Background and Epidemiology
In the United States, roughly 9,000 snake bites are reported annually, with approximately 3,000 being attributed to venomous species and less than 10 resulting in death. Young adult males between the ages of 25-34 incur the largest number of snake bites, and a significant percentage of snake bites occur while a snake (captive or wild) is being intentionally handled. Many bites are associated with (human) consumption of alcohol. Fortunately, overall prognosis for snake envenomation within the U.S. is positive thanks to the widespread availability of antivenom, relatively short transport times to definitive care, and the U.S.'s robust healthcare infrastructure. However, snake envenomation is incredibly dangerous in pregnant populations, with fetal demise is noted in up to 20% of pregnant envenomation cases with or without antivenom administration.
Venomous Snakes in the United States
While many families of venomous snakes exist throughout the world, only two – Elapidae and Viperidae - are endemic to North America. The Elapidae family includes cobras, mambas, kraits, and coral snakes, while the Viperidae family encompasses vipers and pit vipers. These happen to be some of the most medically significant families of venomous snakes globally.
Viperidae
Rattlesnakes, copperheads, and cottonmouths (also called water moccasins) are the three types of pit vipers native to the United States. These snakes have large fangs, high-pressure venom glands, and characteristic heat-sensing pits between the nostril and eye. They are heavy-bodied with triangular heads and have keeled (rough-looking) scales. Pit viper venom causes significant tissue damage and coagulopathies (more on this later).
Elapidae
The southern edge of the U.S. also hosts three species of coral snakes, identifiable by their characteristic banded pattern: red/yellow/black/yellow. Coral snake venoms are some of the most toxic in the world and contain potent neurotoxins. Thankfully, their fangs are small, and bites to humans are uncommon, with less than 1% being attributed to coral snakes annually and even fewer resulting in actual envenomation. It is essential to be aware. However, symptom onset in cases of coral snake envenomation may be delayed up to 12 hours.
There are many look-alike nonvenomous species, which may complicate proper identification and delay patient care. Even if the snake is believed to be non-venomous, the patient should be closely monitored for signs and symptoms of envenomation. Species identification should not be attempted at the expense of safety. One of the primary goals following a snake bite is to avoid another snake bite. The patient, bystanders, and emergency personnel should avoid approaching or handling the snake. Dead snakes may retain bite reflexes and should not be handled.
Whatever you do, do not bring the snake (dead or alive) to the ER with you. The snake won’t like it. Neither will the ER.
Chemical Properties and Clinical Consequences of Venom
Snake venom is comprised of various proteins and enzymes that can cause neurotoxicity, hemotoxicity, and/or local tissue destruction. This division is broad, and some venoms can produce a combination of toxic symptoms with overlapping contributions to systemic effects such as hypotension, sepsis, anaphylaxis, coagulopathy, fluid extravasation, and tissue damage. The particular assembly of compounds within snake venom depends on species, geographical location, climate, etc., and the mechansims underlying their effects are diverse and complex. We'll touch on some of the pathophyisiology below, but don't get too caught up in remembering the small details.
Neurotoxic compounds alter signal transmission pre- or post-synapse. Some venom toxins damage ion channels within cellular membranes or inhibit acetylcholine (ACh) binding at the neuromuscular junction, disrupting impulse transmission and causing respiratory insufficiency or even complete respiratory paralysis. Others prevent ACh release at the synaptic cleft, leading to muscle fasciculation or spasm. Patients may also experience numbness or tingling around their mouth, altered mental status, weakness, cranial nerve dysfunction (difficulty swallowing, unequal pupils, drooping eyelid, etc), trismus, hypersalivation, and seizures. These, as well as descending paralysis are signs of systemic coral snake envenomation in the United States. Mojave rattlesnake bites have also been associated with neurotoxicity.
Hemotoxicity is an all-encompassing term for a variety of cardiovascular and hemostatic effects. Hemostasis may be accelerated (procoagulation) by venom toxins which activate various clotting factors such as factor X/prothrombin or induce platelet aggregation. Other venom toxins carry a fibrinogenolytic effect which hinders coagulation (anticoagulation). Along with inducing coagulopathy, venom toxins may contribute to local and/or systemic hemorrhage and plasma extravasation by means of basement membrane degradation within the vasculature. Complications of hemotoxicity include anemia, thrombocytopenia, petechial, gingival, and/or retinal hemorrhage, pulmonary embolism, and disseminated intravascular coagulopathy. Hemotoxicity, and specifically coagulopathy, is a common complication in moderate to severe pit viper envenomation.
