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Introduction

The United States is home to approximately 30 species of venomous snakes from two snake families: Viperidae and Elapidae.¹ Venomous snakes from the Viperidae family are from the Crotalinae subfamily, collectively referred to as pit vipers. Venomous Crotalinae snakes include species from the genera Crotalus (rattlesnakes), Sistrurus (Massasauga snakes and Pygmy rattlesnakes), and Agkistrodon (Copperhead and Cottonmouth snakes). Pit vipers have specific prominent visual features including a pit-like depression behind the nostrils that allows the snake to sense heat from nearby prey, triangle-shaped heads, elliptical pupils, and fangs. Some rattlesnakes have rattles on their tails and all pit vipers shake their tails when preparing to strike. Cottonmouth snakes (also known as Water Moccasins) get their name from the characteristic white tissue inside their mouths that can be seen when they strike. Copperheads are distinct in appearance, with reddish-brown heads and a pattern of dark hourglass-shaped bands on their bodies.

Venomous snakes from the Elapidae family are from the Micrurus and Micruroides genera and include three species of coral snakes: Eastern (Micrurus fulvius), Texas (Micrurus tener) and Arizona or Sonoran (Micruroides euryxanthus) coral snakes.¹ North American coral snakes can be visually identified by black heads and a distinct red-yellow-black-yellow band pattern on their bodies. The focus of this article is on pit viper envenomation so coral snakes will not be discussed further.

In 2018, approximately 4000 pit viper envenomations were reported to US poison centers.² Another 3000 bites or envenomations from unknown or known nonpoisonous snakes (n=575), exotic snakes (n=73), or unknown snake types (n=2443) were reported in the same year. The true number of bites that occur each year is unknown since many patients do not seek medical attention after a bite and these events are likely underreported by medical professionals.^1,3 For example, the Nationwide Emergency Department Sample shows that 11,138 patients presented to an emergency department with a venomous snake bite in 2016, which is far more than reflected in poison center data.⁴ The other major source of snake bite data is the North American Snakebite Registry.⁵ This prospective registry sponsored by the Toxicology Investigators Consortium of the American College of Medical Toxicology accepts voluntary reports of snake bite cases from 14 sites in 10 states, with a goal of improving treatment and decreasing morbidity and mortality through data analysis. Although poison center data and the North American Snakebite Registry are the most pertinent epidemiologic data available, the potential limitations of voluntary reporting (ie, inaccuracy, incompleteness) must be considered.

Mortality following pit viper envenomation is rare, with only 1 fatality reported to US poison centers in 2018 (from a rattlesnake envenomation).² In general, fatal envenomation is most common with rattlesnakes.^1,3 Copperhead envenomations rarely result in death. Although few pit viper envenomations result in death, 182 patients (about 4.5%) experienced major post-envenomation medical outcomes (defined as life-threatening symptoms or symptoms that resulted in significant residual disability or disfigurement) according to 2018 US poison center data.²

Pit vipers are found throughout the United States and bites have been reported in every state except Hawaii, however, pit viper bites are more common in the southern and western regions.¹ About 70% of pit viper bites in the North American Snakebite Registry occurred in Arizona and Texas.⁶ In the same registry, rattlesnake bites were most common in the west and south (eg, Arizona, California, Colorado, Utah, New Mexico), Copperhead bites usually occurred in the east and south (eg, Texas, North Carolina, Virginia, Pennsylvania, Missouri), and Cottonmouth bites were most common in southern and southeastern states (eg, Texas). Most snake bites occur during the summer months when snakes are more active.¹ Men comprise the majority of bite victims (69% to 75%), but bites in children are also common (10% to 33%).^1,6,7 Populations with the highest risk of snake bite include those who handle known venomous snakes in occupational or recreational settings and males between the ages of 25 and 34 years.¹ Most bites occur to the extremities, but other locations (eg, torso, face, neck) have been reported.^1,3

The fangs of US venomous snakes are located at the front of the mouth and are closely connected to venom-producing glands.¹ Fang length is variable depending on the species and the age/maturity of the snake, but some fangs can be as long as 3 to 4 centimeters and rarely can penetrate deeper than subcutaneous tissue to muscle or blood vessels. All pit vipers can retract their fangs into the roof of the mouth and additional teeth may also be present in the snake’s mouth to facilitate further tissue damage and prey immobilization. Many components can be present in snake venom including proteins, peptides, lipids, carbohydrates, and enzymes. More than 50 components of Crotalinae venom have been identified.⁸ The exact content and potency of venom from an individual snake cannot be predicted because this varies among species, geographic location, age, diet, and the time of year.^1,3,8,9

