Acute necrotic cardiomyopathy in dogs anesthetized with ketamine and xylazine - case report

Hammerschmitt, M.E.; Pereira, P.R.; Caprioli, R.A.; Monteiro, E.R.; Pavarini, S.P.; Driemeier, D.

doi:10.1590/1678-4162-13282

ABSTRACT

The combination of xylazine and ketamine has been used for decades to anesthetize dogs and cats undergoing surgical procedures. Three dogs died two to four days after being anesthetized with this combination without any know complications during the anesthetic procedure. White multifocal areas were present in the hearts of the three dogs, which histologically corresponded to marked necrosis of cardiomyocytes. Epidemiological and anatomopathological findings suggest that the dogs died because of cardiac impairment caused by the anesthetic combination.

Keywords:
canine; myocardium; anesthesia; cardiac necrosis

RESUMO

A combinação de xilazina e quetamina tem sido usada há décadas para anestesiar cães e gatos submetidos a procedimentos cirúrgicos. Três cães morreram dois a quatro dias após serem anestesiados com essa combinação, sem quaisquer complicações conhecidas durante o procedimento anestésico. Foram observadas áreas multifocais brancas no coração dos três cães, o que histologicamente correspondia a acentuada necrose de cardiomiócitos. Achados epidemiológicos e anatomopatológicos sugerem que os cães foram a óbito devido ao comprometimento cardíaco causado pela combinação anestésica.

Palavras-chave:
canino; miocárdio; anestesia; necrose cardíaca

INTRODUCTION

There are numerous causes of myocardial necrosis, including nutritional deficiencies, chemical and herbal toxins, ischemia, metabolic disorders, and inherited diseases (Miller and Gal, 2017). Dissociative anesthetics, such as ketamine, induce functional dissociation between the thalamocortical and limbic systems. These drugs are considered potentially harmful to the cardiovascular system because they exert sympathomimetic action, thereby resulting in increased heart rate, peripheral vasoconstriction, and increased blood pressure (Borgbjerg and Frigast, 1997; Errando et al., 1999; Berry, 2015). Although ketamine provides deep analgesia, it lacks muscle relaxation (Clarke et al., 2014) and, therefore, ketamine is usually administered in combination with other drugs with muscle relaxant properties, such as xylazine (Greene and Thurmon, 1988; Clarke et al., 2014). Adverse cardiovascular effects have been ascribed to combination of xylazine and ketamine, such as decreased cardiac output, heart rate, and stroke volume, increased systemic vascular resistance and arterial blood pressure (Kolata and Rawlings, 1982; Allen et al., 1986; Magoon et al., 1988).

Mortality from anesthesia has decreased in recent years, and trends towards reduction in the risk of anesthesia-related death have been observed over time (Brodbelt et al., 2015). However, the use of specific drugs has been associated with higher mortality in dogs and cats, and cardiovascular and respiratory complications are considered the main causes of many perioperative deaths (Brodbelt et al., 2015). This study describes acute myocardial lesions observed in three dogs previously anesthetized with a combination of xylazine and ketamine.

CASUISTRY

Three dogs (cases 1, 2, and 3) died two to four days after being anesthetized with a combination of xylazine and ketamine at recommended doses. No complications were observed during the anesthetic procedures. All dogs underwent post-mortem examination. Fragments of various organs were collected and fixed in 10% formalin, processed routinely, and stained with hematoxylin and eosin (HE) for histological evaluation.

Case 1, Labrador Retriever, male, three years old, was castrated without any intraoperative complications and died two days after surgery. The dog was administered non-steroidal anti-inflammatory and anti-microbial drugs in the postoperative period and presented no clinical abnormalities prior to death. Case 2, Border Collie, male, four years old, died four days after an oral surgical procedure. In the first 24 hours after surgery, the dog was administered analgesics. The dog presented vomiting after analgesic medication until death. Case 3, Border Collie, male, four years old, underwent dental prophylaxis four days before death. No prescription of medications was reported after prophylaxis. No clinical signs were observed prior to death. None of the dogs described in this report received medications prior to the anesthetic procedures. Cases 1 and 2 had never undergone anesthesia, whereas case 3 had previously undergone two similar procedures, but no previous anesthetic protocols were provided. On post-mortem examination, the hearts of the three dogs showed white multifocal areas, especially in the left ventricle. These areas were observed in the epicardium and myocardium, mainly in the papillary muscle, as well as in the endocardium (Fig. 1A and 1B). The lungs were red to dark red and failed to collapse upon opening the thoracic cavity. Moderate to severe amount of white foamy fluid observed in the lumen of the trachea (Fig. 1C) and large bronchi (pulmonary oedema). No significant gross lesions were observed in any of the other organs.

