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Ann Thorac Surg 1999;67:1669-1676
© 1999 The Society of Thoracic Surgeons

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Original Articles

Determinants of cognitive change after coronary artery bypass surgery: a multifactorial problem

^a Department of Neurology and Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Accepted for publication December 2, 1998.

Address reprint requests to Dr Selnes, Cognitive Neurology, Johns Hopkins Hospital, Meyer 222, 600 North Wolfe St, Baltimore, MD 21287-7222
e-mail: oselnes{at}jhmi.edu

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Several studies have investigated predictors of cognitive decline after coronary artery bypass grafting (CABG), but there is little consensus as to which specific factors are predictive of poor cognitive outcomes.

Methods. We evaluated 127 patients undergoing CABG with standardized neuropsychological tests preoperatively, at 1 month and at 1 year. The outcome measure was a continuous variable reflecting change in z-scores for eight cognitive domains over time for individual patients. Univariate analyses were performed to evaluate the association between the demographic, operative, and postoperative factors and the cognitive outcome variables. Factors that were significant were included in a multiple linear regression analysis.

Results. Among the medical history variables, diabetes was associated with change in executive functions and psychomotor speed. Some of the operative variables were associated with short-term changes, but none with the 1-year outcomes. For example, the surgeon’s rating of degree of difficulty in selecting a cross-clamp site was associated with change in attention. Higher mean pump rate during the procedure was associated with improved performance on tests of language. The cognitive domains associated with medical variables were different from those associated with surgical variables, and the associations observed at 1-year were different from those seen at 1-month.

Conclusions. Change in cognition after CABG is associated with both medical and surgical variables. The specifics of these associations depend on the choice of time points after surgery. This suggests that there are multiple etiologies for these changes, with nonspecific effects of anesthesia and prolonged surgery interacting with the more specific effects of the surgical procedure itself.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Cognitive decline after coronary artery bypass grafting (CABG) is well recognized [1]. There is, however, little agreement on the incidence of adverse cognitive outcomes, the time course and degree of resolution of the cognitive problems, and the mechanisms underlying the cognitive change. Previous attempts to identify specific risk factors for cognitive change after CABG have found certain demographic factors such as age to be predictive, but there is less agreement on perioperative or medical risk factors [2–4]. It is unclear whether this lack of agreement reflects methodological issues such as variability in criteria for patient selection, choice of cognitive outcome measures, choice of time points for measuring cognitive change, differences in the assessment of perioperative variables, or the possibility that the determinants of postoperative cognitive decline are multifactorial with regard to both etiology and mechanisms.

To clarify these issues, we examined the incidence of cognitive problems, using several definitions of cognitive change, in a prospectively followed cohort of patients undergoing CABG at Johns Hopkins Hospital. We identified both short-term and longer-term cognitive changes in a significant proportion of the patients studied. The observed cognitive change after CABG is not global or diffuse, but is relatively selective for certain cognitive domains such as memory and visuoconstruction [5].

In the present study, we assessed demographic, medical, perioperative, and postoperative factors as possible predictors of cognitive change after CABG. The ability to predict which patients may be at increased risk for adverse cognitive outcomes, and to identify potentially modifiable risk factors, is important for the design of trials to evaluate the efficacy of putative neuroprotective agents.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Patients
Details of the patient population, inclusion and exclusion criteria, and methods of recruitment have been described [5]. Briefly, of the 172 patients who completed the preoperative assessments, 127 were tested at all three time points: preoperatively, and at 1 month and 1 year postoperatively. The mean age at entry into the study was 63.4 years, which is somewhat older than that reported for other CABG studies [1]. The mean level of education was 13.3 years. Seventy-nine percent of the participants were male, and 93% were white. All patients in the study completed institutional review board consent (approved January 28, 1992).

Neuropsychological tests
A battery of standardized neuropsychological tests was administered at baseline and at 1 month and 1 year after CABG. These tests, which were selected to be sensitive to impairments in multiple cognitive domains, included measures with demonstrated sensitivity that, based on previous studies of CABG, could be administered in the limited time available for each patient before the actual surgery. Verbal memory was assessed with the Rey Auditory Verbal Learning Test, a list-learning task that measures both new learning, recognition memory, and delayed recall. Visual memory was assessed by delayed recall of the Rey Complex Figure and paired recall of the Symbol Digit Modalities Test. Language was evaluated with a short form of the Boston Naming Test. Attention was measured by the Digit Span Subtest from the WAIS-R and the trial 1 score from the Rey Auditory Verbal Learning test. Visuoconstruction was assessed with the Rey Complex Figure Test (copy). Psychomotor speed included the total score from the Symbol Digit Modalities Test and the Written Alphabet Test. Motor speed was assessed with the Grooved Pegboard Test (dominant and nondominant hands). Executive (or frontal lobe) type functions were evaluated by the Stroop Test [6]. Patients were also administered the National Adult Reading Test (NART) [7] as a screening for premorbid intellectual level, and the Mini-Mental State Exam [8].

