A pharmacodynamic study of propofol or propofol and ketamine infusions in ponies undergoing surgery

Research in VeterinaryScience 1997, 62, 179-184

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A pharmacodynamic study of propofol or propofol and ketamine infusions in ponies undergoing surgery D. FLAHERTY, J. REID, Departmentof Veterinary Clinical Studies, E. WELSH, A. M. MONTEIRO, Departmentof Veterinary Pharmacology, P. LERCHE, Departmentof Veterinary Clinical Studies, A. NOLAN, Departmentof

Pharmacology, Universityof Glasgow, BearsdenRoad, Bearsden, Glasgow G61 1QH

SUMMARY The pharmacodynamics of infusions of propofol alone (group 1) were compared with the pharmacodynamics of infusions of propofol and ketamine together (group 2) in eight ponies undergoing castration. Anaesthesia was induced with detomidine, 20 pg kg -1, followed by ketamine, 2-2 mg kg -1. Subsequently, a bolus dose of propofol, 0.5 mg kg~1, was administered intravenously to both groups, and an infusion of propofol was given for an average of 74 minutes to group 1, and an infusion of propofol and ketamine was given for 60 minutes to group 2. The mean (SD) infusion rates of propofol were 0.330 (0-050) mg kg -1 rain-1 in group l, and 0.124 (0.009) mg kg -1 in group 2, and the ketamine infusion rate was maintained constant at 40 pg kg -1 rain-1. Arterial hypotension and marked respiratory depression were evident in some of the ponies receiving propofol alone, whereas in the ponies anaesthetised with propofol and ketamine, respiratory and cardiovascular parameters were well maintained. All the ponies in both groups recovered quickly from anaesthesia, with mean times to sternal recumbency and standing of 19.8 (8.0) minutes and 27.2 (7-4) minutes respectively for group 1 and 8.4 (3-2) rain and 14.9 (10.1) minutes for group 2.

TOTAL intravenous anaesthesia (TIVA) has become a popular technique in human beings, because it has advantages over inhalational anaesthesia. These advantages may be particularly beneficial in horses, because the inhalational anaesthetic agents used for the maintenance of anaesthesia induced marked cardiorespiratory depression (Steffey and Howland 1980). TIVA eliminates the hazard of atmospheric pollution, and allows easy control over the depth of anaesthesia. Propofol is a drug which is suitable for TIVA owing to its rapid metabolism and short duration of action. Nolan and Hall (1985) first described the use of propofol in a total intravenous anaesthetic regimen in ponies and reported that, after premedication with intravenously administered xylazine, the induction and maintenance of anaesthesia for one hour with propofol was satisfactory, and that recovery from anaesthesia was rapid and excitement-free. Propofol also proved useful for short-term anaesthesia in ponies after detomidine premedication (Nolan and Chambers 1989), and in a pilot study Taylor (1989) commented on the smooth recovery of ponies from propofol anaesthesia. The use of propofol as the sole agent for total intravenous anaesthesia in human surgery has proved unsatisfactory for major procedures, because the doses required to eliminate responses to surgery induce cardiovascular and respiratory depression (Smith et al 1994). As a result, other drugs, such as the opioid agonist alfentanil, are infused together with propofol. However, such drugs, while providing excellent analgesia are associated with respiratory depression (O'Connor et al 1983), and are best used in patients who are artificially ventilated. Other anaesthetic and analgesic agents have been used in horses in a total intravenous technique, including combinations of the alpha2-adrenoceptor agonists, xylazine or detomidine, with ketamine and glyceryl guaicolate (Greene et al 1986, Taylor et al 1992, Young et al 1993). Recent studies have indicated that TIVA with propofol and ketamine provided 0034-5288/97/020179 + 06 $18.00/0

excellent anaesthesia for superficial body surface surgery in sheep, and that the inclusion of ketamine did not alter the pharmacokinetics of propofol (Correia et al 1994). Guit et al (1990) had recommended the use of ketamine as an analgesic for TIVA with propofol in human surgery when stable haemodynamics were required. It was considered that this combination could prove valuable in equine anaesthesia. A recent pharmacokinetic study indicated that, owing to their rapid body clearance and short half-times (Nolan et al 1996), propofol and ketamine were suitable agents for the maintenance of anaesthesia when administered to ponies together. The present study was undertaken to compare the pharmacodynamics of simultaneous infusions of propofol and ketamine, with infusions of propofol alone, in ponies undergoing castration.

