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INTRODUCTION — Snake bites are a significant problem in the United States. Successful treatment requires prompt definitive medical evaluation, careful clinical assessment, and timely administration of antivenom in selected patients. Consultation with a medical toxicologist or other clinician with experience in managing poisonous snake bites is recommended prior to antivenom administration. Phone consultation with a medical toxicologist is available through a United States regional poison control center by calling 1-800-222-1222.
The clinical evaluation and management of poisonous Crotalinae (rattlesnake, water moccasin [cottonmouth] or copperhead) snake bites is reviewed here. The principles of management of coral snake bites and snake bites outside the United States are discussed separately. (See "Evaluation and management of coral snakebites" and "Snakebites worldwide: Clinical manifestations and diagnosis".)
TERMINOLOGY — Rattlesnakes, water moccasins (cottonmouths), and copperheads are members of the family Viperidae, subfamily Crotalinae (formerly Crotalidae). They are also commonly called pit vipers, a name that refers to the heat sensing pit located behind the nostrils.
EPIDEMIOLOGY — Rattlesnakes, water moccasins (cottonmouths), and copperheads are the most numerous and cause the most snake bites in the United States. Elapids (coral snakes) and imported exotic snakes cause a smaller number .
Estimates from the 1960s suggest that there were approximately 8000 bites annually from poisonous snake species in the United States, with 10 to 12 deaths annually . Additional studies of rattlesnake bites suggest that there is an increasing number of significant bites, but mortality has remained at low levels since the 1980s [3,4].
Approximately 5000 snake bites are reported to the American Association of Poison Control Centers annually . Most of these occur in adult males. Hospitalization occurs in about half of all envenomated patients. Clinical effects are more severe in children and in victims of rattlesnake or water moccasin (cottonmouth) envenomation. Among children 18 years of age or younger, venomous snakes, primarily copperheads and rattlesnakes, are responsible for half of the approximately 1300 annual snakebites based upon reports to poison control centers from 2000 to 2013 . Most snake bites occur in the summer months when snakes are most active. Southern and western states with warmer climates report the greatest number of venomous snake bites, including Texas, Florida, California, Arizona, Louisiana, Georgia, and North Carolina.
GEOGRAPHICAL DISTRIBUTION — Rattlesnakes, water moccasins (cottonmouths), and copperheads are widely distributed throughout the United States:
●Rattlesnake (Crotalus and Sistrurus species) – Rattlesnakes live throughout the continental United States; they are native to all states except Alaska, Hawaii, and Maine.
●Water moccasin or cottonmouth (Agkistrodon piscivorus) – These snakes are found in the Southeast and South, from Virginia to Texas.
●Copperhead (Agkistrodon contortrix) – These snakes are common in the Eastern-half of the continental United States, from Massachusetts to Texas.
CLINICAL MANIFESTATIONS — An understanding of the effects of snake venom and United States distribution of snakes is important when assessing and treating patients. Symptomatic Crotalinae (rattlesnake, water moccasin, or copperhead) envenomations are best considered as envenomation syndromes, typically :
●Local tissue damage – Ecchymosis and progressive tissue swelling (picture 1)
●Non-specific systemic effects – Nausea, vomiting, diarrhea, weakness, light-headedness, diaphoresis, or chills
●Coagulopathy – Bleeding
●Rhabdomyolysis with nephrotoxicity
●Increased vascular permeability, tachycardia, tachypnea, and hypotension
●Neurotoxicity (eg, oral paresthesia, unusual taste, fasciculations, altered mental status, seizures)
Crotalid bites usually do not cause neuromuscular weakness with respiratory depression except in victims of Mojave rattlesnake (Crotalus scutulatus).
In general, rattlesnake envenomations cause more severe signs and symptoms than water moccasins (cottonmouths). Copperheads usually cause only limited local tissue swelling and pain with no systemic symptoms . However, the identity of the offending snake is often unknown. In addition, bites from any of the Crotalid snakes (rattlesnake, water moccasin [cottonmouth], or copperhead) may cause clinically significant findings. Thus, treatment of any suspected Crotalid bite should proceed based on signs and symptoms (table 1) irrespective of the snake species, unless a snake expert has made a definite identification. (See 'Supportive care' below and 'Crotalinae (Pit viper) antivenom' below.)
FIRST AID APPROACH — The appropriate management of snake bites is controversial, and management strategies are primarily based on case series and clinical experience . Numerous field measures have been advocated, but none have been shown to improve outcome .
The authors suggest the following measures for United States Crotalinae snake bite victims prior to definitive hospital care :
●Remove the patient from the snake's territory, and keep him or her warm, at rest, and calm.
