David A. Warrell*
* Adapted from The Oxford Textbook of Medicine, edited by DJ Weatherall, JGG Ledingham and DA Warrell (2nd edition, 1987), pp. 6.66-6.77. By permission of Oxford University Press.
A proportion of patients bitten by venomous snakes (60%), depending on the species, will develop minimal or no signs of toxic symptoms (envenoming) despite having puncture marks which indicate that the snake’s fangs have penetrated the skin.
Fear and effects of treatment, as well as the snake’s venom, contribute to the symptoms and signs. Even patients who are not envenomed may feel flushed, dizzy and breathless, with constriction of the chest, palpitations, sweating and acroparaesthesiae. Tight tourniquets may produce congested and ischaemic limbs; local incisions at the site of the bite may cause bleeding and sensory loss; and herbal medicines often induce vomiting.
The earliest symptoms directly attributable to the bite are local pain and bleeding from the fang punctures, followed by pain, tenderness, swelling and bruising extending up the limb, lymphangitis and tender enlargement of regional lymph nodes. Early syncope, vomiting, colic, diarrhoea, angio-oedema and wheezing may occur in patients bitten by European Vipera, Daboia russelii, Bothrops sp, Australian Elapids and Atractaspis engaddensis. Nausea and vomiting are common symptoms of severe envenoming.
Types of bites
Colubridae (back-fanged snakes such as Dispholidus typus, Thelotornis sp, Rhabdophis sp, Philodryas sp)
There is local swelling, bleeding from the fang marks and sometimes (Rhabophis tigrinus) fainting. Later vomiting, colicky abdominal pain and headache, and widespread systemic bleeding with extensive ecchymoses (bruising), incoagulable blood, intravascular haemolysis and kidney failure may develop. Envenoming may develop slowly over several days.
Atractaspididae (burrowing asps, Natal black snake)
Local effects include pain, swelling, blistering, necrosis and tender enlargement of local lymph nodes. Violent gastro-intestinal symptoms (nausea, vomiting and diarrhoea), anaphylaxis (dyspnoea, respiratory failure, shock) and ECG changes (a-v block, ST, T-wave changes) have been described in patients envenomed by A. engaddensis.
Elapidae (cobras, kraits, mambas, coral snakesand Australian venomous snakes)
Bites by kraits, mambas, coral snakes and some cobras (e.g., Naja haje and N. nivea) produce minimal local effects, whereas bites by African spitting cobras (N. nigricollis, N. mossambica, etc.) and Asian cobras (N. naja, N. kaouthia, N. sumatrana, etc.) cause tender local swelling which may be extensive, blistering and superficial necrosis.
Early symptoms of neurotoxicity before there are objective neurological signs include vomiting, “heaviness” of the eyelids, blurred vision, fasciculations, paraesthesiae around the mouth, hyperacusis, headache, dizziness, vertigo, hypersalivation, congested conjunctivae and “gooseflesh”. Paralysis starts as ptosis and external ophthalmoplegia appearing as early as 15 minutes after the bite, but sometimes delayed for ten hours or more. Later the face, palate, jaws, tongue, vocal cords, neck muscles and muscles of deglutition become progressively paralysed. Respiratory failure may be precipitated by upper airway obstruction at this stage, or later after paralysis of intercostal muscles, diaphragm and accessory muscles of respiration. Neurotoxic effects are completely reversible, either acutely in response to antivenom or anticholinesterases (e.g., following bites by Asian cobras, some Latin American coral snakes—Micrurus, and Australian death adders—Acanthophis) or they may wear off spontaneously in one to seven days.
Envenoming by Australian snakes causes early vomiting, headache and syncopal attacks, neurotoxicity, haemostatic disturbances and, with some species, ECG changes, generalized rhabdomyolysis and kidney failure. Painful enlargement of regional lymph nodes suggests impending systemic envenoming, but local signs are usually absent or mild except after bites by Pseudechis sp.
Venom ophthalmia caused by “spitting” elapids
Patients “spat” at by spitting elapids experience intense pain in the eye, conjunctivitis, blepharospasm, palpebral oedema and leucorrhoea. Corneal erosions are detectable in more than half the patients spat at by N. nigricollis. Rarely, venom is absorbed into the anterior chamber, causing hypopyon and anterior uveitis. Secondary infection of corneal abrasions may lead to permanent blinding opacities or panophthalmitis.
