- Email: [email protected]
Detomidine reduces isoflurane anesthetic requirement (MAC) in horses
Veterinary Anaesthesia and Analgesia, 2002, 29, 223^227
B R I E F C O M M U N I C AT I O N
Detomidine reduces isoflurane anesthetic requirement (MAC) in horses Eugene P Ste¡ey VMD, PhD, Diplomate ACVA, Diplomate ECVA, Peter J Pascoe
BVSc, Diplomate ACVA, Diplomate ECVA
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616-8745, USA
Correspondence: Dr Eugene P Ste¡ey, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616-8745, USA. E-mail: epste¡[email protected]
Abstract Objective To quantitate the dose- and time-related magnitude of the anesthetic sparing e¡ect of, and selected physiological responses to detomidine during iso£urane anesthesia in horses. Study design Randomized cross-over study. Animals Three, healthy, young adult horses weighing 485 14 kg. Methods Horses were anesthetized on two occasions to determine the minimum alveolar concentration (MAC) of iso£urane in O2 and then to measure the anesthetic sparing e¡ect (time-related MAC reduction) following IV detomidine (0.03 and 0.06 mg kg1). Selected common measures of cardiopulmonary function, blood glucose and urinary output were also recorded. Results Iso£urane MAC was 1.44 0.07% (mean SEM). This was reduced by 42.8 5.4% and 44.8 3.0% at 83 23 and 125 36 minutes, respectively, following 0.03 and 0.06 mg kg1, detomidine. The MAC reduction was detomidine dose- and time-dependent. There was a tendency for mild cardiovascular and respiratory depression, especially following the higher detomidine dose. Detomidine increased both blood glucose and urine £ow; the magnitude of these changes was time- and dosedependent Conclusions Detomidine reduces anesthetic requirement for iso£urane and increases blood glucose
concentration and urine £ow in horses. These changes were dose- and time-related. Clinical relevance The results imply potent anesthetic sparing actions by detomidine. The detomidine-related increased urine £ow should be considered in designing anesthetic protocols for individual horses. Keywords alpha-2 agonist, detomidine, horse, iso£urane, MAC.
Introduction Alpha-2 adrenergic agonists cause sedation and analgesia and have been reported to markedly reduce inhalation anesthetic requirement in a variety of species including dogs (Tranquilli et al. 1984) and humans (Aantaa et al. 1997). These are commonly administered to horses to provide standing, chemical restraint and as adjuvants for both general and regional anesthesia. Xylazine and detomidine are currently the most commonly used a-2 agonists in clinical management of horses in the USA. Although these drugs are widely administered in clinical practice, there have been few reports that characterize the anesthesia-modifying e¡ects of these drugs in horses (Ste¡ey et al. 2000). Recently, dose- and time-related iso£urane anesthesia-sparing e¡ects of xylazine in horses were reported from this laboratory (Ste¡ey et al. 2000). The present study was pursued to provide similar data for detomidine action in horses. However, owing to limited resources, a study of two doses of detomidine was carried out using only three of the same 223
Detomidine decreases iso£urane MAC EP Ste¡ey & PJ Pascoe
previously studied horses. As in our reported xylazine study, the change in the minimum alveolar concentration (MAC) of iso£urane was used as a measure of detomidine analgesic potency and change in anesthetic requirement (Ste¡ey et al.1977).
