Snakebite

The World Health Organization (WHO) estimates there are up to 1.8 million bites from venomous snakes annually worldwide, causing 20,000-90,000 deaths.[1] The vast majority of venomous snake species are viperids (eg, rattlesnakes, Gaboon vipers) or elapids (eg, cobras, taipans). Although most snakes in the Colubridae family are nonvenomous, some (eg, boomslang) are venomous and responsible for significant morbidity and mortality.

In the United States, several thousand snakebites occur every year, resulting in fewer than 10 deaths.[2, 3, 4, 5] There are four types of venomous snakes native to the United States: copperheads, cottonmouths (water moccasins), rattlesnakes, and coral snakes. The first three are crotalids in the family Viperidae, subfamily Crotalinae. There are approximately 25 species of rattlesnakes in the genera Crotalus and Sistrurus. The genus Agkistrodon has both copperheads (Agkistrodoncontortrix, Agkistrodonlaticinctus) and cottonmouths (Agkistrodonpiscivorus, Agkistrodonconanti). Collectively, these crotalids, also known as pit vipers, account for greater than 95% of all native snake envenomations.

Coral snakes are the only elapids that are native to the Western hemisphere, and the three species of US coral snakes account for less than 5% of all native envenomations.

Crotalids are characterized by large, triangular heads, comparatively small eyes, large and retractable fangs, and a thermoreceptor “pit” located between the eye and the nostril. Pit vipers also have a single row of subcaudal plates distal to the anus, and rattlesnakes have one or more keratin buttons that compose the “rattle” at the distal end. Although some references recommend using the pupil shape as a way of distinguishing a pit vipers from noncrotalids, it should be noted that all snakes can have round or elliptical pupils, depending on the amount of ambient light. Additionally, many nonvenomous snakes can flatten their heads into a triangle shape when they feel threatened. Experts recommend that people learn to recognize the venomous species in their vicinity rather than rely on mnemonics.

See the images below.

Eastern copperhead, Agkistrodon contortrix. Courtesy of Spencer Greene, MD.

Broad-banded copperhead, Agkistrodon laticinctus. Courtesy of Kimberly Wyatt.

Western cottonmouth, Agkistrodon piscivorus leucostoma. Courtesy of Kimberly Wyatt.

Western diamondback rattlesnake, Crotalus atrox.

Juvenile southern Pacific rattlesnake, Crotalus oreganus helleri. Courtesy of Sean Bush, MD.

There are three species of coral snakes in the United States. The Sonoran coral snake, Micruroides euryxanthus euryxanthus, is found in Arizona and western New Mexico. The Texas coral snake, Micrurus tener, is found in Texas, Louisiana, and Arkansas. The Eastern coral snake, Micrurus fulvius, is confined to the Southeastern United States as far north as North Carolina and as far west as Mississippi. The rhyme "red on yellow, kill a fellow; red on black, venom lack" is commonly used to distinguish coral snakes from nonvenomous species, but there are many exceptions. Some native coral snakes have aberrant patterns that do not adhere to the rule, and nonnative coral snakes may have completely different coloration. Conversely, there are nonvenomous snakes such as the shovel-nosed snakes (genus Chionactis) in which "red touches yellow". It is best to look at a combination of features, including head shape, body habitus, and coloration, to make a snake identification. When in doubt, it is prudent to assume a snake is venomous and leave it alone.

See the images below.

Texas coral snake, Micrurus tener. Courtesy of Chip St. John.

Comparison of the harmless Mexican milksnake, Lampropeltis triangulum annulata (top) with the Texas coral snake, Micrurus tener (bottom). Courtesy of Charles Alfaro.

Aberrant Texas coral snake, Micrurus tener. Courtesy of Reece Hammock.

A large number of exotic species are kept by both zoos and private collectors, making bites by nonindigenous species increasingly common. A full review of these snakes is not possible here.

Crotalid venom is produced and stored in paired glands below the eyes. Crotalids have hollow, mobile, relatively long fangs located in the front of the upper jaw and are capable of delivering venom quite efficiently. Less than 10% of crotalid bites are “dry”, meaning there is no venom deposition. A number of factors determine how much venom is delivered, including the species, age, size, and overall health of the snake, as well as its diet and the last time it had fed or released venom.

Coral snakes have shorter, fixed, front fangs and a smaller mouth, which make them deliver venom less efficiently. In the wild, snakes often hang onto their prey until the venom takes effect. However, despite the persistent myth, coral snakes do not need to "chew" in order to envenomate. It is estimated that 30% or more of coral snake bites are dry.

