Effects of plasma expansion on the pituitary-adrenocortical response to halothane anaesthesia in sheep

J . vet. Airaestli. Vol. 26(1) (1999)

Effects of plasma expansion on the pituitary-adrenocortical response to halothane anaesthesia in sheep P. M. Taylor Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 OES, U K

SUMMARY The study aimed to investigate the stimulus to adrenocortical activity that is induced by halothane anaesthesia. Groups of 7 sheep were anaesthetised with thiopentone and halothane (TH) or acepromazine, thiopentone and halothane (ATH). During 120 min of anaesthesia hypotension was prevented (mean arterial blood pressure kept at pre-anaesthetic level) by infusion of a modified gelatine plasma replacer given to effect (0.34-1.1 litres with TH and 1.1-3.1 litres with ATH). Pulse rate, arterial blood pressure and gases were measured and sequential samples withdrawn for analysis of plasma cortisol, adrenocorticotrophic hormone (ACTH), arginine vasopressin (AVP), glucose and lactate. Heart rate increased in the ATH but not the TH group. All sheep were well oxygenated but developed hypercapnia and respiratory acidosis. In both groups, cortisol increased more than 2-fold 20 min after the end of anaesthesia but there were no significant changes in ACTH. AVP was measured in the TH group only and increased 3-fold at the end of anaesthesia. Glucose and lactate remained stable except for lactate in the TH group which decreased during anaesthesia. These data indicate that hypotension is a ma,jor component of the stimulus inducing adrenocortical activity during halothane anaesthesia. However, maintenance of normotension did not entirely depress the response; halothane itself or decreased perfusion may also contribute.

INTRODUCTION Cardiovascular depression leading to hypotension develops during halothane anaesthesia (Steffey ef al. 1974; Steffey and Howland 1978; Taylor 1998b). This is severe in horses and may lead to fatal post operative myopathy (Grandy et al. 1987; Lindsay et al. 1989). In equids, halothane anaesthesia also causes marked adrenocortical activity, which is not seen during iv anaesthesia (Taylor 1989a,b, 1990; Taylor et a / . 1995; Bettschart-Wolfensberger et a/. 1996). An adrenocortical ‘stress response’ usually occurs in response to a noxious stimulus (Selye 1956); the cause of such a response during anaesthesia, which on its own is normally considered benign, merits investigation. Sheep respond to halothane anaesthesia in a similar manner to horses and have been used in studies investigating the phenomenon (Taylor 1987, 1998a,b,c).

Because volatile agent anaesthesia causes hypotension and adrenocortical activity (Taylor 1991) and iv anaesthesia causes neither (Taylor 1989a, 1990; Taylor et a/. 1995; Bettschart-Wolfensberger et al. 1996; Taylor 1998b), the question is raised whether hypotension is the major stimulus to adrenocortical activation. A number of studies have investigated this. In sheep anaesthetised with pentobarbitone, nitroprusside produced marked hypotension and plasma cortisol increased 5-fold; in contrast, low doses of halothane given during pentobarbitone anaesthesia caused less hypotension and a smaller increase in cortisol (Taylor 1998a). Conversely, dobutamine infusion used to maintain normotension during halothane anaesthesia in ponies did not prevent adrenocortical activity although dobutamine infusion alone did not evoke it (Taylor 199Xe). Plasma expansion during halothane anaesthesia produced variable results: hypertonic saline in sheep did not prevent either hypotension or adrenocortical activity (Taylor 1998~)and modified gelatine in ponies prevented hypotension but only partially ameliorated the adrenocortical response (Taylor 1998d). No adrenocortical stimulation was apparent when plasma expansion and inotrope infusion were combined (Taylor 1998d). The studies described above indicate that hypotension is not the sole stimulus to pituitary-adrenocortical activity during halothane anaesthesia although it appears to play it major role. The phenomenon has been studied further in sheep: this paper describes investigation into the adrenocortical effects of normotension maintained with modified gelatine plasma replacer infusion during halothane anaesthesia. Thiopentone-halothane anaesthesia was studied, with the addition, in one group, of acepromazine prernedication because this is a commonly used a-, adrenoceptor antagonist, which also has effects on arterial blood pressure.

