Venomous and Poisonous Animals

75 

Venomous and Poisonous Animals DAVID A. WARRELL

KEY POINTS • Envenomings and poisonings with animal toxins are unusual medical emergencies in most Western temperate countries but, especially in rural areas of tropical developing countries, they may be a common occupational and environmental hazard. • Snakebites kill over 100 000 people each year, many of them children. In India, a well-designed national survey discovered 46 000 deaths in 1 year. Survivors of snakebites may be left with permanent physical handicap, mainly as a result of necrosis of the bitten part. • Scorpion stings and anaphylactic deaths in people hypersensitized to Hymenoptera (bees, wasps and ants) venoms account for several thousand deaths each year. In some countries, they cause more deaths than snakebites. • Antidotes to envenoming are antivenoms, refined plasma from horses or sheep that have been hyperimmunized with selected venoms. They are effective in reversing snake venom-induced anti-haemostatis, shock and post-synaptic neurotoxicity and, if given early, may prevent local necrosis, pre-synaptic neurotoxicity and rhabdomyolysis. They cause many early anaphylactic and pyrogenic and late serum sickness-type reactions, are expensive, in short supply and have a limited shelf-life. • Marine poisoning from fish and shellfish is prevalent and endemic among populations of many oceanic islands but occurs sporadically even in Western temperate countries. Ciguatera fish poisoning may cause persisting morbidity but has a low case fatality.

Introduction Venoms are complex mixtures of proteins, polypeptides and other molecules that exert toxic, irritant or allergic properties when injected into prey or squirted at enemies. Some poisonous and venomous animals are distinctively (aposematically) coloured, conferring protection both on their own species and on other harmless species that mimic their appearance or behaviour (Batesian or Müllerian mimicry). Venoms or poisons secreted on to the skin of some amphibians protect their moist respiratory integument against infection and are distasteful, poisonous and therefore a deterrent to predators. Animals have evolved various methods of injecting venom. Mammals (e.g. monotremes, Insectivora and vampire bats), snakes, lizards, spiders, ticks, leeches and octopuses inject their venoms by biting with teeth, fangs, venom jaws, beaks or other hardened 1096

mouth parts; centipedes sting with a pair of modified claws (forcipules) on the post-cephalic segment; male duck-billed platypuses are armed with venom-injecting spurs; fish, cnidarians (coelenterates), echinoderms, cone shells, insects and scorpions have different kinds of stinging apparatus. Some snakes, toads, scorpions and other arthropods can squirt their venom at enemies. Poisoning results from the ingestion of toxins from the skin of amphibians or the flesh and viscera of aquatic animals. Allergic reactions to injected venoms (e.g. of Hymenoptera: bee, wasp and ant venoms – and cnidarians) are in some cases far more frequent and life-threatening than their direct toxic effects and recurrent ciguatera fish poisoning may be associated with hypersensitivity.1,2 VENOMOUS MAMMALS Bisonalveus browni, an extinct Palaeocene mammal, possessed grooved canines suggesting that it might have been venomous, although some non-venomous animals have similar teeth.3 Several extant mammals are venomous.4 Male duck-billed platypuses (Ornithorhynchus anatinus), aquatic egg-laying mammals (Family Ornithorhynchidae, Order Monotrema) of eastern Australia, can sting one another when fighting. They have venomous spurs on their hind limbs fed by venom glands on the thighs.5 The venom contains C-type natriuretic peptides, defensin-like peptides, nerve growth factor, an L-to-D-peptide isomerase, hyaluronidase and proteases. The venom gland transcriptome contains 83 novel putative platypus venom genes from 13 toxin families homologous to known toxins from fish, reptiles, insectivores, spiders, sea anemones and starfish.6 Only 17 stings have been recorded in the last 100 years. They cause agonizing local pain, persistent local swelling and inflammation with regional lymphadenopathy but are neither necrotic nor life-threatening. Persistent local weakness, stiffness and muscle wasting have been reported. In experimental animals, the venom causes haemolysis, coagulopathy, local haemorrhage, oedema and fatal hypotension.5 Haitian (Solenodon paradoxus) and Cuban (S. [Atopogale] cubanus) solenodons, the European water shrew (Neomys fodiens), Mediterranean shrew (N. anomalous) and short-tailed shrews of the eastern USA and Canada (Blarina brevicauda, B. hylophaga, B. carolinensis, Order Insectivora) secrete venomous saliva from enlarged, granular submaxillary salivary glands that discharge at the base of the grooved lower incisors. Their venom immobilizes invertebrate, amphibian or rodent prey and may be used, lethally, in internecine fights. Blarina brevicauda venom is lethal to rodents, lagomorphs and cats but in humans, bites cause only local burning pain, swelling and inflammation. While vampire bats (Order Chiroptera, Desmodontinae) are taking their blood meal, salivary toxins promote blood flow by



75  Venomous and Poisonous Animals

1097

inhibiting platelet aggregation and activated factors X and IX and by activating plasminogen of the animal on which they are feeding. Brachial glands of slow lorises (Nycticebus coucang) (Family Lorisidae, Order Primates) secrete a toxin that resembles Fel d 1 cat allergen. They lick it up and inject it when they bite, causing pain, swelling, tissue damage, infection and anaphylaxis. VENOMOUS SNAKES Taxonomy, Identification and Distribution Of the 3346 species of snakes, 667 belong to the three families of venomous snakes: Lamprophiidae subfamily Atractaspidinae (burrowing asps); Elapidae (cobras, kraits, mambas, coral snakes, sea snakes, etc.) and Viperidae (old world and pit vipers).7 Only about 200 species have caused death or permanent disability by biting humans.8 The largest family, Colubridae, includes 1748 species of which 100 are capable of producing mild envenoming in humans, but only a few have caused fatalities.9 The giant constrictors (family Boidae) are potentially dangerous to man. There are reliable reports of fatal attacks by South-east Asian (especially Indonesian) reticulated pythons (Python reticulatus), African rock pythons (Python sebae), South American anacondas (Eunectes murinus) and an Australian scrub python (Morelia amethistina). Some of the victims were swallowed. Snake Taxonomy.  Snakes are classified according to morphological characteristics (numbers and arrangement of their scales – lepidosis, dentition, osteology, myology, sensory organs, the form of the hemipenes) and, increasingly, by sequence analysis of DNA encoding important mitochondrial and other enzymes.10–12 Snake-like Animals.  Legless lizards, such as slow worms, glass lizards (family Anguidae), worm-like geckos (family Pygopodidae) and legless skinks, may be distinguished from snakes by their external ears, eyelids (in some cases), fleshy tongues, long friable tails and by the lack of enlarged ventral scales. Some lizards have vestigial limbs. Amphisbaenid lizards have wormlike annular grooves along the length of their bodies and caecilians (legless amphibians) lack obvious eyes and scales. Eels (order Anguilliformes), especially snake eels (family Ophichthidae), and pipe-shaped fish must be distinguished from snakes by their gills and in most cases their fins. Medically Important Snakes.  Medically important snakes possess enlarged grooved or cannulated teeth (fangs) in their upper jaws through which venom is injected into prey or human victims. About 400 species of Colubridae have short, immobile opisthoglyphous (posteriorly placed) fangs or enlarged solid aglyphous (lacking groove or canal) teeth at the posterior end of the maxilla (Figure 75.1). The African and Middle Eastern burrowing asps or stiletto snakes (genus Atractaspis, subfamily Atractaspidinae), also known as burrowing or mole vipers or adders, false vipers, side-stabbing or stiletto snakes, have very long solenoglyphous (hinged erectile) front fangs on which they impale their victims by a side-swiping motion, the fang protruding from the corner of the partially closed mouth (Figure 75.2). The Elapidae (cobras – Naja; kraits – Bungarus; mambas – Dendroaspis; shield-nosed snakes – Aspidelaps; Asian and American coral snakes

Figure 75.1  Rear fangs of the boomslang (Dispholidus typus: family Colubridae). Specimen at Bio-Ken, Watamu, Kenya. (Copyright D. A. Warrell.)

– Calliophis, Maticora, Sinomicrurus, Micrurus; African garter snakes – Elapsoidea; terrestrial venomous Australasian snakes and sea snakes) have relatively short, fixed proteroglyphous (fixed erect) front fangs (Figure 75.3). The Viperidae (vipers, adders, rattlesnakes, moccasins, lance-headed vipers and pit vipers) have long, curved, hinged, solenoglyphous (hinged erectile) front fangs containing a closed venom channel (Figure 75.4). The subfamily Crotalinae (pit vipers) includes rattlesnakes (genera Crotalus and Sistrurus), moccasins (Agkistrodon) and lance-headed vipers (genera Bothrops, Bothriechis, Porthidium, Lachesis, etc.) of the Americas and the Asian pit vipers (genera Gloydius/Agkistrodon, Deinagkistrodon, Calloselasma, Hypnale, Trimeresurus – now divided into several different genera including Cryptelytrops, Himalayophis, Parias, Peltopelor, Popeia, Protobothrops, Viridovipera).12 The pit of crotaline snakes is an infrared/heat-sensitive organ, situated between the eye and nostril, which detects

Figure 75.2  Very long front fang of a West African burrowing asp (Atractaspis aterrima: subfamily Atractaspidinae). Specimen from Zaria, Nigeria (Copyright D. A. Warrell.)

1098

SECTION 13  Environmental Disorders

A

Figure 75.3  Short front fangs of the Indian spectacled cobra (Naja naja: family Elapidae). Specimen from Anuradhapura, Sri Lanka (Copyright D. A. Warrell.)

warm-blooded prey (Figure 75.5A).13 Snakes of the subfamily Viperinae, the Old World vipers and adders, lack this pit organ (Figure 75.5B). The words viper (strictly a snake producing live young – ovoviviparous) and adder (laying eggs) are not used rigorously. B Figure 75.5  (A) North American copper head (Agkistrodon contortrix: family Viperidae; subfamily Crotalinae), a typical pit-viper showing heatsensitive pit (arrow). (B) Ethiopian mountain viper (Bitis parviocula; family Viperidae; subfamily Viperinae), a typical Old World viper (A,B, Copyright D. A. Warrell.)

Figure 75.4  Long hinged front fangs of the puff adder (Bitis arietans: family Viperidae; subfamily Viperinae). Specimen from Garki, Nigeria (Copyright D. A. Warrell.)

Snake Identification.  There is no simple and entirely reliable method for distinguishing venomous from non-venomous snakes. The shaft of a needle passed forward along the maxilla from the angle of the jaw may engage upon and reveal the fangs but these may be very small in elapids and folded back inside a sheath in vipers. The characteristic hood of cobras and some other elapids is erected only when the snake is rearing up in a defensive attitude (Figure 75.6). Vipers may be identifiable by a colourful and sometimes distinctive dorsal pattern (Figure 75.7). Russell’s vipers (Daboia russelii and D. siamensis) and puff adders (Bitis arietans) make a loud hissing sound by expelling air through their large nostrils; the saw-scaled or carpet vipers (genus Echis), lowland viper (Proatheris superciliaris) and desert horned vipers (Cerastes) produce a characteristic rasping sound by rubbing their coils together (Figure 75.8); rattlesnakes produce an unmistakable sound like castanets. Some harmless snakes are easily mistaken for the venomous species that they mimic, e.g. Telescopus (cat snakes) and Dasypeltis (egg-eating snakes) resemble Echis (saw-scaled vipers) in Africa; Boiga multomaculata resembles Daboia siamensis in Thailand; Dryocalamus, Dinodon and Lycodon species resemble kraits in South Asia; Xenodon species resemble Bothrops species in the Amazon region and the colourful venomous coral snakes (Micruroides, Micrurus) of the Western Hemisphere have many nonvenomous mimics. The adage ‘red on yellow kills a fellow, red on black venom lack’ distinguishes corals from their mimics only in North America (Figure 75.9). Table 75.1 lists the species



75  Venomous and Poisonous Animals

Figure 75.6  Egyptian cobra (Naja haje: family Elapidae), showing spread hood in threatening/defensive attitude. Specimen at Bio-Ken, Watamu, Kenya. (Copyright D. A. Warrell.)

1099

Figure 75.8  East African saw-scaled viper (Echis pyramidum) coiling to produce a rasping sound. Specimen from Baringo at Bio-Ken, Watamu, Kenya. (Copyright D. A. Warrell.)

A

A

B B Figure 75.7  (A) Puff adder of the African savanna (Bitis arietans), showing distinctive repeated ‘V’ or ‘U’ dorsal pattern. Specimen at BioKen, Watamu, Kenya. (B) Rhinoceros or nose-horned viper of the African rain forest (Bitis nasicornis) showing distinctive repeated dorsal pattern. (A,B, Copyright D.A. Warrell)

Figure 75.9  (A) Texas coral snake (Micrurus tener). Specimen from Kingsville. (B) South American coral snake (Micrurus frontalis: family Elapidae). Specimen from Brazil. (A,B, Copyright D. A.Warrell.)

1100 TABLE 75.1 

SECTION 13  Environmental Disorders

Species of Snake Responsible for Most Human Snakebite Deaths and Morbidity

Area

Scientific Name

Common Name

North America

Crotalus adamanteus Crotalus atrox Crotalus oreganus and Crotalus helleri Crotalus simus subsp. Bothrops asper Bothrops atrox, B. asper Bothrops jararaca Crotalus durissus subsp. Vipera berus, V. aspis Vipera ammodytes Echis ocellatus, E. leucogaster, E. pyramidum, E. jogeri Bitis arietans Naja nigricollis, N. mossambica, etc. Naja haje Echis spp. Macrovipera lebetina Daboia palaestinae Naja oxiana Naja naja, N. kaouthia, N. siamensis, etc. Bungarus spp. Daboia russelii, D. siamensis Calloselasma rhodostoma Echis carinatus Naja atra etc. Bungarus multicinctus Protobothrops (Trimeresurus) flavoviridis Protobothrops (Trimeresurus) mucrosquamatus Gloydius blomhoffii, G. brevicaudus Acanthophis spp. Pseudonaja spp. Notechis spp. Oxyuranus scutellatus

Eastern diamondback rattlesnake Western diamondback rattlesnake Western rattlesnakes Central American rattlesnakes Terciopelo Fer-de-lance, barba amarilla Jararaca South American rattlesnakes, cascabel Vipers, adders Long-nosed or nose-horned viper Saw-scaled or carpet vipers Puff adders African spitting cobras Egyptian cobra Saw-scaled or carpet vipers Levantine viper Palestine viper Oxus cobra Asian cobras Kraits Russell’s vipers Malayan pit viper Saw-scaled or carpet viper Asian cobras Chinese krait Japanese habu Chinese habu Mamushis Death adders Brown snakes Tiger snakes Taipan

Central America South America Europe Africa

Asia, Middle East

Indian subcontinent and South-east Asia

Far East

Australasia, New Guinea

which, in each continent, are responsible for most snakebite deaths and severe morbidity. African night adders (genus Causus) and burrowing asps (Atractaspis), Asian green pit vipers (genus Trimeresurus sensu lato), North American copperheads (Agkistrodon contortrix) and Latin American hognosed vipers (e.g. Porthidium species) bite many people but rarely cause severe envenoming. Electronic images of snakes responsible for bites may be sent, for example by mobile phone, to expert herpetologists for identification. Distribution of Venomous Snakes.  Venomous snakes are widely distributed (Figure 75.10) from sea level to altitudes of 4000 m (Gloydius himalayanus). European adders (Vipera berus) are found inside the Arctic Circle but no other venomous species occurs in cold regions such as the Arctic, Antarctic and north of about latitude 51°N in North America (Newfoundland, Nova Scotia). There are no venomous snakes in the islands of Crete, Ireland and Iceland, in the western Mediterranean, Atlantic and Caribbean (except for Martinique, Santa Lucia, Margarita, Trinidad and Aruba), New Caledonia, New Zealand, Hawaii and elsewhere in the Pacific. Madagascar and Chile have only mildly venomous colubrid snakes. Sea snakes, sometimes in vast numbers, occur in the Indian and Pacific Oceans between latitudes 30°N and 30°S, as far north as Siberia (Pelamis platura) and as far south as Easter Island and the North Island of New Zealand and in estuaries, rivers and some freshwater lakes (e.g. Hydrophis semperi in Lake Taal, Philippines; Enhydrina schistosa in Ton Ley Sap, Cambodia).

Epidemiology of Snakebite (Table 75.2) Most snakebites are inflicted on the lower limbs of agricultural workers and their children in rural areas of tropical developing countries. Asian kraits (Bungarus spp.) and African spitting cobras (N. nigricollis) enter human dwellings at night and may bite people sleeping on the ground. Seasonal peaks in the incidence of snakebite are associated with rainfall and increased agricultural activities. Floods have caused epidemics of

TABLE 75.2 

Determinants of Snakebite Incidence and Severity of Envenoming

Incidence of Bites

Severity of Envenoming

1. Frequency of contact between snakes and humans, depends on: (a) Population densities (b) Diurnal and seasonal variations in activity (c) Types of behaviour (e.g. human agricultural activities) 2. Snakes’ ‘irritability’ – readiness to strike when alarmed or provoked – varies with species

1. Dose of venom injected – depends on mechanical efficiency of bite and species and size of snake 2. Composition and hence potency of venom – depends on species and, within a species, the geographical location, season and age of the snake 3. Health, age, size and (?) specific immunity of human victim 4. Nature and timings of first aid and medical treatment



75  Venomous and Poisonous Animals

1101

A

B Figure 75.10  (A) Distribution of venomous terrestrial snakes. (B) Distribution of venomous sea snakes. (A,B Copyright D. A. Warrell.)

snakebite in Bangladesh, Nepal, Burma, Vietnam, Pakistan, India and Colombia. In tropical developing countries, most snakebite victims seek traditional treatment and so evade hospital records, the main source of snakebite reporting. Properly designed community surveys, assessing randomly selected households, give the most accurate picture of the incidence of snakebite in the area surveyed. However, the results cannot be

extrapolated to provide national incidences because of wide heterogeneity within countries. Asia.  In India, 46 000 people (99% CI 41 000–51 000) die from snakebite each year, a figure based on verbal autopsy of all deaths in 6671 randomly chosen sample areas (average population ~1000 each) throughout the whole country.14 Snakebite

1102

SECTION 13  Environmental Disorders

was responsible for 0.5% of all deaths, 3% in the age group 5–14 years; 97% of the victims died in rural areas, only 23% in a health facility.14 A cross-sectional study in Bangladesh estimated 590 000 bites with 6000 deaths in one year.15 The highest recorded focal incidence in Asia is 162 deaths per 100 000 population per year in the Eastern Terai of Nepal, where only 20% of the deaths occurred in hospitals. Being bitten inside the house while resting between 2400 and 0060 h carried an increased risk of fatality, suggesting bites by kraits.16 Other risk factors were an initial visit to a traditional healer and delayed transport to hospital. In Burma, mortality from snakebite exceeds 1000 (3.3 per 100 000) per year. Russell’s viper (Daboia siamensis) bite was once the fifth most important single cause of all deaths. In Sri Lanka, there are about 37 000 snakebite admissions to government hospitals each year with 80 fatalities. However, in Monaragala District, hospital records underestimated by 63% the number of snakebite fatalities reported by death certification.17 This discrepancy was partly explained by the fact that 36% of snakebite victims did not seek or achieve hospital treatment. Africa.  In the Benue Valley of north-eastern Nigeria, the incidence of snakebites was 497/100 000 population per year, with a mortality of 12.2%.18 Most bites and deaths were attributed to saw-scaled vipers (Echis ocellatus). In Bandafassi, south-east Senegal, in a population of 10 509, snakebite mortality was 14 per 100 000 per year. Saw-scaled vipers (E. ocellatus), puff adders (Bitis arietans) and spitting cobras (Naja katiensis) were implicated.19A community survey of snakebites by the blacknecked spitting cobra (N. nigricollis) in Malumfashi, northern Nigeria, found that in a population of 43 500 there were 15–20 bites/100 000 per year. Only 8.5% of the victims had visited a hospital. The case fatality was 5%, and 19% of survivors had persistent physical disability from the locally necrotic effects of the venom.20 A community-based study in the coast in Kilifi district, Kenya, discovered 15 adult snakebite fatalities per 100 000 population per year.21 Oceania.  In Australia, there are 1000–2000 bites, with an average of three to four deaths, per year. Brown snakes (Pseudonaja species; Figure 75.11) are the most important. In the Central Province of Papua New Guinea, the incidence of bites, mainly by Papuan Taipans (Oxyuranus scutellatus) was

215, and of deaths 7.9/100 000 population per year, while in Kairuku subprovince there were 526 bites per 100 000 per year.22 Europe.  In Britain, there are an estimated 100 hospital admissions for adder (Vipera berus) bites each year, but there have been only 14 deaths during the last hundred years, the last in 1975.23 There were 44 deaths caused by this species in Sweden between 1911 and 1978; and, in Finland, 21 deaths in 25 years, with an annual incidence of almost 200 bites. Americas.  Snakebite is common in Latin America.24 In Brazil, the case fatality of snakebites in the pre-antivenom era was thought to be about 25%, and the total number of bites 19 200 each year. By 2005, 28 711 bites were reported with 114 deaths (0.4 %). In the USA there are 7000 bites by venomous snakes each year, with 12–15 deaths. Some hunter–gatherer tribes are at high risk of snakebite. Two per cent of adult deaths among the Yanomamo of Venezuela, 5% among the Waorani of Ecuador and 24% among adult Kaxinawa of Acre, Brazil, were attributed to snakebites.25 Snakebite as an Occupational Disease.  Farmers, especially rice farmers, plantation workers, herders and hunters are at high risk of snakebite in many tropical developing countries.26 In the savannah of West Africa, farmers are bitten by Echis species as they dig the fields at the start of the rainy season.18 Rubber-tappers in South-east Asia are bitten by Malayan pit vipers (Calloselasma rhodostoma) as they make their early morning rounds of the rubber trees in the dark. In the jungles of western Brazil, collectors of natural rubber (‘seringueiros’) are bitten by Bothrops atrox.25 When hand nets were widely used throughout South-east Asia,27,28 sea snakebites were an occupational hazard of fishermen but are now uncommon because snakes caught in drift or trawl fishing nets are drowned before they are landed. Bites by Exotic Pet Snakes.  In Western countries, venomous snakes are increasingly popular as exotic or ‘macho’ pets. Many are kept illegally.29 Bites Inflicted on Sleepers.  Kraits, in India,30 Sri Lanka,31 Nepal,16 Thailand and Malaysia,32 and African spitting cobras,33 enter human dwellings at night in pursuit of their prey (rodents, lizards, toads) and may strike at people who move in their sleep. Venom Apparatus34 Colubridae.  In back-fanged Colubridae, the posterior part of the superior labial gland (Duvernoy’s gland) drains into a periodontal fold of buccal mucosa. The venom tracks down grooves in the anterior surfaces of the several enlarged posteriorly situated fangs (Figure 75.1).9 Human envenoming is uncommon, as the snake must seize and chew the finger of its victim, often a herpetologist, in order to inject enough venom to cause symptoms. Atractaspidinae.  The long fangs of Atractaspis species are protruded out of the corner of the mouth to allow a side-swiping strike at their prey encountered underground in a burrow (Figure 75.2).

