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TECHNOLOGY, COMPUTING, AND SIMULATION

The Short-Acting ß₁-Adrenoceptor Antagonists Esmolol and Landiolol Suppress the Bispectral Index Response to Tracheal Intubation During Sevoflurane Anesthesia

Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan

Address correspondence and reprint requests to Yutaka Oda, MD, PhD, Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka City University, 1-5-7 Asahimachi, Abeno-ku, Osaka 545-8586, Japan. Address e-mail to odayou{at}msic.med.osaka-cu.ac.jp.

	Abstract

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In this randomized, double-blind, controlled study, we tested the hypothesis that the short-acting ß₁-adrenoceptor antagonists esmolol and landiolol suppress hemodynamic changes and bispectral index (BIS) increases, both of which are induced by tracheal intubation under general anesthesia with sevoflurane alone. Forty-five patients were randomly assigned to the control, esmolol, and landiolol groups (n = 15 each). Anesthesia was induced with sevoflurane in oxygen, with an end-tidal concentration maintained at 1 minimum alveolar anesthetic concentration (MAC). Infusion of saline (control group), esmolol (bolus of 1 mg/kg and then 0.25 mg · kg^–1 · min^–1; esmolol group), or landiolol (bolus of 0.125 mg/kg and then 0.04 mg · kg^–1 · min^–1; landiolol group) was started 5 min after the induction of anesthesia and was continued throughout the study. Tracheal intubation was performed 12 min after anesthesia induction. There were no differences in overall changes of mean arterial blood pressure among the three groups, whereas, at 1–5 min after tracheal intubation, heart rate increased in all groups but was significantly slower in the esmolol and landiolol groups than in the control group (P < 0.05). BIS was between 96 and 98 for all patients at baseline and decreased during the induction of anesthesia. There were no differences in BIS among the three groups before laryngoscopy (39 ± 5, 39 ± 5, and 38 ± 4 in the control, esmolol, and landiolol groups, respectively). BIS increased significantly in the control group (54 ± 10; P < 0.05) 1 min after intubation, whereas it remained unchanged in the esmolol and landiolol groups (45 ± 10 and 41 ± 6, respectively). In conclusion, the increase in both heart rate and BIS after tracheal intubation under 1 MAC sevoflurane anesthesia was suppressed by the concomitant administration of either esmolol or landiolol.

	Introduction

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Esmolol, a short-acting ß₁-adrenoceptor antagonist, attenuates the hemodynamic changes during anesthesia (1). It also decreases the bispectral index (BIS), a numeric index that directly reflects the activity of the cerebral cortex and correlates with levels of consciousness (2–4). This suggests that esmolol suppresses central nervous system activity and hemodynamic changes during tracheal intubation. Besides exerting these favorable effects, esmolol contributes to decreasing the dose of anesthetics for maintaining an adequate depth of anesthesia (5,6).

A volatile anesthetic can be used for both the induction and maintenance of general anesthesia (7). When combined with IV anesthetics, esmolol is reported to be effective in blunting the hemodynamic and BIS response to tracheal intubation (8); however, there is no report elucidating whether concomitant administration of esmolol with a single volatile anesthetic would exhibit a similar effect or not. Given that increased BIS is associated with inadequate depth of anesthesia and intraoperative awareness, it is postulated that esmolol may contribute to effective reduction of the dose of anesthetic required during tracheal intubation, besides maintaining adequate depth of anesthesia. This study was designed to test the hypothesis that the hemodynamic and BIS changes that occur in response to tracheal intubation during anesthesia with a single anesthetic, sevoflurane, might be suppressed by esmolol and landiolol, a new short-acting ß₁-adrenoceptor antagonist (9).

	Methods

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After obtaining approval from the Institutional Ethics Committee and written informed consent from each patient, we randomly allocated 45 patients of ASA physical status I, aged 20 to 70 yr, scheduled for elective orthopedic surgery, to 3 groups and conducted the following study in a double-blind fashion. Patients with abnormal electrocardiogram; cardiovascular, respiratory, or psychologic diseases; or predicted difficulty in tracheal intubation were excluded from the study.

