Snakebites worldwide: Clinical manifestations and diagnosis

INTRODUCTION — Snakebites account for significant morbidity and mortality worldwide, especially in South and Southeast Asia, sub-Saharan Africa, and Latin America [1]. Venomous snakes are widely distributed around the world and clinical effects from envenomation can overlap to a great degree even among different classes of snakes. This topic will discuss the clinical manifestations and diagnosis of snakebite worldwide.

The principles of management of snakebites and clinical manifestations of venomous snakebite in the United States are discussed separately:

●(See "Snakebites worldwide: Management".)

●(See "Bites by Crotalinae snakes (rattlesnakes, water moccasins [cottonmouths], or copperheads) in the United States: Management".)

●(See "Evaluation and management of coral snakebites".)

●(See "Bites by Crotalinae snakes (rattlesnakes, water moccasins [cottonmouths], or copperheads) in the United States: Clinical manifestations, evaluation, and diagnosis".)

TERMINOLOGY — Although common names are used to describe snakes throughout this topic, the genus and species that correlate with the common names can be found in the following tables for Africa (table 1), Asia (table 2), Central and South America (table 3), Australia and the Pacific Islands (table 4), Europe (table 5), and the Middle East (table 6). Note that due to ongoing taxonomic research, scientific names may change over time and changes may be taxonomically controversial, resulting in multiple scientific names being applied to a given species.

EPIDEMIOLOGY — According to the World Health Organization, more than 5 million snakebites occur worldwide each year, resulting in approximately 2.5 million envenomations and 81,000 to 138,000 deaths [2]. Because most venomous snakebites occur in developing countries with poorly developed health reporting systems and because many deaths occur before medical care can be provided, these numbers are likely underestimates [3].

Regions with the highest incidence of venomous snakebites and snakebite deaths include Southeast and South Asia (eg, India, Pakistan, Sri Lanka, and Bangladesh), sub-Saharan Africa, and Latin America (figure 1) [1,2,4-9]. In many of these regions, access to health care and timely administration of antivenom is limited. In an observational study that mapped dangerous venomous snakes against human populations, access to health care for those populations, and availability of appropriate antivenoms, large parts of sub-Saharan Africa and Southeast Asia are particularly vulnerable [10]. There are 93 million people in the highest risk areas, but many more at risk overall (eg, the population of India exceeds 1.3 billion with an estimated annual mortality from snakebites exceeding 45,000) [2].

In an effort to draw attention to the problem of venomous snakebites worldwide and to spur strategies that improve outcomes, the World Health Organization has designated snakebite envenomation as a neglected tropical disease [11]. The goal of the WHO designation is to raise awareness aiming to increase the availability of safe, universally available antivenoms for populations that are most affected worldwide although antivenom is only one component of snakebite treatment [12,13].

Snakebites disproportionately affect poorer populations in rural areas [9,14]. Two common patterns are described [1,6,15]:

●Bites to the arm, foot, ankle, or lower leg occur in farmers who unintentionally step on or otherwise disturb a snake while working in their fields or rice paddies.

●Bites by nocturnal species (eg, kraits) happen to people sleeping on the ground. These bites are frequently located on the head or trunk.

The risk of snakebite also increases during the rainy season and after floods due to displacement of snakes from their burrows [1,6,15,16].

GEOGRAPHIC DISTRIBUTION AND CHARACTERISTICS — Approximately 600 distinct species of venomous snakes have been described [3,17]. Venomous snakes are widely distributed on every continent except Antarctica from latitudes of 50°N to 50°S. in the western hemisphere and 65°N to 50°S in the eastern hemisphere. Increased numbers of species are located in warm, tropical regions.

A comprehensive listing of venomous snakes by geographical regions and estimated geographical distribution for individual species may be obtained by searching the following database:

●Clinical toxinology resources, The University of Adelaide, Australia: Toxinology snakes search

●World Health Organization website, section on snakebites

The geographic distribution of venomous snakes found in the United States is discussed separately. (See "Evaluation and management of coral snakebites", section on 'Epidemiology' and "Bites by Crotalinae snakes (rattlesnakes, water moccasins [cottonmouths], or copperheads) in the United States: Clinical manifestations, evaluation, and diagnosis", section on 'Appearance and geographical distribution'.)

Most venomous snakes routinely dangerous for humans belong to one of two families, Elapidae and Viperidae [1,17]. However, the "classic" literature suggesting that elapids cause neurotoxic effects and vipers cause local and hemorrhagic effects is misleading and inaccurate. A number of Elapid snakes cause predominantly local effects, rather than systemic effects (typically the "spitting" cobras), while others cause predominantly coagulopathic rather than neurotoxic systemic effects (eg, Australian brown snakes). Similarly, some Viperid snakes cause minimal local effects and predominantly systemic effects, including paralysis, coagulopathy, and/or rhabdomyolysis (eg, South American rattlesnakes).

Geographical distribution, physical characteristics, and venom effects by family are as follows:

●Elapidae – Elapid snakes are found widely throughout tropical and subtropical regions of Asia (table 2), Africa (table 1), Central and South America (table 3), the Middle East (table 6), and Australia (table 4). Common names include cobras (picture 1), kraits (picture 2), mambas (picture 3), coral snakes, Taipans, tiger snakes, copperheads (Australian), death adders (picture 4) (Australia and New Guinea), black snakes (Australia), and brown snakes (Australia). Sea snakes are also Elapid snakes.

