Effects of Epidural and Intravenous Buprenorphine on Halothane Minimum Alveolar Anesthetic Concentration and Hemodynamic Responses

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1 Effects of Epidural and ntravenous Buprenorphine on Halothane Minimum Alveolar Anesthetic Concentration and Hemodynamic Responses Yoshimi nagaki, MD*, and Akiko Kuzukawa, MDt *Department of Anesthesiology, Osaka University Medical School, Osaka, Japan, and tdepartment of Anesthesia, Osaka Prefectural Habikino Hospital, Osaka, Japan There is limited information regarding the effects of epidural or intravenous (V) buprenorphine on minimum alveolar anesthetic concentration (MAC) of volatile anesthetic and hemodynamic responses to tracheal intubation and surgical incision. This study was conducted to find the effects of V and epidural buprenorphine required for postoperative pain relief on halothane MAC and hemodynamic responses to tracheal intubation and surgical incision in 126 female patients. Patients were randomly assigned to the four groups: received V and epidural saline as a control; was given buprenorphine 4 pg/kg V; and s and V received buprenorphine 2 and 4 PLg / kg epidurally, respectively. s -V were divided into two subgroups according to the timing of administration, either at induction of anesthesia in the operating room (OR) (OR group) or 90 min before anesthetic induction in the ward (Ward group). Anesthesia was induced with only halothane in oxygen, and the trachea was intubated without other drugs. Halothane MAC was determined by logistic regression analysis and the Dixon up-and-down method. Halothane MAC in the seven study groups was as follows: 0.75% % (mean? SE) in ; 0.49%? 0.03% and 0.59%? 0.04%, respectively, in s OR and Ward; 0.65%? 0.003% and 0.49% t 0.07%, respectively, in s OR and Ward; and 0.51%? 0.07% and 0.37% %, respectively, in s V OR and Ward. Halothane MAC decreased significantly (P < 0.05) in groups that received buprenorphine except -OR compared with. Systolic blood pressure did not change significantly in s -OR and V-OR after tracheal intubation and in s -Ward and V- Ward after surgical incision but increased significantly (P < 0.05) in the remaining groups in response to noxious stimuli. Heart rate responses to tracheal intubation and surgical incision were similar to those in systolic blood pressure. These results indicate that preanesthetic administration of epidural or V buprenorphine required for postoperative analgesia reduces halothane MAC and attenuates hemodynamic responses to tracheal intubation and surgical incision according to the dose, route, and timing of administration. (Anesth Analg 1997;84:100-5) T o attenuate circulatory responses to tracheal intubation and surgical incision, local anesthetics (1,2) and vasodilators or antihypertensive drugs (3,4) have been administered intravenously (V) prior to the beginning of such procedures. Analgesics also are given to accomplish this aim (5,6). Buprenorphine, a lipid soluble, mixed agonist-antagonist opioid, belongs to category of long-acting and potent opioids and has partial effectiveness in attenuating the cardiovascular response to laryngoscopy and intubation when administered V as a bolus (7). On the other hand, epidural buprenorphine applied for postoperative analgesia also produces a systemic analgesic effect Accepted for publication August 26, Address correspondence and reprint requests to Yoshimi nagaki, MD, Department of Anesthesiology, Osaka University Medical School, 2-2, Yamadaoka, Suita, Osaka 565, Japan. on a par with V buprenorphine via systemic absorption within one hour after a bolus injection (8). Therefore, the administration regimens of buprenorphine for postoperative analgesia may have the ability to attenuate the hemodynamic responses to tracheal intubation and surgical incision. However, there is limited information regarding the effects of epidural or V buprenorphine on hemodynamic responses to noxious stimuli during induction of anesthesia and minimum alveolar anesthetic concentration (MAC) of volatile anesthetic. This prospective, randomized, placebo-controlled study was conducted to clarify whether the dosage of epidural or V buprenorphine applied for postoperative analgesia reduces halothane MAC and attenuates hemodynamic responses to tracheal intubation and surgical incision. 100 An&h Analg 1997;84: by the nternational Anesthesia Research Society /97/$5.00

