The pharmacodynamics of thiopental, medetomidine, butorphanol and atropine in beagle dogs
Abstract
This study evaluated the quality of anaesthesia and some of the haemodynamic effects induced by a combination of thiopental, medetomidine, butorphanol and atropine in healthy beagle dogs (n = 12). Following premedication with atropine (ATR, 0.022 mg/kg intravenously (i.v.)) and butorphanol (BUT, 0.22 mg/kg i.v.), medetomidine (MED, 22 μg/kg intramuscularly (i.m.)) was administered followed in 5 min by thiopental (THIO, 2.2 mg/kg i.v.). Heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MBP) were monitored continuously with an ECG and direct arterial blood pressure monitor. Atipamezole (ATI, 110 μg/kg i.v.) was administered to half of the dogs (n = 6) following surgery to evaluate the speed and quality of arousal from anaesthesia. Anaesthesia was characterized by excellent muscle relaxation, analgesia and absence of purposeful movement in response to surgical castration. Arousal following antagonism of medetomidine was significantly faster (P < 0.05) than in unantagonized dogs. Recoveries were smooth but recovery times following atipamezole administration were highly variable among dogs (sternal time range 6–38 min, standing time range 9–56 min). Medetomidine caused a significant (P < 0.05) increase in SBP, DBP and MBP. Atropine prevented the medetomidine induced bradycardia. In conclusion, this combination provided adequate surgical anaesthesia in healthy beagle dogs. At the dosages used in this study, it seems prudent that this combination should be reserved for dogs free of myocardial disease.
INTRODUCTION
Multimodal balanced anaesthesia is the induction of an anaesthetic state using a combination of drugs with different mechanisms of action that will produce profound muscle relaxation, analgesia and CNS depression. Combining drugs that potentiate one another's pharmacodynamic actions decreases the dose requirement of each drug, minimizing the potential side effects of any single drug when given in a higher dose sufficient to achieve an equivalent response (Heavner, 1996).
The use of an opioid in combination with an alpha-2 adrenergic agonist has been shown to potentiate the degree and duration of analgesia in a number of species. This potentiation has been documented with intrathecal, epidural and intramuscular injection (Spaulding et al., 1979; Ossipov et al., 1990; Branson et al., 1993; Meert & DeKock, 1994). This interaction is believed to be the result of altered neuronal membrane potassium ion conductance due to activation of a G-protein second messenger, common to both alpha-2 and opiate receptors in the central nervous system (Tranquilli & Maze, 1993). Medetomidine, a highly selective alpha-2 adrenoceptor agonist, has been shown to decrease the dose of thiopental, an ultrashort acting thiobarbiturate, necessary to achieve induction of surgical anaesthesia (Bartram et al., 1994; Buhrer et al., 1994). Medetomidine has also been shown to prolong the duration of barbiturate anaesthesia and enhance analgesia (Kauppila et al., 1992).
The present study was designed to evaluate medetomidine in combination with butorphanol (an opioid agonist-antagonist), and thiopental as an injectable anaesthetic combination for routine, short surgical procedures in healthy dogs. We also evaluated the speed and quality of arousal from thiopental-butorphanol-medetomidine anaesthesia by the highly specific alpha-2 adrenergic antagonist, atipamezole.
Materials and Methods
This study was approved by the Office of Laboratory Animal Care at the University of Illinois and was in compliance with local and federal guidelines governing laboratory animal care and housing.
Animals
Twelve intact male beagle dogs were utilized in this study. The dogs were individually housed and fed a commercial canine diet. Weighing from 10 to 16 kg, all free of apparent disease, the dogs were randomly assigned to one of two treatment groups. Group 1 received butorphanol (Torbugesic, Fort Dodge Laboratories, Fort Dodge, IA, USA) (BUT, 0.22 mg/kg intravenously (i.v.)) and atropine (Atropine sulfate, Elkins-Sinn, Inc., Cherry Hill, NJ, USA) (ATR, 0.022 mg/kg i.v.) followed in 5 min by medetomidine (Domitor, Meiji Seika Kaisha Ltd, Tokyo, Japan) (MED, 22 μg/kg intramuscularly (i.m.)), and 5 min later by thiopental (Pentothal, Abbott Laboratories, North Chicago, IL, USA) (THIO, 2.2 mg/kg i.v.), injected over a 30 s period. Dogs in group 2 received the same treatment as group 1 except that atipamezole (Antisedan, Pfizer Animal Health, Exton, PA, USA) (ATI, 110 μg/kg i.v.) was administered immediately following the completion of surgery.
