Snake Bite: Pit Vipers

Home , Crotalus, Crotalus vegrandis, Insect bites and stings, Pit viper

Michael E. Peterson, DVM, MS

Pit vipers are the largest group of venomous snakes in the United States and are involved in an estimated 150,000 bites annually of dogs and cats. The severity of any pit viper bite is related to the volume and toxicity of the venom injected as well as the location of the bite, which may influence the rate of venom uptake. The toxicity of rattlesnake venom varies widely. It is possible for pit vipers’ venom to be strictly neurotoxic with virtually no local signs of envenomation. Venom consists of 90% water and has a minimum of 10 enzymes and 3 to 12 nonenzymatic proteins and peptides in any individual snake. The onset of clinical signs after envenomation may be delayed for several hours. The presence of fang marks does not indicate that envenomation has occurred, only that a bite has taken place. Systemic clinical manifestations encompass a wide variety of problems including pain, weakness, dizziness, nausea, severe hypotension, and thrombocytopenia. The victim’s clotting abnormalities largely depend upon the species of snake involved. Venom induced thrombocytopenia occurs in approximately 30% of envenomations. Many first aid measures have been advocated for pit viper bite victims, none has been shown to prevent morbidity or mortality. Current recommendations for first aid in the field are to keep the victim calm, keep the bite site below heart level if possible, and transport the victim to a veterinary medical facility for primary medical intervention. The patient should be hospitalized and monitored closely for a minimum of 8 hours for the onset of signs of envenomation. The only proven specific therapy against pit viper envenomation is the administration of antivenin. The dosage of antivenin needed is calculated relative to the amount of venom injected, the body mass of the victim, and the bite site. The average dosage in dogs and cats is 1 to 2 vials of antivenin. Clin Tech Small Anim Pract 21:174-182 © 2006 Elsevier Inc. All rights reserved.

KEYWORDS rattlesnake, copperhead, water moccasin, pit viper, envenomation, snake bite, antivenin

wo families of poisonous snakes, the Elapidae and Cro- scales distal to the anal plate, and triangular shaped heads Ttalidae, indigenous to the United States. The Crotalids (Fig. 1).Crotalus and Sistrurus genera (the rattlesnakes) have are represented by the pit vipers. Every state except Maine, special keratin rattles on the ends of their tails, with the Alaska, and Hawaii is home to at least one species of venom- exception of one subspecies (C. catalinensis). Agkistrodon spe- ous snake. cies (the copperheads and water moccasins) are found Pit vipers are the largest group of venomous snakes in the throughout the eastern and central United States. Copper- United States and are involved in an estimated 150,000 bites heads are responsible for the majority of venomous snake annually of dogs and1 Approximatelycats. 99% of all venom-bites in North America because of their habit of living next to ous snake bites in the United States are inflicted by pit vipers. human habitation. Water moccasins can be pugnacious and In North America members of the family Crotalidae belong to have a greater tendency to deliver venom when they bite. three genera: the rattlesnakes (Crotalus and Sistrurus spp.) Rattlesnakes (Crotalus spp., Sistrurus spp.) are found and the copperheads and cottonmouth water moccasins throughout the continental United States and account for the (Agkistrodon spp.). majority of snake bite fatalities. Clinicians should become Pit vipers can be identified by their characteristic retract- familiar with their regional indigenous poisonous snake spe- able front fangs, bilateral heat sensing “pits” between the cies. nostrils and eyes, elliptical pupils, a single row of subcaudal Ninety percent of venomous snake bites occur during the months of April through October. Two-thirds of the bites are inflicted by snakes less than 20 inches in length. These snakes Reid Veterinary Hospital, Albany, OR. can strike approximately one-half of their body length at a Address reprint requests to Michael E. Peterson, DVM, MS, Reid Veterinary Hospital, 933 SW Queen Avenue, Albany, OR 97321. E-mail: speed of 8 feet per second. The heat-sensing pit located be- [email protected] tween the eye and the nostril can differentiate a temperature

Table 2 Examples of Enzymes From Pit Viper Venoms Arginine ester hydrolase Phosphodiesterase Proteolytic enzymes Acetylcholinesterase Thrombinlike enzyme RNAse Collagenase DNAse Hyaluronidase 5’-Nucleotidase Phospholipase A2 NAD-nucleotidase Phospholipase B Lactate dehydrogenase Phosphomonoesterase L-amino acid oxidase

liver a controlled amount of venom into the victim, and agonal bites deliver the entire venom load and are therefore the most dangerous.

