Crotalidae Envenomation

Etiology

In the US, 3 types of Crotalidae exist, copperhead (Agkistrodon contortrix), cottonmouth (Agkistrodon piscivorus), and multiple species of rattlesnakes (Crotalus and Sistrurus sp.), which have a wide distribution throughout the United States except for Hawaii and Alaska.[1][4] Definitive characteristics of these snakes include triangular heads, elliptical eyes, and heat-seeking pits between their eyes and nostrils.[1] Given that particular species vary by state and region, knowledge of local geographic distribution can guide proper identification.[1]

Epidemiology

Estimates of the number of people who suffer a snakebite each year vary between 5000 and 9000.[1][4][5] Males are more likely to suffer envenomations than females, with the vast majority being Caucasian.[4][6] The majority of victims are young adults aged between 20 and 40.[4][1][7][6] A smaller peak in those under 12 years of age leads to the bimodal age distribution of envenomations.[4][1][7][6] Envenomations typically occur in the distal extremities.[4][1][7][6] Lower extremity envenomations are the most common location and usually occur with incidental contact. Upper extremity envenomations, by contrast, are more likely to be due to intentional contact.[1][7][6] Envenomations typically occur when pit vipers are most active in late spring to early fall.[4] There is a higher incidence of bites at dawn and dusk, which are peak hunting times for pit vipers.[4] The majority of envenomations are due to rattlesnakes and copperheads, which account for 50 to 55% and 30 to 45% of cases, respectively. cottonmouth envenomations are rare, contributing to only 5 to 10% of cases.[4][8] Bites involving larger snakes are associated with more severe envenomations, likely due to their more substantial venom reserves.[9]

Pathophysiology

Snake venom is a mixture of multiple compounds with different physiologic effects. The specific constitution of an individual snake’s venom varies by species, geographic location, diet, and even between siblings.[1] Most North American crotalid venom generally contains proinflammatory, hemotoxic, cytotoxic, and myotoxic compounds.[1][2][3] Venom is rapidly absorbed but slowly eliminated.[3] Examples of specific compounds identified and their actions:

• Snake venom metalloproteinase has both pro- and anti-coagulation effects. It also contributes to the development of edema, myotoxicity, and inflammation.[2][3] 
• Snake venom serine protease targets the coagulation cascade and causes platelet aggregation.[2][3]
• Phospholipase A2 has anticoagulant, cytotoxic, and myotoxic effects. It also contributes to the development of edema.[2][3]
• Disintegrins and C-type lectins modulate platelet aggregation.[2][3]

Neurotoxins are uncommon among North American Crotalids. However, 3 particular species: Mojave rattlesnake (C. scutulatus), Timber rattlesnake (C. horridus), Southern Pacific rattlesnakes (C. oreganus helleri) are known to have the Mojave A or a similar presynaptic neurotoxin.[1][9]

History and Physical

The first step when evaluating potential snake envenomation victims is to assess the ABCs: airway, breathing, and circulation.[1] If there is any compromise to these systems, immediate intervention is warranted before continuing with further history and exams. Head and neck envenomation is uncommon but can cause significant swelling, which may affect the airway. If envenomation to the head and neck area results in signs of airway compromise, early endotracheal intubation should occur because of the high likelihood of subsequent airway loss.[10] Distal envenomations can precipitate airway compromise by inducing angioedema.[1][10] Severe envenomations can result in circulatory collapse from massive hemorrhage, third spacing, and hemolysis.[1][10] If the venom contains a neurotoxin, patients may suffer impairment of respiratory function.[1]

When obtaining a history from a victim of potential envenomation without compromised ABCs, several pieces of information are necessary. The time since the envenomation occurred and the anatomic location of the bite should be asked to allow for appropriate monitoring of local symptom progression.[1] While correctly identifying the species involved in the potential envenomation is important, attempting to kill or capture the snake is not advised as it can result in additional bites or victims. A picture obtained with a cellphone or other portable device is usually sufficient for identification and can be obtained from a distance safe enough to avoid further envenomation.[1] Again, it should be stressed that preventing additional bites or victims is more important than correctly identifying the snake. Both the public and medical professionals require education on this recommendation. Despite these recommendations, it is not unusual for victims to bring a dead snake. Healthcare providers should understand that handling dead snakes can be dangerous as post-mortem envenomations can occur.[11]