Physical characteristics that, with some exceptions, distinguish these snakes from members of the Viperidae family include shorter fangs (compared with body size), a less triangular head with a more subtle transition from head to body (but with exceptions, such as Australian death adders), and a larger scale pattern on the head. The way fangs attach to the bone is different in Elapid snakes, compared with Viperid snakes; specifically, the fangs have minimal or no capacity to rotate, unlike Viperid snakes, which can rotate the fang, folding it against the roof of the mouth, thus enabling development of significantly longer fangs, compared with body size, than found in Elapid snakes.

Envenomation from many but not all of these snakes can frequently cause flaccid paralysis. However, bites from individual species may also cause local tissue toxicity, tissue necrosis, coagulopathy, hemorrhage, rhabdomyolysis, hypotension, or acute kidney injury (AKI).

●Viperidae – Viperid snakes have a broad distribution that encompasses many regions that contain elapid snakes but also includes Europe and North America. These snakes are commonly referred to as follows:

•Vipers (subfamily Viperinae; eg, Russell's (picture 5), carpet, saw-scaled (picture 6), or Gaboon viper)

•Adders (eg, puff or night adder)

•Asps (picture 7)

•Pit vipers (subfamily Crotalinae; eg, bushmasters, rattlesnakes, lance-headed vipers, Central Asian green tree vipers (picture 8), habus or Malayan pit viper (picture 9)

The tables list many of the medically important Viperid snakes in Africa (table 1), Asia (table 2), Central and South America (table 3), Europe (table 5), and the Middle East (table 6). Viperid snakes are not native to Australia and the adjacent Pacific.

Snakes belonging to the Viperidae family typically have folding, long fangs, triangular heads with an abrupt transition to the body, and smaller numerous scales on the head. Pit vipers (Crotalinae) also have heat-sensing pits towards the front of the head (for infra-red "vision") and elliptical pupils (for nocturnal species).

Viperid envenomations are frequently associated with local reaction (eg, pain, blistering, bruising, and/or swelling), tissue necrosis, coagulopathy, hemorrhage, rhabdomyolysis, and/or AKI, although some Viperids cause minimal local reactions. Some viperid snakebites can also cause paralysis.

●Other snake families with dangerously venomous species (NFFC snakes) – There are a number of other snake families containing at least some venomous species, some of which are potentially dangerous for humans. These are generally grouped under the heading "non-front-fanged colubrid" (NFFC) snakes [18]. The fang position in these snakes is variable but generally classified as "rear fanged," a deceptive term as the fang position is usually not at the rear of the mouth, but partway back from the snout.

As an example, the side-fanged Atractaspid snakes (family Lamprophiidae, subfamily Atractaspinae) include a number of burrowing snakes with moderate to long fangs that can be protruded from the side of the mouth. Some species in genus Atractaspis are an important cause of snakebites in parts of Africa and the Middle East, causing significant local tissue injury and occasionally fatal systemic reactions:

•The boomslang (Dispholidus typus) and vine snakes (Thelatornis species) of sub-Saharan Africa (family Colubridae, subfamily Colubrinae) can cause severe coagulopathy, which can be fatal [19,20].

•The keelbacks (genus Rhabdophis, family Natricidae) of parts of Asia similarly can cause severe, potentially fatal coagulopathy [21].

There are many other NFFC snakes capable of causing at least local envenoming effects, with some causing systemic effects, occasionally reported as "lethal," although controversy surrounds many of these latter case reports.

VENOM PROPERTIES — Snake venoms have wide variations in composition, potency, and sites of action. A basic understanding of these characteristics helps guide appropriate evaluation and management of snake envenomation.

Composition and sites of action — Snake venom is a complex mixture of toxins used primarily to immobilize and sometimes initiate digestion of prey and secondarily to ward off predators [3,17,22]. Composition of venom varies greatly from one species to another. Within a species the composition can also differ, sometimes according to age of the snake or the geographic location [22]. This venom variability can be important in selecting an appropriate antivenom (eg, for Russell's vipers or saw-scaled vipers).

The identified components and physiologic sites of action for snake venom determine the spectrum of clinical features commonly seen after snakebite as follows (table 7) [3,17,22]:

●Locally acting toxins – These toxins predominantly consist of enzymes that cause tissue destruction through diverse mechanisms (eg, phospholipase A₂ [PLA₂], phosphodiesterases, hyaluronidases, peptidases, metalloproteinases).

Swelling, blistering, ecchymosis, tissue necrosis, and pain indicate the presence of these proteolytic enzymes in the venom and are commonly seen after snakebites by many, but not all Viperid snakes. Local effects are minimal or absent after bites of many elapid snakes (eg, kraits, some mambas, or death adder). However, other elapid snakes can cause serious tissue necrosis (eg, some African and Asian cobras).

●Systemically acting toxins – Systemic toxins may target a wide variety of tissues including [23]:

•Neurotoxins – Neurotoxins generally target the neuromuscular junction (NMJ) presynaptically, postsynaptically, or at both sites and affect skeletal muscle. The site of venom action has significant consequences for the ability to treat the resulting paralysis as follows [23]:

-Presynaptic – Presynaptic neurotoxins are generally based on PLA₂ and damage the terminal axon at the NMJ, through entry into the cell. This type of paralysis, once established, is not reversible with antivenom or anticholinesterase and may take days to weeks for recovery of function as the axon regenerates. Examples of snakes with venom active at the presynaptic NMJ include kraits and many Australian snakes.

-Postsynaptic – Postsynaptic neurotoxins are generally long or short chain peptides that target the acetylcholine receptor on the muscle endplate, blocking response to acetylcholine, external to the cell. This type of paralysis can sometimes be fully reversed with antivenom, or the neuromuscular block overcome with anticholinesterases (eg, neostigmine).

Other types of snake neurotoxins (eg, dendrotoxins and fasciculins in African mamba venoms) are less common or restricted to just a few species (eg, mambas).

