SC8: Special Considerations

The incidence of snakebites worldwide is difficult to ascertain, as there is no systematic reporting mechanism. This fact, when combined with the variable degree of confirmation of snakebites, makes the estimation of an accurate number extremely difficult. Attempts have been made utilizing available data from case reports in the literature, hospital records, surveys, and existing reporting systems. Current estimates place the worldwide annual incidence of snakebites as high as 5.5 million.^11,36 Of these, roughly 50% are thought to be from venomous snakes.⁷ Estimated annual complications include 400,000 amputations³⁶ and approximately 100,000 deaths.^11,36

Snakes, while feared by many, are popular around the world as pets. The desire to keep venomous snakes as pets, which is typically illegal in the United States, and the implications throughout the world make the trade of exotic creatures second only to drugs and weapons on the international black market. In fact, the estimated annual worth of this trade in the United States alone is at least $15 million.¹³

This Special Consideration will discuss the evaluation and management of patients evenomated in the United States by non-native snakes (also known as exotic snakes). From 2007 through 2011, the American Association of Poison Control Centers’ (AAPCC) National Poison Data System (NPDS) recorded 622 nonnative (“exotic”) snakebites, with 250 of these thought to be from a venomous species (Chap. 136).

This same database was reviewed from 1995 through 2004 to characterize the types of exotic snakes involved and circumstances for the envenomations. During that time period, there were 399 exotic snakebites reported, of which 350 were identified by genus and species for a total of 77 different varieties.²⁸ One US expert reported 54 consultations regarding bites from nonnative venomous snakes.¹⁹

In the AAPCC data, the most common family responsible for envenonmations was the viperidae, making up 50% of these bites. Of the Viperidae, almost half of all bites were from four different species: Godman’s Pit Viper (Bothrops Godmanni), Gaboon viper (Bitis gabonica), Bush master (Lachesis mutus), and the Eyelash Viper (Bothrops schlegeli). The second most common family responsible for envenomations was the Elapidaes, resulting in 30% of US exotic snakebites. Sixty percent were from four different species: Indian Cobra (Naja naja naja), Monocellate Cobra (Naja naja kaouthia), Black Necked Spitting Cobra (Naja Nigricollis), and the King Cobra (Ophiophagus Hannah). The Indian Cobra was the most common snake identified during this study. Of note, there was one Atractaspidae bite (small scaled burrowing asp—Atractaspis microlepidota) and one Colubridae (Boomslang—Dispholidus typus).²⁸

The naming of snakes has evolved and the renaming currently continues at a rapid pace due to advances in DNA testing and ongoing research.^23,24,35 There are 2700 snake species in the world,²³ of which approximately 20% of these are known to be venomous to humans.¹⁶ Venomous snakes are divided into four major families as shown in Table SC8–1.^{12,17,22, 23, and 24,35}

The Elapidae family has a wide distribution in primarily tropical or arid desert settings in such continents as Asia, Australia, Africa, North America, and South America, with the sea snakes and sea kraits found in the Pacific and Indian Oceans.¹² Possibly the most well known of this family are the cobras, capable of unique characteristics such as hooding or spitting.¹² In the United States, there are three Elapidae snakes; the Eastern coral snake (Micrurus fulvius fulvius), the Texas coral snake (Micrurus fulvius tenere), and the Sonoran coral snake (Micruruoides euryxanthus).

The Viperidae family, consisting of the three subfamilies (Azemiopinae, Viperinae, Crotalinae), exists throughout the world with a few exceptions. The majority of the snakes in this family can be divided into two main categories: old world vipers (also known as true vipers) and pit vipers.

The Antivenom Index (AI) was created over 25 years ago as a joint effort of the Association of Zoos and Aquariums (AZA) and the AAPCC for the purpose of creating a database that would contain the location of all nonnative snake antivenoms stored throughout the zoos in the United States. For many years, this was kept in paper format at the Arizona Poison and Drug Information Center and was converted to an electronic database in 2006.

