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Anesth Analg 2001;93:1526-1531
© 2001 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Esmolol Promotes Electroencephalographic Burst Suppression During Propofol/Alfentanil Anesthesia

Jay W. Johansen, MD PhD

Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia

Address correspondence and reprint requests to Jay W. Johansen, MD, PhD, Department of Anesthesiology, Grady Health System of Emory University, 80 Butler Street, S.E., Atlanta, GA 30335-3801. Address e-mail to jay_johansen{at}emory.org


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
This study examined the effects of an esmolol infusion on the electroencephalogram during propofol/alfentanil IV anesthesia. After informed consent, 20 patients were randomly assigned into four groups on the basis of two target alfentanil concentrations (alfentanil 50 or 150 ng/mL) and of a saline or esmolol infusion. Bispectral index (BIS), burst suppression ratio (SR), and physiologic variables were continuously monitored. A 30-min blinded infusion of saline or esmolol was started after establishing a stable baseline and followed by a washout period. The electroencephalogram was significantly suppressed by esmolol (BIS, 37 ± 6 to 22 ± 6, 40% decrease [mean ± SD]; SR, 5 ± 7 to 67 ± 23, 13.4-fold increase) compared with baseline in the small-dose alfentanil groups. Discontinuation of esmolol reversed the response. BIS and SR were unaffected by placebo infusion. Twelve-minute to 16-min hysteresis between esmolol administration and the onset of half-maximal cortical suppression was observed. Physiologic variables and serum propofol and alfentanil concentrations were not significantly altered by esmolol. Although the mechanism remains unclear, significant cortical depression and the onset of burst suppression during a stable, computer-controlled propofol/alfentanil anesthetic was associated with esmolol infusion.

IMPLICATIONS: This study demonstrated the suppression of cerebral cortical electrical activity after blinded esmolol infusion during propofol/alfentanil anesthesia. A significant lag was noted between infusion and half-maximal effect (12–16 min). Whether esmolol, a metabolite, or a secondary process was responsible for this cortical suppression remains unknown and requires further study.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Previous work from our group has demonstrated that esmolol, a short-acting ß1-adrenergic receptor antagonist, can reduce the hypnotic requirement for prevention of movement for surgical incision during both IV (propofol/nitrous oxide/morphine) and volatile (isoflurane) anesthesia (1,2). These studies used a single, discrete measurement of anesthetic potency. Although the mechanism of this interaction was unclear, minimum alveolar anesthetic concentration (MAC) reduction by esmolol required the addition of an opioid during isoflurane anesthesia (2).

Electroencephalography (EEG) is a continuous, noninvasive method that has been used as a measure of anesthetic drug action on the central nervous system (3). At deep levels of surgical anesthesia, burst suppression represents a benign pattern frequently seen in the healthy brain (4,5). It can be readily identified in the raw EEG and is composed of short periods of electrocortical silence alternating with periods of low-frequency, high-voltage activity. Burst suppression has been used as a marker for the minimum metabolic activity of the cortex and correlates with cerebral blood flow (5,6). The induction of burst suppression has been used clinically to protect the brain from ischemic injury and to halt status epilepticus (4,7).

This study is designed to investigate the EEG response of esmolol under steady-state conditions during total IV anesthesia. Propofol (8–10) and alfentanil (11) were chosen for their rapid central nervous system equilibration. Blinded, timed infusions and serial serum drug assays were used to help describe and define the cerebral cortical response to esmolol.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval by the Human Investigations Committee (Emory University School of Medicine, Atlanta, GA) and informed written consent, 20 healthy ASA status I or II patients scheduled for elective surgery lasting at least 2 h were enrolled in a prospective, randomized, blinded, two-tiered study design. Patients were excluded if any of the following conditions were met: history of an allergic reaction to any of the study medications; morbid obesity (>=50% of ideal body weight); advanced hepatic, renal or cardiac dysfunction; long-term opioid, sedative, alcohol, or ß-blocker usage; and poorly controlled asthma, diabetes mellitus, or hypertension.

