Volume 61 | Issue 1 Article 8

1999 Pit Viper Envenomation In Dogs: Pathophysiology and Treatment David Senter Iowa State University

Tom Carson Iowa State University

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Recommended Citation Senter, David and Carson, Tom (1999) "Pit Viper Envenomation In Dogs: Pathophysiology and Treatment," Iowa State University Veterinarian: Vol. 61 : Iss. 1 , Article 8. Available at: https://lib.dr.iastate.edu/iowastate_veterinarian/vol61/iss1/8

This Article is brought to you for free and open access by the Journals at Iowa State University Digital Repository. It has been accepted for inclusion in Iowa State University Veterinarian by an authorized editor of Iowa State University Digital Repository. For more information, please contact [email protected]. Pit Viper Envenomation In Dogs: Pathophysiology and Treatment

DAVID SENTER, DVMt, AND TOM CARSON, DVM, PH.D.tt

inflicted by rattlesnakes. 1 Members of the Crotalidae (pit viper) family account for the large majority (95%) of poisonous snakebites. The three main genera in this family are Cro­ talus (rattlesnake),Agkistrodon (copperhead, cottonmouth water moccasin), and Sistrurus (pygmy rattler, massasauga).2 Among these groups, there are at least 26 subspecies of rattlesnakes, five subspecies of copperheads, three subspecies of cottonmouths, three sub­ species of pygmy rattlesnakes, and three sub­ species of massasauga.1 Members of the pit viper family get their name from the facial pits that exist between the nostril and the eye which function to detect heat and vibration. 1,2 Other distinguishing characteristics of the Copperhead (Agkistrodon contortix). This species crotalids include triangular shaped heads, re­ enjoys widespread distribution across the U.S., tractable fangs, a single row of subcaudal ranging from Texas and Oklahoma in the south· west, Iowa to the northwest, New York and Massa· scales, and vertical, elliptical shaped pupils. chusetts to the northeast, and Florida to the south· All pit vipers have movable fangs that inject east. This species is among the most commonly a voluntarily controlled amount ofvenom.2 encountered pit vipers in the U.S., however it is also among the least dangerous in terms of venom toxicity and volume of injection. Pathophysiology In general, pit viper venom is considered Venomous snakes occur throughout a very hemotoxic and proteolytic as opposed to many wide geographic area within the United snakes that are predominately neurotoxic. 3 States. In certain areas of the country, snake­ The Mojave green rattlesnake (Crotalus bites in dogs are diagnosed on a regular basis scutulatus scutulatus) is an exception as its during the warm months of the year when venom contains a very substantial quantity snakes are most active and people and their of neurotoxin. Venom constituents vary con­ pets are most likely to be spending time in siderably between snakes of different species areas that snakes inhabit. The best treatment as well as between individuals within a spe­ for snakebite is a controversial subject among cies depending on geographic location, age, veterinarians and there is no single treatment and season of the year. protocol. Therefore, it is necessary for a clini­ Of the three genera in the pit viper fam­ cian to understand the pathophysiology be­ ily, the rattlesnakes have the most potent hind envenomation in order to make educated venom with the eastern and western diamond­ decisions as to the treatment of each indi­ back rattlesnakes accounting for 95% of fa­ vidual patient. talities in man.2The relative toxicity of venom An estimated 15,000 domestic animals are from several North American snakes are listed bitten by snakes annually in the United in Table 1. States. Approximately 80% of fatal bites are Snake venom consists of a diverse mix­ ture of peptides, enzymes, and proteins. At 'Dr. David Senter is a 1998 graduate of the Iowa State least 26 different enzymes have been defined, University College of Veterinary Medicine. ten of these are common to all pit viper ven­ "Dr. Tom Carson is a professor in the Department of Pathology specializing in toxicology at the Iowa State oms. One major enzyme is hyaluronidase University College of Veterinary Medicine. which allows the venom to spread and pen-

VOL 61, No 1; SPRING 1999 21 Table 1. Venom Toxicity of Some North American Snakes! Snake Median Lethal Dose LD50(mg / kg-l}* Rattlesnakes (Crotalus) Mojave (C. scutulatus scutulatus) 0.23 Eastern diamondback (C. adarnanteus) 1.68 Western diamondback (C. atrox) 2.18 Timber (C. horridus horridus) 2.69 Pygmy rattlesnakes (Sistrurus) Pygmy (8. miliaris) 2.85 Massassauga (8 catentatus) 2.91 Moccasins (Agkistrodon) Cottonmouth (A. piscivorus) 4.19 Copperhead (A. contortrzx) 10.92