Clinical Presentation

Physiological effects of venom are variable and unpredictable.¹ Metalloproteinases, hyaluronidase, and phospholipases A2 can disrupt the extracellular matrix and basement membrane of endothelial cells, leading to tissue damage and increased vascular permeability. Metalloproteinases, phospholipases A2, serine proteases, and other proteins can also produce both anticoagulant and procoagulant effects, some of which are due to platelet aggregation and platelet destruction.^1,8 Rattlesnake venom may uniquely disrupt hemostasis due to the presence of enzymes that degrade fibrinogen, mimic thrombin, and lead to unstable fibrin clots. Phospholipases A2 can cause neurotoxicity, and other venom components can lead to hypotension due to effects on the vascular system.¹

There is a great deal of variability in the clinical presentation of pit viper bites.¹ Presentation can range in severity from asymptomatic bites in which no venom is delivered to life-threatening envenomation, with symptoms developing 8 to 10 hours or later after the bite. Many factors can affect the signs and symptoms of an individual patient, including the snake species, amount of venom exposure, bite location, and patient-specific factors.³ Concurrent medical issues such as fear (sense of impending doom), anxiety, or the effects of alcohol or illicit drugs may also be present and need to be distinguished from the clinical effects of the envenomation. For example, nausea and vomiting may be due to fear/anxiety, venom toxicity, or both.^1,3,10 On physical examination, the patient may have 1 or 2 punctures and other scratches or wounds at the bite location may be present.^1,3 Any signs or symptoms suggestive of snake bite should prompt clinical suspicion and remain part of the differential diagnosis until envenomation has been fully ruled out.

In general, rattlesnakes cause more severe envenomation than Copperheads or Cottonmouths.¹ Copperhead envenomation rarely leads to severe coagulation abnormalities, but since these envenomations have the potential for serious local effects they should be managed the same as envenomations from other pit viper species.^1,9,11-15 Snake identification is a challenge unless the snake is captured or a high quality picture is available. Attempting to capture a live snake is not recommended, and attempting to collect a dead snake is also risky since the bite reflex may be present even after decapitation.^3,9 In many cases, the snake species cannot be definitively determined. Misidentification is also common; in one recent study, 74% of Cottonmouth snakes were incorrectly identified as Copperhead snakes.¹⁶

Approximately 10% to 25% of pit viper bites are dry bites, which is defined as a snake bite that remains asymptomatic after observation for 8 to 12 hours following the bite.^1,3,9,17 Patients with mild envenomation have local, non-progressive erythema, swelling, and discomfort but no systemic or coagulation effects.^1,3 In contrast, moderate or severe envenomation is associated with progressive local symptoms and/or systemic symptoms as described in Table 1. Snake envenomation is a dynamic clinical process and close monitoring in the intensive care unit should be considered since symptom progression and/or clinical deterioration can occur at any time.

Localized swelling is the most common symptom of pit viper envenomation (occurring in >90% of cases), which may begin to develop within minutes of the bite.^1,3 Some patients experience pain, bleeding from the puncture, or hemorrhagic blisters. Tissue edema can progress over the course of hours to several days and swelling can extend as far as the torso or other extremities. Ecchymosis and erythema are common (approximately 62% and 39% of cases, respectively) and envenomation to the foot may result in a bluish skin discoloration.^1,6 Tissue necrosis has been reported in about 8% of patients, typically after rattlesnake envenomation.⁶ Myonecrosis can occur if the fangs penetrate into muscle tissue. Rhabdomyolysis unrelated to swelling has occurred, especially after envenomation from the Timber rattlesnake (C. horridus), which produces venom with direct myotoxic effects.^1,9

The most common systemic symptoms following pit viper envenomation include nausea, metallic taste, weakness, and restlessness.¹ Additional systemic symptoms include vomiting, diarrhea, confusion, seizures, tachycardia, hypotension, stroke, pulmonary embolism, and septic shock.^1,3,18-21 Rarely, patients experience anaphylactoid reactions including shock or airway edema/obstruction, but true anaphylactic reactions can also occur.¹ Symptoms such as pruritis or wheezing should raise clinical concern for anaphylaxis. Patients with prior exposure to antivenom (either from prior envenomation or occupational exposure) may be at increased risk for anaphylaxis due to existing anti-venom IgE antibodies.

