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Sedative and cardiovascular effects of romifidine, alone and in combination with butorphanol, in the horse
1. vet. Anaesth. Vol. 18 (1991)
Sedative and cardiovascular effects of romifidine, alone and in combination with butorphanol, in the horse K. W. Clarke, G. C. W. England and L. Goossens“ Department of Large Animal Medicine and Surgery, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire, UK and “Boehringer Ingelheim Vetmedica GmbH, P.O. Box 200, D-6507 Ingelheim, Germany.
proved effective (Robertson and Muir 1983; Clarke and Paton 1988; Taylor, Browning and Harris 1988) and is The behavioural and sedative effects of intravenous (iv) convenient to use as it is not subject to such stringent romifidine (40 and 80 pg/kg bodyweight [bwtl) alone or in controls as some of the other similar agents. combination with iv butorphanol (50 pg/kg bwt) were Romifidine is a potent and selective a2-adrenoceptor investigated in four ponies and one Thoroughbred horse. agonist, closely related chemically to clonidine, which has Apparent sedation, as judged by the lowering of the head, been used recently for both sedation and pre-medication in and by the response to imposed touch, visual and sound horses (Poulsen-Nautrup 1988; Voegtli 1988). Doses of 80 stimuli was assessed. The combination with butorphanol pg/ kg bodyweight (bwt) romifidine given intravenously reduced the animals’ response to imposed stimuli when (iv) appear to produce maximal sedation, higher doses compared with the effect of the same dose of romifidine lengthening the effect (Voegtli, 1988). However, as with alone. Following the administration of other a2-adrenoceptor agonist drugs, the horses sedated romifidine/ butorphanol combinations muzzle tremor was with romifidine may still be easily aroused and appear noted and some animals attempted to walk forward. sensitive to touch (England, Clarke and Goossens 1991). In a separate series, the cardiopulmonary effects of iv The present study examined the sedative effects of two romifidine (80 pg/kg bwt) alone, or in combination with doses (40 and 80 pg/kg bwt iv) of romifidine alone or in butorphanol(50 pg/kg bwt) were investigated. Romifidine combination with butorphanol (50 pg/kg bwt iv). In a and the romifidine/butorphanol combination caused separate study the cardiopulmonary effects of the higher similar cardiovascular changes, these being bradycardia dose of romifidine alone and in combination with with heart block, and hypertension followed by butorphanol were investigated. hypotension. Romifidine caused a transient decrease in arterial oxygen tensions and arterial carbon dioxide MATERIALS AND METHODS tensions had increased significantly by the end of the 90 Investigations were carried out using four adult Welsh min recording period. Romifidine/ butorphanol combinations produced significantly higher arterial carbon Mountain ponies (weight range 270 to 370 kg) and one dioxide tensions during the first 15 mins after drug adult Thoroughbred horse (weight 520 kg). In all animals, administration than did romifidine alone. the carotid artery had been raised to a subcutaneous Butorphanol at 50 pg/kg bwt iv reduced the response to position (under general anaesthesia) a minimum of two imposed stimuli in horses sedated with romifidine. The years previously. Prior to sedation all animals were combination produced no cardiovascular changes beyond allowed free access to food and water. All drugs were given those induced by romifidine alone, but did increase the through a catheter (18 gauge Angiocath; Deseret Ltd.) placed previously in the jugular vein. A period of at least 6 degree of respiratory depression. days was allowed between drug administrations in each INTRODUCTION animal. SUMMARY
The a2-adrenoceptoragonists xylazine and detomidine have become widely used to sedate horses. However, horses apparently well sedated by these drugs can respond suddenly and unexpectedly to stimuli, and can kick (Clarke and Hall 1969; Tronicke and Vocke 1970; Alitalo 1986; Clarke and Taylor 1986; Ricketts 1986). It has been suggested that these responses are to the stimulus of touch (Tronicke and Vocke 1970; Alitalo 1986). The combination of opioid drugs with the %-adrenoceptor agonists appears to reduce this response (Muir 1981; Taylor 1985; Paton and Clarke 1986; Taylor, Rymaszewska and Young 1990).Of the opioid drugs that have been used, butorphanol tartrate has
Behavioural studies The animals were placed in stocks for restraint and were given one of four drug regimes: 1) Romifidine (Sedivet; Boehringer Ingelheim Vetmedica GmbH, Germany) 40 p g / k g bwt iv; 2) Romifidine 80 pg/kg bwt iv; 3) Romifidine 40 pg/kg bwt iv and butorphanol tartrate (Torbugesic, C-Vet Ltd, Bury St. Edmunds, Suffolk) 50 p g / k g bwt iv; 4) Romifidine 80 pg/kg bwt iv and butorphanol50 pg/kg bwt iv. When both drugs were given, romifidine was administered first, followed immediately by butorphanol. 25
1. vet. Anaesth. Vol. 18 (1991)
Observations and assessments were made before and 5,10, 15,30,45,60, 75 and 90 mins after the drugs were injected. The mean of two measurements taken prior to administration of romifidine was considered to be the presedation measurement. The same observer, who knew whether or not butorphanol had been given but was not aware of the dose of romifidine used, assessed sedation. The degree of sedation and response to stimulation were measured and scored as follows: Height of the head. For the duration of the recordings the front restraints of the stocks were adjusted so as not to interfere with the head position. The height of the head was taken as the distance (in cm) from the floor to the animal's muzzle. The position of the muzzle was marked against the stocks, and this was then measured. Changes in head postion were expressed as a percentage of the unsedated value. Degree of ataxia. Scoring was based on: 3 ) The animal was swaying, staggering, and/or leaning very heavily on any support. Often the hind legs were crossed and the forelegs buckled at the knee. The impression was that if the support was removed the animal would fall. 2) The animal was still swaying and leaning but the legs were in the normal position and there was no indication that it would fall. 1) The animals were stable but swaying slightly. 0) Animals did not appear sedated. Response to touch. The response to touch was assessed using three tests: 1) touching with a pencil on the fore coronets; 2) touching with a pencil on the hind coronets; 3 ) tickling inside the pinna of the ear. The response to touch was scored as follows: 3 ) a rapid and marked response (limb movement or head shake) to stimulation. Score 3 also was awarded where anticipation of the procedure invoked so much response that the test was extremely difficult to perform; 2) response was easily elucidated but was slower and required more pressure or tickling; 1) the response was sluggish and only elicited by prolonged stimulation; 0) no response. For each individual animal the scores for all three touch stimuli were added together, the sum being considered as the 'touch score' for that animal. Response to sound and visual stimulation. Visual testing consisted of flapping a cloth in front of the horse. The sound stimulus was a loud hand clap behind the horse. Scoring for the animal's response to sound was as follows: 3 ) A sudden 'start' in response. The head was usually thrown up, and the horse moved violently away from the stimulus. 2) A definite 'start' and head movement, but the horse did not try to move away. 1) The horse was obviously aware of the stimulus, but only gave a very slight 'start'. 0) Represented no response. For each individual, the scores for the visual and sound stimuli were added together, the total being considered the 'audiovisual score'.