Viperidae (vipers, adders, rattlesnakes, lance-headed vipers, moccasins and pit vipers)
Local envenoming is relatively severe. Swelling may become detectable within 15 minutes but is sometimes delayed for several hours. It spreads rapidly and may involve the whole limb and adjacent trunk. There is associated pain and tenderness in regional lymph nodes. Bruising, blistering and necrosis may appear during the next few days. Necrosis is particularly frequent and severe following bites by some rattlesnakes, lance-headed vipers (genus Bothrops), Asian pit vipers and African vipers (genera Echis and Bitis). When the envenomed tissue is contained in a tight fascial compartment such as the pulp space of the fingers or toes or the anterior tibial compartment, ischaemia may result. If there is no swelling two hours after a viper bite it is usually safe to assume that there has been no envenoming. However, fatal envenoming by a few species can occur in the absence of local signs (e.g., Crotalus durissus terrificus, C. scutulatus and Burmese Russell’s viper).
Blood pressure abnormalities are a consistent feature of envenoming by Viperidae. Persistent bleeding from fang puncture wounds, venepuncture or injection sites, other new and partially healed wounds and post partum, suggests that the blood is incoagulable. Spontaneous systemic haemorrhage is most often detected in the gums, but may also be seen as epistaxis, haematemesis, cutaneous ecchymoses, haemoptysis, subconjunctival, retroperitoneal and intracranial haemorrhages. Patients envenomed by the Burmese Russell’s viper may bleed into the anterior pituitary gland (Sheehan’s syndrome).
Hypotension and shock are common in patients bitten by some of the North American rattlesnakes (e.g., C. adamanteus, C. atrox and C. scutulatus), Bothrops, Daboia and Vipera species (e.g., V. palaestinae and V. berus). The central venous pressure is usually low and the pulse rate rapid, suggesting hypovolaemia, for which the usual cause is extravasation of fluid into the bitten limb. Patients envenomed by Burmese Russell’s vipers show evidence of generally increased vascular permeability. Direct involvement of the heart muscle is suggested by an abnormal ECG or cardiac arrhythmia. Patients envenomed by some species of the genera Vipera and Bothrops may experience transient recurrent fainting attacks associated with features of an autopharmacological or anaphylactic reaction such as vomiting, sweating, colic, diarrhoea, shock and angio-oedema, appearing as early as five minutes or as late as many hours after the bite.
Renal (kidney) failure is the major cause of death in patients envenomed by Russell’s vipers who may become oliguric within a few hours of the bite and have loin pain suggesting renal ischaemia. Renal failure is also a feature of envenoming by Bothrops species and C. d. terrificus.
Neurotoxicity, resembling that seen in patients bitten by Elapidae, is seen after bites by C. d. terrificus, Gloydius blomhoffii, Bitis atropos and Sri Lankan D. russelii pulchella. There may be evidence of generalized rhabdomyolysis. Progression to respiratory or generalized paralysis is unusual.
The peripheral neutrophil count is raised to 20,000 cells per microlitre or more in severely envenomed patients. Initial haemo-concentration, resulting from extravasation of plasma (Crotalus species and Burmese D. russelii), is followed by anaemia caused by bleeding or, more rarely, haemolysis. Thrombocytopenia is common following bites by pit vipers (e.g., C. rhodostoma, Crotalus viridis helleri) and some Viperidae (e.g., Bitis arietans and D. russelii), but is unusual after bites by Echis species. A useful test for venom-induced defibrin(ogen)ation is the simple whole blood clotting test. A few millilitres of venous blood is placed in a new, clean, dry, glass test tube, left undisturbed for 20 minutes at ambient temperature, and then tipped to see if it has clotted or not. Incoagulable blood indicates systemic envenoming and may be diagnostic of a particular species (for example Echis species in Africa). Patients with generalized rhabdomyolysis show a steep rise in serum creatine kinase, myoglobin and potassium. Black or brown urine suggests generalized rhabdomyolysis or intravascular haemolysis. Concentrations of serum enzymes such as creatine phosphokinase and aspartate aminotransferase are moderately raised in patients with severe local envenoming, probably because of local muscle damage at the site of the bite. Urine should be examined for blood/haemoglobin, myoglobin and protein and for microscopic haematuria and red cell casts.
