The effect of pre-anaesthetic medication on the incidence of cardiac arrhythmias during halothane anaesthesia in cats

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1 The effect of pre-anaesthetic medication on the incidence of cardiac arrhythmias during halothane anaesthesia in cats KP Walsh, BVetMed, CertVA, MRCVS, JC Brearley, MA, VetMB, DVA, Dip ECVA, PhD, MRCVS and KS Cullum-Hanshaw, Dip AVN (surgical) The Centre for Small Animal Studies, Animal Health Trust, Newmarket, Suffolk, CB8 7UU, UK. Correspondence: KP Walsh, The Animal Health Trust, Lanwades Park, Newmarket, Suffolk CB8 7UU, UK. Abstract Objective To compare the incidence of arrhythmias in cats receiving either acepromazine or diazepam for pre-anaesthetic medication prior to halothane anaesthesia. Study design A blinded, randomized clinical study. Animals Forty-six healthy cats undergoing surgery. Methods Animals were allocated to one of two groups for pre-anaesthetic medication. Group 1 received diazepam (0.2 mg kg 1 ). Group 2 received acepromazine (0.02 mg kg 1 ). The trial drug was administered intramuscularly in combination with buprenorphine (0.01 mg kg 1 ) 30 minutes prior to induction of anaesthesia with propofol (approximately 5 mg kg 1 ). Anaesthesia was maintained using halothane: delivered concentration was 1 2% carried in oxygen and nitrous oxide via an endotracheal tube attached to an Ayre s T-piece (with Jackson-Rees modification) breathing system. The incidence of cardiac arrhythmias was determined by continuously monitoring the electrocardiogram from the time of induction until recovery occurred. Demographical group characteristics were compared using analysis of variance. The incidence of cardiac arrhythmias was compared by the Chi squared test. Statistical significance was set at the 5% level. Results The two groups were similar in weight, age, length and type of procedure undertaken. The incidence of arrhythmias was the same in each group (3/23 cases) (p = 1.0). Conclusions The incidence of cardiac arrhythmias in this study did not appear to be influenced by the nature of pre-anaesthetic medication. Clinical relevance The incidence of cardiac arrhythmias under halothane anaesthesia was 13% in this study. Acepromazine did not appear to exert an antiarrhythmic effect. This may not be the case in a larger scale study. Keywords Acepromazine, anaesthesia, cardiac arrhythmias, cats, diazepam, pre-anaesthetic medication. Introduction Pre-anaesthetic medication is given for various reasons: to produce conditions that facilitate handling; to reduce doses of induction and/or maintenance anaesthetic agents; to reduce variation in depth of anaesthesia with varying stimulation; to provide pre-emptive analgesia and/or to address particular clinical problems. These requirements are often met when neuroleptanalgesic combinations the combination of a neuroleptic drug with sedative properties and an opioid analgesic drug are used. There is a synergistic effect between each component in producing sedation, which allows a reduction in the dose of neuroleptic agent required to produce a given level of effect. This is desirable because it may reduce the severity and/or incidence of undesirable 45

2 side-effects. However, the magnitude of desirable sideeffects may also be reduced. Acepromazine is a phenothiazine derivative commonly used in veterinary anaesthesia as a sedative tranquilizer. It has an antagonistic effect at various receptors including cholinoreceptors and a 1 adrenoreceptors. These receptors are found in numerous central nervous and autonomic nervous pathways, which may account for acepromazine s widespread effects. One desirable effect attributed to the drug is its myocardial protective effect against catecholamineinduced arrhythmias (Thurmon et al. 1996). In some cases, acepromazine may be administered specifically to achieve this effect. For example, tranquillization may be required before a known arrhythmogenic agent is to be administered, or when the myocardium may is in an unstable, arrhythmia-prone state. The majority of studies investigating the myocardial protective mechanism of acepromazine have involved adrenaline challenge (Claborn & Szabuniewicz 1973; Wiersig et al. 1974; Muir et al. 1975) and abnormally high doses of acepromazine, e.g. 0.4 (Muir et al. 1975) and 1.0 mg kg 1 (Claborn & Szabuniewicz 1973; Wiersig et al. 1974). Moreover, acepromazine was given IV in these studies: the intramuscular and subcutaneous routes are more commonly used in general practice. Diazepam, a benzodiazepine tranquilliser, is not thought to have direct anti-arrhythmic properties per se, but may contribute to cardiac stability by reducing sympathetic tone (Hubbell & et al. 1984). It does not affect cardiac rhythm in dogs (Haskins et al. 1986). The sedative effects of diazepam are less