Snake venom has been described as a "soup of antigens" and comprises a variety of protein and nonprotein substances. Most crotalid venom contains a mixture of metalloproteinases, collagenase, phospholipase, and hyaluronidase that can cause myonecrosis and dermatonecrosis.[6] Multiple venom components, such as serine proteases, disintegrins, metalloproteinases, and C-type lectinlike proteins, produce a variety of hematologic effects, resulting in coagulopathy, platelet aggregation, platelet activation or platelet inhibition, or increased coagulation, leading to thrombotic complications[7]

Certain crotalid species have unique toxins. Crotalocytin, found in the Timber rattlesnake (Crotalus horridus), causes platelet aggregation.[8] Mojave toxin, found in some populations of the Mojave rattlesnake (Crotalus scutulatus), inhibits the presynaptic release of acetylcholine, leading to weakness and paralysis.[9] Pit viper venom may also include bradykinin-related peptides that can lead to angioedema and hypotension.[10]

Coral snake venoms are complex mixtures that include phospholipase A2, multiple proteases, high–molecular-weight protein, and a variety of neurotoxins. Approximately 380 isoforms of phospholipase A2 have been identified in snake venoms, and their effects include neuromuscular paralysis, bleeding, myonecrosis, edema, widespread inflammation, and platelet aggregation.[11, 12] In coral snakes, the neuromuscular effects are most pronounced.

There are several other neurotoxins found in coral snake species. Most are alpha-toxins, which competitively antagonize postsynaptic acetylcholine receptors on the neuromuscular junction. Weakness and paralysis result, although these can be overcome by increasing local acetylcholine concentrations. Myotoxic and edematogenic effects have also been detected in several coral snake venoms, with particularly strong activity the Eastern coral snake Mfulvius.[13] Coral snake venom components can also activate the classic complement pathway and subsequently generate anaphylatoxins, which contribute to vasodilation and allow for greater distribution of other venom components.[14]

Previous studies suggest that most people get envenomated because they are intentionally interacting with the snake.[15] Data from the North American Snakebite Registry (NASBR), which is administered by the American College of Medical Toxicology, Toxicology Investigator’s Consortium (ToxIC), demonstrated that only 19% of bites between 2013 and 2015 were the result of intentional interaction.[16] Males accounted for 91% of these victims, and 100% of bites that resulted from intentional interaction involved the upper extremity.

There is no doubt that antagonizing a venomous snake increases an individual's likelihood of being envenomated, but most bites affected victims who were unaware of the snake's presence prior to being bitten.

However, many bites can be prevented if people would avoid intentionally interacting with venomous snakes whenever possible.

Frequency

United States

Snakebites, especially from nonvenomous snakes, frequently go unreported. Approximately 10,000 bites are reported in the United States annually, particularly in Texas, Florida, California, Arizona, North Carolina, and Georgia. Mortality from snakebites is rare, with 2-10 deadly snakebites annually.

International

Snakebites also go unreported in the developing world. An estimated 1.8 million venomous snakebites occur worldwide each year, resulting in an estimated 20,000-90,000 annual deaths.[1] Worldwide, snakebites disproportionately affect low socioeconomic populations in more rural locations. They often occur as bites to the lower extremities by farmers or workers who step on or disturb a snake in the field or rice paddies, or they can present as a bite to the head or trunk in individuals sleeping outside on the ground.

Race

Of US victims of snakebites in one study, 84.5% were white.[16]

Sex

According to NASBR data, 69.3% of victims are male and 30.7% of victims are female. In males, 45.2% of bites affected the lower extremity and 54.8% of bites involved the upper extremity. Conversely, 77.5% of bites in women were to the lower extremity and only 22.5% affected the upper extremity.[16]

Age

Children younger than 13 years old accounted for 1,286 (10.6%) of the 12,111 snakebites reported to the American Association of Poison Control Centers between 2015 and 2017. Children age 12 and younger comprised 28.2% of snakebite patients recorded in the NASBR between 2013 and 2015.[16] Most (69.5%) bites in children involved the lower extremity.

Role of drugs and alcohol

It is a common misconception that most snakebite victims are under the influence of intoxicating substances when they are envenomated. In a study of snakebite reports to the American Association of Poison Control Centers, only 608 (0.7%) of 92,751 snakebites were associated with concomitant drug or alcohol use.[17] However, those who used alcohol were 27 times as likely to receive antivenom and 31 times as likely to die from the envenomation compared to those who had not consumed ethanol.

Seasonal variation

Although snakebites do occur throughout the year, they are most common in the summer months, from June to September.

Death is rare. Most patients recover fully, although many patients, particularly those who are not treated or are undertreated, may have prolonged or even permanent disability.

Mortality/morbidity

A 20-year review of data from the National Vital Statistics Systems identified 97 fatalities. The state of Texas had the most fatalities (17), followed by Florida (14), and Georgia (12).

Most snakebite victims survive, even without antivenom. However, death may result from intravenous deposition of venom, anaphylaxis, nonimmune anaphylactoid reactions, and following systemic toxicity (eg, cardiovascular collapse, respiratory failure.)

Bites that go untreated or are undertreated may result in prolonged or even permanent disability. Timely administration of antivenom can accelerate recovery and reduce the likelihood of long-term deficits.

Prevention is key in limiting morbidity and mortality from snakebites. People who live in snake-endemic areas and those who engage in high-risk activities should be advised to wear proper attire and footwear and to not place a hand or foot in a bush or other unseen area.

If someone is bitten, he or she should seek medical attention immediately. Victims should call emergency services (911) rather than attempt to drive themselves to the hospital. Many first-aid techniques that were once recommended for snakebites have since proven to be ineffective at best and dangerous at worst. Tourniquets, constriction bandages, pressure immobilization, electric "stun guns", and venom extractors may cause significant harm and should be avoided.

