Prolonging dissociative anaesthesia in horses with a repeated bolus injection

J. vet. Anaesth. Vol. 23(2) (1996)

Prolonging dissociative anaesthesia in horses with a repeated bolus injection S. Marntell and G. Nyman* Delxirtnierit oj Medicine mid Surgey, Fmiilty oj Veteririciry Medicine, Swedish Uiiiversit\~of Agriciiltirrcil Sciences, Bor 7037, 75007 U p ptilti, S n ~ l e i i

SUMMARY

INTRODUCTION

The effects of prolonging romifidine/ketamine anaesthesia in horses with a second injection of ketamine alone or both romifidine/ketamine compared with only induction injection of romifidine and tiletamine/zolazepam were studied in 6 horses anaesthetised in lateral recumbency on 3 random occasions. All horses were sedated with romifidine 0.1 mg/kg bwt iv and, on 2 occasions, anaesthesia was induced by iv injection of ketamine 2.2 mg/kg bwt. To prolong the ketamine-induced anaesthesia, either ketamine ( I . 1 mg/kg bwt iv) or ketamine and romifidine ( I . 1 mg/kg bwt and 0.04 mg/kg bwt iv, respectively) were given 18-20 min after the start of the ketamine injection for induction. On the third occasion, anaesthesia was induced by iv injection of 1.4 mg/kg bwt Zoletil (0.7 mg/kg bwt tiletamhe + 0.7 mg/kg bwt zolazepam). No statistically significant differences in the measured cardiorespiratory function were found between the 3 groups. Heart rate was decreased significantly after sedation but increased during anaesthesia. Arterial blood pressure increased after sedation and remained high during anaesthesia. A significant decrease in arterial oxygen tension was observed in all groups during anaesthesia. The muscle relaxation induced by romifidine was, in most cases, not sufficient to abolish the catalepsy following a repeated injection of ketamine alone. Zoletil or a repeated injection of ketaminehornifidine resulted in smoother anaesthesia. When additional time is required to complete surgery during field anaesthesia, it is advisable to prolong romifidine/ketamine anaesthesia with an injection of both romifidine and ketamine in healthy horses. When a longer procedure is anticipated from the start Zoletil is an alternative for induction of anaesthesia. The mean time to response to noxious stimuli and mean time spent in lateral recumbency was 28 and 38 min for the anaesthesia prolonged with ketamine, 3.5 and 43 rnin for the anaesthesia prolonged with ketaminehornifidine and 33 and 45 min for the anaesthesia with Zoletil. All horses reached a standing position at the first attempt.

A combination of an a?-adrenoceptor agonist and ketaniine is commonly used for short duration field anaesthesia in horses. If a slightly longer operation is anticipated, or when complications lengthen a normally short procedure, additional anaesthesia may be required. Many authors have recommended a repeated iv injection of 25S.5076 of the initial dosages to prolong the anaesthesia (McCarty et (11. 1990; Matthews and Hartsfield 1993). Another way to increase the duration of recumbency and to improve muscle relaxation has been to add a benzodiazepine derivative, eg diazepam, temazepam or zolazepam to an a2-adrenoceptor agonist and a cyclohexamine (Matthews et (11. 1991a; Lin et t i / . 1992; Wan et NI. 1992). Ketamine and tiletarnine are both cyclohexamine anaesthetic agents that induce dissociative anaesthesia. Romifidine is an a2-adrenoceptor agonist with a sedative effect similar to that of xylazine and detomidine, but romifidine is reported to have a longer duration and cause less ataxia (England et (11. 1992). This study was designed to evaluate the cardiorespiratory and anaesthetic effects of romifidine combined with tiletamine/zolazepam, compared with prolonged romifidine and ketamine anaesthesia. A second aim was to determine whether romifidine/ketamine anaesthesia could be prolonged with ketamine alone or whether further doses of both romifidine and ketamine would be appropriate.

M A T E R I A LASN D

METHODS

Horses The study was performed on 6 Standardbred trotters, 3 mares and 3 geldings, weighing 40.5-540 kg (mean 450) and aged 5-14 years (mean 9). The horses were considered healthy on clinical examination.

Anaesthesia Each horse served as its own control and was anaesthetised 3 times, each time with a different drug combination. The order of drug combinations was randomised and there was an interval of at least 7 days between the anaesthetic protocols.