No premedication was given before anesthetic induction. Patients were randomly allocated to one of four groups: A50-S, propofol target (5.5 µg/mL) + alfentanil (50 ng/mL) + saline infusion; A50-E, propofol + alfentanil (50 ng/mL) + esmolol infusion (bolus 1 mg/kg, then 250 µg · kg-1 · min-1); A150-S, propofol + alfentanil (150 ng/mL) + saline infusion; or A150-E, propofol + alfentanil (150 ng/mL) + esmolol. Esmolol was administered at the maximum recommended clinical dose by standard bolus/infusion technique. Standard physiologic monitors and seven frontal, self-prepping EEG electrodes were placed. Two bipolar EEG channels (Fp1-Cz and Fp2-Cz) were monitored by an A1000 Bispectral Index monitor (version 3.3, Aspect Medical Systems, Inc., Newton, MA). After preoxygenation, anesthesia was induced with propofol via a computer-assisted, continuous infusion (CACI) set at an effect-site target of 5.5 µg/mL and an alfentanil CACI set at either 50 or 150 ng/mL (Duke CACI system with Abbott Life Care 4P pumps; Abbott Laboratories, North Chicago, IL) (12). Upon loss of consciousness, endotracheal intubation was facilitated by neuromuscular blockade (vecuronium 0.1 mg/kg). A right radial arterial catheter was inserted for blood sampling. Controlled ventilation was instituted to maintain normocarbia (ETCO2 = 34–38 mm Hg) at an inspired oxygen concentration of 60% (with air). Physiologic variables, end-tidal gases, and raw and processed EEG variables were continuously recorded by computer. Fourier transformations of the EEG and suppression ratio (SR) (percentage of last 60 s in cortical silence x 100) were continuously calculated by the A1000 monitor. Bispectral index (BIS) was calculated off-line from the raw, recorded EEG. Target propofol and alfentanil concentrations were not altered for the duration of the study. Patient temperature was maintained at >=35.5°C. Approximately 30 min after intubation, a blinded IV bolus and infusion, provided by the pharmacy, was started and continued for 30 min via a syringe pump (model AS40a; Baxter Health Care, Deerfield, IL). The infusion delivered either esmolol (1 mg/kg bolus, then 250 µg · kg-1 · min-1) or an equal volume of saline. Upon completion of the blinded infusion, an additional 30 min of EEG and physiologic monitoring was recorded. A balanced anesthetic technique was used for the remainder of the surgical procedure.

Six arterial blood samples, 10 mL each, were drawn from each patient for analysis of propofol and alfentanil serum concentrations (Fig. 1). Samples were obtained at -10, 0 (start), 20, 30 (end), 50, and 60 min from the start of the blinded infusion, stored on ice, serum separated by centrifugation, and frozen at -80°C until analysis. Serum propofol concentrations were measured by the method of Short et al. (13) by using high-pressure liquid chromatography (sensitivity, 0.05 ± 0.1 µg/mL). Alfentanil serum levels were measured by radioimmunoaffinity assay (Research Diagnostics, Inc., Flanders, NJ; sensitivity, 0.2 ± 5 ng/mL).



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  		Figure 1. Experimental design and time course for esmolol or saline infusion on electroencephalogram (EEG) burst suppression (SR) and bispectral index (BIS). Thirty minutes after intubation (time = 0 min), a blinded infusion was started and continued for 30 min that contained either saline (Patient 2) or esmolol (Patient 13) during an IV propofol (5.5 µg/mL)/alfentanil (50 ng/mL) anesthetic by continuous, computer-assisted continuous infusion. Arterial blood samples were drawn at -10, 0, 20, 30, 50, and 60 min from the start of the blinded infusion (designated A–F, respectively). Automated data collection concluded 30 min after termination of the blinded infusion. Bispectral index and SR (SR = percentage of isoelectric EEG in the last 60 s) are represented on a scale of 0 to 100. In Patient 13, the half-maximal decrease in BIS occurred at 5 min and the half-maximal increase in SR at 23 min from the esmolol (bolus/infusion) start.