●Immobilize the injured body part in a functional position at the level of the heart initially . Further actions should be guided by an experienced clinician. Decisions regarding dependency or elevation of the bitten part must balance a potential increase in local injury with that for increased systemic venom absorption. Placing the extremity below the level of the heart may lead to increased tissue damage in some patients but may be appropriate in patients who have systemic effects of envenomation . In contrast, elevation of a swollen extremity to prevent acute swelling in patients without systemic symptoms may subsequently increase systemic venom absorption but may be acceptable if the time to definitive care, including antivenom administration, is short .
●Remove any rings, watches, or constrictive clothing from the affected extremity.
●Do not apply pressure immobilization, tourniquets, or constrictive dressings. (See 'Pressure immobilization' below.)
●Cleanse the wound.
●Withhold alcohol and drugs that may confound clinical assessment.
●Avoid potentially harmful therapies. (See 'Techniques to avoid' below.)
●Transport the patient in the supine position to the nearest medical facility as quickly as possible, preferably using emergency medical services.
●Attempts to identify the snake should not endanger the patient or rescuer and should never delay transport to a medical facility. A digital photo taken at a safe distance may be useful. Snake parts should not be handled directly because the bite reflex may remain intact in recently killed snakes and result in additional envenomation .
Venomous or nonvenomous? — It may be difficult to determine whether a snake is venomous or not. Several characteristics have been proposed, but are not a substitute for expert consultation (figure 1) . Venomous rattlesnakes have a triangular shaped head, elliptical pupils, and hollow, retractable fangs. In contrast, nonvenomous snakes have rounded head, round pupils, and lack fangs.
Misidentification (particularly in an emergency situation) may have potentially serious outcomes, and patients with possible envenomation should be observed closely .
Techniques to avoid — Methods, such as tourniquets, incision and oral suction, mechanical suction devices, cryotherapy, surgery, and electric shock therapy, have been advocated in the past, but are no longer recommended (algorithm 1). Tourniquets can damage nerves, tendons, and blood vessels, and oral suction can lead to infection [1,11,12]. Furthermore, venom removal by mechanical suction is minimal. In a study of mock venom extraction with a mechanical suction device in human volunteers, suction reduced the total body venom burden by only 2 percent .
The suggested first aid approach for patients with suspected Crotalinae envenomation is discussed in detail separately. (See 'First aid approach' above.)
Pressure immobilization — We suggest that patients with Crotalinae envenomation not receive pressure immobilization. Pressure immobilization refers to a procedure in which an elastic bandage is applied to the affected limb with a goal of achieving a bandage pressure of 55 to 70 mmHg. This method may delay systemic absorption of snake venom by preventing lymphatic spread in the affected limb. Although pressure immobilization is mentioned as a potential first aid therapy for snake bites in the United States by the American Heart Association , no studies have demonstrated benefit in humans envenomated by Crotalinae species. Most snake bite experts do not support pressure immobilization for Crotalinae snake bites because these venoms cause local tissue toxicity and sequestering the venom in the affected limb may increase local tissue damage [15-17].
Pressure immobilization may be useful as a first aid procedure for neurotoxic snake bite and is discussed in greater detail separately. (See "Snakebites worldwide: Management", section on 'Pressure immobilization'.)
INITIAL EVALUATION AND MANAGEMENT — A unified treatment algorithm for Crotalinae snake bite management in the United States has been developed based upon literature review and expert opinion . Based upon this approach, clinical assessment and ancillary studies are indicated to determine the degree of toxicity and to guide the use of antivenom (table 1 and algorithm 2).
Clinical assessment — Clinical evaluation begins with an assessment of the wound site and local adjacent tissues. "Dry bites" (in which no venom was injected) occur in approximately 25 percent of Crotalinae snake bites in the United States and show only minimal local irritation. True envenomation produces swelling, pain, ecchymoses, and blistering. Proximal spread of these signs suggests progressive toxicity.
Systemic reactions, such as nausea, vomiting, abdominal pain, paresthesias, and dizziness, suggest more severe envenomation. Hypotension and altered mental status are ominous findings.
Mojave rattlesnake envenomation does not typically produce significant local tissue reaction. With Mojave rattlesnake bites, serial neurologic examinations should be performed for at least 12 hours since onset of neurologic findings may be delayed .
Ancillary studies — Evaluation for suspected Crotalinae envenomation (rattlesnake, water moccasin, or copperhead bite) should include the following studies to assess for evidence of coagulopathy and rhabdomyolysis:
●Complete blood count
●Serum electrolytes and creatinine and blood urea nitrogen
●Serum creatine kinase (CK)
●Prothrombin time (PT) and partial thromboplastin time (PTT)
●International normalized ratio (INR)
●D- dimer or fibrin degradation products (fibrin split products [FSP])
These studies should be repeated at regular intervals. The frequency of repeated measurements varies depending on the patient's clinical status (algorithm 2).