Patients should be moved to the nearest medical facility as quickly and comfortably as possible, avoiding movement of the bitten limb, which should be immobilized with a splint or sling.
Most traditional first-aid methods are potentially harmful and should not be used. Local incisions and suction may introduce infection, damage tissues and cause persistent bleeding, and are unlikely to remove much venom from the wound. The vacuum extractor method is of unproven benefit in human patients and could damage soft tissues. Potassium permanganate and cryotherapy potentiate local necrosis. Electric shock is potentially dangerous and has not proved beneficial. Tourniquets and compression bands can cause gangrene, fibrinolysis, peripheral nerve palsies and increased local envenoming in the occluded limb.
The pressure immobilization method involves firm but not tight bandaging of the entire bitten limb with a crepe bandage 4-5 m long by 10 cm wide starting over the site of the bite and incorporating a splint. In animals, this method was effective in preventing systemic uptake of Australian elapid and other venoms, but in humans it has not been subjected to clinical trials. Pressure immobilization is recommended for bites by snakes with neurotoxic venoms (e.g., Elapidae, Hydrophiidae) but not when local swelling and necrosis may be a problem (e.g., Viperidae).
Pursuing, capturing or killing the snake should not be encouraged, but if the snake has been killed already it should be taken with the patient to hospital. It must not be touched with bare hands, as reflex bites may occur even after the snake is apparently dead.
Patients being transported to hospital should be laid on their side to prevent aspiration of vomit. Persistent vomiting is treated with chlorpromazine by intravenous injection (25 to 50 mg for adults, 1 mg/kg body weight for children). Syncope, shock, angio-oedema and other anaphylactic (autopharmacological) symptoms are treated with 0.1% adrenaline by subcutaneous injection (0.5 ml for adults, 0.01 ml/kg body weight for children), and an antihistamine such as chlorpheniramine maleate is given by slow intravenous injection (10 mg for adults, 0.2 mg/kg body weight for children). Patients with incoagulable blood develop large haematomas after intramuscular and subcutaneous injections; the intravenous route should be used whenever possible. Respiratory distress and cyanosis are treated by establishing an airway, giving oxygen and, if necessary, assisted ventilation. If the patient is unconscious and no femoral or carotid pulses can be detected, cardiopulmonary resuscitation (CPR) should be started immediately.
In most cases of snakebite there are uncertainties about the species responsible and the quantity and composition of venom injected. Ideally, therefore, patients should be admitted to hospital for at least 24 hours of observation. Local swelling is usually detectable within 15 minutes of significant pit viper envenoming and within two hours of envenoming by most other snakes. Bites by kraits (Bungarus), coral snakes (Micrurus, Micruroides), some other elapids and sea snakes may cause no local envenoming. Fang marks are sometimes invisible. Pain and tender enlargement of lymph nodes draining the bitten area is an early sign of envenoming by Viperidae, some Elapidae and Australasian elapids. All the patient’s tooth sockets should be examined meticulously, as this is usually the first site at which spontaneous bleeding can be detected clinically; other common sites are nose, eyes (conjunctivae), skin and gastro-intestinal tract. Bleeding from venipuncture sites and other wounds implies incoagulable blood. Hypotension and shock are important signs of hypovolaemia or cardiotoxicity, seen particularly in patients bitten by North American rattlesnakes and some Viperinae (e.g., V berus, D russelii, V palaestinae). Ptosis (e.g., drooping of the eyelid) is the earliest sign of neurotoxic envenoming. Respiratory muscle power should be assessed objectively—for example, by measuring vital capacity. Trismus, generalized muscle tenderness and brownish-black urine suggests rhabdomyolysis (Hydrophiidae). If a procoagulant venom is suspected, coagulability of whole blood should be checked at the bedside using the 20-minute whole blood clotting test.
Blood pressure, pulse rate, respiratory rate, level of consciousness, presence/absence of ptosis, extent of local swelling and any new symptoms must be recorded at frequent intervals.