M A T E R I A L S AND M E T H O D S

Eight ponies, weighing between 85 and 196 kg and aged between five and 12 months were used. They were kept outdoors at grass, but were brought in and stabled for at least 48 hours before surgery. Food was withdrawn for 16 hours before the induction of anaesthesia, but water was freely available at all times. The ponies were allocated into one of two groups. Group 1 (ponies 1, 2, 3 and 4) received an infusion of propofol alone to maintain anaesthesia, and group 2 (ponies 5, 6, 7 and 8) received propofol in combination with ketamine. Before drug administration, two intravenous cannulae were placed, one in each jugular vein, under local analgesia. In the group 2 ponies, a further cannula was inserted in the left jugular vein. The animals were premedicated with detomidine (Domosedan, SmithKline Animal Health, UK) 20 ~tg kg -1, injected intravenously through one of the catheters in the left jugular vein. After 3 minutes, ketamine (Vetalar, Parke Davis, Gwent), 2.2 mg © 1997 W. B. Saunders Company Ltd

180

D. Flaherty, J. Reid, E. Welsh, A. M. Monteiro, P. Lerche, A. Nolan

kg -1, was given intravenously as a bolus, through the same cannula. Once the ponies became laterally recumbent, the trachea was intubated, a bolus dose of propofol (Rapinovet, Mallinckrodt Veterinary, UK), 0.5 mg kgq , was administered intravenously and the infusions of propofol (group 1), or propofol and ketamine (group 2) were begun. The infusions of propofol and ketamine were given through the two intravenous catheters placed in the left jugular vein. The ponies breathed 100 per cent oxygen from a large-animal circle system with a fresh gas flow rate of 2.5 to 3 litre min q . The ponies were placed in dorsal recumbency within 20 minutes of the induction of anaesthesia, and were given flunixin meglumine (Finadyne, Schering Plough Animal Health, UK), 1 mg kg -1 intravenously, at the end of the procedure, to provide postoperative analgesia. The drugs were infused by using Baxter Flo-Gard 6200 volumetric infusion pumps (Lessines, Belgium). Ketamine was diluted 10-fold with 0.9 per cent saline to a concentration of 10 mg m1-1. In group 1, the infusion rate was initially set at either 0.3 or 0.4 mg kg -1 rain -1 of propofol, and further reductions in the infusion rate were made as necessary; in group 2, the propofol infusion rate was set at 0.15 mg kg -1, and the ketamine was infused at a fixed rate of 40 ~g kg -1 min q . The rate of infusion of propofol in the group 2 ponies was reduced 20 minutes after the start of the infusion to 0.1 mg kg -1 min -1, and in pony 8 it was further reduced to 0.075 mg kg -1 min -1, 40 minutes after the start of the infusion. The ketamine infusion was stopped five minutes before the end of the propofol infusion. Blood samples (9 ml), were taken into fluoride oxalate tubes for propofol analyses, and into lithium heparin tubes (Sarstedt, UK) for ketamine analyses, through the cannula in the fight jugular vein, before the infusion began, 10, 20, 40 and 60 minutes after the infusion began and five, 15, 30, 60 and 120 minutes after the end of the infusion. The fluoride oxalate tubes were stored at 4°C until they were analysed for propofol within three weeks of collection. Blood propofol concentrations were measured by high performance liquid chromatography, using fluorescence detection as described by Plummer (1987). The limit of detection was 10 ng m1-1. The lithium heparin tubes were centrifuged immediately after collection at 1500 g for 15 minutes, the plasma was decanted and frozen, and stored at -20°C until analysed for ketamine within five months of collection. Plasma ketamine was analysed by high performance liquid chromatography, using an ultraviolet detector set at 220 nm, by the method developed by Delatour et al (1991) with minor modifications. The extraction procedure used was that described by Loscher et al (1990) and partitioned ketamine and norketamine against alkalinised" chloroform. The limit of detection of ketamine was 10 ng m1-1, and of norketamine 50 ng m1-1. The depth of anaesthesia was assessed subjectively by recording the responses to palpebral stimulation, the eye position, pulse rate and respiratory rate. The electrocardiogram was monitored continuously using the sternal-withers configuration from standard electrode clips, and arterial blood pressure was measured directly through a cannula placed in the facial artery after the induction of anaesthesia, by using a standard pressure transducer system (Kontron Minimon 7132A). Arterial blood gases were analysed every 20 minutes, although technical difficulties with the arterial cannulation in ponies 1 and 2 delayed the measurements for 30 minutes. Pulse rate, respiratory rate and arterial blood pressure were recorded every 5 minutes. The times to endotracheal extubation, sternal recumbency and standing were

