Ketamine and Sphynx Cats

Sphynx cats are a relatively rare, exotic feline breed with hairless mutation. The current Sphynx breed has been developed from Devon Rex crossed with other feline breeds, and it has a strong genetic relationship with the former.¹

Sphynx cats have unique characteristics in terms of appearance, temperament, and attitude toward other pets and humans.² For these reasons, they may often be perceived by their breeders and owners as extraordinary, special cats. The widespread information that is available on the internet often focuses on breed-related peculiarities, for which a breed-specific medical management approach is recommended when dealing with these cats.^3–5 Particularly, lots of information pertaining to the use of ketamine and Sphynx cats is available online, in websites and blogs mostly managed by Sphynx cats’ breeders and owners.^4,5 According to that widespread information, ketamine is often regarded as a potentially dangerous, even lethal drug for Devon Rex and related cat breeds.^3–5

The aim of this article is to shed light, based on the published literature, on the presumed breed-related toxicity of ketamine in Sphynx cats.

What We Know

Many of the websites dedicated to Sphynx cats report various deaths in apparently healthy Sphynx cats following anesthesia for routine elective procedures, such as dental cleaning and neutering.^4,5 These websites often refer to an article originally published in 1992, in French language, by Houard in a magazine for cat owners.⁶ Although, being a magazine article, the original source is extraordinarily difficult to find, its transcription, as well as the translation of the text in English language, is accessible online.^3–5 Houard reported an unspecified number of deaths of Devon Rex cats following ketamine-based anesthesia that occurred in both France and the Netherlands.

According to the article transcription available on the internet, Houard referred to two different types of ketamine-related accidents: an acute form that would cause death within a few hours owing to seizures and central nervous system excitement, and a subacute form characterized by sharp increase in creatine phosphokinase and progressive muscular pain, often accompanied by signs of liver damage and hypoglycemia.⁶ This article aimed at cat owners has several limitations as many details are missing. There is no information pertaining to the number of cats that died, whether they were in good health or not, which anesthetic/sedative agents other than ketamine were used, and whether postmortem examination was performed. Moreover, it should be mentioned that the transcription of the article, which is the only document ever accessible online, was not made available directly by the author. Nevertheless, for years this article has been cited in various websites and also a doctoral thesis written by a veterinarian and focusing on the characteristics of Sphynx cats warns against the use of ketamine in this cat breed based on the work of Houard.^2–4 The latter, written by a veterinarian, warns against the use of ketamine in Sphynx cats based on the work of Houard.

In 1992, the Bureau of Veterinary Drugs reported the death of two cats, and the occurrence of profound, prolonged sedation in another one, following IV administration of ketamine.⁷ Of the cats that died, one was diagnosed with fatty liver syndrome during necroscopic examination, and the other one had previous history of acute nephritis. In the cat that experienced prolonged recovery, the dose, based on body weight, was inaccurately determined. The breed of the cats, however, was not reported.

Based on the published literature, there is no evidence that ketamine itself may cause death in Sphynx cats owing to some kind of breed-specific toxicity of the drug. The reasons for the adverse reactions anecdotally reported in Sphynx cats may, however, be researched in the predisposition of Sphynx cats to develop certain specific diseases, which may contribute to exacerbate the side effects of ketamine, potentially leading to a lethal outcome.

Cardiovascular Effects of Ketamine and Cardiac Diseases in Sphynx Cats

Ketamine’s effects on the cardiovascular system, in cats as well as other animal models, are well known since the 1970s.^8–10 Besides direct negative inotropy exerted on the myocardium—mostly observed in the face of absent or depleted sympathetic stimulation—the drug can increase arterial blood pressure, heart rate, cardiac output, cardiac work, and myocardial oxygen consumption through stimulation of the sympathetic autonomic nervous system, which ultimately results in a positive inotropic effect.^8–10 Two studies carried out in cats suggested that such stimulating cardiovascular effects are exerted by ketamine via a central, rather than peripheral, mechanism.^9,10 The most significant cardiovascular changes seem to occur in cats between 5 and 45 min after ketamine anesthetic induction.¹¹

