Impairment of cognitive brain function is frequently

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1 ORIGINAL ARTICLES: CARDIOVASCULAR Cardioulmonary Byass Affects Cognitive Brain Function After Coronary Artery Byass Grafting Juliane Kilo, MD, Martin Czerny, MD, Michael Gorlitzer, MD, Daniel Zimfer, MS, Harald Baumer, MD, Ernst Wolner, MD, and Michael Grimm, MD Deartment of Cardiothoracic Surgery, Vienna General Hosital, Vienna, Austria Background. The causes for cognitive imairment after coronary artery byass grafting (CABG) have long been a toic for debate. Methods. We rosectively followed 308 consecutive, unselected survivors of CABG at our institution. In addition to determination of clinical measurements, cognitive brain function was measured objectively by P300 auditory-evoked otentials before CABG, at 7-day and at 4-month follow-u. Standard sychometric tests (Trail Making Test A, Mini Mental State Examination) were also erformed. Results. At 7-day follow-u cognitive P300 auditoryevoked otentials were significantly imaired comared with reoerative levels (eak latencies: ms versus ms, ). P300 measurements were almost normalized at 4-month follow-u (eak latencies: ms, NS versus reoerative). Standard sychometric tests failed to detect this subclinical cognitive imairment. Multile regression analysis revealed that use of cardioulmonary byass was the only indeendent redictor of imaired cognitive brain function at 7-day ( < ) and 4-month follow-u ( ). The resence of diabetes mellitus ( ) or concomitant reair of significant carotid artery stenosis ( ) was redictive of late imrovement of cognitive brain function at 4-month follow-u. Conclusions. Objective cognitive P300 auditory-evoked otential measurements demonstrate that the use of cardioulmonary byass is the only redictor of shortand long-term cognitive brain dysfunction after CABG. Interestingly, the resence of diabetes mellitus and concomitant reair of a significant carotid artery stenosis were redictive for long-term cognitive benefit. (Ann Thorac Surg 2001;72: ) 2001 by The Society of Thoracic Surgeons Imairment of cognitive brain function is frequently associated with coronary artery byass grafting (CABG). The erioerative level of cognitive brain dysfunction after CABG has been shown to be redictive of long-term cognitive brain function u to 5 years after oeration, markedly affecting the rehabilitation rocess, work erformance, and quality of life [1, 2]. By means of standard sychometric testing numerous studies have shown that the incidence of cognitive brain dysfunction after CABG may range from 20% through 80% [1 4]. This wide variability may be related to different sensitivities of the test batteries used to assess cognitive brain function. Because standard sychometric tests are adversely affected by various biases, these findings need to be confirmed by objective measures. P300 cognitive auditory-evoked otentials are a highly sensitive and reroducible tool for evaluation of cognitive function in various neurologic, metabolic, or hemodynamic disorders [5 10]. Evoked otentials are stable sequences of negative and ositive electroencehalograhy (EEG) eaks after a stimulus within a eriod of several hundred milliseconds. P300 event-related otentials are late ositive cortical deflections occurring after Acceted for ublication Aug 2, Address rerint requests to Dr Grimm, Deartment of Cardiothoracic Surgery, Vienna General Hosital, Waehringer Guertel 18-20, A-1090 Vienna, Austria; michael.grimm@akh-wien.ac.at. certain cognitive tasks [11]. They objectively reflect imortant asects of neurocognitive function. P300 latency increases with age and is a neurosychological correlate of information rocessing, such as stimulus evaluation, alertness, and memory udating [11]. Cognitive P300 auditory-evoked otential measurement is an objective tool related to information and cognitive rocessing that allows quantification of imaired cognitive function [5, 6, 12]. The use of the P300 technique has roved to be even more sensitive than EEG and standard sychometric tests for detecting subclinical imairment of cognitive brain function [5, 9, 13]. The aim of this rosective study was to determine redictors of individual changes of cognitive brain function after CABG by means of objective cognitive P300 auditory-evoked otential measurements. Patients and Methods Patients A total of 308 consecutive, unselected survivors of either elective or urgent CABG at our institution entered the study. Preoerative atient characteristics are dislayed in Table 1. If a hemodynamically relevant carotid artery stenosis (of more than 75%) was resent, the carotid endarterectomy was erformed as a combined rocedure. Patency of the internal carotid artery was controlled 2001 by The Society of Thoracic Surgeons /01/$20.00 Published by Elsevier Science Inc PII S (01)03199-X

