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Ann Thorac Surg 2005;80:1327-1335
© 2005 The Society of Thoracic Surgeons
a Evanston Northwestern Healthcare, Evanston, Illinois
b Feinberg School of Medicine of Northwestern University, Chicago, Illinois
Accepted for publication June 17, 2005.
* Address reprint requests to Dr Rosengart, 2650 Ridge Ave, Burch 100, Evanston, IL 60201 (Email: trosengart{at}enh.org).
Presented at the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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METHODS: After excluding patients with conditions known to cause brain dysfunction (eg, hepatic dysfunction, stroke), a group of patients referred for percutaneous coronary intervention (PCI) or CABG (n = 82) was compared with an age- and education-matched control group that did not have clinical evidence of coronary artery disease (n = 41). These subjects underwent a battery of neurocognitive and emotional testing.
RESULTS: Test score means for 5 of 14 different measures were significantly greater (impaired) in cardiac compared with control group subjects. Of cardiac subjects, 20% demonstrated clinical impairment (test result 
1 SD worse than mean for normative standards) in 6 of 14 tests, compared with 10% of the controls. By clinical standards, 46% of cardiac subjects would be considered to be impaired (score 1 SD or more below the control group mean) on 3 or more neuropsychologic measures, compared with 29% of the controls. By this (control group mean) standard, cardiac subjects demonstrated impaired scores on 3.06 ± 2.6 tests compared with impairment in 2.0 ± 2.35 tests for the control group (p = 0.01).
CONCLUSIONS: Even excluding patients at high risk for brain dysfunction, cognitive impairment is found in patients with coronary artery disease before interventional therapy. Baseline impairment must be considered when evaluating outcomes after intervention.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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Use of the heart-lung machine and manipulations of the aorta associated with the performance of cardiopulmonary bypass have most frequently been implicated as the source of neurocognitive decline after CABG [3, 4].Cerebral microemboli induced by perturbation of the atherosclerotic aorta and cerebral hypoperfusion have, more specifically, been cited as key contributors to this complication. As a consequence, either the performance of off-pump CABG (OPCABG) procedures or percutaneous interventions have been advocated as alternatives to on-pump CABG to avoid the potentially devastating sequelae of neurocognitive decline after this procedure.
The great majority of post-CABG neurocognitive studies have consisted of longitudinal evaluations of surgical cohorts without non-CABG controls. As a consequence, the occurrence of neurocognitive decline as a function of the typically advanced age of these patients, or in accordance with the natural history of systemic (cerebrovascular) atherosclerotic disease was not addressed in many of these reports. Further, because of the lack of "normal" controls in these studies, it has been difficult to determine what percentage of CABG patients are cognitively impaired at baseline, and are thus potentially at increased risk for further decline because of impaired cognitive reserve [1, 5].
As a consequence of these limitations in the literature, we compared a cohort of patients undergoing elective CABG at our institution with a matched population of atherosclerotic patients undergoing percutaneous coronary intervention (PCI), and another matched population of patients with no known history of coronary disease. Analysis of the baseline data in this study demonstrated that (CABG and PCI) patients with coronary artery disease demonstrated cognitive impairment compared with a nonatherosclerotic control population and as compared with normative test standards. These findings suggest that cognitive deficiencies reported after CABG in prior studies may have, in part, either been present preoperatively, or may have been precipitated by preexistent cognitive disease [1, 5].
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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The reasons and associated frequencies of exclusion of patients from a total screened population of 645 are presented in Table 1. The cardiac patients enrolled in the study represent patients with low risk of preintervention neurological dysfunction. A second cohort of control subjects free of cardiac and neurologic disease by history and demographically similar to the cardiac patients were recruited from the community. Demographics of the controls and cardiac patients are presented in Table 2. History and physical data were obtained relevant to preoperative risk parameters, as determined by existing literature, and are presented in Table 3.