Ketamine-based anesthesia is considered relatively contraindicated in cats with hypertrophic cardiomyopathy (HCM).¹² The rationale behind this is that the indirect stimulation of the heart caused by ketamine may further exacerbate myocardial oxygen consumption and lead to a critical point where oxygen delivery to the myocardium no longer matches its oxygen demand.^13,14 Moreover, the potential for tachyarrhythmias following ketamine induction may precipitate the oxygen debt further.^13,14

Familial HCM with autosomal dominant inheritance has been described in Maine Coon cats, and a similar inheritance pattern has been reported in Ragdolls, American shorthairs, and British shorthairs.^15–19 Although HCM is a common finding in Sphynx cats—and it is generally believed that a genetic predisposition for this condition does exist in Devon Rex and related breeds—the mode of inheritance for these breeds has not been elucidated yet.²⁰ Beside HCM, the incidence of cardiac abnormalities in Sphynx cats seems to be elevated.^21,22 One study found that of 131 Sphynx cats undergoing cardiac screening prior to breeding, approximately 33% had cardiac abnormalities as detected by echocardiography.²³ Thirty-five cats showed changes compatible with development of HCM, six had congenital abnormalities such as mitral valve dysplasia, and two had a heart rate above 250 beats per min. Moreover, although this finding was explained with their young age compared with the control group, the average heart rate of the Sphynx cats enrolled in the study was significantly higher than in the non-Sphynx cats.²³

Beside the presence of HCM, the administration of ketamine in cats with tachycardia of whatever origin may predispose to the development of oxygen debt as well as potentially dangerous tachyarrhythmias.^13,14

Neuromuscular Effects of Ketamine and Muscular Dystrophy in Sphynx and Devon Rex Cats

The neurophysiological effects of ketamine have been extensively investigated in the feline model in the late 1960s to early 1970s.^24,25 When administered intraperitoneally, racemic ketamine produced dose-dependent behavioral and electroencephalographic (EEG) changes, characterized by restlessness, excitement, and EEG desynchronization at lower doses (10 mg/kg); excitement with inability to move and sporadic EEG hypersynchrony at moderately high doses (>10 and <20 mg/kg); and excitement, profound catatonia with maintained neck muscular tone, and intermittent hypersynchrony at higher doses (20–50 mg/kg).²⁴ Generalized electrographic seizures were detected at high doses even in the absence of behavioral convulsion, suggesting that ketamine may have potential proepileptogenic properties in cats.²⁴

The doses of ketamine used in the aforementioned experimental studies were higher than the currently recommended ones for feline clinical patients, which are between 2 and 10 mg/kg for IV use.²⁶ Nevertheless, it is worth mentioning that the occurrence of behavioral seizures, characterized by tonic and clonic motor activity, muscular hypertonia, loss of sensation, and unconsciousness, has been reported in dogs and humans following administration of clinical doses of S-ketamine and ketamine, respectively.^27,28 Because of its potential proepileptogenic properties, ketamine is usually administered in combination with sedative agents, namely, benzodiazepines and alpha-2 adrenoreceptor agonists, which help to achieve a smoother anesthetic induction.

According to the article transcription, Houard referred to an acute form of adverse reaction to ketamine characterized by seizures and central nervous system excitement that would cause death within a few hours.⁶ It is reasonable to assume that, in cats with undiagnosed intracranial conditions, ketamine may exacerbate a pre-existing predisposition and lower the threshold for seizures acting as proepileptogenic agent. To the best of the authors’ knowledge, however, no breed predisposition to intracranial diseases has been identified for Sphynx cats.

