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Home , Andaman cobra, Animal bite, Banded krait, Boiga multomaculata, Bungarus candidus, Bungarus ceylonicus

GUIDELINES FOR THE MANAGEMENT OF

2nd Edition

guidelines for the management of snakebites

2nd Edition 1. 2. 3. 4.

ISBN 978-92-9022-

© World Health Organization 2016

2nd Edition All rights reserved. Requests for publications, or for permission to reproduce or translate WHO publications, whether for sale or for noncommercial distribution, can be obtained from Publishing and Sales, World Health Organization, Regional Office for South-East , Indraprastha Estate, Mahatma Gandhi Marg, New Delhi-110 002, (fax: +91-11-23370197; e-mail: publications@ searo.who.int).

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Printed in India Contents i. Foreword 7 ii. Acknowledgement 8 iii. Preface 9

1 Executive summary 11

2 Prevention 17 Essentials 19 2.1 Reducing the risk of snakebites 19 2.2 Implementing preventive strategies for community education 22 2.3 Conclusion 23

3 Venomous of the South-East Asia Region, 25 their and pathophysiology of envenoming Essentials 27 3.1 The apparatus 3.2 Classification of venomous snakes 29 3.2.1 Medically important in South-East Asia Region countries 30 3.2.2 Other medically important venomous snakes 63 3.2.3 Non-venomous snakes 64 3.3 Identification of venomous snakes 67 3.4 venoms 67 3.4.1 Venom composition 67 3.4.2 Quantity of venom injected at a bite, “dry bites” 69 3.4.3 Variations in venom composition within 69 individual species of snakes 3.5 Pathophysiology of human envenoming 69

4 Epidemiology of snakebites in South-East Asia Region countries 73 Essentials 75 4.1 Introduction 77 4.2 Determinants of incidence and severity of envenoming 78 4.3 Epidemiological characteristics of snakebite victims 79 4.4 Circumstances of snakebites 79 4.5 Snakebite as an occupational disease 79 4.6 from snakebite 80 4.6.1 Factors contributing to fatal snakebite 80 4.6.2 Time between snakebite and death 80 4.7 Snakebite in different South-East Asia Region countries 80

CONTENTS 3 5 Clinical aspects of snakebites 89 Essentials 91 5.1 When venom has not been injected 94 5.2 When venom has been injected 94 5.2.1 Early symptoms and signs 94 5.2.2 Clinical patterns of envenoming by snakes in South East Asia 95 5.2.3 Local symptoms and signs in the bitten part 95 5.2.4 Generalized (systemic) symptoms and signs 96 5.3 Clinical syndromes of snakebite in South-East Asia 101 5.4 Long-term complications (sequelae) of snakebite 104 5.5 Symptoms and signs of seasnake envenoming 103 5.6 Symptoms and signs of -spit ophthalmia 104 ( from spitting )

6 Management of snakebites in South-East Asia 105 Essentials 107 6.1 Stages of management 115 6.2 First-aid treatment 115 6.2.1 Principles of first-aid 115 6.2.2 The danger of respiratory paralysis and 115 6.2.3 Recommended first-aid methods 116 6.3 Transport to hospital 117 6.4 Medical treatment in the dispensary or hospital 118 6.4.1 Rapid primary clinical assessment and resuscitation 118 6.4.2 Detailed clinical assessment 119 6.4.2.1 History 119 6.4.2.2 Physical examination 120 6.4.2.3 Neurotoxic envenoming: Bulbar and respiratory paralysis 121 6.4.2.4 Generalized rhabdomyolysis 123 6.4.2.5 Examination of pregnant women 123 6.5 Species diagnosis 123 6.6 Investigations/laboratory tests 123 6.6.1 20 minute whole clotting test (20WBCT) 123 6.6.2 Other tests of blood coagulation 126 6.6.3 Other laboratory tests 126 6.6.4 Other investigations 127 6.7 treatment 128 6.7.1 What is antivenom? 128 6.7.2 Indications for antivenom treatment 129 6.7.3 Inappropriate use of antivenom 130 6.7.4 How long after the bite can antivenom be expected to be effective? 130 6.7.5 Antivenom reactions 130 6.7.5.1 Prediction of antivenom reactions 132 6.7.5.2 Contraindications to antivenom: 132 Prophylaxis in high risk patients

4 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES 6.7.5.3 Prevention of antivenom reactions 132 6.7.5.4 Treatment of antivenom reactions 134 6.7.6 Supply, Selection, storage and shelf-life of antivenom 135 6.7.7 Administration of antivenom 136 6.7.8 Dosage of antivenom 138 6.7.9 Recurrence of systemic envenoming 142 6.7.10 Criteria for repeating the initial dose of antivenom 142 6.8 Conservative treatment when no antivenom is available 143 6.9 Supportive/ancillary treatment 144 6.9.1 Treatment of neurotoxic envenoming 144 6.9.2 Practical guide to airway management and respiratory support 144 6.9.3 Trial of anticholinesterase 152 6.9.4 Treatment of hypotension and shock 154 6.9.5 Treatment of oliguria and acute 156 6.9.5.1 Oliguric phase of renal failure 156 6.9.5.2 / blood clotting disturbances in 159 patients with acute kidney injury 6.9.5.3 Prevention of renal damage in patients with myoglobinuria 159 or haemoglobinuria 6.9.5.4 Diuretic phase of renal failure 160 6.9.5.5 Renal recovery phase 160 6.9.5.6 Persisting renal dysfunction 160 6.10 Haemostatic disturbances 160 6.10.1 Dangers of venipuncture in patients with haemostatic abnormalities 160 6.11 Treatment of the bitten part 161 6.11.1 management 161 6.11.2 Bacterial 161 6.11.3 Compartment syndromes and fasciotomy 161 6.12 Rehabilitation 163 6.13 Discharge advice and assessment 163 6.14 Management of cobra spit ophthalmia 164 6.15 Management of snakebites at different levels of the health service 165 6.16 Summary of current evidence for treatment of snakebite envenoming 168

7 References and further reading 169

8 Annexes 185 Annex 1 Algorithm 1: Antivenom treatment of snakebite cases 187 Annex 2 Algorithm 2: Differentiating major Asian snake species by clinical syndrome 188 Annex 3 for treating bites by South-East Asian snakes 191 Annex 4 Pressure-immobilization and pressure pad 195 Annex 5 Measurement of central venous pressure 197 Annex 6 Measurement of intracompartmental pressure 198 Annex 7 List of Contributors 199

CONTENTS 5

Foreword

nakebites are well known medical emergencies and a cause of hospital admission in many countries. The true Sscale of this problem, however is unknown because of inadequate reporting in almost every part of the world. The South-East Asia Region is one of the world’s most affected regions, due to its high population density, widespread agriculture activities, presence of numerous venomous snakes and lack of necessary community awareness to address the problem.

Regardless of the increasing knowledge about the composition of and its mode of action, and a sound understanding of clinical features of envenoming, management of snakebites remains a challenge in the Region. Appropriate and timely use of anti-snake venom reduces morbidity and mortality. Although in the last few production of anti-venom has increased, it is still well below the current estimated annual requirement of 10 million vials. In addition, available anti-venoms do not cover all the important venomous snakes of the Region. Mechanisms need to be developed to ensure timely access and availability of anti-venom to all needy persons. Public-private partnerships, intercountry support, involvement of national, regional, and global agencies are vital to effectively meet the challenge.

The WHO Regional Office for South-East Asia had developed and published Guidelines for the Management of Snakebites as a special issue of the South East Asian Journal of Tropical and Public Health in 1999 followed by publication of the guidelines as independent regional document in 2011. Considering the new technical advances in the field, the guidelines have been revised with the help of regional and globals experts. The geographical area specifically covered by this publication includes the South-East Asia Region of WHO. The fauna of the South-East Asia Region is rich and diverse. It varies within and between countries. Countries such as , , , Lao People’s Democratic Republic, Republic of Korea, , and may share many of the same medically-important species of snakes that occur in the South-East Asia Region and may find these guidelines useful. This publication aims to pass on a digest of available knowledge about all clinical aspects of snake-bite to medically trained personnel.

I am confident that these revised guidelines will help Member States to improve the management of snakebites in the peripheral health services and thereby reduce the morbidity and mortality due to snakebites.

Dr Poonam Khetrapal Singh Regional Director

FOREWORD 7 Acknowledgements Prof David Warrell, Emeritus Professor of Tropical Medicine, University of Oxford, UK, wrote the draft of the guidelines. These were finalized through a meeting of experts held at SEARO, New Delhi, in June 2016 and revised by Dr Warrell. The list of experts who contributed can be seen at Annex 7. Contributions of all the experts and people who helped in the production of this document are sincerely acknowledged.

8 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Preface

Geographical coverage The geographical area specifically covered by this publication includes the South-East Asia Region of WHO including eleven Member States (, , Democratic People’s Republic of Korea, Maldives, , , India, , , , -Leste ). Countries such as Malaysia, Singapore, Cambodia, Lao People’s Democratic Republic, Republic of Korea, Philippines, Pakistan and Afghanistan may share many of the same medically important species of snakes that occur in the South-East Asia Region. It is interesting to note that snakes inhabiting the Indonesian islands East of Wallace’s line (West Papua and ) are part of the Australasian elapid fauna, differing from those West of this line.

Antivenoms are essential drugs The only specific to snake venoms are immunoglobulin antivenoms (WHO, 2010), which are recognized as essential drugs. see http://www.who.int/medicines/ publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1.

Target readership This publication aims to pass on a digest of available knowledge about all clinical aspects of snakebites to medically trained personnel. The guidelines are intended for medical doctors, nurses, paramedics, dispensers and community health workers who have the responsibility of treating victims of snakebites, and also for medical and nursing students and postgraduates as an educational resource. They aim to provide sufficient practical information to allow medically trained personnel to assess and treat patients with snakebites at all the different levels of the health service.

Levels of evidence Recommendations are based largely on observational studies (“O” see below), expert opinion (“E”) and, in some cases, comparative trials (“T”), but in only one case on formal systematic reviews (“S”).

Symbols for the evidence used as the basis of each recommendation (in of level of evidence) are: S formal systematic reviews, such as Cochrane Reviews of which there is only one in the field of snakebites. These include more than one randomized controlled trial; T comparative trials without formal ; O observational studies (e.g. surveillance or pharmacological data); E expert opinion/consensus.

PREFACE 9 10 EXECUTIVE SUMMARY

VENOMOUS SNAKES OF THE searo REGION, 11 THEIR VENOMS, AND THE PATHOPHYSIOLOGY... 12 1 Executive Summary

Epidemiology where it occurs commonly, since it is The venomous snake fauna of the South- largely an occupational disease of - East Asia Region is rich and diverse. It producers such as farmers, plantation varies within and between countries. workers, herdsmen, and fishermen, and Widely distributed species of major also of wild life park rangers, military medical importance, such as Russell’s personnel, snake restaurant workers, snake vipers, show geographical intra-species handlers and collectors of snake skins. It is variation in their venom composition. In recommended that snakebite should be many countries, snakebite is an important formally recognized by the International medical emergency and cause of hospital Labour Office as an important admission, demanding urgent attention by occupational disease in the South-East adequately trained medical staff. It results Asia Region (E). in the death or chronic disability of tens of thousands of active younger people, Prevention especially those involved in farming Detailed consideration of community and plantation work. The true of education on venomous snakes and mortality and acute and chronic morbidity snakebite is outside the scope of this from snakebite is only just beginning publication. However, it is clear that this to be recognized, based on large well- is a most powerful tool and essential designed community-based studies component in any campaign to address (Mohapatra et al., 2011; Rahman et al., the public health challenge posed by 2010; Ediriweera et al, 2016). Persisting snakebite. It is strongly recommended or permanent physical and psychological as the method most likely to succeed in disability in snakebite survivors may confer reducing the risk of snakebites (E). social stigma. The full burden of human suffering remains uncertain because of Health system strengthening, inadequate reporting in almost every part education and training of the Region. To remedy this deficiency, it Some ministries of health in the Region is strongly recommended that snakebite have begun to organise training of be made a specific notifiable disease in all doctors and other medical workers in countries in the South-East Asia Region (E). the clinical management of snakebite patients. However, medical personnel Snakebite is predominantly a rural problem throughout the Region would benefit from that has important implications for the more formal instruction on all aspects nutrition and of the countries of this subject. This should include the

EXECUTIVE SUMMARY 13 medical care at the hospital or dispensary. Most of the familiar methods for first-aid Recommended first-aid methods emphasise reassurance, application of treatment of snakebite, both western and a pressure-pad over the bite wound, “traditional/herbal”, have been found immobilization of the bitten limb and transport of the patient to a place where to result in more harm (risk) than good they can receive medical care without (benefit) and should be firmly discouraged. delay (O).

Diagnosis of the species of snake responsible for the bite is important for identification of medically important optimal clinical management. This may be species of snake, clinical diagnosis and achieved through expert identification of the appropriate use of antivenoms and the dead snake or a (mobile-phone) image ancillary treatments. It is recommended of it, or by inference from the resulting that education and training in the “clinical syndrome” of envenoming. prevention and management of snakebite It is recommended that syndromic should be included in the curriculum of approaches and algorithms for diagnosing medical and nursing schools and should the species responsible for snakebites be be addressed specifically through the developed in different parts of the organization of special training courses Region (E). and other educational events based on nationally agreed guidelines (E). Treatment: antivenom (species-specific These measures should be supported by hyperimmune immunoglobulin), a life- improvements in hospital accommodation saving, WHO-recognized, essential of snake-bitten patients (ideally in medicine, is the only effective specialized units staffed by specially for envenoming. However, there are trained teams), laboratory and challenges surrounding its design, diagnostic facilities, supply, deployment production, distribution, conservation, and conservation/storage of antivenoms, safety, initial dosage and effectiveness. It ambulance services and general is recommended that a critical appraisal community awareness of the problem and of all aspects of antivenom production its potential solutions. should be carried out in South-East Asia Region countries. Although antivenom Management is an essential element of the treatment First-aid: most of the familiar methods of systemic envenoming, it may be for first-aid treatment of snakebite, insufficient on its own to save the both western and “traditional/herbal”, patient’s life. Antivenoms are generally have been found to result in more harm expensive and in short supply. It is (risk) than good (benefit) and should be recommended that antivenom should firmly discouraged. However, in many be used in all patients with signs of communities, traditional therapists and systemic and/or severe local envenoming their practices are respected and it is in whom the benefits of treatment are important to initiate a dialogue with judged to exceed the risks of antivenom these practitioners, perhaps through reactions (E). It should not be used in anthropologists, to encourage their the absence of evidence of envenoming. understanding and cooperation in the Skin/conjunctival hypersensitivity testing timely referral of envenomed patients to does not predict early or late antivenom

14 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES reactions and it is recommended that haemostatic abnormalities have been these tests should not be carried out (T). corrected, clinical features of an intra- Prophylactic subcutaneous adrenaline compartmental syndrome are present and has proved effective in reducing the a consistently raised intra-compartmental frequency and severity of early antivenom pressure has been confirmed by direct reactions and its routine use is, therefore, measurement (E). Before discharge from recommended unless the risk of the medical facility, patients should be reactions associated with a particular given explanation, reassurance, and antivenom is low (less than a few %) advice about avoiding future bites, and (T). It is recommended that whenever the opportunity for follow-up and further possible antivenom should be given by rehabilitation/counselling in case of slow intravenous injection or infusion (O). late antivenom reactions and persistent Adrenaline should always be available in physical or psychological sequelae. readiness at the bedside in case of an early anaphylactic antivenom reaction. When no Research: there have been fewer proper appropriate specific antivenom is available, clinical studies of snakebite than of judicious conservative treatment can in almost any other tropical disease, despite many cases save the life of the patient. its causing more deaths and chronic In the case of neurotoxic envenoming disability in the Region than all the other with bulbar and respiratory paralysis, so-called Neglected Tropical Diseases antivenom alone cannot be relied upon combined. It is recommended that to prevent early death from asphyxiation. governments, academic institutions, Artificial ventilation is essential in such pharmaceutical, agricultural and other cases. In the case of acute kidney injury industries and other funding bodies, associated particularly with envenoming should actively encourage, sponsor by Russell’s vipers, hump-nosed pit-vipers and invest in properly designed clinical and sea snakes, conservative management studies of all aspects of snakebite, and, in some cases renal replacement especially community-based, nation-wide therapy (dialysis), is an effective supportive epidemiological studies, correlation of treatment. It is recommended that clinical syndromes with envenoming by fasciotomy should never be carried out defined species, and antivenom dose- in snakebite patients unless or until finding studies (E).

EXECUTIVE SUMMARY 15 16 Prevention

VENOMOUS SNAKES OF THE searo REGION, 17 THEIR VENOMS, AND THE PATHOPHYSIOLOGY... 18 2 Prevention

Essentials: 2.1 Reducing the risk of Snakebites are environmental, snakebites occupational and climatic hazards, Snakebite is an environmental, predominantly of rural areas. Bites are occupational and climatic hazard in usually inflicted on lower legs, ankles rural and urban areas of many South- and feet of agricultural workers and East Asian countries where most bites their families. Know your local snakes, are inflicted on the lower legs, ankles their favourite habitats, and times of and feet of agricultural workers and day and seasons when they are most their families. Attention to the following active. Never , threaten or attack recommendations for community snakes. Do not attract snakes to homes education will reduce the risk of bites. by keeping livestock indoors or leaving Snakes have adapted to a wide range of food unprotected, encouraging . habitats and prey species. All snakes are Sleep under a well-tucked–in predatory , none is vegetarian net, ideally on a raised bed. Clear rubbish although some eat ’ . Since and undergrowth from around the house. snakes are preyed upon by other , Always use a light and prod with a stick they tend to be secretive and have when walking outside at night, visiting the evolved many survival strategies, including latrine or relieving yourself in the open. camouflage, making them difficult to see. Solid or boots are recommended By understanding something about snakes’ especially during agricultural activities. habits, simple precautions can be adopted Fishermen should avoid touching sea to reduce the chance of encounters, snakes caught in their nets. and consequently bites. Know your local snakes, the sorts of places where they Community education reduces the risk of prefer to live and hide, the times of snakebites. Involve all community workers, and times of day and night, and the kinds traditional healers and villagers. Distribute of weather when they are most likely to be leaflets, banners and posters. Reformat active. Many species are mainly nocturnal these SEARO recommendations for (night hunters) (e.g. kraits) while other national or local use as guidelines, training species (e.g. Australasian brown snakes) modules, leaflets, video clips or posters, are mainly diurnal (daylight hunters). displayed in hospital and clinic waiting Be particularly vigilant about the risk of areas and disseminate them via radio, TV snakebites after rains, during flooding, and social networks. at harvest time and at night and when

PREVENTION 19 walking to and from the fields before (e.g. in the ). Ideally, avoid dawn and after dusk. Snakes prefer not to sleeping unprotected on the ground, but confront large animals such as , if you do choose, or are forced, to sleep and so avoid cornering them and give on the ground, or are able to sleep on a them every opportunity to escape. raised bed, use an insecticide-impregnated mosquito net that is well tucked-in under Inside the house, where snakes may the mattress or sleeping mat. This will enter in search of food or to find hiding protect against mosquitoes and other places, do not keep livestock, especially , , , and , as they are potential prey snakes (Chappuis et al., 2007). (Fig 001) for larger snakes and they may attract No chemical has yet been discovered that rodents upon which many species of is effectively repellent to snakes without snakes will prey. Store food in - being so toxic as to threaten the life of proof containers. Regularly check houses children and domestic animals. for snakes and, if possible, avoid types of house construction that will provide In the farm yard, compound, or snakes with hiding places (e.g. thatched garden: Try not to provide hiding places roofs with open eaves, mud and straw for snakes. Clear away mounds, walls with large cracks and cavities, large heaps of rubbish, building materials etc. unsealed spaces beneath floorboards). In from near the house. Do not have tree , almost all krait () branches touching the house. Keep grass bites are inflicted on people sleeping short or clear the ground around your in their homes, usually on the floor but house and clear underneath low bushes sometimes even in beds and under pillows so that snakes cannot hide close to the

Prevention is the mother of cure Himmatroo Salube Bawaskar, Parag Himmatroo Bawaskar, Pramodini Himmatroo Bawaskar, bawasker Hospital and Clinical Research Center, Mahed Raigad, 402301, India (HSB, PrHB); and Topiwala National Medical College and BYL Hospital, Mumbai, India (PaHB) Many people in India live in villages where mosquitoes, scorpions, and snakes flourish. To help preven , , chikungunya, Japanese encephalities, and lympatic filarias is caused by mosquitoes, as well as life-threatening envenoming from krait bite poisoning and stings, we prepared a poster to promote the health advantage of sleeping in bed or cot and using mosquito nets. Our poster uses local vernacular language communicate this message and was distributed and displayed at primary health centres, rural hospitals, panchayat offices, and temples in the villages in our area.

Figure 001: Protection from sleeping under a mosquito net (H Bawaskar)

20 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES house. Keep your granary away from the house (it may attract rodents that snakes Lamps placed at strategic locations such as will hunt). Water sources, reservoirs, ponds and puddles may also attract prey animals at the to the house, in passages such as and toads. Listen to wild and between houses, in front of the latrine domestic animals, especially birds, as they mob snakes and warn of a snake nearby. outside the house or within the courtyard Use a light when you walk outside the are valuable, provided that they are house, visit the latrine at night, or relieve positioned so as to avoid casting shadows yourself in the open. over corners and niches where snakes may In the countryside: firewood collection be concealed. at night is a high risk activity. Watch where you walk. The value of wearing protective clothing is widely accepted, but there are many practical difficulties, the entrance to the house, in passages including cost, habit, inconvenience and between houses, in front of the latrine discomfort in a tropical climate as well outside the house or within the courtyard as cultural and superstitious objections are valuable, provided that they are making this seem impracticable. However, positioned so as to avoid casting shadows in Myanmar, a specially developed light- over corners and niches where snakes may weight boots proved acceptable to be concealed. Be careful when handling farmers for use during the high risk rice dead or apparently dead snakes – even harvesting season, although these would an accidental scratch from the fang of a be impracticable during rice planting when snake’s severed head may inject venom. the fields are inundated (Tun Pe et al., Snake restaurants pose a threat of bites 2002). Rather than walking bare-footed to staff and customers. Many snakebites or wearing sandals, use proper shoes or occur during ploughing, planting and boots and long trousers, especially when harvesting and in the rainy season. Rain walking in the dark or in undergrowth. may wash snakes and debris into gutters This advice may not be immediately at the edges of roads, and flush burrowing acceptable in some communities because species out of their burrows, so be careful of cost, cultural attitudes, comfort and when walking on roads after heavy rain convenience. However, use of protective especially after dark. clothing (boots and gloves) should be promoted as the most obvious means of On the road: Drivers or cyclists should reducing occupational risk of snakebite. never intentionally run over snakes on Step on to rocks or logs rather than the road. The snake may not be instantly straight over them – snakes may be killed and may lie injured and pose a risk sunning themselves on the sides. Do to pedestrians. The snake may also be not put hands into holes or nests or any injured and trapped under the vehicle, hidden places where snakes might be from where it will crawl out once the resting. Young boys often do this while vehicle has stopped or has been parked in hunting for rodents. Use a light (torch, the house compound or garage. flashlight or ) when walking at night especially after heavy rains and prod the In rivers, estuaries and the sea: To ground ahead of you with a stick. Lamps prevent sea snakebites, fishermen should placed at strategic locations such as at avoid touching sea snakes caught in nets

PREVENTION 21 and on lines. The head and tail are not 2.2 Implementing preventive easily distinguishable. Sea snakes are air- strategies for community breathing and are therefore drowned if education caught in drift or trawl nets, but, unlike Community education has been proved , may survive if laid on the beach. to be an effective strategy for preventing There is a risk of bites to bathers and snakebites. In the Terai region of Nepal, those washing clothes in the muddy a group of villages was targeted for waters of estuaries, river mouths and snakebite awareness sessions, involving some coastlines. political leaders, female health volunteers, community health workers, social workers, General: Avoid snakes as far as possible, traditional healers and other villagers. including those displayed by snake Many leaflets, banners and posters charmers, who are frequently bitten. were distributed. As a result, snakebite Displays by performers such as Austin incidence decreased from 502 bites to Stevens and the late on TV 315 bites/100 000 population in targeted and social media have encouraged people villages (relative risk reduction 0.373 to risk pursuing, attacking and handling (95% CI = 0.245–0.48) but it remained wild snakes. This should be actively constant in the control untargeted discouraged. Never handle, threaten or villages (Sharma et al., 2013). A similar attack a snake and never intentionally scheme in , India involved trap or corner a snake in an enclosed the training of 800 health workers (Vishal space. In many parts of the Region there Santra, Simultala Conservationists). Such are dedicated snake catchers who will programmes should be repeated every remove snakes found in houses and year, using well-designed posters with gardens. For example, in New Delhi, colour photographs of the medically “if you find a snake hissing inside your significant snakes of the Region combined house, just don’t panic or cause it any with clear recommendations for harm. All you need to do is dial a helpline preventing snakebite. In Indonesia, since (9871963535) and dedicated snake 2013, medical staff have collaborated trappers will be at your doorstep to help regularly with herpetologists in learning you” SOS (WSOS). Keep young about snake identification and snakebite children away from areas known to be management, while in West Papua, snake-infested. In occupations that carry a and other religious organizations have an high risk of snakebite, such as rice farming important role in education campaigns and fish farming, employers might be on snakebite. Designers of Information, held responsible for providing protective Education and Communication (IEC) clothing (boots). In Myanmar, farmers activities for preventing snakebites, can take out special low-cost insurance to should bear in mind local infrastructure, cover them specifically against snakebite, demography and topography. An example and India’s National Health Assurance is given in Figure 01 from Duncan Mission envisages treatment for Hospital, Raxaul, , India (Longkumer snakebite. et al., 2016).

22 Recommendations for health care workers Recommendation for health care workers Rationale 1 Use the months of April and May to 80% of bites occur during the months of June- • Procure the necessary stocks of ASV September so preparedness and prevention • Train health care workers in snakebite need particular attention in the time leading prevention and first aid up to this “epidemic” season. 2 should not be excluded by the 3.8% of people without fang marks were absence of fang marks. envenomed. Krait bites, in particular, can be hard to visualise, even a short time after the bite. 3 Consider snakebite in the differential Patients can present with symptoms of diagnosis of unexplained altered sensorium, envenomation, without any history of being alteration to speech and , and bitten by a snake. abdominal , especially during the rainy season. 4 Bites by an unknown predator need to be 14% of people, who were unable to identify taken seriously and observed for signs of what predator bit them were envenomed. envenomation. 5 Don’t rely on the ability of patients or Identification of snake species is poor, relatives to identify snakes. although it is better for cobras. 6 Antivenom should only be given to patients Envenomation of patients only occurred showing symptoms of envenomation in 63.6% of the cases where cobras were brought. To give anti venom without symptoms of envenomation exposes people to the risk of adverse reactions and is costly, especially in a setting where demand exceeds supplies. 7 Consider the production of a bivalent ASV Saw scaled and Russells vipers are not present for regions of and Nepal. in this region and a bivalent anti venom is likely to cause less adverse reactions. Recommendations for Community Education Recommendation for health care workers Rationale 1 A large part of the public health education The 10-19 year old age group is the peak needs to be directed to children and young age interval for bites. Numbers of males and people to both genders. females bitten are almost equal. 2 Encourage the use of footwear and long 67% of bites occur on the feet and legs. pants/trousers. 3 The use of a stick to scare away snakes, This would decrease the number of bites to working in an area wth ones hands. where hands are put into snake micro habitats without prior visualisation of the area. 4 Improved lighting using: 40% of bites occur between 1700-2200 hours. • Torches when walking outside 59.2% of bites occur in and around the house. • Lighting in and around houses. Lighting will enable better visualisation of snakes.

5 Provision of toilets and education regarding 8% of bites occurred when people were their use. going to the fields for the purpose of open defecation. 6 Encourage people to sleep on a bed and 10% of people were bitten while they were under a well tucked-in mosquito net. sleeping. Sleeping on the ground, inceases your risk of envenomation, sixfold. Sleeping under a mosquito net, decreases your risk of envenomation, six fold. 7 Provision of buffer zones between fields and 59.2% of bites occur in and around the house. housing areas. Snakes are attracted to the rodents who come for grain being grown. Keeping these distances separate may help in decreasing the encroachment of snakes in housing areas. 8 Make sleeping areas separate from food The presence of rodents in food related storage, preparation and sonsumption areas. areas is prone to attract snakes. If people sleep in places away from areas of the house connected with food, theis may decrease the risk of people connecting with snakes.

Figure 01: Community Education: recommendations for health-care workers and community education from Duncan Hospital, Raxaul, Bihar, India (see Longkumer et al., 2016)

PREVENTION 23 Religious organizations and charities Raising community awareness about such as Rotary and Clubs might be persuaded to promote snakebite prevention of snakebites is the most awareness. It is especially valuable to win effective strategy for reducing snakebite the support of high profile media figures such as sporting heroes, film stars, morbidity and mortality. pop stars and politicians. Education departments should incorporate appropriate first-aid for snakebite in school textbooks. The above recommendations for preventing snakebite could be reformatted 2.3 Conclusion for national or local use as guidelines, Raising community awareness about training modules, leaflets, video clips and prevention of snakebites is the most posters (Fig 001) that can be displayed effective strategy for reducing snakebite on the walls of hospital and clinic waiting morbidity and mortality. The current areas for the attention of patients and burden of snakebite morbidity can also their families. At the village level, role- be mitigated by providing region-specific playing, drama and puppets have been guidelines and training protocols for used successfully to portray snakebite effective case management. Support scenarios. Media such as radio and TV materials for health-care providers at can be used for health promotion and all levels of the health service could advantage can be taken of FM radio help to disseminate appropriate phone-ins to publicise the problem. scientific knowledge about snakebite Increasingly, young people and advertisers management. Ensuring an efficient use social networking (YouTube, Twitter) supply-chain for antivenom and other to communicate information and mobile supplies can reduce preventable deaths phone messaging might also be employed. from snakebite.

24 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Venomous snakes of the South-East Asia Region, their venoms and the pathophysiology of human envenoming

3 Venomous snakes of the South-East Asia Region, their venoms and the pathophysiology of human envenoming

Essentials: most important species medically are The venom apparatus: venom glands cobras (), kraits (Bungarus), death of and are situated adders, , black and brown snakes behind the eye, surrounded by (, Oxyuranus, , compressor muscles. The venom duct ) and sea-snakes. opens at the base of the fang, conducting venom to its tip through a groove or Viperidae (vipers) are divided into canal. In Viperidae, but not Elapidae or typical vipers () and pit-vipers , fangs are mounted on a (Crotalinae) that have a heat-sensitive rotatable maxilla, making them erectile. loreal pit organ situated between nostril In Colubridae, venom secreted by and eye. Vipers are relatively short, Duvernoy’s (supralabial) glands tracks thick-bodied, short-tailed snakes with down grooves in posterior maxillary fangs. many small rough scales on the top of Spitting cobras squeeze venom forward the head and characteristic patterns of from tips of their fangs in a fine spray coloured markings on their backs. The directed towards the of an aggressor. most important species are: Russell’s vipers (), saw-scaled vipers (), Classification/: there are Malayan pit (), mamushis three families of venomous snakes in (), hump-nosed pit- vipers South East Asia, Elapidae, Viperidae and (), Chinese habu ( Colubridae. mucrosquamatus), and green pit vipers (). Elapidae are relatively long, thin, usually uniformly-coloured snakes with large Among Colubridae, red-necked smooth symmetrical scales on the top keelback ( subminiatus) and of the head. Cobras, raise the front yamakagashi (. tigrinus) are dangerous. part of their body off the ground and More than a dozen other species can spread a . Venomous sea-snakes cause mild local envenoming (e.g. have flattened paddle-like tails. The snakes - ).

Venomous snakes of the South-East Asia Region, their 27 venoms and the pathophysiology of human envenoming haemorrhage, plasma leakage (oedema- Composition and antigenicity of snake formation) and autopharmacological release of histamine and other autacoids. venoms varies greatly between and within species, as snakes mature, seasonally, Polypeptide postsynaptic (α) bind to acetylcholine receptors at between sexes, and throughout the the motor endplate. Presynaptic (β) geographical range. neurotoxins are phospholipases that damage endings irreparably.

Many bites are inflicted by non-venomous Composition and antigenicity of snake or minimally-venomous species of medical venoms varies greatly between and within importance because they may be mistaken species, as snakes mature, seasonally, for venomous species, resulting in between sexes, and throughout the unnecessary, expensive, risky and wasteful geographical range. Thus, envenoming antivenom treatment. Large pythons by a particular species in one part of its (), occasionally attack and even geographical range may not be responsive swallow humans. to an antivenom raised against venom from this same species in another area. Identification: posters and picture cards, with vernacular names are useful. Expert “Dry bites”: about 50% of venomous identification of the snake responsible, or snakebites do not result in envenoming. of a photo image, is recommended. Pathophysiology of human envenoming Snake venoms 90% of dry weight Swelling and bruising result from venom- comprises >100 different : induced increased vascular permeability , non-enzymatic polypeptide and ischaemia caused by thrombosis, tight , and non-toxic proteins. tourniquets applied as first-aid, or swollen Enzymes are digestive hydrolases, muscle within tight fascial compartments. (spreading factor), yellow Hypotension and shock often results L-amino acid oxidases, phospholipases from hypovolaemia caused by leakage of

A2, and peptidases. Snake venom plasma or blood into the bitten limb and metalloproteases (SVMPs) damage elsewhere, vasodilatation and myocardial basement membranes, causing endothelial damage. Oligopeptides (ACE inhibitors cell damage and spontaneous systemic and BPPs) and vasodilating autacoids cause bleeding. Procoagulant enzymes are early transient hypotension. Procoagulant thrombin-like, splitting fibrinogen, or enzymes cause defibrinogenation, DIC activators of factors V, X, prothrombin and consumption coagulopathy. Venom and other clotting factors, causing phospholipases are . DIC, consumption coagulopathy and Platelet activation/inhibition and incoagulable blood. Phospholipases sequestration causes thrombocytopenia.

A2 damage mitochondria, red blood Spontaneous systemic bleeding is cells, leucocytes, platelets, peripheral attributable to Zn metalloproteases nerve endings, skeletal muscle, vascular haemorrhagins. Complement activation endothelium, and other membranes, affects platelets, blood coagulation producing presynaptic neurotoxic activity, and other humoral mediator. With cardiotoxicity, myotoxicity, , elapid and some colubroid venoms hypotension, haemolysis, anti-coagulation, the alternative pathway is triggered by

28 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES “cobra venom factor”, while viperid The ability to inject venom into prey venoms activate the classical pathway. animals by means of cannulated, modified

Neurotoxic polypeptides and PLA2s teeth evolved over 140 million years ago cause paralysis by blocking transmission in -like and later in snakes at neuromuscular junctions, but do not (Gong et al., 2010). The venom glands cross the blood-brain-barrier; there of Elapidae and Viperidae are situated are no direct CNS effects. Descending behind the eye, surrounded by compressor paralysis affects bulbar and respiratory muscles (Fig 1). The venom duct opens muscle causing fatal upper airway within the sheath at the base of the obstruction, aspiration, or respiratory fang and venom is conducted to its tip paralysis. Anticholinesterase drugs (e.g. through a groove or canal, as through neostigmine) prolong activity of ACh a hypodermic needle. In Elapidae, the at neuromuscular junctions, improving (proteroglyph) fangs are mounted on paralytic symptoms when postsynaptic a relatively fixed maxilla at the front of neurotoxins are involved. PLA2 the mouth (Fig. 2a). In Viperidae, the and metalloproteases in venoms of sea (solenoglyph) fangs are mounted on snakes, terrestrial Australasian elapids a rotatable maxilla so that they can be and some kraits and Russell’s vipers folded flat against the roof of the mouth cause generalized rhabdomyolysis, (Fig. 2b). In Colubridae (used here in the myoglobinaemia, myoglobinuria and broad , including some subfamilies acute kidney injury. Acute kidney injury is such as , considered by some associated with histopathological evidence taxonomists to be separate families), of acute tubular necrosis, proliferative venom secreted by Duvernoy’s (supralabial) glomerulonephritis, bilateral renal cortical glands tracks down grooves in the anterior necrosis, acute interstitial nephritis, toxic mesangiolysis with platelet agglutination, fibrin deposition and ischaemic changes. Causes include prolonged hypotension, hypovolaemia, DIC, direct nephrotoxicity, haemoglobinuria, myoglobinuria, and hyperkalaemia. Antivenom can cause immune-complex-mediated kidney injury. DIC may result in deposition of fibrin on vascular endothelium that has been activated by metalloproteases, producing microangiopathic haemolysis and thrombotic microangiopathy, resembling haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), but ADAMTS 13 levels are not depleted. Generalized increase in capillary permeability in Russell’s viper envenoming is attributable to metalloproteases that damage vascular endothelium.

3.1 The venom apparatus (Fig 1) (Gans and Gans 1978; Junghanss Figure 1: Venom apparatus of an eastern Russell’s viper () and Bodio 1995; Weinstein et al. 2009) (Copyright DA Warrell)

Venomous snakes of the South-East Asia Region, their 29 venoms and the pathophysiology of human envenoming surfaces of (opisthoglyph) fangs at the posterior end of the maxilla (Fig 2c) (Weinstein et al., 2011) . Fangs allow the snake to introduced venom deep into the tissues of its natural prey. If a human is bitten, venom is usually injected subcutaneously or intramuscularly. Spitting cobras can squeeze the venom out of the tips of their fangs producing a fine spray directed towards the eyes of an aggressor.

3.2 Classification of venomous snakes 3.2.1 Medically important species in South-East Asia Region countries (Gopalakrishnakone and Chou 1990; Williams et al., 2009; WHO 2010)

There are three families of venomous snakes in South-East Asia, Elapidae, Viperidae and Colubridae.

Figure 2a: Short, permanently erect, front fangs of a typical elapid (Sri Lankan cobra - Naja naja) (Copyright DA Warrell)

Figure 2b: Long, hinged, front fangs of a typical Figure 2c: Rear fangs of a dangerously venomous Colubrid snake, the red- viper (Thailand Russell’s viper Daboia russelii) necked keelback () ) (Copyright DA Warrell) Copyright DA Warrell)

30 Fig 03b Absent loreal scale in Elapid snakes • snake mucosus – non- venomous Colubridae Showing 3 loreal scales (red arrows) between pre-ocular (p) and nasal (n) scales

• Sind krait – venomous Elapidae

Showing no loreal scale between pre- ocular (p) and nasal (n) scales

Figure 3b: Absent loreal scale in Elapid snakes: above - Ptyas mucosus – non-venomous Colubridae, showing 3 loreal scales (red arrows) between pre-ocular (p) and nasal (n) scales (Copyright Mark O’Shea); below - Sind krait Bungarus sindanus – venomous family Elapidae, showing no loreal scale between pre- ocular (p) and nasal (n) scales (Copyright Rom Whitaker)

Elapidae: have relatively short fixed scales (Fig 3b). Some, notably cobras, front (proteroglyph) fangs (Fig 2a). raise the front part of their body off the This family includes cobras, , ground and spread and flatten the neck to kraits, coral snakes, Australasian snakes a hood (Figs 4-9). Several species of and sea snakes. Elapidae are relatively cobra can spit their venom for one metre long, thin, uniformly-coloured snakes or more towards the eyes of perceived with large smooth symmetrical scales enemies. Venomous sea snakes have (plates) on the top (dorsum) of the head flattened paddle-like tails and their ventral (Fig 3b and Fig 9). There is no loreal (belly) scales are greatly reduced in size or scale between the pre-ocular and nasal lost (Figs 20-24).

Venomous snakes of the South-East Asia Region, their 31 venoms and the pathophysiology of human envenoming Some important examples of the (Tun- Pe et al., 1997; Ha-Tran-Hung Elapidae inhabiting South-East Asia et al., 2010) Region countries (References to • . niger (Fig 16) reports or reviews of bites by these (Faiz et al., 2010) species are given in parenthesis): • Sind krait B. sindanus (Pillai et al., • Cobras ( Naja): 2012; in press) (Fig 17) • Common spectacled (Indian) cobra • Wall’s krait B. walli N. naja (Fig 4) (Theakston et al., 1990) • Spotted maculiceps (Fig 18) • North Indian or Oxus cobra N. oxiana (Fig 5) • MacClelland’s coral snake Sinomicrurus maclellandi • Monocellate cobra N. kaouthia (Kramer 1977) (Fig 6a-) (Reid 1964; Warrell 1986; Viravan et al., 1992) • Australasian elapids inhabiting Eastern Indonesia (Maluku and West • Naja sagittifera Papua): (Fig 6d) • Death adders (Genus Acanthophis): • Spitting cobras: N. siamensis (Fig 7) A. rugosus (Fig 19a) (Lalloo et al., (Warrell 1986; Wüster et al., 1997), 1996) • N. sumatrana (Fig 8), N. sputatrix, • small-eyed snake N. mandalayensis etc Micropechis ikaheka (Fig 19b) • King cobra: Ophiophagus hannah (Warrell et al., 1996) (Fig 9) (Tin-Myint et al., 1991) • Papuan Taipan Oxyuranus scutellatus • Kraits (genus Bungarus): canni (Fig 20) (Lalloo et al., 1995) • B. caeruleus (Fig 10) • Pseudechis (Theakston et al., 1990; Ariaratnam papuanus (Fig 21) (Lalloo et al., et al., 2009) 1994) • Malayan krait B. candidus (Fig • Brown snakes (Genus Pseudonaja) 11) (Warrell et al., 1983; Kiem-Xuan- (Fig 22) Trinh et al., 2010) • Sea snakes (Reid 1975, 1979; • Ceylon krait B. ceylonicus (Fig 12) Reid and Lim 1957; Warrell (de Silva et al., 1993) 1994): important species include schistosa ( • B. fasciatus (Fig 13) schistosus) (Fig 23) (Kularatne et • Red-headed krait B. flaviceps al., 2014), Hydrophis sp. (Fig 24) (Fig 14) (Amararasekara et al., 1994; Watt • Lesser black krait B. lividus (Kuch et and Theakston 1985), Lapemis curtus al., 2011) (Fig 25), Pelamis platura (Fig 26) and Laticauda colubrina (Fig 27). • Chinese krait B. multicinctus (Fig 15)

32 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES [a] [b]

[c]

Figures 4: Common spectacled cobra (Naja naja): (a) Sri Lanka; (b) Pune; (c) Kolkata; (d) Bardia, Nepal (a-c Copyright DA Warrell; [d] d Copyright Mark O’Shea)

Venomous snakes of the South-East Asia Region, their 33 venoms and the pathophysiology of human envenoming Figure 5: North Indian or Oxus cobra (Naja oxiana) (Copyright DA Warrell)

34 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES [a]

[b] [d]

[c]

Figures 6 a-c: Monocellate cobra (Naja kaouthia): (a) Thailand nuchal pattern; (b) Thailand; (c) West Bengal (Copyright DA Warrell); (d) Andamans cobra (Naja sagittifera) juvenile specimen (Copyright Ashok Captain)

Venomous snakes of the South-East Asia Region, their 35 venoms and the pathophysiology of human envenoming [a]

[c]

Figures 7: Indo-Chinese spitting cobra (Naja siamensis) Thailand: (a) Black and white specimen with ill-defined spectacle marking on hood; (b, c) Brown-coloured specimen showing spectacle marking on hood (Copyright DA Warrell)

[b]

36 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Figures 8: Sumatran spitting cobra (Naja sumatrana): (a) black phase Singapore (b) golden phase Thailand (Copyright DA Warrell)

[a]

[b]

Venomous snakes of the South-East Asia Region, their 37 venoms and the pathophysiology of human envenoming [a] [b]

[d]

[c] [e]

Figures 9: King cobra or hamadryad (Ophiophagus hannah) (Copyright DA Warrell) (a) The famous king cobra dance in Yangon, Myanmar; (b) Specimen from Trang, southern Thailand more than 3.5 metres in total length; (c, d) Dorsal and lateral views of head of Thai specimens showing the two large occipital scales which distinguish this species from cobras (Naja); (e) Pune, India (Copyright DA Warrell)

38 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Figures 10: Common krait (Bungarus caeruleus): (a) Sri Lankan specimen showing narrow white dorsal bands; (b) Indian specimen showing pure white ventrals (Copyright DA Warrell)

[a]

Figures 11: Malayan krait () Thai specimen: (a) Showing dorsal black saddle- [b] shaped markings; (b) Showing pure white ventrals (Copyright DA Warrell).