The ponies were restrained in stocks as previously. The subcutaneous carotid artery was catheterised with a 16 gauge Angiocath (Deseret Ltd). Arterial blood pressure was measured using a strain gauge transducer (Bell and Howell) attached via saline filled manometer tubing to the arterial catheter and recorded continuously on a chart recorder (Lectromed Ltd). The transducer was placed level with the tip of the sternal manubrium. The electrocardiogram (ECG) was monitored with standard limb leads and recorded continuously on the chart recorder. Heart rate was derived from the recording by counting the beats over a period of 30 secs. Systolic and diastolic arterial blood pressures were measured from the recording, and mean arterial pressure calculated as diastolic pressure plus one third of pulse pressure. Arterial blood samples, collected anaerobically in heparinised syringes, were taken before and 5, 10, 15,30,45, 60, 75 and 90 mins after the administration of the drugs. They were then stored in iced water until analysed for oxygen tension (Pa02),carbon tension (PaC02)and pH using conventional blood gas analysis equipment (Corning),which underwent regular quality control checks using standard solutions (Certain;Corning).
Statistical analysis Statistical analysis of the lowering of the head and of the cardiopulmonary effects of the drug and drug combinations was perfomed by paired Students' t tests, using a Multistat programme. Differences were considered significant when P < 0.05.
RESULTS
Behavioural studies
Following the injection of romifidine at either dose the ponies became sedated in a manner typical of a2adrenoceptor agonists: the head was lowered (Fig 1) ,there were occasional muscle twitches, and the horses swayed slightly particularly after the higher dose (Fig 2). However, although response to the imposed stimuli was reduced, it was not abolished (Fig l), and, in one pony who particularly resented pressure on the coronet, it was still impossible to perform this test safely. With either dose of romifidine the depth of sedation achieved was similar, but the effects of the lower dose were shorter lasting, and at 45 mins after administration, the lowering of the head was significantly less than after the 80 pg/kg bwt dose. Following the injection of either dose of romifidine with butorphanol, sedation was similar to that seen after romifidine alone, but additional side effects were noted. With both butorphanol regimes, three ponies and the Thoroughbred horse showed some muzzle tremor and two ponies and the Thoroughbred tried to move forward, but were prevented from doing so by the stocks. The forward Cardiopulmonay investigations movement was more marked after the lower dose of In a separate investigation, the cardiopulmonary effects romifidine/butorphanol had been used, and the of iv romifidine (80 pg/kg bwt) or a romifidine (80 pg/kg Thoroughbred would have been difficult to control in the bwt) /butorphan01 (50 pg/kg bwt) combination were absence of stocks. Compared with romifidine alone, the romifidine/ investigated in the five animals. 26
J. vet. Anaesth. Vol. 18 (1991) Lowering of head a,
m
Ataxia
1 2 0 ~ a
;100 L
8 a,
80
2
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0
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-8 a, ;
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0 ln 0
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R40 R40 + B
R80
4
X
aR80+B
m
c
c
m
F c i 2
20
e 0
5
10
15
30
45
60
75
0
90
0
Response to touch stimuli
5
10
15 30 45 Time (mins)
60
75
90
Fig 2. The effects on stance in five horses of two doses of romifidine (40 and 80 Fg/kg) alone or in combination with butorphanol (50 pg/kg). An ataxia score of zero represents no ataxia.
b
*
Ln II
3E
30
v
ln
2
8ln
R40 R40 + B R80 R80 + B
20
.c 0
g m
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15
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Response to audio visual stimuli I
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Cardiopulmonary studies
2 0 (0 m
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after the higher dose of romifidine some horses that had appeared very stable standing still showed slight swaying of the hindquarters and dragged their hind feet as they walked. After romifidine/ butorphanol combinations ponies adopted the 'saw horse' position in which all four legs were rigidly spread. In this position the animal appeared very stable, and ataxia scores awarded were low (Fig 2). However, in some cases if the pony did attempt to move it staggered badly and would have proved very difficult to move during the first 15 mins after drug administration.