Wound management — Tetanus prophylaxis should be administered to snake bite patients according to the recommended immunization schedule (table 2). (See "Tetanus-diphtheria toxoid vaccination in adults".)
Although snake bites may result in the inoculation of bacteria, infection is rare. In a prospective observational study of 53 patients, there were no cases of documented infection following snake bite . Antibiotics (such as ampicillin-sulbactam or amoxicillin-clavulanate) should only be administered for established infections  or for heavily contaminated wounds.
Supportive care — Antivenom administration is the mainstay for treatment of significant Crotalinae (rattlesnake, water moccasin, copperhead) envenomation in the United States. The indications and use of antivenom are discussed below. (See 'Crotalinae (Pit viper) antivenom' below.)
In addition, the clinician should monitor for and be ready to manage coagulopathy, rhabdomyolysis, and compartment syndrome following Crotalinae envenomation and respiratory failure following Mojave rattlesnake bite.
Coagulopathy — The coagulopathy associated with Crotalinae (rattlesnake, water moccasin, or copperhead) envenomation is due to thrombin-like glycoproteins within the venom as well as thrombocytopenia . This is in contrast to true disseminated intravascular coagulation (DIC) where fibrinolysis is activated by increased levels of endogenous thrombin. Thus, antivenom administration, and not coagulation factor replacement, is the primary treatment for Crotalinae-induced coagulopathy. (See 'Crotalinae (Pit viper) antivenom' below.)
Transfused platelets and coagulation factors in fresh frozen plasma are inactivated by Crotalinae venom and should be avoided in patients with Crotalinae-induced coagulopathy unless the patient has significant bleeding that is uncontrolled by high dose antivenom administration (algorithm 1) .
Because Crotalinae-induced coagulopathy arises from thrombin-like substances in the venom that are not inhibited by antithrombin III, heparin is also ineffective [6,20].
Rhabdomyolysis — Tissue destruction caused by snake envenomation may lead to muscle cell breakdown (rhabdomyolysis) with significant risk for renal failure. Patients with rhabdomyolysis typically present with the triad of pigmented granular casts in the urine, a red to brown color of the urine supernatant, and a marked elevation in the plasma level of creatine kinase (CK). Primary treatment goals consist of fluid repletion and evaluation for significant electrolyte abnormalities (hyperkalemia, hyperphosphatemia, hypocalcemia). (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury", section on 'Clinical manifestations' and "Prevention and treatment of heme pigment-induced acute kidney injury".)
Elevated tissue pressures and compartment syndrome — Elevated tissue or compartment pressures may complicate Crotalinae (rattlesnake, water moccasin, or copperhead) bites. Any dressing, constriction band, splint, cast, or other restrictive covering should be removed. Venom is usually introduced into the subcutaneous tissues, and most, if not all, edema occurs in this space. Tissue pressures may increase because of the massive amounts of subcutaneous tissue fluid and because the skin has limits to its elasticity. Swelling, pain, and paresthesias may occur in patients after Crotalinae snake bite even in the absence of elevated tissue or compartment pressures. Thus, surgical intervention based on clinical findings alone is inappropriate (algorithm 1).
Generally, increased compartment pressures result from this extrinsic pressure and can be reduced with the administration of adequate amounts of antivenom and elevation. Elevation is usually avoided in true compartment syndromes and prior to antivenom administration in patients with venomous snake bites. After antivenom administration, however, elevation results in the drainage of subcutaneous edema and contributes to the reduction of the source of increased tissue pressure. If there is a concern for clinically significant, increased tissue, or compartment pressures, direct measurement with an appropriate device should be performed to guide additional management with antivenom and elevation. (See "Acute compartment syndrome of the extremities", section on 'Measurement of compartment pressures'.)
Ensuring adequate antivenom treatment is essential. In one case report and one case series, the only patients who received fasciotomy appeared to have inadequate dosing or duration of antivenom therapy [21,22]. The role of dermatomy in the hand, when pressures are high enough to impair distal blood flow despite adequate antivenom and elevation, has never been demonstrated, and it is likely that providing an increased capacity for swelling will only result in additional fluid accumulation, with no ultimate benefit. By contrast, nonsurgical management of acute compartment syndrome in the hand has been described; a patient with a rattlesnake bite to the thenar eminence and a compartment pressure of 55 mmHg had full recovery after receiving large amounts of polyvalent Crotalinae antivenom (46 vials total) and 20 g of intravenous mannitol .
True compartment syndromes may result from direct compartmental injection of venom, particularly with the anterior tibial compartment, which is very close to the skin. In these instances, antivenom and elevation may still reduce compartment pressures by the reduction of extrinsic pressure, but persistent intracompartmental pressures may remain high. The indications for fasciotomy in this context are unclear. An animal model of direct compartmental injection of venom demonstrated improved outcomes with antivenom alone versus antivenom plus fasciotomy . However, in this model, fasciotomy was performed immediately after venom injection. Thus, surgical intervention for elevated compartment pressures following Crotalinae snake bite is controversial and should be guided by a medical toxicologist and surgeon with extensive experience caring for victims with snake bite.