"'cor-r-<~.\/"rr Itlil r,g ( 1 1 1 tlror: 64

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J. vet. Anne\tti. Vol. 23(2) (1996)

assumed sternal recumbency. The horses were not forced or assisted to stand. After the horses reached a standing position one person held the horse’s head to protect the facial arterial catheter. The last measurements and samples were taken with the horse in a standing position 5 rnin after recovery (post). The length of time from ketamine injection to lateral recumbency and muscle relaxation, and the times spent in lateral recumbency and in sternal recumbency were recorded. The induction time was defined as the time from the start of the cyclohexamine injection until the horse reached lateral recumbency. Muscle relaxation was defined to have been obtained when no rigidity or muscle twitching could be observed. All time measurements were recorded with a stopwatch.

Food was withheld for 10 h before anaesthesia but access was given to straw bedding and water. All drugs were administered iv through a catheter placed in the jugular vein. The different anaesthetic groups were as follows:

RK+K: 7 min after premedication with romifidine 0.1 mg/kg bwt (Sedivet vet., 10 mg/ml, Boehringer Ingelheim Vetmedica, Ingelheim am Rhein, Germany), anaesthesia was induced with ketamine 2.2 mg/kg bwt (Ketaminol 100 mg/ml, Veterinaria AG, Zurich, Schweiz). A repeated dose of ketamine 1.1 mg/kg bwt was given 18-20 rnin after the start of the first ketamine injection used for induction. RK+RK: 7 rnin after premedication with romifidine 0.1 m g k g bwt, anaesthesia was induced with ketamine 2.2 mg/kg bwt. Repeated doses of both romifidine 0.04 mg/kg bwt and ketamine 1.1 mg/kg bwt were given 1 8-20 min after the start of the first ketamine injection used for induction.

Haemodynamic measurements Invasive arterial blood pressure was measured through an arterial catheter connected via a fluid-filled line to a pressure transducer (Baxter Medical AB, Eskilstuna, Sweden) positioned at the level of the scapulo-humeral joint in the conscious horse and at the level of the sternal manubrium during lateral recumbency. The pressure was recorded by an ink-jet recorder (Sirecust 730, SiemensElema, Solna, Sweden). A base-apex electrocardiogram was recorded from surface electrodes to obtain the heart rate and rhythm.

RTE: 7 rnin after premedication with romifidine 0.1 mg/kg bwt, anaesthesia was induced with Zoletil 1.4 mg/kg bwt (Zoletil 100 100 mg/ml, Virbac, Carros, France). Zoletil 100 (100 mg/ml) is supplied as a powder mixture ( 5 ml vial) containing 2.50 mg of tiletamine (SO mg/ml) and 250 mg of zolezepam (SO mg/ml).

Catheterisation All catheterisations were performed with the horse standing and unsedated, after local analgesia. An arterial catheter (1 8W1.4 x 200 mm, Ohmeda, Swindon, UK) was introduced percutaneously into the transverse facial artery. A teflon catheter ((314, 10.5 mm, Intranyl, Vygon, Ecouen, France) was introduced percutaneously into a jugular vein.

Respiratory and blood gas measurements The respiratory rate was measured by observing the costoabdominal movements. Arterial blood was obtained anaerobically into heparinised syringes and kept airtight in iced water for 30 min until arterial oxygen and carbon dioxide tensions (Pa02, PaC02) were analysed with a standard electrode technique (ABL 3, Radiometer, Copenhagen, Denmark).

Repeated injection The time of the second injection was set at 20 rnin after the start of the injection of ketamine for induction of anaesthesia, corresponding to 18 min after lateral recumbency. The time of the repeated injection was based on results from a previous study with ketamine and romifidine, in which no horse weighing above 3.50 kg showed signs of light anaesthesia before 18 min of lateral recumbency (Marntell et al. 1994). If the horses in the present study showed signs of light anaesthesia before 18 min had elapsed, including increased nystagmus, a strengthened palpebral reflex, ear movements and/or increased muscle tension, the injection for prolongation of anaesthesia was given earlier.

Response to noxious stimulus The response to noxious stimuli was tested by the pin-prick method on the coronary band of front and hind leg, shoulder and gaskin. The stimuli were performed 5 rnin after induction of anaesthesia and then every 10th min during lateral recumbency. If purposeful skeletal muscle movement was observed, at any of the 4 test sites, this was interpreted as a response to noxious stimulus.

