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

INTRODUCTION — This topic will review the management of Crotalinae (rattlesnake, water moccasin [cottonmouth], or copperhead) snakebites. The clinical manifestations, evaluation, and diagnosis of these snakebites; evaluation and management of bites by coral snakes; and snakebites outside the United States are discussed separately:

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

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

●(See "Snakebites worldwide: Clinical manifestations and diagnosis" and "Snakebites worldwide: Management".)

FIRST AID — The appropriate first aid for snakebites is controversial, and management strategies are primarily based on case series and clinical experience [1,2]. Numerous field measures have been advocated, but none have been shown to improve outcome [3].

We suggest the following approach for North American (NA) Crotalinae snakebite victims prior to definitive hospital care [1,2]:

●Remove the patient from the snake's territory and keep him or her warm, at rest, and calm.

●Remove any rings, watches, or constrictive clothing from the affected extremity.

●Immobilize the injured body part in a functional or extended position at the level of the heart [1,2]. For extremity bites, some experts advise elevation of the extremity to decrease local pain and swelling. Although there is a theoretical concern for increased systemic toxicity during prehospital care with elevation of the bite site, evidence is lacking that systemic toxicity is increased by the elevated position in patients with pit viper bites.

●Do not apply pressure immobilization, tourniquets, or constrictive dressings. Pressure immobilization refers to a procedure in which an elastic bandage is applied to the affected limb with a goal of delaying venom spread through the lymphatics but is not applicable and not advisable for the initial management of Crotalinae bites. Although pressure immobilization is mentioned as a potential first aid therapy for snakebites in the United States by the American Heart Association [4], no clinical studies in human patients have demonstrated benefit. Most snakebite experts do not support pressure immobilization for Crotalinae snakebites because these venoms cause local tissue toxicity, and sequestering the venom in the affected limb may increase local tissue damage [5,6].

Pressure immobilization may be useful as a first aid procedure for neurotoxic snakebites and is discussed in greater detail separately. (See "Snakebites worldwide: Management", section on 'Pressure immobilization'.)

●Cleanse the wound.

●Withhold alcohol and drugs that may confound clinical assessment.

●Transport the patient 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. Snakes and decapitated snake heads should not be handled directly because the bite reflex may remain intact in recently killed snakes and result in additional envenomation.

Misidentification (particularly in an emergency situation) may have potentially serious outcomes, and patients with possible envenomation should be observed closely [7]. 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) [8]. Venomous rattlesnakes have a triangular-shaped head, elliptical pupils, and hollow, retractable fangs. By contrast, nonvenomous snakes have rounded heads and pupils and lack fangs but may be very effective mimics of venomous snakes in terms of appearance or behavior.

Methods such as tourniquets, incision and oral suction, mechanical suction devices, cryotherapy, surgery, and electric shock therapy have no role in snakebite management [5]. Tourniquets can damage nerves, tendons, and blood vessels; and oral suction can lead to infection [8-10]. Furthermore, venom removal by mechanical suction is minimal at best. In a study of attempted mock venom extraction with a mechanical suction device in human volunteers, suction reduced the total body burden by only 2 percent [11].

ACUTE MANAGEMENT — Treatment depends upon the degree of envenomation [5]. (See "Bites by Crotalinae snakes (rattlesnakes, water moccasins [cottonmouths], or copperheads) in the United States: Clinical manifestations, evaluation, and diagnosis", section on 'Evaluation'.)

Initial stabilization — Stabilization of patients with Crotalinae snakebites requires rapid assessment and management of the airway, breathing, and circulation:

●Airway and breathing – In addition to emergency antivenom administration, patients with airway compromise require endotracheal intubation and mechanical ventilation. Patients with the following clinical features are at highest risk:

•Bites to the face or neck – Crotalinae snakebites to the face or neck may result in rapid local tissue swelling with airway obstruction.

•Myokymia (rippling muscle movement of the face and extremities) – Myokymia that is extensive, or involves the muscles of respiration, is associated with respiratory failure [12].

●Mohave or Southern Pacific rattlesnake bite – Some populations of these species possess a neurotoxin that may produce weakness and respiratory failure [13,14]. Although the decision to perform endotracheal intubation and institute mechanical ventilation should be made on clinical grounds (including the need for airway protection associated with bulbar palsy), ancillary studies may provide additional objective information to augment serial clinical assessment in some patients as discussed separately. (See "Evaluation and management of coral snakebites", section on 'Neurologic assessment and respiratory support'.)  

●Circulation – Emergency management of shock and bleeding followed by timely antivenom administration to patients with progressive tissue swelling or systemic toxicity after Crotalinae envenomation are the most common actions needed when stabilizing patients with Crotalinae snakebites.

Hypovolemia from hemorrhage secondary to bleeding, fluid shift into the bitten limb, and/or direct venom effects with vasodilation may cause shock with hypotension. These patients warrant treatment with rapid infusion of isotonic fluids (eg, normal saline or balance crystalloid solutions) or blood (depending upon degree of hemorrhage and to maintain the hematocrit at acceptable levels) and, if shock is not quickly reversed with intravenous fluid boluses, vasoactive medications, like patients with septic shock. (See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)" and "Evaluation and management of suspected sepsis and septic shock in adults".)