CROTALINAE (PIT VIPER) ANTIVENOM
Fab antivenom — Polyvalent Crotalinae ovine immune Fab (FabAV, Crofab, Protherics) is the antivenom commercially available in the United States for Crotalinae (rattlesnake, water moccasin, or copperhead) envenomation. Although an equine F(ab’)2 antivenom (Anavip) has been used successfully to treat United States pit viper envenomation in one study and may reduce the risk of late coagulopathy [25,26], it is not expected to be available for clinical use in the United States until 2018 or 2019. (See 'F(ab')2 antivenom' below.)
An older antidote, Antivenin Crotalidae Polyvalent (ACP, Wyeth), was derived from horse serum and has not been distributed since 2002. All United States stocks of ACP are expired as of March 2007.
●Action – FabAV consists of the purified Fab fragments of sheep immunoglobulin (IgG) raised against the antivenom of four snakes: Crotalus atrox (Western diamondback rattlesnake), Crotalus adamanteus (Eastern diamondback rattlesnake), Crotalus scutulatus (Mojave rattlesnake), and Agkistrodon piscivorus (cottonmouth or water moccasin) . When infused, these Fab fragments bind venom in the intravascular space and are renally excreted. The half-life of FabAV is shorter than Crotalinae venom substances. Thus, recurrent toxicity is possible despite initial control of local and systemic effects and may necessitate repeated FabAV administration. FabAV appears most effective when given within six hours of envenomation .
Indications — Consultation with a medical toxicologist is recommended prior to FabAV administration unless the physician has experience with snake bite treatment. Phone consultation with a medical toxicologist is available through a United States regional poison control center by calling 1-800-222-1222. Antivenom therapy is most effective when given within six hours of envenomation. Its use should be determined by the clinical severity of the bite and not the presumed species of snake responsible for the bite (table 1 and algorithm 2) .
We recommend that patients with Crotalinae bites (rattlesnake, water moccasin [cottonmouth], or copperhead bites) and moderate to severe toxicity (table 1 and algorithm 2) or with bite sites that present a significant possibility for airway obstruction from local tissue swelling (eg, bites to the face or neck) receive FabAV therapy. In such patients, the benefit of treating life-threatening toxicity clearly outweighs the potential risk of hypersensitivity.
Although expert guidelines have suggested that patients with mild envenomations not receive antivenom , some evidence suggests that it may provide short-term benefit, primarily a more rapid return to normal function of the involved limb . Thus, the use of antivenom for patients with mild envenomation should be individualized on a case by case basis with the input from a medical toxicologist or other snakebite expert. For patients with Crotalinae envenomation but minimal and non-progressive swelling, pain, or ecchymosis, and in whom the decision is to withhold antivenom, we suggest close observation for 12 to 24 hours to ensure that progression of toxicity, as indicated by worsening local or systemic effects, does not occur (table 1 and algorithm 2). The duration of observation may vary with a number of factors, including the age and health of the patient, the social supports available on discharge, the presumed species of the snake and the location of the bite.
Patients with confirmed copperhead bites appear to be at a lower risk for systemic toxicity and progressive swelling. Data from case series and one trial suggest that these patients frequently fully recover after mild envenomation without FabAV therapy [29-33]. However, FabAV therapy may change the short-term clinical course. In a blinded trial of 74 patients with confirmed copperhead bites (88 percent with mild envenomation), patients who received FabAV therapy (45 patients) had modestly better limb function at 14 days and lower use of opioid analgesia, but no significant difference in time to return of normal function (full function in 50 percent of patients by 21 days [range 3 days to 4 months]) . Patients who received FabAV had more minor adverse events (eg, pruritus, urticaria, nausea, dizziness, or fever) than those who received placebo (36 versus 10 percent, respectively). Serious adverse events due to administration of FabAV did not occur. Although current expert guidelines recommend treatment only for mild copperhead envenomation with progressive effects, this study suggests that FabAV may provide short term benefit to patients with mild copperhead envenomation with limited risks, primarily minor adverse effects and a potential for an increased cost of care . However, larger trials are needed to establish the use of FabAV for mild, non-progressive copperhead envenomations as routine practice.
Prior to the availability of antivenoms active against Crotalinae snake bites and the widespread availability of emergency departments and critical care units, snake bite mortality ranged from 5 to 36 percent in the United States [34-36].