Procedure

Statistical analyses

Measurements were performed initially in the standing, unsedated horse (baseline) and were repeated 4 rnin after the sedation with romifidine (sedation). The horses were anaesthetised in a padded recovery room with one person holding the horse’s halter during induction. All horses were breathing room air spontaneously. The first measurements and samples during anaesthesia in lateral recumbency were taken 5 min after ketamine injection. Measurements and samples were repeated every 10th rnin until the horse

The data were analysed by 2-way analysis of variance for repeated measures (ANOVA). The test defined differences attributable to drug mixture, time and interaction between drug mixture and time. If ANOVA indicated a significant difference, further analysis was carried out using the Tukey posf hoc test to describe the patterns of differences. The time taken to attain muscle relaxation and the lengths of time in lateral and sternal recumbency were compared by the Wilcoxon rank-sum test. In all tests a P value < 0.0.5 was 65

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significantly increased 5 mill al'tcr hetaminc iiijcction in the K K + R K group (Fig 4).

Indirctiort

consitlered significant. All data are presented ;is iiic;iii v~ilucx a i d standard error ot' the iiiem, In the text ranges ;ire given w i t h i n hracke t s.

R Es u LT s

The iiiduction time varied between 7 5 and 120 s I'roiii the start of the ketaiiiine or Zolctil iii.jcction. The horses that received ke tam i ne a1I had accc pt a b Ic i nducr i on and gradiial Iy stepped backwxcts before going clow,n. The incluction after Zoletil was considered poor in oiic horse which fell I'oru art1 towards the person holding the head. The time from the start of itiLjcction of kctarnine or Zolctil to iiiiiscle rclxwtioii in lateral recumbency was 3.5 -1- 0.5 min in the K K + K group. 3.9 A 0.5 min in the K K + K K group and sigiiil'icaiitly shorter. I .3 A 0. I min. i n the RT/Z group.

Haemodynamic ineasurenzeiits

Aitaesthesia

The heart rate decreased signil'icantly d t e r sedation with ro 1111fid i ne . hut i ncrcasccl ;II't or ad m i 11i x t rat ion ot' c y c lohex ii i n i nc and was 110 I on gc I. s i g n i (_ic ;in t Iy d i fi'e reii t I'rom the baseline v;iIiic at a n y time chiring tlie treatment in any of the ailaesthetic groups (Fig I ). The iiiciiii arterial blood pressure increased after sedation and rcmainccl high during anaesthesia i n all g r o ~ i p(Fig ~ 2 ) . I n the KT/L group. it w a s significantly increased between 5 m c l 25 min of anaes t he si ;I co 111p;ired w i t I1 t hc hasc 1i lie Y:I I LIC. I ii g 1-0 tip K K+K K . the iiiciiii artc ri ;I I b I ood p re s s ti re was s i g i i i fica 11t I y increased 25 and 35 iiiiii after the start ol' anaesthesia n.hereas. i n the K K + K group. t h e increase was not \igiiificant.

Iluring tlie romit'idinelket~iiiiinc~uixsthcsi:i 2 horscs (one horse twice. one horse once) showed signs 01' light I hefore 20 min al'tcr the start 01' the injcctioii of hut am i ne ['or i nd ti c t i on o f i i i i x s t lie s i ii . R c peat ccl i iijcct i o 11s were consequently given twice iil'ter I 8 min and once ~il'tcrI9 m in . The proI o ngccl xiae st lies i ;I produccd h y he ti1 111inc ;IIo lit' was sinooth i n only onc horse. In 5 01. the 6 Iiorws ;I secoiicl iii,jection of ketamine alone resulted in limb rigidity antl muscle tremor. The rigidity and tremor stai-ted approxiiiiatcl) 2 min after thc ketaminc iii.jection and Iaxtecl hctwccn I! aiict 6 min bet'ore muscle relaxation occurred. One horse startccl to move its legs ;is if g;illoping in its sleep and a n o t h e r horse rose to a sternal position 2 min al'tcr the ketaiiiinc in.jcction. hut nu mental contact with the Iiorsc could he estiihlishcd: thc head was held down and at'tcr I! min the horse rclaxecl i n lateral recumbency. Kcpciited iii.jcction 01' romificlinc aiid ketaminc resulted i n a smoother prolongation 01' xixsthesia without the forcefiil reaction to prolongatioii u itli hct;iiiiinc alone. With a repeated iii.jection of both romilicline and hetaiiiine, 3 horsex showctl miiscle tremor i n the neck antl slight rigidity tor 1-2 min. Two horses had no muscle tremor or rigidity. The anaesthesia with Zolctil wiis smooth. The

