Cardiopulmonary effects of a two hour medetomidine infusion and its antagonism by atipamezole in horses and ponies

Transcription

1 J. vet. Anaesth. Vol. 26(1) (19YY) Cardiopulmonary effects of a two hour medetomidine infusion and its antagonism by atipamezole in horses and ponies R. Bettschart-Wolfensberger, R. W. Bettschart, 0. Vainio, D. Marlin and K. W. Clarke Royal Veterinary College, Hawkshead House, Hawkshead Lane, Hatfield, Hertfordshire AL9 7TA, UK SUMMARY The cardiopulmonary effects of an intravenous (iv) medetomidine injection (5 pg/kg) followed 5 min later by its infusion at 3.5 pg/kg/h for 1 15 rnin were studied in 9 horses and ponies. Five minutes after the end of infusion 60 pg/kg atiparnezole were given. Physiological data during infusion were compared with pre-sedation values. Stroke volume was reduced significantly 5 min after initial medetomidine injection. Cardiac index was reduced significantly and systemic vascular resistance increased significantly for the first 20 min, but returned towards pre-sedation values after this time. Arterial blood pressures were reduced significantly from 30 rnin until the end of the procedure (minimum MAP was f 9.61 mmhg). Mixed venous oxygen tension was reduced significantly during the infusion. Respiratory rate fell and PaCO, - rose significantly from 40 min onward. Other variables showed no significant changes. The horses recovered rapidly after atipamezole was injected. Arterial blood pressures remained significantly lowered, but other cardiovascular variables returned towards pre-sedation values. It is concluded that the infusion of medetomidine at 3.5 pg/kg/h causes minimum cardiopulmonary depression once the effects of an initial 5 pg/kg injection have waned, and so could prove suitable as part of an anaesthetic technique in equidae. INTRODUCTION Alpha,-adrenoceptor agonists are used commonly as sedatives for horses before general anaesthesia. They produce sedation, muscle relaxation and allow smooth induction and recovery from anaesthesia, provide analgesia, reduce the doses of anaesthetic agents required (Short 1992; England and Clarke 1996) and their action can be antagonised (Raekallio et al. 1990). All a2-adrenoceptor agonists produce cardiopulmonary changes in horses, eg a decrease in cardiac output and heart rate and, after iv administration, hypertension. The duration and intensity of these effects depend on the a2-agonist used, its dose and route of administration (Garner et al. 1971; Clarke and Taylor 1986; Wagner et al. 1991; England and Clarke 1996). Propofol has been used as a total iv anaesthetic (TIVA) in horses, in combination with xylazine or detomidine and guaiphenesin or ketamine (Aguiar et al. 1993; Hartsfield et al. 1994; Matthews et al. 1994; Flaherty et al. 1997). However, the drug is expensive, and in larger horses the volumes required are impractical. Medetomidine is the most specific and potent a2-agonist available (Pertovaara 1993) and is effective in reducing the quantity of anaesthetic required. In dogs it reduces the dose of propofol needed for induction and maintenance of general anaesthesia by up to 75% (Hammond and England 1994) and so may be of some use in combination with propofol in horses. Medetomidine possesses a short action and half-life in horses and undergoes rapid clearance (Bettschart- Wolfensberger et al. 1999) so it is a suitable agent for infusion, as changes in plasma levels can be achieved rapidly. A medetomidine infusion, wl:lch provides a constant sedative effect, and steady plasma drug levels for 2 h, has already been established (Bettschart-Wolfensberger el al. 1999). If medetomidine infusion is to be incorporated into an anaesthetic, ie with propofol, knowledge of its cardiopulmonary effects is necessary. The aim of this study was to measure