The document discusses the management of snake bite victims presenting with respiratory paralysis in the intensive care unit. It covers epidemiology of snake bites in India, the common venomous snake species, clinical manifestations of different snake envenomations, indications for anti-snake venom, and management of respiratory paralysis with anti-snake venom and other supportive treatments like anticholinesterases and mechanical ventilation.

1. Management of Snake Bite Victims with Respiratory Paralysis in ICU Dr. T.R. Chandrashekar Director Critical Care K.R.Hospital Bangalore DR TRC/ KRH

2. Management of Snake Bite Victims with Respiratory Paralysis in ICU Facts given Snake bite which has lead to Respiratory Paralysis Patient in ICU Answer Management aspects

3. How to prevent snake bites? A world free of snakes Nearly a quarter of us would go hungry Are important elements in the food chain to control the rodent population- Which destroy all major crops. The bottom line is we need snakes to survive

4. Epidemiology India estimates in the region of 200,000 bites and 15-20,000 snake bite deaths per year Originally made in the last century, are still quoted. No reliable national statistics are available. Males are bitten almost twice as often as females Majority of the bites being on the lower extremities. 50% of bites by venomous snakes are dry bites. that result in negligible envenomation.

5. FAB FOUR In India, more than 200 species of snakes but only 52 are poisonous. Saw-scaled viper (Echis carinatus) Russell’s viper (Daboia russelii) Common krait (Bungarus caeruleus) Indian cobra (Naja naja) Majority of bites Nearly 70-80% Hemotoxin Vasculotoxin Neurotoxic 1 2 4 3

6. Species: Medical Implications Yes NO Yes No No Renal Problems No NO No? No? Yes Neostigmine & Atropine Yes Yes Yes No No Coagulation No NO Yes! Yes Yes Ptosis/Neurotoxicity Yes Yes Yes No Yes Local pain/ Tissue Damage Other Vipers Saw Scaled Viper Russell’s Viper Krait Cobra Signs/Symptoms and Potential Treatments

7. Syndromic approach No local signs with Neuro-toxicity- Krait With or with out local signs and Neuo-toxicity-Cobra With or with out Neurotoxicity and local signs and hemotoxicity-Rusell’s Viper Local signs with hemotoxicity-Saw Scaled Viper

8. Snake bite Venomous snakes Anti snake venom Majority is by non-venomous snakes ASV -severe adverse reactions, Costly, Limited supply. Used- benefits of ASV treatment is considered to exceed the risks . About 50% of bites are dry

9. Our statistics Causes ARF, DIC, Shock, Pulmonary edema, Sepsis 6 required MV 8 Neuotoxic bites 20 required MV 33 Hemotoxic bites 45 snake bite admissions 1998-2008

10. Snake bite and Respiratory paralysis Neuromuscular paralysis- blockade of neuromuscular transmission. Cobra- post-synaptic Krait- pre-synaptic Bulbar paralysis-Aspiration Sepsis, DIC-shock ARF-Pulmonary edema Neurotoxic MV for respiratory paralysis ASV MV as Supportive care More cases why ?

11. NEUROTOXICITY Starts early- many die before they reach hospitals Many reverse very well with ASV if started early Less number of cases HEMOTOXICITY Starts late hence most of them reach hospitals Many organ involvement hence MV is mostly supportive to buy time for organs to recover More number of cases 70-80% 20-30%

12. Case scenario……. 34 yr old male shifted from rural health center with H/O snake bite 6 hrs back has ptosis, respiratory distress, RR 35/mt, BP 120/60, oral secretions present, absent gag and cough reflex shifted to ICU for teritary care. On ASV 100ml stat, & 50ml in NS over 6 hrs Oxygen 3l/mt Patient received in casualty Patient is comfortable, vitals stable No ptosis, distress Patient is dead –what do you think went wrong ?

13. What could have been done better ? Bulbar signs-probably aspirated and died Endotracheal intubation can be placed on T-piece Ambuing or Transport Ventilator Anticholienesterases Neostigmine with atropine Patient is dead –what do you think went wrong ?