Respircitioii arid blood gas ineasiireinents The respiratory rate dccre~isedal'tcr roiiiil'idiiie injection but returned t o the baseline \slue or higher al'ter ketamine or Zolctil iii,jcction (Fig 3 ). The ai-tct-ial oxygen tension wax decrcaxed significantly in all g r o i i p tliiring anaesthesia in latcrol rccumhency (Fig 3 ) . The arterial carbon dioxide teii\ion clicl iiot alter greatly cluriiig the experiment. hut was

J. vet. Anaesth. Vol. 23(2) (1996)

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reaching a standing position, especially those that spent little or no time in sternal recumbency.

DISCUSSION The induction of anaesthesia with romifidine (0.1 mgkg bwt) and ketamine (2.2 mg/kg bwt) in horses is similar to that reported with detomidineketamine or xy lazineketamine (Diamond et al. 1993). In RK+K and RK+RK all horses had muscle tonus during induction and usually sat down gradually on the hind legs first. Induction of anaesthesia with RT/Z resulted in rapid muscle relaxation which lasted during the anaesthesia. This was probably due to the musclerelaxing effect of zolazepam, but a disadvantage of the rapid muscle relaxation was observed in one horse, which had an abrupt fall forwards towards the person holding the horse. This may be prevented if a person balances the fall with the horse's tail. Dissociative anaesthesia varies in length between individual horses (Fig 6). A very interesting finding was that the mares spent less time in sternal recumbency, often having an abrupt recovery directly from lateral to standing position (Fig 6). Abrupt recovery is a disadvantage when the anaesthesia has to be induced by the surgeon without an available skilled assistant to monitor the progress of anaesthesia. It seems that the abrupt recovery from ketamine anaesthesia in horses is due mainly to the rapid redistribution of the drug from the central compartment (Waterman ef al. 1987). It would be an advantage if further anaesthesia could be given on a time basis, but in field practice prolongation is often carried out for the reason that the horse is awake sooner than expected, or because the operation is lengthened by complications. In a study on prolongation of xylazine/ ketamine anaesthesia in horses, a third of the initial dosage of xylazineketamine was injected 13 & 4 (mean A sd) rnin after induction of anaesthesia (McCarty et al. 1990). The use of ketamine alone to prolong anaesthesia was chosen because the effect of romifidine has been reported to have a longer duration than that of xylazine and detomidine

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Time of anaesthesia (min)

Fig 5: Mean time to obtain muscle relaxation, to response for noxious stimuli, mean time in lateral and sternal recumbency. Data are mean k se for 6 horses. For abbreviations see Figure 1. # Signijicant differencefrom the other anaesthetic groups (P
response to noxious stimuli occurred on average after 28 rnin in group RK+K, after 35 rnin in RK+RK and after 33 rnin in RT/Z (Fig 5). The average time spent in lateral recumbency in the RK+K group was 38 (range 35-46) min, which was significantly shorter than in RK+RK (43, range 40-49) min and RT/Z (45, range 36-55) rnin (Fig 5).

Recovery The average time spent in sternal recumbency in group RK+K was 5 min (range 0-13), in RK+RK 6 rnin (range CL16) and in RT/Z 11 min (range 0-33) (Fig 5). The mares spent less time in sternal recumbency than the geldings. The recovery was calm and without excitation. All horses reached a standing position at the first attempt. Three of the horses which received RK+K had muscle fasciculations in the pectoralis muscles. The horses of the RT/Z group showed slightly more incoordination of the limbs directly after

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J. vet. Anaesth. Vol. 23(2) ( I 996)

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Fig 6: Individual time spent in lateral and sternal recumbency in each horse. Horses 1-3 are geldings and horses 4 4 are mares. For ubbreviations see Figure 1.

