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Hormonal, metabolic and physiological effects of laparoscopic surgery using a detomidine-buprenorphine combination in standing horses
Veterinary Anaesthesia and Analgesia, 2003, 30, 71^79
Hormonal, metabolic and physiological effects of laparoscopic surgery using a detomidine^buprenorphine combination in standing horses P van Dijk DVM, PhD, Diplomate ECVA, DPK Lankveld FH Jonkerz DVM, PhD
DVM,
ABM Rijkenhuizeny
DVM, PhD, Diplomate ECVS
&
Sections of Anaesthesiology and ySurgery, Department of Equine Sciences and zDepartment of Farm Animal Health, Veterinary Faculty, Utrecht University, Utrecht, The Netherlands
Correspondence: Dr P van Dijk, Section Anaesthesiology, Department of Equine Sciences,Veterinary Faculty, Utrecht University,Yalelaan 12, PO Box 80 153 3508 TD, Utrecht, The Netherlands.
Abstract Objective To assess the hormonal, metabolic and physiological e¡ects of laparascopic surgery performed under a sedative analgesic combination of detomidine and buprenorphine in standing horses. Study design Prospective study. Animals Eight healthy adult Dutch Warmblood horses and ¢ve healthy adult ponies undergoing laparoscopy were studied. Five healthy adult horses not undergoing laparoscopy were used as a control group. Methods The sedative e¡ect of an initial detomidine and buprenorphine injection was maintained using a continuous infusion of detomidine alone. The heart and respiratory rate, arterial blood pH and arterial oxygen and carbon dioxide tensions were monitored, while blood samples were taken for the measurement of glucose, lactate, cortisol, insulin and nonesteri¢ed fatty acids (NEFA). The same variables were monitored in a control group of horses which were sedated, but which did not undergo surgery. At the end of the sedation period the e¡ects of detomidine were antagonized using atipamezole. Results The protocol provided suitable conditions for standing laparoscopy in horses. Laparoscopy induced obvious metabolic and endocrine responses
which, with the exception of NEFA values, were not signi¢cantly di¡erent from changes found in the control group.While atipamezole did not produce detectable adverse e¡ects, it is possible that anatagonism may not be essential. Conclusions The technique described reliably produces adequate sedation and analgesia for laparoscopic procedures. The level of sedation/analgesia was controlled by decreasing or increasing the infusion rate. Antagonism of the e¡ects of detomidine may not be necessary in all cases. Keywords buprenorphine, detomidine, horse, laparoscopy, pony, stress response.
Introduction Use of detomidine^butorphanol combinations to produce sedation and analgesia for surgery in standing horses has been reported by several authors (LeBlanc 1991; Clarke & Paton 1988; Taylor et al. 1988). As butorphanol is not available in the Netherlands, it is a common practice to combine detomidine with buprenorphine to achieve a similar e¡ect. It is possible to maintain sedation and analgesia produced by this combination by infusing detomidine alone. In a pilot study, this method was found to be suitable for procedures lasting up to 3 hours. Dose rates used in the current study were based on the results of this pilot work and that of Daunt et al. (1993) and Wagner 71
Detomidine^buprenorphine combination in standing horses P van Dijk et al.
et al. (1992). As the degree of sedation needed for laparoscopic surgery causes some degree of incoordination in the immediate post-operative period, a second objective of this study was to observe the e¡ect of the a2 antagonist atipamezole on post-operative ataxia. Although there are several reports of the reversal of a2-agonist sedation using antagonists (Luna et al. 1992; Yamashita et al. 1996; Carroll et al. 1997; Ramseyer et al. 1998; Skarda et al. 1998), none have involved animals receiving buprenorphine. We were interested in the e¡ectiveness of buprenorphine for controlling post-operative pain as a2 antagonism is likely to diminish analgesia.
Materials and methods This study received approval from the Ethics andAnimal Research Committee of the Veterinary Faculty of Utrecht University. To avoid circadian in£uences on endocrine responses in individual animals, all experiments were scheduled between 10.00 and 14.00 hours. All animals had water but food was witheld for 36^48 hours before sedation. Three groups of horses were studied. Group P consisted of ¢ve healthy ponies between 2 and 12 years of age, weighing 255^360 kg (mean: 287 kg), undergoing laparoscopic steralisation. Group H consisted of eight healthy horses aged 2^9 years, weighing 308^ 484 kg (mean: 447 kg), undergoing laparoscopic steralisation (n ¼ 5) and diagnostic laparoscopy in three animals with chronic colic. Group C consisted of ¢ve healthy research horses aged 7^14 years, weighing 415^594 kg (mean: 519 kg), which underwent sedation without surgery. Sedation was initially produced in all groups using detomidine (Domosedan, P¢zer Animal Health B.V., Capelle a/d IJssel, the Netherlands) (10 mg kg1), combined with buprenorphine (Temgesic, Schering-Plough B.V., Amstelveen, the Netherlands) (6 mg kg1) injected intravenously. This was given approximately 45 minutes before the start of laparoscopy in groups P and H. When sedation had developed, an 8-cm 12 SWG catheter (Intra£on 2, Vycon, France) was placed percutaneously into the left jugular vein and an infusion of detomidine dissolved in Ringer’s solution (15 mg detomidine in 3 L Ringer’s solution) was begun. The initial infusion rate in the surgical cases was 0.16 mg kg1 minute1. This was adjusted at the discretion of the anaesthetist on the basis of clinical signs. Medical grade carbon dioxide was used to insu¥ate the abdominal cavity. A constant detomidine infusion was used in group C. The rate (0.1 mg kg1 minute1) 72
was based on the requirements of horses in the other two groups. The duration of sedation in groups Pand H was the time needed for the completion of surgery. Horses in group C were sedated for 80 minutes. At the end of sedation, atipamezole (Antisedan, P¢zer Animal Health B.V., Capelle a/d IJssel, the Netherlands) was administered IV using a dose equal to the total cummulative dose of detomidine, which each animal had received. The animals were observed closely for 10 minutes after atipamezole administration after which their ability to walk was assessed. Food and water were witheld for 1 hour after atipamezole injection. Monitoring for post-operative pain was continued for 24 hours after surgery in groups P and H. Venous blood samples were taken in groups P and H before sedation (for baseline values) immediately prior to laparoscopy (T0), at 30-minute intervals throughout surgery and when detomidine infusion was stopped (TEND). Additional samples were taken 3 and 24 hours after the end of the procedure. Heparinized samples were analysed immediately for glucose and lactate using an acid^base laboratory (ABL 700, Radiometer, Copenhagen, Denmark). Samples for cortisol and insulin analysis were collected in EDTA tubes while those for nonesteri¢ed fatty acid (NEFA) assay were stored in sodium £uoride/EDTA tubes. Samples were centrifuged immediately and the plasma stored at 20 8C until the analyses were performed. Insulin (Marschner et al.1974) and cortisol (Ruder et al.1972) were measured by a solid phase radio-immunoassay, using a Coat-A-Count kit from Diagnostic Products Corporation (DPC), Breda, the Netherlands. NEFA was measured by colorimetry (Shimizu et al.1980), using a Randox kit from Randox Laboratories Ltd, Ardmore, UK. Percutaneous arterial blood samples were taken anaerobically from the facial artery at T0 and T30 and TEND for measurement of pH and arterial blood gas tensions. At each sampling time, heart rates were determined by auscultation while respiratory rates were based on thoracic wall movement. Blood sampling times for group C were as for groups Pand H and T0 was taken as 20 minutes after the start of detomidine infusion. No arterial blood samples were taken in this group. Statistics Glucose, lactate, cortisol, insulin, nonesteri¢ed fatty acids, physiological data and procedure characteris# Association of Veterinary Anaesthetists, 2003, 30, 71^79
Detomidine^buprenorphine combination in standing horses P van Dijk et al.
tics are reported as mean SEM. Statistical analysis was performed using analysis of variance (ANOVA). A Dunnet’s t-test was conducted to determine di¡erences between groups; p < 0.05 was considered signi¢cant.