LD50 values are from a study which adminisU!red venom intravenously in 18 to 26 gm mice. etrate tissues by decreasing the viscosity of ocytopenia. Several attempts to measure the connective tissue. 1,4 Another major component amount of histamine released after contact is phospholipase ~ which disrupts cell mem­ with snake venom have been perfQrmed by branes, uncouples phosphorylation, inhibits various in vitro tests with mixed results. How­ cellullar respiration, and may release hista­ ever, no in vivo direct test of the histamine­ mines, kinins, and serotonin. Phospholipase releasing activity of Crotalus species venom A;, acts by liberating arachidonic acid from has been reported.3 The nonenzymatic polypeptide component of Crotalidae venom has more of a direct effect on the cardiovascu­ lar and respiratory system.

Cardiovascular System

A lethal factor in Crotalus species venom dis­ rupts the basal lamina and collagen of the capillaries allowing for leakage of red blood cells and plasma through the endothelial membrane.l ,3 Petechia, ecchymosis, and exten­ sive edema are commonly seen due to the vas­ Prairie rattlesnake, Western rattlesnake, Green cular destruction and increased vascular per­ rattlesnake (Crotalus viridis). This species is meability. Approximately one-third of the total found in all U.S. states west of a line from the circulating fluid volume can be lost into an Dakotas to Texas. It is a locally common species affected extremity within hours of envenoma­ with a variable temperanlent. Despite its rela­ I tively small size, envenomation by this species tion. ,3 Furthermore, severe hypotension com­ has resulted in human fatalities. monly occurs due to pooling of blood in the hepatosplanchnic bed in dogs. 4 This combina­ membrane phospholipids which is then con­ tion can ultimately lead to hemoconcentration, verted to various prostaglandins (PGI2, PGE2, lactic acidosis, and hypovolemic shock. PGF2<) and thromboxane A;,.3 Prostaglandin Some envenomated patients will have E2 and PGI2 cause vasodilation and decrease concurrent thrombocytopenia which may be systemic arterial pressure that contributing due to the aggregation of platelets to areas of to hypotension. Another component, throm­ damaged endothelium and the production of boxane A;" is a potent inducer of platelet ag­ thromboxane A;,and PGE2 from phospholipase gregation which may contribute to thromb- A;,. Venoms from several species of rattle-

22 IOWA STATE UNIVERSITY VETERINARIAN flaccid paralysis. However, its greatest effect is on motor axon terminals of the diaphragm and respiratory paralysis may not occur for several hours after envenomation.

Urinary System

Most pit viper venoms, especially those of the western diamondback rattlesnake and the prairie rattlesnake, cause myonecrosis which could cause the release ofmyoglobin.5 There­ fore, if severe envenomation has occurred, the Mojave rattlesnake, l ..U .....'., nephrotoxic effects of myoglobinuria may re­ (Crotalus scutulatus). Mojave rattlers are sult in acute renal failure. Other potential unique among rattlesnake species in that their venom contains a significant neurotoxic compo­ nephrotoxic factors include hemoglobinuria nent. Per volume, this venom is the most highly (some venoms cause intravascular hemolysis), toxic of all the North American pit vipers. This defibrination syndrome, and hypovolemic species ranges from southwest Utah to south· shock. ern Nevada and the Mojave De ert region and southward to central Mexico. Clinical Signs and Diagnosis snakes have been shown to have direct plate­ Snake envenomation can be difficult to diag­ let-aggregating properties.3 nose ifthe incident was not witnessed. Clini­ In general, snake venom has very com­ cal signs may vary greatly depending on the plex effects on blood coagulation. Many ofthe species of snake involved and the quantity and rattlesnake venoms studied cause the forma­ . toxicity of the venom injected. The potency of tion of an imperfect fibrin clot which results the venom depends on several factors such as in pure defibrination and high levels of fibrin age ofthe snake (young snakes have high pep­ degradation products.3 This cause is differen­ tide fractions), the volume of venom regener­ tiated from disseminated intravascular coagu­ ated since the last bite, aggressiveness of the lation (DIC) by the fact that platelets and fac­ snake, and motivation of the snake (offensive tor VIII are not consumed. Unlike with DIC, strikes are usually more severe).! In addition, this condition is not inhibited by heparin. the enzymatic fraction ofthe venom is higher Cottonmouth and copperhead venom affects in the fall and lower in the spring in relation coagulation in a different manner. Since their to the peptide fraction. venoms interfere with the formation offibrin, Most bites in dogs involve the head, face, defibrination does not occur. However, these or neck.4 Bites to the body rarely occur, but do cause hypofibrinogenemia from the disso­ tend to involve much more severe envenoma­ lution of fibrinogen. 3 Many venoms have tion.! Dogs commonly present with extensive procoagulant properties and anticoagulant edematous swelling, severe pain, ecchymosis, properties.4 Nevertheless, the overall effect and discoloration of the skin in the affected of most severe pit viper envenomations is an area within several hours after the bite. It is anticoagulative state. advisable to clip the hair in the area to search for fang marks (one or more with mUltiple Nervous System strikes). Bleeding puncture wounds may in­ dicate the bite of a pit viper.! Iffang puncture The Mojave rattlesnake is the only member wounds are present in the absence of pain and of Crotalidae found in North America whose swelling, the dog may have received a dry or venom has a significant neurotoxic compo­ nonpoisonous bite. It is estimated that poi­ nent. This toxin (Mojave toxin) interferes with sonous snakes fail to inject venom in up to neuromuscular transmission by a presynap­ 20% of bites.2 However, some bites by the tic nerve-blocking action.5 The major toxic ef­ Mojave rattlesnake may be life-threatening fects involve the peripheral nervous system without pain or swelling.6 All patients should and include respiratory paralysis and general be hospitalized and monitored for at least 24