As mentioned above, the first step in any physical exam is assessing the cardiopulmonary system to identify signs of compromise. Next, examine the envenomation site, which likely reveals 2 puncture wounds a few centimeters apart. The leading edge of the erythema/edema should be marked to monitor for progression.[1][10] Pulse, sensation, and motor function distal to the envenomation also need testing. Remove any restrictive jewelry or clothing, as swelling may progress.[1]A further skin assessment should focus on signs of abnormal bleeding, such as petechiae or ecchymosis. A thorough head-to-toe exam should be completed to look for other sequelae of envenomation.[1]

The most common localized findings following pit viper envenomation are pain, edema, ecchymosis, and erythema in descending order. Tissue necrosis is possible and more likely to occur with rattlesnake envenomation. Systemic symptoms occur in 15% of patients or less. Systemic manifestations include vomiting, bleeding from distal sites (eg, gingival bleeding or epistaxis), and signs of neurotoxicity (eg, fasciculations, myokymia, cranial nerve palsies, paresthesias, or respiratory paralysis).[1] Hypotension and angioedema, though uncommon, require prompt attention and management.[1][10] Providers should assess other symptoms such as chest pain, abdominal pain, headache, etc.[1] These symptoms may be a complication of envenomation, such as hemorrhage or thrombosis, but may represent a completely separate disease process.[1] While rattlesnakes are generally recognized as causing more severe envenomations than their Agkistrodon counterparts, species alone does NOT dictate the degree of envenomation. Management should be based on a combination of history, physical, and lab abnormalities, regardless of the species involved.

Evaluation

All potential victims of pit viper envenomation should have a complete blood count (CBC), partial thromboplastin time (PTT), prothrombin time (PT), international normalized ratio (INR), and fibrinogen level checked where available.[1][10] When reviewing the CBC, note any thrombocytopenia or anemia. The other tests attempt to quantify any degree of coagulopathy.[1][10] If fibrinogen is not available, a D-dimer is an optional substitute. Fibrinogen is more specific for coagulopathies, but the D-dimer is more sensitive.[1] Fibrin splint products have no role in the evaluation of pit viper envenomation.[10] Additional tests are used to evaluate for complications related to envenomations. A comprehensive metabolic profile can be useful to assess for hepatic or renal dysfunction.[1] A urinalysis and total creatine kinase can evaluate for possible rhabdomyolysis.[1] Any further testing should be ordered based on patient complaints, eg, a patient presenting with chest pain after an envenomation should have an EKG and troponin ordered.[1] 

Treatment / Management

As with other soft tissue injuries, all patients with a pit viper envenomation should have their Tetanus updated and receive local wound care with soap/water.[1] Patients should also receive adequate pain control. Despite their efficacy in controlling pain and inflammation, clinicians should avoid NSAIDs due to the potential to worsen coagulopathy and platelet aggregation.[1][10] Because of this theoretical risk, opioid analgesics are the recommended agents for adequate pain control.[1][10] Consultation with the regional poison control center can be extremely valuable in assisting with the nuances of a particular case.[10] Each center can provide access to an on-call toxicologist if sub-specialist level advice is warranted. Further treatment recommendations are based on the severity of envenomation, which broadly falls into 4 categories.(A1)

• Dry: Approximately 20 to 25% of bites result in no envenomation. These patients are largely asymptomatic and have minimal localized edema or erythema. There are no signs of coagulopathy on serial lab assessments.[1][10]
• Mild Envenomation: Approximately 35 to 40% of envenomations result in localized erythema and edema. These symptoms do not involve an entire extremity; again, there are no signs of coagulopathy on serial lab assessments.[1]
• Moderate Envenomations: Approximately 15 to 20% of envenomations result in more significant erythema and edema. These envenomations can affect an entire extremity. Systemic symptoms may or may not be present. Minor lab abnormalities may exist, but clinically significant bleeding does not occur.[1]
• Severe Envenomations: 5 to 10% of envenomations result in life-threatening coagulopathies with profound localized findings of erythema and edema. Severe systemic signs such as hypotension, angioedema, and any signs of neurotoxicity may present. The presence of these symptoms marks a severe envenomation regardless of other findings.[1][10]
(A1)

Patients with an apparent dry bite or mild envenomations should have monitoring for 6 to 8 hours. A CBC, coagulation testing, and fibrinogen should be repeated near the end of this observation period. If there are no signs of worsening envenomation, these patients can be safely discharged but should be counseled to return for any signs of bleeding, swelling, or worsening symptoms.[10] All patients with more than a mild envenomation should receive antivenom.(B3)

In North America, there are 2 Crotalidae Antivenoms approved for use:

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 1/3 and allows tissue penetration. However, it is cleared renally, and repeat dosing is usually necessary.

