Sedation for Cats with Cardiovascular Disease

Cats represent a large part of the US pet population; as of 2012, the approximately 74.1 million cats outnumbered the approximately 69.9 million dogs in this country. Although these numbers represent an overall decline in dog and cat populations, the proportion of cats that are mature (>7 years old) or geriatric (>11 years old) has increased to the point that older cats now represent 50% of the household cat population.^1,2 Although advancing age itself is not a disease, geriatric animals are more likely than young animals to have acquired diseases and to function at near maximum cardiovascular capacity. The majority of cardiac diseases in cats are acquired and progressive; the minority are congenital.³ The limited cardiovascular reserves of geriatric animals and the development of heart disease with increased age place these animals at relatively higher risk during sedation or anesthesia.^4,5

To minimize this risk, keep in mind that there are no safe sedative or anesthetic drugs; there are only safe practices in their delivery. A knowledge of the physical status of the animal and of drug pharmacologic effects as they apply to the cardiovascular system will help you select the safest sedative protocol for the animal.

Physical Status

Development of safe sedative or anesthetic protocols requires an understanding of the type and severity of a patient’s cardiac disease. Unfortunately, this information is often unknown at the time of sedation or anesthesia, sometimes because of the need for sedation before diagnostics can be performed (e.g., physical examination, echocardiography, thoracic radiography, blood collection) and sometimes because the client has declined to pursue some or all of these diagnostics. You may have to develop a sedative or anesthetic protocol without knowing if the cat has underlying cardiovascular disease.

Physical assessment, in particular cardiac auscultation, is always recommended but can be of limited value in determining whether a cat has cardiac disease. The incidence of heart murmurs in apparently healthy cats is only 16% to 44%.^6-8 The prevalence of cardiomyopathy detected by echocardiography in a large population of shelter cats was 15.3%, and the most prevalent primary heart disease in these cats was hypertrophic cardiomyopathy.⁸ For cats with heart disease, arrhythmias may have more predictive value than heart murmurs. In another study, echocardiographic evidence of structural heart disease was present for 96% of cats with ventricular arrhythmias, including premature ventricular complexes, ventricular tachycardia, and accelerated idioventricular rhythm.⁹ Thoracic radiographs are indicated for cats suspected of having heart disease but have low sensitivity for detecting hypertrophic heart disease. To help guide the diagnosis, testing for N-terminal pro B-type natriuretic peptide (NT-proBNP), a peptide rapidly produced by myocardial cells after stretch or hypoxia, can be used. Levels >100 pmol/L are suggestive of myocardial stretch or hypoxia and indicate a need for additional diagnostics for cardiac workup (e.g., thoracic radiographs, blood pressure, blood chemistry, thyroid panel). Respiratory signs accompanying an NT-proBNP level ≥270 pmol/L are suggestive of cardiac disease origin and indicate the need for further cardiac diagnostics.¹⁰ Those cats with symptomatic heart disease often exhibit reduced body conditioning, abnormal lung sounds, and pale or cyanotic mucus membranes, coupled with a history of tachypnea or dyspnea, lethargy, and/or inappetence.

Cats with cardiomyopathies present unique sedation and anesthesia challenges, depending on the type of myocardial disease. Although numerous cardiomyopathies occur in cats, the most common is hypertrophic (obstructive) cardiomyopathy. This disease is characterized by diffuse or segmental hypertrophy of the left ventricular myocardium with development of cardiomyofiber disarray. Left ventricular outflow tract obstruction can develop as a result of systolic anterior motion of the mitral valve leaflet. Also common are left atrial dilation and mitral valve regurgitation. These phenotypic changes result in a heart that consumes more oxygen because the myocardium is performing more work, is prone to arrhythmias, and is sensitive to fluid challenges or overload.¹¹ While cats are in a hospital setting, their increased stress level is reflected by clinically significant increases in heart rate, respiratory rate, and blood pressure.¹² Although these changes did not seem detrimental to healthy cats studied, these changes may cause complications in cats with cardiomyopathy.

Drugs for Sedation of Cats with Cardiac Disease

The ideal sedative or anesthetic agent for cats with cardiac disease would be one that causes sedation or anesthesia without cardiorespiratory depression. Unfortunately, for cats, no single drug provides the optimal balance of sedation without cardiorespiratory depression; therefore, the clinician must select a drug combination that produces the least amount of cardiorespiratory depression with the best quality of sedation. The drugs commonly used to produce sedation or anesthesia in cats are opioids, benzodiazepines, antiepileptics (gabapentin), phenothiazines, alpha-2 agonists, and injectable anesthetics (e.g., ketamine, alfaxalone, propofol, etomidate).