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Because general intelligence, as represented in an intelligence quotient (IQ), is well known to be correlated to most neuropsychologic measures, two regression-based measures of premorbid intellectual functioning were used to determine the need for possible statistical correction of any differences between groups in IQ. The first of these, the Oklahoma Premorbid Intelligence Estimate (OPIE) [7] includes the Wechsler Adult Intelligence Scale-revised vocabulary and picture completion subtests and demographic information as predictors, whereas the second, referred to as the Barona [8] formula, relies solely upon demographic information. Both the OPIE and the Barona indicated above average intellectual functioning in the enrolled subjects (Table 2). Although the controls were only a few mean IQ points lower on the Barona IQ estimate at baseline compared with the PCI group, this difference was found to be significant. The Barona IQ estimate for the control group was not, however, significantly lower than the CABG group. Also, the OPIE IQ estimate, which includes consideration of actual intellectual performances on formal testing in addition to demographic variables, was not significantly different between groups. Thus, we concluded that no meaningful intellectual differences were present between groups.
Neurocognitive Testing Battery
All consenting healthy CABG, PCI, and control patients meeting the inclusion/exclusion criteria described above underwent neurocognitive testing and a set of self-report questionnaires. The neurocognitive test battery was administered by experienced psychometricians who had been trained under the supervision of a board-certified clinical neuropsychologist. Each study subject was tested on all occasions by the same psychometrician. Testing sessions were held in an environment that was comfortable, well lit, and generally free from extraneous visual and auditory distractions.
The test battery required approximately 1 hour to complete and can be represented in the following domains: immediate attention span: digit span forward; working memory: digit span backward; fine motor dexterity: grooved pegs (dominant and nondominant hands); psychomotor speed: digit symbol from the Wechsler Adult Intelligence Scale, third edition, Trail-Making A, Stroop color-word test (word and color pages); language: controlled oral word association and visual naming of the Multilingual Aphasia Examination; verbal learning and memory: Hopkins Verbal Learning Test; nonverbal memory: digit symbol recall from the Wechsler Adult Intelligence Scale, third edition; and executive function: Stroop color-word test (color-word page), Trail-Making B. Additionally, all participants completed the Beck Depression Inventory-II (BDI-II) and the Beck Anxiety Inventory (BAI). Time intervals from baseline testing to initiation of cardiac intervention were comparable between the patient groups, with medians of 1 day for each group.
Statistical Analysis
All statistical analyses were conducted by statisticians at the Center for Research and Education at Evanston Northwestern Healthcare. Analysis of variance (ANOVA) was used to compare IQ among the three groups (CABG, PCI, control). Student's t test was used to compare differences in mean scores between cardiac and control groups. Impairment was defined in comparison with control group means (score 1 SD below [worse than] the control group mean) and to normative standards defined for each neurocognitive test (test result 1 SD below normative standards). The Wilcoxon signed rank test was used to compare the number of impairments between groups, and Fisher's exact test was used to compare the percentage of impaired. All results are presented as mean ± SD. Significance was defined as a p value of less than 0.05.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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Proportions of patients in the CABG and PCI groups demonstrating impairment in each of the 14 neurocognitive instruments were also compared using both control group means and normative standards criteria for individual tests to define impairment. With the exception of one instrument (grooved pegboard, dominant hand), the proportions impaired in the CABG and PCI groups were approximately equal and not statistically significant, and there was no apparent tendency for the proportion impaired in CABG to be higher or lower than in PCI. Therefore, and also because our initial goal was to evaluate baseline neurocognitive function associated with clinically meaningful cardiac disease, rather than an intention to treat with a particular intervention, the two cardiac disease groups were combined (n = 82) and compared both to the normal control sample (n = 41) and to normative standards for each of the tests included in our neurocognitive testing battery.
Intergroup Differences in Neurocognitive Function
Test score means for 5 of 14 different measures were significantly greater (more impaired) in cardiac subjects compared with control group subjects at baseline (Table 4). These five measures included the Wechsler Adult Intelligence Scale, third edition, digit symbol (nonverbal memory deficit), the three components of the Hopkins Verbal Learning Test (verbal learning and memory deficit), and the controlled oral word association (verbal fluency) component of the Multilingual Aphasia Examination.
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1 SD below [worse than] the control group mean) versus normative standards for individual tests (test result 1 SD below normative standards) to define impairment (Table 5). By this analysis, at least 10% more cardiac versus control subjects demonstrated impairment in five tests when using normative standards to define impairment (Fig 1), and in six tests when control group means was used to define impairment (Fig 2). In the most divergent test performances, approximately three times more cardiac than control participants demonstrated impaired performance on controlled oral word association and digit symbol when utilizing a control group mean definition of impairment.
