The United States has > 120 species of snakes, of which 20 are considered venomous. With the exception of the coral snake, all are members of the Crotalidae (pit viper) family, which comprises rattlesnakes, cottonmouths, and copperheads.1 Annually, approximately 3,000 human snakebite envenomings are reported to the American Association of Poison Control Centers, resulting in fewer than 10 fatalities.2 The number of domestic animals bitten by snakes is much higher, with an estimated 150,000 to 300,000 envenomed dogs and cats in the United States annually.3 Ninety-nine percent of human and domestic animal envenomings are caused by crotalid bites.2,3
Crotalid venom is composed of numerous enzymatic proteins that digest cell membranes, endothelium, collagen, and nucleic acids.1 Components of crotalid venom can affect virtually every organ system, resulting in cardiovascular, hemostatic, respiratory, and neurologic derangements.
The only specific treatment for crotalid envenoming is the early IV administration of antivenom. In 1954, the introduction of the first antivenom product, an equine-derived whole IgG antivenom,a resulted in a decrease in the human mortality rate from 25% to 0.5%.1 However, the same product was also associated with a 23% rate of immediate hypersensitivity and a 50% rate of delayed hypersensitivity reactions in humans. Those reactions were attributed to the antigenic Fc portion of the antibody as well as to unpredictable amounts of contaminant equine proteins in each vial.4
During the past decade, purer, less antigenic antivenom products have been developed. Since 2000, an ovine-derived purified productb containing Fab fragments without the Fc portion has replaced the whole IgG product as the preferred antivenom product used in human medicine. The whole IgG antivenom, Fab antivenom, and a recently developed F(ab′)2c antivenom are available for veterinary use and have been evaluated in dogs.
Despite a growing body of literature on snakebites, antivenom use, and survival outcomes in dogs, no such published data exist for cats, to the authors’ knowledge. Furthermore, cats have been considered more resistant to the venom of snakes on a milligram-per-kilogram basis than dogs and less likely to be involved in altercations leading to envenoming. However, considering cats’ antagonistic behavior characteristics, when envenomed they may receive a relatively large venom dose, compared with that in dogs. It is reasonable to expect that because of the growing number of cats with outdoor access and suburban encroachment on snake territory, more cats may require emergency veterinary care for snakebites. The emergency clinician should be knowledgeable about antivenom use, complications, and outcomes in cats.
Anecdotally, clinicians in both private and university hospitals have administered antivenom products to cats for years, but an evaluation of their use has not yet been reported. The objectives of this retrospective study were to evaluate the use of crotalid antivenom in cats, determine the frequency of hypersensitivity reactions, and evaluate factors that may contribute to hypersensitivity reactions and death.
Materials and Methods
Criteria for selection of cases—Medical records were electronically searched for cats treated for snake envenoming between 2000 and 2011 at 5 private and university teaching hospitals located in geographic areas where crotalid envenomings are frequently managed (California, Colorado, Arizona, Texas, and Florida).
Medical records review—A spreadsheetd with 17 questions and multiple-choice answer fields was electronically distributed to the 5 veterinary hospitals. To minimize the response time, maximize the response rate, and facilitate statistical analysis, the number of questions was limited and the responses were standardized. Clinicians or veterinary students with faculty supervision reviewed individual records to provide data for the distributed spreadsheet. All cats treated for clinical signs consistent with crotalid envenoming as the cause for seeking medical attention were included.
The total number of crotalid-envenomed cats seen by each hospital was obtained as well as the number of cats specifically treated with crotalid antivenom. Mortality rate was evaluated for all cats regardless of antivenom treatment. Individual patient data on all antivenom-treated cats were further evaluated, including signalment, diagnostic criteria for envenoming, coagulation values and platelet counts on admission, factors influencing antivenom administration, product administered, dosage, the manner in which it was reconstituted, duration of administration, and premedication used. Frequency of hypersensitivity reactions (acute and delayed) was evaluated in all antivenom-treated cats. Acute reactions were defined as type I hypersensitivity reactions occurring during or within 1 hour of administration, characterized by erythema, vomiting, salivation, facial swelling, or acute death. Delayed reactions were defined as type III hypersensitivity reactions, characterized by fever, malaise, lymphadenopathy, or polyarthropathy within 7 to 21 days after administration. It was anticipated that medical records reflecting hypersensitivity reactions would be most accurate during antivenom administration, immediately after antivenom administration, or for the specific follow-up visit. Therefore, a query into medical records outside those specified periods was not performed.