MATERIALS AND METHODS Animals The studies were performed under the Animals (Scientific Procedures) Act 1986, Project Licence 80/83. Ten nonpregnant Welsh Mountain ewes aged 2-3 years, weighing 39 f 1 kg were used. They were housed indoors with free access

.I. vet. Annrslh. VO/.2 6 ( l ) (1999)

to hay and water but given water only for 18 h before anaesthesia. Four sheep were anaesthetised twice, once with each protocol, in random order with at least 2 weeks between. The remaining sheep were anaesthetised once, making 7 in each group. At least 3 days before any experiment, under halothane anaesthesia, the aorta was catheterised with a polytetrafluoroethylene catheter passed through the femoral artery (Silver 1980). A 14 SWG catheter for thiopentone injection and infusion of plasma replacer was placed in a jugular vein immediately before induction of anaesthesia.

Anaesthesia and infusion Thiopentonelhalothane with gelatine infusion (TH): Anaesthesia was induced, without premedication, with iv thiopentone sufficient to allow intubation ( 16-25 mgkg). The trachea was intubated with a cuffed endotracheal tube and halothane in oxygen administered for 120 min from a Magill breathing circuit with an out-of-circle Fluotec vaporiser. The sheep breathed spontaneously and fresh gas flow rates were adjusted to prevent rebreathing as judged by a Datex infrared carbon dioxide analyser. The vaporiser was set at 2% for 15 min then reduced to between 1.8 and 2.0%. Immediately after intubation and the start of halothane administration an iv infusion of modified gelatine plasma replacer (Haemaccel, Hoechst) was started. The infusion rate was started at 1 0 ml/kg/h and thereafter adjusted to maintain mean arterial blood pressure at pre-anaesthetic control values throughout anaesthesia. Acepromazine-thiopentone-halothane with gelatine infusion (ATH): Premedication with 0.03 mg/kg acepromazine was given intramuscularly 60 min before induction of anaesthesia with 13-15 m g k g thiopentone sufficient to allow intubation given iv. Intubation and maintenance of anaesthesia were as described for the TH group but vaporiser settings between 1.6 and 1.8% were used. Gelatine infusion was started at 10 mg/kg/h as for the TH group and adjusted thereafter to maintain mean arterial blood pressure at control values.

Timing of measurements Pre-anaesthetic control measurements were made in the presence of another sheep with the test ewe standing in a small pen. In the ATH group measurements were made before and after acepromazine premedication; post premedication measurements were taken as ‘control’. At least 10 min continuous arterial blood pressure trace was recorded before the remaining measurements were made. During the 120 min period of anaesthesia, measurements were made every 20 min, with a final measurement 20 min after the end of anaesthesia and infusion. The sheep was allowed to recover in a small cot, breathing air, and the endotracheal tube was removed when swallowing reflexes returned. Food was withheld until the sheep were standing without ataxia.

Biochemistry Plasma cortisol, adrenocorticotrophic hormone (ACTH) and arginine vasopressin (AVP) concentrations were measured by radio immunoassay (RIA) (Silver et al. 1984; Luna and Taylor 1995). Intra- and inter-assay coefficients of variation respectively were 5.6 and 1 1.8% for cortisol, 8. I and 16.4% for ACTH and 16.8 and 21.5% for AVP. Plasma glucose and lactate were measured using standard colorimetric techniques.

Statistics Results are given as means and standard deviations. Changes with time within each group were subjected to analysis of variance (ANOVA) for repeated measures followed by Dunnett’s test, if indicated, to assess changes from control. Differences between groups were analysed by Student’s unpaired t-test of the area under the time-curve taken from control to 20 min after anaesthesia (AUCo,,40))(Matthews et

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Measurements Arterial blood pressure was recorded from the femoral artery catheter using a Lectromed system. Blood was withdrawn from the arterial catheter for pH and blood gas measurement using a Radiometer 130 blood gas analyser. Pulse rate was taken from the pressure trace and respiratory rate by observation of the chest wall. Five millilitres of blood were taken for endocrine and metabolite assay at each sampling point; the blood was divided between tubes containing EDTA and heparin, centrifuged at 4°C and the plasma harvested, frozen and stored at -20°C. Depth of anaesthesia was monitored by an experienced anaesthetist and clinical assessment was used to maintain anaesthesia at a depth similar to that normally used for abdominal surgery. Time to standing was recorded in minutes from the end of the I20 min anaesthetic period.

I 0

Anaesthesia

40

80

120

Time (rnin)

Fig I :Mean f sd mean arterial blood pressure during itiiopentonehalothane anaesthesia (TH: --&) or acepromazine-thiopentonehalothane anaesthesia (ATH;-O-) wiih modijied gelatine (Haemaccel) infusion. AUC: NS :-no significant diJ$rence between the AIJCI,,.,,(,, in

euch group.