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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Preexistent cognitive impairment and thus limited cognitive reserve, as well as the natural history of cognitive decline in the aged, atherosclerotic population [5, 9–14] may have significant implications for the analysis of post-CABG neurocognitive outcomes. For example, patients with cognitive impairment may be less capable of performing the learning functions required for many cognitive batteries, may suffer disproportionate functional deterioration compared with more intact patients if intraoperative injury does occur because of their possession of relatively limited remaining cognitive skills or resources, or may demonstrate postoperativedysfunction as a result of predictable natural patterns of cognitive decline in an aged or impaired population [13]. In this regard, it is important to consider that the cognitive dysfunction we have demonstrated in cardiac patients at baseline has also been supported by evidence of cerebrovascular disease in preoperative CABG patients—the demonstration of multiple, preexisting cerebrovascular lesions (moderate to severe infarcts) on brain magnetic resonance imaging scan [15].
Moreover, it is important to consider that these baseline impairments in many cases are not trivial, and potentially reflect a serious compromise not just in cognitive test taking, but also in day-to-day functioning, despite the fact that these patients appeared to function normally by casual observation and by preenrollment screening parameters specifically designed to detect such abnormalities in the present study. By example, some cardiac subjects demonstrated a fivefold prolongation (deterioration) compared with control means in performing the digit symbol test included in the current study, such that these subjects took five times as long to copy a series of symbols over 2 minutes—in some cases, more than 10 seconds per symbol compared with a norm of 2 seconds. Such degree of functional impairment, seen in approximately 20% the cardiac group versus 5% of the control group, would likely translate into profound impairments in normal daily functionality.
Given these considerations, it is striking that while a few of the many prior published studies of neurocognitive function in CABG patients have commented on baseline parameters, almost none have provided comparisons between CABG patients versus nonsurgical coronary artery disease (CAD) patients and non-CAD patients. For example, Zimpfer and colleagues [16] found no preoperative differences in neurocognitive function between CABG patients and age- and sex-matched nonsurgical controls, but the CAD status of the control group was not defined in this report.16 Similarly, while Selnes and coworkers [17] found no baseline differences between CABG patients and a nonsurgical CAD control group, this study did not include a non-CAD group, and thus does not provide insight into neurocognitive impairment as a function of CAD in this relatively aged population.
Two randomized studies of CABG versus OPCAB patients utilizing normative standards to define neurocognitive function demonstrated impairments at baseline, which were consistent with our own findings. Rankin and coworkers [18] noted impairment in verbal memory and perceptuo-motor speed, while Van Dijk and colleagues [19] demonstrated impairment in verbal and working memory scores and visuo-spatial and information processing speeds. These studies did not, however, provide insight into the extent that these findings represented impairments compared with age-matched controls without coronary disease, nor the extent to which longitudinal changes in their patients were the result of surgery versus disease state.
Similar to the present study, Vingerhoets and associates [20] demonstrated that CAD patients were significantly impaired in comparison with non-CAD controls, in 5 of 12 tests encompassing verbal memory, executive function, and motor speed.20 Keith and coworkers [21] also demonstrated learning defects and impairments in auditory memory in the CABG compared with the non-CAD control patients.21 The conclusion of these studies was that the extent of cardiovascular disease was a significant risk factor for neurocognitive decline. The lack of nonsurgical CAD controls in these studies, however, prevents specific conclusions in these studies as to the specific effects of CABG (as opposed to the effects of CAD) on cognitive decline. Although still other studies have included non-CABG controls, data on baseline impairment were not included in these reports [22, 23].
Conclusions and Limitations
The present data provide substantial evidence of cognitive impairment, even at baseline, in patients undergoing cardiac interventions as compared with normative and age- and education-matched standards. Although our control group was not matched for sex, this would not have been expected to artifactually influence the measures within our particular neuropsychologic test battery [24]. However, because men and women develop heart disease at different ages, relationships between sex and outcomes of each of the 14 neurocognitive tests were examined for each of the three groups in order to explore the possibility that disproportionate sex between the groups might have artificially increased impairment among the cardiac patients. In 37 of the 42 general linear models examined, we found no statistically significant difference in neurocognitive performance by sex, and we noticed no tendency for women to perform better or worse on the exams. For the five models in which there was a statistically significant sex effect, men performed better in three and women performed better in two. Thus, there is no evidence to suggest that differences between the groups were due to the higher proportion of females in the control group, consistent with prior data in this regard [24].
