Cognitive Deficits Following Coronary Artery Bypass

Review Article

Cognitive Deficits Following Coronary Artery Bypass Grafting: Prevalence, Prognosis, and Therapeutic Strategies By Pushpa V. Raja, BA, James A. Blumenthal, PhD, and P. Murali Doraiswamy, MD INTRODUCTION Coronary artery bypass grafting (CABG) is one of the most commonly performed cardiac surgeries today and is recognized to be a highly effective procedure for reducing angina and stabilizing ventricular dysfunction.1 CABG is performed with two primary techniques: on-pump or off-pump. In on-pump surgery, cardiac arrest is induced and cardioplegia solution is used to keep the heart in the arrested state, while a pump takes over cardiopulmonary function. During off-pump procedures, no tubes are placed in the aorta, cardioplegia is not used, and the heart continues to beat and supply oxygenated blood. Offpump procedures, though more technically complex, are thought to be less invasive and only appropriate for a subgroup of CABG candidates.2,3

ABSTRACT There is increasing recognition that coronory artery bypass grafting (CABG) may be a risk factor for subtle cognitive decline although the presence and pattern of such decline has varied across studies. Cognitive deficits may present as short-term memory loss, executive dysfunction and psychomotor slowing. Although they are usually are not severe enough to meet criteria for mild cognitive impairment or vascular dementia, they lower quality of life and add to hospitalization and out-of-hospital costs. Proposed mechanisms include surgical-related trauma, genetic susceptibility (eg, apolipoprotein E4 allele), microembolization, other vascular or ischemic changes, and temperature during surgery. Depression and anxiety levels predict subjective perception of these deficits more than objective cognitive performance. Both nonpharmacologic (eg, emboli reduction, temperature, or glucose management) and pharmacologic (eg, dexanabinol, glypromate, nootropics) strategies to prevent post-CABG cognitive deficits are under investigation. Given the large numbers of subjects who may already have CABG associated cognitive deficits, clinical trials of agents being tested for Alzheimer’s disease (eg, donepezil, rivastigmine, memantine, neramexane, ginkgo) may also be informative. The results of multicenter long-term outcome studies (with matched control groups) as well as ongoing treatment trials will more conclusively address some of these issues. These data emphasize the need for clinicians to monitor cognitive function before and after coronary bypass surgery, and to educate patients. CNS Spectr. 2004;9(10):763-772

COGNITIVE CHANGES AFTER CORONARY ARTERY BYPASS GRAFTING While a number of studies over the past 2 decades have shown that patients experience cognitive changes such as memory loss, poor concentration, and problemsolving difficulties after cardiac surgery,3-6 the focus was mainly on short-term cognitive changes, evaluated days or weeks after the surgery. Recent long-term studies3,7 offer more conclusive evidence that long-term cognitive decline after CABG can be significant in some patients and cannot simply be explained by preexisting cognitive deficits, advanced age, or comorbid conditions like diabetes and hypertension, or depression.3,7,8

Ms. Raja is a first-year medical student at Johns Hopkins School of Medicine in Baltimore, Maryland. Dr. Blumenthal is professor in the Department of Psychiatry and Behavioral Sciences and in the Department of Psychology: Social and Health Sciences at Duke University Medical Center in Durham, North Carolina. Dr. Doraiswamy is associate professor of psychiatry in the Department of Psychiatry and Behavioral Sciences at Duke University Medical Center. Acknowledgment: The authors are grateful to Joseph Mathews, MD, for his helpful comments on the manuscript and for information on treatment strategies. Disclosure: Dr. Doraiswamy has received research grants and honoraria from Eisai, Forest, Janssen, Novartis, Pfizer, and Saegis. Dr. Blumenthal has received a research grant from Eisai and Pfizer. This article was submitted on March 23, 2004, and accepted on August 23, 2004. Please direct all correspondence to: P. Murali Doraiswamy, MD, Duke University Medical Center, Box 3018, Durham, NC 27710; Email: [email protected]. Volume 9 – Number 10 © MBL Communications Inc.

