Envenomation Syndromes
James Tibballs
Kenneth D. Winkel
KEY POINTS
Snakebite causes most mortality attributed to envenomation, particularly in developing countries. The main snake species belong to families of Elapidae and Viperidae. Snake venoms cause neurotoxic, myotoxic, procoagulopathic and anticoagulopathic, cytotoxic, and hemolytic effects.
Snakebite is not always accompanied by envenomation, but its management includes first aid that consists of pressure-immobilization bandaging of the bitten limb (for neurotoxic elapid bites), resuscitation, appropriate antivenom therapy, and treatment of systemic effects of venom. Hypoxemia, hypotension, rhabdomyolysis, and disseminated intravascular coagulation may combine to cause renal failure, for which support may be needed. Antivenom administration should be preceded by the administration of subcutaneous adrenaline to prevent and ameliorate adverse reactions.
Bites by spiders are very common, but only a few species of spider threaten life. These include bites by Australian funnel-web spiders; they cause muscle fasciculation followed by weakness and respiratory failure, which along with bronchorrhea is due to acetylcholine release. Hypertension and coma occur secondary to catecholamine release, which later culminates in heart failure, hypotension, and pulmonary edema. An antivenom is available and pressure-immobilization bandaging of the bitten limb is an effective first-aid technique.
Globally, bites by comb-footed spiders, such as the Australian redback spider and the North American widow spider (genus Latrodectus), are the most important. They cause severe pain, inflammatory signs, and hypertension. Antivenoms are available in several countries.
Bites by some North and South American recluse spiders may cause dermatonecrotic lesions alone or in combination with gastrointestinal illness, coagulopathy, hemolysis, and sometimes rhabdomyolysis, with subsequent renal failure. Antivenoms are sometimes available.
Scorpion stings may threaten life in India, Africa, Brazil, Mexico, and the southern American States. All cause severe pain and, depending on the species, life-threatening cardiovascular effects and a wide range of neurotoxicity. The efficacy of antivenoms is debated, but judicious vasodilator and inotropic therapy, along with mechanical ventilation, may be required.
Bee and wasp stings worldwide and some ant stings may cause life-threatening anaphylaxis. Envenomation syndromes may occasionally be encountered with multiple stings. Prominent bee species are the common honeybee (Apis mellifera) and wasps of the genera Vespa, Vespula, Provespa, and Polistes. Prominent ants are the Australian Myrmecia species (jumping jack and bull-ants) and the American Solenopsis spp. (fire ants). Treatment is as for anaphylaxis and, longer term, venom immunotherapy.
Tick bite may cause allergy and zoonosis, especially rickettsial diseases, Lyme disease, viral encephalitis, and hemorrhagic fever. Species that cause paralysis in North America are of the genera Dermacentor, Amblyomma, and Ixodes; in South Africa, Argas; and in Australia, Ixodes. The onset of flaccid paralysis is slow. Mechanical ventilation may be required until spontaneous recovery after tick removal.
Although many species of jellyfish cause painful stings, few threaten life. Most deaths from jellyfish stings have been due to the chirodropid (jellyfish with many tentacles arising from corners of a bell) Australian box jellyfish (Chironex fleckeri), whose stings cause rapid cardiorespiratory failure by unknown mechanisms. An antivenom is available.
Similar chirodropid jellyfish inhabit the Indo-Pacific region. Of the carybdeid jellyfish (single tentacles arising from corners of a bell), the Hawaiian box jellyfish (Carybdea alata), Australian jimble (Carybdea rastoni), and irukandji (Carukia barnesi) cause significant pain, and stings by the latter may be accompanied by hypertension and late cardiac failure. Treatment includes pain relief, oxygen therapy, diuretics, vasodilators, inotropic support, mechanical ventilation or application of continuous positive airway pressure, and possible antihypertensive therapy.
Although stings by Physalia spp. (Portuguese man-of-war, bluebottle) are the most frequent worldwide, few deaths have been recorded.
Numerous fish have spines that inject venom when they are handled or trodden upon, causing very painful lesions. The most prominent are species of the genus Synanceia (stonefish), which inhabit the Indo-Pacific region. An antivenom is available. Occasionally, the barbs of stingrays cause severe penetrating chest trauma.
Several species of Australian Hapalochlaena (blue-ringed) octopuses inject TTX, which causes the rapid onset of flaccid paralysis, necessitating mechanical ventilation for several hours.