The most important decision is whether or not to give antivenom, as this is the only specific antidote. There is now convincing evidence that in patients with severe envenoming, the benefits of this treatment far outweigh the risk of antivenom reactions (see below).
General indications for antivenom
Antivenom is indicated if there are signs of systemic envenoming such as:
- haemostatic abnormalities such as spontaneous systemic bleeding, incoagulable blood or profound thrombocytopenia (50/l x 10-9)
- hypotension and shock, abnormal ECG or other evidence of cardiovascular dysfunction
- impaired consciousness of any cause
- generalized rhabdomyolysis.
Supporting evidence of severe envenoming is a neutrophil leucocytosis, elevated serum enzymes such as creatine kinase and aminotransferases, haemoconcentration, severe anaemia, myoglobinuria, haemoglobinuria, methaemoglobinuria, hypoxaemia or acidosis.
In the absence of systemic envenoming, local swelling involving more than half the bitten limb, extensive blistering or bruising, bites on digits and rapid progression of swelling are indications for antivenom, especially in patients bitten by species whose venoms are known to cause local necrosis (e.g., Viperidae, Asian cobras and African spitting cobras).
Special indications for antivenom
Some developed countries have the financial and technical resources for a wider range of indications:
United States and Canada: After bites by the most dangerous rattlesnakes (C. atrox, C. adamanteus, C. viridis, C. horridus and C. scutulatus) early antivenom therapy is recommended before systemic envenoming is evident. Rapid spread of local swelling is considered to be an indication for antivenom, as is immediate pain or any other symptom or sign of envenoming after bites by coral snakes (Micruroides euryxanthus and Micrurus fulvius).
Australia: Antivenom is recommended for patients with proved or suspected snakebite if there are tender regional lymph nodes or other evidence of systemic spread of venom, and in anyone effectively bitten by an identified highly venomous species.
Europe: (Adder: Vipera berus and other European Vipera): Antivenom is indicated to prevent morbidity and reduce the length of convalescence in patients with moderately severe envenoming as well as to save the lives of severely envenomed patients. Indications are:
- fall in blood pressure (systolic to less than 80 mmHg, or by more than 50 mmHg from the normal or admission value) with or without signs of shock
- other signs of systemic envenoming (see above), including spontaneous bleeding, coagulopathy, pulmonary oedema or haemorrhage (shown by chest radiograph), ECG abnormalities and a definite peripheral leucocytosis (more than 15,000/ μl) and elevated serum creatine kinase
- severe local envenoming—swelling of more than half the bitten limb developing within 48 hours of the bite—even in the absence of systemic envenoming
- in adults, swelling extending beyond the wrist after bites on the hand or beyond the ankle after bites on the foot within four hours of the bite.
Patients bitten by European Vipera who show any evidence of envenoming should be admitted to hospital for observation for at least 24 hours. Antivenom should be given whenever there is evidence of systemic envenoming—(1) or (2) above—even if its appearance is delayed for several days after the bite.
Prediction of antivenom reactions
It is important to realize that most antivenom reactions are not caused by acquired Type I, IgE-mediated hypersensitivity but by complement activation by IgG aggregates or Fc fragments. Skin and conjunctival tests do not predict early (anaphylactic) or late (serum sickness type) antivenom reactions but delay treatment and may sensitize the patient. They should not be used.
Contraindications to antivenom
Patients with a history of reactions to equine antiserum suffer an increased incidence and severity of reactions when given equine antivenom. Atopic subjects have no increased risk of reactions, but if they develop a reaction it is likely to be severe. In such cases, reactions may be prevented or ameliorated by pretreatment with subcutaneous adrenaline, antihistamine and hydrocortisone, or by continuous intravenous infusion of adrenaline during antivenom administration. Rapid desensitization is not recommended.
Selection and administration of antivenom
Antivenom should be given only if its stated range of specificity includes the species responsible for the bite. Opaque solutions should be discarded, as precipitation of protein indicates loss of activity and increased risk of reactions. Monospecific (monovalent) antivenom is ideal if the biting species is known. Polyspecific (polyvalent) antivenoms are used in many countries because it is difficult to identify the snake responsible. Polyspecific antivenoms may be just as effective as monospecific ones but contain less specific venom-neutralizing activity per unit weight of immunoglobulin. Apart from the venoms used for immunizing the animal in which the antivenom has been produced, other venoms may be covered by paraspecific neutralization (e.g., Hydrophiidae venoms by tiger snake—Notechis scutatus—antivenom).