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Review Article Although some studies have reported decline in cognitive function from baseline to 2 and 5 years post-surgery (specifically, Newman and colleagues4), other studies, including one by Mullges and colleagues,9 have not found notable changes in cognitive function over a 55-month period. Still others found changes in only specific cognitive domains. For example, Keith and colleagues10 found decline only in measures of attention, while Selnes and colleagues8 found long-term changes only in visuoconstruction and psychomotor speed. Most of the studies seem to be in agreement that short-term cognitive decline is apparent in many patients post-CABG; the debate remains over whether the decline is reversible or continues years after the surgery. Table 1 summarizes recent studies and their main findings regarding incidence and predictors of cognitive decline.

tional level, and baseline score were controlled for through multivariate regression analysis. As discussed by Haddock and colleagues,11 the Newman and colleagues study had several strengths, including a large sample size, a diverse test battery, neurocognitive assessment prior to surgery, and a long follow-up period. There were also potential limitations. A 1 standard deviation of decline, though generally regarded as a substantial change cannot necessarily be equated with clinically significant cognitive impairment.11-15 Also, like many other studies of cognitive outcomes after CABG, the Duke study lacked a control group from which to compare changes over time and potential practice effects. Nonetheless, the Duke study demonstrated a potential multi-stage course of cognitive change after surgery that was relatively new to the literature: an initial decline, followed by improvement, followed by late-stage decline. In addition, the connection that the group found between perioperative cognitive function and late-term cognitive level seemed to emphasize the possibility of a causal link between events of the surgical procedure and later decline, as well as the importance of cognitive evaluation and potential interventions in the period immediately following surgery. In a related substudy, Newman and colleagues 4 found a significant relationship between neurocognitive functioning and quality of life (QOL), using selfadministered quality of life instruments at the end of the 5-year period to examine self-perception of QOL. Since baseline data was not collected, this limited the ability to measure QOL change over time. Selnes and colleagues 8 followed 102 CABG patients over a 5-year period. A battery of tests including the Rey Auditory Verbal Learning Test, the Rey Complex Figure test, the Boston Naming Test, the Wechsler Adult Intelligence Scale-Revised Digit Span/Digit Symbol tests, the Grooved Pegboard test, the Stroop Test, and Mini-Mental State Examination were used to measure eight cognitive domains: attention, language, verbal memory, visual memory, visuoconstruction, executive function, psychomotor speed and motor speed. The researchers found that cognitive function improved in all of the domains but visuoconstruction during the baseline to 1-year period. Conversely, the group noted a statistically significant decline in mean scores for six of the eight domains during the 1–5 year time period. In determining the final baseline to 5-year change, the group found that the combined initial increase and the later decline in cognitive function resulted in no significant change between baseline and 5

LONG-TERM STUDIES Two studies in 2001 from Duke University3 and Johns Hopkins8 initiated debate over the incidence and duration of long-term cognitive decline after CABG. Both studies followed CABG patients until 5 years after surgery, becoming two of the first studies to follow patients for a period >2 years. Newman and colleagues3 found long-term cognitive decline after 5 years in 42% of the patients studied, and found that cognitive function at discharge was a significant predictor of long-term function (P70 years of age. With the small sample and large number of covariates measured, it is unlikely that the statistical models were sufficiently stable to draw meaningful conclusions. Thus, despite the large patient cohort, use of tests covering a wide range of neurocognitive domains and long follow-up, the study suffers from the absence of a non-CABG control group with which to determine whether cognitive decline was specific to CABG.11 As Haddock and colleagues11 suggested, the use of a group at equal cardiovascular risk undergoing a cardiovascular procedure not requiring bypass as a control would be ideal, though even the use of a cardiovascular-matched group not undergoing any surgical procedure would provide an appropriate source of comparison. In a recent study, Selnes and colleagues16 used such a group of nonsurgical coronary artery disease patients as a control, with a 1-year follow-up. Interestingly, the study found no significant cognitive test differences between the CABG group and control subjects at 3 months and 1 year, indicating that perhaps certain levels of cognitive change are equally prevalent among all groups with risks for coronary artery disease, and that surgical procedures might not have an effect on cognitive decline. A study comparing cognitive dysfunction in coronary angioplasty patients with cognitive dysfunction in patients undergoing coronary bypass surgery17 also found that the levels of cognitive function after 5 years were similar in both groups in the majority of patients. However, continual follow-up is needed to determine whether a late decline occurs in CABG patients but not nonsurgical control subjects. The recent Selnes and colleagues 16 study and the lack of difference between a control nonsurgical group and CABG patients raises questions of whether cognitive changes are unique to CABG. Studies on non-CABG patients undergoing hip surgery and other non-cardiac surgeries have shown cognitive declines from 10% to 45% of patient samples, although many of these studies have been more short-term (ranging from 7-day follow-up to Volume 9 – Number 10 © MBL Communications Inc.