2 ANESTH ANALG 1997;84: REGONAL ANESTHESA AND PAN MANAGEMENT NAGAK AND KUZUKAWA 101 V AND EPDURAL BUPRENORPHNE AND HALOTHANE MAC Methods After obtaining approval of our institutional review board for human research and written informed consent from each patient, 126 patients of ASA physical status, aged yr, weighing kg, scheduled for abdominal simple hysterectomy in the afternoon were enrolled in the present study. All patients received epidural catheterization at the T12-Ll interspace at least 5 h before induction of anesthesia, and a catheter was threaded cephalad with 5 cm of it remaining within the epidural space. To rule out intravascular or subarachnoid injection, 2 ml of 1% lidocaine with epinephrine 1:200,000 was administered through the epidural catheter. After this, the anesthetized region between the xyphoid and groin was confirmed by the pinprick method 20 min after injection of 10 ml of 0.5% lidocaine. The pinprick method was used to reconfirm whether the local anesthetic block had worn off 3 h after the injection of 0.5% lidocaine. Patients who remained in a hypesthesic or analgesic state at this time were excluded from this study. Patients were assigned randomly to one of four groups. was given saline V and epidurally as a control; was given buprenorphine V by a bolus injection of 4 pg/kg; and s and V received an epidural injection of buprenorphine 2 and 4 pg/kg as a bolus, respectively.,, or V patients were divided into two subgroups for investigating the effects of administration time on halothane MAC and hemodynamic responses; one group received buprenorphine just before induction of anesthesia in the operating room (OR) (OR group) and another group received it 90 min before induction of anesthesia in the ward (Ward group). This timing of administration for determination of halothane MAC was based on our previous results that analgesia produced by V and epidural buprenorphine reached maximum, respectively, 1 and 3 h after administration (8). Buprenorphine was diluted to 10 ml with preservative-free saline. The patients receiving epidural buprenorphine were given V normal saline 10 ml at the same time, and the patients receiving V buprenorphine were given normal saline 10 ml epidurally. No patients received preanesthetic medication. Standard monitoring was used. Lactated Ringer s solution was infused at the rate of 10 ml * kg- * h-* while the patients breathed pure oxygen via an anesthetic mask. The patient spontaneously inhaled halothane in 100% oxygen via a tightly fitted face mask until lack of response to mild prodding or shaking, and then was ventilated manually to maintain an endtidal halothane concentration between 1.7% and 1.8% for at least 10 min. The trachea was intubated without any other drug. After intubation, the end-tidal halothane concentration was adjusted rapidly to a predetermined level and maintained at this concentration for at least 20 min. End-tidal halothane concentration and PETCO~ were monitored continuously by a multiple anesthetic gas monitor (M1025B; Hewlett-Packard, Palo Alto, CA). The anesthetic gas monitor was calibrated with standard gas before each measurement. The lungs were ventilated mechanically to maintain PETCO~ between 30 and 40 mm Hg. The patient was observed by an anesthesiologist, blinded as to drug treatment, for movement, or lack thereof, upon surgical incision. After observation, all patients received an V injection of vecuronium bromide 0.15 mg/kg. Systolic blood pressure (SBP) and diastolic blood pressure and heart rate (HR) were recorded every minute from the beginning of manual ventilation. Hemodynamic data at the following five stages were analyzed to determine cardiovascular responses to tracheal intubation and surgical incision: before administration of buprenorphine at the ward (baseline), 1 min before and after tracheal intubation (pre- and postintubation), 1 min before and after surgical incision (pre- and postincision). MAC of halothane was determined using a logistic regression analysis and the Dixon up-and-down method (9). To estimate the SEM MAC values, MAC in the up-and-down method was determined in six consecutive patients within each group. The end-tidal concentration of halothane