5 0

similar to findings after use of combinations of a2adrenoceptor agonists and cyclohexamine anaesthetics (Muir et al. 1977; Clarke et af. 1986; Hubbell er al. 1989; Grondahl-Nielsen 1992). The mean arterial blood pressure increased in all groups in the present study during anaesthesia. In RT/Z it was significantly increased 5-25 rnin after injection of Zoletil, which is in agreement with results reported after use of xylazine and tiletamine-zolazepam (Hubbell et al. 1989), and detomidine and tiletaminezolazepam (Wan et al. 1992). In RK+RK the mean arterial blood pressure was increased significantly between 25 and 35 rnin of anaesthesia compared with the baseline value, which corresponds to 5-15 rnin after repeated injection of romifidine and ketamine. This significant increase from baseline is probably due to the repeated injection of the 132agonist, since there was no significant increase after repeated administration of ketamine alone. There were no significant differences in arterial blood gases between the different anaesthetic combinations, but Pa02 and PaC02 changed significantly during anaesthesia compared with the baseline values. The lowest mean value of Pa02 (8.0 kPa) was noted 5 rnin after induction of RT/Z anaesthesia, whereas the lowest mean Pa02 value (8.7 kPa) during the course of RK+RK was observed 5 rnin after prolongation of anaesthesia simultaneously, with a slight but not significant increase in PaCO2. The normalisation of Pa02 after recovery was similar in the horses that spent no or only a short time in sternal recumbency to that in horses that spent a long time in this posture. Impaired pulmonary function during anaesthesia with a2agonists and cyclohexamine has been reported (Muir et al. 1977; Hubbell er af. 1989; Matthews er al. 1991b; Wan et af. 1992; Grcdndahl-Nielsen 1992). Impairment of pulmonary function may be attributed to ventilation-perfusion inequality due to recumbency and to anaesthetic drug depression of the regulation of ventilation and perfusion. Interestingly, the most pronounced decrease in Pa02 seems to occur at the same time as the significant increase in mean arterial blood pressure.

(England er al. 1992). In a recent study Kerr et al. (1994) relied on the long acting sedation of romifidine when comparing the cardiopulmonary effects of xylazine/ketamine with those of romifidine/ketamine and maintained anaesthesia with constant infusion of ketamine alone in the romifidineketamine group but infusion of both xylazine and ketamine in the xylazine/ketamine group. However, in our study there was a clear difference in the horses’ reaction between prolongation with ketamine alone and prolongation with both ketamine and romifidine. The horses receiving only ketamine showed more muscle twitching and leg rigidity than those given both ketamine and romifidine. The initial iv romifidine injection did not cause sufficient muscle relaxation to abolish the catalepsy following a repeated injection of ketamine alone. The injection for prolongation of anaesthesia was given earlier on 3 occasions, twice after 16 min and once after 17 min in lateral recumbency, out of 12 prolongations. It is possible that an injection of ketamine even earlier in the anaesthesia would have produced less catalepsy. However, on the basis of the present results, repeated injections of ketamine alone can not be recommended. The smoothest anaesthesia and best muscle relaxation were found with the RT/Z combination. These are probably attributable to the benzodiazepam, zolazepam. Addition of a benzodiazepam to the romifidineketamine anaesthesia would probably enhance the muscle relaxation. The length of time before response to noxious stimuli did not differ significantly between the 3 drug combinations (Fig 5). As no surgery was performed, further investigation during surgery would be of value. The haemodynamic changes following romifidine administration were conformed with those observed in previous investigations in horses (Clarke et al. 1991; England et al. 1992; Grondahl-Nielsen 1992). Romifidine characteristically decreased the heart rate, respiratory rate and Pa02 and increased the blood pressure. An increased heart rate occurred in all groups after cyclohexamine injection compared with the heart rate after sedation. This is 68

