CE Article #3 Rattlesnake Envenomation Laura Najman, DVM, DACVECC Ravi Seshadri, DVM, DACVECC, DAVBP Advanced Critical Care and Internal Medicine Tustin, California ABSTRACT: Snake envenomation has been widely reported throughout the human and veterinary literature.The effects of venom include coagulation disorders, neurotoxicity, and tissue effects, such as local swelling and necrosis. Significant progress has been made in understanding the pathophysiology of envenomation, leading to changes in treatment protocols. Recent developments include the production of a new antivenin and a canine rattlesnake vaccine. ver 120 species of snakes are native to neurotoxin that has been previously described in the United States. Of these species, 20 the veterinary literature.5,6 This article focuses on Oare considered venomous.1 Human Crotalidae envenomation. snakebites are most often reported in the south- Crotalidae are known as pit vipers because eastern, southwestern, and south central United they have heat-sensing pits that allow them to States.2 Most bites reportedly occur in the locate prey and determine the direction of warmer months (i.e., April through September) strike.7 Three genera of crotalids (i.e., Crotalus, when snakes are active.1 North American ven- Sistrurus, and Agkistrodon spp) inhabit the omous snakes can be divided into two families: United States.7 Both Crotalus and Sistrurus spp Crotalidae and Elapidae.2 have rattles.7 In the United States, most reported envenom- ations in animals and humans are due to ENVENOMATION AND VENOM Crotalidae (pit vipers; Table 1), including rattle- COMPOSITION snakes, copperheads, and cottonmouths (water Twenty percent to 25% of rattlesnake bites are moccasins).3 The eastern and western diamond- dry: they penetrate the skin without resulting in back rattlesnakes (Crotalus adamanteus and Cro- envenomation.1 One study8 that surgically talus atrox, respectively) are responsible for most implanted transonic probes to directly measure of the morbidity and mortality from snake venom release in western rattlesnakes reported envenomation because of their widespread geo- the incidence of dry bites to be as high as 35%. graphic distribution and relatively potent This number may be falsely elevated because the venom.3 Copperhead snakes have the least flow probe was implanted in only one of the two potent venom, and their bites rarely require fangs. antivenin therapy.1 Elapidae Crotalid venom consists of 90% water, (i.e., coral snakes) are an infre- numerous enzymes, and peptides.4 Proteins quent cause of envenomation: range in size from six to 100 kD.1 Specific com- •Take CE tests they are involved in less than ponents vary among species and even between • See full-text articles 25 reported cases of venomous different geographic subgroups of the same snakebites in people each year.4 species, resulting in varied effects of envenoma- CompendiumVet.com Their venom contains a potent tion. Many of these proteins have enzymatic COMPENDIUM 166 March 2007 Rattlesnake Envenomation CE 167 Table 1. North American Crotalidsa Scientific Name Common Name Geographic Location Agkistrodon contortrix Copperhead United States Agkistrodon piscivorus Cottonmouth United States Crotalus adamanteus Eastern diamondback rattlesnake United States Crotalus atrox Western diamondback rattlesnake United States, Mexico Crotalus cerastes Sidewinder rattlesnake United States, Mexico Crotalus horridus atricaudatus Canebrake rattlesnake United States Crotalus horridus Timber rattlesnake United States Crotalus lepidus Rock rattlesnake United States Crotalus mitchelli Speckled rattlesnake United States, Mexico Crotalus molossus Black-tailed rattlesnake United States, Mexico Crotalus oreganus abyssus Grand Canyon rattlesnake United States Crotalus oreganus cerberus Arizona black rattlesnake United States Crotalus oreganus concolor Midget faded rattlesnake United States Crotalus oreganus helleri Southern Pacific rattlesnake United States, Mexico Crotalus oreganus lutosus Great Basin rattlesnake United States Crotalus oreganus nuntius Hopi rattlesnake United States Crotalus oreganus oreganus North Pacific rattlesnake United States, Canada Crotalus pricei Twin-spotted rattlesnake United States, Mexico Crotalus ruber Red diamond rattlesnake United States, Mexico Crotalus scutulatus Mojave rattlesnake United States, Mexico Crotalus tigris Tiger rattlesnake United States, Mexico Crotalus viridis viridis Prairie rattlesnake United States Crotalus willardi Ridge-nosed rattlesnake United States, Mexico Sistrurus catenatus Massasauga rattlesnake United States, Mexico Sistrurus miliarius Pigmy rattlesnake United States aThis is a partial list. properties, which aid in immobilization, death, and within the prey. Low-molecular-weight