Van Dijk D, Jansen EWL, Hijman R, Nierich AP, Diephuis JC, Moons KGM, Lahpor JR, Borst C, Keizer AMA, Nathoe HM, Grobbee DE, De Jaegere PPT, Kalkman CJ, for the Octopus Study Group. Cognitive Outcome After Off-Pump and On-Pump Coronary Artery Bypass
Graft SurgeryA Randomized Trial. JAMA. 2002;287(11):1405-1412. doi:10.1001/jama.287.11.1405
Author Affiliations: Departments of Anaesthesiology (Drs Van Dijk, Diephuis, and Kalkman), Cardiothoracic Surgery (Drs Jansen and Lahpor), Psychiatry (Dr Hijman and Ms Keizer), Cardiology (Drs Borst, Nathoe, and De Jaegere), and the Julius Center for Patient Oriented Research (Drs Moons and Grobbee), University Medical Center Utrecht, Utrecht; and Department of Thoracic Anaesthesiology, Isala Clinics, Weezenlanden Hospital, Zwolle (Dr Nierich), the Netherlands.
Context Coronary artery bypass graft (CABG) surgery is associated with a decline
in cognitive function, which has largely been attributed to the use of cardiopulmonary
bypass (on-pump procedures). Cardiac stabilizers facilitate CABG surgery without
use of cardiopulmonary bypass (off-pump procedures) and should reduce the
cognitive decline associated with on-pump procedures.
Objective To compare the effect of CABG surgery with (on-pump) and without (off-pump)
cardiopulmonary bypass on cognitive outcome.
Design and Setting Randomized controlled trial conducted in the Netherlands of CABG surgery
patients enrolled from March 1998 through August 2000, with 3- and 12-month
Participants and Intervention Patients scheduled for their first CABG surgery (mean age, 61 years;
n = 281) were randomly assigned to off-pump surgery (n = 142) or on-pump surgery
(n = 139).
Main Outcome Measures Cognitive outcome at 3 and 12 months, which was determined by psychologists
(blinded for randomization) who administered 10 neuropsychological tests before
and after surgery. Quality of life, stroke rate, and all-cause mortality at
3 and 12 months were secondary outcome measures.
Results Cognitive outcome could be determined at 3 months in 248 patients. Cognitive
decline occurred in 21% in the off-pump group and 29% in the on-pump group
(relative risk [RR], 0.65; 95% confidence interval [CI], 0.36-1.16; P = .15). The overall standardized change score (ie, improvement
of cognitive performance) was 0.19 in the off-pump vs 0.13 in the on-pump
group (P = .03). At 12 months, cognitive decline
occurred in 30.8% in the off-pump group and 33.6% in the on-pump group (RR,
0.88; 95% CI, 0.52-1.49; P = .69). The overall standardized
change score was 0.19 in the off-pump vs 0.12 in the on-pump group (P = .09). No statistically significant differences were
observed between the on-pump and off-pump groups in quality of life, stroke
rate, or all-cause mortality at 3 and 12 months.
Conclusion Patients who received their first CABG surgery without cardiopulmonary
bypass had improved cognitive outcomes 3 months after the procedure, but the
effects were limited and became negligible at 12 months.
Coronary artery bypass graft (CABG) surgery with the use of cardiopulmonary
bypass (CPB) is associated with significant cerebral morbidity, usually manifested
as cognitive decline or stroke.1 The incidence
of cognitive decline ranges from 3% to 50%, depending on patient characteristics,
definition of decline, and timing of neuropsychologic assessment.1,2 A recent pooled analysis of 6 comparable
studies yielded a proportion of 23% of patients with cognitive decline 2 months
after surgery.3 Although this degree of cognitive
decline does not affect most patients in functional terms, a small proportion
of patients with cognitive decline becomes sufficiently disabled to prevent
return to employment.1 Perioperative stroke
occurs in approximately 3% of the patients undergoing CABG surgery.1,4
Cerebral morbidity after CABG surgery has largely been attributed to
the use of CPB.1 Cardiopulmonary bypass increases
the permeability of the blood-brain barrier and generates microemboli, which
may affect cognitive function,5- 7
and also requires cannulation and cross-clamping of the ascending aorta, which
may induce atheromatous macroemboli causing stroke.8
Factors increasing the risk of cerebral morbidity include advanced age and
prolonged time undergoing CPB.1,4
However, the assumption that CPB is the main cause of cerebral morbidity after
CABG surgery has not been quantified in randomized trials of sufficient size.