History usually can be obtained from the patient, although some patients do not see the snake and many patients cannot correctly identify the snake. Patients are encouraged to take a picture of the snake if it is safe to do so and it does not delay transport to the hospital. Identifying the species of snake can be helpful if it expedites treatment, facilitates crotaline antivenom selection where relevant, or enables experts to tailor therapy. Victims and emergency medical service providers should be discouraged from bringing in the snake because even a dead snake can envenomate.[18, 19]

Determine the time of the bite and what signs and symptoms have developed. Inquire about local effects as well as systemic symptoms such as nausea, dyspnea, and lightheadedness. Some snakebite victims describe experiencing a metallic taste.

Ascertain what treatments what have already been attempted and by whom.

Obtain a thorough medical history, including medications and allergies. Ask if the patient has had a previous snakebite and if he or she has had antivenom in the past.

Assess the patency of the patient's airway and the adequacy of oxygenation and ventilation. Ensure the patient has adequate perfusion. 

Document a complete set of vital signs and reassess frequently.

Assess for local damage. Crotalid envenomations are characterized by swelling, tenderness, and bruising. Hemorrhagic blebs may develop over several hours. Fang marks may be obscured by swelling, or there may be one, two, or more punctures. A larger distance between fang puncture wounds suggest a bite by a larger snake. However, smaller distances between fang marks may not represent smaller snakes because crotalid fangs are highly mobile. Patients generally report significant pain, which is often described as "being struck by a hammer". It is important to assess the progression of the damage serially; snakebites are a dynamic process and patients with minimal findings initially may have significant swelling within a few hours.

The local findings from coral snake envenomation are much more subtle. Fang marks may or may not be visible. Some swelling and erythema may be present, but significant bruising is conspicuously absent. Patients may report a "burning" or "electric" pain.

Systemic toxicity following crotalid envenomation may include nonspecific signs and symptoms such as nausea, headache, and lightheadedness. More significant features include hypotension, airway swelling, and refractory vomiting.[20, 21, 22, 23] Hematologic laboratory abnormalities are common, and bleeding is seen in approximately 0.9% of patients.[24, 25, 26, 27] Examine the patient for petechiae, epistaxis, gingival bleeding, and other mucosal bleeding.

Neurological toxicity is not associated with most crotalid envenomations, but envenomations from some species (eg, Mojave rattlesnake [C scutulatus], Southern Pacific rattlesnake [C o halleri]) may result in significant weakness and other neurological abnormalities.[28, 29, 30, 31]

Coral snake envenomation may also be associated with nonspecific systemic symptoms, but the hallmark of coral snake envenomation is neurological toxicity, which may be as subtle as local paresthesias and myokymia or as severe as skeletal and respiratory muscle paralysis. Other signs and symptoms may include diplopia, hyperacusis, odontalgia, ageusia, ptosis, ophthalmoplegia, hypersalivation, and dysphagia.[32, 33]

A typical presentation of crotalid envenomation to foot is shown in the image below.

Swelling and bruising after crotalid envenomation. Courtesy of Spencer Greene, MD.

A hemorrhagic bleb following copperhead envenomation is shown in the image below.

Hemorrhagic bleb following Eastern copperhead (Agkistrodon contortrix) envenomation. Courtesy of Spencer Greene, MD.

The image below shows local effects in a toddler following rattlesnake envenomation.

Moderate rattlesnake envenomation in a toddler after treatment with antivenom. Courtesy of Sean Bush, MD.

The three images below show effects from a severe copperhead bite.

Copperhead bite day 3; initial wounds were to finger.

Copperhead bite day 3; initial wounds were to finger.

Copperhead bite day 3; initial wounds were to finger.

Crotalid envenomation can cause local, systemic, and hematologic toxicity. Antivenom can minimize the local tissue damage but cannot reverse tissue death. Fortunately, many of the local effects are superficial and heal over time.

In the image below is an example of superficial tissue necrosis following copperhead envenomation. The patient improved completely within 1 week.

Superficial necrosis following copperhead envenomation. Courtesy of Spencer Greene, MD.

Infection is uncommon, so antibiotics should not be administered prophylactically.[34] Infection is seen in less than 5% of snake envenomations, and typically only in patients with significant tissue necrosis.[35, 36] Broad-spectrum antibiotics should be administered in these cases.

The biggest local complication of crotalid envenomation is prolonged, and sometimes permanent, swelling and loss of limb function, particularly following exertion. Timely administration of antivenom can significantly reduce the incidence of this disability. In a study of patients with crotalid envenomations in Kentucky, patients who did not receive antivenom lost an average of 14 days from work.[37] Patients with bites to the hand or finger had reduced strength that persisted for a mean of 22 days. Poorly healing wounds took an average of 45 days to heal, with some wounds persisting for 77 days. Additionally, many patients developed recurrent pain and swelling in their hands after normal usage for an average of 1 month. In a study conducted in the Carolinas, the mean duration of disability following mild copperhead envenomation was 42 days, and some subjects had persistent disability at 1 year at the conclusion of the study.[38] Anecdotally, many patients with envenomations that were not treated with antivenom have reported significant postexertional pain and swelling that interferes with activities of daily living.