Statistical analysis—All data were centrally compiled and analyzed. All data were checked for normality with a Kolmogorov-Smirnov test, a D'Agostino and Pearson omnibus test, and a Shapiro-Wilk normality test. Univariate logistic regression was used to determine whether an association existed between continuous variables and frequency of hypersensitivity reactions or death. A Mann-Whitney test was used to compare the median age, dilution, rate, and platelet counts between cats with and without hypersensitivity reactions. A Fisher exact test was performed, and ORs and their 95% CIs were calculated to compare proportions of cats that survived or had hypersensitivity reactions on the basis of the variables collected. A value of P ≤ 0.05 was considered significant for statistical analyses. All analyses were performed with a commercially available statistical software package.e
Results
Four institutions completed the questionnaire for 105 cats that received antivenom. An additional 177 cats were treated for snake envenoming without antivenom at these same institutions. Only mortality rate was recorded for these cats. An additional 10 cats that received antivenom for suspected snake envenomings were added from a fifth institution. This institution was unable to provide data on envenomed cats that did not receive antivenom, and therefore, the 10 cats were not included in comparative statistics. A total of 115 cats that received antivenom for suspected snake envenoming were included in analyses and descriptive data of antivenom alone.
The study group included 5 sexually intact males and 62 castrated males (overall, 58.3% male) and 3 sexually intact females and 45 spayed females (overall, 41.7% female). Median age was 6.0 years (range, 0.1 to 20.0 years). Breeds were identified as domestic shorthair (n = 91 cats), domestic longhair (7), domestic medium hair (4), American Shorthair (3), Siamese (3), Bengal (2), Abyssinian (1), Burmese (1), Devon Rex (1), Ragdoll (1), and unknown (1).
Among the 4 institutions with complete reporting, 37.2% (105/282) of cats received antivenom. In total, 5.08% (9/177) of cats that did not receive antivenom died before discharge, and 6.67% (7/105) of cats that received antivenom died before discharge. This difference was not significant (OR, 1.33; 95% CI, 0.48 to 3.69; P = 0.602).
In the 115 cats that received antivenom from the 5 institutions, the diagnosis of snake envenomation was made on the basis of clinical and historical findings, including a characteristic bite or wound (91.3%; 105/115), suspected exposure and timing (62.6%; 72/115), witnessed bite (10.4%; 12/115), and other criteria (33.0%; 38/115), namely the presence of echinocytes on a blood smear. The criteria for administration of antivenom in envenomed cats included suspected rattlesnake bite (90.4%; 104/115), extent of local tissue damage and necrosis (66.1%; 76/115), hemostatic abnormalities (51.3%; 59/115), systemic signs (12.2%; 14/115), and other miscellaneous signs (6.09%; 7/115). Of the 115 cats, 82.6% (95/115) received whole IgG, 9.57% (11/115) received F(ab′)2, and 3.48% (4/115) received Fab antivenom products. In the remaining 5 cats, the type of antivenom administered was unknown. Of the 115 cats, 4.3% (5/115) received < 1 vial, 87.8% (101/115) received 1 vial, 7.0% (8/115) received 2 vials, and 0.9% (1/115) received 3 vials of antivenom. The median dilution of antivenom was 1 vial/60 mL (range, 1:10 to 1:250) and was given over a median time of 2.0 hours (range, 0.3 to 9.0 hours).
The hemostatic variables analyzed were those available from the time of admission. Median platelet count of all cats was 120,000 platelets/μL (range, 17,000 to 642,000 platelets/μL). There were PT and partial PTT measurements available for 74 and 73 cats, respectively. In total, 33.8% (25/74) of cats had a PT within the reference interval, 14.9% (11/74) had a PT that was longer than the upper limit of the reference interval by < 25%, 5.4% (4/74) had a PT that was longer than the upper limit of the reference interval by 25% to 50%, and 45.9% (34/74) had a PT that was longer than the upper limit of the reference interval by > 50%. In the 73 cats with available PTT measurement, 50.7% (37/73) had a PTT within the reference interval, 4.1% (3/73) had a PTT that was longer than the upper limit of the reference interval by < 25%, 2.7% (2/73) had a PTT that was longer than the upper limit of the reference interval by 25% to 50%, and 43.7% (31/73) had a PTT that was longer than the upper limit of the reference interval by > 50%.