R40 R40 + B R80
Prior to any of the drug treatments the cardiopulmonary values in all animals were within the normal range found R80 + 8 at this laboratory. Following injection of romifidine, there 7J 2 m was a significant fall in heart rate (Table 1).Minimum heart m c rates were recorded 1 to 2 mins after injection and were E n . . . . . . . . 0 5 10 15 30 45 60 75 90 accompanied by atrioventricular heart block; heart rates then increased but remained significantly below preTime (mins) sedation values for 45 mins after injection. Following a Fig 1: The sedative effects in five equines of two doses of romifidine hypertensive phase, (Table 1) arterial blood pressure (40 and 80 pg/kg) alone or in combination with butorphanol (50 decreased, becoming significantly below pre-sedation pg/kg). a ) Effects on head position of the horse were obtained by measuring the distance of the horse's muzzle from the ground (? sd). values 60 mins after injection and remaining so for the b) Effects on reducing the response of the horse to imposed touch remainder of the recording period. Following the injection stimuli. A touch score of zero represents no response. c) Effects on of the romifidine/butorphanol combination changes in reducing the response of the horse to imposed audiovisual stimuli. heart rate and arterial pressure were similar to those seen An audiovisual score of zero represents no response. after romifidine alone. Following romifidine injection, arterial oxygen tensions were depressed (Table 1)significantly 5 mins after injection. butorphanol combinations did not cause significant further Arterial carbon dioxide tensions were significantly elevated lowering of the head, but there was a marked reduction in by the end of the recording period. When compared with response to stimuli (Fig 1). Fifteen mins after the higher the changes induced by romifidine alone, arterial oxygen dose of romifidine with butorphanol, four animals tensions were not further depressed following romifidine/ (including the difficult pony) were unresponsive to any of butorphanol (Table 2), but arterial carbon dioxide tensions the imposed stimuli whereas the remaining pony was were significantly elevated from 10 to 30 mins after unresponsive to all but one touch stimulus, for which it injection of the combination. Arterial pH (Tables 1 and 2) received a score of 1. was not significantly influenced by either drug regime. After romifidine administration ponies swayed and leaned on the stocks, but were never severely ataxic (Fig 21, DISCUSSION and at no time did they seem likely to fall. However, when taken out of the stocks at the end of the recording period, Romifidine given iv to the horse produces sedation of a
3
.._
10
I
27
J. vet. Anaesth. Vol. 18 (1991) TABLE 1: Cardiopulmonary changes in five horse given romifidine (80 pg/kg bwt iv)
Time (mins)
Pre-sedation
Heart rate (beats/min; to the nearest whole beat)
Arterial blood pressure (mmHg) Systolic Diastolic Mean (calculated)
Pa02 (kPa)
Arterial PaCO2 (kPa)
PH
43f3
176 f 21
123f 9
141 f 12
10.9 f0.88
6.11 f 0.45
7.41 f 0.02
16 f 6** 26 f 6** 30 f 7** 32 f 6** 32 f 6** 33 f 6* 33 f 6" 35 f 5" 3627 40 f 9 40f9
219 f 38 221 f 32** 219 f 24, 217 f 27* 209 f 30 202 f 31 174 f 27 159 k 21 147 f 23' 133 f 26* 134 f 20*
137f 17 131 f 19 139 f 16 140 f 15 136 f 13 126 f 17 117f 14 110f 9 100 f 8** 95 f 8** 92 f 8**
165 f 25 161 f 22 166 f 1 7 166 f 18* 160 f 18 150 f 20 136 f 15 128 f 14 115f 13* 108 f 13** 107 f 12**
9.22 f 0.85* 10.04f 0.59 10.37f 0.52 10.75f 0.57 10.68f 0.57 10.51f 0.89 10.55f 1.05 10.28f 0.41
6.51 f 0.27 6.12 f 0.35 6.26 f 0.35 6.35 f 0.33 6.55 f 0.19 6.62 f 0.30 6.74 f 0.27* 6.87f 0.18"
7.40 f 0.02 7.42 f 0.03 7.41 f 0.03 7.41 f 0.04 7.42 f 0.02 7.41 f 0.03 7.42 f 0.02 7.42 f 0.03
After romifidine 1 2 3 5 10 15 30 45 60 75 90
All values are means (fse). Significantly different from pre-sedation values: *P<0.05; **P
TABLE 2: Cardiopulmonary changes in five horse given romifidine (80 pg/kg bwt iv) followed by butorphanol(20 pg/kg bwt iv)
Time (mins)
Pre-sedation After romifidine 1 2 3 5 10 15 30 45 60 75 90
Heart rate (beats/min; to the nearest whole beat)
Arterial blood pressure (mmHg) Systolic Diastolic Mean (calculated)
P a 4 (kPa)
Arterial PaC02 (kPa)
PH
3 7 f 18
182 f 16
123 f 8
144 f 11
11.46 f 0.56
6.21 f 0.48
7.41 k 0.02
18 f 7** 30 f 9** 34 f 5** 33 f 7* 35+8 36f9 38+7 41 f 8 41 f 8 41 f 8 42f 8
231 f 50 212 f 43 215 f 31 208 f 31 191 f 22 180 f 30 165f 28 151 f 31 144 f 24* 137f 19** 140 f 23**
139 f 36 139 f 34 145f 29 140 f 29 127f 22 120 f 28 117 f 20 103f 20 94 f 18* 94 f 18, 96 f 20*
170 f 40 161 f 33 169 f 27 163f 28 147 f 20 140 f 28 133 f 22 1195 9 111 f 19" 108 f 18** 110 f 19,"
8.79 f 1.13, 9.96 f 0.63** 9.95 f 0.79** 10.24 f 1.15 10.59f 0.85 11.12 f 0.78 10.88 f 0.60 10.83f 0.98
6.73 f 0.3fl 6.52 f 0.54t 6.86 k 0.44*+ 6.81 f 0.45 6.76 f 0.48 6.82 f 0.54 6.87 f 0.52 6.78 f 0.49
7.40 f 0.01 7.41 f 0.01 7.40 f 0.01 7.41 f 0.01 7.41 f 0.01 7.41 f 0.01 7.41 f 0.01 7.41 f 0.03
All values are means (fse). Significantly different from pre-sedation values: *P<0.05;**P
similar type to that produced by xylazine and detomidine, the other a2-adrenoceptor agonists used currently (Voegtli 1988).Compared with xylazine and detomidine, the effects of romifidine differ in that the horse's head is lowered to a lesser extent, the horse sways less and seems less likely to fall, and the action is a more prolonged, deep sedation, followed by a period when the horse appears quieter than normal, but is fully rousable (England, Clarke and Goossens 1991). However, as with other 9-adrenoceptor agonists, the horse under romifidine sedation may awake suddenly and respond, in particular to touch stimuli. The addition of opioids to xylazine or detomidine greatly reduces the response to stimuli and detomidine/butorphanol is widely used for clipping horses (Taylor et al1988). Because of the small number of animals and the subjective nature of the assessment, statistical analyses of the sedation parameters are not reported. There were marked differences between individuals in their response before sedation to the imposed stimuli, each animal beiqg
particularly sensitive to one type of stimulus (eg to touching the ears or the feet). These sensitivities were consistent throughout the experiments, showed no signs of adaptation and required the deepest levels of sedation to abolish. There was no difference between the ponies and the Thoroughbred in pre-sedation behaviour or in response to sedation other than that the Thoroughbreds size made walking forward more difficult to control. Ataxia scores were not subjected to statistical analysis because, as described previously, assessment of this parameter was difficult while the animals were restrained by stocks. These experiments demonstrated that the combination of butorphanol with romifidine greatly reduced the response of the horse to touch and audiovisual stimuli. Although the combination with butorphanol improved the efficacy of the lower dose of romifidine, the higher dose (80 pg/kg bwt) with butorphanol was necessary to abolish completely the response to all stimuli in all animals. The effect of the additional butorphanol was surprisingly shortlived, good reduction in response only being evident 28
