to be adherent to wearing the shoes.

4.5.4 Instruct an at-risk patient with diabetes to wear properly fitting footwear to prevent a first foot ulcer, either plantar or non-plantar, or a recurrent non-plantar ulcer. When a foot deformity or a pre-ulcerative sign is present, consider prescribing therapeutic shoes, custom-made insoles, or toe orthosis*. *Toe orthosis:- An in-shoe orthosis to achieve some alteration in the function of the toe. 4.5.5 To prevent a recurrent plantar foot ulcer in an at-risk patient with diabetes, prescribe

therapeutic footwear that has a demonstrated plantar pressure relieving effect during walking and encourage the patient to wear this footwear. 4.5.6 Instruct a patient with diabetes not to use conventional or standard therapeutic footwear to heal a plantar foot ulcer. Explanatory note: Use footwear with following features - Sandals: should have adjustable straps, insole, full heel counter and rigid outsole. Shoes: should have wide toe box extra depth and without laces.

4.5.7 Consider using shoe modifications, temporary footwear, toe spacers or orthoses to offload and heal a non-plantar foot ulcer without ischemia or uncontrolled infection in a patient with diabetes. The specific modality will depend on the type and location of the foot ulcer. 4.5.8 If other forms of biomechanical relief are not available, consider using felted foam* in combination with appropriate footwear to offload and heal a neuropathic foot ulcer without

ischemia or uncontrolled infection in a patient with diabetes. The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

Felted foam - A fibrous, unwoven material backed by foam with absorbing and cushioning characteristics. The foam is generally ‘rubber foam’ or ‘PU foam’ which is formed by either a polyester or polyether polyol resin, in conjunction with water and Toluene di Isocyanate, along with various catalysts and blowing agents and colouring pigments to give the desired compression. 4.6 Treatment of Diabetic foot with osteomyelitis

4.6.1 For an infected open wound, perform a probe-to-bone test; in a patient at low risk for osteomyelitis a negative test largely rules out the diagnosis, while in a high risk patient a positive test is largely diagnostic. 4.6.2 Markedly elevated ESR is suggestive of osteomyelitis in suspected cases. Explanatory note: Tests for serum inflammatory markers are costly and not widely available, except ESR. Also these tests are not diagnostic of DFO.

4.6.3If osteomyelitis is suspected in a person with diabetes but is not confirmed by initial X- ray, consider an MRI to confirm the diagnosis.In places where MRI is unavailable, diagnose osteomyelitis by the PTB test (clinically) and/or taking a Bone biopsy and culture. Explanatory note: “Expert Consensus says that as availability of MRI is limited across the country, it is recommended to use MRI wherever available.” At the primary and secondary

health centre levels, the PTB test and bone biopsy and culture are more feasible and economical and reasonably accurate. 4.6.4 A definite diagnosis of bone infection usually requires positive results on both histological and microbiological examinations of an aseptically obtained bone sample, but this is usually required only when the diagnosis is in doubt or determining the causative pathogen’s antibiotic susceptibility is crucial.

4.6.5 Avoid using results of soft tissue or sinus tract specimens for selecting antibiotic therapy for osteomyelitis as they do not accurately reflect bone culture results. 4.6.6 When a radical resection leaves no remaining infected tissue*, we suggest prescribing antibiotic therapy for only a short duration (2–5 days). When there is persistent infected or necrotic bone, we suggest prolonged (≥4 weeks) antibiotic treatment.

Explanatory note: *A proximal bone histopath to be done if available to get a clear margin and confirm that no infected bone remains. 4.6.7 For specifically treating Diabetic foot osteomyelitis, we do not currently support using adjunctive treatments such as hyperbaric oxygen therapy, growth factors (including granulocyte colony stimulating factor), maggots (larvae), or topical negative pressure therapy (eg, vacuum-assisted closure). The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

4.7. Charcot’s Foot 4.7.1 Suspect acute Charcot arthropathy if there is redness, warmth, swelling or deformity (in particular, when the skin is intact), especially in the presence of peripheral neuropathy or renal failure. Think about acute Charcot arthropathy even when deformity is not present or pain is not reported. 4.7.2 Refer the person with suspected charcot’s foot early (within one week) to the “Diabetic Foot Care Center” to confirm the diagnosis, and offer non-weight-bearing

treatment until definitive treatment can be started. Diabetic Foot care centre:- In India, since there are no minimum standards of services offered to the diabetic foot patients, in our recommendations we have used this term to denote this facility, which may exist at the General Practitioner’s office, Primary health centre, Secondary care centre or at a tertiary care centre. Preferably, the diabetic foot care centre should consist of atleast a surgeon, a physician, and an orthotist.