Two small trials showed conflicting results. One study (n = 40) demonstrated
a marked improvement of cognitive outcome by using off-pump CABG surgery,5 while the other study (n = 60) showed no improvement.6
Recently, cardiac stabilization devices were developed to facilitate
CABG surgery on the beating heart (off-pump CABG), which allow immobilization
and presentation of all sides of the beating heart,9,10
and for many patients complete revascularization can now be achieved without
the use of CPB.10- 12
In a previous article,12 we reported the clinical
outcomes at 1 month after on-pump vs off-pump CABG surgery for patients in
this clinical trial. In this study, we compared the effect of CABG surgery
with and without CPB on cognitive outcome.
The design and methods of the Octopus trial have been described in detail.13 In brief, patients were eligible if referred for
first-time isolated coronary bypass surgery and an off-pump procedure was
deemed technically feasible. Patients were excluded in case of emergency or
concomitant major surgery, Q-wave myocardial infarction in the last 6 weeks,
or poor left ventricular function. Patients who were unlikely to complete
1-year follow-up, unable to give informed consent, or undergo neuropsychologic
testing were excluded. There were no restrictions to age. Eligible patients
were informed with a letter and invited to the outpatient clinic to receive
additional information. After written informed consent was obtained, patients
were randomly assigned by computerized block-randomization, over the telephone,
to off-pump or on-pump CABG surgery. The block size varied from 8 to 20 patients
and was unknown by the physicians who randomized the patients. The study was
approved by the ethics committees of the 3 participating centers.
Between March 1998 and August 2000, 281 patients were enrolled, of whom
265 were treated according to randomization (Figure 1 and Table 1).
Ten patients randomized to off-pump surgery underwent CABG with CPB because
progression of symptoms required emergency surgery or because technical problems
were encountered during the procedure. One other off-pump patient underwent
coronary angioplasty. In 5 patients assigned to on-pump CABG surgery, an off-pump
procedure was performed.
The primary end point of the study was cognitive outcome at 3 months
after surgery. Patients underwent a battery of 10 neuropsychologic tests 1
day before and 3 and 12 months after operation. The tests were administered
in the participating hospitals by trained psychologists who were blinded to
treatment allocation. Administration of the tests lasted approximately 100
In accordance with the Statement of Consensus on Assessment of Neurobehavioral
Outcomes after Cardiac Surgery,14 the battery
included tests for motor skills, verbal memory capacity, and attention. In
addition, tests were included to assess speed and capacity of working memory,
visuospatial capacity, selective and sustained attention, and information
processing. Each test yielded 1 or more variables, with different ranges per
variable. Eleven main variables were chosen a priori to be used in the analyses.
The cognitive domains that were covered, the tests, and the main variables13 are listed in Table 2. Cognitive decline was defined as a decrease in an individual's
performance of at least 20% from baseline, in at least 20% (3) of the main
variables.15 Patients who sustained a stroke
were considered to have cognitive decline. To limit practice effects, 6 of
the 10 tests were also administered 2 weeks before baseline assessment (pretest, Table 2) and, wherever possible, parallel
forms of the tests were used in the consecutive assessments.
In addition to the primary analysis based on a dichotomous cognitive
outcome, 2 additional analyses were performed, both including continuous cognitive
outcome measures. The first consisted of a direct comparison of the continuous
test scores. To estimate the change in performance from baseline to 3 months
after operation, a standardized change score (SCS) was calculated for each
main variable in each patient by subtracting the preoperative score from the
postoperative score and dividing the difference by the preoperative SD of
that variable. If improved performance was reflected by a lower score (eg,
in timed tasks), the directional data were reversed so that all improvements
gave positive change scores. Per subject, the mean of the 11 SCSs was taken
as a quantitative measure of the overall postoperative change in performance.16,17
The second additional analysis of cognitive outcome included a factor
analysis with orthogonal rotation, which was performed to minimize the overlap
between the 11 main test variables and to facilitate interpretation.2,18 This reduced the data set to 4 independent
factor scores, each representing a separate domain of cognitive function:
(1) attention and visuospatial capacity; (2) verbal memory; (3) selective
attention and motor capacity; and (4) working memory. The factor coefficients
needed to calculate the factor scores at the various time points were derived
using the factor loadings and weights from the baseline cognitive data. Factor
change scores were obtained by subtracting the baseline factor scores from
the postoperative factor scores.