.J. vet. Anaesth. Vol. 26(1) (1999)

TABLE 1: Mean f sd arterial oxygen tension (PaO,), carbon dioxide tension (PaCo,) and pH during thiopentone-halothane (TH) or acepromazine-thiopentone-halothane (ATH) anaesthesia with modified gelatine infusion in sheep PaO, (kPa) Time

TH

Control 20 min 40 min 60 min 80 rnin 100 min 120 min 140 rnin AUC

14.0 48.3 50.8 50.7 50.5 49.7 44.0 11.7

PaCO, (kPa) ATH

f 0.7 f 6.8 * f 9.6 * f 10.8'

12.4 f 1.9 14.5 f 5.1 17.6 f 4.3 18.8 f 6.4 f 10.V 19.6 f 10.7 f 8.9 * 18.4 f 8.7 f16.5' 18.0 f 8.8 f 1.3 10.1 f 2.7" THG>ATHG

TH

PH ATH

4.7 f 0.4 8.0 f 0.7 * 8.7 f 0.8 * 8 . 3 f 1.1 8.8 f 0.7 * 8.7 f 0.7 9.2 f 0.5 6.4 f 0.3

5.1 f 0.4 8.3 f 0.8 7.9 f 0.9 * 8.1 f 0.5 8.0 f 0.5 7.7 f 0.9 * 8.3 f 0.8 6.8 f 1.2

TH

ATH

7.44 f 0.04 7.27 f 0.04' 7.26 f 0.02* 7.28 f 0.02' 7.26 f 0.04' 7.24 f 0.06' 7.24 f 0.06' 7.37 f 0.05'

NS

7.51 f 0.03 7.30 f 0.03' 7.29 f 0.03' 7.28 f 0.02* 7.29 f 0.03* 7.27 f 0.02' 7.27 i- 0.01 7.38 0.01 NS

*

*: significant change from control

AUC: difference between AUC~O-140) in each group. NS: no significant difference

TABLE 2: Mean f sd plasma glucose and lactate during thiopentone-halothane (TH) or acepromazine-thiopentonehalothane (ATH) anaesthesia with modified gelatine infusion in sheep Glucose (mmol/l) TH ATH

Lactate (mmol/l) TH ATH

3.7 f 0.6 4.6 f 1.4 4.9 f 1.8 4.3 f 0.8 4.6 f 0.7 4.6 f 1.8 4.6 f 1 .O 4.7 f 0.8 5.1 f 1.3 4.6 f 0.6 4.3 ? 0.4 4.8 f 1.2 4.6 f 0.9 4.5 f 0.7 5.0 f 0.6 * 4.9 f 1.5 NS

2.5 f 0 . 8 1.9f 1.4 0.8 f 0.5 4.2 f 1.7 * 2.9 +0.6 0.8 f 0.4 2.0 fO.8 0.6f 0.4 1 .O f 0 . 3 0.6f 0.4 0.6 f O . l 0.6f 0.5 0.4 fO.l 0.5f 0.4 0.8 f 0.7 1 . O f 1.3 TH>ATH

Time Control 20 rnin 40 rnin 60 rnin 80 rnin 100 rnin 120 rnin 140 rnin AUC

250 200

1

t T

I

AUC: NS

T

11

Anaesthesia

-50

8

-40

0

40 Time (rnin)

80

120

Fig 2: Mean k sd plasma cortiJol during thiopentone-halothane anaesthesia (TH:--A--) or aceprotnazine-thiopentone-halothane anaesthesia (ATH;-@-) with modvied gelatine (Haemaccel) infusion. *: signficant change from control in THG i": sign$icant change from control in ATHG AUC: NS :no significant diflerence between the A U C ~ ~ ~ . in ~ 4each 0,

*: significant change from control

AUC: difference between AUC(o.140) in each group NS: no significant difference

al. 1990). Data that were not normally distributed were log transformed before analysis. P<0.05 was considered significant.

group.

RESULTS

control at 120 min (Fig 4). Glucose tended to increase during anaesthesia, but was significantly higher than control only at 140 min, after halothane supply had been discontinued (Table 2). After an initial peak following induction, plasma lactate fell; between 100 and 140 rnin the values were significantly below the control level (Table 2). Recovery from anaesthesia was smooth. The sheep moved quietly from lateral into sternal recumbency and stood easily 29 f 7 rnin after the halothane was switched off.