Toxic Dose The severity of any pit viper bite is related to the volume and toxicity of the venom injected as well as to the location of the bite, which may influence the rate of venom uptake. Gener- ally, the toxicity of pit viper venoms ranges in descending order from the rattlesnakes to the water moccasins and then to the copperheads (Table 1). The toxicity of rattlesnake venom varies widely. Nine species and 12 subspecies of rat- Figure 1 Pit viper skull retractable front fangs. Note secondary and tlesnakes have populations with venoms containing proteins tertiary fangs. Courtesy of the Arizona Desert Museum, Tucson, AZ. that are immunologically similar to mojave toxin, a potent (Color version of figure is available online.) neurotoxin. It is possible for pit viper venom to be strictly neurotoxic with virtually no local signs of envenomation. Examples of these venom types can be found in certain sub- gradient of 0.003°C at a distance of 14 inches. Rattlesnakes populations of rattlesnakes: Mojave rattlesnakes (C. scutula- do not always rattle before striking. A decapitated snake head tus), canebrake rattlesnakes (C. horridus atricaudatus), and can bite reflexively for up to an hour after decapitation. tiger rattlesnakesC. ( tigris).3-5 The venom is not more toxic in the summer months; however, snakes show increased aggression and venom yield with environmental warming and increased photoperiod (as in the Toxicokinetics spring and summer).2 The maximum venom yields occur It may take weeks for all venom fractions to be cleared by the during the hottest months of summer. body. Because of the complexity of the venom, the victim’s Pit vipers control the amount of venom they inject depend- metabolic response to the venom components varies with the ing on the snake’s perception of the situation. Initial defen- species of snake, the volume of venom injected, and the sive strikes are often nonenvenomating. Offensive bites de- species of the bite recipient.

Table 1 Venom Yields of North American Snakes Mechanism of Toxicity Dry Weight LD50 IV The primary purpose of the venom is not to kill but rather to Snake Species (mg venom) (mice) immobilize the prey and predigest its tissues. The venom is Eastern diamondback 200-850 1.68 derived from modified salivary glands. Pit viper venoms are a (Crotalus complex combination of enzymatic and nonenzymatic pro- adamanteus) teins (Table 2). Venom consists of 90% water and has a Western 175-800 2.18 minimum of 10 enzymes and 3 to 12 nonenzymatic proteins diamondback and peptides in any individual snake. The nonenzymatic (Crotalus atrox) Mojave rattlesnake 75-150 0.23 components, called the “killing fraction,” have a median le- (Crotalus thal dose (LD50) over 50 times smaller than that of the crude scutulatus) venom. Eastern coral 2-20 0.28 Over 60 purified polypeptides have been identified in cro- (Micrurus fulvius) talid venoms. Approximately 50 enzymatic crotalid venom Copperhead 40-75 10.92 fractions have been characterized. Proteolytic-trypsin like en- (Agkistrodon zymes, which are catalyzed by metals (eg, calcium, magne- contortrix) sium, zinc), are common constituents of pit viper venom and Cottonmouth 90-170 4.19 cause marked tissue destruction. Arginine ester hydrolase is a (Agkistrodon bradykinin-releasing agent that may adversely affect clotting piscivorus) activity. Thrombin like enzymes also can mediate increased 176 M.E. Peterson

Table 3 Common Signs of Envenomation Table 4 Variables Affecting the Severity of Envenomation Pain Sloughing tissue Victim Snake Swelling Shock Body mass Species Ecchymosis Puncture(s) Bite location Size Weakness Nausea Time to medical facility Age of snake Type of first aid applied Motivation for bite Concurrent medications Time since last venom use clotting activity. The eastern diamondback rattlesnake (C. (nonsteroidal anti-inflammatory Time of year adamanteus) venom enzyme protease H induces systemic drugs, etc.) hemorrhage.6 Five proteolytic toxins from western -diamond back rattlesnake (C. atrox) venom induce hemorrhage by cleaving laminin and the basement membrane 7,8at band A. Crotavirin, found in prairie rattlesnake (C. viridis viridis) also be present and is responsible for hydrolyzing lysophos- venom, is a potent platelet aggregation inhibitor and prevents phatides. The phosphodiesterases, such as diester phospho- platelet-collagen interaction by binding to collagen fibers. hydrolase, breaks free the 5-mononucleotide, thereby attack- Interference with the platelet-collagen interaction has the net ing DNA and RNA and derivatives of arabinose. effect of blocking collagen-mediated platelet functions such L-amino acid oxidase catalyzes oxidation of L-alpha-amino as adhesion, release reaction, thromboxane formation, and and alpha-hydroxy acids. This is the most active of the aggregation.9 The predominant mechanism of afibrinogene- known amino acid oxidases and has been found in all pit mia seen in a patient after western diamondback rattlesnake viper venoms studied; it is responsible for the yellow color of (C. atrox) envenomation is a reflection of fibrinogenolysis the venom. NAD-nucleotidase is found in Agkistrodon but not and not a primary consumptive coagulopathy. The fibrinog- Crotalus venom. The enzyme catalyzes hydrolysis of nicotin- enolysis results from indirect activation of plasminogen by amide N-ribosidic linkages of NAD, forming adenosine vascular plasminogen activator.10 Zinc metalloproteinase diphosphate riboside and nicotinamide. Other enzymes that with fibrinolytic activity has been isolated from the venom of are possibly present in viper venom include RNAse, DNAse, copperheads (Agkistrodon contortrix) and is called fibrolase. 