12-week follow-up).18,20 In studies examining longer periods of follow-up (6 months to 2 years),21,22 cognitive deficits have been found to persist in a much smaller percentage of samples, from 1% to 5%.Thus, short-term postoperative cognitive deficits may be part of the effects of anesthesia and general surgical insult and may not be unique to CABG, but both the Duke3 and Hopkins4 studies seem to indicate that cognitive deficits in CABG patients appear to persist longer than those in other surgeries, suggesting that the specific causes of decline with CABG will require further investigation. LIMITATIONS AND DISCREPANCIES OF CURRENT STUDIES Although the aforementioned studies indicate that neurocognitive decline represents a widespread, consistent phenomenon, several methodologic limitations and inconsistent findings should be noted. The differences in populations of patients undergoing CABG from study to study have a significant influence on findings. European patient populations undergoing CABG, for instance, are likely to be younger than American counterparts and have fewer comorbid health problems. 1 Also, as Selnes and McKhann23 noted recently, very few of the shortterm or long-term follow-up studies included a control group, and even fewer included control groups with similar cardiovascular characteristics, making it difficult to determine whether the late cognitive decline is a consequence of cardiopulmonary bypass, worsening cerebrovascular disease, or other agerelated conditions. Surgical control groups would allow researchers to determine whether general anesthesia and overall surgical stress play a role in neurocognitive dysfunction regardless of the surgery type, but very few studies used this type of control group either.23 Subject attrition is also a frequent problem for these studies, as elderly participants are often lost to stroke, dementia, or death. Measures of genotype variation may have provided additional useful information, as there is a suggested link between the apolipoprotein E4 (ApoE4) allele and cognitive decline. Follow-up durations also varied widely among studies, from a few days to several years. The validity of the shorter studies is compromised, by the findings of long-term studies, which show that cognitive decline was not fully apparent until 5 years after surgery.3 Also, not all of the studies had stringent requirements for standardizing surgical techniques or post-surgery medications used, introducing the possibility of variance due to the effects of these treatment courses. Finally, the testing procedure itself presented sev765