Materials and methods The study protocol was previously approved by the campus Animal Use and Care Administrative Advisory Committee. Three months after study with xylazine, three healthy, unmedicated, university owned, castrated male, Thoroughbred horses (6.0 0.6 [SEM] years; 485 14 kg) were selected, at random, from the original group of six horses (Ste¡ey et al. 2000). The three horses were anesthetized on two separate occasions to characterize the anesthetic sparing e¡ect of two di¡erent doses of detomidine (detomidine 0.03 and 0.06 mg kg1, IV). Two of the horses initially received the lower dose ¢rst and the other horse ¢rst received the higher dose. Feed was withheld for 8^12 hours before induction of anesthesia but water was always available. Study conditions Anesthesia was induced in unmedicated horses using iso£urane in O2 as described elsewhere (Ste¡ey et al.2000). Following orotracheal intubation, the left laterally recumbent horses were prepared for study during the remainder of the ¢rst hour of anesthesia. Body temperature was measured via a calibrated thermistor probe positioned in the nasopharynx (Yellow Springs Instrument Co., Yellow Springs, OH, USA). A base^apex lead ECG was used to monitor heart rate and rhythm. Carotid artery pressure was measured by a percutaneously positioned catheter connected to a calibrated strain gauge positioned level with the sternum. Mean pulmonary artery pressure was similarly measured with a catheter positioned via the right external jugular vein. Lactated Ringer’s solution was infused into the left saphenous vein at a rate of 2^4 mL kg1 hour1. The urinary bladder was catheterized to permit continuous urine drainage. The horses breathed spontaneously and respiratory rate was counted. End-expired gas samples were obtained by intermittent hand sampling from a catheter positioned near the tracheal end of the tracheal tube. Iso£urane was measured by a calibrated infra-red gas analyzer (Sensor Medics Corp., Anaheim, CA, USA). The concentrations of O2 and CO2 224
were also intermittently monitored with calibrated polarographic and infra-red analyzers (Sensor Medics Corp., Anaheim, CA, USA). Determination of the MAC Determination of predetomidine (control) MAC began about 1 hour after anesthetic induction using techniques previously reported from this laboratory (Ste¡ey et al.1977). The MAC was determined in each animal in triplicate and the average recorded. Following control measurements detomidine was injected IV over 1-minute and MAC re-determined many times during the next 3^5 hours by a modi¢ed technique reported elsewhere (Ste¡ey et al. 2000). The ¢rst determination of MAC after detomidine injection did not occur until about 40 minutes post-injection and determinations continued until MAC returned to within at least 10% of the control MAC value or to about 200 minutes following detomidine injection (whichever occurred ¢rst). Cardiopulmonary measurements Carotid and pulmonary arterial blood pressures and heart rate were determined from records 30^60 seconds before noxious stimulation. Heart rates, blood pressures and respiratory rates were averaged across each determined MAC value. Blood measurements Arterial blood was collected before anesthetic induction and periodically before detomidine injection (at about iso£urane MAC) and at each of the following times after detomidine injection to measure PaO2, PaCO2, and pHa: 1, 2, 4, 6, 8, 10, 12, 18, 30, 45, 60, 90, 120, 150, 180, 210 and 240 minutes.Values were corrected for body temperature. Jugular venous blood was collected from horses before and at 1 hour after and 1 day following anesthetic recovery and at the following times during anesthesia: predetomidine and 12, 30, 60, 120 and 240 minutes after detomidine administration. Serum was harvested and frozen until analyzed for glucose byourVeterinary MedicalTeaching Hospital’s Clinical Pathology Laboratory (usually the next day). Urine measurements The urinary bladder was catheterized during the ¢rst hour of anesthesia and urine collected before and in 2-hour blocks of time after detomidine injection. Veterinary Anaesthesia and Analgesia, 2002, 29, 223^227
Detomidine decreases iso£urane MAC EP Ste¡ey & PJ Pascoe
Total anesthesia time was 8.14 0.14 hours and all horses recovered from anesthesia normally. Total intravenous £uid supplementation during anesthesia was 2.59 0.15 mL kg1 hour1.
pHa was 7.41 0.01 (data from the two dose periods are pooled so n ¼ 6). Before detomidine administration PaO2 and PaCO2 were increased from awake values; PaO2 was 332 54 mm Hg (44.3 7.2 kPa) and PaCO2 was 60.5 2.8 mm Hg (8.1 0.4 kPa). Following low-dose detomidine, there was little change in either PaO2 or PaCO2 compared to both pre-detomidine conditions and over the course of time. Both PaO2 and PaCO2 tended to be lower following high dose detomidine. The pHa decreased following both doses of detomidine in relation to changes in PaCO2. The base balance did not change.
MAC
Blood glucose
The mean of all six determinations of iso£urane MAC in the three horses was 1.44 0.07%. The control MAC for iso£urane according to detomidine dose grouping in the three horses is given in Table 1 with the maximal changes in iso£urane MAC following detomidine. MAC data from individual horses are grouped according to a similar time and the rate of change in return of MAC toward control following detomidine is summarized in Fig. 1.