the cardiopulmonary effects of medetomidine given first by rapid iv injection, followed by infusion for 2 h. MATERIALS AND METHODS The present study was undertaken in 9 clinically healthy horses and ponies (one Thoroughbred and 8 Welsh mountain ponies). Mean age (+ sd [range]) was 10.1 f 9.16 (4-24) years, and weight was f ( ) kg. All animals had previously undergone surgery during which the carotid artery was relocated to a subcutaneous position. Animals were fed hay and grass except during the experimental procedure, and allowed free access to water. Catheters used for cardiopulmonary measurements were positioned 2 h before the study. A catheter placed in the jugular vein was used for drug administration. Immediately before each experimental period, horses were left undisturbed and baseline cardiopulmonary variables were recorded. x

2 J. vel. Anaesth. Vol. 260) (1999) Medetomidine (Domitor, Orion-Farmos, Turku, Finland) was injected iv at 5 pg/kg iv. Five minutes later an infusion of medetomidine (3.5 pg/kg/h) was begun, and maintained for 115 min. The solution infused was made by adding 7 pg/kg medetomidine to 360 ml Hartman's solution and giving one drop/s using a commercially available fluid administration set. At the end of infusion atipamezole (Antisedan, Orion-Farmos, Turku, Finland) was given iv at a dose of 60 p&g. Cardiovascular variables and arterial blood gas values were measured using conventional methods. Arterial blood samples were taken from a carotid arterial catheter. The zero level for pressure measurements was set at the manubrium sternae. Cardiac output (CO) was measured using thermal dilution; a volume of 10 m1/100 kg of iced 5% dextrose solution was used. All data were analysed using a haemodynamic computer (Colormon, Kontron Instruments). Analogue information was recorded continuously on videotape, and digital information at 1 rnin intervals on computer. Heart rate (HR), arterial blood pressure, pulmonary arterial and central venous pressure (CVP) were measured continuously before and during medetomidine administration until signs of sedation were no longer evident. Cardiac output and pulmonary capillary wedge pressure were measured before and at 5, 10 and 20 rnin intervals after drug administration and every 20 rnin thereafter throughout infusion. At these times arterial and mixed venous blood samples were taken for blood gas analyses. Blood samples were stored in iced water and analysed within 2 h using a calibrated blood gas machine (ABLS, Radiometer, Copenhagen, Denmark). Cardiopulmonary variables were recorded for 5 rnin after atipamezole injection in those animals that did not become excessively agitated. Data were recorded as mean f sd. Statistical analyses were performed using Statview I1 (Abacus Concepts. California, USA). All data were analysed by ANOVA for repeated measures. When appropriate, Dunnett's post hoc test was used to determine differences from baseline values. RESULTS Data were recorded as mean f sd. Medetomidine. 5 pg/kg iv followed by infusion produced sedation in all horses. The animal's heads were always lowered, but modest stimuli, eg blood collection, occasionally evoked a response, causing the horse to lift its head and/or move its ears. Within 1-2 mill of atipamezole, horses raised their heads, became alert, and some became intolerant of attached physiological equipment. They became calm, but were not resedated when these were disconnected. Four and 5 min after atipamezole administration 2 ponies began shivering, which lasted 6 and 10 min, respectively. Cardiopulmonary data are represented in Tables 1-4. Heart rates fell after medetomidine in.jection and were reduced significantly (P<0.05) at 5 rnin after injection. returning to pre-sedation values in all but one horse. In this horse, heart rate