Thiopentone-halothane and gelatine infusion (TH) Mean arterial blood pressure (MABP) was retained close to control values throughout the experiment (Fig 1) using 0.341.1 (mean 0.7) 1 gelatine solution. Arterial oxygen tension (Pa02) increased significantly while the sheep breathed a high oxygen fraction; arterial carbon dioxide tension (PaC02) increased significantly and pH fell, also significantly (Table 1). Pulse rate did not change from control values and ranged from mean values of 110 f 18 at control to between 118 f 10 and 125 f 14 beatslmin during anaesthesia. Plasma cortisol changed very little, although it tended to decrease initially, then increase again as anaesthesia progressed; it exceeded control values 20 rnin after anaesthesia ended (Fig 2). ACTH did not change significantly although it tended to fall during anaesthesia and increase again at 100 rnin (Fig 3). AVP increased slightly during anaesthesia, reaching values significantly higher than

Acepromazine-thiopentone-halothane with gelatine infusion (ATH) MABP was kept close to control values throughout anaesthesia using 1.1-3.1 (mean 1.95) 1 gelatine solution. This was significantly more (P
.I. vet. Anuesth. V d . 26(1) (1999)

5 80

-E

401

I T

AUC: NS

-. h

-

-a 20

I

5a

40-

m

E

_m

a

0 -

I

-40

Anaesthesia

-10 0

40 Time (min)

80

120

I

-40

1 0

Anaesthesia

40 Time (rnin)

80

120

Fig 3: Mean f sd plasma ACTH during thiopentone-halothane anaesthesiu (TH;--A--) or acepromazine-thiopentone-halothane anaesthesia (ATH-@-) with modified gelatine (Haemaccel) infusion. AUC: NS :no significant diJ;erencebelween the A U C ( O - ~in ~O each ) group.

Fig 4: Mean f sd plasma AVP during thiopentone-halothane anaesthesia (TH;--A--) with modified gelatine (Haemaccel) infusion. *: signifcant change from control

and pH decreased in a similar manner to the TH group (Table 1). Pre-sedation pulse rates were within the same range as the TH group. During anaesthesia, pulse rate increased from a control (after sedation) value of 76 & 11 beats/min to a plateau ranging between 122 f 10 and 133 f 11. In spite of the higher pulse rates in this group the AUC(,-,,, for the 2 groups were not significantly different. Plasma cortisol rose during anaesthesia; although the increase tended to occur earlier than in the TH group, there was no significant difference in AUCo.,,,,, for the 2 groups (Fig 2). ACTH followed the same pattern as with TH, starting to increase before halothane administration ceased (Fig 3). AVP was not measured in this group. Glucose and lactate did not change significantly during anaesthesia, and the lactate AUC,,_,,,, was lower than that with TH (Table 2). Recovery from anaesthesia appeared similar to that in the TH group: the sheep stood up 40 f 19 min after the halothane supply was turned off. This was not significantly slower than after TH.

enhanced adrenocortical activity was slight, it was not entirely absent. Plasma cortisol was increasing towards the end of anaesthesia, and had risen 2- to 3-fold by 140 min. ACTH changes followed a similar pattern, although they were not statistically significant due to more individual variation. The differences between the TH and ATH groups was minor and the number of animals studied would be insufficient (Florey 1993) to detect a true significant difference in MABP and cortisol. It is unlikely that a difference of some 10 mmHg in MABP, when all values were above 90 mmHg, would have much biological effect. AVP in the TH group also increased before the end of anaesthesia. However, the response was considerably less than that seen in sheep anaesthetised with the same protocol without prevention of hypotension, where a 10-fold increase was sustained throughout anaesthesia (Taylor 1998b). AVP is released from the hypothalamus with corticotrophinreleasing hormone in response to stress (Harbuz and Lightman 1993). It is also released from the posterior pituitary in response to increases in plasma osmolarity and decreased blood volume, but fluid load with isotonic gelatine plasma replacer is unlikely to have evoked this mechanism. AVP was thus most probably released as part of a stress response rather than as a homeostatic process. Hypotension undoubtedly stimulates pituitary adrenocortical activity in sheep (Keller-Wood and Wood 1991) and is likely to make a major contribution to the halothane-induced response. Untreated halothane anaesthesia after thiopentone induction led to a 10-fold increase in plasma AVP concentration in sheep (Taylor 1998b) and nitroprusside-induced hypotension causes marked increases in circulating AVP, ACTH and cortisol (Taylor 199th; Pecins-Thompson and Keller-Wood 1994). Prevention of hypotension in the current study undoubtedly reduced the AVP response greatly; however it was not entirely absent as is the case, for instance, during pentobarbitone anaesthesia (Taylor 1998b). Halothane reduces blood pressure largely through myocardial depression (Steffey and Howland 1978). In the

