Neuropsychological functioning 3 5 years after coronary artery bypass grafting: does the pump make a difference?

Transcription

1 European Journal of Cardio-thoracic Surgery 34 (2008) Neuropsychological functioning 3 5 years after coronary artery bypass grafting: does the pump make a difference? Abstract Nathalie Stroobant a,b, *, Guido van Nooten a, Dirk De Bacquer c, Yves Van Belleghem a, Guy Vingerhoets b a Centre for Cardiac Surgery, University Hospital Ghent, Belgium b Laboratory for Neuropsychology, Department of Internal Medicine - Section Neurology, Ghent University, Belgium c Department of Public Health, Ghent University, Belgium Received 10 September 2007; received in revised form 16 April 2008; accepted 5 May 2008; Available online 3 June 2008 Objective: Neurocognitive sequelae after coronary artery bypass grafting (CABG) are frequently reported. The present study investigated the possible difference between on- and off-pump CABG patients in a long-term perspective. Methods: We administered seven standardized neuropsychological tests 1 day before, 6 days after, 6 months after and 3 5 years after CABG. We measured intra-operative high intensity transient signals (HITS) as a reflection of embolic load by transcranial Doppler ultrasonography. Results: Of the 74 patients originally recruited, 54 of the patients (73%) (mean age 59 years 7.5 years) completed the neuropsychological battery. Cognitive decline was defined as 20% decline on two or more tests. Three to 5 years after the operation, 30% of the patients showed neurocognitive problems in domains of non-verbal immediate memory and attention, speed for visual search, visual attention and mental flexibility. Neither difference in frequency of cognitive dysfunction nor a difference in evolution over the 5 year time period between on- and off-pump patients was observed. No significant predictors for cognitive decline were found. Conclusions: Three to 5 years after the CABG surgery no difference in neurocognitive deficits is found between on- and offpump CABG patients, indicating that the extracorporeal circulation (ECC) may not be the main cause of late neuropsychological decline. # 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved. Keywords: Coronary artery bypass grafting; Cognitive brain function; Neuropsychology; Cardiopulmonary bypass; Off-pump surgery 1. Introduction The neurological and neuropsychological outcomes of coronary artery bypass graft surgery (CABG) procedures range from the well-documented incidence of stroke to less clearly defined and more subtle cognitive changes, which include difficulties in memory, attention, concentration, vasoconstriction and speed of response [1]. The precise pathophysiological features of cognitive impairment are not certain but have been attributed to the micro-embolic, inflammatory and perfusion factors associated with extracorporeal circulation (ECC) [2,3]. Several studies using transcranial Doppler ultrasonography (TCD) have found an association between intra-operative cerebral emboli, operationalized as high intensity transient This research was supported by a grant from the Special Fund for Scientific Research (University Ghent) and a postdoctoral research grant from the Fund for Scientific Research Flanders, both awarded to Nathalie Stroobant. * Corresponding author. Address: Laboratory for Neuropsychology, Department of Internal Medicine-Section Neurology, Ghent University Hospital, 4K3, De Pintelaan 185, B-9000 Ghent, Belgium. Tel.: ; fax: address: Nathalie.Stroobant@ugent.be (N. Stroobant). signals (HITS), and neurocognitive problems [4,5]. CABG without ECC (off-pump surgery) on a beating heart is an increasingly common procedure with a reduction in cerebral embolic load [6] and an interesting alternative to traditional revascularization avoiding some of the morbidity of on-pump CABG surgery. Nevertheless, recent studies examining the cerebroprotective effect of offpump procedures versus conventional CABG yielded inconsistent results [7]. Although most studies of cognitive outcomes report cognitive decline in on- and off-pump patients at the immediate and early postoperative period [6,8], there is still controversy regarding the degree and expected duration of these changes. Recently, the possibility of a delayed or late cognitive decline after CABG is given more attention. Some researchers report a pattern of postoperative decline that consists of a relatively high frequency of early deterioration with short-term improvement within the first few months and consequent secondary decline after 5 years [9,10]. In contrast, a more favorable long-term outcome was found in the study of Müllges et al. [11] where none of the patients showed a neurocognitive decline after 4.5 years. Apart from the debate whether long-term cognitive decline over a /$ see front matter # 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved. doi: /j.ejcts