predictable than those of acepromazine and so it is less commonly used for pre-anaesthetic medication (Brearley 1994). However, it is useful in specific cases, for example, in animals with epilepsy, or when ketamine is to be used. Buprenorphine is a partial opioid agonist commonly given with acepromazine to produce neuroleptanalgesia; the combination is popular in the United Kingdom. It was used for pre-anaesthetic medication in this study: (a) to lower the dose of acepromazine or diazepam required for sedation; and (b) to provide peri-operative analgesia. To our knowledge it has no anti-arrhythmic properties. There appears to be very little information on the incidence of cardiac arrhythmias in cats and dogs during halothane, or any other type of anaesthesia (Cohen & Tilley 1979). In humans, the incidence lies between 20 and 50% (Katz & Bigger 1970). The null hypothesis tested in this study was that the use 46 of acepromazine at clinical doses does not protect the myocardium against spontaneously arising cardiac arrhythmias, when compared with diazepam. Materials and methods Forty-six cats presented for surgery were involved in the study. Pre-operative examination involved a full clinical examination including auscultation of the heart and lungs. Animals suffering from any cardiopulmonary disease, or any condition predisposing to cardiac arrhythmias were excluded from the study. Electrocardiography was not performed. The cats were allocated to one of two treatment groups using a pseudo-random number generator. Cats in Group 1 received 0.2 mg kg 1 of diazepam (Diazamuls: Dumex Ltd, Princes Risborough, Bucks, UK) and 0.01 mg kg 1 buprenorphine (Vetergesic; Animalcare Ltd, Dunnington, York, UK) by intramuscular (IM) injection. Cats in Group 2 received 0.05 mg kg 1 acepromazine (ACP; Vericore, Marlow, UK) and 0.01 mg kg 1 buprenorphine IM. Both combinations were given at least 30 minutes before induction of anaesthesia. The cats also received carprofen (Rimadyl 5%; Pfizer Ltd, Sandwich, Kent, UK) 4 mg kg 1 by subcutaneous injection before surgery began. The anaesthetist was unaware of the treatment allocated. Anaesthesia was induced with propofol (Rapinovet; Schering Plough, Uxbridge, Middlesex, UK) via a pre-placed catheter in the cephalic vein. The drug was injected over approximately 30 seconds after which the laryngeal mucosa was desensitized using a lignocaine aerosol. An uncuffed endotracheal tube ( mm OD) was then inserted. Anaesthesia was maintained with halothane delivered in a carrier gas mixture of oxygen and nitrous oxide (1 : 2 ratio) using a Jackson-Rees modified Ayre s T- piece breathing system. Total gas flow was 3 L min 1. Halothane was delivered using a precision vaporizer (Ohmeda Tec Mark 3; Steeton, West Yorkshire, UK) with delivered concentrations set between 1% and 2% throughout anaesthesia. A heat and moisture exchange device was placed between the endotracheal tube and the anaesthetic breathing system to limit heat loss. During surgery, the patient was placed on a heated waterbed. Monitoring during anaesthesia consisted of: systolic blood pressure (using a Doppler flow probe in combination with an occlusive cuff); capnography; pulse rate by direct palpation of the metatarsal

3 artery; respiratory rate by observation of the reservoir bag and core body temperature using an oesophageal thermistor. The electrocardiogram (ECG) was monitored continuously using lead II. The rhythm and any abnormalities observed were recorded at five minute intervals along with the values of other monitored variables. The electrocardiograph had a cascade display that allowed screen capture of the ECG. This allowed close analysis of any observed arrhythmia. No paper record of rhythm disturbances was taken. An arrhythmia was defined as any ECG pattern other than sinus rhythm. When these led to pulse deficits or a decrease in systolic blood pressure then the inhalation agent was changed from halothane to isoflurane. Arrhythmias were described as being present or absent. Statistical significance between the two groups was assessed by a chi-square test. Significance was taken at the 5% level. Results Twenty-three cats received acepromazine and buprenorphine and 23 cats received diazepam/ buprenorphine. There was no difference in terms of sex, weight and age distribution between the two groups (Table 1). The total dose of propofol required for endotracheal intubation was approximately 5 mg kg 1. The types of surgical procedure performed in each group are shown in Table 2. There was no significant difference between the two groups in terms of heart rate, respiratory rate, end-tidal CO 2 tension and blood pressure during anaesthesia (Table 3). Temperature decreased in all cases during anaesthesia but remained above 37 C in all except one. One cat was anaesthetised for 105 