There was a tendency for blood glucose to increase following induction of general anesthesia. Administration of detomidine caused a substantial increase in blood glucose with peak values of 299 8.7 mg dL1 (16.6 0.5 mmol dL1) and 305.0 30.9 mg dL1 (16.9 1.7 mmol dL1) at 0.03 and 0.06 mg kg1, respectively. The values at 6 hours were 169.3 28.4 mg dL1 (9.4 1.6 mmol dL1) and 165.7 12.1 mg dL1 (9.2 0.7 mmol dL1) at 0.03 and 0.06 mg kg1, respectively. The blood glucose increase tended to be greater and of longer duration following detomidine compared to xylazine (Ste¡ey et al. 2000).
Statistical methods Values are expressed as the mean SEM unless indicated otherwise. Because of the small number of animals (i.e. n ¼ 3), inferential statistics were not determined. Results
Cardiopulmonary responses The heart rate, carotid and pulmonary arterial blood pressures and respiratory frequency were summarized for the same time points during anesthesia (one pre-drug and two post-drug administration) for both doses of detomidine (seeTable 2). Blood gas analyses The values for PaO2 and PaCO2 in the horses while awake and unmedicated were 103.4 2.3 mm Hg (13.8 kPa) and 44.1 0.9 mm Hg (5.9 0.1 kPa). The
Urine Urine £ow increased following both doses of detomidine (Table 3). During the 2 hours following 0.03 and 0.06 mg kg1 detomidine, urine £ow increased by an average of 156 and 350%, respectively. The increase in urine output lasted longer with the larger detomidine dose.
Table 1 Iso£urane minimum alveolar concentration (MAC) in horses before and after intravenous (IV) detomidine
Maximum change in MAC after IV drug
Detomidine dose (mg kg1)
Control MAC
8C
Time (minutes)
Change in MAC (%)
8C
0.03 0.06
1.43 0.14 1.45 0.08
37.5 0.2 37.0 0.3
83 23 125 36
42.8 5.4 44.8 3.0
37.5 0.2 37.2 0.4
All values are given as mean SE. Volumes percent end-expired isoflurane.
Veterinary Anaesthesia and Analgesia, 2002, 29, 223^227
225
Detomidine decreases iso£urane MAC EP Ste¡ey & PJ Pascoe
Fig. 1). Although di⁄cult to compare directly, these MAC reductions are in (qualitative) agreement with those determined for a single dose of detomidine by Muir et al. (1992) in halothane-anesthetized horses. The actions of detomidine were not studied under steady-state (i.e. constant intravenous drug infusion) conditions. As a result, we cannot precisely de¢ne the peak magnitude of its e¡ect on the iso£urane MAC. It is likely that the peak e¡ect is greater than the maximum change in MAC reported here (Table 1). The published work of others ( Jochle & Hamm 1986; England et al. 1992; Wood et al. 1998) with awake horses indicates that detomidine is more potent (on a milligram basis) in its sedative and analgesic properties compared to xylazine. The relative analgesic potency of these two alpha-2 agonists is con¢rmed by comparison of time^MAC reduction curves from previous and presently reported studies (Ste¡ey et al. 2000). The curves for 1.0 mg kg1 xylazine and 0.03 mg kg1 detomidine are overlapping, suggesting dose equivalence. Detomidine, 0.06 mg kg1 is likely to have a noticeable in£uence for more than 6 hours after IV injection in healthy anesthetized horses. Because anesthesia prolongs the elimination of many drugs, similar e¡ects in response to
Figure 1 Detomidine^iso£urane interaction in three horses. A summary of the reduction in iso£urane minimum alveolar concentration (MAC) by two intravenous doses of detomidine is shown. Note, in most cases the horizontal standard error (SE) bars are partially or totally hidden by the symbols.
Discussion Detomidine caused a marked dose- and time-related decrease in iso£urane MAC in each horse (Table 1 &
Table 2 Data from three iso£urane-anesthetized horses before and following intravenous detomidine
Minutes post-detomidine Heart rate (minute1) Mean arterial pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Respiratory rate (minute1)
Detomidine (0.03 mg kg1)
Detomidine (0.06 mg kg1)
Pre
Post
Pre
Post
36 3 97 2 22 2 51
134 7 34 1 79 9 19 1 61
35 2 95 1 22 3 51
198 6 31 1 81 8 17 4 71
167 7 33 1 79 6 22 3 61
278 9 30 1 81 6 17 3 71
Anesthetic doses at all time points are (or are nearly) equipotent (i.e. equivalent to minimum alveolar concentration [MAC] 1.0 isoflurane in O2; isoflurane adjusted to balance time-related decay in plasma detomidine). Mean SE: statistical analyses were not performed on these data owing to the small number of observations.