2 N. Stroobant et al. / European Journal of Cardio-thoracic Surgery 34 (2008) certain time period is existing or not, none of these studies investigated if on- and off-pump CABG patients differed several years after surgery. In the present study we studied the longitudinal neurocognitive problems after CABG and aimed to find out whether there is a relation between pre-, peri- and postoperative variables and these late sequelae. We also wanted to investigate the potential long-term difference in neuropsychological outcome between on- and off-pump CABG. 2. Materials and methods 2.1. Patient selection, anesthesia, surgical management and intra-operative HITS counting Exclusion criteria were carotid artery stenosis (as determined by Duplex B mode Doppler scan), emergency operation, cerebrovascular, neurological, or psychiatric disease, drug and/or alcohol addiction. The incidence of dementia and other neurological disturbances with associated cognitive impairment increases dramatically with advancing age. Therefore we excluded patients >70 years. Each patient who qualified for the study signed an informed consent document that had been approved by our institutional ethical committee (University Hospital Ghent). A Dutch version of the National Adult Reading Test [12] was used to obtain an estimated intelligence quotient (IQ). All patients were potential candidates for off-pump surgery except in case of unstable angina, severe left main stenosis (>95%) and/or hemodynamic instability, or anatomical inaccessibility. In multiple vessel disease, complete revascularization, especially in the region of the distal circumflex or right coronary artery, using the off-pump technique necessitates important prolonged tilting of the heart sometimes leading to hazardous hemodynamic instability. As a consequence, more patients with multiple distal anastomoses in the region of the circumflex and right coronary were selected to be included in the on-pump group. However, since the beginning of the study, the used types of stabilizers have improved considerably, thus broadening the indications for off-pump surgery. For details of the intra-operative HITS measurement and insonation technique we refer to the methods described in earlier research [6,13] Neuropsychological testing One examiner (NS) administered a battery of seven standardized neuropsychological tests 1 day before (T1), 6 days after (T2), 6 months after (T3), and 3 5 years after (T4) surgery. The battery included a broad range of cognitive abilities (attention and concentration, verbal and non-verbal memory, language, visuo-spatial functions, executive functions, motor and psychomotor speed). The tests used in the study are listed below. (1) The Rey auditory verbal learning test (AVLT) assesses verbal memory. The measure retained is the total number of words immediately recalled over the first five trials. (2) The trail making test (TMT Part B) assesses speed for visual search, attention and mental flexibility. The time to completion is the measure taken. (3) The grooved pegboard test (GPT) measures finger and hand dexterity. The sum of the times to completion of theleftandrightplacementofallpegsisthemeasure taken. (4) The block taps test (TAPS) assesses non-verbal immediate memory and attention. The number of errors is the measure retained. (5) The line bisection test (LBT) assesses unilateral visual inattention. Total deviation from the true center is the measure taken. (6) The controlled oral word association test (COWAT, orthographic categories) assesses word fluency. The total number of words (with four given letters) is the measure retained. (7) Judgment of line orientation (JLO) examines the ability to estimate angular relationships between line segments. The measure retained is the correct number of answers Definition of cognitive decline We used the 20%-definition (a decrease in two or more tests by at least 20% from the preoperative baseline) because it is believed to be the most sensitive method for identifying patients with signs of cognitive decline [14] Statistical analysis All continuous variables are expressed as mean (SD). Categorical variables are expressed as percent of those exhibiting the trait out of all patients for whom data were available. The statistical analysis (SPSS/PC+; Chicago, IL) was based on two independent groups of patients (onpump vs off-pump). We compared baseline characteristics, outcome measures, and complications between the two groups with the Mann Whitney test. We analyzed nominal data with chi-square statistics if all expected cell frequencies were greater or equal to five. Otherwise, Fisher s exact test was used. Postoperative changes in absolute neuropsychological test scores and in percentages were compared to the preoperative baseline level with Wilcoxon signed rank tests. We calculated associations between number of HITS, age, IQ and neuropsychological data by Spearman rho correlation coefficients. A mixed effects model was used to study the evolution over time and to observe differences between on- and off-pump patients. 3. Results 3.1. Patient characteristics Of the 74 patients originally recruited into the study, 54 of the patients (73%) completed the neuropsychological assessment at T1, T2, and T4 at the University Hospital Ghent