The AI can be searched by the common name or the scientific name of the venomous snake. This search will result in a list of possible snakes that match the description of the searched term. From there, a list of antivenoms active against that genus and species will be displayed, including which zoos stock them and how many vials are available. With this information, and some help from experts or the closest regional poison center, it can be determined where an adequate supply of antivenom exists and what arrangements are necessary to transport the antivenom to the health care facility where the patient in question is receiving care.

Additional information available in the AI includes package inserts for the antivenoms, many of which are translated into English, the expiration dates of the antivenoms, and additional information such as links to various recommendations on the housing, stocking, or administration of antivenoms.

Access to the AI is limited to the AZA and the AAPCC (all poison centers have access). The AZA have the ability to input updated stocking information, while the AAPCC members can view antivenom supplies. To access the AI, contact your local poison center at 1-800-222-1222. Southern Florida is unique in the storage and distribution of exotic antivenoms. The Miami-Dade Fire Rescue Venom Response Program maintains one of the largest repositories of exotic antivenoms for public use in the United States. They work with the local Poison Information Center in Miami for the clinical expertise to facilitate treatment of the envenomated patient.

Exotic snake envenomations can and certainly do occur in the United States, most often during feeding or handling the snakes, cleaning the cages, or while milking the snakes for venom.^19,34 The most common exotic envenomation between 1995 and 2004 involved male owners bitten in a private residence.²⁸ Of all bites that occurred between 1995 and 2004, 80% were the result of an Elapidae or Viperidae snake.²⁸ The venom components from these two families can be classified as neurotoxic, hemotoxic, and or myotoxic.^5,15,34

The venom from the Elapidae is associated with neurotoxic effects. Signs and symptoms consistent with neurotoxicity include blurred vision, paresthesias, ptosis, paralysis of facial muscles, difficulty swallowing, respiratory paralysis, and generalized flaccid paralysis.³³ The venom from the Viperidae is more commonly associated with hemotoxicity and myotoxicity, although some species also have neurotoxic effects. The hematologic signs and symptoms associated include petechiae, purpura, ecchymosis, or bleeding and changes in blood coagulation parameters, including platelets and fibrinogen, as well as prothrombin and partial thromboplastin time abnormalities. The activity of Viperidae venom on the clotting cascade occurs throughout the cascade, resulting in varying degrees of severity (Chap. 60). The signs and symptoms of myotoxins are consistent with local tissue injury and destruction, including swelling, necrosis, and blebs, and are accompanied by elevations of creatine kinase and aminotransferases with possible impairment of kidney function. While there are some classic differences in the presentation between snakes from the Elapidae and Viperidae families, it is important to note that there can also be similarities based on tremendous venom variability found from species to species and in snakes within the same species.¹⁵

It is always important to consult with an expert to help identify the snake and determine specific signs, symptoms, and treatment options. Experts can be found within the AAPCC by calling 1-800-222-1222, or a local zoological society or serpentarium.

The clinical presentation of patients with exotic snake envenomation is extremely variable as the sequelae depend largely on the type of species involved and the same factors that influence the outcome of patients envenomated by better understood local snakes; premorbid condition of the individual, location of the bite, dose of venom delivered, and delay to health care. Local poison centers or regional experts may be familiar with species kept in area zoos as part of an emergency response system for treatment of zoo workers. People who maintain these animals as pets and subsequently are envenomated while handling become more difficult to treat. Several basic steps can be followed in initial management of these patients as outlined in Table SC8–2.^15,34

Hospitals in the United States are not permitted to stock antivenoms for exotic snakes that are not produced for the US market and have not gone through the Food and Drug Administration (FDA) process for drug sale and administration. Zoos are permitted to stock antivenoms for the species of snakes locally housed for the purpose of treating an unintentional exposure. When zoological staff import antivenom from other countries, they must work with the FDA and the Centers for Biologics Evaluation and Research (CBER). The zoo facility is required to complete an Investigational New Drug (IND) Application, assign one or more local physicians who may administer the antivenom, record the name of each product and associated lot numbers, retain copies of the package insert for each product, and complete a statement that the antivenom is being imported solely for emergency use and will not be resold.³⁰ In addition, a Statement of Investigator must be prepared if any changes to the list of approved personnel for administration of the antivenom occur. When the antivenom is administered, a complete case report must be submitted to the director of CBER.

