1 Département dAnesthésie-Réanimation, Ambroise Pare Hôpital, 9 Avenue Charles de Gaulle, F-92100 Boulogne-Billancourt, France. 2 Outcomes Research® Institute Institute and Department of Anesthesiology, University of Louisville, Kentucky, USA; Ludwig Boltzmann Anesthesia Institute, University of Vienna, Vienna, Austria marcel.chauvin@apr.ap-hop-paris.fr
Declaration of interest. Supported by NIH Grant GM 58273 (Bethesda, MD, USA), the Joseph Drown Foundation (Los Angeles, CA, USA), and the Commonwealth of Kentucky Research Challenge Trust Fund (Louisville, KY, USA). None of the authors has any personal financial interest in this research.
Accepted for publication: July 29, 2002
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. Fifty patients were randomly allocated, in a double-blind fashion, to receive esmolol 1 mg kg1 followed by 250 µg kg1 min1 or saline (control). Esmolol or saline was started 6 min after a target-controlled infusion (TCI) of propofol (effect-site concentration 4 µg ml1). After loss of consciousness, and before administration of vecuronium 0.1 mg kg1, a tourniquet was applied to one arm and inflated to 150 mm Hg greater than systolic pressure. Eleven minutes after the TCI began, the trachea was intubated; gross movement within the first min after orotracheal intubation was recorded. BIS was recorded at 10-s intervals. Mean arterial pressure (MAP) and heart rate were measured non-invasively every min.
Results. There were no intergroup differences in BIS, heart rate or MAP before laryngoscopy. BIS increased significantly after orotracheal intubation (compared with the pre-laryngoscopy values) in the control group only, with a maximum increase of 40 (SD 18)% vs 8 (11)% in the esmolol group (P<0.01). Maximum changes in heart rate [45 (19)% vs 23 (14)%] and MAP [62 (24)% vs 45 (23)%] with orotracheal intubation were also significantly greater in the control group than in the esmolol group. More patients in the control than in the esmolol group moved after orotracheal intubation (23 vs 12, P<0.01).
Conclusion. Esmolol not only attenuated haemodynamic and somatic responses to laryngoscopy and orotracheal intubation, but also prevented BIS arousal reactions in patients anaesthetized with propofol.
Br J Anaesth 2002; 89: 85762
Keywords: anaesthetic techniques, i.v.; intubation tracheal, haemodynamic changes; monitoring, bispectral index; potency, anaesthetic
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Esmolol, a short-acting ß1-adrenoceptor antagonist, produces dose-dependent attenuation of the adrenergic response to laryngoscopy and orotracheal intubation.4 However, previous studies assessing the effectiveness of esmolol in blunting the haemodynamic alterations induced by laryngoscopy and orotracheal intubation failed to monitor electrical activity of the brain. Only a few studies have evaluated the effect of interaction between ß-adrenoceptor antagonists and anaesthetics on BIS.5 6 They raised the possibility that esmolol administration may mask inadequate anaesthesia.
It is also known that esmolol decreases the amount of anaesthesia required to prevent movement in response to skin incision.7 8 Although a correlation between BIS and movement has been observed under some circumstances,9 no relationship has been observed in other studies.10 11 A poor relationship between movement and BIS is understandable since EEG measures cortical activity, whereas movement in response to noxious stimulation originates in the spinal cord.12 Our purpose was therefore to determine whether preventing haemodynamic responses during laryngoscopy and orotracheal intubation with esmolol simultaneously ameliorates somatic and BIS arousal reactions.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients were assigned randomly, in a double-blind fashion, to one of two groups (25 patients per group): control or esmolol. Group allocations were based on computer-generated codes. The hospital pharmacist prepared suitable syringes for each patient: a 10-ml syringe containing either isotonic sodium chloride (saline) or esmolol 100 mg in saline for the initial bolus, and a 50 ml syringe containing either saline or esmolol 250 mg diluted in saline for the continuous infusion. Patients and personnel involved in patient management and data collection were unaware of the group assignment.
