122: Native (US) Venomous Snakes and Lizards

Snakes

Over 3000 species of snakes have been identified worldwide, with nearly 800 species considered venomous. All venomous species are classified taxonomically into one of four general groups. These include the families Viperidae, Elapidae, and Colubridae, as well as the Atractaspidinae, a subfamily of the Lamprophiidae family.⁴⁹ The United States is home to nearly 30 species and subspecies of venomous snakes (Table 122–1), with many more found throughout Mexico. All belong to the Crotalinae subfamily of Viperidae or to the Elapidae family.

Venomous snakes possess glands that are associated with specialized teeth, or fangs, which allow delivery of venom for the purpose of prey immobilization or defense. Fangs are located in the front of the mouth in most venomous species. In addition to fangs, venomous snakes have rows of small teeth that may cause additional injury during a bite.

The majority of snake species in North America are rear-fanged, non-venomous members of the Colubridae family. Bites by these species, which include corn snakes, gopher snakes, and garter snakes, are usually harmless. Colubrids do not possess venom glands, but may produce secretions from Duvernoy’s glands that contain toxins similar to those found in the venom of venomous species. Although the vast majority of bites by nonvenomous colubrids do not produce symptoms, rare cases of envenomation have been documented following a bite by a nonvenomous species.⁵⁷

Venomous snakes are found throughout most of the United States. They are much more common in the southern and western states than in the northern states. Though venomous species are not endemic to Maine, Alaska, or Hawaii, bites have been reported in every state except for Hawaii. The true number of bites that occur each year is not accurately known, but an average of 5000 native venomous snakebites are reported to US poison centers annually.⁴³ Mortality is rare, with fewer than 10 deaths per year reported. Epidemiologic data on snakebites in Mexico is poor, but the number of bites and deaths is thought to be higher.²⁹

The majority of snakebites occur between April and September, with the peak number reported in July. Men comprise 75% of snakebite victims and children represent about 10% to 15% of reported cases.⁴³ Most victims are bitten on an extremity, although bites to the torso, face, and tongue also occur. Over half of reported bites occur when an individual is purposely handling a known venomous snake. Herpetologists, those who capture and keep wild snakes, and religious snake handlers are at highest risk. Occasionally people are envenomed after killing and decapitating a rattlesnake. This is likely due to persistent reflexes in the venom apparatus.

Snake handlers and collectors are at risk for multiple bites during their lifetime. There is no convincing evidence that immunity develops as a result of repeated envenomation. Victims of repeat bites may actually have a greater risk for anaphylaxis because of prior sensitization and the development of IgE antibodies to venom.

Snake enthusiasts often keep nonnative species as pets. Approximately 30 to 50 bites from a large variety of exotic venomous snakes are reported to poison centers each year.⁴⁵

Pit Vipers.

The majority of native venomous snakes are members of the Crotalinae subfamily of Viperidae. These crotaline species are variably referred to as crotalids, new world vipers, or pit vipers. The term ‘pit viper’ describes the presence of a pitlike depression behind the nostril that contains a heat-sensing organ used to locate prey. Native pit vipers include the rattlesnakes (genera Crotalus and Sistrurus) and the cottonmouths and copperheads (genus Agkistrodon). These pit vipers can be distinguished from native nonvenomous species by a triangular-shaped head, vertically elliptical pupils, and easily identifiable fangs (Fig. 122–1). Crotalinae have front, mobile fangs that are paired, needlelike structures that can retract on a hingelike mechanism into the roof of the mouth. Rattlesnakes have the longest fangs, reaching 3 to 4 cm. Pit vipers may also be identified by their scales. Their undersurface has a single row of plates or scales, as opposed to the double row found on nonvenomous species. Rattlesnakes may or may not have rattles, depending on maturity. A rattling sound is often, but not always, heard before a strike. Copperheads and cottonmouths do not have rattles, but may shake their tales similarly to rattlesnakes. Cotton­mouths, which are also commonly known as water moccasins, are semiaquatic and have a distinct white mouth. Copperheads are known for their reddish-brown (copper) heads and hourglass markings on their bodies (Fig. 122–2).

The vast majority of North American snake envenomations are from bites by crotalids. Of those bites for which the type of snake is reported, about half are rattlesnake species, and the remainder copperheads and ­cottonmouths. Rattlesnakes are found throughout most of the United States, but encounters are most common in western and southern states. Rattlesnakes account for the greatest morbidity among the various types of pit vipers. Deaths following snakebite are almost always due to rattlesnakes, although rare deaths have been associated with copperhead bites. Copperhead bites are most often reported in the eastern and southeastern United States, although they also occur in the northeast. Cottonmouths are found mainly in the southeastern United States.⁴³

Coral Snakes.

Coral snakes (genera Micrurus and Micruroides) represent the Elapidae family in North America. These brightly colored snakes typically have easily identifiable red, yellow, and black bands along the length of their bodies. In the United States, coral snakes and the similarly colored nonvenomous scarlet king snake are often confused. Coral and king snakes can be distinguished by their color patterns. Whereas coral snakes have black snouts, king snakes have red snouts. Both species have red, yellow, and black rings, but in different sequences: the red and yellow rings touch in the coral snake but are separated by black rings in king snakes (“Red on yellow kills a fellow; red on black, venom lack”) (Fig. 122–3). This general rule for identifying coral snakes does not apply to Mexican species, some of which may have different color patterns.

Elapids possess front fixed fangs. The fangs of coral snakes are small, and discrete fang marks may not be obvious after envenomation. Coral snakes often latch on to a victim or “chew” for a few seconds in an attempt to deliver venom. A history of this activity may help identify a coral snakebite when the offending reptile cannot be located.

