Comprehensive Clinical Guidelines for the Management of Crotalinae Snakebites: Evaluation, Diagnosis, and Treatment

EPIDEMIOLOGY

Approximately 5000 venomous snakebites are reported annually to the American Association of Poison Control Centers. Among venomous snakes, copperheads, rattlesnakes, and cottonmouths account for the most bites in the United States, with copperheads responsible for nearly half of all venomous snakebites. These snakes are also found in southern Canada and northern Mexico. Approximately 100 snakebites annually are caused by elapids (coral snakes) and imported exotic snakes, responsible for much less envenomation.

It is crucial to be prepared during the summer when snakes are most active and in states with warmer climates, including Texas, Oklahoma, Florida, California, Arizona, Louisiana, Georgia, and North Carolina, which report the greatest number of venomous snakebites.

It is important to note that snakebite fatalities are rare in the United States, which should provide reassurance to healthcare professionals and the general public.

APPEARANCE AND GEOGRAPHICAL DISTRIBUTION

Crotalinae snakes, including rattlesnakes, cottonmouths (water moccasins), and copperheads, belong to the Viperidae family and are frequently designated as "pit vipers." They possess elongated, retractable fangs, triangular crania with a sudden transition to the torso, and an abundance of miniature scales on the head. Pit vipers possess heat-sensing pits at the anterior portion of the head, facilitating infrared perception and exhibiting elliptical pupils. Numerous nonvenomous snakes exhibit proficient mimicry.

Crotalinae snakes are prevalent throughout the United States:

·    Rattlesnake (Crotalus and Sistrurus species): Rattlesnakes live throughout the continental United States and are native to all states except Alaska, Hawaii, and Maine.

·    Cottonmouth (Agkistrodon piscivorus) – Water moccasins, or cottonmouths, are distributed throughout the southeastern and southern United States, extending from Virginia to Florida and west to Texas.

·    Copperhead (Agkistrodon contortrix) – Copperheads are common in the eastern United States, extending westward to east Missouri, Arkansas, and Oklahoma and ranging from Massachusetts to Texas in the north-south axis.

Climate change has significantly influenced snakebite incidence patterns in specific regions of the United States, resulting in regional variations. Comprehensive toxinology databases, such as the Global Snakebite Initiative, classify snake species and subspecies and provide detailed maps of their geographical distributions. 

VENOM PROPERTIES

Crotalinae venom comprises a complex mixture of about 50 toxic constituents, including phospholipase A2 (PLA2), serine proteases, proteases, and metalloproteinases. The venom's composition varies among serpent species. Geography, climatic conditions, seasonal fluctuations, prey choices associated with the ecosystem, and snake size and location significantly influence it.

Crotalinae venom toxins produce various effects after envenomation:

·    Local tissue damage—Enzymatic activity on the extracellular matrix, vascular endothelium, and basement membrane induces edema, erythema, and discomfort. Progressive swelling of the entire extremity and/or tissue necrosis signifies serious envenomation, with the risk of substantial tissue loss, particularly in bites to the fingers or toes, perhaps leading to autoamputation.

·    Hemotoxicity—Hypofibrinogenemia and thrombocytopenia arise from the effects of several venom components, such as thrombin-like enzymes, metalloproteinases, ph phospholipase A2, disintegrins, and C-type lectin-like proteins. This pathophysiology differs from disseminated intravascular coagulation (DIC), where elevated thrombin levels stimulate fibrinolysis.

·    Cardiovascular effects—Hypotension may arise from increased capillary permeability, vasodilation, and bleeding. Angioedema, hypotension, and cardiovascular collapse may occur from aphylactic or anaphylactoid reactions, though these are uncommon. Factors that may elevate the risk of allergy to venom include prior snakebites from analogous US species, consumption of rattlesnake flesh, or interaction with snakes. Venom components like bradykinin, potentiating peptides, and phospholipase A2 (PLA2) can cause hypotension by increasing vascular permeability and vasodilation.

·    Neurotoxicity—Myokymia, severe weakness, and paralysis are rare but may result from the action of beta neurotoxins at the neuromuscular junction. The PLA2s act presynaptically to inhibit the release of acetylcholine. Mohave toxin, a PLA2, is found in some North American rattlesnake species.