Another common complication associated with pit viper envenomation, and a major contributor to morbidity in U.S. snake envenomation cases, is severe tissue damage brought on by venom toxins that either directly damage cells (true cytotoxins) or degrade the extracellular matrix and secondarily cause cellular death. Injection of snake venom may trigger an intense inflammatory response, leading to oxidative stress and the formation of reactive oxygen species (free radicals) and further contributing to local and systemic tissue necrosis. Edema, pain, erythema, ecchymosis, blistering, necrosis, acute kidney injury, compartment syndrome, and sepsis are all complications associated with tissue-damaging toxins.
TL/DR: There are many neurologic, hematologic, and tissue-related signs and symptoms associated with snake envenomation. Your ability to recognize them can help ensure that vital resources are activated in a timely manner.
Pit Viper Antivenom
Antivenoms are comprised of immunoglobulins (antibodies) and are the only curative treatment for snake envenomation. Administration is typically reserved for patients with moderate to severe envenomation unless the bite is on the face, a distal extremity, or involves a major joint. For pit viper envenomation, the marker for successful treatment with antivenom is stopping the progression of coagulopathy (not the immediate normalization of coagulation factors) and correction of other systemic symptoms; however, it will not reverse tissue damage. Coral snake antivenom does not reverse neuromuscular paralysis but can limit progression. Hypersensitivity reactions and serum sickness can occur with antivenom administration. These side effects do not contraindicate antivenom administration and can be treated with antihistamines and epinephrine. Dosing for all antivenom is based on the amount of venom delivered, not patient size, so doses do not vary between adults and pediatrics. Currently, there are two FDA-approved antivenoms for treatment of rattlesnake, copperhead, and cottonmouth envenomation.
CroFab
Many of you are probably at least somewhat familiar with CroFab (crotalidae polyvalent immune Fab) which is created using venom derived from four species of pit vipers native to the U.S. (western diamondback rattlesnake, eastern diamondback rattlesnake, Mojave rattlesnake, and cottonmouths). The venom is injected into sheep, whose robust immune system produces venom-specific immunoglobulins that are then extracted and purified. To reduce size and increase tissue penetration, the antigen binding region (Fab) is then isolated and packaged. When injected into patients suffering envenomation, these fragments bind and neutralize bloodborne venom toxins.
Standard initial dosing for CroFab in both adult and pediatric patients is 4-6 vials. Additional doses may be required and should be continued until symptom progression is halted.
Anavip
The other FDA-approved antivenom is crotalidae immune F(ab)2, known as Anavip. The process for synthesizing Anavip is mechanistically similar to that of CroFrab but with a few key differences. Anavip is derived from the venom of two South American pit viper species: Bothrops asper and Crotalus durissus. The venom in injected into horses and once extracted from serum, is cleaved into a fragment with two active binding sites compared to CroFab’s single binding site. The Anavip fragment is also larger than CroFab, theoretically contributing to longer serum half-life and a longer duration of action. The loading dose for both adults and pediatric patients is 10 vials. Repeat doses may be required until symptoms are controlled.
Coral Snake Antivenom... or not
The general recommendation is to administer coral snake antivenom at the first sign of neurological or respiratory symptoms, if possible. However, the only antivenom to have received FDA approval for coral snake envenomation is North American Coral Snake Antivenin - or NACSA - which had conflicting data behind it and actually ceased production in 2006. The expiration date of remaining stock was extended multiple times by the FDA. If necessary, expired antivenom may be used at an initial dose of 3-5 vials. Posion Control and the FDA Office of Vaccines, Blood, and Biologics may provide guidance and resources for procurement and administration of NACSA. Because NACSA is no longer in production, supply is limited and not always accessible in a timely manner; therefore, Poison Control may also recommend and help mobilize another coral snake antivenom, such as Coralmyn, which is manufactured in Mexico and is currently undergoing clinical trials in the United States.