Delayed and recurrent hematotoxicity is a frequent complication of pit viper snakebite. The mechanism(s) responsible for these phenomena has been debated, but some patients may develop coagulopathy and/or thrombocytopenia up to 2 weeks after envenomation. In a study of rattlesnake bite patients, 24% had late hematotoxicity. In a study of high-risk snakebite victims, late coagulopathy was present in 32% of subjects.

Below is a image of petechiae that developed 1 week after a black-tailed rattlesnake envenomation that was treated with FabAV.

Petechiae 1 week after being treated for black-tailed rattlesnake (Crotalus molossus) envenomation; platelet count = 2,000 (reference range 150,000-450,000). Courtesy of Daniel Jarvis.

Prolonged neuromuscular blockade may occur following coral snake envenomation in which antivenom is not administered in a timely fashion.

Also see Complications in the Treatment section.

Patients with possible snakebite envenomation should have the following laboratory tests performed:

• Complete blood cell count
• Basic metabolic profile
• Prothrombin time
• Fibrinogen value
• Creatine kinase value

Patients with systemic toxicity may warrant additional testing, including liver function tests, urinalysis, blood type and crossmatch, and venous blood gas analysis. Rotational thromboelastometry and thromboelastography are not readily available in many healthcare settings but may have a greater role in evaluating patients for hematotoxicity in the future.

Routine measurement of D-dimer and fibrin split products is not necessary because the results do not change management.

Hematologic toxicity is frequently observed following crotalid envenomation. It may be present on arrival or it may develop after several days. Specific laboratory abnormalities may include the following:

• Coagulopathy (prothrombin time >15 seconds)
• Hypofibrinogenemia (fibrinogen < 150 mg/dL)
• Thrombocytopenia (platelet count < 150 x 10 ³/µL)

In general, copperhead envenomations are associated with the least hematotoxicity. In a study of copperhead envenomations in Virginia, only 14% of copperhead envenomations had any type of hematologic toxicity.[39] A similar percentage of patients developed thrombocytopenia in a study conducted in the Carolinas, although coagulopathy and hypofibrinogenemia were observed in 24% and 63% of patients, respectively.[38]

Coagulopathy was observed in 19% of patients in a multicenter study of cottonmouth envenomations.[40]

Hematologic toxicity was seen in 76% of patients with rattlesnake envenomations. In the same population, 24% of patients had late hematotoxicity. In a study of high-risk snakebite victims, late coagulopathy was present in 32% of subjects.[25, 41]

Routine imaging is not required following snake envenomation. Conventional radiographs of the affected extremity should be considered if there is suspicion for a retained fang or if the diagnosis is uncertain. Chest radiography should be performed in patients with systemic toxicity experiencing dyspnea. Rarely, neuroimaging may be necessary to look for intracranial bleeding in patients with altered mental status.

Ultrasonography of the affected extremity should be obtained in patients when the diagnosis is uncertain and there is clinical concern for a deep venous thromboembolism.

Clinicians should examine the affected extremity for swelling, tenderness, hemorrhagic blebs, and the presence of strong distal pulses. The proximal spread of tenderness and swelling should be recorded every 15-30 minutes to document the progression of the local venom effects. This can be accomplished by palpating the proximal part of the affected extremity and moving distally until tenderness is elicited.

Serial dynamometry and negative inspiratory force assessments should be measured on patients at risk for respiratory and/or skeletal weakness/paralysis (eg, coral snake envenomations, bites from neurotoxic rattlesnakes). Capnography may also be used to identify patients with mild respiratory insufficiency.

True compartment syndrome is exceptionally uncommon following snake envenomation. However, compartmental pressures should be measured in patients with disproportionate pain and significant tissue swelling. Commercially available devices exist that are sterile, simple to assemble and read, and reliable (eg, Stryker pressure monitor).

The overall envenomation severity is determined by local and systemic findings and can be classified as follows:

• Dry bites: These occur when there is no venom deposition, and therefore there are no signs or symptoms beyond a puncture wound. It is estimated that less than 10% of pit viper bites and 30-50% or coral snake bites are dry.
• Minimal envenomations: These are characterized by local findings such as bruising, tenderness immediately adjacent to the bite site, and an absence of laboratory abnormalities and systemic findings.
• Mild envenomations: These also lack laboratory abnormalities and systemic findings, but the local damage extends several centimeters from the bite site, all the way to a major joint (eg, ankle, wrist).
• Moderate envenomations: These may be associated with non–life-threatening signs and symptoms (eg, vomiting, hematotoxicity without bleeding) and/or local damage that extends beyond two joints.
• Severe envenomations: These result in extensive local damage (eg, beyond two joints) and/or significant systemic toxicity (eg, hypotension, airway swelling, muscle paralysis).

Snakebite severity score

Many hospitals rely on the snakebite severity score (SSS) to make treatment decisions. This research tool considers the local findings as well as the following five body systems that may be impacted by an envenomation:

• Gastrointestinal system
• Pulmonary system
• Cardiovascular system
• Central nervous system
• Local wound
• Hematologic system

Scores range from 0 (normal) to a maximum score of 23. Typically, antivenom is withheld for scores less than 5. However, the SSS frequently results in undertreatment. An envenomation causing swelling and ecchymosis beyond an entire extremity, but without systemic effects or laboratory abnormalities, would produce a score of 4 and would not be treated with antivenom, even though this would be considered a severe envenomation by more accepted standards.