2 Ann Thorac Surg KILO ET AL 2001;72: P300 AUDITORY-EVOKED RESPONSE AFTER CABG 1927 Table 1. Patient Characteristics Characteristic Value Number of atients (n) 308 Age (years) Diseased vessels (n) Female gender (%) 16 LVF imaired (%) 26.2 Reoerations (%) 5.6 Diabetes mellitus (%) 31.7 Hyertension (%) 82.5 Carotid stenosis (%) 13.3 Neurologic disorder (%) 5.6 Renal dysfunction (%) 3.5 LVF left ventricular function. by ultrasound at 4-month follow-u. Postoerative outcome was monitored. Perioerative myocardial infarction was defined as any new Q-wave or loss of R in the electrocardiogram, significant creatine kinase (CK)/ CK-MB elevation (CK-MB higher than 40 U/L). Prolonged inotroic suort was defined as inotroic theray for low-outut syndrome for more than 1 day or rolonged intubation as ventilatory suort for more than 5 days. Narcotics for ain relief were restricted to the time of chest tube drainage. Chest tubes were removed on ostoerative day 2. Neurologic disorder was defined as history of revious transient ischemic attacks or stroke, not severely imairing the atient s daily life. Anesthesia and Surgical Technique All atients received a standardized anesthesia with midazolam, etomidate, fentanyl, and ancuronium. Ventilation was erformed with oxygen in air. The atient was hearinized systemically after harvesting of arterial and venous grafts. All atients who underwent cardioulmonary byass (CPB) had normothermic CPB. Intermittent ante- and retrograde cold blood cardiolegia was erformed for myocardial reservation. Flow during CPB was maintained at 2.5 L min 1 m 2. Perfusion ressure during CPB was ket above 50 mm Hg. If CABG was erformed without CPB, a myocardial coronary artery stabilizer system (Cardio Thoracic Systems, Cuertino, CA; Octous, Medtronic, Minneaolis, MN) was used. The vessels were stabilized and snared roximally and distally to the chosen anastomotic site and the anastomosis was erformed on the beating heart. Proximal anastomoses of sahenous vein grafts were erformed on the artially clamed ascending aorta. Cognitive Brain Function Cognitive brain function was evaluated before CABG and at 7-day and 4-month follow-u. Only atients who comleted follow-u were included in the study. Cognitive P300 auditory-evoked otentials were recorded with Ag-AgCl electrodes on a Nicolet Sirit (Audiometrics, Oceanside, CA). P300 evoked otentials were generated after a binaurally resented tone discrimination aradigm with frequent (85%) tones of 1,000 Hz and rare (15%) target tones of 2,000 Hz at 65dB hearing level. Filter band-ass was 0.01 to 30 Hz. Active electrodes were laced at Cz (vertex) and Fz (frontal), resectively, and referenced to a linked earlobe A-12 electrode (10-20 International System). During the aradigm, the subjects were instructed to kee a running mental count of the rare 2,000-Hz target tones. To verify attention, P300 recordings with a discreancy of more than 10% between the actual number of stimuli and the number counted by the subjects were rejected and reeated. P300 auditoryevoked otential recording resulted in a stable sequence of ositive and negative eaks. Latencies (in milliseconds) of the cognitive P300 eak were assessed. To confirm reroducibility, two sets of P300 measurements were recorded in all atients [9]. P300 auditory-evoked otentials were measured with the informed consent of the atient and after aroval of the local ethics commission. Two standard sychometric tests (Mini Mental State Examination, Trail Making Test A) were erformed immediately after P300 measurement to detect any overt cognitive imairment and sychomotor erformance. To minimize learning effects, three different Trail Making tables were used. To avoid any influence of biorhythm alterations, the same hysician erformed the P300 recordings and the sychometric tests in the morning under comarable conditions. Patients had to be in stable condition, free from narcotics for more than 48 hours, and ready for discharge from hosital at 7-day follow-u. Statistical Analysis Data are reorted as mean standard deviation. The influence of different measurements on individual changes in cognitive brain function throughout follow-u was analyzed by linear correlation analysis of differences in P300 eak latencies in each atient. To test the simultaneous influence of variables on changes of P300 eak latencies, multile regression analysis was erformed. The entrance level into multile regression analysis was set to less than or equal to 0.15 based on univariate analysis. Variables with significant influence on cognitive brain function were comared. Student s t test was alied after testing for normality of distribution to analyze grou differences at the three time oints. The time course of cognitive brain function was analyzed by means of aired t test for the different grous. Results Oeration-related variables and ostoerative outcome are shown in Table 2. Because only survivors were entered into the study, mortality was 0%. CPB was used in 72.7% of all study atients. Mean oeration time was 228 minutes, mean intubation time 21.4 hours, and mean intensive care unit stay was 2.2 days. Nonfatal myocardial infarction occurred in 2.1%, and 13.1% needed rolonged inotroic suort. Reexloration for bleeding was required in 2.1% of the atients, and 21.4% develoed atrial fibrillation ostoeratively (Table 2).

