Anaesthesia in horses using halothane and intravenous ketamine^guaiphenesin: a clinical study

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1 Veterinary Anaesthesia and Analgesia, 2002, 29, 2 0^2 8 RESEARCH PAPER Anaesthesia in horses using halothane and intravenous ketamine^guaiphenesin: a clinical study Claudia Spadavecchia DVM, FlurinaStucki DVM,Yves Moens DVM, PhD, Dip ECVA &UrsSchatzmann DVM, PhD, Dip ECVA Department of Veterinary Clinical Studies, Anaesthesiology Section, University of Bern, Switzerland Correspondence: Claudia Spadavecchia, Department of Veterinary Clinical Studies, Anaesthesiology Section, University of Bern, Langassstrasse124,3012 Bern, Switzerland. Abstract Objective The aim of this study was to de ne and evaluate a combined inhalation intravenous anaesthetic protocol for use in equine anaesthesia. Study design Prospective, randomized clinical trial. Animals Twenty-eight horses (body mass ; 330^700 kg [mean SD; range]) with a mean age of 6 4 years (range: 2^18 years) presented to the university hospital for various surgical procedures requiring general anaesthesia. Materials and methods Animals were randomly allocated to one of two treatment groups. Anaesthesia was maintained in 14 horses with halothane alone (H group). The mean end-tidal halothane concentration was 1.24%. In the second group (n ¼ 14) anaesthesia was maintained with both halothane (end-tidal concentration 0.61%) and a continuous infusion of a ketamine^guaiphenesin mixture (HKG group). The two techniques were compared in terms of qualitative di erences and cardiopulmonary e ects. Results The stabilityof anaesthesiawas signi cantly greater in group HKG and the need for dobutamine to maintain blood pressure was signi cantly less. Recovery times and quality were acceptable in all cases. There were no signi cant di erences between the groups. Conclusions The infusion of ketamine and guaiphenesin in horses receiving low inspired concentrations of halothane provides suitable surgical anaesthesia and lowers the risk of hypotension. Clinical relevance The anaesthetic technique described in this study is a useful and practical alternative to inhalation anaesthesia using halothane alone. Keywords anaesthesia, guaiphenesin, halothane, horses, ketamine. Introduction Halothane causes signi cant cardiopulmonary depression in the horse (Ste ey et al. 1977) in a manner which is directly proportional to the inspired anaesthetic gas concentration (Ste ey & Howland 1978). An adequate level of surgical anaesthesia may require high inspiratory and therefore high end-tidal halothane concentrations (FE 0 H), which may result in severe cardiopulmonary depression. Nevertheless, halothane remains a popular agent for maintaining anaesthesia in horses because of its availability, its low cost compared with iso urane and sevo urane, and its ease of administration. A peri-operative mortality rate of 1.6% has been reported in horses (Johnston et al. 1995; Johnston 2000a,b) indicating that anaesthesia in this species is riskier than it is in humans. It has been suggested that intravenous anaesthesia may be associated with a lower incidence of peri-operative cardiovascular 20

2 emergencies and a lower anaesthetic risk (Johnston 2000b). Total intravenous anaesthesia (TIVA) has been investigated as an alternative to inhalation anaesthesia (Young et al. 1993; Taylor & Luna 1995; Bettschart-Wolfensberger et al. 1996; Nolan et al. 1996; Flaherty et al. 1997; Taylor et al. 1998). This involves di erent drug combinations administered either as repeated injections or as infusions. One of the most thoroughly studied and familiar TIVA techniques in horses uses a combination of ketamine, an a 2 agonist and guaiphenesin (Greene et al. 1986; McCarty et al. 1990; Taylor et al. 1992; Young et al. 1993; Taylor & Luna 