I. vet. Anaesth. Vol. 18 (1991) __
up to 30 mins after drug injection. However, the addition of butorphanol was not without side effects. In this series, some animals showed signs associated with opioid excitement; muzzle tremors, head shaking and walking forward. Such signs have been seen with butorphanol on its own (Robertson, Muir and Sams 1981; Kalpravidh, Lumb, Wright and Heath 1984) and with detomidinelbutorphanol combinations (Clarke and Paton 1988). Opioid-induced excitement of a violent nature has not been reported with doses of butorphanol of 100 pg/kg bwt or less (Robertson et al 1981, Kalpravidh et al, 1984). However, the responses seen do suggest it would be inadvisable to increase the dose of butorphanol when combined with romifidine. Many authors have commented on the 'saw horse' stance taken by animals sedated with a2-adrenoceptor agonist/opioid combinations (Muir 1981; Taylor 1985). However, Paton and Clarke (1986/87) noted that in ponies already very ataxic from the effects of detomidine, the addition of any opioid made their stance unstable. Romifidine did not cause severe ataxia and the prolonged effects on gait noted when the horses were moved at the end of the observation period (also noted by Voegtli 1988) did not make it unsafe to move the animal. The addition of butorphanol did not cause any serious problems of stance when the animal was still, but animals that did move forward in the stocks were markedly ataxic. In this series, romifidine at 80 pg/kg bwt caused cardiopulmonary changes similar to those seen after xylazine and detomidine (ie bradycardia, hypertension followed by hypotension and small but significant changes in arterial blood gas tensions). As with xylazine or detomidine, hypertension was least in the individuals that showed the greatest degree of heart block (Clarke 1988). Gasthuys, Parmentier, Goossens and De Moor (1990) demonstrated that atrioventricular and sinus heart block may occur after romifidine administration, and that bradycardia is prevented by prior administration of atropine. However, probably that the use of atropine would increase the severity and duration of hypertension. At the dosage used, butorphanol alone has minimal effects on the cardiovascular system (Robertson and Muir 1983), and when combined with detomidine does not alter the cardiovascular parameters beyond the changes induced by detomidine alone (Clarke and Paton 1988).In this series, adding butorphanol did not alter the cardiovascular parameters beyond the changes induced by romifidine alone. However, butorphanol depressed the respiration further, as shown by the significant increase in carbon-dioxide tension. Arterial oxygen tensions were similar with either drug regime; calculated minimal arterial oxygen saturation never fell below 93 per cent and it is unlikely that respiratory depression would cause problems in fit horses, although it could in horses having a respiratory pathology. In conclusion, the combination of romifidine at doses of 40 or 80 pg/kg bwt with butorphanol (50 pg/kg bwt) greatly reduced the response to stimuli compared with that following the administration of romifidine alone.
The addition of butorphanol did not influence the cardiovascular system any more than romifidine alone, but did cause some increase in respiratory depression.
ACKNOWLEDGEMENTS This project was supported by Boehringer Ingelheim Vet medica GmbH. J. Mould typed the manuscript. Dr. England was a recipient of the Thomas Brown Fellowship.
REFERENCES Alitalo, A. (1986) Clinical experiences with Domosedan in horses and cattle. Acta vet. Scand. Suppl82,193-196. Clarke, K. W. (1988) The clinical pharmacology of detomidine in the horse. DVM Thesis, University of London. Clarke, K. W. and Hall, L. W. (1969) Xylazine - a new sedative for horses and cattle. Vet.Rec. 85,512-517. Clarke, K. W. and Paton, B. S. (1988) Combined use of detomidine with opiates in the horse. Equine vet. J. 20,331-334. Clarke, K. W. and Taylor, P. M. (1986) Detomidine, a new sedative for horses. Equine vet. J. 20,366-370. England, G. C. W., Clarke, K. W. and Goossens, L. (1991) A comparison of the sedative effects of three alpha 2 adrenoceptor agonists, romifidine, detomidine and xylazine, in the horse. J. Vet.Phmzac. Ther. (In press). Gasthuys, F., Parmenter, D., Goossens, L. and De Moor, A. (1990) A preliminary study on the effects of atropine sulphate on bradycardia and heart blocks during romifidine sedation in the horse. Vet.Res. Comm. pp 489-502. Kalpravidh, M., Limb, W. V., Wright, M. and Heath, R. B. (1984) Analgesic effects of butorphanol in horses: dose response studies. Am. J. vet. Res. 45,211-216. Muir, W. W. (1981) Standing chemical restraint in horses. Vet. Clin. N . Am. large Anim. Pract. 3 , 1 7 4 . Paton, B. S. and Clarke, K. W. (1986/87) A preliminary trial of detomidine/opiate combinations in the horse. J. Ass. vet. Anaesth. 14,29-32. Poulsen-Nautrup, B. P. (1988) Clinical trial of the amino-imidazole derivative STH 2130 as a sedative in comparison with acetylpromazine and as a preanaesthetic in horses. DVM thesis, University of Hannover. Ricketts, S. W. (1986) Clinical experiences with Domosedan in equine clinical practice in Newmarket. Acta. Vet. Scand. Suppl. 82,197-202. Robertson, J. T., Muir, W. W. and Sams, R. (1981) Cardiopulmonary effects of butorphanol tartrate in the horse. Am. J. vet. Res. 42,414. Robertson, J. T. and Muir, W. W. (1983) A new analgesic combination in the horse. Am. J. vet. Res. 44,1667-1669. Taylor, P. M. (1985) Chemical restraint of the standing horse. Equine vet. J. 17,269-273. Taylor, I? M., Browning, A. P. and Hams, C. I? (1988) Detomidine butorphanol sedation in equine clinical practice. Vet. Rec. 123, 388-390. Taylor, P. M., Rymaszewska, H. and Young, S. S. (1990) Evaluation of combinations of nalbuphine with acepromazine or detomidine for sedation in ponies. J. Ass. vet. Anaesth. 17,3841. Tronike, R., and Vocke, G. (1970) Contributions to the use of Rompun as a sedative in the horse. Vet. med. Rev. 247-254. Voegtli, K. (1988) Studies on the sedative and analgesic effect of an alpha 2 adrenoceptor agonist, (STH 2130, Boehringer) in horses. DVM thesis, University of Berne. 29
Sedative and cardiovascular effects of romifidine, alone and in combination with butorphanol, in the horse K. W. Clarke, G. C. W. England and L. Goossens“ Department of Large Animal Medicine and Surgery, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire, UK and “Boehringer Ingelheim Vetmedica GmbH, P.O. Box 200, D-6507 Ingelheim, Germany.
