CE Article #3

Rattlesnake Envenomation

Laura Najman, DVM, DACVECC Ravi Seshadri, DVM, DACVECC, DAVBP Advanced Critical Care and Internal Medicine Tustin, California

ABSTRACT: envenomation has been widely reported throughout the human and veterinary literature.The effects of 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 vaccine.

ver 120 species of 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. 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 (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 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

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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 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-

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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 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 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 . 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

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Table 2. Comparison of Disseminated Intravascular Coagulation with Coagulopathy from Crotalid Venoms Disseminated Crotalid Venom- Manifestations/Therapy Intravascular Coagulation Induced Coagulopathy Pathologic thrombin production and activity Yes No Pathologic activation of factor XIII by thrombin Yes No Thrombin production of both fibrinopeptide A and B Yes Uncommon Production of either fibrinopeptide A or B, but not both No Yes Production of cross-linked fibrin Yes Uncommon Production of fibrin degradation (split) products Yes Yes

Production of D-dimer Yes Uncommon Antithrombin depletion Yes No Thrombocytopenia Almost always Sometimes Active bleeding Common Rare Intravascular thrombosis Common Rare Heparin therapy Possibly helpful Not helpful Crotalid antivenin therapy Not helpful Helpful Reprinted from Walter FG, Fernandez MC, Haddad LM: North American venomous snakebite, in Haddad LM, Shannon MW, Winchester JF (eds): Clinical Management of Poisoning and Drug Overdose, ed 3. Philadelphia, WB Saunders, 1998, pp 333–352; with permission from Elsevier. ability to form intravascular clots, elevated fibrin degra- Anticoagulants—Anticoagulant properties in some dation products (FDPs), and prolonged clotting tests.7 snake venoms include protein C activators, phospholi- Patients develop hemorrhagic defibrination coagulopa- pases, antithromboplastic components, and FDPs. Pro- thy.11 Pure defibrination differs from true DIC in that it tein C is a vitamin K–dependent serine protease that does not cause consumption of platelets or factor VIII serves to degrade coagulation cofactors VIIIa and Va, and cannot be inhibited by heparin.12 Unlike true DIC, thus contributing to the regulation of hemostasis.10 Once coagulopathies from rattlesnake envenomation have activated, protein C acts as an anticoagulant. Protein C normal antithrombin, factor XIII, and D-dimer levels7 activators have been isolated from the copperhead (Ag- (Table 2). Also, most of the thrombin-like enzymes are kistrodon contortrix) and closely related species.13 not inhibited by thrombin inhibitors, such as anti- Phospholipases in snake venom have various func- thrombin.10 Because of these differences, treatments for tions, some of which are anticoagulant in nature. Some standard coagulopathies, such as heparin and transfu- phospholipases activate or inhibit platelet aggregation, sions, are ineffective and often harmful.11 True DIC is whereas others can bind to or hydrolyze plasma and rare in rattlesnake envenomation but can occur through platelet phospholipids, hindering their activity.10 Another activation of the coagulation cascade from vascular venom anticoagulant effect is prevention of the forma- endothelial damage caused by the venom or by proteo- tion of the prothrombinase complex (i.e., the interaction lytic enzymes and inflammatory mediators.7 of calcium, factor Xa, factor V, and prothrombin with the Other procoagulants—Some snake venoms contain platelet phospholipid matrix).10 The high level of circu- other procoagulants. Venom can activate prothrombin lating FDPs in snake venom can bind thrombin, inhibit by varying mechanisms.10 Some venom, such as that fibrin polymerization, and inhibit platelet activation, all from the Russell’s viper (Daboia russelii), activates factor of which act as effective anticoagulants.10 X; venom from some other species activates factor V. Platelet function effects—Snake venom has some