3 398 N. Stroobant et al. / European Journal of Cardio-thoracic Surgery 34 (2008) (Belgium). The group of 54 participants consisted of 48 men and 6 women, age range 42 70, mean age 59 years 7.5, onpump (n = 33; 61%), off-pump (n = 21, 39%). Reasons for not attending the long-term follow-up were as follows: 12 patients refused (too busy/not interested), and 8 patients died. Causes of death were CVA (on-pump: n = 1; off-pump: n = 1), sudden death (on-pump: n = 2), traffic accident (on-pump: n = 1), cancer (on-pump: n = 1), perioperative complication (dental surgery) (on-pump: n = 1), suicide (onpump: n = 1). The dropout group (n = 20) showed a significantly worse score for preoperative ( p = 0.013) and immediate postoperative verbal memory (AVLT) ( p = 0.002) compared to the follow-up group. Six months after surgery (T3) 43 patients returned. Demographic, pre-, peri-, and postoperative variables of the patient group are described in Table 1. Although there was a trend towards a lower IQ in the off-pump group, mean IQs were comparable to the (lower) mean IQ level of the general population. On-pump patients were comparable to off-pump patients with the exception of a number of variables, indicating a surgical selection bias (see patient Table 1 Patient characteristics (SD) Characteristics On-pump Off-pump p value Demographics Mean age (years) Sex (% male) IQ estimate (NLV) State-anxiety Preoperative risk factors Hypertension (%) Diabetes (%) Tobacco use (%) Recent MI (%) Ejection fraction (%) Number of diseased vessels BMI Perioperative factors Number of grafts (%) (%) (%) (%) (%) (%) 3.0 Operation time (min) Anesthesia time Total number of emboli (n = 24) (n = 13) Postoperative factors (3 5 years) Cardiac/vascular problems Cardiac (%) 6.1 Peripheral (%) Arrhythmias (%) Angina (%) CVA 4.8 Current smoking selection). Except from one CVA, none of our patients in the follow-up group showed postoperative complications such as TIAs or strokes Pre- and postoperative neuropsychological test results (group level) Except for a higher preoperative word fluency score in the on-pump group, no significant differences between on- and off-pump group were found (Mann Whitney tests). We used Wilcoxon signed rank tests for the significance of each time point versus preoperative baseline level. Table 2 shows us that a significant deterioration was obtained 6 days after surgery for GPT ( p < 0.001), TAPS ( p < 0.001), LBT ( p =0.01)andJLO ( p = 0.03). Six months after surgery a significant improvement was obtained for AVLT ( p < 0.001), GPT ( p =0.02)andCOWAT ( p = 0.002). Three to 5 years after surgery no significant deterioration or improvements were observed. We also calculated differences in neuropsychological outcome compared to preoperative baseline level with changes in percentages and obtained the same results (Wilcoxon signed rank tests). No differences were observed between the on- and off-pump groups. A linear mixed effects model affirmed these results. Moreover, no interaction effect was found between type of surgery and time, thus indicating that the evolution in time was not different between both surgical groups. Table 2 Neuropsychological test scores: absolute mean scores (SD), median and Wilcoxon signed rank tests between preoperative baseline level and each postoperative score Test Time-point N Mean (SD) Median Significance vs baseline ( p value) AVLT T T T T TMT T T T T GPT T T T T TAPS T T T T LBT T T T T COWAT T T T T JLO T T T T

4 N. Stroobant et al. / European Journal of Cardio-thoracic Surgery 34 (2008) Relations between neuropsychological test results and number of HITS, age and IQ (group level) We correlated absolute neurocognitive test scores with age, IQ, and HITS. Age was correlated with worse scores on AVLT (r range between 0.35 and 0.56: p between and <0.001), LBT (r T3 = 0.42) ( p = 0.006) and TMT (r T1 = 0.3, p = 0.036; r T4 = 0.32, p = 0.023), GPT (r T3 = 0.3, p = 0.04), and TAPS (r T1 = 0.27, p = 0.046) ( p = 0.042). A lower IQ was correlated with most tests at most time points. HITS and neurocognitive test scores were not correlated. We correlated changes in percentages in neurocognitive test scores with age, IQ, and HITS. Both age (r = 0.31, p = 0.025) and IQ (r = 0.34, p = 0.025) were correlated with JLO ( p = 0.042). HITS and neurocognitive test scores were not correlated Pre- and postoperative neuropsychological test results (individual level) According to the 20% definition, 16/54 (30%) showed cognitive decline 3 5 years after the operation. 