Important to note: The SSS was not intended to guide patient care and has not been validated for clinical decision making. Its use should be restricted to research.[42]

The general approach to snakebite management is as follows:

• Recognize and correct any immediately life-threatening conditions
• Provide analgesia
• Assess for local and systemic toxicity
• Minimize local tissue damage
• Prevent or correct any systemic toxicity (eg, hypotension, weakness)
• Prevent or correct hematologic toxicity
• Improve limb function
• Minimize harm from unnecessary and potentially dangerous interventions

Treatment includes both nonpharmacologic and pharmacologic interventions.

The first priority in prehospital care is scene safety. It is essential to prevent creating additional victims. There is no need to capture or transport the snake to the hospital. Even a recently killed snake can envenomate because bite reflexes may persist for several hours. Severe envenomation and death have resulted from bites from decapitated snakes.[18, 19] It is reasonable to obtain a photograph of the snake, but only if it can be done so safely and does not delay transport. Identifying the species of snake can be helpful if it expedites treatment, facilitates antivenom selection where relevant, or enables experts to tailor therapy.

The most important prehospital interventions are establishing a patent airway, ensuring adequate oxygenation and ventilation, and maintaining euvolemia.

Analgesia should be provided. Opioids are preferred. Nonsteroidal anti-inflammatory drugs (NSAIDs) are not recommended because of their potential hematologic effects, which could compound with venom-induced coagulopathies.

Proper positioning of the affected extremity in the prehospital setting is controversial. Previously, experts recommended keeping the extremity below heart level to minimize the spread of the venom. However, this could exacerbate local swelling, which is almost always present in crotalid envenomation. Elevating the extremity above heart level can reduce the swelling, and patients often report significant pain relief with elevation. Some people fear that elevation can accelerate systemic absorption of the venom, but there is no evidence demonstrating this occurs. In areas where bites are unlikely to cause significant systemic toxicity, elevation is recommended. If systemic illness is a major concern, it is reasonable to keep the affected extremity at heart level. Once the patient arrives in the hospital, however, elevation is recommended for all pit viper envenomations.[42] Coral snake envenomations do not result in tissue damage. Place the affected extremity in whatever position the patient finds most comfortable.

Unstable patients should generally be taken to the closest hospital. Stable patients should be brought to the closest appropriate hospital, that is, one that carries antivenom and has one or more staff physicians with expertise in managing snake envenomations.

Most of the interventions that had once been proposed to treat snakebites in the prehospital environment have failed to show benefit, and many have proven to be harmful. Tourniquets were once recommended, but the harm of compromising arterial blood supply is much greater than any benefit in limiting the spread of venom. Methods of obstructing lymphatic flow (eg, constriction bands, pressure immobilization) were also once touted because they may limit systemic absorption of venom. However, they also expose the local tissue to venom for a longer duration and increase the local hydrostatic pressure that contributes to tissue injury.[43] The American College of Medical Toxicology issued a position statement condemning these interventions whenever tissue damage is expected.[44] Pressure immobilization may be considered in envenomations from exclusively neurotoxic snakes (eg, Eastern coral snakes.[45]

Electrical therapy has been proposed to treat snakebites as well as other envenomations, but there is no evidence that it neutralizes venom.[46] Furthermore, there is ample evidence of harm, including burns, hypopigmentation, and death.[47]

Prolonged cryotherapy also does not appear to offer any benefit and may be harmful to tissue. Animal studies have indicated that local cooling may increase tissue injury without improving mortality.[48, 49] Anecdotally, some snakebite victims report relief following cold application. It is reasonable to consider using icepacks briefly (eg, 5 min on for every 15-20 min), but prolonged application is discouraged.

Surgical intervention such as excising the affected tissue and “cutting and sucking”, in which an incision is made and then someone uses his or her mouth to “suck” out the venom, confers no benefit and potentially worsens outcomes by causing a bigger wound and introducing mouth flora into the tissue.[50]

The prehospital intervention for which there still seems to be much popularity, despite evidence that it is harmful, is venom extraction. Various commercially available suction devices promise to remove venom if applied shortly after the envenomation. However, the amount of venom they can remove is negligible. In an animal study using radioactive-labeled mock venom, these devices removed 0.04-2% of the envenomation load.[51] In a different animal study, tissue damage was increased following application of the negative-pressure device.[52] An editorial summarizing the use of extraction devices concluded that the risks of harm greatly outweigh any benefits and their use should be abandoned.[53]

Once the patient has arrived at the hospital, definitively manage any life-threatening airway, breathing, and circulatory issues. Airway patency may be compromised in severe envenomations or in the rare case of anaphylaxis in response to snake venom. Epinephrine should be administered to anyone with anaphylaxis, and intubation should be performed if patients do not respond. Intubation is also necessary for patients who have impaired ventilation secondary to respiratory muscle weakness. Intravenous fluid resuscitation may be needed to restore euvolemia in patients with significant hypovolemia secondary to gastrointestinal losses and/or third-spacing. Excessive fluid administration should be avoided because it can theoretically exacerbate tissue swelling.