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components that cause platelet aggregation and others tration membrane.16 Crotalid venom has not been that inhibit it.10 The net effect of venom on hemostasis proven to be directly nephrotoxic. Renal failure is most is an anticoagulative state that is similar to DIC, with often reported following bites by members of the some unique properties. Viperidae group (i.e., vipers), which are not native to North America.19 Thrombocytopenia Thrombocytopenia is common after crotalid enveno- Neurotoxicity mation in both humans and dogs. The mechanism is Most neurologic clinical signs are secondary to Elapi- not entirely understood, but in most cases, thrombocy- dae envenomation, but neurologic signs have also been topenia resolves in 72 hours, although it can last longer observed secondary to envenomation by the Mojave rat- in some patients.14 Proposed mechanisms that may act tlesnake (C. scutulatus), which is found throughout the in combination include7: American Southwest.7 Geographic differences exist in the potency of neurotoxin delivered by envenomation • Phospholipases may damage platelet membranes, within the same species.3 Clinical signs include weak- triggering their destruction. ness and paralysis secondary to noncompetitive calcium • The venom may initiate platelet aggregation. channel blockade in presynaptic neurons that prevents • Platelets may be consumed at the sites of envenoma- the release of acetylcholine at the motor endplate.7 tion and associated inflammation. DIAGNOSIS Thrombocytopenia often improves after antivenin The diagnosis of rattlesnake envenomation is often administration. It is important to note that thrombocy- based on both history (i.e., location of the attack and topenia induced by venom components should not be time of day) and clinical signs. Most puncture wounds interpreted as a sign that DIC is present. Active bleed- are found on the head and neck or, less frequently, on an ing rarely results from thrombocytopenia and coagu- extremity.20 Toxicity depends on the species of snake, its lopathy associated with envenomation. size and health, the venom volume injected, the depth of the bite, and the size of the victim.21 If there has been Renal Failure little or no envenomation, clinical signs will consist of Acute renal failure occasionally occurs secondary to minimal swelling and a lack of systemic signs.22 With rattlesnake envenomation, and causes can be multifactor- moderate to severe envenomation, immediate and pro- ial.15 The pathogenesis of renal lesions includes hypoten- gressive swelling and pain are noted.21 Local signs usu-

The rate of wound infection associated with rattlesnake envenomation is surprisingly low. sion, circulatory collapse, intravascular hemolysis with ally start within 30 to 60 minutes after envenomation.1 resultant hemoglobinuria, myoglobinuria, toxic Ecchymosis at the site of the bite occurs within 6 nephropathy, and DIC (infrequently).15,16 hours.23 These signs are often followed by tissue necro- Myoglobin is released from damaged muscle and fil- sis. Systemic signs reported include lethargy, weakness, tered by the renal glomeruli. Both myoglobin and hypotension, hyperthermia, arrhythmias (e.g., ventricu- hemoglobin can dissociate into a nephrotoxic compo- lar tachycardia, ventricular premature contractions, ven- nent, ferrihemate, at a urine pH of less than 5.6.16,17 tricular fibrillation), ataxia, bleeding, vomiting, diarrhea, Renal histologic changes include epithelial degeneration respiratory distress, and shock.9,22,23 In humans, three and necrosis, basement membrane disruption, heme systems are used to measure the degree of envenomation casts, interstitial edema, and leukocyte infiltration.16,18 and progression2: Hemoglobin released via intravascular hemolysis from envenomation can result in similar histologic changes, • The minimal–moderate–severe scoring method with the addition of possible development of fibrin • The grade 0 through IV scoring method strands adhering to and thickening the glomerular fil- • The snakebite severity score

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Figure 2. Echinocytosis on a blood smear following Figure 3. Rattlesnake puncture and associated rattlesnake envenomation. secondary tissue injury.