Some mollusc cone snails fire a venom-laden mini-harpoon, which bears protein toxins that cause rapid paralysis.
Some fish are poisonous to eat, including numerous worldwide tetrodotoxic species (order tetraodontiformes) that cause paralysis. Tropical and subtropical species cause ciguatera, an acute gastrointestinal illness that is accompanied by a polymorphic long-lasting neurologic illness for which mannitol may be effective. Scombroid poisoning is due to consumption of fish that are contaminated by bacteria that manufacture histamine, which causes flushing, tachycardia, hypotension, and bronchospasm. Consumption of some shellfish may cause toxin-related paralysis or gastrointestinal illness.Numerous terrestrial and marine animals envenomate or poison human victims around the world causing characteristic syndromes. Children are overrepresented among the victims of envenomation. Many envenomation syndromes threaten life and cause serious illness. Treatment in some syndromes requires only mechanical ventilation and intensive cardiovascular support, but others may require specific therapies including the administration of antivenom. This chapter describes the animals, their toxins or poisons, the injuries which they cause, and outlines treatment appropriate for each. The sites of action of toxins and poisons on neuromuscular function are given in Figure 37.1.
SNAKEBITE
Venomous Snakes and Snakebite
The highest incidence of snakebite is in tropical developing countries. Although the true incidence of snakebite is unknown, two million bites are estimated throughout the world annually with 100,000-200,000 deaths (1) of which 46,000 occur in India (2) and 7500 in sub-Saharan Africa (3). Many more survivors have significant handicaps. The greatest burden occurs in highly populated, rural Asian regions with children being frequent victims. A worldwide massive lack of antivenoms contributes to this neglected public health problem (4).
 FIGURE 37.1. Sites of action of some major toxins and poisons on nerve, neuromuscular junction, and muscle. |
Medically significant venomous snakes can be classified into two major families—the Elapidae and Viperidae. Elapids are front fanged terrestrial snakes, and they include most dangerous Australian snakes (taipan, brown, death adder, tiger, and black snakes), the cobras, mambas, and kraits of Asia and Africa, as well as the coral snakes of the Americas. Two coral snakes of medical importance exist in the United States—the eastern coral snake and the Texas coral snake. Elapid venoms are highly neurotoxic with an additional cytotoxicity in some species such as spitting cobras. Vipers have characteristic large front folding fangs and their venom is less likely to cause systemic toxicity than that of the elapids. The venom of vipers is notable for inducing bite site swelling and tissue destruction. These snakes include the rattlesnakes of the Americas, and the old and new world vipers. A small number of venomous Colubridae, a family of back fanged snakes, are also medically important, such as the African Boomslang. The Hydrophiidae is a fourth family of venomous snakes and includes the sea snakes found along much of the Indo-Pacific coastline, predominantly in the tropics.
Venom
Snake venom is a complex mixture of toxic and nontoxic substances, mostly proteins that can have neurotoxic, myotoxic, procoagulant, anticoagulant, cytotoxic, and hemolytic properties. The composition of each venom influences the clinical presentation (Table 37.1).
Diagnosis of Envenomation
A high index of suspicion should be maintained in children who suddenly become sick while unsupervised outdoors, particularly in rural areas and in the summer months.
Signs of Snakebite (Not Necessarily Envenomation) May Include:
Puncture marks (usually on limbs) which:
may be difficult to see;
may consist of single, double, or multiple puncture marks or scratch marks;
may be accompanied by bruising/bleeding/oozing/blistering;
may be multiple, suggesting severe envenomation (although this may occur with nonvenomous snakebites).
Regional tender lymphadenopathy (this, also may be present after bites by nonvenomous snakes, and is thus not by itself an indication for antivenom).
Symptoms of Envenomation May Include
Local Effects
Swelling, bruising/bleeding/oozing/blistering, pain.
Nonspecific Features
Headache, nausea, vomiting, abdominal pain
Collapse, unconsciousness (may be transient).
Specific Features
Painful, tender muscles (myolysis)
Blurred vision, diplopia, difficulty swallowing or breathing, slurred speech, weakness, paresthesia (neurotoxicity)
Spontaneous bleeding from mucosal surfaces, continual bleeding from the bite site or venepunctures (coagulopathy).