View larger version (22K): [in this window] [in a new window]   Fig 1. Scatterplot showing relationship between change in z-score between baseline and 1 month for the cognitive domain verbal memory (y-axis), and mean PO2 during the bypass (x-axis).

The principal outcome measure, thus, was a continuous variable reflecting change in z-scores over time for individual patients for each cognitive domain. We previously described the use of four mutually exclusive patterns of change over time for each cognitive domain to characterize outcome [5]. However, for most cognitive domains, the number of subjects in three of the patterns was too small for meaningful statistical analysis. Therefore, a continuous measurement of change within each cognitive domain was used instead.

We examined both short-term (1-month) and long-term (1-year) outcomes. The short-term outcome was defined as the difference in z-score between 1-month and baseline, and the long-term outcome as the z-score difference between 1-year and baseline, calculated separately for each domain.

Statistical methods
Demographic, medical, operative, and postoperative data were collected on all patients (see Table 1). Each patient was assigned a cardiac sickness score, reflecting the severity of coronary artery disease, which is defined in detail elsewhere [5]. History of general anesthesia was also determined, and was defined as: 0, if there was no history of general anesthesia in the prior 10 years; 1, if there was a history of general anesthesia within the prior year; and as the reciprocal of the number of years before CABG, for those with general anesthesia within the past 1 to 10 years. Intraoperative factors included the surgeon’s impression of the condition of the aorta. At the end of each surgical case, the surgeon completed a study questionnaire rating the nature and severity of aortic disease, the probability of emboli from the aorta, and degree of difficulty in locating a cross-clamp site.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Demographic variables
No demographic factor consistently predicted change in any cognitive domain at either 1-month or 1-year. Female gender was associated with lower scores in the domain of attention at baseline, and also with decline in performance at 1-month. A history of smoking cigarettes for 10 years or longer was associated with lower scores in the domains of visuoconstruction. Unexpectedly, a history of use of alcohol before surgery was associated with improved performance in verbal memory at 1-year.

Medical history variables
Several of the medical history variables were associated with change in multiple cognitive domains. For the short-term outcomes, a history of diabetes was associated with decrease in the domain of psychomotor speed at 1-month. The cardiac sickness index (CSI) was associated with change in the domains of motor and psychomotor speed, in that those with worse CSI scores at baseline had greater improvement in their cognitive scores. A history of syncope was associated with change in verbal memory. The patient’s mean arterial pressure (MAP) before surgery was associated with change in the domain of attention, in that higher MAP readings were correlated with improved scores at 1-month. Patients with history of elevated total cholesterol levels tended to perform worse in the domain of motor speed at 1-month.

At 1-year, a history of diabetes mellitus was associated with worse performance in the domains of executive function and psychomotor speed. Patients with higher CSI at baseline also tended to perform better on tests of motor speed at 1-year.

Operative factors
Several of the operative variables were associated with short-term cognitive changes. At 1-month, higher mean pump rate during the procedure was associated with improved performance on tests of visuoconstruction, while a lower peak mean arterial pressure was associated with improved performance on tests of language. Lower mean partial pressure of oxygen (PO₂) levels (recorded every 15 min during the bypass procedure) was associated with improved performance in verbal memory (Fig 1). The surgeon’s rating of a higher degree of difficulty in locating a cross-clamp site was associated with lower baseline performance on tests of attention, and greater likelihood of decline in performance by 1-month. At 1-year, none of the associations between change in cognitive performance and operative factors reached statistical significance.

Postoperative factors
At 1-month, several of the postoperative variables were associated with cognitive change. Patients with longer time to awaken had lower baseline scores for the domain of psychomotor speed, and were more likely to show improved performance at 1-month. An increase in blood urea nitrogen (BUN) within 7 days postoperatively was associated with change in performance in the domain of motor speed at 1-month. An increase in creatinine levels within 7 days after surgery was associated with change in the domain of executive function at 1-month.