To date, there is no established method in veterinary signs of immune-mediated hemolytic anemia.25 Purified medicine to measure the degree of envenomation. phospholipase A2, a calcium-dependent component of Laboratory abnormalities following envenomation both Crotalidae and Elapidae venom, has induced include echinocytosis, thrombocytopenia, anemia or mild echinocytosis and hemolysis in vitro and is thought to hemoconcentration, hypofibrinogenemia, elevated fibrin be the component in venom responsible for these split products, leukocytosis, and prolonged clotting changes in vivo.25 The mechanism involves incorpora- times.9,20,22 Serial blood testing should be conducted tion of lysolecithin in the outer erythrocyte membrane, because the onset of coagulopathies can often be delayed. leading to expansions and morphologic changes consis- Chemistry profile changes that occur with rattlesnake tent with echinocytosis and spherocytosis.25 Two envenomation include azotemia, hypoalbuminemia, studies20,26 have reported the frequency of echinocytosis hypoproteinemia, and elevated levels of creatinine kinase, in snake envenomation to be 89% to 92% in dogs. alkaline phosphatase, alanine transaminase, γ-glutamyl transferase, and aspartate transaminase.24 TREATMENT Echinocytosis has been associated with rattlesnake The mortality rate of rattlesnake envenomation in envenomation in humans, cats, and dogs and can be dogs has reportedly been as low as 3.7% with used to aid in the diagnosis.25 Echinocytes are erythro- treatment.27 The treatment should initially focus on sta- cytes with uniform, regularly spaced membrane projec- bilization of systemic signs and antivenin administra- tions25 (Figure 2). Echinocyte formation is thought to tion, as needed. A complete physical examination be caused directly by the venom itself, is dose depen- should be performed after standard airway–breathing– dent, and is self limiting; morphologic changes resolve circulation assessment and therapeutic intervention. A within 48 hours.25,26 urinalysis and the following baseline blood work should In one study,25 canine blood was mixed in vitro with be conducted: a complete blood count with a direct western diamondback rattlesnake venom. The degree of smear for erythrocyte morphologic analysis and a man- echinocyte formation was proven to be dose dependent, ual in-house platelet count, a chemistry profile, activated with the lowest doses producing types I and II clotting time, prothrombin time, partial thromboplastin echinocytes and the highest doses producing type III time, fibrinogen level, D-dimers, electrolyte levels, and echinocytes, spheroechinocytes, and spherocytes.25 blood gas analysis. An electrocardiogram should be Hemolysis was noted in all samples.25 Spherocytosis and obtained, and thoracic radiography is indicated after the hemolysis noted after envenomation should be inter- patient has been adequately stabilized. preted as signs of severe envenomation rather than as The area of the puncture should be gently clipped to

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remove fur, lightly cleaned with antiseptic solution, and blood products while unneutralized venom is circulat- kept dry (Figure 3). The circumference of the swelling ing.1 Providing coagulation factors and blood products should be measured and recorded every 15 minutes to adds substrate for unneutralized venom, which leads to help determine progression and requirements for increased FDPs.1,2,11 Current recommendations empha- antivenin administration.1 If the wound progresses and size neutralization of venom with antivenin.1 local necrosis occurs, the affected area should be treated like an open wound until a healthy granulation bed Antivenin forms.1 Surgical debridement may be needed for Antivenin administration is recommended for wors- necrotic tissue after several days.1 In people, if a punc- ening local injury (i.e., ecchymosis, pain, swelling), clini- ture is present with no local or systemic signs, at least 12 cally significant coagulopathy, or systemic signs (e.g., hours of hospitalized observation is recommended.3 hypotension).1,29 The production of antivenin, which began in 1954, contributed to a decrease in human mor- Fluid Therapy tality from 25% in the 19th century to less than 0.5% by Because of increased vascular permeability and subse- 2002.1 Antivenin should ideally be administered within quent third spacing, vomiting, and hemorrhage, many the first 4 hours after envenomation. The benefits of affected patients present with hypovolemia and in antivenin decrease if administration is delayed, but shock. Intravenous fluids should be administered at antivenin can still have clinically positive effects for up presentation. Administration of either crystalloids or a to 24 hours after envenomation.22 When administered combination of crystalloids and colloids should be con- early, antivenin binds to the venom itself, subsequently sidered. Clinical parameters, such as mucous membrane neutralizing it, reversing some clinical manifestations of color and capillary refill time, pulse quality, blood pres- envenomation, and preventing further progression.1 sure, degree of lactic acidosis, and urine output, can all Unfortunately, local tissue necrosis cannot be stopped by be used to help guide fluid therapy. antivenin administration.7 Within 20 minutes of enven- Few studies critically evaluate types of intravenous omation, an irreversible inflammatory cascade begins, fluid therapy for snake envenomation. Previously, con- leading to tissue necrosis.7