Marked local or systemic envenomation — Patients with marked or progressive swelling, hematologic, or other systemic findings of envenomation, or who have bites to the face or neck that show signs of envenomation and a potential for airway obstruction warrant Crotalinae antivenom treatment of local effects, supportive care, and antivenom (algorithm 1). (See 'Antivenom therapy' below.)

Antivenom therapy

Initial treatment — Consultation with a medical toxicologist or other physician with expertise and prior experience treating venomous snakebites is strongly encouraged before initiating antivenom therapy. Emergency consultation with a medical toxicologist in the United States is available at 1-800-222-1222. Regional poison control centers can also assist with locating and facilitating transport of antivenom to the treating facility.

For patients with Crotalinae snakebites and progressive swelling or signs of systemic toxicity, we recommend antivenom therapy (table 1). Antivenom should be administered as soon as possible once manifestations of envenomation (beyond minor localized swelling) are evident to both treat existing effects and prevent progression of venom effects. There is no specific time limit for administration of antivenom. Crotalidae Polyvalent-immune Fab (ovine), brand name CroFab (FabAV) [5,15-24] and Crotalidae Immune F(ab')₂ (equine), brand name Anavip (Fab2AV) [25,26], are each approved for North American (NA) Crotalinae snakebites and have similar efficacy as described below. (See 'Efficacy' below.)

For patients with Crotalinae snakebite sites that present a significant possibility for airway obstruction from local tissue swelling (eg, bites to the face or neck with signs of envenomation), we recommend antivenom administration even for mild swelling in the absence of other signs of envenomation. Patients with bites in these locations can have rapid onset of critical airway compromise from local swelling alone.

For patients exhibiting neurotoxicity (muscle fasciculation and/or motor weakness) after an NA rattlesnake bite, experience using FabAV to reverse these effects is inconsistent: both success and failure in reversing neurotoxic effects with FabAV are reported [27,28], although experience is limited [29]. Patients with airway compromise or depressed respirations warrant emergency endotracheal intubation and mechanical ventilation.

●Relative contraindications – For patients receiving FabAV (CroFab), relative contraindications include allergy to papain, papaya, or FabAV during prior administration.

Relative contraindications for the use of Fab2AV (Anavip) include patients with known allergies to horse protein or who have had an allergic reaction to prior therapy with Fab2AV antivenom.

When relative contraindications are present, antivenom should only be administered when the benefits outweigh the risks [24]. These patients require pretreatment for anaphylaxis and adjustment of the rate of infusion as described separately. (See 'Treatment of acute antivenom reactions' below.)

Pregnancy is not a contraindication to antivenom administration; indirect experience with other antivenoms suggests that potential adverse effects to the fetus following pregnancy are primarily related to venom effects on the mother. Although acute antivenom reactions may occur in the mother, antivenom plus any required anaphylaxis management is likely the best approach to improved fetal outcome [24,26,30]. Case reports have also documented delivery of healthy newborns soon after FabAV antivenom therapy [31-33].

●Dose and administration – The table summarizes dosing, reconstitution, and administration for Crotalidae Immune F(ab')₂ (equine), brand name Anavip (Fab2AV) and Crotalidae Polyvalent-immune Fab (ovine), brand name CroFab (FabAV) (table 1) and is based upon the manufacturer's instructions [24,26]. 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; specifically, higher doses of antivenom are needed for patients with hypotension or serious active bleeding [5].

Antivenom therapy with FabAV or Fab2AV can be associated with potentially severe allergic reactions, but the risk appears to be low (<1 percent) [25]. Nevertheless, antivenom should only be administered in a continuously monitored emergency or intensive care unit setting. Epinephrine ([concentration 1 mg/mL] 0.3 to 0.5 mg intramuscularly [IM] for administration in the anterolateral thigh as well as epinephrine [concentration 0.1 mg/mL] for continuous intravenous [IV] infusion), diphenhydramine or similar antihistamine, IV corticosteroids, and inhaled albuterol should all be immediately available. (See 'Treatment of acute antivenom reactions' below.)

Treatment of acute antivenom reactions — Based upon the comparative trial between FabAV and Fab2AV, the rate of acute serum reaction and serum sickness for patients receiving either FabAV or Fab2AV is approximately 2 to 3 percent [25]. Patients who have previously received Crotalinae antivenom (or, for Fab2AV antivenom, other equine antivenoms) may be predisposed to acute allergic reactions.

In patients who experience signs of acute hypersensitivity (eg, anaphylactic shock, oropharyngeal swelling, bronchospasm, or urticaria) or nonimmunologic acute reactions (eg, nausea, vomiting, arthralgia, headache), the clinician should immediately stop antivenom infusion. Patients with signs suggestive of anaphylaxis should receive emergency treatment as outlined in the rapid overview for adults (table 2) or children (table 3). (See "Anaphylaxis: Emergency treatment", section on 'Immediate management'.)

Consultation with a medical toxicologist experienced in the management of Crotalinae snakebites is strongly encouraged for these patients. Further management depends upon the nature of the reaction [34]:

●Acute hypersensitivity – Once anaphylaxis is controlled, a decision regarding restarting the antivenom infusion should be based on a risk-to-benefit analysis. Clinicians may choose to proceed with antivenom administration in patients who manifest serious systemic toxicity despite the presence of allergy. If resumption of antivenom therapy is chosen, then the patient should 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 IV infusion of 1:10,000 epinephrine 0.1 to 1 microgram per minute, titrated to effect) before administration of any antivenom. Antivenom should be administered at a lower infusion rate (eg, 25 mL/hour or slower).