Figure 75.11  Australian Eastern brown snake (Pseudonaja textilis: family Elapidae). Specimen from Ballarat, Victoria. (Copyright D. A. Warrell.)

Elapidae (Including Sea Snakes) and Viperidae.  The venom glands are surrounded by muscles in Elapidae (adductor superficialis) and Viperidae (compressor glandulae) allowing venom to be squeezed through the venom duct to the base of the fang.

Venom is transmitted to the tip of the fang through a partially or completely closed canal. In African spitting cobras and the ringhals or rinkhals (Hemachatus haemachatus) and Asian spitting cobras, the fang is modified to allow the snake to eject a spray of venom forwards for a metre or more, into the eyes of an aggressor.35–37 Venomous Snakebite without Envenoming (‘Dry Bites’).  Between about 10% (in the case of Echis ocellatus)38 and 80% (Australian eastern brown snake, Pseudonaja textilis)39 of people bitten by venomous snakes, with puncture marks confirming that the fangs penetrated the skin, develop no signs of envenoming. Venom Composition40,41 Snakes have evolved the most complex of all venoms, each containing more than 100 different components.42,43 The variation in venom composition between species and within a single species throughout its geographical distribution, at different seasons of the year and as a result of ageing, contributes to the clinical diversity and unpredictability of snakebite. More than 90% of the dry weight is protein, comprising a variety of enzymes, non-enzymatic polypeptide toxins and non-toxic proteins such as nerve growth factor and cobra venom factor. Nonprotein ingredients include carbohydrates and metals (often part of glycoprotein metalloprotein enzymes), lipids, free amino acids, nucleosides and biogenic amines such as serotonin (5-hydroxytryptamine) and acetylcholine. Enzymes.  Approximately 89–95% of viperid and 25–70% of elapid venoms consist of enzymes (molecular weight 13–15 kDa), including digestive hydrolases, hyaluronidase, and activators or inactivators of the prey’s physiological mechanisms. Most venoms contain L-amino acid oxidase, phosphomono- and di-esterases, 5′-nucleotidase, DNA-ase, NAD-nucleosidase, phospholipase A2 and peptidases. Elapid venoms, in addition, contain acetylcholine esterase, phospholipase B and glycerophosphatase, while viperid venoms have endopeptidase, arginine ester hydrolase kininogenase which releases bradykinin from bradykininogen, oligopeptide ACE-inhibitors/bradykininpotentiating peptides, thrombin-like serine proteases, and factor X- and prothrombin-activating enzymes. Phospholipases A2 are the most widespread venom enzymes. They damage mitochondria, red blood cells, leukocytes, platelets, peripheral nerve endings, skeletal muscle, vascular endothelium and other membranes, produce presynaptic neurotoxic activity, opiatelike sedative effects and the autopharmacological release of histamine. Hyaluronidase promotes the spread of venom through tissues. Proteolytic enzymes (endopeptidases or hydrolases) are responsible for local changes in vascular permeability leading to oedema, blistering and bruising, and to necrosis. Metalloproteinases cause local and systemic haemorrhage and local myonecrosis, blistering and oedema through their actions on vascular endothelium, platelets,44,45 muscle and other tissues. Neurotoxins.  Polypeptide toxins are low-molecular-weight, non-enzymatic proteins found almost exclusively in elapid venoms. Post-synaptic (curaremimetic) neurotoxins, or α-neurotoxins, such as α-bungarotoxin and cobrotoxin bind to nicotinic acetylcholine receptors at the motor end-plates of skeletal muscles, causing generalized flaccid paralysis and death from bulbar and respiratory muscle weakness. They have a distinctive ‘three-finger’ structure, complementary in shape to

75  Venomous and Poisonous Animals

1103

their receptor, and have also been found in some colubrid venoms.46 Presynaptic phospholipases A2, or β-neurotoxins, such as β-bungarotoxin, crotoxin and taipoxin, contain a phospholipase A subunit. These damage nerve endings at neuromuscular junctions, targeting voltage-gated potassium channels and causing sequential suppression, enhancement and finally complete failure of acetylcholine release. Clinical effects are similar to those caused by postsynaptic toxins except that the latter may be ameliorated rapidly by specific antivenoms and anticholinesterase drugs. Some of the neurotoxic phospholipases A2 and other phospholipases have myotoxic activity. Mamba (Dendroaspis) venoms contain unusual neurotoxins.40,41 Dendrotoxins bind to voltage-gated potassium channels at nerve endings, causing acetylcholine release, and calcicludine blocks calcium channels. Two ‘three-finger’ neurotoxins are unique to mamba venoms. Fasciculins inhibit some acetylcholinesterases, causing persistent muscle fasciculations, while calciseptine binds to calcium channels. Krait venom toxins are important tools for experimental neuropharmacologists: presynaptic phospholipases A2, β-bungarotoxins; and postsynaptic α-bungarotoxins; and κ-bungarotoxins, which bind to some specific nicotinic acetylcholine receptors in the brain and various ganglia. Cardiovascular Toxins.  Snake venom toxins can lower blood pressure by various mechanisms. Permeability factors cause extravasation and hypovolaemia. An oligopeptide from the venom of the Brazilian jararaca (Bothrops jararaca) that activates bradykinin, potentiates its action and inhibits the conversion of angiotensin I to angiotensin II was the basis for synthetic angiotensin-converting enzyme (ACE) inhibitors. Sarafotoxins in the venom of the Israeli burrowing asp (Atractaspis engaddensis: Atractaspidinae) have 60% sequence homology with endogenous mammalian endothelins.47 They cause coronary artery vasoconstriction and delay atrioventricular conduction. Natriuretic peptides in snake venoms are also being used as blue-prints or ‘scaffolds’ for drug design. Clinical Features of Envenoming Symptoms and signs in victims of snakebite are caused by anxiety and effects of first-aid and other treatments as well as direct action of venom toxins.8,24,48,49 Local Swelling.  In the bitten limb, increased vascular permeability and extravasation of plasma or blood causes swelling and bruising. Venom metalloproteinase haemorrhagins, membranedamaging polypeptide toxins, phospholipases, and endogenous autacoids such as histamine, serotonin and kinins are responsible. Tissue necrosis is caused by myotoxins and cytotoxins, and secondary effects of first-aid methods such as tight tourniquets. Most myotoxins are phospholipases A2, either enzymatically active (aspartate-49) or enzymatically inactive (lysine-49). Cobra ‘cardiotoxins’ are cytotoxic low-molecularweight polypeptides. Hypotension and Shock.  Extravasation of plasma or blood into the bitten limb and elsewhere or massive gastrointestinal or uterine haemorrhage may cause hypovolaemia after viper bites. Vasodilatation, especially of splanchnic vessels, and a direct effect on the myocardium may contribute to hypotension after viper and rattlesnake bites. Acute profound hypotension with or without other features of anaphylaxis is part of the

1104

SECTION 13  Environmental Disorders

autopharmacological syndrome which may occur within minutes of bites by Vipera berus, Daboia species, Bothrops species, Lachesis species, Actractaspis engaddensis and A. microlepidota and some Australasian elapids. It may be caused by release of endogenous vasoactive compounds such as nitric oxide, kinins, histamine, serotonin and endothelins (see Cardiovascular toxins, above). Snake handlers who have become sensitized to snake venoms may develop life-threatening anaphylactic reactions within minutes of being bitten. Bleeding and Clotting Disturbances.50,51  Incoagulable blood, resulting from consumptive coagulopathy or venom anticoagulants, thrombocytopenia with platelet dysfunction, and vessel wall damage by haemorrhagins combine to cause life-threatening haemorrhage after snakebite. These anti-haemostatic effects are a feature of envenoming by vipers, pit-vipers, Australasian elapids and colubrids. Procoagulant enzymes activate intravascular coagulation which, combined with activation of endogenous fibrinolysis by plasmin, results in consumptive coagulopathy and incoagulable blood. Prothrombin activators are present in venoms of Colubridae, Echis species and Australasian elapids; factor X activators occur in Daboia, Echis, Bothrops and other viperid venoms; thrombin-like enzymes are common in pit-viper venoms. Haemorrhagins are zinc metallo-endopeptidases (reprolysins) which damage vascular endothelium causing spontaneous systemic bleeding. Some have disintegrin-like, cysteine-rich and lectin domains. Venom anticoagulants found in Australian elapid and other venoms are phospholipases. Platelet Activators/Inhibitors.  Snake venom toxins activate or inhibit platelets through GPVI, GPIb, GPIbα, GPIa-IIa and other platelet receptors. Thrombocytopenia is a common accompaniment of systemic envenoming. In patients bitten by Malayan pit vipers and green pit vipers (Cryptelytrops albolabris) there was initially inhibition of platelet agglutination followed by activation and the appearance of circulating clumps of platelets.52 Intravascular Haemolysis.  Most snake venoms are haemolytic in vitro, but its clinical significance is uncertain. In victims of envenoming by Sahara horned-vipers (Cerastes cerastes),53 Australian brown snakes (Pseudonaja),54 taipans (Oxyuranus), Bothrops and some other species, fragmented erythrocytes (schistocytes/helmet cells) are observed in the blood film, indicating microangiopathic haemolysis. This is associated with acute kidney injury, a clinical picture similar to haemolytic uraemic syndrome or thrombotic thrombocytopenic purpura. Complement Activation and Inhibition.55  Elapid and some colubrid venoms activate complement via the alternative pathway (‘cobra venom factor’ is cobra C3b),33 whereas some viperid venoms activate the classical pathway. Complement activation may also affect platelets, the blood coagulation system and other humoral mediators.44,45 Acute Kidney Injury (AKI).56  Acute kidney injury is a common consequence, causing many deaths following bites by Russell’s vipers,26 tropical rattlesnakes (Crotalus durissus subspecies)24 and sea snakes.28 Mechanisms of acute tubular necrosis include prolonged hypotension and hypovolaemia, disseminated intravascular coagulation, microangiopathic haemolysis, a direct

toxic effect of the venom on the renal tubule, haemoglobinuria, myoglobinuria and hyperkalaemia. Russell’s viper venom produces hypotension, disseminated intravascular coagulation, direct nephrotoxicity57 and, in Sri Lanka58 and India, intravascular haemolysis, sometimes with evidence of microangiopathy. In Burmese patients envenomed by Russell’s vipers (D. siamensis), high urinary concentrations of β2-microglobulin, retinal binding protein and N-acetyl glucosaminidase suggested failure of proximal tubular reabsorption and tubular damage. High plasma concentrations of active renin suggested that renal ischaemia with activation of the renin–angiotensin system was involved in the development of AKI. A massive transient capillary and glomerular leak of albumin was an early sign of oliguric renal failure. The mechanism of renal failure in victims of Crotalus durissus is most likely to be generalized rhabdomyolysis, combined with hypotension in some cases.59 A variety of renal histopathological changes have been described after snakebite, including proliferative glomerulonephritis, toxic mesangiolysis with platelet agglutination, fibrin deposition, ischaemic changes, acute tubular necrosis, distal tubular damage (‘lower nephron nephrosis’) suggesting direct venom nephrotoxicity, and bilateral renal cortical necrosis with subsequent calcification.56, Neurotoxicity.  The neurotoxic polypeptides and phospholipases of snake venoms cause paralysis by blocking transmission at peripheral neuromuscular junctions. Paralytic symptoms are characteristic of envenoming by most elapids, such as kraits, coral snakes, mambas and cobras, but not of the African spitting cobras which, unusually among elapids, cause local tissue destruction without detectable neurotoxicity.33 Venoms of terrestrial Australasian snakes, sea snakes and a few species of Viperidae, notably Crotalus durissus terrificus, mamushi (Gloydius blomhoffii, G. brevicaudus etc.) in Japan, China, Korea and Russia, Daboia russelii in Sri Lanka and South Indian, the southern African berg adder (Bitis atropos), some other small Bitis species of southern Africa (B. peringueyi, B. xeropaga), and European Vipera ammodytes and V. aspis from southern France, Hungary, Bulgaria and Rumania and the European Montpellier snake (Malpolon monspessulanus) are neurotoxic in humans. Patients with paralysis of the bulbar muscles may die of upper airway obstruction or aspiration, but the most common mode of death after neurotoxic envenoming is respiratory paralysis. Anticholinesterase drugs, by prolonging the activity of acetylcholine at neuromuscular junctions, may improve paralytic symptoms in patients bitten by snakes whose neurotoxins are predominantly postsynaptic in their action (e.g. Asian cobras,60 Australasian death adders genus Acanthophis, and Latin American coral snakes Micrurus frontalis). Some patients bitten by elapids or vipers become pathologically drowsy in the absence of respiratory or circulatory failure. This may be caused by endogenous opiates released by a venom component. Intracerebral injection of β-RTX (receptor-active protein) or ‘vipoxin’ from Daboia russelii venom produced sedation in rats.61 Rhabdomyolysis.  Generalized rhabdomyolysis with release into the bloodstream of myoglobin, muscle enzymes, uric acid, potassium and other muscle constituents, is an effect in man of phospholipase A2 presynaptic neurotoxins of most species of sea snakes;28 many of the terrestrial Australasian elapids such as tiger snake (Notechis scutatus and N. ater), king brown or mulga snake (Pseudechis australis), taipan (Oxyuranus scutellatus),

rough-scaled snake (Tropidechis carinatus) and small-eyed snake (Cryptophis nigrescens); at least three species of krait (Bungarus niger, B. fasciatus and B. candidus); at least three species of coral snake (Micrurus fulvius, M. laticollaris and M. lemniscatus) and several species of Viperidae; tropical rattlesnake (Crotalus durissus terrificus),56 canebrake rattlesnake (Crotalus horridus atricaudatus), Mohave rattlesnake (Crotalus scutulatus)62 and Sri Lankan Russell’s viper (Daboia russelii).58 Patients may die of bulbar and respiratory muscle weakness, from acute hyperkalaemia or later AKI. Venom Ophthalmia.  Venoms of the spitting cobras and rinkhals are intensely irritant and even destructive on contact with mucous membranes such as the conjunctivae and nasal cavity. Corneal erosions, anterior uveitis and secondary infections may result.37,63 Envenoming by Different Families of Venomous Snakes Colubridae (Back-Fanged Snakes).8,9,24  Mild local envenoming has been described after bites by many colubrid species but only a few species have caused severe or fatal envenoming: in Africa, boomslang (Dispholidus typus) and vine, twig, tree or bird snake (Thelotornis species; Figure 75.12); in Japan – yamakagashi (Rhabdophis tigrinus); and in South-east Asia – rednecked keelback (R. subminiatus). Symptoms may be delayed for many hours or even days after the bite. There is nausea, vomiting, colicky abdominal pain and headache. Bleeding develops from old and recent wounds such as venepunctures, and there is spontaneous gingival bleeding, epistaxis, haematemesis, melaena, subarachnoid or intracerebral haemorrhage, haematuria and extensive ecchymoses. Intravascular haemolysis and microangiopathic haemolysis have been described. Most of the fatal cases died of AKI many days after the bite. Local effects of the venom are usually trivial, but several patients showed some local swelling and one bitten by Dispholidus typus had massive swelling with blood-filled bullae. Investigations reveal incoagulable blood, defibrination, elevated

Figure 75.12  Twig, vine, tree or bird snake (Thelotornis mossambicanus: family Colubridae) Specimen at Bio-Ken, Watamu, Kenya. (Copyright D. A. Warrell.)

75  Venomous and Poisonous Animals

1105

fibrin(ogen) degradation products (FDPs), severe thrombocytopenia, anaemia, and complement activation by the alternative pathway.64 Venoms contain prothrombin activators. Atractaspidinae (Burrowing Asps or Stiletto Snakes and Natal Black Snake).  A total of 17 species of the genus Atractaspis and one species of Macrelaps have been described in Africa and the Middle East. All are venomous, but fatal envenoming has been described by only three species: A. microlepidota, A. irregularis and A. engaddensis. Local effects include pain, swelling, blistering, necrosis, tender enlargement of local lymph nodes, local numbness or paraesthesiae. The most common systemic symptom is fever. Most of the fatal cases died within 45 minutes of the bite, after vomiting, producing profuse saliva and lapsing into coma.65 Severe envenoming by A. engaddensis may produce violent autonomic symptoms (nausea, vomiting, abdominal pain, diarrhoea, sweating and profuse salivation) within minutes of the bite. One patient developed severe dyspnoea with acute respiratory failure; one had weakness, impaired consciousness and transient hypertension; and in three there were electrocardiographic changes (ST–T changes and prolonged PR interval).66 Mild abnormalities of blood coagulation and liver function have also been described. Atractaspis venom has very high lethal toxicity. Elapidae (Cobras, Kraits, Mambas, Coral Snakes, Sea Kraits and True Sea Snakes) Local Envenoming.  In the case of kraits, mambas, coral snakes, most of the Australasian elapids (see below), some of the cobras (e.g. Philippine cobra, Naja philippinensis; Cape cobra, N. nivea) and sea snakes, local effects are usually mild although exceptions do occur. However, patients bitten by African spitting cobras commonly develop tender local swelling, blistering surrounding a demarcated pale or blackened anaesthetic area of necrotic skin and regional lymphadenopathy. The lesion smells putrid and eventually breaks down with extensive loss of skin and subcutaneous tissue. Skip lesions, separated by areas of apparently normal skin, may extend proximally up the limb. Prolonged morbidity may result and some patients may lose a digit or the affected limb if there is secondary infection. Severe envenoming by the king cobra (Ophiophagus hannah) results in swelling of the whole limb and formation of bullae at the site of the bite, but local necrosis is minimal or absent.67 Neurotoxic Effects.  Descending flaccid paralysis is seen in patients envenomed by Asian cobras (it is the main feature in victims of N. philippinensis), king cobras and most other elapids, but not in victims of African spitting cobras. The earliest symptom of systemic envenoming is repeated vomiting. Use of emetic herbal medicines may confuse the interpretation of this symptom. Other early pre-paralytic symptoms include contraction of the frontalis (before there is demonstrable ptosis), blurred vision, paraesthesiae especially around the mouth, hyperacusis, loss of sense of smell and taste, headache, dizziness, vertigo, and signs of autonomic nervous stimulation such as hypersalivation, congested conjunctivae and ‘goose-flesh’. Paralysis is first detectable as ptosis and external ophthalmoplegia (Figure 75.13). These signs may appear as early as 15 minutes after the bite (cobras or mambas), but may be delayed for 10 hours or more following krait bites. Later, the facial muscles, palate, jaws, tongue, vocal cords, neck muscles and muscles of deglutition may become paralysed. The pupils are dilated. Many

1106

SECTION 13  Environmental Disorders

Figure 75.14  Death adder (Acanthophis species). Specimen from Gomore, Papua New Guinea. (Copyright D. A. Warrell.)

Figure 75.13  Early bilateral ptosis in a patient bitten by a Papuan taipan (Oxyuranus scutellatus) in Papua New Guinea. (Copyright D. A. Warrell.)

patients are unable to open their mouths, but this can be overcome by force. In a minority, the jaw is said to hang open. Respiratory arrest may be precipitated by obstruction of the upper airway by the paralysed tongue or inhaled vomitus. Intercostal muscles are affected before the limbs, diaphragm and superficial muscles, and, even in patients with generalized flaccid paralysis, slight movements of the digits may be possible, allowing the patients to signal. Loss of consciousness and generalized convulsions are usually explained by hypoxaemia in patients who have respiratory paralysis. Drooping eyelids from tiredness may be misconstrued as ptosis, unless the extent of lid retraction with upward gaze is formally assessed. Patients with systemic envenoming suffer from headache, malaise and generalized myalgia. Intractable hypotension can occur in patients envenomed by Asian cobras, despite adequate respiratory support. Neurotoxic effects are completely reversible, either acutely in response to antivenom or (e.g. in Asian cobra, South American coral snake and Australasian death adder bites) to anticholinesterases,6 or they may slowly wear off spontaneously. In the absence of specific antivenom, patients supported by mechanical ventilators recover sufficient diaphragmatic movement to breathe adequately in 1–4 days. Ocular muscles recover in 2–4 days and there is usually full recovery of motor function in 3–7 days. Bites by Australasian Elapids.5,68,69  Venoms of these snakes result in four main groups of symptoms: neurotoxicity similar to that seen with other elapid bites (Figure 75.13),68–70 generalized rhabdomyolysis, haemostatic disturbances and AKI associated with microangiopathic haemolysis.54 Local signs are usually mild, but extensive local swelling and bruising with necrosis has been reported, especially after bites by the king brown or mulga snake (Pseudechis australis). Painful and tender local lymph nodes are a common feature in patients developing systemic envenoming. Early symptoms include vomiting, headache and syncope. Electrocardiographic changes were common in patients envenomed by taipans (Oxyuranus scutellatus) in Papua

New Guinea, and some had raised cardiac troponin-T levels suggesting myocardial damage. Persistent bleeding from wounds and spontaneous systemic bleeding from gums and gastrointestinal tract is found in association with incoagulable blood following bites by many Australasian species. Haemostatic abnormalities are particularly frequent and serious in patients bitten by tiger snakes (Notechis species), taipans (Oxyuranus species) and brown snakes (Pseudonaja species), uncommonly with bites by black snakes (Pseudechis species) and rare with bites by death adders (Acanthophis species; Figure 75.14). Snake Venom Ophthalmia.37,63  When venom is spat into the eye, there is intense local pain, blepharospasm, palpebral oedema and leukorrhoea (Figure 75.15). Slit-lamp or fluorescein examination reveals corneal erosions in more than half the patients spat at by Naja nigricollis.37,63 Secondary infection of the corneal lesions may result in permanent opacities causing blindness or panophthalmitis with destruction of the eye. Rarely, venom is absorbed into the anterior chamber, causing hypopyon and anterior uveitis. Seventh (facial) cranial nerve paralysis is a rare complication. Bites by Sea Snakes.5,27,28,71  The bite is usually painless and may not be noticed by the wader or swimmer. Teeth may be left in the wound. There is minimal or no local swelling, and involvement of local lymph nodes is unusual. Generalized

Figure 75.15  Intense conjunctivitis with leukorrhoea in a patient ‘spat’ at 3 hours previously by an African black-necked or spitting cobra (Naja nigricollis). (Copyright D. A. Warrell.)