Coagulopathy induced by rattlesnake envenomation differs from DIC and should be treated by neutralizing the venom with antivenin. cern existed that colloids may worsen coagulopathy Two antivenins are currently available to treat ven- associated with snake envenomation.16 In one study,28 omous snakebites within the United States. Antivenin dextran 40 increased coagulopathy associated with snake (Crotalidae) Polyvalent (ACP; Fort Dodge Animal envenomation in rodents. However, this study did not Health) for animals is reportedly the same as the ACP model most clinical envenomations because the venom produced by Wyeth Laboratories for humans.22 This was injected intravenously, which rarely occurs clinically, antivenin can neutralize venom from all North, Central, and no antivenin was administered. Both of these fac- and South American crotalids.2 ACP is produced by tors limit the application of these findings. With the obtaining serum globulins from equids immunized with known endothelial damage and the subsequent perme- venoms from eastern and western diamondback rat- ability defects to capillary membranes, colloids appear to tlesnakes, Central and South American rattlesnakes, and be beneficial in maintaining vascular volume and colloid the fer-de-lance.30 This antivenin is often ineffective in oncotic pressure. treating venom-induced neurotoxicity.31 In the past, blood and blood products were recom- A second, newer antivenin was recently introduced: mended to correct coagulopathy associated with rat- Crotalidae polyvalent immune Fab (ovine; CroFab, tlesnake envenomation, but this has fallen out of favor. FabAV, Protherics, Nashville, TN) is licensed for use in Coagulopathy associated with rattlesnake envenomation humans.32 It is an ovine-derived antivenin that is pro- is consumptive and unresponsive to either heparin or duced when sheep are inoculated with venom from

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western and eastern diamondback rattlesnakes, Mojave tions, proteins directly activate the complement cascade rattlesnake, and cottonmouth, but it can neutralize and mast cell degranulation rather than indirectly medi- venom from many more species.33 It is considered five ate them through IgE.2 Clinical signs of both anaphylac- times more potent than ACP1 and appears to be effec- tic and anaphylactoid reactions include fever, urticaria, tive in treating crotalid-induced neurotoxicity.31 Instead pruritus, bradycardia, hypotension, and respiratory dis- 2 of containing the entire IgG molecule, it is pure Fab tress. Pretreatment with both H1 (i.e., diphenhydramine) 32 immunoglobulin and less than 3% of the Fc fragment. and H2 blockers has been recommended before antivenin It has a more rapid reconstitution and thus can be administration.3 There have been no controlled human administered earlier to patients.33 The smaller size of the trials to establish the efficacy of pretreatment.1 Once ana- Fab molecule allows it to be renally excreted and thus phylactic and anaphylactoid reactions occur, they can be have a more rapid elimination than does ACP.34 The treated with histamine blockers, systemic corticosteroids, half-life of FabAV in humans is less than 12 hours, epinephrine, and slowed or discontinued administration while the half-life of ACP is 61 to 194 hours.35 The of the antivenin, if indicated. faster half-life of the Fab antivenin allows the effects of Skin testing has been recommended before antivenin

A recently introduced antivenin decreases both anaphylaxis and serum sickness. Because of its short half-life, however, it needs to be redosed often and may not be feasible for use in animals. unneutralized venom to recur. Recurrent coagulopathy administration to help predict which patients are predis- and local tissue effects have been documented in posed to immediate hypersensitivity reactions. This has patients who received the Fab antivenin after enveno- been controversial for many reasons. Both false-positive mation. This has led to recommendations for repeated and false-negative skin testing results occur.38 False-neg- dosing for at least 18 hours, if not longer.36 Therefore, ative rates have reportedly been as high as 10% to 36%, Fab antivenin has not been financially justifiable in ani- and false-positive rates have reportedly been 33%.3 Skin mals at this time. Fab antivenin is more effective than testing also delays antivenin administration. ACP, with fewer cases of both anaphylaxis and serum Delayed hypersensitivity or serum sickness secondary sickness because it does not contain the immuno- to ACP has been extensively documented in the human globulin portion that binds to complement.33 literature and recently documented in the veterinary lit- ACP is an equine-derived product and is reportedly erature. Serum sickness is an immunocomplex disease in highly allergenic, with acute signs in humans reportedly which large foreign proteins stimulate the production of as high as 20%.37 Anaphylactic reactions (i.e., type I antibody and T-cell reponses.27 Clinical signs (e.g., hypersensitivity), anaphylactoid reactions, and delayed urticaria, arthralgia, myalgia, fever, malaise, lym- hypersensitivity or serum sickness (i.e., type III hyper- phadenopathy, and occasionally vasculitis, glomeru- sensitivity) are potential side effects.2 Anaphylactic and lonephritis, and neuritis) usually occur 3 days to 3 weeks anaphylactoid reactions appear identical clinically but dif- after antivenin administration in humans.2 The clinical fer in their pathogeneses.2 Both result in the binding of signs commonly have an average onset of 1 week after complement fragments (i.e., C3a, C5a) to mast cells and administration.2 Serum sickness is self-limiting, and basophils, resulting in the release of histamine, heparin, treatment involves administering a combination of anti- serotonin, prostaglandins, leukotrienes, platelet-activating histamines and glucocorticoids.27 Plasmapheresis has factor, eosinophil chemotactic factor, and other media- been used in the most severe cases.27 tors. Anaphylactic reactions are type I hypersensitivity It is thought that serum sickness secondary to reactions mediated by IgE, with circulating antigen bind- antivenin administration is uncommon in animals ing to Fc receptors on mast cells and basophils, whereas because antivenin is administered less frequently and in anaphylactoid reactions do not involve the IgE molecule smaller overall doses to animals compared with admin- and are rate and dose dependent.2 In anaphylactoid reac- istration in humans. A case of canine serum sickness