minutes and its oesophageal temperature decreased to 36 C. No arrhythmias were observed in this case. Three cats in each group exhibited arrhythmias. Unimorphic premature ventricular complexes (PVCs) were observed in two cats in group 1 while multimorphic premature ventricular complexes were seen in a third. In the latter case, sinus rhythm was restored when the inhalational agent was changed to isoflurane. Occasional ventricular premature complexes were seen in two animals in group 2. A third cat developed sinus bradycardia (HR = 46) and was given atropine, whereupon premature ventricular complexes were seen followed by sinus rhythm. Discussion Possible causes of cardiac arrhythmias during general anaesthesia include myocardial ischaemia, hypoxia, autonomic imbalance, hypercapnia, hypothermia, acid-base and electrolyte abnormalities and surgical manipulation. Direct electrophysiological effects of sedatives and anaesthetic drugs have also been implicated including halothane in dogs (Muir et al. 1975). Halothane has been shown to alter cardiac membrane ionic fluxes, which decrease refractoriness and the conduction velocity of electrical impulses. These may lead to the development of re-entrant types of ventricular arrhythmias (Muir et al. 1988). It is also thought that halothane may stimulate post-synaptic a 1 adrenoreceptors and sensitize the myocardium to adrenaline a possibility that is supported by the observation that a 1 antagonists prevent adrenalineinduced arrhythmias in dogs anaesthetized with halothane (Maze et al. 1985). Pre-anaesthetic medication with acepromazine may counteract the arrhythmogenic effects of halothane in a variety of ways. Phenothiazines may act as membrane stabilisers ; produce a slight ganglionic blocking effect; cause peripheral cholinergic receptor blockade, exert strong adrenergic blocking activity Table 1 Summary statistics showing sample size (n) mean 2 standard deviation and range for weight, age and duration of anaesthesia n Weight (kg) ( ) ( ) Age (years) ( ) ( ) Duration of anaesthesia (minutes) (25 105) (20 105) 47

4 Table 2 Distribution of operations between different pre-anaesthetic medication groups Ovariohysterectomy 8 8 Keratectomy 4 7 Other ophthalmic procedures 3 4 Soft tissue procedures 8 3 Other 0 1 Total Table 3 Summary statistics showing sample size (n) mean 2 standard deviation and range for heart rate, systolic blood pressure, respiratory rate and end-tidal CO 2 tension Heart rate (min 1 ) ( ) (46 200) Respiratory rate (min 1 ) (7 60) (4 60) Systolic blood pressure (mmhg) End-tidal CO 2 tension (kpa) ( ) ( ) and produce a decrease in spontaneous release of catecholamines from catecholamine granules (Muir et al. 1975). However, the true mechanism of its action is unknown and probably consists of a combined effect. Two cats in group 1 that exhibited arrhythmias were not given treatment because disturbances were transient and did not affect blood pressure. In the third animal, further treatment was unnecessary because sinus rhythm replaced multimorphic PVCs when the inhalation agent was changed to isoflurane. This effect has been observed elsewhere: in one study, sinus rhythm was restored in all (n = 9) cats which developed ventricular arrhythmias during halothane anaesthesia, by changing the inhalational agent to isoflurane (Hubbell et al. 1984). This supports the observation that halothane, but not isoflurane, sensitizes the heart to adrenaline-induced PVCs (Bosnnjak & Kampine 1983). Pre-anaesthetic electrocardiography was not performed in this or previous studies (Hubbell et al. 1984) and so the results may have been influenced by the presence of pre-existing cardiac disease. Cardiac auscultation can indicate whether heart valve closure is synchronous and whether the rhythm is 48 regular or otherwise, but a negative finding does not mean that cardiac arrhythmias are absent, or are unlikely to occur during anaesthesia. Electrocardiography was excluded from the pre-operative examination of animals in this study because the normal practice at this institute is to perform advanced studies only when abnormalities are detected on physical examination. For example, an ECG would be taken if irregular rhythms were detected by auscultation or there was a history of syncope or exercise intolerance. Clinical examinations were thoroughly performed in all cases involved in this study and none had a history of cardiac disease or problems with previous anaesthetics. Core body temperature and end-tidal carbon dioxide tensions (P E? CO 2 ) were monitored because hypothermia and hypercapnia are possible causes of cardiac arrhythmias during anaesthesia (Cohen & Tilley 1979). Hypercapnia, in particular, causes a range of adverse effects including myocardial depression and bradyarrhythmias (Hartsfield 1996). Moderate hypercapnia was commonly encountered in this study although P E? CO 2 never exceeded 6.67 kpa (50 mm Hg). Core temperature did not fall