Review Article eral problems. The wide variance in reported incidence of cognitive decline (between 30% and 80%) is due, at least in part, to the differences in tests used to assess cognition and in statistical criteria used to demarcate improvement or decline.14,15,24,25 These test batteries can vary in test-retest reliability, sensitivity, availability of parallel forms of the tests, physical effort required, and overall balance of domains tested, which affects the comparative value of several studies.25 Also, there is no universal agreement as to how “neurocognitive decline” is actually defined, despite recognition that how decline is determined may affect the reported rates of decline.14,15,24,25 This has led to various consensus conferences that have attempted to identify a core set of instruments to document decline.24 Mahanna and colleagues14 compared the postCABG cognitive decline incidences generated using five different sets of criteria to define decline (percent change; a decline of 1 standard deviation; 20% decline from baseline; decline of at least one impairment index rating [IR] without adjusting for age; and IR adjusted for age). They found that the different definitions of decline yielded vastly different results in identifying how many patients declined at each test period: from 15.3% to 66% in the before discharge measures, from 1.1% to 34% at 6 weeks, and from 3.4% to 19.4% at 6 months. Furthermore, the tendency for participants’ test scores to improve as cognitive assessments are repeated—the “practice effect”—can impact findings of studies that involve serial assessments.8,13 Kneebone and colleagues15 highlighted the importance of adjusting for practice effects in their study demonstrating the significant differences in incidences of decline when using different change measure. The study looked at the reliable change (RC) method and the more commonly-used one SD method, which often ignores practice effects. They found significant differences in incidence in 5 of 11 neuropsychological tests. The researchers promoted the RC method, which considers the influence of practice effects and test-retest reliability for each neuropsychological test, as an alternative to minimize underreporting cognitive decline incidence. Most studies attempt to avoid practice effects through variances in the test and time lag between testing periods. Thus, the possible presence of practice effects cannot be ignored, nor can the possibility that when comparing control and CABG patient group scores, the practice effect may be higher for non-surgical control groups who do not experience the cerebrovascular trauma of surgery, complicating the score results.8,13 Volume 9 – Number 10 © MBL Communications Inc.

Additionally, the literature does not seem to show a clear translation of how performance on cognitive tests in a laboratory setting relates to performance in everyday life (ie, their ecological validity) or to rates of clinical cognitive dysfunction (eg, mild cognitive impairment [MCI] or dementia), which potentially limits the usefulness of these studies to routine practice.13 PREDICTORS OF COGNITIVE DECLINE The etiology of the decline remains uncertain, though many of the same factors that predispose to other types of memory loss likely play a role. Microembolization is one leading suspected etiology. Studies have also begun to examine possible links between surgical-related trauma, cerebral edema, hyperthermia, hypoperfusion, genetic factors, other vascular changes, and lasting cognitive decline. Earlier, practicioners thought that post-CABG depression might affect cognitive function, but a 1997 study by McKhann and colleagues7 found no link between depression and cognitive changes in CABG patients. The presence of depression and anxiety have been found to play a role in patients’ subjective reports of cognitive difficulties, however.26,27 Table 2 shows a compilation of risk factors for cognitive decline based on the reviewed studies. Off-pump Versus On-pump

Much of the literature1,5,28-30 hypothesizes that the short-term changes may be due to anesthesia or non-specific effects of cardiopulmonary bypass (CPB) surgery, or on-pump CABG. Recent studies2,5,30 have investigated whether long-term and delayed cognitive changes may result from initial surgical injury from a combination of hypoperfusion and microemboli in brain microcirculation, but results have been inconclusive. A study by Taggart and colleagues30 compared neurocognitive outcomes of a group of 50 patients receiving on-pump CABG, the more common procedure, with a group of 25 patients receiving off-pump CABG, which is thought to be less invasive. The study showed cognitive deficits in both groups at discharge when compared with pre-operative tests. However, by the 3-month period, scores had returned to baseline levels (with the exception of the visual search test). There were no significant differences between the two groups’ test scores even after controlling for variances in baseline scores, suggesting that surgical injury from CPB may not be the central causative factor for cognitive decline after CABG, but the small sample size of the off-pump group makes it difficult to draw firm conclusions.5,11,30 766