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was recently documented in the veterinary literature.27 erature that normalization of coagulation parameters Clinical signs, including fever, anorexia, lethargy, vom- with antivenin administration does not always occur, but iting, and pitting edema, were described in a boxer 3 a trend toward normalization should be considered the days after treatment with ACP.27 The clinical signs end point of treatment. resolved with H1- and H2-blocker and corticosteroid administration.27 Antibiotics Administration of systemic antibiotics following ACP Administration envenomation has traditionally been advocated in the Antivenin should be reconstituted as directed with veterinary literature. The bacteria most commonly iso- diluent or sterile water if significant clinical signs are lated from crotalid mouths include Pseudomonas aerugi- present following envenomation. It should be adminis- nosa, Proteus spp, coagulase-negative Staphylococcus spp, tered as soon as possible, ideally within the first 4 hours Clostridium spp, and Bacteroides fragilis.9 Previous after envenomation. The patient should be closely human studies recommending antibiotics were based on monitored for urticaria or other signs of allergic reac- studies on the oral flora from snakes rather than the tion. The suggested dose is 10 to 50 ml (i.e., one to five incidence of wound infection.2 Although no veterinary vials) IV, depending on the severity of clinical signs, research is available on this topic, multiple, prospective, time since the bite, size of the bite, and size of the controlled human trials have shown no statistically sig- patient.30 Additional doses can be given every 2 hours, nificant difference in the number of wound infections

Although administration of antibiotics may be unnecessary in snake envenomation, these drugs should still be considered until further veterinary data are available. as needed. According to the Fort Dodge package insert following snake envenomation between patients who recommendations, smaller patients may require rela- received antibiotics and those who did not.39–42 In fact, tively higher doses. This recommendation is not sup- the incidence of secondary wound infection was quite ported in the human literature. Although the low in patients who did not receive antibiotics.40 It is milligram-per-kilogram dose of venom administered is unknown whether data from the human literature apply higher in smaller patients, the overall molar dose of across species. There is some evidence that venom has venom is the same regardless of the patient’s size. antibacterial properties.39 It may also be easier to keep Antivenin is generally dosed to reverse the total molar the wound clean in humans compared with animals. amount of venom injected. The doses recommended for Therefore, although administration of antibiotics may smaller pediatric patients are the same as those recom- be unnecessary in snake envenomation, these drugs mended for adults, based on clinical signs and severity should still be considered until further veterinary data score rather than weight or size.2,7 With humans, it is are available. not uncommon to administer at least 10 to 20 vials of antivenin. Opioids Dosing in animals is more difficult and is often based Opioid therapy is recommended for the pain associ- on clinical signs and monitoring of coagulation status. ated with snakebite. To avoid masking effects and allow Serial physical examinations and measuring of tissue accurate assessment of the patient’s neurologic status, it swelling every 15 to 30 minutes should be performed to is recommended that opioids be withheld when neuro- determine whether swelling continues after antivenin logic signs are present.1 administration. If local swelling continues to worsen, administration of another vial of antivenin should be Other Therapies considered. Administration of additional antivenin Corticosteroids were previously used to treat snake- should also be considered for persistent, clinically signif- bites and were considered the standard of care.7 Cur- icant coagulopathy. It has been noted in the human lit- rent human studies have failed to document any