Coral snakes are responsible for approximately 2% of bites reported to US poison centers.⁴³ Micrurus species are found in 11 southeastern states, where up to 100 bites are reported per year. Micrurus fulvius (the Eastern coral snake) is responsible for the greatest morbidity and mortality, while M. tener (the Texas coral snake) seems to be less dangerous. The Sonoran coral snake (Micruroides euryxanthus) does not produce envenomation necessitating medical intervention.⁵⁶

Lizards.

There are two species of lizard that are known to produce envenomation in humans. These are the Gila monster (Heloderma suspectum) (Fig. 122–4), which is native to the desert southwestern United States, and the beaded lizard (H. horridum), which is found in Mexico. Both species are members of the Helodermatidae family. These lizards are slow moving, nocturnal, and thick bodied. Adults may reach a length of 60 cm and are generally shy, so bites are relatively rare and usually occur as a result of handling. Gila monsters are known for their forceful bites. They can hang on and “chew” for as long as 15 minutes, and they may be difficult to disengage.¹⁸

The helodermatid lizards have a less effective venom delivery system than venomous snake species. The lizards possess paired venom glands that are located on either side of the anterior lower mandible. Venom ducts carry the venom from the glands to the base of grooved teeth. When a tooth produces a puncture wound, the venom travels by capillary action into the grooves and then into the wound.⁴⁰

Bites by the Gila monster and beaded lizard are extremely uncommon, even in areas where the lizards are endemic. Bites almost always occur from captive animals, whether found in the wild or kept in a zoo or personal collection. The great majority of reported cases have involved adult men.

Snakes

Snake venom is a complex mixture of proteins, peptides, lipids, carbohydrates, and metal ions. Venom may contain a variety of enzymes including phospholipases A₂ (PLA₂s), metalloproteinases (SVMPs), serine proteases, acetylcholinesterases, L-amino acid oxidases, and hyaluronidases. Non-enzymatic proteins include three finger toxins (3FTXs), sarafotoxins, disintegrins, and C-type lectins among others. The content and potency of venom in any given snake may vary depending on age, diet, and geography. Thus an adult snake may have significantly different venom composition than a young snake of the same species.⁵⁴

Snakes typically produce about 100 to 200 mg dry venom in a ­single milking, although some may produce several hundred mg to over 1 g.⁵⁴ Many venom components are pharmacologically active and target receptors, ion channels, enzymes, or other proteins in mammals. The actions of only a fraction of snake venom components are fully understood. Identification of individual snake venom toxins, understanding of pharmacologic mechanisms, and potential medicinal uses for venom are areas of ongoing research.

Lizards.

Helodermatid venom contains a complex mixture of components similar to those of snake venoms, including numerous enzymes such as hyaluronidase, phospholipase A₂, and serotonin.^40,52 Nonenzymatic components include helospectins and helodermin, which are vasoactive peptides that activate adenylyl cyclase, and exendin-3 and exendin-4, which stimulate glucose-dependent insulin secretion. Discovery of exendins in Heloderma venom lead to development of exenatide (Byetta), a glucagon-like peptide-1 (GLP-1) receptor agonist used in the management of diabetes.^20,52 Another important component of Heloderma venom is gilatoxin. Gilatoxin is a serine protease with kallikreinlike activity, thought to be responsible for the hypotension and angioedema that occur in some human envenomations.⁵²

Snakes

Very few pharmacokinetic studies of snake venom exist, and much remains unknown regarding absorption, distribution, and elimination of venom following a bite. When a snake bites, venom is usually deposited subcutaneously. In some cases fangs may reach muscle or even directly access vasculature. Systemic absorption of venom usually occurs via the lymphatic system. Available human and animal data suggest that venom antigens are absorbed into blood within minutes of envenomation, with peak concentrations detected within 4 hours.^8,26,44 Venom antigen concentrations measured in the first 4 hours following a bite correlate roughly with grade of envenomation.^2,7,26 Venom antigens are also detected in urine as early as 30 minutes after envenomation.²⁶ After administration of adequate doses of antivenom, venom antigens are no longer detected in blood; however, antigenemia may recur, and such recurrence is associated with reemergence of clinical effects.^26,44

The elimination half-life of snake venom appears to be long. Following subcutaneous injection of C atrox venom in a rabbit model, mean half-life was 20 hours, and venom was still detectable in blood at 96 hours.⁸

Lizards.

Pharmacokinetic studies of helodermatid venom are not available. Clinical reports suggest that venom is absorbed systemically within minutes of a bite.

Snakes

Pit Vipers.

Crotaline venom can simultaneously damage tissue, affect blood vessels and blood, and alter transmission at the neuromuscular junction. It is difficult to attribute specific pathology or pathophysiology to any particular component of snake venom. In fact, clinical effects often occur as the result of several venom components (Table 122–2). For instance, local tissue damage results from venom metalloproteinases and hyaluronidase, which both contribute to swelling through disruption of the extracellular matrix and basement membrane surrounding microvascular endothelial cells.²⁴ As a result of reduced blood flow through damaged capillaries, they may also contribute to myonecrosis, which results primarily from the action of phospholipase A₂ enzymes (PLA₂) on muscle.²⁴ Additionally, venom metalloproteinases contribute to dermatonecrosis, both directly and through activation of endogenous inflammatory mediators.^24,48