After the introduction of Antivenin Crotalidae Polyvalent (ACP, Wyeth) in the 1950s and the development of widespread availability of emergency and critical care medicine starting in the 1960s, deaths from snake bite dropped to less than 1 percent. For example, an observational study of 23,676 venomous snake exposures in the United States from 2001 to 2005 found a fatality rate of 0.06 percent . Approximately half of these patients received either ACP or FabAV. Thus, the availability of antivenom for most native Crotalinae snake bites combined with secular trends in emergency and critical care capability has been associated with a marked decrease in snake bite mortality in the United States.
Given this secular trend, most experts feel that performing placebo controlled randomized trials of antivenom administration in patients with severe envenomation is unethical. However, randomized trials in animals indicate that both antivenoms prevent death after injection of a variety of Crotalinae snake venoms [37-39] and that FabAV provides even better protection than ACP . Although these clinical trials did not include patients exhibiting severe envenomation effects at the time of enrollment, some patients developed severe envenomation effects during their course, and subsequent observational evidence confirms that FabAV is effective for severe envenomation . (See 'Efficacy' below.)
Additional observational experience suggests that untreated Crotalinae envenomation is rarely fatal in regions where copperhead bites predominate, but can be life- or limb-threatening. For example, an observational study of 81 adult and pediatric patients who were managed without antivenom therapy after snake bite (45 copperhead, 12 water moccasin [cottonmouth], 10 rattlesnake, and 14 unknown) reported no fatalities or long-term morbidity . However, significant acute toxicity did occur, including coagulopathy (15 patients), skin necrosis (eight patients), respiratory distress requiring endotracheal intubation (three patients), hypotension (two patients), and cardiac arrhythmia (two patients).
Efficacy — Recommendations for the use of FabAV in patients with Crotalinae bites are derived from one small open label trial in which FabAV was given to both treatment groups, observational studies, systematic reviews of individual cases, and post-marketing surveillance of adverse effects [28,30,42-47]. Studies suggest that FabAV controls the toxicity of Crotalinae bites in the majority of patients with minimal to moderate envenomation (table 1):
●An open label multicenter trial of 31 patients 10 years of age or older, with minimal or moderate Crotalinae envenomation, who received FabAV within six hours of snake bite, demonstrated that FabAV controlled systemic toxicities in all 29 patients in whom they occurred and produced a significant reduction in the snake bite severity score . An observational study of 24 children who received FabAV after a presumed Crotalinae snake bite found reduction of local tissue swelling in all patients . Coagulopathy was reversed in 9 of 14 patients. One patient had acute hypersensitivity to FabAV.
●An observational study of 247 United States snake bite victims presenting to 17 hospitals reported that 82 percent of patients achieved initial control of symptoms, defined as a lack of progressive local and systemic effects, no evident bleeding and improvement in platelet, and coagulation studies . In those achieving initial control, the median initial number of vials administered was six, although the median number of vials administered during hospitalization was 10. Thrombocytopenia and/or neurologic effects on presentation were associated with the inability to achieve initial control.
Benefit from FabAV has also been described in patients with severe envenomation (table 1):
●A systematic review of 24 individual cases of severe Crotalinae envenomation taken from cohort studies and case reports found that 50 of 65 severe venom effects improved or resolved after FabAV administration and that control of all signs and symptoms of envenomation occurred in 12 patients . Recurrent or delayed coagulopathy was described in 12 patients.
●An observational study of 209 patients with Crotalinae snake bites reported outcomes after FabAV treatment in 28 patients with severe envenomation . All patients with severe envenomation had clinical improvement after FabAV administration. Initial control of venom effects was achieved in 16 of 28 (57 percent) severely envenomated patients compared with 158 of 181 (87 percent) minimally or moderately envenomated patients.
Together, these studies show that FabAV administration in patients with Crotalinae bites typically results in initial control of local and nonhematologic systemic toxicity. FabAV also halts progression of coagulopathy in most patients and prevents its occurrence. However, Crotalinae-induced coagulopathy or neurologic effects may be relatively resistant to antivenom therapy. FabAV dosing varies with disease severity and is described below. (See 'Initial regimen based upon severity' below.)
Observational studies have identified hypersensitivity reactions as the main risk associated with FabAV therapy. In 2012, a meta-analysis estimated the incidence of immediate and delayed hypersensitivity following FabAV administration as 6 percent (95% CI: 4 to 9 percent, 463 patients) and 8 percent (95% CI: 4 to 16 percent, 298 patients), respectively, when studies confounded by product contamination were excluded . These rates of hypersensitivity reactions are lower than those found in premarketing trials with a product containing a higher degree of Fc contamination [49,50] and much lower than the rates of acute and delayed hypersensitivity previously seen after ACP administration .
Contraindications — Absolute contraindications to FabAV administration comprise known allergy to FabAV, papaya, or papain in patients with minimal toxicity after a Crotalinae snake (rattlesnake, water moccasin [cottonmouth], or copperhead) bite (table 1) .