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benefits of corticosteroid administration in treating REFERENCES snakebites, other than for anaphylactic reactions and 1. Gold B, Dart R, Barish R: Bites of venomous snakes. N Engl J Med 347(5): 347–356, 2002. serum sickness secondary to antivenin administra- 2. Walter FG, Bilden EF, Gilby RL: Envenomations. 15(2): 7,23 Crit Care Clin tion. In the human literature, corticosteroids are not 353–386, ix, 1999. routinely administered to snakebite patients, and the 3. Juckett G, Hancox J: Venomous snakebites in the United States: Manage- use of these drugs in veterinary snakebite patients ment review and update. Am Fam Phys 66(1):30, 2002. 4. Gold BS, Wingert WA: Snake venom poisoning in the United States: A should be questioned. review of therapeutic practice. South Med J 87(6):579–589, 1994. Compartment syndrome has previously been 5. Chrisman CL, Hopkins AL, Ford SL, et al: Acute, flaccid quadriplegia in described in the human literature secondary to myone- three cats with suspected coral snake envenomation. JAAHA 32(4):343–349, crosis from envenomation.1 Although surgical inter- 1996. 6. Marks SL, Manella C, Schaer M: Coral snake envenomation in the dog: vention was previously performed, it has been Report of four cases and review of the literature. JAAHA 26:629–634, 1990. determined that most affected patients respond to fur- 7. Holstege CP, Miller MB, Wermuth M, et al: Crotalid snake envenomation. ther antivenin treatment alone, and fasciotomy is rarely Crit Care Clin 13(4):889–921, 1997. necessary.1–3,7 8. Young BA, Zahn K: Venom flow in rattlesnakes: Mechanics and metering. J Exp Biol 204(Pt 24):4345–4351, 2001. 9. Willey JR, Schaer M: Eastern diamondback rattlesnake envenomation of PREVENTION dogs: 31 cases. JAAHA 41:22–33, 2005. A C. atrox toxoid rattlesnake vaccine (Red Rock Bio- 10. Hutton RA, Warrell DA: Action of snake venom components on the haemo- logics) intended for prophylaxis against the effects of static system. Blood Rev 7(3):176–189, 1993. 11. White J: Snake venoms and coagulopathy. Toxicon 45(8):951–967, 2005. rattlesnake envenomation by the western diamondback 12. Hudelson S, Hudelson P: Pathophysiology of snake envenomation and evalu- 43 rattlesnake is available. The vaccine produces antibod- ation of treatments, part I. Compend Contin Educ Pract Vet 17(7):889–897, ies that are thought to cross-protect against the venom 1995. of many other rattlesnake species.43 The theory behind 13. Meier J, Stocker K: Effects of snake venoms on hemostasis. Crit Rev Toxicol 21(3):171–182, 1991. the vaccination is that it elicits production of IgG, 14. Odeleye AA, Presley AE, Passwater ME, et al: Report of two cases: Rat- which would then neutralize the venom following tlesnake venom-induced thrombocytopenia. Ann Clin Lab Sci 34(4):467–470, envenomation, leading to slowed systemic venom 2004. 15. Karthik S, Phadke KD: Snakebite-induced acute renal failure. Pediatr Nephrol absorption and subsequent lessening of clinical signs. In 19(9):1053–1054, 2004. the company’s murine trials, a higher dose of venom was 16. Hudelson S, Hudelson P: Pathophysiology of snake envenomation and evalu- required to kill vaccinated mice than those that were ation of treatments, part II. Compend Contin Educ Pract Vet 17(8):1035–1041, unvaccinated.44 No peer-reviewed canine studies on the 1995. 17. Anderson WAD, Morrison DB, Williams Jr EF: Pathologic changes follow- efficacy of this vaccine have been published, and its ben- ing injections of ferriheme (hematin) in dogs. Arch Pathol 33:589–602, 1942. efits have not been documented in veterinary medicine 18. Azevedo-Marques MN, Cupo P, Coimbra TN, et al: Myonecrosis, myoglo- at this time. Further studies are needed before the vac- binuria and acute renal failure induced by South American rattlesnake enven- omization in Brazil. Toxicon 23(4):631–636, 1985. cine can be deemed beneficial. 19. Mittal BV: Acute renal failure following poisonous snake bite. J Postgrad Med 40(3):123–126, 1994. CONCLUSION 20. Hackett TB, Wingfield WE, Mazzaferro EM, et al: Clinical findings associ- Rattlesnakes are responsible for most North Ameri- ated with prairie rattlesnake bites in dogs: 100 cases. JAVMA 220(11): 1675–1680, 2002. can snake envenomations. Venom contents vary widely 21. Harned H, Oehme FW: Poisonous snakebites in dogs and cats. Vet Med among snake species and across geographic distribution Small Anim Clin 77(1):73–78, 1982. among snakes of the same species. Mortality rates sec- 22. Mansfield PD: The management of snake venom poisoning in dogs. Com- ondary to rattlesnake envenomation are low as long as pend Contin Educ Pract Vet 6(11):988–995, 1984. 23. Russel FE: Snake venom poisoning in the United States. Annu Rev Med timely treatment is received. The mainstays of treatment 31:247–259, 1980. are fluid therapy and antivenin administration. A new, 24. de Sousa-e-Silva M, Tomy S, Tavares F, et al: Hematological, hemostatic, and more effective antivenin is available that has fewer side clinical chemistry disturbances induced by Crotalus durissus terrificus snake venom in dogs. Hum Exp Toxicol 22(9):491–500, 2003. effects in humans. Because of its short half-life, this 25. Walton RM, Brown DE, Hamar DW, et al: Mechanisms of echinocytosis antivenin requires redosing up to at least 18 hours, induced by Crotalus atrox venom. Vet Pathol 34:442–449, 1997. which may limit its use in animals because of cost. 26. Brown DE, Meyer DJ, Wingfield WE, et al: Echinocytosis associated with However, this antivenin should be considered in treating rattlesnake envenomation in dogs. Vet Pathol 31:654–657, 1994. 27. Berdoulay P, Schaer M, Starr J: Serum sickness in a dog associated with known Mojave rattlesnake envenomation because it can antivenin therapy for snake bite caused by Crotalus adamanteus. J Vet Emerg reverse the neurologic effects. Crit Care 15(3):206–212, 2005.