Review Article Similarly, a larger study by Van Dijk and colleagues,31 also compared cognitive outcomes after off-pump and on-pump CABG over a 12-month period. The study reported a significant difference between the two groups in the overall changes in postoperative neuropsychological test scores (mean of 11 standardized change scores) at 3 months. The authors defined their primary outcome, cognitive decline, as a decrease from baseline of 20% or higher in an individual’s performance in at least 20% of the main variables. The incidence of cognitive decline, however, was similar in the two groups at 3 months: 21% of the off-pump patients (N=128) and 29% of the on-pump patients (N=120). The difference between the groups was not statistically significant at 12 months either; again suggesting that surgical insult from on-pump surgery is not the only contributing factor to cognitive deficiencies after CABG. Both groups also reported statistically similar improvements in overall quality of life at 3 and 12 months.31 A study by Keizer and colleagues32 and associates tested self-assessments by patients of their cognitive decline following both off-pump and on-pump surgery, and found no difference between the subjectively experienced cognitive decline in the two groups. When compared to a control group, the CABG patients reported lower levels of decline than the control subjects. However, in a study by Lee and colleagues,5 marked improvement was noted in the Rey Auditory Learning Test for off-pump patients at 2 weeks and 1 year after surgery, while on-pump patients showed no statistical change. Immer and colleagues6 also demonstrated superior quality of life measurements in off-pump patients (=66) as compared with on-pump patients (n=438); however, too few patients were included in the off-pump group to yield meaningful conclusions. A number of other studies have also found conflicting findings and the rates of cognitive decline even after off-pump surgery approach 30% in a study with 1-year follow up. Thus, the main conclusion that can be drawn is that cognitive deficits can appear after either type of procedure.

6-week test interval.33 It should be noted that the control group was actually part of a different study, a large trial investigating the effects of hypothermic versus normothermic cardiopulmonary bypass on cerebral outcomes after CABG, but the enrollment occurred concomitantly for the two groups. Another study by Engelman and colleagues4 performed 291 CABG perfusions at cold (20o C), tepid (32o C), or warm (37o C) temperatures in a randomized manner. Their findings showed no relationship between differences in perfusion temperature to cognitive function after bypass. They did, however, find persisting postoperative neurocognitive dysfunction at 1 month in 36% of CABG patients. A 2001 study by Khatri and colleagues 36 also noted that temperature conditions during surgery may affect quality of life afterwards; the results showed a statistical association between hypothermic conditions during the surgery and higher levels of anxiety and depression following surgery, which was less evident in the normothermic group. Temperature immediately following the operative process has become a point of interest as well. A 2002 report from Grocott and colleagues37 found a correlation between postoperative hyperthermia and cognitive decline, though further study is required to determine whether hyperthermia was in fact the cause of lowered cognitive function, or instead, if the processes leading to cognitive dysfunction also resulted in hyperthermia. Genetic Factors

Another suggested predictor for cognitive decline is presence of the ApoE4 allele.4,10,38-42 Correlations have been found between the presence of the ApoE4 allele and increased risk for Alzheimer’s disease, which led some researchers to look for a connection between post-CABG cognitive decline and theApoE4 allele.11 The ApoE4 gene codes for a protein involved in cholesterol transport and neuronal repair. It has been hypothesized that the capacity to maintain or repair neuronal damage is weakened in those with the ApoE4 allele. Likewise, such individuals are also reported to have greater burden of beta-amyloid plaques in the brain even before the onset of clinical dementia. A study by Tardiff and colleagues40 showed a statistically significant relationship between the presence of the ApoE4 allele and short-term cognitive decline (6 weeks), and the effect was even more significant in patients with lower educational levels. Steed and colleagues 41 undertook a similar study with the objective of replicating the findings by Tardiff and colleagues40 in a

Temperature

Temperature during the operative process also has been evaluated as a potential predictor of cognitive decline following CABG. A study by Grigore and colleagues33 examined the effect of rewarming rate from hypothermic CPB and increased peak temperature on neurocognitive outcomes. They found a significant association between change in cognitive function and rate of rewarming; slower rewarming rate with a lower peak temperature during CPB was associated with better cognitive performance at the Volume 9 – Number 10 © MBL Communications Inc.