Venom effects on the hematologic system are especially complex. Numerous components act as anticoagulants, and many others act as procoagulants. Similarly, platelets may be inhibited, activated, agglutinated, aggregated, or inhibited from aggregating by various venom components. Venom components can be grouped according to certain characteristics, such as structure and enzymatic activity, but as noted above with local tissue damage, components within several groups may contribute to similar effects. For instance, anticoagulants in snake venoms are found among the C-type lectinlike proteins (CLPs), PLA₂ enzymes, serine proteases, and metalloproteinases. Conversely, components within a single group may have many different actions. Various CLPs in venom act as anticoagulants, procoagulants, or platelet modulators. PLA₂ enzymes are especially diverse, acting as anticoagulants and platelet modulators in addition to producing myotoxic and neurotoxic effects. Platelet effects result mainly from the action of disintegrins, although CLPs, PLA₂ enzymes, and other proteinases also have platelet-modulating effects.^36,60

Specific hematologic effects are species dependent, with no single venom containing all of the identified hemostatically active components. Of particular importance to North American rattlesnake envenomation are the thrombinlike enzymes and fibrinogenolytic enzymes. These are metalloproteinases and serine proteases that preferentially cleave fibrinopeptide A or fibrinopeptide B from fibrinogen. Unlike thrombin, they do not activate factor XIII. The end result is production of a poorly cross-linked fibrin clot that easily degrades. Multiple other venom components exist, some of which affect the vascular system and contribute to the hypotension that sometimes occurs clinically. Examples include bradykinin-potentiating peptides and vascular endothelial growth factors.^47,60

Snake neurotoxins act at the neuromuscular junction and do not cross the blood–brain barrier. They are classified as α-neurotoxins, which act postsynaptically, and β-neurotoxins, which act presynaptically. The Mojave rattlesnake, C. scutulatus, is known for its neurotoxic venom. The neurotoxin, Mojave toxin, is a PLA₂ that acts at the presynaptic terminal of the neuromuscular junction to inhibit acetylcholine release. The presence of Mojave toxin in venom appears to be geographically distributed, with Mojave rattlesnake populations in California and southeast Arizona possessing functional Mojave toxin, and central Arizona populations lacking the neurotoxin.^22,59 Mojave toxin has also been identified in the venom of the Southern Pacific rattlesnake (C. oreganus helleri) found in southern California, and envenomations by this species have produced neurologic symptoms.^10,19

Coral Snakes.

Coral snake venom contains neurotoxins that produce systemic neurotoxicity. Unlike crotaline venom, coral snake venom does not cause local tissue injury. Similar to neurotoxins present in other elapid species, α-neurotoxins bind and competitively block post synaptic acetylcholine receptors at the neuromuscular junction, leading to weakness and paralysis. Phospholipase A₂ can also cause myotoxicity, although this appears to be of less clinical importance. The LD₅₀ of M. fulvius venom is lower than that of M. tener venom, which corresponds to the more severe effects noted in humans following Eastern coral snake envenomations.⁴¹

Lizards.

The pathophysiology of helodermatid venom is poorly understood. It is suggested that hyaluronidase contributes to spreading of venom throughout tissue.⁴⁶ Gilatoxin is believed to produce hypotension and other findings such as angioedema by increasing bradykinin levels.⁵²

Snakes

The clinical presentation of North American snake envenomation is highly variable and depends upon many factors, including the species of snake, the amount and potency of venom deposited, the location of the bite, and patient factors, such as comorbidities. It is important for the clinician to be familiar with endemic venomous snake species in order to anticipate clinical effects when presented with an envenomed patient. For bites by nonnative species, it is imperative to identify the species so that specific antivenom can be sought.

Pit Vipers.

Envenomation by North American pit vipers is characterized by local swelling and cytotoxic effects. Hematologic effects are common, and there is the potential for development of systemic illness and neurotoxicity. Most patients exhibit only a subset of possible effects of envenomation. In addition, some of the signs and symptoms in a given individual, such as nausea or tachycardia, may be related to fear rather than to envenomation.

The clinical presentation following a pit viper bite can range from benign to life threatening (Table 122–3). One finding common to all ­victims is the presence of an identifiable disruption of skin integrity. Most commonly, one or two distinct punctures are present, though occasionally, patients exhibit multiple punctures, small lacerations, or scratches.

Since pit viper bites result in injection of venom only about 75% of the time, approximately 25% of bites do not result in envenomation and are considered “dry bites.” Unfortunately, it is impossible to diagnose a dry bite without an extended period of observation, since some patients may have delayed onset of symptoms for as much as 8 to 10 hours following the bite. On occasion, patients may initially present asymptomatic yet go on to develop serious illness. Even for patients who do present with symptoms, it may require a number of hours for the full extent of clinical illness to become evident. As a general rule, however, it may be assumed that envenomation from a pit viper has not occurred if no symptoms develop within 8 to 10 hours from the time of the bite.

Of the North American pit vipers, rattlesnakes are responsible for the most severe clinical presentations. Agkistrodon (cottonmouth and copperhead) bites generally tend to produce less severe local and systemic pathology than rattlesnake bites. Copperhead bites in particular rarely cause systemic symptoms, and pathology is usually limited to soft tissue swelling without necrosis.⁵⁵ However, serious copperhead envenomations occasionally occur, and at least one death has been reported in association with this species.⁴³

Local reactions.

Generally, within minutes after pit viper envenomation, the area around the puncture site becomes swollen and painful, and oozing of blood from the wound may be noted. Edema may stabilize quickly in mild envenomations, but more commonly, edema will gradually worsen over hours. In severe cases, edema may progress to involve an entire extremity within just a few hours. Swelling can worsen for days when untreated, extending proximally to involve the torso following bites to a distal extremity. Rarely, onset of appreciable swelling is delayed for as long as 10 hours. This is most often noted in lower extremity envenomations.

Ecchymosis may develop early at the wound site. Bites to the feet often exhibit a characteristic bluish tinge over the entire dorsal surface of the foot. Toes remain pink and well perfused, allowing distinction of this ecchymosis from cyanosis (Fig. 122–5). In the days to weeks following the envenomation, ecchymosis will often extend or new ecchymosis may develop proximally, even in the absence of significant venom-induced hematotoxicity.

