The effect of rnedetornidine premedication upon propofol induction and infusion anaesthesia in the dog

J. vet. Anaesth. Vol. 21 uuly 1994) The effect of rnedetornidine premedication upon propofol induction and infusion anaesthesia in the dog R.A. Hammond and G.C.W. England Department of Large Animal Surgery and Medicine, Royal Veterinary College University of London, Hawkshead Lane, North Mymms, Hatfield Hertfordshire AL9 7TA SUMMARY The effect of premedication with four different intramuscular doses of medetomidine (5.0, 10.0,20.0 and 40.0 pg.kg-1) and a saline placebo were compared in a group of six adult beagle dogs anaesthetised with propofol on five separate occasions. Anaesthesia was induced 30 minutes after premedication and maintained by intravenous injection and continuous infusion of propofol. The effects of medetomidine were reversed with atipamezole 30 minutes after anaesthetic induction. The marked synerptic effects of medetomidine with propofol were demonstrated by a dose related reduction in the induction and infusion requirements for a similar degree of anaesthesia. The effect appeared exponential in nature; lower medetomidine doses produced a disproportionately greater effect. The maintenance of anaesthesia with propofol following a saline placebo or low doses of medetomidine proved to be difficult. Higher doses of medetomidine required less propofol for induction and infusion and allowed a more stable anaesthesia to be maintained. Propofol produced no statistically significant change in heart rate during infusion. Changes in respiratory rate were markedly group specific. A significant reduction in respiratory rate was seen in dogs given either 5 pg.kg-1 or 10 pg.kg1 medetomidine. No change was recorded in dogs given 20 pg.kg1 medetomidine and a significant increase was seen in dogs given 40 pg.kg-1 medetomidine. Recovery was monitored following the termination of propofol infusion after the reversal of medetomidine using atipamezole at five times the medetomidine dose. Recovery was slower for dogs given lower doses of medetomidine and consequently higher doses of propofol. INTRODUCTION Medetomidine (4-[1-(2,3-dimethylphenyl)ethyl]-lHimidazole hydrochloride) is a potent and highly specific a2 adrenoceptor agonist which has become widely used as a sedative in veterinary clinical practice. Low doses of medetomidine have anxiolytic properties similar to benzodiazepines (Macdonald et al., 1989). Higher doses produce sedation (Clarke and England, 1989) and analgesia (Ylisela and Vainio, 1989). Marked bradycardia with atrioventricular heart block is a consistent effect in the dog (Clarke and England, 1989; Lombard et al., 1989). Medetomidine produces a decline in the respiratory rate, 24 although in the dog arterial blood oxygen tensions are only slightly depressed (England and Clarke, 1989). Medetomidine has marked anaesthetic sparing properties (England and Clarke, 1989; Vickery and Maze, 1989). Propofol (2,6 di-isopropylphenol) is a substituted phenol derivative intravenous anaesthetic agent which has been shown to be suitable as an induction agent in the dog (Watkins et al., 1987). The administration of propofol to dogs premedicated with acepromazine produces no immediate change in heart rate although during anaesthesia heart rate increases (Hall and Chambers, 1987). The effect of propofol upon the respiratory rate varies greatly between animals (Watkins et al., 1987); the most consistent finding is the production of a period of apnoea during induction (Brearley et al., 1988). The recovery from propofol anaesthesia is characteristically rapid and although reports of recovery times from different studies are similar, they appear to be independent of premedication (Watkins et al., 1987; Morgan and Legge, 1989; Weaver and Raptopoulos, 1990). The combination of medetomidine and propofol for general anaesthesia has been described (Bryant et al., 1990; Vainio, 1991; Cullen and Reynoldson, 1993; Lagerweij et al., 1993) and rapid recovery from anaesthesia can be obtained following the reversal of medetomidine with the specific a2 adrenoceptor antagonist atipamezole (Bryant et al., 1990). The aim of the present study was to obtain baseline data for propofol induction and infusion anaesthesia in the dog in the absence of premedication, and to evaluate the effects of differing doses of medetomidine premedication. The effects on recovery of the subsequent reversal of medetomidine with atipamezole were monitored. MATERIALS AND METHODS Six young adult castrated beagle dogs weighing between 9.0 and 23.0 kg were used in the study. They were starved of food for 18 hours but were allowed free access to water before the study. The study was performed using a random order to determine the sequence of drug treatments and was blinded in that the injection was administered by a person other than the evaluator. The dogs were subjected to the following treatment regimes separated by a minimum of six days; animals were premedicated with either saline placebo (0.04 ml.kg-1 0.9% sodium chloride solution); medetomidine (Domitor, SmithKline Beecham Animal