Figure 75.16  Extensive swelling and bulla formation in a Thai patient 13 hours after being bitten by a Malayan pit viper (Calloselasma rhodostoma). (Copyright D. A. Warrell.)

rhabdomyolysis is the dominant effect of envenoming by these snakes. Early symptoms include headache, a thick feeling of the tongue, thirst, sweating and vomiting. Generalized aching, stiffness and tenderness of the muscles becomes noticeable between 30 minutes and 3.5 hours after the bite. Trismus is common. Passive stretching of the muscles is painful. Later, there is progressive flaccid paralysis starting with ptosis, as in elapid envenoming. The patient remains conscious until the respiratory muscles are sufficiently affected to cause respiratory failure. Myoglobinaemia and myoglobinuria develop 3–8 hours after the bite. These are suspected when the serum/plasma appears brownish and the urine dark reddish brown (‘Coca-Colacoloured’). ‘Stix’ tests will appear positive for haemoglobin/ blood in urine containing myoglobin. Myoglobin and potassium released from damaged skeletal muscles may cause renal failure, while hyperkalaemia developing within 6–12 hours of the bite may precipitate cardiac arrest. Viperidae (Old World Vipers and Adders, New World Pit Vipers, Rattlesnakes, Moccasins and Lance-Headed Vipers, Asian Pit Vipers) Local Envenoming.  Venoms of vipers and pit vipers often produce severe local effect. Swelling may appear within 15 minutes, but rarely is delayed for several hours. It spreads rapidly, sometimes to involve the whole limb and adjacent trunk. There is associated pain, tenderness and enlargement of regional lymph nodes. Bruising, especially along the path of superficial lymphatics and over regional lymph nodes, is common (Figure 75.16). There may be persistent bleeding from the fang marks. Swollen limbs can accommodate many litres of extravasated blood, leading to hypovolaemic shock. Blistering may appear at the bite site as early as 12 hours after the bite (Figures 75.16, 75.17). Blisters contain clear or bloodstained

Figure 75.17  Swelling, blistering and necrosis in a woman 4 days after being bitten by a Malayan pit viper (Calloselasma rhodostoma) in Thailand. Amputation was unavoidable. (Copyright D. A. Warrell.)

75  Venomous and Poisonous Animals

1107

fluid. Necrosis of skin, subcutaneous tissue and muscle (Figure 75.17) develops in up to 10% of hospitalized cases, especially following bites by North American rattlesnakes, South American lance-headed vipers (genus Bothrops), bushmasters (genus Lachesis), Asian pit vipers (e.g. Calloselasma rhodostoma, Deinagkistrodon acutus and Protobothrops flavoviridis), African vipers (genus Bitis), saw-scaled vipers (genus Echis) and Palestine viper (Daboia palaestinae). Bites on the digits and in areas draining into the tight fascial compartments, such as the anterior tibial compartment, are particularly likely to result in necrosis. High intracompartmental pressure may cause ischaemia which contributes, together with direct effects of the venom, to muscle necrosis.72 The absence of detectable local swelling 2 hours after a viper bite usually means that no venom has been injected. However, there are important exceptions to this rule: fatal systemic envenoming by the tropical rattlesnake (Crotalus durissus terrificus), Mohave rattlesnake (Crotalus scutulatus) and Burmese Russell’s viper (Daboia siamensis) may occur in the absence of local signs. Victims of C. d. terrificus and other South American Crotalus species may develop local erythema, but rarely more than mild swelling.24 Haemostatic Abnormalities.  These are characteristic of envenoming by Viperidae, but are usually absent in patients bitten by the smaller European vipers (V. berus, V. aspis, V. ammodytes, etc.) and some species of rattlesnakes. Persistent bleeding (>10 minutes) from the fang puncture wounds and from new injuries such as venepuncture sites and old partially healed wounds is the first clinical evidence of consumption coagulopathy. Spontaneous systemic haemorrhage is most often detected in the gingival sulci (Figure 75.18). Bloodstaining of saliva and sputum usually reflects bleeding gums or epistaxis. True haemoptysis is rare. Haematuria may be detected a few hours after the bite. Other types of spontaneous bleeding are ecchymoses, intracranial and subconjunctival haemorrhages, bleeding into the floor of the mouth, tympanic membrane, and gastrointestinal and genitourinary tracts, petechiae and larger discoid (Figure 75.19) and follicular haemorrhages. Bleeding into the anterior pituitary (resembling Sheehan’s syndrome) may complicate envenoming by Russell’s vipers in Burma, India and Sri Lanka, and one case has been reported following a bite

Figure 75.18  Bleeding from gingival sulci in a patient bitten by a jararaca (Bothrops jararaca) in Brazil. (Copyright D. A. Warrell.)

1108

SECTION 13  Environmental Disorders

Figure 75.19  Extensive swelling, bruising and facial discoid haemorrhages in a 9-year-old Vietnamese girl 12 hours after being bitten on the elbow by a Malayan pit viper (Calloselasma rhodostoma). (Copyright D. A. Warrell.)

Figure 75.21  Juvenile ‘hundred pacer’ (Deinagkistrodon acutus). (Copyright D. A. Warrell.)

by a Bothrops species in Southern Brazil. Menorrhagia and antepartum and postpartum haemorrhage have been described after envenoming by vipers. Severe headache and meningism suggest subarachnoid haemorrhage; evidence of a developing central nervous system lesion (e.g. anisocoria, hemiplegia), irritability, loss of consciousness and convulsions suggest intracranial haemorrhage (Figure 75.20) or cerebral thrombosis. Abdominal distension, tenderness and peritonism with signs of haemorrhagic shock but no external blood loss (haematemesis or melaena) suggest retroperitoneal or intraperitoneal haemorrhage. Incoagulable blood resulting from defibrination or disseminated intravascular coagulation is a common and important finding in patients systemically envenomed by members of many genera: Atheris, Daboia, Vipera, Echis, Lachesis, Agkistrodon, Gloydius, Ovophis, Bothrops, Calloselasma, Crotalus, Deinagkistrodon (Figure 75.21) and Trimeresurus sensu lato. In situ thrombosis of major arteries (cerebral, pulmonary, coronary, etc.) is an important feature of envenoming by the ‘fer-de-lance’

(B. lanceolatus) of Martinique and B. caribbaeus in adjacent St Lucia (Figure 75.22)24 and has been described in envenoming by other Bothrops species, Daboia siamensis (Taiwan), D. russelii (India and Sri Lanka), Bitis arietans, Crotalus helleri and some other Crotalus species.73 Intravascular Haemolysis.  This presents as haemoglobinaemia (pink plasma) and black or greyish urine (haemoglobinuria or methaemoglobinuria). The presence of fragmented erythrocytes (schistocytes, helmet cells) in the blood film may indicate microangiopathic haemolysis, associated with progressive severe anaemia and acute kidney injury (see above).53,54 Circulatory Shock (Hypotensive) Syndromes.  A fall in blood pressure is a common and serious event in patients bitten by vipers, especially in the case of some of the North American rattlesnakes, South American pit-vipers (e.g. Lachesis muta and Bothrops species – Figure 75.23) and Old World Viperinae (e.g.

Figure 75.20  Cerebral CT scan of a 7-year-old Ecuadorian girl who had developed sudden headache followed by loss of consciousness 25 hours after being bitten by a common lancehead (Bothrops atrox). (Copyright D. A. Warrell.)

Figure 75.22  St Lucian ‘fer-de-lance’ (Bothrops caribbaeus). (Copyright D. A. Warrell.)



75  Venomous and Poisonous Animals

1109

Figure 75.23  Colombian lancehead pit-viper (Bothrops colombiensis). (Copyright D. A. Warrell.)

Daboia russelii, D. palaestinae, Vipera berus, Bitis arietans, B. gabonica and B. rhinoceros). Sinus tachycardia suggests hypovolaemia resulting from extravasation into the tissues of the bitten limb, external haemorrhage, or generalized increase in capillary permeability. Patients envenomed by Burmese Russell’s viper (Daboia siamensis) may develop conjunctival oedema (Figure 75.24), serous effusions, pulmonary oedema, haemoconcentration and a fall in serum albumin concentration, evidence of increased vascular permeability.26 The pulse rate may be slow or irregular if the venom is affecting the heart directly or reflexly and vasovagal syncope may be precipitated by fear and pain. Early, repeated and usually transient syncopal attacks with features of anaphylaxis develop in patients bitten by some Viperidae, notably Daboia palaestinae and European Vipera. Hypotension is an important feature of anaphylactic reactions to antivenom (see below) and in cases of venom hypersensitivity. Acute Kidney Injury.  This is most common in victims of Russell’s viper, tropical rattlesnake (Crotalus durissus

Figure 75.24  Conjunctival oedema (chemosis) in a Burmese man bitten 36 hours previously by an Eastern Russell’s viper (Daboia siamensis). (Copyright D. A. Warrell)

Figure 75.25  Sri Lankan man with neurotoxic envenoming by a Western Russell’s viper (Daboia russelii). There is ptosis, ophthalmoplegia, facial paralysis and inability to open the mouth and protrude the tongue. (Copyright D. A. Warrell.)

subspecies) and some species of Bothrops. Patients bitten by Russell’s vipers may become oliguric within a few hours of the bite. Loin pain and tenderness may be experienced within the first 24 hours and, in 3 or 4 days, the patient may become irritable and hypertensive and may convulse and become comatose with evidence of metabolic acidosis. Neurotoxicity.  Viperid neurotoxicity is usually attributable to venom phospholipases A2. It is a feature of envenoming by Crotalus durissus terrificus, Gloydius blomhoffii, G. brevicaudus, Vipera aspis and other European Vipera, Bitis atropos and other small South African Bitis species, and Indian and Sri Lankan Russell’s vipers (Daboia russelii) (Figure 75.25). Paralysis descends as with elapid envenoming and may progress to involve bulbar and respiratory muscles. Associated generalized myalgia and muscle tenderness suggest rhabdomyolysis. Mydriasis, causing visual disturbance from loss of accommodation, is a feature of severe envenoming by tropical rattlesnakes and small Bitis species (e.g. B. peringueyi) and may be a permanent neurological sequela. In North America, severe envenoming by some populations of Mohave rattlesnakes (Crotalus scutulatus scutulatus), Southern Pacific rattlesnakes (C. helleri), timber rattlesnakes (Crotalus horridus horridus) and Western diamondback rattlesnakes (C. atrox) causes weakness and facial or generalized fasciculations (myokymia). In the case of C. helleri envenoming in south-west California and Baja California, neurotoxic clinical effects may be dramatic. There is a metallic taste in the mouth, generalized weakness, ptosis, diplopia, dysphagia, dysphonia, respiratory distress progressing to respiratory paralysis and persisting muscle fasciculations of the face, tongue, and upper extremities, as well as local swelling, shock, coagulopathy and rhabdomyolysis.74,75 Clinical Course and Prognosis Local swelling is usually evident within 2–4 hours of bites by vipers and cytotoxic cobras, and may evolve very rapidly after

1110

SECTION 13  Environmental Disorders

rattlesnake bites. Swelling is maximal and most extensive on the 2nd or 3rd day after the bite. Resolution of swelling and restoration of normal function in the bitten limb may be delayed for months, especially in older people. The earliest systemic symptoms such as vomiting and syncope may develop within minutes of the bite, but even in the case of rapidly absorbed elapid venoms, patients rarely die within 1 hour of the bite. Defibrinogenation may be complete within 1–2 hours of the bite.76 Neurotoxic signs may progress to generalized flaccid paralysis and respiratory arrest within a few hours. If the venom is not neutralized by antivenom, these effects may be prolonged. Defibrinogenation can persist for weeks in untreated patients. Patients with neurotoxic envenoming have recovered after being artificially ventilated for as long as 10 weeks. Tissue necrosis becomes obvious within a day of the bite. Sloughing of necrotic tissue and secondary infections including osteomyelitis develop during subsequent weeks or months. Fatal neurotoxic envenoming results from airway obstruction or respiratory paralysis, whereas later deaths may result from technical complications of mechanical ventilation, aspiration pneumonia or intractable hypotension. Late deaths, more than 5 days after the bite, are usually the result of acute kidney injury. Risk of Death from Envenoming Even when the fangs of a venomous snake have pierced the skin, envenoming is not inevitable (see above ‘Dry bites’). The case fatality of Crotalus durissus terrificus bites is said to have been 74% before and 12% after introduction of antivenom.24 Mortality of Echis ocellatus bites was reduced from about 20% to 3% with antivenom.38 Interval between Bite and Death Death after snakebite may occur as rapidly as ‘a few minutes’ (reputedly after a bite by the king cobra Ophiophagus hannah) or as long as 41 days after a bite by the saw-scaled or carpet viper (Echis carinatus). The speed of killing has been exaggerated. Most elapid deaths occur within hours of the bite, most sea snakebite deaths between 12 and 24 hours, and viper bite deaths within days.8,18,71 Laboratory Investigations Systemic envenoming is usually associated with an inflammatory neutrophil leukocytosis: counts above 20 × 109/L indicate severe envenoming. Initially, haematocrit may be high from haemoconcentration resulting from a generalized increase in capillary permeability. Later, haematocrit falls because of bleeding into the bitten limb and elsewhere, and from intravascular haemolysis or microangiopathic haemolysis in patients with disseminated intravascular coagulation. Thrombocytopenia is common in viper, colubrid and Australasian elapid envenoming. The 20-minute Whole Blood Clotting Test (20WBCT).38,76  Incoagulable blood is a cardinal sign of systemic envenoming by most of the Viperidae and many of the Australasian elapids and medically important Colubridae. For clinical purposes, a simple, bed-side, all-or-nothing test of blood coagulability is adequate. A few millilitres of blood taken by venepuncture is placed immediately in a new, clean, dry, glass vessel; left undisturbed at room temperature for 20 minutes; and then tipped once to see if there is clotting or not. The vessel must be glass in order to activate Hageman factor (FXII).

Depending on the availability and speed of laboratory services, more sensitive tests may be appropriate, such as whole blood or plasma prothrombin times (INR) and detection of elevated concentrations of fibrin degradation products (FDP) by agglutination of sensitized latex particles or of D-dimer. Serum concentrations of creatine kinase, aspartate amino transferase and blood urea are commonly raised in patients with severe envenoming, because of local muscle damage at the site of the bite. Generalized rhabdomyolysis causes a steep rise in serum creatine kinase and other muscle-derived enzymes, myoglobin and sometimes potassium concentrations. Plasma is stained brownish by myoglobin and pink by haemoglobin. Heparinized blood should be allowed to sediment spontaneously (without centrifugation) to reveal these pigments which cannot be satisfactorily distinguished by eye or by simple tests. Blood urea or serum creatinine and potassium concentrations should be measured in patients who become oliguric, especially in patients bitten by species whose venoms cause acute kidney injury (Russell’s vipers, Crotalus durissus terrificus, Bothrops species, terrestrial Australasian snakes, sea snakes and Colubridae). Severely sick, hypotensive and shocked patients develop lactic acidosis (suggested by an increased anion gap). Those with renal failure will also develop a metabolic acidosis (decreased plasma pH and bicarbonate concentration, reduced arterial PCO2), and patients with respiratory paralysis will develop respiratory acidosis (low pH, high arterial PCO2, decreased PO2) or respiratory alkalosis if they are mechanically overventilated. Arterial puncture is contraindicated in patients with incoagulable blood but oximetry is usually adequate to assess oxygenation. Patients should be encouraged to empty their bladders on admission to allow examination for blood/haemoglobin/myoglobin (all positive for ‘blood’) and protein (by ‘stix’ test) and for microscopic haematuria and casts. Other Investigations Electrocardiographic abnormalities include sinus bradycardia, ST–T changes, various degrees of atrioventricular block, evidence of hyperkalaemia and myocardial ischaemia or infarction secondary to shock. Chest radiographs will help to detect pulmonary oedema, pulmonary haemorrhages and infarcts, pleural effusions and secondary bronchopneumonias. CT and MRI imaging are increasingly available for assessment of haemorrhages and infarcts in the brain and elsewhere. Ultrasound will detect pericardial effusion and myocardial dysfunction and bleeding into the pleural and peritoneal cavities. Immunodiagnosis Detection and quantitation of venom antigens in body fluids of snakebite victims using enzyme immunoassays (EIA) has proved a valuable research tool for confirming the species responsible for envenoming (immunodiagnosis), as a prognostic index of the severity of envenoming and to assess the effectiveness of antivenom teatment.77–80 Commercial venom detection kits for rapid clinical diagnosis are available in Australia. They are highly sensitive but their specificity may be inadequate to distinguish between envenoming by different species in the same genus or in closely related genera. Relatively high venom antigen concentrations (e.g. from wound swabs or wound aspirates) can be

detected within 15–30 minutes. For retrospective diagnosis, including forensic cases, tissue around the fang punctures, wound and blister aspirate, serum and urine should be stored for EIA. PCR detection of venom gland mitochondrial DNA in wound swabs is being developed as a highly specific method for determining the identity of the biting species. Management of Snakebite8,24,48,49 First Aid.  First aid must be carried out by bite victims themselves or bystanders, using skills and materials that are immediately available. 1. Reassure the victim, who may be terrified. 2. Do not tamper with the bite wound in any way. Remove tight rings and bracelets from the bitten limb. Immobilize the whole patient, especially their bitten limb, using a splint or sling. Application of pressure-immobilization or a pressure-pad may be possible to delay the systemic absorption of venom (see below). Transport the patient as quickly and as passively as possible to the nearest health clinic, dispensary or hospital where medical treatment can be given. Movement (muscular contraction) will promote spread of venom and so it must be reduced to a minimum. Ideally, the patient should be transported by motor vehicle or boat or carried on a stretcher (ideally in the recovery position, in case they vomit), or by motor bike or bicycle (as a passenger). 3. Avoid harmful and time-wasting treatments. 4. If the snake has already been captured or killed, it should be taken with the patient as potentially valuable evidence. However, if the snake is still at large, neither risk further bites nor waste time searching for it. Snakes, even those apparently dead, should not be touched with the bare hands. Some species (e.g. the rinkhals Hemachatus haemachatus) sham death, and even a severed head can inject venom! Pressure-immobilization (PI).  Classic experiments by Struan Sutherland in Australia proved this technique effective in limiting the absorption of Australian elapid toxins in restrained monkeys.81 Unfortunately, the method was never subjected to formal clinical trials, but it has proved successful, judging by anecdotal reports of delayed systemic envenoming and rapid deterioration after release of the bandage, in some cases supported by measurements of venom antigenaemia. There have been practical difficulties in implementing this discovery. Even in Australia, only a minority of the bandages in place when patients arrived in the hospital had been correctly applied. Some experienced physicians remain skeptical of the benefit of PI and it is impracticable in rural areas of tropical countries such as India, where snakebite is common.82,83 The aim is to exert a pressure of about 55 mmHg, that of a venous tourniquet, which is sufficient to occlude both veins and lymphatic vessels through which larger-molecular-weight toxins spread from the bite site and veins. Elasticated bandages are more effective than the crepe bandages originally recommended.83 In practice, it is difficult to judge how tightly to apply the bandage. Most are applied too loosely. It may be impossible for the victim to apply it unaided. External compression will increase intracompartmental pressure, potentiating intracompartmental ischaemia and, by localizing the injected venom, PI might accentuate the necrotic effects of some snake venoms. However, these concerns have not been confirmed clinically or experimentally.84,85

75  Venomous and Poisonous Animals

1111

The broad (10 cm) elasticated bandage should be applied firmly, but not so tightly as to cause ischaemic pain, cyanosis of the extremity or obliteration of peripheral arterial pulses. Lymphoscintigraphy studies showed that excessive pressure (>70 mmHg) and movement of the other limbs increased lymphatic flow.86 Pressure-pad Method.  A foam rubber or folded fabric pad approximately 5 × 5 × 3 cm, bound firmly over the bite wound, slowed lymphatic flow and delayed spread of a ‘mock venom’ in human subjects.87 In victims of Russell’s viper bite in Burma, systemic envenoming was delayed, as assessed by measurements of venom antigenaemia.88 The method appeared safe and effective in a preliminary field trial in Burma and deserves further attention.89 Victims of neurotoxic elapid envenoming may develop respiratory paralysis before reaching medical care. PI or pressurepad should therefore be applied immediately in all cases of snakebite in which a bite by an elapid snake cannot be confidently excluded. Inhibition of the Lymphatic Pump.  In rats, application of glyceryl trinitrate ointment to the bitten limb reduced lymphatic clearance of venom and prolonged life. In human subjects this treatment slowed lymphatic flow.90 Rejected First-Aid Methods.  Cauterization, incision or excision, amputation of the bitten digit, suction by mouth, vacuum pumps91 or ‘venom-ex’ apparatus, instillation of chemical compounds such as potassium permanganate, application of ice packs (cryotherapy), ‘snake stones’ or electric shocks are absolutely contraindicated as they are harmful and have no proven benefit.92 Incisions provoke uncontrolled bleeding when the blood is incoagulable and may damage nerves, blood vessels or tendons and introduce infection. Suction, chemicals and cryotherapy can cause tissue necrosis. Tight (arterial) tourniquets have been responsible for terrible morbidity and even mortality in snakebite victims and should never be recommended or used. Treatment of Early Symptoms.  Distressing and dangerous effects of envenoming may appear before the patient reaches hospital. Local pain may be intense. Oral paracetamol, codeine phosphate or stronger opiates are preferable to aspirin or nonsteroidal antiinflammatory agents, which carry the risk of gastric bleeding in patients with incoagulable blood. Vomiting is a common early symptom of systemic envenoming. Patients should be placed in the recovery position (prone on their left side) with their head down to avoid aspiration. The airway should be protected (see below). Persistent vomiting can be treated with intravenous or rectal chlorpromazine (25–50 mg in adults, 1 mg/kg in children).* Postural hypotension should be prevented by keeping the patient in the prone position. Syncopal Attacks and Anaphylactic Shock.  Patients who collapse within minutes of the bite may suffer transient profound hypotension. Some show features of either a vasovagal attack with profound bradycardia or of anaphylaxis with tachycardia, hypotension, angio-oedema, urticaria, asthma, abdominal colic and diarrhoea. These patients must be laid down supine or prone. Anaphylaxis should be treated with adrenaline (epinephrine) 0.1% (1 in 1000) (0.5 mL in adults, *In patients with incoagulable blood, injections will cause haematomas. Pressure dressings should be applied to all injection sites to prevent oozing.

