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Cardiovascular Pathology Possibly Associated with Ketamine/Xylazine Anesthesia in Dutch Belted Rabbits

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Cardiovascular Pathology Possibly Associated with Ketamine/Xylazine Anesthesia in Dutch Belted Rabbits Laboratory Animal Science Vol 49, No 2 Copyright 1999 April 1999 by the American Association for Laboratory Animal Science Cardiovascular Pathology Possibly Associated with Ketamine/Xylazine Anesthesia in Dutch Belted Rabbits Robert P. Marini,1 Xiantang Li,2 Neil K Harpster,3 and Charles Dangler1 Background and Purpose: After myocardial necrosis and fibrosis was observed in five rabbits which had been anesthetized a variable number of times, the potential relationship of these lesions and anesthesia was evalu- ated in 35 other rabbits. Methods: Anesthesia was induced by intramuscular administration of ketamine and xylazine followed by infusion of lactated Ringer’s solution also containing ketamine and xylazine. Group A rabbits (n = 9) were subjected to multiple anesthesias and were evaluated by echocardiography, thoracic radiography, electrocar- diography, determination of serum coronavirus titer, vitamin E concentration, and complete necropsy. Prior to a single acute procedure followed by necropsy, group B rabbits (n = 11) were evaluated by echocardiography only. Group C rabbits (n = 10) had never been anesthetized and were necropsied after euthanasia. Group D rabbits (n = 5) had intermediate anesthesia exposure history and were evaluated by echocardiography only. Myocardial fibrosis was scored semi-quantitatively on a scale of 0 to 4. Results: Canine coronavirus test results were negative; hypovitaminosis E was evident, and fibrosis scores were significantly increased in group A, compared with group B or group C, rabbits. a Conclusion: Etiologic differentials included 2-agonist-mediated coronary vasoconstriction with associated myocardial hypoperfusion, hypovitaminosis E and free radical injury, and other anesthetic-induced physi- ologic trespass. Spontaneous myocardial disease in rabbits is infrequently tion—have not been reported in the rabbit. documented. Specific causes for myocardial disease include The cases motivating this study comprised five Dutch hypovitaminosis E, rabbit coronavirus infection, salmonello- belted rabbits that were observed over a 12-month period. sis, pasteurellosis, encephalitozoonosis, and administration Clinical signs of disease included sudden death in three rab- a of anesthetic combinations that contain the 2-agonist seda- bits and tachypnea and anorexia in another. One rabbit tive detomidine (1–6). Heart failure or injury has been in- without clinical signs of disease was euthanized for an unre- duced experimentally through rapid ventricular pacing (7); lated cause. These rabbits were part of a cohort of 21 ani- inoculation of Trypanosoma cruzi (8); surgical induction of mals that had been used in an ophthalmology study and had aortic regurgitation (9); left ventricular catheterization with been anesthetized a variable number of times in electroret- subsequent intravenous inoculation of Streptococcus inography and visual-evoked potential studies. For each an- viridans (10); alloxan-induced diabetes (11); gamma irradia- esthesia episode, anesthesia had been induced by ketamine tion (12, 13); ingestion of coffee senna (Cassia occidentalis) (50 mg/kg, intramuscularly [i.m.]) and xylazine (10 mg/kg, (14, 15); and administration of catecholamines (16–19), 6- i.m.) and subsequently maintained by use of a constant-rate hydroxydopamine (20), emetine (21), cantharidin (22), and intravenous infusion ([6 ml/h] of a 1:1 mixture of ketamine the anthracycline antibiotics daunorubicin, detorubicin, and [5 ml, 100 mg/ml] and xylazine [5 ml, 20 mg/ml]) brought to doxorubicin (23, 24). Congenital heart defects have been re- a total volume of 60 ml with lactated Ringer’s solution (final ported sporadically and include ventricular septal defect concentration, 8.3 mg of ketamine and 1.7 mg of xylazine/ and hemocyst (25). A stress-induced episode of cardiomyopa- ml). Rabbits had been anesthetized three to eight times and thy and sudden death was reported in rabbits in association had received 600 to 1,400 mg of ketamine and 120 to 400 mg, with high housing density (26). Experimentally induced Her- cumulatively, of xylazine. One rabbit was used in a short- pesvirus sylvilagus infection in cottontail rabbits causes term procedure, then was submitted to necropsy; for three lymphocytic myocarditis, necrosis of cardiac myocytes, and other rabbits, 3 to 12 weeks elapsed between the last episode eventual myocardial fibrosis (27). To the authors’ knowledge, of anesthesia and death or euthanasia. Histopathologic find- other spontaneous causes of heart disease—such as taurine ings included moderate to extensive myocardial necrosis and deficiency, toxoplasmosis, and Clostridium