•Myotoxins – Snake venom myotoxins may act either systemically or locally. Chemically, they are primarily based upon PLA₂ and generally target skeletal probably more than smooth muscle. Rhabdomyolysis may occur from enzymatic tissue damage adjacent to the bite wound and, or by actions of systemic venom myotoxins on skeletal muscle (notably some Australian snakes, sea snakes, some kraits, South American rattlesnakes, Sri Lankan Russell's viper). Secondary hyperkalemia and acute kidney injury (AKI) can occur if muscle damage is extensive and may lead to secondary cardiotoxicity.

•Systemic hemostasis toxins – These common snake venom toxins represent a vast array of molecular types, mechanisms and targets. The common theme is interference with blood clotting, usually by increasing bleeding tendency, with resulting consumptive coagulopathy and hemorrhage. The coagulopathy can usually be reversed by timely administration of antivenom, though there is often a delay in return to normal hemostasis while normal coagulation factors are replenished.

Less commonly, clotting and thrombosis may be promoted (eg, Martinique viper venom) and cause deep vein thrombosis, pulmonary emboli, and cerebral infarction.

There are also toxins within this broad group that damage blood vessels, often a synergistic action which, combined with other toxins reducing clotting function, can cause significant hemorrhagic disease. Toxins targeting the coagulation cascade include factor X, IX, and V activators; procoagulants that activate factor II (prothrombin); and direct and indirect fibrinogenolytics or fibrinogenases. There are also toxins causing direct inhibition of parts of the coagulation system (anticoagulants), and toxins either inhibiting or stimulating platelet activation directly or through action on elements, such as Von Willebrand factor. The hemorrhagins target blood vessel walls and are predominantly zinc metalloproteinases.

•Cardiotoxins – Most cardiotoxic effects of snake venoms are secondary to hemorrhage or hypovolemia. Less commonly, hypotension can arise from direct actions of venom components, such as angiotensin-converting enzyme inhibitors and natriuretic peptides.

•Kidney – AKI may occur from the direct action of some venoms (especially some populations of Russell's viper) and frequently accompanies hypotension, coagulopathy or rhabdomyolysis as a secondary effect of envenoming.

•Other toxins – Venoms also may contain a wide array of other, mostly minor toxins, such as histamine, serotonin, and L-amino oxidase.

Potency — A wide variety of methods to determine venom potency have been developed using in vivo and in vitro methods [24]. Median lethal dose in a live mouse (LD50) is a commonly used measure [17,22]. Based upon this approach, several types of elapid venoms appear to be most potent. However, the clinical severity of a bite depends upon several factors other than venom potency such as the amount of venom injected and the site of the bite (eg, extremity, trunk, or head).

In addition, many factors can influence LD50 measurements, including how the venom is collected, stored, reconstituted and injected. Thus, conflicting results appear in the literature, with major differences between research groups. Venom potency (LD50) should be placed in a "real-world" perspective [17,22]. As an example, the saw scaled viper (Echis species) has venom that ranks well down the list in potency. However, because of the coagulopathy that this venom creates in humans and poor access to quality health care that at-risk populations for this envenomation endure, more snakebite mortality and morbidity are anecdotally attributed to Echis species than any other group of snakes.

By contrast, the snake with arguably the most potent venom, the inland taipan (Oxyuranus microlepidotus), has not been recorded as causing any human fatalities, because it is rarely encountered and bites generally occur in keepers with ready access to high quality and effective care, including antivenom.

CLINICAL MANIFESTATIONS

History — When a snakebite is reported or suspected, key information to determine includes [3,17,22]:

●Where and when the bite occurred

●A description of the snake (photos may be useful; if the snake has been killed, the cadaver can confirm identity)

●How the bite occurred and whether there was more than one bite

●Any signs or symptoms and the timing of onset

●Initial treatment and first aid that was provided, including timing of first aid

●Any recent ethanol or recreational drug use that may modify the patient's presentation

●Pertinent past medical history, such as current medications (especially anticoagulants or beta blockers), any prior snakebites for which antivenom was given, or allergy to animals used in antivenom production (eg, horses, sheep, rabbits)

In many cases, the bite is immediately felt and the snake readily identified [17]. However, some snakes, especially elapids, cause limited to no local pain or tissue necrosis when injecting venom. Patients bitten in this way may present with paralysis and/or coagulopathy as the first sign of envenomation. This scenario is common for snakebites by nocturnal species (eg, kraits), which frequently happen to people sleeping on the ground in rural tropical areas. Subsequently, victims may develop progressive paralysis without any history of snake bite.

Similarly, victims of highly toxic snakes, especially children, may present with cardiovascular collapse or seizures without any reported snakebite.

Symptoms of snakebite can be nonspecific and frequently may be difficult to differentiate from manifestations of anxiety and emotional disturbance caused by the bite. However, findings such as nausea, vomiting, abdominal pain, and headache may be the first symptoms of systemic envenomation and warrant close assessment for the other clinical syndromes associated with snake envenomation (table 7) [17]. Syncope, diarrhea, and, especially in children, seizures may also occur, but less commonly.

Symptoms also vary according to the venom characteristics of the biting snake. For example, victims bitten by neurotoxic snakes may report weakness, paralysis, diplopia, or difficulty speaking or swallowing. Taste or smell may be impaired. In addition to local pain and swelling, patients with systemic envenomation by some viper species (eg, North American rattlesnake) may describe a metallic taste in their mouth. (See "Bites by Crotalinae snakes (rattlesnakes, water moccasins [cottonmouths], or copperheads) in the United States: Clinical manifestations, evaluation, and diagnosis", section on 'Clinical manifestations'.)