Signs of Envenomation
Progressive limb swelling, blistering, and discoloration
Irritability, confusion, coma
Bleeding from bite, venepuncture, or other sites (care should be taken with puncture of arterial or central venous sites in the presence of potential coagulopathy, and intramuscular injections should be avoided)
Dark urine (myoglobinuria, hematuria)
Ptosis, dysarthria, weakness/paralysis, dyspnea, respiratory failure (neurotoxicity).
Investigations
Venom detection at bite site, in urine, or in blood using snake venom detection kit (SVDK) (available only for use in Australia and Papua New Guinea)
Blood tests to include:
Coagulation studies INR/PT, APTT, ACT, D-dimer, X-FDP, and fibrinogen. If these tests are unavailable, perform a test “20-minute whole blood clotting test.” A blood sample in a plain glass tube should clot within 10 minutes, if it remains unclotted at 20 minutes, coagulopathy is present.
Creatine kinase level to check for myolysis.
Renal function tests to determine if renal function is impaired secondary to myoglobinuria or hypotension.
Electrolytes because rhabdomyolysis may cause elevated K+ and decreased Ca++ levels.
Complete blood count, while the white cell count is usually acutely mildly elevated, significant leucocytosis may indicate other pathology. Thrombocytopenia may occur with some snakebites in isolation, as part of disseminated intravascular coagulation (DIC), or due to microangiopathic hemolytic anemia.
Urinalysis to check for hemoglobin, myoglobin.
ECG and cardiac troponin in cases of suspected cardiotoxicity. This may be primary or secondary, for example in the case of hyperkalemia associated with rhabdomyolysis.
Differential Diagnosis of Venomous Snakebite
The diagnosis of snakebite may be unclear. This is more likely in young children or others unable to give a clear history (e.g., found unconscious), in patients bitten at night or in dense scrub where snakes may not be seen, or occasionally in persons engaged in catching or keeping snakes.
Differential diagnosis of venomous snakebite includes:
nonvenomous snakebite;
bite or sting by other venomous creature (e.g., Hymenoptera, spider, octopus, jellyfish);
cerebrovascular accident;
ascending neuropathy (Guillain-Barré syndrome);
acute myocardial infarction;
allergic reaction (allergy may also develop to snake venoms, as well as to antivenoms);
hypoglycemia/hyperglycemia;
drug overdose;
closed head injury;
sepsis.
The symptoms and signs of envenomation follow a predictable time sequence (Table 37.2) but may vary enormously between victims, influenced by body weight, amount of venom injected, age and state of health of the patient, time elapsed since the bite, prior bite history and allergy status, as well as the site of the bite. The amount of venom injected may vary between snake species and between snakes of the same species according to size and maturity of the snake and the time since it last injected venom.
Effects of envenomation are specific to snake genera and species. Bite site swelling and tissue necrosis may be severe after Asian cobra and pit viper bites and may lead to a compartment syndrome and even require limb amputation. Myolysis is particularly prominent in envenomations from South American pit vipers, sea snakes, and black snakes, while death adder and king cobra envenomations are specifically neurotoxic. Myolysis may lead to renal failure, a complication that
is particularly severe in cases of Russell’s viper envenomation. Some snake venoms, including many elapid species, contain both postsynaptic and presynaptic neurotoxins, the latter being difficult to reverse if the patient is not treated promptly. Coagulation disturbances, secondary to consumption procoagulopathy, fibrinolysis, or anticoagulation, are common after many elapid and viper bites, although severe hemorrhage is infrequent. Most Australian snake envenomations can be diagnosed within 12 hours of bite by disturbances of coagulation or neurological disturbances (5).
is particularly severe in cases of Russell’s viper envenomation. Some snake venoms, including many elapid species, contain both postsynaptic and presynaptic neurotoxins, the latter being difficult to reverse if the patient is not treated promptly. Coagulation disturbances, secondary to consumption procoagulopathy, fibrinolysis, or anticoagulation, are common after many elapid and viper bites, although severe hemorrhage is infrequent. Most Australian snake envenomations can be diagnosed within 12 hours of bite by disturbances of coagulation or neurological disturbances (5).