proved effective (Robertson and Muir 1983; Clarke and Paton 1988; Taylor, Browning and Harris 1988) and is The behavioural and sedative effects of intravenous (iv) convenient to use as it is not subject to such stringent romifidine (40 and 80 pg/kg bodyweight [bwtl) alone or in controls as some of the other similar agents. combination with iv butorphanol (50 pg/kg bwt) were Romifidine is a potent and selective a2-adrenoceptor investigated in four ponies and one Thoroughbred horse. agonist, closely related chemically to clonidine, which has Apparent sedation, as judged by the lowering of the head, been used recently for both sedation and pre-medication in and by the response to imposed touch, visual and sound horses (Poulsen-Nautrup 1988; Voegtli 1988). Doses of 80 stimuli was assessed. The combination with butorphanol pg/ kg bodyweight (bwt) romifidine given intravenously reduced the animals’ response to imposed stimuli when (iv) appear to produce maximal sedation, higher doses compared with the effect of the same dose of romifidine lengthening the effect (Voegtli, 1988). However, as with alone. Following the administration of other a2-adrenoceptor agonist drugs, the horses sedated romifidine/ butorphanol combinations muzzle tremor was with romifidine may still be easily aroused and appear noted and some animals attempted to walk forward. sensitive to touch (England, Clarke and Goossens 1991). In a separate series, the cardiopulmonary effects of iv The present study examined the sedative effects of two romifidine (80 pg/kg bwt) alone, or in combination with doses (40 and 80 pg/kg bwt iv) of romifidine alone or in butorphanol(50 pg/kg bwt) were investigated. Romifidine combination with butorphanol (50 pg/kg bwt iv). In a and the romifidine/butorphanol combination caused separate study the cardiopulmonary effects of the higher similar cardiovascular changes, these being bradycardia dose of romifidine alone and in combination with with heart block, and hypertension followed by butorphanol were investigated. hypotension. Romifidine caused a transient decrease in arterial oxygen tensions and arterial carbon dioxide MATERIALS AND METHODS tensions had increased significantly by the end of the 90 Investigations were carried out using four adult Welsh min recording period. Romifidine/ butorphanol combinations produced significantly higher arterial carbon Mountain ponies (weight range 270 to 370 kg) and one dioxide tensions during the first 15 mins after drug adult Thoroughbred horse (weight 520 kg). In all animals, administration than did romifidine alone. the carotid artery had been raised to a subcutaneous Butorphanol at 50 pg/kg bwt iv reduced the response to position (under general anaesthesia) a minimum of two imposed stimuli in horses sedated with romifidine. The years previously. Prior to sedation all animals were combination produced no cardiovascular changes beyond allowed free access to food and water. All drugs were given those induced by romifidine alone, but did increase the through a catheter (18 gauge Angiocath; Deseret Ltd.) placed previously in the jugular vein. A period of at least 6 degree of respiratory depression. days was allowed between drug administrations in each INTRODUCTION animal. SUMMARY
The a2-adrenoceptoragonists xylazine and detomidine have become widely used to sedate horses. However, horses apparently well sedated by these drugs can respond suddenly and unexpectedly to stimuli, and can kick (Clarke and Hall 1969; Tronicke and Vocke 1970; Alitalo 1986; Clarke and Taylor 1986; Ricketts 1986). It has been suggested that these responses are to the stimulus of touch (Tronicke and Vocke 1970; Alitalo 1986). The combination of opioid drugs with the %-adrenoceptor agonists appears to reduce this response (Muir 1981; Taylor 1985; Paton and Clarke 1986; Taylor, Rymaszewska and Young 1990).Of the opioid drugs that have been used, butorphanol tartrate has
Behavioural studies The animals were placed in stocks for restraint and were given one of four drug regimes: 1) Romifidine (Sedivet; Boehringer Ingelheim Vetmedica GmbH, Germany) 40 p g / k g bwt iv; 2) Romifidine 80 pg/kg bwt iv; 3) Romifidine 40 pg/kg bwt iv and butorphanol tartrate (Torbugesic, C-Vet Ltd, Bury St. Edmunds, Suffolk) 50 p g / k g bwt iv; 4) Romifidine 80 pg/kg bwt iv and butorphanol50 pg/kg bwt iv. When both drugs were given, romifidine was administered first, followed immediately by butorphanol. 25
1. vet. Anaesth. Vol. 18 (1991)
Observations and assessments were made before and 5,10, 15,30,45,60, 75 and 90 mins after the drugs were injected. The mean of two measurements taken prior to administration of romifidine was considered to be the presedation measurement. The same observer, who knew whether or not butorphanol had been given but was not aware of the dose of romifidine used, assessed sedation. The degree of sedation and response to stimulation were measured and scored as follows: Height of the head. For the duration of the recordings the front restraints of the stocks were adjusted so as not to interfere with the head position. The height of the head was taken as the distance (in cm) from the floor to the animal's muzzle. The position of the muzzle was marked against the stocks, and this was then measured. Changes in head postion were expressed as a percentage of the unsedated value. Degree of ataxia. Scoring was based on: 3 ) The animal was swaying, staggering, and/or leaning very heavily on any support. Often the hind legs were crossed and the forelegs buckled at the knee. The impression was that if the support was removed the animal would fall. 2) The animal was still swaying and leaning but the legs were in the normal position and there was no indication that it would fall. 1) The animals were stable but swaying slightly. 0) Animals did not appear sedated. Response to touch. The response to touch was assessed using three tests: 1) touching with a pencil on the fore coronets; 2) touching with a pencil on the hind coronets; 3 ) tickling inside the pinna of the ear. The response to touch was scored as follows: 3 ) a rapid and marked response (limb movement or head shake) to stimulation. Score 3 also was awarded where anticipation of the procedure invoked so much response that the test was extremely difficult to perform; 2) response was easily elucidated but was slower and required more pressure or tickling; 1) the response was sluggish and only elicited by prolonged stimulation; 0) no response. For each individual animal the scores for all three touch stimuli were added together, the sum being considered as the 'touch score' for that animal. Response to sound and visual stimulation. Visual testing consisted of flapping a cloth in front of the horse. The sound stimulus was a loud hand clap behind the horse. Scoring for the animal's response to sound was as follows: 3 ) A sudden 'start' in response. The head was usually thrown up, and the horse moved violently away from the stimulus. 2) A definite 'start' and head movement, but the horse did not try to move away. 1) The horse was obviously aware of the stimulus, but only gave a very slight 'start'. 0) Represented no response. For each individual, the scores for the visual and sound stimuli were added together, the total being considered the 'audiovisual score'.