No premedication was given. On arrival in the operating room, routine monitors were applied for recording mean arterial blood pressure (MAP), heart rate (HR), and oxygen saturation. BIS (version 3.0) was measured continuously on an electroencephalographic monitor (Model A-2000; Aspect Medical Systems, Newton, MA) by using BisSensor strips (Aspect Medical Systems). The impedance of each electrode was maintained at <2 k. Expired gas was collected via a sampling tube connected to the face mask at 200 mL/min, and carbon dioxide tensions and the concentrations of sevoflurane were measured with a gas analyzer (Capnomac Ultima; Datex Instrumentarium Corp., Helsinki, Finland). We assumed a minimum alveolar anesthetic concentration (MAC) of sevoflurane of 1.71% (10).

Anesthesia was induced with sevoflurane and oxygen via a face mask by using a semiclosed circle system with a total gas flow of 6 L/min. End-tidal carbon dioxide tension was maintained at 35–40 mm Hg. The concentration of sevoflurane was initially 0.5% and was then increased slowly until the end-tidal concentration reached 1 MAC. After loss of consciousness, vecuronium 0.1 mg/kg was given IV. Five minutes after the induction of anesthesia, patients received either 1) a bolus of esmolol 1 mg/kg followed by a continuous infusion of 0.25 mg · kg^–1 · min^–1 (esmolol group) or 2) a bolus of landiolol 0.125 mg/kg followed by an infusion of 0.04 mg · kg^–1 · min^–1 (landiolol group). Patients in the control group were given a comparable volume of saline. Bolus infusion was performed in 20 s by the anesthesiologist who was involved in preparation of the test drug solutions and operation of the infusion pump. The administration of saline, esmolol, or landiolol was continued until 5 min after intubation. Twelve minutes after the induction of anesthesia, the trachea was intubated, and the lungs were ventilated with 1 MAC sevoflurane. No additional drugs were given during the study period. MAP, HR, and BIS were recorded before the induction of anesthesia (baseline), 5 min after induction, immediately before laryngoscopy, and every minute after intubation. No other surgical procedure was performed during the study. The induction of anesthesia and tracheal intubation were performed by one of the authors (YO) while MAP, HR, and BIS were recorded by another; however, both investigators were blinded to group allocation.

The number of patients enrolled in each group was determined according to our preliminary findings for eight patients indicating that BIS increased from 40 ± 8 to 50 ± 8 after intubation. According to the formula for normal theory and assuming a Type I error protection of 0.05 and a power of 0.80 to detect a 20% change in BIS after intubation, 14 patients were required for each of the 3 groups. All data are expressed as the mean ± sd. Statistical analysis was performed with StatView 5.0 (SAS Institute Inc., Cary, NC). Differences in sex ratios among the groups were examined by ² test; differences in MAP, HR, and BIS among the groups were examined with analysis of variance for repeated measures. If a significant difference was observed among groups, overall differences among the values of the 3 groups were analyzed by the Tukey-Kramer multiple comparison test. Furthermore, comparisons of the values at baseline, 5 min after the induction of anesthesia, immediately before laryngoscopy, and 1–5 min after intubation were performed by using one-way analysis of variance for repeated measures followed by the Tukey-Kramer multiple comparison test to determine which time point had values significantly different from baseline or before laryngoscopy. Because BIS at baseline was 96–98 for all patients, it was compared only with the value before laryngoscopy. Values were considered significant when P < 0.05.

	Results

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No differences were observed in patients’ demographic data, baseline hemodynamics, or BIS among the three groups (Tables 1 and 2). Laryngoscopy and tracheal intubation were performed within 20 s in all patients, and no differences were found in the time required for these procedures among groups (data not shown). The end-tidal concentration of sevoflurane was increased to 1.7% within 5 min of anesthesia induction and remained at 1.6%–1.8% for the duration of the study. End-tidal carbon dioxide tensions or sevoflurane concentrations before and after tracheal intubation were comparable in all groups (Table 3). No patient developed systolic blood pressure <80 mm Hg or HR <50 bpm or complained after surgery of awareness during anesthesia.

In all groups, MAP decreased significantly at the time of laryngoscopy compared with baseline (P < 0.05) and increased significantly after tracheal intubation relative to before laryngoscopy (P < 0.01); however, there were no differences in overall changes of MAP among the three groups (Table 2). HR before infusion of saline, esmolol, or landiolol was not different from baseline in any group. In the control group, HR was not different from baseline before laryngoscopy but was significantly increased by tracheal intubation and subsequently returned to baseline. HR decreased significantly before laryngoscopy compared with baseline in the esmolol and landiolol groups (P < 0.01). Although HR increased significantly during tracheal intubation in the esmolol and landiolol groups, it was comparable to baseline and was significantly less than that in the control group 1 to 5 min after intubation (P < 0.01).