Secondary end points included identical measures of cognitive outcome
at 12 months, differences in quality of life at 3 and 12 months, and stroke
rate and all-cause mortality at 3 and 12 months. Health-related quality of
life was assessed using 2 generic questionnaires. The EuroQol questionnaire
generates a single index, ranging from −1 to +1, with −1 reflecting
the worst imaginable quality of life and +1 reflecting the best imaginable
quality of life.19 The Short Form-36 questionnaire
comprises 8 different domains all ranging from 0 to 100. Higher scores indicate
higher levels of functioning or well-being.20
Stroke was defined as focal brain injury, detected by standard neurologic
examination, persisting for more than 24 hours, and combined with an increase
in functional deficit of at least 1 grade on the Rankin Scale.21
The goal of surgery was to obtain complete arterial revascularization.
With the exception of 2 emergency procedures, all operations were performed
by cardiac surgeons experienced in both off-pump and on-pump bypass surgery.
During off-pump procedures, the Octopus method9
(Octopus Device, Medtronic, Minneapolis, Minn) was used for stabilization
of the target coronary artery.
The use of CPB requires full heparinization, which influenced the selection
of anaesthetic technique. In the on-pump group, 99% of the patients received
total intravenous anesthesia including high dose opioids, whereas in the off-pump
group, 54% of the patients received thoracic epidural anesthesia combined
with low-dose opioids. Cardiopulmonary bypass was managed according to the α-stat
principle,22 with a minimal nasopharyngeal
temperature of 32°C and a nonpulsatile perfusion of 2.0 to 2.4 L/m2 per minute. The pump was primed with a crystalloid-colloid mixture.
During rewarming, the maximal gradient between blood and water in the heat
exchanger was 5°C with a maximal water temperature of 39°C. To reduce
blood loss in the CPB group, blood was recollected using a suction cardiotomy
reservoir, without filter or processing. In the off-pump group, a cell-saver
The sample size calculation was based on the assumptions that the incidence
of cognitive decline at 3 months is 21% after on-pump CABG surgery3 and that a two-thirds reduction could be achieved
using an off-pump technique. With the α error set at .05 and β
error set at .10 (power of 90%), a total of 125 patients in each group were
required, which was increased to 140 patients per group because a 10% loss
to follow-up was anticipated.
Data were analyzed according to randomization. Incidences of cognitive
decline and mortality were compared using Fisher exact test and the relative
risk (RR) estimate with 95% confidence interval (CI). Odds ratios were used
as a measure of RR. Continuous outcome measures were compared using the Wilcoxon
nonparametric test. Differences in quality of life are presented as means
with 95% CIs. For the cognitive outcome measures, multivariable regression
models were used to adjust for possible baseline differences.
At 3 months, cognitive outcome and quality of life could be determined
in 128 patients in the off-pump group and 120 patients in the on-pump group
(Figure 1). Within these groups,
4 patients completed fewer neuropsychologic tests during postoperative assessment
than at baseline. In the primary analysis (dichotomous cognitive outcome),
these patients were considered to have a decreased performance of at least
20% on the missing tests (worst-case score).23
To assess the effect of loss to follow-up, several additional analyses were
performed. The baseline characteristics of the patients who completed cognitive
follow-up were compared. A sensitivity analysis was performed in which the
outcome, cognitive decline, was first assigned to the 19 on-pump CABG surgery
patients without 3-month neuropsychologic testing, and then to the 14 off-pump
patients without 3-month neuropsychologic testing. Finally, missing cognitive
data were imputed by means of linear regression modeling using SPSS version
10.0 (SPSS Inc, Chicago, Ill). Such modeling predicts the value of a missing
variable by using all available cognitive and clinical data of that patient.
Analyses were repeated with the completed data set.
Baseline characteristics of the patients, including preoperative cognitive
test performance, were well balanced between the 2 groups (Table 1 and Table 2).
Patients in the off-pump group were on average 1 year older than the on-pump
group and comprised slightly fewer men and patients with diabetes, peripheral
vascular disease, and 3-vessel disease. The latter is reflected by the mean
number of distal anastomoses, which was 2.4 in the off-pump and 2.6 in the
on-pump group. For proximal anastomoses, aortic side clamps were used in 36%
of the off-pump patients and 50% of the on-pump patients. In the on-pump group,
time undergoing CPB averaged 66 minutes with 44 minutes cross-clamp time.
To assess the theoretical possibility of selection bias, the likelihood
of the participants randomized to the off-pump group, which was influenced
by the assignments of the previous patients, was entered in a logistic regression
model. This variable appeared to be no determinant of cognitive outcome (P = .99). We also compared 21 baseline characteristics
from off-pump patients who had a high likelihood of being randomized to off-pump
with the baseline characteristics from on-pump patients with a low likelihood.