Health) 5.0 pgkg-1; medetomidine 10.0 pg.kg-1; medetomidine 20.0 pgkg-1 or medetomidine 40pg.kg-1 administered by intramuscular injection. Doses of medetomidine were calculated in terms of animal surface area normalised to a 15 kg dog, using the formula: Body surface area m2 = (K x W2/3) / l o4 where K = 10.1, and W =body weight in grammes (Hamlin and Bednarski, 1989). Thirty minutes following premedication, anaesthesia was induced with propofol (Rapinovet, Mallinckrodt Veterinary) and maintened by continuous intravenous propofol infusion. Thirty minutes after the induction of anaesthesia, propofol infusion was stopped and either 0.04 ml.kg-1 saline; 25 pg.kg-1 atipamezole (Antisedan, Smith- Mine Beecham Animal Health); 50 pg.kg1; 100 pg.kg-1 atipamezole; or 200 pgkg-1 atipamezole was given by intramuscular injection, such that the dose of atipamezole received equalled five times the dose of medetomidine. The anaesthetic protocol was; after 10 minutes observation, a single set of control data were collected and a 20 G catheter (Cathlon, IV Critikon Ltd.) was placed into the cephalic vein and flushed with saline. Medetomidine or saline was administered by rapid deep intramuscular injection into the quadriceps muscle (time zero). In the 5 pg/kg group, a ten times dilution of the medetomidine was made with sterile water for injection to decrease the inaccuracy of the low injection volume. Thirty minutes after premedication, anaesthesia was induced with propofol, by repeated, incremental, intravenous administration to effect. Propofol was administered via the intavenous cephalic catheter. Increments, (given at 30 second intervals), were calculated to be approximately one tenth of the estimated final induction dose. Induction was considered to be completed at the point where the animal could be easily intubated without inducing a cough. The total induction dose was recorded; five minutes was allowed in the protocol for intubation. Five minutes after induction, infusion of propofol was commenced using a Bard Infus-OX infusion pump (Bard Medical Systems Division). The infusion rate was adjusted each minute to achieve a predetermined level of anaesthesia. This was defined as when the eye was rotated down, the pedal reflex was just abolished, and the response to endotracheal manipulation was absent. Five minutes were allowed for attainment of a steady infusion rate. Infusion was then continued at a constant rate for 15 minutes. The dogs lay unrestrained in lateral recumbency and behavioural characteristics including a subjective assessment of the degree of sedation, position of the eye and relaxation of the jaw were noted throughout the study. Heart rate and rhythm were recorded with continuous lead-i1 electrocardiograms (Cardiocap COS 104, Datex Instruments Ltd.). Respiratory rates were counted over one minute. Rectal temperature was recorded using a Digitron 4701 thermometer (Digitron Instruments Ltd.), no attempt to maintain body temperature was made. All recordings were made at two minute intervals throughout the period of sedation and at 5 minute intervals during steady state anaesthesia. J. vet. Anaesth. Vol. 21 (July 1994) 25 Infusion was stopped 30 minutes after anaesthetic induction and saline or atipamezole was administered by deep intramuscular injection into the quadriceps muscle. A ten times dilution of atipamezole was made with sterile water for injection of the 5 pgkg-1 group. The dogs were left undisturbed and the time to extubation, sternal recumbency and standing were recorded. Heart rates and respiratory rates were not recorded during the recovery period. Measurements were expressed as percentage change from presedation. Differences between induction dose, infusion dose, heart rates, respiratory rates, rectal temperature and recovery parameters were analysed statistically using a one factor repeated measures analysis of variance. Post-hoc testing was performed using painvise contrasts of the coefficients of the means (Systat 5.2 for Macintosh). Values were considered sigruficant when p < 0.05. All values are expressed as a mean & standard error of mean (sem). RESULTS Propofol Alone The placebo saline injection produced no effect on any measured parameter. Induction with propofol was smooth and uneventful although apnoea was consistently noted and lasted for 2 minutes in one dog. The mean induction dose of propofol was found to be 6.0 - + 0.26 mg.kg-1 (Figure 1). 0 10 20 40 Medetomidine Dose (pg/kg) Figure 1: The mean dose of propofol(+ sem)for induction of anaesthesia followingfive different premedication regimes. 0 ' 5 ' 10 ' 20 40 Medetomidine Dose (@g) Figure 2: The mean dose of propofol (k sem) for infusion anaesthesia following propofol induction afterfiue difjeren t premedication regimes. I I