TABLE 37.1 THE CLINICAL FEATURES OF VARIOUS MEDICALLY SIGNIFICANT VENOMOUS SNAKES OF THE WORLD | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Treatment of Venomous Snakebite
First Aid
The role of first aid is important in prehospital and hospital treatment. It is prudent to treat all snakebites as potentially serious envenomations and to apply appropriate first aid even though many snakes are not venomous and a significant number of venomous snakebites, perhaps the majority, do not result in systemic envenomation because no venom or only a small amount of venom is injected. However, the severity of envenomation cannot be predicted at the time of the bite. Since at least 95% of bites occur on the limbs and ˜60% involve a lower limb, they are easily treated with first aid.
There are many first-aid practices that are useless or harmful. Venom may be injected quite deeply, and consequently little venom is removed by incision or excision (cutting or sucking). These practices are not recommended, and indeed may be dangerous, particularly in the coagulopathic patient. The use of arterial tourniquets, especially for prolonged periods, may also be dangerous and not recommended for any type of venomous bite or sting. Local application of chemicals, electricity, or suction is also ineffective and may worsen local tissue damage.
Pressure-Immobilization First Aid
The pressure-immobilization first-aid technique for venomous bites and stings was developed experimentally in the 1970s by Struan Sutherland specifically for Australian elapid envenomation (6). In this technique (Fig. 37.2), a continuous bandage is applied (as tightly as when binding a sprained ankle, 40-70 mm Hg) to the whole limb and then a splint applied to further prevent movement. For example for a bite on the ankle, the bandage is applied continuously from the toes upwards to include the bite site and is extended above the knee and a splint applied to prevent use and movement of the limb. The patient also needs to be kept still as even the movement of a splinted limb undermines the effectiveness of the technique. The rationale is compression of lymphatic channels and inactivation of the “muscle pump” by which lymph flows and by which venom reaches the circulation. Compression without immobilization is ineffective. By retarding the movement of venom from the bite site into the circulation, it “buys time” for the victim to reach medical care.
It is recommended for use in bites by all Australian venomous snakes and other purely neurotoxic elapids such as kraits, mambas, and coral snakes. While clinical trials are lacking, animal studies and human case reports suggest that pressure immobilization is safe and probably effective in delaying the movement of venom into the circulation (7). Its general use has been endorsed by the International Liaison Committee on Resuscitation (8). If applied correctly, pressure-immobilization first aid may be safely left in situ for several hours, unlike arterial tourniquets, which may cause ischemic or nerve damage. Additional studies support the efficacy of this technique to retard the movement of eastern diamond-back rattlesnake (9) and Indian cobra venom (10) but use in these circumstances is controversial. An elasticized bandage is preferred because it retains pressure. A variant of the technique featuring a “pressure pad” applied to Russell’s viper bite sites has been trailed with modest success, in Burma (11).
The timing of removal of a pressure-immobilization bandage (PIB) is important. Once an asymptomatic patient has reached a hospital stocked with appropriate antivenom, first-aid measures may be removed. Bandages and splints should not be left in place for prolonged periods. If, on removal of first-aid measures, the patient’s condition deteriorates, the bandages can be reapplied while antivenom is administered. If a patient arrives at the hospital with obvious envenomation but without pressure immobilization, it should be applied. Pressure bandages may be cut away from a bite site to allow swabs to be taken for venom detection and new bandages quickly applied.
 FIGURE 37.2. Pressure-immobilization first aid. A-C: Commencing distal to bite, apply bandage as tightly as binding a sprained ankle, enveloping the bite site and extending above major joint. D and E: Apply splint to prevent use of limb thereby preventing muscle use and lymph flow. |
Resistance to a universal recommendation for use of pressure immobilization for snakebite has centered on concerns about potentiating local tissue damage by trapping venom locally. The rationale for this concern appears sound when the significant local toxicity of species such as North American crotalids (rattlesnakes) and Asian pit vipers is compared with the limited local effects of most Australian elapids. Therefore, immobilization without pressure remains a routine first-aid recommendation for crotalid and viper bites (12).
Medical Treatment of Envenomation
The management principles are resuscitation, antivenom administration, and treatment of specific effects of venom. A careful history and examination should be undertaken with reference to the features of envenomation described above, as well as to any previous envenomations and allergies to antivenom, to horse serum, or to other venoms, and with reference to allergic illnesses and asthma. Samples for venom detection and for investigations should be obtained, and an attempt made, if possible, to identify the genus of snake (see below). The key question is whether or not to give antivenom, an issue that should be regularly reassessed as envenomation is a highly dynamic situation reflecting ongoing absorption of venom.
