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The Effects of Cardiopulmonary Bypass on the Number of Cerebral Microemboli and the Incidence of Cognitive Dysfunction After Coronary Artery Bypass Graft Surgery

Liu, Ying-Hua, MD*; Wang, Dong-Xin, MD, PhD*; Li, Li-Huan, MD, PhD; Wu, Xin-Min, MD*; Shan, Guo-Jin, MD*; Su, Yu, MD*; Li, Jun, MD*; Yu, Qin-Jun, MD; Shi, Chun-Xia, MD; Huang, Yi-Ning, MD; Sun, Wei, MD

Section Editor(s): Hogue, Charles W. Jr; London, Martin J.; Levy, Jerrold H.

doi: 10.1213/ane.0b013e3181aed2bb
Cardiovascular Anesthesiology: Perioperative Echocardiography and Cardiovascular Education: Hemostasis and Transfusion Medicine: Research Reports
Free
Chinese Language Editions

BACKGROUND: Postoperative cognitive dysfunction (POCD) can be a debilitating complication after coronary artery bypass graft (CABG) surgery. Cerebral microemboli during cardiopulmonary bypass (CPB) are believed to be an important etiologic factor of POCD. In this study, we examined whether avoidance of CPB with “off-pump” surgery reduces the number of cerebral microemboli and the incidence of POCD after CABG surgery in Chinese population.

METHODS: Two hundred twenty-seven patients were enrolled in this prospective cohort study. Fifty-nine patients underwent CABG surgery with CPB and 168 underwent off-pump surgery. Cerebral microemboli were measured continuously with bilateral transcranial Doppler ultrasonography of the middle cerebral arteries. A neuropsychological test battery that included seven tests with nine subscales was administered at baseline, as well as at 1 wk and 3 mo after surgery. POCD was defined using the international study of POCD1 definition.

RESULTS: The median total number of cerebral microemboli for the case was 430 (range: 155–2088) in patients undergoing surgery with CPB and 2 (0–66) in the off-pump patients (P < 0.001). There were no differences in the incidence of POCD between the patients having surgery with or without CPB either at 1 wk (55.2% or 32 of 58 patients [95% confidence interval: 41.5%–68.3%] vs 47.0% or 78 of 166 patients [39.2%–54.9%], P = 0.283) or 3 mo (6.4% or 3 of 47 patients [1.3%–17.5%] vs 13.1% or 16 of 122 of patients [7.7%–20.4%], P = 0.214) after surgery. Increasing age and shorter duration of postoperative hospital stay were independently associated with cognitive dysfunction at 1 wk after surgery. Increasing age and a history of diabetes mellitus were independently associated with cognitive dysfunction 3 mo after surgery. CPB or cerebral microemboli were not significantly related to the occurrence of POCD.

CONCLUSIONS: In Chinese population, avoidance of CPB during CABG surgery significantly decreased the number of cerebral microemboli, but it did not decrease the incidence of POCD at either 1 wk or 3 mo after CABG. Neither CPB nor cerebral microemboli was independently associated with the risk of POCD.

From the *Department of Anesthesiology, Peking University First Hospital, Beijing, China; †Department of Anesthesiology, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and ‡Department of Neurology, Peking University First Hospital, Beijing, China.

Accepted for publication May 15, 2009.

Supported by Capital Medical Development Fund Grant 2002-1006.

Address correspondence and reprints requests to Dong-Xin Wang, MD, PhD, Department of Anesthesiology, Peking University First Hospital, No. 8 Xishiku St., Beijing 100034, China. Address e-mail to wangdongxin@hotmail.com.

Postoperative cognitive dysfunction (POCD) is a common neurologic complication of cardiac surgery affecting approximately 50%–70% of patients at hospital discharge and 20%–40% of patients 6 mo after surgery.1–3 It refers to deficits in a group of cognitive domains including attention, concentration, short-term memory, motor dexterity, and psychomotor speed.1 The occurrence of POCD is associated with increasing duration of hospitalization and impaired long-term quality of life.4,5 The etiology of POCD is incompletely understood, but the use of cardiopulmonary bypass (CPB) has been widely implicated.1,2 CPB and its related procedures (such as cannulation in the aortic root) inevitably produce cerebral microemboli, which could lead to brain injury and neuropsychological deficits.6 In addition, CPB is associated with a profound systemic inflammatory response, which might contribute to brain dysfunction.7 Furthermore, as a nonphysiologic perfusion mode, CPB could provoke imbalance between oxygen supply and demand in the brain.8