Prior to administration of any drug, an intravenous catheter (20 ga. 2.0 in.) (Angiocath, Becton Dickinson, Sandy, UT, USA) was placed in the right cephalic vein after clipping and scrubbing. The skin over the dorsal pedal artery was aseptically prepared. Lidocaine, 0.25 mL of a 2% solution, was injected subcutaneously to desensitize the skin. Through this desensitized area, a catheter (20 ga. 2.0 in.) (Angiocath, Becton Dickinson) was percutaneously placed in the artery for measurement of blood pressure. Catheter placement was confirmed by arterial blood pressure measurement and characteristic pulsatile wave forms appearing on the oscilloscope (oscilloscope; Datascope 3000 A, Datascope Corporation, Paramus, NJ, USA) (blood pressure transducers; Baxter Uniflow Transducer, Baxter Healthcare Corp., Deerfield, IL, USA). All blood pressure measurements were made with the dogs in lateral recumbancy with a pressure transducer zeroed to the level of the right atrium. Heart rate and rhythm were monitored continuously on an oscilloscope using the standard base apex electrocardiogram (ECG) leads.
After recording baseline values for heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MBP), atropine followed immediately by butorphanol was given. Five minutes later, medetomidine was injected into the semi-membranosis muscle. The ECG was monitored continuously for HR and dysrhythmias. Five minutes later thiopental was given over 30 s and the dogs were observed for apnoea, blood pressure changes and dysrhythmias.
Surgical castration was performed using sterile surgical technique as described by Stone (Stone, 1990). The dogs were observed closely for any changes in blood pressure, HR and for gross purposeful movement in response to surgery. Upon completion of surgery, atipamezole was given to group 2 dogs. Changes in HR, SBP, DBP, MBP were recorded before any drugs were given, following atropine and butrophanol injection immediately before medetomidine injection, after medetomidine injection immediately before thiopental injection, 2 min following thiopental injection when values had reached a steady state, and in group 2 dogs, just before atipamezole administration and 5 min following atipamezole administration.
Statistical analysis
The data for HR, SBP, DBP and MBP were analysed using analysis of variance between group means (Remington & Schork, 1985a). When the F-value was significant, a least-significant differences test was used to determine differences among means. A P-value of 0.05 was considered significant. Data for recovery times were analysed using a Student's t-test (Remington & Schork, 1985a, b). A P-value of
0.05 was considered significant. All values are reported as mean ± SEM. Data analysis was performed on a personal computer using a statistical analysis program (Statgraphics Plus for Windows 3.0, Manugistics, Rockville, MD, USA)
Results
Following administration of atropine and butorphanol, all dogs in both groups developed a transient second degree atrioventricular blockade that persisted for 2–3 min. Following disappearance of this dysrhythmia, the heart rhythm became regular and mean HR was 148 ± 10 beats per min (bpm) (Table 1). The administration of atropine and butorphanol did not result in a significant change in SBP, DBP or MBP. Medetomidine administration resulted in a decrease in HR (148 ± 10 to ± 7 bpm). Systolic blood pressure, DBP and MBP increased from 142 ± 3 to 214 ± 7 mmHg, 72 ± 5 to 156 ± 5 mmHg, and 102 ± 5 to 176 ± 6 mmHg, respectively. Following thiopental injection, SBP, DBP and MBP decreased to 188 ± 6, 126 ± 7 and 150 ± 5 mmHg, respectively, while HR remained unchanged.
Quality of anaesthesia was characterized by excellent muscle relaxation, narcosis and analgesia. None of the dogs in this study responded with gross purposeful movement to surgical castration.
At the end of surgery, atipamezole administration to group 2 dogs resulted in rapid antagonism of medetomidine induced haemodynamic effects. Heart rate increased from 86 ± 7–116 ± 12 bpm. Systolic blood pressure, DBP and MBP decreased from 176 ± 8–124 ± 7, 124 ± 9–69 ± 8 and 141 ± 9–88 ± 8 mmHg, respectively. Hypotension (MBP < 60 mmHg) did not occur in any animals anytime during the study. The duration of surgery ranged from 25 to 40 min (mean = 31.3 min) for group 1, and 23–45 min (mean = 32.2 min) for dogs in group 2. Dogs in group 1 required 163.0 ± 40.2 min compared to 78.8 ± 26.2 min for dogs in group 2 to stand after thiopental administration. Group 2 dogs became sternal in 20.2 ± 18.0 min after atipamezole administration, and were able to stand and walk 11 min later. Arousal following atipamezole administration was smooth and not accompanied by excitement or dysphoria.