The initial dose of antivenom is 4 to 6 vials, regardless of age or body mass.[10] A higher dose of 8 to 12 vials merits consideration for patients in shock or with serious bleeding.[10] The initial controlling dose consists of 4-6 vials mixed in 250 mL normal saline administered over 1 hour (same number of vials for children). Initiate treatment at 10 mL/hr, observing for adverse effects. If none, then increase every few minutes to achieve complete administration in 1 hour. Observe patients for local swelling and systemic symptoms. Repeat with 4-6 vials over 1 hour if there are signs of progression. After completing this initial dose, a physical exam and laboratory reassessment must be performed to determine if it achieved initial control.[10] A repeat dose of 4 to 6 vials is indicated if the exam and labs worsen.[10] This cycle gets repeated until obtaining control. Once initial control has been obtained, patients require maintenance dosing of 2 vials at 6, 12, and 18 hours from initial control.[10] If at any point, the envenomation appears to be worsening, the algorithm should be started over with 4 to 6 more vials.[10] All patients requiring antivenom administration should be admitted for continued treatment and monitoring.(B3)

Repeat coagulation panel (PT/PTT/INR), fibrinogen, platelets, and hemoglobin on days 2-3 and 5-7. 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
• Multi-component 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.  Though derived from horses, it is less immunogenic than the original rattlesnake antivenom. It is larger than Crotalidae Polyvalent Immune Fab and persists in the serum longer with a more sustained duration of the activity; therefore, it usually does not require repeat maintenance dosing.

The initial controlling dose consists of 10 vials mixed in 250 mL of normal saline and administered over 1 hour (the 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 remaining 250 ml solution can be given over 1 hour.[12] It is best to evaluate the number of antivenoms 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. Blood products only temporarily correct coagulopathies and thrombocytopenia related to snake envenomation, but this rarely results in long-term correction. With this knowledge, blood products such as fresh frozen plasma, platelets, or packed red blood cells should be reserved for patients with medically significant bleeding or with profound coagulopathies despite appropriate antivenom administration.[1][10](A1)

Aggressive surgical intervention is not indicated, including prophylactic wound excision or fasciotomy. These interventions have not been shown to change outcomes when compared to the administration of antivenom alone and can potentially cause further tissue damage and be disfiguring.[13] Compartment syndrome is a rare but serious complication of pit viper envenomation. Diagnosing compartment syndrome should not rely on “soft” signs but should be through direct compartment pressures or evidence of neurovascular compromise where direct pressures are unobtainable.[13] If compartment syndrome is suspected, administer antivenom as first-line therapy before any fasciotomy or digital dermatome. Antivenom has been shown to reduce compartment pressures significantly.[1][10][13] Several therapies should be avoided as they have not been shown to change outcomes and can potentially cause more harm.(A1)

• Excision & Suction: Remains common practice among the lay public. Patients and healthcare providers understand that this does not remove significant venom and increases local tissue damage.[1][10]
• Ice: Commonly used to control localized swelling due to musculoskeletal injury, ice is ineffective at controlling swelling due to envenomation. Furthermore, intensive cryotherapy has been shown to worsen outcomes.[1][10]
• NSAIDs: These agents are usually effective at pain control and edema reduction. However, they theoretically potentiate the effects of venom on platelet aggregation and thus worsen bleeding. Alternative analgesics, such as opiates, should be given instead.[1][10]
• Electricity: Electricity plays no role in the treatment of envenomations. It increases local tissue damage and does not denature venom.[1][10]
• Prophylactic antibiotics: Infection appears to be a rare complication of snakebites. As such, prophylactic antibiotics are not indicated and have not been shown to change outcomes.[14]  Antibiotics should be used only if signs of secondary infection develop, such as purulence.[1][10]
• Tourniquets: Tourniquets are a commonly deployed strategy despite evidence that they do not inhibit the absorption of venom effectively and can increase tissue damage. If present on the initial evaluation, any tourniquet should be removed.[1][10]
• Steroids: There is no evidence of improved outcomes when patients empirically receive steroids. They should be reserved only for hypersensitivity reactions to either venom or antivenom.[1][10]
(A1)

Differential Diagnosis

It is unlikely that a crotalid envenomation is mistaken for another disease process, given that most patients present complaining of a snakebite. However, patients occasionally report concerns about a snakebite even though they cannot articulate the reason for this suspicion clearly. The primary decision point when evaluating envenomations is determining the degree of envenomation, which guides further treatment. Non-venomous snakes can also cause snakebites; however, these bites don't show any signs of toxicity, given the lack of venom. Localized reactions from other envenomations, such as Hymenoptera, can cause significant localized pain, erythema, and edema. These could be interpreted as a snake envenomation if a patient did not visualize the cause of their injury. However, unlike snakebites, 1 would expect only to see a single puncture wound instead of 2 and generally have limited localized edema and erythema.

