Bottom Line:
The most effective treatment for snake bite envenomation is prompt administration of antivenom which neutralizes venom toxins. Early administration has been shown to improve clinical outcomes by stopping progression of venom effects however it cannot reverse tissue injury that has already occurred making early treatment critical. The potential risk of causing an adverse reactions in non-envenomated patients must be weighed against the benefit of giving antivenom early in patients with significant envenomation.
Additional Information
Worldwide, an estimated 5.4 million snake bites occur every year with approximately 25-50% envenomation rate causing up to 138,000 deaths, and causing permanent sequelae in greater than 400,000 victims according to the World Health Organization (WHO). Snake bites is recognized by the WHO as a high-priority neglected tropical disease. In the United States, approximately 7000-8000 snake bites occur annually with an average of 5-10 deaths per year. Approximately 98% of snake envenomations in the U.S. are due to crotalid family: rattlesnakes, copperheads, and water moccasins.
Snakes are ectothermic (“cold-blooded”) animals that rely on environmental heat sources rather than internal metabolic processes to regulate temperature. During colder months, snakes enter a state of brumation and become less active, reducing their metabolic and bodily functions. They seek shelter usually in underground dens and require little to no food. In nontropical areas, snake bite incidence peaks during the hottest time of the year from spring through fall with most activity occurring in the cooler parts of the day (morning and dusk).
Humans are not prey for snakes. Most bites occur as result of a defensive strike after perceiving a threat. Snakes may only deliver a warning bite and release no venom (aka ”dry bite”) to preserve their venom for future hunting of prey.
Snake venom is a highly complex mixture of over a hundred different peptides, proteins, enzymes, and other bioactive components which produce local tissue damage, hematologic abnormalities, and systemic effects. Envenomation severity depends on the amount of venom injected, venom composition, location of bite, and host specific factors. Distinguishing a dry bite from a true envenomation can be difficult as any bite can cause pain, swelling, inflammation, and emotional distress.
Clinical signs of envenomation and severity include progressive local tissue damage (pain, swelling, discoloration, blistering, tissue necrosis), hematologic effects (coagulopathy or bleeding), and systemic signs attributable to venom (weakness, paresthesia, nausea, hypotension altered mental status). Patients should be reassessed every 2 hours, as clinical findings may evolve rapidly.
- Envenomation can be excluded when there are no local or systemic signs and laboratory studies remain normal after 6- 8 hours observation
- Patients with signs and symptoms of envenomation should be observed for 12-24 hours for signs of clinical progression
Laboratory analyses should include complete blood count, platelet count, PT, PTT, serum fibrinogen level, complete metabolic panel, and creatinine kinase with repeat testing every 6 hours to gauge response to therapy and guide additional antivenom therapy.
Two crotalid antivenoms approved by the FDA are currently on the market for treatment of North American pit viper envenomations: Crofab® and Anavip®. Both are derived from either immunized sheep or horses and fractionated to obtain the less antigenic, smaller, and specific Fab fragments of IgG antibodies. During administration, patients should be closely monitored for adverse reactions and anaphylaxis which most commonly seen within the first few minutes of administration but may develop up to 2 hours after.
CroFab® was first released in 2000, is a F(ab’)1 antivenin product derived from sheep immunized with Western Diamondback rattlesnake (Crotalus atrox), Eastern Diamondback rattlesnake (Crotalus adamanteus), Mojave rattlesnake (Crotalus scutulatus), and the Cottonmouth, or Water Moccasin, (Agkistrodon piscivorus). It has a single toxin binding site and smaller molecular size allowing for good tissue penetration and shorter half-life and elimination.
- Starting dose: 4-6 vials with treatment goal to stop progression of soft tissue swelling and coagulopathy
- Give additional 4-6 vials in 1 hour if treatment goals are not met. No max dose. The dose of antivenom required is proportional to the amount of venom injected.
- Administer additional 2 vials every 6 hours for 3 doses to prevent recurrence
- Research of copper head bites treated with early administration of CroFab show improved outcome (faster recovery, less need for opioids, and reduced risks of prolonged, possibly permanent disability) and lack of need for maintenance dose.
Anavip® was released in 2018 and is an equine derived F(ab?)2 antivenin product derived from horses immunized with Mexico/Central American snakes: Bothrops asper and Crotalus durissus. It has two toxin binding sites, larger molecular size, and a longer half-life.
- Initial dose: 10 vials - if initial control is not obtained repeat dose as needed every hour. No max dose
- Because of its longer half-life compared to Crofab®, no maintenance dose is usually required
- Studies demonstrated a lower incidence of late onset or recurrent coagulopathy when compared to Crotab® likely due to its longer elimination half-life
References
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Snakebite envenoming: A systematic review and meta-anaylysis of global morbidity and mortality. Afroz A, Siddiquea BN, Chowdhury HA, et al. 2024. PLOS Neglected Tropical Diseases 18(4): e0012080. https://doi.org/10.1371/journal.pntd.0012080
Long-Term Clinical Outcomes of Rattlesnake Envenomation in Arizona Following Treatment With Crofab vs Anavip: A Retrospective Observational Study. Smelski GT, Guthrie AM, Axon DR, et al. J Am Coll Emerg Physicians Open. 2025 Jun 12;6(4):100207. doi: 10.1016/j.acepjo.2025.100207. PMID: 40574792; PMCID: PMC12197915.
Efficacy and safety of two Antivenoms in the treatment of eastern copperhead (Agkistrodon contortrix) envenomations in Southeast Texas, Spencer Greene, Alexander Teshon, JACEP Open,Volume 5, Issue 5, 2024,e13310,ISSN 2688-1152,https://doi.org/10.1002/emp2.13310.
The critical time period for administering antivenom: golden hours and missed opportunities. Isbister, G. K. 2024.Clinical Toxicology, 62(5), 277–279. https://doi.org/10.1080/15563650.2024.2352026