Figure 1 shows the time line for the study protocol. No sedative premedication was given. After preoxygenation, the subjects were anaesthetized with i.v. propofol. The patients were manually ventilated to maintain end-tidal carbon dioxide concentration between 30 and 35 mm Hg until laryngoscopy and orotracheal intubation; subsequently, they were mechanically ventilated with oxygen 40%. Propofol was administered via a computer-assisted infusion device (Fresenius Vial Medical, Brezins, France) using a program written in Visual Basic® 5 (Microsoft Corporation, Redmond, OR, USA) by one of the investigators (BG). The pharmacokinetic set published by Marsh and colleagues13 was used to estimate target effect-site concentrations of propofol. The plasma effect-site equilibrium rate constant (Keo) value used for propofol was 0.638 min1.13 Propofol was administered to a target effect-site concentration of 4 µg ml1 (i.e. 2 mg kg1 bolus followed by 225 µg kg1 min1) during the entire study period.
|
Before induction of anaesthesia, silver/silver chloride pre-gelled electrodes (Aspect Medical Systems, Natick, MA, USA) were applied to the left and right frontal (Fp1 and Fp2) regions and referred to a vertex electrode (Cz). We confirmed that electrode impedance was <2000 . The EEG was recorded continuously using an Aspect A-1000 EEG monitor (Aspect Medical Systems, Natick, MA, USA), which also continuously computed the BIS (revision 3.3). A BIS value was generated every 10 s. Arterial pressure and heart rate were measured non-invasively every minute using a Cardiocap monitor (Datex, Helsinki, Finland), and acquired simultaneously with the EEG using multi-serial interfaces between the monitors and a personal computer. All acquired data were stored on disk for subsequent analysis.
The BIS values given are the mean of six measurements taken at each data point. The recordings were taken before induction; before the start of esmolol or saline; 1, 3 and 5 min (pre-laryngoscopy) after the start of the esmolol infusion; and 1, 2 and 5 min after orotracheal intubation.
Changes in BIS, heart rate and MAP with orotracheal intubation (BIS,
HR and
MAP, respectively) were defined as the differences between the pre-laryngoscopy values and the maximal value obtained for each variable within the first 5 min after orotracheal intubation.
On the first postoperative day, patients were asked whether they recalled any intraoperative events.
Statistical analysis
All statistical analyses were performed using Statview (Version 5.0, SAS Institute Inc., Cary, NC, USA). Physical characteristics, durations of laryngoscopy and orotracheal intubation, and maximum BIS,
HR and
MAP during the 5 min following orotracheal intubation were evaluated using analysis of variance (ANOVA). The BIS, heart rate and MAP at each time point in each group and
BIS,
HR and
MAP from baseline were analysed using ANOVA and repeated-measures ANOVA. To evaluate the stability of the BIS recordings, the coefficients of variation of the BIS values obtained within the 1-min periods were calculated for each individual.
Fishers exact test was used to compare the proportion of patients with movement in each group. When a difference in proportions was found betwen the groups, pair-wise comparisons were performed. Results are presented as mean (SD); P<0.05 was considered statistically significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
There is a dose-dependent risk of hypotension and bradycardia before laryngoscopy when esmolol is combined with anaesthesia induction agents.4 However, the esmolol regimen used in the present study did not result in any deleterious haemodynamic effects. We did not use opioids, which may have decreased heart rate and MAP before laryngoscopy in other studies.4 14 Compared with earlier reports,4 14 esmolol was more effective in this study in controlling tachycardia than the pressor response to laryngoscopy and orotracheal intubation. This difference is consistent with the different mechanisms involved in each response: bradycardia results from a direct cardiac effect of esmolol whereas hypotension results from a gradual decrease in renin release.15 As might be expected, the time required to obtain 90% of the maximum decrease in heart rate (4.8 min) is far shorter than that for the same decrease in MAP (42 min).15
Esmolol decreased the incidence of movement in response to laryngoscopy and orotracheal intubation. These results are consistent with reports that esmolol reduces the propofol concentration required to prevent movement in response to skin incision.7 In that study, propofol was combined with nitrous oxide and morphine premedication.7 Interaction between any of the anaesthetic components, specifically with nitrous oxide or morphine and esmolol, may have caused the effect. In fact, the same group found that esmolol had no effects on isoflurane minimum alveolar concentration (MAC) alone, but that MAC was decreased when esmolol was given along with alfentanil, suggesting a possible potentiation of opioid action by esmolol.8 That study only evaluated movement and haemodynamic responses to skin incision. In contrast, our current study indicates that propofol combined with esmolol alone, at a similar dose to that used by Johansen and co-workers,8 blunted nociceptive reactions to laryngoscopy and orotracheal intubation, including changes in BIS, as well as the autonomic and somatic responses. It is unclear whether our results are inconsistent with those of Johansen and co-workers8 because there were differences in the design and anaesthetic regimens between the two studies. However, our results are consistent with two other studies, each of which demonstrated that esmolol can be used as an alternative to opioids for maintaining haemodynamic,6 16 and BIS6 stability during general anaesthesia.
