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Click here to read this article as a CME activity
a Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
b Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
c Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
d Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
e Zanvyl Krieger Mind/Brain Institute, Baltimore, Maryland
Accepted for publication June 18, 2007.
* Address correspondence to Dr Selnes, Department of Neurology, Reed Hall East, 2, 1620 McElderry St, Baltimore, MD 21205-1910 (Email: oselnes{at}jhmi.edu).
| Adult cardiac surgery:
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Abstract |
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Methods: We compared changes in cognitive performance from baseline to 3 years in patients undergoing on-pump CABG (n = 152) with those of three control groups: patients with off-pump surgery (n = 75); with diagnosed coronary artery disease but no surgery (n = 99); and without coronary artery disease risk factors (n = 69). Neuropsychological performance was assessed by standardized tests of attention, language, verbal and visual memory, visuospatial, executive function, and psychomotor and motor speed.
Results: Relative to their baseline performance, no group had significantly lower performance at 36 months for any of the cognitive domains. From 12 to 36 months, there were no statistically significant differences in the degree of change between the on- and off-pump surgery groups. There was a trend toward mild decline in some cognitive domains, but overall differences among groups in degree of change over time were not statistically significant.
Conclusions: We found a mild but nonsignificant trend toward late postoperative cognitive decline for all study groups with coronary artery disease, but no significant differences in the degree of late postoperative cognitive decline after on-pump compared with off-pump surgery. These findings suggest that previously reported late decline after bypass surgery is not specific to use of cardiopulmonary bypass.
It is well documented that some patients experience cognitive decline after on-pump coronary artery bypass surgery (CABG), particularly during the first days to weeks after surgery. The severity, duration, and etiology of these cognitive changes remain poorly understood, however. It has been widely assumed that the post-CABG cognitive changes are associated with the use of cardiopulmonary bypass, but recent studies comparing cognitive outcomes in patients randomized to either on- or off-pump surgery have not found significant differences in the incidence of short-term cognitive decline [1–3], thus questioning the assumption that cardiopulmonary bypass is the sole source of cognitive impairment after bypass surgery. Furthermore, although early postoperative cognitive decline was thought to be transient and reversible, some investigators have now reported that cognitive decline during the immediate postoperative period may be a marker for late cognitive decline after CABG [1, 4, 5].
There is evidence that late cognitive decline does occur 5 years after CABG [6–8], although the explanation for this late decline remains poorly understood. Whereas it has been suggested that such late cognitive decline is also directly attributable to the use of cardiopulmonary bypass (CPB), most studies have not included an appropriate control group. Therefore, the specific etiology of the late cognitive changes remains unclear.
Most patients undergoing CABG are older, placing them at risk for cognitive decline for other reasons, including normal aging, vascular disease, and Alzheimer’s disease. It is well known that patients with severe coronary artery disease who require surgical intervention are also likely to have vascular disease of the brain. In a recent large neuroimaging study of candidates for CABG, nearly 50% of the patients were found to have evidence of mild to moderate cerebrovascular disease on magnetic resonance imaging [9]. Prospective follow-up of patients with cerebrovascular disease has established that the presence of silent brain infarctions on magnetic resonance imaging was associated with greater decline in cognition over a 5-year follow-up period [10]. Therefore, it is possible that the presence of cerebrovascular disease by itself may predict late cognitive decline after CABG. Some have suggested that CABG may be associated with an increased risk of Alzheimer’s disease 5 years after the surgery [11]. Finally, several long-term prospective studies have documented mild cognitive decline even in otherwise healthy community-dwelling older persons [12–14], suggesting that any late cognitive decline observed years after CABG, at least in part, may be due to normal aging.
To further characterize the long-term neurocognitive changes after CABG, we designed a prospective study in which we have compared the longitudinal cognitive test performance of patients undergoing CABG with that of three control groups: (1) patients with off-pump surgery; (2) patients with coronary artery disease but no surgery (NSCC); and (3) a group of "heart-healthy" controls (HHC) with no known risk factors for coronary artery disease. We have previously reported that at baseline, the neuropsychological test performance of the three groups with coronary artery disease was strikingly lower than that of the heart-healthy controls for all cognitive domains, but there were no between-group differences in the degree of change in cognitive test performance for as long as 1 year [15]. We now extend these findings by comparing 3-year follow-up data from the same four study groups.
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Material and Methods |
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Study Groups
Surgical groups
Patients who were native speakers of English, not mechanically ventilated, able to sit upright, and able to give informed consent were eligible for participation. One hundred and fifty-two patients scheduled to undergo isolated on-pump CABG at our institution were enrolled between September 1997 and March 1999. For the off-pump patients, a single institution could not provide enough cases, and the 75 off-pump patients were therefore recruited from five area hospitals. Enrollment dates for the off-pump group were March 1998 to October 2003. Separate IRB approval was obtained from all institutions.