VOL 61, No 1; SPRING 1999 23 hours for signs of systemic envenomation. mixing a drop of isotonic saline with one drop Some laboratories can perform blood analy­ of EDTA-preserved blood on the slide. A cover sis to determine the concentration and type slip is added and the sample observed with a of venom injected, however, this method is not light microscope. The ecchinocytosis is a tran­ routinely used in North America.6.7•8 sient shape change with most cases resolving Systemic signs can vary and may include by 48 hours. hypotension, shock, cardiac arrhythmias, The aforementioned study also reported bleeding disorders, ptyalism, nausea, vomit­ that sixty-four percent of dogs bitten by rattle­ ing, respiratory distress, mental confusion, snakes developed thrombocytopenia, 10 of28 rhabdomyolysis, and acute renal failure. 1.2,6A (36%) dogs had mild anemia, and 14 of 18 (78%) developed hypokalemia.9 Anemia may be due to cell destruction following enveno­ mation. The cause of the hypokalemia was not apparent, however, it does indicate the need for supplementation during treatment;­ On the contrary, hyperkalemia can commonly be seen in severe envenomations that cause extensive necrosis, hemolysis, and oliguric renal failure. If severe rhabdomyolysis has occurred, CPK levels will be markedly el­ evated within the first 12 hours post-enveno­ mation.1 Urine should be analyzed for myo­ globinuria and hemoglobinuria and renal Timber rattlesnake (Crotalus horridus). This is the most common venomous species found in the function should be closely monitored for signs eastern U.S. Its range includes most of the states of renal failure. east of the Mississippi River. West of the Missis­ sippi, the Timber rattlesnake is found as far we t Treatment as Nebraska, Kansas, Oklahoma and Texas, and as far north as Minnesota. This is a fairly large species, with large adults reaching 5 feet in Pre·hospital. The treatment for snakebites length. Timber rattlers have a large amount of in both humans and animals is surrounded venom available for injection, and must cer­ by much folklore and anecdotal evidence of tainly be considered dangerous to animals and successful treatments. Even within the sci­ humans alike. entific literature, there is much controversy baseline oflaboratory data should be obtained regarding the most successful treatment pro­ upon presentation including: complete blood tocols in these patients. The treatment the count, platelets, coagulation profile (prothrom­ animal receives before it gets to the hospital bin time, partial thromboplastin time, fibrino­ can be important in the outcome of these cases. gen), serum electrolytes, blood urea nitrogen, The most important recommendation for cli­ creatinine, creatine phosphokinase (CPK), ents is to strictly limit the physical activity of glucose, and urinalysis. 1 If severe envenoma­ the dog. The venom is spread through the tion is suspected, electrocardiographic moni­ lymphatics and excessive activity will increase toring should be performed. the uptake of the venom.4 If an extremity is Wright-Giemsa stained blood smears bitten, immobilization of the leg with a splint should be evaluated in all suspected cases of may be helpful if this can be rapidly per­ snakebite. A study of 28 cases of rattlesnake formed.2 Noting the levels of swelling every bites in dogs indicated an association of en­ 15 minutes during transport may help to de­ venomation with echinocytosis; 25/28 dogs termine the degree of envenomation. It is not (89%) had echinocytosis within 24 hours af­ advisable to use a tourniquet to stop the ter the bite.9 Since slow drying of blood films spread of venom, pack the area in ice, or in­ can cause the artifactual formation of cise the wound for suction. These practices echinocytes (crenation), a saline wet mount have not proven useful and may cause fur­ preparation should be made of both the sus­ ther injury.2 Recently the popular press has pected victim and a healthy, nonenvenomated described electric shock therapy for treatment dog for comparison. This prep can be done by of poisonous snakebites. Scientific investiga-