9/33 (27.3%) belonged to the on-pump group and 7/21 (33.3%) belonged to the off-pump group. Neurocognitive problems were found in the domains of non-verbal immediate memory and attention, speed for visual search, visual attention and mental flexibility. No significant differences between the on- and the off-pump group were found. To investigate whether 3 5 year postoperative neuropsychological dysfunction in the patients undergoing cardiac surgery was associated with certain pre-, peri- and postoperative variables, we allocated patients to the group of no deficit (n = 38, postoperative decline in 1 test) or deficit group (n = 16, postoperative decline in 2 tests). Both groups were compared on a wide range of demographic, medical and surgical data (age, IQ, years of education, depression score on different time assessments, anxiety score on different time assessments, number of emboli, BMI, left ventricle ejection fraction, number of vessels, number of grafts, operation time, anesthesia time, ventilation time, stay on intensive care unit, smoking, diabetes, hyperuricemia, hyperlipidemia, hypertension, COPD, familial history, recent MI, atrial fibrillation, postoperative cardiac and non-cardiac medical complications 3 5 years after surgery, CABG on- or off-pump. None of these variables showed a significant difference between both groups Relation between neuropsychological test results and number of HITS (individual level) We tested whether patients showing significant cognitive decline (as defined by the 20% definition) received significant more HITS during operation than patients showing no significant decline. A Mann Whitney test with total number of HITS as dependent variable and absence/presence of cognitive decline after 3 5 years as independent variable showed no significant differences between both groups. To examine which variables were predictive of the cognitive decline after 5 years following CABG, we performed an explorative multivariate regression analysis. The number of independent variables was selected on the basis of evidence in previous studies and limited to preserve an adequate ratio of participants per variable (HITS, age, cognitive decline after 6 days, IQ). No significant predictors were found. 4. Discussion The present study investigated neurocognitive sequelae after CABG in a long-term perspective that is of even greater concern than transient acute postoperative changes [15]. Still, it is complicated to determine whether the long-term symptoms are a consequence of the surgery, the result of normal aging in a population with cardiovascular risk factors or a combination of these and other factors. Our attrition rate of 27% is similar (or even better) than dropout rates of other long-term follow-up studies that mention dropout rates of 33 46% [9,10,15]. Baseline data of the dropout patients were comparable to those of our study patients, which argue against a major bias through dropouts. The only significant difference we found was the worse performance of the dropout group on one memory task (AVLT). Compared to 42% of the patients showing cognitive decline after 5 years [9], our rate of 30% is more favorable but disagrees with the results of Müllges et al. [11] where no ECC-patient showed a long-term significant cognitive decline. Strict control of vascular risk factors such as hypertension and hypercholesterolemia was suggested. The hypothesis of Müllges et al. [11] is interesting because it implies prevention of late cognitive decline through stricter postoperative control of risk factors. Nevertheless, although the majority of our patient population also took lipid-lowering medication cognitive decline was found. This issue remains to be further investigated. In contrast to a more global screening like factor analysis [9] or conceptually defined constructs of domains [16], we preferred documenting individual domains of cognitive function. Note that, because of the spontaneous recovery of central nervous system functions, the frequency of measurable deficits in any cognitive domain could decrease over time, which is especially interesting for a long-term study. Measures of visuomotor and psychomotor speed are the most frequently reported vulnerable domains [10,16] and this was confirmed by the present study. In addition, we found deficits to occur in domains of non-verbal immediate memory and attention, visual attention and mental flexibility. The potential impact of these clinically significant neuropsychological sequelae in a variety of the abovementioned domains on the social, professional and recreational daily life of 30% of the patients may not be underestimated. Many authors believe that the use of ECC has a specific damaging effect on cerebral function [4,17]. In contrast to the expectations, several studies found no difference in early neurological and neuropsychological outcomes between onand off-pump patients [18 20]. More recent randomized prospective studies [8,21] found more cognitive decline in the on-pump group than in the off-pump group after 10 weeks [21] and 3 months [8] but the effects were limited and became negligible after 12 months [8]. In one of our own