Hematologic toxicity is common after pit viper envenomation.¹ This adverse venom-induced effect may be more common with rattlesnake envenomation, but it does occur with Cottonmouth and Copperhead envenomation as well. The presentation and severity of hematologic toxicity varies but is generally limited to disruptions in platelet activity and the coagulation cascade. Platelet counts and fibrinogen activity can decrease dramatically within hours of the envenomation or decrease more slowly over the course of several days. Most patients who develop thrombocytopenia or coagulopathy do not experience a bleeding event or experience only minor bleeding.^1,3,6,17 North American Snakebite Registry data notes bleeding in only 6.3% of cases.⁶ However, serious events such as gastrointestinal bleeding or intracranial hemorrhage have occurred and the potential for severe or fatal bleeding warrants close clinical monitoring.^3,17

Neurotoxicity is a rare complication of pit viper envenomation (approximately 5% of cases).^1,6 The species most commonly associated with neurotoxic effects are the Mojave (C. scutulatus) and Southern Pacific (C. helleri) rattlesnakes, which have caused weakness, respiratory paralysis, and toxicity to the cranial nerve.^1,17 Myokymia (fasciculations of the skin) has been reported after envenomation from several rattlesnake species including C. horridus, C. scutulatus, and C. atrox (the Western diamondback). This can be localized to facial muscles; however, more disseminated fasciculations of the chest wall/torso can lead to respiratory failure.

Diagnosis

The diagnosis of snake bite and envenomation is based on history and clinical presentation.¹ Laboratory tests are used to detect and monitor the effects of venom but assays that detect or quantify venom (either locally or systemically) are lacking. Scoring tools have been used in research settings (eg, the Snakebite Severity Score); however, their utility in clinical practice has been limited due to the dynamic nature of snake envenomation and the potential for rapid clinical progression.^1,9,17 Despite these limitations, severity scoring is used by some clinicians and one small retrospective study reported less antivenom use after incorporating the Snakebite Severity Score into an institutional treatment algorithm, with approximate cost savings of $13,200 per patient.²²

Treatment approaches

Standards for the treatment and management of snake bite and envenomation were established in 2011 via a unified treatment algorithm and in 2015 with the publication of a practice guideline from the Wilderness Medical Society.^3,17 Along with these recommendations, new evidence has prompted other reports of current clinical approaches for snake bite and envenomation.^8,9

In the past, a number of interventions to limit blood flow and/or prevent the spread of snake venom were recommended based on anecdotal experience rather than evidence. These techniques include tourniquets, suction or other methods of extracting venom from the wound, laceration/bleeding of the bite site, cryotherapy (ice), and electrotherapy.^1,3,17 Current recommendations for both prehospital and hospital care do not endorse these techniques because they are ineffective, delay the time to appropriate care, and may be harmful. Multiple professional organizations, including the American College of Medical Toxicology, recommend against pressure immobilization bandages for North American pit viper bites due to evidence of harm.²³

Prehospital care

High-quality evidence to guide the immediate management of snake bites is not available. The most helpful intervention is rapidly transporting the patient to an acute care medical facility.^1,3,9 Other management priorities include immobilizing the affected limb, obtaining intravenous (IV) access in a non-affected limb, and providing airway, breathing, and circulation support if severe or life-threatening symptoms are present. Intravenous fluids may be needed for symptoms suggestive of fluid loss (eg, vomiting, diarrhea), or hypotension. If hypotension does not improve after a fluid bolus, the patient may be experiencing anaphylaxis or an anaphylactoid reaction and may require treatment with epinephrine.

Hospital care

Upon arrival in the emergency department, the initial assessment of patients with possible or confirmed snake bite should include airway, breathing, circulation, wound care needs, and the degree of swelling at the bite site (Table 2). The affected limb should be immobilized in a padded splint with joints preferably positioned in near extension.^1,17 Jewelry or tight-fitting clothing near the bite location should be removed before swelling increases.³ Elevating the limb above the level of the heart has been endorsed as a way of minimizing swelling/edema, but this practice remains controversial due to concern that elevating the limb may lead to increased circulatory spread of venom.^1,3,9,17 Guidelines suggest managing pain with analgesics that do not increase bleeding risk (ie, avoid aspirin and non-steroidal anti-inflammatory drugs [NSAIDs]), although limited retrospective data suggests that NSAIDs may be safe in patients with Copperhead envenomation.^3,17,24 Infection following snake bite is rare (about 1% to 3% of cases) and prophylactic antibiotics should be avoided, but wounds should be cleaned and all patients require tetanus prophylaxis.^1,3,17,25,26 Hematologic laboratory parameters should also be checked to establish a baseline.^3,17 Any concern for anaphylaxis, circulatory compromise, or shock should prompt IV fluid therapy and epinephrine (bolus or continuous infusion depending on the clinical presentation) along with other standard treatments for circulatory support (eg, vasopressors).