Opioids

Opioids have minimal negative cardiovascular effects and are thus desirable drugs for sedating or anesthetizing cats with cardiac disease. The most common cardiac side effect of opioids is vagally mediated bradycardia, which may be negligible in cats because of their propensity for increased sympathetic tone while in the hospital and because opioids can also stimulate their sympathetic nervous system.^13-15 The vagally mediated bradycardia can be offset with anticholinergic drugs (e.g., atropine or glycopyrrolate); however, these drugs will increase heart rate, myocardial work, and oxygen consumption, none of which are desirable in cats with hypertrophic heart disease. Therefore, anticholinergics should be considered only if the opioid produces severe bradycardia (i.e., heart rate <120 beats/min). The activation of the sympathetic nervous system has led to the association of opioids and excitement in cats. Morphine and other pure mu opioid agonists have been reported to cause excitation in cats; however, the studies demonstrating this effect used supra clinical doses in cats not experiencing pain.^16,17 Although sedative effects in cats are also minimal when pure mu opioid agonists are administered, the cats often become euphoric, as demonstrated by rubbing, purring, rolling, and kneading with the front paws. An opioid alone provides mild sedation that is usually enhanced by concurrently administering a sedative or low dose of an injectable anesthetic drug. Butorphanol, a mu antagonist and kappa agonist, usually produces good-quality sedation in cats with minimal untoward effects, such as ptyalism or dysphoria.^18,19

Benzodiazepines

Midazolam and diazepam are benzodiazepines commonly used as anesthetic and sedative adjuncts because they augment the effects of other sedatives and anesthetics without producing cardiorespiratory depression. These drugs produce centrally mediated muscle relaxation and anxiolysis by potentiating the neurotransmitter gamma aminobutyric acid (GABA). Despite this mechanism of action, sedation is often mild or may not observed, particularly when one of these drugs is administered alone. Paradoxical responses (e.g., resisting restraint, growling, hissing, attempting to escape) have been observed in cats that initially appear sedate after being given benzodiazepines.^20,21 This potential response is especially noteworthy when the drug is used to facilitate procedures necessitating restraint (e.g., echocardiography, radiography). Although benzodiazepines have a wide therapeutic index and are very effective muscle relaxants when co-administered with other sedatives or injectable anesthetics, supratherapeutic doses (>0.5 mg/kg) can produce muscle rigidity and poor-quality sedation or anesthesia.²²

Phenothiazines

Acepromazine is a phenothiazine sedative that antagonizes the effects of dopaminergic neurotransmission in the limbic and hypothalamic systems. It produces sedative and anxiolytic effects without producing analgesia. Compared with the response in dogs, equal doses in cats produce less profound sedation but adequate tranquilization. Acepromazine produces vasodilation mediated through alpha-1 adrenergic blockade on vascular smooth muscles. This effect might be particularly detrimental in cats with obstructive hypertrophic cardiomyopathy because reducing afterload exacerbates the pressure gradient across the left ventricular outflow tract. In addition, hypotension resulting from alpha-1 blockade could also decrease coronary perfusion pressure. Acepromazine has antiarrhythmic properties, which have been demonstrated by increasing the threshold for epinephrine-induced arrhythmias in dogs.²³ Use of acepromazine in combination with other sedatives/anesthetics to facilitate echocardiography in healthy cats has been evaluated; effects were limited to mild decreases in blood pressure (when administered with an opioid) or increases in heart rate (when administered with an opioid and ketamine).²⁴ Acepromazine use in cats with suspected or confirmed heart disease should be avoided if safer alternatives are available.