5 400 N. Stroobant et al. / European Journal of Cardio-thoracic Surgery 34 (2008) previous studies [22] more favorable results were revealed for the off-pump group after 6 months. This could suggest that at least in the short term (up to 6 months after the surgery) ECC is not favorable for the brain. Our study was limited by the fact that, although we planned a randomized study, the decision regarding the surgical strategy (on-pump vs off-pump) was left to the individual surgeon due to technical reasons. As an implication, patients with more severe pathologies were included in the on-pump group. However, when including the patient, the neuropsychologist was not aware of the surgical technique that was going to be used. Another potential bias was introduced by exclusion criteria (e.g. neurological dysfunction and emergency surgery). So, the true incidence of cognitive disability in the entire population having bypass surgery thus might be underestimated [15]. To our knowledge, this is one of the first reports about cognitive sequelae that compare the two surgical groups on the long-term (more than 1 year after surgery). The most important finding of this study is, that we found no significant difference between on- and off-pump patients for the percentage patients with cognitive decline, for the percentage cognitive impaired tests, for the evolution over time and for the domain of impaired neurocognitive ability 3 5 years after the surgery. However, our ability to detect a significant difference in cognitive function between patients with and without off-pump might be limited by the relatively small sample size of our study. Due to a limited power, false negatives could have occurred. Nevertheless, a recently published large randomized trial was unable too to demonstrate any benefit from avoiding cardiopulmonary bypass on long-term cognitive outcomes [23]. It is suggested that the number of emboli in the brain has been a surrogate marker for cerebrovascular disease [11]. Generally less emboli are found in off-pump surgery [24]. Moreover, the number of emboli has been associated with cognitive sequelae as well [4,5]. Other studies, like the present one, have failed to find any relationship [6]. The composition and size of emboli as well as the ultimate location in the brain might be the best predictors instead of the absolute number [6,10]. Interesting for future perspectives, solid and gaseous cerebral HITS can now be differentiated with multi-frequency TCD [25]. The lack of an association between emboli and cognitive impairment together with the lack of difference in cognitive decline between the on- and off-pump group could suggest that chronic vascular disease, other than ECC, may underlie longer-term cognitive loss in some of the patients. Further research on this topic is needed. Besides emboli during surgery [10] predictors of long-term cognitive decline in other studies, specifically after CABG, were older age [23], fewer years of education [23], higher baseline score [9] cognitive decline at time of discharge [9,10], and degree of recovery between discharge and follow-up testing at 6 8 weeks after surgery [10]. The majority of these variables reflect more general processes rather than the ones specific to CABG [10]. In our study no specific pre-, peri- and postoperative characteristics for the impaired group were found. Neither did we find predictors for cognitive decline. The increased vulnerability for cognitive decline of older patients has been clear in many other short-term studies. Long-term research yielded more inconsistent results [9,10,16]. Wefoundagetobecorrelatedwiththe majority of neuropsychological tests. In common with two other reported studies that have followed CABG patients up to 5 years, an important limitation in the present study is that no control group was included to assess the impact of aging in relation to changes in cognitive performance [9,16]. Controlled studies are needed to demonstrate whether the cognitive decline is caused by the surgery itself or by age-related changes or underlying cerebrovascular disease [15]. To conclude, cognitive decline was found in one third of the CABG patients 3 5 years after surgery in various neurocognitive domains. No differences were found between the on- and off-pump patients, indicating that ECC may not be the only cause of late cognitive deficits. Further research with control groups is recommended. References [1] Newman SP, Stygall J. Neuropsychological outcome following cardiac surgery. In: Newman SP, Harrison MJG, editors. The brain and cardiac surgery: causes of neurological complications and their prevention. 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