Erythema may also develop at the envenomation site and sometimes spreads proximally from the wound along lymphatic pathways. Lymphangitic streaks are occasionally noted in the absence of infection.

Hemorrhagic blisters (blebs or bullae) often form at the site of the bite after rattlesnake envenomations. This most commonly occurs after bites to digits but may occur at any bite location or even in dependent areas distant from the bite (Fig. 122–6). Blebs usually do not appear for several hours after the envenomation but can progress for several days. Tissue underlying blebs is often healthy, but extensive bleb development may signify underlying tissue necrosis (Fig. 122–7).

Myonecrosis is not a feature of most native pit viper envenomations but does sometimes occur. In rare cases fangs may directly penetrate muscle leading to localized necrosis. With subfascial envenomation there is a risk for compartment syndrome, which could lead to necrosis. Compartment syndrome is very rare following North American snakebite and cannot be reliably diagnosed in envenomed extremities without directly measuring compartment pressures. More often than not envenomation simply mimics a compartment syndrome by producing distal paresthesias, tense soft ­tissue swelling, pain on passive stretch of muscles within a compartment, and muscular weakness. One study, using noninvasive vascular arterial studies and skin temperature determinations in patients with rattlesnake envenomation, demonstrated that pulsatile arterial blood flow to an envenomed extremity actually increased after envenomation, even distal to the site of envenomation.¹⁵

In addition to local myonecrosis, generalized severe rhabdomyolysis may occur in the absence of impressive muscular swelling. This finding is considered characteristic after envenomation by the Canebrake rattlesnake (Crotalus horridus atricaudatus), which was previously classified as a subspecies of the Timber rattlesnake (C. horridus). Current prevailing opinion is that they are the same species.^12,50

Hematologic toxicity.

Venom-induced effects on the hematologic system are common following bites by North American pit vipers, in particular rattlesnakes. Coagulopathy, thrombocytopenia, or a combination of the two, may be present despite a paucity of other local or systemic effects. A decrease in platelet count, as well as decreases in fibrinogen with elevation of prothrombin time (PT), may be mild or modest initially and may either remain so or continue to worsen for several days following the envenomation. Alternatively, severe decreases in platelet counts (in the 5000–50,000/mm³ range) and fibrinogen concentrations (to near zero) with immeasurably high PTs may occur within minutes to hours of crotaline envenomation. A rise in PT generally follows a drop in fibrinogen, as concentrations of clotting factors remain normal in case reports of North American crotaline envenomation with coagulopathy.¹¹ The likelihood of thrombocytopenia or coagulopathy occurring after a given snakebite may depend on the particular species and venom populations present in the geographic area. In the desert southwest, coagulopathy occurs in approximately half and thrombocytopenia in one-third of patients presenting with envenomation.³⁹ Thrombocytopenia appears to be especially common and often severe after the bite of the Timber rattlesnake (Crotalus horridus).³ The protein crotalocytin that is found in Timber rattlesnake venom causes platelet aggregation and is thought to be at least partially responsible for the thrombocytopenia.

Despite the high rate of hematologic effects following rattlesnake envenomations, the vast majority of patients have no clinical bleeding, even when severe laboratory abnormalities are present. Bleeding appears to be more common when platelets are very low or when both coagulopathy and thrombocytopenia are present and severe.

Systemic toxicity.

Clinical findings following most pit viper bites are limited to local tissue damage or hematologic pathology, but systemic symptoms may develop. When present, systemic signs and symptoms are often mild and include nausea, metallic taste, restlessness, and nonspecific weakness. Tachycardia, vomiting, diarrhea, and confusion may also occur. These more significant systemic symptoms have been noted to precede severe systemic toxicity. In the most severe cases, patients quickly develop circulatory shock or airway edema with obstruction, which may be caused by anaphylactoid responses to venom components.

Rarely, patients bitten by crotalids may experience classic anaphylaxis from the venom itself, which may complicate evaluation or mimic a severe systemic reaction to venom. Previous sensitization to venom results in development of IgE antibodies to venom in these patients. This is thought to occur more frequently in patients who have previously experienced a snakebite, but it has also been observed in snake handlers who are thought to be sensitized to snake proteins through inhalation or skin contact. The presence of pruritus and urticaria or wheezing, uncommon with envenomation, should suggest anaphylaxis.

There are rare reports of true disseminated intravascular coagulation (DIC) with spontaneous bleeding along with significant hypotension and multiorgan system failure following rattlesnake bite. In such cases of true DIC, the patient has evidence of organ infarction and hemolysis. This has been reported after intravascular envenomation.¹⁶

Neurotoxicity.

Although local tissue destruction dominates the ­picture of Crotalinae envenomations, neurotoxic effects may also occur. The Mojave rattlesnake (C. scutulatus) is best known for its neurotoxic venom. ­Subpopulations of the Mojave rattlesnake that possess the neurotoxic Mojave toxin may produce weakness, cranial nerve dysfunction, and respiratory paralysis in victims.²⁸ The Timber rattlesnake (C. horridus) is noted to commonly cause rippling fasciculations of the skin (myokymia), particularly of the facial muscles.⁴ Fasciculations are reported following envenomation by several other species of rattlesnake, including the Western Diamondback (C. atrox), Mojave (C. scutulatus), and the Southern Pacific (C. o. helleri).¹³ Fasciculations involving the shoulders, chest wall, and torso are associated with development of respiratory failure.⁵³

Coral Snakes.