polypeptides digestion of prey.2 Hyaluronidase and collagenase aid in cause capillary endothelial cell damage, which leads to spreading venom through interstitial spaces, proteases endothelial cell swelling and rupture.2 The resultant are known to lead to coagulopathies and necrosis, and gaps in the microvasculature allow third spacing of phospholipases cause cytotoxic effects that lead to both plasma and erythrocytes, leading to both edema and endothelial cell damage and resultant inflammation.9 ecchymosis2 (Figure 1). This process occurs in any cap- illary exposed to venom, including in the lungs, kid- PATHOPHYSIOLOGY neys, myocardium, peritoneum, and, occasionally, Tissue Injury central nervous system.1 Zinc-based metalloproteinases Crotalid venom increases the permeability of capil- in venom are directly involved with release of tumor lary cell membranes,1 which allows the venom to spread necrosis factor–α, which induces macrophage differen- March 2007 COMPENDIUM 168 CE Rattlesnake Envenomation tiple mechanisms. These components can be categorized as fibrinolytics, fibrinogen-clotting enzymes, procoagu- lants, anticoagulants, proteins affecting platelet function, and proteins affecting the vessel wall.10 Spontaneous bleeding rarely occurs, but significant bleeding can be induced with something as simple as a prick of a needle.11 Snakebite coagulopathy differs from other forms of coagulopathy. Standard treatments, such as transfusions, are often ineffective and even dangerous in cases of envenomation.11 Fibrinolytics, fibrinogen-clotting enzymes, and resulting defibrination—The most common mecha- nism of coagulopathy in North American crotalid envenomation is pure defibrination without dissemi- nated intravascular coagulation (DIC), which results in the depletion of fibrinogen and fibrin.7 Fibrinogen clot- ting and fibrinolytic snake venom toxins directly affect the thrombus-forming protein fibrinogen.11 Although an unstable clot may initially form, the end result is an increased bleeding tendency.11 Many types of venom (i.e., of Crotalidae and other Figure 1. Tissue effects of rattlesnake envenomation genera) contain fibrinolysins, which result in the include swelling, edema, and necrosis. destruction of fibrinogen and fibrin.7 In addition, fi- brinogen-degrading enzymes (i.e., fibrinogenases) are present in Crotalidae venom. These cause degradation tiation, neutrophil degranulation, leukocyte migration, of fibrin by both direct and indirect mechanisms.10 and the release of mediators of inflammation, such as Direct fibrinogenases do not require cofactors and interleukins. This leads to destruction of vascular base- cleave fibrinogen directly, whereas indirect mechanisms ment membranes and perivascular extracellular matri- involve converting plasminogen to plasmin, which in ces, resulting in increased vascular permeability with turn cleaves fibrinogen.10 In the natural coagulation possible hypotension, hypovolemic shock, and lactic process, thrombin hydrolyzes the bonds between fi- 1,2,7 acidosis. brinopeptides and the α and β portions of the Aα and Bβ Venom can contain myotoxin a, a component that chains of fibrinogen.12 The site of cleavage by the venom causes an increase in intracellular calcium, leading to fibrinogenases differs from the natural process, resulting necrosis of skeletal muscle.7 Increased intracellular cal- in cleavage of only one pair rather than both pairs of cium activates damaging enzymes and the troponin fibrinopeptides.10,12 Most crotalid venom cleaves fibro- complex, causing myonecrosis and prolonged contrac- protein A from fibrinogen, which results in a poorly tion of muscle fibers.7 constructed fibrin clot.7,12 One exception is Mojave rat- tlesnake (Crotalus scutulatus) venom, which appears to Cardiovascular Effects have no hemorrhagic properties.12 Most cardiovascular effects are secondary to the Fibrinogen-clotting enzymes are likely the most com- increase in vascular permeability and subsequent third mon form of procoagulant in snake venoms. These are spacing of fluids, often leading to hypotension. often known as thrombin-like enzymes because they act Hypotension can also occur secondary to fluid losses similarly to thrombin, converting fibrinogen to fi- from vomiting and hemorrhage.7 brin.10,13 Thrombin-like enzymes fail to activate factor XIII, which normally cross-links fibrin chains, resulting Coagulopathy in a friable clot.7,10 Snake venom has a complex makeup of proteins and The fibrinolysins and the thrombin-like enzymes enzymes that frequently result in coagulopathy via mul- result in depletion of fibrinogen and fibrin, decreased COMPENDIUM March 2007 Rattlesnake Envenomation CE 169 Table 2. Comparison of Disseminated Intravascular Coagulation with Coagulopathy from