Snake bite - ASV Protocols and Management - Antisnake Venom

Snake bite - ASV Protocols and Management - Dosing protocol for anti snake venom

1. COMPARISON OF DIFFERENT DOSING PROTOCOLS OF ANTI SNAKE VENOM (ASV) IN SNAKE BITE CASES GUIDE: DR SACHIN HOSKATTI STUDENT:DR SUSHMA S BIRADAR Journal of clinical and diagnostic research,2017

2. Snakebite is an acute life threatening time limiting medical emergency Total number of bites may be more than 5.4 million,2.5 million envenomation and 1.25 lakh deaths worldwide 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).  

3. The estimated death in India is 50,000/ yr, an underestimate because of lack of proper registration of snakebite 66-163/1 lakh population suffer from snake bite annually with mortality of 1.1 to 2.4/1 lakh population and case fatality rate of 1.7% to 20%

4. The “Big four” Naja naja (Common cobra) Bungarus caeruleus (common krait) Vipera russelii ( russels viper) Echis carinatus (Saw scaled viper) M edically important species and anti-snake venom (ASV) is the only specific antidote

5. Kraits are active during night hours, often biting a persons 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

6. FIRST AID PROTOCOL   CARRY = Do not allow victim to walk even for a short distance; just carry him in any form, specially when bite is at leg.  No - Tourniquate  No - Electrotherapy  No - Cutting  No - Pressure immobilization  Nitric oxide donor ( Nitrogesic ointment/ Nitrate Spray)  R = Reassure the patient. 70% of all snakebites are from non-venomous species. Only 50% of bites by venomous species actually envenomate the patient.  I = Immobilize in the same way as a fractured limb. Use bandages or cloth to hold the splints, not to block the blood supply or apply pressure. Do not apply any compression in the form of tight ligatures, they don’t work and can be dangerous!  G H = Get to Hospital Immediately. Traditional remedies have NO PROVEN benefit in treating snakebite.  T = Tell the Doctor of any systemic symptoms that manifest on the way of hospital.  

7. Suspected snake bite Overt bite occult bite History of bite no history of bite(?krait) Nonvenoumous (70) neuroparalytic with no /venomous(30) local signs,severe abdominal pain,vomiting asymptomatic symptomatic ASV,AN,ventilation ) anxiety,palpitations,tachycardia

8. symptomatic Progressive painful Neuroparalytic Vasculotoxic Swelling Cobra Russels s viper saw scale viper Viper Krait Local necrosis Ptosis bleeding Diplopia DIC,shock,AKI Ecchymosis Dysarthia Blistering Dysphonia Painful swelling Dyspnea Compartment syndrome Dysphagia Asv,supportive,blood transfusion,dialysis Paralysis ASV ASV,AN,ASSISTED VENTILATION

9. 20 minute whole blood clotting test (20 WBCT): It is a bedside test.   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 of venom-induced consumption coagulopathy If blood clot is formed and signs and symptoms of neurotoxic envenomation present, classify as neurotoxic envenomation

10.   If there is any doubt, repeat the test in duplicate, including a “control” (blood from a healthy person).   Counsel patient and relatives in the beginning that, 20WBCT may be repeated several times before giving any medication.   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. In case of neurotoxic envenomation repeat clotting test after 6 hours.

11. FEATURE COBRA KRAITS RUSSELS VIPER SAW SCALED VIPER HUMPED NOSE VIPER Local pain/tissue damage Yes NO Yes Yes Yes Ptosis , neurological sign Yes Yes No No No Hemostatic abnormality No May occur Yes Yes Yes Renal complication No No Yes No Yes Response to neostigmine Yes ± No No No Response to ASV Yes Yes yes yes No

12. FATAL DOSE VENOM NEUTRALISED BY 1 ML OF ASV TOTAL ASV COBRA 120 0.6MG 200ml RUSSELLS VIPER 150 0.6mg 250ml KRAIT 60 0.45mg 134ml ECHIS CARINATUS 80 0.45mg 10.22ml

13. ASV ADMINISTRATION CRITERIA SYSTEMIC ENVENOMING Evidence of coagulopathy : Primarily detected by 20WBCT or visible spontaneous systemic bleeding.   Evidence of neurotoxicity : ptosis , external ophthalmoplegia , muscle paralysis, inability to lift the head etc.   Cardiovascular abnormalities : hypotension, shock, cardiac arrhythmia, abnormal ECG.  Persistent and severe vomiting or abdominal pain.  