If you remember, coral snake venom can contain potent neurotoxins and can alter acetylcholine activity, leading to a variety of severe neurologic symptoms and even respiratory muscle paralysis. If antivenom is not immediately available, patients with signs and symptoms of neurotoxicity or respiratory compromise may receive an acetylcholinesterase inhibitor such as neostigmine. Neostigmine increases acetylcholine concentration at the neuromuscular junction and may help restore neuromuscular transmission. However, this is only effective if symptoms are due to postsynaptic blockade. Patients may also require pretreatment with atropine to negate potential cholinergic side effects of neostigmine administration.
Prehospital Assessment and Management
When it comes to the physical exam and history taking, thoroughness is key. Providers should perform a careful assessment of the patient’s respiratory and hemodynamic status. The date and time the bite occurred as well as a physical description of the snake should be documented. Evaluation of the wound should include assessment and control of hemorrhage as well as circulatory status above and below the wound. The patient's tetanus status should be recorded. It is prudent to trace the perimeter of pain/tenderness/edema/erythema around the wound at the time of initial contact so that providers may easily monitor progression. Symptom progression is a marker for moderate to severe envenomation, so the patient should be closely monitored for any changes.
Somewhere along the line, you may have heard that you should apply a tourniquet, a pressure dressing, or mechanical suction to the affected extremity/wound. You might have also heard that bloodletting or electrotherapy improves outcomes. None of this is true. Misinformation is abundant when it comes to appropriate management of snake bites. Tourniquets have not been proven to reduce morbidity or mortality; in fact, existing literature demonstrates that tourniquets and pressure dressings actually worsen local tissue necrosis, increase antivenom requirements, and lengthen recovery time, especially in cases of pit viper envenomation. Likewise, electrotherapy, wound suctioning, cold compress, and bloodletting have shown no benefit in current literature. This is the case for both coral snake and pit viper envenomation. So now that we’ve covered the laundry list of what not to do… what should we do?
Upon initial contact with the patient, any jewelry or restrictive clothing should be removed. Washing and dressing of the wound is appropriate but should not delay transport. Immobilization (without compression) of the extremity at or above the level of the heart and with joints in functional position may reduce venom spread and increase patient comfort, especially in the setting of severe edema. Otherwise, care will be largely supportive and dependent on the patient’s unique clinical presentation. Aggressive pain management may be required, but favor should be given to non-sedative analgesic options in the interest of preventing respiratory depression, especially in patients with concern for systemic envenomation. Hypotension and anaphylaxis should be treated with epinephrine following your local guidelines. Blood products may be indicated in patients with severe hemorrhage or anemia. Administration of NSAIDs and ASA is not recommended as they may contribute to platelet dysfunction and rhabdomyolysis.
Rapid transport to definitive care is crucial. The preferential destination is a facility that stocks antivenom but in some instances (lengthy extrication from remote areas, for example), it may be faster to airlift the antivenom to a facility closer to the patient. Overall, the Wilderness Medical Society (WMS) stresses that a “cookbook” approach should not be applied to care of snake bites as each patient can present with different needs. Early consultation with poison control or a venom specialist is recommended for every case.
Hospital Course
In-hospital care varies based on the severity of envenomation. Below are guidelines for pit viper envenomation.
Dry: Up to 25% of pit viper bites are dry bites (no injection of venom). These bites warrant observation for around ~8 hours and lab work. Lab work typically includes a complete blood count, a basic metabolic panel, liver function tests, and a coagulation panel.
Mild: Bites producing only non-progressive, local symptoms will earn the patient a 12-24 hour observation with lab work at intake (same as above) and repeated every 4-6 hours (complete blood count and coagulation panel). Antivenom may be administered if the bite involves the hand or face.
Moderate: Patients with progressive and/or systemic symptoms will receive antivenom and are typically admitted. Initial and repeat lab work are indicated with coagulation panels drawn each hour post-antivenom administration. These patients may require other supportive care depending on their exact symptom cohort.
Severe: Characterized by end-organ dysfunction in conjunction with progressive systemic symptoms. Treatment and observation guidelines are similar to those for moderate envenomation, but will likely require higher levels of supportive care.