recorded for each pony from the time the infusion was switched off. Recovery to standing was assisted, owing to technical difficulties with the recovery area. The results are expressed as mean (so) values.

RESULTS Group 1 (propofol alone) The mean duration of the infusion was 74.3 (13.2) minutes, with a range from 64.5 to 86 minutes. The propofol infusion rate was initially set at 0.4 mg kg-1 min -1 for ponies 1, 2 and 3, and a reduced rate of 0.3 mg kg -1 rain -I was chosen for pony 4, to assess the quality of anaesthesia when a lower infusion rate was used. Two decreases in infusion rate were made in pony 2, and pony 3 also had two decreases 10 and 20 minutes after the start of the infusion, but the infusion rate was increased again 32 minutes after the start of the infusion when the anaesthesia became unacceptably light. Ponies 1 and 4 were maintained at a constant infusion rate, throughout. The total doses (rag kg -1) of propofol infused and the average infusion rates are shown in Table 1. If the initial bolus dose of propofol (0-5 mg kg -1) is included with the total dose of propofol infused, the average infusion rates were 0.41, 0-30, 0.31 and 0.31 mg kg -1 rain -1 for ponies l, 2, 3 and 4 respectively. Mean respiratory rate ranged from 7 to 11 breaths min -1 during the infusion, and respiratory depression, indicated by increased PaCO 2 levels, was evident in all four ponies in the group. It was particularly marked in pony 2, in which arterial cannulation proved difficult. For 20 minutes after this pony was placed in dorsal recumbency, it breathed irregularly and by the time an arterial blood sample was obtained 40 minutes after the infusion began, the PaCO 2 was 16.0 kPa. The depth of anaesthesia was judged to be light because the pony blinked spontaneously throughout. It was later ventilated mechanically and its arterial PaCO 2 10 minutes later was 9.1 kPa. Arterial oxygen levels were also surprisingly poor, with ponies 1, 2 and 3 having PaO 2 values less than 13.3 kPa at some point during the period of anaesthesia, despite breathing 100 per cent oxygen. Pony 1 had developed arterial hypoxaemia (PaO 2 6.7 kPa) 60 minutes after the infusion was started (Table 2). Mean heart rate ranged from 64 to 77 beats rain q during the infusion (Table 3). Ponies 1 and 2 also experienced periods of arterial hypotension, pony 2 having a mean arterial pressure of 39 mm Hg between 35 and 50 minutes after the start of the infusion. This period coincided with marked respiratory acidosis (PaCO 2 16.0 kPa) in pony 2; there was a gradual increase in arterial blood pressure to a more acceptable level (80 mm Hg) once intermittent positive pressure ventilation was started. TABLE 1: Total dose infused and average infusion rates of propofol when used to maintain anaesthesia in ponies either alone or with ketamine administered by intravenous infusion, after a bolus dose of 0.5 mg kg -1 propofol

Anaesthetic agent Propofol

Propofol/ketamine

Pony

Total dose (mg kg-1)

Average infusion rate (mg kg-1 min-1)

1 2 3 4 5 6 7 8

31.3 25.2 19.2 19.5 7.5 7.5 8.3 6.9

0.40 0.29 0.29 0.30 0.12 0.12 0.13 0,11

Propofol infusion in ponies

TABLE 2: Mean (SD) and (ranges) of arterial blood gas values in ponies undergoing surgery. Anaesthesia was maintained with propofol alone in four ponies (group 1) or with propofol and ketamine in four ponies (group 2) given by intravenous infusion. The infusions were started at time 0. Values after 20 minutes are reported for group 2 only, because samples were available from only two of the ponies' in group 1 at this time