Hours post-detomidine Detomidine dose (mg kg1)
0.03 0.06
226
Pre-detomidine
0.74 0.25 0.42 0.05
0–2
2–4
1.91 0.13 1.89 0.08
0.74 0.07 2.39 0.40
Table 3 Urine £ow (mean SE; mL kg1 hour1) measured in horses before and after intravenous (IV) administration of detomidine during iso£urane anesthesia
Veterinary Anaesthesia and Analgesia, 2002, 29, 223^227
Detomidine decreases iso£urane MAC EP Ste¡ey & PJ Pascoe
detomidine are expected to be less prolonged in awake, unmedicated horses (Ste¡ey et al.1977). This study was not designed to characterize the cardiovascular actions of detomidine in iso£uraneanesthetized horses, however, circumstances permitted our gathering limited data immediately before administration of detomidine and at times of equipotent anesthesia following detomidine (Table 2 & Fig. 1). As with previous ¢ndings with xylazine under similar conditions, detomidine seemed to reduce heart rate and systemic blood pressure. Mean pulmonary artery pressure appear lower at the higher dose of detomidine. Similar to our ¢ndings with xylazine, detomidine had no prominent dose- or time-related e¡ect on PaCO2 but may have caused a small decrease in PaO2. The number of observations are too limited to draw broad conclusions. However, present results suggest that further investigation of detomidine in£uence on PaO2 is warranted in this species known for its variability in e⁄ciency of arterial blood oxygenation during general anesthesia. Alpha-2 agonists induce hyperglycemia in awake and anesthetized horses (Thurmon et al.1982; Ste¡ey et al. 2000). Present results are in qualitative agreement. Peak increase in serum glucose and duration of hyperglycemia appears greater with detomidine compared to xylazine, and these e¡ects are also detomidine dose-related (Ste¡ey et al. 2000). Similar to e¡ects of xylazine (Ste¡ey et al. 2000), previous studies have demonstrated the diuretic e¡ect of detomidine in awake and halothaneanesthetized horses (Gasthuys et al.1986). Currently reported results (Table 3) suggest that the in£uence of detomidine is of greater magnitude and that the elevation in urine volume persists substantially beyond the duration noted with xylazine under similar conditions of iso£urane anesthesia (Ste¡ey et al. 2000).
Conclusions Detomidine substantially reduces the anesthetic requirement for iso£urane in the horse. The magnitude of decrease is dose and time dependent. Detomidine increases blood glucose concentration and urine £ow in iso£urane-anesthetized horses and the magnitude of changes are also dose and time dependent. The present data when compared to similarly derived results from prior xylazine studies support the opinion that detomidine is more potent in its
Veterinary Anaesthesia and Analgesia, 2002, 29, 223^227
analgesic, sedative, diuretic and hyperglycemia-promoting properties in anesthetized horses.
Acknowledgements The project was supported by the school’s Center for Equine Health with funds provided by the Oak Tree Racing Association, the State of California Satellite Wagering Fund, and contributions by private donors. The authors gratefully acknowledge the technical support of Richard Morgan, Bill Perkins and Michael Woliner.