5=-nucleotidase, and lactate dehydrogenase. Direct cardio- Age induced differences in venom within a species of the toxic effects of venom proteins have been exhibited in some snake are highlighted by a study of northern Pacific rattle- pit viper venoms, particularly the diamondback rattlesnakes. snakes (C. viridis organus) in which the adult venoms were The envenomation syndrome reflects the complexity of the shown to have approximately fivefold higher fibrinogenolytic venom. The victim’s body has to respond to the effects of protease activity. Two protease bands were identified in ju- multiple venom fractions, metabolize each, and deal with the venile and subadult snakes, and four bands were identified in resultant myriad of metabolites. In addition to the individual adult venom using gel filtration.11 The complexity of the issuepharmacologic properties of these proteins and their metab- of variation of venom components is highlighted by the dif- olites, it has been demonstrated that some components act ferences found in fibrinolysis and complement inactivation synergistically in producing specific effects or reactions. The of venoms from different Blacktail rattlesnakes (C. molossus net effect of this interaction of venom with the victim’s re- molossus). In a study of 72 individual Blacktail rattlesnake sponse is a metabolic stew of toxic peptides and digestive venoms, the following conclusion was made: there were no enzymes. Additionally, the traditional categorization of pit venom differences as a function of geographic distribution; vipers as having only hematoxic venoms should be reevalu- however, individual venom variability was significant ated because some subpopulations of rattlesnakes possess enough to be identified as an important clinical12 reality.only neurotoxic venom. Hyaluronidase, present in most venoms, catalyzes the The average rattlesnake needs 21 days to replenish ex- cleavage of internal glycoside bonds and mucopolysacchar- pended venom. The “lethal fraction” peptides are the first to ides, leading to decreases in the viscosity of connective tis- regenerate; yet another variable to any given envenomation. sues. Hyaluronidase is commonly called the “spreading fac- tor,” because this breakdown facilitates the penetration of other venom components into the tissues. Collagenase is also Table 5 Species of Rattlesnakes That Have Populations Con- found in venom, and its major function is to digest collagen, taining Neurotoxin thereby breaking down connective tissue. Crotalus durissus durissus The enzyme phospholipase A is distributed throughout pit Crotalus durissus terrificus var. cumanensis viper venoms. This enzyme catalyzes the hydrolysis of fatty Crotalus durissus terrificus (Brazil) ester linkages in diacyl phosphatides, which form lysophos- Crotalus horridus atricaudatus phatides and release unsaturated and saturated fatty acids. Crotalus lepidus klauberi There are many antigenically different isoenzymes. Some Crotalus mitchellii mitchellii controversy exists about the extent of any neurotoxic effects Crotalus tigris that these isoenzymes may possess. Many cellular substances Crotalus vegrandis may be released by this enzyme, including histamine, kinins, Crotalus viridis abyssus slow-reacting substance, serotonin, and acetylcholine. The Crotalus viridis concolor extent of the release of these physiologically active com- Crotalus scutulatus scutulatus (venom A) pounds most likely depends on the ability of phospholipase Crotalus scutulatus salvini Sistrurus catenatus catenatus A to degrade membranes. The enzyme phospholipase B may Snake bite: Pit vipers 177

Table 6 Pit Viper Envenomations: Hemostatic Defects of problems including pain, weakness, dizziness, nausea, se- Consumption coagulopathy vere hypotension, thrombocytopenia, fasciculations, re- Diffuse vascular damage gional lymphadenopathy, alterations in respiratory rate, in- Disseminated intravascular coagulation-like syndrome creased clotting times, decreased hemoglobin, abnormal Localized massive clotting electrocardiogram, increased salivation, echinocytosis of red Hyperfibrinolysis cells, cyanosis, proteinuria, bleeding (eg, melena, hematuria, Thrombocytopenia (independent from #1 above) hematemesis), obtundation, and convulsions. Not all of these Blood vessel injury clinical manifestations are seen in each patient, and they are listed in descending order of frequency as documented in human victims. Clinical Signs Severe hypotension results from pooling of blood within the shock organ of the species bitten (ie, the hepatosplanch- The onset of clinical signs after envenomation may be de- nic [dogs] or pulmonary [cats] vascular bed) and fluid loss layed for several hours (Table 3). This phenomenon fromis thehigh- vascular compartment secondary to severe periph- lighted by the fact that 40% of all severe envenomations in eral swelling. This swelling can be significant. A 2-cm in- humans are graded as mild to nonenvenomating sometime crease in the circumference of a human’s swollen thigh can during the syndrome. In humans 20% of all pit viper bites are incorporate one-third of the patient’s circulating fluid vol- nonenvenomating (ie, dry), with an additional 25% classified ume.13 Often this swelling is not edema but rather is because as mild envenomations. It is for this reason that so many of extravascularized blood resulting from damage to blood antidotal treatments are championed, and emphasizes the vessel walls because of swelling and rupturing of the endo- need to rely on scientific evaluation for the various treatment thelial cells of the microvasculature, leaving large gaps in the modalities proposed. vessel walls. Every pit viper envenomation is different for many reasons The victim’s clotting anomalies largely depend on the spe- (Table 4). The victim affects the severity of an envenomationcies of snake involved. Coagulopathies range from direct by such factors as species of victim, body mass, location of blockage or inactivation of various factors in the patient’s bite, postbite excitability, and use of premedications (eg, clotting