Steady state infusion anaesthesia was difficult to maintain for this group, and was only achieved during the last 10 minutes of the anaesthetic period. The mean infusion rate during this time was 0.93 2 0.03 mg.kg-1 /min. (Figure 2). 160, -10 0 10 20 30 40 50 60 70 Time after premedication (mins) Figure 3: Mean percentage change in heart rate (k sern) for animals premedicated with saline placebo (+), 5.0 pg.kgl medetomidine (-C)-), 10.0 pg.kg1 medetomidine (+), 20.0 pg.kgl medetomidine (0) and 40.0 pg.kg-1 medetomidine (-A-) followed by propofol induction and infusion anaesthesia. Arrow indicates onset of propofol administration. For visual clarity, all data points are not shown. "7 304 10+'mT'T-TT, I I I I I I I 1 I I I I I I I I I I -10 0 10 20 30 40 SO 60 70 A Time after premedication (mins) Figure 4: Mean percentage change in respiratory rate {+ sem) for animals premedicated with saline placebo (-@-I, 5.0 pg.kg-1 medetomidine (a), 10.0 pg.kg1 medetomidine (+), 20.0 pg.kg-1 medetomidine (a) and 40.0 pg.kg1 medetomidine (-A-) followed by propofol induction and infusion anaesthesia. Arrow indicates onset of propofol administration. For visual clarity, all data points are not shown. J. vet. Anaesth. Vol. 21 (July 1994) There was a general trend for heart rate to increase throughout anaesthesia (Figure 3) although this was not statistically significant. There was a significant decrease in mean respiratory rate (Figure 4); respiratory pattern was always regular after the induction period. There was no significant change of body temperature during anaesthesia. The dogs recovered smoothly from anaesthesia and the mean times to extubation, sternal recumbency and standing were; 25.7 & 3.6 minutes, 30.7 & 3.3 minutes, and 33.3 - + 2.5 minutes respectively (Table 1). Medetomidine premedication and propofol anaesthesia The mean dose of medetomidine for each group expressed in terms of body weight was as follows: 5 pg.kg-1 group, 4.9820.229 pg.kg1; 10 pg.kg-1 group, 9.935 & 0.435 pg.kg-1; 20 pg.kg-+y-oup, 19.875 & 0.872 pgkg-1 and 40 pg.kg-lgroup, 39.752 & 1.743 pg.kg-1. All doses of medetomidine produced sedation; this was most profound in the 40 pg.kg1group. Pain on injection was noted in all dogs in the 5 pg.kg1 group, two dogs in the 20 pg.kg-1 and three dogs in the 40 pg.kg-1 group. One dog given 40 pgkg-1 medetomidine vomited and two dogs given 20 pgkg-1 retched. Spontaneous muscle twitching was recorded in all dogs given 40 pg.kg-1, two dogs given 20 pg.kg1and one dog given 10 pgkg-1 medetomidine. At 20 minutes after administration of medetomidine heart rate was significantly reduced. One dog given 40 pg.kg-idemonstrated second degree heart block; this finding was transient and spontaneously resolving. A second dog in this group demonstrated 2 episodes of spontaneous tachycardia lasting for less than 20 seconds. No arousal from sedation or extraneous stimulation had occurred. At 20 minutes after administration, respiratory rates were significantly reduced for dogs given 20 pg.kg-1and 40 pg.kg-1 medetomidine. Periodic apnoea lasting up to 45 seconds was seen in all dogs except those given 5 pg.kg1. Medetomidine did not significantly reduce rectal temperature at any dose. Medetomidine produced a dose dependent reduction in the dose requirement of propofol for induction (Figure 1). The mean dose requirement for induction of each group was 5 pg.kg-1; 2.86 & 0.19 mg.kg-1, 10 pg.kg-1; 1.44 & 0.1 mg.kg-1,20 pgkg-1; 1.12 & 0.06 mg.kg-1 and 40 pg.kg-1; 0.77 - + 0.07 mg.kg-1. The values were significantly different from each other. The quality of induction was altered by medetomidine; the period of induction apnoea was reduced, or even absent at the higher levels of medetomidine premedication. Transient arousal occurred during induction, often associated with attempted repositioning to sternal recumbency for dogs given 40 pg.kg-1. Table 1: Mean time (+ sem) to endotracheal extubation, sternal 1 aecumbency and standing for six beagles following termination of propofol anaesthesia after five different premedicant regimes. Premedicant Time to extubation (mins) Time to sternal recumbency (mins) Time to standing (mins) Saline 25.7 k 3.6a Medetomidine 5.0 pg.kg1 19.2 k 1.7b Meditomidine 10.0 pg.kg1 15.0 k 2.4bc Medetomidine 20.0 pg.kg-1 13.8 k 2.0bc Medetomidine 40.0 pg.kg-1 6.3 2.0c 30.7 k 3.3a 23.3 k 3.7b 24.3 k 2.ZbC 19.2 2.2bC 9.2 k 1.2c 33.2 2 2.5a 24.0 3.6b 25.5 2.lbC 19.5 k 2.2bC 10.0 k 1.1c Means with a letter in common are not significantly different. 26