Local poison centers (1-800-222-1222) and medical toxicology experts (if available) should be consulted for all snake bite cases, both for treatment recommendations and to ensure that the bite is reported to the National Poison Data System.^1,3,9,17 Specific clinical situations for which expert consultation may be especially needed include: life-threatening envenomation, envenomation that is difficult to control, venom effects that are recurrent or delayed, allergic or anaphylactic reactions to venom or antivenom, when blood product transfusion is being considered, rhabdomyolysis, suspected compartment syndrome, and other wound-related challenges.¹⁷ Consultation with a medical toxicologist has been shown to significantly decrease hospital length of stay following rattlesnake envenomation.²⁷

Antivenom is not indicated for dry bites.^1,3,17 Clinicians differ in the approach to antivenom use in patients with minimal envenomation symptoms, such as localized swelling and no systemic symptoms or hematologic effects. Some clinicians may use antivenom early in these patients to prevent or delay local symptom progression, while others may withhold antivenom until local symptom progression occurs. If antivenom is not administered, local symptoms do not progress, and systemic/hematologic toxicity does not develop withing 12 to 24 hours of the bite, the patient can be discharged home with a planned follow-up appointment. The patient should be instructed to seek medical evaluation for new or progressive symptoms (eg, swelling, bleeding gums, bruising, melena).

Antivenom is indicated for patients with progressive local tissue effects, hematologic venom effects and/or systemic signs of envenomation, as well as any degree of neurotoxicity.^1,3,17 More than 80% of snake bites in the North American Snakebite Registry were managed with antivenom.⁶ Treatment with antivenom may halt the progression of swelling, normalize platelet counts and coagulation parameters, and resolve systemic effects. Antivenom does not reverse serious pathophysiologic processes including tissue necrosis, respiratory failure, or anaphylactic reactions.^1,9,28 Antivenom is most effective when given early in the treatment course. Continuous monitoring in intensive care settings is needed for patients that require antivenom.

Managing envenomation complications

Detecting and managing hematologic toxicity is a major concern after pit viper envenomation. Abnormal coagulation parameters are common and can be extreme (eg, undetectable fibrinogen, platelets <20,000/mm³, and prothrombin time [PT] >100 seconds).¹ These findings reflect the direct effects of venom on platelets and coagulation factors; therefore, antivenom is the most effective way to normalize laboratory parameters and decrease bleeding risk. Blood products such as platelets, fresh frozen plasma, packed red blood cells, or cryoprecipitate should only be considered for patients with clinically significant bleeding, and should only be administered concurrently with antivenom since blood products can be inactivated by circulating venom.

Patients who experience initial normalization/control may have a recurrence of abnormal coagulation parameters after 2 to 10 days (typically 3 to 7 days).^1,17 The mechanism behind this recurrence is not clear, but some theories include a longer venom half-life than the half-life of antivenom, slow release of stored venom from tissues into the circulation, delayed onset of some venom components, dissociation of venom-antivenom complexes, or anti-venom immune responses.⁹ In the North American Snakebite Registry, the rate of late hematologic toxicity following rattlesnake envenomation was 42.9%.⁶ Minimizing other bleeding risk factors can also decrease post-envenomation morbidity. A careful risk-benefit assessment is needed for patients who require concurrent antiplatelet or anticoagulant medications, dental or surgical procedures should be delayed for 2 to 3 weeks, and high-risk recreational activities (eg, contact sports, tattoos, piercings) should be avoided.^3,9,17

Surgical intervention is very rarely needed for pit viper envenomation.^1,3 Patients with tissue necrosis or hemorrhagic blisters may be candidates for debridement, especially if fingers or toes are involved. Compartment syndrome is often suspected, but few patients have elevated intracompartmental pressures even if swelling is extreme. Elevated intracompartmental pressures may be due to venom-induced myonecrosis rather than vascular insufficiency.⁸ Antivenom may effectively lower intracompartmental pressure on its own and fasciotomy should only be considered for patients who do not respond to antivenom or who have evidence of ischemia.^1,3