Histologically, multifocal areas of cardiomyocyte necrosis (Fig. 1D), characterized by fragmentation and hypereosinophilia of myofibers, and sometimes vacuolation, pyknotic or absent nuclei, were observed. A mild inflammatory infiltrate consisting of macrophages, lymphocytes, and neutrophils associated with oedema between cardiomyocytes was observed. Macrophages in the process of the phagocytosis of sarcoplasmic debris were observed. Severe diffuse alveolar oedema and septal congestion were observed in the lungs. No significant histological lesions were observed in the other organs evaluated.

DISCUSSION

Based on the history and histopathological findings, it is suggested that the cardiac necrosis observed in the dogs in this study is associated with the anesthetics used. Isolated administration of ketamine increases systemic and pulmonary arterial pressures, heart rate, cardiac output, myocardial oxygen requirements, and cardiac work (Berry, 2015). When ketamine is administered in combination with xylazine, the cardiovascular depressing effects of xylazine usually prevail, thereby resulting in decreased heart rate and cardiac output and increased systemic vascular resistance and blood pressure (Kolata and Rawlings, 1982; Allen et al., 1986; Magoon et al., 1988). In addition, the administration of the combination of xylazine and ketamine to dogs increased the serum levels of creatine kinase isoenzyme fraction MB (CK-MB), which is specific to the myocardium and has been used for the detection of heart damage (Franco et al., 2009).

Cardiac necrosis occurs owing to the combination of reduced coronary reserve and insufficient coronary blood flow, thereby resulting in myocardial ischemia. The former is a likely consequence of hypoxemia associated with ketamine and xylazine administration, and the latter is due to the interaction of xylazine with alpha-2 receptors in coronary vessels (Hurley et al., 1994). Myocardial necrosis is frequently observed in the left ventricular wall and interventricular septum (Miller and Gal, 2017), which is probably due to the increased cardiac work and ketamine-induced increase in myocardial oxygen requirements combined with the peripheral vasoconstrictor effect of xylazine.

Figure 1
A. Canine, Border Collie, heart (case 3). White multifocal areas in the left ventricular myocardium, mainly in the papillary muscle. B. Canine, Border Collie, heart (case 2). Cross-sectional view of the heart with white areas of the left ventricle and interventricular septal wall. C. Canine, Border Collie, respiratory tract (case 2). Tracheal lumen filled with white foam. The lungs are diffusely red and uncollapsed. D. Canine, Border Collie, heart (case 2). Area of cardiac necrosis associated with oedema between cardiomyocytes, and inflammatory infiltrate of macrophages, and lymphocytes. Hematoxylin and eosin, 200x.

Sudden death was reported in three rabbits anesthetized more than once with xylazine and ketamine for electroretinography (Marini et al., 1999). Deaths without previous clinical signs were reported by Linde-Sipman et al. (1992) in 32 cats six hours after anesthesia in a study of 85 cats anesthetized with different combinations of ketamine, xylazine, and atropine. In four other cats, Linde-Sipman et al. (1992) observed vomiting, excitation, aqueous liquid in the nostrils, cyanotic mucous membranes, and dyspnea. Of the dogs in this study, two (case 1 and 3) died suddenly without showing clinical signs 48 hours and 96 hours after anesthesia, respectively, and case 2 presented with episodes of vomiting 72 hours after anesthesia followed by death 24 hours after the signs.

Macroscopically, we observed white multifocal areas in the left ventricular musculature, especially in the papillary muscle. Lesions in these cardiac regions are frequently associated with a transient reduction in vascular perfusion (Miller and Gal, 2017). Pulmonary oedema is a frequent complication of many diseases, and thus is one of the most found pulmonary abnormalities (Caswell and Williams, 2016). In cases of severe pulmonary oedema, the bronchi and trachea contain considerable amounts of foamy fluid resulting from the mixture of oedema fluid with air (López and Martinson, 2017). The cardiac lesions observed in the dogs in this study, mainly in the left ventricle, as well as the pulmonary findings corroborate what has been described in the literature.

The microscopic lesions observed in cardiac necrosis depend on the age of the lesion (Miller and Gal, 2017). The microscopic cardiac findings were characterized by hypereosinophilia and fragmentation of myofibers, and pyknotic or absent nuclei. These lesions are described for areas of recent myocardial necrosis (Miller and Gal, 2017) and are consistent with those observed in the histology of the heart of these dogs.