14. Severe Current Local envenoming Severe current, local swelling involving more than half of the bitten limb (in the absence of a tourniquet). In the case of severe swelling after bites on the digits (toes and especially fingers) after a bite from a known necrotic species.  Rapid extension of swelling (for example beyond thewaist or ankle within a few hours of bites on the hands or feet). Swelling a number of hours old is not grounds for giving ASV.  Purely local swelling, even if accompanied by bite mark from an apparently venomous snake, is not grounds for administering ASV.

15. Dose of ASV for neuroparalytic snakebite – ASV 10 vials stat as infusion over 30 minutes followed by 2 nd dose of 10 vials after 1 hour if no improvement within 1 st hour .

16. 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. – 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 or pit viper bite as available ASV does not contain antibodies against them .

17. 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 .

18. 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.  

19. Repeat dose of ASV Vasculotoxic or haemotoxic envenomation   Repeat clotting test every 6 hours until coagulation is restored. Administer ASV every 6 h until coagulation is restored Maximum 30 vials

20. Repeat dose: neuroparalytic or neurotoxic envenomation Repeat ASV when there is worsening neurotoxic or cardiovascular signs even after 1–2 h. Maximum dose 20 vials of ASV for neurotoxically envenomed patients

21. 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. ASV GOLDEN HOURS-within 4 hours

22. 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.

23. ASV REACTION   NO ASV TEST DOSE MUST BE ADMINISTERED. 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.   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.

24. Pyrogenic reactions usually develop 1–2 h after treatment. 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 fever, nausea, vomiting, diarrhoea , itching, recurrent urticaria , arthralgia , myalgia , lymphadenopathy , immune complex nephritis and, rarely, encephalopathy.  

25. Treatment of Early ASV reaction   Stop ASV temporarily. Start fresh IV normal saline infusion with a new IV set 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.   Administer Chlorpheniramine maleate (adult dose 10 mg, in children 0.2 mg/kg) intravenously.   Role of Hydrocortisone in managing ASV reaction is not proved. Once the patient has recovered, re-start ASV slowly for 10-15 minutes keeping the patient under close observation. Then resume normal drip rate.

26. 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. Inj. Adrenaline 0.25 ml of 1:1000 (as available in one ampoule of 1 ml) Subcutaneously just before adding ASV to the running IV fluid.  

27. 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.

28. MANAGEMENT NEUROTOXIC (NEUROPARALYTIC) ENVENOMATION Oxygen and assisted ventilation Administer ‘Atropine Neostigmine (AN)’ schedule described as below 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

29. Tapering dose at 1 hour, 2 hour, 6 hours and 12 hour. 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.

30. 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.

31. If there is no improvement after 3 doses of atropine neostigmine (within 1 h), 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.

32. MANAGEMENT OF VASCULOTOXIC SNAKEBITE: Volume Replacement in snake bite T O Give fluid challenge of 2l of isotonic saline for 1 hour and maintain cvp of 8-10cm To watch for hematuria,bleeding manifestations Closely monitor urine output and maintain 1 ml/kg/h urine output

33. Forced Alkaline Diuresis – oliguria , within first 24 hours of the bite to avoid pigment nephropathy leading to acute tubular necrosis (ATN) .   If patient responds to first cycle continue for 3 cycles – If there is no response to furosemide discontinue FAD and refer patient immediately to a higher center for dialysis.

34. Indications for dialysis are:  Absolute value of Blood urea >130 mg/dl Sr. Creatinine > 4 mg/dl 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 .

35. Shock Correct hypovolaemia with colloid/crystalloids, controlled by observation of the central venous pressure. Infusion of isotonic crystalloids or albumin, with boluses of up to 20 ml/kg for crystalloids (or albumin equivalent) over 5 to 10 mins 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. Ionotropic support given if improved on fluid resuscitation In sepsis, noadrenaline is the inotropic agent of choice. Treat patients with hypotension associated with bradycardia with atropine. coagulopathy – in case of prolonged CT, PT, aPTT administer fresh frozen plasma (FFP) infusion Administer 10-15 ml/kg of FFP within over 30–60 min within 4 hours of ASV administration

37. AIM OF STUDY To obtain data on proportion of poisonous snake among all snake bite cases To compare modified low dose ASV protocol versus conventional ASV protocol

38. Methodology Retrospective study conducted at a tertiary care teaching hospital, Pune , Maharashtra, India. A total of 247 snake bite cases were admitted to the hospital during June 2012 to September 2012, were summarised as case records These records reviewed and analysed

39. Modified protocol for vasculotoxic snakes 5 vials ASV stat followed by 2 vials repeated six hourly till normalization of Whole Blood Clotting Time (WBCT) to less than 20 minutes. In case of frank bleeding, the dose was 10 vials of ASV stat and five vials at two hourly intervals if bleeding continued. If frank bleeding occurred after the first dose, repeat dose was five vials at six hourly intervals in place of two vials, till bleeding stopped. If patient presented with severe cellulitis the dose was five vials stat, Two vials ASV was repeated six hourly only if cellulitis was spreading.