rose from 35 beats/min to a maximum of 61 beats/min 20 rnin after medetomidine and remained elevated until the end of the experiment. Six horses developed cardiac arrhythmias immediately after medetomidine injection; these lasted for up to 7 min. These included first and second degree atrioventricularr block (n=3) and sinus arrhythmia (n=3). Cardiac index (CI) was reduced significantly for the first 20 min, stroke volume (SV) for the first 5 rnin and arterial blood pressure from 30 min onwards until the end of the observation period. Systemic vascular resistance index (SVRI) was increased for the first 20 min. Central venous TABLE 1: Heart rate (HR), cardiac index (Cl), stroke volume (SV), systolic, mean and diastolic arterial blood pressures (SAP, MAP, DAP) and systemic vascular resistance index (SVRI) in 9 ponies and horses given 5 pg/kg medetomidine iv followed after 5 min by 3.5 pg/kg/h medetomidine iv for 115 min followed by 60 pg/kg atipamezole iv after 120 min; mean t sd (range) pre 5min 10min 20min 30min 40min 50min 60min 70min 80min 90min 100min 110min 120min 125min HR 43.3f99 (beatshin) (32-60) 35f7.89t 36 8f t f i8.28 (26-50) (30-47) (3&56) (31-61) (32-59) (33-57) 42.0i t f f i ? f6.92 (34-55) (34-57) (35-56) (35-54) (3553) (3554) (35-55) (36-55) CI 67.7t15.22 (mlikgimin) ( l) sv 0.45fO 27 (Vheart beat) ( ) 41.I f7.78' 46.2f11.55' 49.8f12.30$ 59.2f15.15 ( ) ( ) ( ) ( ) 0.32f0.14t 0 34f fO0.I4 0.38i0.13 ( ) ( ) (O.lW.57) ( ) 63.2M f tl t f17.1T ( ) ( ) ( ) ( )( ) 0.39f f f f f0.15 ( ) (0.2W.64) (0.2I30.77) ( ) ( ) SAP (mmhg) ( ) 168.1f 151.5f 1373f 127.4t f It 8* 13.13' 9.41' ( ) ( ) ( ) ( ) ( ) ( ) 120.9f 120.1t 1201i 121.8f 120.4f 1224t 124.5t 124.6f1 1009' 11 50' 12.69' 13.51' 1264* 13.95' 13.61' 2.91' ( ) ( ) ( ) ( ) ( ) ( ) (10%1451 ( MAP 127.3t (mmhg) 15.3 ( ) 141.3t 129.3f 120.3f 110.4? 106.5t 104.5t * 8.59' 7.05* ( ) ( ) ( ) ( ) ( ) ( ) 105.1i 103.0f 103.8t 103.8f 102.4f 104.9k 107.8i 103.8i 820' 809' 10.00' 10.3* 9.61' 998" 11.70' 12.53' (92-115) (90-113) (90-119) (9&119) (89-114) (89-116) (90-124) (91-124) DAP 109t (mmhg) ( ) 123.1f 115.4f 104.9i 96.4f 92.6t 91.5f * 9.75* 8.19' ( ) ( ) (92-122) ( ) ( ) ( ) 89.6f 89.5f 90.3t 90.0f 89.6f 91.6t 94.6i 89.1f 9.96' 8.02' 9.56' 9.89' 10.23^ 10.16' 12.44$ 12.36' ( ) (77-99) ( ) ( ) ( ) ( ) ( ) ( ) SVRI 1398f 249.6i 202.Of 1788f 131.9f 124.5f 124.li 1149f 123.9t 113.6f (dynes/s/ ' 48.15' 51.70$ cm5kg) ( )( )( I )(I ) ( ) ( ) ( ) ( ) ( ) ( ) pre=previous to drug administration 'Significant difference from pre value (P<O.OI) *Significant difference from pre value (Pc0.05) Y

3 J. vet. Anaesrh. Vol. 26(/) (1999) TABLE 2: Central venous pressure (CVP), mean pulmonary arterial pressure (mpap), pulmonary vascular resistance index (PVRI) and left and right ventricular stroke work index (LVSWI and RVSWI) in 9 ponies and horses given 5 pg/kg medetomidine iv followed after 5 min by 3.5 pg/kg/h medetomidine iv for 115 min followed by 60 pg/kg atipamezole iv after 120 min; mean f sd (range) pre 5 rnin 10 rnin 20 min 40 rnin 60 rnin 80 min 100 rnin 120 min 125 rnin CVP 15.9f f k f k f t k k5.83 (mmhg) (6-23) (9-22) (9-22) 9-23) (9-21) (7-17) (7-20) (7-19) (6-17) (7-27) mpap 28.2k f f k f f f f6.37 (mmhg) (16-36) (23-36) (21-34) (1841) (21-32) (18-36) (1632) (15-33) (17-36) (20-39) PVRI 11.0f k f ? , f k k4.61 idynesis ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) /cm5/kg LVSWI 2.2k f f $ kO.35* k k0.29' (grn/kg/ ( ) ( ) (1.15f2.19) ( = ( ) ( ) ( ) ( ) ( ) ( ) heart beat RVSWI 0.25k f k B fl f k f f f0.04 (gm/kg/ ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) heart beat) TABLE 3: Respiratory rate (RR), blood ph and arterial blood gas values in 8 ponies and one horse given 5 pglkg medetomidine iv followed after 5 rnin by 3.5 pglkglh medetomidine iv for 115 min followed by 60 pglkg atipamezole