Nonsurgical groups
Patients with a diagnosis of coronary artery disease, confirmed by cardiac catheterization, and under medical management were recruited from cardiologists at our institution. Patients with a history of previous cardiac surgery were ineligible. A total of 99 nonsurgical cardiac control patients with coronary artery disease were enrolled between September 1997 and April 2003. The heart-healthy control subjects were recruited by IRB-approved advertisements from November 2001 to September 2003. Subjects with a known history of risk factors for heart disease, including diabetes mellitus, kidney disease, hypertension, myocardial infarction, angina, hyperlipidemia, stroke/transient ischemic attack, peripheral vascular disease, and medications for any of the above conditions, were ineligible for the study. In all, 69 subjects comparable in age, sex, and education level to the other study groups were enrolled.
Surgical Procedures
These procedures are described elsewhere [15, 16].
Neuropsychological and Mood Assessment
A battery of standardized neuropsychological tests (described elsewhere) [17] was administered to all study participants at baseline and at 3, 12, and 36 months. The Center for Epidemiologic Studies Depression Scale (CES-D) [18] and Functional Status Questionnaire (FSQ) were also administered at baseline and follow-up [19]. Over the course of the study, neuropsychological testing was performed by six examiners who had all been trained in the same manner at the Johns Hopkins Medical Institutions. Follow-up evaluations were performed either in a clinic setting or in the participant’s home.
Statistical Methods
The primary analyses examined within-patient changes in neuropsychological test scores from baseline to 3, 12, and 36 months. This methodology quantifies the degree of improvement and decline relative to a participant’s own baseline performance. The neuropsychological test battery yielded 16 tests and subtest scores that were combined into the following eight cognitive domain scores: verbal memory, visual memory, visuoconstruction, language, motor speed, psychomotor speed, attention, and executive function. An overall global domain score was created by calculating the mean of these eight domain scores. Analyses were performed using z-scores derived from the baseline means and standard deviations of each test in the heart-healthy control group. Scores were adjusted for age, sex, and education. For timed neuropsychological tests, the z-score was inverted so that a higher score reflected improved performance for all tests.
To examine the association of subject-specific covariates with changes in neuropsychological z-scores over time, we used a separate linear mixed effects model [20] for the z-scores from each test, estimating a separate practice effect and time trend for each study group. To calculate the change scores in the eight cognitive domains and the global domain, we pooled the estimates from the separate tests in each domain and used bootstrapping [21] to calculate the statistical uncertainty of these pooled values. This methodology has been reported elsewhere [22].
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Results |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Within-Group Changes From 12 to 36 Months
Compared with their performance at 12 months, there was a trend toward lower performance at 36 months for all cognitive domains in the on-pump CABG group, but none reached statistical significance. The off-pump group had significantly lower performance at 36 than at 12 months for the domains of verbal memory, visual memory, and visuoconstruction (p < 0.05). For the NSCC group, the decline from 12 to 36 months was statistically significant (p < 0.05) in all but the domains of executive function and psychomotor speed, whereas the performance of the HHC group remained stable for these two cognitive domains. For other tests, there was a trend toward mild decline for the HHC group, which reached statistical significance only for the domains of visual memory and attention (p < 0.05).
Between-Group Changes in Cognitive Performance From Baseline to Follow-Up
CABG versus off-pump
The within-participant change from baseline to 3, 12, and 36 months for the eight cognitive domains and the global domain scores is shown in Figure 2. As indicated by the overlapping confidence intervals, the degree of change from baseline to 36 months was similar for the CABG and off-pump patients. Both groups show a pattern of improvement between baseline and 12 months, followed by a return toward baseline performance for some domains (motor speed, psychomotor speed, executive function, and visuoconstruction) at 36 months. There were no statistically significant differences between on- and off-pump patients in the longitudinal pattern of change for the global mean. For the domain of visual memory, there was a trend toward less decline in the on-pump group, but this did not reach statistical significance.
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Comment |
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The lack of significant differences in the longitudinal test performance between the CABG and off-pump group in our study suggests that the use of cardiopulmonary bypass is not the sole source of cognitive change after surgery. Although this conclusion is limited by the small size and limited follow-up of our off-pump group, it is nonetheless consistent with results from several recently published large randomized trials comparing cognitive outcomes after CABG and off-pump surgery. For example, Ernest and colleagues [23] found no cross-sectional differences between CABG and off-pump surgery in cognitive test performance at 2 or 6 months after surgery, and no differences in the incidence of cognitive decline. In a study comparing elderly, high-risk patients randomly assigned to on- or off-pump bypass surgery, Jensen and coworkers [24] concluded that there were no differences in cognitive outcomes between the study groups at 3 months. Vedin and colleagues [2] compared 70 patients randomized to on- or off-pump surgery and reported no differences in the incidence of cognitive impairment at 1 and 6 months after surgery. Although our study was not randomized, it is nonetheless one of the first to extend the follow-up period for off-pump patients to 36 months after surgery.
We have previously reported that the longitudinal neuropsychological test performance of CABG patients did not differ from that of a group of comparable NSCC patients with coronary artery disease at 12 or 36 months after their baseline evaluation. That suggests that coronary artery disease (and the presumed coexisting cerebrovascular disease) may be associated with mild decline in performance for some cognitive domains even in the absence of surgery [17].