24 IOWA STATE UNIVERSITY VETERINARIAN tion ofthis technique indicates that it is of no tration. This test is simple to perform and value and may actually be harmful to the ani­ should be utilized on all patients. However, it mal. 6 Transporting the dog as quickly as pos­ is not completely reliable and many false-posi­ sible to the nearest veterinary medical facil­ tive and false-negative test results occur. 1,2,6 ity is the most prudent course of action to take Initially, at least one vial of antivenin should Initial. Some patients may present in be delivered intravenously. By comparison, repiratory distress after envenomation by the as many as 20 vials of antivenin may be used Mojave rattlesnake or due to swelling around in humans that have been bitten by rattle­ the upper airways. Emergency tracheotomy snakes.2 Due to the lack of venom dilution, may be indicated in patients with extensive smaller patients and patients that are bitten swelling in the neck area. After the airway is on digits may require 50% more antivenin secured, intravenous fluid therapy is appro­ than bites in larger animals or bites exclud­ priate to support blood pressure and perfu­ ing digits.6 sion.4,6 Since cardiovascular collapse due to The antivenin should be added to the in­ hypovolemic shock is the primary cause of travenous f1 uids and delivered slowly over one death, aggressive fluid therapy is indicated.1 or more hours while monitoring for signs of Colloids may be needed in severe cases. Six anaphylaxis. Hyperemia of the inner pinna percent hetastarch in 0.9% sodium chloride is a good indicator of a systemic reaction.1 In has been recommended.6 However, hetastarch mild cases of anaphylaxis, slowing the rate of may be contraindicated if bleeding disorders administration may be all that is necessary are present because it prolongs prothrombin, to relieve the symptoms.6 Antihistamines are partial thromboplastin, and clotting times.6 In of little value unless given before the antive­ addition, fresh whole blood, fresh plasma, or nin.6 Epinephrine is the drug of choice for fresh frozen plasma, may be indicated for anaphylaxis and should be readily available coagulopathies.4 during treatment. If swelling increases, Pit viper envenomations can result in in­ coagulopathies continue, or any other prob­ tense pain for the patient. Analgesics may be lem worsens, an additional vial of antivenin warranted provided they do not cause respi­ is probably warranted.2,6 Platelet numbers ratory depression. Aspirin and other nonste­ may be a good indicator of the progress to­ roidal anti-inflammatory drugs with antico­ wards recovery for the patient during treat­ agulant effects should be avoided.4 In human ment. medicine, patients have reported substantial The amount of time from envenomation analgesia from antivenin alone.6 to the delivery of the antivenin is crucial to Antivenin. Once stabilized, the degree the overall prognosis in these cases. It was of envenomation should be evaluated by ana­ found in a study of eastern diamondback lyzing laboratory data and observing the se­ rattlesnake (Crotalus adamanteus) enveno­ verity of systemic and local signs. Dogs that mation in dogs that if antivenin was given 30 have moderate to severe degrees of enveno­ minutes after subcutaneous venom injection, mation should receive antivenin as long as eight out of eight dogs survived.6 If the anti­ there is no history of anaphylaxis. The same venin was administered four hours after en­ antivenin (Antivenin [Crotalidae] Polyvalent venomation, five out of eight dogs survived; if [equine origin], Fort Dodge or Wyeth) is used given at eight hours, only one dog survived. to treat envenomation by all of the pit vipers. Corticosteroids. The use of corticoster­ Copperhead envenomations have proven to be oids is the most controversial issue among cli­ much less toxic than the other pit vipers and nicians who treat pit viper envenomation. can usually be treated conservatively without Support both for and against steroid use can the use of antivenin. 10 be found in the literature. The majority of Although the use of antihistamines is con­ publications do not recommend the use of cor­ troversial, many practitoners administer H ticosteroids except in patients that are in blockers such as diphenhydramine to calm thJ shock or have had hypersensitivity reactions animal and pretreat against allergic responses to the venom. Corticosteroids are not used to to the venom. 1 The antivenin package insert treat envenomation in human patients.2 His­ gives instructions on performing the skin test torically, corticosteroids have been the corner­ for horse serum sensitivity prior to adminis- stone of treatment for venomous snakebites.