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28. Schaeffer RC, Carlson RW, Puri VK, et al: The effects of colloidal and crys- 36. Boyer LV, Seifert SA, Cain JS: Recurrence phenomena after immunoglobulin talloid fluids on rattlesnake venom shock in the rat. J Pharmacol Exp Ther therapy for snake envenomations: Part 2. Guidelines for clinical management 206(3):687–695, 1978. with crotaline Fab antivenom. Ann Emerg Med 37(2):196–201, 2001. 29. Dart RC, McNally J: Efficacy, safety, and use of snake antivenoms in the 37. Offerman SR, Smith TS, Derlet RW, et al: Does aggressive use of polyvalent United States. Ann Emerg Med 37(2):181–188, 2001. antivenin for rattlesnake bites result in serious acute side effects? West J Med 175(2):88–91, 2001. 30. Antivenin (Crotalidae) Polyvalent package insert, Fort Dodge. 38. Heard K, O’Malley GF, Dart RC: Antivenom therapy in the Americas. 31. Clark RF, Williams SR, Nordt SP, et al: Successful treatment of crotalid- Drugs 58(1):5–15, 1999. induced neurotoxicity with new polyspecific crotalid Fab antivenin. Ann 39. Kerrigan KR, Mertz BL, Nelson SJ, et al: Antibiotic prophylaxis for pit viper Emerg Med 30(1):54–57, 1997. envenomation: Prospective, controlled trial. World J Surg 21(4):369–373, 32. Ruha A, Curry SC, Beuhler M: Initial postmarketing experience with Cro- 1997. talidae polyvalent immune Fab for treatment of rattlesnake envenomation. 40. Clark RF, Selden BS, Furbee B: The incidence of wound infection following Ann Emerg Med 39(6):609–615, 2002. crotalid envenomation. J Emerg Med 11(5):583–586, 1993. 33. Gwaltney-Brant SM, Rumbeiha WK: Newer antidotal therapies. Vet Clin 41. Tagwireyi DD, Ball DE, Nhachi CF: Routine antibiotic use in the manage- North Am Small Anim Pract 32(2):323–339, 2002. ment of snakebite. BMB Clin Pharmacol 1:4, 2001. 34. Seifert SA, Boyer LV: Recurrence phenomena after immunoglobulin therapy 42. Terry P, Mackway-Jones K: The use of antibiotics in venomous snake bite. for snake envenomations: Part 1. Pharmacokinetics and pharmacodynamics Emerg Med J 19:48–49, 2002. of immunoglobulin antivenoms and related antibodies. Ann Emerg Med 43. Crotalus atrox toxoid (rattlesnake vaccine) product information, Red Rock 37(2):189–195, 2001. Biologics. 35. Boyer LV, Seifert SA, Clark RF, et al: Recurrent and persistent coagulopathy 44. Wallis DM, Wallis JL: Rattlesnake vaccine to prevent envenomation toxicity following pit viper envenomation. Arch Intern Med 159(7):706–710, 1999. in dogs [abstract]. Western Veterinary Conference, 2005.