Results There was considerable variation in the temperament of the animals prior to sedation. However, responses to sedation and detomidine infusion were uniformly satisfactory. In all cases, the surgical site was prepared without reaction and surgical conditions were highly satisfactory. Two ponies and one horse (group H) sweated profusely during detomidine infusion. Urination occurred during infusion in one pony and two horses in group C (the volume voided was not measured).Atipamezole antagonized the sedative e¡ects of detomidine within 10 minutes of injection. Observation of the animals over the 24 post-operative hours did not reveal signs of post-operative pain and so further analgesia was witheld. Group P Laparoscopic instrument insertion commenced within15^30 minutes (mean:19 1.9 minutes) after beginning of infusion. Duration of detomidine infusion was 80^110 minutes (mean: 96 6.8 minutes). The infusion rate ranged from 0.08 to 0.16 mg kg1 minute1 (mean: 0.11 0.02 mg kg1 minute1). Heart rate decreased after detomidine^buprenorphine injection but remained stable during laparo-
Table 1 Heart rate (HR) and respiratory rate (RR) in eight horses and ¢ve ponies undergoing laparoscopy (group H and P) and in ¢ve horses without laparoscopy (group C) during detomidine infusion after pre-medication with detomidine^buprenorphine and after atipamezole injection at the end of infusion
scopy. In one pony, an atrio-ventricular block was detected at T0 and T30. After atipamezole injection, heart rate increased initially but returned to baseline within 10 minutes. Respiratory rate decreased after detomidine^buprenorphine injection and remained stable during laparoscopy. After atipamezole injection, respiratory rate did not change. Heart and respiratory rates are shown in Table 1. Changes in arterial pH, arterial oxygen and carbon dioxide tensions were not statistically signi¢cant from baseline values and were within physiological ranges (Table 2). Plasma insulin concentration decreased signi¢cantly after detomidine-buprenorphine injection. During the procedure insulin concentration increased, becoming signi¢cantly higher at T3 and T24 compared with baseline (Fig. 1). Plasma cortisol concentration decreased signi¢cantly after detomidinebuprenorphine injection but increased during laparoscopy. At T3 and T24, cortisol concentration was decreased (Fig. 2). Plasma NEFA concentration decreased after detomidine-buprenorphine injection but increased during laparoscopy, peaking at T30, then decreasing at all subsequent measurement times (Fig. 3). Plasma glucose concentration increased signi¢cantly after detomidine-buprenorphine injection and decreased from the end of the procedure onwards. Although changes were statistically signi¢cant, values remained within normal limits (Fig. 4). Plasma lactate concentration increased after detomidine-buprenorphine injection and decreased from TEND onwards. Values at all time points were signi¢cantly higher compared to values in group H and the control group (Fig. 5).
HR (beats minute1)
Control T0 T30 TEND A 5 min A 10 min
RR (breaths minute1)
Group H
Group P
Group C
Group H
Group P
Group C
36 1 30 2 32 2 32 2 42 3 37 2
36 1 32 1 33 1 33 1 41 2 37 1
35 1 29 1 28 2 29 2 36 3 34 3
11 1 8 1 8 1 8 1 9 1 91
10 1 91 91 91 91 91
13 2 10 1 10 2 10 1 10 2 10 1
All values are mean SEM. Control, time point before pre-medication; T0, time point immediately prior to laparoscopy; T30 ¼ T0 þ 30 minutes; TEND, time point at the end of infusion. Time points A, 5 and 10 minutes after atipamezole injection. Denotes statistical significance from values at timepoint control.
# Association of Veterinary Anaesthetists, 2003, 30, 71^79
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Detomidine^buprenorphine combination in standing horses P van Dijk et al.
Table 2 pH, PaO2 and PaCO2 in eight horses and ¢ve ponies undergoing laparoscopy (group H and P) during detomidine infusion after pre-medication with detomidine^buprenorphine
pH
PaO2 in kPa (mm Hg)
PaCO2 in kPa (mm Hg)
GroupH
Group P
Group H
Group P
Group H
Group P
T0
7.418 0.01
7.413 0.01
T30
7.403 0.01
7.408 0.01
TEND
7.394 0.01
7.410 0.01
15.7 1 (118 8) 17.2 1.3 (129 10) 15.5 0.7 (133 5)
18.3 1 (137 8) 15.6 0.9 (117 7) 17.7 1.4 (133 11)
4.9 0.3 (37 1) 5.2 0.1 (39 1) 5.5 0.1 (41 1)
4.7 0.3 (35 2) 5.1 0.3 (38 2) 5.2 0.1 (39 1)
All values are mean SEM. T0, immediately prior to laparoscopy (base line value); T30 ¼ T0 þ 30 minutes; TEND, time point at the end of infusion. No values are significantly different from the values at T0.
Group H Laparoscopy was performed within 20^30 minutes (mean: 23 1.3 minutes) after the start of infusion. Detomidine was infused for 70^100 minutes (mean: 84 5.5 minutes). Overall infusion rate was 0.07^0.14 mg kg1 minute1 (mean: 0.1 0.01 mg kg1 minute1). Heart rate decreased after detomidine^buprenorphine injection but remained stable during the laparoscopy. Heart rate increased after atipamezole injection but returned to baseline
within 10 minutes. The decrease in respiratory rate occurring after detomidine^buprenorphine injection was more marked than that observed in group P. Respiratory rate remained stable during laparoscopy. After atipamezole injection respiratory rate increased slightly. Changes in arterial pH, arterial oxygen and carbon dioxide tensions were not statistically signi¢cant and were within the accepted physiological range (Table 2). Plasma NEFA decreased after detomidine^buprenorphine injection and increased during laparo-
Figure 1 Mean (SEM) insulin concentrations in eight horses and ¢ve ponies during a detomidine^buprenorphine sedative/ analgesic protocol undergoing laparoscopy and in ¢ve horses during the same protocol without laparoscopy (control). Time points: C, before pre-medication; T0, prior to laparoscopy (control group 20 minutes after pre-medication); TEND, end of infusion laparoscopy1; T3 and T24 hours, 3 and 24 hours, respectively, after TEND. () Value di¡ers signi¢cantly from value at time point C. 74
# Association of Veterinary Anaesthetists, 2003, 30, 71^79
Detomidine^buprenorphine combination in standing horses P van Dijk et al.