Addition of esmolol to general anaesthesia with propofol did not affect BIS before laryngoscopy. This observation suggests that esmolol does not modify BIS during general anaesthesia when substantial sympathetic activation is unlikely. It seems likely that esmolol has no anaesthetic effect per se; instead, it acts mainly via ß-adrenergic block and is thus effective only during sympathetic activation. These results are consistent with a recent study reporting that the propofol blood concentration preventing response to command was unaltered by esmolol.17 In contrast, Johansen18 showed that esmolol suppressed the EEG, with a decrease in BIS and an increase in the burst suppression ratio during propofol/alfentanil anaesthesia. However, in the latter study,18 surgical stimuli were not controlled and it seems likely that esmolol blunted the adrenergic response to them.
Our results and previous studies5 6 clearly indicate that ß-adrenoceptor antagonists not only block cardiovascular stress responses after noxious stimulation, which could mask inadequate anaesthesia, but also increase the antinociceptive component of anaesthesia. The mechanism for this effect remains unclear. One explanation may be a central antinociceptive effect of ß-adrenoceptor block. Consistent with this hypothesis is the finding that i.v. esmolol19 decreases nociceptive behaviour in rats after formalin injection, as did intrathecal ONO 1101,20 another ß1-adrenoreceptor antagonist. Noxious stimulation is transmitted through the spinal cord, the brainstem reticular formation and the thalamus to the cerebral cortex, where it evokes an EEG arousal response. Beta-adrenoceptors are present in various parts of the reticular activating system, particularly the medial septal region of the basal forebrain.21 Infusion of ß-adrenoceptor agonists into this region elicits enhancement of behavioural and EEG indices of waking in animals.21 Conversely, infusion of ß-adrenoceptor antagonists decreases EEG indices of arousal.21 Similarly in humans, infusion of isoprenaline22 or epinephrine23 causes clinical signs of arousal associated with an increase in BIS.23 Additionally, BIS levels are significantly correlated with plasma norepinephrine concentrations after oral diazepam premedication.24 This finding suggests that the noxious stimulation of laryngoscopy and orotracheal intubation increases central catecholamine concentrations, and that esmolol prevents the increase in BIS in response to laryngoscopy and orotracheal intubation by blocking ß-adrenoceptors within the reticular formation. However, the pharmacokinetics of esmolol do not entirely support this hypothesis. Esmolol is hydrophilic, as is atenolol;25 and like atenolol, it probably does not readily cross the bloodbrain barrier.26 The brain:plasma ratio for esmolol is unknown, but it was found to be 0.20 for atenolol, compared with 26 and 50, respectively for the lipophilic ß-adrenoreceptor antagonists, propranolol and oxprenolol.
Another explanation may be an alteration of the pharmacokinetics of propofol by esmolol. Doses of esmolol similar to those we used were not found to change the performance of the propofol TCI device in two studies,7 18 whereas it increased the bias and reduced the inaccuracy of the TCI device in another.17 Our finding, that BIS values before laryngoscopy were similar in the two groups, does not support this theory. In addition, esmolol has been shown to control intraoperative nociceptive responses during desflurane anaesthesia in a similar way to a comparative group that received desflurane and an opioid in the anaesthetic regimen.6 In another study, patients ß-blocked with atenolol required less fentanyl and isoflurane than unblocked control patients to produce similar BIS values.5 However, we did not measure propofol concentrations and thus cannot eliminate a potential pharmacokinetic interaction with esmolol. Moreover, esmolol, by attenuating the haemodynamic responses to laryngoscopy and orotracheal intubation, may have prevented the increase in cardiac output that would normally lead to redistribution of blood flow, with a resultant fall in the effect-site concentration of propofol and an increase in BIS. Thus, the exact mechanism of action of esmolol in blocking the BIS response to noxious stimulation is not understood.