Discussion
The use of a combination of medetomidine and butorphanol has been reported by several investigators to provide excellent sedation and analgesia for minor procedures not requiring deep surgical anaesthesia (Bartram et al., 1994; Ko et al., 1996). The potentiation of the antinociceptive action of the opioid agonist-antagonist butorphanol by medetomidine is postulated to be due to the interaction of opioid and alpha-2 adrenoceptors in the spinal cord (Ossipov et al., 1990). Opioid and alpha-2 adrenoceptors are present in the same superficial layers of the spinal cord and both inhibit C-fibre activity (Sullivan et al., 1987). These receptors share a common second messenger mechanism. Activation of both receptors results in hyperpolarization of neurons by altering potassium ion channel conductances by means of a G-protein coupled receptor mechanism resulting in an inhibition of neurotransmitter release (Miyake et al., 1989). Activation of the alpha-2 adrenergic and opioid receptors may elicit an enhanced effect by independently altering intracellular second messenger systems, yielding a net effect greater than the sum of each individual effect (Ossipov et al., 1990).
Alpha-2 adrenergic agonists have an anaesthetic sparing action. Anaesthetic sparing effects have been documented in rats (Segal et al., 1988), dogs (Vickery et al., 1988) and humans (Aantaa et al., 1990a, b; Aantaaet al., 1991; Aho et al., 1991; Jaakola et al., 1992; Scheinin et al., 1992). Presumably, a decrease in thiopental dose requirement after medetomidine administration could be the result of a pharmacokinetic and/or a pharmacodynamic interaction between the two drugs. Buhrer and coworkers demonstrated a pharmacokinetic interaction but failed to show a pharmacodynamic effect after pretreatment with dexmedetomidine (the active stereoisomer of medetomidine) (Buhrer et al., 1994). The alterations in kinetic parameters were a reduction of the apparent volume of distribution of the central compartment and a decrease in the intercompartmental clearance between the central compartment and the peripheral compartment. The plasma concentration of thiopental required to reach the same end point (i.e., EEG burst suppression), was the same as for unpremedicated humans, however, the total amount of drug required to reach the same plasma concentration was less (Buhrer et al., 1994). Confinement of the drug to the central compartment is possibly due to a medetomidine induced decrease in cardiac output and an increase in peripheral vascular resistance.
Medetomidine has been combined with several commonly used injectable anaesthetic drugs to produce anaesthesia in dogs. Recently, medetomidine (40 μg/kg) followed by intravenous ketamine (3.0 mg/kg), medetomidine (60 μg/kg) followed by intravenous propofol (2.0 mg/kg) or fentanyl (2.0 μg/kg) for induction, with repeated administration of the anaesthetic agent for maintenance, were evaluated by Hellebrekers and Sap (Hellebrekers & Sap, 1997) for quality of anaesthesia and cardiopulmonary effects. Medetomidine-propofol and medetomidine-ketamine anaesthesia produced an adequate depth of anaesthesia and no response to surgical manipulation was observed. Muscle relaxation was judged to be more than adequate for abdominal surgery. Medetomidine-fentanyl anaesthesia was difficult to maintain without severely depressing respiratory function in spontaneously breathing dogs. Auditory stimuli frequently resulted in animal response with the latter combination, although none of the animals responded to surgical stimulation. The authors concluded medetomidine-fentanyl, at the dosages used, proved unsatisfactory in spontaneously breathing dogs. Our study demonstrated that small subanaesthetic doses of thiopental (2.2 mg/kg) are capable of producing up to 45 min of surgical anaesthesia in beagles premedicated with atropine, butorphanol and medetomidine. The ability of medetomidine to alter the pharmacokinetics of thiopental combined with its opioid analgesia enhancing properties, allowed the use of small doses of each drug and provided the potential for arousal from the anaesthesia by administration of atipamezole.
The goal of this study was not to quantify the effects of this drug combination on respiratory function in dogs. None of the dogs in our study became apnoeic and unrecorded observations of mucous membrane colour were made. Throughout the experiments mucous membrane colour remained pink to a slight pale pink (likely due to medetomidine induced peripheral vasoconstriction as blood loss from the surgical site was less than 10 mL in all dogs). The potential for some respiratory depression obviously exists as is the case for all anaesthetics or combinations of central nervous system depressant drugs.