No significant differences were observed in all the comparisons on the 21
baseline characteristics. Both analyses indicate that there was no selection
bias (ie, the randomization sequence was well concealed).24
The mean interval between operation and 3-month follow-up was 92 (SD,
17) days in the off-pump group and 96 (SD, 12) days in the on-pump group (P = .06). At 3 months after surgery, cognitive decline
occurred in 21.1% of patients after off-pump CABG surgery and 29.2% after
on-pump CABG surgery (RR, 0.65; 95% CI, 0.36-1.16; P
= .15). The RR did not change after adjusting for baseline differences in
age, sex, diabetes, peripheral vascular disease, and number of diseased vessels
(RR, 0.65; 95% CI, 0.36-1.17; P = .15) or with adjustment
for anesthetic technique (data not shown). Within the off-pump group, cognitive
decline occurred in 22.7% of patients who received epidural anesthesia with
low-dose opioids and 18.9% of patients who received high-dose opioids without
epidural anesthesia (P = .67).
The results per neuropsychologic test variable are presented in Table 3. At 3 months, the patients in both
groups improved on all 11 main variables. The overall postoperative change
in performance (ie, overall improvement; mean of the 11 SCSs) was 0.19 SCS
in the off-pump and 0.13 SCS in the on-pump group (P
= .03). Adjustment for baseline differences did not change the difference
between the groups.
The change in performance per cognitive domain, as calculated with factor
analysis, is presented in Table 4.
Patients improved on all domains from baseline to 3 months after surgery,
but no statistically significant differences between the groups were present.
At 12 months, cognitive decline occurred in 30.8% of patients after
off-pump CABG surgery and 33.6% after on-pump CABG surgery (RR, 0.88; 95%
CI, 0.52-1.49; P = .69). The other analyses (Table 3 and Table 4) also showed nonsignificant differences between the groups.
An exception was the domain verbal memory (factor 2), which had improved twice
as much in the off-pump group (P = .01). At 12 months,
the overall change in cognitive performance was 0.19 SCS in the off-pump group
and 0.12 SCS in the on-pump group (P = .09).
At 3 months, the cognitive outcome of 33 (12%) patients could not be
determined and at 12 months the cognitive data of 29 (10%) patients were not
obtained. Reasons for not obtaining neuropsychological test data testing are
summarized in Table 5. The 3-month
sensitivity analysis yielded an RR of 0.37 (95% CI, 0.22-0.63) and 1.21 (95%
CI, 0.71-2.05), which are the extremes that could be obtained if all patients
had been available for 3-month follow-up. The baseline characteristics of
the patients who were available for analysis of cognitive outcome were comparable
to the baseline characteristics of the entire patient sample. Imputation of
all missing data by means of linear regression increased the differences in
cognitive decline between the 2 groups at 3 months. After imputation, the
rate of cognitive decline at 3 months was 19.0% in the off-pump group and
28.8% in the on-pump group (RR, 0.58; 95% CI, 0.33-1.02; P = .07), and the overall postoperative change in performance became
0.18 SCS and 0.13 SCS in the off-pump and on-pump groups, respectively (P = .25). After imputation, the RR for cognitive decline
at 12 months was 0.90 (95% CI, 0.53-1.54; P = .79)
and the overall postoperative change in performance became 0.20 SCS and 0.12
SCS in the off-pump and on-pump groups, respectively (P = .05).
Both groups reported a marked improvement in overall quality of life
at 3 months as well as each of the 8 subdomains (Table 6). Within these domains, only bodily pain and general health
perceptions improved further from 3 to 12 months. Direct comparison between
the groups of the overall scores and scores per domain at 3 and 12 months
revealed only nonsignificant differences.
At 3 months, 1 nonfatal stroke (perioperative) occurred in the off-pump
group and 2 nonfatal strokes (1 perioperative) in the on-pump group. One off-pump
patient died from gastrointestinal bleeding 49 days after CABG surgery and
1 on-pump patient died 58 days after perioperative myocardial infarction.
At 12 months, the mortality was 2 per group. In the off-pump group,
1 patient died from hepatic cancer 153 days after CABG surgery and in the
on-pump group, 1 patient (who had had a previous stroke just prior to CABG
surgery) died after a second 232 days after CABG surgery. The number of patients
who had experienced stroke at 12 months remained 1 in the off-pump group and
2 in the on-pump group.