5 below 37 C in any case in the study, which represents the threshold value for defining hypothermia in cats (Dhupa 1995). Temperatures lower than 37 C have been associated with bradyarrhythmias and cardiac arrest (Moon & Ilkiw 1993). The frequency of arrhythmias encountered in this study was low and the same in both treatment groups, indicating that acepromazine did not exert an obvious anti-arrhythmic effect. Such an effect has been demonstrated in other studies, in which ventricular arrhythmias were created experimentally using adrenaline, and which were treated using higher acepromazine doses: mg kg 1 (Muir et al. 1975) and 1.0 mg kg 1 (Wiersig et al. 1974). (The manufacturer s recommended dose is mg kg 1 bodyweight by subcutaneous, intramuscular or intravenous injection). Therefore, it is possible that acepromazine only exerts a demonstrable anti-arrhythmic effect at high doses, or when arrhythmias are experimentally produced. Peterson- Jones & Clutton (1994) used low dose acepromazine ( mg kg 1 ) and buprenorphine as preanaesthetic medication before extra-capsular cataract extraction. During surgery, adrenaline was used topically to produce mydriasis. No arrhythmias were encountered during anaesthesia although the incidence of arrhythmias in animals not given acepromazine was not examined. While high doses of acepromazine may exert a useful anti-arrhythmic effect, they are also likely to cause profound sedation, a long duration of action and an increased incidence of dose-related side-effects, e.g. hypotension, predisposition to hypothermia and bradycardia. The results of this study confirm the null hypothesis that there was no difference in the frequency of cardiac arrhythmias after pretreatment with acepromazine or diazepam during halothane anaesthesia in cats. References Bednarski RL, Majors LJ, Atlee JL (1985) Epinephrineinduced ventricular arrhythmias in dogs anesthetized with halothane: Potentiation by thiamylal and thiopental. Am J Vet Res 46, Brearley JC (1994) Sedation, Premedication and Analgesia. In: Anaesthesia of the Cat. Hall LW, Taylor PM (eds). Bailliere Tindall, London, pp Bosjnak ZJ, Kampine JP (1983) Effects of halothane, enflurane and isoflurane on the SA node. Anesthesiology 58, Claborn LD, Szabuniewicz M (1973) Prevention of chloroform and thiobarbiturate cardiac sensitization to catecholamines in dogs. Am J Vet Res 34, Cohen RB, Tilley LP (1979) Cardiac arrhythmias in the anesthetized patient. Vet Clin N Am 9, Dhupa N (1995) Hypothermia in dogs and cats. Comp Cont Educ Pract 17, Hartsfield SM (1996) Airway management and ventilation. In: Lumb and Jones Veterinary Anesthesia. (3rd edn). Thurmon JC, Tranquilli WJ, Benson GJ (eds). Williams & Wilkins, Baltimore, MD, pp Haskins SC, Farver TB, Patz JD (1986). Cardiovascular changes in dogs given diazepam and diazepam-ketamine. Am J Vet Res 47, Hubbell JAE et al. (1984) Change of inhalation anesthetic agents for management of ventricular premature depolarizations in anesthetized cats and dogs. J Am Vet Med Assoc 185, Katz RI, Bigger JT (1970) Cardiac arrhythmias during anesthesia and operation. Anesthesiology 33, Lemke KA, Tranquilli WJ, Thurmon JC, et al. (1993) Alterations in arrhythymogenic dose of epinephrine after xylazine or medetomidine administration in isoflurane anesthetized dogs. Am J Vet Res 34, Maze M, Hayward E, Gaba DM (1985) Alpha1-adrenergic blockade raises epinephrine-arrhythmia threshold in halothane-anesthetized dogs in a dose-dependent fashion. Anesthesiology 63, Moon PF, Ilkiw JE (1993) Surface induced hypothermia in dogs: 19 Cases ( ). J Am Vet Med Assoc 202, Muir WW, Hubbell JAE, Flaherty SA (1988) Increasing halothane concentration abolishes anaesthesia-associated arrhythmias in cats and dogs. J Am Vet Med Assoc 192, Muir WW, Werner LL, Hamlin RL (1975). Effects of xylazine and acetylpromazine upon induced ventricular fibrillation in dogs anesthetized with thiamylal and halothane. Am J Vet Res 36, Peterson-Jones S, Clutton RE (1994) Use of intraocular adrenaline during cataract extractions in dogs. Vet Rec 135, Thurmon JC, Tranquilli WJ, Benson GJ (1996) Preanesthetic and anesthetic adjuncts. In: Lumb and Jones Veterinary Anesthesia (3rd edn). Thurmon JC, Tranquilli WJ, Benson GJ (eds). Williams & Wilkins, Baltimore, MD, p186. Tranquilli WJ, Thurmon JC, Benson GJ (1988) Alterations in epinephrine-induced arrhythmogenesis after xylazine and subsequent yohimbine administration in isofluraneanesthetized dogs. Am J Vet Res 49, Wiersig DO, Davis RH, Szabuniewicz M (1974) Prevention of induced ventricular fibrillation in dogs anesthetized with ultrashort acting barbiturate and halothane. J Am Vet Med Assoc 165, Received 30 November 1998; accepted 10 August