Physical examination — Physical findings of snakebite vary significantly by species and often evolve over time (table 7). Frequent, repeated examinations are important to ensure detection of all signs of snake envenomation and to identify serious local or systemic effects.

All patients with a potentially toxic snakebite warrant frequent measurement of vital signs and, if available, continuous cardio-respiratory and pulse oximetry monitoring. For many species additional monitoring should be performed based upon expected toxicity and may include checking for ptosis and partial ophthalmoplegia (neurotoxic snakes) or persistent oozing from any wounds or gums (venom-induced coagulopathy). For some snake species, primary or secondary acute kidney injury (AKI) is a significant risk; monitoring urine output and quality (eg, albuminuria as early evidence of developing AKI) may facilitate early detection of impending renal problems.

Wound site — The clinician should examine the bite site and surrounding region for the following [17]:

●Presence of fang marks (picture 10) (eg, single or multiple punctures, or scratches; note fang marks may be difficult to visualize in some species).

●Local evidence of envenomation including redness, swelling, blistering, ecchymosis, persistent blood ooze, or tissue necrosis (picture 11 and picture 12 and picture 13).

●Degree of swelling, including circumferential measurement at the point of greatest swelling and demarcation of the extent of swelling from the bite site for reference during repeated examinations.

●Swelling or tenderness of regional lymph nodes indicating venom spread.

There is considerable variation in the local effects of snake venom. With certain species, such as kraits, Asian coral snakes, South American rattlesnakes, some non-spitting cobras, death adders, mambas, taipans, tiger snakes, and brown snakes, little local necrosis or pain may occur. Thus, fang marks may easily be missed. In situations where the snakebite was not felt or observed, the diagnosis may be called into question until the wound is found or the systemic effects recognized as common to snake species in the region. For these snakes, it is possible for the patient to be unaware they have been bitten, so they may present with nonspecific symptoms such as nausea, vomiting, abdominal pain, or headache that may not give rise to snakebite as a possible diagnosis. Young children may present after playing unsupervised and have irritability, occasionally followed by collapse and/or convulsions.

By contrast, many cobras (notably spitting cobras) and vipers frequently cause an immediate onset of pain followed by extensive local tissue effects or destruction that makes recognition of the wound site straightforward.

Systemic findings — Systemic toxicity from snakebites falls into four major categories that may coexist. Findings of systemic toxicity include (table 7) [17]:

Cardiovascular — Tachycardia and findings of shock, including hypotension and/or poor tissue perfusion (eg, prolonged capillary refill time, altered mental status, and decreased urine output) frequently accompany snakebite, especially by species causing major local effects. Causes include venom-induced vasodilation, direct myocardial depression, and/or hypovolemia from bleeding or "third spacing" of fluids into the bitten limb. If available, central venous pressure monitoring may be warranted to guide management. (See "Snakebites worldwide: Management" and "Snakebites worldwide: Management", section on 'Shock'.)

Tissue and muscle toxicity — Muscle pain on palpation or with muscle use, muscle weakness, and dark urine may indicate the presence of rhabdomyolysis. Early findings of rhabdomyolysis may be subtle and frequently require measurement of serum creatine kinase and urine studies for confirmation. (See 'Ancillary studies' below.)

Although uncommon with snakebite, compartment syndrome may occur if marked extremity swelling or direct envenomation of a muscle compartment occurs. Findings of compartment syndrome can significantly overlap with local and systemic effects of snake venom. When suspected, direct compartment measurement should be performed to confirm dangerously elevated pressures, before proceeding to any consideration of surgical intervention. (See "Snakebites worldwide: Management", section on 'Local effects' and "Acute compartment syndrome of the extremities", section on 'Measurement of compartment pressures'.)

Findings suggestive of acute compartment syndrome are as follows (see "Acute compartment syndrome of the extremities", section on 'Clinical features'):

●Pain upon passive stretching of the muscle (although this can also be caused by venom-induced myolysis).

●Marked burning or aching pain that is not controlled despite parenteral opioid analgesia (eg, morphine).

●Paresthesias and/or diminished sensation.

●Muscle weakness (although this can also be caused by venom-induced myolysis or neurotoxicity).

●Tense compartment with a wooden feeling to palpation (late sign).

●Pallor and/or pulselessness (late sign).

Neurotoxicity — Common findings after a neurotoxic snakebite include [3,17,22]:

●Ptosis

●Ophthalmoplegia (partial or complete)

●Pupillary dilation (often unresponsive to light)

●Poor facial tone

●Limited mouth opening or tongue extrusion

●Drooling

●Limb weakness or flaccid paralysis

●Gait disturbance

●Decreased or absent reflexes

The target for most snake neurotoxins is the neuromuscular junction (NMJ). Cranial nerve effects (eg, ptosis, ophthalmoplegia, pupillary dilation, or difficulty with swallowing or speaking) are generally observed first. More generalized muscle weakness or respiratory failure may be delayed by many hours, although paralysis can develop within the first few hours in some severe cases [25].

Victims of snakebite where neurotoxicity may be possible warrant frequent, serial observations that assess the patients’ airway and breathing, in addition to frequent evaluation for early signs of developing neurotoxicity (eg, ptosis or partial ophthalmoplegia). Cyanosis, combativeness, and confusion can indicate serious hypoxia warranting immediate attention.

Serial measurements of maximal inspiratory and expiratory force can also help identify patients who need assisted ventilation. (See "Tests of respiratory muscle strength", section on 'Maximal inspiratory and expiratory pressure'.)

Trial of anticholinesterase (neostigmine or edrophonium) — Clinicians with limited experience using anticholinesterases for neurotoxic snakebites should consult with a poison control center or physician experienced with anticholinesterase treatment of neurotoxic snakebites, if possible. (See 'Additional resources' below.)