cascade to the possible destruction of megakaryo- nonsteroidal anti-inflammatory drugs in older dogs that may cytes in the circulating blood and bone marrow (Table 6). make the dog more susceptible to clotting defects). The snake Approximately 60% of envenomated patients develop a co- affects the severity of the envenomation by species and size of agulopathy, by far the most common is hypofibrinogenemia snake, age of snake, motivation of snake, and degree of with prolonged clotting times. Venom induced thrombocy- venom regeneration since last use. topenia occurs in approximately 30% of envenomations with Cats are more resistant, on the basis of milligram of venom an untreated nadir usually occurring between 72 and 96 per kilogram body mass, to pit viper venom than dogs. How- hours. Some venom fractions inhibit platelet adhesion. Other ever, cats generally present for veterinary care in a more pit viper venoms do not affect clotting per se but rather advanced clinical condition. This is probably because of the destroy clots once they are formed by initiating aggressive cat’s smaller body size and the proclivity of cats to play with fibrinolysis. Syndromes resembling disseminated intravascu- the snake, thereby antagonizing it and inducing an offensive lar coagulation (DIC) are possible with pit viper envenoma- strike, often to the torso. Additionally, cats commonly run off tions. and hide after being bitten before they return home to allow Myokymia, a type of fasciculation of various muscle the owner to identify the injury, thus delaying the time from groups, is frequently reported in humans after bites received bite to veterinary care. Because dogs generally receive more by timber rattlesnakes (C. horridus horridus) and western di- defensive strikes, have a larger body mass, and frequently amondback rattlesnakesC. ( atrox).14 seek immediate human companionship after injury, they are more likely to receive medical attention promptly. It is possible that a life-threatening envenomation may Minimum Database occur with no local clinical signs other than the puncture Monitoring of the severity and progression of the clinical wounds themselves. This is particularly true of those snake envenomation syndrome may be difficult. A tool that has species with primary neurotoxic venoms (Table 5). provenLocal useful is the envenomation severity score system. Use tissue reactions to pit viper envenomation include puncture of this system more accurately quantifies the severity of the wounds, one to six from a single bite, which may be bleeding. patient’s condition over time, and allows a more objective Occasionally, these fang wounds appear as small lacerations. assessment of the patient.15 It is recommended that a severity Rarely, local swelling can obscure puncture wounds from score be acquired on entry, 6 hours, 12 hours, and 24 hours small snakes. Rapid onset of pain may ensue along with pro- postinitial hospitalization. gressive edema. Ecchymosis and petechiation may develop. Tissue necrosis may occur, particularly in envenomations to Snakebite Severity Score areas without a significant subcutaneous tissue mass. The Pulmonary System presence of fang marks does not indicate that envenomation has occurred, only that a bite has taken place. It must be 0—Signs within normal limit reiterated that the severity of local signs does not necessarily 1—Minimal: slight dyspnea reflect the severity of the systemic envenomation. 2—Moderate: respiratory compromise, tachypnea, use of Systemic clinical manifestations encompass a wide variety accessory muscles 178 M.E. Peterson

3—Severe: cyanosis, air hunger, extreme tachypnea, respi- Table 7 First-Aid Measures to Avoid ratory insufficiency or respiratory arrest from any cause 1. Ice, cold packs, or sprays 2. Incision and suction Cardiovascular System 3. Tourniquets 4. Administration of aspirin or tranquilizers 0—Signs within normal limits 5. Waiting to see how significant the envenomation is 1—Minimal: tachycardia, general weakness, benign dys- before seeking medical care rhythmia, hypertension 6. Electroshock 2—Moderate: tachycardia, hypotension (but tarsal pulse 7. Hot packs still palpable) 3—Severe: extreme tachycardia, hypotension (nonpal- Ͻ pable tarsal pulse or systolic blood pressure 80 mm be collected. A coagulation profile should be obtained in- Hg), malignant dysrhythmia or cardiac arrest cluding activated clotting times, prothrombin time (PT), par- tial thromboplastin time (PTT), fibrinogen, and fibrin degra- Local Wound dation products. Urinalysis with macro- and microscopic 0—Signs within normal limits evaluations including free protein and hemoglobin-myoglo- 1—Minimal: pain, swelling, ecchymosis, erythema limited bin should be performed. An electrocardiogram may be in- to bite site dicated in animals with significant envenomations. These 2—Moderate: pain, swelling, ecchymosis, erythema in- laboratory tests should be repeated periodically to monitor volves less than half of extremity and may be spreading the progression of the syndrome and/or the effectiveness of slowly therapy. 3—Severe: pain, swelling, ecchymosis, erythema involves Significant rhabdomyolysis may also occur inducing large most or all of one extremity and is spreading rapidly increases in creatine phosphokinase and urine myoglobin 4—Very severe: pain, swelling, ecchymosis, erythema ex- levels, particularly in envenomations by snakes with potent tends beyond affected extremity, or significant tissue neurotoxins (eg, Mojave, Canebreak, and Tiger rattlesnakes). slough Tiger rattlesnake venom (C. tigris) has been characterized as having a low protease activity, no hemolytic activity and tox- Gastrointestinal System ins that have complete immunoidentity with the potent neurotoxins crotoxin and mojave 3 toxin. 