Increased postoperative length of stay was associated with change in the domain of language at 1-year. Systolic blood pressure during the first 24 h after surgery was associated with change in the domains of visuoconstruction and psychomotor speed: lower systolic blood pressure (the lowest of all values recorded every 15 min) was associated with improved performance. As with 1-month data, an increase in creatinine levels was associated with decrease in performance in the domain of executive function. Finally, an increase in blood urea nitrogen levels after surgery was associated with decreased performance in motor speed.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
In common with many previous studies, we identified both medical and intraoperative factors associated with cognitive change. Factors associated with change in one cognitive domain were not typically associated with change in others, suggesting that the spectrum of cognitive change observed after CABG has multiple determinants, only some of which may be directly related to the surgical procedure itself. Furthermore, factors associated with short-term outcomes (1-month) were not necessarily associated with long-term (1-year) changes, implying that some of the cognitive changes after CABG are time dependent. Both of these observations may provide insights into which cognitive changes at which time points are likely to be specifically related to the surgical procedure.

Among the medical variables, a history of diabetes mellitus was associated with both short-term and long-term change in two cognitive domains. Two previous studies also identified diabetes mellitus as a risk factor for postoperative cognitive impairment [9, 10]. In the present study, the cognitive domains that remained significantly associated with diabetes (psychomotor speed and executive function) after adjusting for other factors were those that are typically associated with subcortical disease, such as subcortical small vessel ischemia [11]. Changes in the predominantly "cortical" domains of language, attention, and memory were not associated with history of diabetes. It is also of note that with the exception of diabetes, the factors that we previously found to be predictive of stroke after CABG were not associated with cognitive change [12]. This suggests that the mechanisms underlying short- or long-term cognitive changes may be different from those associated with stroke.

Of intraoperative variables, the surgeon’s impression of degree of difficulty in selecting a cross-clamp site was associated with short-term changes in attention. Previous studies have identified degree of atherosclerosis of the ascending aorta as a risk factor for postoperative cognitive change [13]. An autopsy study found evidence of brain emboli in 37% of patients with severe disease of the ascending aorta, but only in 2% of patients without significant aortic disease [14]. This, and other lines of evidence, has led investigators to conclude that microemboli are a likely cause of postoperative cognitive impairment after CABG [15]. Total cardiopulmonary bypass time was not associated with cognitive change in any cognitive domain in our study. With few exceptions, previous studies have also found no association between cognitive outcomes and total bypass time. In the two studies that did find an association between duration of cardiopulmonary bypass time and cognitive outcome [10, 16], both were significant at 7 days but not at follow-up 2 months later. The lack of any statistically significant associations between cognitive change at 1-year and operative variables is consistent with multiple etiologies underlying the cognitive changes after CABG.

The postoperative variable, length of stay, was associated with change in the cognitive domain of language at 1-year. We retrospectively reviewed patient’s records for history of atrial fibrillation, neurological problems (postoperative stroke, confusion), respiratory problems (low PO₂, fluid overload), and infections postoperatively to determine if length of stay was associated with any of these variables. We found that patients who stayed for more than 10 days were more likely to have had respiratory complications and somewhat more likely to have had a history of atrial fibrillation. Therefore, length of stay may be a surrogate marker for another medical or neurological complication that is associated with cognitive change after CABG.

We found surprisingly few associations between demographic factors and either short- or long-term cognitive change. Although the mean age of our study group was higher than that in many earlier studies [17–20], increasing age was not associated with change in any of the cognitive domains. Many of the studies that have reported an association between increasing age and cognitive decline investigated short-term outcomes [13, 20], whereas studies investigating longer-term outcomes did not find age to be associated with cognitive change [21]. Unlike other studies [20], years of education was not a predictor of cognitive change in this study. This could be due to the relatively low proportion of subjects (22%) with fewer than 12 years of education in this study.

Are the changes in cognition observed in some patients after CABG specific to the surgical procedure or are there alternate explanations? In weighing the evidence, both the time course of the cognitive changes and the selectivity by which some cognitive domains change and others remain stable appear relevant. Changes in multiple cognitive domains are well documented during the immediate postoperative period after CABG. We hypothesize that some of these may be related to nonspecific factors, such as the stresses of major surgery and anesthesia, whereas others may be related to CABG itself. There are several reasons to suspect that this may the case. First, demographic variables such as age have been shown to be associated with short-term cognitive changes but not later cognitive outcomes. This suggests that older patients may be more vulnerable to the stresses of major surgery in the short term, but have subsequent improvement. Second, previous studies that included surgical control groups have all reported mild but short-term cognitive changes in the controls [16, 22]. Previous studies have also demonstrated short-term changes, particularly in the area of memory, in non-CABG patients undergoing general anesthesia [23]. With spontaneous recovery, however, these nonspecific changes will gradually resolve. Therefore, cognitive changes that persist for months to 1-year after the surgery may be more specific to the CABG itself. If this assumption is correct, it might explain why studies examining short-term cognitive outcomes typically have reached different conclusions from those examining long-term outcomes.