The association of clinical aspects and anatomopathological lesions allowed the diagnosis of post-anesthetic acute cardiac necrosis in dogs administered a combination of xylazine and ketamine prior to death, which may be indicative of a relationship.

ACKNOWLEDGMENTS

This work was supported by the “Conselho Nacional de Desenvolvimento Científico e Tecnológico” (CNPq), and “Coordenação de Aperfeiçoamento de Pessoal de Nível Superior” (CAPES) - Finance Code 001.

REFERENCES

ALLEN, D.G.; DYSON, D.H.; PASCOE, P.J. et al. Evaluation of a xylazine-ketamine hydrochloride combination in the cat. Can. J. Vet. Res., v.50, p.23-26, 1986.
BERRY, S.H. Injectable anesthetics. In: GRIMM, K.A.; LAMONT, L.A.; TRANQUILLI, W.J. et al. (Eds.). Veterinary anesthesia and analgesia. 5.ed. Ames: Wiley-Blackwell, 2015. p.277-296.
BORGBJERG, F.M.; FRIGAST, C. Segmental effects on motor function following different intrathecal receptor agonists and antagonists in rabbits. Acta Anaesthesiol. Scand., v.41, p.586-594, 1997.
BRODBELT, D.C.; FLAHERTY, D.; PETTIFER, G.R. Anesthetic risk and informed consent. In: GRIMM, K.A.; LAMONT, L.A.; WJ TRANQUILLI, W.J. et al. (Eds.). Veterinary anesthesia and analgesia. 5.ed. Ames: Wiley-Blackwell, 2015. p.11-22.
CASWELL, J.L.; WILLIAMS, K.J. Respiratory system. In: MAXIE, M.G. (Ed.). Jubb, Kennedy, and Palmer’s pathology of domestic animals. 6.ed. St. Louis: Saunders, 2016. p.465-591.
CLARKE, K.W.; TRIM, C.M.; HALL, L.W. Anaesthesia of the dog. In: _____. (Eds.). Veterinary anaesthesia. 11.ed. St. Louis: Saunders, 2014. p.404-498.
ERRANDO, C.L.; SIFRE, C.; MOLINER, S. et al. Subarachnoid ketamine in swine-pathological findings after repeated doses: acute toxicity study. Regional Anesth. Pain Med., v.24, p.146-15, 1999.
FRANCO, L.G.; FIORAVANTI, M.C.S.; DAMASCENO, A.D. et al. Assessment of serum enzymatic markers of cardiomyocytes injury in female dogs submitted to ketamine S(+), atropin and xylazine association. Acta Cir. Bras., v.24, p.36-42, 2009.
GREENE, S.A.; THURMON, J.C. Xylazine - a review of its pharmacology and use in veterinary medicine. J. Vet. Pharmacol. Ther., v.11, p.295-313, 1988.
HURLEY, R.J.; MARINI, R.P.; AVISON, D.L. et al. Evaluation of detomidine anesthetic combinations in the rabbit. Lab. Anim. Sci., v.44, p.472-478, 1994.
KOLATA, R.J.; RAWLINGS, C.A. Cardiopulmonary effects of intravenous xylazine, ketamine and atropine in the dog. Am. J. Vet. Res., v.43, p.2196-2198, 1982.
LINDE-SIPMAN, J. VAN DER; HELLEBREKERS, L.J.; LAGERWEY, E. Myocardial damage in cats that died after anaesthesia. Vet. Q., v.14, p.91-94, 1992.
LÓPEZ, A.; MARTINSON, S.A. Respiratory system, mediastinum, and pleurae. In: ZACHARY, J.F. (Ed.). Pathologic basis of veterinary disease. 6.ed. St. Louis: Elsevier, 2017. p.471-560.
MAGOON, K.E.; HSU, W.H.; HEMBROUGH, F.B. The influence of atropine on the cardiopulmonary effects of a xylazine-ketamine combination in dogs. Arch. Int. Pharmacodyn. Thér., v.293, p.143-153, 1988.
MARINI, R.P.; LI, X.; HARPSTER, N.K.; DANGLER, C. Cardiovascular pathology possibly associated with ketamine/xylazine anesthesia in Dutch belted rabbits. Lab. Anim. Sci., v.49, p.153-160, 1999.
MILLER, L.M.; GAL, A. Cardiovascular system and lymphatic vessels. In: ZACHARY, J.F. (Ed.). Pathologic basis of veterinary disease. 6.ed. St. Louis: Elsevier, 2017. p.561-616.