Special populations

Snake envenomation is not uncommon in children. Approximately 15,400 pediatric snake envenomations (from either a known venomous snake or unknown snake) were reported to US poison centers over a 13 year period.⁷ Management is largely the same as in adults, with a similar emphasis on early antivenom administration and a similar need to consult a poison center for patient-specific treatment recommendations.^3,17 Children and adolescents were represented in the major antivenom clinical trials but efficacy and safety results for this population have not been rigorously evaluated.^29-31 The same dose of antivenom should be used in children and adults because dosing is based on the amount of antivenom needed to neutralize the venom delivered from the bite, which is likely the same regardless of patient age. Smaller fluid volumes can be used for diluting antivenom (approximately 20 mL/kg/dose) since smaller children may not be able to tolerate the volumes used for administration in adults (250 mL per dose).^1,3 There is some concern that children may be at a higher risk for recurrent coagulopathy due to increased antivenom clearance rates.⁹

Pregnant patients who experience snake envenomation should be closely managed by both toxicology and obstetric experts.³ Snake venom can harm the fetus even if antivenom is used.^3,28 Antivenom is therefore a potentially life-saving treatment and should be considered in pregnant women with envenomation symptoms that would normally warrant treatment with antivenom, along with close fetal monitoring. Pregnant patients may require more aggressive post-discharge monitoring than other patients due to the potential for recurrent coagulopathy leading to hemorrhage and spontaneous abortion.³²

Antivenom therapy

The goal of treatment with antivenom is to achieve initial control, which is a general term that refers to subjective control of venom-induced clinical effects.¹⁷ Local tissue and muscle effects, such as pain and swelling, stop progressing upon initial control but may not resolve immediately since tissue damage has already occurred. Other markers of initial control include resolution of systemic effects and a trend toward normalization of hematologic parameters. Antivenom works by binding and neutralizing venom toxins, which allows the body to distribute toxins away from the tissues and facilitates elimination from the body.^33,34 Coagulation parameters can be checked within 1 hour of antivenom administration.^3,17 If initial control is not achieved after 2 doses, a toxicology expert or poison center should be consulted if they are not already involved.¹⁷

Scheduled maintenance dosing of antivenom recommended by some manufacturers and is frequently given in practice, but its use is somewhat controversial.^9,17,33,34 One retrospective cohort study of 310 patients with rattlesnake envenomation found that hospital length of stay was shorter (27 hours versus 34 hours, p=0.014) with no difference in readmission, retreatment, or bleeding rates with additional as-needed antivenom administration compared to scheduled maintenance dosing, respectively.³⁵ It is unclear whether the difference in hospital length of stay in this study has clinical or financial significance.

Two pit viper antivenom products are currently available in the United States: ovine-derived Crotalidae polyvalent immune Fab (CroFab) and equine-derived Crotalidae polyvalent immune F(ab’)₂ (ANAVIP).^33,34 These product names reflect the former pit viper subfamily name (Crotalidae), which has now been changed to Crotalinae. For several decades, a different equine-derived polyvalent Crotalidae antivenom product was available (Antivenin (Crotalidae) Polyvalent), but this product was reserved for severe envenomations due to a high rate of hypersensitivity reactions and a lengthy preparation time before administration (up to 60 minutes).^1,29 The currently available antivenoms have better tolerability/safety and pharmacokinetic profiles, which has led to clinical recommendations supporting their more widespread use compared to the previous product.¹

Current antidote stocking guidelines recommend that pit viper antivenom should be routinely stocked in hospitals located in geographic areas where pit vipers are endemic.³⁶ In the case of drug shortage or other availability concerns, local poison centers should be consulted to assess the need for antivenom therapy, recommend appropriate dosing to allow for rationing of the available supply, and assist with obtaining product from nearby institutions. There has been clinical interest in the use of expired antivenom but evidence with this strategy is limited.³⁷