Coral snake fangs are small and nonmobile, and as a result, bites are less likely than pit viper bites to lead to envenomation. An estimated 40% of patients bitten by a coral snake are subsequently determined to have been envenomed, with rates for the Eastern coral snake species possibly higher.³¹ The venom of the Eastern coral snake (Micrurus fulvius) and Texas coral snake (M. tener) are more potent than that of the Sonoran coral snake (Micruroides euryoxanthus). In fact, there have been no reported cases of serious toxicity after the bite of the Sonoran coral snake, which is found primarily in Arizona and western New Mexico.

Coral snake fangs may not produce easily identifiable puncture wounds. In addition to the absence of a discernable wound in some victims, coral snake envenomations are characterized by potentially serious neurotoxicity without impressive local symptoms. The effects of envenomation are characteristically delayed for a number of hours. One report described a patient who had an asymptomatic period of 13 hours followed by rapid development of paralysis severe enough to require ventilatory support.³¹ Neurologic abnormalities reported with coral snake envenomation include paresthesias, slurred speech, ptosis, diplopia, dysphagia, stridor, muscle weakness, fasciculations, and paralysis. The major cause of death is respiratory failure secondary to neuromuscular weakness. Muscle weakness may take weeks to months to resolve completely. With respiratory support, however, paralysis is completely reversible. Pulmonary aspiration is a common sequela in the subacute phase.

Lizards.

The rate of envenomation following Gila monster bites is not known, but one case series reported 40% dry bites.⁴⁰ When a Heloderma species bites, it may release quickly or it may hang on and “chew.” Multiple reports are documented where Gila monsters were attached to the victim for up to 15 minutes, and in some cases teeth have broken off in the wound.

Pain is immediate following a bite, and local soft tissue edema may develop within minutes. Swelling may extend from the puncture site, though not as commonly or dramatically as occurs following pit viper envenomation. Helodermatid venom does not produce local tissue necrosis, but erythema at the wound site and extension of erythema to an entire extremity is well described. Lymphangitic streaking is also reported.^18,27,46

Nausea, vomiting, and diaphoresis may occur following helodermatid envenomation. Patients are often tachycardic and hypotension is common. There are numerous reports of upper airway angioedema developing after bites by both Gila monsters and beaded lizards. There is a single report of a young man developing a myocardial infarction after a Gila monster envenomation.³⁸

Leukocytosis is common following envenomation, with reported white blood cell counts as high as 48,000/mm³.³⁸ Unlike crotaline venom, Gila monster venom does not typically produce abnormalities in platelet counts or clotting factors, although a single report of coagulopathy exists following a Gila monster bite in the patient who also experienced a myocardial infarction.³⁸ It has been suggested that the coagulopathy occurred as a result of endothelial damage rather than direct effect of venom on the hematologic system.⁴⁶

Snakes

Diagnosis of North American snake envenomation is based on a history of a snakebite and presence of clinical signs of envenomation. There are no available laboratory assays for detection of venom in a wound. Although it is possible to measure blood and urine venom antigen concentrations using enzyme-linked immunosorbent assay (ELISA), this is only available in research settings and is not useful for early diagnosis or clinical management of envenomation.

Platelet counts, fibrinogen concentrations, and prothrombin times can be useful in the diagnosis of pit viper envenomation if they are abnormal. However, normal results do not exclude envenomation since thrombocytopenia and coagulopathy do not develop in all patients with pit viper envenomation.

A validated severity score for the objective assessment of crotaline envenomation has been developed and can be useful in a research setting.¹⁷ Its purpose is to assess the clinical condition of patients with snakebite, but it is not intended as a diagnostic tool. Caution should be used when applying this scale because envenomation is a dynamic process and severity can worsen or improve with time, limiting the utility of the score obtained at any given point in time.

Lizards.

The diagnosis of helodermatid envenomation is based on the history of a bite and presence of physical examination findings consistent with envenomation. There are no laboratory studies that are available to confirm or exclude the diagnosis, but a complete blood count may reveal leukocytosis.

Snakes

When a patient with a snake envenomation presents for care, the initial objectives are to determine the presence or absence of envenomation, provide basic supportive therapy, treat the local and systemic effects of envenomation, and limit tissue loss or functional disability (Table 122–3). A combination of medical therapy (mainly supportive care and, often, antivenom) and in some cases conservative surgical treatment (mainly débridement of devitalized tissue), individualized for each patient, will provide the best results. In general, the more rapidly treatment is instituted, the shorter the period of disability.

Pit Vipers

Prehospital care.

No first aid measure or specific field treatment has been proven to positively affect outcome following a crotaline envenomation. Prehospital care should generally be limited to immobilization of the affected limb, placement of an intravenous catheter, treatment of life-threatening clinical findings, and rapid transport to a medical facility. Patients who are volume depleted, vomiting, or experiencing systemic symptoms such as diarrhea should be given an intravenous fluid bolus. Hypotension that does not quickly respond to a fluid bolus should be treated with epinephrine.

In the past, various methods have been advocated to prevent systemic absorption of venom after snakebites. All of these methods are either ineffective and delay time to definitive care, or are potentially harmful. Such useless and potentially dangerous therapies include tourniquets, incision and suction, venom extractors, electrotherapy, and cryotherapy.

Pressure immobilization bandages (PIB), which are lymphatic-restricting bandages that are applied to the bitten extremity prior to immobilization with a splint, are not recommended for use in patients with North American Crotalinae bites. A randomized, controlled study of pressure immobilization versus observation in a porcine model with intramuscular injection of Crotalus atrox venom showed markedly increased compartment pressures in the pressure immobilization group. All animals died in this study, but the pressure immobilization group showed a prolonged time to death as compared to the control group. With local tissue necrosis being the major morbidity associated with pit viper envenomations in humans, not death, the authors concluded that PIB application cannot be suggested as a routine field procedure.⁹ The American College of Medical Toxicology, along with five other international organizations, released a position statement recommending against use of PIB for North American Crotalinae bites.¹

Hospital care.