·    Other systemic effects—Crotalinae envenomation can result in nausea, vomiting, diarrhea, and a metallic taste. Diarrhea may occur due to bradykinin-potentiating peptides present in venom. Myotoxic chemicals have been detected in certain rattlesnake species, leading to systemic rhabdomyolysis.

CLINICAL MANIFESTATIONS

Clinical findings of Crotalinae en enomation vary by geography, snake species, and degree of envenomation. If treatment is delayed, envenomation tends to evolve more dramatically.

·    Local effects – Seen in 90 to 100 percent of Crotalinae envenomations. The bite wound typically shows two puncture wounds (fang marks), with pain, swelling, ecchymoses, and erythema developing within an hour. The proximal spread of swelling and tenderness suggests progressive venom dissemination. Hemorrhagic bullae may develop at the bite site.

·    Hematologic effects – Hemotoxicity occurs in around forty percent of rattlesnake envenomations and up to fifteen percent of copperhead envenomations, characterized by e tended prothrombin time (PT), hypofibrinogenemia, and thrombocytopenia. Profuse bleeding is uncommon.

·    Neurologic effects – Neurotoxicity is uncommon after most North American snakebites. Symptoms include perioral and extremity paresthesias, bulbar abnormalities, and myokymia, characterized by continuous, involuntary muscle twitching. Severe weakness and paralysis are rare but may occur after envenomation by some rattlesnake species. Systemic effects – Symptoms such as nausea, vomiting, diarrhea, t tachycardia, hypotension, and dizziness suggest more severe envenomation. Rhabdomyolysis occurs in less than 10 percent of Crotalinae envenomations. 

EVALUATION

The initial hospital management of Crotalinae snakebite is a critical and comprehensive process that requires immediate action and attention to detail. This ensures that healthcare professionals are well-prepared and confident in their approach.

Stabilization—The hospital management of Crotalinae snakebite requires a comprehensive approach. Emergency airway, breathing, and circulation stabilization should occur concurrently with evaluation. This comprehensive approach is crucial for the best patient outcomes.

History—Obtaining key information is crucial when a snakebite is reported or suspected. This information includes the location and timing of the bite, a description of the snake, the occurrence of multiple bites, the onset of symptoms, initial treatment and first aid provided, any recent ethanol or recreational drug use, and pertinent past medical history.

·    The effects of a Crotalinae snakebite are typically felt instantaneously. Due to their smaller body mass, children may experience a rapid onset of shock or collapse, even if the bite is not immediately apparent.

·    Physical Examination – Physical examination findings fluctuate due to several circumstances about the snake and the patient and may change over time:

o  Vital signs: Mild tachycardia or tachypnea may indicate anxiety, pain, or the first systemic envenomation. Significant tachycardia, tachypnea, or hypotension frequently signifies systemic poisoning.

o  Systemic findings: Tachycardia and shock, including hypotension and/or poor tissue perfusion, signify severe envenomation. Anaphylactic or anaphylactoid reactions may result in angioedema, hypotension, and cardiovascular collapse.

o  Tissue and muscle toxicity: In most patients with Crotalinae envenomation, localized tissue edema is observed near the bite site. Muscle pain, weakness, and dark urine may indicate rhabdomyolysis. Compartment syndrome can occur due to substantial edema in the extremities or direct venom administration into a muscle compartment.

o  Neurotoxicity: Weakness may manifest following bites from certain rattlesnake species. Myokymia (rippling muscle movement) is a more common neurologic manifestation.

o  Wound site: The bite site should be examined for fang marks, local evidence of envenomation, degree of swelling, and swelling or tenderness of regional lymph nodes.

·    Ancillary studies should include a complete blood count, fibrinogen level, prothrombin time (PT), and international normalized ratio (INR). Serum creatine kinase (CK), electrolytes, creatinine, and blood urea nitrogen should also be measured in patients with evidence of systemic toxicity. Depending on clinical presentation, chest radiographs, and electrocardiograms may be warranted.

·    Reassessment—Frequent examinations are important to detect signs of envenomation and identify serious and progressive effects. Frequent blood pressure measurement is essential, and continuous monitoring of cardiorespiratory function and pulse oximetry is recommended. Hematologic studies should be repeated periodically, especially after antivenom administration.