From a methodologic standpoint, differences within the present study between determinations of impairment when using normative standards versus control group means, or when using group means versus one standard deviation outliers, highlight the vagaries in properly defining neurocognitive impairment and the caution that is needed in making such conclusions. More specifically, our finding that the use of normative standards at times led to underreporting of impairments in the cardiac population underscores the importance of including "real-life" standards in neurocognitive studies. In comparison, inclusion of "one standard deviation" analyses of single subjects potentially minimizes the "diluted" reporting conveyed by analyses of group means. We specifically included each of these analyses in our report to provide a more comprehensive picture of the extent of impairment found in our study subjects.
It is also important to emphasize that a substantial number of potential enrollees were excluded because of the presence of risk factors for brain injury, such as prior stroke. The impairment of neurocognitive function in cardiac patients at baseline in the present study is even more striking given the exclusion of these neurocognitive high-risk patients. Failure to take into account and appropriately exclude the relatively frequent occurrence of such patients highlights potentially confounding factors in prior studies in assessing the effects of CABG on a truly normally functioning patient—as opposed to one who may be significantly impaired at baseline—even though these patients might not appear to be impaired to the casual observer.
Given these findings, then, that a subset even of normal CABG patients will demonstrate marginalized baseline cognitive reserve and may be at risk for postoperative decline [23], preoperative cognitive screening may be beneficial, especially if postoperative outcomes are eventually correlated with preoperative status. Further, it is interesting to speculate whether the presence of CAD might serve as a marker for cognitive dysfunction even in settings where CABG is not being considered. Finally, the present evidence of, in some cases, profound cognitive deficits in CABG or PCI patients at baseline, even if these patients do not suffer additional intraoperative injury, suggests that adherence to medical regimen could be a problem for these patients, and warrants caution in postoperative teaching and patient adherence to medical regimens (eg, medication).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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The question I had for you was in your CABG population did you make any distinction between patients who had surgery on-pump or off-pump, or were they all done by one technique or the other? Thank you so much.
DR ROSENGART: This study was originally planned as a randomized OPCAB versus CABG trial. We quite frankly were so pleased about how our CABG patients were doing, overall and from a neurocognitive standpoint that we were uncomfortable from an ethical standpoint with proceeding with OPCABG, and in we actually completed the study as a straight CABG examination.
DR DIMITRI NOVITZKY (Tampa, FL): I am coinvestigator of a VA cooperative study, Outcomes Following Myocardial Revascularization On and Off Cardiopulmonary Bypass. All participating patients undergo preoperative neurocognitive function, then after 3 months and at 1 year. In a substudy, neurocognitive testing is administered to VA patients, who are not subjected to coronary surgery or any other surgical procedures. The objective is to define if there is a decline in cognitive function over 1 year in nonoperated on patients as well as those operated on off-pump or on-pump. Therefore, having a real control group, comparisons with the surgical arms become more meaningful.
The results of the VA study are not available because the study is still ongoing. The protocol design is to reach 2,400 patients on both arms: 1,200 patients on-pump and 1,200 patients off-pump. We expect that within 1 year we will complete the accrual. At the completion of the 1-year follow-up, the study will be completed.
Your study requires further follow-up than a month or 6 weeks. I think you need to expand for 1 or 2 years. We don't know in a perspective randomized fashion what is the effect of anesthesia, surgery, or any other interventions on the neurocognitive function.
DR ROSENGART: Thank you. In response to your comments, first, we are going to continue our follow-up out to 1 year postoperative. I think the fact that there was relatively little difference at three weeks is highly encouraging, and we obviously expect the results to become even more equalized at a year. We struggled with the question of our power and sample size, and certainly a study on the order of that being contemplated by your consortium is going to be important. We quite frankly expect, seeing our results with very similar means, that although a larger sample size may alter the statistical significance, from a pragmatic standpoint we think the similarity in outcomes between our control and CABG group should hold true even as the N of the study is increased.
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Acknowledgments |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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References |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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This article has been cited by other articles:
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