Although the cognitive changes still present 6–12 months postoperatively may be more specifically CABG related, establishing a causal relationship with intraoperative variables has proven very difficult. This may be due largely to small sample size and attrition. Through selective attrition, the more severely impaired patients are more likely to be lost to follow-up. Through spontaneous recovery in patients available for follow-up, the number with significant cognitive changes decreases over time. Thus, at 1-year, an average of less than one-third of patients have significant cognitive change compared with their baseline performance. Therefore, establishing a more robust statistical relationship between late cognitive changes and CABG may not be possible unless the initial sample size is very large, or some strategy can be developed to reduce attrition of patients who are the most cognitively impaired.

Limitations
Several factors might have influenced the validity of our conclusions. Of the 172 patients with baseline neuropsychological testing, only 127 completed both follow-up tests. We have previously shown that the baseline performance of subjects who did not complete 1-month and/or 1-year testing was lower than that of the subjects who completed the follow-up. Therefore, the results of our study may have been biased by selective attrition of patients with the most cognitive impairment.

In addition, the preoperative cognitive performance of a number of patients was lower than would have been expected on the basis of their age and education. We cannot determine if the baseline performance of these subjects was a "true" baseline or not. Several factors might have contributed to lower than average baseline performance, such as the stresses of impending major surgery and less than ideal testing environment. A possible underestimation of the patient’s true baseline performance would decrease the ability to detect postoperative decline.

Improvement in performance with repeated exposure to the same neuropsychological test is known to occur [24], with degree of improvement test specific and influenced by both age and education. For example, tests that rely on verbal abilities tend to have more pronounced practice effects. Alternative forms were not available for all tests in the battery; this may have introduced a bias toward being less able to detect change in cognitive domains where alternate forms were not used.

A large number of variables were tested for associations with the outcomes, and some of the significant findings could have occurred by chance alone. The associations noted here, although statistically significant, are not necessarily strong predictors (Fig 1), thus illustrating the difficulties of identifying specific factors associated with cognitive change.

We did not evaluate genetic risk factors for Alzheimer’s disease, such as, for example, apolipoprotein E testing in this study. Preliminary studies found that CABG patients with the apolipoprotein E-4 allele were more likely to show decline in short-term memory at 6 weeks postoperatively [25]. It has also been reported that patients who died from coronary artery disease have a higher than expected frequency of senile plaques when compared with patients who died from other causes [26], but the potential implications of these observations for CABG-associated cognitive change are not known.

Strengths
In recruiting patients for this study, we did not exclude patients on the basis of comorbid disease, severity of coronary artery disease, or age. As a result, our sample is representative of the population undergoing coronary bypass surgery at Johns Hopkins Hospital. Another strength is our method for measuring cognitive change. Some previous studies have relied on group mean scores to evaluate change in postoperative performance. This is a less sensitive method than the within-subject change in scores from preoperative to postoperative testing. Also, by examining change in different cognitive domains, we were able to determine whether the cognitive effects of CABG are more pronounced in certain domains. We believe that the specificity of the cognitive changes may have implications for possible pathophysiological mechanisms.

In summary, we found the cognitive changes after CABG to be associated with several medical and intraoperative variables. Unlike previous studies, we did not find demographic variables such as age and education to be associated with cognitive change. We propose that this may be due to our choice of time points for postoperative follow-up. These results suggest that the determinants of cognitive change after CABG are both multifactorial and time dependent (Fig 2). Early postoperative cognitive changes (within days to weeks) may reflect a combination of nonspecific effects of surgery and anesthesia, superimposed on the effects of microemboli and/or hypoperfusion, the most frequently postulated pathophysiological mechanisms of cognitive change after CABG. The precise time course and resolution of the cognitive changes for these etiologies are not known. Because of spontaneous recovery of central nervous system functions, however, the prevalence of measurable deficits in any cognitive domain decreases over time. Therefore, the establishment of statistically robust relationships between late cognitive changes and specific pre- or perioperative variables may require larger sample sizes than have been studied until now.