Figure 2 Mean (SEM) cortisol concentrations in eight horses and ¢ve ponies during a detomidine^buprenorphine sedative/ analgesic protocol undergoing laparoscopy and in ¢ve horses during the same protocol without laparoscopy (control). Time points: C, before pre-medication; T0, prior to laparoscopy (control group 20 minutes after pre-medication); T30, T0 þ 30 minutes; TEND, end of infusion laparoscopy1; T3 and T24, 3 and 24 hours, respectively, after TEND. () Value di¡ers signi¢cantly from value at time point C (p < 0.05).
scopy with a peak value at TEND (Fig. 3). Thereafter, concentrations decreased, reaching a minimum at T24. Compared to baseline values, changes were signi¢cant at T30,TEND andT24. Plasma insulin concentration decreased signi¢cantly after detomidine^ buprenorphine injection. During laparoscopy, insulin concentration increased and reached signi¢-
cantly higher values at T3 and T24 compared with baseline (Fig. 1). Cortisol concentration increased after detomidine^buprenorphine injection, remained elevated during laparoscopy and decreased, once surgery was completed. The change was statistically signi¢cant at T3 (Fig. 2). Plasma lactate concentration increased after detomidine^buprenorphine
Figure 3 Mean (SEM) NEFA concentrations in eight horses and ¢ve ponies during a detomidine^buprenorphine sedative/ analgesic protocol undergoing laparoscopy and in ¢ve horses during the same protocol without laparoscopy (control). Time points: C, before pre-medication; T0, prior to laparoscopy (control group 20 minutes after pre-medication); T30, T0 þ 30 minutes; TEND, end of infusion laparoscopy1; T3 and T24, 3 and 24 hours, respectively, after TEND. () Value di¡ers signi¢cantly from value at time point C. (#) Value di¡ers signi¢cantly from control group (p < 0.05). # Association of Veterinary Anaesthetists, 2003, 30, 71^79
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Detomidine^buprenorphine combination in standing horses P van Dijk et al.
Figure 4 Mean (SEM) glucose concentrations in eight horses and ¢ve ponies during a detomidine^buprenorphine sedative/ analgesic protocol undergoing laparoscopy and in ¢ve horses during the same protocol without laparoscopy (control). Time points: C, before pre-medication; T0, prior to laparoscopy (control group 20 minutes after pre-medication); T30, T0 þ 30 minutes; TEND, end of infusion laparoscopy1; T3 and T24, 3 and 24 hours, respectively, after TEND. () Value di¡ers signi¢cantly from value at time point C. (#) Value di¡ers signi¢cantly from control group (p < 0.05).
injection and was still elevated at T24 (Fig. 5). Although changes were signi¢cant, values remained within normal physiological limits. Glucose concentration increased signi¢cantly after detomidine^ buprenorphine injection but decreased when surgery ended (Fig. 4).
Group C Heart rate decreased after detomidine^buprenorphine injection but remained stable during infusion. Heart rate increased after atipamezole injection but had returned to baseline within 10 minutes The
Figure 5 Mean (SEM) lactate concentrations in eight horses and ¢ve ponies during a detomidine^buprenorphine sedative/ analgesic protocol undergoing laparoscopy and in ¢ve horses during the same protocol without laparoscopy (control). Time points: C, before pre-medication; T0, prior to laparoscopy (control group 20 minutes after pre-medication); T30, T0 þ 30 minutes; TEND, end of infusion laparoscopy; T3 and T24, 3 and 24 hours, respectively, after TEND. () Value di¡ers signi¢cantly from value at time point C. (#) Value di¡ers signi¢cantly from control group (p < 0.05). 76
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Detomidine^buprenorphine combination in standing horses P van Dijk et al.
decrease of respiratory rate which occurred after detomidine^buprenorphine injection was greater than that encountered in group P. Respiratory rate remained stable during infusion and after atipamezole injection. No statistically signi¢cant di¡erences were found between the three groups in terms of heart and respiratory rates. Insulin concentration decreased signi¢cantly after detomidine-buprenorphine injection, remained depressed throughout the infusion and was elevated at T3 after the infusion. At T24, values were close to baseline (Fig. 1). Cortisol concentration decreased after detomidine-buprenorphine injection and increased after the termination of infusion. At T24, the concentration decreased to a level below that at T0 (Fig. 2). Plasma NEFA concentration decreased after detomidine-buprenorphine injection, increased between TEND and T3 and then decreased until the ¢nal measurement at T24 (Fig. 3). Plasma glucose concentration increased signi¢cantly after detomidine-buprenorphine injection and decreased from the end of the procedure (Fig. 4). Plasma lactate concentration increased after detomidine-buprenorphine injection and remained elevated with a peak value at T24 (Fig. 5).
Discussion The e¡ect of detomidine on heart rate is well documented (Szoke et al. 1998). Buprenorphine has minimal e¡ects on the cardiovascular system and appears not to cause sedation in its own right (Hall & Clarke 1991). The e¡ect of detomidine on heart rate in this study is typical of a2 adrenergic agonists (Vainio 1985). That atrio-ventricular blockade was detected in only one pony is possibly due to the low initial dose and overall low infusion rate. It is possible that atrio-ventricular blockade occurred in animals between observations as continuous electrocardiography was not performed. Detomidine-induced bradycardia was antagonized by atipamezole, and while heart rate increased, it did not become excessive in any case. The typical depressant e¡ect of detomidine on respiration rate (Short et al. 1985; Vainio 1985) was seen in this study and although buprenorphine may have contributed, we believe this is unikely. Buprenorphine does not cause respiratory depression at clinical doses (Hall & Clarke 1991; Szoke et al. 1998) and the dose employed in the current study did not a¡ect respiratory rate in the pilot, when it was used alone (van Dijk, unpublished data). Synergistic interraction between buprenorphine and # Association of Veterinary Anaesthetists, 2003, 30, 71^79
detomidine may have a¡ected the heart and respiratory rate, but while this was not the subject of this study, we believe that any such e¡ect is unlikely at the doses used. Judging by the arterial oxygen and carbon dioxide tensions, ventilation was adequate in the animals in this study. It is di⁄cult to explain the very high PaO2 values found in some animals of this study. All procedures were performed according to standard practice and the laboratory equipment was calibrated. Consequently, the results are judged to be correct. It is possible that over-pressure caused by the air-condition system (with pressures up to 780 mm Hg recorded) are responsible. Detomidine-induced sedation and ataxia were adequately antagonized by atipamezole so that all horses and ponies could be walked to their stables without di⁄culty. The sedative e¡ect of detomidine is reported to be only transiently reversed by atipamezole (Kamerling et al. 1991). However, in the current study, no relapse into sedation occurred, at least within1 hour of antagonism. The decrease in NEFA following detomidine^ buprenorphine injection in all groups con¢rms the ¢ndings of Carroll et al. (1997) and may be attributed to the sedative e¡ect of detomidine. The signi¢cant increase in NEFA concentration during laparoscopy in both groups, in contrast to the transient fall seen in the control group, may be a sympathetic nervous system response to surgery. In the control group, NEFA increased after administration of atipamezole. This also occurs when tolazoline is used to antagonize detomidine (Carroll et al. 1997). In the animals undergoing laparoscopy, NEFA concentration decreased markedly from the end of procedure until the ¢nal measurement at 24 hours. Antagonism of detomidine e¡ects at the end of surgery did not produce an increase in NEFA concentration, perhaps indicating that the stress response to recovery is minor compared to that of established surgical discomfort. Increase in NEFA concentration can also be induced by hypoxaemia. In this study, arterial oxygen tensions were within the physiological range. This suggests that changes in NEFA concentrations in the animals of this study were produced only by surgically induced stress. Detomidine exerts no e¡ect (Raekallio et al. 1991; Carroll et al. 1997) or slight decrease (Raekallio et al. 1992) on plasma cortisol concentration. Both the sedative e¡ect of detomidine as well as its direct suppression of sympatho-adrenal activity may be important. In the present study, detomidine caused a 77
Detomidine^buprenorphine combination in standing horses P van Dijk et al.