Table 3 summarizes the major clinical aspects of both antivenom products.^33,34 An important difference between the 2 products is that Crotalidae polyvalent immune F(ab’)₂ has a longer half-life due to its different protein structure. Both antibody fragments are obtained by enzymatic cleavage of the full IgG antibody to remove the F_c portion, but the enzyme used to generate Crotalidae polyvalent immune F(ab’)₂ (pepsin) results in a larger antibody fragment than the enzyme used to generate Crotalidae polyvalent immune Fab (papain).^3,28,33,34 The larger size of the Crotalidae polyvalent immune F(ab’)₂ antibody fragment is thought to slow degradation and prolong its clinical effect, which could theoretically lead to a lower incidence of recurrent coagulopathy.^8,28 Although Crotalidae polyvalent immune F(ab’)₂ is produced in horses with exposure to only 2 snake species, it has been shown to neutralize venom from 15 North American snake species including several types of Copperheads, Cottonmouths, rattlesnakes, and Massasauga snakes.^8,28,40

Antivenom efficacy literature

Several clinical trials support the efficacy of pit viper antivenoms. The efficacy of Crotalidae polyvalent immune Fab was demonstrated in 2 prospective, randomized, controlled trials.^29,30 A trial was conducted in 31 patients with minimal or moderate envenomation (mainly to the finger or hand) from rattlesnakes or Cottonmouth snakes.²⁹ Patients with severe envenomation were excluded. After initial dosing of 6 to 12 vials, patients who achieved initial control were randomized to scheduled maintenance dosing (2 vials every 6 hours for 3 doses, with additional doses as needed for worsening symptoms) or additional as-needed doses (2 vials per dose) in an open-label manner. All patients obtained initial control, with 65% requiring 6 vials and 32% requiring 12 vials. Snakebite Severity Scores significantly decreased from baseline in all patients (p<0.001). No patients in the scheduled maintenance dose group required additional as-needed doses and the mean total number of vials administered was similar in both groups (about 13 vials in the scheduled maintenance dosing group versus about 11 vials in the additional as-needed dosing group), which supports the recommendation for scheduled maintenance doses after initial control is achieved. Safety findings included infusion-related reactions (19%) and serum sickness (23%, which was later attributed to impurities in the Crotalidae polyvalent immune Fab lot used during the study). The effect of Crotalidae polyvalent immune Fab on hematologic parameters was not well-described, but the authors stated that recurrent hematologic toxicity occurred. Another limitation of this study is a lack of detail about how snakes were identified.

A larger (n=74) multi-center, prospective, randomized, double-blind, placebo-controlled trial evaluated the efficacy of Crotalidae polyvalent immune Fab in patients with mild to moderate Copperhead snake envenomation.³⁰ Patients with severe envenomation were excluded. A majority of the patients had mild envenomation (87.8%) to the lower extremity (62.2%). Limb function at 14 days after envenomation (the primary endpoint) was significantly better with Crotalidae polyvalent immune Fab versus placebo (p=0.04) as measured by a validated functional score for Copperhead snake envenomation (the Patient Specific Functional Scale) and the difference between groups achieved the threshold for a clinically important difference.^30,41,42 All other functional assessments were better with Crotalidae polyvalent immune Fab than placebo, and fewer patients in the Crotalidae polyvalent immune Fab group received opioids at various time points throughout the study and through 28 days of follow-up.^30,43 All patients recovered within 4 months. Adverse events related to treatment occurred in 36% of the Crotalidae polyvalent immune Fab group compared to 10% of the placebo group. The most common adverse events were headache, dizziness, nausea, pyrexia, urticaria, and pruritis. The means of snake identification in half of the cases was the patient (or parent) choosing a Copperhead snake from among several photographs, which may have resulted in misidentification. A secondary analysis of this trial found that early Crotalidae polyvalent immune Fab administration (within 5.47 hours of the bite) shortened the time to full recovery (17 days) compared to late administration (28 days, p=0.025).⁴⁴