Time (min)

Group

pH

PaCO2 (kPa)

PaO2 (kPa)

20

2

7.37 (0.04) (7.32-7.40)

6.0 (0-5) (5.5-6-6)

47.1 (8.6) (35.7-58.3)

40

1

7.18 (0.09) (7.05-7.28) 7.38 (0.04) (7.33-7.43)

10.2 (3.9) (8-1-16.0) 6.3 (0-8) (5.5-7.3)

20.9 (17.9) (9.6-47.5) 49.7 (9.3) (37.6-60.7)

7.24 (0.05) (7.18-7.29) 7.41 (0.04) (7.38-7-46)

9.1 (1.5) (7.0-10.7) 5.9 (0.4) (5-4-6.3)

19-2 (14-0) (6.7-38.5) 41.8 (22.8) (14-0-67.2)

2 60

1 2

181

10

8

6 5

48 3 2 1

TABLE 3: Mean (SD) and [ranges] of heart rates and arterial blood pressures in four ponies during anaesthesia with infusions of propofol alone (group 1) and during infusions of propofol and ketamine in four ponies (group 2). The infusions were started at time 0

Time (min) 10 20 30 40 50 60

Mean arterial blood pressure (mm Hg) (ram Hg) Group 1 Group 2 105" [85-125] 89* [77-102] 71 (11) [56-80] 90 (41) [39-129] 86 (28) [58-124] 90 (25) [70-127]

119 (16) [101-1421 122 (16) [106-142] 108 (14) [96-104] 106 (12) [94-122] 106 (12) [89-118] 108 (10) [95-116]

Mean heat rate (beats min-1) Group 1 Group 2 72 (24) [58-108] 72 (13) [68-88] 77 (18) [56-99] 70 (15) [57-88] 64 (6) [57-72] 64 (12) [52-81]

40 (8) [34-48] 40 (4) [36-45] 40 (4) [36-46] 44 (12) [36-60] 48 (10) [40-60] 47 (14) [36-66]

0

10

20

30 40 50 'rime (minutes)

60

70

FIG 1: Mean blood propofol concentrations (pg m1-1) during the infusion period for four ponies maintained on propofol alone (G1), and mean blood propofol and plasma ketamine end norketamine concentrations (pg m1-1) for four ponies maintained on propofol and ketamine infusions (G2). Time 0 is the start of the infusion. Key: - 0 - Propofol (G1), - B - Propofol (G2), qZKetamine (G2), - A - Norketamine (G2)

10

8

I b£

©

* Results for two ponies

7 6 5 4

Whole blood concentrations of propofol ranged from 3.27 to 9.44 ~tg m1-1 during the infusion, with a mean concentration between 4-77 and 7.18 pg m1-1 from 10 to 60 minutes (Fig 1). The blood propofol concentrations at the time the infusion was switched off ranged from 5.39 to 9.44 ~g m1-1 (mean 7.87 ~tg ml-1), and declined rapidly thereafter (Fig 2). Recovery from anaesthesia was satisfactory in all the ponies, although pony 1 appeared slightly hyperaesthetic. Mean times to endotracheal extubation, sternal recumbency and standing were 14.5 (8-2), 19-8 (8-0) and 27-2 (7.4) minutes, respectively. Recoveries were assisted in all four ponies. Blood propofol concentration at the time the ponies assumed sternal recumbency, was determined by extrapolation from the individual drug concentration curves, and ranged from 1.06 to 2-60 pg m1-1 (mean 2.12 pg ml-1).

Group 2 (propofol and ketamine) The infusion of ketamine was stopped after 60 minutes in all the ponies, followed five minutes later by the propofol infusion. The infusion rate of propofol was set at 0.15 mg kg -1 rain -1 for each animal for the first 20 minutes, thereafter decreasing to 0-1 mg kg -1 min -1 for the remainder of the infusion for ponies 5, 6 and 7. In pony 8 the propofol infusion rate was reduced again to 0-075 mg kg -1 min -1, 40 minutes after the start of the infusion. The total doses of propofol (mg kg -1) infused in each pony, excluding the bolus dose, are shown in Table 1.