Clinicians may choose to proceed with FabAV administration in patients who manifest serious systemic toxicity despite the presence of allergy. If this course of action is taken, then the patient should also receive pretreatment to blunt the allergic response (eg, IV diphenhydramine 1.25 mg/kg, maximum single dose 100 mg and/or IV methylprednisolone 2 mg/kg, maximum single dose 125 mg), and the clinician should ensure preparation and immediate availability of epinephrine (0.3 to 0.5 mg IM to the anterolateral thigh, 1:1000 preparation or continuous intravenous infusion of 1:10,000 epinephrine 0.1 to 1 microgram per minute, titrated to effect) before administration of any antivenom.
Assessment of response — The response to FabAV determines whether or not further and/or increasing doses are required. The adequacy of dosing should be evaluated based upon:
●Lack of progression of tissue swelling and ecchymosis adjacent to the bite site
●Improvement in vital signs, including decrease in tachycardia, tachypnea, and hypotension
●Improvement in other systemic findings including vomiting, diarrhea, pain, oral paresthesias, or altered mental status
●Partial or complete reversal of coagulopathy
Initial regimen based upon severity — Antivenom administration is associated with severe allergic reactions; it should only occur in a continuously monitored emergency or intensive care unit setting. Consultation with a medical toxicologist or other physician with expertise and prior experience treating venomous snake bites is strongly recommended before initiating antivenom therapy. Emergency consultation with a medical toxicologist in the United States is available at 1-800-222-1222. Outside of the United States, the World Health Organization provides a listing of international poison centers at its website: www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html.
FabAV is supplied as a lyophilized powder that can be reconstituted in 10 mL within 20 minutes, but may take longer than 30 minutes . Each vial supplies approximately 1 g of total neutralizing proteins. The antivenom should be infused within four hours of preparation. The clinician should review the manufacturer's instructions prior to infusion .
Although studies have demonstrated low rates of acute reactions with FabAV , we advocate the immediate availability of epinephrine (1:1000 [1 mg/mL] 0.3 to 0.5 mg IM in the anterolateral thigh or 1:10,000 [0.1 mg/mL] prepared for continuous intravenous infusion), diphenhydramine or similar antihistamine, intravenous corticosteroids, and inhaled albuterol during antivenom administration. (See "Anaphylaxis: Emergency treatment", section on 'Pharmacologic treatments'.)
Snakes inject the same quantity of venom into children and adults. Thus, the dosage of antivenom is not dependent upon age or weight but does vary with the severity of envenomation (table 1 and algorithm 2) :
●For patients with mild to moderate envenomation, FabAV is given in a dose of approximately 4 to 6 g (four to six vials) reconstituted and administered over 60 minutes, with repeat dosing of approximately 4 to 6 g (four to six vials) over 30 to 60 minutes if the patient has not responded after one hour .
●Higher doses are generally given to patients with severe envenomation (algorithm 2). In one study, initial control of severe venom effects occurred after a median of two doses of FabAV . The doses consisted of a median of nine vials, with 25 percent of patients receiving more than 15 vials per dose.
Treatment of acute hypersensitivity — The clinician should immediately stop antivenom infusion in patients who experience signs of acute hypersensitivity (eg, anaphylactic shock, oropharyngeal swelling, bronchospasm, urticaria). These patients should receive treatment for anaphylaxis as outlined in the rapid overviews for anaphylaxis in adults (table 3) and in children (table 4). (See "Anaphylaxis: Emergency treatment", section on 'Immediate management'.)
As acute reactions are often nonimmunologic in nature, the antivenom infusion may be resumed cautiously and completed at a lower infusion rate once initial signs of acute hypersensitivity have been treated.
Allergic reactions can be secondary to venom sensitivity, particularly in those who have been bitten before or who handle snakes. In all cases of anaphylaxis, cessation of antivenom administration is part of the management of anaphylaxis. Once anaphylaxis is controlled, a decision regarding restarting the antivenom infusion should be based on a risk-to-benefit analysis, and antivenom should be administered at a lower infusion rate. Consultation with a medical toxicologist experienced in the management of Crotalinae snake bites is strongly recommended for these patients.
Treatment of recurrent toxicity — All patients who receive antivenom warrant close observation for recurrent toxicity over the first 24 hours after initial FabAV administration . Recurrent toxicity may occur despite initial control with antivenom. Recurrent symptoms may be local (eg, swelling), or systemic (eg, deterioration in the coagulation parameters following initial normalization). Recurrence may be related to the short half-life of Fab fragments or possibly dissociation of Fab fragment-venom complexes. In addition, antivenom may not reverse the thrombocytopenia following timber rattlesnake envenomation .