decrease in cortisol concentration in two groups (ponies and the control group) but a statistically insigni¢cant increase in the horse group. There is no obvious explanation for this as the clinical e¡ect of the detomidine^buprenorphine injection in all three groups was similar. The increase of cortisol in both the laparoscopic groups compared to the transient decrease in the control group probably demonstrates the normal hormonal response to surgical stress. This ¢nding suggests that detomidine does not prevent surgical sympathetic stimulation. The increase in cortisol concentration in the control group after antagonism of detomidine con¢rms the ¢ndings of Carroll et al. (1997) and is associated with a decrease in the level of sedation and a return of normal sympatho-adrenal activity. After termination of the laparoscopic procedure the sympathetic stimulation waned and plasma cortisol levels decreased. In this situation the antagonism of detomidine has no detectable in£uence on cortisol release. Plasma insulin concentrations found in this study are the end result of two opposing e¡ects. Detomidine, in common with other a2 agonists, decreases plasma insulin concentration (Thurmon et al. 1982; Brown et al. 1985). Hsu & Hummel (1981) suggest that this e¡ect is based on a2-receptor activation in the beta cells of the Islets of Langerhans which leads to hypoinsulinism and hyperglycaemia. This is countered by the stress response to surgery. Laparoscopy causes less tissue damage than conventional surgical techniques, but there is still some tissue trauma and pain, which in turn produces a surgical stress response. Stress response is characterized by production and secretion of catabolic hormones such as cortisol which have an anti-insulin e¡ect. The rise in insulin concentration after antagonization of detomidine in all three groups demonstrates the removal of the suppressing e¡ect of detomidine. Signi¢cant di¡erences in insulin release between surgical groups and control group were not found. This suggests that the inhibition of insulin release by detomidine is more pronounced than the stressinduced anti-insulin e¡ect. Hypoinsulinism causes hyperglycaemia, with a decrease of blood glucose concentration after antagonism of detomidine. The only signi¢cant di¡erence between the control group and the patient groups at 24 hours after the end of the surgery seems to be caused more by the small numerical size of the control group than by any real di¡erence. 78
In this study, we found no di¡erences between horses and ponies regarding clinical parameters and behaviour during the sedative protocol. The only statistically signi¢cant di¡erence between horses and ponies in physiological, biochemical or endocrine parameters was found in the blood lactate concentrations. As baseline values of lactate concentrations in the ponies were signi¢cantly higher than in the two horse groups, this di¡erence was judged to be neither clinically signi¢cant nor to a¡ect the validity of the study. Laparoscopy induced metabolic and endocrine responses. Compared to the control group, these responses were very clear, but with the exception of the NEFA, statistically not signi¢cant. This failure to reach statistical signi¢cance can be partly explained by the variability of the values between individual horses and ponies. Even using larger groups may not improve the outcome of statistical analysis because of the large variability of these factors in normal horses and ponies. The clinically useful sedative e¡ects of detomidine and buprenorphine were obvious in all animals. They also had e¡ects which reduced the physiological response to surgery. In conclusion, this study suggests that the protocol described produces su⁄ciently reliable sedation and analgesia for laparoscopic procedures. The level of sedation/analgesia was easy to control by decreasing or increasing the infusion rate. It is possible that deep sedation could lead to locomotor instability of horses, which could easily be interpreted as inadequate sedation. Inexperienced anaesthetists may tend to increase the infusion rate, which would lead to worsening instability. In fact, there should be harmonization between the level of sedation and the stage of the surgical procedure; this requires continuous monitoring of the patient and appropriate adjustment of the infusion rate. Although antagonism of the e¡ects of detomidine can be achieved using atipamezole at the described dose rate, this may not be necessary on all occasions and should be left to the judgement of the anaesthetist on a case-by-case basis.
Acknowledgements The authors gratefully thank Mr Peter Dobromylskyj for his comments and editorial assistance and Dr Marianne Sloet van Oldruitenborgh-Oosterbaan for her graphical assistance. # Association of Veterinary Anaesthetists, 2003, 30, 71^79
Detomidine^buprenorphine combination in standing horses P van Dijk et al.
References Brown MJ, Struthers AD, Di Silvio L et al. (1985) Metabolic and haemodynamic e¡ects of alpha 2-adrenoceptor stimulation and antagonism in man. Clin Sci 68, 137^139. Carroll GL, Matthews NS, Harts¢eld SM et al. (1997) The e¡ect of detomidine and its antagonism with tolazoline on stress-related hormones, metabolites, physiologic responses, and behavior in awake ponies. Vet Anesth Vet Surg 26,69^77. Clarke KW, Paton BS (1988) Combined use of detomidine with opiates in the horse. EqVet J 20,331^334. Daunt DA, Dunlop CI, Chapman PL et al. (1993) Cardiopulmonary and behavioural responses to computer-driven infusion of detomidine in standing horses. Am J Vet Res 54, 2075^2082. Hall LW, Clarke KW (1991) Vet Anaesth, 9th edn. Baillie're Tindall, London, UK, p.69. Hsu WH, Hummel SK (1981) Xylazine-induced hyperglycemia in cattle: a possible involvement of alpha 2-adrenergic receptors regulating insuline release. Endocrinology 109,825^829. Kamerling J, Wilson R, Hatch R et al. (1991) Antagonism of the e¡ects of detomidine by atipamezole. Acta Vet Scand 87,163^165. LeBlanc PH (1991) Chemical restraint for surgery in the standing horse. Vet Clin North Am Eq Pract 7, 521^533. Luna SP, Beale NJ,Taylor PM (1992) E¡ects of atipamezole on xylazine sedation in ponies.Vet Rec130, 268^271. Marschner I, Bottermann P, Erhardt F et al. (1974) Group experiments on the radioimmunological insulin determination. Horm Metab Res 6, 293^296. Raekallio M, Leino A, Vainio O (1992) Sympatho-adrenal activity and the clinical sedative e¡ect of detomidine in horses. EqVet J 11 (Suppl February),66^68. Raekallio M,Vainio O, Scheinin M (1991) Detomidine reduces the plasma catecholamine, but not cortisol concentrations in horses. J Vet Med Assoc 38,153^156.
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Ramseyer B, Schmucker N, Schatzmann U et al. (1998) Antagonism of detomidine sedation with atipamezole in horses. J Vet Anaesth 25, 47^51. Ruder HJ, Guy RL, Lipsett MB (1972) A radioimmunoassay for cortisol in plasma and urine. J Clin Endocrinol Metab 35, 219^224. Shimizu S,TaniY,Yamada H et al. (1980) Enzymatic determination of serum-free fatty acids: a colorimetric method. Anal Biochem107,193^198. Short CE, Matthews N,Tyner CL et al. (1985) Cardiovascular and pulmonary function studies of a new sedative/ analgesic (detomidine). Proceedings of the 30th Convention of Am. Assoc. Equine Pract., Dallas, Texas. Skarda RT, Muir WW III, (1998) In£uence of atipamezole on e¡ects of midsacral subarachnoidally administered detomidine in mares. Am J Vet Res 59, 468^477. Szoke MO, Blais D, Cuvelliez SG et al. (1998) E¡ects of buprenorphine on cardiovascular and pulmonary function in clinically normal horses and horses with chronic obstructive pulmonary disease. Am J Vet Res 59, 287^291. Taylor PM, Browning AP, Harris CP (1988) Detomidine^ butorphanol sedation in equine clinical practice.Vet Rec 123,388^390. Thurmon JC, Ne¡-Davis CA, Davis LE et al. (1982) Xylazine hydrochloride-induced hyperglycemia and hypoinsulinemia in thoroughbred horses. J Vet Pharmacol Ther 5, 241^245. Vainio O (1985) Detomidine, a New Sedative and Analgesic Drug for Veterinary Use. Pharmacological and Clinical Studies in Laboratory Animals, Horses and Cattle. PhD Thesis, Helsinki College of Veterinary Medicine, Helsinki. WagnerAE, Dunlop CI, Heath RB et al. (1992) Hemodynamic function during neurectomy in halothane anesthetized horses with or without constant dose detomidine infusion.Vet Surg 21, 248^255. Yamashita K,Yonezawa K, IzumisawaYet al. (1996) Antagonistic e¡ects of atipamezole on medetomidine-induced sedation in horses. J Vet Med Sci 58,1049^1052. Received19 February 2001; accepted 7 August 2001.