ARTICLE #3 CE TEST This article qualifies for 2 contact hours of continuing education credit from the Auburn University College of Veterinary CE Medicine. Subscribers may purchase individual CE tests or sign up for our annual CE program. Those who wish to apply this credit to fulfill state relicensure requirements should consult their respective state authorities regarding the applicability of this program. CE subscribers can take CE tests online and get real-time scores at CompendiumVet.com.

1. What percentage of snakebites is considered dry 5. Which statement regarding ACP is incorrect? bites with no envenomation? a. It can be used to treat envenomation by many differ- a. 10% ent rattlesnake species. b. 20% to 35% b. It has renal clearance and a short half-life. c. 50% c. It is associated with a higher rate of anaphylaxis and d. 65% serum sickness than is the Fab antivenin. d. It is ideally administered within 4 hours of envenoma- 2. Coagulopathy from snake envenomation and tion. DIC are alike in that they both a. frequently cause massive hemorrhage. 6. Which statement regarding serum sickness is b. activate factor XIII. correct? c. cause elevated FDPs. a. It has recently been reported in a dog. d. cause antithrombin depletion. b. It is a type III hypersensitivity reaction. c. It usually occurs 1 week after antivenin administra- 3. Coagulopathy from rattlesnake envenomation tion but can occur 3 days to 3 weeks after. should be treated with d. all of the above a. fresh-frozen plasma, as needed. b. antivenin. c. heparin. 7. Prophylactic antibiotics for rattlesnake evenoma- d. all of the above tion are not usually administered to humans because 4. Which was found to induce echinocyte forma- a. rattlesnakes have minimal natural flora in their oral tion on canine blood in vitro? cavity. a. collagenase b. the rate of wound infection is low. b. myotoxin a c. these drugs have not been proven to prevent infec-

c. phospholipase A2 tion. d. zinc-based metalloproteinases d. b and c

COMPENDIUM March 2007 Rattlesnake Envenomation CE 177

8. Which statement regarding the C. atrox toxoid b. They can be treated with diphenhydramine, cortico- rattlesnake vaccine is correct? steroids, and epinephrine, if needed. a. It is intended to provide protection against many c. They can be life threatening. species of rattlesnakes. d. It can be almost impossible to tell them apart. b. Administration of it induces IgG production. 10. Which statement regarding skin testing before c. A higher dose of venom was needed to induce death antivenin administration is correct? in mice that were vaccinated compared with those a. Skin testing accurately predicts which patients will that were not. react to antivenin administration. d. all of the above b. Skin testing does not delay antivenin administration. c. Both false-positive and false-negative results are 9. Which statement about anaphylactic and ana- reported. phylactoid reactions is incorrect? d. The antivenin manufacturer does not recommend a. They both cause reactions directly mediated by IgE. skin testing before antivenin administration.

March 2007 COMPENDIUM