The ponies were restrained in stocks as previously. The subcutaneous carotid artery was catheterised with a 16 gauge Angiocath (Deseret Ltd). Arterial blood pressure was measured using a strain gauge transducer (Bell and Howell) attached via saline filled manometer tubing to the arterial catheter and recorded continuously on a chart recorder (Lectromed Ltd). The transducer was placed level with the tip of the sternal manubrium. The electrocardiogram (ECG) was monitored with standard limb leads and recorded continuously on the chart recorder. Heart rate was derived from the recording by counting the beats over a period of 30 secs. Systolic and diastolic arterial blood pressures were measured from the recording, and mean arterial pressure calculated as diastolic pressure plus one third of pulse pressure. Arterial blood samples, collected anaerobically in heparinised syringes, were taken before and 5, 10, 15,30,45, 60, 75 and 90 mins after the administration of the drugs. They were then stored in iced water until analysed for oxygen tension (Pa02),carbon tension (PaC02)and pH using conventional blood gas analysis equipment (Corning),which underwent regular quality control checks using standard solutions (Certain;Corning).
Statistical analysis Statistical analysis of the lowering of the head and of the cardiopulmonary effects of the drug and drug combinations was perfomed by paired Students' t tests, using a Multistat programme. Differences were considered significant when P < 0.05.
RESULTS
Behavioural studies
Following the injection of romifidine at either dose the ponies became sedated in a manner typical of a2adrenoceptor agonists: the head was lowered (Fig 1) ,there were occasional muscle twitches, and the horses swayed slightly particularly after the higher dose (Fig 2). However, although response to the imposed stimuli was reduced, it was not abolished (Fig l), and, in one pony who particularly resented pressure on the coronet, it was still impossible to perform this test safely. With either dose of romifidine the depth of sedation achieved was similar, but the effects of the lower dose were shorter lasting, and at 45 mins after administration, the lowering of the head was significantly less than after the 80 pg/kg bwt dose. Following the injection of either dose of romifidine with butorphanol, sedation was similar to that seen after romifidine alone, but additional side effects were noted. With both butorphanol regimes, three ponies and the Thoroughbred horse showed some muzzle tremor and two ponies and the Thoroughbred tried to move forward, but were prevented from doing so by the stocks. The forward Cardiopulmonay investigations movement was more marked after the lower dose of In a separate investigation, the cardiopulmonary effects romifidine/butorphanol had been used, and the of iv romifidine (80 pg/kg bwt) or a romifidine (80 pg/kg Thoroughbred would have been difficult to control in the bwt) /butorphan01 (50 pg/kg bwt) combination were absence of stocks. Compared with romifidine alone, the romifidine/ investigated in the five animals. 26
J. vet. Anaesth. Vol. 18 (1991) Lowering of head a,
m
Ataxia
1 2 0 ~ a
;100 L
8 a,
80
2
60
0
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2
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-8 a, ;
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0 ln 0
._ m
R40 R40 + B
R80
4
X
aR80+B
m
c
c
m
F c i 2
20
e 0
5
10
15
30
45
60
75
0
90
0
Response to touch stimuli
5
10
15 30 45 Time (mins)
60
75
90
Fig 2. The effects on stance in five horses of two doses of romifidine (40 and 80 Fg/kg) alone or in combination with butorphanol (50 pg/kg). An ataxia score of zero represents no ataxia.
b
*
Ln II
3E
30
v
ln
2
8ln
R40 R40 + B R80 R80 + B
20
.c 0
g m
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I
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15
30
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60
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Response to audio visual stimuli I
II
20
Cardiopulmonary studies
2 0 (0 m
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-z
5
after the higher dose of romifidine some horses that had appeared very stable standing still showed slight swaying of the hindquarters and dragged their hind feet as they walked. After romifidine/ butorphanol combinations ponies adopted the 'saw horse' position in which all four legs were rigidly spread. In this position the animal appeared very stable, and ataxia scores awarded were low (Fig 2). However, in some cases if the pony did attempt to move it staggered badly and would have proved very difficult to move during the first 15 mins after drug administration.