79
Hormonal, metabolic and physiological effects of laparoscopic surgery using a detomidine^buprenorphine combination in standing horses P van Dijk DVM, PhD, Diplomate ECVA, DPK Lankveld FH Jonkerz DVM, PhD
DVM,
ABM Rijkenhuizeny
DVM, PhD, Diplomate ECVS
&
Sections of Anaesthesiology and ySurgery, Department of Equine Sciences and zDepartment of Farm Animal Health, Veterinary Faculty, Utrecht University, Utrecht, The Netherlands
Correspondence: Dr P van Dijk, Section Anaesthesiology, Department of Equine Sciences,Veterinary Faculty, Utrecht University,Yalelaan 12, PO Box 80 153 3508 TD, Utrecht, The Netherlands.
Abstract Objective To assess the hormonal, metabolic and physiological e¡ects of laparascopic surgery performed under a sedative analgesic combination of detomidine and buprenorphine in standing horses. Study design Prospective study. Animals Eight healthy adult Dutch Warmblood horses and ¢ve healthy adult ponies undergoing laparoscopy were studied. Five healthy adult horses not undergoing laparoscopy were used as a control group. Methods The sedative e¡ect of an initial detomidine and buprenorphine injection was maintained using a continuous infusion of detomidine alone. The heart and respiratory rate, arterial blood pH and arterial oxygen and carbon dioxide tensions were monitored, while blood samples were taken for the measurement of glucose, lactate, cortisol, insulin and nonesteri¢ed fatty acids (NEFA). The same variables were monitored in a control group of horses which were sedated, but which did not undergo surgery. At the end of the sedation period the e¡ects of detomidine were antagonized using atipamezole. Results The protocol provided suitable conditions for standing laparoscopy in horses. Laparoscopy induced obvious metabolic and endocrine responses
which, with the exception of NEFA values, were not signi¢cantly di¡erent from changes found in the control group.While atipamezole did not produce detectable adverse e¡ects, it is possible that anatagonism may not be essential. Conclusions The technique described reliably produces adequate sedation and analgesia for laparoscopic procedures. The level of sedation/analgesia was controlled by decreasing or increasing the infusion rate. Antagonism of the e¡ects of detomidine may not be necessary in all cases. Keywords buprenorphine, detomidine, horse, laparoscopy, pony, stress response.
Introduction Use of detomidine^butorphanol combinations to produce sedation and analgesia for surgery in standing horses has been reported by several authors (LeBlanc 1991; Clarke & Paton 1988; Taylor et al. 1988). As butorphanol is not available in the Netherlands, it is a common practice to combine detomidine with buprenorphine to achieve a similar e¡ect. It is possible to maintain sedation and analgesia produced by this combination by infusing detomidine alone. In a pilot study, this method was found to be suitable for procedures lasting up to 3 hours. Dose rates used in the current study were based on the results of this pilot work and that of Daunt et al. (1993) and Wagner 71
Detomidine^buprenorphine combination in standing horses P van Dijk et al.
et al. (1992). As the degree of sedation needed for laparoscopic surgery causes some degree of incoordination in the immediate post-operative period, a second objective of this study was to observe the e¡ect of the a2 antagonist atipamezole on post-operative ataxia. Although there are several reports of the reversal of a2-agonist sedation using antagonists (Luna et al. 1992; Yamashita et al. 1996; Carroll et al. 1997; Ramseyer et al. 1998; Skarda et al. 1998), none have involved animals receiving buprenorphine. We were interested in the e¡ectiveness of buprenorphine for controlling post-operative pain as a2 antagonism is likely to diminish analgesia.
Materials and methods This study received approval from the Ethics andAnimal Research Committee of the Veterinary Faculty of Utrecht University. To avoid circadian in£uences on endocrine responses in individual animals, all experiments were scheduled between 10.00 and 14.00 hours. All animals had water but food was witheld for 36^48 hours before sedation. Three groups of horses were studied. Group P consisted of ¢ve healthy ponies between 2 and 12 years of age, weighing 255^360 kg (mean: 287 kg), undergoing laparoscopic steralisation. Group H consisted of eight healthy horses aged 2^9 years, weighing 308^ 484 kg (mean: 447 kg), undergoing laparoscopic steralisation (n ¼ 5) and diagnostic laparoscopy in three animals with chronic colic. Group C consisted of ¢ve healthy research horses aged 7^14 years, weighing 415^594 kg (mean: 519 kg), which underwent sedation without surgery. Sedation was initially produced in all groups using detomidine (Domosedan, P¢zer Animal Health B.V., Capelle a/d IJssel, the Netherlands) (10 mg kg1), combined with buprenorphine (Temgesic, Schering-Plough B.V., Amstelveen, the Netherlands) (6 mg kg1) injected intravenously. This was given approximately 45 minutes before the start of laparoscopy in groups P and H. When sedation had developed, an 8-cm 12 SWG catheter (Intra£on 2, Vycon, France) was placed percutaneously into the left jugular vein and an infusion of detomidine dissolved in Ringer’s solution (15 mg detomidine in 3 L Ringer’s solution) was begun. The initial infusion rate in the surgical cases was 0.16 mg kg1 minute1. This was adjusted at the discretion of the anaesthetist on the basis of clinical signs. Medical grade carbon dioxide was used to insu¥ate the abdominal cavity. A constant detomidine infusion was used in group C. The rate (0.1 mg kg1 minute1) 72
was based on the requirements of horses in the other two groups. The duration of sedation in groups Pand H was the time needed for the completion of surgery. Horses in group C were sedated for 80 minutes. At the end of sedation, atipamezole (Antisedan, P¢zer Animal Health B.V., Capelle a/d IJssel, the Netherlands) was administered IV using a dose equal to the total cummulative dose of detomidine, which each animal had received. The animals were observed closely for 10 minutes after atipamezole administration after which their ability to walk was assessed. Food and water were witheld for 1 hour after atipamezole injection. Monitoring for post-operative pain was continued for 24 hours after surgery in groups P and H. Venous blood samples were taken in groups P and H before sedation (for baseline values) immediately prior to laparoscopy (T0), at 30-minute intervals throughout surgery and when detomidine infusion was stopped (TEND). Additional samples were taken 3 and 24 hours after the end of the procedure. Heparinized samples were analysed immediately for glucose and lactate using an acid^base laboratory (ABL 700, Radiometer, Copenhagen, Denmark). Samples for cortisol and insulin analysis were collected in EDTA tubes while those for nonesteri¢ed fatty acid (NEFA) assay were stored in sodium £uoride/EDTA tubes. Samples were centrifuged immediately and the plasma stored at 20 8C until the analyses were performed. Insulin (Marschner et al.1974) and cortisol (Ruder et al.1972) were measured by a solid phase radio-immunoassay, using a Coat-A-Count kit from Diagnostic Products Corporation (DPC), Breda, the Netherlands. NEFA was measured by colorimetry (Shimizu et al.1980), using a Randox kit from Randox Laboratories Ltd, Ardmore, UK. Percutaneous arterial blood samples were taken anaerobically from the facial artery at T0 and T30 and TEND for measurement of pH and arterial blood gas tensions. At each sampling time, heart rates were determined by auscultation while respiratory rates were based on thoracic wall movement. Blood sampling times for group C were as for groups Pand H and T0 was taken as 20 minutes after the start of detomidine infusion. No arterial blood samples were taken in this group. Statistics Glucose, lactate, cortisol, insulin, nonesteri¢ed fatty acids, physiological data and procedure characteris# Association of Veterinary Anaesthetists, 2003, 30, 71^79
Detomidine^buprenorphine combination in standing horses P van Dijk et al.
tics are reported as mean SEM. Statistical analysis was performed using analysis of variance (ANOVA). A Dunnet’s t-test was conducted to determine di¡erences between groups; p < 0.05 was considered signi¢cant.
