ToxCard: Crotalid Envenomation Part 1: Management of the Crotalid Envenomation

Authors: Sean Trostel, MD (EM Resident Physician, Carolinas Medical Center, Charlotte, NC); Kathryn T Kopec, DO (@KopecToxEM, EM Attending Physician, Medical Toxicologist, Carolinas Medical Center, Charlotte, NC) // Reviewed by: James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case:

A 2-year-old boy was transferred to your Emergency Department (ED) with severe pain, swelling, and ecchymosis of the right ankle 5 hours after being bitten by a snake. His father confirmed the snake was a copperhead. He was initially seen at a regional ED and was administered 10 vials of crotalidae equine immune F(ab’)₂ (ANAVIP®) antivenom before transfer to your referral center.

On arrival, the patient is clearly uncomfortable but nontoxic appearing. He has two punctate fang marks at the right lateral ankle with swelling and tenderness extending from the distal foot proximally to the right knee. Vital signs are HR 142 bpm, BP 133/86 mmHg, RR 22 breaths/min, SpO₂ 98% on room air, T 98.7°F. Laboratory testing demonstrated platelets 482 × 10⁹/L, fibrinogen 241 mg/dL, and INR 1.2. He was admitted to the pediatrics service for further management.

Questions:

1. What are the primary clinical manifestations of crotalid envenomation?
2. How do you manage crotalid envenomations?
3. What are the indications for antivenom administration?
4. What antivenoms are available to treat crotalid envenomation?
5. What is the dosing schedule for antivenom?
6. What are the indications for repeat dosing of antivenom?

Background:

• According to the Center for Disease Control (CDC), approximately 7,000-8,000 people in the United States (US) suffer envenomation by a snake each year. Envenomation by crotalidae (pit vipers) represent 99% of snake envenomations in the US.¹
• Copperhead (Agkistrodon contortrix) and cottonmouth / water moccasin (Agkistrodon piscivorus) are the two species of pit viper responsible for the majority of snake envenomations in many regions of eastern and southeastern US²
• Other crotalids found in North America include:
  • Timber/canebrake and pigmy rattlesnakes found in the eastern/southeastern US
  • Eastern and western diamondback rattlesnakes, found in eastern and western North America, respectively
  • Several additional species of rattlesnakes found west of the Mississippi
• Crotalid venom contains a variable mixture of compounds including proteases, metalloproteinases, phospholipases, disintegrins, and rarely neurotoxins.^3,4 These venom components contribute to primarily cytotoxic, hemotoxic, myotoxic, and proinflammatory effects.
• Crotalid envenomation is characterized by rapid onset and progression of local tissue injury characterized by severe pain and hyperalgesia, swelling, ecchymosis, and ultimately necrosis if left untreated
• Systemic effects are primarily coagulopathic and characterized by thrombocytopenia and hypofibrinogenemia
• The genus of snake influences its predominant toxic effects
  • Genus Agkistrodon (copperhead and cottonmouth) envenomations tend to cause primarily local tissue injury, while genus Crotalus (rattlesnake) envenomations will often cause local tissue injury and significant coagulopathic effects, which may rebound even after treatment with antivenom
• For severe crotalid envenomations, rapid administration of antivenom is indicated to halt the progression of both local tissue injury and coagulopathy

Management:

Out of Hospital Initial Management:

• Address scene safety. Avoid additional bites to yourself or the patient and move the patient safely away from the snake. Do NOT attempt to capture or kill the snake.
  • Remember that a dead snake still has a bite reflex and may still cause envenomation
• Do NOT apply tourniquets, ice, or direct pressure
• Do NOT incise the wound, “suck and spit”, or apply a suction device
• Remove any tight-fitting clothing and jewelry
• Immobilize the bite site and attempt to keep in a neutral position until able to reach a healthcare facility with antivenom.
• Evacuate the patient to the nearest ED or hospital with antivenom available
• Consider contacting your local poison control center for further guidance at 800-222-1222

Emergency Department and Inpatient Management:

• Assess airway, breathing, and circulation
• Consult your local poison control center (800-222-1222) and/or medical toxicologist
• Monitor and assess the extent of local swelling, tenderness, and hemorrhagic blebs frequently (every 30-60 minutes) until progression has halted
• Measure and record the circumference of the affected limb at multiple intervals, such as mid-foot, ankle, mid-calf, and thigh for a lower extremity bite
  • Clearly mark these points of measurement for future comparison so measurements are taken at the same locations
    • Remember to mark both sides of the limb and both sides of the tape so that repeat measurements can be performed in the same fashion
  • Small increases in proximal swelling are expected as edema mobilizes with elevation, however progression of swelling more distally may indicate worsening tissue injury
• If there is a well-demarcated line of swelling or discoloration, mark this with a pen, indicating the date and time
• Elevate the affected limb and maintain gentle extension of the joints
  • Mechanisms for elevation may include:
    • Multiple pillows or sheets/blankets under the limb
    • Putting limb up on a table next to the bed
    • Raising the end of the hospital bed
    • Finger traps to keep arm elevation – but if bite is in hand or fingers would be concern for compression and tissue injury
  • Can splint in relative extension if necessary to promote lymphatic drainage.
  • Give analgesics for pain control but avoid NSAIDs due to their inhibitory effect on platelets
  • Obtain initial labs including CBC, BMP, PT/INR, and fibrinogen. Repeat labs approximately 6 hours after initial control and/or prior to discharge.
    • If there is concern for envenomation by rattlesnake, repeat labs may be indicated 2-3 days and 5-7 days after antivenom administration
  • Consider serial negative inspiratory force (NIF)/maximum inspiratory pressure (MIP) or EtCO₂ monitoring if concerned for neurotoxicity
    • Be aware that several species of North American rattlesnake have the potential to cause neurotoxic effects, most notably the Mojave rattlesnake, tiger rattlesnake, Southern Pacific, and some populations of timber/canebrake rattlesnakes^3,5
  • Patients who have minimal or no local symptoms, no evidence of progression after 8 hours, normal labs, and no indication for antivenom may be considered for discharge
  • Patients should be monitored for 12 hours or longer if symptoms are more than minimal⁶
  • Patients with evidence of significant systemic toxicity (hemodynamic instability, airway involvement, neurotoxicity, or evidence of severe hematologic toxicity on labs) should be considered for ICU admission
  • It is unlikely that these patients develop compartment syndrome and do not tend to need surgical procedures/intervention. If you are concerned for elevated compartment pressures, the patient needs to be treated with antivenom.