A type I hypersensitivity reaction was diagnosed in 22.6% (26/115) of cats. By use of logistic regression, no significant associations existed between dilution of antivenom, rate of administration, platelet count, PT, or PTT and the frequency of type I hypersensitivity reactions or mortality rate (Table 1). Additionally, there were no differences in the median age, dilution, administration rate, or platelet count between cats that did or did not have a type I hypersensitivity reaction (Table 2). However, cats that were administered antivenom during a period of < 1 hour were 2.81 times as likely to have a type I hypersensitivity reaction as those that received the total dose during a period longer than 1 hour; this finding approached significance (P = 0.052; 95% CI, 1.06 to 7.43). In total, 6.09% (7/115) of cats that received antivenom died before discharge; 3 of them died acutely. Cats were 10.33 times as likely to die prior to discharge if they had a type I hypersensitivity reaction (P = 0.006; 95% CI, 1.88 to 57.2). One of 115 cats that received antivenom was rechecked at the time of expected delayed reaction, and this cat did not have signs of type III hypersensitivity.
Results of univariate analysis of variables evaluated for association with the presence of a type I hypersensitivity reaction or death in 110 envenomed cats treated with antivenom.
| Type I hypersensitivity reaction | Death prior to discharge | |||||
|---|---|---|---|---|---|---|
| Variable | OR | 95% CI | P | OR | 95% CI | P |
| Volume of antivenom dilution | 1.00 | 0.99–1.01 | 0.933 | 1.01 | 0.98–1.03 | 0.461 |
| Duration (h) of antivenom administration | 1.05 | 0.81–1.37 | 0.713 | 1.49 | 0.68–3.26 | 0.313 |
| Platelet count on admission | 1 | 0.99–1.00 | 0.351 | 1 | 0.99–1.00 | 0.643 |
| PT on admission | 1.04 | 0.70–1.53 | 0.854 | NA | NA | NA |
| PTT on admission | 1.02 | 0.72–1.45 | 0.913 | 0.94 | 0.47–1.87 | 0.853 |
NA = Not applicable (values could not be determined by means of logistic regression because univariate analysis predicted failure perfectly).
Variables (median [range]) evaluated for association with a type I hypersensitivity reaction in the same cats as in Table 1.
| Variable | Type I hypersensitivity | No type I hypersensitivity | P value |
|---|---|---|---|
| Age (y) | 6.0 (1.0–20.0) | 6.0 (0.1–19.0) | 0.450 |
| Volume of antivenom dilution (mL) | 60.0 (10.0–250.0) | 60.0 (10.0–250.0) | 0.575 |
| Duration of antivenom administration (h) | 1.0 (0.3–9.0) | 2.0 (0.5–8.0) | 0.256 |
| Platelet count on admission (per μL) | 118,000 (33,000–270,000) | 126,000 (17,000–642,000) | 0.850 |
Premedications were administered to 57 of the 115 cats that received antivenom (diphenhydramine [n = 31], diphenhydramine and glucocorticoids [22], or other unlisted premedication [4]), whereas 58 cats did not receive any premedication. No cats received glucocorticoids alone. Of the cats that received premedication, 19.3% (11/57) had a type I hypersensitivity reaction. Of the cats that did not receive premedication, 25.9% (15/58) had a type I hypersensitivity reaction; however, this was not significant (P = 0.505). There was also no difference in the likelihood of a type I hypersensitivity reaction between cats that received diphenhydramine alone or diphenhydramine and a glucocorticoid (P = 0.746). Finally, there was no difference in mortality rate between cats that did or did not receive premedications (P = 0.442).
Overall, 24.2% (23/95) of cats that received whole IgG had a type I hypersensitivity reaction, whereas a single cat (1/11) that received F(ab′)2 had a type I hypersensitivity reaction. There were no reactions reported for the 4 cats that received the Fab antivenom. There was no significant difference in likelihood of having a type I hypersensitivity reaction between cats that received whole IgG and cats that received F(ab′)2 or Fab (P = 0.183).
Discussion
Results indicated that hypersensitivity reactions were recognized in 22.6% of cats that received antivenom and that the use of premedications did not decrease this frequency. The study found no associations between commonly measured hemostatic variables or type of antivenom and mortality rate. Of clinical importance was the possible association between faster rates of antivenom administration and a higher frequency of type I hypersensitivity reactions. Cats that had a type I hypersensitivity reaction were 10 times as likely to die before discharge as those that did not have such a reaction.
Five institutions reported the use of whole IgG, Fab, or F(ab′)2 antivenom in 115 cats. The most frequently administered product was whole IgG antivenom, which was used in 82.6% of cats and is presently the only product approved for veterinary use. The cost of 1 vial of whole IgG antivenom approaches $500, which is one-fourth the cost of 1 vial of Fab antivenom. Presently, F(ab′)2 has not attained USDA approval for commercial distribution, and its use requires an import permit. The use of all 3 products in cats is presently off-label.