J. vet. Anaesth. Vol. 23(2) (1996)

butorphanol in the horse. J . vet. Armestb. 18, 25-29. Clarke, K.W., Taylor, P.M. and Watkins, S.B. (1986) Detomidineketamine anaesthesia in the horse. Acta Veterinaria Scandinavica, 82, 167-179. Diamond, M.J., Young, L.E., Bartram, D.H., Gregg, A.S., Clutton. R.E., Long, K.J. and Jones, R.S. (1993) Clinical evaluation of romifidine ketamineihalothane anaesthesia in horses. Vet. Rec. 132,572-575. England, G.C.W., Clarke, K.W. and Goossens, L. (1992) A comparison of the sedative effects of three cz2-adrenoceptor agonists (romifidine. detomidine and xylazine) in the horse. J vet. Pharmacol. Therap. 15, 194-201. Grgndahl-Nielsen, C. (1992) Sedrition and Anaesthesia in Horses with a2Agonisrs and Tifetamine-Zo[azeparn.Ph D thesis, Department of Clinical studies, Royal Veterinary & Agricultural University, Frederiksberg, Denmark. (In Danish, with English summary) Hubbell, J.A.E., Bebnarski, R.M. and Muir, W.W. (1989) Xylazine and tiletarnine-zolazepam anesthesia in horses. Am. J. vcr. Res. 50. 737-742. Kerr, C., Young, S. and McDonell, W. (1994) Comparison of the cardiopulmonary effects of romifidinelketamine and xylazine/ketamine for short duration Anesthesia in the horse. Proc. 5th int. Cong. vet. Anaes. p 129. Lin, H.C., Branson, K.R.,Thurman, J.C., Benson, G.J., Tranquilli, W.J., Olson, W.A. and Vaha-Vahe. A.T. ( 1992) Ketamine, telazol, xylazine and detomidine a comparative anesthetic drug combinations study in ponies. Acra Veterinaria Scandinavica, 33, 109-1 15. Marntell, S., Emmesjo, A. and Nyman, G. (1994) Romifidine, a new sedative drug for the horse. Svensk Veteriniir Tidning, 46, 537-547. (In Swedish, with English summary) Matthews, N.S., Dollars, N.S., Young, D.B. and Shawley, R.V. (1991a) Prolongation of xylazidketamine induced recumbency time with temazepam in horses, Equine vet. J. 23, 8-10, Matthews, N.S. and Hartsfield, S.M. (1993) Using injectable aneasthetic drugs safely in horses. Vet. Med. 88, 154-159. Matthews, N.S., Hartsfield, S.M., Cornick, J.L., Williams, J.D. and Beasley, A.A. (1991b) Comparison of injectable anaesthetic combinations in horses. Vet. Surg. 20, 268-273. McCarty, J.E., Trim, C.M. and Ferguson, D. (1990) Prolongation of anesthesia with xylazine, ketamine, and guaifenesin in horses: 64 cases (1986-1989). J. Am. vet. tried. Ass. 197, 1646-1650. Muir, W.W., Skarda, R.T. and Milne, D.W. (1977) Evaluation of xylazine and ketamine hydrochloride for anesthesia in horses. Am. J. vet. Res. 38, 118-124 Wan, P.Y., Trim, C.M. and Mueller, P.O.E. (1992) Xylazine-ketamine and detomidine-tiletamine-zolazepamanesthesia in horses. Vet. Surg. 21, 3 12-3 18. Waterman, A.E., Robertson, S.A. and Lane, J.G. (1987) Pharmacokinetics of intravenously administered ketamine in the horse. Res. vet. Sci. 42, 162- 166.

We agree with the advice not to use repeated injection of a2-agonists and ketamine for prolonged surgical procedures in which inhalation anaesthesia ordinarily would be used (McCarty ef al. 1990). When a slightly longer operation is anticipated, or when complications lengthen a normally short procedure, particular care and attention should be paid to adequacy of ventilation. Maintenance of anaesthesia with any injectable drug for more than 60 min without oxygen supplementation is not recommended because of the danger of hypoxia and myositis (Matthews and Hartsfield 1993). The most pronounced cardiorespiratory changes during the anaesthesia with RT/Z were observed after induction. In contrast, &he greatest impairment during RK+RK was noted after the repeated injections for prolongation of anaesthesia. RK+K resulted in less pronounced cardiorespiratory changes, but the quality of anaesthesia was poorer after prolongation. With all drug combinations the recoveries were calm without excitation and the horses reached a standing position at the first attempt. If additional time is required to complete surgery during field anaesthesia, it may be advisable to prolong romifidineketamine anaesthesia with an injection of both romifidine and ketamine. Because no significant differences in cardiorespiratory function were found between the 3 drug combinations used in this study, we conclude that RTIZ may be an appropriate alternative if a longer surgical procedure is anticipated.

ACKNOWLEDGEMENTS The authors gratefully acknowledge the expert technical assistance provided by Ann-Marie Lofgren, Pia Funkquist and Karin Morgan. This work was supported by a scholarship from the Michael Forsgren Foundation and by BI-vet, Malmo, Sweden.

REFERENCES Clarke, K.W., England, G.C.W. and Goossens, L. (1991) Sedative and cardiovascular effects of romifidine alone and in combination with

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