References Aantaa R, Jaakola M-L, KallioA et al. (1997) Reduction of the minimum alveolar concentration of iso£urane by dexmedetomidine. Anesthesiology 86,1055^1060. England GCW, Clarke KW, Goossens L (1992) A comparison of the sedative e¡ects of three a2-adrenoceptor agonists (romi¢dine, detomidine and xylazine) in the horse. J Vet Pharmacol Therap15,194^201. Gasthuys F,Vandenhende C, de Moor A (1986) Study of some ionary parameters in horse serum and urine during halothane anaesthesiawith xylazine premedication. ZentralblVeterinarmed 33,791^800. Jochle W, Hamm D (1986) Sedation and analgesia with domosedan (detomidine hydrochloride) in horses ^ dose response studies on e⁄cacy and its duration. Acta Vet Scand (suppl 82),69^85. Muir WW III, Wagner AE, Hinchcli¡ KW (1992) Cardiorespiratory and MAC-reducing e¡ects of a2-adrenoreceptor agonists in horses. In: Animal Pain. Short CE,Van Poznak A (eds). Churchill Livingstone, NewYork, pp. 201^212. Ste¡ey EP, Howland DJ, Giri S et al. (1977) En£urane, halothane and iso£urane potency in horses. Am J Vet Res 38,1037^1039. Ste¡ey EP, Pascoe PJ,Woliner MJ et al. (2000) E¡ects of xylazine hydrochloride during iso£urane-induced anesthesia in horses. Am J Vet Res 61,1225^1231. Thurmon JC, Ne¡-Davis CA, Davis LE et al. (1982) Xylazine hydrochloride-induced hyperglycemia and hypoinsulinemia in thoroughbred horses. J Vet Pharmacol Therap 5, 241^245. Tranquilli WJ, Thurmon JC, Corbin JE et al. (1984) Halothane-sparing e¡ect of xylazine in dogs and subsequent reversal with tolazoline. J Vet Pharmacol Therap 7, 23^28. Wood T, Weckman T, Woods WE et al. (1998) Detomidine: a preliminary analysis of its duration of action in the horse by variable interval responding. Equine Vet J 20, 320^322. Received14 February 2002; accepted1 July 2002.
227
B R I E F C O M M U N I C AT I O N
Detomidine reduces isoflurane anesthetic requirement (MAC) in horses Eugene P Ste¡ey VMD, PhD, Diplomate ACVA, Diplomate ECVA, Peter J Pascoe
BVSc, Diplomate ACVA, Diplomate ECVA
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616-8745, USA
Correspondence: Dr Eugene P Ste¡ey, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616-8745, USA. E-mail: epste¡[email protected]
Abstract Objective To quantitate the dose- and time-related magnitude of the anesthetic sparing e¡ect of, and selected physiological responses to detomidine during iso£urane anesthesia in horses. Study design Randomized cross-over study. Animals Three, healthy, young adult horses weighing 485 14 kg. Methods Horses were anesthetized on two occasions to determine the minimum alveolar concentration (MAC) of iso£urane in O2 and then to measure the anesthetic sparing e¡ect (time-related MAC reduction) following IV detomidine (0.03 and 0.06 mg kg1). Selected common measures of cardiopulmonary function, blood glucose and urinary output were also recorded. Results Iso£urane MAC was 1.44 0.07% (mean SEM). This was reduced by 42.8 5.4% and 44.8 3.0% at 83 23 and 125 36 minutes, respectively, following 0.03 and 0.06 mg kg1, detomidine. The MAC reduction was detomidine dose- and time-dependent. There was a tendency for mild cardiovascular and respiratory depression, especially following the higher detomidine dose. Detomidine increased both blood glucose and urine £ow; the magnitude of these changes was time- and dosedependent Conclusions Detomidine reduces anesthetic requirement for iso£urane and increases blood glucose
concentration and urine £ow in horses. These changes were dose- and time-related. Clinical relevance The results imply potent anesthetic sparing actions by detomidine. The detomidine-related increased urine £ow should be considered in designing anesthetic protocols for individual horses. Keywords alpha-2 agonist, detomidine, horse, iso£urane, MAC.
Introduction Alpha-2 adrenergic agonists cause sedation and analgesia and have been reported to markedly reduce inhalation anesthetic requirement in a variety of species including dogs (Tranquilli et al. 1984) and humans (Aantaa et al. 1997). These are commonly administered to horses to provide standing, chemical restraint and as adjuvants for both general and regional anesthesia. Xylazine and detomidine are currently the most commonly used a-2 agonists in clinical management of horses in the USA. Although these drugs are widely administered in clinical practice, there have been few reports that characterize the anesthesia-modifying e¡ects of these drugs in horses (Ste¡ey et al. 2000). Recently, dose- and time-related iso£urane anesthesia-sparing e¡ects of xylazine in horses were reported from this laboratory (Ste¡ey et al. 2000). The present study was pursued to provide similar data for detomidine action in horses. However, owing to limited resources, a study of two doses of detomidine was carried out using only three of the same 223
Detomidine decreases iso£urane MAC EP Ste¡ey & PJ Pascoe
previously studied horses. As in our reported xylazine study, the change in the minimum alveolar concentration (MAC) of iso£urane was used as a measure of detomidine analgesic potency and change in anesthetic requirement (Ste¡ey et al.1977).