[a] [b]

Venomous snakes of the South-East Asia Region, their 39 venoms and the pathophysiology of human envenoming [a]

[b]

[c]

Figures 12: Ceylon krait (): (a) showing incomplete white bands (spots); (b) head; (c) showing white bands and dark ventral scales. Perideniya, Sri Lanka (Copyright DA Warrell)

40 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES [a] [b]

Figures 13: Banded krait (Bungarus fasciatus) Thai specimens: (a) Showing black and yellow bands; (b) Showing circumferential black bands and blunt-tipped tail (Copyright DA Warrell)

Figure 14: Red-headed krait (Bungarus flaviceps) Thailand (Copyright DA Warrell)

Venomous snakes of the South-East Asia Region, their 41 venoms and the pathophysiology of human envenoming Figure 15: Chinese krait (Bungarus multicinctus) Figure 16: Greater black krait (Bungarus niger) Nepal (Copyright DA Warrell) (Copyright F. Tillack)

[a]

Figures 17: Sind krait (Bungarus sindanus): (a) specimen from Bikaner (Copyright Rom Whitaker); (b) head of specimen from Maharashtra, India (Copyright DA Warrell)

[b]

42 Figure 18: Spotted coral snake (Calliophis maculiceps) Thai specimen (Copyright DA Warrell)

[a] [b]

Figures 19: Death adders (Acanthophis rugosus): (a) Specimen from West Irian, Indonesia; (b) Specimen from Seram, Indonesia

Venomous snakes of the South-East Asia Region, their 43 venoms and the pathophysiology of human envenoming Figure 19c: New Guinea small-eyed snake (Micropechis ikaheka). Specimen from Arso, West Irian, Indonesia 1.69m in total length responsible for a case of envenoming (see Warrell et al., 1996).; (Copyright DA Warrell)

Figure 20: Papuan taipan (Oxuyuranus scutellatus) SaiBai Island, Torres Strait Islands (Copyright DA Warrell)

44 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Figure 21: Papuan black snake (Pseudechis papuanus) SaiBai Island, Torres Strait Islands (Copyright DA Warrell)

Figure 22: (Pseudechis textilis) Figure 23: Beaked (Enhydrina schistose or (Copyright DA Warrell) Hydrophis schistosus) Bunapas Mission, Ramu River, Papua New Guinea (Copyright DA Warrell)

Figure 24a: Blue (Hydrophis cyanocinctus) Thailand (Copyright DA Warrell)

Venomous snakes of the South-East Asia Region, their 45 venoms and the pathophysiology of human envenoming Figure 24b: Banded sea snake ( atriceps) Thailand (Copyright DA Warrell)

Figure 24c: Flattened paddle-like tail of sea snakes: Hydrophis cyanocinctus (above); Lapemis curtus (below) Thailand (Copyright DA Warrell)

Figure 25: Hardwick’s sea snake (Lapemis curtus) showing tiny fangs (Copyright DA Warrell)

46 Figure 26: Yellow-bellied sea snake (Pelamis platurus) Watamu, Kenya (Copyright Royjan Taylor)

[a] [b]

Figures 27: (Laticauda colubrina) Madang, Papua New Guinea: (a) Showing blue and banded pattern and amphibious behaviour; (b) Showing fangs (Copyright DA Warrell)

Venomous snakes of the South-East Asia Region, their 47 venoms and the pathophysiology of human envenoming Viperidae have relatively long fangs to detect their warm-blooded prey. This (solenoglyph) which are normally folded is situated between the nostril and the flat against the upper but, when eye (Fig. 28). Viperidae are relatively the snake strikes, are erected (Fig 2b). short, thick-bodied snakes with many There are two subfamilies, typical vipers small rough scales on the top (dorsum) (Viperinae) and pit-vipers (Crotalinae). of the head and characteristic patterns of The Crotalinae possess a special infra-red coloured markings on the dorsal surface of heat-sensing organ, the loreal pit organ, the body (Fig 29).

Pit Viper (Trimeresurus T. Macrops)

Showing heat sensitive pit organ (red arrow)

Figure 28: Head of a typical - dark green pit viper (Trimeresurus T. macrops) showing the pit organ situated between the nostril and the eye (red arrow) (Copyright DA Warrell)

48 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES [a] [b]

[c]

[d] [e]

Figures 29: Western Russell’s viper (Daboia russelii): (a) Specimen from Sri Lanka; (b, c) Specimens from , southern India; (d, e) specimens from Pune, India (Copyright DA Warrell)

Venomous snakes of the South-East Asia Region, their 49 venoms and the pathophysiology of human envenoming Some important examples of the (Craspedocephalus) gramineus (Fig 38) Viperidae inhabiting South-East Malabar rock pit viper Trimeresurus Asia Region countries (References to (Crapedocephalus) malabaricus (Fig 39) reports of reviews of bites by these (Gowda et al., 2006) species are given in parenthesis): Palm viper Trimeresurus Typical vipers (subfamily Viperinae): (Craspedocephalus) puniceus (Fig 40) Russell’s vipers, Western, Daboia russelii (Fig 29 a-e) (Phillips et al., 1988; Warrell Sri Lankan viper Trimeresurus 1989; Gawarammana et al., 2009); and (Craspedocephalus) trigonocephalus (Fig Eastern, D. siamensis (Fig 30) (Myint-Lwin 41) (Warrell 1995) et al., 1985; Tun-Pe et al., 1987; Than- Hagen’s pit viper Trimeresurus (Parias) Than et al., 1987; Than-Than et al., 1988; hageni (Fig 42) Warrell 1989; Than- Than et al., 1989; ’s pit viper Trimeresurus (Popeia) Thein-Than et al., 1991; Tin-Nu-Swe et al., popeiorum (Fig 43) 1993; Belt et al., 1997) Chinese viper Trimeresurus Saw-scaled or carpet vipers Echis c. (Viridovipera) stejnegeri (Fig 44) carinatus (Fig 31) (Bhat 1974; Warrell and (Warrell 1995) Arnett 1976) and E. c. sochureki (Fig 31c) (Kochar et al., 2007). White-lipped green pit viper Trimeresurus (Trimeresurus) albolabris (Fig 45) (Hutton Levantine or blunt-nosed viper et al., 1990; Rojnuckarin et al., 1998) lebetina (Fig 32) (Sharma et al., 2008) Dark green pit viper Trimeresurus (Trimeresurus) macrops (Fig 28, 46) Pit vipers (subfamily Crotalinae): (Hutton et al., 1990; Warrell 1990b) Malayan pit viper Calloselasma Spot-tailed green pit viper Trimeresurus rhodostoma (Fig 33) (Reid et al., 1963a; (Trimeresurus) erythrurus (Fig 47) (Warrell Reid et al., 1963b; 1995) Reid 1968; Warrell et al., 1986) White-lipped island viper Trimeresurus Mount Kinabalu pit viper Garthia chaseni (Trimeresurus) insularis (Fig 48) (Fig 34) (Haile 1963; Warrell 1995) Kanchanburi pit viper Trimeresurus Mamushis (Genus Gloydius): G. (Trimeresurus) kanburiensis (Warrell et al., brevicaudus (Fig 35) (Warrell 1995) 1992) Hump-nosed pit viper pit viper Trimeresurus (Fig 36) (de Silva et al., 1994; Joseph et (Trimeresurus) purpureomaculatus (Fig 49) al., 2007; (Warrell 1995) Ariaratnam et al., 2008; Premawardhena Northern white-lipped pit viper et al, 1998) and other Hypnale species Trimeresurus (Trimeresurus) septentrionalis (Maduwage et al., 2011). (Whitaker) Chinese habu Protobothrops Beautiful pit viper Trimeresurus mucrosquamatus (Fig 37) (Warrell 1995) (Trimeresurus) venustus (Fig 50) Green pit vipers, bamboo vipers, palm Wagler’s (temple) pit viper vipers and habus (formerly all genus wagleri (Fig 51a) (Reid 1968) Trimeresurus) Banded temple viper Tropidolaemus Indian bamboo viper Trimeresurus subannulatus (Fig 51b)

50 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES [a] [b]

Figures 30: Eastern Russell’s viper (Daboia siamensis): (a) Specimen from Myanmar; (b) Specimen from Thailand; (c) Specimen from East , Indonesia; (d) Specimen from , Indonesia (Copyright DA [c] [d] Warrell)

[a] [b]

Figures 31: Saw-scaled viper (): (a) Echis carinatus carinatus Specimen from southern India; (b) Echis carinatus carinatus Specimen from Sri Lanka; (c) Echis carinatus sochureki Specimen from [c] Chhattagharh Rajisthan (Copyright DA Warrell)

Venomous snakes of the South-East Asia Region, their 51 venoms and the pathophysiology of human envenoming Figure 32: Levantine viper (Macrovipera lebetina) Specimen from Cyprus (Copyright DA Warrell)

[a] [b]

Figures 33: Malayan pit viper (Calloselasma rhodostoma) Thai specimens: (a) Showing characteristic posture and triangular dorsal markings; (b) Showing supralabial markings (Copyright DA Warrell)

Figure 34: Mount Kinabalu pit viper (Garthia Figure 35: or Fu-she (Gloydius chaseni) (Copyright Prof RS Thorpe) brevicaudus) from (Copyright DA Warrell)

52 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES [a] [b]

[c] [d]

Figures 36 a-d: Hump-nosed viper (Hynpale hypnale) (Copyright DA Warrell) a) Specimen from Sri Lanka; (b) Specimen from Sri Lanka showing long fangs; (c) Specimen from south western India; (d) Specimen from south western India showing upturned snout

Figure 37: Chinese habu (Protobothrops mucrosquamatus) Specimen from China (Copyright DA Warrell)

Venomous snakes of the South-East Asia Region, their 53 venoms and the pathophysiology of human envenoming Figure 38: Indian bamboo viper (Trimeresurus Craspedocephalus gramineus) (Copyright DA Warrell)

[a]

54 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES [b]

Figures 39 a, b: Malabar rock pit viper (Trimeresurus Craspedocephalus malabaricus) (Copyright DA Warrell)

Figure 40: Palm viper (Trimeresurus Craspedocephalus puniceus) Specimen from Cilacap, West Java, Indonesia (Copyright DA Warrell)

Venomous snakes of the South-East Asia Region, their 55 venoms and the pathophysiology of human envenoming Figure 41: Sri Lankan pit viper (Trimeresurus Craspedocephalus trigonocephalus) (Copyright DA Warrell

56 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Figure 42: Hagen’s pit viper (Trimeresurus Parias hageni) Trang, Thailand (Copyright DA Warrell)

Figure 43: Pope’s pit viper (Trimeresurus Popeia popeiorum) Thailand (Copyright DA Warrell)

Venomous snakes of the South-East Asia Region, their 57 venoms and the pathophysiology of human envenoming Figure 44: Chinese bamboo viper (Viridovipera stejnegeri) Specimen from China (Copyright DA Warrell)

[a] [b]

Figures 45 a,b: White-lipped green pit viper (Cryptelytrops albolabris) Thai specimen: (a) Showing colouring and distinctive brown-topped tail; (b) Showing details of the head: note smooth temporal scales (Copyright DA Warrell)

58 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES [a]

[b]

Figure 46: Dark green pit viper (Trimeresurus T. macrops) Figures 47 a, b: Spot-tailed green pit viper (Cryptelytrops erythrurus) Specimen Thai specimen (Copyright DA Warrell) from near Yangon, Myanmar: (a) Showing colouring and brown spotted tail; (b) Showing details of head; note keeled temporal scales (Copyright DA Warrell)

Figure 48: White-lipped island viper (Trimeresurus T. insularis) specimen from Tutuala Sub-district Lautem District Timor-Leste (Copyright Mark O'Shea)

Venomous snakes of the South-East Asia Region, their 59 venoms and the pathophysiology of human envenoming Figures 49 a,b: Mangrove pit viper (Trimeresurus T. purpureomaculatus): (a) Specimen from Kanchanburi, Thailand; (b) Specimen from [a] [b] upper Myanmar (Copyright DA Warrell)

Figure 50: Beautiful pit viper (Cryptelytrops venustus) specimen from Thung Song, Thailand (Copyright DA Warrell)

60 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Figure 51a: Wagler’s pit (temple) viper () specimens in the snake temple, Penang, Malaysia (Copyright DA Warrell)

Figure 51b: Banded temple viper (Tropidolaemus semiannulatus)

Venomous snakes of the South-East Asia Region, their 61 venoms and the pathophysiology of human envenoming 3.2.2 Other medically important venomous snakes Several species of medically important Colubridae (sensu lato) have been identified in the South-East Asia Region. The red-necked keelback Rhabdophis subminiatus (Fig 2c and 52a) and yamakagashi R. tigrinus (Fig 52b) (Warrell 1995) can cause severe life-threatening anti-haemostatic disturbances and acute kidney injury (Fig 52c, 52d). A case of systemic envenoming by the Sri Lankan keelback (Balanophis ceylonicus) with similar Figure 52a: Red-necked keelback (Rhabdophis features has also been reported subminiatus) Thai specimen (Copyright DA Warrell)

Figure 52b: Yamakagashi () (Copyright S Mishima The Snake 1974 6-1 Courtesy of Dr Y Sawai)

62 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES (Fernando et al 2015). More than a dozen other species have proved capable of causing local envenoming [e.g. mangrove snake () (Weinstein et al., 2014) Warrell, 1995) and other cat snakes (Boiga species); long-nosed whip snake ( nasuta) (Fig 52e); - faced water snake ( rhynchops); and water snakes/ snakes ( species) (Fig 52f and 53c). Undoubtedly more will be described as the concept of “non-venomous” is further reviewed (Weinstein et al., 2011) Figure 52c: Extensive bruising from envenoming by R. tigrinus in

Figure 52d: Intracerebral haemorrhage (Courtesy of the late Dr Y Sawai)

Figure 52f: Paddy field snake (Enhydris plumbea)

Figure 52e: Long-nosed whip snake () Sri Lanka (Copyright DA Warrell)

Venomous snakes of the South-East Asia Region, their 63 venoms and the pathophysiology of human envenoming 3.2.3 Non-venomous snakes Many species of non-venomous or only trivially-venomous species are responsible for bites, especially those that are aggressive, irritable or prone to strike at humans who approach to closely or that commonly inhabit urban and rural gardens and compounds.

Apart from the taxa mentioned above, these include paradise or flying snakes ( species) (Fig 52g), striped keelbacks (Amphiesma species) (Fig 52h), kukri snakes ( species) (Fig 52i), checkered keelbacks or Asian water snake ( species) (Fig 52j), snakes ( or Dinodon species) (Fig 52k), bridle snakes (Dryocalamus) (Fig 52m) and rat snakes (Ptyas, , , Goniosoma etc.) (Fig 52n). Their medical importance is that they may be mistaken for venomous species (notably the krait mimics Lycodon and Dryocalamus), resulting in unnecessary and wasteful antivenom treatment (Viravan et al., 1992; Ariaratnam et al., 2009).

Large pythons (Boidae), notably the reticulated Python reticularis in Indonesia, have been reported to attack and even ingest humans, usually inebriated

Figure 52g: Paradise or flying snakes () farmers (Fig 52o). (Copyright Mark O’Shea)

Figure 52i: Kukri snakes () Figure 52h: Striped keelbacks (Amphiesma stolatum) (Copyright Mark O’Shea) (Copyright DA Warrell)

64 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Figure 52k: Wolf snakes () (Copyright DA Warrell)

Figure 52l: Yellow-necked wolf snake (Lycodon flavicollis) biting (Copyright DA Warrell)

Figure 52j: Chequered keelback (Xenochrophis piscator) Figure 52m: Bridle snake (Dryocalamus davisoni) brought by bite victim Chittagong Bangladesh (Copyright DA Warrell)

Venomous snakes of the South-East Asia Region, their 65 venoms and the pathophysiology of human envenoming Figure 52n: Rat snake (Ptyas mucosus) (Copyright Marl O'Shea)

Figure 52o: (Python reticularis) containing the body of a farmer it had swallowed at Palu, , Indonesia (Copyright Excel Sawuwu)

66 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES 3.3 Identification of 3.4.1 Venom composition venomous snakes Modern techniques of “venomics” Unfortunately, there is no simple rule for (proteomics as applied to venoms) such as identifying a dangerous venomous snake. high performance liquid chromatography, However, public educational materials SDS-PAGE, and mass spectrometry are such as posters and cards with pictures revealing the enormous complexity of of medically significant species of that snake venoms (Warrell et al., 2013). More region with short one line or two line than 90% of snake venom (dry weight) is notes of identifying features below the . Each venom contains more than pictures in the local language will be very a hundred different proteins: enzymes useful. In a dead snake, a needle may (constituting 80-90 % of viperid and 25- be drawn along the upper jaw from the 70 % of elapid venoms), non-enzymatic angle of the jaw to the snout to snag and polypeptide toxins, and non-toxic proteins reveal the fangs. Some harmless snakes such as . Nonprotein have evolved to look almost identical to ingredients include carbohydrates and venomous ones. Examples are various (often part of glycoprotein species of Lycodon, Dryocalamus and metalloprotein enzymes), lipids, free amino Cercaspis that mimic the appearance of acids, nucleosides, and biogenic amines the kraits B. candidus, B. caeruleus and such as serotonin and acetylcholine. B. ceylonicus; Cylindropis ruffus, whose tail raising display and colouring may Venom enzymes mimic coral snakes (Calliophis species), These include digestive hydrolases and that mimics (proteinases, exopeptidase, Daboia siamensis. However, some of endopeptidases, phosphodiesterases, the most notorious venomous snakes metalloproteinases, and phospholipases), can be recognized by their size, shape, hyaluronidase (spreading fator), and colour, pattern of markings, behaviour activators or inactivators of physiological and the sound they make when they feel processes, such as kininogenases. Most threatened. For example, the defensive venoms contain l-amino acid oxidase behaviour of the cobras is well known (Fig (containing a riboflavin 5’-phosphate 4-9): they rear up, spread a hood, hiss prosthetic group that confers the yellow and make repeated strikes towards the colour of many venoms), phospho mono- aggressor. Colouring can vary enormously. and di- esterases, 5'-nucleotidase, DNAase,

However, some patterns, like the NAD-nucleosidase, phospholipase A2, and longitudinal rows of large, dark-rimmed, peptidases. pale-centred spots of the Russell’s vipers (Figs 29, 30), or the alternating black Zinc metalloproteinases/ and yellow circumferential bands of the metalloproteases (metalloproteinase- banded krait (Fig 13), are distinctive. The like, disintegrin-like, cysteine-rich) blowing hiss of the Russell’s viper and the haemorrhagins (snake venom grating rasp of the saw-scaled viper are metalloproteinases, SVMPs): degrade warning and identifying sounds, even in basement membrane components, the dark. leading to endothelial cell damage and contributing to spontaneous systemic 3.4 Snake venoms bleeding. (Bucherl et al., 1968,1971; Gans and Gans 1978; Lee 1979; Harvey 1991; Ménez Procoagulant enzymes: venoms 2003; Mackessy 2009; Warrell 2010) of Viperidae and some Elapidae and

Venomous snakes of the South-East Asia Region, their 67 venoms and the pathophysiology of human envenoming Acetylcholinesterases: although found in most elapid venoms, may cause Envenoming by juvenile and adult fasciculation. snakes may cause qualitatively different Hyaluronidase: promotes the spread clinical effects of venom through tissues by increasing permeability but can also contribute to tissue damage. Colubridae contain serine proteases and other procoagulant enzymes that are Proteolytic enzymes thrombin-like or activate factors V, X, (metalloproteinases, endopeptidases prothrombin and other clotting factors. or hydrolases) and polypetide These enzymes stimulate blood clotting cytotoxins (“cardiotoxins”): increase with formation of fibrin in the blood vascular permeability causing oedema, stream. Paradoxically, this process results blistering, bruising and necrosis at the site in incoagulable blood because most of of the bite. the fibrin clot is broken down immediately by the body’s own plasmin fibrinolytic Venom polypeptide toxins system. Sometimes within 30 minutes (“neurotoxins”) of the bite, the levels of clotting factors Postsynaptic (α) neurotoxins such as have been so depleted that the blood will α- and cobrotoxin, consist of not clot (“consumption coagulopathy”). 60-62 or 66- 74 amino acids. They bind Some venoms contain multiple anti- to acetylcholine receptors at the motor haemostatic factors. For example, Russell’s endplate. Presynaptic (β) neurotoxins such viper venom contains toxins that activate as β-bungarotoxin, and taipoxin, contain factors II (prothrombin), V, X, IX and 120-140 amino-acids and a phospholipase XIII, fibrinolysis and protein C, and cause A subunit. These release acetylcholine platelet aggregation, anticoagulation and at the nerve endings at neuromuscular haemorrhage. junctions and then damage the endings, preventing further release of transmitter.

Phospholipases A2 (lecithinase): are most widespread and extensively Variation in venom composition studied of all venom enzymes. They within species damages mitochondria, red blood The composition of snake venoms, and cells, leucocytes, platelets, peripheral hence their antigenicities in inducing nerve endings, skeletal muscle, vascular specific neutralizing during endothelium, and other membranes, antivenom manufacture, varies greatly producing presynaptic neurotoxic between different species, but also within activity, cardiotoxicity, myotoxicity, an individual species, as the snake matures necrosis, hypotension, haemolysis, (ontogenic variation), seasonally, between haemorrhage, plasma leakage (oedema- sexes, and throughout the geographical induction), opiate-like sedative effects and range (Warrell, 1997; Mackessy et al., autopharmacological release of histamine 2003). The two important implications and other autacoids. They are anti- of venom variation are 1- envenoming coagulant, either by hydrolysing plasma by juvenile and adult snakes may cause or platelet membrane phospholipids, or qualitatively different clinical effects and 2- by interacting with different coagulation envenoming by a snake in one part of its factors. geographical range may not be neutralized

68 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES by an antivenom raised using venom from another part of the range. Recommendations: Bites by small snakes should not 3.4.2 Quantity of venom injected at a be ignored or dismissed. bite, “dry bites” They should be taken just as This is very variable, depending on seriously as bites by large the species and size of the snake, the snakes of the same species mechanical efficiency of the bite, whether (O). Design and manufacture one or two fangs penetrated the skin and of antivenoms should take whether there were repeated strikes. The account of geographical and average dry weight of venom injected ontogenic variation in venom at a strike is approximately 60 mg in N. composition within individual naja, 13 mg in E. carinatus and 63 mg species (O). in D. russelii. In the case of D. siamensis in Myanmar, the total yield of desiccated venom extracted by milking ranged from 21-268 mg (127 +/- 13 mg, mean +/- 3.5 Pathophysiology of 1SE) in adults (mean total length 111 human envenoming +/- 1.8 cm) and 8-79 mg (45 +/- 7 mg) Local envenoming in juveniles (mean total length 79 +/- 2.8 Swelling and bruising result from increased cm). Adults inject 45% of the venom vascular permeability attributable to glands' content in the first bite (Tun-Pe venom endopeptidases, metalloproteinase and Khin-Aung Cho, 1986). Either because hemorrhagins, membrane-damaging of mechanical inefficiency or the snake’s polypeptide toxins, phospholipases, control of venom discharge, a proportion and endogenous autacoids released by of bites by venomous snakes does not the venom, such as histamine, 5-HT, result in the injection of sufficient venom and kinins. Local tissue necrosis results to cause clinical effects. About 50% of from the direct action of myotoxins bites by Malayan pit vipers and Russell’s and cytotoxins, and ischemia caused vipers, 30% of bites by cobras and 5-10% by thrombosis; compression of blood of bites by saw-scaled vipers do not result vessels by first-aid methods such as in any symptoms or signs of envenoming. tight tourniquets; or by swollen muscle Snakes do not exhaust their store of within a tight fascial compartment. venom, even after several strikes, and they Myotoxins damage the muscle cell plasma are no less venomous after eating their membrane directly. Most are PLA2s, either prey (Tun-Pe et al., 1991). enzymatically active (aspartate-49) or enzymatically inactive (lysine-49). Cobra 3.4.3 Variations in venom cardiotoxins are low-molecular weight composition within individual polypeptides with cytotoxic action. species of snakes Although large snakes tend to inject more Hypotension and shock venom than smaller specimens of the same After viper bites, leakage of plasma or species, the venom of smaller, younger blood into the bitten limb and elsewhere, vipers may be richer in some dangerous or massive gastrointestinal haemorrhage, components, such as those affecting may cause hypovolaemia. Vasodilation, haemostasis because venom composition especially of splanchnic vessels, and a direct varies (ontogenically) with the snake’s age effect on the myocardium may contribute and hence size (Tun-Pe et al., 1995a). to hypotension. Profound hypotension

Venomous snakes of the South-East Asia Region, their 69 venoms and the pathophysiology of human envenoming is part of the autopharmacological Neurotoxicity syndrome that occurs within minutes Neurotoxic polypeptides and PLA2s of of bites by D. siamensis, D. russelii, and snake venoms cause paralysis by blocking Australasian elapids, attributable to transmission at the neuromuscular oligopeptides (ACE inhibitors and BPPs) junction. Patients with paralysis of and vasodilating autacoids. In some cases, the bulbar muscles may die of upper direct myocardial effects of venom may airway obstruction or aspiration, but be suggested by electrocardiographic the most common mode of death after (ECG) changes and autopsy findings of neurotoxic envenoming is respiratory epicardial or endocardial haemorrhages paralysis. By prolonging activity of and histopathological evidence of cardiac ACh at neuromuscular junctions, myonecrosis. anticholinesterase drugs may improve paralytic symptoms in patients bitten Bleeding and blood clotting by snakes with neurotoxins that are disturbances predominantly postsynaptic in their Snake venoms affect haemostasis in action (e.g., cobras and Australasian several ways. Procoagulant enzymes death adders [genus Acanthophis]). Some activate intravascular coagulation, patients bitten by elapids or vipers are producing consumption coagulopathy drowsy in the absence of respiratory or and incoagulable blood. Procoagulants of circulatory failure. This is unlikely to be an Colubridae, Australasian Elapidae, Echis, effect of neurotoxic polypeptides, which and Daboia species activate prothrombin, do not cross the blood-brain barrier. whereas those in venoms of Daboia russelii and D. siamensis also activate factors V Myotoxicity

and X. Thrombin-like enzymes in pit-viper PLA2 myotoxins and metalloproteinases are venoms have a direct action on fibrinogen. principally responsible. They are present Some venoms cause defibrinogenation in venoms of most species of sea snakes, by activating the endogenous fibrinolytic many terrestrial Australasian elapids, some (plasmin) system. Anticoagulant activity species of krait (Bungarus), and Viperidae, is attributable to venom phospholipases. such as the Sri Lankan Russell’s viper (D. Platelet activation or inhibition results russelii). Release into the bloodstream of in thrombocytopenia in victims of myoglobin, muscle enzymes, , Trimeresurus and Viridovipera species, potassium, and other muscle constituents Calloselasma rhodostoma, is an effect in humans of presynaptic acutus, and Daboia siamensis. Potentially neurotoxins. Patients may die of bulbar lethal spontaneous systemic bleeding is and respiratory , acute attributable venom haemorrhagins (Zn hyperkalaemia, or acute kidney injury. metalloproteases). Acute kidney injury Complement Activation A wide range of renal histological changes Elapid and some colubroid venoms has been described after snakebite. Acute activate complement via the alternative tubular necrosis is the most common, but pathway (“cobra venom factor” is the proliferative glomerulonephritis, interstitial snake’s C3b), whereas some viperid nephritis, toxic mesangiolysis with platelet venoms activate the classic pathway. agglutination, fibrin deposition, ischaemic Complement activation affects platelets, changes, and distal tubular damage the blood coagulation system, and other (“lower nephron nephrosis”), suggesting humoral mediators. direct venom nephrotoxicity attributable

70 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES to venom PLA2 and metalloproteases , was an early sign of oliguric renal and bilateral renal cortical necrosis with failure. Snake venom–induced DIC may subsequent calcification are also reported. result in deposition of fibrin on vascular Antivenom can cause immune-complex- endothelium that has been activated mediated kidney injury. Acute tubular by, for example, metalloproteinases, necrosis may result from prolonged producing microangiopathic haemolysis. hypotension and hypovolaemia, DIC, direct Although the clinical picture is reminiscent toxic effect of the venom on the renal of haemolytic uraemic syndrome (HUS) tubules, haemoglobinuria, myoglobinuria, and thrombotic thrombocytopenic and hyperkalaemia. Russell’s viper purpura (TTP), there is no evidence of venom produces hypotension, DIC, depleted ADAMTS-13 levels and, therefore direct nephrotoxicity, and, in Sri Lanka no justification for cryosupernatant and India, intravascular haemolysis and plasmapheresis (Ho et al., 2010). rhabdomyolysis.In Burmese patients envenomed by Russell’s vipers (D. Generalized increase in capillary siamensis), high urinary concentrations permeability of β2-microglobulin, retinal binding Venoms of some Viperidae, such as protein, and N-acetyl glucosaminidase D. russelii and D. siamensis, can cause suggested failure of proximal tubular a generalized increase in vascular reabsorption and tubular damage. permeability, resulting in pulmonary High plasma concentrations of active oedema, serous effusions, conjunctival, renin suggested that renal ischaemia periorbital, facial and retinal oedema, with activation of the renin-angiotensin bilateral parotid enlargement, albuminuria, system was involved in development of and haemoconcentration. The likely cause renal failure. A massive but transient is metalloproteases that damage vascular capillary and glomerular leak of albumin endothelium.

Venomous snakes of the South-East Asia Region, their 71 venoms and the pathophysiology of human envenoming 72 Epidemiology of snakebite in South-East Asia Region countries

Epidemiology of snakebite 73 in South-East Asia Region countries 74 4 Epidemiology of snakebite in South-East Asia Regioncountries

Essentials: venomous snake cause no envenoming Most published data, based on hospital (“dry bites”), a figure ranging 5-80% with returns, are incomplete because many different species. patients are treated by traditional healers. However, three large, well-designed, national, Snakebite epidemics follow flooding, community-based studies from Bangladesh, cyclones and invasion of snakes’ habitats India and Sri Lanka have produced reliable for road building, irrigation schemes estimates. Data are inadequately reported and logging. These activities cause long and so snakebite should be made a notifiable term changes in climate and ecology and disease in all South-East Asia Region encourage influx of human settlers. countries. Death certification should use International Classification of Diseases code Males are more often bitten than females. T63.0 (Toxic effect of contact with venomous Peak incidence is in children and young animals – snake venom and sea-snake adults. Pregnant women and their fetuses venom) (ICD-10 Version:2015 http://apps. are at increased risk of dying. Snakebite who.int/classifications/icd10/browse/2015/ is an occupational disease of farmers, en#/T63.0) plantation workers, herders, hunters, fishermen, fish farmers, snake restaurant Incidence of snakebite varies diurnally and workers and snake charmers. Factors seasonally. It is highest during agricultural contributing to fatal snakebite include activities and seasonal rains. Most bites problems with choice and dosage of are inflicted on the feet and ankles of antivenom, delay from visiting traditional bare-footed agricultural workers who healers, transportation difficulties, tread on snakes inadvertently while death in transit, airway obstruction, walking in the dark or working in fields failure to attempt assisted ventilation or and plantations. Snake species differ in problems in carrying it out, failure to treat their inclination to strike when disturbed. hypovolaemia, complicating infections, Notoriously “irritable” species include failure to observe deterioration in hospital. Russell’s and saw-scaled vipers. Cobras and Hours usually elapse between bite and kraits enter human dwellings. Kraits bite neurotoxic deaths from elapid envenoming people who are asleep on the ground at and several days or longer, from viper night. On average, about 50% of bites by envenoming.

Epidemiology of snakebite 75 in South-East Asia Region countries Snakebite in different South-East Asia Direct estimate of deaths attributable to Region countries snakebite in 2005 was 46 000 (99%CI 41 Bangladesh: medically important species 000-51 000), (1 snakebite death for every include B. caeruleus, B. niger, B. walli; 2 HIV/AIDS deaths). Snakebites caused N. kaouthia, N. naja; D. russelii and T. (T.) 0.5% of all deaths, 3% in 5-14 year-olds. erythrurus. 97% died in rural areas, only 23% in health facilities. The highest numbers of deaths In 2009, 9000 people were questioned in were in (8,700), Andhra about 4000 randomly selected households Pradesh (5,200), and Bihar (4,500). throughout all 6 administrative divisions. 589,919 snakebites and 6,041 deaths per Indonesia: medically important species year were estimated in rural areas (case- throughout the >18 000 islands include fatality 1%). B. candidus, N. sputatrix, N. sumatrana, C. rhodostoma , T. (T.) albolabris; D. Green pit vipers cause many bites, some siamensis and, in West Papua and Maluku, morbidity but few deaths. D. russelii Acanthophis laevis. Hundreds of bites each is restricted to western and southern year are treated in , Java, East areas. B. niger, previously unknown Kalimantan, Sulawesi, Wetar and West in Bangladesh, has caused deaths. N. Papua. kaouthia causes most cobra bites. Maldives: there is one species of sea Bhutan: medically-important species snake but no terrestrial venomous snake. include cobras, kraits and pit-vipers. No No recent data on bites. recent data on bites. Myanmar: medically important Democratic People’s Republic of species include B. magnimaculatus, (North) Korea: medically-important B. multicinctus; N. kaouthia, N. species include adders ( berus and V. mandalayensis; Trimeresurus (T.) albolabris, sachalinensis), several species of mamushi T. (T.) erythrurus; D. siamensis (genus Gloydius) and Rhabdophis tigrinus. In 2014, 15,080 bites with 305 deaths No recent data on bites. were reported to the Ministry of Health (case-fatality 2.02%). D. siamensis causes India: medically important species include 90% of bites. N. naja, N. kaouthia; B. caeruleus; D. russelii, E. carinatus; Hypnale hypnale, Nepal: medically important species Trimeresurus. Registrar General of India’s include B. caeruleus, B. niger, B. walli; N. “Million Death Study” assigned causes of naja, N. kaouthia; D. russelii and all deaths in about 7000 randomly chosen monticola. In the Eastern Terai, there were sample areas, each with a population 162 snakebite deaths/100 000/year. Only of about 1000 throughout the whole 20% of deaths occurred in hospitals. Most country. Verbal autopsy (questioning were attributed to krait. National totals of bereaved relatives and neighbours about between 1000 bites and 200 deaths and the circumstances of the deceased’s 20 000 bites and 1000 deaths/year have death), proved reliable for an event as been suggested. In 2000, the Ministry of distinctive, dramatic and memorable Health reported 480 bites with 22 deaths, as snakebite fatality. Results were while 4,078 bites with 81 deaths were independent of hospital underreporting recorded at 10 hospitals in eastern Nepal and were nationally representative. (case-fatality 3-58%).

76 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Sri Lanka: medically important species include B. caeruleus; N. naja; D. russelii, The total number of snakebites each year Echis carinatus and Hypnale hypnale. Bites are caused by D. russelii, (30%), H. hypnale might exceed 5 million with a snakebite (22%), N. naja (17%) and B. caeruleus. A mortality of 125 000 each year in the world recent community-based, countrywide survey of snakebite included nearly 1% of as a whole. (Chippaux,1998) the country’s population. The incidence of bites, envenoming and mortality from snakebite was found to be 398 (95% been made to assess global snakebite CI: 356–441), 151 (130–173) and 2.3 mortality. In 1954, Swaroop and Grab (0.2– 4.4)/100 000/year, respectively, of the Statistical Studies Section, WHO, amounting to more than 80 000 bites, 30 estimated that among half a million 000 envenomings and 400 deaths in the snakebites and between 30 000 and 40 country each year. 000 snakebite deaths each year in the world as a whole, with between 25 000 Thailand: medically important species and 35 000 deaths in Asia. Their analysis include B. candidus; N. kaouthia, N. was based on registration of deaths in siamensis; C. rhodostoma; Trimeresurus different countries, but they recognized (T.) albolabris and D. siamensis. Incidence the following deficiencies in this method: of bites has declined from 9,071 bites (14.5/100 000) in 2002 to 457 (0.7/100 1. “Available statistical data are known to 000) in 2015. Mortality has declined from be unreliable and, at best, can serve to an average of 178/year in the 1950s to provide only an approximate and highly fewer than 2/year since 2008 (case-fatality conservative estimate of the relative <0.5%). Calloselasma rhodostoma causes magnitude of the snakebite problem.” 38% of attributable bites, Trimeresurus (T.) albolabris and T. (T). macrops 30 %, 2. “The chance of snakebite deaths being Naja kaouthia and N. siamensis 23% missed are perhaps even greater than and Daboia siamensis 2%. B. candidus for deaths occurring from several other causes as many fatalities as the far better causes.” recognized Calloselasma rhodostoma). 3. “The recorded figures of snakebite Timor-Leste: T. (T.) insularis causes bites deaths may therefore be regarded as and a few fatalities. underestimates of the total fatality from this cause, the degree of 4.1 Introduction underrecording varying from place to It is generally recognized that the place.” epidemiology of snakebite in the South- East Asia Region has not been adequately In 1998, Chippaux published an appraisal studied and that the published data, based of the global situation, again based mainly almost exclusively on hospital returns on hospital records or health authority to ministries of health, are likely to be statistics, quoting 114 publications. He unreliable and therefore misleading. One speculated that the total number of reason is that many snakebite victims are snakebites each year might exceed 5 treated not in hospitals but by traditional million with a snakebite mortality of 125 healers (Warrell, 1992). In the past 000 each year in the world as a whole, half century, only three attempts have including 4 million snakebites, 2 million

Epidemiology of snakebite 77 in South-East Asia Region countries snakebite envenomings, and 100 000 The continuing inadequacies in the snakebite deaths each year in Asia. reporting of snakebite incidence, morbidity and mortality, prompts the following In 2008 Kasturiratne et al estimated 237 recommendation. 379–1 184 550 envenomings with 15 385 - 57 636 deaths in the Asia- Pacific region (South 14 112-33 666 Recommendation: To – rate 0.912- 2.175/100 000/year; East remedy the deficiency in 462-4 829 – rate 0.033- 0.347/100 000/ reliable snakebite data, it is year). Their most conservative estimate strongly recommended that of the highest number of deaths due to snakebites should be made snake bite was 14 000 in South Asia. a specific notifiable disease Various studies suggest that bites with in all countries in the South- envenoming constitute 12-50% of the East Asia Region and that total number of bites in Asia and 18-30% death certification should in India and Pakistan. use the specific International Classification of Diseases code A fundamental problem throughout T63.0 (Toxic effect of contact much of the Region is that snakebite with venomous animals – snake treatment has remained in the domain venom and sea-snake venom) of traditional, herbal or ayurvedic (ICD-10 Version:2015 http:// practitioners, so that the majority of apps.who.int/classifications/ snakebite victims are not seen or recorded icd10/browse/2015/en#/T63.0 (E) in western-style hospitals or dispensaries. (T63.0) Snake venom For example, in Wat Promlok, Nakorn Srithamarat, Thailand, one “moor glang baan” (traditional therapist) treated 72- 393 snakebite victims each year between 4.2 Determinants of 1985 and 2002. snakebite incidence and severity of envenoming In the Terai of Nepal, a community-based The incidence of snakebites depends study established the high fatality rate of critically on the frequency of contact 161/100 000/year, attributable mainly to between snakes and humans. Except at krait bites (Sharma et al., 2004). Few other times of flooding, snakes are elusive and community studies have been attempted reclusive and so contact with humans is (Hati et al 1992). In some countries, such likely only when humans move into the as Sri Lanka, there has, over the last two snakes’ favoured habitat (rice fields in decades, been a dramatic shift in patients’ the case of Russell’s vipers and cobras; preference for treatment from ayurvedic to rubber and coffee plantations in the case western medicine. of Malayan pit vipers) or when nocturnally active snakes are trodden upon by people The true scale of mortality from snakebite walking along paths in the dark. Seasonal is just beginning to be revealed, thanks to peaks of snakebite incidence are usually three large, well-designed, community- associated with increases in agricultural based studies that have recently been activity or seasonal rains, perhaps published from India (Mohapatra et al., coinciding with unusual movements and 2011), Bangladesh (Rahman et al., 2010) activity by the snakes. Different species and Sri Lanka (Ediriweera et al, 2016). of snake vary in their willingness to strike

78 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES when disturbed. Typically “irritable” is in young children and the elderly. In species are Russell’s vipers (Daboia russelii pregnant women, snakebite carries and D. siamensis) and saw-scaled vipers definite but largely unquantified risks to (Echis). Bites may be inflicted in the home mother (perhaps 4-5% case-fatality) and by peri-domestic species such as cobras fetus (perhaps 20% case-fatality), mainly (Naja) which may live in roof spaces or from bleeding and stillbirth/abortion under the floor and by kraits (Bungarus) (Seneviratne at al, 2002; Langley, 2010). which enter human dwellings at night Most snakebites are inflicted on the feet in search of their prey and may bite and ankles of agricultural workers. people who move in their sleep. Bites in which a venomous snake’s fangs pierce 4.4 Circumstances of the skin but no envenoming results are snakebites known as “dry bites”. The incidence of Most snakebites happen when the snake dry bites varies with the species, from is trodden on, either in the dark or in 5-80%, average about 50% (Reid et al., undergrowth, by someone who is bare- 1963a; de Rezende et al., 1998; Silveira footed or wearing only sandals. The and Nishioka, 1995). The explanation for snake may be picked up, unintentionally dry bites is either mechanical inefficiency in a handful of foliage or intentionally of the venom apparatus striking at an by someone who is unwise or boastful. unnatural angle or through clothing, or Some bites occur when the snake (usually perhaps voluntary defensive retention a krait) comes in to the home at night in (metering) of venom by the snake. search ofits prey (other snakes, , frogs, mice) and someone sleeping on Snakebite epidemics follow flooding the floor rolls over onto the snake in their (India, Bangladesh, Myanmar and sleep. Not all snakebites happen in rural Indonesia), cyclones and invasion of areas. For example, in some large cities, snakes’ habitats for road building, such as Jammu in India, people who irrigation schemes (e.g. Mahaweli Ganga sleep in small huts (jhuggies) are bitten Irrigation Project in Sri Lanka) and by kraits during the night and wake with logging. These activities cause long-term paralysis (Saini et al., 1986). In parts of changes in climate and ecology that may India, Hindu pilgrims travel bare-footed encourage influx of venomous snakes though overgrown and mountainous and human settlers into deforested areas areas in the dark of early morning to that have been developed for farming reach a holy place and are at increased and plantations. There was no immediate risk of snakebites (e.g. Sabarimala in the increase in snakebites in Myanmar after Periyar Tiger Reserve, , India). Sea Cyclone Nargis, but there was in the snakebites usually occur when fishermen aftermath 9-12 months later. pick the animals out of their hand nets or when people are bathing or washing 4.3 Epidemiological clothes in estauaries. characteristics of snakebite victims 4.5 Snakebite as an Males are more often bitten than occupational disease females, except where the work force In South-East Asia Region countries, the is predominantly female (e.g. tea and risk of snakebite is strongly associated coffee picking). The peak age for bites with occupations: farming (rice), is in children and young adults. There plantation work (rubber, coffee), herding, is some evidence that peak case fatality hunting, fishing and fish farming,

Epidemiology of snakebite 79 in South-East Asia Region countries (Calloselasma rhodostoma) and cobras Inadequacies in ambulance transport (Naja species) (Looareesuwan et al., 1988). Factors identified as contributing to a from rural locations to properly fatal outcome included problems with equipped hospitals is an important antivenom use (inadequate dose or use of a monospecific antivenom for a bite cause of death. by a different species), delayed hospital treatment resulting from prolonged visits to traditional healers and problems with catching and handling snakes for food transportation, death on the way to (in snake restaurants), displaying and hospital, inadequate artificial ventilation or performing with snakes (snake charmers), failure to attempt such treatment, failure manufacturing leather (especially sea to treat hypovolaemia in shocked patients, snakes), and in the preparation of airway obstruction, complicating infections, traditional (Chinese) . and failure to observe patients closely after they had been admitted to hospital. Inadequacies in ambulance transport Snakebite: from rural locations to properly equipped an occupational disease in hospitals is an important cause of death South-East Asia (Gimkala et al., 2016). In India, the majority of deaths occur outside a hospital • Farmers (rice, etc.,) facility (Mohapatra et al. 2011). Peripheral • Plantation workers (rubber, hospitals often have inadequate medical coffee, cacao, oil palm etc.) and nursing staffing. It is very important • Herdsmen that relatives be effectively deployed to monitor snakebite victims, particularly • Hunters those with neurotoxic envenoming, to • Snake handlers (snake charmers detect progression of weakness and early and in snake restaurants and signs of respiratory paralysis. traditional Chinese • pharmacies) 4.6.2 Time between snakebite and death • Fishermen and fish farmers Although very rapid death after snakebite • Sea-snake catchers (for sea-snake has, rarely, been reported (e.g. reputedly skins, leather) “a few minutes” after a bite by the king cobra Ophiophagus hannah), it is clear from studies of large series of snakebite deaths that many hours usually elapse 4.6 Death from snakebite between bite and death in the case of 4.6.1 Factors contributing to fatal elapid envenoming, and several days, snakebite or even longer, in the case of viper Few attempts have been made to examine envenoming (Reid 1968; Warrell 1995). the factors responsible for death in cases of bites by identified species of snakes. 4.7 Snakebite in different In a study of 46 cases of identified South-East Asia Region snakebite in Thailand, the three species countries causing most deaths were Malayan krait For each South-East Asia Region country, (Bungarus candidus), Malayan pit viper some information about the estimated