Results There was considerable variation in the temperament of the animals prior to sedation. However, responses to sedation and detomidine infusion were uniformly satisfactory. In all cases, the surgical site was prepared without reaction and surgical conditions were highly satisfactory. Two ponies and one horse (group H) sweated profusely during detomidine infusion. Urination occurred during infusion in one pony and two horses in group C (the volume voided was not measured).Atipamezole antagonized the sedative e¡ects of detomidine within 10 minutes of injection. Observation of the animals over the 24 post-operative hours did not reveal signs of post-operative pain and so further analgesia was witheld. Group P Laparoscopic instrument insertion commenced within15^30 minutes (mean:19 1.9 minutes) after beginning of infusion. Duration of detomidine infusion was 80^110 minutes (mean: 96 6.8 minutes). The infusion rate ranged from 0.08 to 0.16 mg kg1 minute1 (mean: 0.11 0.02 mg kg1 minute1). Heart rate decreased after detomidine^buprenorphine injection but remained stable during laparo-
Table 1 Heart rate (HR) and respiratory rate (RR) in eight horses and ¢ve ponies undergoing laparoscopy (group H and P) and in ¢ve horses without laparoscopy (group C) during detomidine infusion after pre-medication with detomidine^buprenorphine and after atipamezole injection at the end of infusion
scopy. In one pony, an atrio-ventricular block was detected at T0 and T30. After atipamezole injection, heart rate increased initially but returned to baseline within 10 minutes. Respiratory rate decreased after detomidine^buprenorphine injection and remained stable during laparoscopy. After atipamezole injection, respiratory rate did not change. Heart and respiratory rates are shown in Table 1. Changes in arterial pH, arterial oxygen and carbon dioxide tensions were not statistically signi¢cant from baseline values and were within physiological ranges (Table 2). Plasma insulin concentration decreased signi¢cantly after detomidine-buprenorphine injection. During the procedure insulin concentration increased, becoming signi¢cantly higher at T3 and T24 compared with baseline (Fig. 1). Plasma cortisol concentration decreased signi¢cantly after detomidinebuprenorphine injection but increased during laparoscopy. At T3 and T24, cortisol concentration was decreased (Fig. 2). Plasma NEFA concentration decreased after detomidine-buprenorphine injection but increased during laparoscopy, peaking at T30, then decreasing at all subsequent measurement times (Fig. 3). Plasma glucose concentration increased signi¢cantly after detomidine-buprenorphine injection and decreased from the end of the procedure onwards. Although changes were statistically signi¢cant, values remained within normal limits (Fig. 4). Plasma lactate concentration increased after detomidine-buprenorphine injection and decreased from TEND onwards. Values at all time points were signi¢cantly higher compared to values in group H and the control group (Fig. 5).
HR (beats minute1)
Control T0 T30 TEND A 5 min A 10 min
RR (breaths minute1)
Group H
Group P
Group C
Group H
Group P
Group C
36 1 30 2 32 2 32 2 42 3 37 2
36 1 32 1 33 1 33 1 41 2 37 1
35 1 29 1 28 2 29 2 36 3 34 3
11 1 8 1 8 1 8 1 9 1 91
10 1 91 91 91 91 91
13 2 10 1 10 2 10 1 10 2 10 1
All values are mean SEM. Control, time point before pre-medication; T0, time point immediately prior to laparoscopy; T30 ¼ T0 þ 30 minutes; TEND, time point at the end of infusion. Time points A, 5 and 10 minutes after atipamezole injection. Denotes statistical significance from values at timepoint control.
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Table 2 pH, PaO2 and PaCO2 in eight horses and ¢ve ponies undergoing laparoscopy (group H and P) during detomidine infusion after pre-medication with detomidine^buprenorphine
pH
PaO2 in kPa (mm Hg)
PaCO2 in kPa (mm Hg)
GroupH
Group P
Group H
Group P
Group H
Group P
T0
7.418 0.01
7.413 0.01
T30
7.403 0.01
7.408 0.01
TEND
7.394 0.01
7.410 0.01
15.7 1 (118 8) 17.2 1.3 (129 10) 15.5 0.7 (133 5)
18.3 1 (137 8) 15.6 0.9 (117 7) 17.7 1.4 (133 11)
4.9 0.3 (37 1) 5.2 0.1 (39 1) 5.5 0.1 (41 1)
4.7 0.3 (35 2) 5.1 0.3 (38 2) 5.2 0.1 (39 1)
All values are mean SEM. T0, immediately prior to laparoscopy (base line value); T30 ¼ T0 þ 30 minutes; TEND, time point at the end of infusion. No values are significantly different from the values at T0.
Group H Laparoscopy was performed within 20^30 minutes (mean: 23 1.3 minutes) after the start of infusion. Detomidine was infused for 70^100 minutes (mean: 84 5.5 minutes). Overall infusion rate was 0.07^0.14 mg kg1 minute1 (mean: 0.1 0.01 mg kg1 minute1). Heart rate decreased after detomidine^buprenorphine injection but remained stable during the laparoscopy. Heart rate increased after atipamezole injection but returned to baseline
within 10 minutes. The decrease in respiratory rate occurring after detomidine^buprenorphine injection was more marked than that observed in group P. Respiratory rate remained stable during laparoscopy. After atipamezole injection respiratory rate increased slightly. Changes in arterial pH, arterial oxygen and carbon dioxide tensions were not statistically signi¢cant and were within the accepted physiological range (Table 2). Plasma NEFA decreased after detomidine^buprenorphine injection and increased during laparo-
Figure 1 Mean (SEM) insulin concentrations in eight horses and ¢ve ponies during a detomidine^buprenorphine sedative/ analgesic protocol undergoing laparoscopy and in ¢ve horses during the same protocol without laparoscopy (control). Time points: C, before pre-medication; T0, prior to laparoscopy (control group 20 minutes after pre-medication); TEND, end of infusion laparoscopy1; T3 and T24 hours, 3 and 24 hours, respectively, after TEND. () Value di¡ers signi¢cantly from value at time point C. 74
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Detomidine^buprenorphine combination in standing horses P van Dijk et al.
Figure 2 Mean (SEM) cortisol concentrations in eight horses and ¢ve ponies during a detomidine^buprenorphine sedative/ analgesic protocol undergoing laparoscopy and in ¢ve horses during the same protocol without laparoscopy (control). Time points: C, before pre-medication; T0, prior to laparoscopy (control group 20 minutes after pre-medication); T30, T0 þ 30 minutes; TEND, end of infusion laparoscopy1; T3 and T24, 3 and 24 hours, respectively, after TEND. () Value di¡ers signi¢cantly from value at time point C (p < 0.05).
scopy with a peak value at TEND (Fig. 3). Thereafter, concentrations decreased, reaching a minimum at T24. Compared to baseline values, changes were signi¢cant at T30,TEND andT24. Plasma insulin concentration decreased signi¢cantly after detomidine^ buprenorphine injection. During laparoscopy, insulin concentration increased and reached signi¢-
cantly higher values at T3 and T24 compared with baseline (Fig. 1). Cortisol concentration increased after detomidine^buprenorphine injection, remained elevated during laparoscopy and decreased, once surgery was completed. The change was statistically signi¢cant at T3 (Fig. 2). Plasma lactate concentration increased after detomidine^buprenorphine
Figure 3 Mean (SEM) NEFA concentrations in eight horses and ¢ve ponies during a detomidine^buprenorphine sedative/ analgesic protocol undergoing laparoscopy and in ¢ve horses during the same protocol without laparoscopy (control). Time points: C, before pre-medication; T0, prior to laparoscopy (control group 20 minutes after pre-medication); T30, T0 þ 30 minutes; TEND, end of infusion laparoscopy1; T3 and T24, 3 and 24 hours, respectively, after TEND. () Value di¡ers signi¢cantly from value at time point C. (#) Value di¡ers signi¢cantly from control group (p < 0.05). # Association of Veterinary Anaesthetists, 2003, 30, 71^79
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Detomidine^buprenorphine combination in standing horses P van Dijk et al.