administered to the first patient in each group was 0.7%. t was changed according to patient s response to surgical incision; if movement occurred in response to surgical incision at 0.7%, the end-tidal concentration was increased by 0.1% for the next patient; if no movement occurred, the end-tidal concentration was decreased by 0.1%. Parametric data between groups were analyzed by one-way analysis of variance and results assessed by Newman-Keuls post-hoc test. Hemodynamic data within each group were analyzed by two-way analysis of variance followed by Bonferroni correction of t-test. A P value less than 0.05 was considered statistically significant. Results There were no significant differences in demographic data, i.e., age, height, weight, and times from induction to tracheal intubation and from tracheal intubation to surgical incision among the seven groups (Table 1). The conditions of patients at the surgical incision were similar among the seven groups (Table 1). Figure 1 shows individual responses to surgical incision. Halothane MAC determined using two methods is summarized in Table 2. Halothane MAC in the

3 102 REGONAL ANESTHESA AND PAN MANAGEMENT NAGAK AND KUZUKAWA ANESTH ANALG V AND EPDURAL BUPRENORPHNE AND HALOTHANE MAC 1997;84: Table 1. Demographic Data and Conditions at Surgical ncision in the Seven Study s Demographic data he 64 Weight (kg) Height (cm) Conditions at surgical incision Respiratory rate (breaths/ min) PETCO, (mm Hg) Rectal temperature ( C) Time (min) Time (min) Time (min) OR Ward t 8 39 t k k c t t ? 7 48 k 8 OR ? ? ? z!z Ward OR V Ward k t t2 7k2 7?2 33 k 1 32 t c ? t ? 2 29 t ? k 13 Values are expressed as mean -c SD. received epidural saline;, intravenous buprenorphine 4 pg/kg;, epidural buprenorphine 2 pg/kg; and V, epidural buprenorphine 4 pg/ kg. OR = operating room; Time = duration between induction of anesthesia and tracheal intubation; Time = duration between tracheal intubation and surgical incision; Time = duration between administration of buprenorphine and surgical incision... no move move......,.. OR no move moye Ward no move move ll OR no move mclve Ward no move mcwe OR V 0 move m.xe ( V Ward no move move End-lfdal Habthane Concentration ph) Figure 1. ndividual patient responses upon surgical incision. Each dot represents the response of one patient to surgical incision. The position of the dot along the horizontal axis represents end-tidal halothane concentration during at least 20 min before surgical incision. groups receiving buprenorphine, except for the group given epidural buprenorphine 2 pg/kg in the OR ( -OR) reduced significantly (P < 0.05) compared with that in the group receiving epidural saline ( ). No patients needed any treatments during induction of anesthesia for correcting the hemodynamic abnormalities; hypertension (SBP > 180 mm Hg) and hypotension (SBP < 80 mm Hg), or tachycardia (HR > 120 bpm) and bradycardia (HR < 40 bpm) continued for at least 2 min. There were no significant differences in SBP at baseline among the seven groups (Figure 2). However, the hemodynamic responses to tracheal intubation and surgical incision differed among the seven groups. After tracheal intubation, SBP was maintained at the level of baseline value in the two groups receiving the larger doses of V and epidural buprenorphine in the OR (s and V). t increased significantly (P < 0.05) in the remaining groups compared with baseline values. The increase in SBP after surgical incision was markedly attenuated in both groups receiving epidural buprenorphine in the ward (s and V). SBP in all study groups was reduced significantly (P < 0.01) compared with baseline values before tracheal intubation and surgical incision. HR at baseline was similar among the seven groups (Figure 3). After tracheal intubation, HR was maintained at the level of baseline value in the two groups receiving the larger doses of V and epidural buprenorphine in the OR (s and V). t increased significantly (P < 0.01) in the remaining groups compared with baseline values. The significant increase in HR after surgical incision was not observed in the two groups receiving epidural buprenorphine in the ward (s and V). n the remaining groups, HR increased significantly (P < 0.01) compared with baseline values. HR decreased significantly (P < 0.01) in all groups receiving buprenorphine treatment before tracheal intubation compared with baseline values, although it was maintained at the level of baseline value in the group receiving epidural saline ( ). Before surgical incision, HR returned to the level of