1995). Although intravenous agents are associated with more stable physiological conditions they are likely to contribute to prolonged recovery, as drug redistribution, and/or metabolism are required to terminate their e ect. To date, therefore, TIVA has been used for relatively short operations. Ketamine is commonly used for the induction of anaesthesia in horses and is known to be safe as a top-up agent during inhalation anaesthesia (Grosenbaugh & Muir 1998). Its use as a halothanesparing agent has also been investigated in horses. Muir & Sams (1992) used a continuous ketamine infusion while administering di erent halothane concentrations and found a positive correlation between the ketamine plasma concentration and the reduction in halothane minimum alveolar concentration (MAC) requirements. Cardiac output was positively correlated with plasma ketamine concentrations. These results indicated the feasibility and positive features of combining intravenous and inhalation anaesthesia in horses. The aim of combining halothane with ketamine and guaiphenesin was to obtain loss of consciousness, muscle relaxation and analgesia using a lower inspired concentration of halothane. The purpose of this study was to compare the physiological e ects and quality of anaesthesia produced by a combined injectable (low-dose) halothane technique with that produced by (highdose) halothane alone. Materials and methods Twenty-eight adult horses referred to the equine hospital of the University of Bern for elective (n ¼ 24) and emergency colic surgery (n ¼ 4) were included in the study. Animals weighed between 330 and 700 kg (mean kg) and ranged in age between 2and 18 years (mean 6 4 years). The horses were randomlyallocated to one of two groups, H and HGK; see Table 1. Horses in group H (n ¼ 14) received only halothane (Halocarbon Laboratory, River Edge, NJ, USA), whereas those in group HGK (n ¼ 14) received halothane at lower inspired concentrations and a continuous infusion of guaiphenesin (Myolaxin; Chassot AG, Belp Bern, Switzerland) and ketamine (Narketan 10; Chassot AG). Horses facing elective surgery were deprived of food overnight. In each animal, the skin overlying the jugular vein was clipped and aseptically prepared for intravenous catheter [Intranule (PP) 13 G,Vygon, Ecouen, France] placement before pre-anaesthetic medication. In all horses, pre-anaesthetic medication was a combination of xylazine (Rompun 2%; Bayer AG, Leverkusen) (0.6 mg kg 1 )andl-methadone (Polamivet; Hoechst Roussel Vet) (0.05 mg kg 1 ) given intravenously (IV). General anaesthesiawas induced with an IV infusion of guaiphenesin (60 mg kg 1 ) followed by the rapid IV injection of ketamine (2.2 mg kg 1 ). Following endotracheal intubation, horses were attached to a large animal circle system (Stephan Anaesthesie GME 3 Gackenbach, Germany). Animals were allowed to breathe spontaneously and anaesthesia was maintained with halothane in oxygen (Carbagas, Liebefeld, Switzerland) 10 ml kg 1 minute 1. A methane-insensitive infrared gas analyser (Compact AS/3 Datex-Engstrom, Finland) (Moens et al. 1991) was used to continuously monitor FE 0 H, which in group HKG was maintained at 0.6%. In group H, the vaporizer setting was adjusted to maintain a stable surgical anaesthetic plane. All horses received intravenous Ringer s lactate solution (Laboratorium Bichsel AG, Interlaken, Switzerland) at a rate of 10 ml kg 1 hour 1. In group HKG a ketamine^guaiphenesin mixture containing 6 mg ml 1 ketamine and 150 mg ml 1 guaiphenesin was infused from the start of inhalation anaesthesia using a peristaltic pump (Mod. 313, Watson Marlow Ltd., Falmouth, UK). This was driven by a computer-controlled stepper motor, which allowed ow regulation as well as the recording of infusion rates over time (for subsequent o -line analysis using dedicated software; Spadavecchia et al. 1998). It also allowed infusion system calibration before each anaesthetic using a graduated test tube for volume comparison. Pharmacokinetic data estimated by Waterman et al. (1987) were programmed into the implemented algorithm described by Maitre & Shafer (1990), which allowed the continuous on-line prediction of plasma ketamine concentration. The initial infusion rate was set at 7^9 ml kg 1 minute 1 and adjusted as needed according to the animal s requirements. Veterinary Anaesthesia and Analgesia, 2002, 29, 2 0^

