Evaluation and Treatment of Snake Envenomations

Etiology

Snake envenomation worldwide is primarily related to occupational exposure, such as in farmers and hunters, but is also seen among tourists exploring the outdoors. When snake envenomation occurs in humans, the initial damage is local around the site of the bite and may spread to systemic toxicity depending on the species. Snakes primarily use their venom production for targeting prey, but it is also a form of self-defense. Some species can selectively release their venom leading to the occurrence of “dry bites,” in which there is the delivery of no venom. When venom gets released with their bite, the overall toxicity is dependent on both the volume of the venom released and the median lethal dose (LD50) of the venom.

Epidemiology

There are an estimated 1.2 to 5.5 million people affected by snake bites worldwide each year, with as many as 94,000 of these leading to death. The regional variation is quite staggering, with only 5 snakebite-related deaths occurring in the United States (US) in comparison to India, which has one of the world’s largest number of snake bites annually, with an estimated 50,000 snakebite-related deaths.[1][2] The cause of this variation is twofold. The first is a higher prevalence of venomous snakes in a more densely populated region with poorer living conditions. The second factor is that the access to healthcare in these regions is limited with long travel times to reach a suitable treatment center and lack of antivenom availability. Within the US, the vast majority of snake envenomations occur in the southwest states with envenomations from the Viperidae family. Children only comprised 28% of envenomations, and males were more likely to be victims at 59%.[3]

Pathophysiology

The symptoms seen from snake envenomations are mainly due to the toxic components in their venom. The exact composition ranges from species to species and can vary significantly from localized tissue destruction to profound coagulopathies. The clinical effect on humans is related to both the potency and the volume of the toxin released during the snake bite. The venom released by the inland Taipan from Australia is the most potent in the world with a lethal dose of only 0.01 mg/kg with an average envenomation of 44 mg. Their envenomations have greater than 80% mortality. 

Toxicokinetics

The composition of snake venom from a single species of venomous snake can consist of up to 100 different toxic elements. Local tissue destruction is primarily due to hyaluronidase and proteolytic enzymes in the snake venom, which can lead to local tissue edema, blistering, and tissue necrosis. Phospholipase A2 is a common component of snake venom and causes local tissue damage. This compound has both local effects on the surrounding tissues as well as systemic effects on the vascular system and nerve endings. There are a variety of other proteins and polypeptides with toxic effects, such as neurotoxins and hemotoxins. Most of the neurotoxic effects are secondary to damage at both the presynaptic and postsynaptic terminals of the neuromuscular junction. Presynaptic neurotoxins, such as phospholipase A2, damage the terminal axon, which prevents the release of acetylcholine, causing diffuse paralysis. In contrast, postsynaptic neurotoxins, such as alpha neurotoxin, respond well to antivenom and anticholinesterase administration as the toxin binds directly to the acetylcholine receptor.[4] There are a wide variety of hemotoxins with effects on the coagulation cascade, platelet activation, and fibrin clot formation. Most of the toxins lead to an increased bleeding tendency secondary to a consumptive coagulopathy and defibrination. There are, however, some hemotoxins that promote clotting and thrombosis.

History and Physical

A detailed history of a patient suspected of having a snakebite is essential to delineate treatment options moving forward. Information to obtain includes the timing and location of the bite, the onset of any symptoms the patient has been experiencing, and any first aid administered in the field. Gathering a past medical history with details as to which medications they are on, specifically anti-platelet and anti-coagulant medications, and any allergies that would prohibit them from receiving an antivenom, such as horses. If possible, information on the offending snake should be gathered. This information should be compared to the local database of venomous snakes located on the WHO website to see if a local antivenom exists. Factors that contribute to the severity of the bite include size of the victim, with larger patients doing better, part of the body bitten, exertion following the bite, depth of the bite, species of snake causing the bite, time to the presentation at the hospital, and initial first aid given at the scene [5].

The physical exam may or may not reveal fang marks at the injury site. There could be local tissue damage, such as ecchymosis, blistering, or even tissue necrosis. Neurotoxic effects will initially present with generalized weakness, ptosis, and ophthalmoplegia; this may progress to paralysis of the facial muscles and, eventually, respiratory failure secondary to obstruction or paralysis of the diaphragm. Significant bleeding from the puncture site, epistaxis, or evidence of spontaneous bleeding could indicate a hemotoxic effect. Patients may present with signs of shock secondary to venom-induced vasodilation, hypovolemia, or even anaphylaxis in some patients [6].