Antivenom treatment is indicated as long as signs of systemic envenoming persist (i.e., for several days) but ideally it should be given as soon as these signs appear. The intravenous route is the most effective. Infusion of antivenom diluted in approximately 5 ml of isotonic fluid/kg body weight is easier to control than intravenous “push” injection of undiluted antivenom given at the rate of about 4 ml/min, but there is no difference in the incidence or severity of antivenom reactions in patients treated by these two methods.
Dose of antivenom
Manufacturers’ recommendations are based on mouse protection tests and may be misleading. Clinical trials are needed to establish appropriate starting doses of major antivenoms. In most countries the dose of antivenom is empirical. Children must be given the same dose as adults.
Response to antivenom
Marked symptomatic improvement may be seen soon after antivenom has been injected. In shocked patients, the blood pressure may rise and consciousness return (C. rhodostoma, V. berus, Bitis arietans). Neurotoxic signs may improve within 30 minutes (Acanthophis sp, N. kaouthia), but this usually takes several hours. Spontaneous systemic bleeding usually stops within 15 to 30 minutes, and blood coagulability is restored within six hours of antivenom, provided that a neutralizing dose has been given. More antivenom should be given if severe signs of envenoming persist after one to two hours or if blood coagulability is not restored within about six hours. Systemic envenoming may recur hours or days after an initially good response to antivenom. This is explained by continuing absorption of venom from the injection site and the clearance of antivenom from the bloodstream. The apparent serum half-lives of equine F(ab’)2 antivenoms in envenomed patients range from 26 to 95 hours. Envenomed patients should therefore be assessed daily for at least three or four days.
- Early (anaphylactic) reactions develop within 10 to 180 minutes of starting antivenom in 3 to 84% of patients. The incidence increases with dose and decreases when more highly refined antivenom is used and administration is by intramuscular rather than intravenous injection. The symptoms are itching, urticaria, cough, nausea, vomiting, other manifestations of autonomic nervous system stimulation, fever, tachycardia, bronchospasm and shock. Very few of these reactions can be attributed to acquired Type I IgE-mediated hypersensitivity.
- Pyrogenic reactions result from contamination of the antivenom with endotoxins. Fever, rigors, vasodilatation and a fall in blood pressure develop one to two hours after treatment. In children, febrile convulsions may be precipitated.
- Late reactions of serum sickness (immune complex) type may develop 5 to 24 (mean 7) days after antivenom. The incidence of those reactions and the speed of their development increases with the dose of antivenom. Clinical features include fever, itching, urticaria, arthralgia (including the temporomandibular joint), lymphadenopathy, periarticular swellings, mononeuritis multiplex, albuminuria and, rarely, encephalopathy.
Treatment of antivenom reactions
Adrenaline (epinephrine) is the effective treatment for early reactions; 0.5 to 1.0 ml of 0.1% (1 in 1000, 1 mg/ml) is given by subcutaneous injection to adults (children 0.01 ml/kg) at the first signs of a reaction. The dose may be repeated if the reaction is not controlled. An antihistamine H1 antagonist, such as chlorpheniramine maleate (10 mg for adults, 0.2 mg/kg for children) should be given by intravenous injection to combat the effects of histamine release during the reaction. Pyrogenic reactions are treated by cooling the patient and giving antipyretics (paracetamol). Late reactions respond to an oral antihistamine such as chlorpheniramine (2 mg every six hours for adults, 0.25 mg/kg/day in divided doses for children) or to oral prednisolone (5 mg every six hours for five to seven days for adults, 0.7 mg/kg/day in divided doses for children).