Alpha-2 Agonists

Dexmedetomidine is a highly selective alpha-2 adrenoceptor agonist that produces excellent centrally mediated sedation and dose-dependent analgesia. However, it also causes profound cardiovascular depression.²⁵ Alpha-2 adrenoceptor agonists produce a biphasic cardiovascular response. Initially, alpha-1 and alpha-2 adrenoceptor-mediated vasoconstriction causes increased systemic vascular resistance and blood pressure, resulting in a baroreceptor reflex mediated decrease in heart rate. Subsequently, the bradycardia persists and blood pressure decreases because of reduced sympathetic outflow and circulating catecholamines and an impaired stress response (reduced cortisol secretion).²⁶ Use of this class of drugs should generally be avoided in animals with cardiovascular disease; however, in one study, when administered intramuscularly, medetomidine had the desirable effects of reducing heart rate and eliminating left ventricular outflow tract obstruction in cats with hypertrophic obstructive cardiomyopathy.²⁷

Gabapentin

Gabapentin is an antiepileptic drug that consists of a GABA molecule covalently bound to a lipophilic cyclohexane ring. It produces antihyperalgesic effects on neuropathic pain in people and certain neuropathic pain conditions in dogs and cats. The exact mechanism of action for the analgesic and mild sedative effects are unknown, but gabapentin does bind the α2δ-1 subunit of N-type voltage-gated calcium channels, which are densely populated in the dorsal horn of the spinal cord and interfere with sodium entry through presynaptic N-methyl-D-aspartate (NMDA) receptor channels. A supraspinal effect also may contribute to the analgesic and sedative effects. Descending bulbospinal noradrenergic inhibition is activated in the locus coeruleus that enhances noradrenergic release at the spinal level.^28,29 A side effect of gabapentin can be mild sedation, which can be desirable in certain conditions. For cats at home, even those without neuropathic pain, gabapentin can be a sedative option. Gabapentin can also be used when clients are taking cats to the veterinary hospital; 50 to 100 mg PO administered 2 to 3 hours beforehand will produce mild to heavy sedation and possible ataxia. Gabapentin produces no known cardiovascular effects, direct or indirect, in cats.

Injectable Anesthetics

Ketamine
Ketamine is an NMDA receptor antagonist. It is thought to produce anesthesia by overstimulating selective sites in the central nervous system (CNS) and inducing a cataleptic state. It depresses the thalamoneocortical system and activates the limbic system, thereby producing a dissociative state.³⁰ Ketamine produces both direct and indirect effects on the cardiovascular system. Stimulation of the CNS produces a sympathomimetic effect that allows ketamine to indirectly increase cardiovascular parameters (cardiac output, heart rate, mean aortic pressure, and pulmonary artery pressure) via norepinephrine release. This increased myocardial work and oxygen consumption is most profound at anesthetic doses (5 to 10 mg/kg IV) and can be detrimental to cats with cardiovascular disease, especially hypertrophic heart disease, potentially causing ventricular arrhythmias. Ketamine produces direct myocardial depressant and vasodilatory effects that occur in the absence of sympathomimetic effects; the overall cardiovascular effect is probably a product of the patient’s underlying sympathetic tone.^31,32 Cats anesthetized with ketamine retain protective reflexes (coughing, swallowing) and other reflexes (corneal, pedal). This drug is also considered a potent noncompetitive antagonist at NMDA receptors in the spinal cord, which are thought to be responsible for wind-up pain. Ketamine is unique in that it provides analgesia and with increasing doses; its effects range from sedation to general anesthesia. Low doses (1 to 3 mg/kg IM) of ketamine coadministered with an opioid and sedative or muscle relaxant can produce profound sedation with minimal cardiovascular changes.²⁴ When cats with unknown cardiovascular status need to be sedated or chemically restrained because they are difficult to handle (e.g., aggressive cats), a low-dose ketamine-based sedation protocol (≤2 mg/kg IM or IV) may produce the least harmful side effects compared with alternative options (alpha-2 agonists, volatile inhalant chamber induction). For cats with confirmed hypertrophic cardiomyopathy, alternative anesthetics that do not have such a profound stimulant effect on the cardiovascular system (e.g., alfaxalone) may be used.

Alfaxalone
Alfaxalone is a synthetic water-soluble neurosteroidal anesthetic that binds GABA type A receptors and potentiates the effect of endogenous GABA to create a hypnotic anesthetic state. Increasing doses of alfaxalone in cats will produce a dose-dependent decrease in cardiac output and arterial blood pressure; however, at clinical doses, heart rate is preserved and decreases in systemic vascular resistance are minimal.^33,34 Alfaxalone presents an advantage over other injectable anesthetics in its ability to be injected intramuscularly to facilitate sedation and physical restraint, which could be advantageous for echocardiographic analysis in difficult-to-handle cats. Recumbency and sedation after intramuscular injection is generally observed within 2 to 15 minutes and lasts approximately 30 minutes.