The largest clinical trial to date compared both of the currently available antivenom products.³¹ In a multi-center, prospective, double-blind, randomized trial in 121 patients with pit viper bites (21 Copperhead, 1 Cottonmouth, 102 rattlesnake or unidentified), late hematologic toxicity was compared between Crotalidae polyvalent immune Fab and Crotalidae polyvalent immune F(ab’)₂. After achieving initial control with one of the antivenom products, patients were randomized to scheduled maintenance therapy with the same antivenom or placebo (Crotalidae polyvalent immune F(ab’)₂ only), yielding a total of 3 patient groups. Most envenomations were mild (based on Snakebite Severity Score). The primary endpoint (defined as platelets <150,000/mm³, fibrinogen <150 mg/dL, or use of antivenom for coagulopathy between the end of scheduled maintenance therapy and the first 5 days) at day 8 occurred in 29.7% of patients who received both initial and scheduled maintenance doses of Crotalidae polyvalent immune Fab versus 10.3% of patients who received both initial and scheduled maintenance doses of Crotalidae polyvalent immune F(ab’)₂ (absolute risk reduction, 0.195; 95% confidence interval, 0.014 to 0.367; p<0.05). Late hematologic toxicity occurred in 5.3% of patients who received only initial Crotalidae polyvalent immune F(ab’)₂ without scheduled maintenance therapy (absolute risk reduction, 0.245; 95% confidence interval, 0.073 to 0.410; p<0.05 compared to the Crotalidae polyvalent immune Fab group). Extra antivenom dose requirements were similar between the Crotalidae polyvalent immune Fab and combined Crotalidae polyvalent immune F(ab’)₂ groups. Serum sickness reactions were similar between groups (1 reaction per group). Although this is the most robust clinical data that exists for Crotalidae polyvalent immune F(ab’)₂ in the United States, some clinicians may be hesitant to extrapolate these results to Copperhead or Cottonmouth envenomation since few patients with envenomation from these snakes (13 and 0 patients, respectively) received Crotalidae polyvalent immune F(ab’)₂.

Overall, clinical trials suggest that late hematologic toxicity is less with Crotalidae polyvalent immune F(ab’)₂, likely due to its longer half-life compared to Crotalidae polyvalent immune Fab.³¹ This finding of less late hematologic toxicity is consistent with an exploratory phase 2 study in 12 patients with pit viper envenomation, which found that Crotalidae polyvalent immune F(ab’)₂ had significantly higher nadir platelet levels during the 2-week follow-up (214,000/mm³) compared to Crotalidae polyvalent immune Fab (87,000/mm³, p=0.007) and significantly lower plasma venom concentrations (p=0.022) throughout follow-up.⁴⁵ The only efficacy outcome evaluated in these comparative studies is late hematologic toxicity, so the difference between Crotalidae polyvalent immune Fab and Crotalidae polyvalent immune F(ab’)₂ for other efficacy parameters (such as initial control or physical function) is unknown and too few patients have been studied to detect differences in safety (eg, hypersensitivity reactions).^31,45

Data on the use of pit viper antivenom for envenomation from snake species that are not native to the US is scarce. One animal study and a single case report suggest that Crotalidae polyvalent immune Fab may neutralize venom from certain South American snakes (C. durissus terrificus and B. atrox).^46,47 A poison center should be contacted in cases of non-native snake envenomation so that the most effective management strategy can be undertaken, which may include specialized antivenom obtained from an alternative source such as a zoo or aquarium.^9.48

Antivenom safety

Antivenom is generally well-tolerated. Only 2.7% of patients reported to the North American Snakebite Registry experienced an acute adverse event after Crotalidae polyvalent immune Fab therapy (most commonly rash).⁴⁹ However, several potential complications of antivenom administration warrant clinical awareness, including anaphylactoid reactions and anaphylaxis.^{3.17,28,33,34} Some sources state that these reactions occur in 6% to 8% of patients, but a recent retrospective evaluation of poison center data found that only 1.4% of patients who received Crotalidae polyvalent immune Fab experienced hypersensitivity reactions.^3,17,50 Anaphylactoid reactions are characterized by pruritus, urticaria, and wheezing, and are generally self-limiting.^3,17 Minor infusion-related reactions such as fever, low back pain, wheezing, and nausea can also occur.³⁴ However, due to the potential for anaphylactic reactions, the first dose of antivenom should be administered in a medical facility with equipment to manage airway emergencies.^3,17 Patients with a history of antivenom exposure for a prior envenomation may be sensitized and more likely to experience hypersensitivity reactions with subsequent exposure.^9,34 Pretreatment with corticosteroids, antihistamines, and/or epinephrine can be considered for these patients, or for patients with asthma, atopy, or other predisposing factors for allergic reactions.³ The clinical need for antivenom remains even after patients experience anaphylactic or hypersensitivity reactions, so antivenom therapy should be resumed but at a slower administration rate (and possibly a larger dilution volume and/or concurrent epinephrine infusion) after a careful risk/benefit assessment.^3,28

Serum sickness (a type III hypersensitivity reaction) can occur in 5% to 16% of patients after antivenom administration.^3,8,17,28 These reactions may be delayed until 7 to 21 days after antivenom treatment.⁸ Symptoms of serum sickness such as fever, rash, myalgia, arthralgia, urticaria, and pruritis can typically be managed outpatient with oral antihistamines or corticosteroids.