iv after 120 min; mean f sd (range) pre 5rnin 10min 20rnin 30rnin 40min 50min 60min 70min 80min 90min 100min 110rnin 120rnin 125min RR 25 8f f f t f4 12' 11.8f1.56' 10 Of2.00' 9.8f1.92' 9.4f1.67' 8.8i1.72' 8.8?1 49' 7.8f1.28' 9.5f2.07' (breathdmin) (12-42) (12-32) (10-27) (12-46) (12-44) (10-20) 8-20) (10-14) (8-12) (8-12) (8-12) (6-12) (8-12) (6-10) (8-12) PH 7.42f f tO t f f f f0.01 ( )( )( ) ( ) ( ) ( ) ( ) ( ) ( ) pc0, 5.9f f t $ 6.4rO f0.41$ 6.6i0.26' 6.5t0.18' 6.5f0.43' (kpa) (5.S.7) ( ) (5.M.5) ( ) ( ) ( ) ( ) ( ) ( ) PO, 14.1? rO f1.14* 12.6f fI rO ? rO f0.43 (kpa) ( )( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) HCO, f f il.20' 31.2fl.30' tl 01 * 31.6fl.81' mmolil (26-30) (27-31) (27-31 j (27-31 j (28-32) (30-34) (30-34) (30-33) (28-34) ABE 3.4? i f i fl.09' 6.1 fl.of 6 1?0.93* * 6.4fl.33 mmolil (2-6) (2-5) (2-6) (2-6) (3-6) (5-8) (5-8) (5-7) (4-8) 'Significant difference from pre value (P<O.Ol) *Significant difference from pre value (P<0.05) TABLE 4: Mixed venous blood ph and mixed venous blood gas vallues in 9 ponies and horses given 5 pg/kg medetomidine iv followed after 5 min by 3.5 pg/kg/h medetomidine iv for 115 rnin followed by 60 pg/kg atipamezole iv after 120 min; mean f sd (range) pre 5 min 10 min 20 min 40 min 60 min 80 min 100 min 120 rnin PH 7.39k fl f k B k f0.02 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) PCO, 6.7f k k f t f * (kp4 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) PO2 4.45f k0.51* 3.6t0.44* 3.8f0.36* 3.8f0.46' 3.8f0.38' 3.8k0.29' * 3.8k0.34' (W ( ) ( ) ( ) ( ) ( ) ( ) (26-4.3) (3.24.3) ( ) HCO, f k t1.04* 32.2f1.60t * * mmol/l (27-33) (2&32) (2SG32) (29-32) (27-33) (31-34) 29-34) 31-35) (31-36) ABE 3.8f k k I 6 4.8k f1.13* * 6.2?1.04* 6.6f1.06' mmolll (2-6) (2-6) (3-6) (3-6) (3-7) (4-7) (3-7) (5-8) (5-8) pre=previous to drug administration 'Significant difference from pre value (P<O.Ol) 'Significant difference from pre value (P<O 05)

4 - -.I. vel Anaesth. Vol 26(1/ (1999) pressure, pulmonary arterial pressure and pulmonary vascular resistance index (PVRI) did not change significantly when compared to pre-sedation values. Respiratory rate (RR) was reduced significantly 40 rnin after medetomidine injection and remained depressed until the end of the experiment. This coincided with a significant increase in PCO, which developed 20 min after injection and persisted throughout the second hour of observation. There were no significant changes in PO,. Mixed venous PO, was significantly lower than baseline values after 5 rnin while mixed venous PCO, increased after 120 min. Base excess (BE) and bicarbonate (HCO,) were significantly elevated from 60 rnin after injection until the end of the measurement period. One pony, whose resting respiratory rate had been 16 breaths/min, became tachypnoeic with respiratory rates between 44 and 46 breaths/min 20 and 30 rnin after medetomidine injection. At these time points, all other variables were similar to the mean values of other animals. Six of the 9 animals urinated up to 4 times during the infusion period. DISCUSSION In the current study, 5 pg/kg medetomidine injection followed by its infusion at 3.5 pg/kg/h produced constant sedation, with minimal ataxia. The degree of sedation was similar to that reported previously (Bettschart- Wolfensberger et al. 1999) and appeared comparable with the sedation observed in horses at mean detomidine plasma levels of 19.1 ng/ml (Daunt et a/. 