VOL 61, No 1; SPRING 1999 25 The ability to block the action of phospholi­ snakes in the area and the idiosyncrasies of pase A , the major active component of most their venom components in order to make snake ~enom, would seem to be an advantage educated decisions regarding therapy for their of steroid use.6 Disadvantages of corticoster­ victims. oids include the impairment of wound heal­ ing, the masking of clinical signs and infec­ References tions, the alteration of important laboratory data, and the possibility of interfering with 1. Peterson ME, Meerdink GL. Bites and stings ofven­ omous animals. In: Kirk RW, eds. Current veterinary the binding of antivenin to venom.1,2,6 therapy. Vol 10. Philadelphia: WB Saunders Co., 1989; Antibiotics. It has been shown that a 177-180. wide variety of both aerobic and anaerobic bac­ 2. Ellenhorn MJ, et al. Ellenhorn's medical toxicology: teria can be found as part of the natural flora diagnosis and treatment of human poisoning. 2nd ed. of a snake's mouth. Bacteria of major con­ Baltimore: Williams and Wilkins, 1998;1759-1769. 3. Hudelson S, Hudelson P. Pathophysiology of snake cern are Clostridium species and Pseudomo­ envenomization and evaluation of treatments-part 1. nas.6 The choice of antibiotic should be based Compend Cont EdPract Vet 1995; 17:889-896. on culture and sensitivity testing of the bite 4. Geller RW, Messonnier SP. Handbook of small ani­ wound. Broad spectrum antibiotic therapy is mal toxicology and poisonings. St. Louis: Mosby, 1998; 223-229. recommended pending test results. 5. Hudelson S, Hudelson P. Pathophysiology of snake envenomization and evaluation of treatments-part 2. Conclusion Compend ContEdPract Vet 1995; 17:1035-1038. 6. Hudelson S, Hudelson P. Pathophysiology of snake envenomization and evaluation of treatments-part 3. The diagnosis and treatment of pit viper en­ Compend ContEdPract Vet 1995; 17:1385-1393. venomation in dogs can be very challenging. 7. Moisdis AV, James T, Smith HY, Cox, JC. Snake The wide variety of clinical signs and degrees envenomation in cats and its detection by rapid immu­ of toxicity can make each case vastly differ­ noassay.Australian Veterinary Journal 1996; 74:143-146. 8. Cooper JE, Mosha RD. Diagnosis of snakebite. The ent in presentation and response to treatment. Veterinary Record 1992; 10:324. It is important for the clinician to be familiar 9. Brown DE, Meyer DJ, Wingfield WE, Walton RM. with the pathophysiology of envenomation in Echinocytosis associated with rattlesnake envenomation order to understand the multisystemic effects in dogs. Vet Pathol1994; 31:654-657. 10. Whitley RE. Conservative treatment of copperhead that may be presented. The clinician should snakebites without antivenin. JTrauma 1996; 41 :219- become knowledgeable about the poisonous 221.

Dr. Adams, continued from page 6. lab in large dumpsters, on that particular balmed cadavers. year, I managed to have Wolfgang wheel in Dr. Adams has been an almost institution a dumpster with me in it dressed up in a for freshman veterinary students at the mask and such, and when he wheeled in the Iowa State University College ofVeterinary cart to freshman lab, I jumped out and Medicine and he will be sorely missed. We scared all the freshman." wish him good luck with future endeavors Dr. Adams feels happy to have had a and we look forward to using the interac­ chance to provide laboratory instruction tive CD-ROM instructional programs. Best with not just embalmed cadavers but has wishes with your move and enjoy the fish­ been able to provide more fresh or non-em- ing wherever it may take you!.

26 IOWA STATE UNIVERSITY VETERINARIAN