80 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES incidence of snakebite is reviewed below, large disparities between the results of based on published and unpublished these two surveys must be explained by reports. The most important snake their design and assumptions made in species from a medical point of view calculating the national estimates. are given in the boxes, according to the following definitions (WHO, 2010): In 1988-1989, a study had discovered records of 764 bites and 168 deaths (22% CATEGORY 1: Highest Medical case fatality). 34% were cobra (Naja naja, Importance - highly venomous snakes N. kaouthia) bites, carrying a 40% case that are common or widespread and cause fatality. A total of 8000 bites per year numerous snakebites, resulting in high across Bangladesh was estimated (Sarkar levels of morbidity, disability or mortality. et al., 1999). A postal survey suggested 4.3 bites/100 000/year, rising to 7 per 100 CATEGORY 2: Secondary Medical 000 in areas like Chittagong Division, with Importance - highly venomous snakes an overall case fatality of 20% (Huq et al., capable of causing morbidity, disability 1995). Forty-five percent of victims are or death, but for which (a) exact said to be farmers and 23% housewives. epidemiological or clinical data are lacking Most patients are treated by traditional or (b) are less frequently implicated healers (“ozhas”) and 20% of fatal cases because of their behaviour, habitat receive no conventional medical treatment preferences or occurrence in areas remote (Ali Reza Khan. Indo-Asian News Service, from large human populations. Dhaka October 12, 2001). In one five- year study of 336 cases of snakebite at Bangladesh: In 2003, about 170 Mymensingh Medical College Hospital, 000 households were surveyed in 12 70% of cases were aged 11-30 years and randomly selected districts. A national 75% were males (Bhuiyan WHO New Delhi total was estimated of 15 372 bites 1981, unpublished). During the severe and 1709 deaths (Case Fatality 11%). flooding of July-August 2007, there were The risk in rural areas was 10.54 times 76 cases of snakebite with 13 deaths. that in urban areas. 94% victims lived under poor socioeconomic conditions Only 3% of bite victims attend hospital and 61% sought immediate treatment or seek help from a trained doctor, 6% from traditional healers (Hossain et al., seek assistance from village doctors and 2016). In 2009, a survey, funded by the most of the rest used traditional healers government and World Bank, questioned “Ojhas”. About 75 % of snakebite victims 9000 people questioned in about 4000 receive some kind of treatment within randomly selected households throughout two hours of being bitten. Peak snakebite all 6 administrative divisions. Results incidence is during May-October. It was suggested an incidence of 623.4 (95% highest in Barisal (2667/100 000/year) and CI 513.4–789.2) snakebites per 100 000 lowest in Sylhet (321/100 000/year). In person-years. There were an estimated Dhaka, incidence was 440/100 000/year. 710 159 episodes of snakebites occur A study carried out in 4 tertiary referral annually in rural Bangladesh. An estimated hospitals estimated the economic cost 589 919 individuals are bitten by snakes of snakebite to the victims’ families. The and 6041 die from snakebites every year total expenditure related to snakebite was in rural (Case Fatality 1%) (Rahman et al., mean US$124 (4 – 2294) with a mean 2010). This is a much higher incidence income loss of US$93. Cost of a venomous than formerly had been imagined. The snakebite was US$231, 7 times higher

Epidemiology of snakebite 81 in South-East Asia Region countries than for a non-venomous snakebite. Cat 1: Elapidae: Bungarus Treatment imposes a major economic caeruleus, Bungarus niger, burden on affected families, especially Bungarus walli; Naja kaouthia; in venomous snakebite cases (Hasan et Viperidae: Daboia russelii, al., 2012). Trimeresurus (T.) erythrurus

Green pit vipers Trimeresurus (Trimeresurus) erythrurus cause many Cat 2: Elapidae: Bungarus bites and some morbidity but few if any fasciatus, Bungarus lividus; Naja fatalities. Russell’s Viper (Daboia russelii) naja; Ophiophagus hannah; appears to be rare. It is restricted to Viperidae: Trimeresurus (T.) western and southern parts of the purpureomaculatus, Trimeresurus country. There are recent reports of (T.) septentrionalis envenoming in the Rajshahi area (Ghose and Faiz, 2015; Ghose et al., 2015). Kraits are responsible for many bites and fatalities. The importance of the Bhutan: In 2000, 2085 bites and stings greater black krait (Bungarus niger), were reported. Five elapid species have a species previously unreported from been reported from lowland regions Bangladesh, has only recently emerged. of Bhutan (less than 500 metres above Based on their frequencies among mean sea level): cobra (Naja naja), king proven krait bites in Bangladesh and cobra (Ophiophagus hannah) and two their geographical distribution, it is species of krait (Bungarus niger and B. estimated that Wall’s krait (Bungarus fasciatus). Other venomous species such walli) causes about 40% of all krait bites as N. kaouthia, Sinomicrurus macclellandi, in the country, greater black krait Daboia russelii (“Bhutan Hills” according (B. niger) and common krait (B. to MA Smith 1943), and several pit vipers caeruleus) about 28% each, and banded may well occur there as well. There is no (B. fasciatus) and lesser black kraits published information on snakebites in (B. lividus) very few. In Bangladesh, Bhutan but there are said to be many B. lividus is known only from the bites causing local pain and swelling and northwest, B. walli and B. caeruleus are there were a minimum of 2 fatalities in absent from southeastern Bangladesh, one year. Antivenom is imported from but B. fasciatus and B. niger occur India (200 vials each year). No recent data throughout the country. Monocled on bites. cobras Naja kaouthia occur throughout the country and cause most cobra bites. They are the only cobras found Cat 1: Elapidae: Bungarus niger; in southeastern Bangladesh (including Naja naja Chittagong, Cox’s Bazar and Chittagong Hill Tract Districts). Spectacled cobras Cat 2: Elapidae: Bungarus Naja naja occur around Dhaka and fasciatus; Ophiophagus hannah; to the west and north of the capital. Viperidae: Trimeresurus (T.) King cobras (Ophiophagus hannah) erythrurus; Daboia russelii occur wherever relatively undisturbed bamboo stands and forests remain in Bangladesh, but have not caused Democratic People’s Republic of documented bites in recent years. (North) Korea: Two species of adders

82 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES ( and V. sachalinensis), several species of mamushi (genus Gloydius) and The direct estimate of deaths attributable the yamakagashi (Rhabdophis tigrinus) occur in North Korea but there is no to snakebite in India in 2005 was 46 000 information on snakebites. (99%CI 41 000-51 000), or 1 snakebite

Published data are restricted to the death for every 2 HIV/AIDS deaths. Republic of (South) Korea (eg Soh et al., 1978; Sawai,1993). No recent data on bites. figure from health facilities and more than 4 times higher than WHO-sponsored guesstimate (Kasturiratne et al, 2008). Cat 1: Gloydius brevicaudus Snakebites caused 0.5% of all deaths, but 3% in the age group 5-14 years. The Cat 2: Gloydius intermedius; proportion of victims dying in rural areas Gloydius ussuriensis; Vipera berus was 97%. Only 23% had died in a health facility. The highest number of deaths were in Uttar Pradesh (8700), India: the numbers of snakebite fatalities (5200), and Bihar (4500). in India has long been controversial. The Government of India’s web-site Previous studies had included a field reported an average of only 1350 deaths/ survey in randomly selected villages in year between 2003 and 2008, whereas Barddhaman (Burdwan) District, West Kastururatne et al., 2008 estimated about Bengal that suggested that among the 11 000 deaths/year. Estimates as low as 61 total population of nearly 5 million people, 507 bites and 1124 deaths in 2006 and 76 nearly 8000 were bitten and 800 killed 948 bites and 1359 deaths in 2007 and by snakes each year, an average incidence as high as 50 000 deaths each year have of 16.4 deaths/100 000/year (Hati et al., been published. The Registrar General of 1992). In Maharashtra State, between India’s “Million Death Study”, 2001-2003, 1974 and 78, there was an average of assigned causes of all deaths, using verbal 1224 deaths/year (2.43 deaths/100 000/ autopsy, in about 7000 randomly chosen year). “The big four” medically important sample areas, each with a population species had been considered to be Naja of about 1000 throughout the whole naja, Bungarus caeruleus, Daboia russelii country. Verbal autopsy (questioning and Echis carinatus but other species have bereaved relatives and neighbours about now been proved important in particular the circumstances of the deceased’s areas, such as Naja oxiana (north), N. death), proved reliable for an event as kaouthia (north east), Hypnale hypnale distinctive, dramatic and memorable as (south-west coast and snakebite fatality (Mohapatra et al., 2011). (Joseph et al., 2007)), Echis carinatus The results were independent of hospital sochureki (Rajisthan) (Kochar et al., 2007) underreporting and were nationally and Trimeresurus (Craspedocephalus) representative. The direct estimate of malabaricus (Hassan District, Mysore, deaths attributable to snakebite in 2005 ). Bites by non-venomous was 46 000 (99%CI 41 000-51 000), or species such as /Asiatic 1 snakebite death for every 2 HIV/AIDS water snake (Xenochrophis piscator) are deaths. This figure was more than 20 common and may cause confusion among times higher than Government of India’s medical staff and to inappropriate

Epidemiology of snakebite 83 in South-East Asia Region countries antivenom treatment. There is variation (Trimeresurus) albolabris, Bungarus in the pattern of syndromes across India, candidus (Kuch and Mebs 2007), spitting with predominance of haemotoxic viper cobras (Naja sumatrana and N. sputatrix), bites in and neurotoxic elapid Calloselasma rhodostoma (Java, Madura), bites in north India. Syndrome-species Daboia siamensis (East Java, , correlation studies in Tamil Nadu suggest Flores and Lomblen) and death adders the validity of the main syndromes in (Acanthophis spp.)(West Irian). The identifying the four main venomous snakes national antivenom producer BioFarma in this geographical region: haemotoxicity manufactures a trivalent antivenom without acute kidney injury (Echis against Naja sputatrix, Bungarus fasciatus carinatus); haemotoxicity and neurotoxicity and Calloselasma rhodostoma. No with or without renal failure (Daboia cases of B. fasciatus bites are known russelii); neurotoxicity with local swelling but deaths from B. candidus (Java), D. (Naja naja); and neurotoxicity without local siamensis (Java, Flores, Komodo) and swelling (Bungarus caeruleus). Acanthophis (West Irian) have been reported.

Cat 1: Elapidae: Bungarus Sumatra: in Bengkulu, 2-4 case of caeruleus; Naja kaouthia (east), Naja snakebite /week; Java (West): in naja (throughout); Semarang 1-3 case/week, in Serang, 5-8 Viperidae: Daboia russelii; Echis case /week, in Madiun 1-3 case/week, in carinatus; Hypnale hypnale (south-west) Jogjarkarta 5-6 case/week; Java East: in Surabaya and Sidoarjo 2-5 case/week, Cat 2: Elapidae: Bungarus in Bondowoso, 148 cases of snakebite fasciatus, Bungarus niger, Bungarus were treated between March 2015 and sindanus, Bungarus walli; Naja May 2016 (15 months): Trimeresurus oxiana (north west), Naja sagittifera (T.) insularis - 85 cases, Bungarus sp – 5, (); Ophiophagus Naja sp -15, Calleselasma rhodostoma – hannah (south, north-east, 2, non-venomous snakes - 5, unidentified Andaman Islands); snakes – 36; : 5-8 case/week; Viperidae: Trimeresurus (T.) East Kalimantan, Borneo: in Samarinda albolabris (northeast); Trimeresurus 1-4 case/week; Sulawesi: in Palu 1-2 (T.) erythrurus (northeast); case/week; Weta: 5-8 case/week; West Trimeresurus (T.) purpureomaculatus Papua: in Timika 1-3 case/week (Dr Tri (east); Trimeresurus Maharani, personal communication). (Craspedocephalus) malabaricus (south-west), Trimeresurus Indonesia (Sumatra, Java, Borneo, (Craspedocephalus) gramineus (south Sulawesi & but India, Andaman & ), West of Wallace’s line i.e. excluding West Macrovipera lebetina (north) Papua and Maluku Islands):

Indonesia: Although fewer than 20 Cat 1: Elapidae: Bungarus snakebite deaths are registered each year candidus (Sumatra, Java, east to in this vast archipelago of more than ); Naja sputatrix (Java & Lesser 18 000 islands, several thousand deaths Sunda Islands), Naja sumatrana are suspected to occur. Species responsible (Sumatra & Borneo); for most bites include Trimeresurus

84 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES and is now the 12th leading cause of Viperidae: Calloselasma rhodostoma death in this country. In 1991, there were (Java, Madura); Trimeresurus (T.) 14 000 bites with 1000 deaths and in albolabris (Java, Sumatra, Borneo); 1997, 8000 bites with 500 deaths. From Daboia siamensis (formerly D. s. 2005 until 2008, 8994-11172 bites were limitis and D.s . sublimitis) reported annually with 748-794 deaths. In 2012, there were 13 867 snakebites in Cat 2: Elapidae: Bungarus the whole country with 285 deaths (case- fasciatus, Bungarus flaviceps fatality 2.06%). In 2014, there were 15 (Sumatra & Borneo); Calliophis 080 bites with 305 deaths (case-fatality bivirgatus; Ophiophagus hannah 2.02%). Russell’s vipers (Daboia siamensis) (Sumatra, Borneo & Java); cause 90% of bites. Other important Viperidae: Trimeresurus (T.) insularis species are cobras (Naja kaouthia and N. (Java, Bali, Komodo, Wetar, Bangka, mandalayensis), kraits (Bungarus spp.) Sumatra, Sulawesi), Trimeresurus (T.) and green pit vipers [Trimeresurus (T.) purpureomaculatus (Sumatra) erythrurus]. In the recent past, antivenom has been imported from Thailand and India to supplement national production. Indonesia (East of Wallace’s line, i.e. West However, the latest annual production by Papua and Maluku): Myanmar Pharmaceutical Factory (Insein) is 73 000 vials of Russell’s viper and 7000 vials of Cobra antivenom, with a predicted Cat 1: Elapidae: Acanthophis production of 100 000 vials of antivenom laevis in 2016-2017 financial year that will fulfil national requirements. Cat 2: Elapidae: Acanthophis rugosus; Micropechis ikaheka; Oxyuranus scutellatus; Pseudechis Cat 1: Elapidae: Bungarus papuanus, Pseudechis rossignolii; magnimaculatus, Bungarus Pseudonaja textilis multicinctus; Naja kaouthia, Naja mandalayensis; Viperidae: Trimeresurus (T.) Maldives: Only one species of sea snake albolabris, Trimeresurus (T.) (Pelamis platurus) and two species of erythrurus; Daboia siamensis harmless land snakes (Lycodon aulicus or L. capucinus and brahminus) Cat 2: Elapidae: Bungarus occur. There have been no reports of bites. candidus; Ophiophagus hannah; A living specimen of Naja kaouthia was Viperidae: Calloselasma found in the wild. It had presumably been rhodostoma (southern imported in cargo from South Asia. No Peninsula); Trimeresurus (T.) recent data on bites. purpureomaculatus; , Protobothrops kaulbacki, Myanmar: In the 1930s the annual Protobothrops mucrosquamatus snakebite mortality reported in Burma exceeded 2000 (15.4/100 000/year). Thirty years later it was still estimated to exceed Nepal: Sixteen species of known or 1000 (3.3/100 000/year). Russell’s viper potential medical importance occur in (Daboia siamensis) bite was once the 5th Nepal (Sharma et al, 2013). The highest

Epidemiology of snakebite 85 in South-East Asia Region countries According to the Epidemiology Unit, Ministry fasciatus; Bungarus lividus; Bungarus walli; Ophiophagus of Health, reported snakebite numbers hannah; Hemibungarus increased from 12 175 per year in 1991 to (Sinomicrurus) macclellandii Viperidae: Trimeresurus (T.) peak at 37 244 in 2002 and 36 861 in 2005. septentrionalis; Cryptelytrops Trimeresurus (T.) albolabris; Trimeresurus (T.) erythrurus; recorded focal incidence, for Nepal or Trimeresurus (Crapedocephalus) for the whole world, was 162 snakebite gramineus; ; deaths/100 000/year, determined in the Ovophis monticola; Himalayophis Eastern Terai (Sharma et al., 2004). In this tibetanus; Protobothrops jerdonii; study, only 20% of the deaths occurred Trimeresurus (Viridovipera) in hospitals. Increased risk of fatality was stejnegeri; Trimeresurus associated with being bitten inside the (Viridovipera) yunnanensis house while resting between 2400 and 0060 hr, suggesting bites by the common krait (Bungarus caeruleus) (see below). Sri Lanka: According to the Other risk factors were an initial visit to a Epidemiology Unit, Ministry of Health, traditional healer and delayed transport reported snakebite numbers increased to hospital. Medically important species from 12 175 per year in 1991 to peak include Naja naja, Bungarus caeruleus, B. at 37 244 in 2002 and 36 861 in 2005. walli and Daboia russelii. In the Kathmandu Fatalities peaked at 194 in 2000 and valley and foothills of the Himalaya, there were 134 in 2005. There are Ovophis monticola and Trimeresurus pit- currently 30 000 – 35 000 bites and vipers cause some bites. Russell’s viper (D. 100-150 deaths each year. In hospitals, russelii) causes bites in a few parts of the case fatality decreased from 3.5% in Terai (e.g. Nawalparasi). In the country 1985 to 0.2% in 2006. However, these as a whole, 1000 bites and 200 deaths data are based on hospital returns which have been estimated but one survey are likely to miss at least 5% of deaths. suggested 20 000 bites and 1000 deaths/ Comparison of hospital data with death year (Bhetwal et al., 1998). In 2000, the certifications in Monaragala District Ministry of Health reported 480 bites with during a 5-year period (1999-2003) 22 deaths, while 4078 bites with 81 deaths revealed a 63% underestimate by hospital were recorded at 10 hospitals in eastern records of the true number of snakebite Nepal. The case-fatality varied from 3 to deaths ( et al., 2006), partly explained 58% in different hospitals (Sharma, 2003). by the fact that 36% of snakebite victims did not seek or achieve hospital treatment. In district, snakebite Cat 1: Elapidae: Bungarus fatality based on death certification caeruleus, Bungarus niger; was 2/100 000/year during the period Naja naja; Naja kaouthia 1967-1987, amounting to about 0.5% Viperidae: Daboia russelii of all deaths. Bites are caused by Daboia russelii, (30%), hump-nosed viper Cat 2: Elapidae: Elapidae: (Hypnale hypnale) (22%), Naja naja (17%) Bungarus bungaroides, Bungarus and kraits (mainly Bungarus caeruleus but a few B. ceylonicus ) (15%).

86 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES A recent community based, countrywide survey of snakebite included nearly 1% of Cat 1: Elapidae: Bungarus the country’s population. The incidence candidus; Naja kaouthia, Naja of bites, envenoming and mortality from siamensis; Viperidae: Calloselasma snakebite was found to be 398 (95% rhodostoma; Trimeresurus (T.) CI: 356–441), 151 (130–173) and 2.3 albolabris; Daboia siamensis (0.2– 4.4)/100 000/year, respectively. This Cat 2: Elapidae: Bungarus amounts to more than 80 000 bites, 30 fasciatus, Bungarus flaviceps; Naja 000 envenomings and 400 deaths in the sumatrana; Ophiophagus hannah; country each year (Ediriweera et al, 2016). Viperidae: Trimeresurus (T.) macrops, Trimeresurus (T. ) purpureomaculatus

Cat 1: Elapidae: Bungarus caeruleus; Naja naja; Viperidae: Timor-Leste: the white-lipped island viper Daboia russelii; Hypnale hypnale Trimeresurus (T.) insularis is very common on the main island of Timor, on the small Cat 2: Elapidae: Bungarus Ataúro Island to the north and on at least ceylonicus; Viperidae: Echis 18 other islands in Indonesia. On Timor carinatus; , Hypnale L’Este, it does cause bites including a few walli; Trimeresurus trigonocephalus fatalities. The spitting cobra (Naja sputatrix) is still unconfirmed but suspected and ophthalmic injuries from spitting have been Thailand: Improved surveillance rumoured (http://www.markoshea.info/ explained the reporting of increasing timor.php) No recent data on bites. numbers of snakebite cases from an average of 2316/year in the 1950s to 9071 (14.5/100 000) in 2002 and Cat 1: Viperidae: Trimeresurus (T.) 8299 (13.25/100 000) in 2006. Cases insularis have subsequently declined from 7835 (12.35/100 000) in 2008 to 5077 (7.9/100 Cat 2: Elapidae: Naja sputatrix 000) in 2012, 1962 (3.06/100 000) in (unconfirmed) 2013, 1219 (1.88/100 000) in 2014 and 457 (0.7/100 000) in 2015. Mortality has declined from an average of 178/year Summary: There is great diversity in the 1950s to fewer than 2/year since of venomous snake species in 2008. Over the last 5 years, both incidence the Region. There are in excess and case fatality have declined to 500– of one million envenomings 5000 bites/year (1-10/100 000/year) with and 75 000 deaths/year in the an admirably low case fatality less than Region. Important species 0.05%. Calloselasma rhodostoma causes include Naja naja, N. kaouthia, 38% of attributable bites, Trimeresurus N. oxiana, Bungarus caeruleus, (T.) albolabris and T. (T). macrops 30 %, B. multicinctus, Daboia russelii, Naja kaouthia and N. siamensis 23% and D. siamensis, Echis carinatus, Daboia siamensis 2%. However, Calloselasma rhodostoma, Bungarus candidus causes as many Hypnale hypnale, Trimeresurus fatalities as the far better recognized (T.) albolabris and Trimeresurus Calloselasma rhodostoma) (Looareesuwan (Craspedocephalus) gramineus. (O) et al., 1988).

Epidemiology of snakebite 87 in South-East Asia Region countries 88 Clinical effects of snakebite

Clinical effects of snakebite 89 90 5 Clinical effects of snakebite

Essentials: usually painless), local swelling spreading In patients with suspected snakebite there proximally, tender, painful swelling of may be 1-Puncture mark(s) only, caused regional lymph nodes draining bite by “dry bite” from venomous snake, bite site. Other signs: fang mark, persistent by non-venomous snake, bite/scratch by local bleeding, bruising, lymphangitis, another (, fish, rodent, spider (swelling, redness, heat), etc.), or puncture by sharp vegetation; blistering (blebs, bullae, vesicles), , 2-Local pain/swelling at bite site that may abscess formation, necrosis. be transient, persistent or complicated by necrosis or infection leading to permanent Systemic envenoming: nausea, , disability; 3-Local and/or systemic malaise, abdominal pain, weakness, envenoming affecting organs and tissues drowsiness, prostration. distant from bite site that may be transient, persistent, life-threatening or permanently Cardiovascular (Viperidae): visual debilitating; 4-Signs of extreme anxiety disturbances, dizziness, faintness, collapse, prompted by the frightening experience: shock, hypotension, cardiac arrhythmias, hyperventilation, acroparaesthesiae, tetany, myocardial damage. Generalized increase dizziness/syncope, vasovagal shock with in capillary permeability: facial, periorbital, profound bradycardia, diarrhoea and conjunctival oedema (chemosis), bilateral vomiting, agitation, irrational behaviour, parotid enlargement, pleural and hypertension, tachycardia, sweating, pericardial effusions, pulmonary oedema, trembling that may mislead medical massive albuminuria, haemoconcentration. staff and lead to persistent psychological Bleeding and clotting disorders (Viperidae): morbidity; 5-Effects of first-aid and local traumatic bleeding from recent and other pre-hospital treatments such as partly-healed and venepuncture pain, swelling and congestion from tight sites; spontaneous systemic bleeding tourniquet and effects of herbal and other (gums, epistaxis, haematemesis, traditional remedies. meningism from subarachnoid haemorrhage, lateralising signs and/ Summary of symptoms and signs or coma from cerebral haemorrhage/ General: and foreboding are very thrombosis), haemoptysis, haematemesis, common rectal bleeding or melaena, haematuria, vaginal bleeding, subconjunctival Local envenoming: increasing local haemorrhages, skin petechiae, purpura, pain at the site of the bite (krait bites discoid haemorrhages, ecchymoses.

Clinical effects of snakebite 91 Neurological (Elapidae, Viperidae eg SYNDROME 4: Paralysis with minimal Russell’s viper D. russelii, Gloydius or no local envenoming: species): bilateral ptosis, external Bitten on land while sleeping on the ophthalmoplegia, descending paralysis ground with/without abdominal pain progressing to generalized flaccid = krait paralysis. Generalized rhabdomyolysis: muscles stiff, tender, painful on passive Bitten in the sea, estuary and some stretching, trismus, dark brown urine. freshwater lakes = sea snake Acute kidney injury: loin (lower back) pain, haematuria, haemoglobinuria, Bitten in Indonesia Maluku or West myoglobinuria, oliguria/anuria, uraemia Papua with/without bleeding/clotting (acidotic breathing, hiccups, nausea, disturbance = Australasian elapid pleuritic chest pain, encephalopathy). SYNDROME 5: Paralysis with dark Acute pituitary insufficiency (Russell’s brown urine and acute kidney injury: viper): acute - shock, hypoglycaemia; Bitten on land (with bleeding/clotting chronic - weakness, loss of secondary disturbance) = Russell’s viper, Sri Lanka sexual hair, loss of libido, amenorrhoea, or South India testicular atrophy, hypothyroidism etc. Bitten on land while sleeping indoors Clinical syndromes of snakebite in South- = krait (B. niger, B. candidus, B. East Asia: although there may be overlap multicinctus), Bangladesh, Thailand of clinical features caused by venoms of different species of snake, especially Bitten in the sea, estuary and some as knowledge advances, a “syndromic freshwater lakes (no bleeding/clotting approach” is useful, especially when the disturbances) = sea snake snake has not been identified and only monospecific antivenoms are available. Long term complications: at the bite site - tissue loss, , SYNDROME 1: Local envenoming chronic ulceration (risk of malignant (swelling etc) with bleeding/clotting change), infection, osteomyelitis, disturbances = Viperidae (all species) arthritis, arthrodesis, contracture and hypertrophic or keloid scars SYNDROME 2: Local envenoming cause permanent physical disability. (swelling etc) with bleeding/clotting Chronic kidney disease, chronic disturbances, shock or acute kidney panhypopituitarism, chronic injury = Russell’s viper; with conjunctival neurological deficits after strokes. oedema (chemosis) and acute pituitary Chronic psychological morbidity insufficiency = Russell’s viper, Myanmar (depression, anxiety, impaired function, and South India with bilateral ptosis, -traumatic stress disorder, external ophthalmoplegia, facial paralysis unexplained residual physical disability). etc. and dark brown urine = Russell’s viper, Sri Lanka and South India Cobra-spit ophthalmia: there is immediate intense pain, profuse SYNDROME 3: Local envenoming watering with whitish discharge, (swelling etc.) with paralysis = cobra or congested conjunctivae and spasm and king cobra swelling of eyelids.

92 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Victims of snakebite may suffer any or all snakes in which no venom was of the following: injected. Patients who develop no 1. No physical effects other than the fang/ or negligible local swelling and no puncture. This is explained by systemic envenoming are identified bites by non-venomous snakes, animals by clinical evaluation. They can be other than snakes (e.g. lizards, fish, managed at the most peripheral rodents, spiders see Fig 53), by being level of the health service without impaled on a thorn or other sharp referral to higher centres (Harris et object, or “dry bites” by venomous al., 2010).

[a] [b]

[c] [d]

[e] [f]

Figures 53: marks: (a) venomous European adder (Vipera berus); (b) venomous Western Russell’s viper (Daboia russelii) (fatal case); (c) non-venomous back-fanged rice paddy or plumbeous water snake (Enhydris plumbea); (d) rat; (e) Brazilian wandering spider (Phoneutria nigriventer); (f) (Siluridae) (Copyright DA Warrell)

Clinical effects of snakebite 93 2. Local envenoming confined to the part slowing of the . Others may become of the body that has been bitten. These highly agitated and irrational and may effects may be transient, resolving in develop a wide range of misleading hours or a few days; persistent for symptoms. Blood pressure and pulse rate weeks; or debilitating, sometimes may increase and there may be sweating permanently, due to locally necrotic and trembling. Others may vomit and have effects of venom and complicating diarrhoea. infections. Another source of symptoms and signs 3. Systemic envenoming involving organs not caused by snake venom is first aid and and tissues distant from the part of traditional treatments (Harris et al., 2010). the body that has been bitten. These Constricting bands or tourniquets may effects may be transient, persistent, cause pain, swelling and congestion that life threatening and debilitating, suggest local envenoming. Ingested herbal sometimes permanently. remedies may cause vomiting. Instillation of irritant plant juices into the eyes may 4. Effects of anxiety prompted by the cause conjunctivitis. Forcible insufflation frightening experience of being bitten of oils into the respiratory tract may lead (real or imagined) and by exaggerated to aspiration pneumonia, bronchospasm, beliefs about the potency and speed ruptured ear drums and pneumothorax. of action of snake venoms. These Incisions, cauterisation, immersion in symptoms can be misleading for scalding liquid and heating over a fire can medical personnel. They may persist result in devastating injuries. causing psychological morbidity (Williams et al., 2011). 5.2 When venom has been injected 5. Effects of first-aid and other pre- 5.2.1 Early symptoms and signs hospital treatments that may cause Following the immediate pain of misleading clinical features. These may mechanical penetration of the skin by the be debilitating and rarely even life- snake’s fangs, and the fear associated threatening. (Harris et al., 2010) with such a terrifying experience as being bitten by a snake, there may be increasing 5.1 When venom has not local pain (burning, bursting, throbbing) been injected at the site of the bite, local swelling that Some people who are bitten by snakes gradually extends proximally up the bitten or suspect or imagine that they have limb and tender, painful enlargement of been bitten, may develop quite striking the regional lymph nodes draining the symptoms and signs, even when no site of the bite (in the groin - femoral or venom has been injected. This results inguinal, following bites in the lower limb; from an understandable fear, and at the elbow – epitrochlear - or in the foreboding about the consequences of a axilla following bites in the upper limb). real venomous bite. Anxious people may However, bites by kraits, sea snakes and over breathe so that they develop pins and Philippine cobras may be virtually painless needles (paraesthesiae) of the extremities, and may cause negligible local swelling. stiffness or tetany of their hands and Someone who is sleeping may not even feet and dizziness. Others may develop wake up when bitten by a krait and there vasovagal shock after the bite or suspected may be no detectable fang marks or signs bite - faintness and collapse with profound of local envenoming.

94 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES 5.2.2 Clinical patterns of envenoming which may suggest which species was by snakes in South East Asia responsible. Symptoms and signs vary according to the species of snake responsible for the 5.2.3 Local symptoms and signs in the bite and the amount of venom injected. bitten part Sometimes the identity of the biting • fang marks (Fig 54a) snake can be confirmed by examining the dead snake or an image of the snake • local pain sent by mobile ‘phone; it may be strongly • local bleeding (Fig 54b) suspected from the patient’s description or the circumstances of the bite or from • bruising (Fig 54c) knowledge of the clinical effects of the • spreading local swelling (Fig 55) venom of that species. This information will enable the doctor to choose an • lymphangitis appropriate antivenom, anticipate the • enlargement likely complications and therefore take appropriate action. If the biting species • inflammation (swelling, redness, heat) is unknown, the patient should be • blistering (Fig 54c, 54d, 54e) observed closely to allow recognition of • local infection, abscess formation the emerging pattern of symptoms, signs (Fig 56) and results of laboratory tests (“the clinical syndrome”), together with other evidence, • necrosis (Fig 57)

[a] [b]

[d] [e] [c]

Figures 54: Local signs of envenoming: (a) Fang marks 2.5 cm apart inflicted by a large Russell’s viper in Sri Lanka; (b) Persistent local bleeding from fang marks 40 minutes after a bite by a Malayan pit viper; (c) Swelling, blistering and bruising following a bite by a Malayan pit viper; (d) Blistering with early necrosis at the site of a monocellate cobra bite; (e) blistering and early tissue necrosis following a bite by an Indo-Chinese spitting cobra (Naja siamensis) in south Viet Nam. (Copyright DA Warrell)

Clinical effects of snakebite 95 Figure 55: Local swelling after a saw-scaled viper () bite on the hand rapidly extending proximally (Copyright DA Warrell)

[a]

Figure 56: Local abscess at the site of a 5.2.4 Generalized (systemic) Western Russell’s viper (Daboia russelii) bite in symptoms and signs Sri Lanka (Copyright DA Warrell) General Fear, anxiety, nausea, vomiting, malaise, abdominal pain, weakness, drowsiness, prostration.

Cardiovascular (Viperidae) Visual disturbances, dizziness, faintness, collapse, shock, hypotension, cardiac arrhythmias, myocardial damage (reduced ejection fraction).

Generalized increase in capillary permeability (“capillary leak syndrome”) (Russell’s vipers: D. siamensis in Myanmar (Myint- Lwin et al., 1985) and D. russelii in India; Facial and conjunctival oedema (chemosis) (Fig 58), bilateral parotid [b] enlargement (Fig 59 a, b) (Chakraborty and Bhattachcharjee, 2010; Deepak et al., Figures 57: Local necrosis that required 2013), pleural and pericardial effusions, surgical debridement: (a) after Malayan pit viper (Calloselasma rhodostoma) bite in Thailand; pulmonary oedema, massive albuminuria, (b) after spectacled cobra (Naja naja) bite in Sri haemoconcentration. Lanka (Copyright DA Warrell)

96 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Figure 58 Bilateral conjunctival oedema (chemosis) after bite of Eastern Russel’s viper (Daboia siamensis) in Myanmar (Copyright DA Warrell)

Bleeding and clotting disorders (Viperidae) - traumatic bleeding from recent wounds (including prolonged bleeding from the fang marks (Fig 54b, venipunctures etc) and from old partly-healed wounds - spontaneous systemic bleeding - from gums (Fig 60a), epistaxis, bleeding into the tears, intracranial haemorrhage (meningism from subarachnoid haemorrhage - Fig 60b, lateralising signs and/or coma from cerebral haemorrhage – Fig 61), haemoptysis (Fig 62), haematemesis), rectal bleeding or melaena, haematuria, vaginal bleeding, bleeding into the mucosae (eg conjunctivae [a] [b] – Fig 63), skin (petechiae, purpura, discoid Figure 59 a, b: Bilateral parotid gland enlargement (“viper’s head” appearance) haemorrhages – Fig 64 and ecchymoses. after bite of Western Russel’s viper (Daboia russelii) in Kerala, India (Copyright Dr Joseph K Joseph)

[A] [b]

Figures 60: Spontaneous systemic bleeding: (a) from gingival sulci in a patient [a] bitten by a Malayan pit viper; (b) neck stiffness (meningism) from sub-arachnoid haemorrhage after a saw-scaled viper bite (Copyright DA Warrell)

Clinical effects of snakebite 97 [a] [b] [c]

Figures 61: Strokes after Russell’s viper bites: (a) fatal cerebral haemorrhage in Myanmar (Copyright Dr U Hla Mon); (b) intra cerebral haemorrhages in Maharashtra, India; (c) ischaemic/thrombotic stroke in Maharashtra, India (b, c, Copyright Dr Suvarna Patil)

Figure 62: Haemoptysis from a Figure 63: Subconjunctival haemorrhages in a patient bitten by a Burmese Russell’s viper tuberculous cavity in a patient (Copyright DA Warrell) bitten by a Malayan pit viper (Copyright DA Warrell)

Figure 64: Cutaneous signs: (a) lymphangitic lines extending towards regional lymph nodes (b) Cutaneous discoid haemorrhages in a patient bitten by a Malayan pit viper in Viet Nam (Copyright DA Warrell)

98 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Cerebral arterial thrombosis (Russell’s Neurological (Elapidae, Viperidae vipers Daboia russelii and D. siamensis) eg Russell’s viper D. russelii, Thrombotic strokes, confirmed by Gloydius species) angiography or imaging, are increasingly Drowsiness, paraesthesiae, recognized after envenoming by D. abnormalities of taste and smell, russelii in India (Fig 61c), Sri Lanka “heavy” eyelids, ptosis (Fig 65a,b), (Gawarammana et al., 2009) and . external ophthalmoplegia (Fig 66),

[a] [b]

Figures 65a,b: Bilateral ptosis: (a) in a patient bitten by a common krait in Sri Lanka; (b) in a patient bitten by a Russell’s viper in Sri Lankan (Copyright DA Warrell)

Figure 66: External ophthalmoplegia in a patient bitten by a Russell’s viper in Sri Lanka. The patient is attempting to look to his right. The eyes must be held open becauseof the bilateral ptosis (Copyright DA Warrell)

Clinical effects of snakebite 99 paralysis of facial muscles and other niger and B. candidus, western muscles innervated by the cranial , Russell’s viper Daboia russelii) nasal voice or aphonia, regurgitation through the nose, difficulty in swallowing Generalized pain, stiffness and secretions, respiratory and generalized tenderness of muscles, pain on flaccid paralysis. passive stretching (Fig 71b) trismus, myoglobinuria (Fig 67, 71c), Skeletal muscle breakdown (sea hyperkalaemia, cardiac arrest, acute snakes, some krait species – Bungarus kidney injury.

Figure 67: Patient bitten by a Russell’s viper in Sri Lanka. She began to pass dark brown urine containing myoglobin and haemoglobin 8 hours after the bite. (Copyright DA Warrell)

Renal (Viperidae, sea snakes) Endocrine (acute pituitary/adrenal Loin (lower back) pain (Tin-Nu-Swe et al. insufficiency from infarction of the anterior 1993), haematuria, haemoglobinuria, pituitary – (Fig 68 a,b) (Russell’s viper in myoglobinuria, oliguria/anuria, symptoms Myanmar and several parts of India) (Eapen at and signs of acute kidney injury/ uraemia al., 1976; Tun-Pe et al., 1987; Bandyopadhyay (acidotic breathing, hiccups, nausea, et al 2012; Chatterjee et al., 2008; Golay et pleuritic chest pain etc., see below). al., 2014; Murthy et al., 2002)

100 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES [a] [b]

Figures 68: Haemorrhagic infarction of the anterior pituitary resulting in Sheehan’s-like syndrome (pan-hypopituitarism) after Russell’s viper bite in Myanmar: (a) appearances at the base of the brain at autopsy in a patient who died acutely after the bite (Copyright Dr U Hla Mon); (b) Patient presenting with symptoms and signs of panhypopituitarism three years after severe envenoming by Russell’s viper. There is loss of secondary sexual hair and testicular atrophy (Copyright DA Warrell)

Acute phase: shock, hypoglycaemia example, some elapid venoms, such as Chronic phase (months to years after the those of Asian cobras, can cause severe bite): weakness, loss of secondary sexual local envenoming (Fig 54d, 54e, 57b, hair, loss of libido, amenorrhoea, testicular 66), formerly thought to be an effect only atrophy, hypothyroidism etc (Fig 68b). of viper venoms. In Sri Lanka and India, Russell’s viper venom causes paralytic Hyponatraemia has been observed in signs (ptosis etc.) (Figs 65b, 66, 67), victims of krait bites in the area of Hanoi suggesting elapid neurotoxicity, and and around Ho Chi Minh City in Viet muscle and dark brown urine (Fig Nam (Bungarus nr. multicinctus/candidus) 67), suggesting sea-snake rhabdomyolysis. (Hung and Höjer 2009; Kiem-Xuan-Trinh Envenoming by the greater black et al., 2010; Höjer et al., 2010), implying krait (B. niger) can cause generalized natriuretic hormone like activity in the rhabdomyolysis leading to acute kidney venom. injury (Faiz et al., 2010). Although there may be considerable overlap of clinical 5.3 Clinical syndromes of features caused by venoms of different snakebite in South-East Asia species of snake, a “syndromic approach” Limitations of syndromic approach: may still be useful, especially when the The more carefully the clinical effects snake has not been identified and only of snakebites are studied, the more it monospecific antivenoms are available (see is realised that the range of activities Annexes 1 and 2) (Pathmeswaran et al, of a particular venom is very wide. For 2006; Ariaratnam et al., 2009).

Clinical effects of snakebite 101 SYNDROME 1: Local envenoming SYNDROME 5: Paralysis with dark (swelling etc) with bleeding/clotting brown urine and acute kidney injury: disturbances = Viperidae (all species) Bitten on land (with bleeding/clotting SYNDROME 2: Local envenoming disturbance) = Russell’s viper, Sri (swelling etc) with bleeding/clotting Lanka or South India disturbances, shock or acute kidney injury = Russell’s viper with conjunctival Bitten on land while sleeping indoors = oedema (chemosis) and acute pituitary krait (B. niger, B. candidus, insufficiency = Russell’s viper, B. multicinctus), Bangladesh, Myanmar and South India with ptosis, Thailand external ophthalmoplegia, facial paralysis etc. and dark brown urine = Russell’s Bitten in the sea, estuary and some viper, Sri Lanka and South India freshwater lakes (no bleeding/clotting (?Myanmar) disturbances) = sea-snake

SYNDROME 3: Local envenoming 5.4 Long term complications (swelling etc) with paralysis = cobra or (sequelae) of snakebite king cobra At the site of the bite, loss of tissue may result from sloughing or surgical SYNDROME 4: Paralysis with minimal or débridement of necrotic areas or no local envenoming: amputation: chronic ulceration, infection, Bitten on land while sleeping on the osteomyelitis or arthritis may persist ground with/without abdominal pain causing severe physical disability (Fig = krait 70a). Malignant transformation may occur in skin ulcers after a number of Bitten in the sea, estuary and some years (Marjolin’s ulcer) (Fig 70b). freshwater lakes = sea snake Chronic kidney disease (renal failure) Bitten in Indonesia Maluku or West may occur after bilateral cortical necrosis Papua with/without bleeding/clotting (Russell’s viper and hump-nosed pit viper disturbance = Australasian elapid bites) (Ariaratnam et al., 2008b); and

[a] [b]

Figures 70: Chronic physical handicap resulting from necrotic envenoming by Malayan pit vipers: (a) Deformity and dysfunction after a snakebite and subsequent necrosis of the calf; (b) Squamous cell carcinoma arising at the site of a chronic skin ulcer with osteomyelitis 8 years after the bite (Copyright DA Warrell)

102 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES chronic panhypopituitarism or diabetes ulcer, and persisting lump to . insipidus after Russell’s viper (Daboia (Jayawardene et al., submitted for russelii and D. siamensis) bites in India publication). Unexplained residual (Golay et al., 2014) and Sri Lanka and, symptoms have also been reported most commonly, in Myanmar, following snakebite in Tamil Nadu, India (Fig 68b). Chronic neurological deficit is (Vaiyapuri et al, 2013). seen in patients who survive intracranial haemorrhages and thromboses 5.5 Symptoms and signs (Viperidae). of sea-snake envenoming (Reid, 1979; Warrell, 1994) Abnormalities of electrophysiological Envenoming by sea snakes (Hydrophiinae) tests can persist for over 12 months and sea kraits (Laticaudinae): the bite is following elapid bites in Sri Lanka (Bell et usually painless and may not be noticed al, 2010). by the wader or swimmer. Fangs and other teeth may be left in the wound. Delayed psychological morbidity has been reported one to four years after snakebite envenoming in Sri Lanka. Depression and anxiety, impaired functioning, post- traumatic stress disorder and unexplained residual physical disability were reported (Williams et al, 2011). Chronic musculoskeletal disabilities have been reported following snake envenoming in Sri Lanka. The disabilities involved mostly the lower limbs. They ranged from swelling, muscle wasting, stiff joints, reduced muscle power, impaired balance, fixed deformities, chronic non-healing [c]

[a] [b]

Figures 71: Sea-snake bite in North-west Malaysia: (a) Ptosis, facial paralysis and trismus; (b) Generalised myalgia making passive movement of the limbs extremely painful; (c) myoglobinuria (Copyright the late H Alistair Reid)

Clinical effects of snakebite 103 conscious until the respiratory muscles are If the “spat” venom enters the eyes, sufficiently affected to cause respiratory failure. Myoglobinaemia and myoglobinuria there is immediate and persistent develop 3–8 hours after the bite (Fig 71c). intense burning, stinging pain, followed These are suspected when the serum/ plasma appears brownish and the urine by profuse watering of the eyes with dark reddish brown (‘Coca-Cola-coloured’). production of whitish discharge, congested Bedside ‘sticks’ tests will appear positive for haemoglobin/blood in urine containing conjunctivae, spasm and swelling of the myoglobin. Myoglobin and potassium eyelids, photophobia, clouding of vision released from damaged skeletal muscles and temporary blindness. may contribute to acute kidney injury, while hyperkalaemia developing within 6–12 hours of the bite may precipitate cardiac arrest. There is minimal or no local swelling and involvement of local lymph nodes is 5.6 Symptoms and signs of unusual. Generalized rhabdomyolysis is cobra-spit ophthalmia the dominant effect of envenoming by (eye injuries from spitting cobras) these snakes although patients without (Fig 72) this feature have been described. Early If the “spat” venom enters the eyes, there is symptoms include headache, a thick immediate and persistent intense burning, feeling of the tongue, thirst, sweating stinging pain, followed by profuse watering and vomiting. Generalized aching, of the eyes with production of whitish stiffness and tenderness of the muscles discharge, congested conjunctivae, spasm becomes noticeable between 30 minutes and swelling of the eyelids, photophobia, and 3½ hours after the bite. Trismus is clouding of vision and temporary blindness. common (Fig 71a). Passive stretching of Corneal ulceration, permanent corneal the muscles is painful (Fig 71b). Later, scarring and secondary endophthalmitis there is progressive flaccid paralysis are recognized complications of African starting with ptosis, as in other neurotoxic spitting cobra venom but have not been envenomings. The patient remains described in Asia.

Figure 72: Bilateral conjunctivitis in a patient who had venom spat into both eyes by an Indo-Chinese spitting cobra (Naja siamensis) (Copyright DA Warrell)

104 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Management of snakebites in South-East Asia

Management of snakebites 105 in South-East Asia 106 6 Management of snakebites in South-East Asia

Essentials: asphyxiated patients. Clear airway, give First-aid should be carried out immediately oxygen, establish intravenous access, after the bite, by the victim or others monitor vital signs. Beware of removing present. Most traditional methods are tight tourniquets before antivenom and useless and harmful. To prevent deaths resuscitation facilities are available. from respiratory paralysis or shock before victims reach medical care, delay venom Key questions: “Where (in which part of spread with pressure-pad or pressure- your body) were you bitten? Point to the bandage plus immobilization, accelerate place”; “When were you bitten and what transport to hospital (improve ambulance were you doing then?”; “Where is the services), and train accompanying medical snake that bit you?” or “What did it look workers in airway management, assisted like; did anyone take a picture?”; “How ventilation and resuscitation. The snake are you feeling now?” is valuable evidence, but should not be pursued, killed or handled. Close-up Examination of the bitten part: extent mobile ‘phone images ’ are useful. of tenderness/swelling, lymph nodes draining bitten limb, early signs of Recommended first-aid: reassurance, necrosis (blistering, demarcated altered immobilization of the whole patient, pigmentation, putrefaction odour. especially their bitten limb, accelerated General: blood pressure (postural drop transport to medical care (summoned by indicates hypovolaemia), gingival sulci, emergency telephone helpline) ideally in nose, skin and mucosae for evidence recovery position. Unless neurotoxic elapid of bleeding, chemosis, abdominal bite can be excluded, pressure-pad tenderness, loin pain and tenderness, (simpler, more practicable than pressure- meningism, lateralising neurological bandage immobilization). Never use, signs (asymmetrical ), impaired recommend or condone tight (arterial) consciousness, bilateral ptosis, diplopia, tourniquets. external ophthalmoplegia, mouth opening/ closing, trismus, tongue protrusion, facial Medical treatment in dispensary or hospital muscles, gag reflex neck flexors “broken Rapid clinical assessment accompanies neck sign”, swallowing, “paradoxical urgent resuscitation of shocked or respiration”, fasciculations or myokymia,

Management of snakebites 107 in South-East Asia measure ventilatory capacity. If adequately measuring INR and D-dimer unreliable in ventilated, totally paralysed patient are snakebite victims. fully conscious and can communicate by flexing a digit. Conventional tests of brain Other laboratory tests: haemoglobin death misleading. Generalised tender, concentration/haematocrit, painful muscles and dark brown urine thrombocytopenia, neutrophil leucocytosis, suggest rhabdomyolysis. Pregnant women: fragmented red cells (“helmet cell”, suspect antepartum or postpartum schistocytes) signifying microangiopathic haemorrhage, vaginal bleeding, premature haemolysis. Observe spontaneously labour, fetal distress, intra-uterine fetal sedimented plasma for haemoglobinaemia/ death, abortion/stillbirth. myoglobinaemia.