Based upon small trials, observational studies, and case reports, administration of anticholinesterases (eg, edrophonium, where available, or neostigmine) can identify whether paralysis is due to snakes with purely or predominantly post-synaptic venom effects (eg, cobras, some coral snakes). In addition, some Australian snakes, such as death adders, brown snakes, and copperheads, though possessing presynaptic neurotoxins, may in some cases show predominantly postsynaptic paralysis [26-35]. When associated with significant improvement, anticholinesterases can also provide treatment for paralysis when administration of antivenom is delayed or antivenom is in low supply or not available. Thus, the utility of administration of anticholinesterases depends upon a knowledge of the common snakes in the region, the severity of envenomation and paralysis, and availability of supportive treatment. It is not without risk and should be performed with appropriate medical supervision. (See "Snakebites worldwide: Management", section on 'Anticholinesterases'.)

However, for snakes with predominant presynaptic neurotoxicity, it is quite unlikely that anticholinesterase therapy will be of benefit. Thus, for these snakes, use of edrophonium or neostigmine should not be routine but carefully evaluated on a case-by-case basis, preferably after seeking expert opinion. Snakes falling in this category include several Australian snakes (eg, tiger snakes, rough-scaled snake, taipans) and Asian kraits.

Historically, edrophonium has been preferred to neostigmine as a trial anticholinesterase because it is shorter acting, but edrophonium is not widely available. Before attempting administration of edrophonium or neostigmine, intravenous atropine 0.6 mg (0.02 mg/kg in children, maximum 0.6 mg) or glycopyrrolate should be drawn up, and intravenous access should be established. Edrophonium or neostigmine is relatively contraindicated in patients with asthma, cardiac disease, or advanced age. However, if antivenom is not available, the risks posed by envenomation may outweigh the risks of anticholinesterase administration in such patients.

●Dosing – The dosing varies by age and by agent used as follows:

•Neostigmine – Give atropine 0.6 mg (0.02 mg/kg in children up to 0.6 mg) or glycopyrrolate (0.2 mg per 1 mg neostigmine dose) immediately prior to neostigmine. In adults, give neostigmine as a single intravenous dose of 0.02 mg/kg (0.025 to 0.04 mg/kg in children). Observe for improvement in ptosis, upward eye gaze, and respiratory weakness over 30 to 60 minutes.

•Edrophonium (where available) – Have atropine 0.6 mg (0.02 mg/kg in children up to 0.6 mg) or glycopyrrolate drawn up and immediately available in case of excess cholinergic symptoms. In adults, give edrophonium in an initial intravenous dose of 2 mg over 15 to 30 seconds. Then, after 45 seconds, give 8 mg if no response.

In children, give edrophonium in an initial intravenous dose of 0.04 mg/kg over one minute followed by 0.16 mg/kg if no response up to a maximum total dose of 5 mg for children <34 kg, or 10 mg for children >34 kg. Observe for improvement in ptosis, upward eye gaze, and respiratory weakness over 10 to 20 minutes.

Edrophonium is not available in the United States, Canada, the United Kingdom, and many other countries.

Coagulopathy — Venom may affect the hemostasis system in a variety of ways, including procoagulant, anticoagulant, direct fibrinolytic, and anti- or pro-platelet activation, but in general all produce similar coagulation dysfunction, often rapidly. (See 'Composition and sites of action' above.)

Signs of overt bleeding should be sought following a snake bite. Low-grade bleeding from gums, oozing from needle puncture sites, and epistaxis are common. Hematemesis and hematochezia may also be present. Signs of hemorrhage into internal organs may occur as well. For example, stroke resulting primarily from intracranial hemorrhage complicated Bothrops spp snakebites in 2.6 percent of cases in a series from Ecuador [36] and is a well-recognized complication following Australian and South American snakebites [37,38].

A few species (eg, Martinique viper [Bothrops lanceolatus]) primarily cause thrombosis, including deep vein thrombosis, pulmonary embolus, and cerebral infarction, rather than hemorrhagic problems [25].

The natural history of snakebite coagulopathy is highly variable, depending upon species and venom mechanism involved. In some species (eg, Australian tiger snake [Notechis scutatus]) the coagulopathy develops very rapidly but reverses spontaneously around 12 to 15 hours after the bite, even without antivenom. In other species (eg, Malayan pit viper [Calloselasma rhodostoma]) the coagulopathy may continue for up to two weeks, unless reversed with antivenom. The combination of coagulopathic venom toxins plus hemorrhagins can cause rapid and severe effects as seen in victims of saw scaled viper (Echis spp) bites.

Ancillary studies — Diagnostic testing is based upon clinical findings and targeted towards the expected spectrum of toxicity from snakebites within the specific region. As with physical examination findings, serial measurements should be performed to identify evolving signs of systemic toxicity and to assess response to treatment.

Potentially useful ancillary studies are described below (table 7).

Coagulopathy — Clotting parameters should be measured as follows:

●Complete blood count with platelets

●Prothrombin time (PT)/International normalized ratio (INR) and activated partial thromboplastin time (aPTT)

●Fibrinogen (only direct fibrinogen measurement is reliable; derived fibrinogen is not reliable in snakebite)

●Fibrinogen and fibrin degradation products or D-dimer

The 20 minute whole blood clotting test (20WBCT) has also been considered a useful bedside screening test when more formal coagulation testing is not available; failure of the blood to clot in a clean glass tube after 20 minutes has been considered evidence of severe hypofibrinogenemia [39].