Analgesia is an essential component to snakebite management. Intravenous opioids are preferred initially. NSAIDs are discouraged because of the potential hematologic effects.

There is consensus that the crotalid-envenomated limb should be elevated once the patient has arrived at the hospital. This prevents the venom from accumulating in the extremity and reduces the hydrostatic pressures that can exacerbate tissue swelling. The authors recommend using plaster to prevent the extremity from bending, but it is important to splint loosely; there should be no constriction and no obstruction to lymphatic flow.

Coral snake envenomations are not associated with tissue injury, and patients should be allowed to maintain a position of comfort.

Pictured below is proper elevation of an affected extremity. Notice that this is loosely applied so there is no obstruction to lymphatic flow.

Proper elevation of upper extremity bite. Courtesy of Spencer Greene, MD.

Laboratory tests should be obtained, and the affected extremity should be monitored for progression of swelling and tenderness. Evaluation of neuromuscular strength is recommended for envenomations from suspected neurotoxic snakes.

Physicians who are inexperienced with snakebites sometimes delay treatment until the exact species has been identified. This is unnecessary. Crotalid envenomation is generally a clinical diagnosis, and any pit viper can cause a combination of local damage, hematologic laboratory abnormalities, and systemic toxicity. It has also been demonstrated that many physicians cannot adequately distinguish one crotalid species from another.[54] It is easy to distinguish a crotalid envenomation from a coral snake envenomation, which is characterized by varying degrees of motor and sensory abnormalities but not by local tissue injury.

The specific treatment for crotalid envenomations is antivenom, and each patient should be assessed individually to determine if antivenom is indicated. As of March 2020, there are there two US Food and Drug Administration (FDA)–approved products. Crotalidae Polyvalent Immune Fab Ovine (CroFab®, FabAV) was first studied in 1993 and has been commercially available since 2000.[55] It is approved by the FDA for the treatment of all North American crotalid envenomation, so it can be used even when the species has not been determined. It is made by immunizing different flocks of sheep with the venom of one of four crotalid species: Western diamondback rattlesnake (Crotalus atrox), Eastern diamondback rattlesnake (Crotalus adamanteus), Mojave rattlesnake (C scutulatus), and cottonmouth (A piscivorus). The antibodies collected from the sheep are then treated with papain to liberate the individual Fab fragments of the immunoglobulin molecule. It has proven to terminate both local and systemic venom effects, resulting in faster and more complete recovery from envenomation when compared with placebo.[56, 57]

Crotalidae Immune F(ab’)2 Equine (Anavip®) was first used in Mexico in 1994 and became available in the United States in October, 2018.[58] It is approved by the FDA for the treatment of North American rattlesnake bites but not envenomations from copperheads or cottonmouths. It is made by immunizing horses with venoms from the Terciopelo (Bothrops asper) and the South American rattlesnake (Crotalus durissus). The antibodies are then treated with pepsin to create a F(ab)2 fragment without the Fc portion of the immunoglobulin that is typically responsible for adverse reactions to antivenom.

Indications for antivenom use include progression of local tissue findings and/or evidence of systemic toxicity (eg, hematotoxicity, airway swelling, cardiovascular collapse). The precise definition of hematologic toxicity is unclear, but many providers use prothrombin time greater than >15 seconds, platelet count less than 150 x 103/µL, or fibrinogen level less than 220 mg/dL, or a significant change from baseline, as indications to treat. It should be emphasized that the SSS should not be used to determine the need for treatment. Reliance on this scale can result in significant undertreatment.

If the swelling and tenderness are more than minimal and have extended beyond a major joint (eg, wrist, ankle), antivenom is warranted.[42] If there is significant local tissue injury (eg, necrosis), antivenom is also indicated, even if the swelling has not progressed across a joint. A randomized clinical trial studying the effects of FabAV on copperhead bites demonstrated that even mild bites recovered better when treated with antivenom.[59] Specifically, patients had improved limb function at 7, 10, and 14 days post envenomation compared with the placebo group, and 75% of treated patients had full recovery of limb use by day 31, whereas the control group did reach this milestone until 57 days. Treatment was especially beneficial in patients who were treated within 5.5 hours of envenomation.[60] Additionally, people who were treated with antivenom required opioids for a much shorter duration.[61]

The decision to use one over the other will likely be based on several variables, including availability, cost, and safety concerns, such as prior sensitization to equine- or ovine-derived products.

Epinephrine is useful in patients with anaphylaxis, and diphenhydramine can help with mild urticaria and pruritus, but neither is a substitute for antivenom.

Coral snakes are elapids, not crotalids, and neither FabAV or F(ab)2AV is indicated for coral snake envenomations. There is only one FDA-approved antivenom for native coral snake envenomations.[62] The North American Coral Snake Antivenom (NACSAV) (Micrurus fulvius) (Equine Origin) was first developed in the 1960s. Production was halted in 2010. However, some lots of antivenom are still in circulation, and as of late 2019, production has resumed. Most hospitals will not keep NACSAV in stock, and it may be necessary to contact poison control to locate the antivenom or a suitable alternative.