In conclusion, esmolol had no significant effect on BIS before laryngoscopy and orotracheal intubation in patients anaesthetized with propofol. However, it not only attenuated the haemodynamic responses, but also prevented movement and BIS increases in response to laryngoscopy and orotracheal intubation. These results suggest that esmolol may produce a clinically important antinociceptive effect.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Guignard B, Menigaux C, Dupont X, et al. The effect of remifentanil on the bispectral index change and hemodynamic responses after orotracheal intubation. Anesth Analg 2000; 90: 1617
3 Ropcke H, Rehberg B, Koenen-Bergmann M, et al. Surgical stimulation shifts EEG concentration-response relationship of desflurane. Anesthesiology 2001; 94: 3909[ISI][Medline]
4 Figueredo E, Garcia-Fuentes EM. Assessment of the efficacy of esmolol on the haemodynamic changes induced by laryngoscopy and tracheal intubation: a meta-analysis. Acta Anaesthesiol Scand 2001; 45: 101122[ISI][Medline]
5 Zaugg M, Tagliente T, Lucchinetti E, et al. Beneficial effects from beta-adrenergic blockade in elderly patients undergoing noncardiac surgery. Anesthesiology 1999; 91: 167486[ISI][Medline]
6 Coloma M, Chiu JW, White PF, Armbruster SC. The use of esmolol as an alternative to remifentanil during desflurane anesthesia for fast-track outpatient gynecologic laparoscopic surgery. Anesth Analg 2001; 92: 3527
7 Johansen JW, Flaishon R, Sebel PS. Esmolol reduces anesthetic requirement for skin incision during propofol/nitrous oxide/morphine anesthesia. Anesthesiology 1997; 86: 36471[ISI][Medline]
8 Johansen JW, Schneider G, Windsor AM, Sebel PS. Esmolol potentiates reduction of minimum alveolar isoflurane concentration by alfentanil. Anesth Analg 1998; 87: 6716[Abstract]
9 Leslie K, Sessler DI, Smith WD, et al. Prediction of movement during propofol/nitrous oxide anesthesia. Anesthesiology 1996; 84: 5263[ISI][Medline]
10 Dwyer RC, Rampil IJ, Eger EI, Bennett HL. The electroencephalogram does not predict depth of isoflurane anesthesia. Anesthesiology 1994; 81: 4039[ISI][Medline]
11 Coste C, Guignard B, Menigaux C, Chauvin M. Nitrous oxide prevents movement during orotracheal intubation without affecting BIS value. Anesth Analg 2000; 91: 1305
12 Rampil IJ. Anesthetic potency is not altered after hypothermic spinal cord transection in rats. Anesthesiology 1994; 80: 60610[ISI][Medline]
13 Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth 1991; 67: 418[Abstract]
14 Miller DR, Martineau RJ, Wynands JE, Hill J. Bolus administration of esmolol for controlling the haemodynamic response to tracheal intubation: the Canadian Multicentre Trial. Can J Anaesth 1991; 38: 84958[Abstract]
15 Ornstein E, Young WL, Ostapkovich N, et al. Are all effects of esmolol equally rapid in onset? Anesth Analg 1995; 81: 297300[Abstract]
16 Smith I, Van Hemelrijck J, White PF. Efficacy of esmolol versus alfentanil as a supplement to propofolnitrous oxide anesthesia. Anesth Analg 1991; 73: 5406[Abstract]
17 Orme R, Leslie K, Umranikar A, Ugoni A. Esmolol and anesthetic requirement for loss of responsiveness during propofol anesthesia. Anesth Analg 2002; 93: 11216
18 Johansen JW. Esmolol promotes electroencephalographic burst suppression during propofol/alfentanil anesthesia. Anesth Analg 2001; 93: 152631
19 Davidson EM, Doursout MF, Szmuk P, Chelly JE. Antinociceptive and cardiovascular properties of esmolol following formalin injection in rats. Can J Anaesth 2001; 48: 5964
20 Taira Y, Kakinohana M, Kakinohana O, Okuda Y. ONO 1101, a novel ultra-short acting ß1 blocker can reduce pain behaviour in the rat formalin test. Anesthesiology 1998; 89: A1128
21 Berridge CW, Foote SL. Enhancement of behavioral and electroencephalographic indices of waking following stimulation of noradrenergic ß-receptors within the medial septal region of the basal forebrain. J Neurosci 1996; 16: 69997009
22 Johnson IA, Andrzejowski J, Sikiotis L. Arousal following isoprenaline. Anaesth Intens Care 1999; 27: 221
23 Andrzejowski J, Sleigh JW, Johnson IAT, Sikiotis L. The effect of intravenous epinephrine on the bispectral index and sedation. Anaesthesia 2000; 55: 7613[ISI][Medline]
24 Hirota K, Matsunami K, Kudo T, et al. Relation between bispectral index and plasma catecholamines after oral diazepam premedication. Eur J Anaesthesiol 1999; 16: 51618[ISI][Medline]
25 Neil-Dwyer G, Bartlett J, McAinsh J, Cruickshank JM. ß-Adrenoceptor blockers and the blood-brian barrier. Br J Clin Pharmacol 1981; 11: 54953[ISI][Medline]
26 Sum CY, Yacobi A, Kartzinel R, Stampfli H, et al. Kinetics of esmolol, an ultra-short-acting beta blocker, and of its major metabolite. Clin Pharmacol Ther 1983; 34: 42734[ISI][Medline]