The collective data indicated that antivenom products were administered to cats in the same dosages and dilutions as reported in dogs.5,a Most cats received 1 vial of antivenom product diluted to 60 mL with crystalloid solution, which was administered during a median period of 2 hours. The reconstituted vial is sometimes diluted in a 250-mL crystalloid solution for administration in dogs; however, this may result in volume overload in cats. A smaller volume of dilution is therefore necessary to achieve a reasonable rate of administration. When volume of dilution was considered as a continuous variable, no associations existed between the volume of dilution or number of vials administered and rate of hypersensitivity reactions. However, when the cats that received antivenom in < 1 hour were compared with the cats that received antivenom in ≥ 1 hour, the latter were 2.81 times as likely to have a type I hypersensitivity reaction. Although this finding was not significant, the P value approached significance, and further prospective investigation may be warranted. Because cats, compared with dogs, have smaller circulating blood volume and less tolerance of IV fluid administration during critical illness, they may require antivenom administration at a slower rate and in a smaller volume.
The diagnosis of snake envenoming in domestic animals is largely one of clinical and historical suspicion; only 10.4% of the bites in the present study were reportedly witnessed. In comparison, a recent study5 reported snake identification in 40% of envenomed dogs. In both species, a characteristic appearance to the bite site remains the most diagnostic factor for envenoming (91.3% of the cats in the present study). Crotalid bites typically cause 1 or 2 fang puncture wounds with variable bruising and edema; however, a puncture wound is frequently not identified.6 Envenoming can result in local tissue injury within 30 minutes, and delayed signs can be observed for up to 24 hours. Evidence of systemic envenoming is sometimes observed and includes hypotension, hemolysis, coagulopathy with defibrination, thrombocytopenia, and alterations of respiratory, cardiac, and CNS functions.5,7,8 The exception to this clinical picture is envenoming by the neurotoxic Mojave rattlesnake (Crotalus scutulatus), where a rapidly ascending flaccid paralysis caused by Mojave toxin A is the main clinical sign. A recent report9 also describes flaccid paralysis as the main clinical finding in a patient envenomed by a hemotoxic rattlesnake, suggesting that the expected venom profiles in certain geographic areas are changing. Consequently, antivenom may be indicated in patients without apparent tissue damage, coagulopathy, or echinocytosis.
Early IV administration of antivenom is the only specific treatment for crotalid envenoming.1,7,8 However, the human literature reports immediate and delayed hypersensitivity reactions in up to 50% of humans, making this treatment controversial.1,10,11 The reported rates of hypersensitivity in humans were largely attributed to the use of the equine-derived whole IgG antivenom product, which has been replaced in human medicine with the less antigenic ovine-derived Fab product. Although human reaction rates are lower with this product (5% to 19%), its faster clearance and shorter half-life in circulation may necessitate readministration because of re-envenoming and recurrent coagulopathy.10–13
Substantial controversy exists over the appropriate indications for use of antivenom in human and veterinary medicine. Results of the present study indicated that a suspected rattlesnake bite was overwhelmingly the most common indication for antivenom administration. Although rattlesnakes are regarded as the most venomous pit vipers, it is important to recognize that factors such as seasonality, weather conditions, age, and size of the snake also can affect the amount of venom injected.14 In addition, the encounter is rarely witnessed, and species identification is seldom possible. Thus, if signs of systemic envenoming or coagulopathy exist in any envenomed patient, antivenom administration is indicated.
The frequency of acute hypersensitivity reactions in this study was 22.6%, with no significant difference among products. Because of the disproportionately high use of whole IgG antivenom, compared with the Fab and F(ab′)2 products, a prospective study with a more equal distribution of use could better elucidate whether there is truly no difference in acute hypersensitivity reactions among antivenoms. Acute reactions have been reported in 7% of envenomed dogs that received whole IgG antivenom, 5.2% of envenomed dogs that received Fab antivenom, and 6.7% of healthy dogs that received F(ab′)2 antivenom.5,15,16 An additional evaluationf of F(ab′)2 in envenomed dogs reported no adverse events related to their use. The cats in the present study appeared to have a rate of acute hypersensitivity reactions 3 times that of the rates in those studies.5,15,16,f Because of the different designs of the antivenom studies in dogs and the present study, the authors cannot draw direct comparisons. Clinical judgment is warranted in every case in which antivenom administration is considered, and it is the authors’ recommendation that severely envenomed cats should receive appropriate antivenom treatment; however, the risk of hypersensitivity reactions may outweigh the benefit of antivenom use in less envenomed cats. When further information regarding the safety profile of newer antivenom products in cats becomes available, this statement may be reconsidered.