~ J. vet. Anaesth. Vol. 21 auly 1994) Stable infusion anaesthesia was easily obtained in each group with the exception of 5 pg.kg-1 medetomidine in which stability was achieved only during the last 10 minutes of anaesthesia. Medetomidine produced a dose dependent reduction in the propofol requirement for infusion anaesthesia (Figure 2). The mean infusion rate for each group was 5 pg.kg-1; 0.40 0.04 mg.kg-l.min-l., 10 pg.kg-1; 0.34 0.02 mg.kgl.min-l., 20 pg/kg; 0.19 0.09 mg.kg-1.min-1. and 40 pg.kg-1; 0.06 5 0.003 mg.kgl.min-1. The dose requirements were statistically different from each other with the exception of the 5 pg.kg1and 10 pgkg-1 groups. Propofol produced no statistically significant change in heart rate during infusion in any group, although heart rate increased towards presedation values (Figure 3). The changes in respiratory rate during infusion were markedly group specific. There was a significant reduction in dogs given either 5 pg.kg-lor 10 pg.kg-1 medetomidine, no change in dogs given 20 pg.kg-1 and a significant increase in dogs given 40 pg.kg1 (Figure 4). There was no change in rectal temperature during propofol infusion. Recovery from anaesthesia was smooth and of a similar quality in all cases. The time to extubation, sternal recumbency and standing was slower for dogs given lower doses of medetomidine and consequently higher induction and infusion rates of propofol. Significant differences were however only demonstrated between dogs pen 5 pg.kg1and 40 pg.kg-1 medetomidine (Table 1). midine and therefore high propofol infusion rates demonstrated a continued decline in respiratory rate, whilst dogs given higher doses of medetomidine demonstrated an increase towards presedation values. The final depression of respiration appeared to be related therefore to the degree of anaesthesia which was similar in all groups, this finding has been previously reported (Goodman et al., 1987). When recovery time was examined it was found to be dependent on the the dose rate of propofol, since the action of medetomidine was probably completely antagonised and the duration of anaesthesia was the same for each group. This conflicts with the findings of Watluns et al. (1987) and Morgan and Legge (1989) who found no differences in recovery time for premedicated and unpremedicated dogs even though premedication was shown to decrease the dose rate of propofol. However in these studies (Watkins et al., 1987; Morgan and Legge, 1989) the premedicant was not reversed at the end of anaesthesia. Wright et al., (1984) demonstrated that recovery from propofol anaesthesia in man was directly related to the infusion rate, similar to the present study. The maintenance of anaesthesia using propofol infusion with no premedicant or using medetomidine at 5 pg.kg-1 proved to be difficult and would be unsuitable for clinical procedures. Higher doses of medetomidine (20 and 40 pgkg-1) allowed stable anaesthesia to be maintained. Lower induction and infusion doses of propofol were required and the recovery time following administration of atipamezole was reduced. The saline placebo produced no effect in this study. The subsequent induction of anaesthesia with propofol was smooth and the dose required was similar to that previously reported (Watkins et al., 1987; Morgan and Legge, 1989; Weaver and Raptopoulos, 1990; Lagenveij et al., 1993). It was, however, difficult to stabilise the depth of anaesthesia using continuous infusion of propofol, but when achieved, the dosage requirement was similar to that estimated from values given for intermittent injection (Watkins et al., 1987). These data are interesting since in man infusion doses are lower than those required by intermittent injection (Wright et al., 1984). The time to standing following propofol alone was approximately 35 minutes, similar to that reported by Morgan and Legge (1989) and Weaver and Raptopoulos (1990), but longer than reported by Watkins et al. (1987). Medetomidine produced characteristic effects of this agent, including sedation, bradycardia and