Publication Dates

Publication in this collection
27 Jan 2025
Date of issue
Jan-Feb 2025

History

Received
18 Apr 2024
Accepted
10 Aug 2024

This is an open-access article distributed under the terms of the Creative Commons Attribution License

[1] ALLEN, D.G.; DYSON, D.H.; PASCOE, P.J. et al. Evaluation of a xylazine-ketamine hydrochloride combination in the cat. Can. J. Vet. Res., v.50, p.23-26, 1986.

[2] BERRY, S.H. Injectable anesthetics. In: GRIMM, K.A.; LAMONT, L.A.; TRANQUILLI, W.J. et al. (Eds.). Veterinary anesthesia and analgesia. 5.ed. Ames: Wiley-Blackwell, 2015. p.277-296.

[3] BORGBJERG, F.M.; FRIGAST, C. Segmental effects on motor function following different intrathecal receptor agonists and antagonists in rabbits. Acta Anaesthesiol. Scand., v.41, p.586-594, 1997.

[4] BRODBELT, D.C.; FLAHERTY, D.; PETTIFER, G.R. Anesthetic risk and informed consent. In: GRIMM, K.A.; LAMONT, L.A.; WJ TRANQUILLI, W.J. et al. (Eds.). Veterinary anesthesia and analgesia. 5.ed. Ames: Wiley-Blackwell, 2015. p.11-22.

[5] CASWELL, J.L.; WILLIAMS, K.J. Respiratory system. In: MAXIE, M.G. (Ed.). Jubb, Kennedy, and Palmer’s pathology of domestic animals. 6.ed. St. Louis: Saunders, 2016. p.465-591.

[6] CLARKE, K.W.; TRIM, C.M.; HALL, L.W. Anaesthesia of the dog. In: _____. (Eds.). Veterinary anaesthesia. 11.ed. St. Louis: Saunders, 2014. p.404-498.

[7] ERRANDO, C.L.; SIFRE, C.; MOLINER, S. et al. Subarachnoid ketamine in swine-pathological findings after repeated doses: acute toxicity study. Regional Anesth. Pain Med., v.24, p.146-15, 1999.

[8] FRANCO, L.G.; FIORAVANTI, M.C.S.; DAMASCENO, A.D. et al. Assessment of serum enzymatic markers of cardiomyocytes injury in female dogs submitted to ketamine S(+), atropin and xylazine association. Acta Cir. Bras., v.24, p.36-42, 2009.

[9] GREENE, S.A.; THURMON, J.C. Xylazine - a review of its pharmacology and use in veterinary medicine. J. Vet. Pharmacol. Ther., v.11, p.295-313, 1988.

[10] HURLEY, R.J.; MARINI, R.P.; AVISON, D.L. et al. Evaluation of detomidine anesthetic combinations in the rabbit. Lab. Anim. Sci., v.44, p.472-478, 1994.

[11] KOLATA, R.J.; RAWLINGS, C.A. Cardiopulmonary effects of intravenous xylazine, ketamine and atropine in the dog. Am. J. Vet. Res., v.43, p.2196-2198, 1982.

[12] LINDE-SIPMAN, J. VAN DER; HELLEBREKERS, L.J.; LAGERWEY, E. Myocardial damage in cats that died after anaesthesia. Vet. Q., v.14, p.91-94, 1992.

[13] LÓPEZ, A.; MARTINSON, S.A. Respiratory system, mediastinum, and pleurae. In: ZACHARY, J.F. (Ed.). Pathologic basis of veterinary disease. 6.ed. St. Louis: Elsevier, 2017. p.471-560.

[14] MAGOON, K.E.; HSU, W.H.; HEMBROUGH, F.B. The influence of atropine on the cardiopulmonary effects of a xylazine-ketamine combination in dogs. Arch. Int. Pharmacodyn. Thér., v.293, p.143-153, 1988.

[15] MARINI, R.P.; LI, X.; HARPSTER, N.K.; DANGLER, C. Cardiovascular pathology possibly associated with ketamine/xylazine anesthesia in Dutch belted rabbits. Lab. Anim. Sci., v.49, p.153-160, 1999.

[16] MILLER, L.M.; GAL, A. Cardiovascular system and lymphatic vessels. In: ZACHARY, J.F. (Ed.). Pathologic basis of veterinary disease. 6.ed. St. Louis: Elsevier, 2017. p.561-616.