Recurrent toxicity can occur after initial control, even with antivenom scheduled maintenance dosing. Recurrent local effects including swelling may develop within 6 to 36 hours after initial control.¹ Repeat antivenom administration is generally undertaken in this situation, but efficacy may be less robust than during the initial treatment course.^17,39,51 Recurrent hematologic toxicity that warrants antivenom therapy includes moderate or severe thrombocytopenia (platelets <50,000/mm³), decreased fibrinogen levels (<80 mg/dL), or evidence of bleeding.¹

Upon hospital discharge, all patients who receive antivenom should be counseled on the potential for serum sickness and delayed coagulopathy and receive instruction on symptoms that require urgent medical evaluation.³

Summary

Pit viper envenomations have been reported throughout the United States. Clinical practice guidelines exist, but management strategies are based on limited high quality evidence. Local poison centers and/or a medical toxicologist (if available) should be consulted for all snake envenomation cases. Pit viper envenomation may require antivenom administration if progressive or systemic symptoms are present. The efficacy of Crotalidae polyvalent immune Fab and Crotalidae polyvalent immune F(ab’)₂ have been studied in randomized, controlled clinical trials. Limited comparative data suggest that late hematologic toxicity may be less frequent with Crotalidae polyvalent immune F(ab’)₂ compared to Crotalidae polyvalent immune Fab. All patients should be closely monitored both in the hospital and after discharge for recurrent symptoms and delayed hematologic toxicity.

Case studies

Case study 1:

A 34 year old male presents to the emergency department after receiving a snake bite to the hand while camping. A picture of the snake is not available but his description is consistent with a rattlesnake. At approximately 3 hours after the bite, the initial physical examination reveals swelling of the hand and forearm, ecchymosis, stable vital signs, and shallow breathing and diaphoresis consistent with anxiety. The patient is also complaining of pain and nausea. Platelet counts are low (132,000/mm³); other coagulation parameters are normal. What is an appropriate antivenom dosing and monitoring plan for this patient?

Answer:

The patient has progressive venom effects and is a candidate for antivenom therapy. According to product labeling, initial dosing of Crotalidae polyvalent immune Fab is 4 to 6 vials, with repeat doses of 4 to 6 vials until initial control is achieved. Initial dosing of Crotalidae polyvalent immune F(ab’)₂ is 10 vials, with repeat doses of 10 vials until initial control is achieved. For both antivenom products, the initial dose should be diluted in 250 mL of 0.9% sodium chloride and given as an IV infusion over 60 minutes. The first 10 minutes of the infusion should be at a slow rate (25 to 50 mL/hr) with close observation for hypersensitivity reactions. After antivenom administration, ongoing monitoring should include vital signs (continuous cardiac monitoring can be considered), progression of swelling every 15 to 30 minutes, and hourly hematologic and coagulation studies until stable then every 4 to 6 hours. After initial control is achieved, the Crotalidae polyvalent immune Fab package insert recommends scheduled maintenance dosing with 2 vials every 6 hours for a total of 3 doses. Additional as-needed dosing for Crotalidae polyvalent immune F(ab’)₂ is 4 vials given for recurrent venom effects.

Case study 2:

A 21 year old male who experienced Cottonmouth envenomation to the forearm received antivenom and was discharged home after an otherwise uneventful hospital course. Thirty six hours after discharge, the patient presents to the emergency department with complaints of ongoing epistaxis for 20 minutes. Laboratory findings include thrombocytopenia (87,000/mm³) and hypofibrinogenemia (95 mg/dL). How should this patient be managed?

Answer:

This patient is experiencing late hematologic venom toxicity. Uncontrolled bleeding, even though not life-threatening, warrants the use of antivenom. Dosing recommendations include 2 vials of Crotalidae polyvalent immune Fab or 4 vials of Crotalidae polyvalent immune F(ab’)₂, but clinical response may not be robust in this setting and more aggressive antivenom doses may be needed. A toxicologist or poison center should be consulted for antivenom dosing recommendations. If the bleeding becomes severe, the patient can be treated with blood products per institutional protocol, but only during/after appropriate antivenom doses have been administered.

References

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