●Acute reactions without hypersensitivity – Because acute reactions are often nonimmunologic in nature, the antivenom infusion may be resumed cautiously and completed at a lower infusion rate (eg, 25 mL/hour).

If signs or symptoms of anaphylaxis or hypersensitivity reactions occur again, antivenom administration should be discontinued immediately, appropriate therapy instituted, and the need for further antivenom treatment re-evaluated.

Assessment of response and need for redosing — The response to antivenom determines whether or not further doses are required (table 1). Control of envenomation is indicated by all of the following [34]:

●Hemodynamic stability.

●Improvement in other systemic findings such as vomiting, diarrhea, or altered mental status.

●Lack of progression of tissue swelling adjacent to the bite site.

●Partial or complete reversal of hematologic toxicity based upon repeated laboratory studies performed one hour after each dose of antivenom. Studies should include a complete blood count, prothrombin time (PT), international normalized ratio (INR), and fibrinogen.

Patients who do not achieve control of envenomation after the initial dose of antivenom warrant repeat dosing under the guidance of a medical toxicologist or physician with similar expertise managing Crotalinae snakebites.

Prevention of early recurrent toxicity — Crotalidae Polyvalent-immune Fab (ovine), brand name CroFab (FabAV), and Crotalidae Immune F(ab')₂ (equine), brand name Anavip (Fab2AV), the antivenoms available for Crotalinae snakebites in North America, differ in their rates of early recurrence and duration of effect (see 'Efficacy' below). Thus, the approach to preventing early recurrent toxicity depends upon the antivenom used:

●FabAV (CroFab) – To prevent recurrent toxicity marked by subsequent worsening of local (eg, swelling) or hematologic (eg, platelets or fibrinogen) effects after initial improvement, we suggest that patients with Crotalinae envenomation who have undergone FabAV administration receive scheduled doses of antivenom (two vials every six hours for three doses) (table 1) [5,19,24]. Alternatively, if medical toxicology oversight and resources allow, the clinician may choose to perform careful clinical assessment of the bite site and measurement of coagulation studies every six hours to determine the need for additional antivenom [35].

Provision of scheduled maintenance doses of FabAV after initial control is achieved may limit recurrence of local venom effects and decrease rates of late hemotoxicity [21,26]. Yet even with use of maintenance doses, late hemotoxicity is reported in approximately 30 percent of patients [22,25,36]. Some experts suggest that in settings where close monitoring of local swelling and coagulation parameters can occur, as-needed dosing of FabAV antivenom may be more appropriate than scheduled dosing. For example, in a retrospective observational study of 310 adults that compared hospital length of stay and total vials used between patients treated with an as-needed versus a scheduled maintenance antivenom regimen, the as-needed group received fewer vials overall (8 versus 16 vials) and had a shorter hospital length of stay (27 versus 34 hours) [35]. Follow-up information was available for over 90 percent of patients in this study, and there were no differences in hospital readmissions, retreatment with antivenom, bleeding, or procedures between groups. However, patients were admitted to a toxicology service managed by full-time toxicology faculty practicing at the bedside and covered by 24-hour onsite medical toxicology fellows. The immediate availability of physicians with a high level of snakebite expertise likely optimized timely detection of local recurrence and hastened administration of antivenom when necessary. From a practical standpoint, this degree of monitoring is not available at most hospitals where snakebite victims are managed. In those settings, a delay in recognition of and response to recurrence of local venom effects could result in increased local tissue injury, and scheduled maintenance dosing of FabAV is preferred.

●Fab2AV (Anavip) – Once initial control is achieved (local effects are no longer progressing, hematologic and systemic effects are improving), maintenance doses of Fab2AV are not needed. However, patients should be observed for an additional 18 hours for re-emergence of local or hematologic effects. If these occur, additional doses of antivenom are indicated [26].

Identification and treatment of late hemotoxicity

Risk of late hemotoxicity — Among patients with rattlesnake envenomation who receive FabAV, the risk of late hemotoxicity is approximately 30 percent depending upon the geographic region and snake species involved [22,25,36]. Late hemotoxicity describes either recurrent, delayed onset, or persistent thrombocytopenia, prolonged PT and/or decreased fibrinogen.

Late hemotoxicity appears to be much less common in patients treated with Fab2AV. In a randomized clinical trial of 121 patients receiving antivenom for a Crotalinae snakebite, 8 percent of patients who received Fab2AV experienced late hemotoxicity compared with 30 percent in the FabAV group [25]. Subsequent small observational studies from New Mexico and Arizona have revealed even lower rates of late hemotoxicity with use of Fab2AV (0 to 5 percent) [29,37]. Recurrent and delayed hemotoxicity may become apparent as early as 24 hours after treatment with FabAV but can develop up to 14 days after initial control with antivenom [25]. This risk is increased in patients with abnormal platelets or fibrinogen within the first 12 hours after FabAV administration [38]. Risk may also be increased in patients with normal platelets and fibrinogen but who exhibit an elevated D-dimer or fibrin split products [39]. However, late, new-onset hematologic abnormalities may develop even without these indicators, likely due to early administration of antivenom to treat swelling, and prevention of onset of hemotoxicity with this treatment [40].