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Review Article larger sample size (N=111). Unlike Tardiff and colleagues, however, Steed and colleagues did not find a significant association between the presence of the ApoE4 allele and cognitive decline after CABG at 4 and 7 weeks. Ti and colleagues42 investigated the mechanism of ApoE4-associated decline by comparing autoregulation of cerebral blood flow (CBF) and oxygen delivery/extraction during CPB in patients with and without the ApoE4 allele. They did not find a significant correlation between the presence of the ApoE4 allele and alterations in CBF and oxygen delivery/extraction, and concluded that the mechanism for the ApoE4 effect occurs through other pathways. Some other investigators continue to question whether the ApoE4 allele indeed has an effect on cognitive decline; the Selnes and colleagues8 study also tested patients at the 5-year follow-up for ApoE4 genotype analysis, but no association was found between cognitive dysfunction and genotype. The brain-derived S100B protein is a serum marker for brain damage, and higher levels of S100B immediately after surgery are also thought to predict adverse neurological and cognitive outcomes after CABG.42 A study by Westaby and colleagues44 was one of the first to find that S100B protein may be a marker for cerebral injury. The study examined a group of patients (N=32) undergoing CABG, and found that S100B was not detected in blood samples before sternotomy, but in patients who underwent CPB, the blood levels of S100B increased significantly. The biological halflife of S100B is 25 minutes, so a sustained increase in S100B levels in patients undergoing cardiac surgery is thought to indicate a continuous release of the enzyme from damaged tissue. Snyder-Ramos and colleagues 45 found a correlation between persistent increases in S100B levels on days 2 and 7 after surgery and neurological dysfunction in CABG patients. The increase in S100B levels immediately after surgery, however, did not appear to be directly correlated with neurological dysfunction.

cases,4,12 Some recent studies suggest that the cognitive change noted in CABG patients is correlated with an abnormal pre-operative state, indicating that patients in need of CABG may already have comorbid undetected cerebrovascular disease or undiagnosed cognitive impairment resulting from their condition.8 In some cases, cognitive improvements in the baseline to 1-year period were seen, leading investigators to hypothesize that these improvements were results of improved cardiovascular function in an initially-impaired group.8 Lower level of education has also been seen to be a predictor of cognitive decline in several studies.3,4 THERAPEUTIC STRATEGIES FOR PREVENTION AND TREATMENT With a growing awareness of the possibilities of cognitive decline following CABG, researchers have begun to investigate preventative methods to lower the risk as well as methods to symptomatically improve cognitive deficits in those who have already developed them. Such methods include both nonpharmacologic and pharmacologic strategies. A complete description of all such studies is beyond the scope of this review and we only list the key strategies in this article. Readers seeking a more complete review of specific study results with each of these strategies are referred elsewhere.46-55 Nonpharmacologic strategies for preventing cognitive decline can broadly be classified into those focusing on emboli reduction, glucose management, temperature regulation, pH management, and cannulae. Emboli reduction techniques include cardiotomy/cell-saver, arterial line filtration, atheroma management, anastomotic devices/off-pump coronary artery bypass and carbon dioxide insufflation (Matthews J, MD, written communication, July, 2004). More than a dozen pharmacologic strategies have been proposed or investigated for preventing post-CABG cognitive decline and these are listed in Table 3. A number of other agents (eg, cholinesterase inhibitors, memantine, neramexane, growth factors, chelators, ampakines) have also been shown to have potential effects in animal models of ischemia or cell loss but to our knowledge,55 none of these drugs has been systematically evaluated for efficacy in preventing post-CABG cognitive decline. Another therapeutic approach may be the early treatment of memory loss immediately after it has occurred. Acetylcholinesterase inhibitors (eg, donepezil, rivastigmine), ginkgo biloba, stimulants (eg, methylphenidate), statins, and N-methyl-D-aspartate antagonists (eg, memantine) are being studied for treating or preventing memory loss in mild cognitive impairment or vascular dementia.56,57 None of these

Preexisting Demographic and Clinical Factors

As with many neurological conditions, preexisting factors are thought to play a role in developing post-CABG cognitive deficits. There are well-documented age, gender-, and education-related differences in normal cognitive performance. Elderly patients undergoing CABG seem to be at the greatest risk for postoperative cognitive decline,3,4,8,11 and other factors that seem to increase risk are previous physiological conditions such as hypertension, diabetes, and peripheral vascular disease.3,4,8,11,28 However, these conditions do not seem to reliably predict cognitive decline in all Volume 9 – Number 10 © MBL Communications Inc.