Performing surgery without CPB (i.e., off-pump surgery) has been suggested as an alternative approach to coronary artery bypass graft (CABG) surgery to reduce complications. Several studies have shown that, when compared with conventional CABG surgery with CPB, off-pump surgery decreased the number of cerebral microemboli9 and the degree of inflammatory response.10 However, it remains controversial whether off-pump CABG can decrease the occurrence of POCD. Some investigators reported that the recovery of cognitive function early after surgery was improved in patients undergoing off-pump CABG.9,11 However, others found that there was no significant difference in the incidence of POCD between the two surgical methods.12,13 Moreover, none of the studies were performed in Chinese population whose risk factors for brain injury might vary compared with predominantly Caucasian populations.14,15 The purpose of this study was to examine whether off-pump CABG surgery reduces the number of cerebral microemboli and the incidence of POCD compared with on-pump surgery in Chinese population.

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METHODS

The study protocol was approved by the local Clinical Research Ethics Committee and all patients gave written informed consent.

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Subject Enrollment

This was a prospective cohort study. Patients who lived in the Beijing metropolitan area who were referred for elective CABG at Peking University First Hospital and Beijing Fuwai Hospital between January and December 2004 were candidates for inclusion in the study. The method of surgery (on-pump surgery or off-pump surgery) and the number of CABGs were determined by the surgeons. Exclusion criteria included the following: (1) previous cardiothoracic surgery; (2) previous psychiatric disease; (3) preoperative biochemical evidence of renal dysfunction (serum creatinine >177 μmol/L) or active hepatic disease; (4) severely impaired left ventricular function ([echocardiography, Simpson’s method] <20%); (5) inability to complete preoperative neuropsychological tests; (6) absence of an acoustic window for transcranial Doppler (TCD) ultrasonography in the preoperative evaluation; and (7) concomitant surgery other than CABG, such as valve replacement or surgery on great vessels.

For the purpose of estimating the magnitude of practice effect for the neuropsychological tests used in this study, a group of control subjects were enrolled. These subjects were recruited primarily from friends and family members of patients undergoing CABG surgery. The inclusion and exclusion criteria for control subjects were the same as that for patients, with the exception of surgically related items. These individuals underwent neuropsychological testing at the same time intervals as the patients. Control subjects did not undergo any surgical procedures or anesthesia during the period of study.

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Neurocognitive Assessment

Neuropsychological tests were administered the day before surgery, as well as at 1 wk and 3 mo after surgery. The test battery was chosen according to the Statement of Consensus on Assessment of Neurobehavioral Outcomes after Cardiac Surgery and included seven tests with nine subscales (Table 1).16,17 All examiners were trained on psychometric test administration and relevant interview techniques and were blinded to the method of surgery. Testing was performed and scored in a standardized manner to minimize differences between test administrators. Repeat assessments for each patient were conducted by the same psychometrician. Parallel forms of tests were used in sequential testing in a randomized manner when available to minimize practice effect.

Table 1

Table 1

POCD was diagnosed using the same definition used in the international study of POCD1 investigation.18,19 To quantify the practice effect, we compared baseline scores with subsequent test results 1 wk and 3 mo later in control subjects. For patients, we compared baseline scores with 1-wk and 3-mo postoperative test results, subtracted the average practice effect from these changes, and divided the result by the control group sd to obtain a Z score for each test. The test results are adjusted such that a positive Z score indicates deterioration from the baseline test. The Z scores for all tests in an individual patient were then summarized and divided by the sd for this sum of Z scores in the control group, creating a global Z score. A patient was defined as having POCD when two Z scores in individual tests or the combined Z score were 1.96 or more. This definition identifies patients with general deterioration in all tests or substantial deterioration on only some tests. We chose a Z score limit of 1.96 so as to give a confidence level of 95%. Patients who were unable to complete testing as a result of debilitating stroke or death were given the worst scores and thus were considered to have POCD.11

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Anesthesia, Surgery, and Cardiopulmonary Bypass