However, in one series of 140 patients with Russell's viper envenomation, the sensitivity of the 20WBCT for an international normalized ratio of >1.5 was only 40 percent, regardless of the severity of the coagulopathy, and use of the 20WBCT was associated with a delay in antivenom administration [40]. On the other hand, the 20WBCT had a specificity of 100 percent in this study. Thus, a positive 20WBCT is a reasonable indication for antivenom administration, but a negative 20WBCT does not mean that antivenom should be withheld, especially if other clinical findings of coagulopathy (eg, blood oozing at puncture sites, bleeding gums, or epistaxis) are present. Furthermore, if more formal coagulation tests are available, they should be used in preference to the 20WBCT.

Point of care (POC) coagulation tests may also give erroneous results in some forms of snakebite coagulopathy and generally should not be relied upon to make decisions regarding antivenom administration. As an example, in an observational study of 15 Australian patients with snakebite that compared POC INR with conventional coagulation studies, measurement of INR by a POC device gave a false negative result in three of seven patients with venom-induced coagulopathy and one patient with anticoagulant induced coagulopathy and a false positive result in one of seven patients without coagulopathy [41].

Rhabdomyolysis — Studies helpful in identifying rhabdomyolysis include:

●Rapid urine dipstick for blood

●Urine for myoglobin

●Microscopic urinalysis

●Serum creatine kinase

●Serum electrolytes, calcium, phosphate, uric acid, blood urea nitrogen, and creatinine

●12-lead electrocardiogram

Venom-induced myolysis causing massive rises in CK levels and myoglobinuria (picture 14) is indicative of systemic poisoning. Furthermore, secondary renal damage, although uncommon, remains a risk in these patients. Muscle breakdown when associated with renal failure may cause a marked and rapid increase in serum potassium with resulting cardiac arrhythmias. Byproducts of muscle breakdown may also cause AKI with resulting increase in blood urea nitrogen and serum creatinine, hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia. (See "Rhabdomyolysis: Clinical manifestations and diagnosis", section on 'Clinical manifestations' and "Rhabdomyolysis: Clinical manifestations and diagnosis", section on 'Laboratory findings'.)

Respiratory failure — In regions where neurotoxic snakebites can also cause muscle toxicity or coagulopathy, laboratory studies as previously described should be obtained. Patients with neurotoxicity after snakebite also frequently exhibit signs of respiratory failure including:

●Carbon dioxide retention with respiratory acidosis on venous or arterial blood gases

●Maximal inspiratory and expiratory force below normal for age and gender (table 8)

●Decreased pulse oximetry (late finding)

Shock — Envenomations that cause shock frequently also cause myotoxicity and coagulopathy. Thus, suggested laboratory studies include the testing described above. Blood lactate levels may also be helpful in determining the presence of early shock and provide evidence of improvement with therapy. (See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Approach'.)

Venom identification — In Australia and New Guinea, swabs, ideally from an expressed and unwashed bite site, or urine can undergo snake venom detection using a commercially available immunosorbent assay [17,42]. Results need to be interpreted based upon the clinical setting. A positive result confirms the snakebite and identifies the most appropriate antivenom to be used but is not, by itself, an indication for antivenom administration in otherwise asymptomatic patients. The assay is highly dependent upon the specimen and how it was obtained and can have low sensitivity. Thus, a negative assay does not rule out snakebite.

In patients with systemic envenoming, where antivenom is indicated, it is advisable to compare the venom detection result with a venom immunotype determined by diagnostic algorithms for Australian snakes; if the two routes provide a similar answer, an appropriate specific antivenom can be used with confidence, but if each route gives a different answer, expert advice should be sought from a clinical toxinologist, or if that will entail an unacceptable delay in treatment, polyvalent antivenom should be used.

When performing the test, carefully read the manufacturer's instructions. Although the manufacturer provides instructions for testing of blood, the results are typically unreliable and, whenever possible, swabs from the bite site or urine should be used [42]. Technique for blood testing differs from what is recommended for urine or swabs from the bite site.

DIAGNOSIS — In some patients, diagnosis of snakebite is straightforward because the bite is immediately felt and a snake is seen, but often a snake is not reliably witnessed and at least for some snake species, the act of biting may cause minor effects to the human victim and may go unnoticed. However, depending upon the region, snakebite should remain in the differential diagnosis of abrupt onset of paralysis, coagulopathy, myolysis, renal failure, collapse, and, especially in children, seizures, syncope, or cardiovascular collapse.

The effects of snake venom can be divided into distinct syndromes, which may vary in severity depending upon the species of snake (table 7 and table 1 and table 2 and table 3 and table 4 and table 5 and table 6) [43]. The evaluation of the patient should take into account each syndrome. In particular, the presence of coagulopathy may occasionally be useful in the clinical diagnosis of snake bite. As an example, in Papua New Guinea, envenomation from the death adder rarely causes a significant coagulopathy in contrast to taipan snakebites. In some regions, such as Sri Lanka, Myanmar, and Australia, there are diagnostic algorithms that may assist in determining the most likely type of snake in patients based upon local and systemic findings (algorithm 1 and algorithm 2A-B).