DIAGNOSIS

The diagnosis of Crotalinae snakebites is usually straightforward due to the fang mark, pain, and local effects such as swelling, ecchymosis, and blistering. However, snakebites may go unrecognized in young children or cause sudden collapse in older children and adults. The clinician must uphold a heightened suspicion for a Crotalinae snakebite in instances of abrupt irritability, unilateral limb swelling, cardiovascular failure, or neurological deficits in areas where venomous snakes are prevalent.

DIFFERENTIAL DIAGNOSIS

Clinical observations have confirmed the diagnosis of snakebite in numerous patients. The primary differential diagnosis is between venomous (Crotalinae) bites and nonvenomous snakes. To differentiate between envenomation and "dry bites," which do not involve the injection of venom, a minimum observation period of 8 to 12 hours is required. Other conditions to consider include hematologic disease with coagulopathy, rhabdomyolysis, acute weakness, and paralysis caused by other medical conditions. 

FIRST AID

First aid for snakebites includes removing the patient from the snake's vicinity, immobilizing the affected limb, and avoiding constrictive dressings or tourniquets. Suction, cryotherapy, and electric shock therapy have no role in snakebite management. The patient must be promptly taken to the nearest medical facility with expertise in snakebite management.

ACUTE MANAGEMENT

Treatment depends on the degree of envenomation:

1.    Initial Stabilization:

·    Stabilization of the airway, breathing, and circulation is crucial.

·    Patients with facial or neck bites, myokymia, or systemic toxicity may necessitate endotracheal intubation and mechanical ventilation.

·    Emergency management of shock includes a rapid infusion of isotonic fluids and, if necessary, vasoactive medications.

1.    Antivenom Therapy:

·    Initial Treatment: Antivenom should be administered for patients with progressive swelling or signs of systemic toxicity. There is no specific time limit for antivenom administration. F(ab')2 (Anavip) and FabAV (CroFab) are the two main antivenoms used to treat North American Crotalinae snakebites.

·    Relative Contraindications: Patients with known allergies to antivenom components should be pre-treated for anaphylaxis. Pregnancy is not a contraindication for antivenom.

·    Dose and Administration: The dosage of antivenom varies with the severity of envenomation. Due to the risk of allergic reactions, both FabAV and Fab2AV should be administered in a continuously monitored setting.

1.    Supportive Care:

·    Pain Management: Opioid analgesics may be required for severe pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be used cautiously in patients without significant risk of coagulopathy.

·    Coagulation Abnormalities and Thrombocytopenia: Antivenom, not coagulation factor replacement, is the primary treatment. Platelets and fresh frozen plasma should be avoided unless significant bleeding occurs.

·    Rhabdomyolysis: Rhabdomyolysis may occur in about 5 percent of patients bitten by rattlesnakes or cottonmouths and requires intravenous fluid administration and monitoring of electrolyte abnormalities.

·    Elevated Tissue Pressures: Antivenom administration and elevation of the affected extremity are the primary treatments. True compartment syndrome requiring fasciotomy is rare.

·    Neurotoxicity: Individuals with airway obstruction or diminished respiratory function may necessitate mechanical ventilation. Antivenom may not reliably reverse neurotoxic effects.

1.    Observation and Monitoring:

·    Patients with minor envenomation should be observed for at least 24 hours, with repeated laboratory studies every 6 to 8 hours, depending on the severity of symptoms. Progressive swelling or abnormal coagulation tests warrant antivenom administration and assessment for rhabdomyolysis.

DISCHARGE INSTRUCTIONS

If patients display symptoms of serum sickness or hemorrhage after being discharged following antivenom administration, they should be advised to seek medical attention. Follow-up platelet and fibrinogen studies should be performed according to the type of antivenom received. Patients with thrombocytopenia or coagulation abnormalities during treatment should avoid activities like contact sports, surgery, or dental work for at least two weeks or until cleared by follow-up blood tests.

SERUM SICKNESS

Serum sickness occurs in 2 to 3 percent of patients receiving either FabAV or Fab2AV. The evaluation and management of serum sickness are discussed separately.

OUTCOMES

Most individuals bitten by venomous snakes in North America achieve complete recovery. Permanent consequences are infrequent but may encompass loss of range of motion, weakness, pain, altered feeling, skin discoloration, or tissue loss, including digit amputation. Tissue necrosis is common and may necessitate surgical debridement. Death following Crotalinae snakebite is unusual, with a mortality rate of less than 1 percent.