Snake Toxicity

Etiology

Venomous snakebites generally occur when venomous snakes (most commonly pit vipers) are cornered or startled by humans. Increased interest in warm weather outdoor activities like hiking, backpacking, and fishing, as well as the increasing number of venomous snakes being kept as pets, has increased the number of venomous snakebites in recent decades. Many snakebites do not result in envenomation, although it is initially quite difficult to distinguish between an envenomated and non-envenomated bite.

Epidemiology

There are about 3000 species of snakes worldwide, 10% to 15% of which are venomous. These snakes primarily use their venom to obtain food.

In the United States, greater than 95% of snakebites are caused by the Crotalidae ("pit viper") family of snakes, so named because of heat-sensitive "pits" between the eyes and the nostrils used to sense their prey. The Crotalidae family includes the following snakes:

• Rattlesnakes, genera Crotalus and Sistrurus 
• Copperheads, Agkistrodon contortrix
• Cottonmouths, or water moccasins, Agkistrodon piscivorous

The Elapidae or coral snakes (Micrurus species) account for a much smaller proportion of snakebites in the United States. Elapids are found along the southern edge of the United States, whereas pit vipers are dispersed throughout most of the continent. Rattlesnakes account for most snakebite-related deaths in people and domestic animals in the United States. Most coral snake bites in the United States occur in southern states, with Florida, Texas, North Carolina, and Georgia among the most common. Risk factors for snake bites include male sex, handling or disturbing a snake, and owning a venomous snake.[1][2][3]

Pathophysiology

Venomous snakes in the United States were previously classified as having either hemotoxic or neurotoxic venom, although more recent toxicology research suggests this binary classification is inadequate.[4] The venom contains proteins, phospholipases, enzymes that can cause necrosis, and hemolysis via mechanisms that are still under study.[5] A concomitant allergic response leading to the release of histamine and bradykinin may also contribute to the systemic effects seen in more severe envenomations. Hypotension after a snakebite is likely caused by a variety of mechanisms, including increased permeability of capillaries, leading to extravasation of plasma and direct effects of toxins on the cardiac muscle, smooth muscle, and other tissues.[4]

History and Physical

A focused history and physical should be performed, starting with a primary survey of the patient's airway, breathing, and circulation. Shock and respiratory failure are common sequelae of snakebites, so close observation is crucial. Establishing the time of the bite as well as any previous interventions and asking about existing medical problems (eg, cardiac, pulmonary, and renal disease), current symptoms, allergies, and last tetanus immunization are also important. Close examination and documentation of the patient's injuries are crucial, as worsening erythema, swelling, or blistering around the snakebite site could precede clinical deterioration. Although not advised, if the patient was able to take a sufficient quality photograph or physically capture the snake, identification of the species could be useful in guiding management. Time should not be wasted trying to find, photograph, or kill the snake. Bedside ultrasound of the bite location can be utilized to evaluate the depth and extent of associated skin and soft tissue involvement.[3]

Evaluation

Initial evaluation of suspected or confirmed venomous snakebite patients should include the following:

• Routine vital signs
• Electrocardiogram and continuous cardiac monitoring
• Complete blood count 
• Urinalysis 
• Prothrombin time
• Partial thromboplastin time
• Fibrinogen
• Complete metabolic panel (including blood urea nitrogen and creatinine) 
• Blood type and cross-matched for 2 to 4 units of packed red blood cells [3]

Treatment / Management

The initial management of suspected or confirmed venomous snakebites is divided into pre-hospital and emergency department care.

Prehospital Setting

• Ensuring the patient is in a safe, comfortable place (away from the snake)
• Calming and reassuring the patient
• Immobilization of the affected extremity with a sling, if possible
• Cleansing the wound
• Monitoring for swelling or skin changes surrounding the wound
• Oral hydration with clear fluids if the patient can tolerate them
• Identifying the snake only if it does not put the patient or others at risk of further injury
• Rapidly evacuating the patient to an emergency center

Do not incise the wound or attempt to suck the venom out by mouth or with commercial suction devices. Avoid applying ice to the wound or giving the patient alcoholic beverages. 

Emergency Department

• Placing 2 large-bore intravenous catheters
• Initiating of intravenous fluid (lactated Ringer solution or normal saline)
• Rapidly determining the severity of envenomation and whether to give antivenom
• Cleaning the snakebite wound
• Considering surgical consultation if compartment syndrome unresponsive to antivenom is suspected
• Monitoring minimal or moderate envenomation patients for at least 12 to 24 hours
• Immunizing (tetanus), as indicated

Envenomation severity is classified into 5 grades (0 to IV), with grade IV being very severe envenomation characterized by rapidly progressing swelling, bleb formation, and necrosis, as well as systemic symptoms including weakness, nausea, vomiting, muscle cramping, and convulsions. Minimal envenomation (grade 0) is characterized by fang wounds without other signs of envenomation and less than 1 inch of surrounding erythema, without systemic signs or symptoms of envenomation. Current treatment recommendations for crotalid (pit viper) envenomation include antivenom for progressive swelling, moderate envenomation, or laboratory findings or coagulopathy. Dosing is primarily based on the severity of symptoms at initial presentation and response to treatment; treating moderate envenomation should start with at least 4 vials.