14. Case scenario……. 34 yr old male shifted from rural health center with H/O snake bite 6 hrs back has ptosis, respiratory distress, RR 35/mt, BP 120/60, oral secretions present, absent gag and cough reflex shifted to ICU for teritary care. On ASV 100ml stat, & 50ml in NS over 6 hrs Oxygen 3l/mt Why does Neurotoxicity occur What are the Management issues? ASV, Anticholineesterases, MV…

15. Snake venom components

16. Krait- Pre-synaptic action Beta-bungarotoxin- Phospholipases A2 1) Inhibiting the release of acetylcholine from the presynaptic membrane 2) Presynaptic nerve terminals exhibited signs of irreversible physical damage and are devoid of synaptic vesicles 3) Antivenoms & anticholinesterases have no effect Paralysis lasts several weeks and frequently requires prolonged MV. Recovery is dependent upon regeneration of the terminal axon.

17. Cobra –post-synaptic alpha-neurotoxins “ Curare-mimetic toxins’’ Bind specifically to acetylcholine receptors, preventing the interaction between acetylcholine and receptors on postsynaptic membrane. Prevents the opening of the sodium channel associated with the acetylcholine receptor and results in neuromuscular blockade. ASV -rapid reversal of paralysis. Dissociation of the toxin-receptor complex, which leads to a reversal of Paralysis Anticholinesterases reverse the neuromuscular blockade

18. Snake envenomation in a north Indian hospital Ptosis RS involvement Bulbar weakness N Sharma, S Chauhan, S Faruqi, P Bhat, S Varma, Emerg Med J 2005;22:118–120 Ophthalmoplegia

19. Neurotoxic envenoming-Examination Ask the patient to look up and observe whether the upper lids retract fully. Test eye movements for evidence of early external ophthalmoplegia . Check the size and reaction of the pupils. Krait can cause fixed, dilated non reactive pupils simulating brain stem death – however, it can recover fully Ask the patient to open their mouth wide and protrude their tongue; early restriction often paralysis of pterygoid muscles. The muscles flexing the neck may be paralysed, giving the “broken neck sign

20. Bulbar paralysis Can the patient swallow or are secretions accumulating in the pharynx- an early sign of bulbar paralysis? Ask the patient to take deep breaths in and out. “Paradoxical respiration”. Objective measurement of ventilatory capacity is very useful. Use a peak flow metre, spirometer (FEV1 and FVC) Ask the patient to blow into the tube of a sphygmomanometer to record the maximum expiratory pressure (mmHg).

21. Local examination During the initial evaluation, the bite site should be examined for signs of local envenomation (edema, petechiae, bullae, oozing from the wound, etc) and for the extent of swelling. The bite site and at least two other, more proximal, locations should be marked and the circumference of the bitten limb should be measured every 15 min thereafter, until the swelling is no longer progressing.

22. Treatment Anti Snake Venom Polyvalent /Monovalent Dose-large vs small Timing Repeat dose Hypersensitivity Anticholinesterases- Tensilon test Mechanical ventilation

23. ASV The decision to treat a snake bite with antivenin is largely based on clinical parameters. Trying to capture, kill, or transport a snake for identification purposes seems of little value and possibly dangerous ASV is polyvalent Syndromic approach helps in examination and investigations and outcome predictions

24. Skin testing for ASV Skin/conjunctival hypersensitivity testing does not reliably predict early or late antivenom reactions and is not recommended.

25. What is ASV? Antivenom is immunoglobulin (usually the enzyme refined F(ab)2 fragment of IgG) purified from the serum or plasma of a horse or sheep that has been immunised with the venoms of one or more species of snake. Monovalent or monospecific antivenom neutralises the venom of only one species of snake Polyvalent or polyspecific antivenom neutralises the venoms of several different species of snakes The ASV that is available in India is a polyvalent type which is active against the commonly found snakes in India including the FAB Four .

26. Indications for ASV Neurotoxicity ARF Bleeding/coagulopathy Myoglobinuria/haemoglobinuria Cardiac toxicity Local swelling involving more than half of the bitten limb Rapid extension of swelling Development of an enlarged tender lymph node draining the bitten limb

27. Timing of ASV There is no consensus as to the outer limit of time of administration of antivenom. Best effects are observed within four hours of bite . It has been noted to be effective in symptomatic patients even when administered up to 48 hours after bite. Reports suggest that antivenom is efficacious even 6-7 days after the bite from vipers When there are signs of local envenoming, without systemic envenoming, antivenom will be effective only if it can be given within the first few hours after the bite