We suggest that patients with Crotalinae bites and moderate-severe envenomation who have undergone FabAV administration receive scheduled doses of 2 g (two vials) every six hours for three doses to prevent recurrent toxicity (table 1 and algorithm 2 and algorithm 1). Alternatively, the clinician may chose to perform careful clinical assessment of the bite site and measurement of coagulation studies every six hours to determine the need for additional antivenom. Scheduled doses of FabAV appear to prevent recurrent toxicity. In an open label, multicenter trial of 31 patients who received an initial dose of FabAV with control of toxicity, the 15 patients who received scheduled treatment of approximately 2 g (two vials) every six hours for three doses did not experience recurrence while 8 of 16 patients in the group who only received further antivenom if recurrent symptoms developed required no further antivenom therapy .
In some instances, total reversal of coagulopathy with FabAV is not possible, and the clinician may choose improvement in coagulation parameters towards normal as an acceptable outcome in patients who have no significant bleeding .
●Risk of late coagulopathy – Patients with abnormal coagulation within the first 12 hours after FabAV administration have a 67 percent chance of developing recurrent coagulopathy and should have repeat coagulation profiles checked every 48 hours until normal . The mechanism of late recurrent coagulopathy is not known, but various mechanisms involving dissociation of venom-antivenom complexes have been suggested.
Additional markers for late, persistent, or recurrent coagulopathy in patients who have received FabAV include abnormalities within 48 hours of a snake bite in platelet count, PT, PTT, INR, D-dimer, fibrinogen, or fibrin split products or a rise of ≥20 percent in platelet count within four hours of FabAV administration regardless of initial platelet count . Patients who have normal coagulation testing and <20 percent increase in platelet count within four hours of FabAV administration may be at lower risk. However, all patients who receive FabAV should have reassessment of their coagulation status within five days after antivenom administration.
Redosing of FabAV after the initial phase of treatment and maintenance antivenom therapy is warranted even up to several weeks after envenomation. For patients who have bleeding or any of the following findings suggestive of ongoing venom effects on reassessment of coagulation . An initial bolus dose of 2 g (two vials) is a reasonable starting point, with additional doses titrated to the neutralization of ongoing venom effects. A continuous infusion of FabAV may be a more efficient way to maintain a continuously protective, circulating concentration of antivenom, but should only be performed in consultation with a medical toxicologist with expertise in managing Crotalinae snake bites.
•Plasma fibrinogen <50 mcg/mL
•Platelet count <25,000/mL
•International normalized ratio (INR) >3.0
•Activated PTT >50 seconds
•Multiple defects in coagulation parameters
•Comorbid conditions or behaviors that increase hemorrhagic risk
If late recurrent, persistent or late, new onset hematologic abnormalities develop, they may persist for more than two weeks .
F(ab')2 antivenom — Polyvalent equine F(ab’)2 antivenom (Anavip) is derived from Bothrops asper and Crotalus simus immunizing venoms. It is approved for use by the US Food and Drug Administration (FDA), but it is not expected to be commercially available for clinical use in the United States until 2018 or 2019. It differs from the commercially available Fab antivenom (FabAV, Crofab) in that cleavage occurs on the Fc portion so that the Fab regions have a molecular weight that is above the threshold for renal clearance and thus have a much longer half-life. The longer half-life provides greater protection against recurrent hematological toxicity. In a phase 3 clinical trial involving 114 children and adults with clinical signs of Crotalinae snake bites, patients who received F(ab’)2 had a significantly lower frequency of late coagulopathy than patients who received Fab antivenom (5 to 10 percent versus 30 percent) [25,26]. The rate of acute serum reaction and serum sickness was low in all groups regardless of antivenom received (2 to 3 percent).
DISPOSITION — All patients who require treatment with antivenom require hospital admission for further observation and supportive care. Hospitalization is also warranted in the United States for exotic, non-United States snake bites, even in the setting of initially normal clinical appearance. (See "Snakebites worldwide: Clinical manifestations and diagnosis".)
Patients with possible Crotalinae (rattlesnake, water moccasin [cottonmouth], copperhead) envenomation who initially have mild or no toxicity on clinical assessment and normal baseline testing, may be observed for features of local and systemic toxicity. If the patient appears well and repeat laboratory tests remain normal at 8 to 12 hours, it is likely that no significant envenomation has occurred, and the patient may be discharged. A longer period of observation up to 24 hours may be necessary for children and the elderly, those with significant comorbidities, those with poor social supports, patients with some symptoms of envenomation and bites involving the lower limb or face/neck.
A somewhat longer period of observation (12 to 24 hours) is necessary for asymptomatic patients with suspected Mojave rattlesnake bites, since neurotoxicity may be delayed .
Discharge instructions — Patients who do not receive antivenom should be instructed to seek medical care for increased swelling not relieved by elevation, signs of coagulopathy (easy bruising, petechiae, bleeding from gums or hematochezia), or pain not controlled by oral analgesia (algorithm 1).