Patients with skin and soft tissue infections may present with concern for a snakebite. Erythema and edema from secondary infection after an injury may be mistaken for an envenomation. The development of symptoms many hours or several days after an injury is much more suggestive of secondary infection. Though not impossible, it is unlikely that a patient would suffer a snakebite without actually visualizing a snake.

Toxicity and Adverse Effect Management

Modern crotalid antivenom Fab, approved by the FDA in 2000, was developed from the serum of sheep inoculated with 4 species native to the United States: eastern diamondback (C. adamanteus), western diamondback (C. atrox), Mojave rattlesnake (C. scutulatus), cottonmouth (A. piscivorus).[15] The isolated antibodies then undergo proteolytic cleavage into the Fc and Fab portions. The Fab portion, which is less immunogenic, is then isolated and processed into the final product.[15]This modern preparation is responsible for the decreased incidence of immune reactions compared to the older preparation.[15]

• Hypersensitivity: Type I hypersensitivity is relatively uncommon, with 1 review showing an incidence of 8%.[15] While rash was the most commonly reported symptom, there are also reports of other symptoms such as urticaria, wheezing, oral swelling, and dyspnea.[15]
• Serum Sickness: Serum sickness has also been reported, with a slightly higher incidence of 13%.[15] Rash/urticaria is, again, the most commonly reported symptom. Other symptoms such as myalgias, arthralgias, fever, and anorexia may be present.[15])
• Pre-treatment does not decrease the incidence of hypersensitivity reactions.[1] As indicated, reactions are treated like other hypersensitivity reactions, ie, epinephrine, steroids, antihistamines, and airway management.[1] Once reaction symptoms are under control, antivenom therapy should restart slowly.[1] Most patients can complete their antivenom without further incident.[1][15]

Prognosis

Death

Rattlesnake envenomations resulted in 0 to 4 deaths from 1000 to 1300 exposures per year between 2000 to 2007.[13] Deaths from copperheads are even more rare, with 1 study showing only 1 death in 5 years.[13] Based on the available evidence, most patients receiving prompt evaluation and treatment are expected to survive.

Prolonged Disability

Patients suffering pit viper envenomation can have symptoms that persist for multiple weeks after their initial treatment. Symptom duration varies by patient and by the severity of envenomation. Generally, patients can expect symptoms to last for at least 2 to 3 weeks. Pain, decreased function of an affected extremity, persistent edema, and lost time from work can last 2 to 4 weeks. Recurrent edema and pain may occur for 1 to 2 months after envenomation.[16]

Recurrent Symptoms

Up to 5% of patients evaluated and treated for envenomations are readmitted after discharge. Patients are typically readmitted due to worsening symptoms, including edema/erythema or signs of coagulopathy. Recurrent coagulopathy with bleeding affects less than 1% of victims. Even fewer victims, about 0.5%, develop medically significant late bleeding.[5] These patients are much more likely to have been the victims of rattlesnake envenomation.

Complications

Myonecrosis/Rhabdomyolysis: Rhabdomyolysis may develop as a result of venom-induced myonecrosis. A patient’s total creatine kinase and renal function require monitoring if rhabdomyolysis is suspected. Treatment does not differ from other causes of rhabdomyolysis.[1][3][10]

Compartment syndrome: As addressed in the previous sections, compartment syndrome is a rare but serious complication of pit viper envenomation. Any patients with suspected compartment syndrome should receive antivenom before any surgical fasciotomy or digital dermatomy. Serial compartment pressures can be obtained to monitor progression or improvement.[1][10][13]

Bleeding: Though clinically significant bleeding is rare, bleeding may occur either at the envenomation site or at distal sites due to the venom’s effect on both the coagulation pathways and platelet aggregation.[1][3][10] Signs of distal bleeding commonly include gingival bleeding, epistaxis, and petechiae. However, bleeding can also present as headache or abdominal pain in the rare instance of intracranial or intraabdominal/retroperitoneal bleeding, respectively.[1][3][10]

Anemia/Thrombocytopenia: Antivenom is the first-line treatment for any hematologic abnormalities. Transfusion should only be a consideration after administering antivenom.

Angioedema/hives: As discussed in the previous sections, hypersensitivity reactions are uncommon. If present, treatment includes steroids, epinephrine, and antihistamines in addition to antivenom. Airway management may be necessary if significant angioedema is present.[1][10]