28. Dose 5 vials(50ml) 5-10 vials (50-100ml) 10-20 vials (100-200ml)

29. Large vs small dose Low dose of snake antivenom is as effective as high dose in patients with severe neurotoxic snake envenoming Agarwal, Aggarwal, Gupta, et al Emerg Med J 2005;22:397–399 . High dose group 100ml stat and 100 ml every 6 hrs Low dose group 100ml stat and 50 ml every 6 hrs Until recovery of neurological signs

30. High vs low ASV When a person is bitten by a snake, the major part of the toxin gets fixed to the tissues and only a relatively small part remains in the cirulation by the time the patient is brought to the hospital. Though it is useful and essential to neutralize the circulating toxin, it is more important to treat the systems involved effectively and aggressively.

31. Repeat dose Signs of systemic envenoming may recur within 24-48 hrs Criteria for repeating the initial dose of antivenom Persistence or recurrence of blood incoagulability after 1-2 hr Deteriorating neurotoxic or cardiovascular signs after 1-2 hr Continuing absorption- due to improved blood supply following correction of shock, hypovolaemia etc, After elimination of antivenom A redistribution of venom from the tissues into the vascular space. Causes

32. Observation of the response to Antivenom Cobra bites-Post synaptic May begin to improve as early as 30 minutes after anti-venom, but usually take several hours . Krait and sea snakes- Pre synaptic Depends on the timing of ASV administration If delayed may not produce any action or Minimal delayed action

33. Antivenom reactions Complement activation by IgG aggregates or residual Fc fragments or direct stimulation of mast cells or basophils by antivenom protein are more likely mechanisms for these reactions. 20%, of patients, usually more than develop a reaction Types Early anaphylactic reactions- within 10-180 min Pyrogenic (endotoxin) reactions- develop 1-2 hours Late (serum sickness type) reactions- develop 1-12 (mean 7) days. Fatal reactions have probably been under-reported as death after snake bite is usually attributed to the venom .

34. Antivenom reactions At the earliest sign of a reaction: Antivenom administration must be temporarily suspended Adrenaline-0.1% solution, 1 in 1,000, 1 mg/ml is the effective treatment for early anaphylactic reactions. IV hydrocortisone (adults 100 mg, children 2 mg/kg body weight). The corticosteroid is unlikely to act for several hours, but may prevent recurrent anaphylaxis There is increasing evidence for anti H2 antihistamines-Ranitidine – adults 50 mg, children 1 mg/kg. Pyrogenic reactions require- antipyretics. In case of circulatory collapse- start fluids, inotropes along with IV adrenaline 5-day course of oral antihistamine/ Prednisolone. Chlorpheniramine: 2 mg six hourly Prednisolone: 5 mg six hourly Serum sickness

35. Trial of anticholinesterase Anticholinesterase (“Tensilon”/Edrophonium) test Record baseline parameters Give atropine IV Give anticholinesterase drug edrophonium chloride (adults 10 mg, children 0.25 mg/kg body weight) given intravenously over 3 or 4 minutes Observe Improvement in ptosis, Respiratory distress, better cough effort, decrease in RR Tearing, salivation, muscle fasciculation, abdominal cramp, bronchospasm, bradycardia, cardiac arrest Neostigmine Positive response Atropine IV Negative response Dose of Neostigmine Neostigmine 25µg/kr/hr Neostigmine 0.5 mg / 6 hr IV atropine 0.5 mg / 12 hr

36. 34 yr old male shifted from rural health center with H/O snake bite 6 hrs back has ptosis, respiratory distress, RR 35/mt, BP 120/60, oral secretions present, absent gag and cough reflex shifted to ICU for tertiary care. On ASV 100ml stat, & 50ml in NS over 6 hrs Oxygen 3l/mt Is given neostigmine 0.6mg and 0.6 mg atropine iv You can have alive but a sicker patient You can have dead patient Cobra Krait

37. Alive but a sicker patient Shifted to ICU placed on a Ventilator lot of secretions Do we continue anticholinesterases ? Issues to consider Increased secretions Increased incidence of VAP ? We rarely use these drugs once the patient is in the ICU under observation