Monitoring — Since late hemotoxicity can develop following use of FabAV or Fab2AV, and risk cannot be predicted, all patients who receive antivenom warrant monitoring (physical assessment and laboratory studies) for late thrombocytopenia or hypofibrinogenemia according to the antivenom received [19] (see 'Prevention of early recurrent toxicity' above):

●FabAV (CroFab) – Obtain a platelet count and fibrinogen level two to three days after and again five to seven days after last administration of FabAV.

●Fab2AV (Anavip) – Obtain a platelet count and fibrinogen level five to seven days after last Fab2AV administration.

If any abnormal trends are noted, further laboratory monitoring is indicated. Additionally, patients with additional risk factors for bleeding may require early or more frequent assessments.

Treatment — For patients in whom late hemotoxicity is identified, further management is determined based on the specific laboratory values, signs of bleeding, or presence of risk factors for serious bleeding [17,41-43].

Indications for antivenom therapy of late hemotoxicity with antivenom include:

●Any bleeding

●Platelet count <25,000/mL

●Multicomponent coagulation abnormalities (eg, platelets <50,000/mL and fibrinogen <80mg/dL)

●Comorbid conditions or behaviors that increase hemorrhagic risk such as pregnancy, use of antiplatelet or anticoagulant medications, injury prone behaviors or activities, or recent venom-induced systemic shock

Retreatment should be performed in consultation with a medical toxicologist or other physician with expertise in managing Crotalinae snakebites. An initial bolus dose of two vials of FabAV or four vials of Fab2AV is a reasonable starting point, with additional doses titrated to the neutralization of ongoing venom effects [38]. In some instances, total reversal of hemotoxicity with FabAV is not possible. In patients who have no significant bleeding, the clinician may choose improvement in coagulation parameters towards normal as an acceptable outcome [21]. Based on limited evidence, Fab2AV may be a more effective treatment for late hemotoxicity that occurs following use of FabAV [44].

Isolated late hypofibrinogenemia may be observed in healthy, nonpregnant patients without other risk factors for bleeding. These patients should be monitored for resolution of coagulation abnormalities, should not use medications that inhibit platelets, and should not undergo any surgical procedures or engage in activities that risk injury until hemotoxicity is resolved. Complete resolution may take up to three weeks from the time of envenomation [41-43].

Efficacy — Crotalidae Polyvalent-immune Fab (ovine), brand name CroFab (FabAV); and Crotalidae Immune F(ab')₂ (equine), brand name Anavip (Fab2AV) are the two antivenoms available for bites by Crotalinae snakes in North America:

●FabAV (CroFab) – FabAV consists of the purified Fab fragments of sheep immunoglobulin (IgG) raised against the venom of four snakes: Crotalus atrox (western diamondback rattlesnake), Crotalus adamanteus (eastern diamondback rattlesnake), Crotalus scutulatus (Mohave rattlesnake), and Agkistrodon piscivorus (cottonmouth or water moccasin) [16,38,45]. When infused, these Fab fragments bind venom in the intravascular space and are renally excreted. The larger volume of distribution, compared with IgG and Fab2AV, results in more rapid decline in circulating antivenom levels.

Because approximately 50 percent of patients in the first phase of the clinical trial developed recurrence of local venom effects, routine maintenance doses in the first 18 hours are recommended for control of local effects. The half-life of FabAV is approximately 15 hours and shorter than Crotalinae venom substances, which may be detected for more than two weeks post-envenomation. Thus, recurrence or delayed onset of hemotoxicity is possible in the days to weeks following treatment as antivenom levels decline and may necessitate repeated antivenom administration.

●Fab2AV (Anavip) – Fab2AV consists of the purified F(ab')₂ fragments of equine IgG raised against the venom of Bothrops asper and Crotalus simus [25,46]. When infused, these F(ab')₂ fragments bind venom in the intravascular space. Because of the smaller volume of distribution compared with FabAV, circulating antivenom concentrations do not decline as rapidly, and routine maintenance doses in the first 18 hours following initial control are not required. Although no studies have specifically looked at the effectiveness of Fab2AV and time to treatment, it had similar effectiveness to FabAV when given in the same timeframe [25].

Because the molecular weight of Fab2AV is above the threshold for renal clearance, these fragments are not cleared renally and have a longer half-life (133 hours) than FabAV [26]. Thus, recurrent hematologic toxicities occur at a lower rate than with FabAV [25].

Based upon small trials and observational studies, the majority of envenomated patients achieve control of toxicity (local swelling and systemic effects) after initial administration of one or two loading doses of either FabAV or Fab2AV, with some patients requiring additional doses [18-21,23,25,29,37,47,48]. There is an approximately 2 to 3 percent risk of adverse immune reactions or type 1 (acute) and type 3 (delayed, "serum sickness") hypersensitivity; these are typically minor [25].