Species diagnosis: expert identification Biochemical abnormalities: plasma of dead snake or a mobile ‘phone photo creatinine, urea/blood urea and image is useful. Otherwise, infer species potassium concentrations raised in acute from the patient’s description and kidney injury (Russell’s viper, hump-nosed circumstances of bite (e.g. nocturnal bite pit-viper, sea-snake envenoming). Elevated while sleeping on ground suggests krait) aminotransferases and muscle enzymes and clinical syndrome. (creatine kinase, aldolase etc.) indicate local and generalized muscle damage (sea Investigations/laboratory tests: 20 minute snakes, some kraits, some Australasian whole blood clotting test (20WBCT) Elapidae and Russell’s viper bites). is a simple, informative bedside test Hyponatraemia associated with krait bites. requiring only a new, clean, dry, ordinary glass tube, , vial or syringe. Positive Urine examination: dipsticks test for (non-clotting) result indicates severe blood, haemoglobin or myoglobin consumption coagulopathy and need and proteinuria. Microscopy to detect for immediate antivenom treatment. erythrocytes and red cell casts, indicating False positive (non-clotting) 20WBCT glomerular bleeding, eosinophilia results from use of plastic, polystyrene or suggesting acute interstitial nephritis. polypropylene rather than ordinary glass, or glass cleaned with detergent, soap Other investigations: chest radiography or washing fluid that destroy surface- for detecting pulmonary oedema, activation of blood coagulation. If new haemorrhages, infarcts, pleural effusions, glass tubes not available, re-use ordinary secondary bronchopneumonia; ultrasound glass vessels (e.g. bottles), for assessing local envenoming, deep washed with “normal 0.9% saline” for vein thrombosis, pleural and pericardial intravenous infusion, without detergent or effusion and bleeding; echocardiography other cleaning agent, dried in hot air. for myocardial dysfunction; CT and MRI imaging for intracranial and Other more sensitive laboratory tests spinal haemorrhages and infarcts and of blood coagulation: International osteomyelitis at the bite site; ECG for Normalized Ratio (INR) based on arrhythmias, myocardial damage, evidence prothrombin time (PT) (> or =1.2 is of hyperkalaemia. abnormal), activated partial thromboplastin time (aPPT), fibrin(ogen) related Antivenom treatment (fibrin degradation products -FDP) or Antivenom (= antivenin, anti-snakebite D-dimer. Point-of-care (bedside) devices for serum, ASV etc.) is the only specific

108 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES antidote to snake venom. A most important decision in managing A most important decision in managing snakebite victims is whether or not they need antivenom. It is immunoglobulin snakebite victims is whether or not they [usually pepsin-refined F(ab’)2 fragments need antivenom. of whole IgG] purified from plasma of horses or sheep hyperimmunised with venoms of one (to make mono- specific antivenom) or more (to make haemolysis/generalized rhabdomyolysis); poly-specific antivenom) snake species, supporting laboratory evidence. medically the most important species in a Local envenoming: local swelling involving particular geographical area. Paraspecific more than half bitten limb (in absence neutralization of venoms of closely related of tourniquet) within 48 hr of the bite; species is possible but not certain. Indian swelling after bites on digits; rapid “polyvalent anti-snake venom serum” extension of swelling beyond wrist/ankle (ASV) is raised against venoms of their “big within few hours of bites on hand/foot); four” species: spectacled cobra (N. naja); enlarged tender lymph node draining common krait (B. caeruleus), Russell’s viper bitten limb (D. russelii), saw-scaled viper (E. carinatus), but other species, now recognized as Antivenom should be given only being important, are not covered. Thai when benefits exceeds risks. Since it is Red Cross Society manufactures “neuro expensive and in limited supply, it must polyvalent snake antivenin” covering 4 not be used indiscriminately. It should be elapids and “haemato polyvalent snake given as soon as it is indicated and as long antivenin” covering 3 vipers. as anti-haemostatic abnormalities persist, even two weeks after the bite. It is unlikely Design, quantity, quality, stability, safety to prevent/limit local tissue damage and dosage guidelines of antivenoms unless given within a few hours of require review and improvement. the bite.

Antivenom treatment is indicated Antivenom reactions: many patients if/when patients with proven/ develop early (within a few hours) or suspected snakebite develop one late (after 5 days or more) reactions. or more of the following signs. Depending on of antivenom and Systemic envenoming: haemostatic dose, the incidence may be as high as abnormalities [spontaneous systemic 81% (43% severe) of early anaphylactic bleeding, coagulopathy (+ve non-clotting or pyrogenic reactions or as low as 3.5%. 20WBCT, INR >1.2, or prothrombin time IgE-mediated Type I hypersensitivity after >4-5 seconds longer than control), or previous exposure to equine serum is thrombocytopenia; neurotoxicity (bilateral uncommon. ptosis, external ophthalmoplegia, paralysis etc.); cardiovascular abnormalities Early anaphylactic reactions (1 - 180 (hypotension, shock, cardiac arrhythmia, minutes after starting antivenom) can abnormal ECG); Acute kidney injury have all classic features of (oliguria/anuria, rising blood creatinine/ from urticaria to life-threatening shock, urea); haemoglobin-/myoglobin-uria bronchospasm and angio-oedema. Most (dark brown/black urine, +ve urine are attributable to complement activation dipsticks, other evidence of intravascular by IgG aggregates/residual Fc fragments,

Management of snakebites 109 in South-East Asia or stimulation of mast cells/basophils by intramuscular injection of antivenom proteins. 0.1% adrenaline, initial adult dose 0.5 ml/mg (0.01 mg/kg body weight for Pyrogenic (endotoxin) reactions (within 1-2 children). Since severe, life-threatening hours) involve rigors, fever (risk of febrile anaphylaxis can evolve rapidly, adrenaline convulsions in children), vasodilatation, must be available at the bed-side hypotension and a fall in blood pressure. and should be given at the first sign Attributable to pyrogen contamination of anaphylaxis (e.g. when itching, during manufacture. tachycardia, restlessness develop and a few spots of urticaria appear). Repeat Late (serum sickness-type) reactions (1-12, adrenaline every 5-10 minutes if reaction mean 7, days after treatment) involve persists or worsens. Adrenaline safe in fever, nausea, vomiting, diarrhoea, itching, pregnancy. In case of asthmatic symptoms, recurrent urticaria, arthralgia, myalgia, given salbutamol bronchodilator. After lymphadenopathy, periarticular swellings, adrenaline, give intravenous antihistamine mononeuritis multiplex, proteinuria, anti-H1 blocker (e.g. chlorphenamine immune complex nephritis, rarely maleate, adults 10 mg, children 0.2 mg/ encephalopathy. kg intravenously) and hydrocortisone (adults 100 mg, children 2 mg/kg body Prediction: skin and conjunctival weight). Anaphylactic shock unresponsive “hypersensitivity” tests, often to adrenaline is treated by laying recommended in “package inserts” patient supine, legs elevated, and giving predict acquired IgE-mediated Type intravenous volume replacement (0.9% I hypersensitivity to horse/sheep saline, adults 1-2 litres rapidly). Consider proteins, but not large majority of early intravenous adrenaline infusion (adults (anaphylactic) or late (serum sickness type) 1mg/1.0 ml of 0.1% solution in 250 ml antivenom reactions. Their use is strongly IV fluid) infused at 15–60 drops/min discouraged. using micro-dropper burette chamber, or dopamine. Unresponsive bronchospasm Prevention: or angioedema is treated with optimal A powerful, well-designed study in Sri nebulised/inhaled and/or parenteral Lanka showed that adrenaline (0.25 ml/ bronchodilator and oxygen. mg of 0.1% solution subcutaneously) given before antivenom was started Pyrogenic reactions are treated by reduced severe reactions by 43% (95% physical cooling (undressing, tepid CI 25–67) at 1 h and by 38% (95% CI sponging, fanning) and giving antipyretic 26–49) up to and including 48 h after paracetamol. Intravenous fluids should be antivenom administration; hydrocortisone given to correct hypovolaemia. Patients (200 mg intravenously) and promethazine with features of anaphylaxis should be (25 mg intravenously) were ineffective. given adrenaline. Hydrocortisone negated benefit of adrenaline. Dilution and slow infusion After recovery from early reactions, (10-120 minutes) does not alter risk of cautiously resume and complete reactions. administration of the dose of antivenom.

At the earliest sign of early anaphylactic Late (serum sickness) reactions respond antivenom reaction, temporarily suspend to 5-day course of oral antihistamine or, antivenom administration and give failing that, 5-day course of prednisolone.

110 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Supply, selection, storage and shelf-life of Geographical intra-species variation, in antivenom venom composition and antigenicity, explains why antivenoms raised against Polyvalent (polyspecific) antivenoms are venom of a species (e.g. Russell’s viper) from preferred in many countries because one area (e.g. Tamil Nadu, India) may not of problems with specific diagnosis. be effective in patients envenomed by the Antivenom should be given only if its same species elsewhere in its geographical stated range of specificity and paraspecific range (e.g. Kerala, Maharashtra). Regional neutralization includes the species known polyspecific antivenoms may not cover or suspected to have been responsible for all medically important snakes (e.g. N. the bite. Lyophilised antivenoms (shelf life kaouthia, H. hypnale, T. (Craspedocephalus) about 5 years) are stored <25ºC, liquid malabaricus, T (T.) erythrurus in parts of antivenoms (shelf life 2-3 years) at 2-8 India). ºC. Ideally, antivenoms should be used before stated expiry dates, antivenoms Response to antivenom includes rapid retain useful activity for months or even decrease in general malaise (?placebo years after these dates. In patients with effect), cessation of spontaneous systemic severe envenoming, recently expired bleeding (in 15-30 minutes), restoration antivenoms may be considered if there is of blood coagulability (in 3-9 hours), no alternative. normalisation of blood pressure in shocked patients (in 30-60 minutes) and sinus Intravenous administration is mandatory, rhythm, reversal of post-synaptic type either by slow “push” injection (maximum neurotoxicity (after cobra bite) (after 30 2ml/minute) or by intravenous infusion, minutes), cessation of active haemolysis diluted in 5 ml of isotonic fluid/kg and rhabdomyolysis (within a few hours). body weight, over 30-60 minutes. Intramuscularly administered antivenom is After an initial response to antivenom, poorly bioavailable. This route should be signs of systemic envenoming may recur considered only in the absence of anyone within 24-48 hours. Improved perfusion of capable of giving an intravenous injection. the bite site following correction of shock/ hypovolaemia increases venom absorption Initial dose of antivenom: from bite site “depot” and redistribution Guidance on average initial dose of a of venom from tissues to vascular space at particular antivenom, appropriate for a time when therapeutic antivenom has envenoming of different severities, in been eliminated. patients bitten by different species based on clinical trials is rarely available. Usually, After the first dose of antivenom, the dosages quoted on manufacturers’ initial dose should be repeated 6 hours package inserts are based on laboratory later if blood remains incoagulable, or LD50s and ED50s which are 1 hour later if spontaneous systemic unreliable clinically. In practice, choice of bleeding continues, or neurotoxic or initial dose is usually empirical. Regimens cardiovascular signs persist or deteriorate. based on a higher initial (loading) dose are However, further doses of antivenom have more logical than low doses repeated over no proven value in paralysed patients who several days. are being ventilated.

Antivenom failure (ineffectiveness) may be When no appropriate antivenom is due to batch-to-batch variations in potency. available, patients must be treated

Management of snakebites 111 in South-East Asia For acute airway obstruction (e.g. if patient is unresponsive, summon angioedema) perform cricothyroidotomy. assistanceby ‘phone, open and maintain Resuscitation: if patient is unresponsive, airway using “head tilt - chin ” or “jaw summon assistanceby ‘phone, open and maintain airway using “head tilt - chin lift” thrust” manoeuvres to improve air flow or “jaw thrust” manoeuvres to improve air by dislodging tongue and reopening flow by dislodging tongue and reopening upper airway. Remove foreign material upper airway. from upper airway (suction or forceps, not finger) and insert oropharyngeal (Guedel) airway. Administer oxygen by any available conservatively. Respiratory paralysis: means and assess breathing. If breathing try anticholinesterases, but without is adequate, lay victim in recovery position delaying assisted ventilation. Haemostatic (important because of venom-induced abnormalities: rest in bed to avoid trauma, vomiting, bleeding and hypersalivation transfuse cryoprecipitate, fresh frozen with loss of airway-protective reflexes), but plasma, fresh whole blood and platelets. check breathing every 2 minutes. Shock, myocardial damage: correct hypovolaemia and consider vasopressor If breathing is inadequate or not drugs. In hypotension with bradycardia, try discernible, respiratory rate low, atropine. Acute kidney injury: conservative respirations shallow, patient taking agonal treatment or renal replacement therapy. (gasping) breaths, central cyanosis, finger Rhabdomyolysis: correct hypovolaemia oximeter oxygen saturation <90%, end-

with intravenous fluid, acidosis with tidal PCO2 high or increasing - assisted sodium bicarbonate. Severe local ventilation is required. envenoming: surgical intervention, prophylactic broad spectrum antimibiotics. Techniques: If no health facilities are immediately Supportive/ancillary treatment available - Expired Air Resuscitation Neurotoxic envenoming Indications for intubation: imminent In health care centre - Non-invasive respiratory arrest (respiratory distress, ventilation using bag-mask/bag-mask-valve breathing absent/inadequate); neck ventilation muscle weakness with shallow respiration or paradoxical breathing; secretions In hospital - Invasive Ventilation (intubation pooling in pharynx with loss of gag/ and mechanical ventilation) for Type cough reflexes; upper airway obstruction I respiratory failure (primary failure of with stridor (secondary to anaphylaxis oxygenation as in pulmonary oedema angioedema); oxygen saturation <90% in Russell’s viper envenoming) and Type (equivalent to Pa02 <60 mmHg) despite II respiratory failure (primary ventilatory high flow oxygen; respiratory acidosis failure due to respiratory muscle paralysis (hypoxia PaO2 < 60 mm Hg with PaCO2 or obstruction as in elapid envenoming). > 45 mm Hg) Indications for invasive ventilation: Insert cuffed endotracheal tube using patients who, despite receiving oxygen by laryngoscope under sedation,or laryngeal mask or nasal catheters remain tachpnoeic mask airway or i-gel supraglottic airway. (respiratory rate > 25/min), have

112 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES paradoxical respirations and deteriorating (nausea, vomiting, acidotic breathing, ventilatory capacity, hypoxia, respiratory hiccups, fetor, drowsiness, confusion, acidosis. Sedate them with fentanyl and coma, flapping tremor, muscle twitching, midazolam, or morphine and lorazepam. convulsions, pericardial friction rub, signs Ensure adequate hydration, nutrition, of fluid overload). Patients with any of physiotherapy, regular turning to prevent these features should be monitored for pressure areas and lung collapse, eye care other clinical signs of “uraemic syndrome”, and safe weaning from ventilation. pulse rate, postural blood pressure, height of jugular venous pulse, respiratory rate, Trial of anticholinesterase: temperature, auscultation of lung bases after making baseline observations, give for crepitations, fluid balance chart and/or atropine sulphate intravenously followed daily weight. by intramuscular neostigmine (or, ideally, slow intravenous injection of short-acting Most patients with AKI become oliguric edrophonium chloride – Tensilon, but (urine output < 400 ml/day or < 30 ml rarely available), and observe over next (children < 0.5ml/kg bodyweight /hour). 10-60 minutes for disappearance of ptosis Conservative management may tide the or improved ventilatory capacity. Treat patient over, avoiding the need for renal patients who respond convincingly with replacement therapy (dialysis). repeated neostigmine and atropine. In patients with intravascular volume Hypotension and shock depletion: establish intravenous access, Primary causes are anaphylaxis, give cautious fluid challenge (adult 250- vasodilatation, cardiotoxicity, 500 ml of isotonic saline over one hour). hypovolaemia; secondary causes are Stop challenge immediately if pulmonary antivenom reactions, respiratory failure, oedema develops. If the urine output does acute pituitary adrenal insufficiency, not improve, perform furosemide stress/ septicaemia challenge test, if that fails to increase urine output, switch to conservative Measure postural change in blood pressure management. or passive leg raising test to determine fluid responsiveness. Control fluid therapy Conservative management of AKI: no using jugular/central venous pressure, further diuretics, restrict fluid intake to respiratory rate, detection of crepitations. previous day’s output plus “insensible Selective vasoconstrictor such as dopamine losses” (500-1000 ml/day) and refer to may be used. renal unit. Diet bland, high calorie, normal protein, low potassium, low in salt. Acute pituitary/adrenal insufficiency may occur in victims of Russell’s viper Measure serum/plasma urea, bites (Myanmar, India, Sri Lanka). creatinine and electrolytes daily until Hydrocortisone is life-saving in these cases. renal failure is resolving. Examine ECG for evidence of hyperkalaemia, for which Oliguria and acute kidney injury (AKI) emergency treatments include calcium Impending AKI signalled by abrupt gluconate, β2 agonist aerosol inhaler, reduction in kidney function over 48 50% dextrose with insulin and sodium hours: decreasing/no urine output, bicarbonate, followed by a low potassium increased/increasing serum creatinine diet. Severe acidosis is corrected with concentration, clinical “uraemia syndrome” sodium bicarbonate.

Management of snakebites 113 in South-East Asia Renal replacement therapy/dialysis secondary infections involve aerobic and Patient with clinical uraemia anaerobic from the snake’s oral (encephalopathy, pericarditis etc.), fluid flora, patient’s skin and asterile incisions. overload not responding to diuretics, Tetanus toxoid booster and prompt hyperkalaemia or hyperkalaemic ECG antibiotic treatment of necrotic wounds is changes, symptomatic acidosis, raised recommended. plasma/serum creatinine and/or urea should be transferred to a health facility Compartmental syndromes are often where they can receive renal replacement misdiagnosed and fasciotomies performed therapy. unnecessarily. Since classical signs of compartment syndrome are difficult In patients with AKI associated with to assess in snake-bitten limbs, direct thrombotic microangiopathy, there is measurement of intracompartmental no evidence for plasmapheresis using pressure is mandatory and fasciotomy cryosupernatant. In patients with must not be attempted before myoglobinuria or haemoglobinuria, haemostatic disturbances have been correct hypovolaemia, maintain urine corrected by antivenom. output 200-300 ml/hour, correct severe acidosis with bicarbonate, promote Rehabilitation: conventional alkalinise diuresis, continuing until CK physiotherapy accelerates functional level <5000 U. recovery of the bitten limb, but is often forgotten. Diuretic phase of AKI: some patients develop persistent polyuria of 5-10 Discharge assessment: discussion, litres/24 hours and may become volume encouragement, follow-up, warning and electrolyte depleted. about late serum sickness-type reactions and advice about reducing risk of future Chronic kidney disease: oliguria and snakebites are important. dialysis-dependence for more than 4 weeks demands referral to nephrologist Management of cobra spit ophthalmia: to consider kidney biopsy. first aid is irrigation of affected eyes and other mucous membranes with liberal Haemostatic disturbances: usually quantities of water; medical treatment corrected by antivenom, but recurrent involves analgesia, exclusion of corneal coagulopathy is possible. Exceptionally, in abrasions and application of prophylactic patients already treated with antivenom topical . but who have persistent severe bleeding or require urgent surgery, restoration Management of snakebites at different of coagulability can be accelerated with levels of the health service: all levels blood products. of the health service can contribute to the management of patients with Treatment of the bitten part: suspected snakebite. In rural areas, where Nurse painful, swollen limb in the most snakebites are most common, transfer comfortable position, avoiding excessively to a hospital may not be feasible, and elevation. Leave , aspirate so a lower level of health facility must abscesses and culture pus. Necrotic tissue cope with these medical emergencies. demands early surgical débridement Training of doctors, nurses, dispensers, and split-skin grafting. Primary and health assistants and paramedics in

114 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES diagnosis (including snake identification), Unfortunately, most of the traditional, early management and indications for and popular, available and affordable first aid practicalities of administering antivenom is methods have proved to be useless or essential. even frankly dangerous. These methods include: making local incisions or pricks/ Snakebite treatment in developing punctures (“tattooing”) at the site of the countries is challenging, creating many bite or in the bitten limb, attempts to management problems. It is, therefore, of suck the venom out of the wound, use utmost importance to train doctors and of (black) snake stones, tying tight bands other health- care workers in the effective (tourniquets) around the limb, electric care of snakebite patients. shock, topical instillation or application of chemicals, herbs or ice packs. Local people 6.1 Stages of management may have great confidence in traditional The following steps or stages are often (herbal) treatments, but they must not be involved: allowed to delay medical treatment or to do harm.

Management of snakebite

• First-aid treatment Aims of first aid • Transport to hospital • reassure the snakebite victim • Rapid clinical assessment and • attempt to delay systemic resuscitation absorption of venom • Detailed clinical assessment and • preserve life and prevent species diagnosis complications before the patient • Investigations/laboratory tests can receive medical care at a • Antivenom treatment dispensary or hospital • Observing the response to • control distressing or dangerous antivenom early symptoms of envenoming • Deciding whether further dose(s) • arrange the transport of the of antivenom are needed patient to a place where they • Supportive/ancillary treatment can receive medical care • Treatment of the bitten part ABOVE ALL, AIM TO DO NO HARM! • Rehabilitation • Treatment of chronic complications 6.2.2 The danger of respiratory • Advising how to avoid future bites paralysis and shock The greatest fear is that a snakebite victim might develop fatal respiratory paralysis 6.2 First-aid treatment or shock before reaching a place where 6.2.1 Principles of first-aid they may be resuscitated (Looareesuwan First-aid treatment is carried out et al., 1988). This risk may be reduced immediately or very soon after the bite, by speeding up transport to hospital, before the patient reaches a dispensary by improving free ambulance services or hospital. It can be performed by the (Gimkala et al., 2016) or by recruiting snakebite victim himself/herself or by village-based motor cyclist volunteers anyone else who is present and able. who transport the victim propped

Management of snakebites 115 in South-East Asia hands as even a severed head can bite! Several close-up mobile ‘phone images of the snake should be taken if possible to allow expert identification.

MOST TRADITIONAL FIRST-AID METHODS SHOULD BE DISCOURAGED: THEY DO MORE HARM THAN GOOD!

6.2.3 Recommended first-aid methods • Reassure the victim who may be very anxious. Reassurance will drive away their fear and excitement, slow the patient’s heart rate and reduce the spread of venom. Grounds for reassurance include the possibility of a “dry bite” even if the snake was venomous, the usually slow evolution Figure 73: Evacuation of a snakebite victim showing early signs of paralysis by a village-based motorcycle volunteer in the Terai region of Nepal. The victim is of severe envenoming allowing time supported between the driver and a pillion passenger (Copyright Dr Sanjib Sharma) for treatment, and the effectiveness [CAUTION - If this method of transport has to be employed, because of local conditions and the terrain, ideally helmets should be worn and the legs of the of modern medical management of passengers protected from exhaust ] snakebite.

upright between the driver in front and • Immobilize the whole of the patient’s a supporting pillion passenger behind. body by laying him/her down in a This has proved effective in villages in the comfortable and safe position, ideally Nepal Terai (Sharma et al., 2013) (Figure in the recovery position (lying prone 73). Medical workers can be trained on the left side in case vomiting in airway management and assisted threatens to result in aspiration), and ventilation (see below). The special danger immobilize the bitten limb with a splint of rapidly developing paralytic envenoming or sling. Any movement or muscular after bites by some elapid snakes has contraction, even undressing or prompted the use of pressure-bandage walking, will increase absorption and immobilization (Sutherland et al., 1979) spread of venom by squeezing veins and pressure-pad immobilization (Anker and lymphatics. 1982; Tun-Pe et al.,1995b )(ANNEX 4). Pressure bandage immobilization requires • Unless the possibility of an elapid equipment (long elasticated bandages and bite can confidently be excluded, splints) (Canale et al., 2009; Currie et al., apply pressure-pad immobilization 2008 ) and skill. (See ANNEX 4), or, if the necessary equipment and skills are available, As far as the snake is concerned - do pressure-bandage immobilization. In not attempt to kill it as this may be Myanmar, the pressure-pad method dangerous.However, if the snake has has proved effective in reducing spread already been killed, it should be taken to of venom in victims of Russell’s viper the dispensary or hospital with the patient bite (Tun Pe et al., 1995b). Pressure- in case it can be identified. However, do bandage immobilization has not not handle the snake with your bare become widely used in this Region,

116 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Figure 74: Gangrenous because provision of the necessary 6.3 Transport to hospital limb caused by a tight equipment (long, wide elasticated Emergency Helpline Numbers tourniquet after a bite by Malayan pit viper bandages), training and skills required Linkage with an emergency helpline (Copyright DA Warrell) to apply it safely and reliably have number (e.g. in India 108 see http:// proved impossible to achieve. The www.emri.in/) can speed up the pressure-pad immobilization method is transport of a patient to a higher preferred and recommended as being referral centre when emergency simpler and more practicable (O). treatment is required. This will decrease delays in accessing emergency care and • Avoid any interference with the bite reduce mortality. Information about wound (incisions, rubbing, vigorous helpline numbers could be widely cleaning, massage, application of herbs disseminated. or chemicals) as this may introduce infection, increase absorption of the The patient must be transported to a venom and increase local bleeding. place where they can receive medical care (dispensary or hospital) as quickly, CAUTION Delay the release of tight but as safely and comfortably as bands, bandages and ligatures: if the possible. Any movement, but especially patient has already applied these very movement of the bitten limb, must be popular methods of first-aid, they should reduced to an absolute minimum to not be released until the patient is under avoid increasing the systemic absorption medical care in hospital, medical staff and of venom. Any muscular contraction resuscitation facilities are available and will increase spread of venom from the antivenom treatment has been started site of the bite in veins and lymphatics. (Watt et al., 1988) see Caution below. Where a conventional motor vehicle ambulance is not available or feasible, Tight (arterial) tourniquets must stretcher, bicycle, motorbike (Patel never be recommended or condoned! and Ekkiswata, 2010) - by recruiting Traditional tight (arterial) tourniquets. village-based motorbike owners/ If applied tightly around the upper part cyclists (Sharma et al., 2013) (Fig 73), of the limb, these bands, bandages or cart, horse, train or boat may have to ligatures are extremely painful as the limb be considered, or the patient can be becomes ischaemic and are very dangerous carried (e.g. using the “fireman’s lift” if left in place for long periods. Many method). If possible, patients should be gangrenous limbs have resulted! placed in the recovery position during (Fig 74) transit, in case they vomit.

Management of snakebites 117 in South-East Asia 6.4 Treatment in the dispensary or hospital Rapid primary clinical assessment (Warrell 1990; 1995) and resuscitation: ABCDE approach Airway Medical management of envenomed patients in dispensary Breathing (respiratory movements) or hospital Circulation (arterial pulse) • Rapid primary clinical assessment Disability of the (level and resuscitation of consciousness) • Detailed clinical history, physical Exposure and environmental control examination and species diagnosis (protect from cold, risk of drowning • Simple test of blood coagulability etc) [20-minute-whole-blood-clotting- test (20WBCT)] Airway patency, respiratory movements, • Antivenom: indications, initial arterial pulse and level of consciousness and repeated dosage, response, must be checked immediately. Record the reactions vital signs. • Treatment of organ and system failures The Glasgow Coma Scale cannot be used to assess the level of consciousness of • Treatment of the bitten limb patients paralysed by neurotoxic venoms • Rehabilitation, restoration of (see below). function • Advice at discharge from hospital Clinical situations in which and follow-up snakebite victims might require urgent resuscitation: • Preventive health education a) Profound hypotension and shock: towards reducing risk of future resulting from direct cardiovascular bites effects of the venom or secondary effects, such as hypovolaemia, release of inflammatory vasoactive mediators, 6.4.1 Rapid primary clinical haemorrhagic shock or rarely primary assessment and resuscitation anaphylaxis induced by the venom itself. Snakebite is a medical emergency: history, symptoms and signs must be b) Terminal respiratory failure: from obtained rapidly so that appropriate, progressive neurotoxic envenoming urgent and life-saving treatment can that has led to paralysis of the be given respiratory muscles; or simple airway obstruction. Cardiopulmonary resuscitation may be needed, including administration of c) Respiratory distress: from oxygen and establishment of intravenous generalized increase in capillary access. permeability (Russell’s viper bite victims)

118 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES d) Sudden deterioration: or rapid development of severe systemic A common early symptom of systemic envenoming after releasing a tight tourniquet or compression bandage envenoming is vomiting and, after bites (see Caution above). by some species, fainting and collapsing e) Cardiac arrest: precipitated by (sometimes causing injury) with transient hyperkalaemia resulting from skeletal unconsciousness and features of anaphylaxis muscle breakdown (rhabdomyolysis) after bites by sea snakes, certain kraits (angioedema etc.) and Russell’s vipers. f) Late results of severe envenoming: take a picture?” If the snake has been in someone arriving days/weeks after the killed and brought, or an adequate bite: with severe bleeding/blood clotting photo image is available (e.g. taken disturbances, acute kidney injury or by mobile ‘phone at the scene of the septicaemia complicating local necrosis. bite), its correct identification can be very helpful. If it is obviously a harmless 6.4.2 Detailed clinical assessment and species (or not a snake at all!), the species diagnosis patient can be quickly reassured and discharged from hospital. If it was 6.4.2.1 History killed and left at home, send someone A precise history of the circumstances to fetch it, in whatever condition! of the bite and the progression of local 4. “How are you feeling now?” and systemic symptoms and signs is very important. Have any symptoms of envenoming developed? Four useful initial questions: 1. “Where (in what part of your body) were A common early symptom of systemic you bitten? Point to the place” Observe envenoming is vomiting and, after any local signs – fang marks, swelling, bites by some species, fainting and bruising, persistent bleeding, pre- collapsing (sometimes causing injury) hospital traditional treatment. with transient unconsciousness and features of anaphylaxis (angioedema etc.). 2. “When were you bitten and what were Patients who become defibrinogenated you doing when were you bitten?” If or thrombocytopenic may begin to bleed the bite was very recent, there may not from old, partially-healed wounds as well have been time for signs of envenoming as bleeding persistently from the fang to develop. If the patient was bitten at marks. The patient should be asked how night while asleep, a krait was probably much urine they have passed since the bite implicated; if in a paddy field, a cobra or and whether it was a normal colour or very Russell’s viper; if while tending fruit trees, dark (implying haemoglobin/myoglobin – a green pit viper; if while swimming or uria). Patients who complain of sleepiness, wading in water a cobra (fresh water) or drooping eyelids or blurred or double sea snake (sea or estuary). vision may have neurotoxic envenoming. An important early symptom of sea snake 3. “Where is the snake that bit you?” envenoming that may develop as soon as or “What did it look like; did anyone 30 minutes after the bite is generalized

Management of snakebites 119 in South-East Asia pain, tenderness and stiffness of muscles lines noted. A bitten limb may be and trismus. tensely oedematous, cold, immobile, painful on passive movement and with impalpable arterial pulses. These Early clues that a patient has appearances may suggest intravascular severe envenoming: thrombosis, which is exceptionally rare after snakebite, or a compartmental • Snake identified as a very syndrome, which is uncommon. If dangerous one or a large possible, intracompartmental pressure specimen should be measured (see Annex 5) and • Widely spaced fang puncture the blood flow and patency of arteries marks or evidence of multiple and veins assessed (e.g. by doppler strikes ultrasound). Early signs of necrosis may • Rapid early extension of local include blistering, demarcated darkening swelling from the site of the bite (easily confused with bruising) (Fig 54 d, e, Fig 69) or paleness of the skin, loss • Early tender enlargement of local of sensation and a smell of putrefaction lymph nodes, indicating spread of (rotting flesh). venom in the • lymphatic system General examination: Measure the blood pressure (sitting up and lying • Early systemic symptoms: to detect a postural drop indicative of collapse (hypotension, shock), hypovolaemia – see 14 Management nausea, vomiting, diarrhoea, of hypotension and shock) and heart severe headache, “heaviness” rate. Examine the skin and mucous of the eyelids, inappropriate membranes for evidence of petechiae, (pathological) drowsiness or early purpura, discoid haemorrhages (Fig ptosis/ophthalmoplegia 64b) and, ecchymoses, the conjunctivae, • Early spontaneous systemic for haemorrhages (Fig 63) and bleeding chemosis (Fig 58), and the optic fundi • No urine passed since the bite for retinal haemorrhages. Examine the gingival sulci thoroughly, using a • Passage of dark brown/black urine torch and spatula/tongue depressor, as these may show the earliest evidence of spontaneous systemic bleeding (Fig 6.4.2.2 Physical examination 60a), a very valuable sign. Examine This should start with careful assessment the nose for epistaxis. Abdominal of the site of the bite and signs of local tenderness may suggest gastrointestinal envenoming. or . Loin (low back) pain and tenderness suggest Examination of the bitten part: The acute renal ischaemia (Russell’s viper extent of swelling, which is usually also bites). Subarachnoid haemorrhage is the extent of tenderness to palpation suggested by neck stiffness (meningism) (start proximally and squeeze gently (Fig 60b). Intracranial haemorrhage is while watching the patient’s expression), suggested by lateralising neurological should be recorded. Lymph nodes signs, asymmetrical pupils, convulsions or draining the limb should be palpated and impaired consciousness (in the absence overlying ecchymoses and lymphangitic of respiratory or circulatory failure).

120 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES 5.4.2.3 Neurotoxic envenoming: Bulbar and respiratory paralysis To exclude early neurotoxic envenoming, ask the patient to look up and observe whether the upper lids retract fully (Fig 75). Ask about diplopia and test eye movements for evidence of early external ophthalmoplegia (Fig 66). Check the size and reaction of the pupils. Ask the patient to open their mouth wide and protrude their tongue; early restriction in mouth opening may indicate trismus (sea snake envenoming) (Fig 71a) or, more often, paralysis of pterygoid muscles (Fig 76).

Check other muscles innervated by the cranial nerves (facial muscles, tongue, gag reflex etc.).

The muscles flexing the neck may be paralysed, giving the “broken neck sign” Figure 75: Examination for ptosis in a patient with neurotoxic envenoming by a Papuan taipan. This is (Fig 77). usually the earliest sign of neurotoxic envenoming (Copyright DA Warrell)

Figure 77: Broken neck sign in a child envenomed by a krait in Sri Lanka Figure 76: Examination for ability to open the mouth (Copyright DA Warrell) and protrude the tongue in a patient with neurotoxic envenoming from the Malayan krait (Copyright DA Warrell)

Can the patient swallow or are (abdomen expands rather than the chest secretions accumulating in the pharynx, on attempted inspiration) indicates an early sign of bulbar paralysis? Ask that the diaphragm is still contracting the patient to take deep breaths in but that the intercostal muscles and and out. “Paradoxical respiration” accessory muscles of inspiration are

Management of snakebites 121 in South-East Asia profound generalized flaccid paralysis from neurotoxic envenoming are fully conscious (Fig 78).

Lifting their paralysed upper eyelids allows them to see their surroundings which they find very reassuring. If asked, they may still be able to flex a finger or toe, allowing simple communication. However, because their eyes are closed and they do not move or speak, they are commonly assumed to be unconscious or even dead. Conventional tests of brain death can prove misleading (Dayal et al., 2014) and there are media reports of a child with snakebite paralysis who was about to be placed on a funeral pyre before she was seen to be breathing and of snakebite victims being rescued when they were about to be buried alive.

Test the tone and power of limb muscles and the superficial and deep tendon reflexes. Look for lateralising signs suggesting intracranial haemorrhage or thrombosis. Observe involuntary movements such as fasciculations/ myokymia (as in anticholinesterase Figure 78: Generalized flaccid paralysis in a patient envenomed by a common overdose or organo-phosphate poisoning) krait in Sri Lanka. The patient was fully conscious and was able to communicate by flexing his index fingers (Copyright DA Warrell) and writhing choreo-athetotic movements suggesting hypoglycaemia (Russell’s viper envenoming). paralysed. Where possible, serial objective measurements of ventilatory capacity are very useful. Use a peak flow metre, Do not assume that snake-bitten

spirometer (to measure FEV1 and FVC) patients are unconscious or even or ask the patient to blow into the tube irreversibly “brain dead” just of a sphygmomanometer ( or because their eyes are closed, aneroid) to record the maximum expiratory they are unresponsive to painful pressure (mmHg) or use the single-breath stimuli, are areflexic, or have counting test (SBC). SBC measures how fixed dilated pupils. They may far the patient can count at two numbers merely be paralysed! They may per second in a normal speaking voice be severely paralysed and lack after taking a maximal inhalation (Ali et motor responses or spontaneous al., 2011). A finger oximeter will detect eye movements mimicking coma decreasing arterial oxygen saturation. (locked-in syndrome). Check pulse, Remember that, provided their heart sounds and, if possible, ECG. are adequately ventilated, patients with

122 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES 6.4.2.4 Generalized rhabdomyolysis carinatus) bites in SW India (Joseph et In victims of envenoming by sea snakes, al., 2007); or mistaken for Russell’s viper some species of kraits (B. niger and B. (Daboia russelii) bites in Sri Lanka, since candidus), some Australasian elapids and available polyvalent antivenoms do not Russell’s vipers in Sri Lanka and South cover the venom of this species. An India, muscles, especially of the neck, image of the dead snake may be taken trunk and proximal part of the limbs, may and then easily sent by mobile ‘phone, become tender and painful on active or “What’s App”, or to a local, passive movement (Fig 71b) and later national or international snake expert or may become paralysed. In sea snakebite Information Centre for definitive envenoming, there is pseudotrismus that identification. Otherwise, the species can be overcome by sustained pressure responsible must be inferred indirectly on the lower jaw. Myoglobinuria may be from the patient’s description of the evident 3 hours after the bite (Figs 67, snake, circumstances of the bite (e.g. 71c). nocturnal bites by kraits in people sleeping on the ground, Ariaratnam et al., 2008), 6.4.2.5 Examination of pregnant and the clinical syndrome of symptoms women and signs (see above and Annexes 1 Potential complications of envenoming and 2). This was particularly important in pregnancy include antepartum and in countries where only monospecific postpartum hemorrhage indicated by antivenoms are available. vaginal bleeding, premature labour, abortion/stillbirth, fetal distress or intra- 6.6 Investigations/ uterine fetal death. If possible, uterine laboratory tests contractions and fetal heart rate should 6.6.1 20 minute whole blood be monitored continuously. Fetal distress clotting test may be signalled by fetal bradycardia, (20WBCT) (Warrell et a., 1977; tachycardia, or late deceleration after Sano-Martins et al., 1994) (Fig 79) each uterine contraction. If there is This very useful and informative bedside test vaginal bleeding or the need for imminent requires very little skill and only one piece of surgery, correction of antihaemostatic abnormalities after antivenom treatment should be accelerated using blood products. Lactating women should be encouraged to continue breastfeeding.

6.5 Species diagnosis If the dead snake has been brought, it can be identified, but this requires skill and even experienced medical personnel may mistake harmless mimics for venomous snake, or they may confuse different venomous species (Viravan et al., 1992; Ariaratnam et al., 2009). As a result, the patient may be given antivenom unnecessarily, as in the case of hump- Figure 79: 20 minute whole blood clotting test in a patient still bleeding from nosed pit viper (Hypnale hypnale) bites incisions made at the site of the bite. The blood is icoagulable indicating venom- mistaken for saw-scaled viper (Echis induced consumption coagulopathy (Copyright DA Warrell)

Management of snakebites 123 in South-East Asia apparatus - a new, clean, dry, ordinary glass these cases, surface activation of blood vessel (tube, bottle or syringe). coagulation by the glass surface, mediated by Hageman Factor XII is lacking or has been destroyed by cleaning with the result 20 minute whole blood clotting that blood coagulation is not activated and test (20WBCT) the blood will not clot. • Place 2 mls of freshly sampled venous blood in a small, new, dry, A major difficulty is that many hospitals/ glass vessel dispensaries in countries where snakebites- • Leave undisturbed for 20 minutes are common, cannot afford to provide a at ambient temperature new, unwashed, un-recycled bottle, tube, • Tip the vessel once syringe or other vessel for each test and • If the blood is still liquid ordinary glass tubes/vessels may be difficult (unclotted) and runs out, the to purchase in this age of plastic. However, patient has hypofibrinogenaemia the commonly used recycled glass (“incoagulable blood”) as a result antibiotic bottles can be made suitable and of venom-induced consumption reliable, provided that they are cleaned coagulopathy by washing with “normal 0.9% saline” • In the South-East Asia Region, for intravenous infusion, without any incoagulable blood is diagnostic added detergent of other cleansing agent, of a viper bite and rules out an followed by hot air drying. elapid bite • Warning! If the vessel used Variants of the 20WBCT, such as the 30 for the test is not made of minute WBCT, “2,3,5 syringe test” used in ordinary glass, or if it has Myanmar, or the capillary tube test have been cleaned with detergent, not been standardised or validated and its wall may not stimulate are susceptible to the same risks of false clotting of the blood sample positivity outlined above. (surface activation of factor XII – Hageman factor) and test False negative results: a “false will be invalid negative” (i.e. clotting) 20WBCT may • If there is any doubt, repeat the occur in patients with milder degrees test in duplicate, including a of coagulopathy. The 20WBCT is less healthy “control” (blood from a sensitive to mild depletion of fibrinogen healthy person such as a relative) and other clotting factors, in the early stages of evolving snake venom induced Problems with the 20WBCT DIC and consumption coagulopathy, than False positive results: a “false positive” laboratory tests such as prothrombin time (i.e. non-clotting) 20WBCT in a patient (PT), activated partial thromboplastin time who is not envenomed and has normal (aPPT), and fibrinogen . The 20WBCT blood coagulation, results from the use of becomes positive (i.e. non-clotting) at a tube, bottle, syringe or other vessel that is plasma fibrinogen concentrations below made of plastic, polystyrene, polypropylene 0.5g/L (Sano-Martins et al., 1994). A rather than ordinary glass, or a glass vessel study of 20WBCT in victims of taipan bites that has been cleaned with detergent, soap (Oxyuranus scutellatus) in Papua New or washing fluid or is wet or contaminated, Guinea found that a positive 20WBCT or in the case of some glass syringes, (i.e. non-clotting) was associated with has a lubricant that is anticoagulant. In a median PT of 120.0s (IQR 24.4-200s),

124 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES median aPTT of 132 sec (IQR=69.1-180s) and median fibrinogen concentration of 0.01 g/L (IQR=0.01-0.18 g/L). A positive Every effort should be made to eliminate (i.e. non-clotting) 20WBCT had a positive false positive (non-clotting) results by predictive value of 89.7%, negative predictive value of 93.5%, sensitivity ensuring that ordinary glass is used, that of 92.9% and specificity of 90.6% for recycled glass vessels are not cleaned with fibrinogen concentrations of <0.5 g/L. detergents or other cleansing fluids and (Paiva et al., 2015). However, a study in Sri Lanka that is open to many criticisms that a normal control blood is used for found that in some patients bitten by comparison in cases where the 20WBCT Russell’s vipers, whose 20WBCTs were negative (i.e. clotting) on admission result is inconsistent with the patient’s to hospital, blood samples taken up clinical condition. to one hour later, frozen and flown to Australia for testing, showed prolonged prothrombin times [International Normalized Ratio (INR) >1.5 see below]. This was not a comparison of 20WBCT and INR in blood sample taken at the same Recommendation: in the absence time. In every case, the INR sample was of an alternative simple bed- taken later than the 20WBCT sample, by side test of blood coagulability which time the process of venom-induced available in hospitals in the DIC and consumption coagulopathy developing world, the 20WBCT in the envenomed patient would have should continue to be used. evolved. The authors considered that the However, every effort should use of the 20WBCT was associated with be made to eliminate false an unacceptable level of false negative positive (non-clotting) results by (clotting) results and that it consequently ensuring that ordinary glass is delayed antivenom treatment. However, used, that recycled glass vessels if blood clots in the 20WBCT, the sample are not cleaned with detergents must contain sufficient clotting factors, or other cleansing fluids and albeit at reduced levels, to make this that a normal control blood is possible, indicating that haemostasis is used for comparison in cases maintained. However, no evidence was where the 20WBCT result is adduced that this false negative result inconsistent with the patient’s was in any way deleterious to the patients clinical condition. Accepting whose antivenom treatment was delayed that the 20WBCT may remain until their 20WBCTs became positive (i.e. negative (clotting) in patients non-clotting) some hours later (Isbister with evolving venom-induced et al., 2013). The authors admitted DIC, the test should be repeated that prothrombin times could not be frequently and antivenom performed in Sri Lankan hospitals and, treatment should not be delayed unfortunately, they were unable to suggest if there is other evidence of anti- any practicable alternative to the 20WBCT haemostatic disturbances (e.g. for the many provincial and rural hospitals spontaneous systemic bleeding in tropical developing countries where distant from the bite site) snakebites are common.