Premedication was with midazolam (5–7.5 mg per os) and morphine (10 mg IM). Anesthesia was induced with midazolam (0.1–0.2 mg/kg), sufentanil (0.6–1.2 μg/kg), etomidate (0.2–0.4 mg/kg), and rocuronium (0.6 mg/kg). Anesthesia was maintained with sufentanil (0.4–0.6 μg · kg−1 · h−1), sevoflurane (0.5%–1.0%), and propofol (2.4–4.0 mg · kg−1 · h−1during CPB). Intraoperative monitoring included five-lead electrocardiogram, radial arterial pressure, central venous pressure, pulmonary arterial pressure, pulse O2 saturation, nasopharyngeal temperature, end-tidal expiratory CO2, and urine output.

All patients underwent CABG surgery through a median sternotomy. Aortic palpation was used to detect atherosclerosis and, if present, to select an appropriate site for cannulation and clamping. For patients undergoing off-pump surgery, distal anastomoses were performed with the help of an Octopus tissue stabilizer (Medtronic, Minneapolis, MN), and proximal anastomoses were then fashioned onto the aorta using a single side clamp. Nasopharyngeal temperature was maintained more than 35°C, and systolic blood pressure was kept at 80 mm Hg or higher throughout the procedure. The cell saver (Jingjing Corporation, Beijing, China) was used to process shed blood before returning it back to the patient.

For patients undergoing on-pump surgery, CPB was established with a roller pump (Stöckert S3, Munich, Germany), a membrane oxygenator (Maxima Forte, Medtronic, Minneapolis, MN), and a 40-μm arterial blood filter (Dideco, Mirandola, Italy). Moderate hypothermia (32°C) and α-stat pH management were used. Perfusion pressure was kept at 60–80 mm Hg, and a pump flow was maintained between 2 and 2.4 L · min−1 · m−2. After completing all distal anastomoses, the aortic cross-clamp was removed, and proximal anastomoses were then performed using a single side clamp on the aorta. During the period of CPB, the cardiotomy suction was used in a standard closed venous reservoir where cardiotomy blood was collected and reinfused through the arterial circuit back to the patient. The cell saver was only used to process shed blood before heparinization and after the initial dose of protamine was given.

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Monitoring the Intraoperative Cerebral Microemboli

Cerebral microemboli in the right and left middle cerebral arteries were monitored using a TCD ultrasonograph (Companion TC2021-III, EME GmbH, Kleinostheim, Germany) by a technician who did not participate in the neuropsychological test. The numbers of microemboli in both right and left sides were then combined to provide total microembolic count for analysis. Two 2 MHz transducers were placed on the bilateral transtemporal windows. The middle cerebral arteries were identified at a depth of 46–64 mm, and the transducers were fixed in position using a Welder headset (EME GmbH, Kleinostheim, Germany). The software Win TCD 3.7.0 was applied, with a sampling interval of 6.0 mm and a sampling volume of 8.0 mm set for all patients. A 128-point fast Fourier transform was used for spectral analysis. Fast Fourier transform time window overlap was more than 50%. The Doppler signals were continuously monitored and stored onto digital audiotapes from opening of the pericardium until closure of the sternum. The time of surgical maneuver was also recorded by an experienced physician.

The audiotapes were individually coded and played back in the same TCD machine for off-line analysis at a later date. A single observer (YL), who was blinded to subject identity and surgery type, conducted the analysis. A microembolic signal was defined according to the criteria of consensus on microembolus detection by TCD as a unidirectional transient intensity increase (intensity >7 dB), associated with a characteristic “click” or “chirp” sound.20,21 The number of microemboli for 1 min after a surgical maneuver and the total number of microemboli for the case were counted.

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Sample Size Calculation and Statistical Analysis

We assumed that the incidence of POCD 1 wk after CABG surgery would be 26.5% in the off-pump patients and 53% in the on-pump patients.3 The calculated sample size that would provide 80% power to see this difference based on a two-tailed significance level of 0.05 is 120 patients in a randomized schedule. Considering the asymmetric distribution of cases between the two surgical methods in this study (about one fourth of patients would undergo on-pump surgery) and an estimated attrition rate of 10%, the final sample size was increased to total 178 patients. The sample size calculation was performed on STATA 10.0 software (StataCorp LP, College Station, TX). We also included approximately 70 control subjects to calculate the practice effect of repeated neuropsychological testing.