Fab2AV appears to have similar initial therapeutic benefit compared with FabAV. For example, in a trial of over 110 children and adults with Crotalinae envenomation, Fab2AV was found to have comparable efficacy as FabAV in terms of initial control of hemotoxicity after rattlesnake envenomation. Individuals receiving Fab2AV also did not require maintenance dosing for continued control of local envenomation effects, had a lower incidence of late hemotoxicity (5 to 10 percent for Fab2AV versus 30 percent for FabAV [relative risk reduction 0.20, 95% CI 0.01-0.37]), and had similar rates of type 1 and type 3 hypersensitivity reactions (2 to 3 percent) [25]. In an observational study of 37 patients with rattlesnake envenomation from the New Mexico regional poison control center, both Fab2AV and FabAV achieved initial control of local effects and managed initial hemotoxicity [37]. The lower risk of late hemotoxicity following use of Fab2AV makes it attractive for use in patients with rattlesnake envenomation. Although uncommon, late thrombocytopenia and coagulation abnormalities have been associated with serious bleeding and mortality [41-43].

Among patients receiving FabAV, thrombocytopenia and/or neurologic effects on presentation have been associated with difficulty achieving initial control [18]. In addition, FabAV antivenom did not reverse the thrombocytopenia following a reported timber rattlesnake envenomation [49].

Prior to the availability of antivenoms active against Crotalinae snakebites and the widespread availability of emergency departments and critical care units, snakebite mortality ranged from 5 to 36 percent in the United States [50-52]. 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 snakebites dropped to less than 1 percent. For example, analysis of 23,676 venomous snake exposures from 2001 to 2005 reported to the American Association of Poison Control Centers database found a fatality rate of 0.06 percent [53]. Similarly, no fatalities occurred in a United States registry study of 442 native pit viper snakebites occurring from 2013 to 2015 [54]. Thus, the availability of antivenom for most native Crotalinae snakebites combined with other trends in emergency and critical care capability has been associated with a marked and sustained decrease in snakebite mortality in the United States.

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 snakebite (45 copperhead, 12 water moccasin [cottonmouth], 10 rattlesnake, and 14 unknown) reported no fatalities or long-term morbidity [55]. However, significant acute toxicity did occur, including hemotoxicity (15 patients), skin necrosis (8 patients), respiratory distress requiring endotracheal intubation (3 patients), hypotension (2 patients), and cardiac arrhythmia (2 patients).

Supportive care — Antivenom administration is the mainstay for treatment of envenomation by NA Crotalinae snakes.

In addition, the clinician should provide pain control and monitor for and be ready to manage hypotension, bleeding, rhabdomyolysis, elevated tissue and/or compartment pressures, and, rarely, respiratory failure.

Pain control — Although evidence is limited, patients with rattlesnake or water moccasin bites whose clinical course suggests that the risk of coagulation abnormalities or thrombocytopenia is low or patients with copperhead bites and minimal hemotoxicity may receive analgesia for mild to moderate pain with acetaminophen or nonsteroidal antiinflammatory medications (eg, ibuprofen) [56,57]. Severe pain after snakebite frequently warrants treatment with opioid medications (eg, fentanyl or morphine).

Coagulation abnormalities and thrombocytopenia — Coagulation abnormalities associated with Crotalinae envenomation is primarily due to thrombin-like enzymes or fibrinogenases within the venom. Fibrinogen levels decline without a decrease in other clotting factors [43,58,59]. This pathophysiology contrasts with 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 hemotoxicity. (See 'Antivenom therapy' above.)

Multiple venom components may affect platelets, and the mechanism by which thrombocytopenia occurs is complex [59]. Transfused platelets and coagulation factors in fresh frozen plasma are inactivated by Crotalinae venom and should be avoided in patients with Crotalinae-induced hemotoxicity unless the patient has significant bleeding that is uncontrolled by high-dose antivenom administration [60]. If blood products are given in response to acute blood loss, they should be given with additional antivenom to prevent rapid depletion of those components. Venom-induced thrombocytopenia and venom-induced coagulation abnormalities in the absence of blood loss are not indications for administration of blood products.

Rhabdomyolysis — Rhabdomyolysis (creatine kinase [CK] ≥1,000 IU/L) with potential for renal failure has been described in approximately 5 percent of patients bitten by rattlesnakes or water moccasins (cottonmouths) but is rare after copperhead bites [54]. The classic triad of rhabdomyolysis consists of pigmented granular casts in the urine, a red to brown color of the urine supernatant, and a marked elevation in the plasma 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 (including rhabdomyolysis)".)

Elevated tissue pressures — Elevated tissue pressures may complicate Crotalinae 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 snakebite, but true elevation in compartment pressure is uncommon. Antivenom administration is the primary treatment in this situation; surgical intervention based on clinical findings alone is inappropriate.

Generally, increased compartment pressures result from this extrinsic pressure and can be reduced with the administration of adequate amounts of antivenom and elevation. Elevation results in the drainage of subcutaneous edema and contributes to the reduction of the source of increased tissue pressure. (See 'Minor envenomation' below.)

Compartment syndrome — True compartment syndrome with documented elevations of muscle compartment pressure is uncommon after Crotalinae snakebites, and fasciotomy is rarely indicated. For example, among 442 patients with a snakebite from the North American Snakebite Registry, only eight (2 percent) had clinical findings concerning for compartment syndrome and only two (0.5 percent) had elevated intracompartmental pressure documented, although six received fasciotomy [54].