While zoos are permitted to have antivenom stocked at the facility, a recent study demonstrated that of the 106 zoos and 19 aquaria whose representatives responded, only 33 facilities stocked antivenom.³² In the 10 years prior to the study, these facilities reported a total of 39 separate incidents associated with venomous animals. It is unclear why so few facilities with potential for employee exposure do not carry the antivenom required for their local species, as it is possible that a commercially available product could prove essential. Most facilities reported some internal process to respond following an envenomation, including coordinating with the regional poison center, the local emergency medical services, and a local hospital, or have internally developed protocols.

The American College of Medical Toxicology (ACMT) recommends that a zoo or facility that houses exotic snakes have a written plan for management of an envenomation.¹ A study published in 2012 reviewed and tested the effectiveness of an emergency operation procedure.²¹ Zoo Atlanta, the Georgia Poison Center, and the Grady Health System established a procedure to manage an envenomation due to any of the 13 species of snakes housed at the zoo. All three organizations participated in the simulated drill and were evaluated on the functional aspects of coordinating patient care from the time of envenomation through stabilization. In this scenario, all personnel involved were previously alerted to the drill and had additional training as to what was to be expected. Even in this “best case” scenario that included preparation for a patient with an exotic envenomation, problems were still encountered. For instance, the protocol given to the hospital personnel lacked details about specific signs and symptoms expected, clear instructions for antivenom indication, and specific dosing and reconstitution instructions for the antivenom. There were also some general problems with personnel coordination. This study highlights the importance of having a plan in place prior to the emergency that includes the zoo facility, a regional poison center, and the treating institution.

Hospital Use of Exotic Antivenoms

Because exotic antivenoms are not readily available, it may be difficult to obtain the species specific correct antivenom in the appropriate amount. The local poison centers become a critical resources during this time. Often they can locate the closest supply and coordinate delivery. In the case of an envenomation at a zoo, the appropriate antivenom may arrive with the patient. In the case of the exotic snake owner, the poison center may help facilitate borrowing antivenom from local sources, such as zoos, known to stock the antivenom for emergency use. If there are no local sources, the poison center staff can easily access the AI to locate the closest available stock of antivenom. In one case report, it took a regional poison center 5 hours to locate and organize airborne delivery of the appropriate antivenom to the treating facility.¹³ A similar report described a 3 hour delay to administration even when the antivenom was present in the local zoo.⁹ During that delay, the patient required intubation.

Once brought to the facility, a series of steps must occur prior to the patient administration of the non FDA approved antivenom. The treating physician should contact the FDA to obtain approval to administer the antivenom as an IND under emergency use.²⁹ Contact numbers can be found at http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/InvestigationalNewDrugINDorDeviceExemptionIDEProcess/default.htm.

In addition, the treating physician will need to obtain informed consent from the patient prior to administration. Since the antivenom is considered an investigational product, both the Institutional Review Board (IRB) and Drug and Formulary Committee must be notified and provide approval. Many IRBs have emergency processes to expedite such a request. If such approval cannot be obtained in a clinically relevant time, the IRB must be notified of the emergency treatment within 5 working days of the administration.^1,21 The physician must also complete the appropriate IND paperwork (Form FDA 1571) and submit a comprehensive case report.³⁰

In addition to the legalities involved in using an investigational product, there are significant operational and logistical issues necessary to assure appropriate preparation of the product. The pharmacy department should be notified as soon as possible to allow the staff time to begin researching preparation instructions. Clinical pharmacists provide additional support for both the treating physician and drug preparation aspects in many emergency departments.²¹ The utilization of such individuals can greatly facilitate the medication preparation.