Figure 4 Mean (SEM) glucose concentrations in eight horses and ¢ve ponies during a detomidine^buprenorphine sedative/ analgesic protocol undergoing laparoscopy and in ¢ve horses during the same protocol without laparoscopy (control). Time points: C, before pre-medication; T0, prior to laparoscopy (control group 20 minutes after pre-medication); T30, T0 þ 30 minutes; TEND, end of infusion laparoscopy1; T3 and T24, 3 and 24 hours, respectively, after TEND. () Value di¡ers signi¢cantly from value at time point C. (#) Value di¡ers signi¢cantly from control group (p < 0.05).
injection and was still elevated at T24 (Fig. 5). Although changes were signi¢cant, values remained within normal physiological limits. Glucose concentration increased signi¢cantly after detomidine^ buprenorphine injection but decreased when surgery ended (Fig. 4).
Group C Heart rate decreased after detomidine^buprenorphine injection but remained stable during infusion. Heart rate increased after atipamezole injection but had returned to baseline within 10 minutes The
Figure 5 Mean (SEM) lactate concentrations in eight horses and ¢ve ponies during a detomidine^buprenorphine sedative/ analgesic protocol undergoing laparoscopy and in ¢ve horses during the same protocol without laparoscopy (control). Time points: C, before pre-medication; T0, prior to laparoscopy (control group 20 minutes after pre-medication); T30, T0 þ 30 minutes; TEND, end of infusion laparoscopy; T3 and T24, 3 and 24 hours, respectively, after TEND. () Value di¡ers signi¢cantly from value at time point C. (#) Value di¡ers signi¢cantly from control group (p < 0.05). 76
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Detomidine^buprenorphine combination in standing horses P van Dijk et al.
decrease of respiratory rate which occurred after detomidine^buprenorphine injection was greater than that encountered in group P. Respiratory rate remained stable during infusion and after atipamezole injection. No statistically signi¢cant di¡erences were found between the three groups in terms of heart and respiratory rates. Insulin concentration decreased signi¢cantly after detomidine-buprenorphine injection, remained depressed throughout the infusion and was elevated at T3 after the infusion. At T24, values were close to baseline (Fig. 1). Cortisol concentration decreased after detomidine-buprenorphine injection and increased after the termination of infusion. At T24, the concentration decreased to a level below that at T0 (Fig. 2). Plasma NEFA concentration decreased after detomidine-buprenorphine injection, increased between TEND and T3 and then decreased until the ¢nal measurement at T24 (Fig. 3). Plasma glucose concentration increased signi¢cantly after detomidine-buprenorphine injection and decreased from the end of the procedure (Fig. 4). Plasma lactate concentration increased after detomidine-buprenorphine injection and remained elevated with a peak value at T24 (Fig. 5).
Discussion The e¡ect of detomidine on heart rate is well documented (Szoke et al. 1998). Buprenorphine has minimal e¡ects on the cardiovascular system and appears not to cause sedation in its own right (Hall & Clarke 1991). The e¡ect of detomidine on heart rate in this study is typical of a2 adrenergic agonists (Vainio 1985). That atrio-ventricular blockade was detected in only one pony is possibly due to the low initial dose and overall low infusion rate. It is possible that atrio-ventricular blockade occurred in animals between observations as continuous electrocardiography was not performed. Detomidine-induced bradycardia was antagonized by atipamezole, and while heart rate increased, it did not become excessive in any case. The typical depressant e¡ect of detomidine on respiration rate (Short et al. 1985; Vainio 1985) was seen in this study and although buprenorphine may have contributed, we believe this is unikely. Buprenorphine does not cause respiratory depression at clinical doses (Hall & Clarke 1991; Szoke et al. 1998) and the dose employed in the current study did not a¡ect respiratory rate in the pilot, when it was used alone (van Dijk, unpublished data). Synergistic interraction between buprenorphine and # Association of Veterinary Anaesthetists, 2003, 30, 71^79
detomidine may have a¡ected the heart and respiratory rate, but while this was not the subject of this study, we believe that any such e¡ect is unlikely at the doses used. Judging by the arterial oxygen and carbon dioxide tensions, ventilation was adequate in the animals in this study. It is di⁄cult to explain the very high PaO2 values found in some animals of this study. All procedures were performed according to standard practice and the laboratory equipment was calibrated. Consequently, the results are judged to be correct. It is possible that over-pressure caused by the air-condition system (with pressures up to 780 mm Hg recorded) are responsible. Detomidine-induced sedation and ataxia were adequately antagonized by atipamezole so that all horses and ponies could be walked to their stables without di⁄culty. The sedative e¡ect of detomidine is reported to be only transiently reversed by atipamezole (Kamerling et al. 1991). However, in the current study, no relapse into sedation occurred, at least within1 hour of antagonism. The decrease in NEFA following detomidine^ buprenorphine injection in all groups con¢rms the ¢ndings of Carroll et al. (1997) and may be attributed to the sedative e¡ect of detomidine. The signi¢cant increase in NEFA concentration during laparoscopy in both groups, in contrast to the transient fall seen in the control group, may be a sympathetic nervous system response to surgery. In the control group, NEFA increased after administration of atipamezole. This also occurs when tolazoline is used to antagonize detomidine (Carroll et al. 1997). In the animals undergoing laparoscopy, NEFA concentration decreased markedly from the end of procedure until the ¢nal measurement at 24 hours. Antagonism of detomidine e¡ects at the end of surgery did not produce an increase in NEFA concentration, perhaps indicating that the stress response to recovery is minor compared to that of established surgical discomfort. Increase in NEFA concentration can also be induced by hypoxaemia. In this study, arterial oxygen tensions were within the physiological range. This suggests that changes in NEFA concentrations in the animals of this study were produced only by surgically induced stress. Detomidine exerts no e¡ect (Raekallio et al. 1991; Carroll et al. 1997) or slight decrease (Raekallio et al. 1992) on plasma cortisol concentration. Both the sedative e¡ect of detomidine as well as its direct suppression of sympatho-adrenal activity may be important. In the present study, detomidine caused a 77
Detomidine^buprenorphine combination in standing horses P van Dijk et al.