The physical exam could help indicate the species of snake inflicting the bite. In general, Elapidae bites are associated with minimal local tissue damage and have a neurotoxic syndrome with systemic toxicity. Viperid bites are associated with profound local tissue damage and have hemotoxic syndrome with systemic toxicity. Symptoms that may suggest systemic effects of the envenomation include nausea, vomiting, abdominal pain, lethargy, muscle weakness, muscle fasciculation, and severe headache. Recognizing these symptoms early to prompt the initiation of antivenom administration is vital.

Evaluation

Ancillary study testing should target the suspected toxin envenomation. In the case of unknown exposure and signs of systemic toxicity, a broad initial workup should take place. Laboratory testing would include a complete blood count, prothrombin time, partial thromboplastin time, fibrinogen in the case of suspected hemotoxin and a creatinine kinase, basic electrolytes, and urinalysis for possible developing hematuria or proteinuria. For cases of neurotoxicity, the patient requires end-tidal CO₂ monitoring, or serial arterial blood gases to evaluate for developing respiratory acidosis. They should also undergo frequent neurologic checks to monitor the progression of the toxicity. There has been the development of rapid venom testing within some centers (mostly Australia), but the data shows that these are only useful to confirm the suspected species of envenomation and that a negative result cannot exclude a particular species. Additionally, the wound site should be monitored carefully for the spread of edema, development of blisters, or signs of compartment syndrome. If compartment syndrome becomes a concern clinically, the definitive diagnosis is possible by obtaining a direct compartment pressure. If this is greater than 30 mmHg of pressure, it is consistent with the early development of compartment syndrome. 

Treatment / Management

The initial first aid at the scene should be minimal and aim at getting the patient to the nearest treatment center quickly. Varying opinions exist regarding the usefulness of placing the affected extremity in a splint and keeping it at heart level. Therefore, this should only occur if it will not delay transportation. Removal of jewelry and any constrictive clothing on the affected limb is necessary due to the possibility of swelling and circulatory compromise. The patient should be kept calm and encouraged not to exert themselves as this could increase snake venom absorption. Pressure bandages are another controversial topic. If the identity of the snake species is known to cause neurotoxicity and no local tissue damage, the application of a pressure bandage could slow the spread of the venom. However, if the venom is known to cause local tissue damage, the implementation of the pressure bandage may worsen the damage inflicted on the extremity. Application of a tourniquet proximal to the bite results in higher morbidity without any improvement in outcomes, so this practice has been discouraged. The use of venom extractors has also been demonstrated to be ineffective. Local wound manipulation, such as incision or washout, is generally not suggested.[7][8]

Measurement of the progression of swelling from Crotalidae envenomation is essential to decide if antivenom is indicated. Place an ink mark on the proximal edge of the bite swelling as a baseline for serial measurements. Mark the progression of swelling with a skin marker, noting the time. Measure the circumference of the affected extremity at the same level each time (ie, mid-forearm or mid-shin). Measure the swelling extension and record circumference every 15 to 30 minutes. Once there has not been any progression of edema after four consecutive measurements, then decrease measurement frequency to every hour. Antivenom is indicated if swelling progresses beyond the bite site. Identification of the offending snake species will help determine the appropriate antivenom treatment. Two antivenoms against Crotalidae have been approved in the US.

Crotalidae polyvalent immune Fab—Initial Controlling Dose.

• Crotalidae polyvalent immune Fab is an antivenom approved for use in the US and has antivenom components for four species of Crotalids.
• Infuse 4-6 vials (the pediatric dose is the same as an adult) for usual envenomations.
• Infuse 8-12 vials for cases with shock, airway involvement, or envenomation on the face or neck
• Each vial of Crotalidae polyvalent immune Fab is reconstituted with 18 mL of 0.9% normal saline and mixed by continuous inversion until no solid particles are noted. Do not shake. Further, dilute all reconstituted vials to a total volume of 250 mL with 0.9% normal saline. Start infusion at 25-50 mL/hr. for the first 10 minutes and monitor for allergic reactions. If no acute reaction is noted, infuse the remainder of 250 cc over 1 hr. Once initial control is achieved by the cessation of proximal swelling, give 2 vials of antivenom IV every 6 hrs for 3 additional doses.