When a patient presents to the hospital with history of crotaline snakebite, it is important to first determine whether an envenomation has occurred. While most patients do show early evidence of envenomation, absence of symptoms at presentation is not uncommon, and not all asymptomatic patients ultimately have “dry” bites. Patients who present with puncture wounds but without swelling or other evidence of envenomation must be observed for delayed onset of symptoms. Victims of a rattlesnake bite should be observed for 8 to 12 hours after the bite. If no swelling develops and laboratory studies remain normal, the bite is likely “dry,” and the patient may be discharged from medical care. A shorter, 6-hour observation period may be appropriate for copperhead bite victims prior to medical clearance.

Supportive.

The initial in-hospital assessment of North American crotaline envenomation should focus on airway, breathing, and circulation. Early airway management with endotracheal intubation should be considered in all patients with evidence of angioedema or with bites to the face or tongue. All patients, regardless of presenting symptoms, should have an intravenous catheter placed in an unaffected extremity and receive a bolus of IV fluids. Patients presenting with cardiovascular collapse should receive large volumes of fluid. An epinephrine continuous infusion, starting at 0.1 μg/kg/min and titrating as needed, is the vasopressor of choice for signs of shock.

The affected extremity should be immobilized in a padded splint in near-full extension and elevated above the level of the heart to avoid dependent edema. Although there are no studies to determine the effect of limb elevation on outcome, the authors believe this to be helpful since it may decrease dependent edema, which contributes to increased pain and physical examination findings concerning for compartment syndrome. The authors maximally elevate affected upper extremities by applying stocking net around the limb and attaching the distal end to a raised IV pole.

Marking the leading edge of swelling with a pen will help to identify progression of edema. A baseline complete blood count, PT, and fibrinogen concentration should be obtained initially and repeated in 4 to 6 hours. Patients who are systemically ill should also have electrolytes, creatinine phosphokinase, creatinine, glucose, and urinalysis checked. An electrocardiogram, chest radiograph, and blood gas may also be indicated in ill patients.

A comprehensive physical examination should be done, with emphasis on vital signs, cardiorespiratory and neurologic status, neurovascular ­status of the affected extremity, and evaluation for evidence of bleeding. Pain should be treated with opioid analgesics as needed, and tetanus prophylaxis should be addressed. The patient should be reassessed frequently with repeat physical examinations, specifically noting any progression of swelling. This may be accomplished by taking serial circumferential measurements of the involved extremity at multiple points proximal to the wound.

Prophylactic antibiotics are not indicated as studies show extremely low (0%–3%) rates of wound infections.³⁵ There is no indication for corticosteroids or antihistamines in the routine treatment of patients with snakebites, except for treatment of anaphylaxis.

Antivenom.

Patients with dry bites or with mild envenomations, such as those who present only with localized swelling that does not progress, do not meet criteria for antivenom³⁴ (Table 122–3). Patients who present with progressive swelling, thrombocytopenia, coagulopathy, neurotoxicity, or significant systemic toxicity are candidates for antivenom therapy. Antivenom given in a timely manner can reverse coagulopathy and thrombocytopenia and halt progression of local swelling. There is no evidence, however, that antivenom can prevent or reverse the development of tissue necrosis, so patients should be informed of the risk of tissue loss. This is most commonly noted with rattlesnake bites to the fingers, which occasionally lead to amputation of the digit despite appropriate treatment with antivenom.

The only currently FDA approved antivenom for North American pit viper envenomation is Crotalidae polyvalent immune Fab (CroFab, BTG). CroFab is an ovine-derived Fab fragment antivenom developed from commonly encountered North American pit vipers (C. atrox, C. adamanteus, C. scutulatus, A. piscivorus). CroFab is administered IV in an initial dose of four to six vials reconstituted in 0.9% sodium chloride solution. Patients who present with cardiovascular collapse or other life-threatening ­toxicity should be treated aggressively with a starting dose of 8 to 12 vials of CroFab.³⁴ The infusion is initiated at a slow rate for several minutes, and if no signs of an anaphylactoid reaction develop, increased to complete the infusion over one hour. The patient should be reassessed after completion of the infusion for evidence of continued swelling or worsening thrombocytopenia, and, if present, an additional four- to six-vial dose is infused. This process is repeated until control of symptoms is achieved. Fibrinogen and PT may be slower to recover in response to antivenom. If these are the only findings that continue to be abnormal after antivenom, it is reasonable to repeat these studies in 4 hours to determine if redosing of antivenom is necessary. Control is generally considered cessation of progression of swelling and systemic symptoms in addition to improvement in coagulopathy and thrombocytopenia. After control has been achieved, maintenance doses of antivenom are given as two vials every 2 hours for three doses (six total additional vials after control). Although recommended in the package insert for CroFab, maintenance therapy is not routinely administered by all practitioners.⁵ For example, maintenance doses may be unnecessary in the management of copperhead envenomations. Practitioners can learn local practices and recommendations through consultation with regional poison centers. An algorithm for treatment of North American crotaline snakebite is also available online.³⁴ Antivenom therapy is discussed in detail in Antidotes in Depth: A37.

Antivenom administration in children follows the same guidelines as adults, with doses based on clinical presentation and laboratory findings rather than weight. Attention should be paid to total amount of fluid received, and if necessary, antivenom can be reconstituted in a smaller total volume of fluid. Generally, patients with severe snake envenomation have large fluid requirements, and fluid overload is not a problem.