Materials and methods The study protocol was previously approved by the campus Animal Use and Care Administrative Advisory Committee. Three months after study with xylazine, three healthy, unmedicated, university owned, castrated male, Thoroughbred horses (6.0 0.6 [SEM] years; 485 14 kg) were selected, at random, from the original group of six horses (Ste¡ey et al. 2000). The three horses were anesthetized on two separate occasions to characterize the anesthetic sparing e¡ect of two di¡erent doses of detomidine (detomidine 0.03 and 0.06 mg kg1, IV). Two of the horses initially received the lower dose ¢rst and the other horse ¢rst received the higher dose. Feed was withheld for 8^12 hours before induction of anesthesia but water was always available. Study conditions Anesthesia was induced in unmedicated horses using iso£urane in O2 as described elsewhere (Ste¡ey et al.2000). Following orotracheal intubation, the left laterally recumbent horses were prepared for study during the remainder of the ¢rst hour of anesthesia. Body temperature was measured via a calibrated thermistor probe positioned in the nasopharynx (Yellow Springs Instrument Co., Yellow Springs, OH, USA). A base^apex lead ECG was used to monitor heart rate and rhythm. Carotid artery pressure was measured by a percutaneously positioned catheter connected to a calibrated strain gauge positioned level with the sternum. Mean pulmonary artery pressure was similarly measured with a catheter positioned via the right external jugular vein. Lactated Ringer’s solution was infused into the left saphenous vein at a rate of 2^4 mL kg1 hour1. The urinary bladder was catheterized to permit continuous urine drainage. The horses breathed spontaneously and respiratory rate was counted. End-expired gas samples were obtained by intermittent hand sampling from a catheter positioned near the tracheal end of the tracheal tube. Iso£urane was measured by a calibrated infra-red gas analyzer (Sensor Medics Corp., Anaheim, CA, USA). The concentrations of O2 and CO2 224
were also intermittently monitored with calibrated polarographic and infra-red analyzers (Sensor Medics Corp., Anaheim, CA, USA). Determination of the MAC Determination of predetomidine (control) MAC began about 1 hour after anesthetic induction using techniques previously reported from this laboratory (Ste¡ey et al.1977). The MAC was determined in each animal in triplicate and the average recorded. Following control measurements detomidine was injected IV over 1-minute and MAC re-determined many times during the next 3^5 hours by a modi¢ed technique reported elsewhere (Ste¡ey et al. 2000). The ¢rst determination of MAC after detomidine injection did not occur until about 40 minutes post-injection and determinations continued until MAC returned to within at least 10% of the control MAC value or to about 200 minutes following detomidine injection (whichever occurred ¢rst). Cardiopulmonary measurements Carotid and pulmonary arterial blood pressures and heart rate were determined from records 30^60 seconds before noxious stimulation. Heart rates, blood pressures and respiratory rates were averaged across each determined MAC value. Blood measurements Arterial blood was collected before anesthetic induction and periodically before detomidine injection (at about iso£urane MAC) and at each of the following times after detomidine injection to measure PaO2, PaCO2, and pHa: 1, 2, 4, 6, 8, 10, 12, 18, 30, 45, 60, 90, 120, 150, 180, 210 and 240 minutes.Values were corrected for body temperature. Jugular venous blood was collected from horses before and at 1 hour after and 1 day following anesthetic recovery and at the following times during anesthesia: predetomidine and 12, 30, 60, 120 and 240 minutes after detomidine administration. Serum was harvested and frozen until analyzed for glucose byourVeterinary MedicalTeaching Hospital’s Clinical Pathology Laboratory (usually the next day). Urine measurements The urinary bladder was catheterized during the ¢rst hour of anesthesia and urine collected before and in 2-hour blocks of time after detomidine injection. Veterinary Anaesthesia and Analgesia, 2002, 29, 223^227
Detomidine decreases iso£urane MAC EP Ste¡ey & PJ Pascoe
Total anesthesia time was 8.14 0.14 hours and all horses recovered from anesthesia normally. Total intravenous £uid supplementation during anesthesia was 2.59 0.15 mL kg1 hour1.
pHa was 7.41 0.01 (data from the two dose periods are pooled so n ¼ 6). Before detomidine administration PaO2 and PaCO2 were increased from awake values; PaO2 was 332 54 mm Hg (44.3 7.2 kPa) and PaCO2 was 60.5 2.8 mm Hg (8.1 0.4 kPa). Following low-dose detomidine, there was little change in either PaO2 or PaCO2 compared to both pre-detomidine conditions and over the course of time. Both PaO2 and PaCO2 tended to be lower following high dose detomidine. The pHa decreased following both doses of detomidine in relation to changes in PaCO2. The base balance did not change.