0—Signs within normal limits Circumferential measurements of the affected body part at, 1—Minimal: abdominal pain, tenesmus above, and below the bite site at set time intervals aid in 2—Moderate: vomiting, diarrhea objective monitoring of the progression of the swelling sec- 3—Severe: repetitive vomiting, diarrhea, or hematemesis ondary to many pit viper bites. Transient (within 48 hours) echinocytosis has been reported in dogs after envenomation, Hematological System and its presence is an indicator of envenomation. However, absence of this morphologic change is not an indicator of lack 0—Signs within normal limits of envenomation.16 1—Minimal: coagulation parameters slightly abnormal, Hypokalemia has been reported subsequent to pit viper Ͻ Ͻ PT 20 sec, PTT 50 sec, platelets 100,000 to envenomations.16 In one series potassium levels of less than 3 150,000/mm 3.5 mEq/liter were observed in 11% of 97 pit viper enveno- 2—Moderate: coagulation parameters abnormal, PT 20 to mated dogs (M. Peterson, unpublished data). It is postulated 50 sec, PTT 50 to 75 sec, platelets 50,000 to 100,000/ that this decrease is secondary to the release of epinephrine 3 mm by the patient, inducing serum insulin elevation and thereby 3—Severe: coagulation parameters abnormal, PT 50 to driving potassium into the cells. This is a transient phenom- 100 sec, PTT 75 to 100 sec, platelets 20,000 to 50,000/ enon, which corrects with intravenous fluid and antivenin 3 mm administration. 4—Very severe: coagulation parameters markedly abnormal with bleeding present or the threat of spontaneous bleeding, including PT unmeasurable, PTT unmeasur- Treatment Ͻ 3 able, platelets 20,000/mm Although many first-aid measures have been advocated for pit viper bite victims, none has been shown to prevent mor- Central Nervous System bidity or mortality.17 Long-term follow-up of pit viper- en venomated human patients has revealed that the majority of 0—Signs within normal limits individuals with permanent loss of motion of the affected 1—Minimal: apprehension area or other negative sequelae had received some form of 2—Moderate: chills, weakness, faintness, ataxia traditional first aid (eg, cut and suck, constriction bands, and 3—Severe: lethargy, seizures, coma so forth).18 The primary rule of first aid is to do no additional Total Score Possible: 0 to 20 harm. One human study followed 147 patients who had A complete blood count with differential, including plate- received first aid and 78 who had not; there was no evidence let counts, should be obtained; red blood cell morphology that first aid had made any difference in the patients’ short- along with baseline serum chemistry with electrolytes should term outcome.19 Snake bite: Pit vipers 179

Table 8 Pit Viper Envenomation Treatment Outline duced by inoculating horses with the venoms collected from 1. Aggressive intravenous fluid therapy C. atrox (western diamondback rattlesnake), C. adamenteus 2. Early intravenous antivenin administration (eastern diamondback rattlesnake), C. terrificus (South Amer- 3. Monitoring of hemostasis and biochemical profiles ican rattlesnake), and Brothrops atrox (fer-de-lance). Once a 4. Antibiotic administration horse attains a certain titer, serum is harvested and processed 5. No corticosteroids to concentrate the antivenom immunoglobulins. The pro- cesses used to extract these proteins results in a final product that, though rich in antibodies, has very high equine protein First-aid measures to be avoided include ice, incision and contaminant and albumin components, often in the range of suction, tourniquets (that constriction bands quickly become 50%. It is these proteins that are primarily responsible for the with progressive limb swelling), and hot packs (Tableallergic 7 reactions). that can be associated with antivenin usage. Electroshock has been definitively shown to be ineffective in Skin testing for allergic reactions to the horse serum is the treatment of pit viper envenomations and should not be difficult to evaluate in veterinary patients, and a test dose is attempted.20,21 Current recommendations for first aid innot the provided in the Fort Dodge packaging as it was in the field are to keep the victim calm, keep the bite site below Wyeth human product. Human victims of snake bites were heart level if possible, and transport the victim to a veterinary often subjected to cutaneous hypersensitivity testing before medical facility for primary medical intervention. One study equine origin antivenin was administered. In one study none has reported (in abstract form only) that suction devices, of 12 early (anaphylactic) reactions were predicted by this capable of asserting two atmospheres of pressure, when ap- test.28 Generally, slow administration of the antivenin- ini plied over the bite wounds within 3 minutes after the bite and tially will identify those patients who may have an allergic left in place for 30 minutes, may remove up to 30% of the reaction. injected venom volume.22 Antivenin should be reconstituted with the provided di- The patient should be hospitalized and monitored closely luent; saline may be added to completely fill the vial, ensur- for a minimum of 8 hours for the onset of signs of enveno- ing that the antivenin is totally submerged to speed reconsti- mation. A severity score sheet should be recorded on entry tution. It should not be shaken but can be swirled to facilitate and at 6 hours posthospitalization at a minimum for every reconstitution. This usually takes between 10 and 15 min- suspected snakebite victim. This advice cannot be overem- utes. Warming the vial to body temperature aids in dissolu- phasized since the onset of clinical signs may be significantly tion into the liquid state. Shaking or overheating can destroy delayed. One report in a human victim described resolution the proteins and causes foaming, which makes it difficult to of mild swelling over 3 hours, at which time the patient was collect the antivenin into a syringe. discharged. The