4.7.3 If acute Charcot arthropathy is suspected, X-ray the affected foot. Consider an MRI if the X-ray is normal but clinical suspicion still remains. 4.7.4 Distinguishing the bony changes of osteomyelitis from those of the less common entity of diabetic neuro-osteoarthropathy (Charcot foot) may be particularly challenging and requires considering clinical information in conjunction with imaging. 4.7.5 Clinical clues supporting neuro-osteoarthropathy in this context include midfoot

location and absence of a soft tissue wound, whereas those favoring osteomyelitis include presence of an overlying ulcer (especially of the forefoot or heel), either alone or superimposed on Charcot changes. 4.7.6 If the films show classic changes suggestive of osteomyelitis (cortical erosion, periosteal reaction, mixed lucency, and sclerosis), and if there is little likelihood of neuro- osteoarthropathy, it is reasonable to initiate treatment for presumptive osteomyelitis,

preferably after obtaining appropriate specimens for culture. 4.7.7 If the Diabetic Foot Care Center suspects acute Charcot arthropathy, offer treatment with a non-removable off-loading device. Only consider treatment with a removable off- loading device if a non-removable device is not advisable because of the clinical or the person’s circumstances. 4.7.8 Do not offer bisphosphonates to treat acute Charcot arthropathy, unless as part of a clinical trial.

4.7.9 Monitor the treatment of acute Charcot arthropathy using clinical assessment. This should include measuring foot–skin temperature difference and taking serial X-rays until the acute Charcot arthropathy resolves. Acute Charcot arthropathy is likely to resolve when there is a sustained temperature difference of less than 2 degrees centigrade between both feet and when X-ray changes show no further progression. 4.7.10 The Diabetic Foot care centre should care for people who have a foot deformity

resulting from a previous Charcot’s arthropathy as they are at high risk of ulceration. The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

Clinical Pathway 3.3 - Management of Charcot’s Foot CHARCOT’S FOOT suspected when Long-standing Diabetes, in the setting of peripheral Swollen joint, Redness, neuropathy and/or CKD Warmth & Intact skin Refer to Higher Centre X-ray Inconclusive High Suspicion Confirmed Charcot’s Foot MRI Acute Chronic Off-loading Foot Unstable Foot Stable for 4-6 months Bracing Therapeutic Footwear Monitor for Resolution by Orthosis Patient Education - serial X-rays Custom-made Periodic Evaluation to

- skin temperature difference shoes prevent recurrence between both legs Convert to Stable Foot Once quiescent, treat as Chronic Foot remains Unstable not responsive to Off-loading and Immobilization Consider Surgical Stabilization Ulcer recurs Remains Unstable Chronic Ulceration treat appropriately Chronic Osteomyelitis as per flowchart of ulcer Consider AMPUTATION The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

4.8: SURGICAL INTERVENTIONS AND REVASCULARIZATION 4.8.1 Consult a surgical specialist in all cases of diabetic foot infections that are moderate or severe. 4.8.2 Perform urgent surgical intervention in most cases of deep abscesses, compartment syndrome and virtually all necrotizing soft tissue infections. 4.8.3 Debride any wound that has necrotic tissue or surrounding callus; the required procedure may range from minor to extensive.

4.8.4 Perform urgent surgical intervention for most foot infections accompanied by gas in the deeper tissues, an abscess, or necrotizing fasciitis, and less urgent surgery for wounds with substantial nonviable tissue or extensive bone or joint involvement. Additional note: In those with a non-severe infection, carefully observing the effectiveness of medical therapy and the demarcation line between necrotic and viable tissue before operating may be prudent.