R40 R40 + B R80
Prior to any of the drug treatments the cardiopulmonary values in all animals were within the normal range found R80 + 8 at this laboratory. Following injection of romifidine, there 7J 2 m was a significant fall in heart rate (Table 1).Minimum heart m c rates were recorded 1 to 2 mins after injection and were E n . . . . . . . . 0 5 10 15 30 45 60 75 90 accompanied by atrioventricular heart block; heart rates then increased but remained significantly below preTime (mins) sedation values for 45 mins after injection. Following a Fig 1: The sedative effects in five equines of two doses of romifidine hypertensive phase, (Table 1) arterial blood pressure (40 and 80 pg/kg) alone or in combination with butorphanol (50 decreased, becoming significantly below pre-sedation pg/kg). a ) Effects on head position of the horse were obtained by measuring the distance of the horse's muzzle from the ground (? sd). values 60 mins after injection and remaining so for the b) Effects on reducing the response of the horse to imposed touch remainder of the recording period. Following the injection stimuli. A touch score of zero represents no response. c) Effects on of the romifidine/butorphanol combination changes in reducing the response of the horse to imposed audiovisual stimuli. heart rate and arterial pressure were similar to those seen An audiovisual score of zero represents no response. after romifidine alone. Following romifidine injection, arterial oxygen tensions were depressed (Table 1)significantly 5 mins after injection. butorphanol combinations did not cause significant further Arterial carbon dioxide tensions were significantly elevated lowering of the head, but there was a marked reduction in by the end of the recording period. When compared with response to stimuli (Fig 1). Fifteen mins after the higher the changes induced by romifidine alone, arterial oxygen dose of romifidine with butorphanol, four animals tensions were not further depressed following romifidine/ (including the difficult pony) were unresponsive to any of butorphanol (Table 2), but arterial carbon dioxide tensions the imposed stimuli whereas the remaining pony was were significantly elevated from 10 to 30 mins after unresponsive to all but one touch stimulus, for which it injection of the combination. Arterial pH (Tables 1 and 2) received a score of 1. was not significantly influenced by either drug regime. After romifidine administration ponies swayed and leaned on the stocks, but were never severely ataxic (Fig 21, DISCUSSION and at no time did they seem likely to fall. However, when taken out of the stocks at the end of the recording period, Romifidine given iv to the horse produces sedation of a
3
.._
10
I
27
J. vet. Anaesth. Vol. 18 (1991) TABLE 1: Cardiopulmonary changes in five horse given romifidine (80 pg/kg bwt iv)
Time (mins)
Pre-sedation
Heart rate (beats/min; to the nearest whole beat)
Arterial blood pressure (mmHg) Systolic Diastolic Mean (calculated)
Pa02 (kPa)
Arterial PaCO2 (kPa)
PH
43f3
176 f 21
123f 9
141 f 12
10.9 f0.88
6.11 f 0.45
7.41 f 0.02
16 f 6** 26 f 6** 30 f 7** 32 f 6** 32 f 6** 33 f 6* 33 f 6" 35 f 5" 3627 40 f 9 40f9
219 f 38 221 f 32** 219 f 24, 217 f 27* 209 f 30 202 f 31 174 f 27 159 k 21 147 f 23' 133 f 26* 134 f 20*
137f 17 131 f 19 139 f 16 140 f 15 136 f 13 126 f 17 117f 14 110f 9 100 f 8** 95 f 8** 92 f 8**
165 f 25 161 f 22 166 f 1 7 166 f 18* 160 f 18 150 f 20 136 f 15 128 f 14 115f 13* 108 f 13** 107 f 12**
9.22 f 0.85* 10.04f 0.59 10.37f 0.52 10.75f 0.57 10.68f 0.57 10.51f 0.89 10.55f 1.05 10.28f 0.41
6.51 f 0.27 6.12 f 0.35 6.26 f 0.35 6.35 f 0.33 6.55 f 0.19 6.62 f 0.30 6.74 f 0.27* 6.87f 0.18"
7.40 f 0.02 7.42 f 0.03 7.41 f 0.03 7.41 f 0.04 7.42 f 0.02 7.41 f 0.03 7.42 f 0.02 7.42 f 0.03
After romifidine 1 2 3 5 10 15 30 45 60 75 90
All values are means (fse). Significantly different from pre-sedation values: *P<0.05; **P
TABLE 2: Cardiopulmonary changes in five horse given romifidine (80 pg/kg bwt iv) followed by butorphanol(20 pg/kg bwt iv)
Time (mins)
Pre-sedation After romifidine 1 2 3 5 10 15 30 45 60 75 90
Heart rate (beats/min; to the nearest whole beat)
Arterial blood pressure (mmHg) Systolic Diastolic Mean (calculated)
P a 4 (kPa)
Arterial PaC02 (kPa)
PH
3 7 f 18
182 f 16
123 f 8
144 f 11
11.46 f 0.56
6.21 f 0.48
7.41 k 0.02
18 f 7** 30 f 9** 34 f 5** 33 f 7* 35+8 36f9 38+7 41 f 8 41 f 8 41 f 8 42f 8
231 f 50 212 f 43 215 f 31 208 f 31 191 f 22 180 f 30 165f 28 151 f 31 144 f 24* 137f 19** 140 f 23**
139 f 36 139 f 34 145f 29 140 f 29 127f 22 120 f 28 117 f 20 103f 20 94 f 18* 94 f 18, 96 f 20*
170 f 40 161 f 33 169 f 27 163f 28 147 f 20 140 f 28 133 f 22 1195 9 111 f 19" 108 f 18** 110 f 19,"
8.79 f 1.13, 9.96 f 0.63** 9.95 f 0.79** 10.24 f 1.15 10.59f 0.85 11.12 f 0.78 10.88 f 0.60 10.83f 0.98
6.73 f 0.3fl 6.52 f 0.54t 6.86 k 0.44*+ 6.81 f 0.45 6.76 f 0.48 6.82 f 0.54 6.87 f 0.52 6.78 f 0.49
7.40 f 0.01 7.41 f 0.01 7.40 f 0.01 7.41 f 0.01 7.41 f 0.01 7.41 f 0.01 7.41 f 0.01 7.41 f 0.03
All values are means (fse). Significantly different from pre-sedation values: *P<0.05;**P
similar type to that produced by xylazine and detomidine, the other a2-adrenoceptor agonists used currently (Voegtli 1988).Compared with xylazine and detomidine, the effects of romifidine differ in that the horse's head is lowered to a lesser extent, the horse sways less and seems less likely to fall, and the action is a more prolonged, deep sedation, followed by a period when the horse appears quieter than normal, but is fully rousable (England, Clarke and Goossens 1991). However, as with other 9-adrenoceptor agonists, the horse under romifidine sedation may awake suddenly and respond, in particular to touch stimuli. The addition of opioids to xylazine or detomidine greatly reduces the response to stimuli and detomidine/butorphanol is widely used for clipping horses (Taylor et al1988). Because of the small number of animals and the subjective nature of the assessment, statistical analyses of the sedation parameters are not reported. There were marked differences between individuals in their response before sedation to the imposed stimuli, each animal beiqg
particularly sensitive to one type of stimulus (eg to touching the ears or the feet). These sensitivities were consistent throughout the experiments, showed no signs of adaptation and required the deepest levels of sedation to abolish. There was no difference between the ponies and the Thoroughbred in pre-sedation behaviour or in response to sedation other than that the Thoroughbreds size made walking forward more difficult to control. Ataxia scores were not subjected to statistical analysis because, as described previously, assessment of this parameter was difficult while the animals were restrained by stocks. These experiments demonstrated that the combination of butorphanol with romifidine greatly reduced the response of the horse to touch and audiovisual stimuli. Although the combination with butorphanol improved the efficacy of the lower dose of romifidine, the higher dose (80 pg/kg bwt) with butorphanol was necessary to abolish completely the response to all stimuli in all animals. The effect of the additional butorphanol was surprisingly shortlived, good reduction in response only being evident 28