The present study revealed that median patient age, antivenom dilution volume, platelet count, and prolongation of PT and PTT were not associated with the occurrence of acute hypersensitivity reactions. Additionally, dilution of antivenom, rate of administration, platelet count, PT, PTT, and the frequency of type I hypersensitivity were not associated with mortality rate. In a retrospective study17 of factors associated with mortality rate in dogs, thrombocytopenia, but not PT or PTT, was associated with a higher mortality rate. Fifty percent of the cats in the present study received premedication prior to antivenom administration, with no effect on frequency of acute hypersensitivity reactions or mortality rate. Notably, none of the cats received glucocorticoids alone as a premedication; therefore, no conclusions could be made about the association between glucocorticoids alone and hypersensitivity reactions or mortality rate. A retrospective study of factors affecting mortality rate in dogs envenomed by the Israeli viper (Vipera palestinae) found that a significant increase in mortality rate was associated with glucocorticoid administration; however, recent evaluations of glucocorticoid use with American vipers have revealed no correlation with outcome.5,17,18 The same studies also had different results regarding antihistamine administration and associations with outcome. On the basis of the adverse-effect profile of glucocorticoids in critically ill cats, their administration for treatment of envenoming or as a premedication cannot be recommended.
The survey used in this study did not investigate the use of antimicrobials, blood products, or NSAIDs, all of which are controversial in crotalid envenomings. Crotalid venom is sterile, and data in human literature indicate a wound infection frequency as low as 0% to 3%.19,20 Thus, routine antimicrobial use is not justified in bites associated only with bruising and edema. Where tissue necrosis is present, standard wound care, culture and susceptibility testing, and broad-spectrum antimicrobial administration are used as indicated.8 Nonsteroidal anti-inflammatory drugs have a lesser margin of safety in cats, compared with dogs, in addition to impairing platelet function in both species.8,21 Combined with the nephrotoxic effects of crotalid venom, NSAIDs cannot be recommended for use in envenomed cats.
Cats that received antivenom had a mortality rate (6.67%) similar to that of cats that did not receive antivenom (5.08%). An important shortcoming of the study, however, was that illness severity scores were not obtained, and it is reasonable to suspect that some cats that did not receive antivenom were less envenomed than those that did. If a large proportion of the untreated cats had mild envenomation and a large proportion of the treated cats had severe envenomation, any survival benefit associated with antivenom treatment may have been masked. However, treatment was associated with type I hypersensitivity reactions that were associated with a risk of death 10 times that of cats without hypersensitivity reactions. There were no other factors prognostic of death, on the basis of the information gathered in our survey.
Because of the standardized survey format and its retrospective nature, the study had several limitations. For each cat that received antivenom, the survey posed 17 questions, which required time and effort to answer on behalf of the responders. The answers were standardized at the expense of additional information that could have been relevant (such as the use of antimicrobials, blood products, location of the bite, physical examination findings, and clinicopathologic variables that may reflect illness severity). Additionally, medical records were incomplete in several cases, and follow-up for delayed reactions was largely unavailable.
The survey used in this study revealed areas for further investigation. Envenomed cats would benefit from the use of an objective scoring system, which would serve as a monitoring tool for antivenom treatment as well as assist in the quantification of illness severity for statistical analysis. A prospective randomized and masked clinical trial comparing different antivenoms would allow for direct comparison of reaction rates and efficacy. Future studies should include follow-up data on discharged cats that were treated with antivenom to identify possible type III hypersensitivity. Though the present study aimed to identify delayed hypersensitivity reactions in cats that received antivenom, only 1 of the 115 cats had follow-up information available. It is likely that delayed hypersensitivity reactions occurred but were either subclinical or were treated by the referring veterinarian and were therefore not reported by the participating institutions. Although many of the cats survived to discharge, their ultimate outcome was unknown.
ABBREVIATIONS
| CI | Confidence interval |
| PT | Prothrombin time |
| PTT | Partial thromboplastin time |
Antivenin (Crotalidae) Polyvalent (ACP), Boehringer Ingelheim Vetmedica Inc, St Joseph, Mo.
Crofab, Crotalidae polyvalent immune Fab, Protherics Inc, Brentwood, Tenn.
Polyvalent F(ab′)2 pit viper antivenom (Crotalus durissus and Bothrops asper), Instituto Bioclon SA de CV, Mexico City, Mexico.
A copy of the spreadsheet is available electronically upon request.
Prism, version 5, GraphPad Software Inc, La Jolla, Calif.
Seibold KE, Wells RJ, Bordelon DJ, et al. Evaluation of an antivenom F(AB)2 in 74 dogs envenomed by North American pit vipers (abstr). J Vet Emerg Crit Care 2010;20s1:A13.
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