patient returned to the emergency depart- Antivenin should be diluted at a ratio of 1 vial to 100 to ment 12 hours later with severe pain and swelling and a 250 mL of crystalloid fluids. In smaller victims the clinician marked coagulopathy.23 The effects of snake venom are shouldtime adjust the fluid infusion volume to prevent fluid over- dependent, any delay in initiating medical treatment is dele- load of the patient. In one report, antivenin labeled with terious to the patient and may result in complications that radioactive iodine (131I) was given intravenously, 85% accu- cannot be corrected. mulated at the site of envenomation within29 In 2 hours. The initial medical response to a snake-bitten patient is to contrast, there was a 1.4% local concentration when it was collect the appropriate pretreatment laboratory samples (see given intramuscularly and a 5.6% local concentration when earlier section, Minimum Database) and make circumferen- given subcutaneously. Antivenin should not be injected into tial measurements at, above, and below the bite site to allow the bite site, and its uptake can be delayed for up to 12 hours quantitative monitoring of the progression of swelling. An when it is given intramuscularly. Administration should be- intravenous catheter should be placed and a crystalloid fluid gin slowly as an intravenous infusion. If there is no evidence drip started. of an allergic reaction (eg, nausea, hyperemia of inner pinna, The patient can be pretreated with diphenhydramine fluffing of tail, pruritus), the rate of infusion can be increased. given IV or subcutaneously (SC) (small dogs and cats, 10 mg; The entire initial dosage should be given within a half hour. large dog, 25-50 mg). Antihistamines have no effect on the The patient then should be reevaluated for further progres- venom or the course of the envenomation itself; however, sion of the envenomation syndrome using the appropriate they can calm the fractious patient to facilitate intravenous clinical and laboratory parameters. catheterization and theoretically minimize possible allergic The dosage of antivenin needed is calculated relative to the reactions to antivenin. amount of venom injected, the body mass of the victim, and The only proven specific therapy against pit viper enveno- the bite site. Bites to the torso, tongue, or intravascular are mation is the administration of 24-27antivenin Coagulation. severe envenomations that require prompt, aggressive anti- deficits, fluid loss, changes in neurologic status, cardiac con- venin administration. Smaller patients require higher doses duction abnormalities, and the necrotizing effect of the of antivenin because the dose of venom per kilogram body venom can be dramatically reversed when antivenin treat- weight of the victim is higher. Multiple vials may be necessary ment is initiated appropriately (Table 8). to treat severe envenomations adequately. The average hu- In North America polyvalent antivenin, which is effective man patient receives 12 vials, and individuals receiving 75 against the venoms of all endemic pit viper species, is avail- vials have been documented. These data are skewed, how- able. This polyvalent equine origin antivenin (Crotalidae)is ever, because antivenin is withheld from human patients un- made and marketed to the veterinary community by Fort less a moderate to severe envenomation is identified. This Dodge Laboratories (Fort Dodge, IA). The antivenin is pro- policy ensures that larger doses will be required if antivenin is 180 M.E. Peterson given, because early administration is more effective (one vial because of the smaller volumes of antivenin administered given early may be as effective as five vials given later). It relative to those given to human patients. Onset of delayed should also be noted that at these dosages the incidence of serum sickness usually occurs 7 to 14 days after antivenin allergic reactions (primarily delayed serum reactions) is more administration. If it does occur, treatment consists of antihis- frequent. The average dosage in dogs and cats is one to two tamines, often type 1 and type 2 inhibitors, and/or cortico- vials of antivenin. steroids. The earlier antivenin is administered, the more effective it If the patient is in severe hypovolemic shock, hemoglobin is. The package insert advises using it within the first 4 hours. glutamer-200 (bovine) (Oxyglobin, Biopure) may be admin- However, the product is effective as long as active venom istered as a colloid volume replacer and to increase oxygen components are found in the bloodstream. Tissue necrosis delivery to damaged tissues. Oxyglobin has an advantage will not be reversed once it has occurred, but additional over other colloids in that it does not run the risk of inducing damage may be prevented. Antivenin is extremely effective in additional clotting abnormalities in the patient. There is de- reversing venom-induced coagulation defects. Coagulation bate about the use of colloidal fluids in pit viper envenomated defects can be abated several days after envenomation. If patients because leakage of the colloid through damaged vas- clotting defects continue to be manifest, additional antivenin cular walls may pull fluid out of the vascular space and into should be administered. Disseminated intravascular coagu- areas with rich capillary beds such as the pulmonary tissues. lation like syndromes should be treated with additional an- Broad-spectrum antibiotics are recommended in veteri- tivenin. Rattlesnake venom thrombin-like enzymes are not nary patients after envenomation because of the number of inhibited by heparin, and it should not be administered. pathogenic bacteria found in snakes’ mouths and the amount Clotting anomalies secondary to envenomations are ex- of local tissue damage at the bite site. This is an area of tremely difficult to reverse with blood products and transfu- controversy