3 Table 1 Biographical information Horse Groups Breed Age (years) Sex Weight (kg) Procedure Duration of anaesthesia (minutes) Position 1 HKG Westfalen 3 C 500 Castration 60 Dorsal 2 HKG Freiberger 5 F 515 Tooth extraction 85 Left lat. 3 HKG Berber 2 C 330 Mandibular fistula excision 60 Right lat. 4 HKG Klatruber 11 G 594 Arthroscopy 100 Dorsal 5 HKG Freiberger 3 F 500 Laparotomy 150 Dorsal 6 HKG Swissbred 9 G 615 Wound suture 80 Right lat. 7 HKG Thoroughbred 2 C 430 Arthroscopy 110 Dorsal 8 HKG Selle francais 15 F 490 Corneal ulceration 60 Left lat. 9 HKG Russian Thorough 5 G 459 Splint bone excision 105 Right lat. 10 HKG Swissbred 5 G 540 Laparotomy 80 Dorsal 11 HKG Angloaraber 7 G 500 Tongue suture 65 Left lat. 12 HKG Swissbred 3 G 570 Tenovaginotomy 90 Left lat. 13 HKG Holsteiener 9 G 637 Arthroscopy 85 Dorsal 14 HKG Swissbred 5 F 520 Arthroscopy 145 Dorsal 15 H Holland 4 G 490 Funiculitis 60 Dorsal 16 H Holstein 2 C 505 Arthroscopy 95 Dorsal 17 H Swissbred 8 F 540 Sarcoid 80 Right lat. 18 H Hannover 15 G 600 Arthroscopy 70 Dorsal 19 H Swissbred 18 G 680 Laparotomy 120 Dorsal 20 H Swissbred 6 G 507 Arthroscopy 65 Dorsal 21 H Swissbred 4 C 450 Castration 60 Dorsal 22 H Freiberger 7 F 520 Metatarsal fracture 85 Right lat. 23 H Trotter 3 F 430 Arthroscopy 155 Dorsal 24 H Swissbred 12 F 585 Metatarsal fracture 95 Left lat. 25 H Morgan 3 F 400 Laparotomy 120 Dorsal 26 H Swissbred 5 G 470 Sesamoiditis 190 Right lat. 27 H Swissbred 14 G 700 Facial tumor extraction 60 Left lat. 28 H Swissbred 2 F 550 Bone fragment extraction 90 Right lat. H, halothane group; HKG, halothane/ketamine/guaiphenesin group. F, mares; G, geldings; C, colts. Position: lat, lateral. Emergencies. Depth of anaesthesia was assessed subjectively by evaluating the response to palpebral stimulation, eye position, pulse rate and respiratory rate. The electrocardiogram (Cardiocap Ultima, Datex, Helsinki, Finland) was monitored continuously using a base apex con guration from standard electrode clips, and arterial blood pressure was measured directly through a catheter (Optiva 18 SWG, Ethicon S.p.A., Pomezia, Italy) placed in the facial artery, using a standard calibrated pressure transducer system (Mediserve Transducer, Homedica AG, Cham, Switzerland). Arterial blood samples were withdrawn every 20 minutes and analyzed immediately (ph/ Blutgas-System Serie 840-Ciba Corning Diagnostic AG, Dietlikon, Switzerland). Respiratory gases were sampled continuously from the distal end of the endotracheal tube and automatically analyzed for inspiratory and expiratory fractions of O 2,CO 2 and halothane. Pulse and respiratory rate, end-tidal CO 2 (FE 0 CO 2 ) and FE 0 H were recorded every 5 minutes. At the same time interval, the stability of anaesthesia was evaluated using a scoring system (Table 2). Ketamine 0.2 mg kg 1 was injected Table 2 Scoring system for anaesthetic stability and recoverycharacteristics Score Anaesthetic stability 1 No response to stimuli 2 Nystagmus or haemodynamic response to surgery 3 Movement of limbs, neck or head Score Recovery characteristics 1 Standing at first attempt, minimal ataxia 2 Standing at first or second attempt, slight ataxia 3 Two or 3 attempts to stand, slight ataxia 4 Several attempts to stand, ataxia 5 Weak attempts, ataxia, risk of injury 22 Veterinary Anaesthesia and Analgesia, 2002, 29, 2 0^2 8