There are several foreign antivenoms that have demonstrated efficacy against native coral snake venom.[63, 64, 65] Coralmyn®, manufactured by Bioclon, has proven to be effective in the treatment of Eastern coral snake (M fulvius) envenomations. Another antivenom, produced by Costa Rica’s Instituto Clodomiro Picado, has also been used successfully in the treatment of US coral snake envenomations.

Neostigmine is a peripherally acting cholinesterase inhibitor that can increase synaptic concentrations of acetylcholine, allowing the neurotransmitter to compete with the toxins, preventing paralysis. Several case reports have suggested a modest temporizing benefit in envenomations from coral snake and other elapids.[66, 67] There are few adverse effects from neostigmine at therapeutic doses, so it is reasonable to administer it following Eastern coral snake (M fulvius) envenomations in which the likelihood of objective neurotoxicity is high.

Patients with suspected dry bites should be monitored for at least 8 hours, and laboratory tests should be rechecked prior to discharge. Snakebites are dynamic, and bites that appear insignificant at first can evolve into severe envenomations. Minimal envenomations that do not require antivenom initially should be observed for a minimum of 12-24 hours to see if there is any progression of the local effects and/or the development of any systemic or hematologic toxicity.

Patients should be admitted to the hospital or an observation unit if there is any evidence of envenomation, whether or not antivenom has been administered. The decision to admit to a general medical ward versus the ICU depends on the severity of the envenomation, the availability of resources, and specific hospital protocols. The authors recommend that the initial dose of antivenom should be administered in a monitored setting (eg, emergency department, ICU).

Most snake envenomations do not require prolonged hospitalization. Unless the patient requires a prolonged course of antivenom, develops end-organ damage, or requires parenteral narcotics, most snakebite victims can be discharged within 24-36 hours. During the hospitalization, it is advisable to have a physical therapist consult on patients with lower extremity bites to assist them with crutches training. Consultation with an occupational therapist and/or a hand specialist may be indicated for bites to the hand.

Patients may be discharged home once the following criteria are satisfied:

• The antivenom course has been completed
• Pain can be controlled with oral medication
• Vital signs have stabilized
• The patient can tolerate a regular diet
• Any hematologic laboratory abnormalities have normalized
• All of the appropriate consultations have been completed

Patients with a crotalid envenomation should be instructed to keep the affected extremity elevated as much as possible. The authors also recommend no weight-bearing for at least 1 week and until it is no longer painful. Snakebite victims should follow up 3-4 days post discharge with a snakebite expert, if possible, or their primary care provider for reassessment and, if indicated, repeat bloodwork. Patients should be instructed to avoid NSAIDs if there is any risk of hematologic toxicity. Surgery should also be avoided for the first 2 weeks post envenomation.

Although surgeons are often involved in the management of snake envenomation in the United States, it is essential to recognize that snakebites are a medical, not surgical, condition. Excision of the bite site was once recommended, but it is now understood that this is a disfiguring procedure that does not confer any survival benefit.

Compartment syndrome is an exceptionally uncommon complication from crotalid envenomation, and prophylactic fasciotomies are no longer recommended. Animal studies prove that morbidity and mortality are increased following prophylactic fasciotomy when compared with antivenom therapy.[68, 69, 70] In a review of 99 publications evaluating the efficacy of fasciotomy in animals and humans, the author could not identify any situation in which surgical intervention was beneficial.[71] An expert panel consisting of trauma surgeons and medical toxicologists also concluded that prophylactic fasciotomy was not beneficial and was possibly harmful.[50] The same authors concluded that even in the exceptionally rare case of confirmed compartment syndrome, the initial treatment should be additional doses of antivenom, not fasciotomy. The rationale, supported by animal studies, is that elevated compartment pressure represents a severe envenomation but is not the cause of the morbidity. Rather, it is the venom that is causing the damage, and neutralizing the venom is the definitive treatment.[72] Fasciotomy should only be considered in those patients with persistently elevated compartment pressures despite adequate antivenom therapy.

Delayed surgical intervention following envenomation is indicated when there is full-thickness necrosis requiring amputation. Premature surgery must be avoided, however, because many patients with superficial necrosis recover fully if managed with conservative wound care.

Coral snake envenomations are not characterized by tissue injury and do not require surgical intervention.

Consulting your local or regional snakebite expert early in the hospital course is recommended. Medical toxicologists are often the physicians with the most knowledge and experience managing envenomations, but some institutions have experts from other specialties. Help is also available by calling the regional poison center at 1-800-222-1222.

Antivenom-associated complications are rare but may include immediate (anaphylaxis, type I) and delayed (serum sickness, type III) hypersensitivity reactions. Anaphylaxis is an event mediated by IgE, involving degranulation of mast cells that can result in laryngospasm, vasodilatation, and leaky capillaries. Death is common without pharmacological intervention. Serum sickness occurs 1-2 weeks after administering antivenom. Precipitation of antigen-IgG complexes in the skin, joints, and kidneys is responsible for the arthralgias, urticaria, and glomerulonephritis (rarely).