MAC
Blood glucose
The mean of all six determinations of iso£urane MAC in the three horses was 1.44 0.07%. The control MAC for iso£urane according to detomidine dose grouping in the three horses is given in Table 1 with the maximal changes in iso£urane MAC following detomidine. MAC data from individual horses are grouped according to a similar time and the rate of change in return of MAC toward control following detomidine is summarized in Fig. 1.
There was a tendency for blood glucose to increase following induction of general anesthesia. Administration of detomidine caused a substantial increase in blood glucose with peak values of 299 8.7 mg dL1 (16.6 0.5 mmol dL1) and 305.0 30.9 mg dL1 (16.9 1.7 mmol dL1) at 0.03 and 0.06 mg kg1, respectively. The values at 6 hours were 169.3 28.4 mg dL1 (9.4 1.6 mmol dL1) and 165.7 12.1 mg dL1 (9.2 0.7 mmol dL1) at 0.03 and 0.06 mg kg1, respectively. The blood glucose increase tended to be greater and of longer duration following detomidine compared to xylazine (Ste¡ey et al. 2000).
Statistical methods Values are expressed as the mean SEM unless indicated otherwise. Because of the small number of animals (i.e. n ¼ 3), inferential statistics were not determined. Results
Cardiopulmonary responses The heart rate, carotid and pulmonary arterial blood pressures and respiratory frequency were summarized for the same time points during anesthesia (one pre-drug and two post-drug administration) for both doses of detomidine (seeTable 2). Blood gas analyses The values for PaO2 and PaCO2 in the horses while awake and unmedicated were 103.4 2.3 mm Hg (13.8 kPa) and 44.1 0.9 mm Hg (5.9 0.1 kPa). The
Urine Urine £ow increased following both doses of detomidine (Table 3). During the 2 hours following 0.03 and 0.06 mg kg1 detomidine, urine £ow increased by an average of 156 and 350%, respectively. The increase in urine output lasted longer with the larger detomidine dose.
Table 1 Iso£urane minimum alveolar concentration (MAC) in horses before and after intravenous (IV) detomidine
Maximum change in MAC after IV drug
Detomidine dose (mg kg1)
Control MAC
8C
Time (minutes)
Change in MAC (%)
8C
0.03 0.06
1.43 0.14 1.45 0.08
37.5 0.2 37.0 0.3
83 23 125 36
42.8 5.4 44.8 3.0
37.5 0.2 37.2 0.4
All values are given as mean SE. Volumes percent end-expired isoflurane.
Veterinary Anaesthesia and Analgesia, 2002, 29, 223^227
225
Detomidine decreases iso£urane MAC EP Ste¡ey & PJ Pascoe
Fig. 1). Although di⁄cult to compare directly, these MAC reductions are in (qualitative) agreement with those determined for a single dose of detomidine by Muir et al. (1992) in halothane-anesthetized horses. The actions of detomidine were not studied under steady-state (i.e. constant intravenous drug infusion) conditions. As a result, we cannot precisely de¢ne the peak magnitude of its e¡ect on the iso£urane MAC. It is likely that the peak e¡ect is greater than the maximum change in MAC reported here (Table 1). The published work of others ( Jochle & Hamm 1986; England et al. 1992; Wood et al. 1998) with awake horses indicates that detomidine is more potent (on a milligram basis) in its sedative and analgesic properties compared to xylazine. The relative analgesic potency of these two alpha-2 agonists is con¢rmed by comparison of time^MAC reduction curves from previous and presently reported studies (Ste¡ey et al. 2000). The curves for 1.0 mg kg1 xylazine and 0.03 mg kg1 detomidine are overlapping, suggesting dose equivalence. Detomidine, 0.06 mg kg1 is likely to have a noticeable in£uence for more than 6 hours after IV injection in healthy anesthetized horses. Because anesthesia prolongs the elimination of many drugs, similar e¡ects in response to
Figure 1 Detomidine^iso£urane interaction in three horses. A summary of the reduction in iso£urane minimum alveolar concentration (MAC) by two intravenous doses of detomidine is shown. Note, in most cases the horizontal standard error (SE) bars are partially or totally hidden by the symbols.