4.8.5 Consider surgical intervention in cases of osteomyelitis accompanied by: spreading soft tissue infection; destroyed soft tissue envelope; progressive bone destruction on X-ray; or, bone protruding through the ulcer. 4.8.6 Remove slough, necrotic tissue & surrounding callus with sharp debridement in preference to other methods, taking relative contraindications such as severe ischemia into account. 4.8.7 Consider digital flexor tenotomy to prevent a toe ulcer when conservative treatment

fails in a high-risk patient with diabetes, hammertoes and either a pre-ulcerative sign or an ulcer on the toe. 4.8.8 Consider Achilles tendon lengthening, joint arthroplasty, single or pan metatarsal head resection or osteotomy to prevent a recurrent foot ulcer when conservative treatment fails in a high-risk patient with diabetes and a plantar foot ulcer. Management of Peripheral Artery Disease in patients with Diabetic foot problems

4.8.9 Examine a patient with diabetes annually for the presence of peripheral artery disease (PAD); this should include, at a minimum, taking a history and palpating foot pulses. 4.8.10 Evaluate a patient with diabetes and a foot ulcer for the presence of PAD. Determine, as part of this examination, ankle or pedal Doppler arterial waveforms; measure both ankle systolic pressure and systolic ankle brachial index (ABI). 4.8.11 Use bedside non-invasive tests to exclude PAD. No single modality has been shown to

be optimal. Measuring ABI (with <0.9 considered abnormal) is useful for the detection of PAD. Tests that largely exclude PAD are the presence of ABI 0.9-1.3, toe brachial index (TBI) ≥0.75 and the presence of triphasic pedal Doppler arterial waveforms. 4.8.12 In patients with a non-healing ulcer with either an ankle pressure <50mmHg or ABI <0.5 consider urgent vascular imaging and revascularisation. The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)

4.8.13 Consider vascular imaging and revascularisation in all patients with a foot ulcer in diabetes and PAD, irrespective of the results of bedside tests, when the ulcer does not improve within 6 weeks despite optimal management. 4.8.14 Do not consider Diabetic microangiopathy to be the cause of poor wound healing in patients with a foot ulcer. 4.8.15 To obtain anatomical information when revascularisation is being considered, use

one of these tests - Colour Doppler ultrasound, CT-angiography, MR-angiography or intra- arterial digital subtraction angiography. Evaluate the entire lower extremity arterial circulation, with detailed visualization of below-the-knee and pedal arteries. 4.8.16 Offer duplex ultrasound as first-line imaging to all people with peripheral arterial disease for whom revascularization is being considered. Take the decision of revascularisation on the basis of colour doppler findings and use DSA for defining the

vascular anatomy prior to the procedure. 4.8.17 The aim of revascularisation is to restore direct flow to at least one of the foot arteries, preferably the artery that supplies the anatomical region of the wound, and adequate revascularization should be assessed post-operatively with a colour Doppler wave- fronts (preferable) or a hand held Doppler probe used bedside. 4.8.18 A centre treating patients with a foot ulcer in diabetes should have liaison /

association with a centre having the expertise necessary to diagnose and treat PAD; both endovascular techniques and bypass surgery should be available. 4.8.19 The multidisciplinary team should treat the patient after a revascularisation procedure for a foot ulcer in diabetes, as part of a comprehensive care plan. 4.8.20 There is inadequate evidence to establish which revascularisation technique is superior and a multidisciplinary team should decide the technique of revascularization for a

patient based on a number of individual factors, such as morphological distribution of PAD, availability of autogenous vein, patient co-morbidities and local expertise. 4.8.21 Give emergency treatment to patients with signs of PAD and a foot infection as they are at particularly high risk for major limb amputation. 4.8.22 Avoid revascularisation in patients in whom, from the patient perspective, the risk- benefit ratio for the probability of success is unfavourable*.

*Explanatory note: Unfavorable risk benefit ratio would indicate those patients who are frail, elderly, bed ridden, having low life expectancy, multiple co-morbidities imposing high risk for surgical intervention, etc 4.8.23 All patients with diabetes and an ischemic foot ulcer should receive aggressive cardiovascular risk management including support for cessation of smoking, treatment of hypertension and prescription of a statin as well as low-dose aspirin or clopidogrel.

4.8.24 Do not offer major amputation to people with critical limb ischaemia unless all options for revascularisation have been considered by a vascular multidisciplinary team. Major amputation without giving a chance for revascularization is indicated only in lifesaving situations like foot causing septicemia, wet gangrene, or completely destroyed foot (post charcot’s or osteomyelitis etc) The Diabetic Foot – Quick Reference Guide Ver. 3.0 (Draft)