 
Five patients were excluded and the blinded protocol repeated because of an inability to achieve a stable BIS (variation within 20% over 30 min) preinfusion baseline. Data are represented as mean ± SD. Between-group comparisons were performed with two-sided, unpaired Student’s t-tests or by {chi}2 (categoric data) tests. Changes in continuous physiologic and EEG variables were analyzed by repeated-measures analysis of variance (simple contrast to individual preinfusion baselines) at each alfentanil target concentration. Within-subjects analysis evaluated statistically significant changes from baseline in an individual group, whereas between-subjects factor analysis examined the effects of esmolol versus placebo at a given alfentanil CACI target. Post hoc Bonferroni corrections were used and adjusted for small sample size. Statistical significance was set at P <= 0.05.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The two-tiered experimental design included two alfentanil effect-site CACI targets with or without a 30-min esmolol infusion (four groups of five patients each). Eight men and 12 women with an average age of 35 ± 10 yr (95% confidence interval [CI], 31–40 yr) participated in the study. The average weight was 81 ± 14 kg (95% CI, 75–87 kg), and height was 171 ± 11 cm (95% CI, 165–176 cm). There were no differences in demographic data among groups (Table 1). Tracheal intubation was performed between 4 and 8 min after anesthetic induction during orthopedic (40%), gynecologic (50%), and general (10%) surgical procedures. Surgical incision took place 37 ± 16 min after induction. The average total propofol dose was 2056 ± 525 mg at the conclusion of the 90-min experimental course. The average alfentanil total dose was 1.9 ± 0.5 mg in the small-dose groups and 5.6 ± 0.2 mg in the larger-dose groups, respectively. In patients receiving esmolol, an average total dose of 662 ± 114 mg was administered.


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  		Table 1. Demographic Variables
 
Figure 1 illustrates two individual patient responses with or without esmolol at the small-dose alfentanil CACI target (50 ng/mL). A 30-min baseline (BIS and SR) was obtained before starting the blinded infusion and was followed by a 30-min washout period. This preinfusion baseline provided each patient with an internal control. The average preinfusion BIS was 37 ± 6 and was similar in all four groups at both alfentanil doses (Fig. 2). The average preinfusion SR was 5 ± 7 in the small-dose alfentanil groups and 9 ± 7 in the larger-dose alfentanil groups. Hemodynamic and EEG variables were collected and averaged over the 2-min period spanning each blood sampling time. Average baseline heart rate (HR) and blood pressure (BP) were 80 ± 14 bpm and 114 ± 16/67 ± 12 mm Hg, respectively.



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  		Figure 2. Bispectral index (BIS) and suppression ratio (SR; percentage of isoelectric electroencephalogram [EEG] in the last 60 s) response to blinded infusion of esmolol or saline at two alfentanil doses (50 [A, B] or 150 ng/mL [C, D]) during propofol anesthesia. Average BIS (A, C) or SR (B, D) at preinfusion baseline, infusion end, and after a 30-min washout were compared by repeated-mea-sures analysis of variance and post hoc Bonferroni’s corrections. EEG variables were averaged over 2 min at each arterial blood sampling (error bars represent SD) and correspond to samples B, D and F, respectively (Fig. 1). Statistically significant changes (P < 0.05) from baseline within a group (*) and between esmolol and placebo (#) are indicated.