40. Modified protocol for neurotoxic snake bites 5 ASV vials stat followed by 5 vials ASV repeated once after two hours, if symptoms were unimproved or progressing. Patients showing no response to neostigmine or requiring ventilator support were administered 10 vials stat and 10 vials after two hours. No neurotoxic snake bite patient received more than 20 vials in total

41. results PARAMETER CONVENTIONAL PROTOCOL(N=77) MODIFIED PROTOCOL(N=78) AGE(YEARS) 39.26±1.73 36.19±1.78 SEX(M:F) 46:31 47:31 ASV VIALS 28.17±2.75 10.74±0.95 NUMBER OF PATIENTS REQUIRING FFP 18 12 FFP UNITS(BAGS) 7.33±1.51 4.08±0.43 NUMBER OF PATIENTS REQUIRING DIALYSIS 2 5 DURATION OF STAY IN HOSPITAL 4.81 4.88 NUMBER OF PPATIENTS IN MICU\ 15 31

42. Of the 78 cases with known outcome in modified protocol group, five had mixed, six had neurotoxic and 67 had vasculotoxic manifestations. The average requirements of ASV were 11.19±3.99 vials for vasculotoxic manifestations and 7.5±1.11 vials for neurotoxic manifestations (p=0.029)

43. The ASV requirement for mixed manifestations was intermediate (8.6±1.50 vials). Mortality was 8 of 67 (11.94%) with vasculotoxic manifestations and 1 of 5 (20%) with mixed manifestations No deaths (0%) among those with neurotoxic manifestations

44. A single vial of polyvalent ASV costs around 687.00 INR and the average reduction of around 17.43 vials achieved with the modified protocol results is significant reduction in average cost of ASV by 11974.41 INR per treated patient.

45. Other studies Kothari D et al., compared a low dose continuous intravenous regimen (20 ml over two hours followed by 20 ml every 24 hours) with high dose intermittent bolus regimen (30-100 ml over one hour followed by of 30-100 ml every 24 hours) of ASV till correction of coagulation parameters or neurological signs in total 100 patients and reported that low dose ASV had lower mortality and shorter duration for recovery of coagulation parameters and hospital stay as well as the reaction to ASV was not different

46. Thomas PP and Jacob J et al., compared a protocol of four ampoules of antivenom in the first hour, four in the next two hours, four in the next three hours, and then three every subsequent three hours to one group with two ampoules of antivenom in the first hour, two in the next two hours, and two every subsequent three hours to another group till clotting time became normal (under 10 minutes) followed by two or three ampoules of antivenom over 24 hours to neutralise any further venom that might be absorbed. They observed that the low dose protocol was as effective as the higher doses

47. Paul V et al., treated snake bite cases with six vials or 12 vials of ASV, irrespective of type of snake or severity of bite and concluded that high dose of ASV did not offer any additional advantage. On the contrary, most of the parameters like mortality, duration of hospital stay and need for dialysis showed a beneficial trend for the low-dose group along with considerable financial gain

48. A systematic review of five randomized clinical trials comparing low versus high dose ASV in poisonous snake bite reported that low-dose ASV is equivalent or may be superior to high-dose ASV in management of poisonous snake bite. They also found that low dose is highly cost-effective as compared to the high dose

49. In the present study, we found that our modified protocol resulted in significant reduction in requirement for ASV without any adverse impact on outcome. The duration for hospitalization and mortality was similar in both groups. The patients from modified protocol group required fewer average number of dialysis and relatively fewer units of fresh frozen plasma

50. REFERENCES STANDARD TREATMENT GUIDELINES   ,Management of Snake Bite, Quick Reference Guide,January 2016,Ministry of Health & Family Welfare,Government of India   Comparison of Different Dosing Protocols of Anti-Snake Venom (ASV) india Snake Bite Cases, BR DaSwani1, aS ChanDanwale2, DB KaDam3, BB GhonGane4, VS GhoRPaDe5, hC manu6, Journal of Clinical and Diagnostic Research. 2017 Sep, Vol-11(9): FC17-FC21  Management of Snake Bite in India Shibendu Ghosh , Prabuddha Mukhopadhyay.JAPI