These data demonstrate that normotension can be maintained in sheep during halothane anaesthesia by plasma expansion and that the pituitary adrenocortical respmse was considerably ameliorated, but not entirely suppressed. The data are similar to those reported in ponies (Taylor 1998d), except that sheep tolerated the plasma expansion with little clinical sign of fluid overload. The ponies received larger volumes (per kg) of gelatine than the sheep in the TH group but less than those in the ATH group; sheep appeared to tolerate fluid overload better than ponies, who suffered from excessive respiratory secretions, with one death. During halothane anaesthesia, after acepromazine premedication and thiopentone induction, without any attempt to prevent hypotension, 5-fold increases in plasma ACTH and 7-fold increases in cortisol were recorded (Taylor 1998b,c). In the present study, although evidence of 35

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Anaesth. Vol. 26(1) (1YYY)

ACKNOWLEDGEMENTS

present study blood pressure was maintained by giving fluid to increase venous return thereby increasing cardiac output through the Frank-Starling mechanism. Increased atrial filling would reduce baroreflex stimulus to ACTH release (Gann et al. 1977). The pulse rate in the present study was higher in both groups than in sheep anaesthetised with similar protocols without the gelatine infusion, where rate remained close to 100/min throughout anaesthesia (Taylor 1998b). The Bainbridge reflex was presumably responsible for the relatively high pulse rate. Acepromazine, through its a-, adrenoceptor antagonist action, decreases systemic vascular resistance and decreases arterial blood pressure, an effect particularly marked in hypovolaemic animals (Hall and Clarke 1991). Fluid infusion would increase blood pressure in such cases by filling up the vascular bed. This effect might be expected to be more obvious in the ATH group; however, blood pressure was always slightly lower in this group, despite larger volumes of gelatine infusion. The fluid volume may have been insufficient to fill up the vascular bed or myocardial depression may have been enhanced by acepromazine. Similar to the present study, in an investigation in ponies (Taylor 1998d), adrenocortical activity was suppressed initially, but prolonged treatment led to late ACTH and cortisol increases. In ponies, the eventual response was attributed to undesirable effects of over infusion. Clinical signs of over infusion were not seen in the sheep but may have been more subtle and thus not recognised. Hypercarbia and acidosis might be expected to contribute to pituitary-adrenal stimulation and to have led to the minimal response observed. However, pentobarbitone anaesthesia induced almost as much hypercarbia and similar acidosis without any pituitary-adrenal stimulation, so this is unlikely (Taylor 1998b). There was little evidence of metabolic stimulation during anaesthesia and lactate decreased in the TH group. Lactate values in the ATH group were always lower which may relate to sympathetic blockade by acepromazine. Alternatively, low lactate may reflect better peripheral perfusion (Cooper et al. 1979). It is unlikely that oxygen supply was limited by low blood content leading to more anaerobic metabolism in one group. Although Pa02 was higher in the TH group breathing a higher oxygen fraction, all animals had above 95% oxygen haemoglobin saturation; blood content would be similar. Less thiopentone and halothane were required in the ATH group, presumably as a result of the anaesthetic sparing effect of acepromazine (Hall and Clarke 1991). Although this might be expected to affect the endocrine and metabolic effects, the relative contributions of the different drugs is difficult to judge. This is unlikely to have had any major effect as, for example, the hypotensive effect of acepromazine would be counteracted by a lower dose of halothane. In conclusion, this paper suggests that hypotension plays a major role in stimulating pituitary adrenocortical activity during halothane anaesthesia, but it cannot be regarded as the sole cause. Some effect of decreased tissue perfusion or a specific action of halothane itself may also contribute.

To the Wellcome Trust for financial support; to Marian Silver who collaborated in these studies but died before the work was completed; to Paul Hughes and Jean Knox for technical assistance.

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Taylor, P.M. ( 1 9 9 8 ~ ) Effects of hypertonic saline infusion on the adrenocortical response to thiopental-halothane onesthehia i n sheep aftcr prcmedication with acepromazine. Vrl. Surg. 28, 7 7 4 2 . Taylor, P.M. (1998d) Endocrine and metabolic responses to plasma volunie expansion during halothane anaesthesia in ponies. J . re/. Phrrrrmrcol. Ther. 21,485-490. Taylor, P.M. (1 998e) Adrenocortical and metabolic responses to dobutaminr infusion during halothane anacsthesia in ponies. J . vet. Pharrf?crco/.Ther. 21, 282-287.

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