4 Veterinary Anaesthesia and Analgesia, 2002, 29, 2 0^ Table 3 Heart rate, respiratory rate, meanarterial blood pressure and end-tidal CO 2 at di erent anaesthetic time points; mean SD and medianvalues over 2hours of anaesthesia for the two groups HKG and H Time (minutes) n Heart rate beats minute 1 Respiratory rate breaths minute 1 Mean arterial pressure mm Hg End tidal CO 2 kpa (mm Hg) HKG n H HKG H HKG H HKG H (69 10) (70 10) (77 18) (86 13) (92 24) (116 12) Mean SD (86 11) Median (85) 9.04 (68) p < (54 11) (55 10) (66 16) (72 14) (65 7) (70 14) (66 5) (52 6) (54 6) (52 5) (52 5) (53 6) (46 6) (51 2) 6.91 (52) (55 4) (52 4) (52 5) (53 5) (48 7) (49 10) (51 2) 6.91 (52) Balanced anaesthesia in horses C Spadavecchia et al.

5 24 Veterinary Anaesthesia and Analgesia, 2002, 29, 2 0^2 8 Table 4 Arterial blood gas values at 20 minute intervals duringanaesthesia for the twogroups (HKGand H). Meanvalues SD for partial pressure of oxygen (P a O 2 ), of carbon dioxide (P a CO 2 ) and ph. Mean SD and median values over 2hours of anaesthesia Time (minutes) n P a O 2 kpa (mm Hg) P a CO 2 kpa (mm Hg) ph HKG n H HKG H HKG H (286 87) ( ) (54 3) (58 4) (292 71) ( ) (55 5) (60 5) (272 66) ( ) (55 7) (63 6) (248 70) ( ) (58 4) (62 4) (212 91) ( ) (59 3) (61 5) (136 42) ( ) (56 3) (65 5) Mean SD (241 59) (230 18) (56 2) (61 2) Median (260) (223) (56) (62) p < Balanced anaesthesia in horses C Spadavecchia et al.

6 whenever anaesthesia was inadequate, or when surgical stimulation provoked an increase in heart rate and/or blood pressure, or movement. The cumulative dose of additional ketamine required to maintain anaesthesia was averaged over the total anaesthetic time. Hypotension (mean arterial pressure <70 mm Hg) was treated with dobutamine (Dobutrex; Eli Lilly, Vernier/Geneve, Switzerland) infused IV to e ect and the total dose given averaged with respect to total anaesthesia time. The times from discontinuation of anaesthesia to endotracheal extubation, sternal recumbency and standing were recorded for each horse. Recovery quality was scored using the scheme detailed in Table 2. Values are reported as mean and standard deviations. The groups were compared at 5-minute intervals (cardiovascular variables) and 20-minute intervals (blood gas values) using the nonparametric Wilcoxon Mann^Whitney test, corrected using the Bonferroni method. The level of signi cance was set at p < A repeated measures ANOVA was performed to compare arterial oxygen tension in the two groups over the rst 60 minutes. Results Figure 1 Mean infusion rate SD of ketamine^guaiphenesin infusion during 2hours of anaesthesia for the HKG group. Drug concentrations: ketamine 6 mg ml 1 ;guaiphenesin150 mg ml 1. Animals in the two groups did not di er signi cantly in terms of weight, age and gender. The minimum duration of anaesthesia was 60 minutes and mean duration was minutes. Cardiac arrhythmias were not detected in any of the anaesthetized horses. There were no signi cant di erences between the two groups for heart rate, respiratory rate, systolic, mean and diastolic blood pressure, end-tidal CO 2 lesions (FE 0 CO 2 ) and arterial carbon dioxide partial pressure (PaCO 2 ) seetables 3 and 4. Arterial oxygen tension (PaO 2 ) decreased signi cantly over the rst 60 minutes in group H (p ¼ 0.013), whereas in group HKG it remained stable (p ¼ 0.32). The end-tidal halothane concentration in group HKG was controlled and xed at %, whereas in group H the (FE 0 H)requiredtomaintain anaesthesia was %. In group HKG, anaesthetic infusion rates were reduced progressively during anaesthesia (Fig. 1) with an initial mean value of ml kg 1 minute 1 and a mean of ml kg 1 minute 1 at 120 minutes. Mean infusion rates for ketamine and guaiphenesin at 20 minutes were mg kg 1 minute 1 