If the patient has not developed any symptoms or signs of envenomation, nor any indication of coagulopathy or myolysis within 4-6 hours after the removal of first aid (or after the bite if no first aid was used), significant envenomation has not occurred. However, the delayed onset of symptoms, particularly relating to neurotoxicity and rhabdomyolysis, for up to 24 hours after bites has been described. Particular care is required if a neurotoxic elapid bite is suspected, as few signs may be present apart from late-onset neurotoxicity. Overnight observation is highly desirable, especially if the victim is a young child or comes from a remote area. Ideally, envenomated patients should be admitted to hospital and observed for a period of at least 24 hours, depending on the clinical circumstances. Frequent neurological observations should be performed and pathology studies repeated regularly to monitor progression of the illness.
Local Effects. Vipers cause local effects such as skin blistering, limb swelling, and tissue necrosis. Although progressive limb swelling is an indication for antivenom use, its effectiveness at reducing local venom effects remains controversial. The role of fasciotomy in North American Crotaline (pit viper) envenomation causing limb swelling has been controversial but at present, fasciotomy is generally considered not useful when crotaline antivenom has been administered (13). As compartment syndrome is an infrequent complication of necrotizing snakebites, intracompartment pressures should be carefully monitored before surgical intervention (14). Local blistering may progress to full-thickness skin necrosis over 3-7 days—such sites are particularly prone to infection. Some such cases have been treated with the application of medical leeches in attempts to revitalize the affected tissue (15).
Coagulopathy. Procoagulants in Australian elapid venoms initiate the consumption of coagulation factors (16) with possible thrombotic sequelae, such as thrombotic microangiopathic renal failure. Platelets may be consumed and fibrinolysis may occur as a primary or secondary phenomenon resembling the findings in DIC caused by other conditions. After circulating venom has been neutralized, it may be 4-6 hours or longer before reconstitution of plasma clotting factors can normalize coagulation tests.
Whether to give or withhold coagulation factors, for example in the form of fresh frozen plasma (FFP), has always been a vexed question (17) in the treatment of Australian snake envenomation. While FFP would restore coagulation in the absence of free toxin, it may exacerbate the effects of coagulopathy in the presence of venom. A rational decision to give or withhold coagulation factor therapy is hampered by the lack of a rapid test for detection of exogenous enzymatically active prothrombin activator in blood. A lack of improvement in a victim’s clotting times on retesting may therefore represent either insufficient antivenom or insufficient time for hepatic regeneration of clotting factors, while improvement in coagulation may represent the efficacy of antivenom or natural hepatic regeneration of clotting factors. While it is reasonable to withhold FFP unless coagulation restores itself within 6 hours after antivenom therapy, active bleeding or such risk, despite adequate quantities of antivenom, is an indication for factor replacement after antivenom. Whole blood should only be reserved for significant anemia and volume loss. In North America, extrapolation from other hematologic conditions suggests that coagulopathy with parameters exceeding critical thresholds (INR > 3, aPTT > 50 seconds, platelets < 50,000/mm3, and fibrinogen < 75 mg/dL) is associated with a major bleeding risk of 1% over a few days and thus warrants coagulation factor replacement (18).
Neurotoxicity. Descending paralysis, starting with ptosis and external ophthalmoplegia and progressing to respiratory failure, is typical of bites by Elapidae (including sea snakes) and a few species of Viperidae (14). In severe envenomations, resulting in respiratory failure, supplemental oxygen and endotracheal intubation with mechanical ventilation are indicated. If antivenom is delayed or inadequate doses given, recovery may be prolonged (days-weeks). Additional possible neurotoxic complications of snakebite include dysgeusia and hypopituitarism (19).
Rhabdomyolysis and Renal Failure. Many factors may contribute to renal failure including shock, a direct toxic effect of venom, rhabdomyolysis, and DIC. Although various measures (such as alkalization of the urine with bicarbonate and mannitol to create a forced diuresis) have been advocated, these practices remain controversial with poor evidence of effectiveness (20). Hyperkalemia secondary to rhabdomyolysis may be treated with calcium, insulin and glucose, salbutamol, or sodium polystyrene sulfonate. Hemodialysis may occasionally be required, particularly in delayed antivenom treatment. Long-term renal morbidity may occur (21).