Management of snakebites 125 in South-East Asia 6.6.2 Other tests of blood haematocrit: a transient increase coagulation indicates haemoconcentration resulting More sensitive laboratory tests that are from a generalized increase in capillary rapid and relatively simple to perform permeability (e.g. in Russell’s viper bite). are plasma prothrombin time (PT) or activated partial thromboplastin time More often, there is a decrease reflecting (aPPT) and measurement of fibrin(ogen) blood loss or, in the case of Indian, related antigens, also known as fibrin Thai and Sri Lankan Russell’s viper bite, degradation products (FDP) or fibrin intravascular haemolysis. split products (FSP), by agglutination of sensitized latex particles or of D-dimer Platelet count: this may be decreased (cross-linked fibrin fragments) by assays in victims of envenoming by vipers and using monoclonal antibodies that detect Australasian elapids. an epitope that is present in the factor XIIIa–crosslinked fragment D domain of count: an early fibrin. The International Normalized Ratio neutrophil leucocytosis is evidence of (INR) is the patient’s PT divided by the systemic envenoming by any species. laboratory control PT (normal range 0.8 Lymphopenia has been described in - 1.2). An abnormal INR result, indicating patients envenomed by Australasian coagulopathy, is 1.2 or above. Point of Elapidae. care (bed-side) devices for measuring INR and D-dimer are expensive and are Blood film: fragmented red cells unreliable in snakebite victims (Cubitt (“helmet cell”, schistocytes) are seen et al., 2013). Measurement of plasma when there is microangiopathic concentrations of fibrinogen and other haemolysis or thrombotic individual clotting factors are more microangiopathy (TMA). Haemolytic demanding in time and laboratory skills. uraemic syndrome (HUS) consists of persistent, profound thrombocytopenia, Thrombo-elastography (TEG) and microangiopathic haemolytic anaemia thromboelastometry (TEM, ROTEG, (fragmented red cells, “helmet cells”, ROTEM) have been suggested as a or schistocytes) and acute kidney simple bed-side method for assessing injury. It is associated with envenoming coagulopathy in snakebite victims but the by Russell’s vipers, hump-nosed pit equipment is expensive. Analysis of the vipers and Australian Elapidae. The TEG tracing provides measures of time pathophysiology of TMA is unknown, to initiation of clotting, speed of clot but in other diseases, such as thrombotic formation and clot strength that reflect thrombocytopenic purpura (TPP), it is coagulation factor activity, fibrinolysis thought to be due to deficiency of the and platelet function. In a study of metalloproteinase ADAMTS 13 which envenomed children in South , cleaves von Willebrand multimers. These TEG predicted severe multimers initiate platelet activation in 50% of patients with 94% sensitivity and formation of microthrombi which (Hadley et al., 1999). It has also been is the key factor in the development of used in envenomed (Armentano et acute kidney injury. In an Australian tiger al., 2014). snake (Notechis scutatus) bite victim with TMA, ADAMTS 13 levels were 6.6.3 Other laboratory tests normal before and after plasmapheresis Haemoglobin concentration/ with cryosupernatant (Ho et al., 2010).

126 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Plasma/serum in blood samples to an arterial PO2 of less than 60 mmHg allowed to sediment spontaneously (8.8 kPa). (without centrifugation) may be stained pinkish or brownish if there is gross Urine examination: the urine haemoglobinaemia or myoglobinaemia. should be tested by dipsticks for blood or haemoglobin or myoglobin. Biochemical abnormalities: plasma Standard dipsticks do not distinguish creatinine, urea/blood urea nitrogen and blood, haemoglobin and myoglobin. potassium concentrations are raised in Haemoglobin and myoglobin can be the acute kidney injury of Russell’s viper, separated by immunoassays but there is hump-nosed pit-viper and sea-snake no easy or reliable test. Microscopy will envenoming. Aminotransferases and confirm whether there are erythrocytes in muscle enzymes (creatine kinase, aldolase the urine. etc.) will be elevated if there is severe local damage or, particularly, if there is Red cell casts indicate glomerular generalized muscle damage (sea-snakes, bleeding. Massive proteinuria is an some kraits, some Australasian Elapidae early sign of the generalized increase in and Sri Lankan, Indian, Bangladeshi and capillary permeability in Russell’s viper Myanmar Russell’s viper bites). Mild envenoming and an early indicator of hepatic dysfunction is reflected in slight acute kidney injury. Urine eosinophilia increases in other serum enzymes. Bilirubin suggests acute interstitial nephritis, but is elevated following massive extravasation this can be confirmed only by renal biopsy of blood. Early hyperkalaemia may be (Priyamvada et al., 2016). seen following extensive rhabdomyolysis in sea snakebites. Bicarbonate will be low 6.6.4 Other investigations in metabolic acidosis (e.g. acute kidney Radiography: chest radiography is injury). Hyponatraemia is reported in useful for detecting pulmonary oedema victims of krait bites in northern Viet Nam (e.g. after bites by Vipera and Daboia (Bungarus near candidus). species), pulmonary haemorrhages and infarcts, pleural effusions, and secondary Arterial blood gases and pH may show bronchopneumonia. evidence of respiratory failure (neurotoxic envenoming) and acidaemia (respiratory or Ultrasound: ultrasonography was found to metabolic acidosis). be useful for assessing local envenoming, including deep vein thrombosis in a case of Russell’s viper bite in Pondicherry, India, Warning: arterial puncture is and for detecting pleural and pericardial contraindicated in patients effusion and bleeding into serous cavities. with haemostatic abnormalities (Viperidae and some Australasian Echocardiography has proved useful in Elapidae) detecting reduced left ventricular ejection fraction in hypotensive and shocked patients envenomed by Russell’s vipers in Desaturation: arterial oxygen saturation Sri Lanka.. can be assessed non-invasively in patients with respiratory failure or shock using a Imaging: CT and MRI imaging is finger pulse oximeter. Remember that an increasingly available in the Region. It has oxygen saturation below 90% is equivalent detected haemorrhages and ischaemic

Management of snakebites 127 in South-East Asia infarcts in the brain (subarachnoid, that has been immunised with the venoms subdural, cerebral, cerebellar, brainstem) of one or more species of snake. “Specific” (Figs 61b, 61c, 52d), spinal cord, antivenom, implies that the antivenom peritoneum and elsewhere in Russell’s has been raised against the venom of the viper victims in India, Sri Lanka and snake that has bitten the patient and that Myanmar. Cerebral imaging has shown it can therefore be expected to contain pituitary shrinkage in cases of chronic specific that will neutralize that panhypopituitarism and unexplained particular venom and perhaps the venoms haemorrhagic and demyelinating of closely related species (paraspecific leucoencephalopathies after Russell’s viper neutralization). Monovalent (monospecific) bites in India. Imaging can show oedema antivenom neutralizes the venom of and haemorrhage in fascial compartment only one species of snake. Polyvalent muscles and the degree of osteomyletis (polyspecific) antivenom neutralizes and soft tissue changes in chronic the venoms of several different species snakebite ulcers that have undergone of snakes, usually the most important malignant change to squamous cell species, from a medical point of view, in a carcinomas (Marjolin’s ulcers). particular geographical area.

Electrocardiography: ECG abnormalities For example, the Indian antivenom reported in snakebite victims include manufacturers’ “polyvalent anti-snake tachyarrhythmias, sinus bradycardia, venom serum” is raised in horses, using ST-T wave changes, varying degrees the venoms of the four most important of atrioventricular block, and evidence venomous snakes in India (, of hyperkalaemia. Shock may induce Naja naja; Indian krait, Bungarus caeruleus; myocardial ischaemia or infarction in Russell’s viper, Daboia russelii; saw-scaled patients with diseased coronary arteries. viper, Echis carinatus), although the validity of the concept of “the big four” is 6.7 Antivenom treatment increasingly challenged by the discovery that other species are also important in certain regions [e.g. Echis carinatus Antivenom is the only specific sochureki in (Kochar et al., antidote to snake venom. 2007); H. hypnale in SW India (Joseph et A most important decision in al., 2007); Trimeresurus (Craspedocephalus) the management of a snakebite malabaricus in southern India; Trimeresurus victim is whether or not to give (Peltopelor) macrolepis (ref) in hilly regions antivenom. of Tamil Nadu and Kerala; Trimeresurus (T.) erythrurus in and ; Naja kaouthia in North east India; Bungarus 6.7.1 What is antivenom? sindanus in W and NW India (Pillai et al., (WHO 2010) 2012); B. walli and possibly B. niger in NE Antivenom treatment for cobra bites India (Faiz et al., 2010)] (Whitaker and was introduced by at Martin 2014; Whitaker 2015). Antibodies the Institut Pasteur in Saigon, Viet Nam raised against the venom of one species in the 1890s (Bon and Goyffon 1996). may have cross-neutralizing activity against Antivenom is immunoglobulin [usually other venoms, usually from closely related

pepsin-refined F(ab’)2 fragment of whole species. This is known as paraspecific IgG] purified from the plasma of a horse, activity. For example, the manufacturers mule or donkey (equine) or sheep (ovine) of Haffkine polyvalent anti-snake venom

128 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES serum claim that this antivenom also neutralizes venoms of two Trimeresurus There is an urgent need to improve the species. design (species cover), quantity, and quality The Thai Red Cross Society now of antivenoms produced in South-East Asia manufactures two polyvalent antivenoms to cover the venoms of neurotoxic Elapidae Region countries, in the interests of reducing (Naja kaouthia, O. hannah, Bungarus snakebite mortality and morbidity. candidus, B. fasciatus) and haematotoxic Viperidae (Daboia russelii, Calloselasma rhodostoma, Trimeresurus (T.) albolabris). Systemic envenoming In Indonesia, Biofarma produces a • Haemostatic abnormalities: polyvalent antivenom to cover venoms spontaneous systemic bleeding of neurotoxic Naja sputatix, Bungarus distant from the bite site (clinical), fasciatus (that rarely, if ever, bites humans) coagulopathy [+ve (non-clotting) and Calloselasma rhodostoma, but, 20WBCT or other laboratory tests unaccountably, ignores important species such as INR >1.2 or patient’s such as Bungarus candidus, Daboia prothrombin time >4-5 seconds siamensis, Trimeresurus species and all the longer than laboratory control value] Eastern Indonesian Australasian Elapidae. or thrombocytopenia [<100 x 109/ litre, or <100 000/cu mm, or (India) There is an urgent need to improve the < 1.0 lakh per microlitre of blood)] design (species cover), quantity, and (laboratory) quality of antivenoms produced in South- East Asia Region countries, in the interests • Neurotoxic signs: ptosis, external of reducing snakebite mortality and ophthalmoplegia, paralysis etc (clinical) morbidity. • Cardiovascular abnormalities: 6.7.2 Indications for antivenom hypotension, shock, cardiac arrhythmia treatment (see also Annexes 1 and 2) (clinical), abnormal ECG

Antivenom should be given only • Acute kidney injury (renal failure): to patients in whom its benefits oliguria/anuria (clinical), rising blood are considered likely to exceed creatinine/ urea (laboratory) its risks. Since antivenom is relatively costly and often in • Haemoglobin-/myoglobin-uria: limited supply, it should not be dark brown urine (clinical), urine used indiscriminately. The risk of dipsticks, other evidence of reactions should always be taken intravascular haemolysis or generalized into consideration. rhabdomyolysis (generalized muscle aches, pains, tenderness, pain on passive stretching (hyperkalaemia) Indications for antivenom (clinical, laboratory) Antivenom treatment is recommended if and when a patient with proven or • Supporting laboratory evidence of suspected snakebite develops one or more systemic envenoming (see above) Local of the following signs: envenoming

Management of snakebites 129 in South-East Asia • Local swelling involving more than half give antivenom for as long as evidence of the bitten limb (in the absence of of the coagulopathy persists. Whether a tourniquet) within 48 hr of the bite antivenom can prevent local necrosis Swelling after bites on the digits (toes remains controversial, but there is some and especially fingers) clinical evidence that, to be effective in this situation, it must be given within the • Rapid extension of swelling (for first few hours after the bite (Warrell et example beyond the wrist or ankle al., 1976; Tilbury 1982). within a few hours of bites on the hands or feet) 6.7.5 Antivenom reactions A substantial proportion of patients • Development of an enlarged tender develop reactions, either early (within lymph node draining the bitten limb a few hours) or late (5 days or more) after being given antivenom. In Sri 6.7.3 Inappropriate use of antivenom Lanka, Indian polyvalent antivenoms In some parts of the world, a small incur reactions in as many as 81% of standard dose of antivenom is given recipients and severe reactions in as routinely to any patient claiming to many as 43% (Ariaratnam et al. 2001, have been bitten by a snake, irrespective de Silva et al, 2016). In India, these of symptoms or signs of envenoming. antivenoms cause reactions in 5.6 to Sometimes the local community are 56% of recipients, 10-15% of which are so frightened of snakebite that they moderate to severe (Srimannarayana compel the doctor to give antivenom et al., 2004; Deshpande et al., 2013; against medical judgement. Even doctors Cherian et al., 2013; Menon et al., themselves may administer antivenom to 2016a). Other antivenoms have much patients envenomed by snakes against lower reported reaction rates. In which the antivenom is known to be Thailand, among 254 patients receiving ineffective (Seneviratne et al, 2000). Thai Red Cross (TRC) antivenoms during 1997–2006, early reactions occurred in 9 (3.5%) including 3 (1.2%) with Inappropriate use of antivenom hypotension. Most patients were being should be strongly discouraged treated for Trimeresurus (84%) and Naja as they expose patients who may (13%) bites, in whom the incidence not need treatment to the risks of reactions was 2.3% and 12.5% of antivenom reactions; they also respectively, reflecting the difference waste valuable and scarce stocks in dose (3 and 10 vials respectively) of antivenom. (Thiansookon and Rojnukarin, 2008). In Australia, use of CSL antivenoms incurred early anaphylactic reactions 6.7.4 How long after the bite in 25% and severe raections in 5% of can antivenom be expected to be recipients (Isbister et al., 2008). The risk effective? of antivenom reactions is dose-related, Antivenom treatment should be given except in rare cases in which there has as soon as it is indicated. It may reverse been sensitisation (IgE-mediated Type systemic envenoming even when this has I hypersensitivity) by previous exposure persisted for several days or, in the case to animal serum, for example to equine of haemostatic abnormalities, for two or antivenom, tetanus-immune globulin or more weeks. It is, therefore, appropriate to -immune globulin.

130 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES [b]

[a]

Figures 80: Early anaphylactic reaction to antivenom: (a, b) urticaria and pruritus of the trunk and face; (c) life-threatening angioedema of face tongue, gums, throat, neck and upper airway (Copyright DA Warrell)

1. Early anaphylactic reactions: basophils by antivenom usually within minutes and up to 180 protein are more likely minutes after starting antivenom, the mechanisms for these patient begins to (often over the reactions. scalp) and develops urticaria (Fig 80 a,b), dry cough, fever, nausea, 2. Pyrogenic vomiting, abdominal colic, diarrhoea (endotoxin) and tachycardia. A minority of these reactions: usually patients may develop severe life- develop 1-2 hours after [c] threatening anaphylaxis: hypotension, treatment. Symptoms bronchospasm and angio-oedema include shaking (Fig 80c). chills (rigors), fever, vasodilatation and a fall in blood pressure. Febrile Fatal reactions have probably been convulsions may be precipitated in under-reported as death after snakebite children. These reactions are caused is usually attributed to the venom by pyrogen contamination during and patients may not be monitored the manufacturing process. They are carefully after treatment. commonly reported.

In most cases, these reactions are 3. Late (serum sickness type) not truly “allergic”. They are not reactions: develop 1-12 (mean 7) IgE-mediated type Ihypersensitivity days after treatment. Clinical features reactions to horse or sheep proteins include fever, nausea, vomiting, as there is no evidence of specific diarrhoea, itching, recurrent urticaria, IgE, either by skin testing or arthralgia, myalgia, lymphadenopathy, radioallergosorbent tests (RAST). periarticular swellings, mononeuritis Complement activation by IgG multiplex, proteinuria with immune aggregates or residual Fc fragments complex nephritis and rarely or direct stimulation of mast cells or encephalopathy. Patients who suffer

Management of snakebites 131 in South-East Asia (adrenaline) *adult dose 0.25mg of 0.1% Adrenaline (epinephrine) is the most solution is given just before antivenom treatment is started (see below), followed effective treatment for anaphylactic by an intravenous anti-H1antihistamines reactions, by reducing bronchospasm and such as chlorphenamine. In asthmatic patients, prophylactic use of an inhaled capillary permeability. adrenergic β2 agonist such as salbutamol may prevent bronchospasm.

6.7.5.3 Prevention of antivenom early reactions that are treated with reactions antihistamines and corticosteroid are One of only two systematic reviews less likely to develop late reactions. carried out in the field of snakebite treatment (Nuchpraryoon and 6.7.5.1 Prediction of antivenom Garner, 2000) concluded that routine reactions prophylactic adrenaline for antivenom known to have high adverse event rates Skin and conjunctival “hypersensitivity” seemed sensible, based on only one tests can only detect IgE mediated trial (Premawardhena et al., 1999) and Type I hypersensitivity to horse or that antihistamine appeared to be of sheep proteins. However, the large no obvious benefit, again based on one majority of early (anaphylactic) or trial (Fan et al., 1999). Since then, more late (serum sickness type) antivenom definitive data have been published. reactions result from direct dose- related complement activation rather 1. Prophylactic drugs (adrenaline, than from non-dose-related IgE- antihistamine anti-H1 blockers, mediated hypersensitivity, and so these corticosteroids) tests are not predictive. Since they may Adrenaline (epinephrine) is the most delay treatment and can in themselves effective treatment for anaphylactic be sensitising, these tests should not reactions, by reducing bronchospasm be used. and capillary permeability. However, the risks of adrenaline make it less attractive for prophylaxis (Rusznak and Peebles, 6.7.5.2 Contraindications to 2002). Premawardhena et al. (1999) antivenom: Prophylaxis of high risk used premedication with subcutaneous patients adrenaline in 105 snakebite victims There is no absolute contraindication to and found a reduction from 43% to antivenom treatment, but patients who 11% (p=0.04) in the incidence of have reacted to horse (equine) or sheep acute adverse reactions compared (ovine) serum in the past (for example after to placebo. No adverse reactions to

treatment with equine anti-tetanus serum, the adrenaline were observed in this equine anti-rabies serum or equine or study. However, a subsequent fatality ovine antivenom) and those with a strong (Dassanayake et al., 2002) raised history of atopic diseases (especially severe concerns about intracranial bleeding asthma) are at high risk of severe reactions (a known complication of systemic and should therefore be given antivenom envenoming following bites by vipers and only if they have signs of systemic Australian elapid snakes), hypertension envenoming. Subcutaneous epinephrine and arrhythmias if adrenaline prophylaxis

132 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES were to be used routinely especially reactions to antivenom by 43% (95% in children, pregnant women and in CI 25–67) at 1 h and by 38% (95% patients with heart disease who had been CI 26–49) up to and including 48 excluded from the trial. Gawarammana et h after antivenom administration; al. (2004) tested parallel pre-antivenom hydrocortisone and promethazine did infusion of placebo, hydrocortisone not. Adding hydrocortisone negated the alone, or hydrocortisone plus benefit of adrenaline. The plasma half- chlorphenamine in 52 patients. Reactions life of adrenaline is about 2-3 minutes. were reduced from approximately 80% However, when given by subcutaneous in the first two groups to 52% in the or intramuscular injection, local premedicated group though the results vasoconstriction may delay absorption so did not achieve statistical significance that the effects may last longer than the and the study was underpowered. A half-life suggests. randomized placebo-controlled trial of 101 patients in by Fan et al. 2. Speed and dilution of intravenous (1999) showed that premedication antivenom administration with intramuscular promethazine had The in vitro anti-complementary activity no significant effect on the high rate of several commercial antivenoms (68%) of anaphylactic reactions to led Sutherland (1977) and others to antivenom. A review of 10 years of advocate dilution and slow infusion of experience with various premedication antivenom (Reid, 1980; WHO, 1981). regimens in Papua New Guinea (Williams However, in a small randomized study, et al., 2007) further illustrates the Malasit et al. (1986) found no difference heterogeneity and lack of standardization in rate or severity of reactions in patients of snakebite victim care in developing given diluted antivenom over 30 minutes countries where most venomous compared to those in whom intravenous snakebites occur but suggested efficacy push injection over 10 minutes was used. of some prophylactic regimes, as did the In , Caron et al., 2009 found a study of Caron et al., 2009 in Ecuador. strikingly lower incidence of reactions in a group of patients premedicated A large and well-designed study was with intravenous hydrocortisone and carried out in Sri Lanka. In total, 1,007 diphenhydramine and given antivenom patients were randomized, using a 2 by infusion over 60 minutes compared x 2 x 2 factorial design, in a double- to a group of historical controls who blind, placebo-controlled trial of had been given no prophylaxis and in adrenaline (0.25 ml of a 0.1% solution whom antivenom had been injected subcutaneously), promethazine (25 intravenously over 10 minutes. In Sri mg intravenously), and hydrocortisone Lanka, 104 patients were randomly (200 mg intravenously), each alone allocated to receive antivenom by and in all possible combinations. The intravenous infusion over 20 minutes and interventions, or matching placebo, 94 by infusion over 2 hours. There was were given immediately before infusion no difference in the incidence of early of antivenom. Patients were monitored severe anaphylactic reactions in the two for mild, moderate, or severe adverse groups (32% vs. 35%; difference 3%; reactions for at least 96 h. (de Silva et 95% CI: -10% to +17%; p = 0.65). The al., 2011). Compared with placebo, frequency of mild/moderate reactions adrenaline significantly reduced severe was also similar (Isbister et al., 2012).

Management of snakebites 133 in South-East Asia Additional treatment: After epinephrine Recommendation: based on (adrenaline), patients with bronchospasm

the results of a powerful and should be given an inhaled short-acting β2 well-designed trial in Sri Lanka, agonist bronchodilator such as salbutamol routine use of prophylactic or terbutaline ideally by oxygen- adrenaline is recommended driven nebuliser) and an antihistamine

before antivenom treatment, anti-H1 blocker can be given, such as except in those older patients chlorphenamine maleate (adults 10 in whom there is evidence mg, children 0.2 mg/kg by intravenous or suspicion of underlying injection over a few minutes). Intravenous cerebrovascular disease and hydrocortisone (adults 100 mg, children when the particular antivenom in 2 mg/kg body weight) can be given, use has a proven low incidence but it is unlikely to act for several hours. of reactions (<5%). The adult Corticosteroids do not reduce the risk of dose of epinephrine (adrenaline) recurrence (biphasic) anaphylaxis (Grunau is 0.25ml of 0.1% solution (0.25 et al., 2015). mg) by sub-cutaneous injection (children 0.005 ml/kg body Anaphylaxis unresponsive to weight of 0.1% solution) (T). intramuscular epinephrine (adrenaline): a few patients may not Use of histamine anti-H1 and respond to single or repeated doses of anti-H2 blockers, corticosteroid, intramuscular epinephrine (adrenaline). and the rate of intravenous infusion of antivenom (between Patients who remain shocked and 10 and 120 minutes), do not hypotensive should be laid supine with affect the incidence or severity of their legs elevated and given intravenous early antivenom reactions (T,O). volume replacement with 0.9% saline (1-2 litres rapidly in an adult). Intravenous epinephrine (adrenaline) infusion should 6.7.5.4 Treatment of antivenom be considered [adult dose 1mg (1.0 ml) reactions of 0.1% solution in 250 ml 5% dextrose Early anaphylactic antivenom or 0.9% saline - i.e. 4 μ (micro) g/ml reactions: Epinephrine (adrenaline) is concentration) - infused at 1–4 μ (micro) given intramuscularly (ideally into the g/minute (15–60 drops/min usin a upper lateral thigh) in an initial dose microdropper burette chamber), increasing of 0.5 mg for adults, 0.01 mg/kg body to maximum 10 μ (micro) g/min] and, weight for children. Because severe, in patients who remain hypotensive, a life-threatening anaphylaxis can evolve vasopressor agent such as dopamine [dose so rapidly, epinephrine (adrenaline) 400mg in 500ml 5% dextrose or 0.9% should be given at the very first sign of saline infused at 2–5 μ (micro) g/kg/min]. a reaction, even when only a few spots of urticaria have appeared or at the start Patients who remain dyspnoeic, with of itching, tachycardia or restlessness. bronchospasm or angioedema, should The dose can be repeated every 5-10 be propped up at 45 degrees and given minutes if the reaction persists or the supplemental oxygen by any available symptoms become worse. Adrenaline has route together with optimal nebulised/ proved safe in pregnant women, whereas inhaled and/or parenteral bronchodilator

anaphylaxis can induce abortion. (β2 agonist) (Kemp and Kemp 2014).

134 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Pyrogenic reactions: the patient must 6.7.6 Supply, selection, storage and be cooled physically (remove clothing, shelf-life of antivenom tepid sponging with fanning) and given an Supply: it is important to determine antipyretic (e.g. paracetamol by mouth or how much antivenom remains unused suppository). Intravenous fluids should be at the end of each year in different parts given to correct hypovolaemia. Patients who of the country, to allow the calculation also exhibit features of anaphylaxis should of antivenom requirements, and the be given adrenaline as well (see above). efficient deployment of adequate stocks of this scarce resource to areas where it is most needed. Adequate buffer stocks At the earliest sign of a reaction: are mandatory in areas where natural disasters, such as the annual floods • Antivenom administration in Bangladesh, cause epidemics of must be temporarily snakebite. These provisions will reduce suspended preventable deaths. Adequate training • Epinephrine (adrenaline) of medical personnel in the rational use (0.1% solution, 1 in of antivenom is important to reduce 1 000, 1 mg/ml) given by mortality and morbidity and minimise intramuscular injection is wastage. the effective treatment for early anaphylactic antivenom Selection: Polyvalent (polyspecific) reactions antivenoms are preferred in many countries because of the difficulty in identifying species responsible for Completion of administration of bites. They can be just as effective antivenom dose: as monovalent (monospecific) ones. After the patient has recovered from the An antivenom should be given only early anaphylactic or pyrogenic reaction, the if its stated range of specificity and indications for antivenom therapy should paraspecific neutralization includes be critically re-examined. If antivenom is the species known or suspected to still indicated, intravenous administration have been responsible for the bite. If should be cautiously resumed until the total the biting species is known, the ideal dose has been given. treatment may be with a monovalent (monospecific) antivenom, as this may Treatment of late (serum sickness) be less expensive and may involve reactions: Late (serum sickness) reactions administration of a lower dose may respond to a 5-day course of oral of antivenom protein than with a antihistamine. Patients who fail to respond polyvalent (polyspecific) antivenom. within 24-48 hours should be given a However, immunisation of a horse or 5-day course of prednisolone. sheep with venoms of several related species of snakes (e.g. Viperidae) Doses: Chlorphenamine: adults 2 mg six may produce an enhanced antibody hourly, children 0.25 mg/kg /day in divided response to common antigens, making doses. the resulting polyvalent antivenom more rather than less potent than a Prednisolone: adults 5 mg six hourly, monovalent antivenom (Raweerith children 0.7 mg/kg/day in divided doses and Ratanabanangkoon, 2005; WHO, for 5-7 Days 2010).

Management of snakebites 135 in South-East Asia Storage and shelf-life: to retain their Freeze-dried (lyophilised) antivenoms full potency within the limits of stated are reconstituted, usually with 10 ml of expiry dates, lyophilised antivenoms sterile water for injection per ampoule. (shelf life about 5 years) should be stored If the freeze-dried protein is difficult to at below 25ºC and liquid antivenoms dissolve, it may have been denatured by (shelf life 2-3 years) should be stored a faulty freeze-drying technique during at 2-8 ºC and not frozen. Ideally, manufacture (WHO, 2010). antivenoms should be used before the stated expiry dates but, provided that Two methods of administration are they have been properly stored, they can recommended: be expected to retain useful activity for months or even years after these dates 1. Intravenous “push” injection: (WHO, 1981; O’Leary et al., 2009). TRC reconstituted freeze-dried antivenom antivenoms retain their potency after 5 or neat liquid antivenom is given by years even when stored temperatures slow intravenous injection (not more of 25-50 °C (Prof Sumana Komvilai, than 2 ml/minute). This method has personal communication). the advantage that the doctor, nurse, or dispenser giving the antivenom must In patients with severe envenoming, remain with the patient during the recently expired antivenoms may time when some early reactions may be used if there is no alternative. develop. It is also economical, saving However, liquid antivenoms that have the use of intravenous fluids, giving become opaque or which contain sets, cannulae etc. visible particles should not be used as precipitation of protein indicates 2. Intravenous infusion: reconstituted loss of activity and an increased risk of freeze-dried or neat liquid antivenom is reactions. diluted in about 5 ml of isotonic fluid per kg body weight (i.e. about 250 ml 6.7.7 Administration of antivenom of isotonic saline or 5% dextrose in the case of an adult patient) and is infused at a constant rate over a period of • Epinephrine (adrenaline) about 30-60 minutes. should always be available at the bed-side, ideally drawn up in readiness, Patients must be closely observed before antivenom is for at least one hour after administered. starting intravenous antivenom administration, so that early • Antivenom should be given anaphylactic antivenom reactions by the intravenous (iv) route can be detected and treated early whenever possible, either with epinephrine (adrenaline). by slow iv “push” injection (maximum 2 ml/minute) Local administration of antivenom or by iv infusion diluted in at the site of the bite is not about 5 ml of isotonic fluid recommended! Although this per kg body weight over route may seem rational, it about 30-60 minutes. should not be used as it is

136 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES extremely painful, may increase 1 Vial Fab Antivenom I.V.I. Compared with 1 Vial I.M.I. intracompartmental pressure and (9 patients via each route) proved to be much less effective 0.5 than by the intravenous route (O). Fab AV I.V. Fab AV I.M.

0.4

Intramuscular injection of antivenom: 0.3 Antivenoms are large molecules, [F(ab’)2 fragments or sometimes whole IgG] which, after intramuscular injection, are absorbed 0.2 slowly via lymphatics. Bioavailability is Fab antivenom (ul/ml) Fab poor, especially after intragluteal injection, 0.1 and blood levels of antivenom never reach those achieved rapidly by intravenous 0 0 1 3 6 12 24 48 administration (Fig 81) Theakston Time after antivenom (hr) RDG, Warrell DA unpublished). Other disadvantages are the pain of injection of large volumes of antivenom and the risk of haematoma formation in patients with Figure 81: Comparison of intravenous and intramuscular administration of an haemostatic abnormalities. Fab fragment antivenom. Antivenom administered intramuscularly appeared slowly in the bloodstream (dashed line) compared to that given by the intravenous route (solid line). (RDG Theakston and DA Warrell unpublished data). The only situations in which intramuscular administration might be considered is in the absence of anyone capable of giving an Antivenom should never be intravenous injection: injected into the gluteal region (upper outer quadrant of 1. at a peripheral first aid station, before the buttock) as absorption is a patient with obvious envenoming is exceptionally slow and unreliable put in an ambulance for a journey to and there is always the danger hospital that may last several hours of sciatic nerve damage when (Win-Aung et al., 1996); the injection is given by an 2. on an expedition exploring a remote inexperienced operator. area very far from medical care; 3. when intravenous access has proved impossible. Under these exceptional circumstances, the dose of antivenom should be divided Although the risk of antivenom reactions between a number of sites in the upper is less with intramuscular than intravenous anterolateral region of both thighs. A administration, epinephrine (adrenaline) maximum of 5-10 ml should be given at must be readily available each site by deep intramuscular injection followed by massage to aid absorption. Local bleeding and haematoma formation Antivenom must never be given is a problem in patients with incoagulable by the intramuscular route if it blood. Finding enough muscle mass to could be given intravenously. contain such large volumes of antivenom is particularly difficult in children.

Management of snakebites 137 in South-East Asia 6.7.8 Dosage of antivenom “push” injection, is followed by infusion (Table 1 and Annex 3) of 4 vials over 4 hours, and, as long as Initial dose of antivenom signs of envenoming persist, 4 vials over A fundamental piece of information for 4 hours every 4 hours for a further 12 those treating envenomed patients is hours, followed by 2 vials over 4 hours, the average initial dose of a particular repeated until recovery. Following this antivenom appropriate for different regimen, cumulative doses may reach 140 levels of clinical severity in patients bitten vials (1000 ml) in patients with neurotoxic by different species. Unfortunately, envenoming by kraits (Magar et al., 2013). these data, based on clinical trials, are A recent study in Nepal compared the rarely available. In any case, since the effectiveness and safety of this regimen neutralizing power of antivenoms varies with a single higher initial dose of 10 from batch to batch, and between vials given over 1 hour in patients with different antivenoms, the results of a neurotoxic envenoming. There was no clinical trial may soon become obsolete if statistically significant difference between the manufacturers change the strength the two regimens in the proportion of of their antivenom. This happened patients reaching the primary endpoint in Myanmar in the 1990s, when the (48.7% in the low initial dose arm national producer arbitrarily halved the versus 38.5% in the high initial dose strength of their antivenom. As a result, arm, p=0.264). Likewise, there was no medical personnel must usually rely difference in the incidence of antivenom on manufacturers’ recommendations reactions (53.8% of patients given the stated in the package insert. These high dose compared to 52.6% given the are usually based on laboratory assays low initial dose). Among the 51 patients in which venom and antivenom are in whom the snake species could be incubated in vitro before being injected identified, 29 had been bitten by cobras into the test animals, usually mice. The (Naja spp) and 22 by kraits (Bungarus recommended dose is usually the amount spp.). Patients bitten by kraits were more of antivenom required to neutralize the severely envenomed and recovered less average venom yield when captive snakes often (40.9% versus 96.5%, p<0.001) are milked of their venom, but, quite and more slowly (mean recovery time 18 apart from many theoretical objections hours versus 5 hours, p<0.001) than did to this protocol, the maximum venom patients bitten by cobras. These findings yield may be seriously underestimated suggested that there was no difference in (Tun Pe and Khin Aung Cho, 1986). effectiveness and safety between initially In practice, the choice of an initial low and high doses of antivenom for dose of antivenom is usually empirical. neurotoxic snakebite in southern Nepal, Some antivenom dosage regimens and that systemic envenoming due to krait recommended in national management bites was less responsive to antivenom guidelines seem illogical, based on what than that following cobra bites (Alirol E, is known of the pharmacokinetics and Sharma SK et al., in press). Since the high pharmacodynamics of venom-antivenom single initial dose was non-inferior to the interactions. low initial dose (but much higher total dose), the former is preferred on grounds Nepal: the Nepalese national guidelines of cost and convenience. recommend prolonged and repeated dosage of antivenom. An initial dose India: there have been many publications of 2 vials of antivenom given by IV on treatment of snakebite with national

138 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES polyvalent antivenoms, but there is little reliable evidence to guide initial dosage. In clinical practice, the dose of antivenom Manufacturers’ recommendations are based on the amount of venom (mg) used is very variable. In government neutralized by 1 ml of antivenom. The hospitals where antivenom is freely Indian national snakebite protocol (Directorate General of Health Services, available, higher doses of antivenom are 2009) and previous editions of WHO prescribed, often exceeding 20 vials. guidelines recommend immediate administration of 5 vials, and a recent consensus 4-6 vials (Menon et al., 2916b) was effective in permanently restoring in the case of Echis carinatus; and 10 blood coagulability. Subsequently, in vials for patients envenomed by the 2003-4, a retrospective study of 225 C. other species, with repeated dosing if the rhodostoma victims suggested that 4-9 patient fails to improve, to a maximum vials of Thai Red Cross (TRC) Malayan Pit of 20 vials. There are no adequately Viper antivenin was effective in correcting designed dose finding studies that selected coagulopathy and systemic symptoms snakebites by identified species, controlled but appeared to do little to counteract for clinical severity, were randomised local tissue necrosis (Wongtongkam et and employed defined clinical end points al., 2005). In a small observational study, including measurement of antigaenemia an average dose of 165 (+/- 59.3) ml of (Warrell, 2011). In clinical practice, the TRC Russell’s Viper antivenin corrected dose of antivenom used is very variable. In blood incoagulability in a group of 38 government hospitals where antivenom is patients envenomed by D. siamensis. The freely available, higher doses of antivenom authors recommended that 60 ml of this are prescribed, often exceeding 20 vials. antivenom should be administered at Other non-profit rural hospitals use a low 6-hour intervals until blood coagulability dose regimen of less than 10 vials in view was restored (Karnchanachetanee et of the high cost and scarcity of antivenom. al., 1994). In the case of cobra (Naja Several randomised controlled trials from kaouthia) bite victims with respiratory such hospitals claimed to demonstrate paralysis, envenoming, treated between that lower doses were equally effective 1981 and 1991, a single dose of 100 ml in victims of predominantly haemotoxic of TRC Cobra antivenin reduced time on snakebites in South India in (Thomas and a respirator from approximately 40 h if Jacob, 1985; Tariang et al., 1999; Paul et no antivenin or an inadequate dose was al., 2004; Srimannarayana et al., 2004; used to 10h (Pochanagool et al., 1997). Cherian et al., 2013). However, these Increasing the dose did not lead to added studies, without exception, had severe benefits. In victims of Trimeresurus (T.) limitations in patient slection and case albolabris or T.(T.) macrops, 50 ml of TRC definition, snake species identification, Green Pit Viper antivenin rapidly corrected design, end-points and power, rendering coagulopathy (Hutton et al., 1990). A their results uninterpretable. large retrospective review of patients envenomed by these species found that Thailand: in 1984, a small randomised TRC Green Pit Viper antivenin given on controlled trial was carried out in patients average 21 hours after the bite for the with systemic C. rhodostoma envenoming, treatment of severe coagulopathy did not comparing three antivenoms that were affect the risk of their developing local then available. An initial dose of 5 vials necrosis (Chotenimitkhun and Rojnuckarin,

Management of snakebites 139 in South-East Asia 2008). A randomized, double-blind, geographical intra-species venom placebo-controlled trial of TRC Green Pit variation, lack of adequate neutralizing Viper antivenin in patients bitten by these antibodies against key toxic venom Trimeresurus species who had marked proteins, inability of the antibodies to limb swelling, but no severe coagulopathy neutralize toxins that are tissue bound or suggested that antivenom accelerated to reverse the pathological consequences resolution of local swelling, although not of tissue injury. Envenoming by the larger to a clinically useful degree (Rojnukarin et northern sub-species of saw-scaled viper al., 2006). (Echis carinatus sochureki) requires larger antivenom doses (Kochar et al., 2007) and envenoming by Russell’s vipers in Reasons for antivenom Kerala and Maharashtra require higher ineffectiveness antivenom doses (Warrell et al., 2013). Biochemical studies have shown variations There is an urgent need for in venom composition in different parts well-designed and adequately- of India for Naja naja (Mukherjee and powered national clinical dose- Maity., 1998; Shashidharamurthy and finding studies to establish Kemparaju, 2007) and Daboia russelii initial doses of antivenom for (Jayanthi and Gowda, 1988; Prasad et al., patients with different severities 1999). Antivenom raised against venom of envenoming by the major from one geographical location may not medically important species in be as effective against envenoming in the Region. These should focus other geographical locations. In India, on bites by reliably-identified most of the venom used for antivenom species, should be randomised, manufacture is obtained from the Irula comparing two doses of the cooperative in Mammallapuram (Warrell same antivenom or two different et al., 2013). A recent comparison of two antivenoms, should have commercially available antivenoms showed objective end-points to assess that one had a higher protein content, and effectiveness and safety, and antibody binding and neutralizing capacity should, ideally, be blinded to for Echis carinatus and Daboia russellii exclude bias. venom. Indian polyvalent antivenoms are raised against venoms of the classic “big four” species and may not neutralize There have been anecdotal and venoms of other medically important unpublished reports of clinical snakes, such as monocellate cobra (N. ineffectiveness of individual batches of kaouthia) in the North-East and any of the antivenom. The variable efficacy may Indian pit-vipers, notably the hump-nosed be due to lower antibody titre, reduced pit-viper (Hypnale hypnale) and Malabar antibody binding specificities and lack pit-viper (Trimeresurus (Craspedocephalus) of antibodies to low molecular weight malabaricus) of the south-west coast. proteins. Studies have shown batch to batch variability in effectiveness Suggested initial doses of some of of Indian antivenoms, manifested by the available antivenoms are given in increased complications and mortality Table 1 (by species of snake), based with particular batches (Zachariah A, on clinical experience; and in Annex 3 personal communication; Zacharaiah, (by country),based on manufacturers’ 2015). Possible explanations include recommendations.

140 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Table 1: Guide to initial dosage of some antivenoms for treating bites by medically-important snakes in the South-East Asia Region, based on clinical experience, rather than manufacturers’ recommendations (E)

Latin name English Name Manufacturer, antivenom Approximate average initial dose Acanthophis species death adder CSL1 Death Adder or Polyvalent Antivenom 1-3 vials Bungarus caeruleus common krait Indian manufacturers2 polyvalent 100 ml Bungarus candidus Malayan krait TRC3 Malayan Krait Antivenin Mono 50-100 ml OR TRC3 Neuro Polyvalent 100 ml Bungarus fasciatus banded krait TRC3 Malayan Krait Antivenin 50-100 ml OR TRC3 Neuro Polyvalent 100 ml Bungarus multicinctus Chinese krait Shanghai Vaccine & Serum Institute 5 vials NIPM Taipei Naja-Bungarus antivenin 5 vials Calloselasma () Malayan pit viper TRC3 Malayan Pit Viper Antivenin Monovalent 30-50 ml rhodostoma OR TRC3 Hemato Polyvalent 30-30 ml Daboia russelii Western Russell’s viper Indian manufacturers2 polyvalent 100 ml Daboia siamensis Eastern Russell’s viper Myanmar Pharmaceutical Factory 80 ml TRC3 Russell’s Viper Antivenin Monovalent 30-50 m OR TRC3 Hemato Polyvalent 30 ml Echis carinatus India saw-scaled viper Indian manufacturers4 polyvalent 50 ml Gloydius (Agkistrodon) Chinese Mamushi Shanghai Vaccine & Serum Institute brevicaudus Mamushi antivenom 1 vial Hydrophiinae sea snakes CSL1Sea 1-10 vials Micropechis ikaheka New Guinean CSL1 Polyvalent Antivenom 2 vials small-eyed snake Naja kaouthia monocellate Thai cobra TRC3 Cobra Antivenin Mono 100 ml OR TRC3 Neuro Polyvalent 100 ml Naja naja, N oxiana Indian cobras Indian manufacturers2 polyvalent 50 ml Ophiophagus hannah king cobra TRC3 King Cobra Antivenin Mono 100 ml OR TRC3 Neuro Polyvalent 100 ml Oxyuranus scutellatus Australian/Papuan CSL1 Taipan or Polvalent Antivenom 1-6+ vials Pseudonaja species Australian brown CSL1 Brown Snake or Polyvalent 1-2 vials snakes Antivenom\ Pseudechis species Australian black snakes CSL1 Black Snake Antivenom 1-3 vials Rhabdophis tigrinus, Japanese yamakagashi, Japanese Snake Institute, Nitta-gun R. subminiatus SE Asian red-necked Yamakagashi antivenom 1-2 vials keelback Trimeresurus (T.) albolabris Green pit-vipers TRC3 Green Pit Viper Antivenin 30-50 ml T. (T.) macrops etc. OR TRC3 Hemato Polyvalent 30-50 ml

1 CSL, Parkville, Australia http://www.toxinology.com/fusebox.cfm?staticaction=generic_static_files/avp-csl-01. 2 Indian Manufacturers: Bharat Serums & Vaccines, Mumbai https://www.bharatserums.com/; Central Research Institute, Kasauli http://www. nti.org/learn/facilities/145/ ; Haffkine Biopharma, Mumbai; Serum Institute of India, Pune http://www.seruminstitute.com/content/products/ product_list.htm ; Vins Bioproducts, Hyderabad: Premium Serums and Vaccines, Narayangaon http://www.premiumserums.com/ 3 Thai Red Cross, Queen Saovabha Memorial Institute, , Thailand http://www.snake-antivenin.com/

Management of snakebites 141 in South-East Asia f) Active haemolysis and Snakes inject the same dose rhabdomyolysis may cease within a of venom into children and few hours and urine colour returns to adults. Children must therefore normal. be given exactly the same dose of antivenom as adults 6.7.9 Recurrence of systemic Antivenom manufacturers, health envenoming institutions and medical research In patients envenomed by vipers, organizations should encourage after an initial response to antivenom and promote the proper clinical (cessation of bleeding, restoration of testing of antivenoms as with blood coagulability), signs of systemic other therapeutic agents. This envenoming may recur within 24-48 hours. is the only reliable guide to the initial dose (and safety) of an This is attributable to: antivenom. 1. continuing absorption of venom from the “depot” at the site of the bite, perhaps promoted by improved blood Observation of the response to supply following correction of shock, antivenom: If an adequate dose of hypovolaemia etc., after elimination an appropriate antivenom has been of antivenom (range of elimination

administered, the following responses may half-lives: IgG 45 hours; F(ab’)2 80-100 be seen. hours; Fab 12-18 hours) (Ho et al., 1986; Ho et al., 1990) a) General: the patient feels better. Nausea, headache and generalized 2. redistribution of venom from the aches and pains may disappear very tissues into the vascular space, as the quickly. This may be partly attributable result of antivenom treatment (Rivière to a placebo effect. et al.,1997). b) Spontaneous systemic bleeding (e.g. from the gums) usually stops Recurrent neurotoxic envenoming after within 15-30 minutes. treatment of cobra bite has also been c) Blood coagulability (as measured described. by 20WBCT) is usually restored in 3-9 hours. Bleeding from new and partly 5.7.10 Criteria for repeating the initial healed wounds usually stops much dose of antivenom sooner than this. d) In shocked patients, blood pressure Criteria for giving more may increase within the first 30-60 antivenom minutes and arrhythmias such as sinus bradycardia may resolve. • Persistence or e) Neurotoxic envenoming of the post- recurrence of blood synaptic type (cobra bites) may begin incoagulability after 6 hr or to improve as early as 30 minutes after of bleeding after 1-2 hr antivenom (Faiz et al., cobra bites in • Deteriorating neurotoxic press), but may take several hours. or cardiovascular signs Envenoming by presynaptic toxins after 1 hr (kraits and sea snakes) will not respond in this way.