3

3 2

0

20

40

60 80 100 Time (minutes)

120

140

FIG 2: Mean blood propofol concentrations (IJg ml-1) in the post-infusion period for four ponies maintained on propofol alone (G1), and mean blood propofol and plasma ketamine and norketamine concentrations (IJg m1-1) in the post-infusion period for four ponies maintained on propofol and ketamine infusions (G2). Time 0 is the end of the infusion. Key: - 0 - Propofol (G1),-BPropofol (G2), -q2~- Ketamine (G2), 4 - Norketamine (G2)

The mean respiratory rate ranged from 9 to 16 breaths min -1 during the infusion period, and arterial blood gases were well maintained (Table 2). Apnoea was not observed in any of the ponies. Mean pulse rate ranged from 40 to 48 beats min -1 during the infusion, and mean arterial blood pressure was maintained between 106 and 122 mm Hg (Table 3). Mean blood propofol concentrations remained relatively constant during the infusion (range 1.9 to 2.7 lag ml-1), and the mean propofol concentration at the time the infusion was switched off was 1.9 (0.94) ~tg m1-1 (Fig 1). Thereafter, blood propofol levels declined rapidly (Fig 2). The mean total dose of ketamine was 4.60 mg kg -1, that is the induction dose and the total infusion dose. Plasma

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D. Flaherty, J. Reid, E. Welsh, A. M. Monteiro, P. Lerche, A. Nolan

concentrations of ketamine varied from 1.90 ~tg m1-1 to 2.63 gg m1-1 during the infusion period (Fig 2), but the mean concentration remained relatively constant (range 1.90 to 2-2 ~g m1-1) between 10 and 60 minutes after the infusion was started. Once the infusion was stopped, plasma ketamine levels declined rapidly (Fig 3). The plasma concentration of norketamine rose progressively to a maximum mean value of 0.90 (0.18) gg m1-1, 60 minutes into the infusion as the ketamine infusion was turned off, and then peaked at a mean of 1.00 (0.22) ~tg m1-1, 10 minutes after the infusion was stopped. Norketamine concentrations declined during the two-hour post-infusion sampling period (Fig 2). Recovery from anaesthesia was smooth and satisfactory in all the ponies, with no evidence of excitement. The mean times to endotracheal extubation, assuming sternal recumbency and standing were 1.9 (0.2), 8.4 (3.2) and 14.9 (10.1) minutes respectively.

DISCUSSION Propofol has pharmacokinetic properties, including rapid body clearance, which make it suitable for use by continuous infusion in human beings (Shafer et al 1988), dogs (Nolan and Reid 1993) and sheep (Correia et al 1994). However, supplementation of propofol anaesthesia with other drugs is advisable in order to improve the quality of anaesthesia for surgery. Because many procedures in animals are performed in spontaneously breathing patients, it was considered appropriate to investigate drugs which would complement propofol infusions without depressing the respiratory system. Ketamine was chosen, first, because it does not have marked depressant activity on the cardiovascular or respiratory systems in horses (Muir et al 1977); secondly, ketamine was considered to be useful as an analgesic, it has been recommended for use during surgery in horses for that purpose (Nolan 1995) and it has been shown to be analgesic in humans at sub-anaesthetic doses (Owen et al 1987). Pharmacokinetic studies of ketamine in horses indicate that it is rapidly cleared from the body, thus making it a suitable drug for infusion regimens (Kaka et al 1979, Waterman et al 1987). There are few reports of this drug combination in human beings, but where investigated, it has been associated with haemodynamic stability (Guit et al 1990, Schuttler et al 1991) and good analgesia (Mayer et al 1990). Propofol can decrease arterial blood pressure by depressing central sympathetic neural outflow which results in decreased systemic vascular resistance (Claeys et al 1988); the mean arterial blood pressure in the ponies given propofol alone ranged from 71 mm Hg to 90 mm Hg. These values are similar to those reported by Nolan and Hall (1985), although the infusion rates in that study were lower (0.15 mg kg -1 min -1 and 0-2 mg kg -1 rain-l), and suggest that arterial hypotension induced by propofol anaesthesia in ponies is not prevented by surgical stimulation. Marked arterial hypotension occured in pony 2, despite it having a blood propofol concentration which, although high (7.3 ~g m1-1 40 minutes into the infusion), was within the range of values in the other three ponies in the group. In contrast, mean arterial blood pressure was well maintained in all the ponies anaesthetised with propofol and ketamine (106 to 122 mm Hg), probably owing to a combination of the stimulant effect of ketamine on the cardiovascular system in vivo (Cook et al 1991) and the lower blood propofol con-