Bulbar and respiratory paralysis may lead to death from aspiration, airway obstruction or respiratory failure. A clear airway must be maintained and, if respiratory distress develops, a cuffed endotracheal tube should be inserted or tracheostomy performed. Anticholinesterases have a variable but potentially useful effect in patients with neurotoxic envenoming, especially when post-synaptic neurotoxins are involved. The “Tensilon test” should be done in all cases of severe neurotoxic envenoming as with suspected myasthenia gravis. Atropine sulphate (0.6 mg for adults, 50 μg/kg body weight for children) is given by intravenous injection (to block muscarinic effects of acetylcholine) followed by an intravenous injection of edrophonium chloride (10 mg for adults, 0.25 mg/kg for children). Patients who respond convincingly can be maintained on neostigmine methyl sulphate (50 to 100 μg/kg body weight) and atropine, every four hours or by continuous infusion.
Hypotension and shock
If the jugular or central venous pressure is low or there is other clinical evidence of hypovolaemia or exsanguination, a plasma expander, preferably fresh whole blood or fresh frozen plasma, should be infused. If there is persistent or profound hypotension or evidence of increased capillary permeability (e.g., facial and conjunctival oedema, serous effusions, haemoconcentration, hypoalbuminaemia) a selective vasoconstrictor such as dopamine (starting dose 2.5 to 5 μg/kg body weight/min by infusion into a central vein) should be used.
Oliguria and renal failure
Urine output, serum creatinine, urea and electrolytes should be measured each day in patients with severe envenoming and in those bitten by species known to cause renal failure (e.g., D. russelii, C. d. terrificus, Bothrops species, sea snakes). If urine output drops below 400 ml in 24 hours, urethral and central venous catheters should be inserted. If urine flow fails to increase after cautious rehydration and diuretics (e.g., frusemide up to 1000 mg by intravenous infusion), dopamine (2.5 μg/kg body weight/min by intravenous infusion) should be tried and the patient placed on strict fluid balance. If these measures are ineffective, peritoneal or haemodialysis or haemofiltration are usually required.
Local infection at the site of the bite
Bites by some species (e.g., Bothrops sp, C. rhodostoma) seem particularly likely to be complicated by local infections caused by bacteria in the snake’s venom or on its fangs. These should be prevented with penicillin, chloramphenicol or erythromycin and a booster dose of tetanus toxoid, especially if the wound has been incised or tampered with in any way. An aminoglycoside such as gentamicin and metronidazole should be added if there is evidence of local necrosis.
Management of local envenoming
Bullae can be drained with a fine needle. The bitten limb should be nursed in the most comfortable position. Once definite signs of necrosis have appeared (blackened anaesthetic area with putrid odour or signs of sloughing), surgical debridement, immediate split skin grafting and broad-spectrum antimicrobial cover are indicated. Increased pressure within tight fascial compartments such as the digital pulp spaces and anterior tibial compartment may cause ischaemic damage. This complication is most likely after bites by North American rattlesnakes such as C. adamanteus, Calloselasma rhodostoma, Trimeresurus flavoviridis, Bothrops sp and Bitis arietans. The signs are excessive pain, weakness of the compartmental muscles and pain when they are passively stretched, hypaesthesia of areas of skin supplied by nerves running through the compartment, and obvious tenseness of the compartment. Detection of arterial pulses (e.g., by Doppler ultrasound) does not exclude intracompartmental ischaemia. Intracompartmental pressures exceeding 45 mm Hg are associated with a high risk of ischaemic necrosis. In these circumstances, fasciotomy may be considered but must not be attempted until blood coagulability and a platelet count of more than 50,000/ μl have been restored. Early adequate antivenom treatment will prevent the development of intracompartmental syndromes in most cases.
Once specific antivenom has been given to neutralize venom procoagulants, restoration of coagulability and platelet function may be accelerated by giving fresh whole blood, fresh frozen plasma, cryoprecipitates (containing fibrinogen, factor VIII, fibronectin and some factors V and XIII) or platelet concentrates. Heparin must not be used. Corticosterioids have no place in the treatment of envenoming.
Treatment of snake venom ophthalmia
When cobra venom is “spat” into the eyes, first aid consists of irrigation with generous volumes of water or any other bland liquid which is available. Adrenaline drops (0.1 per cent) may relieve the pain. Unless a corneal abrasion can be excluded by fluorescein staining or slit lamp examination, treatment should be the same as for any corneal injury: a topical antimicrobial such as tetracycline or chloramphenicol should be applied. Instillation of diluted antivenom is not currently recommended.