Crotalidae immune F(ab)2 Equine is the second antivenom product approved in the United States for Crotalidae envenomation. It is derived from two snakes, from North and South America, and is an F(ab)2 derivative of the immunoglobulin, which has a longer duration of activity than the Fab fragment in Crotalidae polyvalent immune Fab. Once it is decided that envenomation has occurred and Crotalidae immune F(ab)2 is the agent available for use, infuse 10 vials (the pediatric dose is the same as an adult). Each vial is reconstituted with 10 mL of 0.9% normal saline and mixed by continuous gentle swirling. Combine the contents of reconstituted vials promptly and further dilute to a total volume of 250 mL with sterile normal saline. Start infusion at 25 to 50 mL/hr. for the first 10 minutes and monitor for allergic reactions. If no acute reaction is noted, infuse the remainder of 250 cc over 1 hr.

In countries like India and Australia, with a more significant variation in venomous snake species, there are multiple targeted antivenoms. In high-prevalence areas, these antivenoms are stored at a central facility to aid in proper storage and distribution as needed. Antivenom should be administered within four hours, or as soon as possible thereafter, from the snakebite for optimal effect. Antivenom administration is intravenous, as a local subcutaneous injection has not been proven to result in improved outcomes. There have been reported cases of recurrent neurotoxic envenomation after the initial dosing of a proper antivenom, which may be secondary to manipulation at the bite site, releasing a non-neutralized toxin into the bloodstream. All these cases improved after re-administration of the proper antivenom.

The primary treatment should also include resuscitation of the patient, including intubation for those with respiratory distress or paralysis and IV fluids for those exhibiting signs of shock. Some patients may require the use of vasopressors to counteract the vasodilatory effects of the envenomation. Recognizing that systemic toxicity may progress rapidly, so early recognition and treatment are paramount. Some patients will develop severe coagulopathies from their snake envenomations. Treat life-threatening bleeding with direct pressure. There is no evidence of the empiric use of blood products, such as platelets or fresh frozen plasma. Transfuse-packed red blood cells in cases of severe blood loss. Some studies have demonstrated the benefit of edrophonium and other long-acting anticholinesterase medications in countering the effects of the venom's neurotoxic components.

Differential Diagnosis

In the absence of an observed snake bite, alternative envenomation, such as scorpion, tick, or spider bite, should be considered based on the region. For patients with a neurotoxic syndrome, one must consider Guillain-Barre as an alternative. Tick paralysis can also produce similar symptoms. Those with coagulopathies should undergo evaluation for an underlying hereditary abnormality or an acquired disease, such as disseminated intravascular coagulation or idiopathic thrombocytopenic purpura. Local tissue destruction can be related to trauma to that area or a soft tissue infection, such as cellulitis, abscess formation, or necrotizing fasciitis.

Treatment Planning

In areas with known snakes, hospitals should maintain an adequate supply to treat at least 2 victims of snakebite and order more antivenom as supplies are used or expire.

Prognosis

The majority of morbidity and mortality from snake bites are secondary to the toxin production associated with the bite. Patients who seek proper medical attention within the first 6 hours after the bite have significantly lower morbidity and mortality.  Patients who are monitored and given supportive treatment during this period typically do not have any long-term side effects. Those with significant local tissue injury secondary to the snake envenomation may develop longstanding paresthesia, muscle damage, or even amputation in severe cases.

Complications

The primary complications from snake envenomations are due to the direct toxic effects. The localized tissue damage may require debridement or even amputation in severe cases. Reports exist of massive coagulopathies leading to profound blood loss. These coagulopathies usually resolve within 48 hours of the snake envenomation. Profound neuromuscular blockade can also occur, leading to pulmonary insufficiency if the diaphragm is involved. These symptoms also typically resolve within 72 hours of envenomation.

The administration of snake antivenom requires monitoring for signs of adverse reactions. These include an anaphylactic reaction that may occur within the first few minutes of administration and up to 2 hours. If a severe anaphylactic response is suspected, the infusion should stop, and the administration of epinephrine and an anti-histamine should follow. Patients may also develop a hypersensitivity reaction leading to pruritus, hives, nausea, and mild hypotension. This reaction may occur at any time during the antivenom administration and will dissipate once the infusion is complete. There are also documented cases of serum sickness as a side effect that may occur up to 2 weeks after administration. This usually presents as an influenza-like illness with a rash, and possible microhematuria. This condition responds well to a short course of antihistamines and oral corticosteroids.[9][10]