Minimal envenomation does not require treatment with antivenom, but these patients in this category should be monitored for a minimum of 12 hours.[3][6][7] A patient with minimal signs of envenomation should have a repeat coagulation panel performed to evaluate for delayed coagulopathy before discharge, and patients with progressive swelling, moderate envenomation, or coagulopathy should be given antivenom. In North America, there are 2 Crotalidae antivenoms approved for use.(B3)

Crotalidae Polyvalent Immune Fab Dosing

Crotalidae polyvalent immune Fab is derived from 4 snake species (Western diamondback, Eastern diamondback, Mojave rattlesnake, and cottonmouth) and immunized into sheep (ovine-derived). The whole immunoglobin is extracted, affinity purified, and cleaved by papain into the terminal Fab fragment of the immunoglobin. This reduces its size by about one-third and allows tissue penetration. However, it is cleared renally, and repeat dosing is usually necessary.

The initial controlling dose consists of 4 to 6 vials mixed in 250 mL of normal saline administered over 1 hour; the same number of vials is used for children. Initiate treatment at 10 mL/hr, observing for adverse events. If none are noted, increase every few minutes to complete administration in 1 hour. Observe patients for local swelling and systemic symptoms. Repeat with 4 to 6 vials over 1 hour if there are signs of progression. Do not administer to try to normalize abnormal coagulation markers completely. Repeat until initial control is achieved (eg, local swelling improves or stops, systemic signs are resolved, and clinically relevant bleeding is resolved). After achieving control, maintenance doses of 2 vials every 6 hours for 18 hours are recommended for rattlesnakes, patients with coagulopathy, and those with severe clinical envenomations. This is not usually required for moderate copperhead envenomations. However, if only a controlling dose is used, close and repeated monitoring for progression is important to decide if additional doses are required. Repeat the initial bolus protocol if recurrent swelling or coagulopathy occurs during maintenance doses.

Repeat coagulation panel (prothrombin time [PT]/partial thromboplastin time [PTT]/international normalized ratio [INR]), fibrinogen, platelets, and hemoglobin on days 2 to 3 and days 5 to 7. Recurrent coagulopathy without clinically significant bleeding has been known to occur. Some repeat and follow parameters to normalization. Indications for repeat dosing if coagulopathy occurs between 3 and 7 days after the last dose of Crofab are:

• INR >3.0
• PTT >50 seconds
• Platelet count <25,000
• Fibrinogen <50 ug/ml
• Multicomponent coagulopathy

Crotalidae Immune F(ab)2 Dosing

Crotalidae Immune F(ab)2 is derived from 2 snake species (Bothris asper and Crotalus duressis) and immunized in horses (equine-derived). The whole immunoglobin is extracted, purified, and cleaved by pepsin digestion into a fragment with 2 binding sites for venom components, F(ab)2. Despite being derived from horses, it is less immunogenic than the original rattlesnake antivenom produced; it is larger than Crotalidae polyvalent immune Fab and persists in the serum longer with a more sustained duration of the activity, therefore usually not requiring repeat maintenance dosing.

The initial controlling dose consists of 10 vials mixed in 250 mL normal saline (NS) administered over 1 hour (same number of vials for children). The initial infusion rate for the first 10 minutes should start at 25 to 50 ml/hr, then if no adverse reaction occurs the remained of the 250 ml solution can be given over 1 hour.[8]

Evaluate the number of each antivenom available and not mix loading and maintenance doses between the 2 products. In rare severe envenomations, a repeat dose of 10 vials of Anavip may be needed. Crotalidae polyvalent immune Fab is contraindicated in a patient with a known allergy to sheep protein, in which case Crotalidae immune F(ab)2 can be administered. Crotalidae immune F(ab)2 is contraindicated with a known allergy to horse protein, in which case Crotalidae polyvalent immune Fab should be used.

Differential Diagnosis

Although venomous snakebites are usually fairly straightforward to diagnose, the differential diagnosis includes:

• Snakebites from nonvenomous snakes
• Spider bites
• Tick bites
• Scorpion bites
• Hymenoptera stings
• Soft-tissue infections (folliculitis or furuncle)

Prognosis

If treated promptly, the prognosis of most venomous snakebites in the United States is quite good. There is an estimation that 25% of snakebites from venomous snakes do not result in envenomation.[3] Even though several thousand venomous snakebites occur each year in the United States, there are usually less than 10 reported deaths; deaths that occur are generally in those who delay or avoid treatment.

Complications

Complications of venomous snakebite include: 

• Coagulopathy
• Shock
• Respiratory failure
• Acute renal failure
• Local skin infection
• Compartment syndrome
• Serum sickness