Shock and Cardiotoxicity. Central venous pressure monitoring may help titration of intravenous fluid in hypotensive patients not responding to volume replacement. The etiology of shock may vary with the snake species and includes fluid sequestration into necrotic tissue, altered vascular permeability, autopharmacological phenomena, acute reactions to venom or antivenom, and cardiotoxicity either direct or secondary to hypoxemia or hypotension. Shock occurs for example with Echis and Bitis species envenomation in which electrocardiographic abnormalities, such as septal T-wave inversion, sinus bradycardia, atrioventricular block, and other conduction defects are observed, but their clinical significance has not been well defined. Procoagulopathy may contribute to myocardial ischemia and pulmonary hypertension. Acute systemic hypotension after Australian brown snakebite may be lethal (22).
Other. Spitting cobras of Asia and Africa and the South African rinkhals spray venom from their fangs into a victim’s eyes, potentially causing blindness (venom ophthalmia) with painful chemical conjunctivitis, corneal ulceration, anterior uveitis, and possible secondary infection (23). The eyes should be irrigated immediately with generous volumes of water followed by other treatment such as cycloplegics, topical antibiotics, and analgesia.
All victims should receive appropriate tetanus prophylaxis but antibiotic prophylaxis is only routinely warranted if the bite wound is contaminated. Rarely, the snake’s fangs may break and become embedded in the wound, acting as a foreign body and a nidus for infection. Other treatments include analgesia (avoid sedating agents such as morphine if possible). Prolonged bed rest may cause contractures, which may be prevented by splinting. Rehabilitation physiotherapy should be started as early as possible (14).
Antivenom
Antivenom is the only specific treatment for bites by venomous snakes. The type of antivenom is determined by the genus or species of snake or by geographic factors if unknown.
Indications for Antivenom
Antivenom should be administered for systemic envenomation, progressive limb swelling, or limb necrosis. If pressure-immobilization first aid is in place, be aware that symptoms or signs of envenomation, including laboratory signs, may only become rapidly apparent when it is removed. Evidence of systemic envenomation includes physical symptoms or signs such as headache, nausea or vomiting, irritability, confusion, collapse, hypotension, neurologic impairment, abnormal bleeding, hematuria, or myoglobinuria. Laboratory investigations consistent with systemic envenomation include a disordered coagulation profile (or incoagulable blood in whole blood clotting test), low or undetectable levels of fibrinogen or raised levels of fibrin degradation products, elevated serum creatine kinase level, hemoglobinuria, or myoglobinuria. Puncture marks and lymphadenopathy are not indications, per se, for antivenom, as these can occur in bites from nonvenomous snakes, or in cases where little or no venom is injected. Similarly, a positive SVDK result (see below) at the bite site (or in urine or blood) is not in itself an indication for antivenom, as venom may be present on the skin or clothing, or in the circulation, but not in sufficient quantity to cause systemic envenomation.
Choice of Antivenom
The correct choice is crucial. Antivenoms only neutralize the venoms used in their production. Generally they provide little or no neutralization of other snake venoms, although some neutralization of other species, particularly within the same genus, may be expected. The correct antivenom may be selected on the basis of unequivocal morphological identification of the snake, use of a SVDK (only available in Australia and Papua New Guinea) or on geographical location, combined with a specific clinical syndrome.
Identification of the offending snake aids the choice of the appropriate antivenom and alerts clinicians to particular features characteristic of envenomation by that type of snake. In cases of snakebite involving zoo staff, herpetologists, or other experienced snake handlers, the snake’s identity may be known (although this should not be relied upon, particularly in the case of amateur collectors). Identification of snakes by the general public or by hospital staff, even when the offending snake accompanies the patient to hospital, is frequently unreliable. Formal identification by a highly experienced professional herpetologist is ideal. Sometimes, the snake is not seen, or is only glimpsed in retreat, rendering species identification impossible or unreliable. In addition, especially in the case of snakebite involving small children, a history may be vague or entirely lacking. In all these circumstances a contingency plan for choice of antivenom should be based on knowledge of local species. Bites by exotic snakes, i.e., snakes from other countries or regions kept in zoos or private collections, are very problematic. Local poison information centers may be able to source appropriate antivenom. The US Antivenom Handbook is now available online for selected user groups (http://www.aza.org/antivenom-index), while the many other antivenom stockholders, stocking lists, and antivenom recommendations are available as open-access resources (http://www.who.int/bloodproducts/snake_antivenoms/en).