View larger version (16K): [in this window] [in a new window]   Fig 2. Hypothetical time course of rate of onset and resolution of cognitive symptoms after CABG, illustrating the multifactorial and time-dependent nature of the cognitive impairment. Dotted line illustrates transient cognitive deficits associated with surgical factors and anesthesia; stippled line illustrates time course of cognitive deficits resulting from multiple emboli; solid line depicts time course of delayed cognitive symptoms possibly related to effects of hypoperfusion. The cognitive changes associated with surgery and anesthesia may be relatively nonspecific. The intermediary cognitive symptoms related to multiple emboli are particularly common in areas of memory function, while the late or delayed cognitive changes related to hypoperfusion or the combined effect of microemboli and hypoperfusion tend to affect visuo-spatial abilities. The choice of time points along the x-axis is relatively arbitrary and for illustrative purposes only.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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				C. K. Haddock, W. S. C. Poston, and J. E. Taylor Neurocognitive Sequelae Following Coronary Artery Bypass Graft: A Research Agenda for Behavioral Scientists Behav Modif, January 1, 2003; 27(1): 68 - 82. [Abstract] [PDF]

				J. S. Savino, T. F. Floyd, and A. T. Cheung Cardiac Anesthesia Card. Surg. Adult, January 1, 2003; 2(2003): 249 - 281. [Full Text]

				L. Restrepo, R. J. Wityk, M. A. Grega, L. Borowicz Jr, P. B. Barker, M. A. Jacobs, N. J. Beauchamp, A. E. Hillis, and G. M. McKhann Diffusion- and Perfusion-Weighted Magnetic Resonance Imaging of the Brain Before and After Coronary Artery Bypass Grafting Surgery Stroke, December 1, 2002; 33(12): 2909 - 2915. [Abstract] [Full Text] [PDF]

				C. Bergh, M. Backstrom, H. Jonsson, L. Havinder, and P. Johnsson In the eye of both patient and spouse: memory is poor 1 to 2 years after coronary bypass and angioplasty Ann. Thorac. Surg., September 1, 2002; 74(3): 689 - 693. [Abstract] [Full Text] [PDF]

				J.C. de la Torre Alzheimer Disease as a Vascular Disorder: Nosological Evidence Stroke, April 1, 2002; 33(4): 1152 - 1162. [Abstract] [Full Text] [PDF]

				J. Kilo, M. Czerny, M. Gorlitzer, D. Zimpfer, H. Baumer, E. Wolner, and M. Grimm Cardiopulmonary bypass affects cognitive brain function after coronary artery bypass grafting Ann. Thorac. Surg., December 1, 2001; 72(6): 1926 - 1932. [Abstract] [Full Text] [PDF]

				M. F. Newman, H. P. Grocott, J. P. Mathew, W. D. White, K. Landolfo, J. G. Reves, D. T. Laskowitz, D. B. Mark, J. A. Blumenthal, and J. M. Swearer Report of the Substudy Assessing the Impact of Neurocognitive Function on Quality of Life 5 Years After Cardiac Surgery Editorial Comment Stroke, December 1, 2001; 32(12): 2874 - 2881. [Abstract] [Full Text] [PDF]

				M. J. A. Robson, R. P. Alston, I. J. Deary, P. J. D. Andrews, and M. J. Souter Jugular Bulb Oxyhemoglobin Desaturation, S100{beta}, and Neurologic and Cognitive Outcomes After Coronary Artery Surgery Anesth. Analg., October 1, 2001; 93(4): 839 - 845. [Abstract] [Full Text] [PDF]

				O. A. Selnes, R. M. Royall, M. A. Grega, L. M. Borowicz Jr, S. Quaskey, and G. M. McKhann Cognitive Changes 5 Years After Coronary Artery Bypass Grafting: Is There Evidence of Late Decline? Arch Neurol, April 1, 2001; 58(4): 598 - 604. [Abstract] [Full Text] [PDF]

				O. A. Selnes and G. M. McKhann Coronary-Artery Bypass Surgery and the Brain N. Engl. J. Med., February 8, 2001; 344(6): 451 - 452. [Full Text] [PDF]

				S. Wan and A. P. C. Yim Is Off-Pump Cardiac Surgery Better for the Brain? Chest, January 1, 2001; 119(1): 1 - 1. [Full Text] [PDF]