Workup for coral snake envenomation may include similar lab work, although repeat coagulation panels are not generally useful. Even asymptomatic patients should be observed from 12-24 hours to watch for delayed onset neurotoxicity. Pulmonary function tests, imaging studies, and arterial blood gases may be helpful in identifying impending respiratory failure. In severe envenomation, intubation and mechanical ventilation may be required. Muscle weakness can persist for weeks and requires close followup.
Exotic Pets
One last thing - it is important to be aware that some people keep exotic venomous snakes as pets. Antivenoms for exotic snakes may not be routinely stocked in even the most capable hospitals. In these cases, zoos and aquariums (in addition to toxicologists and poison control) can be helpful resources for antivenom procurement.
Summary – the Do/Don’t of Snake Bites
X - DON’T treat snake bites with a tourniquet, pressure dressing, suction, electrotherapy, cold compress, or bloodletting
X - DON’T approach, handle, or transport a snake - even if it's dead
X - DON’T delay patient transport
⎷ - DO provide supportive care including airway management, hemodynamic stabilization, and analgesia
⎷ - DO document the date and time the bite occurred, as well as a physical description of the snake if possible
⎷ - DO monitor/report the onset and progression of all symptoms
⎷ - DO contact poison control and the recieving facility as early as possible
References
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Bush, Sean. “Rattlesnake Envenomation Treatment & Management: Prehospital Care, Emergency Department Care, Consultations.” MedScape, 13 June 2023, emedicine.medscape.com/article/771455-treatment?form=fpf. Accessed 25 July 2024.
“ClinicalTrials.gov.” Clinicaltrials.gov, National Library of Medicine, 26 May 2023, clinicaltrials.gov/study/NCT01337245?tab=table. Accessed 25 July 2024.
“CroFab (Crotalidae Polyvalent Immune FAB [Ovine]) Dosing, Indications, Interactions, Adverse Effects, and More.” Reference.medscape.com, Medscape, reference.medscape.com/drug/crofab-crotalidae-polyvalent-immune-fab-ovine-343716#91. Accessed 25 July 2024.
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Kanaan, Nicholas C., et al. “Wilderness Medical Society Practice Guidelines for the Treatment of Pitviper Envenomations in the United States and Canada.” Wilderness & Environmental Medicine, vol. 26, no. 4, Dec. 2015, pp. 472–487, wms.org/common/Uploaded%20files/Magazine/PitViperEnvenomations.pdf, https://doi.org/10.1016/j.wem.2015.05.007. Accessed 10 July 2024.
Meyers, Stephen E., and Prasanna Tadi. “Snake Toxicity.” PubMed, StatPearls Publishing, 19 Sept. 2022, www.ncbi.nlm.nih.gov/books/NBK557565/. Accessed 13 July 2024.
Parker-Cote, Jennifer, and William Meggs. “First Aid and Pre-Hospital Management of Venomous Snakebites.” Tropical Medicine and Infectious Disease, vol. 3, no. 2, 24 Apr. 2018, p. 45, www.ncbi.nlm.nih.gov/pmc/articles/PMC6073535/, https://doi.org/10.3390/tropicalmed3020045. Accessed 10 July 2024.
Thornton, Stephen. “Coral Snake Envenomation Treatment & Management: Prehospital Care, Emergency Department Care.” EMedicine, 24 Aug. 2022. Medscape, emedicine.medscape.com/article/771701-treatment. Accessed 21 July 2024.
“Types of Venomous Snakes | NIOSH | CDC.” Www.cdc.gov, Center for Disease Control and Prevention, 21 Feb. 2020, www.cdc.gov/niosh/topics/snakes/types.html. Accessed 10 July 2024.
“Venomous Snakes - Big Thicket National Preserve (U.S. National Park Service).” Www.nps.gov, U.S. National Park System, 23 Dec. 2023, www.nps.gov/bith/learn/nature/venomous-snakes.htm. Accessed 10 July 2024.
MD, Sam Ashoo. “Emergency Department Management of North American Snake Envenomations.” EB Medicine, 1 Sept. 2018, foamed.ebmedicine.net/podcast/episode-20-emergency-department-management-of-north-american-snake-envenomations/. Accessed 27 July 2024.
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