38. Repeat dose Signs of systemic envenoming may recur within 24-48 hrs Criteria for repeating the initial dose of antivenom Persistence or recurrence of blood incoagulability after 1-2 hr Deteriorating neurotoxic or cardiovascular signs after 1-2 hr Continuing absorption of venom from the “depot” at the site of the bite, due to improved blood supply following correction of shock, hypovolaemia etc, After elimination of antivenom A redistribution of venom from the tissues into the vascular space, as the result of antivenom treatment

39. Mechanical ventilation If patient has respiratory distress or bulbar paralysis-intubate and ventilate. If delayed can cause aspiration or hypoxia and cardiac arrest. Even if the facility for MV is not available Ambuing can save the day. This helps even during transport. MV is not complicated is like ventilating a patient with curare over-dosage

40. ASV and children Dose of antivenom Snakes inject the same dose of venom into children and adults. Children must therefore be given exactly the same dose of antivenom as adults.

41. Pregnancy and snake bite Pregnant patient is treated the same manner as the nonpregnant patient. Spontaneous abortion, bleeding, fetal death & malformations are common. Lactating mothers can continue lactating Fetal demise is difficult to predict because of associated symptoms, such as coagulopathy or hypotension, and complications of treatment including anaphylaxis. Generally speaking, the severity of the mother's clinical course seems to be the best indicator of the fetal survival.

42. Treatment issues in non Neurotoxic respiratory paralysis Aspiration can complicate MV Respiratory paralysis due to Shock, ARF, Sepsis, etc.. MV is instituted to buy time till the organs recover Treatment is directed towards the cause ASV Antibiotics Source control-Fasciotomies ? Dialysis Inotropes Blood and blood products

43. A 25 yr old male with snake bite has signs of compartment syndrome and the pressure is 60 mmHg is undergoing surgery has a Hb of 6 gm%, is hypotensive 100/60, on noradrenalin, acidotic,coagulation profile is normal Blood is started After 15 mts of surgical time patient develops Dark colored urine Bp drops to 80/60 What are the possibilities ? Rhabdomyolysis Mismatched Blood transfusion Treatment Fluids, Mannitol, Alkalinize the urine, Manage electrolytes Fasciotomy RRT

44. Fasciotomy

45. Krait Bites by krait, coral snake, and some cobras are associated with minimal local changes; However, bite by the Indian cobra (Naja naja) results in tender local swelling, blistering, and necrosis. Local necrosis causes a picture of wet gangrene with a characteristic putrid smell due to the direct cytolytic action of the venom. Skip lesions are typical findings

46. Viper Viper bite is primarily vasculotoxic. It causes rapidly developing swelling of the bitten part. Local necrosis is mainly ischemic as thrombosis blocks the local blood vessels and causes a dry gangrene

47. 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 Criteria for fasciotomy in snake-bitten limbs 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

48. Summary Snake bites may be by an non venomous snake or a dry bite Not all snake bites require ASV ASV is the main stay in the treatment of snake bites ASV must be initiated if indicated at the earliest Respiratory paralysis can be because of different reasons-Neurotoxicity, shock, sepsis, ARF… MV may be main stay of treatment or just supportive depending on the cause of failure.

49. Thank you Wishing you all a wonderful 2009

50. Fasciotomy Fasciotomy should not be carried out in snake bite patients unless or until haemostatic abnormalities have been corrected. Clinical features of an intracompartmental syndrome are present and a high intracompartmental pressure has been confirmed by direct measurement

51. High-Dose Anti-Snake Venom Versus Low-Dose Anti- Snake Venom in The Treatment of Poisonous Snake Bites — A Critical Study Results : In the low-dose group Mortality rate of 10%, 18% required dialysis and 6% required ventilatory support. LOS 8.42 days In the high-dose group Mortality rate of 14%, 26% required dialysis 6% required ventilatory support.LOS 9.02 days Conclusion : While there was no additional advantage in following a high-dose regime for snake bite cases, there was considerable financial gain by following the low-dose regime, Most of the parameters showed a beneficial trend for the low-dose group though the differences were not statistically significant JAPI • VOL. 52 • JANUARY 2004

52. High vs low ASV Repeated high doses of ASV to restore the clotting time to normal within the shortest time, do not seem to be necessary to reduce the ultimate morbidity and mortality. A smaller dose sufficient to make the clotting time graph take a downward trend is sufficient. The body’s detoxifying system will bring down the clotting time eventually though it may take a slightly longer time. This delay does not seem to affect the morbidity and mortality as shown by the results of this trial.