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Review Article TABLE 1. DEMOGRAPHICS, STUDY DESIGNS, AND OBSERVATIONS FROM STUDIES ON COGNTIVE DECLINE AFTER CABG Study (Year)

Number of subjects

Follow-up intervals

Main findings

Newman et al (2001)4

172 patients, completed 5 years of 261 originally enrolled

Pre-op; discharge; 6 weeks; 6 months; 5 years

Significant correlation between No control group; early post-operative cognitive patients lost to follow-up decline and long-term decline; baseline to 5 year decline in 42% of patients

Mullges et al (2002)9

52 patients completed 5 years, of 91 originally enrolled

Pre-op; discharge; 32-65 month range

Most patients showed improved cognitive function scores at 5 years; only small group had mild cognitive decline

Sicker or more impaired patients lost to follow-up; higher baseline performance than most other studies

Keith et al (2002)10

39 CPB patients, 49 healthy control patients

Pre-op; discharge; 3-4 weeks

CABG (CPB) group had lower scores on attention tests than healthy elderly control group

Control group of healthy participants did not have matching cardiovascular characteristics

McKhann 124 patients et al (1997)7

Pre-op; 1 month; 1 year

No link between depressed mood and cognitive decline after CABG

No significant limitations

Grigore et al (2002)33

100 conventional rewarm, 65 slow rewarm

Pre-op; 6 weeks

Slower rewarming rate with lower peak temperatures during CPB may help prevent neurocognitive decline

Early study on the topic, therefore it must be replicated to demonstrate validity

Selnes et al (2003)16

140 CABG Pre-op; patients, 92 non3 months; surgical control 12 months patients with similar risk factors for CAD

No significant cognitive test Evaluation will need to be differences between CABG and continued to look for late control subjects at 3 months decline in CABG group and 1 year; minimal cognitive decline in both groups

Rodig et al (1999)34

24 CABG patients, 22 vascular surgery patients

Pre-op; 2 months

No significant difference between proportion of CABG and vascular surgery patients with cognitive decline

Small sample size limits statistical accuracy; brief follow-up period could not capture persistent deficits

Taggart et al (1999)30

25 on-pump CABG patients, 25 off-pump CABG patients

Pre-op, at discharge, 3 months

All tests but visual search test returned to baseline by 3 months; no significant difference between groups’ tests

Small sample size; only compared group means on cognitive tests, rather than comparing incidence of cognitive decline

Selnes et al (2001)1

102 patients completed 5 years, of 172 patients

Pre-op; 1 month, 1 year, 5 years

Significant decline between 1 year and 5 years suggests a late cognitive decline

No control group; patients lost to follow-up; practice effects may have occurred

Keizer et al (2003)32

45 off-pump patients, 36 onpump patients, 112 healthy control subjects

Pre-op, 1 year

Control patients self-reported more cognitive decline than CABG patients; no difference between on-pump and offpump reporting

Subjective self-ratings may not reflect absolute levels of everyday competence; no data for earlier periods after surgery

Van Dijk et al (2002)29

142 off-pump patients, 139 onpump patients

Pre-op; 3 months, 1 year

Off-pump CABG patients had higher cognitive outcomes at 3 months, but the difference was negligible at 1 year

Relatively young group of patients (mean=61 years), who had fewer comorbidities

Lee et al (2003)45

30 off-pump patients, 30 onpump patients

Pre-op; 2 weeks; 1 year

Showed improvement of cognitive outcome with off-pump CABG only

Small study size, not generalizable; short follow-up

Limitations

Pre-op=pre-operation; CABG=coronary artery bypass grafting; CPB=cardiopulmonary bypass; CAD=coronary artery disease. Raja PV, Blumenthal JA, Doraiswamy PM. CNS Spectr. Vol 9, No 10. 2004.

