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Background Awareness during anesthesia is a serious complication with potential long-term psychological consequences. Use of the bispectral index (BIS), developed from a processed electroencephalogram, has been reported to decrease the incidence of anesthesia awareness when the BIS value is maintained below 60. In this trial, we sought to determine whether a BIS-based protocol is better than a protocol based on a measurement of end-tidal anesthetic gas (ETAG) for decreasing anesthesia awareness in patients at high risk for this complication.
Methods We randomly assigned 2000 patients to BIS-guided anesthesia (target BIS range, 40 to 60) or ETAG-guided anesthesia (target ETAG range, 0.7 to 1.3 minimum alveolar concentration [MAC]). Postoperatively, patients were assessed for anesthesia awareness at three intervals (0 to 24 hours, 24 to 72 hours, and 30 days after extubation).
Results We assessed 967 and 974 patients from the BIS and ETAG groups, respectively. Two cases of definite anesthesia awareness occurred in each group (absolute difference, 0%; 95% confidence interval [CI], –0.56 to 0.57%). The BIS value was greater than 60 in one case of definite anesthesia awareness, and the ETAG concentrations were less than 0.7 MAC in three cases. For all patients, the mean (±SD) time-averaged ETAG concentration was 0.81±0.25 MAC in the BIS group and 0.82±0.23 MAC in the ETAG group (P=0.10; 95% CI for the difference between the BIS and ETAG groups, –0.04 to 0.01 MAC).
Conclusions We did not reproduce the results of previous studies that reported a lower incidence of anesthesia awareness with BIS monitoring, and the use of the BIS protocol was not associated with reduced administration of volatile anesthetic gases. Anesthesia awareness occurred even when BIS values and ETAG concentrations were within the target ranges. Our findings do not support routine BIS monitoring as part of standard practice. (ClinicalTrials.gov number, NCT00281489
[ClinicalTrials.gov]
.)
Of the 21 million patients who are given general anesthesia annually in the United States,7 the vast majority inhale an anesthetic gas. It is routine to monitor the concentration of exhaled anesthetic gases by analyzing the absorption of infrared light, which provides accurate identification and quantification of the exhaled gases.9 The minimum alveolar concentration (MAC) is the concentration of anesthetic gas required to prevent 50% of subjects from moving in response to a painful stimulus.10 The standard metric for assessing and comparing the potency of anesthetic-gas concentrations is the MAC equivalent; when anesthetic gases are used in combination, their MAC equivalents are additive. When the end-tidal anesthetic gas (ETAG) concentration is approximately one third of the MAC, 50% of subjects are not awake.10 Maintaining the ETAG concentration above 0.7 MAC may decrease the likelihood of anesthesia awareness.11,12
Several brain-function monitors based on the processed electroencephalogram or evoked potentials have been developed to assess anesthetic depth. The most widely used is the bispectral index (BIS) monitor (Aspect Medical Systems), which has been approved by the Food and Drug Administration. The BIS monitor processes a single frontal electroencephalographic signal to calculate a dimensionless number that provides a measure of the patient's level of consciousness. BIS values range from 100 to 0, reflecting the awake state and the absence of brain activity, respectively. Although the algorithm used to calculate the BIS number is proprietary, the electroencephalographic components of the algorithm have been identified: the frequency below which 95% of the power spectrum resides, the relative beta ratio, the relative synchrony of fast and slow waves, and the burst-suppression ratio.13 BIS values between 40 and 60 purportedly indicate adequate general anesthesia for surgery, and values below 40 indicate a deep hypnotic state.14 Targeting a range of BIS values between 40 and 60 is advocated to prevent anesthesia awareness while allowing a reduction in the administration of anesthetic agents.15,16
The B-Aware study showed an absolute risk reduction of 0.74% in anesthesia awareness among high-risk patients to whom anesthesia was administered according to a BIS-guided protocol, as compared with a control group who received no protocol-driven care.3 In a large, multicenter cohort study, BIS monitoring was used in about 40% of the patients without a specified BIS-guided protocol, and there was no reduction in anesthesia awareness associated with BIS monitoring.1 Despite the limited evidence, the BIS has been widely adopted, and many clinicians are administering anesthesia while aiming for BIS values below 60 in order to prevent anesthesia awareness.
We conducted the B-Unaware Trial to determine whether, in patients at high risk, the incidence of anesthesia awareness is reduced when clinicians follow a BIS-guided protocol rather than an ETAG-guided protocol.
Methods
Patients
The Washington University Human Research Protection Office approved the study. The Consolidated Standards of Reporting Trials guidelines were followed.17 We evaluated patients who were older than 18 years of age who were undergoing surgery at Barnes–Jewish Hospital for eligibility on the day before or the day of their surgery on the basis of preoperative assessment records. Patients were required to be at high risk for anesthesia awareness, to have general anesthesia with isoflurane, sevoflurane, or desflurane, and supplemental nitrous oxide was permitted. The criteria for identifying patients at high risk for anesthesia awareness were based on previous studies, reviews, and guidelines.3,4,5,7,8 The major criteria were preoperative long-term use of anticonvulsant agents, opiates, benzodiazepines, or cocaine; a cardiac ejection fraction less than 40%; a history of anesthesia awareness; a history of difficult intubation or anticipated difficult intubation; ASA physical status class 4 (those who have systemic disease that is a constant threat to life) or class 5 (those who are not expected to survive without the operation); aortic stenosis; end-stage lung disease; marginal exercise tolerance not resulting from musculoskeletal dysfunction; pulmonary hypertension; planned open-heart surgery; and daily alcohol consumption. The minor criteria were preoperative use of beta-blockers, chronic obstructive pulmonary disease, moderate exercise tolerance not resulting from musculoskeletal dysfunction, smoking two or more packs of cigarettes per day, and obesity, defined as a body-mass index (the weight in kilograms divided by the square of the height in meters) of more than 30. Patients at high risk were defined as those with at least one major criterion or two minor criteria. Patients were excluded if the surgical procedure or positioning of the patient prevented BIS monitoring or if the surgery required a wake-up test. Also excluded were patients who had dementia, who were unable to provide informed consent, or who had a history of stroke with residual neurologic deficits.
Study Design
The design was a single-center, prospective study, in which 2000 patients underwent prerandomization electronically in blocks of 100, with 50 patients assigned to a BIS-guided protocol and 50 to an ETAG-guided protocol. Eligible patients underwent randomization after providing written informed consent. The anesthesia practitioners were aware of the assignments of the patients, but the patients, the postoperative interviewers, the expert reviewers, and the statistician were not.
The manufacturer of the BIS monitor (Aspect Medical Systems) had no role in the study design, data collection, data analysis, or manuscript preparation. No study monitors or other means of support were provided by Aspect Medical Systems.
Procedures
A BIS Quatro Sensor (Aspect Medical Systems) was applied to the forehead of each patient. The anesthesia practitioners caring for the patients in the ETAG group used a monitor configuration that omitted the BIS number, so they were unaware of the BIS values. The practitioners in both groups could view the ETAG concentrations. In the BIS group, an audible alarm was set to indicate when the BIS value exceeded 60 or fell below 40; no ETAG alarms were set in the BIS group, and the practitioners were not instructed to maintain the ETAG concentration within any range.
In the ETAG group, an audible alarm was set to indicate when the ETAG concentration fell below 0.7 MAC or exceeded 1.3 MAC. Nitrous oxide was taken into account in the MAC calculations. During cardiopulmonary bypass, the anesthetic-gas concentration was measured from the effluent of the cardiopulmonary-bypass machine.18 A sign was affixed to the anesthesia machines reminding the practitioners to check the BIS value or ETAG concentration and to consider whether the patient might have intraoperative awareness. BIS values and ETAG concentrations were collected at 1-second intervals and were downloaded to a computer for subsequent analysis with TrendFace Solo software (ixellence). Manual records of anesthesia and digital photographs of monitor trends were used as alternatives in the event that the computer data were incomplete.
Anesthesia awareness was assessed with the use of the Brice questionnaire.19 The investigators were unaware of the patients' assignments and of previous assessments of their anesthesia awareness. Patients were contacted within 24 hours, between 24 and 72 hours, and at 30 days after extubation. Previous studies have shown that anesthesia awareness is not reliably detected with only a single interview.3,20 While the study was ongoing, the quality-assurance coordinator in the anesthesiology department contacted the patients who had reported memories of the period between "going to sleep" and "waking up" at any interview and obtained further information about their experiences. The coordinator offered all patients who reported such memories referral for counseling.
After all patients had completed the study, three experts who were unaware of the assignments of the patients independently reviewed the questionnaire responses and decided whether each patient definitely had had anesthesia awareness, might have had anesthesia awareness, or did not have anesthesia awareness. In assessing whether anesthesia awareness occurred, the experts were instructed to focus on memories of events that could occur only in the operating room during the anesthetic and surgical periods. The outcome was determined when at least two of the experts were in agreement. If two experts held opposing views, a fourth expert was asked to review the questionnaires.
On the basis of the accounts given by the patients and the information in the anesthesia records, an investigator who was unaware of the assignments identified a time window during which anesthesia awareness was likely to have occurred. When a specific time window could not be identified, the entire anesthetic period was considered.
To identify the maintenance period of anesthesia, researchers who were unaware of the treatment assignments systematically reviewed the BIS and ETAG traces from each patient who did not report anesthesia awareness. After the administration of the intravenous induction agent, there was a characteristic nadir in the BIS trace. The start of the maintenance period was defined as 3 minutes after the nadir unless the BIS rose above the upper bound of 60 during this time. Three minutes was predetermined to be adequate to account for the transition from an intravenous induction to a volatile gas-based general anesthetic. The end of the maintenance period and the start of emergence was defined as the beginning of a consistent and final decrease in the ETAG concentration to less than 0.2 MAC. If emergence did not occur in the operating room, the final data points were included in the maintenance period. Every trace was analyzed for sustained 30-second periods of BIS values above the threshold of 60 or ETAG concentrations below the threshold of 0.7 MAC during the maintenance period. Periods with missing data were excluded from the analysis.
Statistical Analysis
The primary outcome of the study was a decrease in definite anesthesia awareness in the BIS group as compared with the ETAG group. The anticipated incidence of anesthesia awareness was 1% for the ETAG group, on the basis of the incidence rates reported for patients at high risk for anesthesia awareness,3,4,5 and 0.1% for the BIS group, on the basis of previous studies.3,21 A total of 940 patients would be required in each group to detect this 0.9% difference with a one-tailed alpha of 0.05 and a power of 80% with the use of Fisher's exact test. Confidence intervals for absolute risk reduction were calculated with the use of Newcombe's method without continuity correction.22 There was no interim analysis. The chi-square test, Fisher's exact test, an unpaired t-test, and an unpaired Mann–Whitney test were used for other comparisons between groups. Intention-to-treat analysis was planned. Agreement among the experts who were assessing anesthesia awareness was quantified with the use of a two-way, random-effects, intraclass correlation coefficient for absolute agreement according to the following metric23: no=0, maybe=1, and yes=2. All reported P values are two-sided, and a P value less than 0.05 was considered to indicate statistical significance. Statistical analysis was performed with the R statistical environment (R Foundation for Statistical Computing).
Results
Of 2000 patients enrolled during a 14-month period (from September 2005 to October 2006), 1941 completed the study (Figure 1). Patients were excluded as a result of changes in the planned anesthetic technique or canceled surgery. No patients who were assigned to the ETAG group were treated with the BIS protocol, and no patients assigned to BIS were treated with the ETAG protocol. A total of 1754 patients (90.4%) completed all three interviews, 133 patients (6.9%) completed only two interviews, and 18 patients (0.9%) completed only one interview. Table 1 shows the characteristics of the patients. There were significantly more patients with underlying neurologic disease in the ETAG group than in the BIS group (22.0% vs. 17.2%, P=0.008). The groups were similar with respect to other baseline characteristics. Overall, 71.4% of patients had an ASA physical status class of 3 (severe systemic disease), 4, or 5; 27.0% underwent open-heart surgery; 74.6% had three or more inclusion criteria; and 61.6% had two or more preexisting medical conditions. Nitrous oxide was administered to 350 patients in the BIS group and 351 patients in the ETAG group.
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Figure 2 shows the BIS values and ETAG concentrations for the six patients in the BIS-guided group with definite (Patients 3 and 4) or possible (Patients 5 through 8) anesthesia awareness. Figure 3 shows the corresponding data for the three patients in the ETAG-guided group with definite (Patients 1 and 2) or possible (Patient 9) anesthesia awareness. The BIS value was above 60 in one of the four patients with definite anesthesia awareness and in three of the nine patients with possible or definite anesthesia awareness. The ETAG concentration was below 0.7 MAC in three of the four patients with definite anesthesia awareness and in seven of the nine with possible or definite anesthesia awareness.
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Discussion
In the B-Unaware Trial, a structured protocol based on the BIS resulted in neither a lower incidence of anesthesia awareness nor a reduced administration of volatile anesthetic gas as compared with a structured protocol based on ETAG. It has been suggested that when the BIS value is less than 60, anesthesia awareness is unlikely.3,15,21 In the majority of cases of definite or possible anesthesia awareness, BIS values were persistently under 60 during the period when anesthesia awareness was likely to have occurred (Figure 2 and Figure 3).
There were sustained periods when BIS values were greater than 60 in 55.0% of patients and ETAG concentrations were under 0.7 MAC in 74.5% of patients who did not have anesthesia awareness. The low mean BIS values in the BIS group could reflect the unwillingness of the anesthesia practitioners to decrease anesthetic administration solely on the basis of the BIS. The mean BIS value of the BIS group in the B-Aware study was low and almost identical to that in the present study.3 Both the BIS values and the ETAG concentrations were frequently outside the target ranges, possibly because of the difficulty of adhering to the prescribed protocols or reluctance on the part of the anesthesia practitioners to follow the protocols.
This trial has some important limitations. Although the trial did not demonstrate a reduction in anesthesia awareness, with 95% confidence intervals for absolute risk reduction of definite anesthesia awareness of –0.56 to 0.57%, the results remain consistent with a clinically significant number needed to treat in order to benefit of 179 and a clinically significant number needed to treat in order to harm of 175 with the BIS protocol. This study is also subject to some concerns common to all studies of anesthesia awareness: the diagnosis of anesthesia awareness may be subjective, the awareness interview may be invalid because repeated questioning may induce false memories, and it may be difficult to distinguish between memories of events in the operating room and events in the intensive care unit. It is encouraging that there was good agreement among the three assessors, who were unaware of the treatment assignments, and it was unnecessary to refer any decision to a fourth assessor.
It is important to emphasize that the results of this trial should not be extrapolated to patients receiving total intravenous anesthesia, which is considered to be a risk factor for anesthesia awareness.7 Indeed, BIS monitoring may be useful during total intravenous anesthesia, since it is not presently possible to monitor the blood concentrations of anesthetic agents continuously.
Anesthesia awareness cannot predictably be prevented in all patients with the BIS monitoring protocol used in this study. When a potent volatile anesthetic gas was administered, a structured protocol based on the BIS was not shown to be superior to a protocol based on ETAG concentrations for preventing anesthesia awareness. Reliance on BIS technology24 may provide patients and health care practitioners with a false sense of security about the reduction in the risk of anesthesia awareness. If BIS monitoring were routinely applied to all patients in the United States receiving general anesthesia,7 the cost of disposable electrodes alone would exceed $360 million annually. Our study was unable to demonstrate superiority of a BIS-guided protocol over an ETAG-guided protocol for preventing anesthesia awareness and does not provide support for the additional cost of BIS monitoring as part of standard practice.
Supported by a grant from the Barnes–Jewish Hospital Foundation (to Dr. Avidan).
No potential conflict of interest relevant to this article was reported.
We thank Jane Cueto, Dusica Stamenkovic, Elika Safarzadeh, Furqaan Sadiq, Barry Hong, Heiko Kaiser, Laura Veremakis, Brian Torres, Katy Dustman, Jeanine Riddle, Michael Rybak, Dia Tite, Nicholas Girdner, Bernadette Henrichs, and the many anesthesiologists, certified registered nurse anesthetists, and surgeons who facilitated the conduct of this study.
Source Information
From the Department of Anesthesiology, Washington University School of Medicine, St. Louis.
Address reprint requests to Dr. Avidan at Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8054, St. Louis, MO 63110, or at avidanm{at}wustl.edu.
References
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Related Letters:
Anesthesia Awareness and the Bispectral Index
Kelley S. D., Manberg P. J., Sigl J. C., Myles P. S., Leslie K., Forbes A., Bo L., Li J., Deng X., Aretha D., Kiekkas P., Panteli E., Cook T. M., Avidan M. S., Searleman A. C., Evers A. S., Orser B. A.
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N Engl J Med 2008;
359:427-431, Jul 24, 2008.
Correspondence
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