Australia and Papua New Guinea are the only countries that have a commercially available SVDK. This test is a rapid two-step enzyme immunoassay, which uses antibodies to the venoms of major Australian snake genera. Venom from a bite site swab and blood or urine sample reacts with specific antibodies in different reaction wells, resulting in a rapid color change indicating the snake group involved and thus helping to select the type of snake antivenom that may be required.
Bite site swabs are the most reliable sample for use in an SVDK, provided the bite site has not been washed. Blood and urine samples (or other biological sample) may also be used but are less reliable. Urine in particular may be useful when presentation is delayed, or if the bite site cannot be identified. The kit has “built-in” positive and negative controls that need to be checked to validate the test results. The test is regarded as highly reliable but, like all tests, it must have an (unknown) rate of false negatives and false positives. Initial studies suggest that the latter is likely to be very low (24).
Although a positive SVDK test of blood or urine confirms that envenomation has occurred, it is not per se an indication to give antivenom. Conversely, a negative SVDK result does not mean that envenomation has not occurred since venom may be present in concentration below the detection limit or may not yet have reached the blood or have been excreted in urine. In addition, not all snake venom is detected by the kit (25). The information should be used in conjunction with other information (such as clinical presentation, knowledge of snakes in the geographic area, identification of snakes brought to hospital with the patient) to determine which antivenom to use if the patient is significantly envenomated.
If a reliable identification of the snake cannot be made, then polyvalent antivenom or a selection of monovalent antivenoms, which covers likely species, should be used. For example, in Australia, a combination of brown and tiger snake antivenoms is satisfactory for all snake envenomation (by indigenous species) in the state of Victoria and tiger snake antivenom alone is satisfactory for the state of Tasmania but elsewhere polyvalent antivenom containing tiger, brown, black, death adder, and taipan antivenoms is required.
Administration of Antivenom
Snake antivenoms are given intravenously. Skin testing for allergy to antivenom is not recommended, as it is unreliable and may delay urgent therapy. Antivenoms should be diluted in at least 100 mL of normal saline, 5% dextrose, Ringer’s lactated solution, or Hartmann’s solution immediately prior to administration. Note that some antivenoms are lyophilized for storage and must be solubilized before administration. Initial administration should be slow while the patient is observed for signs of allergic reaction. If no reaction is observed, the infusion may be run over 15-30 minutes. If the patient reacts to the antivenom, the rate may be slowed or the infusion ceased temporarily. If the reaction is severe, treatment with epinephrine, antihistamines, corticosteroids, and plasma volume expanders should be undertaken as required. The decision to recommence antivenom should be based on the clinical state of the patient. In the case of the patient with a known allergy to antivenom or to horse serum, the decision to withhold antivenom should be based on the severity of envenomation and availability of resuscitation facilities and skills. Note that prior allergy to antivenom is not an absolute contraindication to subsequent administration.
The neutralization doses of antivenoms are variable. The initial doses recommended for particular envenomations are provided by product information and are based on the average venom yields from the snake concerned and the severity of the presenting signs and symptoms. The amount of venom injected is quite variable. For example, 1 vial of bioCSL Ltd antivenom (10-40 mL of 17% equine Fab2 IgG) (AAT) is comparable to 10 vials of US CroFab (26). Few rigorous clinical trials have been undertaken on the efficacy of antivenoms internationally. Further, antivenoms are often used for their “para-specific” efficacy, most notably the bioCSL Ltd sea snake antivenom (27) in that the identity of the snake is unknown and that venom from only a few, or single, species are used to manufacture polyvalent antivenoms. In Australia, there is evidence, however, that manufacturer-recommended doses may be insufficient to reverse coagulopathy associated with the bites of several Australian venomous snakes, notably the brown snake (28,29). However, some authors have also argued a contrary case (30). Larger initial doses should also be considered if there is evidence of severe envenomation (multiple bites, rapidly progressive symptoms, large snakes). The dose of antivenom for children should not be reduced according to their weight, since the amount of venom injected by the snake is independent of the victim’s size.
Thus, the dose of antivenom cannot be initially specified with absolute reliability. Antivenom requirements of individual patients will vary considerably. Some patients with minimal envenomation may not require antivenom, whereas severely envenomated patients may require multiple doses. Recurrence of coagulopathy may occur, particularly with the use of newer Fab-type antivenoms, leading to the need for further doses of antivenom (18). Advice may be available from local Poisons Information (Control) Centers.