Severe envenomation is suggested by one or more of the following findings [3,17,22]:

●Confirmation of a bite from a dangerous snake (digital photograph or verified snake specimen) in a symptomatic patient

●Rapidly progressive swelling from the bite site

●Rapid development of local blistering or bruising

●Persistent oozing of blood from bite marks and other wounds (including venipunctures), suggesting coagulopathy

●Enlarged, painful lymph nodes draining the region of the bite

●Symptoms of systemic envenomation, such as:

•Nausea, vomiting, abdominal pain, or diarrhea (but be cautious as these may result from an anxiety reaction)

•Severe headache

•Lethargy

•Muscle weakness marked by ptosis or "heavy" eyelids, ophthalmoplegia, difficulty with speech, swallowing, drooling, "broken neck" sign, limb weakness, or respiratory difficulty

•Muscle fasciculation (especially for mamba bites)

•Epistaxis, bleeding from the gums, hematemesis, hematochezia, or hematuria

•Sudden collapse with shock

•Seizures

•Brown or black urine indicating hematuria or myoglobinuria

DIFFERENTIAL DIAGNOSIS — In many patients the diagnosis of snakebite is obvious based upon clinical findings. However, sudden collapse, seizure, syncope, unexplained coagulopathy/bleeding, developing descending flaccid paralysis, rhabdomyolysis, or renal failure should raise the possibility of snakebite within a wider set of differential diagnoses. In addition, a patient stating that they have suffered a snakebite may potentially present with clinical features that could have other etiologies that might become apparent by detailed history taking.

The differential diagnosis varies according to the primary clinical features snakebite victims might develop:

●Paralysis – Toxic encounters in addition to snake bite that may cause flaccid paralysis include:

•Tick paralysis (see "Tick paralysis")

•Paralytic shellfish poisoning (see "Overview of shellfish, pufferfish, and other marine toxin poisoning")

•Nicotine poisoning (ingestion or dermal exposure) (see "Toxic plant ingestions in children: Management", section on 'Nicotine poisoning (muscarinic and/or nicotinic findings)')

•Botulism (see "Botulism")

•Guillain-Barré syndrome (see "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis")

•Blue-ringed octopus or cone snail envenomation (rare) (see "Marine envenomations from corals, sea urchins, fish, or stingrays", section on 'Blue-ringed octopus (Hapalochlaena maculosa)' and "Marine envenomations from corals, sea urchins, fish, or stingrays", section on 'Cone snail')

Differentiating features include the following:

•Bites by neurotoxic snakes (eg, most Australian dangerous elapid snakes, coral snakes, kraits, many cobras (picture 1), king cobra, many sea snakes, selected rattlesnakes (particularly Latin American species, western races of Russell's viper, some European viper species) are associated with descending paralysis while tick paralysis or paralysis caused by Guillain-Barré typically is ascending. (See "Tick paralysis", section on 'Clinical manifestations' and "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)

•Food history including ingestion of shellfish (especially non-commercially harvested bivalve mollusks) or home canned foods help to identify paralytic shellfish poisoning or foodborne botulism, respectively. (See "Overview of shellfish, pufferfish, and other marine toxin poisoning", section on 'Paralytic shellfish poisoning' and "Botulism", section on 'Clinical manifestations'.)

•Secondary muscarinic symptoms (eg, salivation, lacrimation, vomiting, diarrhea, wheezing, diaphoresis, small pupils) and primary nicotinic signs (eg, tachycardia, hypertension, and seizures) suggest nicotine poisoning. (See "Nicotine poisoning (e-cigarettes, tobacco products, plants, and pesticides)", section on 'Clinical features of poisoning'.)

•The blue-ringed octopus (Hapalochlaena maculosa) is found in ocean waters in Papua New Guinea and Australia and cone snails are primarily located in warm regions of the Indian and Pacific oceans. Envenomation occurs when these unusual animals are handled.

The approach to muscle weakness caused by other medical illness is described separately. (See "Approach to the patient with muscle weakness" and "Etiology and evaluation of the child with weakness" and "Evaluation of the adult with acute weakness in the emergency department".)

●Rhabdomyolysis – Rhabdomyolysis may be caused by other disease states. The causes of rhabdomyolysis can be broadly divided into three categories: traumatic or muscle compression (eg, crush syndrome or prolonged immobilization), nontraumatic exertional (eg, marked exercise, hyperthermia, or metabolic myopathies), and nontraumatic nonexertional (eg, drugs or toxins, such as snake venoms, infections, or electrolyte disorders). In most instances, rhabdomyolysis caused by snake bite is associated with pain and sometimes local swelling and thus is readily distinguished from other causes. The causes of rhabdomyolysis and its diagnosis are discussed in detail separately. (See "Rhabdomyolysis: Epidemiology and etiology" and "Rhabdomyolysis: Clinical manifestations and diagnosis".)

●Coagulopathy – Consumptive coagulopathy with bleeding is a common feature of bites by many snake species and, given the effect of snake venoms on multiple pathways, is characterized by prolongation of both prothrombin (PT) and activated partial thromboplastin times (aPTT) in association with decreased fibrinogen. Such primary consumptive coagulopathy is not generally a feature of other types of envenoming, except for South American Lonomia caterpillars, skin contact with which can cause a profound and potentially fatal coagulopathy similar to snakebite (see "Lepidopterism: Skin disorders secondary to caterpillars and moths", section on 'Lonomism'). A number of other types of envenoming can cause major systemic illness, with intravascular hemolysis, multi-organ failure and secondary disseminated intravascular coagulation (DIC), in some ways similar to sepsis, but rather distinct from the primary coagulopathy caused by some snakes.

Sepsis, multiple trauma, obstetrical complications, or malignancy may present with similar hematologic features as snake envenomation but are readily distinguished by clinical findings (eg, the presence of fever and signs of infection [eg, pneumonia, urinary tract infection, and/or petechiae] in patients with sepsis, evidence of multiple trauma, or known or suspected malignancy). (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

Bleeding may also be caused by a wide array of other disease states, including hereditary abnormalities of the hemostasis system (such as hemophilia or Von Willebrand disease). Of note, mild variants of such congenital abnormalities are an important underlying cause for unexplained, but minor changes in coagulation tests in a snakebite patient who otherwise shows no evidence of significant envenoming. In many instances, a careful history and physical examination and more rigorous laboratory testing can define the underlying cause. (See "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder".)