The use of CPB is generally regarded as the main cause of cognitive
decline following heart surgery.1 The present
study demonstrates limited improvement of cognitive outcome at 3 months in
patients undergoing off-pump CABG surgery. The 29% incidence of cognitive
decline after on-pump CABG surgery is consistent with previous, uncontrolled
studies2,3 but the benefit of
avoiding CPB was smaller than was anticipated. Moreover, at 12 months, the
small differences between the groups had become negligible.
The present study is to our knowledge the largest randomized trial on
cognitive outcome after off-pump and on-pump CABG surgery. Two other randomized
studies on cognitive outcome after CABG surgery were published recently. Age
and extent of coronary disease of the participants of both studies were comparable
with the present study. Diegeler et al5 administered
the Syndrom Kurz Test to 40 patients and demonstrated a marked improvement
of cognitive outcome after 7 days by using off-pump CABG surgery. Lloyd et
al,6 in contrast, administered 7 tests from
the Wechsler Memory Scale and Wechsler Adult Intelligence Scale to 60 patients
and found no difference in cognitive function after 3 months.
Several reasons may be considered to explain the limited difference
in cognitive outcome between the treatment groups observed in the present
study. First, factors other than CPB may cause cognitive decline after CABG
surgery. It is conceivable that undergoing anesthesia affects cognitive function,
though in the present study no association was found between cognitive decline
and type of anesthetic technique. Moller et al25
demonstrated a 10% incidence of cognitive decline after noncardiac surgery,
independent of regional or general anesthesia. These observations suggest
that surgical trauma could be a source of cognitive decline.
Second, to minimize crossovers from off-pump to on-pump groups, stringent
patient selection criteria were used. This has resulted in a relatively young
group of patients (mean, 61 years) with less advanced coronary artery disease
and limited comorbidity. The effects of an off-pump technique may be more
marked in older patients, patients with more extensive coronary artery and
aortic disease, and patients with substantial comorbidity.1,4,26
Third, the off-pump technique may be a new source of cognitive decline.
Exposure of the posterior cardiac wall frequently leads to transient episodes
of elevated central venous pressure and concurrent decreased systemic blood
pressure, resulting in a decreased cerebral perfusion pressure.27
Fourth, improved cognitive outcome by using an off-pump technique may
only become more clear in the long term. In a recent long-term follow-up study
by Newman et al,2 cognitive decline was found
in 24% of the patients 6 months after on-pump CABG surgery, which increased
to 42% after 5 years. The present study demonstrated an increasing incidence
of cognitive decline from 3 to 12 months, but the difference in cognitive
decline observed earlier between patients in the on-pump group and the off-pump
A final explanation involves the definition of cognitive decline (20%
decrease in performance in 20% of the variables), which appears to have limited
precision. Although this definition has been reported to be sensitive and
the cut-off value may be within the range of an individual's natural fluctuations
in performance. Recently, the International Study of Post-Operative Cognitive
Dysfunction group applied an almost similar definition to 176 volunteers undergoing
5 neuropsychologic tests.30 After 3 months,
25% of the volunteers were identified as having cognitive decline. Therefore,
it is likely that the true incidence of cognitive decline after CABG surgery
is lower than generally assumed.30 Moreover,
measurement errors may have diluted the difference in cognitive decline found
in the present study. Because of the methodological difficulties associated
with defining cognitive outcome at the individual patient level, we regard
the analysis based on comparison of the continuous neuropsychologic test scores
more reliable than the analysis based on the dichotomous outcome measure.
The present study has several limitations, including single blinding
and a 12% loss to follow-up. It is unlikely, however, that the differences
in cognitive outcome found between the groups were caused by loss to follow-up.
Both the drop-out rate and the baseline characteristics of the remaining patients
were largely similar across the groups. Adjustments for small inequalities
in baseline characteristics did not affect the results. Imputation of cognitive
data for the patients that were lost to follow-up increased the difference
in cognitive decline between the groups. Only a small number of the patients
in whom cognitive outcome could not be determined lost motivation for cognitive
follow-up after their surgery. A relation between loss to follow-up and cognitive
outcome may therefore be present in only a very small proportion of the patients.
In addition, the sample size calculation was based on achieving a two-thirds
reduction in cognitive decline at 3 months. Thus, a more modest benefit in
reducing cognitive decline cannot be excluded and would need to be evaluated
in larger randomized trials.
We conclude that patients who received their first CABG surgery without
CPB had improved cognitive outcomes 3 months after the procedure, but the
effects were limited and became negligible at 12 months.