 
Statistically significant changes in BIS and SR were found both within Group 2 and between Groups 1 and 2 after infusion (Fig. 2). Esmolol and infusion timing were significant factors in within- and between-group analysis. Esmolol significantly decreased BIS from 37 ± 6 to 22 ± 6 (40% decrease) and increased SR from 5 ± 7 to 67 ± 23 (13.4-fold, or increase in average isoelectric period from 3 to 40 s) for these two groups. After a 30-min washout, BIS was not significantly different from preinfusion values. SR decreased significantly from the end of esmolol infusion but did not return to baseline within the 30-min washout period. Placebo infusion did not significantly alter BIS or SR. Although BIS (37 ± 8 to 25 ± 7, 32% significant decrease from baseline) and SR increased (14 ± 11 to 49 ± 34, not significant) in association with esmolol infusion in Groups 3 and 4 (large-dose alfentanil), statistical comparison between esmolol and placebo was not significant (power 24%). Preinfusion and washout EEG averages were not significantly different between Groups 3 and 4. Processed EEG variables, such as the median frequency and spectral edge frequency (95%), did not change significantly with esmolol infusion at either alfentanil target (data not shown). Esmolol infusion produced a nonsignificant decrease (16%) in HR in the small-dose alfentanil group, but not in the large-dose groups (data not shown). No significant changes in systolic or diastolic BP were detected within any group during the three experimental phases. After a 30-min washout period, BIS and SR were not significantly different from the preinfusion baseline or saline control.

After the esmolol bolus/infusion at the maximum clinically recommended dose, BIS and SR were affected after an unpredictable interval, which was not influenced by the alfentanil dose (data not shown). In some cases (Patient 13, Fig. 1), BIS depression occurred first and was temporally dissociated from the increase in SR. The average time to half-maximal response from the start of the esmolol bolus was 12 ± 11 min for BIS decrease and 16 ± 9 min for SR increase. In two cases, the maximum EEG response occurred during the washout phase.

The average measured baseline propofol serum concentration was 5.7 ± 1.3 µg/mL. At baseline, the end of blinded infusion, and after the 30-min washout, propofol serum concentration did not change significantly within any group (Table 2). Measured average alfentanil serum concentrations were 39 ± 11 and 122 ± 27 ng/mL in the small- and large-dose tiers, respectively. Serum concentrations were stable during the experiment and did not change significantly after saline or esmolol infusion. Esmolol and its metabolites were not assayed.


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  		Table 2. Serum Propofol and Alfentanil Concentrations
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This experiment examined the effect of esmolol on the cerebrocortical EEG during total IV anesthesia in patients undergoing elective surgery and whether this response could be replicated by a larger opioid dose. A continuous esmolol infusion added to a stable, computer-controlled propofol/alfentanil anesthetic was found to suppress cerebral cortical electrical activity, resulting in a burst-suppression pattern. The effect was reversible, returning approximately to baseline 30 minutes after discontinuation of the infusion (Fig. 1). After esmolol bolus and infusion, hysteresis was noted in the onset of half-maximal cortical suppression, appearing 12 to 16 minutes afterward (BIS and SR, respectively). In addition to individual baseline controls, matched groups of blinded saline controls demonstrated no significant change in EEG or hemodynamic variables, suggesting that surgical stimulation was not a significant factor. Serum concentrations of propofol and alfentanil taken at fixed intervals before, during, and after the blinded CACI infusions did not change significantly from baseline in any group. Tripling the alfentanil target concentration did not significantly alter the baseline BIS or SR and did not induce burst suppression, suggesting that esmolol was not acting by simply increasing the effective concentration of alfentanil. It is possible that regional effects on cerebral blood flow could be responsible for the cortical suppression by esmolol. In the rat, propranolol significantly decreases the average cerebral blood flow and average cerebral metabolic rate under isoflurane anesthesia (14,15).

The response was robust and reversible and could be directly observed in the unprocessed EEG. SR is an increasingly major component of the BIS calculation at BIS values <35 (3). Esmolol is not believed to cross the blood-brain barrier (16). The hysteresis between IV esmolol administration and EEG suppression may indicate that the intravascular compartment was not the primary site of action or that a secondary process, e.g., metabolism or release of a second factor, may have been involved. The hysteresis may also explain why other researchers who administered a single bolus or administered limited infusions have not described this response to esmolol. Ornstein et al. (17) have shown that the time courses of bradycardia and the hypotensive effects of esmolol are different (t1/2 1.2 vs 17.8 minutes). These researchers correlated the delay in mean arterial pressure decrease with a reduction in ß-adrenoreceptor-stimulated synthesis of plasma renin.