BIS was between 96 and 98 at baseline and decreased during the induction of anesthesia; it reached <50 in all patients before laryngoscopy. There were no intergroup differences in BIS up to the time of laryngoscopy. One minute after intubation, BIS was significantly higher than that observed before tracheal intubation in the control group (P < 0.01), but it remained unchanged in the esmolol and landiolol groups. BIS was lower in the esmolol and landiolol groups than in the control group 1 and 2 min after intubation. Three to 5 min after intubation, BIS was comparable to the preintubation value in all groups, and there were no differences among the three groups.

	Discussion

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In this study, both esmolol and landiolol decreased HR during the induction of anesthesia. Although the increase in HR in response to tracheal intubation was not entirely suppressed, the increase was significantly blunted by esmolol or landiolol after tracheal intubation. Neither of these drugs affected overall changes of MAP during induction or after tracheal intubation, and this is consistent with previous reports using a similar dose of esmolol during anesthesia with propofol and isoflurane (8,11).

However, the increase in BIS in response to tracheal intubation during anesthesia with 1 MAC sevoflurane was suppressed by both esmolol and landiolol. Several studies have been conducted with the use of IV anesthetics (4,5,8,12), yet relatively few studies have monitored changes of BIS during anesthesia with volatile anesthetics (3,13–15). Our present study revealed that BIS changes in the control group were comparable to those observed during anesthesia with propofol (8). In contrast, Nakayama et al. (13) showed that isoflurane and sevoflurane completely inhibited the increase in BIS after tracheal intubation. These differences could be attributed to the use of sevoflurane at a larger concentration (2 MAC) in their study than in ours. Thiopental, used for the induction of anesthesia in the study of Nakayama et al. (13), might also be responsible for their results. Given that the increase of BIS was suppressed by concomitant use of either esmolol or landiolol with 1 MAC sevoflurane, our results suggest that these ß₁-adrenoceptor antagonists would be conducive to dose saving of sevoflurane during tracheal intubation because of prevention of the hemodynamic response and maintenance of an adequate depth of anesthesia.

The dose of esmolol was selected in accordance with previous reports in which concomitant use of esmolol with propofol showed a successful reduction of the required dose for anesthesia and a favorable inhibition of the BIS response to tracheal intubation (5,8). The dose of landiolol was chosen on the basis of its effectiveness in blunting the hemodynamic response to tracheal intubation during anesthesia with thiamylal or isoflurane (16,17). However, plasma concentrations of esmolol or landiolol were not measured, so the relationships between concentrations and their effect on BIS remain unclear. Furthermore, the dose-dependent effect of these drugs or the mechanism responsible for suppressing the increase of BIS has not been investigated, and these are the major limitations of our study. Although changes in cardiac output may affect the pharmacokinetics of anesthetics, the alveolar concentrations of poorly soluble drugs such as sevoflurane are the least sensitive to cardiac output changes (18,19). The unchanged end-tidal concentration of sevoflurane by esmolol or landiolol in our study would suggest that the effect of these drugs on the change of BIS in response to tracheal intubation was not likely to have resulted from altered alveolar concentrations of sevoflurane.

In contrast to numerous reports regarding esmolol, few studies have been performed to address the effect of landiolol, (–)-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl-3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbonylamino)ethylamino]proxy]phenylpropinate (9), on hemodynamic changes during anesthesia (17). This is the first report investigating the effect of landiolol on BIS. Unlike esmolol, which is a racemic mixture of stereoisomers, landiolol is an optically active compound with the highest ß₁-adrenoceptor selectivity and inhibition potency among the four stereoisomers with the same chemical structure (20). The dose of landiolol used before tracheal intubation in our study accounted for approximately 15% of that of esmolol (0.41 versus 2.75 mg/kg), but the effects of these drugs on HR and BIS were equipotent, suggesting that landiolol is severalfold more potent than esmolol in controlling BIS and HR during tracheal intubation.

In conclusion, we have shown that the increase of BIS produced by tracheal intubation during anesthesia with 1 MAC sevoflurane was suppressed by esmolol and landiolol. In particular, landiolol, a new short-acting ß₁-adrenoceptor antagonist with high ß₁-adrenoceptor selectivity and inhibition potency, is also effective in suppressing intubation-induced increases of BIS.

	References

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