and mg kg 1 minute 1,respectively, and at 120 minutes were 13 1 mg kg 1 minute 1 and mg kg 1 minute 1, respectively. The calculated mean ketamine plasma concentration (estimate) over 120 minutes was mg ml 1. Scores for anaesthetic stability were signi cantly di erent between the two groups (p ¼ 0.007). In group HKG four horses showed a haemodynamic response to surgical stimulation, whereas in group H six showed haemodynamic responses and ve moved. The averaged dose of ketamine required to top-up anaesthesia was signi cantly higher in group H, with 0.37 mg kg 1 hour 1 needed compared with 0.06 mg kg 1 hour 1 in group HKG (p ¼ 0.006) see Fig. 2. Dobutamine administration was necessary in two cases in group HKG compared with eight in group H. The mean dobutamine infusion rate was signi cantly higher in group H ( mg kg 1 hour 1 ) than in group HGK ( mg kg 1 Figure 2 Mean dose of ketamine required to maintain anaesthesia. Veterinary Anaesthesia and Analgesia, 2002, 29, 2 0^

7 hour 1 ; p ¼ 0.01). The clinical signs of anaesthesia di ered in the two groups with palpebral re exes always being stronger in group HKG. There also appeared to be greater tear production in this group. There were no statistically signi cant di erences betweenthe two groups in the time from discontinuation of anaesthesia to time at swallowing, achieving sternal recumbency and at standing. The times for groups H and HKG, respectively, were 6 8 and 8 7 minutes (swallowing), and minutes (sternal recumbency) and and minutes (standing). Recovery quality was acceptable and similar in all cases; in both groups, six horses were given a score of 1, seven a score of 2 and only one a score of 3 (p ¼ 1). Discussion In order to optimize the acceptabilityof the combined intravenous^inhalation technique described in this study in clinical practice, drugs were chosen on the basis of: availability; widespread familiarity with use, and approval for use in horses. For the same reason, animals were not allocated to groups on a matched pair basis; all horses admitted to our clinic requiring general anaesthesia were included in the study, until the required number of cases was reached, irrespective of the operation required. Whereas halothane and other inhalation anaesthetics depress central nervous function in a generalized and reversible manner (Thurmon et al. 1996), ketamine provokes an electrophysiological dissociation between the thalamo-neocortical and limbic systems (Kohrs & Durieux1998). Halothane causes a dose-dependent reduction in cardiac output by decreasing stroke volume and depressing myocardial contractility (Ste ey & Howland 1978). In contrast, ketamine can exert a sympathomimetic action and stimulate cardiovascular function by directly stimulating CNS centres (White et al. 1982). During simultaneous administration of halothane and ketamine in horses under experimental conditions, the cardiac output increased at higher ketamine plasma concentrations when lower halothane percentages were used (Muir & Sams 1992). Low ketamine doses (plasma concentration >0.1 mg ml 1 ) provide analgesia and can inhibit wind-up in the development of chronic pain in people and experimental animals (Nimmo & Clements 1984; Arendt-Nielsen et al. 1996). Guaiphenesin was included in the combined intravenous^inhalation technique described here because our clinical experience indicates that it provides skeletal muscle relaxation per se, suppresses ketamine-induced muscular hypertonus and spontaneous movement, and does not increase unsteadiness during recovery. The positive e ects of a single dose of guaiphenesin on the quality of anaesthesia produced by romi dine and ketamine have been observed by Walsh et al. (1999). Hubbell et al. (1980) showed that guaiphenesin, administered as a sole agent (mean dose 134 mg kg 1 ) to produce recumbency in