in the therapy of human snake 32,33bite victims. sions. Pain is usually controlled with the antivenin. However, in Antivenin is extremely effective in reversing most rattle- patients in which no or limited amounts of antivenin are snake venom induced thrombocytopenias. However, in tim- administered, pain control may require IV narcotics during ber rattlesnake (C. horridus) bites a platelet aggregating pro- the first 24 hours. Fentanyl is preferred and can be adminis- tein induces thrombocytopenia which is resistant to tered as a continuous rate infusion (loading dose 2 æg/kg antivenin administration even though PT and PTT are re- then 0.5 æg/kg/hr). Morphine should be avoided because of stored.30 In humans, serum levels of polyvalent equine itsorigin histamine-releasing activity, which may be confused with antivenin [(Crotalidae) Wyeth Laboratories (Marietta, PA)] the onset of anaphylaxis. Nonsteroidal medications com- were highest in the first 3 days postadministration and were pound the risk of developing blood dyscrasias and clotting still detectable 4 months later. C. atrox (western diamond- anomalies. back rattlesnake) venom was detectable in the victim’s urine The use of corticosteroids in the treatment of pit viper 6 days after envenomation.31 envenomation is not generally recommended. Treatment of Patients exhibiting allergic reactions to antivenin can still pit viper envenomations with corticosteroids has been re- receive it if needed in severe envenomations. It can be given peatedly advocated, yet the rationale for their use is obscure as a slow intravenous drip and piggybacked with diphenhy- and their ultimate therapeutic value is controversial. Numer- dramine and possibly epinephrine. Data in both human en- ous studies have examined the effects of treating venomous venomation and veterinary envenomation databases has not snake bites with corticosteroids. Most report a worsening of identified a significantly higher reaction rate in patients who or no improvement in the patient’s condition (J. Glen, per- have received antivenin previously (M. Peterson, unpub- sonal communication).33-45 Some studies have shown- dra lished data).18 Some veterinary patients have received- antimatic increases in mortality with the use of corticoste- venin yearly for several consecutive years with no evidence of roids.46,47 The proposed detrimental effects of corticosteroids increased allergic reactions (M. Peterson, unpublished data). are inhibition of the victim’s natural defenses against the Allergic reactions, though rare, are possible when admin- venom, interference with the antivenin, and potentiation of istering antivenin. These can become manifest in one of three the venom itself. Also, they potentially confound diagnostic ways; by true anaphylaxis, an anaphylactoid reaction, and testing, altering coagulation and other objective laboratory delayed serum sickness. The most common reaction to anti- monitoring parameters useful in evaluating the clinical pro- venin is an anaphylactoid reaction. This is a complement- gression of the envenomation syndrome. In addition, human mediated reaction to the rapid administration of a foreign clinical trials have shown no beneficial effects of treatment of protein, such as those seen in rapidly administered blood pit viper envenomation with corticosteroids.43 Corticoste- transfusions. Anaphylactoid reactions can usually be treated roids are of little use in a hypotensive crisis and have little if by stopping the antivenin infusion, administering diphenhy- any effect on the local tissue response to pit viper venom. dramine intravenously (small dogs and cats, 10 mg; large Fasciotomy is not indicated in the dog and cat. The ratio- dogs, 25-50 mg), waiting 5 minutes, and then restarting the nale for this procedure is to combat damage from compart- infusion of antivenin at a slower rate. Anaphylaxis is treated ment syndromes, which are extremely rare in dogs and cats by stopping the infusion of antivenin and administering epi- and uncommon in humans.48 The theory used to advocate nephrine, corticosteroids, and crystalloid fluid infusion. Pa- surgical intervention is that a deep bite injecting venom into tients taking beta-blockers must be monitored very closely. the muscle causes that tissue to swell, leading to pressure Beta-blockers can mask the early onset of anaphylaxis, which necrosis when the muscle sheath restricts the ability of the becomes more difficult to reverse as the reaction progresses. tissue to expand. Fasciotomy is performed to open the mus- Delayed serum sickness is rare in dogs and cats. This may be cle sheath, preventing the pressure necrosis. However, most Snake bite: Pit vipers 181 bites are subcutaneous, and compartment syndromes are Vaccination rare. The risks associated with fasciotomy include surgery in the presence of significant coagulopathies, infection, and In 2004 an antipit viper venom vaccine was introduced com- marked disfigurement after surgery with questionable out- mercially for use in dogs. The manufacturer claims protec- comes.49 One report that compared antivenin treatment tionwith against the venom of all North American pit vipers, with fasciotomy-debridement revealed 100% survival with anti- the exception of Mojave toxin. The package insert states that venin treatment alone, 80% survival in those treated with vaccination does not preclude the necessity for veterinary antivenin and surgery, 30% survival with surgery alone, and intervention. Titers have been followed in dogs but no chal- 30% survival in the untreated 50controls. In patients that maylenge studies have been performed, most of the evidence for develop a compartment syndrome secondary to pit viper en- efficacy is based on a small study in mice. There is no pub- venomation, administration of additional antivenin has been lished data on what the titers are against and majority of