decreased respiratory rate (Clarke and England, 1989). Anaesthesia was smoothly induced by propofol administration to dogs sedated with medetomidine at doses greater than 5 pg.kg1. The marked synergistic effects of medetomidine with propofol were demonstrated by a dose related reduction in the induction and infusion dose requirements for propofol anaesthesia (Figures 1 and 2). Medetomidine at 5 pg.kg1 had a disproportionately large dose reducing effect, halving the dose requirement for induction and infusion. Propofol produced no further change in heart rate during infusion, however respiratory rate was depressed in a dose related manner. Dogs given low doses of medeto- 27 ACKNOWLEDGEMENTS We thank Dr. K.W. Clarke, for her help, advice and encouragement during the study and Dr Simon Baker for statistical advice. REFERENCES Brearley JC, Kellagher REB, Hall LW. (1988) Propofol anaesthesia in cats. Journal of Small Animal Practice 29,315-322. Bryant CE, Clarke KW, White RN, England GCW. (1990) A preliminary investigation of medetomidine prior to propofol anaesthesia in the dog, and the effects of the subsequent administration of atipamezole. Proceedings ofthe British Small Animal Veterina ry Association Conference, p208. Clarke KW, England GCW (1989) Medetomidine a new sedative and analgesic for use in the dog, and its reversal with atipamezolcjournal of Small Animal Practice 30,343-348. Cullen LK, Reynoldson JA. (1993) Xylazine or medetomidine premedication before propofol anaesthesia.veterinary Record 132,378-383. England GCW, Clarke KW (1989) The use of medetomidine/fentanyl combinations in the dog.acta Veterinaria Scandinavica 85, 179-186. Goodman NW, Black AMS, Carter JA. (1987) Some ventilatory effects of propofol as a sole anaesthetic agent.british Journal of Anaesthesia 59, 1497-1503. Hall LW, Chambers JP. (1987) A clinical trial of propofol infusion anaesthesia in dogs. Journal of Small Animal Practice 28,623-637. Hamlin RL, Bednarski LS. (1989) Studies to determine the optimal dose of medetomidine for the dog.acta Veterinaria Scandinavica 85,89-95. Lagerweij E, Hall LW, Nolan AM (1993) Effects of medetomidine premedication on propofol infusion anaesthesia in dogs.journal of Veterinary Anaesthesia 20,78-83.

J. vet. Anaesth. Vol. 21 (July 1994) Lombard CW, Kvart C, Sateri, H. Holm, G, Nilsfors, L. (1989) Effects of medetomidine in dogs with rnitral regurgitation. Acta Veterinaria Scandinavica 85,167-174. Macdonald E, Haapalinna A, Virtanen R, Lammintausta R. (1989) Effects of acute administration of medetomidine on the behavior, temperature and turnover rates of brain biogenic amines in rodents and reversal of these effects by atipamezole. Acta Veterinaria Scandinavica 85, 77-81. Morgan DWT, Legge K. (1989) Clinical evaluation of propofol as an intravenous anaesthetic agent in cats and dogs.veterinnry Record 124,31-33. Vainio 0. (1992) Propofol infusion anaesthesia in dogs prernedicated with medetomidine.journa1 of Veterinary Anaesthesia 18,35-37. Vickery R, Maze M. (1989) Action of the sterioisomers of rnedetomidine, in halothane-anesthetized dogs.acta Veterinaria Scandinmica 85, 71-76. Watkins SB, Hall LW, Clarke KW. (1987) Propofol as an intravenous anaesthetic agent in dogs.veterinary Record 120,326-329. Weaver BMQ, Raptopoulos D. (1990) Induction of anaesthesia in dogs and cats with propofo1,veterinary Record 126,617-620. Wright PJ, Clarke RSJ, Dundee JW, Briggs LP, Greenfield AA. (1984) Infusion rates for anaesthesia with propofol. British journal of Anaesthesia 56,613-616. Ylisela E, Vainio 0. (1989) Effects of medetomidine on the experimental auricular pain in dogs. Acta Veterinaria Scandinavica 85, 187-191. COX-ACOMA Cat. No. 188 736 1 A compact Veterinary Vapouriser, incorporating an accurate control system, with the capacity to maintain a stabilised vapourising function with a high degree of accuracy. Temperature, gas flow and pressure fluctuations do no affect the accuracy of the Cox-Acoma Vapouriser. lus ANAESTHETIC ClRCUlTS GILL CIRCUIT Cat. No. 188 670 in lightweight plastic AYRES CIRCUIT Cat. No. 188 682 Non rebreathing circuit for cats and small dogs up to about 7kg. COAXIAL CIRCUIT Cat. No. 189 754 features fresh gas flow - CIRCLE CIRCUIT Cat. No. 188 3 1 1 lightweight plastic circle circuit which will fit just about any anaesthetic machine. New additions to the wide range of Cox Veterinary Anaesthetic Equipment Detailed information covering the whole range, available or request. Available from your Veterinary Wholesaler COX SURGICAL Edward Road, Coulsdon, Surrey. CR5 2XA Tel 081 668 2131 Fax 081 668 4196 Telex 947946 COXSUR G 28