Continuous variables are expressed as mean ± sd or median (range). Data were analyzed with independent samples t-test or Mann-Whitney U-test. Categorical variables are expressed as numbers of patients (percentages). Data were analyzed with χ2 analysis or Fisher’s exact test. The binary outcomes of POCD were modeled in a multivariate logistic regression to determine predictors of the occurrence of POCD after adjusting for other factors. All factors that differed in the bivariate analyses (P < 0.10) together with the use of CPB during surgery or the number of cerebral microemboli were included in the logistic regression model. A P value <0.05 was considered significant. Statistical analyses were performed on SPSS 14.0 software (SPSS, Chicago, IL).

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RESULTS

Patient Population and Control Subjects

Two hundred twenty-seven patients completed the preoperative neuropsychological tests. Fifty-nine patients underwent CABG surgery with CPB and 168 underwent off-pump surgery. The two groups of patients had similar baseline characteristics as shown in Table 2. Perioperative characteristics of the patients are listed in Table 3.

Table 2

Table 2

Table 3

Table 3

One patient was converted from off-pump surgery to on-pump surgery because of hemodynamic instability. This patient was excluded from further analyses. One week after surgery, two patients refused to complete the follow-up tests (one each from on-pump and off-pump surgery groups). Thus, 224 patients were included in the in-hospital analysis. Three months after surgery, eight patients refused continued study participation (two from the CPB surgery group; six from the off-pump surgery group) whereas another 49 patients were unable to be contacted for follow-up testing (10 from the on-pump surgery group; 39 from the off-pump surgery group). Thus, 169 of the 227 patients (74.4%) were included in 3-mo data analysis.

A comparison between patients who completed the 3-mo follow-up with those who did not indicated that the latter group of patients were younger, had fewer women, and less distal anastomoses were performed (Tables 2 and 3). Seventy-five control subjects were enrolled. Patients and control subjects were similar with respect to age, body mass index, sex distribution, and educational level (Table 4).

Table 4

Table 4

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Incidence of Stroke and Mortality

Nonfatal stroke occurred in two patients (0.9%) during hospitalization after surgery: one patient in the CPB surgery group (1.7%, 1 of 59) and one patient in the off-pump surgery group (0.6%, 1 of 168) (P = 0.453). These two patients were unable to complete the follow-up neuropsychological tests at 1 wk after surgery because of limb disability. Of these patients, one (on-pump surgery group) remained unable to complete the neuropsychological tests at 3 mo after surgery. There was one in-hospital death in a patient who underwent off-pump surgery, resulting in an overall mortality rate of 0.4% (1 of 227). This occurred on the sixth postoperative day as a result of heart failure and sudden cardiac arrest. These patients were defined as having POCD at the corresponding test sessions.

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Intraoperative Cerebral Microemboli

TCD monitoring was performed in 208 patients. In 10 patients, however, Doppler signals were lost during surgery. In another 16 patients, high-quality Doppler signals were only obtained from one of the middle cerebral arteries. Because there was no difference in the number of microemboli in the right and left middle cerebral arteries from the remaining 182 patients, the numbers of microemboli of the 16 patients with unilateral Doppler monitoring were doubled for the calculation of the total microemboli count. The median numbers of TCD-detected cerebral microembolic events at the various surgical interventions are shown in Figures 1A and 1B. In patients undergoing on-pump surgery, cerebral microemboli chiefly occurred during the period of CPB. The start of CPB and the removal of side clamp were the main maneuvers associated with the occurrence of microemboli (Fig. 1A). In patients undergoing off-pump surgery, the highest rate of microemboli detection occurred during the removal of side clamp (Fig. 1B).

Figure 1.

Figure 1.

The median total number (range) of microemboli for the case was 430 (155–2088) in the CPB patients and 2 (0–66) in the off-pump patients (P < 0.001) (Table 3). The median number of microemboli at the time of side clamp removal was significantly higher in the on-pump patients (29 [0–530]) than in the off-pump patients (2 [0–40]; P < 0.001).

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Neuropsychological Outcome

Baseline psychometric testing results for the control group are listed in Table 4. Control subjects had significantly better results in paired associate verbal learning test, digit span (backward) subtest, digit symbol test, and grooved pegboard tasks (dominant and nondominant hands) compared with CABG surgery patients.