Pregnant patients who meet criteria for treatment should also receive antivenom. Crotalidae polyvalent Fab (ovine) is currently listed as pregnancy category C, but it has been used safely during pregnancy.³² Given the relative safety of this antivenom and the potential for fetal demise after envenomation, a low threshold for treatment should be considered. Fetal and maternal monitoring should be carried out throughout the patient’s care.³³

Surgery.

Surgery is not routinely indicated following snakebites. An extensive review of the literature failed to identify any evidence to support the use of fasciotomy in the treatment of snakebites.¹⁴ A single case of elevated compartment pressure (55 mm Hg) after rattlesnake envenomation was managed without fasciotomy. The authors treated this patient with antivenom, as well as mannitol and hyperbaric oxygen.²³ When compartment syndrome is suspected, intracompartmental pressures should be measured. It is reasonable to attempt to treat moderately elevated compartment pressures with antivenom initially, but clinical examination and compartment pressures should be followed closely. Just as there is no strong evidence to support the use of fasciotomy, similarly there is a lack of evidence demonstrating that surgery is unnecessary when intracompartmental pressures are high. If the patient develops evidence of limb ischemia or increasing compartment pressures, fasciotomy may be indicated.

Patients with bites to the digit may present with evidence of ischemia. The finger may appear cyanotic or pale, tense, and lack sensation. The small diameter of the digit and limited ability of the skin to expand essentially creates a small compartment. In such cases it may be reasonable to perform a digital dermotomy, where a longitudinal incision is made through the skin on the medial or lateral aspect of the digit in order to decompress the neurovascular structures. Although there are no studies evaluating the efficacy of dermotomy in preventing tissue loss, the authors have seen patients with cyanotic and insensate digits regain color and sensation immediately following this procedure. Dermotomy should not be performed prophylactically in cases of digital envenomation, as most patients have good outcome without any surgical intervention.²⁵

Debridement of hemorrhagic blebs and blisters is often performed to evaluate underlying tissue and relieve discomfort. Some patients may require surgical debridement of necrotic tissue or even amputation of a digit 1 to 2 weeks after the bite. Referral to a hand surgeon is appropriate for patients with evidence of extensive tissue necrosis.

Blood Products.

Immeasurably low fibrinogen concentrations, prothrombin times greater than 100 seconds, and platelet counts lower than 20,000 K/mm³ are routinely encountered after rattlesnake envenomation. Such abnormal laboratory results alone should not prompt the clinician to treat with blood products in the absence of clinically significant bleeding. The circulating crotaline venom responsible for the thrombocytopenia and coagulopathy is still present and will likely inactivate any transfused components. For this reason, the mainstay of treatment for crotaline envenomation–induced coagulopathy and thrombocytopenia is antivenom, not blood products. Correction of coagulopathy, thrombocytopenia, and bleeding can frequently be achieved with antivenom alone. Rarely, a patient will have active bleeding, and antivenom alone will not correct the platelets and fibrinogen. In such cases, fresh frozen plasma, cryoprecipitate, packed red blood cells, or platelet transfusions may be required.

In some cases, thrombocytopenia may be difficult, or impossible, to correct with even large amounts of antivenom. The Timber rattlesnake, for example, is known for producing thrombocytopenia resistant to antivenom. The initial correction of platelet counts after treatment may be transient (lasting only 12–24 hours), with thrombocytopenia sometimes persisting for days to weeks after normalization of other coagulation parameters. In the absence of bleeding, thrombocytopenia is a benign, self-limiting disorder, resolving within 2 to 3 weeks of envenomation. It may be best to closely follow patients with resistant thrombocytopenia who are not bleeding, rather than attempt further platelet transfusions or antivenom administration.³⁷

Follow-up care.

Hospital stays for patients with uncomplicated pit viper envenomations are typically short, lasting approximately 1 to 2 days.³⁹ Upon discharge from the hospital, patients often have residual swelling and functional disability. They may have continued progression of hemorrhagic bullae with underlying necrosis. Patients should have an out-patient follow-up evaluation to ensure wounds are healing appropriately and extremity function is returning. If joint mobility does not return to baseline as swelling resolves, the patient should be referred for physical and occupational therapy.

In a significant proportion of rattlesnake bite patients treated with Crotalidae polyvalent immune Fab antivenom, a return of swelling, coagulopathy, or thrombocytopenia may be noted after initial resolution of the effect after initial treatment with antivenom. This has been termed “recurrence” of venom effect and is attributed to the interrelated kinetics and dynamics of venom and antivenom.^39,42 Simply stated, Fab antivenom has a clinical half-life shorter than that of venom. Administration of maintenance doses of antivenom is used in an attempt to prevent development of recurrent effects. Maintenance doses appear to be effective in preventing recurrence of local swelling in most cases, but many patients develop hematologic recurrence within 3 to 7 days of antivenom treatment despite administration of maintenance doses. Additionally, patients who never manifested thrombocytopenia or coagulopathy during their hospital presentation may later develop the effect, presumably because of initial “masking” of the effect by early antivenom administration. These recurrent or late hematologic effects have been associated with life-threatening bleeding.³⁰ No risk factors have been identified to predict which patients will develop late thrombocytopenia or coagulopathy.