1993). The horses reacted slightly when being approached, although the degree of sedation present would probably have been adequate for standing chemical restraint. Medetomidine reduces the dose of propofol required to produce anaesthetic in a dosedependent manner in dogs (Hammond and England 1994). In horses, medetomidine administration is limited by the degree of ataxia produced (Bryant ef al. 1991). The infusion rate used in the current study was considered to be the greatest that would not cause ataxia Alpha2-adrenoceptor agonists produce similar cardiopulmonary changes in horses (England and Clarke 1996). These include: a fall in heart rate, a reduction in cardiac output and a biphasic change in blood pressure. lnitial hypertension is due to stimulation of peripheral a2- receptors (Docherty and McGrath 1980) and not as compensation for bradycardia (Sarazan et al. 1989; Bryant et al. 1991). Injection of medetomidine 5 or 10 pg/kg produces similar changes in ponies (Bryant et a/. 1991). In the current study, cardiovascular changes began after the initial injection of medetomidine and were similar to those described above. However, within 30 min, when steady state medetomidine plasma levels would have been reached (Bettschart-Wolfensberger et a/. 1999) the values of variables other than blood pressure did not differ significantly from those recorded before treatment. Studies in man suggest that bradycardia following dexmedetomidine (the active enantiomer of medetomidine) depends on plasma levels of the drug (Dyck et al. 1993; Jalonen et al. 1997). Simon el a/. (1989) and Hayashi et a/. (199.5) suggested that decreases in heart rate in dogs are independent of dose and mode of medetomidine administration, but the doses they used were high (20 pg/kg) and it is possible that lower dose rates would cause less bradycardia. In the present study bradyarrythmias were observed in 6 ponies, but these had disappeared within 7 min, possibly because plasma drug levels had fallen below a dysrhythmogenic threshold value. In the current study. the bradycardia observed was less severe, and of shorter duration, than that seen with detomidine infusions which produce similar degrees of sedation (Daunt eta/. 1993). The reason why the heart rate increased, rather than decreased, in one horse is difficult to explain given that variables were similar to those observed in the other animals. The reduction of CI that occurred within 5 min of medetomidine injection was similar to that seen after iv xylazine (1.1 mag, Kerr et al. 1972). In the current study cardiac output was reduced both by a reduction in HR and in SV, but the reduction was short-lived. From 40 rnin onward it did not differ significantly from pre-sedation values and remained stable during infusion. The initial rise in blood pressure encountered in the present study was not statistically significant (probably because of high pre-sedation MAP) but by 30 rnin after starting infusion it had fallen significantly and remained low thereafter. The onset of the hypotensive phase coincided with a fall in SVRI. Similar hypotensive changes have been reported following xylazine, detomidine and romifidine (Clarke el af. 1991; Wagner et a/. 1991). Although hypotension was observed in the present study MAP was stable from 30 rnin onwards and remained within the accepted physiological ranges (Dyson and Pascoe 1990). The transient increase in SVRI which occurred during the first 20 rnin correlates with that seen after other a?- adrenoceptor agonists (Wagner et al. 1991). Daunt et al. (1 993) gave an infusion of detomidine to horses using increasing doses to determine cardiopulmonary side-effects of different plasma levels. At plasma detomidine concentrations which produced degrees of sedation similar to those seen in the current study, MAP was not significantly different from pre-sedation values, but systemic vascular resistance was increased significantly. Increasing dose rates of detomidine causes hypertension that corresponds with further increases in systemic vascular resistance. With the infusion rate used in the present study, it is possible that the plasma level of medetomidine achieved was insufficient to induce vasoconstriction Alpha2-adrenoceptor agonists can cause respiratory depression in horses (Short et al. 1986; Wagner el a/. 