decrease in cortisol concentration in two groups (ponies and the control group) but a statistically insigni¢cant increase in the horse group. There is no obvious explanation for this as the clinical e¡ect of the detomidine^buprenorphine injection in all three groups was similar. The increase of cortisol in both the laparoscopic groups compared to the transient decrease in the control group probably demonstrates the normal hormonal response to surgical stress. This ¢nding suggests that detomidine does not prevent surgical sympathetic stimulation. The increase in cortisol concentration in the control group after antagonism of detomidine con¢rms the ¢ndings of Carroll et al. (1997) and is associated with a decrease in the level of sedation and a return of normal sympatho-adrenal activity. After termination of the laparoscopic procedure the sympathetic stimulation waned and plasma cortisol levels decreased. In this situation the antagonism of detomidine has no detectable in£uence on cortisol release. Plasma insulin concentrations found in this study are the end result of two opposing e¡ects. Detomidine, in common with other a2 agonists, decreases plasma insulin concentration (Thurmon et al. 1982; Brown et al. 1985). Hsu & Hummel (1981) suggest that this e¡ect is based on a2-receptor activation in the beta cells of the Islets of Langerhans which leads to hypoinsulinism and hyperglycaemia. This is countered by the stress response to surgery. Laparoscopy causes less tissue damage than conventional surgical techniques, but there is still some tissue trauma and pain, which in turn produces a surgical stress response. Stress response is characterized by production and secretion of catabolic hormones such as cortisol which have an anti-insulin e¡ect. The rise in insulin concentration after antagonization of detomidine in all three groups demonstrates the removal of the suppressing e¡ect of detomidine. Signi¢cant di¡erences in insulin release between surgical groups and control group were not found. This suggests that the inhibition of insulin release by detomidine is more pronounced than the stressinduced anti-insulin e¡ect. Hypoinsulinism causes hyperglycaemia, with a decrease of blood glucose concentration after antagonism of detomidine. The only signi¢cant di¡erence between the control group and the patient groups at 24 hours after the end of the surgery seems to be caused more by the small numerical size of the control group than by any real di¡erence. 78
In this study, we found no di¡erences between horses and ponies regarding clinical parameters and behaviour during the sedative protocol. The only statistically signi¢cant di¡erence between horses and ponies in physiological, biochemical or endocrine parameters was found in the blood lactate concentrations. As baseline values of lactate concentrations in the ponies were signi¢cantly higher than in the two horse groups, this di¡erence was judged to be neither clinically signi¢cant nor to a¡ect the validity of the study. Laparoscopy induced metabolic and endocrine responses. Compared to the control group, these responses were very clear, but with the exception of the NEFA, statistically not signi¢cant. This failure to reach statistical signi¢cance can be partly explained by the variability of the values between individual horses and ponies. Even using larger groups may not improve the outcome of statistical analysis because of the large variability of these factors in normal horses and ponies. The clinically useful sedative e¡ects of detomidine and buprenorphine were obvious in all animals. They also had e¡ects which reduced the physiological response to surgery. In conclusion, this study suggests that the protocol described produces su⁄ciently reliable sedation and analgesia for laparoscopic procedures. The level of sedation/analgesia was easy to control by decreasing or increasing the infusion rate. It is possible that deep sedation could lead to locomotor instability of horses, which could easily be interpreted as inadequate sedation. Inexperienced anaesthetists may tend to increase the infusion rate, which would lead to worsening instability. In fact, there should be harmonization between the level of sedation and the stage of the surgical procedure; this requires continuous monitoring of the patient and appropriate adjustment of the infusion rate. Although antagonism of the e¡ects of detomidine can be achieved using atipamezole at the described dose rate, this may not be necessary on all occasions and should be left to the judgement of the anaesthetist on a case-by-case basis.
Acknowledgements The authors gratefully thank Mr Peter Dobromylskyj for his comments and editorial assistance and Dr Marianne Sloet van Oldruitenborgh-Oosterbaan for her graphical assistance. # Association of Veterinary Anaesthetists, 2003, 30, 71^79
Detomidine^buprenorphine combination in standing horses P van Dijk et al.
References Brown MJ, Struthers AD, Di Silvio L et al. (1985) Metabolic and haemodynamic e¡ects of alpha 2-adrenoceptor stimulation and antagonism in man. Clin Sci 68, 137^139. Carroll GL, Matthews NS, Harts¢eld SM et al. (1997) The e¡ect of detomidine and its antagonism with tolazoline on stress-related hormones, metabolites, physiologic responses, and behavior in awake ponies. Vet Anesth Vet Surg 26,69^77. Clarke KW, Paton BS (1988) Combined use of detomidine with opiates in the horse. EqVet J 20,331^334. Daunt DA, Dunlop CI, Chapman PL et al. (1993) Cardiopulmonary and behavioural responses to computer-driven infusion of detomidine in standing horses. Am J Vet Res 54, 2075^2082. Hall LW, Clarke KW (1991) Vet Anaesth, 9th edn. Baillie're Tindall, London, UK, p.69. Hsu WH, Hummel SK (1981) Xylazine-induced hyperglycemia in cattle: a possible involvement of alpha 2-adrenergic receptors regulating insuline release. Endocrinology 109,825^829. Kamerling J, Wilson R, Hatch R et al. (1991) Antagonism of the e¡ects of detomidine by atipamezole. Acta Vet Scand 87,163^165. LeBlanc PH (1991) Chemical restraint for surgery in the standing horse. Vet Clin North Am Eq Pract 7, 521^533. Luna SP, Beale NJ,Taylor PM (1992) E¡ects of atipamezole on xylazine sedation in ponies.Vet Rec130, 268^271. Marschner I, Bottermann P, Erhardt F et al. (1974) Group experiments on the radioimmunological insulin determination. Horm Metab Res 6, 293^296. Raekallio M, Leino A, Vainio O (1992) Sympatho-adrenal activity and the clinical sedative e¡ect of detomidine in horses. EqVet J 11 (Suppl February),66^68. Raekallio M,Vainio O, Scheinin M (1991) Detomidine reduces the plasma catecholamine, but not cortisol concentrations in horses. J Vet Med Assoc 38,153^156.
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Ramseyer B, Schmucker N, Schatzmann U et al. (1998) Antagonism of detomidine sedation with atipamezole in horses. J Vet Anaesth 25, 47^51. Ruder HJ, Guy RL, Lipsett MB (1972) A radioimmunoassay for cortisol in plasma and urine. J Clin Endocrinol Metab 35, 219^224. Shimizu S,TaniY,Yamada H et al. (1980) Enzymatic determination of serum-free fatty acids: a colorimetric method. Anal Biochem107,193^198. Short CE, Matthews N,Tyner CL et al. (1985) Cardiovascular and pulmonary function studies of a new sedative/ analgesic (detomidine). Proceedings of the 30th Convention of Am. Assoc. Equine Pract., Dallas, Texas. Skarda RT, Muir WW III, (1998) In£uence of atipamezole on e¡ects of midsacral subarachnoidally administered detomidine in mares. Am J Vet Res 59, 468^477. Szoke MO, Blais D, Cuvelliez SG et al. (1998) E¡ects of buprenorphine on cardiovascular and pulmonary function in clinically normal horses and horses with chronic obstructive pulmonary disease. Am J Vet Res 59, 287^291. Taylor PM, Browning AP, Harris CP (1988) Detomidine^ butorphanol sedation in equine clinical practice.Vet Rec 123,388^390. Thurmon JC, Ne¡-Davis CA, Davis LE et al. (1982) Xylazine hydrochloride-induced hyperglycemia and hypoinsulinemia in thoroughbred horses. J Vet Pharmacol Ther 5, 241^245. Vainio O (1985) Detomidine, a New Sedative and Analgesic Drug for Veterinary Use. Pharmacological and Clinical Studies in Laboratory Animals, Horses and Cattle. PhD Thesis, Helsinki College of Veterinary Medicine, Helsinki. WagnerAE, Dunlop CI, Heath RB et al. (1992) Hemodynamic function during neurectomy in halothane anesthetized horses with or without constant dose detomidine infusion.Vet Surg 21, 248^255. Yamashita K,Yonezawa K, IzumisawaYet al. (1996) Antagonistic e¡ects of atipamezole on medetomidine-induced sedation in horses. J Vet Med Sci 58,1049^1052. Received19 February 2001; accepted 7 August 2001.
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