the demonstrated to lower the intramuscular 51pressure. evidence for its use is anecdotal. The author is aware of mul- Excision of the snake bite site is generally ineffective and tiple vaccinated dogs that have died subsequent to rattle- can be complicated by coagulation defects secondary to the snake envenomation. There have been no peer reviewed envenomation. Allen52 demonstrated that in cats and rabbitsstudies of efficacy; additionally there is no published data on injected with crotalid venoms, excision of the bite area even 5 exactly with what the dogs are being injected. Until these to 15 minutes after the injection of venom was “useless,” and questions are answered it is difficult to advocate its use. even when a large mass of skin and muscle around the injection site was removed, all the animals died. References 1. Peterson M, Meerdink G: Venomous bites and stings, in Kirk R (ed): Current Veterinary Therapy X. Philadelphia, WB Saunders, 1989; pp Differential Diagnoses 177-186 Trauma, angioedema (eg, insect bites and stings), other ani- 2. Gregory-Dwyer V, Bianchi Bosisio A, Righetti P: An isoelectric focusing study of seasonal variation in rattlesnake venom proteins. Toxicon mal bites, draining abscesses, and penetrating wounds com- 24:995-1000, 1986 prise the differential diagnoses for snake bites. 3. Weinstein S, Smith L: Preliminary fractionation of tiger rattlesnake (Crotalus tigris) venom. Toxicon 28:1447-1455, 1990 4. Glen J, Straight R: Mojave rattlesnake (Crotalus scutulatus scutulatus) Advances in Antivenin venom: Variation in toxicity with geographical origin. Toxicon 16:81- 84, 1978 A new antivenom (Crotalidae polyvalent immune Fab Ovine, 5. Glen J, Straight R, Wolt T: Regional variation in the presence of cane- Protherics Inc., Brentwood, TN) was approved for the human break toxin in Crotalus horridus venom. Comp Biochem Physiol C Phar- use by the U.S. Food and Drug Administration in late 2000. macol Toxicol Endocrinol 107:337-346, 1994 The new antivenom is a purified and lyophilized preparation 6. Anderson S, Ownby C: Pathogenesis of hemorrhage induced by pro- of ovine Fab immunoglobin fragments. The ovine IgG mole- teinase H from eastern diamondback rattlesnake (Crotalus adamanteus) venom. Toxicon 35:1291-1300, 1997 cules are cleaved to discard the inflammatory stimulating Fc 7. Retzios A, Markland F: Fibrinolytic enzymes from the venoms of Agkis- portion of the antibody, retaining only the Fab molecules. trodon contortrix contortrix and Crotalus basiliscus basiliscus: Cleavage site The product is affinity purified and contains negligible specificity towards the alpha-chain of fibrin. Thromb Res 74:355-367, amounts of extraneous proteins such as albumin. Advantages 1994 of this product include a high affinity for venom antigens, 8. Bjarnason J, Hamilton D, Fox J: Studies on the mechanism of hemorrhage production by five proteolytic hemorrhagic toxins from Crotalus improved penetration into tissues (because of the smaller size atrox venom. Biochem Hoppe Seyler 369(Suppl):121-129, 1988 of Fab compared with whole IgG), and decreased antigenic 9. Liu C, Huang T: Crovidisin, a collagen binding protein isolated from potential, thereby decreasing the risk of possible allergic re- snake venom of Crotalus viridis, prevents platelet: Collagen interaction. actions. A disadvantage may be the potential need for re- Arch Biochem Biophys 337:291-299, 1997 peated administration because the smaller Fab molecules 10. Budzynski A, Pandya B, Rubin R, et al: Fibrinogenolytic afibrinogene- mia after envenomation by western diamondback rattlesnake (Crotalus may be more rapidly cleared from the body. atrox). Blood 63:1-14, 1984 Crotalidae polyvalent immune Fab (ovine) antivenom is 11. MacKessy S: Fibrinogenolytic proteases from venoms of juvenile and prepared from the blood of healthy sheep immunized in adult northern Pacific rattlesnakes (Crotalus viridis oreganus). Comp groups with one of the following North American crotalid Biochem Physiol B Comp Biochem 106:181-186, 1993 venoms: C. atrox (western diamondback rattlesnake), C. ada- 12. Rael E, Rivas J, Chen T, et al: Differences in fibrinolysis and complement inactivation by venom from different northern blacktail rattle- manteus (eastern diamondback rattlesnake), C. scutulatus snakes (Crotalus molossus molossus). Toxicon 35:505-513, 1997 scutulatus (Mojave rattlesnake), and Agkistrodon piscivorus 13. Russell F: Snake Venom Poisoning. Great Neck, Scholium Interna- (cottonmouth or water moccasin). A monospecific anti- tional, 1983, p 213 venom is produced from each sheep group, and these four 14. Clark R, Williams S, Nordt S, et al: Successful treatment of crotalid monospecific antivenoms are then mixed to prepare the final induced neurotoxicity with a new polyspecific crotalid Fab antivenom. Ann Emerg Med 30:54-57, 1997 polyvalent antivenom. In theory, the immune response by 15. Dart R, Hulburt K, Garcia R, et al: Validation of a severity score for the each sheep to a single venom creates a monospecific antibody assessment of crotalid snakebite. Ann Emerg Med 27:3: 321-326, 1996 with a wider band of activity against the venom than would 16. Brown D, Meyer D, Wingfield W, et al: Echinocytosis associated with be gained by mounting a response to several venoms at once. rattlesnake envenomation in dogs. Vet Pathol 31:654-657, 1994 In addition, the four immunizing snakes are all North Amer- 17. Stewart M, Greenland S, Hoffman J: First-aid treatment of poisonous snakebite: Are currently recommended procedures justified? Ann ican species and have been selected to provide the widest Emerg Med 10:331-335, 1981 immune response to the venoms of pit vipers indigenous to 18. McNalley J, Dart R, O’Brien P: Southwestern rattlesnake envenomation the continent. database (abstract). Vet Hum Toxicol 29:486, 1987 182 M.E. Peterson

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