In our study, medetomidine was administered intramuscularly while all other drugs were administered intravenously. Intramuscular administration should increase the duration of effect of the medetomidine over what would be expected by intravenous administration. Also, the intravenous administration of relatively large doses of alpha-2 adrenergic agonists including medetomidine, has been associated with more dramatic cardiovascular effects. The intramuscular administration of medetomidine may dampen the increase in blood pressure and decreases in heart rate observed with this class of drugs.
A 5 min period between the administration of medetomidine and thiopental was allowed so that the most intense surgical stimulation paralleled the effective analgesic actions of both butorphanol and medetomidine in addition to the central nervous system depressant effects of thiopental.
Medetomidine has been shown to induce haemodynamic alterations that raise questions of its safe use in dogs afflicted with cardiovascular disease. By using only approximately one-half of the highest recommended intramuscular dose of medetomidine (22 μg/kg) it was thought that the initial hypertension and subsequent hypotension reported by other investigators could be avoided (Savola, 1989; Vainio, 1989). However, results of our study are in agreement with those reported earlier (Ko et al., 1996), demonstrating reduced doses of intramuscular medetomidine do not completely eliminate vasoconstriction and thus increases in blood pressure and afterload. The results of the current study reveal that a 22 μg/kg dose of medetomidine, when combined with atropine and butorphanol, can cause a rather acute increase in blood pressure in some dogs. As a result, it seems prudent that this combination, at the dosages used in the present study, should be reserved for healthy dogs without myocardial disease.
It is well documented that atipamezole antagonism of the effects of medetomidine is rapid and smooth without any long lasting adverse effects (Vainio & Vaha-Vahe, 1990). Although brief periods of tachycardia (250–279 bpm) have been observed after atipamezole administration (Ko et al., 1994) we observed no such episodes in the present study. Heart rates did increase to levels that were significantly above the baseline value.
Atipamezole antagonism of medetomidine decreased the time required for dogs to become sternal and stand unassisted. The ability of atipamezole to antagonize the anaesthetic potentiating actions of medetomidine is reportedly less in the presence of barbiturates. Atipamezole administration increased the duration of pentobarbital induced loss of the righting reflex in rats that received medetomidine as a premedication (Kauppila et al., 1992). Methohexital induced loss of righting reflex also increased in duration compared to saline controls following atipamezole administration (Kauppila et al., 1992). In our study the length of time required to return to a sternal position and to standing was highly variable among group 2 dogs (ranging from 6 to 38 min for return to sternal and 9–56 min for time until standing.) All dogs in group 2 were given atipamezole intravenously at 5 times the medetomidine dose. Intravenous administration was chosen in order to decrease variation in bioavailability associated with i.m. injection. Interestingly, the time required for arousal was longer than that required for dogs receiving medetomidine and butorphanol, at the same doses, and propofol (Thurmon et al., 1997). Arousal from anaesthesia after atipamezole administration likely resulted from thiopental redistribution into peripheral tissue compartments as well as reversal of medetomidine sedation. Atipamezole has been shown to increase the clearance of medetomidine (Salonen et al., 1995). Medetomidine may have the ability to decrease the elimination of itself, thiopental and butorphanol, prolonging the combined effects of these drugs within the central nervous system. If normal haemodynamics are restored following atipamezole administration, distribution and elimination processes of all of the drugs could be normalized to their original rates (Salonen et al., 1995), shortening the time of anaesthetic action. In this study however, wide variation of recovery times cannot be explained solely by alterations in pharmacokinetic parameters and cardiovascular function as the haemodynamic changes observed were consistent among all dogs given atipamezole while arousal times varied greatly. It may be possible that a pharmacodynamic interaction between low concentrations of thiopental and medetomidine and/or atipamezole (Kauppila et al., 1992) was responsible for the variation in recovery times allowing some dogs to continue to be depressed even though significant changes in haemodynamic and pharmacokinetic parameters had occurred.
Conclusion
In this study, subanaesthetic doses of thiopental in combination with relatively low doses (below manufacturer dose recommendations) of medetomidine and butorphanol induced central nervous system depression, analgesia and muscle relaxation adequate for surgical castration in healthy beagles. Atropine at the dose of 0.22 mg/kg was able to prevent bradycardia following medetomidine administration. Thiopental at 2.2 mg/kg did not effectively dampen medetomidine induced hypertension. The increase in blood pressure induced by medetomidine at a dose of 22 μg/kg would appear to limit its use in dogs with compromised cardiovascular function. Intravenous atipamezole administration decreased recovery time but unlike observations in dogs anaesthetized with similar doses of medetomidine, butorphanol and propofol, time to arousal was variable in dogs anaesthetized with a combination of medetomidine, butorphanol and thiopental.