The only other injectable anesthetic labeled for intramuscular use is ketamine. Combinations of alfaxalone with butorphanol administered intramuscularly to healthy cats produced significant decreases in fractional shortening and ejection fraction but no effect on heart rate or left ventricular internal diameter at systole or diastole.³⁵

Propofol
Propofol is a short-acting sedative hypnotic that produces anesthesia by binding GABAA receptors and potentiating GABA-induced chloride conductance. Although its mechanism of action is similar to that of increasing doses of alfaxalone, propofol differs from alfaxalone in its cardiovascular effects. Propofol produces dose-dependent reductions in systemic blood pressure, myocardial contractility (negative inotropy), and cardiac output; these effects are more pronounced in the hypovolemic animal.³⁶ In addition to arteriolar dilation, which serves to decrease afterload, venodilation also occurs and results in reduced preload and cardiac output.³⁷ In general, because of propofol’s vasodilatory effects, its use in cats with hypertrophic cardiomyopathy should be avoided if other sedative or anesthetic options are available.

Etomidate
Etomidate is a short-acting hypnotic anesthetic that produces its anesthetic action through binding and positive modulation of GABA_A receptors in the CNS. Cardiovascular function is largely preserved, with minimal changes to heart rate, blood pressure, or cardiac output. Because of its hyperosmolarity, etomidate is considered a vascular irritant and therefore can be administered intravenously only. It is highly desirable for anesthetic induction of cats with cardiovascular disease but is not useful as a sedative.

Cardiovascular Drugs That Affect Anesthesia

Cats with cardiomyopathy that need to be sedated or immobilized are often receiving cardiac drugs that can affect the sedation or anesthetic period. To develop a safe sedative protocol, a working knowledge of the effects of these drugs is necessary.

When dynamic left ventricular outflow tract obstruction is present in the absence of congestive heart failure, beta-blockers such as atenolol are used. Atenolol unloads the work of the hypertrophic heart through its negative chronotropic (decreased heart rate), dromotropic (decreased conduction), and inotropic (decreased contractility) as well as its antiarrhythmic and ischemic effects. These effects will be compounded by sedative or anesthetic drugs that have myocardial depressant effects (propofol, alfaxalone, alpha-2 agonists, and inhalant anesthetics) and bradycardic effects (opioids). Withdrawal of beta-blockers before inducing sedation or anesthesia is generally not indicated.

For bradycardic or hypotensive cats, heart rate and blood pressure support during deep sedation or anesthesia may be necessary.

For cats with echocardiographic evidence of systolic dysfunction, pimobendan, a phosphodiesterase 3 inhibitor, is used because of its inodilator (positive inotropic and vasodilatory) effects. These effects are generally desirable, and pimobendan should not be withdrawn before inducing anesthesia.

For cats that have a current thrombus, a history of thromboembolic disease, spontaneous echogenic contrast, and left atrial enlargement, antithrombotic drugs are used. These include both antiplatelet (clopidogrel, aspirin) and anticoagulant (enoxaparin, dalteparin, apixaban, rivaroxaban, and factor IIa inhibitors) drugs. Hemodynamic effects (i.e., hypotension resulting from hemorrhage) might be expected if antithrombotic drugs are not withdrawn before surgical procedures are performed or if inadequate hemostasis occurs during surgery.

Risk Reduction

Isoflurane and sevoflurane are halogenated volatile inhalant anesthetic drugs used to maintain anesthesia in small animals. These drugs produce dose-dependent cardiovascular depression through depression of inward calcium currents through the sarcolemma and decreased sarcoplasmic reticulum function. The result is reduced myocardial contractility (negative inotropy) and vasodilation, which are more profound in hypertrophic myocardium.^38,39 Given the dose-dependent depression of myocardial contractility and vasodilation, it is never advised to use chamber or mask induction or immobilization with a volatile inhalant anesthetic in difficult-to-handle cats that have or are suspected to have cardiovascular disease. This technique induces a profound stress response and requires excessive anesthetic depth to facilitate handling or anesthetic induction.

Other ways to reduce risk for death associated with administration of sedatives or anesthetics, even if only for brief periods of sedation, is to monitor pulse and pulse oximetry, which is strongly recommended.⁴ For cats with cardiovascular disease, additional monitoring (e.g., performing electrocardiography and measuring blood pressure and temperature) is also advised.