1112

SECTION 13  Environmental Disorders

0.01 mL/kg in children) by intramuscular* injection. The value of histamine H1-blockers such as chlorphenamine maleate (10 mg in adults, 0.2 mg/kg in children) by intravenous or intramuscular* injection and hydrocortisone is unproven. Respiratory Distress.  This may result from upper airway obstruction if the jaw, tongue and bulbar muscles are paralysed or from paralysis of the respiratory muscles. Patients should be placed in the recovery position, the airway cleared, if possible using a suction pump, an oral airway inserted and the jaw elevated. If the patient is cyanosed, in respiratory distress, or respiratory movements are very weak, oxygen should be given by any available means. If clearing the airway does not produce immediate relief, artificial ventilation must be initiated. In the absence of any equipment, mouth-to-mouth or mouth-to-nose ventilation can be life-saving. Non-invasive manual ventilation by Ambu bag and anaesthetic mask is rarely effective. Ideally, a cuffed endotracheal tube should be introduced, using a laryngoscope, or a cuffed tracheostomy tube inserted. Laryngeal mask airways and i-gel supraglottic airways have proved effective in some situations. The patient can then be ventilated by Ambu bag. If no femoral or carotid pulse can be felt, external cardiac massage must be started. Treatment at Health Clinic, Dispensary or Hospital by Medically Trained Staff Clinical Assessment.  Snakebite is a medical emergency. The history, symptoms and signs must be elicited rapidly so that urgent and appropriate treatment can be given. Four important preliminary questions are: • Show me in which part of your body you were bitten? (Quickly observe any local signs – fang marks, swelling, bruising, persistent bleeding) • When were you bitten? (If the bite was very recent, there may not have been time for signs of envenoming to develop) • Where is the snake that bit you or what did it look like? (If it was killed and left at home, ask someone to fetch it) • How are you feeling now? (Have any symptoms of envenoming developed). Patients should be asked whether they have taken any herbal or other treatment, whether they have vomited, fainted or have noticed any bleeding, weakness, visual disturbance or other illeffects of the bite and whether they have passed urine since being bitten. Before removing any compression bandage or tourniquet, put up an intravenous line and be prepared to resuscitate the patient, as they may deteriorate dramatically. Paired puncture marks suggest a bite by a venomous snake but fang marks are sometimes invisible and may be confused with bites by other animal. Local swelling, tenderness and lymph node involvement are early signs of envenoming. The gingival sulci are an early site of detectable spontaneous bleeding. Persistent bleeding from venepuncture sites, recent wounds and skin lesions suggests incoagulable blood. If the patient is shocked (collapsed, sweating, cold, cyanosed extremities, low blood pressure, tachycardia), the foot of the bed should be raised immediately, and intravenous fluid should be infused. The jugular or central venous pressure should be observed. The earliest symptom of neurotoxicity after elapid bites is often blurred vision, a feeling of heaviness in the eyelids and *In patients with incoagulable blood, injections will cause haematomas. Pressure dressings should be applied to all injection sites to prevent oozing.

drowsiness. The earliest sign is contraction of the frontalis muscle (raised eyebrows and puckered forehead) and tilting back the head, even before true ptosis can be demonstrated. Signs of respiratory muscle paralysis (dyspnoea, ‘paradoxical’ abdominal respiration, use of accessory muscles and cyanosis) are ominous. Patients with generalized rhabdomyolysis may have trismus and muscles that are stiff, tender and resistant to passive stretching. Urine output may dwindle or cease very early after Russell’s viper bites. Black urine suggests myoglobinuria or haemoglobinuria. If the responsible snake was brought and can be identified confidently as non-venomous, the patient can be discharged after a booster dose of tetanus toxoid. All other patients giving a history of snakebite should be admitted for 24 hours observation, even if there is no evidence of envenoming when they first arrive. Symptoms, level of consciousness, ptosis, pulse rate and rhythm, blood pressure, respiratory rate, extent of local swelling and other new signs should be recorded every hour. If there is any evidence of neurotoxicity, the ventilatory capacity or expiratory pressure should also be recorded every hour. Useful investigations include the 20-minute whole blood clotting test (or other tests of coagulation), peripheral leukocyte count, haematocrit, urine microscopy and ‘stix’ testing, and electrocardiography. Antivenom (also known as Antivenin, Antivenene, AntiSnakebite Serum, Anti-Snake Venom – ASV).  Antivenom is the immunoglobulin of animals, usually horses or sheep, which have been immunized with one or more venoms. It is the only specific antidote available and has proved effective against many of the lethal and damaging effects of venoms. In the management of snakebite, the most important clinical decision is whether or not to give antivenom. Only a minority of snakebitten patients require antivenom, which may cause severe reactions, is expensive and is often in short supply. Indications for Antivenom Systemic Envenoming: 1. Haemostatic abnormalities: spontaneous systemic bleeding (including evidence of internal haemorrhage – antepartum, intracranial, gastrointestinal etc.), incoagulable blood (20WBCT) or prolonged clotting time, elevated FDP or D-dimer, thrombocytopenia. 2. Cardiovascular abnormalities: hypotension, shock, cardiac arrhythmia, reduced ejection fraction (echocardiogram). 3. Neurotoxicity (paralysis, fasciculations). 4. Black urine indicating generalized rhabdomyolysis or intravascular haemolysis. 5. In patients with definite signs of local envenoming, the following confirm systemic envenoming: neutrophil leukocytosis, elevated serum enzymes such as creatine kinase and aminotransferases, haemoconcentration, uraemia, hypercreatininaemia, oliguria, hypoxaemia and acidosis. Severe Local Envenoming.  In the absence of 1–5 above, the development at any stage of local swelling involving more than half the bitten limb or extensive blistering or bruising, especially in patients showing the abnormalities listed above under (5) and in patients bitten by species known to cause local necrosis (e.g. Viperidae, Asian cobras, African spitting cobras). Bites on the digits by these species carry a high risk of necrosis. Wealthy countries can afford a wider range of indications for the use of antivenom. The following additional indications have been suggested.

USA and Canada.  Following bites by the most dangerous rattlesnakes (Crotalus atrox, C. adamanteus, C. viridis, C. helleri, C. horridus and C. scutulatus), antivenom is recommended if there is rapid spread of local swelling, even without evidence of systemic envenoming, and after bites by coral snakes (Micruroides euryxanthus, Micrurus fulvius, M. tener) if there is immediate pain or any other symptom or sign of envenoming. Australia.  Antivenom is recommended in any proved or suspected case of snakebite if there is any evidence of systemic spread of venom, including tender regional lymph nodes, and if there has been an effective bite by any identified highly venomous species.5 Europe.  To improve the rate of recovery of local swelling after bites by Vipera berus, antivenom has been recommended in adults with swelling extending up the forearm or leg within 2 hours of the bite.23,93 Contraindications.  There is no absolute contraindication to antivenom treatment in severely envenomed patients. However, atopic patients and those who have had reactions to equine antiserum on previous occasions have an increased risk of developing severe antivenom reactions. In such cases, antivenom should not be given unless there are definite signs of severe (potentially life-threatening) systemic envenoming. Pretreatment with adrenaline (epinephrine) 0.25 ml of 0.01% solution subcutaneously (see below) followed by empirical histamine H1-blocker and corticosteroid by intravenous injection is recommended. The patient should be closely observed for 3 hours after antivenom has been given. Rapid desensitization is not recommended. Prediction of Antivenom Reactions.  Hypersensitivity testing by intradermal or subcutaneous injection or intraconjunctival instillation of diluted antivenom has been widely practised in the past. However, these tests delay the start of antivenom treatment, are not without risk of sensitizing the patient, and have no predictive value. Most early (anaphylactic and pyrogenic) antivenom reactions are the result of direct complement activation by aggregates, other physicochemical properties of the antivenom or endotoxin contamination and are not manifestations of IgE-mediated (reaginic) type I hypersensitivity.94,95 Prevention of Antivenom Reactions.  In a large, welldesigned randomized, double-blind trial, subcutaneous adrenaline (epinephrine) (0.1%; adult dose, 0.25 mg), given just before antivenom administration, reduced the rate of severe adverse reactions over the first hour by 43% and over the first 48 hours by 38%.96 Intravenous promethazine and hydrocortisone, compared alone and in all possible combinations, were ineffective. Monovalent and Polyvalent Antivenoms.  The range of venoms neutralized by an antivenom is usually stated in the package insert and is to be found in compendia of antivenoms.97 If the biting species is known or strongly suspected, an appropriate monospecific (monovalent) antivenom can be used. However, in most parts of the world, polyspecific (polyvalent) antivenoms are used to cover the venoms of the most important species in the region. Polyvalent antivenoms are no less specific than monovalent ones and may have a wider range of paraspecific activity extending to the venoms of closely related species. Expiry Dates.  Useful neutralizing activity of antivenoms may be retained for years after the manufacturers’ stated expiry dates. Liquid lyophilized antivenoms stored at below 8°C usually retain most of their activity for 5 years or more.98,99 Solutions

75  Venomous and Poisonous Animals

1113

that are opaque or contain visible particles should not be given, as precipitation of protein indicates loss of activity and an increased risk of reactions. Timing of Antivenom Administration.  Antivenom should be given as soon as it is indicated, but it is almost never too late to give it as long as signs of systemic envenoming persist (e.g. up to 2 days after a sea snakebite and many days or even weeks for prolonged defibrinogenation following bites by Viperidae). In contrast, local effects of venoms are probably not reversible or preventable by antivenom delayed more than a few hours after the bite. Intravenous Administration.  The intravenous route is the most effective. An infusion over 30–60 minutes of antivenom diluted in isotonic fluid may be easier to control than a slow intravenous ‘push’ injection of reconstituted but undiluted antivenom given over 10–20 minutes. There is no difference in the incidence or severity of antivenom reactions in patients treated by these two methods.94 In the rural tropics, the intravenous push method has the advantage that it involves less expensive equipment, is quicker to initiate, and compels someone to remain with the patient at least while the injection is being given. Intramuscular Administration.  Bioavailability of antivenom, even Fab fragments, given intramuscularly is very slow and incomplete. However, in case of emergency and in the absence of anyone capable of giving an intravenous injection, antivenom might be given by this route. Deep intramuscular injection (e.g. at several sites into the anterolateral aspect of the thighs but not into the gluteal region) could be followed by massage to promote absorption and application of pressure dressings over the injection sites to restrict bleeding. However, the volumes of antivenom normally required would make this route impracticable, especially in children, as would the risk of haematoma formation in patients with incoagulable blood. Local injection of antivenom, for example into the fang marks, seems rational by analogy with local infiltration of rabies immune globulin but it is difficult, painful, hazardous (especially when the bite is on a digit or other tight compartment) and has not proved effective in animal studies. Initial Dose.  The average initial dose of antivenom required for envenoming by different species should be based on results of clinical studies, but few data are available. Most manufacturers base their recommendations on the mouse assay, which may not correlate with clinical findings.100 Initial doses of some important antivenoms are given in Table 75.3. The apparent serum half-lives of antivenoms in envenomed patients range from 26 to 95 hours, depending on which IgG fragment they contain.100,101 Children must be given the same dose of antivenom as adults since the same amount of venom has been injected. Recurrent Envenoming.  Recurrence of clinical and laboratory features of systemic envenoming, including recurrent venom antigenaemia several days after an initially good response to antivenom, was clearly documented in patients envenomed by Malayan pit vipers (Calloselasma rhodostoma) in Thailand in the 1980s and the phenomenon was rediscovered after the introduction of CroFab in the USA.102 Recurrent envenoming is probably the result of continuing absorption of venom from the injection site after antivenom has been largely cleared from the circulation or perhaps by redistribution of venom from tissue in response to antivenom.103 Venom absorption may increase after a hypotensive, shocked patient has been

1114 TABLE 75.3 

SECTION 13  Environmental Disorders

Guide to Initial Dosage of Some Important Antivenoms Species

Antivenom

Latin Name

English Name

Manufacturer, Antivenom (Abbreviations Explained at Foot of Table)

Approximate Initial Dose

Acanthophis spp.

Death adders

CSL, death adder or polyvalent

Bitis arietans

African puff adders

Bothrops asper

Terciopelo

Bothrops atrox

Common lancehead

Bothrops bilineatus Bothrops jararaca

Papagaio Jararaca

Bungarus caeruleus Bungarus candidus

Common krait Malayan krait

Bungarus fasciatus

Banded krait

Calloselasma (Agkistrodon) rhodostoma Cerastes species

Malayan pit viper

SAVP, polyvalent Sanofi-Pasteur (‘Fav Afrique’ and ‘FaviRept’), polyvalent ICP polyvalent LBS Antivipmyn Trivalent Brazilian manufacturers, Bothrops polyvalent Butantan polyvalent Brazilian manufacturers, Bothrops polyvalent Indian manufacturers, polyvalent TRC Malayan krait antivenin monovalent or ‘neuro-polyvalent’ TRC Banded krait antivenin or ‘neuropolyvalent’ TRC monovalent or ‘haemato-polyvalent’

6000–18 000 units (1–3 vials) 80 mL 80 mL

Desert (horned) vipers

NAVPC polyvalent

30–50 mL

Vacsera AntiViper or polyvalent

30–50 mL

Crotalus adamanteus Crotalus atrox Crotalus viridis, C. oreganus, C. helleri Crotalus durissus

Eastern diamondback rattlesnakes Western diamondback rattlesnakes Western rattlesnakes

Crotalus simus

Tropical (South American) rattlesnakes Central American rattlesnakes

Cryptelytrops (Trimeresurus) albolabris and C. macrops Daboia (Vipera) palaestinae

White-lipped green pit viper and dark green pit viper Palestine viper

Daboia (Vipera) russelii Daboia (Vipera) siamensis

Western Russell’s viper Eastern Russell’s viper (Thailand)

Daboia (Vipera) siamensis

Eastern Russell’s viper (Burma)

Dendroaspis species Dispholidus typus Echis carinatus Asia Echis species Africa

Mambas Boomslang Asian saw-scaled viper African saw-scaled or carpet vipers

Echis species Middle East

Middle Eastern saw-scaled vipers

Hydrophiinae Lachesis species

Sea snakes Bushmasters

Micrurus species Central America Micrurus species South America Naja kaouthia and N. siamensis etc.

Central American coral snakes South American coral snakes Monocellate Thai cobra and SE Asian spitting cobras Egyptian cobra, black-necked spitting cobra, Cape cobra etc. Arabian and Egyptian cobras

Naja haje, N. nigricollis and other African cobras Naja arabica and N. haje (Egypt and Middle East) Naja naja, N. oxiana Notechis scutatus

Indian cobras Tiger snake

Oxyuranus scutellatus Pseudechis species

Taipan Australian black snakes and king brown snake

}

5–20 vials 2–12 vials 2–4 vials 2–12 vials 100 mL 50 mL 50 mL 100 mL

7–15 vials Protherics (‘CroFab’) Brazilian manufacturers Crotalus or Bothrops-Crotalus ICP polyvalent LBS polyvalent TRC Green pit viper antivenin or ‘haemato-polyvalent’ Rogoff Medical Research Institute, Tel Aviv, Palestine viper monovalent Indian manufacturers, polyspecific TRC Russell’s viper antivenin ‘haemato-polyvalent’ Myanmar Pharmaceutical Factory monovalent SAVP Dendroaspis or polyvalent SAVP boomslang monovalent Indian manufacturers polyvalent MicroPharm EchiTAb-G ICP EchiTAb-Plus SAVP Echis monospecific Sanofi-Pasteur (‘Fav Afrique’) NAVPC polyvalent Vacsera polyvalent or antiViper CSL, sea snake ICP polyvalent FED Bothrops Lachesis Butantan polyvalent ICP coral snake antivenom Butantan anti Elapid antivenom TRC cobra antivenin or ‘neuro-polyvalent’

5–20 vials

SAVP polyvalent Sanofi-Pasteur FaviRept and Fav Afrique Vacsera polyvalent NAVPC bivalent Naja/Walterinnesia or polyvalent Indian manufacturers, polyspecific CSL tiger snake or polyvalent

100 mL 100 mL 100 mL 100 mL

CSL taipan or polyvalent CSL black snake antivenom or polyvalent

5–15 vials 5–15 vials 50–100 mL 50–80 mL 100 mL 50 mL 80 mL 50–100 mL 1–2 vials 50 mL 10 mL 30 mL 20 mL 100 mL 50 mL 50 mL 1000 units 10–20 vials 10–20 vials 10–20 vials 1–5 vials 1–5 vials 100 mL

100 mL 3000–6000 units 1–2 vials 12 000 units 18 000–54 000 units 1–3 vials



75  Venomous and Poisonous Animals

TABLE

75.3

1115

Guide to Initial Dosage of Some Important Antivenoms—cont‘d Species

Pseudonaja species Rhabdophis tigrinus and R. subminiatus Vipera berus

Walterinnesia species

Australian brown snakes Japanese yamakagashi and rednecked keelback European adder

Black desert cobras

Antivenom CSL brown snake or polyvalent Japanese Snake Institute Nitta-gun Yamakagashi antivenom Immunoloski Zavod-Zagreb, Vipera polyvalent Therapeutic Antibodies Inc. (‘ViperaTAb’), Fab monospecific NAVPC bivalent Naja/Walterinnesia or polyvalent

1000 units 1–2 vials 10–20 mL 100–200 mg 50 mL

Brazilian Manufacturers – Instituto Butantan, São Paulo and Fundação Ezequel Dias (FED), Belo Horizonte; CSL, Commonwealth Serum Laboratories, Australia; ICP, Instituto Clodomiro Picado, San José, Costa Rica; Indian Manufacturers – Bharat Serums and Vaccines, Mumbai – Premium Serums and Vaccines and Biological Evans, Hyderabad – Vins Bioproducts, Hyderabad; LBS, Laboratorios Bioclon/Silanes, Mexico City; NAVPC, National Antivenom and Vaccine production Center, National Guard Health Affairs, Riyadh, KSA; SAVP, South African Vaccine Producers (formerly SAIMR); TRC, Thai Red Cross Society, Bangkok.

