Download Bispectral Index Monitoring, Duration of Bispectral Index Below 45

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
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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
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Kertai et al.
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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.
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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
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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
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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.
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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
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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.
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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.
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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.
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likely coincidental, not causal. Putting these data together, if
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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
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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].
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