centrations required to maintain anaesthesia in this group of ponies. Muir and Sams (1992) reported that an infusion of ketamine in halothane-anaesthetised horses improved the haemodynamics in these animals and they speculated that the improvement was greater than that to be expected by reductions in halothane alone. The mean pulse rates were greater than expected in the ponies receiving propofol alone (64 to 77 beats min -1) compared with 40 to 48 beats min -1 in the ponies receiving propofol and ketamine; however, the mean pre-induction pulse rate in the group 1 ponies was also high (78 beats min-1), compared with a mean value of 55 beats rain q in group 2, and this may have contributed to the high pulse rate during anaesthesia. All the ponies in both groups were young and although used to people, they had not been handled frequently and were quite excitable. Respiratory depression is a complication of the administration of propofol in human beings, cats and dogs (Goodman et al 1987, Morgan and Legge 1989, Sebel and Lowdon 1989), and so the marked respiratory depression observed in the ponies which received propofol alone and which had higher blood levels of propofol than those in group 2, was not unexpected. Previous work with propofol infusions in ponies recorded respiratory depression, although it was not marked (Nolan and Hall 1985). These authors reported that respiratory rate decreased significantly from a mean value of 13 breaths rain-1 before anaesthesia to 5 breaths min q within 45 minutes of the induction of anaesthesia. However, although PaCO 2 increased significantly, the mean maximum PaCO 2 value, 6.5 kPa, was considerably lower than the mean values recorded in the present study. This may have been due to the low infusion rate used, 0.2 mg kg -1 min -1, which was adequate for the maintenance of anaesthesia in ponies not undergoing surgery. In this study, pony 2 suffered the most marked respiratory depression of the group and coincidentally this was the animal with the most severe hypotension, which improved considerably when intermittent positive pressure ventilation was applied. The fact that the blood pressure improved as the arterial carbon dioxide level returned to normal might suggest that the hypotension was related to the high PaCO 2 levels in this animal. However, this is contrary to the cardiovascular effects of hypercapnia described in the literature, which are tachycardia and hypertension. Sechzer et al (1960) found increases in systolic and diastolic blood pressure and heart rate in conscious hypercapnic volunteers, and Wagner et al (1990) reported that arterial blood pressure rose consistently in ventilated horses anaesthetised with halothane exposed to increasing concentrations of CO 2, although the maximum arterial PaCO 2 was 11.3 kPa, considerably less than the 16.0 kPa recorded in pony 2. Whether propofol may have blunted the pressor response to high levels of CO 2 is a matter of conjecture. In contrast to the respiratory depression observed in all the ponies in group 1, PaCO 2 tensions were lower in the ponies in group 2 given propofol and ketamine. These data are similar to the results of studies in which ketamine has been infused in combination with other drugs in horses undergoing anaesthesia and surgery (Young et al 1993) or anaesthesia alone (Taylor et al 1995). Arterial oxygen tensions <13-3 kPa were frequently recorded in three of the four ponies in group 1, which was surprising given the size of the animals and the fact that they were breathing 100 per cent oxygen. All the ponies in group 1 appeared to be in a light plane of anaesthesia and they blinked spontaneously throughout; attempts to counteract this by increasing the rate of infusion