resuscitated and the bite site becomes better perfused. Recurrent envenoming is more likely when a rapidly eliminated small IgG fragment antivenom is used, such as Fab, or an antivenom of low potency. In this case, an initial dose of antivenom, however large, may not prevent late or recurrent envenoming. Repeated Dosing.  The response to antivenom will determine whether further doses are required. Where post-synaptic neurotoxins are involved, as in the case of envenoming by cobras and Australasian death adders, signs may improve as early as within 30–60 minutes of antivenom treatment. Hypotension, sinus bradycardia and spontaneous systemic bleeding may respond within 10–20 minutes and blood coagulability is usually restored within 6 hours, provided sufficient specific antivenom has been given. A second dose of antivenom should be given if severe cardiorespiratory symptoms persist for more than about 30–60 minutes, and incoagulable blood persists for more than 6 hours, after the start of the first dose. The ‘6-Hour Rule’.  Studies of envenoming by several species of snakes whose venoms cause coagulopathy have demonstrated that, once an adequate neutralizing dose of antivenom has been given, blood coagulability (assessed by 20WBCT, see above)38,76 will be restored within a median of 6 hours.104 This reflects the ability of the liver, highly activated by circulating fibrin(ogen) breakdown products and inflammatory mediators, to restore coagulable levels of clotting factors in patients with consumption coagulopathy. This important observation is the basis for a simple method of titrating antivenom dosage in individual patients whose blood is initially incoagulable. The 20WBCT is performed at 6-hourly intervals and the initial dose of antivenom is repeated every 6 hours until blood coagulability is restored. After that, the 20WBCT is checked at 12-hourly intervals for at least 48 hours to detect recurrent envenoming (see above). Antivenom Reactions.  Early (anaphylactic), pyrogenic, or late (serum sickness-type) reactions may occur. Early antivenom reactions are not predicted by hypersensitivity tests (see above) because they are not type I IgE-mediated hypersensitivity reactions to equine serum protein.94 Itching, urticaria, fever, tachycardia, palpitations, cough, nausea and vomiting develop within 10 to 180 minutes of starting antivenom. Incidence, which varies from 3% to 84%, increases with dose and decreases when highly refined antivenom is used and intramuscular rather than intravenous injection is used. Unless

patients are watched carefully for 3 hours after treatment, mild reactions may be missed. Up to 40% of patients with early reactions show features of severe systemic anaphylaxis – bronchospasm, hypotension or angio-oedema – but deaths are rare, although they might be misattributed to the envenoming itself. Adrenaline (epinephrine) in an initial dose of 0.5 mL of 0.1% (1 : 1000, 1 mg/mL) for adults (children, 0.01 mL/kg) should be given at the first sign of a reaction, followed by histamine H1blockers such as chlorphenamine maleate (adult dose, 10 mg; children, 0.2 mg/kg) by intravenous injection. Pyrogenic reactions are caused by contamination during antivenom manufacture. High fever and rigors develop 1–2 hours after treatment, followed by vasodilatation and a fall in blood pressure. Febrile convulsions may be precipitated in children. Patients should be cooled using physical methods and given antipyretic drugs such as paracetamol. Late (serum sickness-type) reactions develop 5–24 (mean, 7) days after treatment. Their incidence and speed of development increase with the dose of antivenom. They are underreported because patients have usually left hospital by the time they occur. Symptoms include fever, itching, urticaria, arthralgia, which may involve the temporomandibular joint, lymphadenopathy, periarticular swellings, mononeuritis multiplex, albuminuria and, rarely, encephalopathy. Treatment is a histamine H1-blocker such as chlorphenamine (adults, 2 mg four times a day; children, 0.25 mg/kg per day in divided doses), or, in more severe cases, prednisolone (5 mg four times a day for 5 days in adults; 0.7 mg/kg per day in divided doses for 5 days for children). Supportive Treatment (in Addition to Antivenom).  Artificial ventilation was first suggested for neurotoxic envenoming more than 120 years ago but patients continue to die for lack of respiratory support. Antivenom alone cannot be relied upon to reverse established bulbar and respiratory paralysis. However, neurotoxic effects are fully reversible with time: a patient bitten by Bungarus multicinctus in Canton recovered completely after being ventilated manually for 30 days, and a patient probably envenomed by a rough-scaled snake Tropidechis carinatus recovered after 10 weeks of mechanical ventilation in Queensland, Australia. Anticholinesterase drugs may produce a rapid, useful improvement in neuromuscular transmission in patients envenomed by some species of Asian and African cobras, death adders

1116

SECTION 13  Environmental Disorders

(Acanthophis species), coral snakes (Micrurus species) and kraits.60 It is worth trying the ‘Tensilon test’ in all cases of severe neurotoxic envenoming, as with suspected myasthenia gravis. Atropine sulphate (adults, 0.6 mg; children, 50 µg/kg) is given first by intravenous injection to block unpleasant muscarinic effects of acetylcholine such as increased secretions and abdominal colic. Edrophonium chloride (Tensilon®) is then given by slow intravenous injection in an adult dose of 10 mg, or 0.25 mg/kg for children, or neostigmine bromide or methylsulphate (Prostigmin®) by intramuscular injection, 0.02 mg/kg for adults, 0.04 mg/kg for children. A simple alternative might be the ‘ice test’ in which an ice-filled plastic glove is applied to the closed lid of one eye for 2 minutes. If this improves the ptosis on that side compared to the other, effectiveness of anticholinesterase may be inferred.105 Patients who respond convincingly can be maintained on neostigmine methylsulphate, 0.5–2.5 mg every 1–3 hours up to 10 mg/24 hours maximum for adults or 0.01–0.04 mg/kg every 2–4 hours for children, by intramuscular, intravenous or subcutaneous injection. Hypotension and Shock.  Hypovolaemia is the commonest cause in patients with extensive local swelling. It is confirmed by detecting a postural drop in blood pressure (from supine to 45° or sitting) and treated with intravenous isotonic saline. Central venous pressure monitoring or observation of jugular venous pressure can be used to control volume replacement. Dopamine, initial dose 2.5 µm/kg per minute by intravenous infusion, restored blood pressure in patients envenomed by Burmese Russell’s vipers.26 Acute Kidney Injury (AKI).48,56  If urine output drops below 400 mL/24 hours, urethral and central venous catheters should be inserted. If urine flow fails to increase after cautious rehydration, diuretics should be tried, e.g. furosemide (frusemide) by slow intravenous injection, 100 mg followed by 200 mg if urine output fails to increase, and then mannitol, but these are of no proven benefit. If these measures fail to restore urine flow, the patient should be placed on strict fluid balance. Renal replacement therapy (peritoneal dialysis, haemodialysis or haemoperfusion) will be required in most patients with AKI. Local Infection.  A booster dose of tetanus toxoid should be given. A variety of bacteria have been isolated from snakebite wounds.106,107 Local wound abscesses are common after bites by some species such as South American pit vipers (Bothrops)24 and Malayan pit vipers (Calloselasma rhodostoma).107 Prophylactic antibiotics are not justified unless the wound has been incised or there is evidence of necrosis.108 Penicillin, erythromycin or chloramphenicol are appropriate, or an antibiotic effective against the bacterial flora of the buccal cavity and venoms of local snakes.106 An aminoglycoside such as gentamicin should be added for 48 hours. Intracompartmental Syndrome and Fasciotomy.  In a snake-bitten limb, swelling of muscles within tight fascial compartments, such as the anterior tibial compartment, may raise the tissue pressure to such an extent that perfusion is impaired. Ischaemic damage (as in Volkmann’s contracture of the forearm) is added to direct effects of the venom. Excessive elevation of the bitten limb reduces arterial perfusion pressure in the compartment decreasing muscle PO2 and nerve conduction velocity.72 The classic signs of intracompartmental syndrome include excessive pain, weakness of the compartmental muscle, pain on passive movement, hypoaesthesia of skin supplied by nerves running through the compartment and obvious tenseness of the compartment. These features have been characterized as ‘the

7 Ps’: Pain at rest, Pain on passive movement, Paralysis, Pallor, Paraesthesiae, Poikilothermia and Pulselessness. However, local envenoming can cause these features in the absence of greatly increased compartment pressure. Inexperienced surgeons may proceed to fasciotomy, at which the discovery of black-looking muscle fasciculi may reassure them that the operation was necessary. However, envenomed but viable muscle often looks black because of haemorrhage and may regenerate. Dangers of fasciotomy include severe persistent bleeding if the venominduced haemostatic abnormalities have not been corrected by adequate doses of antivenom, delayed recovery of function, prolonged hospital admission and persistent morbidity from damage to sensory nerves and contractures from keloid formation or hypertrophic scarring especially in African patients. Detection of peripheral pulses by palpation or Doppler ultrasound does not exclude intracompartmental ischaemia. However, direct measurement of intracompartmental pressure is reasonably simple, using a perfusion pump and saline manometer system or a commercial transducer such as the Stryker apparatus. An intracompartmental pressure of more than 45 mmHg in an adult or 30 mmHg in a child is associated with a high risk of ischaemic necrosis. In these circumstances, fasciotomy might be justified to relieve the pressure in the compartment. However, decompression did not prove effective in saving envenomed muscle in animal experiments.109 Necrosis occurs most frequently after digital bites. Fasciotomy must never be embarked upon until blood coagulability has been restored by adequate doses of specific antivenom, followed by the transfusion of fresh whole blood, clotting factors or platelets to hasten restoration of haemostasis. Unproven Treatments.  Corticosteroids, heparin, antifibrinolytic agents such as aprotinin (Trasylol®) and ε-aminocaproic acid, antihistamines, trypsin and a variety of traditional herbal remedies have been used and advocated for snakebite. Most are potentially harmful and none has been proved to be effective. Snake Venom Ophthalmia.37  Urgent decontamination is achieved by irrigating the affected eye or mucous membrane as soon as possible using large volumes of water or other bland fluids (saline, milk or even urine, in an emergency). Pain is relieved by instilling adrenaline (epinephrine) eyedrops (0.1%) or cautious temporary use of local anaesthetic drops such as tetracaine. Corneal abrasions must be excluded by fluorescein staining or slit lamp examination or prevented by application of prophylactic topical antibiotics such as tetracycline, chloramphenicol, framycetin (‘Soframycin’), ciprofloxacin, penicillinstreptomycin ointment, polymixin B sulphate, gatifloxacin or moxifloxacin. Posterior synechiae formation and ciliary spasm are prevented with topical cycloplegics. In cases of allergic kerato-conjunctivitis in snake keepers, systemic antihistamines are indicated. Topical or intravenous antivenom and topical corticosteroids are contraindicated. Prevention.  Greater efforts should be made through community education to reduce the risk of snakebites. Safer walking could be encouraged by wearing solid footwear such as the lightweight boot tested in rice farmers in Burma110 and using a light when moving about after dark. Sleeping could be made safer by sleeping on a raised bed, or, where this is impracticable, by sleeping under a well tucked-in mosquito bed net.111 Highrisk habitats, times of day and seasons of the year should be



75  Venomous and Poisonous Animals

identified, together with the increased danger following floods. Unfortunately, many obvious preventive strategies are impracticable for those, such as farmers in tropical countries, who have to do hard physical work in hot snake-infested areas. Snakes should never be disturbed, attacked or handled unnecessarily even if they are thought to be harmless species or appear to be dead. Venomous species should never be kept as pets or as performing animals. Particular care should be taken while collecting firewood, moving logs, boulders, boxes or debris likely to conceal a snake, and climbing rocks and trees covered with dense foliage or swimming in overgrown lakes and rivers. Domestic animals such as chickens and rodent pests attract snakes into human dwellings. Snakes can be discouraged by rodent-proofing, by removing unnecessary junk and litter, and by using solid building materials. Various toxic chemicals such as naphthalene, sulphur, insecticides (e.g. DDT, dieldrin and pyrethrins) and fumigants (e.g. methyl bromide, formaldehyde, tetrachloroethane) are lethal to snakes and some plants, such as ‘Indian snake root’ (Rauvolfia serpentina), are said to repel them. VENOMOUS LIZARDS Two species of venomous lizard112 (genus Heloderma) have proved capable of envenoming humans. Venom from glands in the mandible is conducted along grooves in the lower teeth. The Gila monster (H. suspectum), which occurs in the south-western USA and the adjacent areas of Mexico, grows up to 60 cm in length and is striped (Figure 75.26). The Mexican beaded lizard or escorpión of western Mexico and Central America as far south to Guatemala (H. horridum) reaches 80 cm in length and is spotted. Heloderma venoms contain lethal glycoprotein

A

1117

Figure 75.27  Komodo dragon (Varanus komodoensis) dribbling venom-containing saliva. (Copyright D. A. Warrell.)

toxins, phospholipase A2 and five interesting bioactive peptides: vasoactive intestinal peptide (VIP) analogues – helospectins I and II and helodermin and glucagon-like peptide-1 (GLP-1) analogues – exendins-3 and -4 which have been developed for the treatment of type 2 diabetes mellitus.113 Bites are rare and almost always provoked by attempts to handle or molest the animals. These lizards have a powerful grip making the bite difficult to disengage. Radiolucent teeth may be left in the wound. There is immediate severe local pain with tender swelling and regional lymphadenopathy. Both species cause similar symptoms. Pain starts immediately and radiates up the bitten limb to the shoulder, chest and epigastrium. It is often excruciating in intensity and may persist for 24 hours or more. Swelling may extend to involve the whole limb. Red lymphangitic lines extend up the limb and regional lymph glands may become tender and enlarged. Local paraesthesia, hyperaesthesia and paralysis have been described. Systemic symptoms start within 5 minutes of the bite. They include dizziness, weakness, nausea, vomiting, profuse generalized sweating and breathlessness. Hypotension and tachycardia are common. Less commonly, there is angioedema (swelling of lips, tongue, throat and upper airway), increased secretions, chills, fever and tinnitus. Leukocytosis, coagulopathy, electrocardiographic changes, myocardial infarction and acute kidney injury are reported but there have been no confirmed fatalities. Antivenom is not available. A powerful analgesic may be required. Hypotension should be treated with plasma expanders and adrenaline (epinephrine) or a pressor agent such as dopamine. Salivary venom secretion has been discovered in two other groups of lizards, iguanas (Iguanidae) and monitors (Varanidae), notably the Komodo dragon (Varanus komodoensis, Figure 75.27).114 VENOMOUS FISH

B Figure 75.26  (A) Gila monster (Heloderma suspectum: family Helodermatidae) eating a bird’s egg. (B) Detail – showing venom-conducting lower incisor teeth. (B, Copyright D. A. Warrell.)

Taxonomy About 200 species of fish,5,115,116 inhabiting temperate and tropical seas, possess a defensive venom-injecting apparatus that can inflict dangerous stings, but more than 1200 species are now thought to be venomous.117 Fatal stings have been reported from cartilaginous fish (class Chondrichthyes) such as sharks

1118

SECTION 13  Environmental Disorders

and dogfish (order Squaliformes) and stingrays and mantas (order Rajiformes); and bony fish (superclass Osteichthyes), such as ray-finned fish (class Actinopterygii) of the orders Siluriformes (catfish), Perciformes (families Trachinidae, weever fish; Uranoscopidae, stargazers or stone-lifters; and others) and Scorpaeniformes (scorpion fish, stonefish). Venom Apparatus Venom is secreted around spines or barbs in front of the dorsal, anal or pectoral fins and tail and opercular spines in the gill covers.115,116 The venom gland in stingrays lies in a groove beneath a membrane covering the barbed precaudal spine up to 30 cm long. The most advanced venom apparatus is found in the genus Synanceia (stonefish, family Synanceiidae): bulky venom glands drain through paired ducts to the tips of the short, thick spines. Venom Composition Fish venoms are unstable at normal ambient temperatures and so have been difficult to study. Proteinaceous toxins with potent haemolytic and lethal activities have been purified from stonefish (Synanceia): trachynilysin releases catecholamine from chromaffin cells and acetylcholine from atrial cholinergic and motor nerve terminals; stonustoxin and verrucotoxin and neoverrucotoxin are proteins of unknown function. Venom of the toad fish (Thalassophryne nattereri order Batrachoidiformes), a marine stinging fish of the Brazilian coast, contains a kininogen-like protein. Venoms of the North American round stingray (Urolophus halleri) and weever fish (Trachinus) contain peptides, protein, enzymes and a variety of vasoactive compounds (kinins, serotonin, histamine, adrenaline and noradrenaline).118 Toxic effects include local necrosis, direct actions on cardiac, skeletal and smooth muscle, causing electrocardiographic changes, hypotension and paralysis, and central nervous system depression.115,116

Stingrays.  These fish are widely distributed in oceans and rivers. The large barbed spine can cause fatal lacerating injuries, usually to the lower part of the legs but occasionally penetrating the body cavities, heart and viscera when the swimmer falls on, or swims over, the ray (as in the case of Steve Irwin, the Australian wildlife presenter). Systemic effects include hypotension, cardiac arrhythmias, muscle spasms, generalized convulsions, vomiting, diarrhoea, sweating and hypersalivation.115,120 The venom produces local swelling and sometimes necrosis, with a high risk of secondary infection with unusual marine bacteria capable of causing fatal septicaemias, such as Photobacterium, Vibrio vulnificus and other Vibrio species, Shewanella putrefaciens, Staphylococcus and Micrococcus species and Halomonas venusta. Weevers.  Stings by Trachinidae produce intense local pain with slight swelling. Systemic symptoms are rare but some patients develop severe chest pain simulating myocardial ischaemia, cardiac arrhythmias and hypotension.121 Scorpion Fish and Stonefish.  The family Scorpaenidae comprises more than 350 species which are widely distributed in some temperate and all tropical seas and are especially abundant around the coral reefs of the Indo-Pacific region. Stonefish (genus Synanceia) are the most dangerous venomous fish. They occur from East Africa, across the Indian Ocean, to the Pacific. Stings are excruciatingly painful and symptoms may persist for 2 days or more. There is local swelling, discolouration, sweating and paraesthesia and sometimes local lymphadenopathy and necrosis.122 Systemic symptoms include nausea, vomiting, hypotension, cardiac arrhythmias, respiratory distress, neurological signs, convulsions and evidence of autonomic nervous system stimulation.122 Fatalities are very rare.

Epidemiology of Fish Stings There are hundreds of weever fish stings around the British coast each year, especially in Cornwall. The peak incidence is in August and September. Some 58 cases were seen at a hospital in Pula on the Adriatic over 13 years. In the USA, 1500 stings by rays and 300 stings by scorpion fish are thought to occur each year. A total of 81 cases of stonefish sting were seen over a 4-year period at a hospital in Pulau Bukom, an island near Singapore. Stings by venomous freshwater rays (Potamotrygon species) are common in the Amazon region and equatorial Africa.119 Ornate but highly venomous and aggressive members of the genera Pterois and Dendrochirus (zebra, lion, tiger, turkey or red fire fish or coral or fire cod, family Scorpaenidae) are popular aquarium pets. Fatal fish stings are very rarely reported. Stings occur when people wading near the shore tread on fish which are lying in the sand or shallow water. Most victims are stung on the sole of the foot, but stingrays lash their tails upwards and impale the ankle. Fishermen, scuba divers and aquarium enthusiasts are stung on the fingers while handling or attempting to fondle the fish.

Treatment The most effective treatment for pain is to immerse the stung limb in water that is uncomfortably hot but not scalding (i.e. just under 45°C). Temperature can be assessed with the unstung limb. Injection of local anaesthetic such as 1% lidocaine, for example as a ring block in the case of stung digits, is less effective. The spine, membrane and other foreign material must be removed from the wound. Prophylactic antibiotics and tetanus toxoid should be given to patients stung by rays or scorpion fish. In the rare cases of severe systemic envenoming, an adequate airway should be established and cardiorespiratory resuscitation instituted when necessary. Severe hypotension can be treated with adrenaline (epinephrine) and bradycardia with atropine. The only antivenom now available commercially is manufactured by the Commonwealth Serum Laboratories in Australia. It neutralizes the venoms of Synanceia trachynis, S. verrucosa and S. horrida and has paraspecific activity against venoms of the North American scorpion fish (Scorpaena guttata) and other members of the Scorpaenidae family. One 2 mL ampoule (2000 units) is given intravenously for each two puncture marks found at the site of the sting. The dose is increased in patients with severe symptoms.

Symptoms of Envenoming Immediate, sharp, agonizing pain is the dominant symptom. Bleeding may be seen from single or multiple puncture sites. Hot, erythematous swelling extends rapidly up the stung limb.

Prevention Bathers and waders should adopt a shuffling gait to reduce the risk of stepping on a venomous fish skulking in sand or mud. Footwear protects against most species except stingrays.



75  Venomous and Poisonous Animals

1119

VENOMOUS MARINE INVERTEBRATES Cnidarians (Coelenterates): Hydroids, Stinging Corals, Medusae, Portuguese Men-O’-War or Bluebottles, Jellyfish, Blubbers, Box-Jellies, Stinging Algae, Sea Anemones and Sea Pansies Cnidarian stinging capsules or nematocysts are triggered by physical contact or chemicals. They evert at enormous speed, acceleration and force, plunging a thread-like tubule with a sharpened tip into the skin as far as the dermo-epidermal junction and injecting toxin. The tentacles of cnidarians are armed with millions of these nematocysts which produce lines of painful irritant wheals on the skin of swimmers unlucky enough to be embraced by them. Cnidarian venoms contain peptides together with vasoactive compounds such as serotonin, histamine, prostaglandins and kinins which cause immediate severe pain, inflammation, urticaria and sometimes cardiovascular or peripheral vascular problems.5,115,116 Epidemiology.  Cnidarian stings are common in most parts of the world. The most dangerous, the Australian box-jellyfish (Chironex fleckeri), occurs along the north coast of Australia from Broome to Port Curtis. It has caused more than 70 deaths since 1883. Most stings occur in December and January. Other lethal chirodropid cnidarians such as Chiropsalmus quadrigatus occur in the Indo-Pacific Ocean. During a 3.5-year period, 116 cases of marine stings were seen in Cairns, north Queensland.123 Some 40% of the patients had clinical features of ‘Irukandji sting’ caused by Carukia barnesi. Fatal stings by Stomolophus nomurai have been reported from China. Prodigious swarms of the scyphomedusa Pelagia noctiluca appeared along the northern Adriatic coast during the summers of 1977–1979. In 1978, it was estimated that 250 000 swimmers had been stung. The North American sea nettle (Chrysaora quinquecirrha) (Figure 75.28) is widely distributed throughout the Atlantic and Indo-Pacific oceans and is especially abundant in Chesapeake Bay on the Maryland coast. There are millions of stings each year but no fatalities. Clinical Features.  The imprint of nematocyst stings on the skin may have a diagnostic pattern. Chironex fleckeri produces immediate brownish or purplish wheals 8–10 mm wide with cross-striations. More extensive swelling, erythema and vesiculation develop, with areas of necrosis and eventual healing with scar formation. Carukia barnesi produces an oval erythematous area about 7 cm in diameter and then transient papules with surrounding hyperhidrosis. Portuguese man-o’-war (Physalia) stings produce chains of oval wheals surrounded by erythema. These lesions persist for only about 24 hours. Histological sections of the skin lesions may reveal identifiable nematocysts, allowing differentiation between stings by different genera. Severe pain is the dominant symptom. Systemic symptoms are most severe following stings by cubomedusae (box-jellyfish), genera Chironex and Chiropsalmus. The victim, usually a child swimming in shallow water, suddenly screams with pain and within minutes becomes cyanosed, suffers generalized convulsions and is found to be pulseless. The whole jellyfish or a length of tentacles may still be adherent to the patient’s skin. Autopsies reveal pulmonary oedema suggesting a cardiac death. Carukia barnesi stings cause severe systemic effects minutes to hours after the sting, attributed to catecholamine-induced hypertension, but with little or no local effect. Systemic effects of

Figure 75.28  East Coast sea nettle (Chryasaora quiquecirrha) an abundant jellyfish in Chesapeake Bay, USA. (Copyright D. A. Warrell.)