ADDITIONAL RESOURCES

Region-specific resources — Resources that provide information about specific regions or snake species include:

●African snakebites – Guidelines for the prevention and clinical management of snakebite in Africa. World Health Organization Regional Office for Africa, Brazzaville, Mauritius, 2010. Available at WHO African snakebites guidelines.

●South-East Asian snakebites – Warrell DA. Guidelines for the management of snake-bites. World Health Organization Regional Office for South-East Asia, India, 2016. Available at WHO South-East Asian snakebites guidelines.

●Australian snakebites – White J. Snakebite & spiderbite management guidelines South Australia, Department of Health, Adelaide 2018. Available at South Australian snake- and spiderbite management guidelines

●An extensive database of the distribution for snake species, their clinical manifestations, and treatment of envenomation provided by the University of Adelaide, Australia. Available at www.toxinology.com

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Envenomation by snakes, arthropods (spiders and scorpions), and marine animals".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Snakebites result in significant morbidity and mortality worldwide. Approximately 600 distinct species of venomous snakes have been described. A comprehensive listing of venomous snakes by geographical regions and estimated geographical distribution for individual species may be obtained at Toxinology snakes search. Some medically important snakes by region are provided in the tables for Africa (table 1), Asia (table 2), Central and South America (table 3), Australia and the Pacific Islands (table 4), Europe (table 5), and the Middle East (table 6). (See 'Epidemiology' above and 'Geographic distribution and characteristics' above and 'Additional resources' above.)

●Venom properties and clinical manifestations – The identified components and physiologic sites of action for snake venom determine the spectrum of clinical features commonly seen after snakebite. Diagnostic testing is based upon clinical findings and targeted towards the expected spectrum of toxicity from snakebites within the specific region. Major clinical manifestations are provided in the table (table 7). (See 'Composition and sites of action' above and 'Clinical manifestations' above.)

●History – In many cases, the bite is immediately felt and the snake readily identified. However, some snakes, especially elapids, cause limited to no local pain or tissue necrosis when injecting venom. Patients bitten in this way may present with paralysis and/or coagulopathy as the first sign of envenomation with no history of snakebite. This scenario is common for snakebites by nocturnal species (eg, kraits) in rural tropical regions. Similarly, victims of highly toxic snakes, especially children, may present with cardiovascular collapse or seizures without any reported snakebite. (See 'History' above.)

●Physical examination – Physical findings of snakebite vary significantly by species and often evolve over time (table 7). Frequent, repeated examinations are important to ensure detection of all signs of snake envenomation and to identify serious local or systemic effects. All patients with a potentially toxic snakebite warrant frequent measurement of vital signs and, if available, continuous cardio-respiratory and pulse oximetry monitoring. For many species additional monitoring may include checking for ptosis, partial ophthalmoplegia, or persistent oozing from any wounds or gums. A fluid balance chart should also be maintained. (See 'Physical examination' above.)

●Ancillary studies – Ancillary studies are based upon clinical findings and targeted towards the expected spectrum of toxicity from snakebites within the specific region.

•Coagulation studies – When assessing for coagulopathy in snakebite victims, traditional coagulation studies (ie, D-dimer or fibrin degradation products, complete blood count, prothrombin time, activated partial thromboplastin time, and international normalized ratio) are preferred to the whole blood clotting test whenever possible. Point of care coagulation tests should not be used. (See 'Coagulopathy' above.)

•Anticholinesterase trial – Administration of anticholinesterases (eg, edrophonium, where available, or neostigmine) can identify whether paralysis is due to snakes with purely or predominantly post-synaptic neurotoxic venom effects. When associated with significant improvement, anticholinesterases can also provide treatment for paralysis when administration of antivenom is delayed or antivenom is in low supply or not available. Precautions and dosing of anticholinesterases for an edrophonium (Tensilon) or neostigmine test are provided. (See 'Trial of anticholinesterase (neostigmine or edrophonium)' above and "Snakebites worldwide: Management", section on 'Anticholinesterases'.)

•Venom identification – In Australia and New Guinea, swabs from an expressed and unwashed bite site, or urine samples can provide snake venom detection using a commercially available immunosorbent assay. Results need to be interpreted based upon the clinical setting. (See 'Venom identification' above.)

●Diagnosis – In some patients, diagnosis of snakebite is straightforward based upon clinical grounds because the bite is immediately felt and a snake is seen. However, often a snake is not reliably witnessed and at least for some snake species, the act of biting may cause minor effects to the human victim and may go unnoticed. Thus, depending upon the region, snakebite should remain in the differential diagnosis of abrupt onset of paralysis, coagulopathy, myolysis, renal failure, collapse, and, especially in children, seizures, syncope, or cardiovascular collapse. (See 'Diagnosis' above and 'Differential diagnosis' above.)

In some regions, such as Sri Lanka and Australia, there are diagnostic algorithms that may assist in determining the most likely type of snake based upon local and systemic findings (algorithm 1 and algorithm 2A-B). (See 'Diagnosis' above.)

Severe envenomation is suggested by confirmation of a bite from a dangerous snake (digital photograph or verified snake specimen), rapidly progressive local effects (swelling, blistering, or bruising), signs of coagulopathy (oozing of blood from the bite site, phlebotomy sites, or gums), and other findings of systemic envenomation including lethargy, nausea, vomiting, headache, epistaxis, weakness, sudden collapse, seizures, or evidence of rhabdomyolysis. (See 'Diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Allen Cheng, MB, BS, who contributed to earlier versions of this topic review.