142 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES If the blood remains incoagulable periods of more than one month. Manual (as measured by 20WBCT) six hours ventilation (anaesthetic bag) by relays after the initial dose of antivenom, the of doctors, medical students, relatives same dose should be repeated. This is and nurses has been effective where based on the observation that, if a large no mechanical ventilator was available. dose of antivenom (more than enough Anticholinesterases should always be tried to neutralize the venom procoagulant (see below). enzymes) is given initially, the time taken for the to restore coagulable levels of Haemostatic abnormalities - strict bed fibrinogen and other clotting factors is 3-9 rest to avoid even minor trauma including hours. intramuscular injections; transfusion of clotting factors and platelets; ideally, fresh In patients who continue to bleed frozen plasma (FFP) or cryoprecipitate briskly, the dose of antivenom should be with platelet concentrates or, if these are repeated within 1-2 hours. not available, fresh whole blood. The indications for these blood components In case of deteriorating neurotoxicity are the same as those for antivenom or cardiovascular signs. There is no administration for bleeding tendency, but evidence to guide the exact timing for it is important to recognize that, in the repeating the dose of antivenom for presence of un-neutralized circulating paralysis or shock, but it seems reasonable venom procoagulant toxins, administered to repeat the initial dose after 1 hour if the clotting factors will be rapidly consumed, patient’s condition is deteriorating. Full with the potential danger of formation of supportive treatment must be considered. microthrombi. Repeating doses of antivenom after the patient is paralysed and being ventilated Shock, myocardial damage: has no proven value, increases the risk hypovolaemia should be corrected of reactions, is expensive and wastes a with colloid/crystalloids, controlled by valuable resource. observation of the central venous pressure. Ancillary pressor drugs (dopamine or 6.8 Conservative treatment epinephrine-adrenaline) may also be when no antivenom is needed. Patients with hypotension available associated with bradycardia should be This will be the situation in many parts of treated with atropine. the Region, where supplies of antivenom run out or where the bite is known to Acute kidney injury: conservative have been inflicted by a species against treatment or dialysis (see below). whose venom there is no available specific antivenom. Dark brown urine (myoglobinuria or haemoglobinuria): correct hypovolaemia The following conservative measures are with intravenous fluid, correct acidosis suggested: with a slow intravenous infusion of 50-100 mmol of sodium bicarbonate. Neurotoxic envenoming with respiratory paralysis: assisted Severe local envenoming: local ventilation. This has proved effective, necrosis, intracompartmental syndromes and has been followed by complete and even thrombosis of major vessels recovery, even after being maintained for is more likely in patients who cannot

Management of snakebites 143 in South-East Asia be treated with antivenom. Surgical antivenom and fresh-frozen intervention may be needed but the risks plasma or clotting factors will be of surgery in a patient with consumption needed to control bleeding after this coagulopathy, thrombocytopenia and procedure.) enhanced fibrinolysis must be balanced against the life threatening complications In urgent situations where acute airway of local envenoming. Prophylactic broad obstruction has developed and where spectrum antimicrobial treatment is the patient cannot be intubated, justified (see below). cricothyroidotomy will establish an airway faster than tracheostomy. 6.9 Supportive/ancillary treatment Antivenom treatment can be expected to Although artificial ventilation was neutralize free circulating venom, prevent first suggested for neurotoxic progression of envenoming and allow envenoming 140 years ago, recovery. However, these processes take patients continue to die of time and the severely envenomed patient asphyxiation because some may require life support systems such as doctors believe that antivenom treatment of shock, assisted ventilation alone is sufficient treatment. and renal dialysis until the severely damaged organs and tissues have had time to recover. 6.9.2 Practical guide to airway management and respiratory support 6.9.1 Treatment of neurotoxic The following guidelines have been envenoming produced specifically to aid health care workers in the acute management of snakebite patients. However, it is Antivenom treatment alone important to recognize that the techniques cannot be relied upon to save the described below are applicable to the care life of a patient with bulbar and of all critically ill patients. respiratory paralysis. The techniques discussed below are not complicated. However, expert instruction Death may result from aspiration, airway is desirable, ideally from a fully trained obstruction or respiratory failure. A doctor, nurse, first-aid worker or other clear airway must be maintained. Once health professional, with experience in there is loss of gag reflex and pooling resuscitation, airway management, use of secretions in the pharynx, failure of of the necessary equipment, intubation the cough reflex or respiratory distress, and assisted ventilation. These techniques a cuffed endotracheal, laryngeal mask must be practised frequently, under airway or i-gel supraglottic airway should supervision, using a manikin (dummy/ be inserted. If this is impossible for model – see Fig 82a) or, but only where any reason, or the need for prolonged appropriate and culturally acceptable, a ventilation is anticipated, a tracheostomy dead body in the mortuary, to acquire should be performed and a snugly- essential understanding of the fitting or cuffed tracheostomy tube of the upper airway and the techniques inserted (Caution – in patients with themselves, and to maintain an adequate uncorrected coagulopathy, more baseline level of skill (Fig 82b).

144 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Importance of training (Fig 82a)

Figure 82b: Anatomy of the upper airway

Resuscitation This follows the general principles of life support given below:

DRABCDE D - DANGER R - RESPONSE A - AIRWAY B – BREATHING C - CIRCULATION D - DISABILITY Figure 82: Treatment of neurotoxic envenoming: (a) Training health workers in E – EXPOSE THE PATIENT techniques of endrotracheal intubation and airway management in Papua New (Only DRAB are discussed here) Guinea (Copyright DJ Williams)

D - DANGER - Scene safety: The If there is no response, or limited response, rescuer should ensure that there is no summon assistance. Call out for help, send risk of exposure to danger of a further someone for medical assistance, or make a snakebite to the victim, to themselves, very quick telephone call. or to other helpers by observing standard precautions possible under the Making an emergency call circumstances (e.g. removing the victim If the victim does not respond: from undergrowth and, in the case of 1. In a field situation: emergency medical sea snakebite, removal from the water services (EMS) are activated by calling to avoid drowning) and ensuring that the local emergency number (either any snake brought to hospital with the by a second rescuer or by the first patient, for identification, will not bite rescuer him/herself). The response another person. team (ambulance) is asked to bring the necessary resuscitation equipment (also R - RESPONSE -The rescuer checks termed “code cart” or “code blue cart” responsiveness of the victim (e.g. vocal - in some hospitals/clinics), including an “Are you all right?”, with gentle shaking). automated external defibrillator (AED).

Management of snakebites 145 in South-East Asia 2. In a health centre: emergency cart catheter (attempts should not be longer and defibrillator are summoned. Once than 10 seconds) or by using forceps. the EMS/emergency cart has been Use of a gloved finger is discouraged summoned, the rescuer starts airway as this may push the material or object management further down the airway and may put the rescuer at risk of being bitten. A – AIRWAY PROTECTION AND MANAGEMENT Finally, insert an oropharyngeal (Guedel) Basic Airway Management (BAM) airway (OPA), measured to suit the Opening and maintaining the airway: patient (from the corner of the mouth The airway can be opened using the to the angle of the jaw), being sure to “head tilt - chin lift” manoeuvre (Fig avoid causing trauma to the lips and 82c), bringing the patient’s head into the mouth, especially if there is evidence of “sniffing” position. If there is any suspicion bleeding or the if the patient has been of cervical spine trauma, jaw thrust should bitten by a snake which causes bleeding be used rather than this procedure. abnormalities. While nasopharyngeal airway (NPA) devices are better tolerated by semi-conscious patients, who may still have a gag reflex, or in those who have trismus, they are more likely to cause nasal bleeding, and so are not preferred.

If an OPA device cannot be inserted because of trismus (rigidity of the chewing muscles, preventing opening of the mouth), the patient may have one of Figure 82c: Head-tilt, chin-lift (left) and jaw-thrust manoeuvres (right) the following life-threatening conditions, which must be urgently treated: If this does not improve air flow, the “jaw thrust” manoeuvre (Fig 82c) should be • Severe hypoxia; performed as the tongue may have fallen • Hypoglycaemia; or been sucked backwards, obstructing the • Seizure; oropharynx. “Jaw thrust” helps to lift the • Active rhabdomyolysis affecting tongue forward, and is often effective in the masseter muscles (e.g. in sea- improving air flow as lifting the patient’s snakebite envenoming) chin and extending their neck serves to • Or they may, in fact, be awake and dislodge the tongue and reopen the upper simply resisting you. airway. Advanced Airway Management Next look inside the victim’s mouth. (AAM) There may be blood, vomit or excessive AAM is defined as the use of more oral secretions contributing to airway advanced techniques in airway obstruction and putting the patient at management. It may be used in the risk of aspirating (inhaling) this material following circumstances: into their lungs. Remove any foreign material by suction, using a suitable • To maintain (keep open) the airway suction catheter, such as a Yankeur suction over long periods;

146 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES • To protect the airway (prevent the inhalation/pulmonary aspiration of , vomit or blood):

• To ventilate a paralysed patient (such as after a bite by a snake with neurotoxic venom);

• To allow high concentrations of oxygen (up to 100%) to be delivered;

• To remove, and control the concentration of, dioxide in the Figure 82d: “Supraglottic (above the larynx) devices” Laryngeal mask airway, blood. introduction and position

work, but they may not be freely available Indications for intubation in peripheral hospitals. They do not require [insertion of endotracheal tube special equipment to insert them, and (ETT) or other airway]: even medically untrained people can be taught to insert them successfully after a. Imminent respiratory arrest minimal (as little as one hour’s) tuition, (breathing is absent or making them potentially ideal in a low-skill inadequate) setting. However, they not provide good b. Neck muscle weakness protection of the airway as, potentially, with shallow respiration or fluids can still leak past them into the paradoxical breathing patient’s lungs. They do not permit high c. Upper airway obstruction ventilation/airway pressures, and require with stridor (secondary to a gastric tube to reduce the risk of gastric anaphylaxis) insufflation (distension with gas) and the d. Oxygen saturation <90% risk of gastro-oesophageal reflux.

(equivalent to Pa02 <60 mmHg) despite high flow i-gel supraglottic airway. i-gel oxygen airways are made of a thermoplastic e. Blood gas measurement elastomer, which is soft, gel-like and showing respiratory acidosis transparent. They are designed to create

(hypoxia PaO2 < 60 mm Hg a non-inflatable anatomical seal of the

with PaCO2 > 45 mm Hg) pharyngeal, laryngeal and perilaryngeal structures. Insert with the i-gel cuff outlet facing towards the patient’s chin with The devices used for this type of airway head extended and neck flexed in the management are divided into 2 categories: “sniffing” position (see above). Glide the device downwards and backwards Supraglottic (above the larynx) along the hard palate with a continuous devices (Fig 82d) but gentle push until a definitive Laryngeal mask airways. Many resistance is felt. At this point the tip of models with different features benefits the airway should be located into the and disadvantages are now available, upper oesophageal opening and the cuff depending on the country in which you should be located against the laryngeal

Management of snakebites 147 in South-East Asia (Fig 82e) i-gel supraglottic airway and hence the risk of hypoxia) experience is required.

Induction/intubation drugs should be used, though these may not be available or the staff may not be experienced in their safe use.

Discussion of the actual techniques involved is beyond the scope of this document. However, essentially an endotracheal tube is inserted under laryngoscopic vision between the vocal cords so that its tip lies in the mid trachea (Fig 82f).

An endotracheal tube is inserted under laryngoscopic vision between the vocal Figure 82e: Treatment of neurotoxic envenoming i-gel supraglottic airway cords so that its tip lies in the mid trachea. Intubation is more invasive than supra- glottic devices and needs laryngoscopy framework. The incisors should be resting and more skill to perform. on the integral bite-block. Surgical airway devices Infraglottic (extending below the (tracheostomy) larynx) devices: These are discouraged and are rarely The most familiar, and by far the most necessary because: readily available, is the endotracheal tube (ETT), typically a cuffed tube for adults and Patients rarely require ventilation beyond an uncuffed tube for children, though the a week, once the correct type and dose use of cuffed (low pressure, high volume) of antivenom has been given; Many tubes for children is becoming more patient venom-induced bleeding disorders acceptable. and will bleed excessively from any such

These do provide protection of the lower airway (the lungs) against contamination by fluids and also permit higher ventilation pressures and the highest inspired oxygen concentrations.

However, they require a laryngoscope of some sort to permit visualization of the laryngeal structures, and even the most basic of these are not available in small health centres.

To insert these devices safely and quickly (to reduce the period of no ventilation, Figure 82f: Insertion of an endotracheal tube

148 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES intervention. Therefore, “tracheostomy” If breathing stops at any time, lay the is a term that should be removed from victim supine, go through the airway snakebite management protocols. opening manoeuvres again, and then provide breathing artificially, if required. B – BREATHING – Assessing breathing: Place your ear near the victim’s mouth If breathing is absent or inadequate, such and nose, keeping your gaze towards as if: the victim’s chest. Look for chest to rise and fall, listen for air escaping during exhalation, feel for the flow of air against your cheek. Take at least 5 seconds but no more than 10 seconds to make this assessment.

If oxygen is available, it should be administered by any available means (nasal Figure 82g: The recovery position prongs/catheters, mask, bag-valve-mask etc.) between each suctioning attempt • No breathing is discernible within 10 (which should not be prolonged). [Arterial seconds (or 5 seconds in a child, 2 Peripheral oxygen saturation (SpO2) seconds in a baby); should be monitored by digital oximeter, if available.] • The respiratory rate is low (a general idea of normal ranges of age-related Positioning the patient to protect airway respiratory rates and other basic patency (Dangers of vomiting and physiological parameters is required aspiration) of all health care workers, or this information should be readily available If breathing is present and adequate (with to them); or without airway opening manoeuvres), put the victim in the recovery position (Fig • The depth of respiration is inadequate 82g) and keep checking for breathing (shallow) (the tidal volume is low); every 2 minutes. This position and a chin- up tilt can be maintained using pillows, • The patient is taking agonal (gasping) sand bags or an assistant, often the breaths; patient’s relative. The recovery position is especially important in envenomed patients • The patient is cyanosed centrally (blue because vomiting is such a common early lips, ears, or tongue) (this might not symptom, oral bleeding is common if be visible if the patient is very anaemic, there is a bleeding disorder, there may be such as from malnutrition, chronic hypersalivation and, since patients with malaria or chronic gastrointestinal neurotoxicity cannot cough or swallow, parasite infestation), or they are at increased risk of inhaling any of these secretions and fluids. However, when • The measured blood peripheral oxygen the patient is placed in the correct recovery saturation is low (a poor trace, and position, these fluids will drain harmlessly so a potentially low reading, may from their mouth. The recovery position be obtained if the patient has cold will also help to stop the tongue from peripheries or a low blood pressure falling back and blocking the airway. -shock);

Management of snakebites 149 in South-East Asia patient’s mouth and deliver a breath over If chest movement is inadequate, a a second, enough to see the chest rise, and allowing 4 seconds for exhalation correctly-sized OPA should be inserted. before giving a second breath. In the case This will usually assist with air flow in and of a small child the mouth and nose may be covered by the rescuer’s mouth. out of the lungs. If there is no bleeding disorder, a NPA (or 2) may be used instead Assisted ventilation by this means will provide a maximum of approximately only of, or in addition to, an OPA. 16% inspired oxygen concentration (FIO2 0.16).

• The end-tidal CO2, by whichever The risk of communicable disease method is being used, is high, or transmission to the rescuer is low, but can climbing; be diminished further by the use of:

ASSISTED VENTILATION IS REQUIRED! • A special EAR face shield, How this is delivered will depend on: manufactured for this purpose; • A mask of the type used with Bag- • The clinical circumstances, i.e. whether Valve-Mask (devices); the patient is in the bush, in an small • A piece of cloth thin enough to allow health centre or in a hospital; for the free passage of air. • The skills of the rescuer; • The availability of assistants; If the patient does not begin to breathe, or • Equipment available. to breathe more effectively, at this point, the decision will need to be made about Methods for providing assisted how long to continue this method of ventilation assisted ventilation. Expired Air Resuscitation (EAR) (no health facilities immediately available): This will depend on:

Deliver 2 initial “rescue breaths” as follows • The clinical circumstances, e.g. the (Fig 82h): close the patient’s nose with likely diagnosis, the age of the patient one hand and pull the jaw down with (the rescuer might reasonably persist the other, and place your mouth over the for longer if the patient is a small child), or the distance from medical assistance or from more advanced health care facilities;

• The presence of effective cardiac activity; as determined by the presence of a carotid pulse (palpate on both sides before determining that this is absent), more advanced tests such as auscultation of audible heart sounds, or visible cardiac contraction on ultrasound; are supportive tests which Figure 82h: Technique of giving “rescue breaths” may be available.

150 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES The presence of electrical activity, as determined using a cardiac monitor of some kind, with no demonstrable cardiac output or pulse (so-called “pulse-less electrical activity”) usually carries a very poor prognosis, though there is a list of potentially reversible conditions which may cause this. This topic is not covered in these guidelines, but should be covered in any advanced life support course material. Figure 82i: bag-mask/Bag-Valve-Mask (BVM) (resuscitator bag) Non-invasive ventilation: Bag-mask/Bag-mask-valve ventilation: In term respiratory support but if there is no a health-care centre, a commonly used breathing or inadequate breathing that method for providing initial respiratory needs longer term support, the airway assistance is with a bag-mask/Bag-Valve- needs to be secured more definitively and Mask (BVM) (resuscitator bag) (Fig 82i) even the bag may have to be replaced Even the simplest health-care centre with a ventilator. However, many snakebite should have these, with different sizes patients around the developing world have required for different ages of patients, been kept alive for days, or week, using and the staff should be well versed in how simply an OPA and a BVM, or with an ETT to check that the device is functioning and a BVM, using relatives to squeeze the correctly and know how to use it correctly bag, though this is far from ideal. and safely. Invasive Ventilation: The rescuer positions him/herself at the Indications for intubation and mechanical victim’s head end. Holding the bag with ventilation are Type I respiratory failure one hand, he/she places the mask on the (primary failure of oxygenation as in victim’s face with the apex of the mask pulmonary oedema in Russell’s viper on the bridge of the nose and its base on envenoming) and Type II respiratory the groove over the chin. With the other failure (primary ventilatory failure due to hand, he/she seals the mask around the respiratory muscle paralysis or obstruction victim’s nose and mouth, tilts (extends) as in elapid envenoming). Suggestive the victim’s head, lifts the jaw forward clinical features in patients receiving and gives breaths at approximately the oxygen by mask or nasal catheters include normal respiratory rate for the patient by tachpnoea (respiratory rate > 25/min) or squeezing/pressing the bag, looking for paradoxical respirations (abdomen moves visible chest rise. Any chest movement is out on inspiration) and deteriorating usually adequate, especially in children. ventilatory capacity (see above); hypoxia (central cyanosis, SpO2 < 90%, arterial

If chest movement is inadequate, a PO2 < 50 mm Hg, < 6.7 kPa); and correctly-sized OPA should be inserted. respiratory acidosis (arterial PCO2 > 50 This will usually assist with air flow in and mm Hg, < 6.7 kPa, arterial pH <7.36). out of the lungs. If there is no bleeding Supraglottic or infraglottic devices are disorder, a NPA (or 2) may be used instead used to open the airway and assist with of, or in addition to, an OPA. both the supply of oxygen to the lungs and removal of carbon dioxide from the Bag-mask breathing suffices for short- lungs. Generally, and where possible,

Management of snakebites 151 in South-East Asia endotracheal intubation (insertion of • Physiotherapy (including chest an ETT) should be performed and the physiotherapy, regular turning to patient placed on a ventilator, attended prevent pressure areas and lung constantly by a suitably qualified nurse, collapse, and maintenance of the range with a suitably qualified doctor always of motion of paralysed, immobile on call to provide additional assistance, if joints and muscles, as well as limbs required. Tube blockages are a frequent where significant cytotoxicity and tissue cause of morbidity and mortality. They damage has occurred). are prevented by regular suctioning, humidification and training of staff to • Eye care (synthetic tears and closure recognize the symptoms of a blocked tube. of the eyelids to prevent drying and damage to in patients on Sedation for patients being ventilators). mechanically ventilated: fentanyl 2-40 microg/hour and midazolam 2-4 mg/hour • Safe and effective weaning from OR (to avoid acute kidney injury) morphine ventilation. 1-5 mg/hour with lorazepam 1-2 mg/hour. Always be careful to minimize trauma Adequacy of respiratory assistance can to the airway of a snakebite patient; this be assessed by reversal of clinical signs of includes the insertion of basic airway inadequate respiration and stabilization devices, advanced airway devices and

of SpO2 and end-tidal CO2 (where gastric tubes. Orogastric tubes are much available) and improvement in the victim’s preferred over nasogastric ones – the level of consciousness if respiratory latter often lead to bleeding which is failure was the sole cause of his/her difficult to deal with in the patient who unresponsiveness. However, assessing the has a coagulopathy, and may even level of consciousness of a patient with lead inexperienced staff to give more neurotoxic envenoming can be difficult antivenom or blood products when these because of their often generalized flaccid are not necessary. paralysis, such that the normal method of ascertaining the level of consciousness (the Such care also applies to the insertion of Glasgow Coma Scale – GCS) is irrelevant intravenous catheters and urinary (urethral) since the patient is unable to open their catheters. Central venous lines may be eyes, unable to speak and often unable inserted, if required and possible, but the to obey commands. They are, contrary insertion site will depend on the presence to common belief, awake, able to hear or absence of a bleeding disorder. Intra- everything which is said around them. They arterial lines may be useful in many should be sedated during the period of respects, but, again, are discouraged in their ventilation. the presence of a bleeding disorder.

Other important aspects of the care of a 6.9.3 Trial of anticholinesterase ventilated patient include: Anticholinesterase drugs have a variable, but potentially very useful effect in • Adequate hydration, monitoring of patients with neurotoxic envenoming, renal function and of fluid balance; especially those bitten by cobras (Banerji et al., 1972; Watt et al., 1986; Watt et al., • Nutrition (in addition to the minimal 1989; Faiz et al., cobra in press), but not nutrition contained in normal IV fluids); usually in those envenomed by kraits (Anil

152 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES et al., 2010). However, recent claims that intra-nasal neostigmine might provide a universal first-aid method for snakebite victims have achieved a high media profile but are unsubstantiated, misleading and fanciful (Lewin et al., 2013; Lewin et al., 2014). [a] [b]

A trial of anticholinesterase Figures 83: Anti-cholinesterase: (a) Before and (b) after intravenous atropine followed by intravenous edrophonium chloride in a patient envenomed by a (e.g. “Tensilon test”) should Malayan krait (Bungarus candidus) (Copyright DA Warrell) be performed in every patient with neurotoxic envenoming, as it would be in any patient 10-20 minutes (edrophonium) for with suspected myasthenia signs of improved neuromuscular gravis. However, this should not transmission. Ptosis may disappear delay antivenom treatment or (Fig 83) and ventilatory capacity endotracheal intubation. Patients (peak flow, FEV-1 or maximum must be observed closely as they expiratory pressure) may improve. may deteriorate while the trial of anticholinesterase is being 4. Patients who respond convincingly carried out can be maintained on neostigmine methylsulphate, 0.5-2.5 mg every 1-3 hours up to 10 mg/24 hours Procedure maximum for adults or 0.01-0.04 1. Baseline observations or mg/kg every 2-4 hours for children measurements are made against by intramuscular, intravenous or which to assess the effectiveness of subcutaneous injection together the anticholinesterase. with atropine to block muscarinic side effects. Patients able to swallow 2. Atropine sulphate (0.6 mg for tablets may be maintained on adults; 50 µg/kg for children) or atropine 0.6 mg twice each day, glycopyrronium is given by intravenous neostigmine 15 mg four times each injection followed by neostigmine day or pyridostigmine 60 mg four bromide or methylsulphate times each day. (Prostigmin) (or distigmine, pyridostigmine, ambenomium etc. in appropriate doses) by intramuscular Anticholinesterase (e.g. injection 0.02 mg/kg for adults, 0.04 “Tensilon”) test mg/kg for children. Short acting • Baseline observations edrophonium chloride (Tensilon) is • Give atropine intravenously ideal for this test but is rarely available • Give anticholinesterase in the Region. It is given by slow drug (e.g. neostigmine intravenous injection in an adult dose intramuscularly) of 10 mg, or 0.25 mg/kg for children. • Observe effect • If positive, institute regular 3. The patient is observed over the atropine and neostigmine next 30-60 minutes (neostigmine) or

Management of snakebites 153 in South-East Asia Suggested method: in a patient with bilateral ptosis from neurotoxic snake-bite, the distance between the upper and lower lid margins of both eyes (palpebral fissures) is measured using a mm ruler. Digital pressure is applied to the frontalis muscle to avoid its influencing upper eyelid retraction. An ice-filled plastic glove or frozen ice pack is then gently applied to one eyelid for 2 minutes, after which the palpebral fissures of both eyes are immediately re-measured. A more-than-2mm difference in palpebral fissure between the cooled and control eyelids might be considered a positive result (Fig 84).

6.9.4 Treatment of Hypotension and shock This is usually the result of hypovolaemia [from loss of circulating volume into the swollen limb, as a result of generalized increase in capillary permeability (e.g. Russell’s viper envenoming in Myanmar) or internal/external haemorrhage], venom- induced vasodilatation or direct myocardial effects with or without arrhythmias.

Postural (orthostatic) blood pressure measurement: hypovolaemia is best detected by measuring blood pressure with the patient lying supine, and repeating the measurement when the patient is propped up, ideally in a fully Figure 84: Ice test sitting position but, depending on their recovery of ptosis in the left eye after applying The “ice pack test” as a possible condition, at 45 degrees if 90 degrees an ice pad that inhibits alternative to the Tensilon test is not tolerated (Fig 85). A clinically intrinsic cholinesterase in a patient with post-synaptic (Golnik et al., 1999). significant fall in blood pressure during blockade of neuro- In patients with who have this procedure (orthostatic hypotension) is muscular transmission. ptosis, cooling of the ptotoc (drooping) a fall in systolic blood pressure of 20 mm (Delaney Y, Khooshabeh R, Benjamin L (2002). Acute eyelid results in improvement in ptosis, Hg or diastolic blood pressure of 10 mm severe ocular myasthenia due to inhibition of intrinsic cholinesterase Hg or more. in a 92-year-old woman. Eye (Lond);16(3):323-4). (Golnik et al., 1999). This quick and simple test might obviate the need for the Tensilon Passive leg raising test (fig. test in predicting the effectiveness of 85c): another way of assessing fluid anticholinesterase (neostigmine) treatment. responsiveness is to sit the patient in a 45 However, it has not yet been evaluated in degrees head-up semi-recumbent position. patients with neurotoxic envenoming. This Lower their upper body to the horizontal study must be done! and passively raise their legs at 45 degrees

154 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES [a] [b]

Figures 85 a, b: measurement of postural change in blood pressure as evidence of hypovolaemia: (a) supine; (b) sitting up (Copyright DA Warrell)

transfer of blood from the legs and abdominal compartments

= test for fluid responsiveness

Passive leg raising Passive leg raising. The passive leg raising test consists in measuring the hemodynamic effects of a leg elevation up to 45º. A simple way to perform the postural maneuver is to transfer the patient from the semirecumbent posture to the passive leg raising position by using the automatic motion of the bed.

Figure 85. c: Passive leg raising test to guide fluid therapy (see Marik et al., 2011) up, increasing circulating volume by may be given by intravenous infusion, about 150-300 ml. The maximal effect preferably into a central vein (starting dose of this “auto-infusion” occurs at 30-90 2.5-5 μ (micro) g/kg/minute). seconds, measured by clinical features of improved cardiac output (e.g. increase in Snakebite: causes of hypotension pulse pressure and decrease in heart rate) and shock (Boulain et al., 2002; Marik et al., 2014). 1º Anaphylaxis Treatment with crystalloids should Vasodilatation be controlled by observation of the Cardiotoxicity fluid status (jugular venous pressure, Hypovolaemia respiratory rates and crepitations, see 2º Antivenom reaction Annex 6). Excessive volume replacement Respiratory failure may cause pulmonary oedema when Acute pituitary adrenal plasma extravasated in the bitten limb insufficiency and elsewhere is reabsorbed into the Septicaemia circulation.

In patients with evidence of a generalized In victims of Russell’s viper bites in increase in capillary permeability, a Myanmar, India and Sri Lanka, acute selective vasoconstrictor such as dopamine pituitary adrenal insufficiency resulting

Management of snakebites 155 in South-East Asia from haemorrhagic infarction of the In patients with any of the above anterior pituitary may contribute to features, the following should be shock, while neurological manifestations monitored of hypoclycaemia, such as impaired consciousness, extensor posturing and • other signs of “uraemia syndrome” other involuntary movements, may be • pulse rate presenting signs that respond to a test • blood pressure, lying and sitting, to dose of intravenous 50% dextrose injection detect postural hypotension (see 14 (Warrell, 2009) (Tun-Pe et al., 1987) (Fig Treatment of hypotension and shock) 52a). Hydrocortisone, fluid and electrolyte • respiratory rate replacement may needed acutely in these • temperature patients. In chronic cases, addition of • height of jugular venous pulse thyroxin, oestrogen or testosterone may be • auscultation of lung bases for needed (Antonypillai et al., 2011; Jeevagan crepitations et al., 2013). • fluid balance chart and/or daily weight

6.9.5 Treatment of oliguria and acute 6.9.5.1 Oliguric phase of renal failure kidney injury Most, but not all, patients with acute (Sitprija and Boonpucknavig 1979; renal failure are oliguric, defined as a Chugh 1989) urine output of less than 400 ml/day or less than 30 ml/hour (children less than 0.5ml/kg bodyweight /hour). Conservative Detection of acute kidney injury management may tide the patient over, avoiding the need for renal replacement • Abrupt (within 48h) reduction therapy (dialysis). in kidney function (Acute Kidney Injury Network criteria) If the patient has intravascular volume Decreasing or no urine output depletion, indicated by supine or postural (<0.5 mL/kg/h for more than hypotension, or empty neck veins, 6 h) proceed as follows: Increase in serum creatinine concentration [serum 1. Establish intravenous access creatinine ≥26.5 μmol/L (≥0.3 mg/dL)] or increasing by ≥150 2. Give a cautious fluid challenge: an - 200% (x 1.5 - 2) compared to adult patient can be given 250-500 baseline [?urea] ml of isotonic saline over one hour or, until the jugular venous pressure/ • Clinical “uraemia syndrome”: central venous pressure has risen to nausea, vomiting, 8-10 cm above the sternal angle (with acidotic (“Kussmaul”) the patient propped up at 45º). The breathing patient must be closely observed while hiccups, fetor, this is being done. The fluid challenge drowsiness, confusion, coma, must be stopped flapping tremor, muscle immediately if pulmonary oedema twitching, convulsions develops. If the urine output does not pericardial friction rub, improve it is reasonable to perform a signs of fluid overload furosemide stress/challenge test (see below for details).

156 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Note – in some patients it can be 5. Conservative management for acute difficult to determine the height of kidney injury: if the urine output does the central venous pressure by clinical not improve, despite these challenges, examination. Direct measurement of no further diuretics should be given central venous ( vena caval) and fluid intake should be restricted pressure through a long catheter, to a total of the previous day’s output preferably inserted at the antecubital plus “insensible losses” (500-1000 ml/ fossa (see Annex 6), can be helpful day). If possible, the patient should be in this circumstance. The catheter is referred to a renal unit. The diet should connected to a saline manometer, be bland, high in calories (1800/ the 0 point of which must be placed day), normal in protein (0.8-1 g/day), at the same level as the right atrium low in potassium (avoid fruit, fruit (that is, at the sternal angle when the juices, energy drinks and potassium- patient is propped up at 45º). This containing drugs) and low in salt. measurement is reliable only if the Infections will cause tissue breakdown level varies freely with respiration and and increase urea levels. They should the zero point is correctly positioned. be prevented or treated promptly with non-nephrotoxic antibiotics (i.e. avoid In a patient who is obviously volume- aminoglycosides such as gentamicin). depleted, resuscitation should start immediately, and not be delayed 6. Biochemical monitoring: In patients until a central venous line has been with acute kidney injury it is inserted. recommended that serum/plasma urea, creatinine and electrolytes be 3. Insert a urethral catheter (full sterile monitored daily if possible, until renal precautions!) but in male patients, try failure is resolving. Serum potassium, using a condom catheter first. urea, creatinine and, if possible, pH, bicarbonate, calcium and phosphate 4. Furosemide (frusemide) stress/ should be measured. If this is not challenge: once the patient has been possible the electrocardiogram (ECG) given adequate fluid replacement should be examined for evidence of 1-1.5 mg/kg of furosemide is injected hyperkalaemia, especially following slowly (4-5 mg/minute) intravenously bites by sea snakes, or Sri Lankan, and urine output is monitored for 2 Indian, Bangladeshi or Myanmar h. A urine output of < 200 ml in hour Russell’s vipers or if the patient is (100 ml/hour) predicts progression passing dark brown urine, suggestive of renal failure (Chawla et al., 2013). of rhabdomyolysis or intravascular In this case, the patient is likely to haemolysis. progress to acute kidney injury and requires conservative management. 7. Detection and management of Results of a small study done in hyperkalaemia (UK Renal Association, Myanmar, showed a statistically 2014) significant lower requirement for renal replacement therapy (acute peritoneal • ECG evidence of hyperkalaemia: tall dialysis) in patients given furosemide peaked T waves, prolonged P-R interval, infusion compared to those given absent P waves, wide QRS complexes. placebo (Kyaw San Lwin, personal Emergency treatments, which will communication, 2012). control hyperkalaemia for 3-6 hours

Management of snakebites 157 in South-East Asia only, should be given if serum potassium profoundly acidotic (deep sighing >6.5 mmol/l or ECG changes “Kussmaul” respirations, very low plasma bicarbonate concentration • Calcium Gluconate 10%: 0.5 ml/kg or very low pH - <7.10),Sodium 10 ml slow intravenous injection over bicarbonate should be given. 2-5 minutes if haemodynamically Based on volume of distribution of unstable, or over 15-20min if stable bicarbonate which is 40% of body (onset of action 3 minutes). Check weight, bicarbonate deficit can be for normalisation of ECG. Repeat if calculated. Usually 2-3 ampoules necessary. (40 ml. of 8.4% sodium bicarbonate equivalent to 1 mmol/ml) in 5% • β2 agonist aerosol by inhaler (e.g. dextrose water, or half of the salbutamol nebulisation 5mg q 1-2h calculated deficit can be replaced in - onset of action 30 minutes - up to 3-4 hours. Severe acidosis in snakebite 10-20 mg. is usually associated with acute renal failure. Volume expansion by sodium • Give 50 ml of 50% dextrose with 10 bicarbonate can cause fluid overload. units of soluble insulin intravenously Therefore, if there is no clinical (onset of action 15 minutes) improvement dialysis is required. Caution: Intravenous bicarbonate may • Sodium Bicarbonate 8.4% 1 ml/kg IV precipitate profound hypocalcaemia slow over 5 minutes and fitting, especially in patients with rhabdomyolysis. Followed by a low potassium diet. 8. Management of severe acidosis 9. Renal replacement therapy Dialysis If the patient is hypotensive and (Fig 86)

Figures 86: Dialysis for treatment of acute kidney injury: (a) Peritoneal dialysis in a township hospital in Myanmar; (b) Haemodialysis in a district hospital in India [a] [b] (Copyright DA Warrell)

158 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Transfer the patient who has developed 6.9.5.2 Bleeding/ blood clotting the following indications to a health disturbances in patients with acute facility where they can receive renal kidney injury replacement therapy. Most patients with acute kidney injury associated with snakebite will have been envenomed by Viperidae, notably Daboia, Indications for dialysis Hypnale and Trimeresurus species. The only major exception is sea snakebites. a) clinical uraemia Viper-bite victims may have venom- (encephalopathy, pericarditis induced bleeding and blood coagulation etc.) disturbances although in most Daboia b) fluid overload not cases these will have been corrected by responding to diuretics antivenom before acute kidney injury has c) plasma potassium developed. However, patients who still concentration > 7 mmol/l (or have active bleeding/clotting disturbances hyperkalaemic ECG changes) require fresh frozen plasma and platelet d) symptomatic acidosis infusions to cover insertion of dialysis e) blood biochemistry - one or catheters and dialysis. more of the following Creatinine > 4 mg/ dl (354 In patients with snakebite related micromol/l) thrombotic microangiopathy with acute Urea > 130 mg/ dl (46 kidney injury, the role of plasmapheresis mmol/l) using cryosupernatant (by analogy with Caution: biochemical criteria thrombotic thrombocytopenic purpura/ alone is not sufficient to start haemolytic uraemic syndrome) is not clear dialysis and has no sound theoretical basis.

6.9.5.3 Prevention of renal damage The choice between peritoneal dialysis in patients with myoglobinuria or and haemodialysis depends on haemoglobinuria availability. Haemodialysis is referred for management of hyperkalaemia, fluid overload and hypercatabolic patients. To minimise the risk of renal Each dialysis session should be decided damage from excreted myoglobin based on daily clinical assessment (fluid and/or haemoglobin: status, urine output and biochemical • correct hypovolaemia (see data). In patients who are hypotensive, above) and maintain urine slow efficiency daily dialysis (SLEDD) or output of 200-300 ml/hour. continuous renal replacement therapy • correct severe acidosis with (CRRT [dialysis over 24 hours]) is bicarbonate preferred. However, these are available • promote alkalinise diuresis only in well-equipped ICUs. In patients (urine pH > 6.5) with acute kidney injury, dialysis may be • continue these measures required for up to 3 weeks. After that until there is evidence that of time, the kidney should be biopsied rhabdomyolysis is decreasing to establish the diagnosis and indicate (CK level <5000 U). prognosis.

Management of snakebites 159 in South-East Asia 6.9.5.4 Diuretic phase of renal failure urgent surgery, once specific antivenom Some patients will develop polyuria that is has been given to neutralize venom as important and as life-threatening as the procoagulants and other antihaemostatic oliguric phase. Urine output increases to toxins, restoration of coagulability and 5-10 litres/24 hours following the period platelet function can be accelerated by of anuria. The patient may become volume giving fresh frozen plasma, cryoprecipitate depleted so that salt and water must be (fibrinogen, factor VIII), fresh whole blood carefully replaced. or platelet concentrates. Hypokalaemia may develop, in which case a diet rich in potassium (fruit and fruit juices) is recommended. Heparin is ineffective against venom-induced thrombin and 6.9.5.5 Renal recovery phase may cause bleeding on its own The diuretic phase may last for months account. It should never be used after Russell’s viper bite. in cases of snakebite.

6.9.5.6 Persisting renal dysfunction In Myanmar, persistent tubular Antifibrinolytic agents are not effective degenerative changes were observed in and should not be used in victims of Russell’s viper bite victims who showed snakebite. continuing albuminuria, hypertension and nocturia for up to 11 months after the 6.10.1 Dangers of venipuncture bite, despite apparent recovery in renal in patients with haemostatic function. In India, 20-25% of patients abnormalities referred to renal units with acute kidney In patients with incoagulable blood, any injury following Russell’s viper bite injection (subcutaneous, intramuscular) suffered oliguria for more than 4 weeks and, particularly venipuncture, carries a suggesting the possibility of bilateral renal risk of persistent bleeding and haematoma cortical necrosis and the need for referral formation. to a nephrologist. Patients with patchy cortical necrosis show delayed and partial Arterial puncture is contraindicated recovery of renal function but those with in such patients. diffuse cortical necrosis require regular Repeated venipuncture can be avoided by maintenance dialysis and eventual renal using an indwelling cannula and three- transplantation. way tap system. When blood coagulability has been restored, the dead space should 6.10 Haemostatic be filled with heparinised saline, but disturbances beware! If this is not flushed out before Bleeding and clotting disturbances usually blood sampling, misleading results will be respond satisfactorily to treatment with obtained in clotting tests, including the specific antivenom, but the dose may 20WBCT. need to be repeated several times, at six hourly intervals, before blood coagulability In patients with coagulopathy, sites (assessed by the 20WBCT) is finally and of venous access and placement of permanently restored. intravenous cannulae or catheters should be chosen where haemostasis by external In exceptional circumstances, such as pressure is most likely to be effective, eg persistent severe bleeding or imminent the antecubital fossa. If possible, avoid

160 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES jugular, subclavian and femoral vein and Enterococcus), aerobic gram-negative puncture. A pressure pad must be applied bacterial (E. coli, Klebsiella, Pseudomonas, at the site of any venipuncture. Enterobacter, Morganella morganii), anaerobic bacteria (Peptostreptococcus 6.11 Treatment of the and Bacteroides fragilis) (Theakston et bitten part al., 1990; Chena et al., 2011; Garg et al., The bitten limb, which may be painful 2009). Infection at the time of the bite and swollen, should be nursed in the with from the snake’s venom most comfortable position, but not and buccal cavity is a problem with some excessively elevated as this may reduce species such as the Malayan pit viper arterial perfusion pressure in a tensely (Calloselasma rhodostoma) and severe and swollen limb and increase the risk of intra- fatal tetanus has been reported. However, compartmental ischaemia. prophylactic antibiotics were not effective in a controlled study in Brazil (Jorge et 6.11.1 Wound management al., 2004). Interference with the wound Blisters/bullae/”blebs” may be large and (incisions made with an unsterilised razor tense but they should not be de-roofed blade/knife etc.) creates a risk of secondary and require aspiration only if they threaten bacterial infection and justifies the use to rupture. Abscesses should be aspirated of immediate broad spectrum antibiotics with a needle and the pus cultured (e.g. gentamicin with benzyl penicillin, (see below infection). Once frank skin amoxycillin or a cephalosporin plus a single necrosis is detected (demarcated, hypo/ dose only of gentamicin – to avoid the hyperpigmented areas with an odour of risk of kidney injury- plus ) putrefaction), surgical débridement is and tetanus prophylaxis. Other possible indicated to remove the risk of anaerobic antibiotics include amoxycillin/caluvulenic sepsis. During debridement, all unhealthy acid, piperacillin/tazobactam, ciprofloxacin tissue should be excised till viable tissue and third generation cephalosporin margins are achieved. However, bruised (Mao et al., 2016). Mao YC, Liu PY, Hung muscle may appear dead but should DZ, Lai WC, Huang ST, Hung YM, Yang not be excised as muscle fibres may CC. Bacteriology of Naja atra Snakebite regenerate. Amputation may be indicated Wound and Its Implications for Antibiotic in case of gangrene of toes or limbs. Therapy. Am J Trop Med Hyg. 2016 May 4;94(5):1129-35Later infections in patients 6.11.2 Bacterial infections treated in hospital include nosocomial The oral flora of wild snakes includes pneumonias and urinary tract infections. aerobic and anaerobic bacteria, especially the faecal gram-negative rods as their prey 6.11.3 Compartmental syndromes may defecate while being ingested. Oral and fasciotomy and venom cultures from American snakes (Fig 83) (Matsen 1980; Mars and Hadley yielded Enterobacteriaceae including 1998; Mars et al., 1991) Morganella spp., Escherichia coli, Group D streptococci, Aeromonas spp., and The appearance of an immobile, tensely- anaerobes such as Clostridium spp. swollen, cold and apparently pulseless snake-bitten limb may suggest to In Asia, local bite wound infections may surgeons the possibility of increased be due to single or multiple bacteria intracompartmental pressure, especially including gram-positive aerobes (Staph. if the digital pulp spaces or the anterior aureus, coagulase-negative Staphylococcus tibial compartment are involved. Swelling

Management of snakebites 161 in South-East Asia [a] [b]

Figure 87: Results of unnecessary fasciotomies in snakebite victims in Thailand: (a) profuse bleeding in a patient with mild local envenoming but severe coagulopathy following bites by green pit vipers (Trimeresurus T. albolabris); (b) Residual skin loss and exposure of tendons following fasciotomy for mild local envenoming in a patient bitten by a green pit viper (Trimeresurus T. albolabris) (Copyright the late Sornchai Looareesuwan); (c) Persistent bleeding for 10 days, resulting in haemorrhagic shock despite transfusion of 20 unites of blood, in a victim of Malayan pit viper bite in whom fasciotomy was performed before adequate antivenom treatment had been given to correct the coagulopathy (Copyright DA Warrell)

of envenomed muscle Clinical features of a within such tight fascial compartmental syndrome compartments could • Disproportionately severe pain result in an increase • Weakness of intracompartmental in tissue pressure muscles above the venous • Pain on passive stretching of pressure, resulting in intracompartmental muscles ischaemia. However, • Hypoaesthesia of areas of skin the classical signs of supplied by nerves running an intracompartmental through the compartment pressure syndrome • Obvious tenseness of the may be difficult to compartment on palpation assess in snakebite victims and many unnecessary, dangerous and debilitating Detection of arterial pulses by palpation fasciotomies are or doppler ultrasound probes, does not performed, especially exclude intracompartmental ischaemia. where surgeons The most reliable test is to measure rather than physicians intracompartmental pressure directly [c] have the primary through a cannula introduced into the responsibility for compartment and connected to a pressure managing snakebite transducer or manometer (Annex 5). In cases (Fig 87). Fasciotomy is generally orthopaedic practice, intracompartmental falling out of favour for the treatment of pressures exceeding 40 mmHg (less in snake-bitten limbs (Cumpston, 2011). children) may carry a risk of ischaemic

162 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES necrosis (eg Volkmann’s ischaemia or 6.12 Rehabilitation anterior tibial compartment syndrome). In patients with severe local envenoming, However, envenomed muscle may not the limb should be maintained in a be saved by fasciotomy. Animal studies functional position. For example, in the have suggested that muscle sufficiently leg, equinus deformity of the ankle should envenomed and swollen to cause be prevented by application of a back slab intracompartmental syndromes, may and avoiding the pressure of heavy bed already be irreversibly damaged by the clothes. direct effects of the venom (Garfin et al., 1984). In any case, fasciotomy should Functional effects of local envenoming not be contemplated until haemostatic range from persistent stiffness and abnormalities have been corrected, induration due to sclerosis of veins, otherwise the patient may bleed to death lymphatics and tissue planes through (Fig 66c). which the venom has spread, to severe deformity, arthrodeses, contractures, Among 105 cases of rattle snakebites tissue loss, especially dermonecrosis and in USA in which fasciotomy was either chronic ulceration requiring skin grafting, just discussed or actually carried out, and gangrene requiring débridement the 28 patients given surgery showed and amputation. Restoration of normal no advantage in morbidity, but spent on function in the bitten part should be average 2 extra days in hospital (Darracq et started by simple exercises while the al., 2015). patient is still in hospital. After the patient has been discharged from hospital In green pit viper bite (genus Trimeresurus) rehabilitation is rarely supervised but victims, antivenom not only reversed relatives can be instructed and given a coagulopathy, but also reducing severe time table of rehabilitating activities. limb oedema (Rojnuckarin et al., 2006). Conventional physiotherapy may accelerate However, corticosteroids are not effective functional rec overy of the bitten limb. in ameliorating local effects of envenoming and, since they carry the risk of side-effects, 6.13 Discharge assessment they should not be used (Reid et al., 1963; Before the patient leaves hospital, discuss Nuchprayoon et al., 2008). the following topics with them and their accompanying family members. Early treatment with antivenom remains the best way of preventing • Implications of having had a snakebite: irreversible muscle damage. most patients can be assured of a full recovery in time.