cnidarian stings include cough, nausea, vomiting, abdominal colic, diarrhoea, rigors, severe musculoskeletal pains, syncope and signs of autonomic nervous system stimulation such as profuse sweating. The Portuguese man-o’-war (Physalia) stings may cause local vasospasm leading to gangrene and occasionally cause systemic symptoms, intravascular haemolysis, haemoglobinuria, AKI and rare fatalities. The sea anemone Anemonia sulcata produces painful local papules, erythema, oedema and vesiculation and occasional systemic symptoms such as sleepiness, dizziness, nausea, vomiting, myalgia and periorbital oedema.124 Treatment.  Appropriate first aid is urgent as patients may die within minutes of the sting by box-jellyfish. The victim is taken out of the water, adherent tentacles are washed off with sea water or removed by shaving the skin and hot water is applied to relieve pain (see above, as for fish stings).125 Undischarged nematocysts in adherent tentacles should be inhibited. For Chironex and other cubozoans, including Irukandji, commercial vinegar or 3–10% aqueous acetic acid inhibits further nematocysts discharge but is not recommended for stings by Physalia or Stomolophus. For Chrysaora stings, baking soda and water (50% w/v) is used. In vitro, several popular remedies, such as alcohol (in sun lotion), ammonia, acetic acid

1120

SECTION 13  Environmental Disorders

and meat tenderizer, caused massive discharge of Chrysaora quinquecirrha and Physalia physalis tentacles. However, 5–15% lignocaine hydrochloride prevented discharge and relieved the pain of Chiropsalmus quadrumanus and Chrysaora quinquecirrha stings, in proportion to the concentration applied.126 Pressure immobilization with a crepe bandage may increase the amount of venom injected and is not recommended.127 CPR on the beach has proved life-saving in several patients who collapsed, cyanosed and pulseless. Verapamil is not recommended. A specific ‘sea wasp’ antivenom is manufactured by the Commonwealth Serum Laboratories in Australia for Chironex fleckeri stings. Its effectiveness is uncertain. Prevention.  People, and especially children, should keep out of the sea at times of the year when dangerous cnidarians are most prevalent and especially when they have been sighted and warning notices are being displayed on beaches. Wet suits and other clothing, including fine mesh nylon stockings, are protective. Echinoderms (Starfish and Sea Urchins) Echinoderms5,115,116,128 have hard protective exoskeletons. Starfish (Asteroidea) sprout numerous sharp spines which can penetrate human skin, releasing a violet-coloured liquid that stains the wound. The crown of thorns starfish (Acanthaster planci) of the Red Sea and Indian and Pacific Oceans is up to 60 cm in diameter and possesses venomous spines 6 cm long. The venom causes severe local pain, redness and swelling, severe vomiting that may be persistent and, in cases of severe systemic envenoming, hepatic dysfunction, muscle weakness, hyper/hypoaesthesia, facial oedema, cardiac arrhythmias, and paralysis. There is a risk of secondary infection of the wound.5,116, 129 Sea urchins (Echinoidea), especially of the tropical families Diadematidae and Echinothuridae, have brittle, articulated spines (30 cm long in the black or long-spined sea urchin Diadema setosum, Figure 75.29) and grapples (globiferous pedicellariae). Both contain venom which is released when they are embedded in the skin. Impalement and stings by D. setosum

Figure 75.30  Geography cone (Conus geographus). (Copyright D. A. Warrell.)

and the flower sea urchin (Toxopneustes pileolus) cause severe local pain and swelling and, if there is severe systemic envenoming, nausea, syncope, numbness, generalized paralysis, aphonia, and respiratory distress. Fatalities have occurred among indigenous peoples.5,116 The fragments of spines embedded in the skin may cause secondary infection, and granuloma formation several months later. Penetration of bones and joints may be destructive. Treatment.  Spines and pedicellariae must be removed as soon as possible as they may continue to inject venom and give rise to later complications. The sites of penetration are usually on the soles of the feet. The superficial layer of thickened epidermis should be pared down and 2% salicylic acid ointment applied for 24–48 hours to soften the skin. Most spines can then be extruded, but deeply embedded ones may require surgical removal under local anaesthetic. Molluscs (Cone Shells and Octopuses) Cone shells (family Conidae) (Figure 75.30) of the Pacific and Indian Oceans and blue-ringed octopuses of Australia and New Guinea (genus Hapalochlaena) (Figure 75.31) are rare causes of marine envenoming but there have been a few fatalities. No antivenoms are available.5,115,116,130 ARTHROPOD BITES AND STINGS (PHYLUM ARTHROPODA)

Figure 75.29  Long-spined sea urchin (Diadema setosum) Madang, Papua New Guinea. (Copyright D. A. Warrell.)

Insect Stings (Class Insecta) – Hymenoptera Stings (Bees, Wasps, Yellow Jackets, Hornets, Ants) (Order Hymenoptera) Fatal sting anaphylaxis in those who have become hypersensitized to the venoms is reported from most parts of the world and is a leading cause of anaphylactic deaths in Western countries. Hymenoptera venoms also have direct toxic effects but these are not seen in man unless there have been many, usually hundreds of, stings, as in the case of mass attacks by Africanized honey-bees (Apis mellifera scutellata) in the Americas.132,133 Apidae (e.g. honey-bees Apis mellifera), Vespidae (e.g. wasps, yellow jackets and hornets), fire ants (Solenopsis) in the



Figure 75.31  Southern blue-ringed octopus (Hapalochlaena maculosa) Point York, South Australia. (Copyright D. A. Warrell.)

Americas and jumper ants (Myrmecia)131,135 in Australia are important causes of sting anaphylaxis.5,134 Venom Apparatus and Composition.131,135  Venoms are injected through a barbed sting. Bees leave the stings embedded in the skin, but wasps and hornets can sting repeatedly. The venoms contain biogenic amines (histamine, serotonin and acetylcholine), enzymes such as phospholipase A and hyaluronidase, and toxic peptides; kinins in the case of Vespidae; apamin, melittin and antiinflammatory compounds such as mast-cell degranulating peptide in Apidae. Clinical Features Direct Toxic Effects in Non-allergic Subjects.  Single stings produce only local effects attributable to venom biogenic amines. Pain, and an area of heat, redness, swelling and wealing develop rapidly but rarely exceed 2–3 cm in diameter or last more than a few hours. These effects are dangerous only if the airway is obstructed, e.g. following stings on the tongue. Fatal systemic toxicity can result from as few as 30 stings in children, while adults have survived more than 2000 stings by Apis mellifera. Clinical effects of massive envenoming may resemble histamine overdose: vasodilatation, hypotension, vomiting, diarrhoea, throbbing headache and coma. Mass attacks by Africanized bees in Latin America can cause intravascular haemolysis, generalized rhabdomyolysis, hypertension, pulmonary oedema, myocardial damage, bleeding, hepatic dysfunction and AKI.133 Hepatic dysfunction and rhabdomyolysis followed by myoglobinuria and AKI can occur after multiple hornet stings (Vespa affinis). Intravascular haemolysis with haemoglobinuria (Vespa orientalis), thrombocytopenic purpura, myasthenia gravis (Polistes species) and various renal lesions, including nephrotic syndrome, have also been described. Allergic Effects.136  Between 3% and 4% of the population may be hypersensitive to Hymenoptera venoms. Clinical suspicion of venom hypersensitivity arises when systemic symptoms follow a sting. Most patients allergic to bee venom are bee-keepers or their relatives. Systemic symptoms include tingling scalp, flushing, dizziness, visual disturbances, syncope,

75  Venomous and Poisonous Animals

1121

wheezing, abdominal colic, diarrhoea and tachycardia developing within a few minutes of the sting, progressing to urticaria, angio-oedema, oedema of the glottis, bronchospasm, profound hypotension and coma may develop. Patients may die within minutes of the sting. Raised serum concentrations of mast-cell tryptase, which may persist for up to 6 hours, confirm the diagnosis of anaphylaxis. Serum sickness may develop a week or more after the sting. Atopy does not predispose to sting allergy but asthmatics who are allergic to venom are likely to suffer severe reactions. Reactions are enhanced by β-blockers. The diagnosis of venom hypersensitivity can be confirmed by intradermal prick skin testing with dialysed venoms, or by detecting specific IgE antibodies in serum by the radioallergosorbent test (RAST). A postmortem diagnosis of insect sting anaphylaxis is supported by detecting specific IgE in the victim’s serum. Pathological findings in cases of fatal systemic anaphylaxis include acute pulmonary hyperinflation, laryngeal oedema, pulmonary oedema and intra-alveolar haemorrhage. Treatment.  The embedded bee sting must be extracted as quickly as possible. Toxic Effects of Mass Attacks.  Adrenaline, bronchodilators, histamine H1-blockers and corticosteroids may be needed. No antivenoms are commercially available. AKI is prevented by correcting hypovolaemia and giving mannitol and bicarbonate or treated with renal replacement therapy. Allergic Effects.  Adrenaline (epinephrine) (initial adult dose 0.5 ml of 0.1% solution, children 0.01 mL/kg) is given by intramuscular injection. Those known to be hypersensitive should wear an identifying tag (e.g. ‘Medic-Alert’) as they may be discovered unconscious after a sting. They should be trained to self-administer adrenaline (e.g. ‘EpiPen’ delivering 0.3 mg adult, or 0.15 mg child, doses of 0.1% adrenaline). Injection of a histamine H1-blocker (e.g. chlorphenamine maleate, 10 mg intravenously or intramuscularly) will alleviate the mild urticarial symptoms, and combat the effects of massive histamine release during the reaction. Corticosteroid may prevent recurrence of anaphylaxis, which is said to occur after about 6 hours in up to 10% of cases. Severe reactions may require cardiorespiratory resuscitation, fluid volume replacement and vasopressor drugs. β2 agonists such as salbutamol are needed if there is marked bronchospasm. Respiratory tract obstruction is the main cause of death. Prevention of Hymenoptera Sting Anaphylaxis.  Patients with histories of systemic anaphylaxis and demonstrable venom-specific IgE can be desesensitized.137 Scorpion Stings (Order Scorpiones)131 Scorpions capable of inflicting fatal stings in humans belong to the families Buthidae (thick-tailed scorpions) and Hemiscorpiidae (rock, creeping or tree scorpions). The most important species include: • Family Buthidae – Androctonus, Buthus and Leiurus species in North Africa and the Middle East; Parabuthus species in East and South Africa; Centruroides species in Arizona and Mexico (Figure 75.32); Tityus species in Latin America and Hottentota (Mesobuthus) tamulus in India and Nepal. • Family Hemiscorpiidae – Hemiscorpius lepturus (Middle East).

1122

SECTION 13  Environmental Disorders

Antivenom is recommended. A recent trial in children stung by C. sculpturatus in Arizona, antivenom treatment was associated with more rapid resolution of symptoms and less requirement for midazolam sedation than placebo.140 In India, two studies found that addition of a new antivenom raised against H. tamulus concanensis venom produced more rapid recovery than prazosin alone.141,142 For patients with cardiovascular symptoms (hypertension, bradycardia and early pulmonary oedema) vasodilators such as the α1-blocker prazosin are recommended. Patients who develop left ventricular failure despite early prazosin therapy benefit from dobutamine.143 The use of atropine (except in cases of life-threatening sinus bradycardia), cardiac glycosides and β-blockers is not recommended.138

Figure 75.32  Arizona bark scorpion (Centruroides sculpturatus) Tucson, Arizona. (Copyright D. A. Warrell.)

Epidemiology.  Painful scorpion stings are a common event throughout the tropics but fatal envenoming is frequent only in parts of Latin America, North Africa, the Middle East and India. In Mexico, about 250 000 stings are reported each year throughout the country with 70 fatalities. In Brazil, among 36 558 reported stings there were 50 deaths. Clinical Features.  Rapidly developing, excruciating local pain is the most common symptom. Local blistering and necrosis occur only after stings by Hemiscorpius lepturus. Systemic symptoms may develop within minutes, but may be delayed for as much as 24 hours. Features of autonomic nervous system excitation are initially cholinergic and later adrenergic. There is hypersalivation, profuse sweating, lacrimation, hyperthermia, vomiting, diarrhoea, abdominal distension, loss of sphincter control, and priapism. Massive release of catecholamines, as in phaeochromocytoma, produces piloerection (‘gooseflesh’), tachycardia, hyperglycaemia, hypertension and toxic myocarditis with arrhythmias (most commonly sinus tachycardia), electrocardiographic S–T segment changes, cardiac failure and pulmonary oedema. These cardiovascular effects are particularly prominent following stings by Leiurus quinquestriatus, Tityus species138and H. tamulus.139 Fasciculation, muscle spasms that can be misinterpreted as tonic-clonic convulsive movements, and respiratory distress are a particular feature of stings by Centruroides species. Parabuthus transvaalicus envenoming is more likely to cause ptosis and dysphagia. Strokes are described after stings by Nebo hierichonticus and H. tamulus. Hypercatecholaminaemia could explain hyperglycaemia and glycosuria but, in the case of stings by Trinidadian black scorpions (T. trinitatis), there is acute pancreatitis. Treatment.  Pain is most effectively treated by local infiltration of 1% lidocaine or xylocaine, using digital block for stings on digits. Parenteral opiate analgesics such as pethidine and morphine may be required.

Spider Bites (Order Aranea) The spiders (Order Aranea)144 are an enormous group but only about 20 species are known to cause dangerous envenoming in humans. Many others have been wrongly accused of inflicting harmful bites.145 Spiders bite with a pair of fangs, the chelicerae, to which the venom glands are connected.131 A central venom duct opens near the tip of the fang. In Brazil, in 2005, 19 634 spider bites were reported, with nine deaths (0.05%). Clinical Features.  Spider bites can cause two main clinical syndromes, ‘necrotic loxoscelism’ and ‘neurotoxic araneism’. Necrotic Loxoscelism.  Skin lesions, varying in severity from mild localized erythema and blistering to extensive tissue necrosis, have been falsely attributed to species of familiar peridomestic species, such as the Australian white-tailed spider (Lampona cylindrata), North American hobo spider (Tegenaria agrestis), European and South American wolf spiders (Lycosa, including the Italian ‘tarantula’ L. terentula) and cosmopolitan sac spiders (Cheiracanthium).145 Only members of the genus Loxosceles (American recluse spiders) have proved capable of causing ‘necrotic arachnidism/araneism’. Loxosceles species are extending their geographical ranges in Central and South America, the USA and in the Mediterranean region, North Africa, Israel and elsewhere. Some 80% of patients are bitten indoors, usually in their bedrooms while asleep or dressing. The bite may be painless initially but a burning pain develops at the site over the next 12–36 hours with local oedema. An ischaemic lesion (‘redwhite-and-blue’ sign), coloured red (vasodilatation), white (vasoconstriction) and blue (pre-necrotic cyanosis) appears (Figure 75.33) and, over the course of a few days, becomes a black eschar (Figure 75.34), which sloughs in a few weeks, sometimes leaving a necrotic ulcer. Rarely, the necrotic area may cover an entire limb. In 12% of cases there are systemic effects including fever, methaemoglobinaemia, haemoglobinuria and jaundice resulting from haemolytic anaemia, scarlatiniform rash, respiratory distress, collapse and AKI. The case fatality is less than 5%.146 Neurotoxic Araneism.  Widow, hour-glass, button or redback spiders (genus Latrodectus) are the most widespread and numerous of all venomous animals dangerous to man. L. mactans (black widow spider) occurs in the Americas. Latrodectus tredecimguttatus, widely but incorrectly known as a ‘tarantula’, lives in fields in the Mediterranean countries, where it has been responsible for epidemics of bites. The Australian red-back spider or New Zealand katipo (L. hasselti) causes up to 340 reported bites each year in Australia, where 20 deaths are known to have occurred.5,39 This adaptable species has settled in Japan,



Figure 75.33  Early lesion at the site of the bite of a Brazilian recluse spider (Loxosceles gaucho), showing the ‘red-white-and-blue’ sign. (Copyright D. A. Warrell.)

the Middle East, New Caledonia and elsewhere. Latrodectus mactans and the brown widow (L. geometricus), cause bites in South and eastern Africa. Latrodectus hasselti bites produce local heat, swelling and redness, which is rarely extensive. Intense local pain develops in about 5 minutes; after 30 minutes, there is pain in local lymph nodes, and after about an hour, headache, nausea, vomiting and sweating occur. Tachycardia and hypertension may follow but muscle tremors and spasms are uncommon.5,39 Latrodectus mactans bites produce minimal local changes. Local dull aching or numbness may develop after 30–40 minutes. Painful muscle spasms and lymphadenopathy spread and increase in intensity during the next few hours until the trunk, abdomen and limbs are involved and respiration may be embarrassed. An acute abdomen may be simulated by the painful spasms and rigidity. Other features include profuse

Figure 75.34  Necrotic eschar at the site of a bite by a Brazilian recluse spider (Loxosceles gaucho). (Scale in cm.) (Copyright D. A. Warrell.)

75  Venomous and Poisonous Animals

1123

generalized sweating, tachycardia, hypertension, irritability, psychosis, vomiting and priapism.144 Similar effects are produced by the Brazilian ‘banana’, ‘armed’ or ‘wandering’ spider (Phoneutria nigriventer) and related species, which cause bites and deaths in South American countries. These spiders may be exported in bunches of bananas to temperate countries, where they have been responsible for bites and a few deaths. Funnel web spiders, genera Atrax and Hadronyche, are confined to south-eastern Australia, the Adelaide area and eastern Tasmania.5 Atrax robustus, the Sydney funnel-web spider, occurs within a 160 km radius of Sydney. Unusually among spiders, the aggressive male is more dangerous to man than the larger female. The powerful chelicerae of this large spider produce a painful bite but there is minimal local envenoming. Numbness around the mouth and spasm of the tongue may develop within 10 minutes, followed by nausea and vomiting, abdominal colic, profuse sweating, salivation and lacrimation, dyspnoea and coma. There are local or generalized muscle fasciculations and spasms, hypertension, and, in some of the fatal cases, pulmonary oedema, thought to be neurogenic in origin. Thirteen deaths, occurring between 15 minutes and 6 days after the bite, were reported between 1927 and 1980.5 Treatment First-Aid Treatment.  Pressure-immobilization (see Snakebite above) is recommended for bites by Australian funnel web spiders.5 Specific Treatment.  Neurotoxic araneism seems more responsive to antivenom than does necrotic loxoscelism.147 Atrax robustus antivenom is effective against the venom of other Atrax and Hadronyche species. Supportive Treatment.  The use of dapsone for necrotic loxoscelism and intravenous calcium gluconate for Latrodectus bite muscle spasms is not evidence based. Antihistamines, corticosteroids, β-blockers and atropine have also been advocated. Surgical debridement for necrotic lesions caused by Loxosceles species is not recommended, and corticosteroids, antihistamines and hyperbaric oxygen have not proved helpful. Tick Bite Paralysis (Order Acari or Acarina, Superfamily Ixodoidea)148,149 Taxonomy and Epidemiology.  Adult females of about 30 species of hard tick (family Ixodidae) and immature specimens of six species of soft tick (family Argasidae) have been implicated in human tick paralysis. The tick’s saliva contains a neurotoxin which causes presynaptic neuromuscular block and decreased nerve conduction velocity.148,149 The tick embeds itself in the skin with its barbed hypostome, introducing the salivary toxin while it engorges with blood. Although tick paralysis has been reported from all continents, including Europe, most cases occur in western North America (Dermacentor andersoni), eastern USA (D. variabilis) and eastern Australia from north Queensland to Victoria (Ixodes holocyclus, known as the bush, scrub, paralysis or dog tick). In British Columbia, there were 305 cases with 10% mortality between 1900 and 1968. About 120 cases have been reported in the USA, and in New South Wales there were at least 20 deaths between 1900 and 1945. Clinical Features.150  Ticks are picked up in the countryside or in the home from domestic animals, particularly dogs. Most victims are children. After the tick has been attached for about

1124

SECTION 13  Environmental Disorders

5 or 6 days, a progressive ascending, lower motor neurone paralysis develops with paraesthesiae. Often, a child, who may have been irritable for the previous 24 hours, falls on getting out of bed first thing in the morning, and is found to be weak or ataxic. Paralysis increases over the next few days: death results from bulbar and respiratory paralysis and aspiration of stomach contents. Vomiting is a feature of the more acute course of Ixodes holocyclus envenoming. In the past, this clinical picture was misinterpreted as poliomyelitis. Other neurological conditions, including Guillain–Barré syndrome, paralytic rabies, Eaton– Lambert syndrome, myasthenia gravis or botulism, may also be suspected. Diagnosis depends on finding the tick, which is likely to be concealed in a crevice, orifice, or hairy area of the body such as the scalp or external auditory meatus. Treatment.  The tick must be detached without being squeezed. It can be painted with ether, chloroform, paraffin, petrol or turpentine, or prised out between the partially separated tips of a pair of small curved forceps. Following removal of the tick, there is usually rapid and complete recovery. Ventilatory support may be needed. No antivenom is currently available. Centipede Stings and Millipede Envenoming (Subphylum Myriapoda)131 Centipedes (Class Chilopoda).  Many species of centipede (Chilopoda) can inflict painful stings through venomous claws (forcipules) arising from the first thoracic segment just behind the mouth parts. Local pain, swelling, inflammation and lymphangitis may develop. Systemic effects such as vomiting, headache, cardiac arrhythmias and convulsions are extremely rare and the risk of mortality was greatly exaggerated in the older literature. The most important genus is Scolopendra, which is distributed throughout tropical countries. Local treatment is the same as for scorpion stings. No antivenom is available. Millipede Envenoming (Class Diplopoda).151  Venom glands in each of the body segments secrete or squirt out irritant liquids for defensive purposes. These contain hydrogen cyanide and various aldehydes, esters, phenols and quinonoids. Members of at least eight genera of millipedes have proved injurious to man. Children are particularly at risk when they handle or try to eat these large arthropods. When venom is squirted into the eye, intense conjunctivitis, corneal ulceration and blindness may result. Skin lesions are initially stained brown or purple, blister after a few days, and then peel. First aid is generous irrigation with water. Eye injuries should be treated as for snake venom ophthalmia.