Bites to muscles in compartments that are very close to the skin (eg, anterior tibial, hand, or foot compartments) have a higher potential for compartment syndrome. For these patients, 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 immediate fasciotomy [61]. 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 [62,63] (see "Acute compartment syndrome of the extremities", section on 'Measurement of compartment pressures'). Further management should be guided by a medical toxicologist and surgeon with extensive experience caring for victims with a snakebite.

Full recovery has been described with nonsurgical management of acute compartment syndrome in the hand (compartment pressure of 55 mmHg) in a patient with a rattlesnake bite to the thenar eminence [64]. The patient received large amounts of polyvalent Crotalinae antivenom (46 vials total) and 20 g of IV mannitol.

Neurotoxicity — Neurotoxicity may rarely occur after bites by selected NA rattlesnakes (eg, Mohave, Southern Pacific, or timber rattlesnakes). Although antivenom is recommended, it may not reliably reverse neurotoxicity. Patients with airway compromise or depressed respirations warrant emergency endotracheal intubation and mechanical ventilation. (See 'Initial stabilization' above and 'Initial treatment' above.)

Wound management — All patients also require wound management as described below. (See 'Minor envenomation' below.)

Disposition — All patients with signs of envenomation require admission for further observation or for treatment with antivenom and supportive care. Hospitalization is also warranted in the United States for exotic, non-United States snakebites, even in the setting of initially normal clinical appearance. (See "Snakebites worldwide: Clinical manifestations and diagnosis".)

At discharge, patients who have received antivenom should also receive the following instructions and be scheduled for recommended follow-up:

●Seek care if they develop symptoms of serum sickness (fever, rash, muscle pain, arthralgia, or arthritis).

●Seek care for immediate assessment of platelets and fibrinogen level if they develop bleeding (such as epistaxis, gingival bleeding, vaginal bleeding, or rectal bleeding) in the two weeks following the bite.

●If they had thrombocytopenia or coagulation abnormalities during their care or were victims of a rattlesnake envenomation, they should avoid contact sports, surgery, or dental work for two weeks.

●For patients bitten by a rattlesnake or cottonmouth, measurement of PT, fibrinogen, hemoglobin, and platelets according to antivenom received:

•FabAV – Two to three days after and then again five to seven days after the last dose of antivenom

•Fab2AV – Five to seven days after the last dose of antivenom

Minor envenomation — Patients with minor envenomation after an NA Crotalinae snakebite have swelling that is localized to the bite site, and do not have other signs of envenomation should not routinely receive antivenom. Bites to the face or neck are an important exception. (See 'Initial treatment' above.)

Management should focus on pain control, wound care, immobilization and positioning of the bite site with close monitoring for progression of swelling or development of hemotoxicity or other signs of envenomation (algorithm 1):

●Pain control – Patients with mild to moderate pain may receive oral analgesia with acetaminophen. Patients with rattlesnake or water moccasin snakebites whose clinical course suggests that the risk of coagulation abnormalities or thrombocytopenia is low and patients with copperhead bites and minimal hemotoxicity may receive nonsteroidal antiinflammatory medications (eg, ibuprofen) [56,57]. Severe pain warrants treatment with IV opioid medications (eg, fentanyl or morphine).

●Wound management – Wound management includes cleansing the skin surface around the bite site with an iodine-containing or other antiseptic solution such as chlorhexidine, removal of any visible foreign bodies, and administration of tetanus prophylaxis according to the recommended immunization schedule (table 4). (See "Tetanus-diphtheria toxoid vaccination in adults".)

The leading edge of swelling and tenderness, when apparent, should be marked and reassessed every 15 to 30 minutes. Alternatively, extremity circumference can be measured both distal and proximal to the bite site. A marker is used to outline the location of the tape measure on the skin so the same locations are used consistently [34].

Bedside superficial debridement of hemorrhagic bullae (should they occur) to permit recognition of underlying necrosis and to help decide further intervention has been proposed [65]. However, we do not recommend this approach because there are insufficient data demonstrating benefit or evaluating the risks, such as infection, of unroofing intact bullae.

Antibiotic prophylaxis is not indicated. Although snakebites may result in the inoculation of bacteria, infection is rare. A retrospective analysis of over 2500 rattlesnake bites reported to a regional poison control center found an infection rate of at most 1 percent based, in most cases, on clinical appearance [66]. These results may overestimate the frequency of infection in snakebites because inflammation from venom effects may track up lymphatic channels and mimic cellulitis. Thus, only patients with established infections or heavily contaminated wounds should receive antibiotics [2]. Empiric treatment should cover Salmonella species and common human organisms (eg, Staphylococcus aureus and group A streptococcus) until wound culture results are available. (See "Acute cellulitis and erysipelas in adults: Treatment" and "Skin and soft tissue infections in children >28 days: Evaluation and management" and "Nontyphoidal Salmonella bacteremia and extraintestinal infection", section on 'Management'.)

●Immobilization and positioning – Proper immobilization and positioning for snakebites to the distal extremities consists of placement of a well-padded posterior splint (preformed, plaster, or fiberglass) in a position of extension that is gently secured to the extremity with a gauze or elastic wrap applied to avoid excessive pressure or restriction of circulation. During hospital care, we advise elevation of the extremity to reduce acute swelling. (See 'First aid' above.)