Adverse Reactions to Antivenom
As snake antivenoms are biological products manufactured by a variety of techniques from animal sources, the rate of
adverse reaction varies considerably in frequency and severity. Overall, adverse reactions are common and may be divided into early hypersensitivity reactions (true anaphylactic reactions are probably less common compared with anaphylactoid reactions), pyrogenic reactions, and late allergic reactions (serum sickness). Limited data are available to estimate the incidence of each type of reaction. In general, the highest rates of acute reaction, up to 70%-80%, occur in unfractionated equine antivenoms, whereas the incidence of immediate hypersensitivity and serum sickness after ovine North American Crotaline polyvalent immune Fab antivenom is 8% and 13%, respectively (31).
adverse reaction varies considerably in frequency and severity. Overall, adverse reactions are common and may be divided into early hypersensitivity reactions (true anaphylactic reactions are probably less common compared with anaphylactoid reactions), pyrogenic reactions, and late allergic reactions (serum sickness). Limited data are available to estimate the incidence of each type of reaction. In general, the highest rates of acute reaction, up to 70%-80%, occur in unfractionated equine antivenoms, whereas the incidence of immediate hypersensitivity and serum sickness after ovine North American Crotaline polyvalent immune Fab antivenom is 8% and 13%, respectively (31).
Facilities and skills should be immediately at hand for dealing with complications, such as anaphylaxis, before continuing the administration of antivenoms. In particular, prior to the administration of antivenom, epinephrine (10 µg/kg) should be prepared for use in the event of hypotension or bronchospasm. Epinephrine is the treatment of choice in conjunction with bronchodilators, H1 receptor blockers, fluid replacement, and corticosteroids.
Premedication for Antivenom
Premedication to reduce adverse antivenom reactions had been controversial but now endorsed by a systematic review and meta-analysis of studies (32). The best study is a randomized, double-blind, placebo-controlled trial of the efficacy of low-dose subcutaneous epinephrine to prevent acute adverse reactions to snake antivenom in Sri Lanka, which demonstrated a fourfold reduction in such reactions (33). In addition, no adverse reactions (such as intracranial hemorrhages) were observed in the premedicated patients, supporting the safety of this recommendation. Although this study has been criticized for lacking statistical power and its relevance to antivenoms with much lower reaction rates (20), premedication with subcutaneous epinephrine is particularly recommended for polyvalent antivenom in a low-resource setting and for higher-risk patients, such as those with equine allergy and asthma. Adults should receive 0.25 mg of epinephrine by the subcutaneous route (0.005 mg/kg for a child). Epinephrine as a premedicant should not be given intravenously because it might result in hypertension in a coagulopathic patient with the potential for bleeding. Similarly, epinephrine should not be administered intramuscularly, as this may also lead to hypertension, as well as to hematoma formation in the presence of coagulopathy. Although traditionally used, antihistamines are not recommended on the basis of ineffectiveness in a randomized, placebo-controlled trial in Brazil (34) and because they may confound the effects of venom through their sedative and hypotensive actions.
Serum Sickness
Serum sickness, due to the deposition of immune complexes, is a recognized complication of the administration of foreign protein solutions such as antivenoms. Symptoms include fever, rash, arthralgia, lymphadenopathy, and a flu-like illness. It usually occurs 7-10 days after antivenom administration. The possibility of serum sickness, and the usual symptoms and signs, should be discussed with a patient prior to discharge, so that it may be recognized and treated early. Corticosteroids should be considered if a large volume of antivenom, such as polyvalent antivenom or multiple ampules of monovalent antivenom, has been administered, or if the patient has a past history of exposure to equine protein. Both the incidence and severity of delayed serum sickness may be reduced by the administration of prednisolone, 1-2 mg/kg daily for 5 days after the administration of antivenom.
Anticholinesterase Treatment
Anticholinesterase inhibitors such as neostigmine may assist in the emergency management of predominantly postjunctional neurotoxic envenomations, such as by the Philippine cobra (35) and Papuan death adder (20), due to the curare-like actions of their neurotoxins but it is not helpful for Indian common krait (Bungarus caerulus) envenomation (36). It may also assist in the diagnosis of ophthalmoplegia post-snakebite (37).
SPIDERBITE
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