The package insert for the specific antivenom will be most helpful for the pharmacist in the preparation process. Specific instructions on diluents, storage, light or heat sensitivities, compatibility, and rate of administration are usually found in the package insert. If the specific antivenom product is known in advance, the pharmacist can begin to research these issues. Many package inserts are found in the Antivenom Index (AI) and can be obtained with the help of the regional poison center. However, not all package inserts are in English, and some must be translated or a translated copy must be located.¹⁶ Once preparation has begun, reconstitution of the antivenom can take minutes to hours to completely dissolve all the lyophilized particles. In addition to preparation, there is often a significant amount of documentation required when dispensing an IND approved drug. Having knowledge of the required procedure will expedite the administration of the antivenom.

Other Therapies

In principle, snake venoms should have some commonality, as they share the purposes of immobilizing or killing prey and beginning the digestive process, and have some common genetic linkage. In practicality, many venoms from snakes found from diverse area of the globe share constituents or antigenic characteristics.^4,6,27,37 It may therefore be possible to use antivenoms derived against specific snakes in the treatment of envenomation from other snakes with related venoms. FDA approved coral snake antivenom was used in an experimental model of nonnative elapid envenomation.²⁶ Similarly, FDA approved crotalid antivenom demonstrated efficacy against mice treated with venom from Crotalus durissus terrificus, Bothrops atrox, and Bitis gabonica.^18,25 In fact, a single case report demonstrates utilization of this principle of cross reactivity when a patient envenomated by C. durissus terrificus was successfully treated with US FDA approved CroFab.¹⁴ Such cross-reactivity should never be assumed based on common or taxonomic identification. The manufacturer of CroFab has listed experimental cross-reactivity with a number of species in the AI (Table SC8–3). The clinical decision to use CroFab for a patient envenomated by a non-US species of snake with known experimental cross-reactivity should be based on the severity of envenomation, the availability of species specific antivenom, and the risks associated with administration of species specific antivenom versus the risks of CroFab administration (Antidotes in Depth: A37).

The venom of many neurotoxic snakes interferes with neuromuscular transmission similar to neuromuscular blockers used in clinical medicine (Chap. 69). Neostigmine and other cholinesterase inhibitors increase the LD₅₀ of animals treated with Naja haje haje venom.¹⁰ Additionally, case reports and case series suggest a benefit of neostigmine with or without atropine in humans suffering neurotoxic snake envenomation.^3,8,20,31 In these reports, patients typically received 0.5 to 1 mg of neostigmine IV immediately following pretreatment with 0.5 to 0.6 mg of atropine IV. In some cases, this is repeated every 10 to 30 minutes based on response. Unfortunately, this benefit is not universal² and may be dependent on a number of factors, including differences in the mechanism of neuromuscular blockade between snake species. However, since the complications of atropine and neostigmine at these doses are small and there is a suggestion that they may reverse neuromuscular blockade, administration may be indicated if antivenom is unavailable or delayed. Further guidance can be found in Chap. 69 and in Table 69–5.

It is important to remember that there is a wide variation in the standards for preparation of antivenoms around the world. While many products are highly purified antibody fragments, some continue to use whole immunoglobulins that maintain the risk for anaphylaxis. Prior to antivenom administration, preparations must be made to treat life-threatening anaphylaxis. The appropriate level of nursing care and monitoring should be available, IV access should be secured, typical drugs (epinephrine, corticosteroids, antihistamines) and airway management tools should be present at the bedside.

• Many venomous snakes are available in homes and zoos far from their native habitats.

• It is essential to develop sophisticated systems of care in collaboration with poison centers and zoos assuring preparedness for worker or hobbyist injury.

• The use of internationally prepared antivenom may be life-saving and hazardous. The risks can be limited by understanding the risks and benefits of available internationally prepared antivenoms.

• The Antivenom Index, available to poison centers and the AZA, provides invaluable information about matching an antivenom to a particular snake, location of antivenoms, package inserts, and often English translations of foreign package inserts.

• The use of antivenoms not FDA approved must follow the rules for an IND.

• FDA approved antivenoms may have cross reactivity against some nonnative snakes.

References