Poisoning by Ingestion of Marine Animals A variety of illnesses, usually categorized as ‘food poisoning’, are caused by eating seafood.115,116,152,153 The best known are attributable to bacterial or viral infections, including Vibrio parahaemolyticus, V. cholerae, non-O1 V. cholerae, V. vulnificus, Aeromonas hydrophila, Plesiomonas shigelloides, Salmonella typhi, Campylobacter jejuni, Shigella species, hepatitis A virus, Norwalk virus and astro- and caliciviruses. Botulism has been reported in people eating uneviscerated, smoked and canned fish.

Various clinical syndromes are associated with ingestion of flesh or viscera of marine animals containing toxins derived from marine microalgae or bacteria (e.g. ciguatera, tetrodotoxic or paralytic shellfish poisoning) or resulting from bacterial decomposition of fish during storage (scombrotoxic fish poisoning).154,155 GASTROINTESTINAL AND NEUROTOXIC SYNDROMES Nausea, vomiting, abdominal colic, tenesmus and watery diarrhoea may precede the development of neurotoxic symptoms.152,153 Paraesthesiae of the lips, buccal cavity and extremities are early symptoms. Other neurotoxic manifestations include a peculiar distortion of temperature perception so that cold objects feel hot (like dry ice) and vice versa, dizziness, myalgia, weakness starting with muscles of phonation and deglutition and progressing to respiratory paralysis and flaccid quadriplegia in some cases, ataxia, involuntary movements, convulsions, visual disturbances, hallucinations and psychoses, cranial nerve lesions and pupillary abnormalities. Cardiovascular abnormalities include hypotension and bradycardia and some patients develop florid cutaneous rashes. Ciguatera Fish Poisoning Ciguatera fish poisoning156 results from ingestion of any of more than 400 species of warm-water, shore or reef fish between latitudes 35°N and 34°S, especially in the South Pacific and Caribbean (including Florida). These fish are now widely available in fish markets in temperate northern countries to meet the demands of immigrant populations. Overall, there must be more than 50 000 cases in the world each year, with an incidence of up to 2% of the population each year and a case fatality of about 0.1%. The fish most often associated with ciguatera are ray-finned fish (order Perciformes) of the families Serranidae (sea basses and groupers); Lutjanidae (snappers); Scaridae (parrot fish); Scombridae (mackerels, tunas, skipjacks and binitos); Sphyraenidae (barracudas) and Carangidae (jacks, pompanos, jack mackerels, scads) and eels (order Anguilliformes), notably Muraenidae (moray eels). Causative polyether ciguatoxins, maitotoxins and scaritoxins originate from benthic dinoflagellates such as Gambierdiscus toxicus that are ingested by herbivorous fish and in turn become the prey of the carnivorous fish eaten by humans. They excite Na+ channels and voltage-independent Ca2+ channels. Ciguatoxins are concentrated in the fishes’ intestine, gonads and viscera. The risk of poisoning is greater with some species, e.g. moray eels and parrot fish (Scarus sordidus) and increases as the fish gets older and larger. Clinical Features.  Symptoms first appear minutes to 30 (mean 1–6) hours after eating the poisoned fish. In many cases, especially with milder poisoning, the earliest symptoms are gastrointestinal: sudden abdominal colic, nausea, vomiting and watery diarrhoea. The earliest neurotoxic symptom is numbness or tingling of the lips, tongue, throat and extremities, a metallic taste, and a dry mouth or hypersalivation. Reversed perception of heat and cold is a distinctive symptom. Myalgia, ataxia, vertigo, visual disturbances and pruritic skin eruptions develop later. In severely neurotoxic cases, flaccid paralysis and respiratory arrest may develop. Gastrointestinal symptoms resolve



75  Venomous and Poisonous Animals

1125

Paralytic Shellfish Poisoning114,115,152–154

Figure 75.35  Striped burrfish or spiney box-fish (Chilomycterus schoepfi: family Diodontinae). (Copyright D. A. Warrell.)

within a few hours but paraesthesiae and myalgias may persist for a week, months or even years. Chelonitoxication from ingestion of marine turtles (Chelonia) resembles ciguatera poisoning. Most outbreaks have been in the Indo-Pacific area. The species usually implicated are green hawksbill and leathery turtles. The case fatality among reported cases is 28%.115, 116, 156 Tetrodotoxic (Puffer Fish) Poisoning More than 50 species of tropical scaleless fish (Order Tetraodonitiformes) have proved poisonous. They include porcupine fish (Chilomycterus; Figure 75.35), molas or sunfish (Mola), and puffer fish or toadfish (Tetraodontidae – genera Arothron, Fugu, Lagocephalus, etc.). The flesh of the puffer fish (Japanese fugu) is a delicacy in Japan, where, despite stringent regulations and skilful fugu cooks, tetrodotoxin poisoning continues to occur, causing around four deaths each year. Cases have been reported in Thailand and many other Indo-Pacific countries. Tetrodotoxin, an aminoperhydroquinazoline, is one of the most potent non-protein toxins known. It is concentrated in the fishes’ ovaries, viscera and skin. There is a definite seasonal variation in toxin concentration, reaching a peak during the spawning season (May–June in Japan). Tetrodotoxin impairs nervous conduction by blocking the sodium ion flux without affecting movement of potassium, producing neurotoxic and cardiotoxic effects. It may be synthesized by Pseudomonas bacteria and acquired through the food chain. An identical toxin has been found in the skin of newts (genus Taricha), frogs (genus Atelopus) and salamanders, the saliva of octopuses (genus Hapalochlaena), in the digestive glands of several species of gastropod mollusc and in xanthid and horseshoe crabs, starfish, flat worms (Planorbis) and nemertine worms in Japan. Paralytic fresh-water puffer fish poisoning attributable to saxitoxin has been reported in Thailand. Clinical Features.  Paraesthesiae, dizziness and ataxia become noticeable within 10–45 minutes of eating the fish. Generalized numbness, hypersalivation, sweating and hypotension may develop. Some patients remain aware of their surroundings despite appearing comatose while others may appear brain dead. Gastrointestinal symptoms may be completely absent. Death from respiratory paralysis usually occurs within the first 6 hours and is unusual more than 12 hours after eating the fish. Erythema, petechiae, blistering and desquamation may appear.

Bivalve molluscs such as mussels, clams (Saxidomus), oysters, cockles and scallops may acquire neurotoxins such as saxitoxins from the dinoflagellates Alexandrium species (formerly Gymnodinium catenatum) and Pyrodinium bahamense which occur between latitudes 30°N and 30°S. These dinoflagellates may be sufficiently abundant during the warmer months of May– October to produce a ‘red tide’. The dangerous season is announced by the discovery of unusual numbers of dead fish and sea birds. Symptoms develop within 30 minutes of ingestion. They include perioral paraesthesia, gastrointestinal symptoms, ataxia, visual disturbances and pareses, progressing to respiratory paralysis within 12 hours in 8% of cases. Milder gastrointestinal and neurotoxic symptoms without paralysis have been associated with ingestion of molluscs contaminated by neurotoxic brevetoxins from Gymnodinium breve, which act on sodium channels. These microalgae also produce a ‘red tide’. Histamine Syndrome (Scombrotoxic Poisoning) The dark red flesh of scombroid fish such as tuna, mackerel, bonito and skipjack, and of canned non-scombroid fish such as sardines and pilchards, may be decomposed by the action of bacteria such as Proteus morgani, decarboxylating muscle histidine into histamine, saurine, cadaverine and other toxins. Toxic fish may produce a warning tingling or smarting sensation in the mouth when eaten. Between minutes and up to 24 hours after ingestion, flushing, burning, urticaria and pruritus of the skin, headache, abdominal colic, nausea, vomiting, diarrhoea, hypotensive shock and bronchial asthma may develop. Exogenous histamine may be detected in patients’ plasma and urine and in the fish.155 Identical symptoms have been described in Sri Lankan patients who ate fish while taking the antituberculosis drug isoniazid, which inhibits the enzyme normally responsible for inactivating histamine.157 Poisoning by Ingestion of Carp’s Gallbladder158 In parts of the Far East, the raw bile and gallbladder of various species of freshwater carp are believed to have medicinal properties. Patients develop acute abdominal pain, vomiting and watery diarrhoea 2–18 hours after drinking the raw bile or eating the raw gallbladder of these fish. Hepatic and renal damage may develop, progressing to hepatic failure and oliguric or non-oliguric AKI. The hepatonephrotoxin has not been identified, but is heat-stable and may be derived from the carp’s diet. TREATMENT OF MARINE POISONING The differential diagnosis includes bacterial and viral food poisoning and allergic reactions. No specific treatments or antidotes are available. If ingestion was recent, gastrointestinal contents should be gently eliminated by emetics and purges. Activated charcoal absorbs saxitoxin and other shellfish toxins. Atropine is said to improve gastrointestinal symptoms and sinus bradycardia in patients with gastrointestinal and neurotoxic poisoning. Oximes, such as pralidoxime and 2-pyridine aldoxime, have been claimed to benefit the anticholinesterase features of ciguatera poisoning, but the evidence is not convincing. Calcium gluconate may relieve mild neuromuscular symptoms. In scombroid poisoning, adrenaline (epinephrine), histamine H1-blocker, corticosteroids and bronchodilators

1126

SECTION 13  Environmental Disorders

Figure 75.36  Spotted salamander (Ambystoma maculatum: family Ambystomatidae). (Copyright D. A. Warrell.) Figure 75.37  Dyeing dart frog (Dendrobates tinctorius: family Dendrobatidae). (Copyright D. A. Warrell.)

should be used, depending on severity. In cases of paralytic poisoning, endotracheal intubation and mechanical ventilation and cardiac resuscitation have proved life-saving. In Malaysia, a patient with tetrodotoxin poisoning developed fixed dilated pupils and brain stem areflexia, so appearing brain dead, but made a complete recovery after being mechanically ventilated.159 The use of mannitol intravenously in acute ciguatera poisoning is not supported by convincing evidence.160,161 Gabapentin has been suggested as a treatment for chronic persisting paraesthesiae after ciguatera poisoning.162 PREVENTION OF MARINE POISONING Ciguatera, tetrodotoxin and histamine are heat-stable, so cooking does not prevent poisoning. In tropical areas, the flesh of fish should be separated, as soon as possible, from the head, skin, intestines, gonads and other viscera, which may have high concentrations of toxin. All scaleless fish should be regarded as potentially tetrodotoxic, while very large fish carry an increased risk of being ciguateratoxic. Tetraodontiform fish, Moray eels and parrot fish should never be eaten. Some toxins are fairly water-soluble and may be leeched out, so water in which fish

are cooked should be thrown away. Scombroid poisoning can be prevented by prompt freezing or by eating the fish fresh. Shellfish should not be eaten during the dangerous season and when there are red tides. POISONOUS AMPHIBIANS163 The moist skin of amphibians such as frogs (Figure 75.37), toads, newts, and salamanders (Figure 75.36) is an accessory respiratory organ that is protected from micro-organisms by highly toxic secretions containing amines, peptides, proteins, steroids, and alkaloids. Ingesting these animals can be fatal. Some toads can squirt from their parotid glands venom containing bufadienolides which affect membrane Na+/K+-ATPase. When licked or put in the mouth by dogs or children or when ingested as Chinese traditional medicines, the poisons can cause fatal digoxin-like poisoning. Symptoms include hypersalivation, cyanosis, cardiac arrhythmias, and generalized convulsions. Antidigoxin antibodies (‘Digibind’, ‘DigiTAb’) have some therapeutic effect.

REFERENCES 5. Sutherland SK, Tibballs J. Australian Animal Toxins. The Creatures, their Toxins and Care of the Poisoned Patient. 2nd ed. Melbourne: Oxford University Press; 2001. 8. Meier J, White J, editors. Handbook of Clinical Toxicology of Animal Venoms and Poisons. Boca Raton: CRC Press; 1995.

24. Warrell DA. Epidemiology, clinical features and management of snakebites in Central and South America. In: Campbell J, Lamar WW, editors. Venomous Reptiles of the Western Hemisphere. Ithaca: Cornell University Press; 2004. p. 709–61.

81. Sutherland SK, Coulter AR, Harris RD. Rationalization of first-aid measures for elapid snakebite. Lancet 1979;i:183–6. 115. Halstead BW. Poisonous and Venomous Marine Animals of the World. 2nd ed. New Jersey: Darwin Press; 1988.

WHO Snakebite in South and South-east Asia: http://www.searo.who.int/entity/emergencies/ documents/9789290223774/en/index.html

WHO Venomous snakes distribution: http://apps. who.int/bloodproducts/snakeantivenoms/data base/ WHO Guidelines for the Production, Control and Regulation of Snake Antivenom Immunoglobulins: http://www.who.int/bloodproducts/snake_ antivenoms/snakeantivenomguide/en/

USEFUL WEBSITES Envenoming General: http://vapaguide.info General, especially in Australasia: http://www. toxinology.com/ WHO Snakebite in Africa: http://www.afro.who. int/en/clusters-a-programmes/hss/essentialmedicines/highlights/2731-guidelines-for-theprevention-and-clinical-management-of-snake bite-in-africa.html

Antivenoms General Global crisis: http://globalcrisis.info/latestantivenom. htm Munich AntiVenomINdex (MAVIN): http://toxinfo. org/antivenoms/



75  Venomous and Poisonous Animals

1127

European Antivenoms Zagreb Immunology Institute in Croatia: http:// www.imz.hr/english/products/DescriptionEuropean-Viper-Venom-Antiserum.pdf

South African Antivenoms South African Vaccine Producers: http://www.savp .co.za/

Scorpions Norwegian University of Science and Technology: http://www.ub.ntnu.no/scorpion-files/index.php

Australian Antivenoms CSL antivenom handbook: http://www.toxinology. com/generic_static_files/cslavh_antivenom.html

Venomous Snake Taxonomy Updates School Of Biological Sciences: http://pages.bangor .ac.uk/~bss166/update.htm

Access the complete references online at www.expertconsult.com

75  Venomous and Poisonous Animals 1127.e1

REFERENCES 1. Bagnis R, Kaeuffer H. Perpectives immunologiques en matière de ciguatéra. Med Trop Marseille 1974;34:25–7. 2. Kaeuffer H, Bagnis R, Chanteau S, et al. [Hypersensitivity in ciguatera ichthyosarcotoxism: an experimental model]. Bull Soc Pathol Exot Filiales. 1976;69(5):446–9. 3. Folinsbee K, Muller J, Reisz RR. Canine grooves: morphology, function, and relevance to venom. J Vertebrate Paleontol 2007;27:547–51. 4. Dufton MJ. Venomous mammals. Pharmacol Ther 1992;53:199–215. 5. Sutherland SK, Tibballs J. Australian Animal Toxins. The Creatures, their Toxins and Care of the Poisoned Patient. 2nd ed. Melbourne: Oxford University Press; 2001. 6. Whittington CM, Papenfuss AT, Locke DP, et al. Novel venom gene discovery in the platypus. Genome Biol. 2010;11(9):R95. 7. Uetz P. The EMBL Reptile Database, Peter Uetz and the European Molecular Biology Laboratory, Heidelberg, Germany, 2006. Online. Available: http://www.reptile-database.org/dbinfo/taxa.html#Ser. 8. Meier J, White J, editors. Handbook of Clinical Toxicology of Animal Venoms and Poisons. Boca Raton: CRC Press; 1995. 9. Weinstein SA, Warrell DA, White J, et al. ‘Venomous’ bites from non-venomous snakes: A critical analysis of risk and management of ‘colubrid’ snakebites. Waltham: Elsevier; 2011. 10. Vidal N, Hedges SB. The phylogeny of squamate reptiles (lizards, snakes, and amphisbaenians) inferred from nine nuclear proteincoding genes. C R Biol 2005;328:1000–8. 11. Lee MS, Scanlon JD. Snake phylogeny based on osteology, soft anatomy and ecology. Biol Rev Camb Philos Soc 2002;77:333–401. 12. Malhotra A, Thorpe RS. A phylogeny of four mitochondrial gene regions suggests a revised taxonomy for Asian pitvipers (Trimeresurus and Ovophis). Mol Phylogenet Evol 2004;32: 83–100. 13. Sichert AB, Friedel P, van Hemmen JL. Snake’s perspective on heat: reconstruction of input using an imperfect detection system. Phys Rev Lett 2006;97:068105. 14. Mohapatra B, Warrell DA, Suraweera W, et al; Million Death Study Collaborators. Snakebite mortality in India: a nationally representative mortality survey. PLoS Negl Trop Dis 2011;5 (4):e1018. 15. Rahman R, Faiz MA, Selim S, et al. Annual incidence of snakebite in rural Bangladesh. PLoS Negl Trop Dis 2010;4(10):e860. 16. Sharma SK, Chappuis F, Jha N, et al. Impact of snakebites and determinants of fatal outcomes in southeastern Nepal. Am J Trop Med Hyg 2004;71:234–8. 17. Fox S, Rathuwithana AC, Kasturiratne A, et al. Underestimation of snakebite mortality by hospital statistics in the Monaragala District of Sri Lanka. Trans R Soc Trop Med Hyg 2006;100:693–5. 18. Warrell DA, Arnett C. The importance of bites by the saw-scaled or carpet viper (Echis carinatus). Epidemiological studies in Nigeria and a review of the world literature. Acta Trop (Basel) 1976;33:307–41. 19. Trape JF, Pison G, Guyavarch E, et al. High mortality from snakebite in south-eastern Senegal. Trans R Soc Trop Med Hyg 2001;95: 420–3.

20. Pugh RNH, Theakston RDG, Reid HA, et al. Malumfashi endemic diseases research project. XIII. Epidemiology of human encounters with the spitting cobra, Naja nigricollis, in the Malumfashi area of northern Nigeria. Ann Trop Med Parasitol 1980;74:523–30. 21. Snow RW, Bronzan R, Roques T, et al. The prevalence and morbidity of snakebite and treatment-seeking behaviour among a rural Kenyan population. Ann Trop Med Parasitol 1994;88:665–71. 22. Lalloo DG, Trevett AJ, Saweri A, et al. The epidemiology of snakebite in Central Province and National Capital District, Papua New Guinea. Trans R Soc Trop Med Hyg 1995;89: 178–82. 23. Warrell DA. Treatment of bites by adders and exotic venomous snakes. BMJ 2005;331:1244–7. 24. Warrell DA. Epidemiology, clinical features and management of snakebites in Central and South America. In: Campbell J, Lamar WW, editors. Venomous Reptiles of the Western Hemisphere. Ithaca: Cornell University Press; 2004. p. 709–61. 25. Pierini S, Warrell DA, de Paulo A, et al. High incidence of bites and stings by snakes and other animals among rubber tappers and Amazonian Indians of the Jurua Valley, Acré State, Brazil. Toxicon 1996;34:225–36. 26. Myint-Lwin, Warrell DA, Phillips RE, et al. Bites by Russell’s viper (Vipera russelli siamensis) in Burma: haemostatic, vascular and renal disturbances and response to treatment. Lancet 1985;ii:1259–64. 27. Reid HA, Lim KJ. Sea-snakebite. A survey of fishing villages in northwest Malaya. BMJ 1957;ii:1266–72. 28. Warrell DA. Sea snakebites in the Asia-Pacific region. In: Gopalkrishnakone P, editor. Sea Snake Toxinology. Singapore: Singapore University Press; 1994:1–36. 29. Warrell DA. Commissioned article: management of exotic snakebites. Q J Med 2009; 102(9):593–601. 30. Faiz A, Ghose A, Ahsan F, et al. The greater black krait (Bungarus niger), a newly recognized cause of neuro-myotoxic snakebite envenoming in Bangladesh. Brain 2010;133: 3181–93. 31. Ariaratnam CA, Sheriff MH, Theakston RD, et al. Distinctive epidemiologic and clinical features of common krait (Bungarus caeruleus) bites in Sri Lanka. Am J Trop Med Hyg 2008; 79(3):458–62. 32. Warrell DA, Looareesuwan S, White NJ, et al. Severe neurotoxic envenoming by the Malayan krait Bungarus candidus (Linnaeus): response to antivenom and anticholinesterase. BMJ 1983;286:678–80. 33. Warrell DA, Greenwood BM, Davidson NMcD, et al. Necrosis, haemorrhage and complement depletion following bites by the spitting cobra (Naja nigricollis). Q J Med 1976;45:1–22. 34. Kochva E. Oral Glands of the Reptilia. In: Gans C, Gans KA, editors. Biology of the Reptilia. London: Academic Press; 1978:43– 161. 35. Bogert CM. Dentitional phenomena in cobras and other Elapids with notes on adaptive modifications of fangs. Bull Am Mus Nat Hist 1943;81:285–360. 36. Wüster W, Thorpe RS. Dentitional phenomena in cobras revisited: spitting and fang structure

in the Asiatic species of Naja (Serpentes: Elapidae). Herpetologica 1992;48:424–34. 37. Chu ER, Weinstein SA, White J, et al. Venom ophthalmia caused by venoms of spitting elapid and other snakes: Report of ten cases with review of epidemiology, clinical features, pathophysiology and management. Toxicon 2010;56(3):259–72. 38. Warrell DA, Davidson NMcD, Greenwood BM, et al. Poisoning by bites of the saw-scaled or carpet viper (Echis carinatus) in Nigeria. Q J Med 1977;46:33–62. 39. White J. Snakebite and Spiderbite. Management Guidelines, South Australia. Adelaide: Department of Health; 2006. 40. Ménez A. The Subtle Beast. Snakes, from Myth to Medicine. London: Taylor & Francis; 2003. 41. Mackessy SP, editor. Handbook of Venoms and Toxins of Reptiles. Boca Raton: CRC Press; 2010. 42. Fry BG. From genome to ‘venome’: molecular origin and evolution of the snake venom proteome inferred from phylogenetic analysis of toxin sequences and related body proteins. Genome Res 2005;15:403–20. 43. Fry BG, Vidal N, van der Weerd L, et al. Evolution and diversification of the Toxicofera reptile venom system. J Proteomics 2009;72(2): 127–36. 44. Kamiguti AS. Platelets as targets of snake venom metalloproteinases. Toxicon 2005;45: 1041–9. 45. Clemetson KJ. Snaclecs (snake C-type lectins) that inhibit or activate platelets by binding to receptors. Toxicon 2010;56(7):1236–46. 46. Fry BG, Lumsden NG, Wüster W, et al. Isolation of a neurotoxin (alpha-colubritoxin) from a non-venomous colubrid: evidence for early origin of venom in snakes. J Mol Evol 2003; 57:446–52. 47. Ducancel F. Endothelin-like peptides. Cell Mol Life Sci 2005;62:2828–39. 48. WHO. Online. Available: http://www.searo .who.int/entity/emergencies/documents/ 9789290223774/en/index.html. 49. WHO. Online. Available: http://www.afro.who. int/en/clusters-a-programmes/hss/essentialmedicines/highlights/2731-guidelines-for-theprevention-and-clinical-management-ofsnakebite-in-africa.html. 50. Hutton RA, Warrell DA. Action of snake venom components on the haemostatic system. Blood Rev 1993;7:176–89. 51. Lu Q, Clemetson JM, Clemetson KJ. Snake venoms and hemostasis. J Thromb Haemost 2005;3(8):1791–9. 52. Hutton RA, Looareesuwan S, Ho M, et al. Arboreal pit vipers (genus Trimeresurus) of Southeast Asia: bites by T. albolabris and T. macrops in Thailand and a review of the literature. Trans R Soc Trop Med Hyg 1990;84: 866–74. 53. Schneemann M, Cathomas R, Laidlaw ST, et al. Life-threatening envenoming by the Saharan horned viper (Cerastes cerastes) causing microangiopathic haemolysis, coagulopathy and acute renal failure: clinical cases and review. Q J Med 2004;97:717–27. 54. Isbister GK, Little M, Cull G, et al. Thrombotic microangiopathy from Australian brown snake (Pseudonaja) envenoming. Intern Med J 2007; 37(8):523–8.