adult horses, exerted no signi cant depressant e ects upon cardiac output or arterial blood pressure. Guaiphenesin has a wide margin of safety and its sedative properties are potentiated by combination with sedative drugs (Schatzmann 1974; Schatzmann et al.1978; Brouwer1985). The continuous monitoring applied in our study was considered adequate for establishing the level of anaesthesia, and consequently for making appropriate alterations in the delivered halothane concentration and, or ketamine^guaiphenesin infusion rate. It was possible to obtain surgical anaesthesia in both groups although maintenance was more straightforward in group HKG, in which no subjects moved and only four animals showed haemodynamic responses to surgery. The lower requirement for additional ketamine to maintain anaesthesia supports this. The quality of recovery was acceptable and similar in both groups and shows that continuous infusion of guaiphenesin and ketamine does not compromise recovery. Animals are able to achieve sternal recumbency after a continuous ketamine infusion when plasma concentrations reach 1.15 mg ml 1 (Kaka et al. 1978). In this study, the ketamine administration rate was adapted to each animal s needs and was decreased from 40 to 15 mg kg 1 minute 1 during the 2hours of anaesthesia. The calculated estimate of the mean plasma ketamine concentration (0.8 mg ml 1 ) would suggest that the infusion provided analgesia without exerting any negative e ect on the rate and quality of recovery. It is also possible that guaiphenesin contributed to the smooth recovery given its ability to mask the psychotomimetic e ects of ketamine. Given that the MAC value for halothane in horses is 0.88% (Ste ey et al. 1977) the use of a mean FE 0 H of 0.6% in group HKG (compared with 1.24% in group H) indicates that ketamine^guaiphenesin infusion exerts a halothane-sparing e ect. The cardiovascular and respiratory depressant properties of halothane are proportional to the end-tidal 26 Veterinary Anaesthesia and Analgesia, 2002, 29, 2 0^2 8

8 concentration (Ste ey & Howland1978) and so di erences in the cardiopulmonary variables observed in each group may have arisen because of di erences in the FE 0 H used to maintain anaesthesia. The cardiopulmonary depressant properties of ketamine and guaiphenesin at the doses used in this studyare small (Taylor et al. 1998). Arterial blood pressure was similar in both groups although this is largely predictable because dobutamine was given whenever mean arterial pressure fell below 70 mm Hg. However, the number of horses needing inotropic support and the total dose administered was signi cantly lower in group HKG, suggesting that on balance, arterial blood pressure was preserved. That PaO 2 was maintained during the rst 60 minutes of anaesthesia in group HGK, whereas it fell signi cantly in group H merits further investigation. In conclusion, the infusion of ketamine and guaiphenesin in horses receiving low delivered concentrations of halothane appears to be a safe technique for producing surgical anaesthesia. Compared with the use of halothane alone, the combined infusioninhalation technique produced more stable anaesthesia and a lowered requirement for pressor agents. At the doses used the intravenous agents did not in uence the duration or quality of recovery. References Arendt-Nielsen L, Nielsen J, Petersen-Felix S et al. (1996) E ect of racemic mixture and (Sþ)-isomer of ketamine on temporal and spatial summation of pain. Br J Anaesth 77,626^631. Bettschart-Wolfensberger R,Taylor PM, Sear JWet al. (1996) Physiologic e ects of anesthesia induced and maintained by intravenous administration of a climazolam ketamine combination in ponies premedicated with acepromazine and xylazine. Am J Vet Res 57,1472^1477. 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