Criteria for fasciotomy in snake- • Rehabilitation exercises: encourage bitten limbs them to continue until normal function haemostatic abnormalities have been is restored to the bitten limb. corrected (antivenom with or without clotting factors) • Follow-up appointment: encourage the • clinical evidence of an patient to return after an interval of 1-2 intracompartmental syndrome weeks to check on their progress and • intracompartmental pressure >40 to allow further reassurance. mmHg (in adults) • Late serum sickness-type reactions:

Management of snakebites 163 in South-East Asia effective but, by rendering the eye Consists of urgent irrigating the affected eyes temporarily insensitive, may allow trauma to the . They should be and other mucous membranes with liberal applied only once and the eye must quantities of water, saline, Ringer’s lactate, be protected until sensation returns. By overcoming blepharospasm, milk or any other available bland liquid. these drugs may allow more efficient irrigation.

warn them of the symptoms and 3. Corneal abrasions must be excluded reassure them that this complication of by fluorescein staining and/or slit antivenom can be treated. lamp examination

• Reducing the risk of further bites: 4. Endophthalmitis or blinding corneal provide advice, ideally in the form of opacities must be prevented a leaflet, explaining the principles of by application of prophylactic snakebite prevention (see Section 1 topical antibiotics (eg tetracycline, above), to be shared with their families chloramphenicol, 0.5% framycetin and neighbours. “Soframycin”, ciprofloxacin, penicillin- streptomycin ointment, polymixin 6.14 Management of cobra B sulphate, gatifloxacin, and spit ophthalmia moxifloxacin). (Chu et al., 2010) First aid: consists of urgent irrigating 5. Posterior synechiae, ciliary spasm and the affected eyes and other mucous discomfort can be prevented with membranes with liberal quantities of topical cycloplegics (e.g. 2% atropine, water, saline, Ringer’s lactate, milk or any scopolamine or homatropine). other available bland liquid (even urine However, beware, these mydriatics has been used). No medicines, oils or may precipitate acute glaucoma. traditional ointments should be put in the eye(s) and there should be no delay 6. Allergic kerato-conjunctivitis may in going to hospital. The spitting cobra develop in those previously sensitised should not be pursued or killed as this may by spitting or other habitual exposure result in further multiple spits. to snake venoms. It is treated with antihistamines. Medical treatment consists of: 1. Further urgent decontamination is Instillation of diluted antivenom achieved by copious irrigation causes irritation and is of no benefit since any residual venom in the 2. Pain is intense. Topical vasoconstrictors conjunctival sac is removed by liberal with weak mydriatic activity [e.g. irrigation. instillation of 0.5% epinephrine (adrenaline) drops] relieve pain and Topical corticosteroids are inflammation. However, topical local contraindicated because of the risk of anaesthetics (eg 0.4% oxybuprocaine Herpes simplex keratitis. hydrochloride (“Novesin”), 4% lidocaine hydrochloride or tetracaine Some ophthalmologists recommend the hydrochloride (“Decicaine”) are more use of a dressing pad to close the eye.

164 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES 6.15 Management of patient to medical care as quickly, snakebites at different levels safely and passively as possible by of the health service vehicle, boat, bicycle, motorbike, (refer to sections above for details of stretcher etc. Ideally the patient should treatments etc.) lie in the recovery position (prone, All levels of the health service can contribute on the left side) with his/her airway to the management of patients with protected to minimise the risk of shock suspected snakebite. Since the treatment of and inhalation of vomit. severe envenoming is a medical emergency that may require a range of medical skills, 5. Snake: if the snake responsible has equipment, antivenom and other medicines, already been caught or killed take it referral should be to the highest level of (safely in a bag or container) with the care that is readily available. However, in patient or take images on a mobile the rural areas where snakebites are most ‘phone , but ensure safety by avoiding frequent, transfer to a hospital may not direct contact. be feasible within the reasonable time of a few hours. In that case, a lower 6. Traditional treatment: discourage level of health facility must cope with the time-wasting and potentially dangerous emergency as suggested below. Ideally, a traditional treatments such as tight specialist team and a defined area or ward ligatures (tourniquets), incisions, should be allocated for the management suction and application of herbs, ice, of snakebite victims. Training of doctors, chemicals, “snakestones” etc. nurses, dispensers, health assistants and paramedics in all the skills B. At the Rural Clinic, Dispensary, required for diagnosis (including snake Health Post, or Primary Health Centre identification) and early management 1. Assess for signs of local and of snakebite patients (including systemic envenoming: carry out a indications for and practicalities of simple medical assessment including administering antivenom) is essential history and simple physical examination at every level. – local swelling, painful tender enlarged local lymph glands, persistent A. At community or village level bleeding from the bite wound, blood 1. Assess: check history of snakebite pressure, pulse rate, bleeding (gums, and look for obvious evidence of a bite nose, vomit, stool or urine), level of (fang puncture marks, swelling of the consciousness, drooping eyelids (ptosis) bitten part). and other signs of paralysis. Monitor these signs hourly. 2. Reassure 2. Check: 20 minute whole blood 3. First-aid: immobilize the whole clotting test (20WBCT), urine patient as far as possible by laying him/ examination (appearance, sticks testing her down in a relaxed but safe position for blood etc.). Identify the snake or a (e.g. recovery position), immobilize photo of it (if brought). the bitten limb with a splint and apply pressure-pad. 3. Analgesia: give analgesia by mouth if required: paracetamol (acetaminophen) 4. Transport: Arrange (by emergency (adult dose 500 mg to 1 g maximum contact number) transport of the 4 g in 24 hours; children 10-15 mg/

Management of snakebites 165 in South-East Asia kg maximum 100mg/kg/day) or 9. Assess the need and feasibility of codeine phosphate (adult dose 30-60 transporting the patient to a higher mg maximum 240 mg in 24 hours; level of the health service (see A above) children more than 2 years old, 0.5 especially in case of: mg/kg, maximum 2 mg/kg/day) can be given every 4-6 hours by mouth as a. Substantial bleeding, 20WBCT still required (not aspirin or non-steroidal positive (non-clotting) 6 hours after anti-inflammatory drugs which can initial antivenom dose cause bleeding). b. Progressive paralysis (muscle weakness) or respiratory difficulty 4. Antivenom: if the patient fulfils c. Reduced urine output criteria for antivenom treatment and d. Anaphylaxis –unresponsive to if the necessary skills, equipment, adrenaline antivenom, adrenaline and other e. Shock/hypotension- unresponsive to necessary drugs are available, give fluids antivenom. These skills include f. Severe local necrosis or signs suggestive ability to diagnose local and systemic of compartment syndrome envenoming, set up intravenous infusion or intravenous injection, 10. Discourage the use of ineffective identify the early signs of anaphylaxis and potentially harmful drugs (e.g. and treat it with intramuscular corticosteroids, antihistamines, and adrenaline. Reasess for repeated heparin). dose(s) of antivenom. If no antivenom is available, transfer to a hospital. C. At the District Hospital Proceed as in B above plus: 5. If the patient is shocked/ hypotensive: give cautious 1. Assessment: carry out a more intravenous fluid challenge (adult detailed clinical and laboratory 250-500 ml of 0.9% saline) to correct assessment including biochemical and hypovolaemic shock. haematological measurements, ECG or radiography, as indicated. 6. If the patient has evidence of respiratory paralysis: give oxygen 2. Antivenom: if no antivenom is by mask, consider atropine and available, transfer to a hospital that has neostigmine, and transfer to hospital. antivenom or treat conservatively; this It is assumed that assisted ventilation may require transfusion of blood or other than by a tight-fitting face mask fresh frozen plasma (see above). connected to an anaesthetic (Ambu) bag will not be possible at this level. 3. Analgesia: (see B above) and, if required, consider stronger parenteral 7. If the patient is oliguric: initiate opioid drugs as required all with conservative management. great caution (e.g. subcutaneous, intramuscular or even intravenous 8. The bite wound: if necrotic, tampered pethidine, initial adult dose 50- with (incisions etc.) or obviously 100 mg; children 1-1.5 mg/kg; or septic, give antibiotics and tetanus morphine, initial adult dose 5-10 mg; prophylaxis. children 0.03-0.05 mg/kg,).

166 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES 4. If the patient has evidence of local be improved at various levels. The necrosis (gangrene): give tetanus government must develop a policy for toxoid booster, antibiotics and do snakebite, making it a notifiable disease, surgical débridement of dead tissue. developing a snakebite programme that includes standard treatment guidelines, 5. If the patient has evidence of bulbar training of health personnel and ensures or respiratory paralysis: insert an adequate supply, distribution and endotracheal tube, laryngeal mask storage of good quality antivenom. airway or i-gel aiway. If there is Strengthening of public health systems evidence of respiratory failure, assist ventilation manually by anaesthetic Figure 88 Health system strengthening (Ambu) bag or mechanical ventilator.

6. If the patient has evidence of acute Government kidney injury: treat with peritoneal Snakebite policy dialysis. If this is not available, transfer 1. Making snakebite reportable to a specialized hospital. 2. Developing a snakebite programme 3. Standard treatment guidelines 7. If the patient is bleeding severely or is 4. Ensuring production and supply of adequate already seriously anaemic: cross-match quantity and quality of antivenom and transfuse. 5. Training of health personnel at all levels 6. Research 8. Rehabilitation: encourage exercising of bitten limb. HEALTH SYSTEM D. At the Referral (Specialized) Hospital TERTIARY REFERRAL Proceed as in B and C above plus: HOSPITAL Infrastructure- dialysis and ICU, surgical set up, coagulation lab 1. More advanced surgical management of Personnel- physician, surgeon, local necrosis (e.g. split skin grafting). nephrologist, anaesthetist Strengthening of health 2. More advanced investigations including DISTRICT HOSPITAL system bacterial cultures and imaging (CT Infrastructure- blood bank, 1. Training of all levels of scans) as indicated. ICU, surgical set up health system Personnel- physician, surgeon 2. Ensuring infrastructure at 3. If the patient has evidence of acute each level renal failure peritoneal or haemodialysis PRIMARY HEALTH CENTRE 3. Antivenom availability or haemofiltration. Infrastructure- basic emergency 4. Epidemiological care and resuscitation, airway and Ambu bag, monitoring of snak-bite, 4. Implement rehabilitation by antivenom administration deaths, complications and physiotherapists. Personnel- doctor, nurse antivenom reactions 5. Community education Conclusions: Strengthening of health VILLAGE system in managing snakebite Infrastructure- ambulance Transport Personnel- health aid, health To reduce complications and deathsfrom worker, paramedic snakebites, health systems need to

Management of snakebites 167 in South-East Asia requires an appropriate infrastructure of 4. Antihistamines (H1 blockers) and facilities and drugs at each level, training corticosteroids of personnel, epidemiological monitoring Benefits: late serum sickness-type and community education. reactions

6.16 Summary of current 5. Antibiotics evidence for treatment of Benefits: treating secondary and primary snakebite envenoming bite wound infections, prophylaxis in Currently proposed treatment and necrotic wounds or those that have their likely benefit been tampered with using non-sterile instruments 1. Antivenom: Benefits: recommended for treatment 6. Renal replacement therapy and of bleeding/blood clotting disturbances, assisted ventilation: shock/hypotension, post-synaptic Benefits: life-saving in patients with neurotoxicity (cobras, death adders, acute kidney injury and respiratory failure rhabdomyolysis (sea snakes). Optimal initial dosage largely unknown 7. Anticolinesterase (neostigmine) with atropine Risks: early anaphylactic and pyrogenic Benefits: can rapidly improve neuro reactions, late serum sickness-like reactions muscular transmission in some patients with post-synaptic neurotoxicity (cobras, 2. Adrenaline (epinephrine) Australasian death adders) Benefits: recommended for prevention and treatment of early antivenom Risks: muscarinic side-effects, reactions cholinergic crisis

Risks: cerebral haemorrhage in elderly 8. Traditional first-aid methods patients with underlying cerebrovascular (incisions, tourniquets, suction, tattooing, disease topical herbal remedies, black “snake- stone”, electric shocks etc.) 3. Blood clotting factors Benefits: recommended to speed up Risks: harmful and useless – should never restoration of normal haemostasis in be used patients already treated with antivenom and for conservative treatment of 9. First-aid pressure pad bleeding/blood clotting disturbances, immobilization, rapid transport to when antivenom is not available medical care Benefits: reduces venom spread and risk Risks: fatalities reported (reactions and of early death possibly thromboses)

168 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES 7 References and further reading

Ali SS, O’Connell C, Kass L, Graff G Single- Ariaratnam CA, Sjöström L, Raziek Z, breath counting: a pilot study of a novel Kularatne SA, Arachchi RW, Sheriff MH, et technique for measuring pulmonary al. An open, randomized comparative trial function in children. Am J Emerg of two antivenoms for the treatment of Med.2011 Jan;29(1):33-6. envenoming by Sri Lankan Russell’s viper (Daboia russelii russelii). Trans R Soc Trop Amarasekera N, Jayawardena A, Med Hyg. 2001 Jan- Feb;95(1):74-80. Ariyaratnam A, Hewage UC, de Silva A. Bite of a sea snake (): Ariaratnam CA, Sheriff MH, Theakston a case report from Sri Lanka. J Trop Med RD, Warrell DA Distinctive epidemiologic Hyg. 1994;97(4):195-8. and clinical features of common krait (Bungarus caeruleus) bites in Sri Lanka. Am J Trop Med Hyg. 2008 Sept;79 (3):458-62. Anil A, Singh S, Bhalla A, Sharma N, Agarwal R, Simpson ID. Role of Ariaratnam CA, Thuraisingam V, Kularatne neostigmine and polyvalent antivenom in SA, Sheriff MH, Theakston RD, de Silva Indian common krait (Bungarus caeruleus) A, et al. Frequent and potentially fatal bite. Journal of Infection and Public envenoming by hump-nosed pit vipers Health. 2010;3(2):83-7. (Hypnale hypnale and H. nepa) in Sri Lanka: lack of effective antivenom. Trans R Soc Anker RL, Anker KM, Straffon WG, Loiselle Trop Med Hyg. 2008 Nov; 102:1120-6. DS, Retarding the uptake of “mock venom” in humans: comparison of three Ariaratnam CA, Sheriff MH, Arambepola first-aid treatments. Med J Aust. 1982 C, Theakston RD, Warrell DA. Syndromic Mar 6, (5):212-4. approach to treatment of snakebite in Sri Lanka based on results of a prospective Antonypillai CN, Wass JA, Warrell DA, national hospital-based survey of patients Rajaratnam HN. Hypopituitarism following envenomed by identified snakes. Am J envenoming by Russell’s vipers (Daboia Trop Med Hyg. 2009 Oct;81(4):725-31. siamensis and D. russelii) resembling Sheehan’s syndrome: first case report Armentano RA, Bandt C, Schaer M, from Sri Lanka, a review of the literature Pritchett J, Shih A. Thromboelastographic and recommendations for endocrine evaluation of hemostatic function in dogs management. QJM. 2011 Feb;104(2):97- treated for crotalid snake envenomation. 108. J Vet Emerg Crit Care (San Antonio). 2014 Mar-Apr;24(2):144-53.

Management of snakebites 169 in South-East Asia Bandyopadhyay SK, Bandyopadhyay R, Caron EJ, Manock SR, Maudlin J, Koleski J, Dutta A, Pal SK. Hypopituitarism following Theakston RD, Warrell DA, et al. Apparent poisonous viperbite. J Indian Med Assoc. marked reduction in early antivenom 2012 Feb; 110(2):120, 122. reactions compared to historical controls: was it prophylaxis or method Banerji RN, Sahni AL, Chacko KA. of administration? Toxicon. 2009 Nov; Neostigmine in the treatment of Elapidae 54(6):779-83. bites. J Ass Physicins India 1972 July 20(7):503-9. Chappuis F, Sharma SK, Jha N, Loutan L, Bovier PA. Protection against snakebites by sleeping under a bed net in southeastern Bell DJ, Wijegunasinghe D, Samarakoon Nepal. Am J Trop Med Hyg. 2007; S, Palipana H, Gunasekera S, de Silva 77(1):197-9. HA, et al. Neurophysiological findings in patients one year after snakebite induced Chakraborty PP, Bhattacharjee R. Bilateral neurotoxicity in Sri Lanka. Transactions of parotid swelling: an unusual complication the Royal Society of Tropical Medicine and of viper bite. J Assoc Phys India. 2010 Jul; Hygiene 2010 May; 104(5): 351-6. 58: 460.

Belt PJ Malhotra A. Thorpe RS, Warrell Chatterjee P, Mukhopadhyay P, Pandit K, DA, Wuster W. Russell’s viper in Indonesia: Roychowdhury B, Sarkar D, Mukherjee S, snakebite and systematics. In: Thorpe RS, et al. Profile of hypopituitarism in atertiary Wüster W, Malhotra A editions, Venomous care hospital of eastern India--is quality snakes. Ecology, evolution and snakebite of life different in patients with growth Oxford. , Clarendon Press, 1997 p. 219-34. hormone deficiency? J Indian Med Assoc. 2008 Jun; 106(6):384-5, 388. Bhat RN. Viperine snakebite poisoning in Jammu. J Indian Med Assoc. 1974 Dec 16; Chawla LS, Davison DL, Brasha- Mitchell 63(12): 383-92. E, Koyner JL, Arthur JM, Shaw AD, et al. Development and standardization of Bhetwal BB, O’Shea M, Warrell DA Snakes a furosemide stress test to predict the and snakebite in Nepal. Tropical Doctor severity of acute kidney injury. Crit Care 1998 Oct; 28(4): 193-5. 2013 Sep 20; R207.

Chen CM, Wu KG, Chen CJ, Wang Bon C, Goyffon M. Envenomings and their CM. Bacterial infection in association treatments. Lyon: Ed: Fondation Marcel with snakebite: a 10-year experience Mérieux; 1995. 343 p.. in a northern Taiwan medical center. J Microbiol Immunol Infect. 2011 Bücherl W, Buckley EE & Deulofeu V (eds). Dec;44(6):456-60. Venomous animals and their venoms. Vols 1 and 2. Academic Press, New York. Cherian AM, Girish TS, Jagannati M, (1968, 1971) Lakshmi M. High or Low- A Trial of Low Dose Anti Snake Venom in the Treatment Canale E, Isbister GK, Currie BJ. of Poisonous Snakebites J Assoc Physicians Investigating pressure bandaging for of India 2013 Jun; 61(6): 387-9, 396. snakebite in a simulated setting: bandage type, training and the effect of transport. Chippaux JP. Snakebites: appraisal of the Emerg Med Australas. 2009 Jun; global situation. Bull World Health Organ. 21(3):184-90. 1998;76(5):515-24.

170 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Chotenimitkhun R, Rojnuckarin P. Systemic Dayal M, Prakash S, Verma PK, Pawar M. antivenom and skin necrosis after green envenomation mimicking brain pit viper bites. Clin Toxicol (Phila). 2008 death in a child: A case report and review Feb;46(2):122-5. of literature. Indian J Anaesth. 2014 Jul; 58(4):458-60. Chu ER, Weinstein SA, White J, Warrell DA. Venom ophthalmia caused by venoms Deepak M, Basavaprabhu A, Ramapuram of spitting elapid and other snakes: Report JT, Nithyananda C, Mahalingam S. Bilateral of ten cases with review of epidemiology, parotid enlargement following snakebite clinical features, pathophysiology and : A rare sign. Asian PAc J Trop Biomed. management. Toxicon. 2010; 56(3):259- 2013; 3(2): 154-5. 72. de Rezende NA, Torres FM, Dias Chugh KS. Snakebite-induced acute renal MB, Campolina D, Chavez-Olortegui failure in India. Kidney International. 1989; C, Amaral CF. South American 35: 891-907. rattlesnakebite ( durissus SP) without envenoming: insights on Cubitt M, Armstrong J, McCoubrie D, diagnosis and treatment. Toxicon. 1998 White J, Williams V, Isbister GK. Point-of- Dec;36(12):2029-32. care testing in snakebite: an envenomed case with false negative coagulation de Silva A, Mendis S, Warrell DA. studies. Emerg Med Australas. 2013; Neurotoxic envenoming by the Sri Lankan 25(4):372-3. krait (Bungarus ceylonicus) complicated by traditional treatment and a reaction Cumpston KL. Is there a role for to antivenom. Trans R Soc Trop Med Hyg. fasciotomy in Crotalinae in 1993;87(6):682-4. ? Clin Toxicol (Phila). 2011; 49(5):351-65. de Silva HA, Pathmeswaran A, Ranasinha CD, Jayamanne S, Samarakoon SB, Currie BJ, Canale E, Isbister GK. Hittharage A, et al. Low-dose adrenaline, Effectiveness of pressure-immobilization promethazine, and hydrocortisone in the first aid for snakebite requires further prevention of acute adverse reactions study. Emerg Med Australas. 2008 Jun; to antivenom following snakebite: a 20(3):267-70. randomised, double-blind, placebo- controlled trial. PLoS Med. 2011 May; Darracq MA, Cantrell FL, Klauk B, Thornton 8(5):e1000435. SL. A chance to cut is not always a chance to cure- fasciotomy in the treatment of de Silva HA, Ryan NM, de Silva HJ. envenomation: A retrospective Prevention and treatment of adverse center study. Toxicon. 2015; reactions to snake antivenom. British 101:23-6. Journal of Clinical Pharmacology 2016; 81: 446-452. Dassanayake AS, Karunanayake P, Kasturiatne KT, Fonseka MM, Deshpande RP, Motghare VM, Padwal SL, Wijesirwardena B, Gunatilake SB et al., Pore RR, Bhamare CG, Deshmukh VS, et al. Safety of subcutaneous adrenaline as Adverse drug reaction profile of anti-snake prophylaxis against acute adverse reactions venom in a rural tertiary care teaching to anti-venom serum in snakebite. Ceylon hospital. Journal of Young Pharmacists. Med J. 2002; 47:48-9. 2013 June; 5(2): 41-45.

Management of snakebites 171 in South-East Asia Directorate General of Health Services Fernando WK, Kularatne SA, Wathudura Ministry of Health and Family Welfare SP, de Silva A, Mori A, Mahaulpatha D. Government of India. National First reported case of systemic envenoming Snakebite Management Protocol by the Sri Lankan keelback (Balanophis [internet]. New Delhi,2009. Available ceylonensis). Toxicon. 2015;93:20-3. from http://164.100.130.11:8091/ Fox S, Rathuwithana AC, Kasturiratne A, nationalsnakebitemanagementprotocol. Lalloo DG, de silva HJ. Underestimation of pdf snakebite mortality by hospital statistics in the Monaragala District of Sri Lanka. Trans Eapen CK, Chandy N, Kochuvarkey R Soc Trop Med Hyg. 2006;100:693-5 KL, Zacharia PK, Thomas PJ, Ipe TI. Unusual complication of snakebite : Gans C, Gans KA eds. Biology of the hypopituitarism after viper bites. In Ohsaka reptilia. Vol 8. London: Academic Press, A, Hayashi K, Sawai Y, editors. Animal, 1978.782p . plant and microbial toxins 2nd edition New York, Plenum; 1976.p. 467-473. Garg A, Sujatha S, Garg J, Acharya NS, Chandra Parija S. Wound infections Ediriweera DS, Kasturiratne A, secondary to snakebite. J Infect Dev Ctries. Pathmeswaran A, Gunawardena NK, 2009 Apr 30;3(3):221-3. Wijayawickrama BA, Jayamanne SF, et al. Gawarammana IB, Kularatne SA, Mapping the risk of snakebite in Sri Lanka- Dissanayake WP, Kumarasiri RP, Senanayake A national survey with geospatial analysis. N, Ariyasena H. Parallel infusion of PLoS Negl Trop Dis. 2016 July; 10(7): hydrocortisone +/- chlorpheniramine e0004813. bolus injection to prevent acute adverse reactions to antivenom for snakebites. Faiz A, Ghose A, Ahsan F, Rahman R, Amin Med J Aust. 2004 Jan 5;180:20-3. R, Hassan MU, et al. The greater black krait (Bungarus niger), a newly recognized Garfin S R, Castilonia RR, Mubarak cause of neuro-myotoxic snakebite S. Rattle snakebites and surgical envenoming in Bangladesh. Brain. decompression: results using a laboratory 2010;133(11):3181-93. model. Toxicon 1984; 22:177–82.

Faiz, M.A, Ahsan MF, Ghose A, Rahman Gawarammana I, Mendis S, Jeganathan K. Acute ischemic strokes due to bites MR, Amin R, Hossain M, et al. Bites by by Daboia russelii in Sri Lanka - first the , Naja kaouthia, authenticated case series. Toxicon in Chittagong Division, Bangladesh: 2009;54:421-8. epidemiology, clinical features of envenoming and management of 70 Ghose A, Faiz MA. Snake envenomation identified cases. (in press) in Bangladesh. In: Gopalakrishnakone P, Faiz SM, Gnanathasan CA, Habib AG, Fan HW, Marcopito LF, Cardoso Jl, Franca Fernando R, Yang CC. Clinical Toxinology FO, Malaque CM, Ferrari RA, et al. in Asia Pacific and Africa [internet]. Sequential randomised and double blind . Springer 2015. Chapter 11. trial of promethazine prophylaxis against Available from: http://link.springer.com/ early anaphylactic reactions to antivenom referencework/10.1007/978-94-007- for snakebites. BMJ. 1999 May 6288-6/page/2 DOI: 10.1007/978-94-007- 29;318(7196):1451-2. 6288-6_25-1ISBN: 978-94-007-6288-6

172 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Ghose A, Amin MR, Haq MA, Islam A, Grunau BE, Wiens MO, Rowe BH, Chowdhury FR, Miah T, et al. Russell’s McKay R, Li J, Yi TW, et al. Emergency Viper (Daboia russelii): A newly Department Corticosteroid Use for recognized cause of neuro-myo-renal or Anaphylaxis Is Not Associated toxic envenomation in Bangladesh. In With Decreased Relapses. Ann Emerg Med. 2015 Oct,66(a):381-9. Available Proceedings 18th World Congress of the from: http://www.ncbi.nlm.nih.gov/ International Society on Toxinology; 2015 pubmed/25820033 doi: 10.1016/j. Sept 25-30; Oxford (United Kingdom); annemergmed.2015.03.003. c2015. P.91. Gutiérrez JM, Warrell DA, Williams DJ, Gimkala A, Ramana Rao GV, Bharti Jensen S, Brown N, Calvete JJ, et al. OK. Transporting Snakebite Victims to Global Snakebite Initiative. The need for Appropriate Health Facility within Golden full integration of snakebite envenoming Hour through Toll Free Emergency within a global strategy to combat the Ambulance Service in India, Save Lives. Int neglected tropical diseases: the way forward. PLoS Negl Trop Dis. 2013 Jun J Trop Dis Health. 2016; 17(2): 1-12. 13;7(6):e2162.

Golay V, Roychowdhary A, Dasgupta S, Haile NS. Snakebites man: two recent Pandey R. Hypopituitarism in patients Borneo cases. Mus J. 1963; with vasculotoxic snakebite envenomation 11:291-8. related acute kidney injury: a prospective study on the prevalence and outcomes Harris JB, Faiz MA, Rahman MR, Jalil MM, Ahsan MF, Theakston RD, et all Snakebite of this complication. Pituitary. 2014; in Chittagong Division, Bangladesh: a 17(2):125-31. study of bitten patients who developed no signs of systemic envenoming. Trans R Soc Golnik KC, Pena R, Lee AG, Eggenberger Trop Med Hyg. 2010 May;104(5):320-7. ER. An ice test for the diagnosis of myasthenia gravis. Ophthalmology Harvey AL. Snake toxins. New York: 1999;106:1282–6. Pergamon Press, 1991.

Hasan SM, Basher A, Molla AA, Sultana Gong E, Martin LD, Burnham DA, Falk, AR. NK, Faiz MA. The impact of snakebite on The birdlike raptor Sinornithosaurus was household economy in Bangladesh. Trop venomous. PNAS. 2009; 107:766–768. Doct. 2012; 42(1):41-3.

Gopalakrishnakone P, Chou LM. Snakes Hati AK, Mandal M, De NK, Mukherjee H, of medical importance (Asia-Pacific Hati RN. Epidemiology of snakebite in the region). Singapore. National University of district of Burdwan, West Bengal. J Indian Singapore Press; 1990. Med Assoc. 1992 Jun; 90:145-7.

Ho M, Warrell DA, Looareesuwan S, Gowda CD, Rajesh R, Nataraju A, Phillips RE, Chanthavanich P, Karbwang Dhananjaya BL, Raghupathi AR, Gowda J, et al. Clinical significance of venom TV, et al. Strong myotoxic activity of levels in patients envenomed venom: role of by he Malayan pit viper (Calloselasma metalloproteases. Mol Cell Biochem. 2006 rhodostoma). American J Trop Med Hyg Jan; 282(1-2):147-55. 1986 May; 35(3): 579-87.

Management of snakebites 173 in South-East Asia Ho M, Silmut K, White NK, et al. Isbister GK, Maduwage K, Shahmy S, Pharmacokinetics of three commercial Mohamed F, Abeysinghe C, Karunathilake antivenoms in patients envenomed by H, et al. Diagnostic 20-min whole blood the Malayan pit viper (Calloselasma clotting test in Russell’s viper envenoming rhodostoma) in Thailand. AmJ Trop Med delays antivenom administration. QJM. Hyg 1990; 42: 260-6. 2013,106(10):925-32.

Ho WK, Verner E, Dauer R, Isbister GK, Shahmy S, Mohamed Duggan J. ADAMTS-13 activity, F, Abeysinghe C, Karunathilake H, microangiopathic haemolytic anaemia Ariaratnam A. A randomised controlled and thrombocytopenia following trial of two injusion rates to decrease snakebite envenomation. Pathology. 2010 reactions to antivenom. PLoS One 2012, Feb;42(2):200-2. 7(6) e38739.

Höjer J, Tran Hung H, Warrell D. Life- Jayanthi GP, Gowda TV Geographical threatening hyponatremia after krait bite envenoming - a new syndrome. Clin variation in India in the composition and Toxicol (Phila). 2010;48(9):956-7. lethal potency of Russell’s viper (Vipera russelli) venom. Toxicon. 1988;26(3):257- Hossain, J, Biswas, A., Rahman, F, 64. Mashreky SR, Dalal K, Rahman A. Snakebite Epidemiology in Bangladesh—A Jeevagan V, Katulanda P, Gnanathasan CA, National Community Based Health and Warrell DA. Acute pituitary insufficiency Injury Survey. Health, 2016; 8, 479-86. and hypokalaemia following envenoming by Russell’s viper (Daboia russelii) in Sri Hung HT, Höjer J, Du NT. Clinical features Lanka: Exploring the pathophysiological of 60 consecutive ICU-treated patients mechanisms. Toxicon. 2013 Mar 1;63:78- envenomed by Bungarus multicinctus. 82. Southeast Asian J Trop Med Public Health. 2009 May; 40(3):518-24. Jorge MT, Malaque C, Ribeiro LA, Fan HW, Cardoso JL, Nishioka SA, et al. Failure of Huq F, Islam MA, Sarker MH, Chowdhury chloramphenicol prophylaxis to reduce B, Ali MW, Kabir MM. Epidemiology of the frequency of abscess formation snakebite in Bangladesh. Bangladesh J as a complication of envenoming by Zool 1995, 23: 61-4. Bothrops snakes in Brazil: a double-blind randomized controlled trial. Trans R Soc Hutton RA, Looareeuwan S, Ho M, Trop Med Hyg. 2004 Sep; 98(9):529-34. Silamut K, Chanthavanich P, Karbwang J, et al. Arboreal green pit vipers (genus Joseph JK, Simpsonn ID, Menon NC, Trimeresurus) of South-East Asia: bites by T Jose MP, Kulkarni KJ, Raghavendra GB albolabris and T macrops in Thailand and et al. First authenticated cases of life- a review of the literature. Trans R Soc Trop Med Hyg 1990 Nov-Dec; 84(6): 866-74. threatening envenoming by the hump- nosed pit viper (Hypnale hypnale) in Isbister GK, Brown SG, MacDonald India. Trans R Soc Trop Med Hyg. 2007 E, White J, Currie BJ. Current use Jan;101(1):85-90. of Australian snake antivenoms and frequency of immediate-type Junghanss T & Bodio M. Notfal- Handbuch hypersensitivity reactions and anaphylaxis. Gifttiere. Diagnose-Terapie- Biologie. Med J Aust 2008; 188 (8): 473-476. Stuttgart Georg Thieme Verlag. 1995.

174 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Karnchanachetanee C, Hanvivatvong O, Kuch U, Mebs D. The identity of the Javan Mahasandana S. Monospecific antivenin Krait, Bungarus javanicus Kopstein, 1932, therapy in Russell‘s viper bite. J Med Assoc (: Elapidae): evidence from Thai. 1994 Jun;77(6):293-7. mitochondrial and nuclear DNA sequence analyses and morphology. 2007; Zootaxa Kasturiratne A, Wickremasinghe AR, de 1426: 1–26. Silva N, Gunawardena NK, Pathmeswaran A, Ranjan Premaratna et al. The global Kularatne SA, Hettiarachchi R, Dalpathadu burden of snakebite: a literature analysis and modelling based on regional estimates J, Mendis AS, Appuhamy PD, Zoysa HD, of envenoming and deaths. PLoS Med. et al. (Elapidae: 2008 Nov 4, 5(11):e218. Hydrophiinae) the most dangerous sea snake in Sri Lanka: three case studies of Kellum JA KDIGO Clinical Practice severe envenoming. Toxicon 2014 Jan; 77: Guideline for Acute Kidney Injury. Kidney 78-86 International Supplements Volume 2, [internet]. Brussell, International Society of Lalloo D, Trevett A, Black J, Mapao J, Nephrology; 2012. 138 p. Available from Naraqi S, Owens D et al. Neurotoxicity http://www.kdigo.org/ clinical_practice_ and haemostatic disturbances in patients guidelines/pdf/KDIGO%20AKI%20 envenomed by the Papuan black snake Guideline.pdf. DOI:10.1038/kisup.2012.1. (Pseudechis papuanus). Toxicon. 1994; Kemp AM, Kemp SF. Pharmacotherapy in 32(8):927-36 refractory anaphylaxis: when intramuscular epinephrine fails. Curr Opin Allergy Clin Lalloo DG, Trevett AJ, Karinhona A, Immunol. 2014;14(4):371-8. Nwokolo N, Laurenson IF, Paul M, et al. Snakebites by the Papuan taipan Kiem-Xuan-Trinh, Le-Khac-Quyen, Long- (Oxyuranus scutellatus canni). Paralysis, Xuan-Trinh, Warrell DA. Hyponatraemia, hemostatic and electrocardiographic rhabdomyolysis, alterations in blood abnormalities, and effects of antivenom. pressure and persistent mydriasis in Am J Trop Med Hyg 1995 June; 52(6): patients envenomed by Malayan kraits 525-31. (Bungarus candidus) in southern Viet Nam. Toxicon 2010 Nov; 56(6): 1070-5 Lalloo DG, Trevett AJ, Black J, Mapao J, Kochar DK, Tanwar PD, Norris RL, Sabir M, Saweri A. Neurotoxicity, anticoagulant Nayak KC, Agrawal TD, et al. Rediscovery activity and evidence of rhabdomyolysis of severe saw-scaled viper (Echis sochureki) in patients bitten by death adders envenoming in the Thar region of (Acanthophis sp.) in southern Papua New Rajasthan, India. Wilderness Environ Med. Guinea. QJM. 1996; 89:25-35. 2007; 18(2):75-85. Langley RL. Snakebite during pregnancy: a Kramer E. Zur Schlangenfauna Nepals. Rev literature review. Wilderness Environ Med. suisse Zool 1977, 84 (3): 721-61. 2010 Mar;21(1):54-60. Kuch U, Sharma SK, Alirol E, Chappuis F. Fatal neurotoxic envenomation from Lee C-Y. Snake venoms. Handbook of the bite of a Lesser Black Krait (Bungarus experimental pharmacology. Berlin: lividus) in Nepal. Southeast Asian J Trop Springer-Verlag, Berlin Heidelberg 1979. Med Public Health. 2011 Jul; 42(4):960-4. 1132 p.

Management of snakebites 175 in South-East Asia Lewin MR, Bickler P, Heier T, Feiner Malasit P, Warrell DA, Chanthavanich P, J, Montauk L, Mensh B. Reversal of Viravan C, Mongkolsapaya J, Singthong experimental paralysis in a human by B, et al. Prediction, prevention and intranasal neostigmine aerosol suggests a mechanism of early (anaphylactic) novel approach to the early treatment of antivenom reactions in victims of neurotoxic envenomation. Clin Case Rep. snakebites. Br Med J (Clin Res ED). 1986 2013; 1(1):7-15. Jan 4; 292(6512): 17-20.

Lewin MR, Samuel SP, Wexler DS, Bickler Mao YC, Liu PY, Hung DZ, Lai WC, Huang P, Vaiyapuri S, Mensh BD. Early Treatment ST, Hung YM, et al. Bacteriology of Naja with Intranasal Neostigmine Reduces atra Snakebite Wound and Its Implications Mortality in a Mouse Model of Naja naja for Antibiotic Therapy. Am J Trop Med (Indian Cobra) Envenomation. J Trop Med. Hyg. 2016 May 4;94(5):1129-35. 2014:131835.

Marik PE, Lemson J. Fluid responsiveness: Longkumer T, Armstrong LJ, Santra V, an evolution of our understanding Br J Finny P. Human, snake, and environmental Anaesth. 2014 Apr;112(4):617-20 factors in human-snake conflict in North Bihar - A descriptive study [internet]. Marik PE, Monnet X, Teboul JL Christian Journal for Global Health. Hemodynamic parameters to guide fluid 2016 May, 3(1) available from: http:// therapy. Ann Intensive Care. 2011 Mar journal.cjgh.org/index.php/cjgh/article/ 21;1(1):1 view/77/290

Mars M, Hadley, GP. Raised Looareesuwan S, Viravan C, Warrell DA. intracompartmental pressure and Factors contributing to fatal snakebite in compartment syndromes. Injury 29 (6), the rural tropics: analysis of 46 cases in 403 – 11. Thailand. Trans Roy Soc Trop Med Hyg 1988; 82(6): 930-4. Mars M, Hadley GP, Aitchison JM. Direct intracompartmental pressure Mackessy SP, Williams K,, Ashton measurement of snakebites in children. S KG. Ontogenetic variation in venom composition and diet of Crotalus Afr Med J. 1991;80: 227-8. oreganus concolor: A case of venom paedomorphosis. Copeia 2003;4:769–82. Matsen FA . Compartmental syndromes. New York: Grune & Stratton. 1980 Maduwage K, Kularatne K, Wazil A, Gawarammana I. Coagulopthy, acute Ménez A. The subtle beast. Snakes, from kidney injury and death following Hypnale myth to medicine. London: Taylor and zara envenoming: the first case report from Francis. 2003. 176 p. Sri Lanka. Toxicon.2011; 58(8):641-3. Menon JC, Joseph JK, Jose MP, Dhananjaya Magar CT, Devkota K, Gupta R, Shrestha BL, Oommen OV. Clinical Profile and RK, Sharma SK, Pandey DP. A hospital laboratory parameters in 1051 Victims of based epidemiological study of snakebite Snakebite from a Single Centre in Kerala, in Western Development Region, Nepal. South India. J Assoc Physicians of India Toxicon. 2013 Jul;69:98-102. 2016 Aug; 64:18-26.

176 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Menon JC, Joseph JK, Jose MP, Punde Pathmeswaran A, Kasturiratne A, Fonseka D, Mazumdar DB, Bawaskar HS, et al. M, Nandasena S, Lalloo DG, de Silva HJ. Management protocol of venomous Identifying the biting species in snakebite snakebite in India: a consensus statement, by clinical features: an epidemiological Reviews. 2016 May 24; 35(3-4): tool for community surveys.Trans R Soc 147-51 Trop Med Hyg. 2006 Sep; 100(9): 874-8.

Mohapatra B, Warrell DA, Suraweera Patel FN, Ekkiswata MM. Motor cycle W, Bhatia P, Dhingra N, Jotkar RM, et al. ambulance: a cheaper and faster Snakebite mortality in India: a nationally alternative. Indian J Appl Basic Med Sci representative mortality survey. PLoS Negl 2010; 126: 50-54. Trop Dis. 2011 Apr 12; 5(4):e1018. Paul V, Pratibha S, Prahlad KA, Earali J, Mukherjee AK, Maity CR. The composition Francis S, Lewis F. High-dose anti-snake of Naja naja venom samples from three venom versus low-dose anti-snake venom districts of West Bengal, India. Comp in the treatment of poisonous snakebites- Biochem Physiol A Mol Integr Physiol. -a critical study. The Journal of the 1998 Feb; 119(2):621-7. Association of Physicians of India 2004 Jan;52:14-7. Murthy GL, Krishanaprasad A, Srinivasan VR, Sundaram S. Acute pituitary necrosis Phillips RE, Theakston RD, Warrell DA, following snake envenomation. J Assoc Galigedara Y, Abeysekera DT, Dissanayaka Physicians India. 2002 Mar; 50:452-3 P. Paralysis, rhabdomyolysis and haemolysis caused by bites of Russell’s viper (Vipera Myint-Lwin Warrell DA, Philips RE, Tin- Nu- russelli pulchella) in Sri Lanka: failure of Swe, Tun-Pe, Maung-Maung-Lay. Bites by Indian (Haffkine) antivenom. Q J Med. Russell’s viper (Vipera russelli siamensis) 1988 Sep; 68: 691-716. in Burma: haemostatic, vascular and renal disturbances in response to treatment. Lancet. 1985 Dec 7; 2(8467)1259-64. Pillai LV, Ambike D, Husainy S, Khaire A, Captain A, Kuch U. Severe Neurotoxic Envenoming and Cardiac Complications Nuchprayoon I, Garner P. Interventions for preventing reactions to snake antivenom. after the Bite of a ‘Sind Krait’ (Bungarus cf. Cochrane of Systematic Reviews; sindanus) in Maharashtra, India. Trop Med 1999 Jul 6; 4 Art No.: CD002153 Health. 2012 Sep; 40(3):103-8.

Nuchprayoon I, Pongpan C, Sripaiboonkij Pochanugool C, Limthongkul S, Wilde N. The role of prednisolone in reducing H. Management of thai cobra bites with limb oedema in children bitten by green a single bolus of antivenin. Wilderness pit vipers: a randomized, controlled trial. Environ Med. 1997 Feb;8(1):20-3. Ann Trop Med Parasitol. 2008;102:643-9. Prasad NB, Uma B, Bhatt SK, Gowda VT. O’Leary MA, Kornhauser RS, Hodgson WC, Comparative characterisation of Russell’s Isbister GK. An examination of the activity viper (Daboia/Vipera russelli) venoms from of expired and mistreated commercial different regions of the Indian peninsula. Australian antivenoms. Trans R Soc Trop Biochim Biophys Acta. 1999 Aug Med Hyg. 2009 Sep;103(9): 937-42. 5;1428(2-3):121-36. Premawardena AP, Seneviratne SL, Reid HA. Symptomatology, pathology and Gunatilake SB, de Silva HJ. Excessive treatment of land snakebite in India and fibrinolysis: the coagulopathy following South-East Asia. In: Bücherl W, Buckley EE Merrem’s hump-nosed viper (Hypnale & Deulofeu V editors. Venomous Animals hypnale) bites. Am J Trop Med Hyg. 1998 and their Venoms. New York. Academic Jun;58(6):821-3. Press; 1968. p. 611-42.