Discussion Detomidine caused a marked dose- and time-related decrease in iso£urane MAC in each horse (Table 1 &
Table 2 Data from three iso£urane-anesthetized horses before and following intravenous detomidine
Minutes post-detomidine Heart rate (minute1) Mean arterial pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Respiratory rate (minute1)
Detomidine (0.03 mg kg1)
Detomidine (0.06 mg kg1)
Pre
Post
Pre
Post
36 3 97 2 22 2 51
134 7 34 1 79 9 19 1 61
35 2 95 1 22 3 51
198 6 31 1 81 8 17 4 71
167 7 33 1 79 6 22 3 61
278 9 30 1 81 6 17 3 71
Anesthetic doses at all time points are (or are nearly) equipotent (i.e. equivalent to minimum alveolar concentration [MAC] 1.0 isoflurane in O2; isoflurane adjusted to balance time-related decay in plasma detomidine). Mean SE: statistical analyses were not performed on these data owing to the small number of observations.
Hours post-detomidine Detomidine dose (mg kg1)
0.03 0.06
226
Pre-detomidine
0.74 0.25 0.42 0.05
0–2
2–4
1.91 0.13 1.89 0.08
0.74 0.07 2.39 0.40
Table 3 Urine £ow (mean SE; mL kg1 hour1) measured in horses before and after intravenous (IV) administration of detomidine during iso£urane anesthesia
Veterinary Anaesthesia and Analgesia, 2002, 29, 223^227
Detomidine decreases iso£urane MAC EP Ste¡ey & PJ Pascoe
detomidine are expected to be less prolonged in awake, unmedicated horses (Ste¡ey et al.1977). This study was not designed to characterize the cardiovascular actions of detomidine in iso£uraneanesthetized horses, however, circumstances permitted our gathering limited data immediately before administration of detomidine and at times of equipotent anesthesia following detomidine (Table 2 & Fig. 1). As with previous ¢ndings with xylazine under similar conditions, detomidine seemed to reduce heart rate and systemic blood pressure. Mean pulmonary artery pressure appear lower at the higher dose of detomidine. Similar to our ¢ndings with xylazine, detomidine had no prominent dose- or time-related e¡ect on PaCO2 but may have caused a small decrease in PaO2. The number of observations are too limited to draw broad conclusions. However, present results suggest that further investigation of detomidine in£uence on PaO2 is warranted in this species known for its variability in e⁄ciency of arterial blood oxygenation during general anesthesia. Alpha-2 agonists induce hyperglycemia in awake and anesthetized horses (Thurmon et al.1982; Ste¡ey et al. 2000). Present results are in qualitative agreement. Peak increase in serum glucose and duration of hyperglycemia appears greater with detomidine compared to xylazine, and these e¡ects are also detomidine dose-related (Ste¡ey et al. 2000). Similar to e¡ects of xylazine (Ste¡ey et al. 2000), previous studies have demonstrated the diuretic e¡ect of detomidine in awake and halothaneanesthetized horses (Gasthuys et al.1986). Currently reported results (Table 3) suggest that the in£uence of detomidine is of greater magnitude and that the elevation in urine volume persists substantially beyond the duration noted with xylazine under similar conditions of iso£urane anesthesia (Ste¡ey et al. 2000).
Conclusions Detomidine substantially reduces the anesthetic requirement for iso£urane in the horse. The magnitude of decrease is dose and time dependent. Detomidine increases blood glucose concentration and urine £ow in iso£urane-anesthetized horses and the magnitude of changes are also dose and time dependent. The present data when compared to similarly derived results from prior xylazine studies support the opinion that detomidine is more potent in its
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analgesic, sedative, diuretic and hyperglycemia-promoting properties in anesthetized horses.
Acknowledgements The project was supported by the school’s Center for Equine Health with funds provided by the Oak Tree Racing Association, the State of California Satellite Wagering Fund, and contributions by private donors. The authors gratefully acknowledge the technical support of Richard Morgan, Bill Perkins and Michael Woliner.
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