Patients who have received antivenom should also receive the following instructions (algorithm 1):
●Seek care if they develop symptoms of serum sickness (fever, rash, muscle pain, arthralgia, or arthritis).
●If they had coagulopathy during their care or were victims of a rattlesnake envenomation, they should avoid contact sports, surgery, or dental work for two weeks.
●Patients bitten by a rattlesnake or water moccasin (cottonmouth) should also have prothrombin time, fibrinogen, hemoglobin, and platelets measured two to three days and five to seven days after the bite.
OUTCOMES — Most victims of venomous North American snakes fully recover. Morbidity is uncommon and associated with bites to the face or upper extremity . Loss of range of motion is most common. Other permanent sequelae include weakness, pain, abnormal sensation (paresthesia, hypesthesia, anesthesia), or skin discoloration.
Death following Crotalinae snake bite is unusual (<1 percent of all bites). Mortality is associated with rattlesnake bites, proximal bite sites (eg, face, neck, trunk), no antivenom therapy or inadequate antivenom dosing, or inadequate fluid resuscitation of shock .
ADDITIONAL RESOURCES — The phone number for the National Poisons Information hotline, administered by the American Association of Poison Control Centers, is 1-800-222-1222. For clinicians outside of the United States, the World Health Organization provides a listing of international poison centers at its website.
SUMMARY AND RECOMMENDATIONS
●Most bites in the United States are caused by rattlesnakes, water moccasins (or cottonmouths), and copperheads (family Viperidae, subfamily Crotalinae). (See 'Epidemiology' above.)
●Symptomatic Crotalinae (rattlesnake, water moccasin, or copperhead) envenomation typically causes local tissue damage with ecchymosis (picture 1) and coagulopathy. Other potential sequelae include marked tissue swelling with compartment syndrome, rhabdomyolysis with renal failure, shock, hemorrhage, coma, and seizures. (See 'Clinical Manifestations' above.)
●First aid measures for patients with Crotalinae (rattlesnake, water moccasin [cottonmouth], or copperhead) bites consist of removal from the vicinity of the snake, keeping the patient calm and at rest, immobilizing the affected extremity above the level of the heart, and rapid transport to definitive care. (See 'First aid approach' above.)
●Evaluation and management of Crotalinae (rattlesnake, water moccasin, or copperhead) envenomation is outlined in the algorithm (algorithm 2). The severity of the bite (table 1) determines the need to give polyvalent Crotalinae ovine immune Fab (FabAV, Crofab, Protherics). (See 'Indications' above and 'Crotalinae (Pit viper) antivenom' above and 'Supportive care' above.)
●Consultation with a medical toxicologist or other physician with experience in managing North American snake bites is strongly recommended prior to antivenom administration. Phone consultation with a medical toxicologist is available through a United States regional poison control center by calling 1-800-222-1222.
●We recommend that patients with Crotalinae bites (rattlesnake, water moccasin [cottonmouth], or copperhead bites) and moderate to severe toxicity (table 1 and algorithm 2) or with bite sites that present a significant possibility for airway obstruction from local tissue swelling (eg, bites to the face or neck) receive FabAV therapy (Grade 1A). (See 'Indications' above and 'Initial regimen based upon severity' above.)
●We suggest that patients with Crotalinae bites with moderate to severe envenomation who have received FabAV be given additional scheduled doses of FabAV to prevent recurrent toxicity (Grade 2C). (See 'Treatment of recurrent toxicity' above.)
●Although expert guidelines have suggested that patients with mild envenomations not receive antivenom, some evidence suggests that it may provide short-term benefit, primarily a more rapid return to normal function of the involved limb. Thus, the use of antivenom for patients with mild envenomation should be individualized on a case by case basis with the input of a medical toxicologist or other snakebite expert. (See 'Indications' above.)
●We suggest that patients with Crotalinae envenomation but minimal and non-progressive swelling, pain, or ecchymosis and in whom the decision is to withhold antivenom, be closely observed for 12 to 24 hours to ensure that progression of toxicity, as indicated by worsening local or systemic effects, do not occur (table 1 and algorithm 2). The duration of observation may vary with a number of factors, including the age and health of the patient, the social supports available on discharge, the presumed species of the snake and the location of the bite. (See 'Indications' above.)
●The clinician should immediately stop antivenom infusion in patients who experience signs of acute hypersensitivity (eg, anaphylactic shock, oropharyngeal swelling, bronchospasm, urticaria). These patients should receive treatment for anaphylaxis as outlined in the rapid overviews for anaphylaxis in adults (table 3) and in children (table 4). Cautious resumption of antivenom administration may be appropriate in patients in whom the benefit of antivenom outweighs the risk of continued exposure. (See 'Treatment of acute hypersensitivity' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Allen Cheng, MB, BS, who contributed to an earlier version of this topic review.
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