Premawardhena AP, de Silva CE, Fonseka Reid HA. Symptomatology, pathology and MM, Gunatilake SB, de Silva HJ. Low dose treatment of the bites of sea snakes. In subcutaneous adrenaline to prevent acute Lee C Y, editor. Snake Venoms. Handbook adverse reactions to antivenom serum of Experimental Pharmacology. Berlin: in people bitten by snakes: randomised, Springe Berlin Heidelberg; 1979.p.922–55. placebo controlled trial. BMJ. 1999 Apr 17; 318(7190):1041-3. Reid HA. Epidemiology of sea snakebites. J

Priyamvada PS, Shankar V, Srinivas Trop Med Hyg 1975 May; 78(5): 106-13. BH, Rajesh NG, Parameswaran S. Acute Interstitial Nephritis Following Reid HA & Lim KJ. Sea snakebite. A survey Snake Envenomation: A Single-Center of fishing villages in northwest Malaya. Experience. Wilderness Environ Med. 2016 BMJ. 1957; 2: 1266-72. Jun; 27(2):302-6. Reid HA, Thean PC & Martin WJ. Specific Rahman R, Faiz MA, Selim S, Rahman B, antivenene and prednisone in viper bite Basher A, Jones A. Annual incidence of poisoning: controlled trial. BMJ. 1963; 2: snakebite in rural Bangladesh, PLoS Negl 1378-80. Trop Dis. 2010 Oct 26; 4(10):e860. Rivière G, Choumet V, Audebert F, Raweerith R, Ratanabanangkoon K. Sabouraud A, Debray M, Schermann Immunochemical and biochemical JM et al. Effect of antivenom on venom comparisons of equine monovalent and pharmacokinetics in experimentally polyvalent snake antivenoms. Toxicon. envenomed : toward an 2005 Mar 1,45(3):369-75. optimization of antivenom therapy. J Pharmacol Exp Ther. 1997 Apri; 281(1): Reid HA, Thean PC, Chan KE, Baharom AR. 1–8 Clinical effects of bites by Malayan viper (Ancistrodon rhodostoma). Lancet. 1963 Mar 23; 1(7282): 617-21. Rojnuckarin P, Mahasandana S, Intragumthornchai T, Sutcharitchan P, Swasdikul D. Prognostic factors of green Reid HA, Chan KE & Thean PC. Prolonged coagulation defect (defibrination pit viper bites. Am J Trop Med Hyg. 1998 syndrome) in Malayan viper bite. Lancet. Jan; 58(1):22-5. 1963 Mar 23; 281(7282) 621-26. Rojnuckarin P, Chanthawibun W, Reid HA. Cobra bites. Br Med J. 1964 Aug Noiphrom J, et al. A randomized, 29; 2(5408): 540-5. double-blind, placebo-controlled trial of antivenom for local effects of green pit Reid HA. Antivenom reactions and efficacy. viper bites. Trans R Soc Trop Med Hyg. Lancet. 1980;1:1024-5. 2006; 100:879-84.

178 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Rusznak C, Peebles RS. Anaphylaxis and Sharma SK, Alirol E, Ghimire A, Poncet A, anaphylactoid reactions. A guide to Mostaguir K, Combescure C, et al. editors. prevention, recognition, and emergent A randomized, double blind, clinical trial treatment. Postgrad Med. 2002 May; of two dose regimens of VINS polyvalent 111(5):101-4, 107- 8, 111-4. antivenom for the treatment of snakebite with neurotoxic envenomation in Nepal In: Saini RK, Singh S, Sharma S, Rampal 18th World Congress of the International V, Manhas AS, Gupta VK. Snakebite Society-IST 2015; Sept 25-30; London poisoning presenting as early morning (United Kingdom) neuroparalytic symptoms in jhuggi dwellers. 1986 Jun; J Assoc Physicians Sharma SK, Chappuis F, Jha N, Bovier PA, India 34(6): 415-7. Loutan L, Koirala S. Impact of snakebites and determinants of fatal outcomes in Sano-Martins IS, Fan HW, Castro SC, southeastern Nepal. Am J Trop Med Hyg. Tomy SC, Franca FO, Jorge MT, et al 2004 Aug;71(2):234-8. (1994). Reliability of the simple 20 minute whole blood clotting test (WBCT20) as Sharma SK, Bovier P, Jha N, Alirol E, an indicator of low plasma fibrinogen Loutan L, Chappuis F. Effectiveness of concentration in patients envenomed rapid transport of victims and community Toxicon. 1994 Sep; by Bothrops snakes. health education on snakebite fatalities in 32(9): 1045-50. rural Nepal. Am J Trop Med Hyg. 2013 Jul; 89(1):145-50. Sarkar MSU, Sarkar NJ, Patwary MS. Epidemiological Survey of Snakebite in Sharma SK, Khanal B, Pokhrel P, Khan A, Bangladesh. Dhaka (Bangladesh) Ministry Koirala S. Snakebite-reappraisal of the of Science and Technology, Government of situation in Eastern Nepal. Toxicon. 2003 the People’s Republic of Bangladesh; 1999 Mar 1;41(3):285-9. Sawai Y. Clinical problem of snakebites Sharma SK, Pandey DP, Shah KB, Tillack in . In: Tu AT editors F, Chappuis F, Thapa CL, et al. Venomous Toxin- related diseases, Oxford and IBH Snakes of Nepal, A Photographic Publishing Co, 1993. p: 445-69. Guide [internet]. Dharan: B.P. Koirala Seneviratne SL, Opanayaka CJ, Ratnayake Institute of Health Sciences;2013, 78 p. NSL, Sarath Kumara KE, Sugathadasa AM, Available from http://www.bik-f-de/flies/ Weerasuriya N, et al. Use of antivenom publications/ kuch_venomous_snake_of_ serum in snakebite: a prospective study of nepal_english_e dition.pdf hospital practice in the Gampaha district. Shashidharamurthy R, Kemparaju K. Ceylon Medical J 2000 Jun; 4(2): 65-8. Region-specific neutralization of Indian Seneviratne SL, de Silva CE, Fonseka MM, cobra (Naja naja) venom by polyclonal Pathmeswaran A, Gunatilake SB, de Silva antibody raised against the eastern HJ. Envenoming due to snakebite during regional venom: A comparative study pregnancy. Trans R Soc Trop Med Hyg. of the venoms from three different 2002 may-jun; 96(3): 272-4. geographical distributions. Int Immunopharmacol. 2007 Jan;7(1):61-9. Sharma LR , Lal V, Simpson ID. Snakes of medical significance in India: the first Silveira PV, Nishioka Sde A. Venomous reported case of envenoming by the snakebite without clinical envenoming Levantine viper (Macrovipera lebetina). (‘dry-bite’). A neglected problem in Brazil. Wilderness Environ Med. 2008; 19(3):195-8. Trop Geogr Med. 1995;47(2):82-5.

Management of snakebites 179 in South-East Asia Soh C-T, et al. Current status of snakebite Than-Than, Khin-Ei-Han, Hutton RA, in Korea. Yonsei Reports on Trop Med. Myint-Lwin, Tin-Nu-Swe, Phillips RE et al. 1978; 9:48-56. Evolution of coagulation abnormalities following Russell’s viper bite in Burma. Sitprija V, Boonpucknavig V. Snake venoms British J Haematology 1987; 65: 193-198. and nephrotoxicity. In: Lee C-Y editors. Snake venoms. Handbook of Experimental Than-Than, Hutton RA, Myint-Lwin, Pharmacology. Berlin Springer Verlag, Khin- Ei-Han, Soe-Soe, Tin-Nu Swe, et 1979. p. 997-1018. al. Haemostatic disturbances in patients bitten by Russell’s viper (Vipera russelli siamensis) in Burma. British J Haematology Smith MA. The Fauna of British India, 1988 Aug; 69(4): 513-520. Ceylon and Burma, inlcuding the whole of the Indo-Chinese subregion. Reptilia and Than-Than, Francis N, Tin-Nu-Swe, Myint- Amphibia. Vol III Serpentes. London, Taylor Lwin, Tun-pe, Soe-Soe, et al. Contribution and Prancis: 1943. p.482-5. of focal haemorrhage and microvascular fibrin deposition to fatal envenoming by Srimannarayana J, Dutta , Sahai A, Russell’s viper (Vipera russelli siamensis) Badrinath S. Rational use of anti-snake in Burma. Acta Tropica, 1989 Jan; 46(1): venom: Trial of various regimens in 23-38. Hemotoxic Snake envenomation. J Assoc Phys India 2004 Oct;52:788-93 Theakston RDG, Phillips RE, Looareesuwan S, Echeverria P, Makin T, Warrell DA. Sutherland SK. Serum reactions. An Bacteriological studies of the venom and analysis of commercial antivenoms and the mouth cavities of wild Malayan pit vipers possible role of anticomplementary activity (Calloselasma rhodostoma) in southern in de-novo reactions to antivenoms and Thailand. Trans Roy Soc Trop Med Hyg. antitoxins. Med J Aust. 1977; 1:613-5. 1990; 84: 875-9.

Sutherland SK, Coulter AR and Harris RD. Theakston RDG, Phillips RE, Warrell Rationalisation of first-aid measures for DA,Galagedera Y, Abeysekera DT, elapid snakebite. Lancet. 1979; 313(8109): Dissanayaka P, et al. Envenomingby the 183-6. common krait (Bungarus caeruleus) and Sri Lankan cobra (Naja naja naja): efficacy and complications of therapy with Sutherland SK, Tibballs J. Australian animal Haffkine antivenoms. Trans R Soc Trop toxins: The creatures, their toxins and Med Hyg. 1990 Mar-Apr:84(2): 301-8. care of the poisoned patient 2nd edition. Melbourne, Oxford University Press; 2001. Thein T, Tin T, Hla P, Phillips RD, Myint L, Tin Nu S, et al. Development of renal Swaroop S, Grab B. Snakebite mortality in function abnormalities following Russell’s the world. Bull World Health Org. 1954; viper (Vipera russelli siamensis) bite in 10:35-76. Myanmar. Trans R Soc Trop Med Hyg 1991; 85: 404-409. Tariang DD, Philip PJ, Alexander G, Macaden S, Jeyaseelan L, Peter JV, et al. Thiansookon A, Rojnuckarin P. Low Randomized controlled trial on the effective incidence of early reactions to horse- dose of anti-snake venom in cases of derived F(ab’)(2) antivenom for snakebite with systemic envenomation. J snakebites in Thailand. Acta Trop. 2008 Assoc Physicians India 1999; 47(4):369-71. Feb;105(2):203-5.

180 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Thomas PP, Jacob J. Randomised trial of Tun-Pe, Aye-Aye-Mying, Khin-Aye-Han et antivenom in snake envenomation with al. Local compression pads as a first-aid prolonged clotting time. British medical measure for victims of bites by Russell’s journal (Clinical research ed.) 1985 viper (Daboia russelii siamensis) in Aug;291(6489):177-8. Myanmar. Trans Roy Soc Trop Med Hyg 1995; 89:293-5. Tilbury CR. Observations on the bite of the Mozambique spitting cobra (Naja Tun-Pe, Aye-Aye-Myint, Khin-Aye-Kyu, mossambica mossambica). S African Med J Maung-Maung-Toe. Acceptability study 1982;27 Feb:308-313. of protective boots among farmers of Taungdwingyi township. New Delhi: WHO Tin-Nu-Swe, Tin-Tun, Myint-Lwin, Thein- Regional Office for South-East Asia, 2002: Than, Tun-Pe, Robertson JL, et al. Renal pp. 7–11. ischaemia, transient glomerular leak and acute renal tubular damage in patients Vaiyapuri S, Vaiyapuri R, Ashokan R, envenomed by Russell’s vipers (Daboia Ramasamy K, Nattamaisundar K, Jeyaraj russelii siamensis) in Myanmar. Trans Roy A, et al. Snakebite and its socioeconomic Soc Trop Med Hyg 1993, 87: 678-81. impact on the rural population of Tamil Nadu, India. PLoSOne. 2013 Nov 21; Tin-Myint, Rai-Mra, Maung-Chit, Tun- 8(11):e80090. Pe, Warell DA. Bites by the king cobra (Ophiophagus hannah) in Myanamar: Viravan C, Veeravat U, Warrell MU, et successful treatment of severe neurotoxic al. ELISA- ofacute and past envenoming. QJM. 1991; 80(3): 751-62. envenoming by the monocellate Thai cobra (Naja kaouthia). American J Trop Tun Pe, Khin Aung Cho. Amount of venom Med Hyg 1986; 35(1): 173-181. injected by Russell’s viper (Vipera russelli). Toxicon. 1986;24(7):730-3. Viravan C, Looareesuwan S, Kosakarn W, Wuthiekanun V, McCarthy CJ, Stimson AF Tun-Pe, Phillips RE, Warrell DA, Moore et al. A national hospital-based survey of RA, Tin-Nu-Swe, Myint-Lwin, et al. Acute snakes responsible for bites in Thailand. and chronic pituitary failure resembling Transactions Roy Soc Trop Med Hyg. 1992 Sheehan’s syndrome following bites by Jan-Feb; 86(1): 100-6. Russell’s viper in Burma. Lancet. 1987 Oct 3;2(8562)763-7. Warrell DA. Tropical snakebite: clinical studies in South-East Asia. In: Harris JB, Tun-Pe, Ba-Aye, Aye-Aye-Myint, Tin- Nu- editors. Natural Toxins. Animal, plant and Swe, Warrell DA. Bites by Russell’s viper microbial. Oxford: Clarendon Press; 1986 (Daboia russelii siamensis) in Myanmar: p.25-45. effect of snake’s length and recent feeding on venom antigenaemia and severity of Warrell DA. Russell’s viper: biology, venom envenoming. Trans Roy Soc Trop Med Hyg and treatment of bites. Trans Roy Soc Trop 1991 Nov-Dec; 85(6) 85: 804-8. Med Hyg 1989 Nov-Dec; 83(6): 732-40.

Tun-Pe, Nu-Nu-Lwin, Aye-Aye-Myint, Kyi- Warrell DA. Treatment of snakebite in the May-Htwe, Khin-Aung-Cho. Biochemical Asia-Pacific Region: a personal view. In: and biological properties of the venom Gopalakrishnakone P, Chou LM editions. from Russell’s viper (Daboia russelli Snakes of medical importance (Asia-Pacific siamensis) of varying ages. Toxicon. 1995; region). singapore: National University of 33(6):817-21. Singapore Press, 1990. p. pp 641-670.

Management of snakebites 181 in South-East Asia Warrell DA. Bites by dark green pit vipers Warrell DA, Greenwood BM, Davidson in Bangkok. Am. J. Trop. Med. Hyg. 1990; NM, Ormerod LD, Prentice CR. Necrosis, 42: 623-624. haemorrhage and complement depletion following bites by the spitting cobra (Naja Warrell DA. The global problem of nigricollis). Q J Med. 1976 Jan; 45(177):1- snakebite: its prevention and treatment. 22. In: Gopalakrishnakone P, Tan CK, editions. Recent Advances in Toxinology Research Warrell DA, Davidson NMcD, Greenwood Singapore: National University of BM, Ormerod LD, Pope HM, Watkins BJ et Singapore Press, 1992. p. 121-153. al. Poisoning by bites of the saw-scaled or carpet viper (Echis carinatus) in Nigeria. Q Warrell DA. Sea snakebites in the Asia- J Med.1977 Jan; 46(181): 33-62. Pacific region. In Gopalkrishnakone P editions. Sea Snake Toxinology. Singapore Warrell DA, Looareesuwan S, White NJ, Singapore University Press, 1994. p. 1-36. Theakston RD, Warrell MU, Kosakarn W, et al. Severe neurotoxic envenoming by the Malayan krait Bungarus candidus Warrell DA. Clinical of snakebite (Linnaeus): response to antivenom and in Asia. In: Meier J, White J, editions. anticholinesterase. BMJ 286: 678-80. Clinial Toxicology of Animal Venoms and Poisons. Boca Ranton: CRC Press; 1995.p. Warrell DA, Looareesuwan S, Theakston 493-594. RD, Phillips RE, Chanthavanich P, Viravan C, et al. Randomised comparative trial of Warrell DA. Geographical and intraspecies three monospecific antivenoms for bites variation in the clinical manifestations by the Malayan pit viper (Calloselasma of envenoming by snakes. In Thorpe RS, rhodostoma) in southern Thailand: clinical Wüster W, Malhotra A, editors: Venomous and laboratory correlations. Am J Trop snakes: Ecology, evolution and snakebite, Med Hyg. 1986 Nov; 35(6): 1235-47. Oxford: Clarendon Press,1997. p. 189- 203. Warrell DA, Looareesuwan S, Stimson AF. Rediscovery and redefinition of Malcolm Warrell DA. Researching nature’s venoms Smith’s Trimeresurus kanburiensis in and poisons. Trans R Soc Trop Med Hyg. Thailand, with a report of envenoming. 2009 Sep;103(9):860-6. Trans R Soc Trop Med Hyg. 1992;86:95-9.

Warrell DA. Snakebite. Lancet 2010 Jan 2; Warrell DA, Hudson BJ, Lalloo DG, Trevett 375(9708): 77-88. AJ, Whitehead P, Bamler PR, et al. The emerging syndrome of envenoming Warrell DA. Snakebite: a neglected problem by the New Guinea small- eyed snake in twenty-first century India. Natl Med J Micropechis ikaheka. Quart J Med. 1996 India. 2011 Nov-Dec; 24(6):321-4. Jul; 89(7):523-30.

Warrell DA, Arnett C. The importance of Warrell DA, Gutiérrez JM, Calvete bites by the saw-scaled or carpet viper JJ, Williams D. New approaches & (Echis carinatus). Epidemiological studies technologies of venomics to meet the in Nigeria and a review of the world challenge of human envenoming by literature. Acta Tropica Basel, 1976; 33: snakebites in India. Indian J Med Res. 307-41. 2013;138:38-59

182 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Watt G, Theakston RD, Hayes CG, Yambao Weinstein SA, White J, Westerström A, ML, Sangalang R, Ranoa CP, et al. Positive Warrell DA. Anecdote vs. Substantiated response to edrophonium in patients with Fact: The Problem of Unverified Reports neurotoxic envenoming by cobras (Naja in the Toxinological and Herpetological naja philippinensis): a placebo- controlled Literature Describing Non-front-fanged study. New Engl J Med. 1986; 315(23): Colubroid (“Colubrid”) Snakebites. 1444-8. Herpetological Review, 2013 March; 44(1), 23–29.

Watt G, Padre LP, Tuazon ML, Theakston Whitaker R. Snakebite in India today. RD, Laughlin LW. Tourniquet application Neurol India. 2015 63(3) : 300-3. after cobra bite: delay in the onset of neurotoxicity and the dangers of sudden Whitaker R, Martin G. Diversity and release. Am J Trop Med & Hyg. 1988; 38: distribution of the medically important 618-22. snakes of India. Clinical Toxinology in Asia and Africa. 2015 January 2015; 2:115-36. Watt G, Meade BD, Theakston RD, Padre LP, Tuazon ML, Calubaquib C, et al. Williams DJ, Jensen SD, Nimorakiotakis Comparison of tensilon and antivenom for B, Muller R, Winkel KD. Antivenom use, the treatment of cobra-bite paralysis. Trans premedication and early adverse reactions Roy Soc Trop Med Hyg. 1989 83: 570-3. in the management of snakebites in rural Papua New Guinea. Toxicon. 2007 49(6):780-92. Watt G, Theakston RD. Seasnakebites in a freshwater lake. Am J Trop Med Hyg. Williams DJ, Jensen SD, O’Shea M. 1985; 34(4):770-3. Snakebite management in Cambodia: towards improved prevention, clinical Weinstein SA, R, Ismail AK.Non- treatment and rehabilitation. Manila: front-fanged colubroid (“colubrid”) WHO WPRO. 2009. snakebites: three cases of local envenoming by the mangrove or ringed Williams D, Gultierrez JM, Harrison R, cat-eyed snake (Boiga dendrophila; Warrell DA, White J, Winkel, et al. The Colubridae, ), the Western Global Snakebite Initiative: an antidote for beaked snake ( oxyrhynchus; snakebite. Lancet. 2010 Jan 2; 375(9708): , Psammophinae) and the 89–91. rain forest cat-eyed snake ( Williams SS, Wijesinghe CA, Jayamanne frenata; Dipsadidae). Clin Toxicol (Phila). SF, Buckley NA, Dawson AH, Lalloo DG, 2014; 52(4):277-82. et al. Delayed psychological morbidity associated with snakebite envenoming. Weinstein SA, Smith TL, Kardong KV. PLoS Negl Trop Dis. 2011 August 2; venom glands: Form, function, and 5(8):e1255. future, In Mackessy SP, editor: Handbook of venoms and toxins of , Boca Win-Aung, Tin-Tun, Khin-Maung-Maung, Raton: CRC Press, 2009. P 65-91. Aye-Kyaw, Hla-Pe, Tin-Nu-Swe, et al. Clinical trial of intramuscular anti-snake Weinstein SA, Warrell DA, White J, Keyler venom administration as a first aid DE. (2011). “Venomous” bites from measure in the field in the management non- venomous snakes: A critical analysis of Russell’s viper bite patients. Southeast of risk and management of “colubrid” Asian J Trop Med Public Health 1996 Sep; snakebites, London: Elsevier; 2011. 364 p. 27(3):494-7.

Management of snakebites 183 in South-East Asia Wongtongkam N, Wilde H, Sitthi-Amorn Wüster W, Warrell DA, Cox MJ, Jaintakune C, Ratanabanangkoon K. A study of 225 P, Narhitabhata. Redescription of Naja Malayan pit viper bites in Thailand. Mil siamensis (Serpentes: Elapidae), a widely Med. 2005 Apr;170(4):342-8. overlooked spitting cobra from South- East Asia: geographic variation, medical World Health Organization. Progress importance and designation of neotype. J in the characterization of venoms and Zool Lond. 1997; 243(4): 771-88. standardization of antivenoms. Geneva: WHO Press; 1981. Report No. 58. Zakariah A. Presentation on variability of polyvalent ASV efficacy- Clinical Experience World Health Organization Rabies and at Christian Medical College, Vellore 3rd envenomings. A neglected public health national conference on Tropical Medicine issue. Report of a Consultative Meeting, and Toxicology in Bangladesh. Dhaka Geneva, 10 January 2007. 32 p. (Bd); December 2014. Available from: http:// medicinesomc.com/wp-content/ World Health Organization: WHO uploads/2015/01/Variability-of- Polyvalent- guidelines for the production, control ASV-efficacy-Clinical- experience-of- and regulation of snake antivenom Christian-Medical-College- Vellore.pptx immunoglobulins and Venomous snakes distribution and species risk categories [internet] Geneva, WHO Press; 2008. Available from . http://www.who.int/ bloodproducts/snake_ antivenoms/ snakeantivenomguideline.pdf?ua=1.

184 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES ANNEXure

ANNEXURE 185 186 1annex Algorithm: Diagnosis of snakebite cases based on clinical data as a basis for antivenom treatment

Algorithms should be created based on local data so that they can be relevant for local use. The example below is intended for use in Sri Lanka (Ariaratnam et al., 2009).

Patient presents with a Hx of snake bite BUT no dead snake and little/no description of the snake

Non clothing blood/ YES YES Neurotoxic signs Marked local swelling spontaneous systemic bleeding

YES NO YES

Non clothing blood/ spontaneous Neurotoxic signs Neurotoxic signs systemic bleeding NO YES YES NO

Early Acute Bitten on land blistering/ Renal sleeping on Bitten in Acute Renal necrosis Failure floor of house sea Failure

YES NO

Cobra Russell’s Krait Sea Snake Hump Nosed Saw Scaled bite Viper bite bite bite Viper bite Viper bite

Figure 89a. Algorithm for diagnosis of the snake responsible for a bite in Sri Lanka (Ariaratnam et al., 2009)

ANNEXURE 187 2annex Algorithm: Differentiating major Asian snake species by clinical syndrome

These should be created based on local data so that they can be relevant for local use. The example below is intended for use in Sri Lanka (Ariaratnam et al., 2009).

VIPERIDAE

Daboia russelii Echis carinatus

Trimeresurus trigonocephalus Hypnale hypnale

188 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES elapidae

Naja naja

Bungarus caeruleus Bungarus ceylonicus

elapidae

Hydrophis cyanocinctus

Figure 89b: Syndromic approach to snakebite management in Sri Lanka: venomous snakes of Sri Lanka (Ariaratnam et al., 2009)

ANNEXURE 189 Clinical spectrum of syndromes of snakebites, Sri Lanka Species No. Local effects Coagulopathy Neurotoxicity Renal Myotoxicity (%) (%) (%) (%) (%)

Russell’s viper 319 96 76 59 19 24

Hump-nosed viper 302 91 39 - 10 -

Common krait 88 9 - 95 - -

Cobra 45 91 - 80 - -

Sensitivity and specificity of clinical syndromes as a screening test in identifying snakebites, Sri Lanka

Snake Sensitivity (%) Specificity (%)

Russell’s viper 14 100

Cobra 78 96

Common krait 66 100

Hump-nosed viper 10 97

190 3annex

Antivenoms for treatment of bites by South-East Asian snakes (list is compiled by the experts contributed to this publication and may not be inclusive of all antivenoms available in countries). Recommended doses are those quoted by the manufacturers. For recommended initial doses of some of these antivenoms, according to the species of snake responsible for envenoming, based on clinical experience, are given in Table 1

A. Australia “Agkistrodon” acutus antivenin (purified) Bio CSL Commonwealth Serum (= Deinagkistrodon acutus, found in North Laboratories Viet Nam).

45 Poplar Rd Recommended initial dose: 8000 IU Parkville, Victoria 3052, Australia (= 4 ampoules) Phone: +61 3 9389 1911 Fax: +61 3 9389 1434 “Agkistrodon halys” (= Gloydius [email protected] brevicaudus) antivenin (purified) (said to be Phone: +61 39389 1204 active against venoms of Protobothrops/ Trimeresurus mucrosquamatus and Black snake (Pseudechis spp.), brown Viridovipera/). snake (Pseudonaja spp.), death adder Recommended initial dose: 6000 IU (Acanthophis spp.), polyvalent, sea snake (= 1 ampoule) antivenoms. Recommended initial dose: 1-3 vials Bungarus multicinctus antivenin (purified) (said to be effective against the venom of B. China Ophiophagus hannah). Shanghai Institute of Biological Products, Recommended initial dose; for bites Ministry of Health, 1262 Yan An Road (W), by both species 10 000 IU (= 1.25 Shanghai 200052, China (Tel ++ 8621- ampoules) 62803189; Fax ++ 8621-62801807). Contact: Ms Minzhi Lu, Manager, “Naja naja” antivenom (purified) (= Naja International Affairs & Trade Department atra). (Tel ++ 8621-62805234) Recommended initial dose: 2000 IU (liquid antivenoms, 10-15 ml/ampoule) (= 2 ampoules)

ANNEXURE 191 C. India 3. Bengal Chemicals and Polyvalent antivenoms raised in Pharmaceuticals Ltd, equines against venoms of Bungarus 6 Ganesh Chunder Avenue 700013 caeruleus, Naja naja, Daboia russelii, Echis Kolkota carinatus collected in Mamallapuram, Tel: +91-33-2237-1525 Tamil Nadu but more recently also from Fax:+91-33-2225-7697 other areas (to be confirmed). Antivenoms (currently stopped production) are lyophilised (reconstituted to 10ml per vial) or liquid. 4. King Institute, Chennai (in 2016, announced resumption of production Recommended initial dosage for all after a 15 year break) these antivenoms is: Bungarus caeruleus: 10-20 vials Private sector Naja naja: 10-20 vials Daboia/Vipera russelli: 10 vials 1. Serum Institute of India Echis carinatus: 5 vials (10 vials for E. c. 212/2, Hadapsar sochureki in N and NW India) Off Soli Poonawalla Road 411028 Pune Tel:+91-20-26993900 Note: venoms of other species (including Fax:+91-20-26993921 hump-nosed pit-viper Hypnale hypnale (reduced/stopped production) – SW India and Sri Lanka, and all other pit-vipers) are not covered by Indian 2. VINS Bioproducts Ltd polyvalent antivenoms, nor are venoms by 806,Essjay House, Naja, Daboia or Echis species, sea snakes Road Nr 3, Banjara Hills 500034 or other species occurring outside India. Hyderabad Tel:+91-40-23354550, Fax:+91-40-23350410 Cobra Annual production estimates of Antivenin, Russell’s Antivenin, Anti number of 10 ml vials of polyvalent snake Venom Polyvalent antivenom (“ASV”) (2015-16) are given in (production 2015-16: 1 000 000 vials) parentheses. 3. Biological E. (Evans) Limited 18/1 and Public sector 3, Azamabad 500020 Hyderabad 1. Central Research Institute, Kasauli Tel:+91-40-30213999, 173204 Kasauli (H.P.) Fax:+91-40-27615309 Tel:+91-1-792-72114 E-mail [email protected] Fax:+91-1-792-72049 (production 2015-16: 500 000 vials of (reduced/stopped production)] liquid antivenom only)

2. Haffkine Institute 4. Bharat Serum and Vaccine Haffkine Bio-Pharmaceutical Acharya Plot No. K-27, Anand Nagar, Additional Donde Marg, M.I.D.C. Ambernath (East) Parel -400012 Mumbai Tel:+91-251-2621 645, Tel:+91-22-412-9320, Fax:+91-251-2621 089 Fax:+91-22-416-8578 Snake Venom Antiserum I.P. (production 2015-16: 400 000 vials) (production 2015-16: 800,00) (supplying Maharashtra State)

192 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES 5. Mediclone Biotech Pvt. Ltd., 36/37 E. Millenium House, M.K.Srinivasan Nagar State Serum & Vaccine Institute, Main road, Perungudi, Chennai Razi Hessarek, bP 656, Teheran Tel +91-44-24963845 (liquid antivenoms, 10 ml/ampoule) Fax +91-44-24963846 (Tel ++ 98 2221 2005) (production 2015-16: 40 000 vials) Polyvalent snake antivenom (equine) (reducing production) (said to neutralize the venoms of two South-East 6. Premium Serum and Vaccines Asian species - Naja oxiana and Echis Narayangaon carinatus (probably E sochureki), Vipera 406, B Wing, Highway Rose Co-op. lebetina (= Macrovipera lebetina) and Housing Society, Pseudocerastes persicus 92 Dixit Road Extensions, Recommended initial dose: ? Vile Parle (East), Mumbai 400057, F Japan Maharashtra, Japan Snake Institute Farm and manufacturing facility Nihon Hebizoku Gakujutsu Kenkyujo S.No 354-1,354-2A/1 At and post 3318 Yunoiri Yabuzuka Narayangaon, near Champagne India, Yabuzukahonmachi Nittagun Tal- Junnar, Dist- Pune-410504, Gunmaken 379-2301 Maharashtra, Tel 0277 785193 Fax 0277 785520 E-mail [email protected] [email protected] [email protected] www.sunfield.ne.jp/~snake-c/ : www.premiumserums.com Polyvalent Snake Venom Antiserum Yamakagashi (Rhabdophis tigrinus) both in Lyophilized or liquid form antivenom (also effective against red- (production 2015-16: 600 000 vials) necked keelback R. subminiatus venom) Venom sources Maharashtra and Uttar Pradesh in addition to Irula Society in G Myanmar (Burma) Tamilnadu. Myanmar Pharmaceutical Factory, Insein, Yangon (production capacity 100 000 D. Indonesia vials/year)

PT Bio Farma (persero) (lyophilized and liquid equine F(ab’)2 Jl Pasteur no 28 Bandung - 40161 antivenoms, 10 ml/ampoule) Tel. +62 22033375 Viper antivenom (V. russelli = Daboia Fax +62 222041306 siamensis) Website: www.biofarma.co.id Cobra antivenom (N. kaouthia) Email : [email protected] Recommended initial dose: 8 vials for D. Recommended initial dose: 2 x 5 ml siamensis, 4 vials for N. kaouthia vials (maximum 80-100 ml) A new ovine D. siamensis antivenom is Liquid antivenom now in production (Dr Aung Zaw, personal communication). Biosave (polyvalent Anti-Snake Venom Sera, Equine) “serum anti bisa ular H Pakistan polivalen (kuda)” Naja sputatrix-cobra, National Institute of Health, Bungarus fasciatus - banded krait, Biological Production Division, Islamabad Agkistrodon rhodostoma – Malayan pit (Tel ++ 9251- 240946; viper Fax ++ 9251-20797; Telex 5811-NAIB-PK) (no recent information available)

ANNEXURE 193 Dr. Birjees Mazher Kazi, Executive Director D. russelii, E. carinatus, H. hypnale, and National Institute of Health, Islamabad N. naja. It showed satisfactory preclinical Tel: (051) 9255117 potency and will be subjected to clinical Fax: (051) 9255099, 9255125 trials in Sri Lanka. Antivenom against Email: [email protected]. B. caeruleus is also being developed, to net.pk @nih.org.pk provide cover against all five medically Contact: Shahid Akhtar important snakes. (liquid and lyophilized antivenoms, 10 ml/ampoule) L Thailand Polyvalent anti-snake venom serum The Thai Red Cross Society (production (B. caeruleus, E. carinatus, N. naja, capacity 75 000 – 82 000 vials/year) V. lebetina (=Macrovipera lebetina), Queen Saovabha Memorial Institute, V. russelli (= Daboia russelii) 1871 Rama VI Road, Bangkok 10330 Recommended initial dose: 5 vials for Tel ++ 662-2520161-4; Echis carinatus, 10 vials for other species. Fax ++ 662-2540212; Telex 82535 THRESCO TH) J Taiwan (freeze-dried monovalent antivenoms, National Institute of Preventive Medicine, 10 ml/ampoule) 161 Kun-Yang Street, Nan-Kang, Taipei, ROC 1. Cobra antivenom (Naja kaouthia): 11513 (Tel ++ 8862-7859215; recommended dose 100 ml* Fax ++ 8862-7853944). 2. King cobra antivenin (Ophiophagus Contact: Dr Gong-Ren Wang, Director hannah): 50 ml* (lyophilised antivenoms, 10 ml/ 4. Russell’s viper antivenin (Daboia ampoule) siamensis): 30 ml* Bungarus multicinctus and N atra bivalent 5. Malayan pit viper antivenin antivenom (Calloselasma rhodostoma): 30 ml* Trimeresurus mucrosquamatus (= 6. Green pit viper antivenin (Cryptelytrops Protobothrops mucrosquamatus) and – ): 30 ml* Trimeresurus grammineus (= Viridovipera 7. Malayan Krait Antivenin (Bungarus stejnegeri) bivalent antivenom candidus): 50 ml* Recommended initial dose: 5 vials (freeze-dried polyvalent antivenoms, Agkistrodon acutus (= Deinagkistrodon 10 ml/ampoule) acutus) antivenom Neuro polyvalent (raised against 1-3 Recommended initial dose: ? and 7): 20 ml* for all species

K Sri Lanka Haemato polyvalent (raised against 4-6): A new polyspecific, freeze-dried whole 20 ml* for all species IgG antivenom, manufactured by caprylic acid precipitation, has been developed *Recommended doses according through a collaboration between to approved registration dossiers Instituto Clodomiro Picado (University from Thai FDA (Professor Sumana of ), Animal Venom Research Khomvilai, personal communcation International (AVRI), USA, and University 21-07-2016). These differ from of Peradeniya. The antivenom has been suggested initial doses quoted in raised against venoms from Sri Lankan Table 1, based on clinical experience.

194 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES 4annex Pressure-immobilization and pressure

Pressure-immobilization methods A rubber and/or folded material pad Bites by cobras, king cobras, kraits, approximately 5 cm square and 2-3 cm Australasian elapids or sea snakes may thick is placed directly over the bite site lead, on rare occasions, to the rapid anywhere on the body and bound in place development of life-threatening respiratory with a non-elastic bandage at a pressure paralysis. This paralysis might be delayed of at least 70 mmHg. by slowing down the absorption of venom from the site of the bite. The following Pressure-bandage plus immobilization techniques are currently recommended: Sutherland et al., 1979 ; Sutherland and Tibballs, 2001) (Fig 91). Pressure-pad plus immobilization (Anker et al., 1982; Tun-Pe et al., 1995) Ideally, an elasticated bandage, (Fig 90) approximately 10 – 15 cm wide and at least

• pad of rubber or cloth approx. 6 x 6 x 3 cm applied directly over bite site • secured tightly with inelastic bandage at approx 70 mmHg pressure

Figure 90: Pressure-pad immobilization method (Copyright Dr David J Williams)

ANNEXURE 195 4.5 metres long should be used (Canale et a rigid splint. The bandage is bound firmly al., 2009). If that it not available, any long (at a pressure of 50-70 mmHg), but not strips of material can be used. The bandage so tightly that the peripheral pulse (radial, is bound firmly around the entire bitten posterior tibial, dorsalis pedis) is occluded limb, starting distally around the fingers or that the patient develops severe or toes and moving proximally, to include (ischaemic) pain in the limb.

Sutherland’s Pressure bandage -immobilisation: Elastic (not crepe) bandages 10 cm wide x 3.5 - 4.5 m long Figure 91: Pressure-bandage immobilization: left – lower limb; right - upper limb (Copyright Dr David J Williams)

196 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES 5annex Measurement of central venous pressure

In seriously ill patients with shock or renal failure in whom clinical assessment of the jugular venous pressure is difficult or considered inaccurate, a central venous catheter should be inserted percutaneously. In those with no haemostatic problems, a catheter may be inserted into the jugular or subclavian vein provided adequate facilities for a sterile procedure and subsequent nursing are available. However, patients who have been bitten by vipers may have obvious haemostatic problems or may develop coagulopathy. In these cases, the [a] antecubital approach is by far the safest as haemostasis can be achieved by local pressure. A long catheter (at least 50-70 cm for an adult) is required (Fig 92a). The catheter is connected via a three-way tap and pressure tubing to a manometer. The whole system is filled with sterile isotonic saline. Before readings can be taken, the zero on the manometer must be aligned as accurately as possible with the horizontal plane of the left atrium. A simple spiritlevel (eg a 20 ml glass ampoule with bubble, taped to a ruler) can be used to locate the manometer zero at the same height as an appropriate chest-wall landmark, such as the midaxillary line, in the supine [b] patient (Fig 92b) or the sternal angle in a patient sitting up at 45º. There should be Figures 92: Central venous pressure monitoring in patients with shock: (a) 70 cm long catheter inserted into an antecubital vein (Seldinger percutaneous guidewire strict attention to asepsis. Infection and technique) and advanced until its tip was in the superior vena cava. An extension thrombosis are potential complications; tube connects with a simple saline manometer whose zero point is at the level of the mid-axillary line; (b) Adjusting the zero point of the central venous pressure especially if the catheter remains in place manometer to the midaxillary line, using a home-made ruler-plus-glass-ampoule for a long time. “spirit level” (Copyright DA Warrell)

ANNEXURE 197 6annex Measurement of intracompartmental pressure

Measurement of intracompartmental way tap, the system is connected, through pressure in tensely swollen snake- a side arm to a blood pressure transducer bitten limbs or saline or mercury manometer (Fig 93a). To confirm a clinical suspicion of The system is filled with sterile isotonic intracompartmental syndrome (see saline. If a syringe-type infusion pump 5.8.2) the pressure inside the particular and arterial blood pressure transducer compartment should be measured directly with monitor is used, the pressure can (Matsen 1980; Mars and Hadley 1998; be measured continuously at a very slow Mars et al., 1991). rate of infusion (eg 0.7 ml/day). If a saline or mercury manometer is used, a much The threshold pressure required to higher rate of infusion is required to initiate the flow of liquid into the fascial initiate flow into the compartment. These compartment is a measure of the tissue systems are not suitable for continuous pressure inside that compartment. With intracompartmental pressure monitoring. full sterile precautions and after infiltrating Alternatively, the simple but expensive local anaesthetic, a 21 or 22 gauge Stryker pressure monitor can be used cannula, approximately 3-4 cm long, is (Fig 93b). inserted into the compartment through or around an introducing 20 or 21 gauge Whatever system is employed, the zero needle. The cannula is connected through point in the pressure measuring device narrow pressure tubing to a syringe or low must be aligned to the level at which the speed infusion pump. Through a three- cannula enters the fascial compartment.

[a] [b]

Figures 93: Measurement of intracompartmental pressure to exclude compartment syndrome in a snakebite victim: (a) infusion pump, saline manometer system in use for measuring the tissue pressure inside the anterior tibial compartment; (b) Stryker pressure monitor in use for measurement of intracompartmental pressure (Copyright DA Warrell)

198 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES 7annex List of Contributors

Professor Mohammad Abul Faiz VINS Bioproducts Ld Professor of Medicine (Retired) & Former Hyderabad, India Director General of Health Services Dhaka, Bangladesh Dr A.K. Gadpayle Consultant Physician Dr Md. Taufiqui Islam Department of Medicine Civil Surgeon Dr R.M.L Hospital Kurigram New Delhi, India Bangladesh Dr Anand Zachariah Mr Nechen Dorji Professor and Head, Department of Health Assistant Medicine Trongsa Hospital Medicine Unit 1 Thimphu, Bhutan Christian Medical College, Vellore, India Dr Shiv Lal Senior Advisor (Public Health) Dr Tri Maharani National Institute of Health and Family Head of Emergency department Lung Welfare Hospital Dungus Ministry of Health and Family Welfare Madiun, Indonesia New Delhi, India Mrs Ipah Epalia Dr Mradul Kumar Daga Senior Representative Professor of Medicine Bio Farma Maulana Azad Medical College Bandung, Indonesia New Delhi, India Dr Fathimath Zuwaida Mr Ajit Nair Medical Officer Director Indira Gandhi Memorial Hospital VINS Bioproducts Ld Male, Maldives Hyderabad, India Dr Aung Zaw Mr D.G. Kulkarni Deputy General Manager / Programme Vice President – Technical Manager

ANNEXURE 199 Myanmar pharmaceutical Industry Professor Christeine Ariaranee Ministry of Industry Gnanathasan Yangon, Myanmar Professor in Medicine, Faculty of Medicine, Professor Khin Thida Thwin University of Colombo Programme Manager, Colombo, Sri Lanka WHO Snakebite Control Project, Myanmar Professor and Head of Department Dr H.M.K. Wickramanayake Department of Renal Medicine, Director University of Medicine (I) Primary Care Services, Ministry of 500 Beded Yangon Speciality Hospital Healthcare & Nutrition Yangon, Myanmar Colombo, Sri Lanka

Dr Khin Saw Than Dr Suchai Suteparuk Associate Professor Expert Toxinologist Yangon General Hospital WHO Collaborating Centre for Venomous Yangon, Myanmar Snake Toxicology and Research Queen Saovabha Memorial Institute Dr Maung Maung Thai Red Cross Society General Manager Bangkok, Thailand Myanmar Pharmaceutical Factory Yangon, Myanmar Professor Dr Sumana Khomvilai Deputy Technical Director and Deputy Mr Naing Linn Director in Administrative Affairs Manager WHO Collaborating Centre for Venomous Myanmar PharmaceuticalFactory Snake Toxicology and Research Yangon, Myanmar Queen Saovabha Memorial Institute Thai Red Cross Society Dr Sanjib Kumar Sharma Bangkok, Thailand Professor, Department of Internal Medicine B P Koirala Institute of Health Sciences Prof Dr Visith Sitprija Dharan, Nepal Director Queen Saovabha Memorial Institute Dr Chhabi Lal Thapa The Thai Red Cross Society, Medical Superintendent Bangkok, Thailand Sindhuli Hospital Nepal Professor David Warrell Emeritus Professor of Tropical Medicine Dr Bhola Ram Shrestha Nuffield Department of Clinical Medicine Senior Consultant Medical Generalist University of Oxford Bharatpur Hospital, Nepal John Radcliffe Hospital Oxford,United Kingdom Professor H Janaka de Silva Senior Professor of Medicine Fan Hui Wen Faculty of Medicine, University of Kelaniya Colombo, Sri Lanka Sau Paulo, Brazil

200 GUIDELINES FOR THE MANAGEMENT OF SNAKEBITES Dr Simon D. Jensen Dr Aparna Singh Shah Consultant Emergency Physician Regional Adviser Nambour General Hospital Health Laboratory Services , Australia and Blood Safety WHO SEARO Dr Rajesh Bhatia New Delhi, India Ex-Director Communicable Diseases WHO SEARO Dwi Adi Maryandi New Delhi, India Junior Public Health Professional Health Laboratory Services Dr Lin Aung and Blood Safety Coordinator Emerging Diseases WHO SEARO WHO SEARO, New Delhi, India New Delhi, India

ANNEXURE 201

VENOMOUS SNAKES OF THE searo REGION, 203 THEIR VENOMS, AND THE PATHOPHYSIOLOGY...

Snakebites are well-known medical emergencies in many parts of the world, especially in rural areas. Agricultural workers and children are the most affected. The incidence of snakebite mortality is particularly high in South-East Asia. Rational use of snake anti-venom can substantially reduce mortality and morbidity due to snakebites. These guidelines are a revised and updated version of Regional Guidelines for the Management of snakebites published by the WHO Regional Office in South-East Asia in 2011. These guidelines aim to promote the rational management of snakebite cases in various health facilities where trained health functionaries and quality snake anti- venom are available.

ISBN: 978-92-9022-530-0

World Health House Indraprastha Estate, Mahatma Gandhi Marg, New Delhi-110002, India Website: www.searo.who.int