This experiment was designed with variables identified during MAC reduction protocols without a standardized stimulus. The saline-control groups did not change significantly from baseline, suggesting that surgical stimuli did not significantly change the EEG under these conditions. This experiment did not evaluate blockade of surgical stimuli-induced EEG changes. The relationship of MAC reduction (18,19) and cortical EEG suppression by esmolol may represent distinct pharmacologic effects of esmolol infusions during anesthesia, because cortical suppression and MAC have been dissociated anatomically in animals (20,21).

The esmolol effect on cortical suppression requires further characterization. Descriptions of the esmolol dose response, variability of response, opioid requirement, and whether other ß-adrenergic blockers depress electrocortical activity are needed. The site of interaction and the mechanism remain unclear. A number of relevant comments can be made. 1) The sample size in the current experiment was small. 2) Surgical stimuli were not controlled. 3) The preinfusion hypnotic state may have been sufficiently deep to prevent measurement of significant changes in other EEG power spectral variables. 4) EEG analysis was linked to fixed blood sampling times and not to maximal response. This increased the experimental variability in EEG analysis, with several patients achieving maximal suppression in the washout phase. 5) A 30-minute esmolol infusion may have been insufficient to maximize the EEG response. On the basis of the half-maximal response (x3), at least a 36- to 48-minute esmolol infusion would be required to maximize both BIS depression and burst suppression (SR). 6) Esmolol and its metabolites were not assayed. 7) The experiment was constrained by the surgical operation, and full washout/reversal of the response was not observed. 8) Although SR was used as a variable, the mechanism of burst suppression is poorly understood and may represent more than a single discreet process. Because the BIS changes monotonically across the full range of hypnosis, BIS represents a more robust single measurement of cortical activity for future investigations (22).

Clinically esmolol is effective in blunting the adrenergic response to a number of perioperative stimuli, including laryngoscopy and anesthetic emergence (23,24). Although patients receiving chronic ß-adrenergic blockade are often seen perioperatively, and although acute atenolol administration (25) reduces mortality during hospitalization and up to two additional years after noncardiac surgery in patients at risk for coronary artery disease, it is unknown whether ß-adrenergic antagonists other than esmolol induce electrocortical suppression during anesthesia. The clinical relevance of this response remains unknown.

This experiment provided evidence for cortical EEG suppression by an esmolol infusion during a stable, total IV, computer-controlled anesthetic with propofol and alfentanil. The induction of burst suppression was directly observed in the raw, unprocessed EEG but was best quantified by a decrease in BIS and an increase in SR. The response was reversible with discontinuation of the esmolol infusion. Individual patients served as their own baseline controls before the blinded infusions. Saline control infusions had stable EEG and hemodynamic values during the experiment. No significant change in HR or BP could account for this suppression. Plasma propofol and alfentanil concentrations remained unchanged, suggesting that esmolol did not significantly interact with the pharmacokinetic distribution of these drugs. The exact mechanism of this response requires further characterization.


   Acknowledgments
 
Supported by a research grant from the Emory Medical Care Foundation, Grady Memorial Health System of Emory University School of Medicine, Atlanta, GA.

We thank Fania Szlam for technical support and processing of alfentanil, propofol, and esmolol assays.


   Footnotes
 
Presented in part at the annual meeting of American Society of Anesthesiologists, San Diego, CA, October 16, 1997.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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  19. Johansen JW, Schneider G, Windsor A, Sebel PS. Esmolol potentiates reduction of minimum alveolar isoflurane concentration by alfentanil. Anesth Analg 1998; 87: 671–6.
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Accepted for publication August 17, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press