Which patients require treatment with antivenom?

Indications:^6,7

• Significant or progressive local tissue damage (swelling, tenderness, hemorrhagic blebs)
  • There are controversial and varying opinions on what determines “significant”
    • Some authors used the number of centimeters from envenomation site, others use anything more than “minimal” and others differentiate between snake species.
    • Clinically often swelling and tenderness may be considered significant if they extend beyond one major joint from the bite site (e.g., past ankle or wrist) or there is rapid progression of swelling up the affected extremity
  • Localized signs of tissue injury may be considered significant if they involve the hands, face, neck, or other sensitive areas as determined by the treating provider
• Significant local tissue injury (necrosis) without extensive swelling
• Systemic toxicity (hypotension, airway swelling, neurotoxicity)
• Significant or progressive hematologic toxicity (platelets < 50 × 10⁹/L, fibrinogen < 50 mg/dL)
  • Serial testing is warranted for less severe laboratory abnormalities (fibrinogen < 150 mg/dL, etc.)
• Recurrent progression of symptoms after initial control

Dosing of antivenom:^6,8–10

• F(ab) (CroFab®)
  • Initial dose: 4-6 vials IV over 60 minutes (8-12 vials for shock or serious active bleeding)
  • Reexamine within 1 hour and repeat initial dose until symptoms are no longer progressive
  • Maintenance dose: 2 vials every 6 hours for 3 additional doses
  • Recurrent symptoms: Additional 2 vials
•  F(ab’)₂ (ANAVIP®)
  • Initial dose: 10 vials IV over 60 minutes
  • Reexamine within 1 hour and repeat initial dose until symptoms are no longer progressive
  • Maintenance dose: None
  • Recurrent symptoms: Additional 4 vials
• Note – Pediatric dose is the same as adult dose

Please see Part 2 of this Series for a more in-depth discussion on the similarities and differences between F(ab) and F(ab’)₂ antivenoms as well as the continuation and conclusion of our case!

Clinical Pearls:

• Most snake envenomations in the US are caused by pit vipers (crotalidae) and are characterized by local tissue injury and coagulopathic effects
• Copperhead and cottonmouth (Agkistrodon sp.) envenomations are generally characterized by prominent local tissue effects without laboratory abnormalities, while rattlesnake (Crotalus) envenomations often cause early, late, and recurrent coagulopathy in addition to local tissue effects.
• Initial management steps include elevation, serial exams, and pain control
• F(ab) (CroFab®) and F(ab’)₂ (ANAVIP®) crotalid antivenoms are FDA approved and indicated for severe crotalid envenomation with severe or progressive localized symptoms, systemic symptoms, and/or signs of coagulopathy on labs

References:

1. Smith TA, Figge HL. Treatment of snakebite poisoning. Am J Hosp Pharm. 1991;48(10):2190-2196.
2. Venomous Snakes | NIOSH | CDC. Published April 15, 2022. Accessed May 7, 2022. https://www.cdc.gov/niosh/topics/snakes/default.html
3. Buchanan JT, Thurman J. Crotalidae Envenomation. In: StatPearls. StatPearls Publishing; 2022. Accessed May 17, 2022. http://www.ncbi.nlm.nih.gov/books/NBK551615/
4. Kanaan NC, Ray J, Stewart M, et al. Wilderness Medical Society Practice Guidelines for the Treatment of Pitviper Envenomations in the United States and Canada. Wilderness Environ Med. 2015;26(4):472-487. doi:10.1016/j.wem.2015.05.007
5. Rolan TD. Neurotoxic snakes of the Americas. Neurol Clin Pract. 2015;5(5):383-388. doi:10.1212/CPJ.0000000000000180
6. Lavonas EJ, Ruha AM, Banner W. et al. Unified Treatment Algorithm for the management of crotalid snakebite in the United States: results of an evidence-informed consensus workshop. BMC Emerg Med. 2011;3(11):2.
7. Clinical Practice Statements. AAEM – American Academy of Emergency Medicine. Accessed May 7, 2022. https://www.aaem.org/resources/statements/clinical-practice
8. Antivenom administration North American Crotalinae snakebites – UpToDate. Accessed May 7, 2022. https://www.uptodate.com/contents/image/print?imageKey=EM%2F122011&topicKey=EM%2F8365&source=see_link
9. Highlights of prescribing information. ANAVIP. Crotalidae Immune F(ab’)2 (Equine). Published online April 2021. Accessed May 7, 2022. https://www.fda.gov/media/92139/download
10. CroFab Snakebite Treatment Dosing | CroFab.com. Accessed May 7, 2022. https://crofab.com/treating-with-crofab/dosing