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Review Article CONCLUSION Though the association, prevalence and incidence levels of post-CABG cognitive decline as well as the potential risk factors remain controversial, a relatively large number of patients appear to experience some type of cognitive decline following CABG. There is no consensus about the clinical significance of the decline nor of the mechanisms responsible for the deficits. In addition, it is not yet established how to prevent or treat such changes. These findings emphasize the need for further research into long-term outcomes and prevention but also for practical strategies to monitor cognitive function and quality of life after cardiac surgery. Readers seeking additional information on how to assess cognition in older subjects are referred elsewhere.60 There is also a need for developing strategies for treating patients currently experiencing cognitive losses due to the effects of CABG. Consensus guidelines for the routine use of cognitive testing and genotyping in such patients are also needed. CNS

agents have yet been carefully tested for treatment of post-CABG cognitive decline. A randomized placebo-controlled study is currently underway at Duke to test the efficacy of a cholinesterase inhibitor for treating post-CABG cognitive decline and results are expected to be available in the near future. In addition to cognitive and clinical measures, the use of surrogate markers of brain damage may also be worth considering as outcomes in future clinical trials of neuroprotective agents for CABG cognitive decline. A number of magnetic resonance imaging (MRI) markers have been used with success in other neurologic disorders. Diffusion weighted imaging can provide evidence of acute tissue changes and ischemia. N-acetyl aspartate (NAA) measured using magnetic resonance spectroscopy (MRS) may be a useful marker of neuronal function and damage.58,59 A recent study examined brain damage before and after CABG using MRS and diffusion-weighted imaging in 35 patients.60 Diffusion imaging revealed new ischemic lesions in 26% of the patients. Post-surgery NAA levels declined significantly and the extent of the decline was closely related to the degree of decline in cognitive test scores. Post-surgical follow up MRS scans revealed that normalization of NAA ratios was accompanied by a recovery in neuropsychological test scores. The authors concluded that CABG is associated with transient neuronal metabolic disturbances that could be detected using magnetic resonance measures and that this correlated with cognitive decline.59 Functional MRI, can be used to study brain activation patterns during cognitive performance tasks. Controlled longitudinal studies of these markers in larger samples are lacking but nevertheless these studies using such surrogate markers may not only yield mechanistic insights into brain changes after CABG but may also potentially serve as outcome measures in future prevention or treatment trials.

TABLE 3. POTENTIAL PHARMACOLOGIC STRATEGIES FOR PREVENTION OR TREATMENT* Piracetam Cholinesterase inhibitors (eg, donepezil, rivastigmine) Glutamate NMDA antagonists (eg, memantine, neramexane) Glutamate AMPA receptor modulators GABA-B antagonists Calcium channel blockers/modulators Dexanabinol Nicotinic receptor agonists

TABLE 2. FACTORS LEADING TO INCREASED RISK OF COGNITIVE DECLINE

Dopamine/norepinephrine reuptake inhibitors

• Age

Ginkgo biloba, coenzyme Q, antioxidants

•Education level

Growth factors

• Diabetes, hypertension, other pre-existing conditions

Glial modulators

• Cardiopulmonary procedures/microemboli

β-blockers

• Fast rewarming rate during CPB

* This listing does not necessarily mean that these agents were used in human trials.

Phosphodiesterase inhibitors

• Genetic tendency (ApoE4) CPB=cardiopulmonary bypass; ApoE4=apolipoprotein E4.

NMDA=N-methyl-D-aspartate; AMPA=α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid; GABA-B=γ-aminobutyric acid B.

Raja PV, Blumenthal JA, Doraiswamy PM. CNS Spectr. Vol 9, No 10. 2004.

Raja PV, Blumenthal JA, Doraiswamy PM. CNS Spectr. Vol 9, No 10. 2004.


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