4 ANESTH ANALG 1997:84: REGONAL ANESTHESlA AND PAN MANAGEMENT NAGAK AND KUZUKAWA 103 V AND EPDURAL BUPRENOR HNE AND HALOTHANE MAC Table 2. Halothane Minimum Alveol.ar Anesthetic Concentration (MAC) Values in the Seven Study s Halothane MAC (k) Logistic Up-and-down regression (95% confidence interval) method (epidural saline) t ( ) 0.74 O.05 (intravenous buprenorphine 4 pg / kg) OR ( ) 0.49 i 0.03* Ward i ( ) 0.59 t 0.04" (epidural buprenorphine 2 pg/kg) OR ( ) t Ward c ( ) 0.49 t 0.07" V (epidural buprenorphine 4 pg/kg) OR 0.517? ( ) 0.51 t- 0.07" Ward 0.379? ( ) t 0.02+*s Values are expressed as mean i SE. OR = operating room. * P < 0.05, versus. + P < 0.001, versus. * P < 0.05, versus Ward. s < 0.01, versus OR. Meant SE Figure 2. Changes of systolic blood pressure over time after induction of anesthesia in the seven study groups. Systolic blood pressure in all groups before tracheal intubation or surgical incision decreased significantly (t P < 0.01) compared to baseline values. After tracheal intubation, systolic blood pressure maintained the level of baseline value in s -OR (A) and V-OR (m) but increased significantly ($ P < 0.01) in the remaining groups. After surgical incision, systolic blood pressure did not change significantly in s -Ward (0) and V-Ward (0) compared to baseline values but increased significantly (#D < 0.01) in the remaining groups. Values are expressed as mean? SE. baseline value in all groups receiving buprenorphine treatment, while it was still higher (P < 0.01) than baseline value in the group receiving epidural saline. Discussion The present study showed clearly the effects of dosage, route, and timing of administration of buprenorphine on halothane MAC and hemodynamic responses to tracheal intubation and surgical incision. Regarding halothane MAC, the administration of buprenorphine prior to anesthetic induction significantly Figure 3. Changes of heart rate over time after induction of anesthesia in the seven study groups. Heart rate did not change slgmficantly in (0) before tracheal intubatlon compared to baseline value but decreased significantly (a P < 0 01) m the other groups. After tracheal intubatlon, heart rate maintained the level of baseline value in s -OR (A) and V-OR (m) but mcreased significantly ($ P < 0.01) in the remammg groups Before surgical mcision, heart rate was still greater (11 < 0.01) than the baselme value in (0) but returned to baseline values in the other groups. After skin ncision, the heart rate did not change signiflcantly in s -Ward (0) and V-Ward (0) compared to baseline values but increased sigmflcantly (# P < 0.01) m the remainmg groups. Values are expressed as mean i st. reduced halothane MAC compared to epidural saline as a control, except for the smaller dose of epidural buprenorphine given in the OR. The smaller dose of epidural buprenorphine reduced halothane MAC significantly greater when administered in the ward. The larger dose of epidural buprenorphine provided a reduction in halothane MAC similar to V buprenorphine when administered in the OR, while it reduced halothane MAC significantly greater than V buprenorphine when administered in the ward. These

5 104 REGONAL ANESTHESA AND PAN MANAGEMENT NAGAK AND KUZUKAWA V AND EPDURAL BU RENORPHNE AND HALOTHANE MAC ANESTH ANALG 1997;84: findings indicate that the time from administration to peak analgesic effect of epidural buprenorphine depends on both dose and route of administration, supporting our previous observation on the mode and site of analgesic action of epidural buprenorphine (8). That is, the larger doses of epidural and V buprenorphine are likely to produce earlier analgesia through central (supraspinal) sites of action, and both doses of epidural buprenorphine develop delayed analgesia, which could be a spinal segmental analgesia. Thus, much attention should be given to the timing of administration when the effects of epidural opioids on anesthetic MAC are investigated, particularly in the case of opioids such as fentanyl and morphine which produce the spinal segmental analgesia (10,ll). Recent experimental studies (12,13) revealed that the spinal cord, rather than the supraspinal region of the central nervous system (CNS), played a predominant role in determining the volatile anesthetic MAC. Reduction in the intensity of nociceptive input at the level of the spinal cord may contribute to loss of consciousness (14). The spinal analgesic action of buprenorphine penetrating across the dura matter from the epidural space is likely to modulate nociceptive input to the spinal cord before nociceptive input is relayed through ascending pain pathways to the brain, resulting in significant halothane MAC reduction in the groups receiving epidural buprenorphine in the ward. Since buprenorphine is a potent, centrally acting opioid with a long duration of action (15), the sites of action of V buprenorphine to modify the volatile anesthetic MAC have been thought to be the supraspinal region of the CNS. However, the abovementioned experimental studies suggest that it is possible for V buprenorphine to act upon the spinal cord via systemic circulation. t has been reported that systemically administered opioids induce analgesia in part by spinal noradrenergic, serotonergic, and cholinergic mechanisms (16). n the present study, it is unclear at which site V buprenorphine acts predominantly for modifying halothane MAC-the spinal cord or the supraspinal region of the CNS. Otherwise, the lack of movement in response to noxious stimuli as an index of MAC determination is modulated by the. extent of depression of a-motor neuron excitability due to a volatile anesthetic (17); the excitability decreases 50% between 0.8 and 1.2 MAC but not between 0.5 and 0.8 MAC. Therefore, this depression of motor neuron activity by a volatile anesthetic itself might have affected halothane MAC in the present study groups, except for the group receiving the larger dose of epidural buprenorphine in the ward, because nearly all the patients in this group had inhaled less than 0.8 MAC halothane at the time they were observed for movement. The larger dose of epidural buprenorphine and V buprenorphine given in the OR significantly attenuated the increase in systolic blood pressure after tracheal intubation compared to the remaining administration regimens. This similar attenuation appears to arise from the cardiovascular stability produced by a central action of buprenorphine (l&19), suggesting that the larger dose of epidural buprenorphine acts at the supraspinal region of the CNS on a par with V buprenorphine within 20 minutes after administration. Pharmacokinetic characteristics of buprenorphine may help to explain the similar central efficacy; the onset of action is slow and its peak effect is between 2 and 10 minutes when administered V (20) and the plasma concentration reaches maximum within 10 minutes after epidural administration (21). After surgical incision, the increase in SBP was significantly reduced by both doses of epidural buprenorphine given in the ward. The potent spinal analgesic effect of epidural buprenorphine is likely to induce this significant attenuation of blood pressure after surgical incision as well as reduce halothane MAC. However, both doses of epidural buprenorphine given in the OR failed to reduce the increase in SBP after surgical incision. This finding appears to show an insufficient development of the spinal analgesic effect to modulate noxious input to the spinal cord. Significant reduction in SBP from baseline values before tracheal intubation and surgical incision in all study groups could be induced by the circulatory depression of halothane because halothane depresses cardiac output, stroke volume, and myocardial contractility as the inhaled concentration increases (22) while buprenorphine does not suppress blood pressure (7). The increase in HR after tracheal intubation was significantly attenuated in the two groups receiving the larger doses of epidural buprenorphine and V buprenorphine in the OR. After surgical incision, it was markedly attenuated in both groups given epidural buprenorphine in the ward. These attenuations in HR also could be elicited by the same mechanism of attenuation in blood pressure response, the supraspinal action of buprenorphine. Significant reduction of HR from baseline values before tracheal intubation and prompt return to the level of baseline value before surgical incision in all groups receiving buprenorphine treatment seem to be provided by bradyarrythmia due to buprenorphine (18), which could be a result of direct depression of conduction or a stimulant action on the vagal nucleus (7) because HR is unchanged with increased halothane concentration (22). n conclusion, the administration regimens of buprenorphine needed for postoperative analgesia modify halothane MAC according to the dose, route, and timing of administration. More effective suppression of hemodynamic responses to tracheal intubation and