●Impaired limb function – Because complete recovery is expected with supportive care alone in patients with minor Crotalinae envenomation that does not progress, expert guidelines recommend that antivenom therapy in patients with bites to a limb be reserved for those who have swelling that is extending from the bite site or is progressing, or have hemotoxic, systemic, or neurotoxic venom effects [5,67-71]. Patients with confirmed copperhead bites appear to be at a lower risk for systemic toxicity and progressive swelling but may have impairment of function due to swelling and pain in the involved extremity long enough to cause significant short-term morbidity (eg, inability to work or attend school). In one study, the duration of this impairment was a median of three weeks with a range of three days to four months [67].

Some experts have suggested that antivenom may provide short-term benefit to patients with mild copperhead envenomation with acceptable risk, primarily minor adverse effects, and increased cost of care. However, more data are needed to identify which patients are most likely to benefit and to establish if antivenom improves function enough to offset the potential risk of serious adverse effects, such as anaphylaxis, when only local venom effects are present. As an example, in one small trial of 74 patients with copperhead bites, treatment with polyvalent Crotalinae ovine immune Fab (FabAV, CroFab) modestly improved limb function and reduced use of opioid pain medication at two weeks but did not shorten the time to full recovery compared with placebo [67]. Although the benefit regarding local venom effects in rattlesnake envenomations has not been studied, there is no reason to believe that similar benefits would not apply to these cases as well. Patients who received FabAV had more minor adverse events (eg, pruritus, urticaria, nausea, dizziness, or fever) but no severe effects.

●Observation and monitoring – Patients with minor Crotalinae envenomation should be observed for 24 hours for progression of tissue swelling, hemotoxicity, and other systemic toxicity. Platelet and fibrinogen studies should be repeated every six to eight hours after the initial set of studies.

Patients with progressive swelling or abnormal coagulation testing during the observation period should receive antivenom as described below. They also warrant assessment for rhabdomyolysis. (See 'Antivenom therapy' above and 'Supportive care' above.)

●Discharge instructions – Patients should be instructed to seek medical care for:

•Increased swelling not relieved by elevation

•Signs of coagulation abnormalities and/or thrombocytopenia (eg, easy bruising, petechiae, bleeding from gums or hematochezia)

•Signs of infection (eg, fever or pus drainage)

•Tissue necrosis

•Pain not controlled by oral analgesia

•Any other acutely concerning changes in signs or symptoms

Potential dry bite — Up to 25 percent of patients with Crotalinae bite will not develop clinical envenomation. However, some patients may be asymptomatic at presentation, yet go on to develop swelling and/or hematologic toxicity over time. All patients presenting with report of potentially venomous snakebites should be placed on a cardiac monitor, have initial laboratory studies obtained, and observed for signs of toxicity (eg, progressive swelling, tachycardia, hypotension, or bleeding).

For patients with a potential dry Crotalinae snakebite who are at high risk should they have late progression of envenomation including patients with bites to the face, neck, or lower extremity; children <10 years old; adults >65 years old; and patients with medical comorbidities or poor social supports, we suggest hospital admission and observation for 24 hours with repeat laboratory studies every 8 hours.

All other patients warrant observation for 8 to 12 hours (algorithm 1).

It is likely that no significant envenomation has occurred if all of the following criteria are met:

●The patient appears well during observation

●Repeat laboratory tests (ie, platelet count, PT, INR, and fibrinogen) at six hours are normal (when fibrinogen testing is not available, no elevation in fibrin degradation products [ie, D-dimer or fibrin split products])

●No progressive tissue swelling and no systemic toxicity develops during the observation period

SERUM SICKNESS — Serum sickness occurs in about 2 to 3 percent of patients receiving either FabAV or Fab2AV. The evaluation and management of serum sickness is discussed separately. (See "Serum sickness and serum sickness-like reactions".)

OUTCOMES — Most victims of venomous North American snakebites fully recover. Permanent sequelae are uncommon but may include loss of range of motion, weakness, pain, abnormal sensation (paresthesia, hypesthesia, anesthesia), skin discoloration or tissue loss such as amputation of a digit.

Tissue necrosis occurs frequently and may require operative debridement. For example, in a prospective cohort of rattlesnake envenomation, tissue necrosis was seen in 40 percent of upper extremity envenomations, despite antivenom administration [65]. Signs on presentation associated with increased risk of necrosis included cyanosis and ecchymosis. In addition, patients with social or regular ethanol use were more likely to develop necrosis, and regular cocaine use was associated with an increased risk of surgical debridement.

Death following Crotalinae snakebite is unusual (<1 percent of all bites) [53,54]. Mortality is most often associated with rattlesnake bites [72].

ADDITIONAL RESOURCES

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

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

SUMMARY AND RECOMMENDATIONS

●First aid – First aid measures for patients with bites by North American (NA) Crotalinae snakes (rattlesnakes, water moccasins [cottonmouths], or copperheads) include (see 'First aid' above):

•Move them away from the snake and keep them calm.

•For extremity bites, remove any jewelry or constricting clothing and immobilize the affected extremity in a functional position at the level of the heart; some experts prefer elevation of extremity bites to reduce tissue swelling and pain.

•Rapidly transport to definitive care.

•Do not apply pressure immobilization.

●Initial stabilization – In addition to antivenom, patients with a NA Crotalinae snakebite, may require (see 'Initial stabilization' above):

•Emergency endotracheal intubation and mechanical ventilation for patients with:

-Bites to the face or neck

-Myokymia (rippling muscle movement of the face and extremities) with airway compromise

-Weakness and respiratory failure

•Treatment of shock including:

-Fluid resuscitation with isotonic saline or balanced crystalloid solutions

-Blood as needed to maintain an acceptable hematocrit

-For fluid-refractory shock, vasoactive medications as for septic shock (see "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)" and "Evaluation and management of suspected sepsis and septic shock in adults")

●Antivenom (marked local or systemic envenomation) – The decision to administer antivenom is based upon clinical findings (algorithm 1). Consultation with a medical toxicologist or other physician with expertise managing NA Crotalinae snakebites is encouraged before giving antivenom and to guide decisions about redosing of antivenom, prevention of early recurrent toxicity, and treatment of late hemotoxicity.

•Indications – For patients with NA Crotalinae bites with any of the following, we recommend antivenom therapy (Grade 1B) (see 'Initial treatment' above):

-Progressive swelling

-Signs of hemotoxicity or other systemic toxicity (table 5)

-Potential for airway obstruction (bites to the face or neck with any swelling)

•Initial dosing – The recommended antivenom dosing is provided in the table (table 1). Crotalidae Immune F(a_b')₂ (equine), brand name Anavip (Fab2AV), and Crotalidae Polyvalent-immune Fab (ovine), brand name CroFab (FabAV), have similar efficacy for initial control of typical toxic effects; FabAV is associated with a higher risk for late hemotoxicity. For patients exhibiting neurotoxicity (muscle fasciculation and/or motor weakness), FabAV has been used with varying success; the efficacy of Fab2AV in patients with neurotoxicity is unknown. (See 'Initial treatment' above and 'Efficacy' above.)

•Treatment of acute reactions – Antivenom administration should occur in a continuously monitored emergency or intensive care unit setting because it can cause anaphylaxis that requires emergency treatment as described in the rapid overviews for anaphylaxis in adults (table 2) and children (table 3). (See 'Treatment of acute antivenom reactions' above.)

•Redosing – The need for repeat antivenom doses depends on the response to initial therapy and the agent used (table 1):

-Inadequate response to initial dose – Regardless of the agent used, patients who do not achieve control of envenomation after the initial dose (eg, ongoing hemodynamic instability, persistent signs of systemic toxicity, progressive swelling, persistent hematologic toxicity) generally warrant repeat dosing under the guidance of a medical toxicologist. (See 'Assessment of response and need for redosing' above.)

-FabAV (CroFab) maintenance dosing – For most patients receiving FabAV, we suggest regularly scheduled maintenance doses (two vials every six hours for three doses) rather than as-needed dosing alone (Grade 2C). (See 'Prevention of early recurrent toxicity' above.)

-Fab2AV (Anavip) as-needed dosing – Scheduled maintenance dosing is not necessary for patients receiving Fab2AV; however, they should be observed for 18 hours after receiving antivenom and additional doses may be required if local or hematologic effects re-emerge. (See 'Assessment of response and need for redosing' above.)

•Rhabdomyolysis – Rhabdomyolysis and elevated tissue pressures are additional complications of severe NA Crotalinae envenomation. Primary treatment of rhabdomyolysis consists of fluid repletion and evaluation for significant electrolyte abnormalities such as hyperkalemia, hyperphosphatemia, and/or 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 (including rhabdomyolysis)".)

•Compartment syndrome – Envenomation may rarely increase tissue pressures in the subcutaneous space and cause significant swelling, pain, and paresthesias. Patients with these findings should undergo removal of any dressing, constriction band, splint, cast, or restrictive clothing and elevation of the extremity. Antivenom administration is sufficient treatment in most patients; compartment syndrome requiring fasciotomy is rare. (See 'Elevated tissue pressures' above and 'Compartment syndrome' above.)

●Minor envenomation (nonprogressive, local swelling and no systemic toxicity) – Initial management of patients with minor envenomation (swelling and skin changes adjacent to the bite site only without progressive swelling) and no bite to the face or neck consists of pain control, local wound care, elevating and immobilizing the affected limb, and tetanus immunization as needed. These patients do not require antivenom unless they develop marked or progressive swelling or systemic toxicity on repeated laboratory studies during 24 hours of observation. (See 'Minor envenomation' above.)

●Potential dry bite – Management of patients with a potential dry bite also consists of local wound care and tetanus prophylaxis, as needed. The need for hospitalization and duration of observation depends on the patient's risk of complications if they develop late progression of envenomation (see 'Potential dry bite' above):

•High risk – Hospital admission and observation for 24 hours with repeat laboratory studies every 8 hours is warranted for patients with any of the following risk factors for complications:

-Patients with bites to the face, neck, or lower extremity

-Children <10 years old

-Adults >65 years old

-Patients with medical comorbidities or poor social supports

•Not at high risk – All other patients warrant observation for 8 to 12 hours.

ACKNOWLEDGMENT — We are saddened by the death of Steven A Seifert, MD, FAACT, FACMT, who passed away in May 2022. UpToDate gratefully acknowledges Dr. Seifert's outstanding work as an author for this topic.