A possible, less likely alternative explanation for the unexplained acute deaths in Sphynx cats anesthetized with ketamine is that the altered muscular tone often observed during ketamine anesthesia may perturb the homeostasis of already diseased skeletal muscles, leading to postanesthetic muscular dysfunction. A form of congenital muscular dystrophy associated with α-dystroglycan deficiency, characterized by excessive variability in myofiber size and internal nuclei, has been identified in Sphynx and Devon Rex cats.²⁹ Common physical findings in the affected subjects are appendicular weakness, fatigability, passive ventroflexion of the head and neck, and megaesophagus; death is often caused by aspiration and choking.²⁹ Another type of myopathy characterized by tubulin-reactive inclusions was identified in two cats, one of whom was a Devon Rex.³⁰ Although these cats mostly showed generalized weakness, the Devon Rex also had episodes of spastic behavior with stiff thoracic and pelvic limbs, a condition that could potentially be exacerbated by ketamine-induced muscular hypertonia. Another neuromuscular condition characterized by spasticity, assumed to be inherited as a recessive trait from normal parents, was described in Sphynx kittens during the late 1980s.³¹

In various dedicated websites, the “spasticity gene” has often been considered implicated in the ketamine-related deaths of Sphynx cats.^4,5 Nevertheless, it is worth considering that death of cats with pre-existing muscular disease was never reported following ketamine administration. Moreover, the congenital myopathies of Sphynx cats are usually associated with severe symptoms, which makes the occurrence of undetected, subclinical muscular abnormalities unlikely in these cats.

These authors’ opinion is that if any death occurred in Sphynx cats after ketamine as a result of muscular hypertonia, the latter was more likely to be part of a convulsive syndrome, rather than the effect of ketamine on diseased skeletal muscles.

Other Theories: Effects of Ketamine on Renal Function

In cats, ketamine is considered contraindicated in the presence of severe renal insufficiency.³² The rationale for this is that cats are different from most animal species with respect to the metabolization and elimination of ketamine. Whereas in most species ketamine is metabolized in the liver by demethylation and hydroxylation, and the resulting inactive metabolites are excreted in the urine along with the parent compound, in cats ketamine is excreted either unchanged or as norketamine, an active compound produced from ketamine degradation, in the urine.^33–36 Therefore, an underlying kidney dysfunction may slow down the elimination of the active drug from the body, potentially prolonging the anesthetic effects of ketamine.

Among the ketamine-related deaths reported in cats by the Bureau of Veterinary Drugs, one cat of unknown breed had previous history of acute nephritis and was diagnosed with nephrosis at necroscopic examination.⁷ However, although it is probably advisable to use ketamine with care in those cat breeds with a genetic predisposition to develop renal diseases, such as Persian and Exotic shorthairs,^37,38 whether Sphynx cats suffer from inherited kidney abnormalities remains debatable.

Idiosyncratic Drug-Induced Acute Liver Failure

In the United States, idiosyncratic drug‐induced liver injury ranks second in the overall causes of acute liver failure affecting human patients, behind acetaminophen‐induced hepatotoxicity.³⁹ Although the exact pathogenesis of the syndrome has never been fully elucidated, the word “idiosyncratic” itself implies the presence of a unique feature within the patient affected that makes them unable to deal with the drug that has been administered. The fatal drug reaction appears randomly, certainly unexpected, because of unique genetic reasons for each case. The production of reactive metabolites following drug administration, as well as the development of immune-mediated reactions, with or without the involvement of macrophages, has been proposed as a potential cause; however, the specific mechanisms remain to be identified.^40–42

It cannot be excluded that some of the reported ketamine-induced deaths in Sphynx cats were caused by an idiosyncratic reaction. Nevertheless, such cases would be rare and should be interpreted as individual-related—rather than breed-related—accidents.

Authors’ Conclusions

Based on the published literature, there is no evidence that ketamine would cause death in Sphynx cats for a breed-specific sensitivity to the drug itself.

There is, however, some evidence that Sphynx cats are prone to develop certain specific conditions, particularly cardiac diseases, which could exacerbate the undesired effects of ketamine, potentially leading to lethal outcome.

In the absence of a proper medical examination that could help exclude the presence of underlying cardiac dysfunctions, a precautionary measure could be to avoid the use of ketamine for anesthetic induction in both Sphynx and Devon Rex cats.