1991). After xylazine or detomidine Wagner el a/. ( 1991) reported a transient initial fall in PaO, without a change in PaC0,. probably due to ventilation-perfusion imbalance. However, changes in arterial blood gas tensions have not been significant in all reports (Bryant et al. 1991; Daunt et a/ 1993). In the present study there was a marked reduction in RR in all but one pony, and a small rise in PaCO,. but this may become significant at the end of the infusion. In most animals Pa0, did not change although, in one pony, it fell to

5 J. vel. Anuesth. Vol. X (I/ (1999) a minimum value of 9.2 kpa. Values for PvO, were reduced significantly from pre-sedation values throughout the procedure, the greatest fall corresponding to significant falls in CI. The hyperventilation seen in one pony was similar to that seen during medetomidine infusion (Bettschart- Wolfensberger et al. 1999) and after the rapid injection of other a,-adrenoceptor agonists (Clarke and Geering et al. 1989). The cause is unknown. The cardiopulmonary effects of atipamezole could not be measured accurately for a definite period because the antagonism of sedation caused animals to shake their heads, producing measurement artefacts. The effects of atipamezole on cardiopulmonary function after constant medetomidine infusion remain to be determined. Nevertheless, all horses in the present study showed a prompt recovery after atipamezole administration, and the dose chosen (60 pg/kg) was sufficient to antagonise sedation, without causing stimulation. The dose of atipamezole required to antagonise medetomidine incorporated in a general anaesthetic technique remains to be established. It should be noted that atipamezole will antagonise the analgesic effects of medetomidine (Ewing el al. 1993). Furthermore, its use may be unnecessary as, at the doses used, there is no accumulation of medetomidine (Bettschart-Wolfensberger, et cil. 1999). The present study demonstrated that an iv injection of medetomidine (5 pg/kg) causes similar cardiopulmonary changes to those caused by other a,-adrenoceptor agonists. However, cardiovascular variables improve during the subsequent 2 h infusion of medetomidine at 3.5 pg/kg/h. The present data indicate that medetomidine infusion warrants further investigation as part of a total iv anaesthetic regime in equidae. The availability of a rapid and specific-acting antagonist is an additional advantage. REFERENCES Aguiar, A,. Hussni, C.A., Luna. St. P.. Ca,tro, G.B., Massone, F. and Alvea, A.L.G. ( 1993) Propofol compared with propofol/guaifenesin after detomidine premedication for equine surgery. J. vet. Anuesih. 20, Bettschart-Wolfcnsberger. R., Clarke, K.W., Vainio, O., Shojaee Aliabadi, F. and Demuth, D. (1999) Pharmacokinetics of medetomidine in ponies and elaboration of a medetomidine infusion regime which provides a constant level of scdation. Res. vet. Sci. 67, Bryant, C.E., England, G.C.W. and Clarke, K.W. (1991) Comparison of the sedative effects of medetomidine and xylazine in horses. Vet. Rec. 129, Bryant. C.E., Clarke, K.W. and Thompson, J. (1996) Cardiopulmonary effects of medetornidine in sheep and ponies. Res. vet. Sci. 60, Clarke. K.W. and Taylor, P.M. (1986) Detomidine: A new sedative for horses. Eqirine vet. J. 18, Clarke, K.W., England, G.C.W. and Goossens, L. (1991) Sedative and cardiovascular effects of romifidine alone, and in combination with hutorphanol. in the horse..j. vet. Anuesih. 