Propofol infusion in ponies

of propofol led to obvious cardiovascular and respiratory depression and was therefore unsuccessful. The use of propofol alone to maintain anaesthesia in spontaneously breathing ponies undergoing surgery cannot therefore be recommended. Studies in human beings and dogs have shown that individual variation in blood propofol levels can be a feature of propofol infusions (Shafer et al 1988, Nolan and Reid 1993), and the decision to alter the infusion rate of propofol on the basis of clinical and physiological observations was made in order to adopt a practical approach to total intravenous anaesthesia. Two of the ponies in group 1 moved in response to surgical stimulation when their blood propofol concentrations lay in the range 5-26 to 6.23 tag m1-1 (pony 3), and 4-74 to 6.17 lag m1-1 (pony 4). The other two ponies had blood propofol concentrations greater than 6 lag m1-1 during surgery, and this level would appear to be the approximate minimum which will prevent movement in response to surgical stimulation when propofol is used on its own. These blood propofol concentrations compare favourably with those reported in human beings in which propofol alone was used to maintain anaesthesia for surgical procedures (for review see Smith et al 1994). These data suggest that although the blood propofol levels required to prevent responses to surgical stimulation vary among individuals, they lie within a similar range in different species (Dixon et 1990, Nolan and Reid 1993, Correia et al 1994). The concomitant infusion of ketamine markedly decreased the blood propofol concentration required to provide surgical anaesthesia (mean range, 1.9 to 2-7 lag ml-1). The plasma levels of ketamine in the ponies in group 2 ranged from 1-90 to 2-63 lag m1-1 during the infusion and were remarkably constant with little individual variation. These concentrations were considered ideal for ponies undergoing surgery. Waterman et al (1987) reported that concentrations of ketamine less than 1 lag m1-1, were associated with the recovery of consciousness in horses, while Muir and Sams (1992), using step-wise increases in the rate of infusion of ketamine in horses anaesthetised with halothane, reported that plasma ketamine concentrations above 1.0 lag m1-1 were necessary to reduce the minimum alveolar concentration (MAC) of halothane in horses and that at plasma concentrations more than 2 lag m1-1, the beneficial effects of ketamine in reducing the MAC of halothane reached a plateau. Taylor et al (1995) reported plasma levels of ketamine during TIVA with detomidine, ketamine and guaiphenesin for two hours. The ketamine infusion rate chosen for the first 60 minutes was 53 lag kg -1 min -1 which was gradually reduced to 33 lag kg -1 rain -1, and these workers reported a mean plasma ketamine concentration of 2.52 lag m1-1, 60 minutes after the infusion began. These infusion rates and plasma concentrations are similar to those used and measured in this study. Ketamine is used clinically as a racemic mixture of both optically active isomers, R(-) and S(+), which differ in their pharmacodynamic effects (Graf et al 1995). S(+)ketamine is approximately four times as potent as R(-)ketamine as an analgesic and hypnotic, but psychomimetic emergence reactions in human beings are more commonly associated with the R(-)-isomer (Klepstad et al 1990). The stereoisomers of ketamine and norketamine were not separated by the extraction procedure and chromatography described. Delatour et al (1991) reported that the metabolism of ketamine to norketamine was highly enantioselective in horses, in favour of the S(+)-isomer.

183

Recovery from anaesthesia was smooth and rapid for all the ponies. Work carried out by Waterman et al (1987) indicated that recovery from the actions of a bolus dose of ketamine was almost entirely due to the rapid and extensive redistribution of the drug from central to peripheral compartments. Nolan et al (1996) confirmed the rapid clearance of ketamine in horses given propofol and ketamine infusions, but observed that the metabolite, norketamine, was present in plasma for considerably longer than the parent compound. The presence of this active metabolite in plasma may be significant during infusions lasting more than an hour, and may ultimately affect the quality of recovery. The use of propofol alone for the maintenance of surgical anaesthesia in ponies, was associated with respiratory depression, and arterial hypotension was observed in two of four ponies. However, when propofol was administered at lower infusion rates together with ketamine, these adverse effects were not observed. Further studies will be undertaken to determine the effects of extending the period of anaesthesia with infusions of propofol and ketamine.

ACKNOWLEDGEMENTS The authors are grateful to Parke Davis Veterinary for generous supplies of ketamine and for providing norketamine, and to Mallinckrodt Veterinary for supplies of propofol.

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Received May 7, 1996 Accepted September 26, 1996