I. vet. Anaesth. Vol. 18 (1991) __
up to 30 mins after drug injection. However, the addition of butorphanol was not without side effects. In this series, some animals showed signs associated with opioid excitement; muzzle tremors, head shaking and walking forward. Such signs have been seen with butorphanol on its own (Robertson, Muir and Sams 1981; Kalpravidh, Lumb, Wright and Heath 1984) and with detomidinelbutorphanol combinations (Clarke and Paton 1988). Opioid-induced excitement of a violent nature has not been reported with doses of butorphanol of 100 pg/kg bwt or less (Robertson et al 1981, Kalpravidh et al, 1984). However, the responses seen do suggest it would be inadvisable to increase the dose of butorphanol when combined with romifidine. Many authors have commented on the 'saw horse' stance taken by animals sedated with a2-adrenoceptor agonist/opioid combinations (Muir 1981; Taylor 1985). However, Paton and Clarke (1986/87) noted that in ponies already very ataxic from the effects of detomidine, the addition of any opioid made their stance unstable. Romifidine did not cause severe ataxia and the prolonged effects on gait noted when the horses were moved at the end of the observation period (also noted by Voegtli 1988) did not make it unsafe to move the animal. The addition of butorphanol did not cause any serious problems of stance when the animal was still, but animals that did move forward in the stocks were markedly ataxic. In this series, romifidine at 80 pg/kg bwt caused cardiopulmonary changes similar to those seen after xylazine and detomidine (ie bradycardia, hypertension followed by hypotension and small but significant changes in arterial blood gas tensions). As with xylazine or detomidine, hypertension was least in the individuals that showed the greatest degree of heart block (Clarke 1988). Gasthuys, Parmentier, Goossens and De Moor (1990) demonstrated that atrioventricular and sinus heart block may occur after romifidine administration, and that bradycardia is prevented by prior administration of atropine. However, probably that the use of atropine would increase the severity and duration of hypertension. At the dosage used, butorphanol alone has minimal effects on the cardiovascular system (Robertson and Muir 1983), and when combined with detomidine does not alter the cardiovascular parameters beyond the changes induced by detomidine alone (Clarke and Paton 1988).In this series, adding butorphanol did not alter the cardiovascular parameters beyond the changes induced by romifidine alone. However, butorphanol depressed the respiration further, as shown by the significant increase in carbon-dioxide tension. Arterial oxygen tensions were similar with either drug regime; calculated minimal arterial oxygen saturation never fell below 93 per cent and it is unlikely that respiratory depression would cause problems in fit horses, although it could in horses having a respiratory pathology. In conclusion, the combination of romifidine at doses of 40 or 80 pg/kg bwt with butorphanol (50 pg/kg bwt) greatly reduced the response to stimuli compared with that following the administration of romifidine alone.
The addition of butorphanol did not influence the cardiovascular system any more than romifidine alone, but did cause some increase in respiratory depression.
ACKNOWLEDGEMENTS This project was supported by Boehringer Ingelheim Vet medica GmbH. J. Mould typed the manuscript. Dr. England was a recipient of the Thomas Brown Fellowship.
REFERENCES Alitalo, A. (1986) Clinical experiences with Domosedan in horses and cattle. Acta vet. Scand. Suppl82,193-196. Clarke, K. W. (1988) The clinical pharmacology of detomidine in the horse. DVM Thesis, University of London. Clarke, K. W. and Hall, L. W. (1969) Xylazine - a new sedative for horses and cattle. Vet.Rec. 85,512-517. Clarke, K. W. and Paton, B. S. (1988) Combined use of detomidine with opiates in the horse. Equine vet. J. 20,331-334. Clarke, K. W. and Taylor, P. M. (1986) Detomidine, a new sedative for horses. Equine vet. J. 20,366-370. England, G. C. W., Clarke, K. W. and Goossens, L. (1991) A comparison of the sedative effects of three alpha 2 adrenoceptor agonists, romifidine, detomidine and xylazine, in the horse. J. Vet.Phmzac. Ther. (In press). Gasthuys, F., Parmenter, D., Goossens, L. and De Moor, A. (1990) A preliminary study on the effects of atropine sulphate on bradycardia and heart blocks during romifidine sedation in the horse. Vet.Res. Comm. pp 489-502. Kalpravidh, M., Limb, W. V., Wright, M. and Heath, R. B. (1984) Analgesic effects of butorphanol in horses: dose response studies. Am. J. vet. Res. 45,211-216. Muir, W. W. (1981) Standing chemical restraint in horses. Vet. Clin. N . Am. large Anim. Pract. 3 , 1 7 4 . Paton, B. S. and Clarke, K. W. (1986/87) A preliminary trial of detomidine/opiate combinations in the horse. J. Ass. vet. Anaesth. 14,29-32. Poulsen-Nautrup, B. P. (1988) Clinical trial of the amino-imidazole derivative STH 2130 as a sedative in comparison with acetylpromazine and as a preanaesthetic in horses. DVM thesis, University of Hannover. Ricketts, S. W. (1986) Clinical experiences with Domosedan in equine clinical practice in Newmarket. Acta. Vet. Scand. Suppl. 82,197-202. Robertson, J. T., Muir, W. W. and Sams, R. (1981) Cardiopulmonary effects of butorphanol tartrate in the horse. Am. J. vet. Res. 42,414. Robertson, J. T. and Muir, W. W. (1983) A new analgesic combination in the horse. Am. J. vet. Res. 44,1667-1669. Taylor, P. M. (1985) Chemical restraint of the standing horse. Equine vet. J. 17,269-273. Taylor, I? M., Browning, A. P. and Hams, C. I? (1988) Detomidine butorphanol sedation in equine clinical practice. Vet. Rec. 123, 388-390. Taylor, P. M., Rymaszewska, H. and Young, S. S. (1990) Evaluation of combinations of nalbuphine with acepromazine or detomidine for sedation in ponies. J. Ass. vet. Anaesth. 17,3841. Tronike, R., and Vocke, G. (1970) Contributions to the use of Rompun as a sedative in the horse. Vet. med. Rev. 247-254. Voegtli, K. (1988) Studies on the sedative and analgesic effect of an alpha 2 adrenoceptor agonist, (STH 2130, Boehringer) in horses. DVM thesis, University of Berne. 29