In a meta-analysis of 11 studies, Schaeffer et al reported an 8% incidence of acute adverse reactions following FabAV use.[73] Data from the North American Snakebite Registry indicated that only 2.3% of adults and 2.7% of children who received FabAV had acute adverse reactions, including rash (0.9%), hypotension (0.9%), and bronchospasm (0.9%).[74] Finally, in a study of 1,340 patients treated with FabAV in Arizona, the incidence of acute adverse reactions was 1.4%.[75] None was serious enough to require discontinuation. Serum sickness was reported in 13% of patients in the meta-analysis. Serum sickness from FabAV was not observed in the other studies.

There are no studies that specifically measure the incidence of adverse reactions following F(ab’)2AV use. The package insert cites an incidence of 76%, including pruritus (43%) and rash (12%). In a randomized clinical trial comparing F(ab’)2AV to FabAV, the incidences of pruritus and rash were 42.5% and 12.5%, respectively, in the F(ab’)2AV group.[76]

There is an unfounded fear of administering antivenom to patients who have previously received it. Most people who have been treated with FabAV more than once have no adverse reaction to the second and subsequent exposures. In one exceptional case, a man who received FabAV at least 19 times had two episodes of mild acute hypersensitivity but tolerated the antivenom the other 17 times without incident.[77]

Also see Complications in Presentation.

While in the hospital and for approximately 1 week after discharge, the patient should not bear weight with the affected extremity.

Prevention is key; people who live in snake-endemic areas should wear appropriate footwear and avoid placing their hands and feet where they cannot see.

The goals of pharmacotherapy in the treatment of snakebite are to alleviate pain, prevent paralysis, minimize tissue damage, correct hematologic toxicity, and maintain adequate perfusion.

Class Summary

Available antivenin in the United States include Crotalidae Polyvalent Immune Fab Ovine (CroFab; FabAV) and Crotalidae Immune F(ab’)2 equine (Anavip; Fab2AV). Each are indicated for envenomation from American pit vipers, including rattlesnakes, copperheads, and cottonmouths (water moccasins).

Indications for antivenin use in crotalid envenomation include significant or progressive local tissue findings, hematologic laboratory abnormalities, and/or evidence of systemic toxicity (eg, airway swelling, neurological toxicity, cardiovascular collapse). The sooner antivenin is initiated, the more effective it is.

Regardless of the antivenin used, the goal is to establish “initial control”, which means any systemic illness has resolved, any hematologic laboratory abnormalities have begun to improve, and there is no further progression of the local effects. In 95% of patients, control is achieved within 1 hour following the initial dose of FabAV.

There is only one FDA-approved antivenin for native coral snake envenomations. Most hospitals do not keep NACSAV in stock, and it may be necessary to contact poison control or a regional snakebite expert for dosing instructions and to locate the antivenin or a suitable alternative.

Crotalidae polyvalent immune FAB (ovine) (CroFab)

Crotalidae polyvalent immune Fab is an affinity-purified, mixed monospecific Crotalidae antivenin indicated for the treatment of envenomation caused by North American pit vipers.

It can minimize local, hematologic, and systemic effects following copperhead, cottonmouth, and rattlesnake envenomation. Although it is most useful if started within 5.5 hours of the envenomation, it can still provide benefit even several days after the envenomation.

A randomized clinical trial of FabAV use in copperhead envenomations demonstrated that even mild bites recover faster when treated with antivenin.

Crotalidae immune FAB (equine) (Anavip)

Crotalidae Immune F(ab’)2 Equine is an equine-derived F(ab’)2AV that is indicated for the treatment of envenomation caused by North American pit vipers.

A randomized clinical trial demonstrated that F(ab’)2AV can reduce the risk of subacute coagulopathy and bleeding following treatment of envenomation.

Class Summary

Infections following snakebite are exceptionally uncommon. Prophylactic antibiotics are not recommended. They do not improve outcomes, and indiscriminate antibiotic use leads to adverse effects, antibiotic resistance, and unnecessary costs.

Antibiotics should only be administered if there is clinical evidence of an infection. The choice of oral versus parenteral antibiotic should be based on the patient’s overall condition, but coverage should be broad.

Class Summary

Snakes do not harbor Clostridium tetani in their mouths, and the risk of acquiring tetanus following snake envenomation is exceptionally low. That said, if a patient's tetanus immunization is not current, a TDaP should be administered while the patient is being evaluated. However, tetanus immunoglobulin in unnecessary.

Diphtheria-tetanus toxoid (Decavac)

Diphtheria-tetanus toxoid is used to induce active immunity against tetanus in selected patients. The immunizing agents of choice for most adults and children older than 7 years are tetanus and diphtheria toxoids. It is necessary to administer booster doses to maintain tetanus immunity throughout life.

Pregnant patients should receive only tetanus toxoid, not a product containing the diphtheria antigen.

In children and adults, one may administer into the deltoid or midlateral thigh muscles. In infants, the preferred site of administration is the mid thigh laterally.

Class Summary

Anticholinesterase inhibitors interfere with the degradation of acetylcholine by acetylcholinesterase, thereby increasing the amount of acetylcholine available at the neuromuscular junction and increasing the chance of activating the acetylcholine receptors.

Neostigmine (Bloxiverz, Prostigmin)

Neostigmine is a peripherally acting inhibitor of acetylcholinesterase. It allows acetylcholine concentrations at the neuromuscular junction to rise and overcome any postsynaptic blockade by the alpha-toxins that may be present in coral snake venom.