The mean scores of the neuropsychological tests at baseline and at 1 wk and 3 mo after surgery are presented in Table 5. At baseline, the off-pump patients had significantly better result in trail making (Part A) test compared with the on-pump ones. However, there were no significant differences between the two groups in any of the test results at either 1 wk or 3 mo after surgery.

Table 5

Table 5

The incidences of POCD at two testing sessions are presented in Table 6. At 1 wk after surgery, POCD occurred in 55.2% of on-pump patients and 47.0% of off-pump patients (P = 0.283), resulting in an overall incidence of 49.1% (110 of 224). The incidences of POCD in both groups of patients were significantly more frequent than that in control subjects (5.3%) (P < 0.001). At 3 mo after surgery, POCD occurred in 6.4% of on-pump patients and 13.1% of off-pump patients (P = 0.214), resulting in an overall incidence of 11.2% (19 of 169). The incidence of POCD in off-pump patients was significantly more frequent than in control subjects (2.7%) (P = 0.013).

Table 6

Table 6

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Factors Associated with the Occurrence of Postoperative Cognitive Dysfunction

Variables found to be associated with POCD 1 wk after surgery are listed in Table 7. Factors that differed in bivariate analyses (P < 0.10) between patients with and without POCD and the use of CPB during surgery were included in the multiple logistic regression analysis. Increasing age and shorter duration of postoperative hospital stay were independently associated with POCD 1 wk after surgery. Variables found to be associated with POCD 3 mo after surgery are listed in Table 8. Multiple logistic regression analysis was performed in the same manner as earlier. Increasing age and a history of diabetes mellitus remained significantly associated with the occurrence of POCD.

Table 7

Table 7

Table 8

Table 8

Because the number of microemboli was not normally distributed, it was log transformed after adding one to the total number to deal with the patients with zero emboli. The use of CPB was then replaced with the log of the number of cerebral microemboli in the multiple logistic regression analysis that was performed as earlier. Results also showed that there were no significant associations between the number of cerebral microemboli and the occurrence of POCD at either testing session.

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DISCUSSION

Our study demonstrated that there were more than 200 times more cerebral microemboli during on-pump compared with off-pump CABG surgery. Despite the reduction in cerebral microembolic count, we did not find significant differences in the incidence of POCD at either 1 wk or 3 mo after surgery between patients undergoing CABG surgery with or without CPB. Increasing age and shorter duration of postoperative hospital stay were independently associated with POCD 1 wk after surgery, and increasing age and a history of diabetes mellitus were independently associated with POCD 3 mo after surgery. Neither CPB nor cerebral microemboli number were independent factors associated with the risk of POCD.

The etiology of POCD in patients undergoing CABG remains unknown but it is widely speculated that cerebral microemboli resulting from the use of CPB contributes to this complication.6,22–25 Our findings of a reduction in cerebral microemboli with off-pump compared with surgery using CPB is consistent with other investigations. In the study by Lund et al.,26 the number of cerebral microemboli was significantly less during off-pump compared with on-pump surgery (16.3 [range: 0–131] vs 90.0 [range: 15–274]; P < 0.0001). Abu-Omar et al.27 showed that the median number (interquartile range) of microemboli in the off-pump CABG, on-pump CABG, and open cardiac procedure groups were 40 (28–80), 275 (199–472), and 860 (393–1321), respectively (P < 0.01). Motallebzadeh et al.9 also reported that there were more than 100 times more cerebral emboli during on-pump CABG compared with off-pump surgery. Nonetheless, the relationship between total cerebral microembolic signals and POCD has been debated.28 Some investigations have found a link between the number of microembolic signals during CABC surgery and POCD, whereas this relationship was not found by other investigations.9,29–32

Despite the reduction in cerebral microembolic signals with off-pump surgery, whether avoiding CPB for CABG surgery improves cognitive function has not been clearly established. In a prospectively randomized study, van Dijk et al.11 found that patients undergoing first time CABG surgery without CPB had improved cognitive outcomes 3 mo after the procedure, but the effects were limited and became negligible at 12 mo. In a randomized study of 212 patients, Motallebzadeh et al.9 reported that a composite neurocognitive score was better after off-pump surgery at hospital discharge compared with scores of patients undergoing on-pump surgery, but the difference did not persist 6 wk and 6 mo after surgery. Conversely, many studies found no differences in the incidence of POCD between patients having CABG with or without CPB 1 wk to 5 yr after surgery, which are consistent with the current results.12,13,33,34