Several studies have reported that cardiovascular risk factors predict performance on neuropsychological tests, in particular measures of processing speed and executive function [25, 26]. More recent large-scale prospective population-based studies have also confirmed that cardiovascular risk factors are associated with incident cognitive decline [27], and there is some evidence that treatment of the underlying cardiovascular risk factors may reduce the degree of cognitive decline over time [28].
Although the mechanisms by which atherosclerotic disease cause cognitive decline are not known, there are several possibilities. There is considerable overlap between risk factors for coronary artery disease and cerebrovascular disease, and it is therefore likely that patients with coronary artery disease also have some degree of coexisting cerebrovascular disease. We do not have neuroimaging data to quantify the degree of cerebrovascular disease in our patients with coronary artery disease, but several previous studies have demonstrated a high incidence of white matter abnormalities in candidates for coronary artery bypass surgery [9, 29]. There is also increasing evidence that the presence and degree of cerebrovascular disease in elderly patients is associated with mild decline in cognition over time. In a population-based study, structural brain changes on magnetic resonance imaging thought to be associated with small-vessel disease were found to be associated with the rate of decline in cognitive test performance over time. This decline was mild, and generally more prominent in areas of psychomotor speed and executive function [10].
The above findings are also consistent with the results from our baseline comparison of the cognitive performance of the three groups with coronary artery disease and the HHC group. At the cross-sectional level, the three groups with coronary artery disease had significantly lower performance than the HHC group on measures of motor speed and executive functions. For other cognitive domains, such as language and visuoconstruction, the performance of the HHC group and those with coronary artery disease did not differ significantly.
Differences between the groups with coronary artery disease and HHC group were less evident when the degrees of change from baseline performance were compared. This finding has important methodologic implications, in that it suggests that the degree of practice effects from repeated administration of the same tests is not significantly altered by the presence of coronary artery disease or cardiac surgery. It has been proposed that the magnitude of practice effects in surgery patients and controls may be different, thus obscuring possible adverse cognitive effects of the surgery. Therefore, Keith and colleagues [30] have recommended abandoning the use of preoperative baseline testing as a reference point for measuring postoperative change. Instead, they propose using a single, cross-sectional assessment of cardiac surgery patients with no control patients [30]. We believe that such an approach would result in the misleading conclusion that any significant differences in the postoperative cross-sectional level of performance between surgery patients and controls were caused by the surgery. Rather, our prospective observations support the interpretation that postoperative differences in overall levels of performance simply reflect preoperative differences that are unrelated to the surgical intervention.
There are now several reports of an association between the ApoE4 allele and risk of developing late-onset Alzheimer’s disease, and it has been hypothesized that it may also predict worse cognitive outcomes after cardiac surgery. In a preliminary report, it was found that the ApoE4 allele was associated with greater risk of postoperative decline after CABG, particularly in patients with lower levels of education [31]. Nonetheless, subsequent studies have not replicated these cross-sectional findings [32–34]. The relationship between ApoE genotype and risk of late cognitive decline over time has not been explored in previous studies, but in our sample, we found no evidence to suggest that participants with an ApoE4 allele had greater cognitive decline between 12 and 36 months.
The main strengths of this study are the inclusion of three control groups and the duration of follow-up. The majority of previous prospective studies of long-term cognitive outcomes after CABG did not include surgical or nonsurgical controls. This is also the first study to extend the follow-up of off-pump patients to 3 years after surgery. An additional strength of our study is the use of individual cognitive domains, which enables us to evaluate whether the patterns of cognitive change are consistent with a specific disease process. For example, Alzheimer’s disease is typically associated with disproportionate decline in memory and new learning. This was not observed in our study, thus questioning the assumption that the late cognitive changes might be due to Alzheimer’s disease. The pattern of late decline in motor speed and executive function observed in our study is more consistent with the pattern of cognitive change that has been reported in patients with cerebrovascular disease.
Because we failed to observe significant differences between the on-pump CABG group and the other study groups in the degree of cognitive change from 12 to 36 months, an important question is what magnitude of difference we would have been able to observe given our sample sizes? To detect a 0.2 SD (baseline) difference in the degree of change in the global mean from 12 to 36 months, we had 92% power to detect such a difference for the on-pump to off-pump CABG comparison; 99% power to detect this difference for the comparison of the two surgical groups with the heart healthy controls; and for comparison of all coronary artery disease patients to the heart-healthy controls.
A weakness is that this was not a randomized study of interventions for patients with coronary artery disease. Although such a design would have been scientifically more rigorous, it was not feasible in our environment at the time of the inception of this study. Our study is also limited by the number of participants who did not return for their follow-up testing at 36 months.
These findings reconfirm conclusions from our previously published observations demonstrating that patients who undergo on-pump surgery do not have greater decline in cognitive performance at 3 years after surgery than nonsurgical controls with comparable degrees of coronary artery disease [17]. The addition of the off-pump group further amplifies these findings by showing that there appear to be no long-term cognitive disadvantages of on-pump compared with off-pump surgery. The results from the heart-healthy control group establish that all three groups with coronary artery disease have substantially lower cognitive test performance even before surgery, and therefore that postoperative differences in absolute level of cognitive performance cannot be attributed to the surgical intervention.
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