1127.e2

SECTION 13  Environmental Disorders

55. Vogt W. Snake venom constituents affecting the complement system. In: Stocker KF, editor. Medical Use of Snake Venom Proteins. Boca Raton: CRC Press; 1990. p. 79–96. 56. Sitprija V, Chaiyabutr N. Nephrotoxicity in snake envenomation. J Nat Toxins 1999;8: 271–7. 57. Ratcliffe PJ, Pukrittayakamee S, Ledingham JGG, et al. Direct nephrotoxicity of Russell’s viper venom demonstrated in the isolated perfused rat kidney. Am J Trop Med Hyg 1989; 40:312–19. 58. Phillips RE, Theakston RDG, Warrell DA, et al. Paralysis, rhabdomyolysis and haemolysis caused by bites of Russell’s viper (Vipera russelli pulchella) in Sri Lanka: failure of Indian (Haffkine) antivenom. Q J Med 1988;68: 691–716. 59. Azevedo-Marques MM, Hering SE, Cupo P. Evidence that Crotalus durissus terrificus (South American rattlesnake) envenomation in humans causes myolysis rather than hemolysis. Toxicon 1987;25:1163–8. 60. Watt G, Theakston RDG, Hayes CG, et al. Positive response to edrophonium in patients with neurotoxic envenoming by cobras (Naja naja philippinensis). A placebo-controlled study. N Engl J Med 1986;315:1444–8. 61. Bevan P, Hiestand P. Beta-RTX. A receptoractive protein from Russell’s viper (Vipera russelli russelli) venom. J Biol Chem 1983;258: 5319–26. 62. Jansen PW, Perkin RM, Van Stralen D. Mojave rattlesnake envenomation: prolonged neurotoxicity and rhabdomyolysis. Ann Emerg Med 1992;21(3):322–5. 63. Warrell DA, Ormerod LD. Snake venom ophthalmia and blindness caused by the spitting cobra (Naja nigricollis) in Nigeria. Am J Trop Med Hyg 1976;25:525–9. 64. Nicolson IC, Ashby PA, Johnson ND, et al. Boomslang bite with haemorrhage and activation of complement by the alternate pathway. Clin Exp Immunol 1974;16:295–9. 65. Warrell DA, Ormerod LD, Davidson NMcD. Bites by the night adder (Causus maculatus) and burrowing vipers (genus Atractaspis) in Nigeria. Am J Trop Med Hyg 1976;25:517– 24. 66. Kurnik D, Haviv Y, Kochva E. A snakebite by the burrowing asp, Atractaspis engaddensis. Toxicon 1999;37:223–7. 67. Tin-Myint, Rai-Mra, Maung-Chit, et al. Bites by the king cobra (Ophiophagus hannah) in Myanmar: successful treatment of severe neurotoxic envenoming. Q J Med 1991;80:751– 62. 68. Campbell CH. Symptomatology, pathology and treatment of the bites of elapid snakes. In: Lee CY, editor. Snake Venoms. Handbook of Experimental Pharmacology, vol. 52. Berlin: Springer; 1979:898–921. 69. Lalloo DG, Trevett AJ, Korinhona A, et al. Snakebites by the Papuan taipan (Oxyuranus scutellatus canni). Paralysis, hemostatic and electrocardiographic abnormalities, and effects of antivenom. Am Trop Med Hyg 1995;52: 525–31. 70. Connolly S, Trevett AJ, Nwokolo NC, et al. Neuromuscular effects of Papuan taipan snake venom. Ann Neurol 1995;38:916–20. 71. Reid HA. Symptomatology, pathology and treatment of the bites of sea snakes. In: Lee CY, editor. Snake Venoms. Handbook of Experimental Pharmacology, vol. 52. Berlin: Springer; 1979:922–55.

72. Matsen FA. Compartmental Syndromes. New York: Grune & Stratton; 1980. p. 162. 73. Malbranque S, Piercecchi-Marti MD, Thomas L, et al. Fatal diffuse thrombotic microangiopathy after a bite by the ‘Fer-de-Lance’ pit viper (Bothrops lanceolatus) of Martinique. Am J Trop Med Hyg 2008;78(6):856–61. 74. Bush SP, Siedenburg E. Neurotoxicity associated with suspected southern Pacific rattlesnake (Crotalus viridis helleri) envenomation. Wilderness Environ Med 1999;10:247–9. 75. Hardy DL. Envenomation by the Mojave rattlesnake (Crotalus scutulatus scutulatus) in southern Arizona, USA. Toxicon 1983;21: 111–18. 76. Sano-Martins IS, Fan HW, Castro SC, et al. Reliability of the simple 20 minute whole blood clotting test (WBCT20) as an indicator of low plasma fibrinogen concentration in patients envenomed by Bothrops snakes. Toxicon 1994;32:1045–50. 77. Theakston RDG, Lloyd-Jones MJ, Reid HA. Micro-ELISA for detecting and assaying snake venom and venom-antibody. Lancet 1977;ii: 639–41. 78. Ho M, Warrell MJ, Warrell DA, et al. A critical reappraisal of the use of enzyme-lined immunosorbent assays in the study of snakebite. Toxicon 1986;24:211–21. 79. Dong le V, Selvanayagam ZE, Gopalakrishnakone P, et al. A new avidin-biotin optical immunoassay for the detection of betabungarotoxin and application in diagnosis of experimental snake envenomation. J Immunol Methods 2002;260:125–36. 80. O’Leary MA, Isbister GK, Schneider JJ, et al. Enzyme immunoassays in brown snake (Pseudonaja spp.) envenoming: detecting venom, antivenom and venom-antivenom complexes. Toxicon 2006;48(1):4–11. 81. Sutherland SK, Coulter AR, Harris RD. Rationalization of first-aid measures for elapid snakebite. Lancet 1979;i:183–6. 82. Cheng AC, Currie BJ. Venomous snakebites worldwide with a focus on the AustraliaPacific region: current management and controversies. J Intensive Care Med 2004;19: 259–69. 83. Canale E, Isbister GK, Currie BJ. Investigating pressure bandaging for snakebite in a simulated setting: bandage type, training and the effect of transport. Emerg Med Australas 2009;21(3):184–90. 84. Bush SP, Green SM, Laack TA, et al. Pressure immobilization delays mortality and increases intracompartmental pressure after artificial intramuscular rattlesnake envenomation in a porcine model. Ann Emerg Med 2004;44(6): 599–604. 85. Meggs WJ, Courtney C, O’Rourke D, et al. Pilot studies of pressure-immobilization bandages for rattlesnake envenomations. Clin Toxicol (Phila) 2010;48(1):61–3. 86. Howarth DM, Southee AE, Whyte IM. Lymphatic flow rates and first-aid in simulated peripheral snake or spider envenomation. Med J Aust 1994;161:695–700. 87. Anker RL, Straffon WG, Loiselle DS, et al. Snakebite. Comparison of three methods designed to delay uptake of ‘mock venom’. Aust Fam Physician 1983;12(5):365–8. 88. Tun-Pe, Aye-Aye-Myint, Khin-Ei-Han, et al. Local compression pads as a first-aid measure for victims of bites by Russell’s viper (Daboia russelii siamensis) in Myanmar. Trans R Soc Trop Med Hyg 1995;89(3):293–5.

89. Pe T, Mya S, Myint AA, et al. Field trial of efficacy of local compression immobilization first-aid technique in Russell’s viper (Daboia russelii siamensis) bite patients. Southeast Asian J Trop Med Public Health 2000;31 (2):346–8. 90. Saul ME, Dosen PJ, Isbister GK, et al. A pharmacological approach to first aid treatment for snakebite. Nat Med 2011;17:809–11. 91. Bush SP, Hegewald KG, Green SM, et al. Effects of a negative pressure venom extraction device (Extractor) on local tissue injury after artificial rattlesnake envenomation in a porcine model. Wilderness Environ Med 2000;11:180–8. 92. Hardy DL. A review of first aid measures for pit viper bite in North America with an appraisal of Extractor suction and stun gun electroshock. In: Campbell JA, Brodie ED, editors. Biology of the Pit Vipers. Tyler: Selva; 1992:405–14. 93. Reid HA. Adder bites in Britain. BMJ 1976;ii:153–6. 94. Malasit P, Warrell DA, Chanthavanich P, et al. Prediction, prevention and mechanism of early (anaphylactic) antivenom reactions in victims of snakebites. BMJ 1986;292:17–20. 95. Cupo P, Azevedo-Marques MM, de Menezes JB, et al. Immediate hypersensitivity reactions after intravenous use of antivenin sera: prognostic value of intradermal sensitivity tests. Rev Inst Med Trop Sao Paulo 1991;33:115– 22. 96. de Silva HA, Pathmeswaran A, Ranasinha CD, et al. Low-dose adrenaline, promethazine, and hydrocortisone in the prevention of acute adverse reactions to antivenom following snakebite: a randomised, double-blind, placebo-controlled trial. PLoS Med 2011;8 (5):e1000435. 97. Theakston RDG, Warrell DA. Antivenoms: a list of hyperimmune sera currently available for the treatment of envenoming by bites and stings. Toxicon 1991;29:1419–70. 98. WHO. Progress in the Characterization of Venoms and Standardization of Antivenoms. Offset Publications No. 58. Geneva: World Health Organization; 1981. 99. O’Leary MA, Kornhauser RS, Hodgson WC, et al. An examination of the activity of expired and mistreated commercial Australian antivenoms. Trans R Soc Trop Med Hyg 2009;103(9): 937–42. 100. WHO. Online. Available: http://www.who.int/ bloodproducts/snake_antivenoms/en/. 101. Ho M, Silamut K, White NJ, et al. Pharmacokinetics of three commercial antivenoms in patients envenomed by the Malayan pit viper (Calloselasma rhodostoma) in Thailand. Am J Trop Med Hyg 1990;42:260–6. 102. Ho M, Warrell DA, Looareesuwan S, et al. Clinical significance of venom antigen levels in patients envenomed by the Malayan pit viper (Calloselasma rhodostoma). Am J Trop Med Hyg 1986;35:579–87. 103. Audebert F, Sorkine M, Bon C. Envenoming by viper bites in France: clinical gradation and biological quantification by ELISA. Toxicon 1992;30:599–609. 104. Warrell DA. Snakebite. Lancet. 2010;375 (9708):77–88. 105. Golnik KC, Pena R, Lee AG, et al. An ice test for the diagnosis of myasthenia gravis. Ophthalmology 1999;106:1282–6. 106. Abrahamian FM, Goldstein EJ. Microbiology of animal bite wound infections. Clin Microbiol Rev 2011;24(2):231–46.

107. Theakston RDG, Phillips RE, Looareesuwan S, et al. Bacteriological studies of the venom and mouth cavities of wild Malayan pit vipers (Calloselasma rhodostoma) in southern Thailand. Trans R Soc Trop Med Hyg 1990; 84:875–9. 108. Jorge MT, Malaque C, Ribeiro LA, et al. Failure of chloramphenicol prophylaxis to reduce the frequency of abscess formation as a complication of envenoming by Bothrops snakes in Brazil: a double-blind randomized controlled trial. Trans R Soc Trop Med Hyg 2004;98: 529–34. 109. Garfin SR, Castilonia RR, Mubarak SJ, et al. Rattlesnake bites and surgical decompression: results using a laboratory model. Toxicon 1984;22:177–82. 110. Tun-Pe, Aye-Aye-Myint, Khin-Aye-Kyu, et al. Acceptability study of protective boots among farmers of Taungdwingyi township. Myanmar Health Sci Res J 1998;10(2):57–60 (also In: Management of Snakebite and Research. New Delhi: WHO/SEARO; 2002:7–11. 111. Chappuis F, Sharma SK, Jha N, et al. Protection against snakebites by sleeping under a bed net in southeastern Nepal. Am J Trop Med Hyg 2007;77:197–9. 112. Russell FE, Bogert CM. Gila monster, venom and bite: a review. Toxicon 1981;19:341–59. 113. Raufman J-P. Review. Bioactive peptides from lizard venoms. Regul Pept 1996;61:1–18. 114. Fry BG, Vidal N, Norman JA, et al. Early evolution of the venom system in lizards and snakes. Nature 2006;439:584–8. 115. Halstead BW. Poisonous and Venomous Marine Animals of the World. 2nd ed. New Jersey: Darwin Press; 1988. 116. Williamson JA, Fenner PJ, Burnett JW, et al, editors. Venomous and Poisonous Marine Animals: A Medical and Biological Handbook. Sydney: University of New South Wales Press; 1996. 117. Smith WL, Wheeler WC. Venom evolution widespread in fishes: a phylogenetic road map for the bioprospecting of piscine venoms. J Hered 2006;97:206–17. 118. Khoo HE. Bioactive proteins from stonefish venom. Clin Exp Pharmacol Physiol 2002; 29:802–6. 119. Castex MN. Freshwater venomous rays. In: Russell FE, Saunders PR, editors. Animal Toxins. Oxford: Pergamon Press; 1967. p. 167– 76. 120. Russell FE. Stingray injuries. A review and discussion of their treatment. Am J Med Sci 1953;226:611–22. 121. Maretic Z. Some epidemiological, clinical and therapeutic aspects of envenomation by weeverfish sting. In: De Vries A, Kochva E, editors. Toxins of Animals and Plant Origin, vol. 3. New York: Gordon & Breach; 1973. p. 1055– 65. 122. Lee JY, Teoh LC, Leo SP. Stonefish envenomations of the hand – a local marine hazard: a series of 8 cases and review of the literature. Ann Acad Med Singapore. 2004;33:515–20. 123. Barnes JH. Observations on jellyfish stingings in North Queensland. Med J Aust 1960;2: 993–9.

75  Venomous and Poisonous Animals 1127.e3 124. Maretić Z, Russell FE. Stings by the sea anemone Anemonia sulcata in the Adriatic Sea. Am J Trop Med Hyg 1983;32(4):891–6. 125. Little M. First aid for jellyfish stings: do we really know what we are doing? Emerg Med Australas 2008;20(1):78–80. 126. Birsa LM, Verity PG, Lee RF. Evaluation of the effects of various chemicals on discharge of and pain caused by jellyfish nematocysts. Comp Biochem Physiol C Toxicol Pharmacol 2010;151(4):426–30. 127. Seymour J, Carrette T, Cullen P, et al. The use of pressure immobilization bandages in the first aid management of cubozoan envenomings. Toxicon 2002;40:1503–5. 128. Alender CB, Russell FE. Pharmacology. In: Boolootian RA, editor. Physiology of Echinodermata. New York: Interscience; 1966. p. 529– 43. 129. Sato H, Tsuruta Y, Yamamoto Y, et al. Case of skin injuries due to stings by crown-of-thorns starfish (Acanthaster planci). J Dermatol 2008;35(3):162–7. 130. Olivera BM. Conus peptides: biodiversitybased discovery and exogenomics. J Biol Chem 2006;281:31173–7. 131. Bettini S, editor. Arthropod Venoms. Handbook of Experimental Pharmacology, vol. 48. Berlin: Springer; 1978. 132. Winston ML. Killer Bees: The Africanized Honey Bee in the Americas. Cambridge: Harvard University Press; 1992. 133. França FOS, Benvenuti LA, Fan HW, et al. Severe and fatal mass attacks by ‘killer’ bees (Africanised honey bees – Apis mellifera scutellata) in Brazil: clinicopathological studies with measurement of serum venom concentrations. Q J Med 1994;87:269–82. 134. Warrell DA. Taking the sting out of ant stings: venom immunotherapy to prevent anaphylaxis. Lancet 2003;361:979–80. 135. Piek T. Venoms of the Hymenoptera. Biochemical, Pharmacological and Behavioural Aspects. London: Academic Press; 1986. 136. Ewan PW. Allergy to insect stings: a review. J R Soc Med 1984;78:234–9. 137. Hunt KJ, Valentine MD, Sobotka AK, et al. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978;299: 157–61. 138. Freire-Maia L, Campos JA, Amaral CFS. Treatment of scorpion envenoming in Brazil. In: Bon C, Goyffon M, editors. Envenomings and their Treatments. Lyon: Fondation Marcel Mérieux; 1996. p. 301–10. 139. Bawaskar HS. Diagnostic cardiac premonitory signs and symptoms of red scorpion sting. Lancet 1982;i:552–4. 140. Boyer LV, Theodorou AA, Berg RA, et al. Antivenom for critically ill children with neurotoxicity from scorpion stings. N Engl J Med 2009;360:2090–8. 141. Natu VS, Kamerkar SB, Geeta K, et al. Efficacy of anti-scorpion venom serum over prazosin in the management of severe scorpion envenomation. J Postgrad Med 2010;56: 275–80. 142. Bawaskar AS, Bawaskar PH. Severe envenoming by the Indian red scorpion (Mesobuthus

143.

144. 145. 146.

147. 148.

149. 150. 151. 152. 153. 154. 155.

156.

157. 158.

159. 160.

161.

162. 163.

tamulus): the use of prazosin therapy. Q J Med 1996;89:701–4. Patil SN. A retrospective analysis of a rural set up experience with special reference to dobutamine in prazosin-resistant scorpion sting cases. J Assoc Physicians India 2009;57:301–4. Maretic Z, Lebez D. Araneism. Pula: Novit; 1979. Isbister GK, White J, Currie BJ, et al. Spider bites: addressing mythology and poor evidence. Am J Trop Med Hyg 2005;72:361–4. Rosen JL, Dumitru JK, Langley EW, et al. Emergency department death from systemic loxoscelism. Ann Emerg Med 2012;60(4):439– 41. Pauli I, Puka J, Gubert IC, et al. The efficacy of antivenom in loxoscelism treatment. Toxicon 2006;48:123–37. Murnaghan MF, O’Rourke FJ. Tick paralysis. In: Bettini S, editor. Arthropod Venoms. Handbook of Experimental Pharmacology, vol. 48. Berlin: Springer; 1978. p. 419–64. Gothe R, Kunze K, Hoogstraal H. The mechanism of pathogenicity in the tick paralyses. J Med Entomol 1979;16:357–69. Pearn J. The clinical features of tick bite. Med J Aust 1977;2:313. Radford AJ. Millipede burns in man. Trop Geogr Med 1975;27:279–87. Salzman M, Madsen JM, Greenberg MI. Toxins: bacterial and marine toxins. Clin Lab Med 2006;26:397–419, ix. Sobel J, Painter J. Illnesses caused by marine toxins. Clin Infect Dis 2005;41:1290–6. Daranas AH, Norte M, Fernández JJ. Review. Toxic marine micro-algae. Toxicon 2001;39: 1101–32. Morrow JD, Margolies GR, Rowland J, et al. Evidence that histamine is the causative toxin of scombroid-fish poisoning. N Engl J Med 1991;324:716–20. Bagnis R, Kuberski T, Laugier S. Clinical observations on 3,009 cases of ciguatera (fish poisoning) in the South Pacific. Am J Trop Med Hyg. 1979;28(6):1067–73. Uragoda CG, Kottegoda SR. Adverse reactions to isoniazid on ingestion of fish with a high histamine content. Tubercle 1977;58:83–9. Lin YF, Lin SH. Simultaneous acute renal and hepatic failure after ingesting raw carp gall bladder. Nephrol Dial Transplant 1999;14: 2011–12. Loke YK, Tan MH. A unique case of tetrodotoxin poisoning. Med J Malaysia 1997;52: 172–4. Schnorf H, Taurarii M, Cundy T. Ciguatera fish poisoning: a double-blind randomized trial of mannitol therapy. Neurology 2002;58 (6):873–80. Friedman MA, Fleming LE, Fernandez M, et al. Ciguatera fish poisoning: treatment, prevention and management. Mar Drugs 2008;6(3): 456–79. Perez CM, Vasquez PA, Perret CF. Treatment of ciguatera poisoning with gabapentin. N Engl J Med 2001;344(9):692–3. Daly JW. The chemistry of poisons in amphibian skin. Proc Natl Acad Sci U S A 1995;92 (1):9–13.