6 ANESTH ANALG REGONAL ANESTHESA AND PAN MANAGEMENT NAGAK AND KUZUKAWA :84: V AND EPDURAL BUPRENOR HNE AND HALOTHANE MAC surgical incision are provided, respectively, by epidural and V buprenorphine 4 pg/kg given 20 minutes before tracheal intubation and by epidural buprenorphine 2 and 4 pg/kg given 150 minutes before surgical incision. No administration regimens of buprenorphine in the present study attenuated both cardiovascular responses to tracheal intubation and surgical incision. The authors are grateful to Monica M. Sa Rego, MD, for her helpful advice. References Lev R, Rosen. Prophylactic lidocaine use preintubation: a review. J Emerg Med 1994;12: Sklar BZ, Lurie S, Ezri T, et al. Lidocaine inhalation attenuates the circulatory response to laryngoscopy and endotracheal intubation. J Clin Anesth 1992;4: Singh H, Vichitvejpaisal, Gaines GY, White PF. Comparative effects of lidocaine, esmolol, and nitroglycerin in modifying the hemodynamic response to laryngoscopy and intubation. J Clin Anesth 1995;7:5-8. Fujii Y, Tanaka H, Saitoh Y, Toyooka H. Effects of calcium channel blockers on circulatory response to tracheal intubation in hypertensive patients: nicardipine versus diltiazem. Can J Anaesth 1995;42: ChraemmerJorgensen B, Hertel S, Strom J, et al. Catecholamine response to laryngoscopy and intubation. The influence of three different drug combinations commonly used for induction of anaesthesia. Anaesthesia 1992;47: Carabine UA, Allen RW, Moore J. Partial attenuation of the pressor response to endotracheal intubation. A comparison of the effects of intravenous clonidine and fentanyl. Eur J Anaesthesiol 1992;9: Khan FA, Kamal RS. Effect of buprenorphine on the cardiovascular response to tracheal intubation. Anaesthesia 1989;44: nagaki Y, Mashimo T, Yoshiya. Mode and site of analgesic action of epidural buprenorphine. Anesth Analg 1996;83: Dixon WJ. Quanta1 response variable experimentation: the up and down method. n McArthur JW, Colton T, eds. Statistic in endocrinology, proceedings. Cambridge, MA: MT Press, 1970: nagaki Y, Mashimo T, Yoshiya. Segmental analgesic effect and reduction of halothane MAC from epidural fentanyl in humans. Anesth Analg 1992;74: nagaki Y, Mashimo T, Yoshiya. Time-related differential effects of epidural morphine on the neuraxis. Anesth Analg 1993; 76: Rampil J, Mason, Singh H. Anesthetic potency (MAC) is independent of forebrain structures in the rat. Anesthesiology 1993;78: Rampil J. Anesthetic potency is not altered after hypothermic spinal cord transection in rats. Anesthesiology 1994;80: Kendig JJ. Spinal cord as a site of anesthetic action [editorial]. Anesthesiology 1993;79: Heel RC, Brogden RN, Speight TM, Avery GS. Buprenorphine: a review of its pharmacological properties and therapeutic efficacy. Drugs 1979;17: Eisenach JC, Gebhart GF. ntrathecal amitriptyline. Antinociceptive interactions with intravenous morphine and intrathecal clonidine, neostigmine, and carbamylcholine in rats. Anesthesiology 1995;83: King BS, Rampil J. Anesthetic depression of spinal motor neurons may contribute to lack of movement in response to noxious stimuli. Anesthesiology 1994;81: Kay B. A double-blind comparison between fentanyl and buprenorphine in analgesic-supplemented anaesthesia. Br J Anaesth 1980;52: Green DW, Sinclair JR, Mikhael MS. Buprenorphine versus morphine. A comparison of intra-operative and postoperative analgesia. Anaesthesia 1985;40: Bullingham RES, McQuay HJ, Moore A, Bennet MRD. Buprenorphine kinetics. Clin Pharmacol Ther 1980;37: Naito H. Pharmacokinetics of intravenous and epidural buprenorphine analgesia. Masui 1988;37: Eger E,, Smith NT, Stoelting RK, et al. Cardiovascular effects of halothane in man. Anesthesiology 1970;32: