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Bispectral Index Monitoring, Duration of Bispectral Index Below 45, Patient Risk Factors, and Intermediate-term Mortality after Noncardiac Surgery in the B-Unaware Trial Miklos D. Kertai, M.D., Ph.D.,* Ben J. A. Palanca, M.D., Ph.D.,† Nirvik Pal, M.D.,** Beth A. Burnside, B.A.,‡ Lini Zhang, M.D.,‡ Furqaan Sadiq, D.J.,‡ Kevin J. Finkel, M.D.,§ Michael S. Avidan, M.B.B.Ch.,# and the B-Unaware Study Group储 ABSTRACT What We Already Know about This Topic • Processed electroencephalogram indices are used to assess depth of hypnosis. • Prolonged periods of deep anesthetic levels (i.e., bispectral index less than 45) have been associated with increased postoperative mortality. Background: Postoperative mortality has been associated with cumulative anesthetic duration below an arbitrary processed electroencephalographic threshold (bispectral index [BIS] ⬍45). This substudy of the B-Unaware Trial tested whether cumulative duration of BIS values lower than 45, cumulative anesthetic dose, comorbidities, or intraoperative events were independently associated with postoperative mortality. Methods: The authors studied 1,473 patients (mean ⫾ SD age, 57.9 ⫾ 14.4 yr; 749 men) who underwent noncardiac surgery at Barnes-Jewish Hospital in St. Louis, Missouri. Multivariable Cox regression analysis was used to determine whether perioperative factors were independently associated with all-cause mortality. Results: A total of 358 patients (24.3%) died during a follow-up of 3.2 ⫾ 1.1 yr. There were statistically significant associations among various perioperative risk factors, including malignancy and intermediate-term mortality. BIS-monitored patients did not have lower mortality than unmonitored patients (24.9 vs. 23.7%; difference ⫽ 1.2%, 95% CI, ⫺3.3 to 5.6%). Cumulative duration of BIS values less than 45 was not associated with mortality (multivariable hazard What This Article Tells Us That Is New • As a substudy of the B-Unaware Trial, the current study with noncardiac patients (N ⫽ 1,473) found no evidence that either bispectral index monitoring or avoidance of prolonged periods of low bispectral index values (i.e., below 45) decreased intermediate-term mortality (3.2 ⫾ 1.1 yr). • Instead several patient characteristics were associated with increased mortality, namely: male sex, previous stroke, type II diabetes, surgery for malignancy, higher ASA (American Society of Anesthesiologists) Physical Status Classification System category, and extended intensive care unit treatment time. ratio, 1.03; 95% CI, 0.93–1.14). Increasing mean and cumulative end-tidal anesthetic concentrations were not associated with mortality. The multivariable Cox regression model showed a good discriminative ability (c-index ⫽ 0.795). Conclusions: This study found no evidence that either cumulative BIS values below a threshold of 40 or 45 or cumulative inhalational anesthetic dose is injurious to patients. These results do not support the hypothesis that limiting depth of anesthesia either by titration to a specific BIS threshold or by limiting end-tidal volatile agent concentrations will decrease postoperative mortality. * Instructor in Anesthesiology, Cardiothoracic Anesthesiology and Cardiothoracic Intensive Care, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri. Current position: Assistant Professor of Anesthesiology, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina. † Clinical Fellow in Cardiothoracic Anesthesiology, ** Instructor, ‡ Research Assistant, § Staff Anesthesiologist, # Associate Professor of Anesthesiology and Surgery, Division Chief, Cardiothoracic Anesthesiology and Cardiothoracic Intensive Care, Department of Anesthesiology, Washington University School of Medicine. 储 Members of the B-Unaware Study Group are listed in the appendix. Received from the B-Unaware Study Group, St. Louis, Missouri. Submitted for publication May 10, 2010. Accepted for publication September 30, 2010. Supported by Barnes-Jewish Hospital Foundation (St. Louis, Missouri) Grant no. 6043-02 (to Dr. Avidan) as well as institutional and/or departmental sources. Address correspondence to Dr. Kertai: Department of Anesthesiology, Duke University Medical Center, 2301 Erwin Road, 5693 HAFS Bldg, DUMC 3094, Durham, North Carolina 27710. [email protected]. This article may be accessed for personal use at no charge through the Journal Web site, www.anesthesiology.org. T HE rates of early (30 day) and intermediate term (less than 5 yr) postoperative mortality can be substantial in patients undergoing noncardiac surgery.1,2 Several patient- and surgery-related factors that may impact the survival of noncardiac surgical patients have been identified during the past several 䉫 This article is featured in “This Month in Anesthesiology.” Please see this issue of ANESTHESIOLOGY, page 9A. 䉬 This article is accompanied by an Editorial View. Please see: Kalkman CJ, Peelen LM, Moons KG: Depth of anesthesia and long-term mortality. ANESTHESIOLOGY 2011; 114:485–7. Copyright © 2011, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2011; 114: 545–56 Anesthesiology, V 114 • No 3 545 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931111/ on 06/11/2017 March 2011 Bispectral Index and Mortality in Noncardiac Surgery decades. In contrast, less attention has been focused on anesthesia-related factors and their possible associations with short- and intermediate-term survival after noncardiac surgery. It has been suggested that, when a processed electroencephalographic index is used during general anesthesia, patients generally receive lower doses of hypnotic drugs and emerge faster from anesthesia with less postoperative nausea and vomiting.3 It has also been proposed that lower doses of anesthetics could lead to a reduction in serious morbidity or mortality through avoidance of intraoperative hypotension and potential organ toxicity.4 The bispectral index monitor (BIS威 monitor; Covidien, Boulder, CO) is one of several candidate depth-of-anesthesia monitors based on processed electroencephalography. It has been reported that the cumulative duration of BIS values below certain arbitrary thresholds was associated with increased morbidity and intermediate-term postoperative mortality.5,6 These studies have led to speculation of a mortality-hypnosis association, whereby a relative overdose of anesthetic agents causes poorer outcomes in patients with anesthetic hypersensitivity.7 It has been further proposed that the outcome of surgical patients could be improved in patients receiving BIS-guided anesthesia.6,8 In a planned substudy of the B-Unaware Trial in cardiac surgery patients,9 we assessed relationships among cumulative duration of low BIS values (arbitrarily defined as less than 45 or 40), perioperative risk factors, anesthetic dose, and intermediate-term mortality after cardiac surgery.10 Analysis using a multivariate model demonstrated that cumulative durations of BIS values at these levels were associated with a higher risk of intermediate-term mortality, independent of average end-tidal anesthetic concentration (ETAC), duration of anesthesia, or the use of BIS monitoring.10 Parallel to our substudy in cardiac surgery patients, we undertook a similar predetermined substudy of the B-Unaware Trial in patients who underwent noncardiac surgery to further investigate relationships among perioperative factors and mortality. Through a comprehensive, multivariable model of an extensive dataset, we sought to test the hypotheses that cumulative duration of BIS values that were less than 40 or 45, cumulative anesthetic dose, comorbidities, and intraoperative events are independently associated with increased intermediate-term postoperative mortality. We specifically aimed to shed more light on the low BIS mortality hypothesis, and to question whether, in a clinically relevant range (e.g., 0.5 to 1.5 age-adjusted minimum alveolar concentration [MAC]) increasing anesthetic exposure is dangerous. the study, which was conducted at Barnes-Jewish Hospital (St. Louis) between September 2005 and October 2006. The study protocol had several predetermined secondary outcomes, including the aim to study the association between perioperative factors and intermediate-term mortality after surgery. A population of 1,941 surgical patients, aged at least 18 yr, were screened and prospectively enrolled after written informed consent was obtained. Patients at high-risk for intraoperative awareness were identified based on the presence of one major criterion or two minor criteria. The major criteria were ASA (American Society of Anesthesiologists) Physical Status Classification System category P4 (systemic life-threatening disease) or P5 (not expected to survive without the operation); marginal exercise tolerance not resulting from musculoskeletal dysfunction; pulmonary hypertension; a left ventricular ejection fraction lower than 40%; aortic stenosis; pulmonary hypertension; end-stage lung disease; planned open heart surgery; preoperative long-term use of anticonvulsant agents, opiates, benzodiazepines, or cocaine; and daily alcohol consumption. The minor criteria were as follows: moderate exercise tolerance not resulting from musculoskeletal dysfunction, smoking two or more packs of cigarettes per day, chronic obstructive pulmonary disease, preoperative use of -blockers, and obesity (body mass index [weight in kilograms divided by the square of height in meters] of more than 30 kg/m2). Of the 1,941 patients, 1,473 underwent noncardiac surgery and were included in this B-Unaware Trial substudy. Conduct of the Trial According to the original study design of the B-Unaware Trial, the only protocol-based restriction of anesthetic technique required desflurane, sevoflurane, or isoflurane as the primary agent for the maintenance of general anesthesia. When supplemental nitrous oxide was administered, it was factored into the MAC calculation. Patients were randomly assigned to a BIS-guided protocol or an ETAC-guided protocol. Practitioners in both groups could view ETACs. In the BIS group, an audible alarm was set to indicate when values exceeded 60 or fell below 40. No ETAC alarms were set in the BIS group, and practitioners were not instructed to maintain ETACs within any range. In the ETAC group, an audible alarm was set to indicate when values either fell below 0.7 MAC or exceeded 1.3 MAC. Peripheral intravenous, and, if indicated on clinical grounds, radial artery or central venous catheters were inserted. ETAC was monitored throughout the case. A BIS威 Quatro Sensor (version XP; Covidien) was applied to the forehead of each patient. BIS, hemodynamic, and anesthetic parameters were recorded at 1-s intervals and downloaded to a centralized database for subsequent analysis with TrendFace Solo software (ixellence GmbH, Wildau, Germany). For patients with incomplete datasets, manual records of anesthesia and digital photographs of monitor trends were used as alternatives. Materials and Methods Study Population The B-Unaware Trial was a randomized controlled trial (NCT00281489) that enrolled patients at high risk for perioperative awareness and tested whether the incidence of awareness during general anesthesia was reduced when clinicians followed a BIS-guided protocol rather than an ETAC-guided protocol.9 The Human Research Protection Office at the Washington University School of Medicine (St. Louis, Missouri) approved Anesthesiology 2011; 114:545–56 546 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931111/ on 06/11/2017 Kertai et al. PERIOPERATIVE MEDICINE were also noted. Intraoperative use of inotropes, vasopressors, and vasodilators were recorded. To study the possible association between cumulative and average ETACs of different volatile anesthetics and mortality, age-adjusted MAC values were calculated according to the recommendations published by Nickalls and Mapleson,12 which include adjustments for nitrous oxide. BIS and end-tidal age-adjusted MAC values recorded at 1-s intervals were processed using MATLAB statistical software (version 7.8; The MathWorks Inc., Natick, MA) with anesthetic maintenance values defined as greater than 0.4 MAC and within ⫾ 0.2 MAC within 3-min periods. As it was unclear whether the average anesthetic concentration or the cumulative duration of anesthetic exposure might lead to poor outcomes, average ETAC and cumulative maintenance anesthetic dose (MAC ⫺ hours ⫽ average ETAC ⫻ hours of anesthetic maintenance) were determined. Data on preexisting malignancies (for which surgery was performed) were obtained from reviewing medical records, surgical notes, and histopathologic results. Subsequently, patients were classified into subgroups according to whether the indication for surgery was performed for preexisting malignancy, and whether that malignancy was primary or a metastatic disease. Surgery type was also noted and classified into categories according to risk of mortality,2 including high risk (vascular surgery; prolonged surgery [i.e., more than 2 h], anticipated large fluid shift or blood loss [Whipple procedure, major spinal surgery]), intermediate risk (orthopedic, urologic, abdominal or thoracic, head and neck, or prostate surgery; carotid endarterectomy), and low risk (endoscopy, bronchoscopy, hysteroscopy, cystoscopy, dermatologic procedures, breast biopsy or other breast surgery, ophthalmologic procedures). In addition, the hospital’s electronic database was reviewed for the length of stay in the intensive care unit. In order to avoid misclassification of the cause of death, all-cause mortality was chosen as the study’s outcome. Nevertheless, we made every effort to ascertain the cause of death through medical records and death certificates. Data Collection A standard set of perioperative data were collected using information from medical records, surgical and pathology reports, anesthetic and postoperative records, discharge letters, and records of the outpatient clinic visit. All data were entered in a standard electronic data-collection form. Two investigators (M.D.K., N.P.) ascertained the quality of data collection through regular checks for completeness of the collected data and cross-checking for inconsistencies or missing information between the collected database and medical records. Aspect Medical Systems, the manufacturer of the BIS威 monitor at the time the trial was conducted, had no role in the study design, data collection, data analysis, or manuscript preparation. In addition, no study monitors or other means of support were provided by Aspect Medical Systems. Follow-up According to the original study protocol of the B-Unaware Trial, patients were observed prospectively after surgery. In addition, telephone interviews were conducted at 30 days and 1 yr after surgery. The Social Security Death Index†† was used to checked for vital status. This follow-up regimen was further extended with final follow-up performed in January 2010. In addition, for any patients who died after surgery, we used a variety of approaches to ascertain the cause and time of death. Thirty-day mortality and cause of death was ascertained using hospital records, discharge letters, and, whenever available, autopsy reports. For patients who survived beyond 30-day follow-up, information about the vital status was ascertained using a two-step approach. First, any subsequent hospital admissions, treatments, and follow-up visits were determined using the hospital’s database. Next, the Social Security Death Index was accessed to verify vital status as of January 28, 2010. Potential clinical determinants of intermediate-term mortality included patient characteristics, ASA Physical Status Classification System category, chronic medication use, preoperative laboratory values (hemoglobin, leukocyte count, serum creatinine). In addition, we collected information on potential intraoperative outcome determinants, including type and dose of intravenous anesthetic drugs, duration of general anesthesia, the duration of low and high mean arterial pressure, and the durations that bradycardia and tachycardia occured. Intraoperative hypotension (mean arterial pressure lower than 55 mmHg) or hypertension (mean arterial pressure higher than 100 mmHg), and intraoperative bradycardia (heart rate less than 45) and tachycardia (heart rate higher than 110) were defined according to the methodology of Reich et al11 The number of erythrocyte, fresh frozen plasma, and platelet units transfused intraoperatively Statistical Analysis Descriptive statistics are presented as frequency and percentage for categorical variables and mean ⫾ SD or median (interquartile range) for continuous variables. Comparisons were made using the Student t test, ANOVA, Kruskal-Wallis test, or chi-square test, as appropriate. Two recent studies reported that patients with increased cumulative duration of BIS less than 45 had an increased risk of short- and intermediate-term mortality.5,13 The study of the association between cumulative duration of BIS values lower than 45 and intermediate-term mortality after noncardiac surgery was specified a priori based on the original study design of the B-Unaware Trial. The Kaplan–Meier method was applied to evaluate the prognostic importance of the duration of BIS values less than 45 with respect to survival. Differences among survival curves were compared using the †† Social Security Death Index. RootsWeb Web site. Available at: http://ssdi.rootsweb.ancestry.com/cgi-bin/ssdi.cgi. Accessed January 4, 2011. Anesthesiology 2011; 114:545–56 547 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931111/ on 06/11/2017 Kertai et al. Bispectral Index and Mortality in Noncardiac Surgery tion; 9.1%, chronic renal dysfunction; 8.7%, chronic congestive heart failure; and 6.2%, cerebrovascular disease. Thirty-seven percent of the cohort was classified as category P1 or P2 using the ASA Physical Status Classification System; 54.7%, P3; and 8.2%, P4. Sixty-five percent of patients underwent an operation other than surgery for cancer, 26.9% had surgery for primary cancer, and 8.6% had surgery for metastatic cancer. The majority of patients (48.1%) underwent intermediate risk surgical procedures, 27% had a highrisk surgical procedure, and 24.9% had a low-risk surgical procedure. The average duration of general anesthesia was 3.4 h (interquartile range, 2.1– 4.9 h), the average intraoperative BIS value was 45.0 ⫾ 7.8, and the average cumulative duration of BIS values lower than 45 was 1.2 h (interquartile range, 0.4 –2.4 h). Baseline and clinical characteristics of the patients stratified according to the quartiles of the cumulative duration of BIS levels lower than 45 are presented in tables 1 and 2. Mean ⫾ SD follow-up was 3.2 ⫾ 1.1 yr. Mortality rate was 1.5% (22 of 1,473) at 30 days and 22.8% (336 of 1,473) 3.2 yr after noncardiac surgery. The average BIS value was not significantly different between patients who were randomized to the BIS-guided protocol compared with the average BIS value among patients who were randomized to the ETAC-guided protocol (42.9 ⫾ 8.0 vs. 43.3 ⫾ 9.4; P ⫽ 0.50). We found no significant difference in mortality rates between patients whose general anesthesia was managed according to the BIS-guided protocol compared with patients who were managed according to the ETAC-guided protocol (24.9% [180 of 723], 95% CI, 21.8 –28.1 vs. 23.7% [178 of 750], 95% CI, 20.7–26.8; P ⫽ 0.63). The causes of death are shown in table 3. Univariable predictors of intermediate-term mortality that were significant at a nominal two-tailed P ⬍ 0.25 are shown in table 4. Many baseline characteristics as well as preoperative, intraoperative, and postoperative predictors were associated with an increased risk of intermediate-term mortality (table 4; figs. 1 and 2). There was no association between the quartiles of cumulative duration of BIS less than 45 and event-free survival reflected by the event-free survival curves (fig. 3). The results of univariable analysis showed no significant association between increased intermediate-term mortality and mean age–adjusted MAC equivalents (ETAC), and cumulative anesthetic exposure (expressed as age-adjusted MAC equivalent-hours), or with the availability of BISmonitoring during anesthesia; and between increased intermediate-term mortality and cumulative anesthetic exposure (expressed as age-adjusted MAC equivalent-hours); or between increased intermediate-term mortality and the availability of BIS monitoring during anesthesia. In multivariable analysis, male sex, history of stroke, type II diabetes mellitus, surgery for primary and metastatic cancer, ASA Physical Status Classification System category, and an increased duration of stay in intensive care unit were significant predictors of intermediate-term mortality (table 5). Higher log-rank test. Univariable and multivariable Cox proportional hazards regression models were applied to evaluate relations among preoperative, intraoperative, and postoperative clinical variables, duration of BIS values less than 45, and all-cause mortality. Univariable associations to which P values of less than 0.25 had been assigned were considered in the construction of the multivariable Cox proportional hazards regression model. The final multivariable Cox proportional hazards regression model was then derived according to the backward deletion of least-significant predictors. This statistical model is a class of survival model in which predetermined covariates or risk factors (such as patient characteristics and comorbidities) are assessed for their independent association with hazard of an event occurring or rate to a negative outcome (i.e., mortality). Hazard ratios and corresponding 95% CIs are reported. These analyses were performed using SPSS statistical software (version 16.0; SPSS Inc., Chicago, IL). Furthermore, we quantified the discriminatory power of the final multivariable model by the c-index, which corresponds to the area under the receiver operating characteristic curve, ranging from 0.5 (performance at chance) to 1.0 (perfect performance). To evaluate the discriminatory power of the final multivariable model, a bootstrap method was used to assess the degree of over-optimism. Over-optimism occurs when application of statistical modeling techniques results in models that inaccurately predict outcomes on subsequent datasets. A bootstrapping procedure is one method which can be used to try to correct for this over-optimism.14 The covariates in the final model were fitted for each bootstrap sample. The original dataset was fitted using the coefficients of the bootstrap sample model and, thus, a c-index statistic was generated from this fit on the original dataset. Optimism was then estimated as the difference in the c-index statistic from the bootstrap sample and that from the bootstrap model fit on the original sample. These differences were averaged across 100 bootstrapped samples and the difference in the original model c-index statistic and the average optimism provided the model c-index statistic corrected for optimism. These analyses were performed using the survival and design libraries within the Software R statistical environment (version 2.9.1; The R Foundation for Statistical Computing, Vienna, Austria). Results Patient Characteristics There were 1,473 noncardiac surgery patients included in this study. Mean ⫾ SD patient age was 57.9 ⫾ 14.4 yr. Seven hundred forty-nine patients (50.8%) were men. Sixty-one percent of the enrolled study population had a history of hypertension; 27.8%, ischemic heart disease; 25.1%, chronic pulmonary disease; 19.9%, type 2 diabetes mellitus; and 14.5%, significant extracardiac arteriopathy. Eleven percent of patients had a history of previous coronary artery bypass surgery; 10.3%, previous percutaneous coronary intervenAnesthesiology 2011; 114:545–56 548 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931111/ on 06/11/2017 Kertai et al. PERIOPERATIVE MEDICINE Table 1. Demographic, Chronic Medication Use, and Cardiac-related Patient Characteristics (N ⫽ 1,473) Characteristics — — Demographics Age, yr Sex, female Race White Black Other Body mass index, kg/m2 Smoking history Never Past Current Medical History Atrial fibrillation Coronary artery disease Congestive heart failure Hypertension Peripheral vascular disease Previous Coronary Intervention CABG PCI Stroke Chronic obstructive pulmonary disease Chronic renal dysfunction Diabetes mellitus No history Type I Type II Chronic Medication Use Aspirin Angiotensin-converting enzyme inhibitors ␣ receptor blockers  receptor blockers Calcium-channel blockers No use Dihydropyridine Non-dihydropyridine Clopidogrel Coumadin Diuretics Nitrates Statins Cumulative Duration of Bispectral Index ⬍ 45 — P Value ⱕ 0.4 h (n ⫽ 373; 25.3%) 0.41 h to 1 h 17 min (n ⫽ 382; 25.9%) 1 h 18 min to 2 h 37 min (n ⫽ 352; 23.9%) ⬎ 2 h 38 min (n ⫽ 366; 24.8%) — — 58.7 ⫾ 15.3 174 (46.6) — 331 (88.7) 41 (11.0) 1 (0.3) 30.3 ⫾ 8.4 — 108 (29.0) 163 (43.7) 102 (27.3) — 29 (7.8) 100 (26.8) 33 (8.8) 226 (60.6) 49 (13.1) — — 58.9 ⫾ 14.8 181 (47.4) — 328 (85.9) 50 (13.1) 4 (1.0) 30.1 ⫾ 8.5 — 128 (33.5) 153 (40.1) 101 (26.4) — 28 (7.3) 115 (30.1) 43 (11.3) 240 (62.8) 48 (12.6) — — 58.1 ⫾ 13.5 191 (54.3) — 304 (86.4) 44 (12.5) 4 (1.1) 30.6 ⫾ 9.9 — 124 (35.2) 139 (39.5) 89 (25.3) — 22 (6.2) 92 (26.1) 35 (9.9) 214 (60.8) 52 (14.8) — — 56.1 ⫾ 13.6 178 (48.6) — 331 (90.4) 33 (9.0) 2 (0.5) 30.3 ⫾ 10.2 — 114 (31.1) 144 (39.3) 108 (29.5) — 14 (3.8) 103 (28.1) 14 (4.6) 219 (59.8) 64 (17.5) — — 0.02 0.27 0.57 — — — 0.90 0.87 — — — — 0.02 0.99 0.03 0.71 0.06 — 38 (10.2) 37 (9.9) 27 (7.2) 98 (26.3) 47 (12.3) 37 (9.7) 21 (5.5) 87 (22.8) 39 (11.1) 34 (9.7) 32 (9.1) 95 (27.0) 35 (9.6) 43 (11.7) 19 (5.2) 89 (24.3) 0.66 0.44 0.42 0.87 29 (7.8) — 311 (83.4) 10 (2.7) 52 (13.9) — 114 (30.6) 122 (32.7) 45 (11.8) — 288 (75.4) 7 (1.8) 87 (22.8) — 133 (34.8) 133 (34.8) 32 (9.1) — 269 (76.4) 12 (3.4) 71 (20.2) — 119 (33.8) 118 (33.5) 28 (7.7) — 296 (80.9) 9 (2.5) 61 (16.7) — 97 (26.5) 113 (30.9) 0.65 0.21 — — — — 0.22 0.53 14 (3.8) 140 (37.5) — 303 (81.2) 48 (12.9) 22 (5.9) 28 (7.5) 41 (11.0) 79 (21.2) 15 (4.0) 118 (31.6) 24 (6.3) 156 (40.8) — 330 (86.4) 37 (9.7) 15 (3.9) 28 (7.3) 28 (7.3) 94 (24.6) 30 (7.9) 111 (29.1) 16 (4.5) 134 (38.1) — 303 (86.1) 31 (8.8) 18 (5.1) 34 (9.7) 20 (5.7) 84 (23.9) 26 (7.4) 100 (28.4) 19 (5.2) 149 (40.7) — 319 (87.2) 32 (8.7) 15 (4.1) 28 (7.7) 11 (3.0) 69 (18.9) 21 (5.7) 106 (29.0) 0.61 0.55 0.03 — — — 0.67 ⬍ 0.0001 0.42 0.41 0.42 — Data are presented as mean ⫾ SD or No. (%). CABG ⫽ coronary artery bypass surgery; PCI ⫽ percutaneous coronary intervention. body mass index and hemoglobin concentrations as well as intermediate-risk surgery were associated with decreased intermediate-term mortality. After correcting for differences in baseline characteristics as well as preoperative, intraoperative, and postoperative characteristics, there was no significant association beAnesthesiology 2011; 114:545–56 tween the cumulative duration of BIS values less than 45 and the risk of intermediate-term mortality (multivariable hazard ratio, 1.03; 95% CI, 0.93–1.14; P ⫽ 0.56). Since the cutoff BIS number of 45 for low BIS is arbitrary and is higher than the more generally accepted arbitrary 549 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931111/ on 06/11/2017 Kertai et al. Bispectral Index and Mortality in Noncardiac Surgery Table 2. Intraoperative and Postoperative Characteristics (N ⫽ 1,473) Characteristics Cumulative Duration of Bispectral Index ⬍ 45 — P Value — ⱕ 0.4 h (n ⫽ 373; 25.3%) 0.41 h to 1 h 17 min (n ⫽ 382; 25.9%) 1 h 18 min to 2 h 37 min (n ⫽ 352; 23.9%) ⬎ 2 h 38 min (n ⫽ 366; 24.8%) — Preoperative Laboratory Values Hemoglobin, g/dl White blood cell count, 103/mm3 Serum creatinine, mg/dl Intraoperative Variables Surgery type* High risk Intermediate risk Low risk Indication for surgery No cancer surgery Surgery for primary cancer Surgery for metastatic cancer Anesthesia Related ASA category P1 or P2 P3 P4 Median anesthetic dosing Propofol, mg Fentanyl, mcg Midazolam, mg Vecuronium, mg Median anesthesia duration, h Number of pts MAP episode ⬍ 55 mmHg ⬎ 100 mmHg Number of pts heart rate episode ⬍ 45 beats/min ⬎ 110 beats/min Number of pts red blood cell transfusion Fresh frozen plasma transfusion Platelets transfusion Median amount, ml Crystalloid Colloid Blood loss, ml Ephedrine Phenylephrine Average age-adjusted MAC Cumulative end-tidal anesthetic gas concentration (MAC ⫻ h) Postoperative Variable Intensive care unit stay, d (median) — — — — — 13.1 ⫾ 1.8 7.7 (6.3–9.5) 12.8 ⫾ 1.9 7.7 (6.3–9.6) 12.9 ⫾ 1.8 7.2 (6.0–9.6) 12.9 ⫾ 1.9 7.6 (6.4–9.5) 0.24 0.51 0.9 (0.7–1.1) — — 68 (18.2) 153 (41.0) 152 (40.8) — 249 (66.8) 94 (25.2) 0.9 (0.7–1.1) — — 86 (22.5) 162 (42.4) 134 (35.1) — 264 (69.1) 86 (22.5) 0.8 (0.7–1.1) — — 108 (30.7) 197 (56.0) 47 (13.4) — 226 (64.2) 95 (27.0) 0.9 (0.7–1.1) — — 135 (36.9) 197 (53.8) 34 (9.3) — 212 (57.9) 121 (33.1) 0.20 — ⬍ 0.0001 — — — 0.02 — — 30 (8.0) 32 (8.4) 31 (8.8) 33 (9.0) — — — 156 (41.8) 196 (52.5) 21 (5.6) — — — 134 (35.1) 213 (55.8) 35 (9.2) — — — 131 (37.2) 189 (53.7) 32 (9.1) — — — 126 (34.4) 207 (56.6) 33 (9.0) — — 0.03 — — — — 160.0 (130.0–200.0) 200.0 (100.0–250.0) 2.0 (2.0–2.0) 10.0 (7.0–12.0) 2.2 (1.4–3.6) 150.0 (120.0–200.0) 250.0 (125.0–250.0) 2.0 (2.0–2.0) 8.0 (6.0–12.5) 2.3 (1.6–3.6) 173.0 (126.0–200.0) 250.0 (175.0–350.0) 2.0 (2.0–4.0) 10.0 (7.0–14.0) 3.3 (2.7–4.4) 180.0 (140.0–200.0) 350 (250.0–550.0) 2.0 (2.0–5.0) 13.0 (10.0–19.5) 5.3 (4.4–6.7) 0.1 ⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001 — — — — — 32 (8.6) 0 — 82 (21.4) 0 — 101 (29) 0 — 154 (39.6) 0 — ⬍ 0.0001 1.0 — 80 (21.4) 172 (46.1) 20 (5.4) 122 (32) 255 (66.8) 28 (7.4) 135 (53.6) 272 (77.2) 29 (8.3) 185 (50.5) 312 (85.2) 79 (21.6) ⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001 6 (1.6) 3 (0.8) 4 (1.1) 16 (4.4) 0.13 1 (0.3) 2 (0.5) 0 6 (1.6) 0.19 1,300 (800–2,600) 0 (0–0) 50.0 (0–237.5) 47 (12.6) 58 (15.5) 0.86 ⫾ 0.19 1,200 (800–2,400) 0 (0–0) 62.5 (0–200.0) 62 (16.2) 65 (17.0) 0.90 ⫾ 0.19 2,000 (1,200–3,000) 0 (0–0) 150.0 (50.0–300.0) 57 (16.2) 54 (15.3) 0.91 ⫾ 0.19 3,000 (2,075–4,500) 0 (0–500) 300.0 (150.0–620.0) 55 (15.0) 60 (16.4) 0.92 ⫾ 0.16 ⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001 0.38 0.92 0.001 0.53 (0.17–1.16) 0.89 (0.52–1.86) 1.61 (1.07–2.39) 3.28 (2.43–4.21) ⬍ 0.0001 — 0 (0–0) — 0 (0–0) — 0 (0–0) — 0 (0–1) — ⬍ 0.0001 Data are presented as mean ⫾ SD, median (interquartile range), or No. (%). * Surgery type was noted and classified into risk categories. High risk included vascular surgery, prolonged surgery (⬎ 2 h), surgery with anticipated large fluid shift or blood loss (e.g., Whipple procedure, major spinal surgery). Intermediate risk included orthopedic surgery, urologic surgery, abdominal or thoracic surgery, head and neck surgery, carotid endarterectomy, and prostate surgery. Low risk included endoscopy, bronchoscopy, hysteroscopy, cystoscopy, dermatologic procedures, breast biopsy or other breast surgery, and ophthalmologic procedures. ASA ⫽ American Society of Anesthesiologists Physical Status Classification System; MAC ⫽ minimum alveolar concentration; MAP ⫽ mean arterial pressure. Anesthesiology 2011; 114:545–56 550 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931111/ on 06/11/2017 Kertai et al. PERIOPERATIVE MEDICINE Table 3. Cause of Intermediate-term Mortality (n ⫽ 358) Cause of Mortality No. (%) Cancer Cardiovascular Sepsis Respiratory failure Renal failure Other Unknown 218 (61) 72 (20) 22 (6) 20 (6) 8 (2) 8 (2) 10 (3) than 5 min and a group that did not. The results of that study suggested that BIS monitoring and the absence of BIS values less than 40 for more than 5 min were associated with improved survival and less serious morbidity. However, BIS values were obtained only for patients randomized to BISguided care. In addition, investigators did not test for the effect of several important risk factors including cardiac comorbidities, surgery type, preexisting malignancy status, and the intraoperative type and dose of anesthetic drugs. We attempted to address some of these methodological limitations in a recently published study10 on a subset of 460 patients in the B-Unaware Trial who had undergone cardiac surgery. In that study investigation, we observed an association among clinical variables, intraoperative factors, and the cumulative duration of BIS values less than 45.10 In contrast, there was no association between cumulative duration of BIS values lower than 45 and volatile anesthetic concentration or average total dose of intravenous drugs. These results in our companion study of cardiac surgery patients indicate that BIS values lower than 45 are likely markers of systemic illness, poor cardiac function, or complicated intraoperative course.10 It is noteworthy that, in the cardiac surgery substudy, we found an independent association between cumulative duration of BIS values less than 45 and mortality.10 In the current study, we sought to clarify further the association between clinical variables and the cumulative duration of BIS values less than 45. In addition, we sought to determine the possible role of BIS monitoring in relation to intermediate-term mortality in high-risk patients who underwent noncardiac surgery in the B-Unaware Trial. In contrast to our study of cardiac surgery patients,10 the current substudy found no relationship between cumulative duration of BIS values less than 45 and mortality. The fact that an independent association between BIS values less than 45 and mortality has been found in some trials,5,10 but not others,13 including the current study, suggests that the association is likely epiphenomenal and, when present, is reflective of patient factors or comorbidities rather than anesthetic management. For example, in our cardiac surgery companion study, low ejection fraction was associated with cumulative duration of BIS values less than 45, whereas anesthetic dose was not.10 The role of optimal perioperative management strategies for high-risk patients undergoing noncardiac surgery in the prevention of intermediate- and long-term mortality has been controversial. In our study, we confirmed the predictive value of many previously described risk factors for intermediateterm mortality after noncardiac surgery. Male sex,15 history of stroke,2 diabetes mellitus,16 higher categories within the ASA Physical Status Classification System,17 surgery for preexisting malignancy status,15 and length of intensive care unit stay18 were all significant predictors of intermediate-term mortality. The findings of our study that intermediate-risk surgery leads to threshold of 40 for surgical anesthesia, we repeated our multivariable analysis and found that cumulative duration of BIS less than 40 (multivariable hazard ratio, 1.08; 95% CI, 0.98 – 1.20; P ⫽ 0.18) similarly had no significant predictive value for intermediate-term mortality. The results of the multivariable analysis also showed that allocation to the BIS-guided protocol was not associated with a decreased risk of intermediate-term mortality (multivariable hazard ratio, 1.03; 95% CI, 0.83–1.28; P ⫽ 0.78). The final multivariable model had a good c-index of 0.795, and the degree of over-optimism was minimal at 0.00413 (resulting in an adjusted c-index of 0.791). Increasing mean and cumulative ETAC were not significantly associated with intermediate-term mortality after multivariable adjustment. Discussion This study of patients at high risk for intraoperative awareness while undergoing noncardiac surgery found no evidence that BIS monitoring or the avoidance of prolonged periods of BIS values less than 45 leads to improved intermediate-term survival. There was also no indication that higher mean or cumulative inhalational anesthetic doses, within clinically standard ranges, were associated with increased mortality. In contrast, these results suggest that specific patient characteristics and perioperative risk factors are strongly associated with intermediate-term postoperative mortality. Several large studies have explored the association between cumulative duration of BIS values below certain arbitrary thresholds and mortality after noncardiac surgery. Monk et al.5 studied 1,046 patients undergoing noncardiac surgery. Cumulative duration of BIS values lower than 45 was a significant independent predictor of 1-yr mortality. However, investigators did not stratify patients for preexisting malignant disease despite the fact that malignancy was the most common cause of death. Lindholm et al.13 studied 4,087 patients undergoing noncardiac surgery who had BIS monitoring during general anesthesia. Cumulative duration of BIS values that were less than 45 was a significant predictor of 2-yr mortality, but only when preexisting malignancy status was not taken into consideration. Recently, Leslie et al.6 studied 2,463 patients undergoing cardiac and noncardiac surgery who were randomized to BIS-guided anesthesia or routine care. Within the BIS group, patients were further divided into a group that had BIS values less than 40 for more Anesthesiology 2011; 114:545–56 551 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931111/ on 06/11/2017 Kertai et al. Bispectral Index and Mortality in Noncardiac Surgery Table 4. Univariable Predictors of Intermediate-term Mortality Predictors Hazard Ratio (95% CI) P Value Demographics Age, per 10-yr increase Male sex Body mass index, kg/m2 Smoking history Never Past Current Medical History Atrial fibrillation Coronary artery disease Congestive heart failure Hypertension Peripheral vascular disease Coronary artery bypass surgery Percutaneous coronary intervention Stroke Chronic obstructive pulmonary disease Chronic renal dysfunction Diabetes mellitus No history Type I Type II Chronic Medication Use -adrenergic receptor blockers Calcium channel-blockers No use Dihydropyridine Non-dihydropyridine Clopidogrel Coumadin Diuretics Preoperative Laboratory Values Hemoglobin, per 1 g/dl increase Intraoperative Variables Surgery type High risk Intermediate risk Low risk Indication for surgery No cancer surgery Surgery for primary cancer Surgery for metastatic cancer Anesthesia Related ASA category P1 or P2 P3 P4 Duration of anesthesia, per hour Duration of mean arterial pressure ⬍ 55 mmHg, per min Duration of heart rate ⬎ 110 beats/min, per min Red blood cell transfusion per unit increase Cumulative duration of bispectral index ⬍ 45, per hour Infusion/administration Cumulative propofol dose, per 50 mg increase Cumulative Midazolam dose, per mg increase Phenylephrine administration Cumulative crystalloid dose, per 500 ml increase Cumulative colloid dose, per 500 ml increase Postoperative variable Intensive care unit stay, per day increase — 1.32 (1.22–1.42) 1.44 (1.16–1.77) 0.97 (0.95–0.98) — 1.0 1.72 (1.33–2.23) 1.45 (1.10–1.94) — 1.48 (1.02–2.15) 1.58 (1.28–1.97) 1.74 (1.29–2.35) 1.43 (1.14–1.79) 1.31 (1.0–1.72) 1.58 (1.18–2.10) 1.38 (1.01–1.89) 1.91 (1.35–2.70) 1.60 (1.28–2.0) 1.77 (1.31–2.40) — 1.0 1.10 (0.60–2.10) 1.63 (1.29–2.10) — 1.32 (1.07–1.63) — 1.0 1.61 (1.07–2.42) 0.84 (0.58–1.21) 1.64 (1.19–2.28) 1.30 (0.89–1.91) 1.19 (0.94–1.51) — 0.81 (0.77–0.85) — — 1.0 0.70 (0.54–0.90) 1.22 (0.93–1.58) — 1.0 2.26 (1.77–2.90) 10.96 (8.46–14.19) — — 1.0 2.45 (1.88–3.21) 5.10 (3.60–7.18) 1.03 (0.98–1.08) 1.03 (1.01–1.05) 1.04 (1.01–1.07) 1.09 (1.02–1.16) 1.06 (0.99–1.13) — 0.94 (0.88–0.99) 0.88 (0.83–0.94) 1.43 (1.10–1.84) 0.96 (0.93–0.99) 1.42 (1.0–1.30) — 1.05 (1.04–1.08) — ⬍ 0.0001 0.001 ⬍ 0.0001 — — ⬍ 0.0001 0.01 — 0.04 ⬍ 0.0001 ⬍ 0.0001 0.002 0.05 0.002 0.04 ⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001 — — 0.83 ⬍ 0.0001 — 0.008 — — 0.02 0.35 0.003 0.17 0.15 — ⬍ 0.0001 — — — 0.006 0.15 — — ⬍ 0.0001 ⬍ 0.0001 — — — ⬍ 0.0001 ⬍ 0.0001 0.20 0.02 0.005 0.01 0.10 — 0.03 ⬍ 0.0001 0.007 0.02 0.04 — ⬍ 0.0001 ASA ⫽ American Society of Anesthesiologists Physical Status Classification System. Anesthesiology 2011; 114:545–56 552 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931111/ on 06/11/2017 Kertai et al. PERIOPERATIVE MEDICINE Fig. 1. Kaplan–Meier estimates of all-cause mortality according to the indication for surgery for preexisting cancer. P value (log-rank test) indicates the differences in survival. Fig. 3. Kaplan–Meier estimates of all-cause mortality according to the quartiles of duration of cumulative bispectral index suppression. P value (log-rank test) indicates the differences in survival. lower mortality contradicts the results of previous studies and current guidelines.2,6 It is likely that discrepancies arise from the differences in classification criteria; prolonged surgery for cancer is considered high-risk surgery, whereas short procedures for cancer diagnosis are classified as low risk. Low body mass index and anemia, as in previous studies, are likely to reflect the presence of general poor health or a more advanced stage of preexisting malignancy status.19 –22 Low body mass index has been described as a marker of patients who are more likely to have advanced disease including esophageal,20 gastric,21 and lung22 cancers. Anemia has also been shown prospectively to be associated with increased risk for perioperative infection and adverse outcome in surgical patients.23 In addition, it has been described as being associated with increased risk for hospitalization and all-cause mortality.19 Many of the risk factors of poor general health including cardiovascular, metabolic, and surgery-related factors have previously been identified as modifiable predictors of long-term outcome after noncardiac surgery.16,24,25 It is strategically necessary to identify and address modifiable risk factors so that both early- and long-term postoperative outcomes might be improved. inhalational anesthetic agents, assessing the potential impact of anesthetic dose on mortality is challenging. We tried to address this challenge by incorporating cumulative inhalational anesthetic dose in the model, by adjusting for factors such as patient age, and by including as many anestheticrelated factors (e.g., doses of intravenous anesthetic agents) as possible in the multivariable model. Similar to a previously published substudy10 of the B-Unaware Trial, patients in the current substudy were screened and selected according to the Table 5. Multivariable Predictors of Intermediate-term Mortality Predictors Male sex 1.25 (1.01–1.56) Body mass index, kg/m2 0.97 (0.96–0.99) History of stroke 1.87 (1.31–2.66) Diabetes mellitus — No history 1.0 Type I 1.16 (0.60–2.28) Type II 1.76 (1.37–2.26) Preoperative hemoglobin, 0.84 (0.80–0.89) per 1 g/dl increase Surgery type — High risk 1.0 Intermediate risk 0.62 (0.48–0.82) Low risk 1.15 (0.87–1.52) Indication for surgery — No cancer surgery 1.0 Surgery for primary 2.51 (1.92–3.27) cancer Surgery for metastatic 11.50 (8.76–15.10) cancer Anesthesia related — ASA category — P1 or P2 1.0 P3 1.80 (1.37–2.38) P4 3.33 (2.31–4.79) Intensive care unit stay, 1.03 (1.01–1.06) per day increase Study Limitations With modern multimodal anesthesia, where patients receive a combination of intravenous and varying concentrations of Fig. 2. Kaplan–Meier estimates of all-cause mortality according to the ASA (American Society of Anesthesiologists) Physical Status Classification System. P value (log-rank test) indicates the differences in survival. Anesthesiology 2011; 114:545–56 Hazard Ratio (95% CI) P Value 0.04 ⬍ 0.0001 0.001 — — 0.66 ⬍ 0.0001 ⬍ 0.0001 — — 0.01 0.34 — — ⬍ 0.0001 ⬍ 0.0001 — — — ⬍ 0.0001 ⬍ 0.0001 0.01 ASA ⫽ American Society of Anesthesiologists Physical Status Classification System. 553 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931111/ on 06/11/2017 Kertai et al. Bispectral Index and Mortality in Noncardiac Surgery less than 45 (e.g., BIS ⫽ 39), the appropriate initial intervention might not be to decrease anesthesia. Instead, it might be preferable to treat hypotension with fluids, for example, or a drug such as norepinephrine or phenylephrine. In conclusion, this second substudy of the B-Unaware Trial found no evidence that either cumulative BIS values below a threshold of 40 or 45, or cumulative inhalational anesthetic dose is injurious to patients. In contrast, there was a strong association among perioperative risk factors, preexisting malignancy, and mortality. This study does not support the hypothesis that titrating anesthesia according to an arbitrary BIS threshold or limiting anesthetic dose would decrease intermediate-term mortality after noncardiac surgery. We do acknowledge, however, that only an appropriately designed, randomized, prospective trial might clarify further the possible presence, strength, or indeed absence of an association between a low processed electroencephalograph index and mortality. predefined criteria of the trial, but information on some important predictors of intermediate-term mortality was not prospectively collected. Therefore, additional information was collected on perioperative risk factors using administrative data and medical records, based on physician documentation of clinical risk factors. Moreover, information was collected on preexisting malignancy, which was used to classify patients into subgroups according to whether the indication for surgery was preexisting malignancy, and whether the malignancy was primary or metastatic. Thus, the effects of some of the perioperative risk factors and preexisting malignancy status may be biased. Nevertheless, the results of the current study, similar to the findings of other studies, confirmed the predictive values of perioperative risk factors and preexisting malignancy status.13 The observed mortality rates in the current study may seem higher than those reported in earlier studies.5,13 However, studies with lower mortality rates may have selected patients at low risk for perioperative and late mortality. The mortality substudy of the B-Aware Trial6 as well as the current substudy of the B-Unaware Trial had similarly high mortality rates, which is not surprising because both trials enrolled largely high-risk surgical patients.9,26 It is noteworthy that the results of the current study do not exclude the possibility that there might be electroencephalographic features—such as prolonged or multiple episodes of burst suppression or seizure activity— during anesthesia, which are associated with increased mortality risk. The best way to investigate candidate electroencephalographic associations with adverse postoperative outcomes would be to analyze the raw electroencephalograph trace rather than a processed index, which incorporates multiple electroencephalographic components. The authors thank the many anesthesiologists, certified registered nurse anesthetists, and surgeons who facilitated this B-Unaware Trial substudy. In addition, they thank Cynthia M. Westerhout, Ph.D. (Research Associate, Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada), for help with statistical analysis. References 1. Noordzij PG, Poldermans D, Schouten O, Bax JJ, Schreiner FA, Boersma E: Postoperative mortality in The Netherlands: A population-based analysis of surgery-specific risk in adults. ANESTHESIOLOGY 2010; 112:1105–15 2. Calkins H, Chaikof EL, Chaikof E, Fleischmann KE, Freeman WK, Froehlich JB, Kasper EK, Kersten JR, Riegel B, Robb JF, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Buller CE, Creager MA, Ettinger SM, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B, Tarkington LG, Yancy CW: ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: Executive Summary: A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) Developed in Collaboration With the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. J Am Coll Cardiol 2007; 50:1707–32 3. Liu SS: Effects of Bispectral Index monitoring on ambulatory anesthesia: A meta-analysis of randomized controlled trials and a cost analysis. ANESTHESIOLOGY 2004; 101:311–5 4. Cohen NH: Anesthetic depth is not (yet) a predictor of mortality! Anesth Analg 2005; 100:1–3 5. Monk TG, Saini V, Weldon BC, Sigl JC: Anesthetic management and one-year mortality after noncardiac surgery. Anesth Analg 2005; 100:4 –10 6. Leslie K, Myles PS, Forbes A, Chan MT: The effect of bispectral index monitoring on long-term survival in the B-aware trial. Anesth Analg 2010; 110:816 –22 7. Monk TG, Weldon BC: Anesthetic depth is a predictor of mortality: It’s time to take the next step. ANESTHESIOLOGY 2010; 112:1070 –2 Conclusions This study touches on the controversy of how wide the therapeutic index is for volatile anesthetics. Insufficient anesthesia is dangerous, being associated with intraoperative awareness and a high incidence of postoperative posttraumatic stress disorder.27 In contrast, anesthesia dosage above a certain concentration likely becomes excessive and potentially hazardous. The question is whether, within a clinically relevant range (e.g., 0.5–1.5 age-adjusted MAC), anesthesia is dangerous. In both B-Unaware Trial substudies,10 we have tried to incorporate as many relevant potential confounding factors as possible; however, we have not found an association between higher doses of inhalational anesthetic and mortality. The previously noted association between cumulative duration of BIS values less than 45 and mortality is likely coincidental, not causal. Putting these data together, if a pharmacologically paralyzed patient were hypotensive and anesthetic was delivered at a clinically acceptable concentration (e.g., 0.7 end-tidal age-adjusted MAC) with BIS values Anesthesiology 2011; 114:545–56 554 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931111/ on 06/11/2017 Kertai et al. PERIOPERATIVE MEDICINE tween long-term statin use and mortality after successful abdominal aortic aneurysm surgery. Am J Med 2004; 116: 96 –103 25. Birkmeyer JD, Sun Y, Wong SL, Stukel TA: Hospital volume and late survival after cancer surgery. Ann Surg 2007; 245: 777– 83 26. Myles PS, Leslie K, McNeil J, Forbes A, Chan MT: Bispectral index monitoring to prevent awareness during anaesthesia: The B-Aware randomised controlled trial. Lancet 2004; 363: 1757– 63 27. Leslie K, Chan MT, Myles PS, Forbes A, McCulloch TJ: Posttraumatic stress disorder in aware patients from the B-aware trial. Anesth Analg 2010; 110:823– 8 8. Kurata J: Deep hypnosis as a sign of “imbalance” in balanced anesthesia. Anesth Analg 2010; 110:663–5 9. Avidan MS, Zhang L, Burnside BA, Finkel KJ, Searleman AC, Selvidge JA, Saager L, Turner MS, Rao S, Bottros M, Hantler C, Jacobsohn E, Evers AS: Anesthesia awareness and the bispectral index. N Engl J Med 2008; 358:1097–108 10. Kertai MD, Pal N, Palanca BJ, Lin N, Searleman SA, Zhang L, Burnside BA, Finkel KJ, Avidan MS, B-Unaware Study Group: Association of perioperative risk factors and cumulative duration of low bispectral index with intermediate-term mortality after cardiac surgery in the B-Unaware Trial. ANESTHESIOLOGY 2010; 112:1116 –27 11. Reich DL, Bennett-Guerrero E, Bodian CA, Hossain S, Winfree W, Krol M: Intraoperative tachycardia and hypertension are independently associated with adverse outcome in noncardiac surgery of long duration. Anesth Analg 2002; 95: 273–7 12. Nickalls RW, Mapleson WW: Age-related iso-MAC charts for isoflurane, sevoflurane and desflurane in man. Br J Anaesth 2003; 91:170 – 4 13. Lindholm ML, Träff S, Granath F, Greenwald SD, Ekbom A, Lennmarken C, Sandin RH: Mortality within 2 years after surgery in relation to low intraoperative bispectral index values and preexisting malignant disease. Anesth Analg 2009; 108:508 –12 14. Babyak MA: What you see may not be what you get: A brief, nontechnical introduction to overfitting in regression-type models. Psychosom Med 2004; 66:411–21 15. Blanchon F, Grivaux M, Asselain B, Lebas FX, Orlando JP, Piquet J, Zureik M: 4-year mortality in patients with nonsmall-cell lung cancer: Development and validation of a prognostic index. Lancet Oncol 2006; 7:829 –36 16. Juul AB, Wetterslev J, Kofoed-Enevoldsen A: Long-term postoperative mortality in diabetic patients undergoing major non-cardiac surgery. Eur J Anaesthesiol 2004; 21:523–9 17. Daley J, Khuri SF, Henderson W, Hur K, Gibbs JO, Barbour G, Demakis J, Irvin G 3rd, Stremple JF, Grover F, McDonald G, Passaro E Jr, Fabri PJ, Spencer J, Hammermeister K, Aust JB, Oprian C: Risk adjustment of the postoperative morbidity rate for the comparative assessment of the quality of surgical care: Results of the National Veterans Affairs Surgical Risk Study. J Am Coll Surg 1997; 185:328 – 40 18. Ouellette JR, Small DG, Termuhlen PM: Evaluation of Charlson-Age Comorbidity Index as predictor of morbidity and mortality in patients with colorectal carcinoma. J Gastrointest Surg 2004; 8:1061–7 19. Riva E, Tettamanti M, Mosconi P, Apolone G, Gandini F, Nobili A, Tallone MV, Detoma P, Giacomin A, Clerico M, Tempia P, Guala A, Fasolo G, Lucca U: Association of mild anemia with hospitalization and mortality in the elderly: The Health and Anemia population-based study. Haematologica 2009; 94:22– 8 20. Skipworth J, Foster J, Raptis D, Hughes F: The effect of preoperative weight loss and body mass index on postoperative outcome in patients with esophagogastric carcinoma. Dis Esophagus 2009; 22:559 – 63 21. Murphy PM, Blackshaw GR, Paris HJ, Edwards P, Barry JD, Lewis WG: Prospective evaluation of nutritional status related to body mass indices and outcomes after modified D2 gastrectomy for carcinoma. Clin Nutr 2004; 23:477– 83 22. Tewari N, Martin-Ucar AE, Black E, Beggs L, Beggs FD, Duffy JP, Morgan WE: Nutritional status affects long term survival after lobectomy for lung cancer. Lung Cancer 2007; 57: 389 –94 23. Dunne JR, Malone D, Tracy JK, Gannon C, Napolitano LM: Perioperative anemia: An independent risk factor for infection, mortality, and resource utilization in surgery. J Surg Res 2002; 102:237– 44 24. Kertai MD, Boersma E, Westerhout CM, van Domburg R, Klein J, Bax JJ, van Urk H, Poldermans D: Association beAnesthesiology 2011; 114:545–56 Appendix: B-Unaware Study Group Michael S. Avidan M.B.B.Ch., F.C.A.S.A. (Associate Professor of Anesthesiology, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri); Michael Bottros, M.D. (Resident, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri); Beth A. Burnside, B.A. (Research Assistant, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri); Alex S. Evers, M.D. (Henry E. Mallinckrodt Professor, Anesthesiology Head, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri); Kevin J. Finkel, M.D. (Resident, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri); Charles B. Hantler, M.D. (Professor of Anesthesiology, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri); Bernadette Henrichs Ph.D., C.R.N.A., C.C.R.N. (Director, Nurse Anesthesia Program, Goldfarb School of Nursing at Barnes-Jewish College, St. Louis, Missouri); Eric Jacobsohn, M.B.Ch.B., M.H.P.E., F.R.C.P.C. (Professor and Chair Department of Anesthesia, Department of Anesthesia and Perioperative Medicine, University of Manitoba, Winnipeg, Manitoba, Canada); Heiko Kaiser, M.D. (Research Fellow, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri); Miklos D. Kertai, M.D., Ph.D. (Instructor in Anesthesiology, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri); Andrew Leitner, B.S. (Medical Student, Washington University School of Medicine, St. Louis, Missouri); Nirvik Pal, M.D. (Instructor in Anesthesiology, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri); Deepika Rao, B.S (Medical Student, Washington University School of Medicine, St. Louis, Missouri); Srikar Rao, B.S. (Medical Student, Washington University School of Medicine, St. Louis, Missouri); Clare Ridley, M.D. (Resident, Department of Anesthesiology, Washington University School of Medicine, St. Louis Missouri); Leif Saager, M.D. (Instructor in Anesthesiology, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri); Furqaan Sadiq, B.J. (Research Assistant, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Mis555 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931111/ on 06/11/2017 Kertai et al. Bispectral Index and Mortality in Noncardiac Surgery souri); Elika Safarzadeh, M.D. (Research Assistant, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri); Adam C. Searleman, B.S. (Medical Student, Washington University School of Medicine, St. Louis, Missouri); Sylvia A. Searleman, B.S. (Research Assistant, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri); Jacqueline A. Selvidge, M.S. (Research Assistant, Washington University School of Medicine, St. Louis, Missouri); Brian Torres, B.S.N., R.N., C.C.R.N. (Research Assistant, Washington University School of Medicine, St. Louis, Missouri); Michelle S. Turner, M.S. (Research Assistant, Washington University School of Medicine, St. Louis, Missouri); Heidi Tymkew, M.H.S. (Research Coordinator, Washington University School of Medicine, St. Louis, Missouri); Anna Woodbury, B.S. (Medical Student, Washington University, School of Medicine, St. Louis, Missouri); Lini Zhang, M.D. (Research Assistant, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri). ANESTHESIOLOGY REFLECTIONS Early Fall at the Waters-Morton House by Vandam Two decades before serving as Editor of ANESTHESIOLOGY, surgeon Leroy D. “Roy” Vandam, M.D. (1914 – 2004), began losing sight in his left eye. His monocular vision neither precluded Vandam from succeeding in academic anesthesiology (at universities such as Johns Hopkins, Pennsylvania, and Harvard) nor from expressing his artistic talents. Painting the untitled watercolor (above) early one autumn, Vandam captured once again in watercolor the second home of celebrated etherizer William T. G. Morton. (Copyright © the American Society of Anesthesiologists, Inc. This image also appears in the Anesthesiology Reflections online collection available at www.anesthesiology.org.) George S. Bause, M.D., M.P.H., Honorary Curator, ASA’s Wood Library-Museum of Anesthesiology, Park Ridge, Illinois, and Clinical Associate Professor, Case Western Reserve University, Cleveland, Ohio. [email protected]. Anesthesiology 2011; 114:545–56 556 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/journals/jasa/931111/ on 06/11/2017 Kertai et al.