The most reasonable way to address possible late hematologic effects of crotaline envenomation is careful outpatient follow-up after hospital discharge. Patients with copperhead bites may be followed as needed.^34,39 The safest approach is to provide careful discharge instructions and consider all patients who have been treated with Crotalidae polyvalent immune Fab antivenom to be at risk for late hematologic toxicity. Patients who use antiplatelet or anticoagulant medications should be continued on these medications only after a careful risk-benefit analysis. Whenever possible the medications should be discontinued until the risk of recurrent or late hematologic toxicity passes. Patients must be warned not to undergo dental or surgical procedures for up to 3 weeks unless platelet and coagulation studies are documented to be normal immediately prior to the procedure. High-risk activities, such as contact sports, should be avoided. All patients should have platelets and coagulation studies measured 2 to 3 days, and again 5 to 7 days, after the last antivenom treatment. If values are abnormal or trending in the wrong direction, the studies should be repeated every few days until normalized. Patients should be advised to avoid surgical procedures and activities that place them at risk for injury. Opinions on when to retreat patients exhibiting late hematologic toxicity with antivenom vary. The general approach of the authors is to retreat any patient with evidence of bleeding, as well as patients with severe isolated thrombocytopenia (platelets <25,000/mm³) or moderate thrombocytopenia (platelets 25,000–50,000/mm³) in combination with severe coagulopathy (fibrinogen <80 mg/dL).³⁹ Many clinicians choose to observe patients with isolated coagulopathy cautiously as outpatients rather than to retreat them with antivenom. However, if patients with isolated severe coagulopathy have other risk factors for bleeding, such as use of antiplatelet medications, retreatment with antivenom should be considered.

When the decision has been made to retreat a patient with late hematotoxicity with antivenom, an initial starting dose of two vials is recommended. Late thrombocytopenia appears to be more resistant to antivenom than early venom-induced thrombocytopenia, and it is unclear whether a different mechanism may be responsible for the late effect. It is unknown how much antivenom is needed to reverse late thrombocytopenia or at what dose a patient may be considered “resistant” to antivenom. Patients who have evidence of bleeding with severe thrombocytopenia may require platelet transfusion. Some clinicians have also given steroids to patients who have not responded to antivenom and platelet transfusions, but there is no evidence to support the efficacy of steroids in this setting.

Coral Snakes

As with North American pit viper bites, patients who are bitten by North American coral snakes should be taken to a hospital for definitive medical care as soon as possible. There are no field treatments that have been shown to affect outcome in these patients. Pressure immobilization bandages (PIB) have been shown to delay the systemic absorption of venom from Australian elapid snakes. A swine model of coral snake envenomation suggests that pressure immobilization bandaging may be effective in delaying systemic absorption of venom following coral snakebite.²¹ Patients who present for care after a PIB has been placed should have the dressing left in place until resuscitative equipment and personnel are present and, ideally, antivenom is available. The PIB should be checked to ensure it is not functioning as a tourniquet.

Patients with a history concerning for possible Eastern or Texas coral snakebite should be observed for 24 hours in a monitored unit where resuscitative measures, including endotracheal intubation, can be performed. Since neuromuscular weakness and respiratory paralysis can develop quickly, endotracheal intubation should be considered at the first sign of bulbar paralysis. Traditionally, treatment with Wyeth Antivenin (Micrurus fulvius) (equine origin) North American Coral Snake Antivenin (NACSA) has been recommended for all patients in whom there is strong suspicion of coral snakebite, even in the absence of signs of envenomation. This is mainly because paralysis can develop quickly and symptoms may not reverse following antivenom treatment. Approximately 10 years ago Wyeth ceased production of NACSA, creating a shortage of antivenom and prompting many clinicians to take a more conservative approach to treating patients with coral snakebites. A recent study comparing patients who received empiric treatment with antivenom to patients who were treated when symptoms developed suggests that a conservative approach (waiting for symptoms to develop before administering antivenom) does not result in worse outcomes for patients.⁵⁸ The expiration date of current supplies of NACSA was extended to April 2014.⁵¹ Pfizer is expected to take over production of this antivenom in the near future.

If a patient is symptomatic following a coral snake envenomation, antivenom, if available, is indicated. If antivenom is unavailable, patients may be managed with supportive care alone. Mechanical ventilation may be necessary for many weeks. Acetylcholinesterase inhibitors, neostigmine and edrophonium, have been successfully used to treat patients with South American coral snakebites, but their use should be considered experimental.⁶

Sonoran coral snakes, indigenous to Arizona and California, have never been reported to cause significant toxicity, and bite victims do not require observation in the hospital or antivenom administration.

Lizards.

Management of helodermatid envenomation consists of supportive care. There is no antivenom available against lizard venom. Routine wound care should be performed, and the clinician should look for the presence of teeth in the wound. There is no evidence to guide clinicians when deciding whether to administer antibiotics to patients with erythema surrounding and extending from the bite site. Most case reports describing patients with erythema also report empiric use of antibiotics. There are no reports of confirmed infections following these bites.

Patients who are symptomatic following a bite should be attached to a cardiac monitor and have an intravenous catheter placed. Although serious morbidity from lizard bites is unusual, envenomation may be life threatening. Angioedema, other evidence of respiratory compromise, or airway obstruction should prompt endotracheal intubation. Hypotension may require treatment with intravenous fluid boluses as well as vasopressors such as epinephrine. Epinephrine, corticosteroids, and antihistamines may be indicated for the treatment of anaphylactoid reactions.

• Most native snake envenomations result from bites by Crotalinae ­species of snakes, also known as pit vipers, and commonly produce local tissue swelling and hematologic toxicity.

• A small percentage of envenomations are due to bites by coral snakes, which are known for producing neurotoxicity without local tissue effects.

• Management of patients with pit viper and coral snake envenomation should focus on aggressive supportive care and specific antivenom when indicated.

• Envenomations by Helodermatid lizards are often associated with local pain, erythema, hypotension, and angioedema.

• Clinicians are encouraged to contact a regional poison control center when a patient presents after a snake or lizard envenomation.

Acknowledgment

Bradley D. Riley, MD, contributed to this chapter in previous editions.

References