18, Clarke, K.W. and Gerring, E.L. (1989) Detoniidine as a sedativc and premedicant in the horse ( ) Proc. Am. Ass. equine Prac/. pp Daunt, D.A., Dunlop, C.I.. Chapman, Ph. L., Shafer, St. L., Ruskoaho, H., Vdkkuri, 0.. Hodgson, D.S., Tyler, L.M. and Maze, M. (1993) Cardiopulmonary and behavioral responses to computer-driven infusion of detomidine in standing horses. Am. J. rvi. Res. 54, Docherty, J.R. and McGrath, J.C. (1980) A comparison of pre- and postjunctional potencies of several alpha-adrcnoceptor agonists in the cardiova5cular system and anococcygeus muscle of thc rat. Evidence for two types of postjunctional alpha-adrenoceptor. Nairnvn-Schmipclc.h~.r~t:',s Arch. Pharmucol. 312, Dyck, J.B., Maze, M., Haak, C., Vuorilehto, L. (1903) Thc pharmacokinctics and hemodynamic elfects of intravenous and intramuscular dexmedetomidine hydrochloride in adult human voulnteers. Anesthesiology 78, Dyson, H.D. and Pascoe, P.J. (1990) Influence of preinduction methoxamine, lactated ringer solution, or hypertonic saline solution infusion or postinduction dobulamine infusion on anesthetic-induced hypotension in horses. Am. J. vet. Rex 51, England. G.C.W. and Clarke, K.W. (1996) Alpha? adrcnoccptor ngonists in the horse- a rcview. Br. vet..i. 152, Ewing, K.K.. Mohammed, H.O., Scarlett. J.M. and Short. C1i.E. (1993) Reduction of isollurane anesthetic requircmcnt by medetomidine and its restoration by atipamezole in dogs. Am. J. vet. Res. 54, Flaherty, D., Reid, J., Welsh, E., Monteiro, A.M., Lerche, P. and Nolan, A. (1997) A pharniacodynamic study of propofol or propofol and ketatnine in ponies undergoing surgery. Rex. ve/. Sci. 62, Garner, H.E., Amend, J.F. and Rosborough, J.P. (1971) Effects of Bay Va 1470 on cardiovascular parameters in ponics. Ve/. Med. & sndl Anim. Clin. 66, Hammond, R.A. and England, G.C.W. (1994) Thc cffcct of medetomidine premedication upon propofol induction and infusion anaesthesia in the dog..i. vet. Anaesth. 21, Hartsfield, S.M., Matthews, N.S., Taylor. T.S., Hooper, R.N. and Erickson, S.W. (1994) Detomidine-propofol anesthesia for carotid artery translocation in donkeys. Vet. Sirrg. 23, Hayashi, K., Nishimura, R., Ydmaki, A., Kim, H. Y., Matsunaga, S., Sasaki. N. and Takeuchi, A. (I 995) Cardiopulmonary effects of niedetoniidine. medetomidine-niidazolam and medetornidinc-midazolan~-ati~~iiiie~~~le in dogs. J. vet. med. Sci. 57, Jalonen, J., Hynynen, M., Kuitunen, A,, Hcikkilii. H., Perttilii. J.. Salnienperii, M., Valtonen, M., Aantaa, R. and Kallio, A. (1997) Dcxmcdetornidine as an anesthetic adjunct in coronary artery bypass grafting. Anesthesiology 86, Ken; D. D., Jones, E. W., Huggins, K. and Edwards, W. C. (1972) Sedative and other effects of xylazine given intravenously to horses. Ant. J. re/. Res. 33, Matthews, N. S., Chaffin, N. K., Hartsfield, S. M. and Overhulse. W. A. (1994) Propofol for immobilization of neonatal foals. k/. Swg. 23, 76, Pertovaara, A. ( 1993) Antinociception induced by alpha,-adrcnoceptor agonists. with special emphasis on medetomidine studies. Progr. Neurohiol. 40, Raekallio, M., Vainio. 0. and Karjalainen, J. (1990) The intlucncc of alipamerole on thc cardiovascular effects of detomidine in horscs..j. t'et. Anuesih. 17, Sarazan, R. D., Starkc. W. A., Krause. G. F. and Garner. H. E. (1089) cardiovascular effects of detomidine, a new a,-adrenoccptor agonist in thc conscious pony..i. vet. Pharmncol. Therap: 12, Short, C. E. (1992). Alpha2-ugenls in Animals. Smfation. Antrlgc.sitr urid Aneslhesin. Santa Barbara, CA. U.S.A.: Veterinary Practice Publishing Company. Short, C. E.. Matthews. N., Harvey, R. and Tyner. C. L. (1086) Cardiovascular and pulmonary function studies of a new sedative/analgesic (detomidine/domosedaii~) for use alone in horses or preanesthetic. Actu vet. Scund. 82, Simon, F., Romviry, A. and Mora, S. (1989) Clinical investigations ol medetomidine in dogs. Acia vel. Scund. 85, I6 I Wagner, A. E., Muir, W. W. and Hinchcliff, K. W. (1991) Cardiovascular effects of xylazine and detomidine in horses. Am. J. PI. Res. 52, I2