In this study, a cell saver device was used to process blood suctioned from the pericardium during the procedure in off-pump patients but only before and after the CPB period in on-pump patients. Cardiotomy suction had been found to be a major source of fat emboli during CPB because current blood filtering methods are not effective in removing fat globules.35,36 Recently, Djaiani et al.37 demonstrated that processing of shed mediastinal blood with a continuous flow cell saver before its return to the CPB circuit resulted in a reduction in POCD 6 wk after on-pump CABG surgery compared with mediastinal blood that was returned to the CPB circuit unprocessed. Although no difference was found in the TCD-detected embolic count, they ascribed the better cognitive results primarily to the lower lipid cerebral embolic load undetectable by the TCD device. Conversely, in a randomized trial Rubens et al.38 found that processing of cardiotomy blood before reinfusion did not lead to a reduced frequency of POCD 3 mo after surgery.

There are several possible explanations for our finding that a reduction in TCD microembolic signals in the off-pump surgery group was not associated with a reduction in the frequency of POCD compared with the on-pump group. First, the TCD ultrasonography as used in our study does not distinguish gaseous emboli from solid microemboli. It is proposed that the quality, but not the number of microemboli, might have a more profound effect on clinical neurological outcomes.1 Second, the location of microembolization in the brain may be more important in determining brain consequences of cerebral embolization.39 Third, in addition to cerebral microemboli, other factors may also contribute to the development of POCD, including existing cerebral vascular disease and other patient and surgery-related factors.40 Therefore, POCD after CABG does not seem to be specific to the use of CPB. In fact, the longitudinal studies by Selnes et al.41–43 found that the rate of cognitive decline in patients having CABG surgery with CPB was not different 1, 3, and 6 yr postoperatively compared with a similar group of patients with documented coronary artery disease undergoing medical management. In another recent study, van Dijk et al.44 reported that patients’ cognitive outcomes 5 yr after CABG surgery were found to be similar to that from control subjects who did not have coronary artery disease. Our findings that POCD was more common in patients undergoing CABG surgery with or without CPB compared with controls are consistent with these previous results. Together the data suggest that age-associated cardiovascular disease rather than CABG surgery per se seems to be a more important factor determining cognitive decline across time.

A unique aspect of this study was that it was performed in an exclusively Chinese population. Differences in the frequency and distribution of cerebral and coronary atherosclerosis have been recognized between Chinese and Caucasian populations (i.e., coronary artery lesions tend to be less severe, whereas intracranial cerebral artery lesions tend to be more severe in Chinese compared with Caucasian populations).14,15,45,46 The presence of intracranial artery disease was associated with increased risk of central nervous system complications after CABG surgery.47,48 Despite the above differences, the current finding that CPB does not influence the frequency of POCD seems to be a universal phenomenon in both Asian and Caucasian populations.12,13,33,34

Our study has several limitations. First, we used a nonrandomized study design that could have led to bias in the patients’ risk for POCD between the two surgical approaches. Although patients undergoing on-pump and off-pump surgery had similar baseline demographic characteristics, there was a difference in baseline trail making test result (the on-pump patients did worse than the off-pump patients). Second, we did not attempt to control the techniques of individual surgeons. Hammon et al.49 found that surgical technique was also an important determinant of POCD after CABG. Third, the rate of follow-up 3 mo after surgery was low (74.4%) in our study. Analysis showed that patients who did not complete 3-mo follow-up were younger and, therefore, at less risk for POCD.3,9 Thus, the incidence of POCD 3 mo after surgery might be overestimated in our study. Fourth, the study sample size was relatively small. Using the incidence of POCD reported in this study, we calculated that a sample size of 1600 patients would be needed to provide 80% power to exclude the influence of CPB on the risk of POCD after CABG surgery.

In conclusion, the results of our study suggest that avoidance of CPB during CABG surgery significantly decreased the number of intraoperative cerebral microemboli but did not decrease the incidence of cognitive dysfunction at either 1 wk or 3 mo after surgery. Neither CPB nor cerebral microemboli was independently associated with the risk of POCD.

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