piliforme infec- fibrosis (four rabbits), and mild multifocal myofiber hyper- trophy with interstitial fibrosis (one rabbit). Four rabbits Division of Comparative Medicine, Massachusetts Institute of Technology, had moderate to severe, acute diffuse interstitial pneumoni- Cambridge, Massachusetts1; Animal Resources Center, University of Chi- tis characterized by high numbers of alveolar macrophages; cago, Chicago, Illinois2; Angell Memorial Hospital, Boston, Massachusetts3 153 Vol 49, No 2 Laboratory Animal Science April 1999 exudation of eosinophils and fibrin; hypercellular, thick al- those of group B in that the latter were ketamine/xylazine- veolar septa; and foci of septal necrosis. Interstitial edema naive at the time of echocardiography. occurred in the interlobular stroma and large arteries, with Rabbits received only ketamine/xylazine systemically; multifocal vasculitis and perivasculitis affecting large- and ophthalmic atropine, phenylephrine, and tropicamide were medium-caliber arteries and veins. The medium- and large- delivered topically to one eye. Animals breathed room air caliber arteries were characterized by medial hypertrophy spontaneously and were kept on circulating hot-water blan- and a few multifocal intimal plaques. The remaining rabbit kets; respiration was continuously monitored. For rabbits of had prominent medial hypertrophy of medium- to large-cali- group A, biomaterials were implanted into the eye at the sec- ber arteries and mild, multifocal periarteritis. Three rabbits ond anesthesia episode to generate compatibility informa- had pleural effusion, one of which also had a diaphragmatic tion before developing a retinal prosthesis. hernia. Echocardiography: Rabbits were sedated with diaz- Myocardial fibrosis had been observed previously by us in epam (1 mg/kg, intravenously [i.v.]), then restrained manu- New Zealand White rabbits given anesthetic combinations ally in right or left lateral recumbency. Seven rabbits from a containing the 2-agonist detomidine (5). A report of group A (six males, one female), six rabbits from group B (six ketamine/xylazine-associated mortality in New Zealand females), and five rabbits from group D (five females) were White rabbits implicates acidosis as the etiologic factor (28). used to determine differences in echocardiographic profiles In that study, however, rabbits were given ketamine/ attributable to ketamine/xylazine exposure. Echo-cardiogra- xylazine after recovery from lidocaine-induced epidural an- phy was performed, using a 7.5-MHz transducer and an ATL esthesia; necropsy results were not reported. We sought to Apogee Model CX (Bothell, Wash.) echocardiograph. correlate the lesions in these rabbits with repeated anesthe- Serum IgG coronavirus titers: Pleural effusion dis- sia episodes of ketamine/xylazine, and attempted to identify ease/infectious cardiomyopathy virus status was evaluated cardiac dysfunction through the noninvasive diagnostic by examining serum from seven group A rabbits, using an techniques of echocardiography, electrocardiography, and indirect fluorescent antibody (IFA) test, for antibody to the thoracic radiography. cross-reacting canine coronavirus (Washington Animal Dis- ease Diagnostic Laboratory, College of Veterinary Medicine, Materials and Methods Washington State University, Pullman, Wash.). Animals: Thirty-five specific-pathogen-free Dutch belted Vitamin E concentrations: Vitamin E concentrations in rabbits (Oryctolagus cuniculus), Hra:(DB) Covance (formerly serum from the five rabbits in group A with the most extensive Hazleton Research Products Inc., Denver, Pa.) were studied. cardiac lesions, as determined by histologic examination, were Twenty-five of the rabbits were individually housed in stain- determined by using normal-phase high-performance liquid less steel cages (24 x 30 x 17 in) with slotted floors and re- chromatography (Animal Health Diagnostic Laboratory, Col- ceived water and a commercial rabbit chow (Purina rabbit lege of Veterinary Medicine, Michigan State University, chow HF326; Ralston Purina Co., St. Louis, Mo.) ad libitum, Lansing, Mich.). in a facility that has animal care and use programs accred- Radiography and electrocardiography: Right lateral ited by AAALAC, International. The environment was con- and ventrodorsal radiographs were obtained from seven rab- trolled for temperature (15.5 to 20.58C), relative humidity bits of group A. These rabbits were sedated with diazepam (1 (40 to 65%), light (12/12-h light/dark cycle), and ventilation mg/kg, i.v.) and restrained in right lateral recumbency. A six- (100% fresh air with 12 air changes/h). Ten rabbits were lead electrocardiogram was obtained, using a PhysioControl housed by the vendor until euthanasia. monitor/recorder (Life Pak 5S; PhysioControl, Redmond, Rabbits were separated into four groups on the basis of Wash.). After electrocardiography, rabbits were anesthetized
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