3 1928 KILO ET AL Ann Thorac Surg P300 AUDITORY-EVOKED RESPONSE AFTER CABG 2001;72: Table 2. Oerative Variables and Postoerative Outcome Variable Value Patients (n) 308 Number of grafts (n) CABG with CPB (%) 72.7 Nonfatal myocardial infarction (%) 2.1 Prolonged inotroic suort (%) 13.1 Reexloration for bleeding (%) 2.1 Prolonged intubation ( 5 days) (%) 2.1 Stroke (%) 0.7 Hemofiltration (%) 1.4 Atrial fibrillation (%) 21.4 Wound infections (%) 6.2 Oeration time (min) Intubation time (hours) ICU stay (days) Postoerative stay (days) CABG coronary artery byass grafting; byass; ICU intensive care unit. Cognitive Brain Function COGNITIVE P300 AUDITORY-EVOKED POTENTIALS. A reresentative tracing of a P300 measurement is shown in Figure 1. Coronary artery byass grafting resulted in a significant rolongation ( imairment) of cognitive P300 eak latencies at 7-day follow-u as comared with before CABG ( ms versus ms; ). At 4-month follow-u, P300 eak latencies almost normalized ( ms) as comared with reoerative values ( ; Fig 2). STANDARD PSYCHOMETRIC TESTS. Using the Mini Mental State Examination it was not ossible to detect any overt cognitive changes throughout the whole study eriod (before CABG: ; 7-day follow-u: , versus before CABG; 4-month follow-u: , versus before CABG). Using the Trail Making Test we also failed to detect any significant changes at either 7-day or 4-month follow-u (before CABG: seconds; 7-day follow-u: seconds, versus before CABG; and 4-month Fig 1. Reresentative tracing of P300 measurement. CPB cardioulmonary Fig 2. Serial recordings of P300 eak latencies before coronary artery byass grafting (CABG), at 7-day and at 4-month follow-u. (Solid line P300 eak latencies recorded at CZ. Dotted line P300 eak latencies recorded at FZ Imairment of P300 eak latencies, 0.05 versus reoerative.) follow-u: seconds, versus before CABG). Predictors of Individual Changes of Cognitive P300 Peak Latencies UNIVARIATE LINEAR CORRELATION ANALYSIS. From reoeratively through 7-day follow-u, the use of CPB ( ), number of grafts ( ), and number of diseased vessels ( ) were associated with an imairment of cognitive P300 eak latencies (Table 3). From reoeratively through 4-month follow-u, the use of CPB ( ) and number of diseased vessels ( ) were associated with imaired cognitive P300 eak latencies. In contrast, concomitant reair of significant carotid artery stenosis was associated with imrovement of P300 eak latencies from reoeratively through 4-month follow-u ( , Table 3). MULTIPLE LINEAR REGRESSION ANALYSIS. The use of CPB was the only indeendent redictor for individual imairment of cognitive P300 eak latencies from reoeratively through 7-day ( ) and 4-month follow-u ( , Table 4). However, concomitant reair of significant carotid artery stenosis ( ) and the resence of diabetes mellitus ( ) were indeendently associated with imrovement of cognitive brain function through 4-month follow-u. The number of diseased vessels, number of grafts, and the occurrence of ostoerative atrial fibrillation failed to show any influence on individual changes of P300 eak latencies (Table 4). The use of CPB resulted in marked imairment cognitive brain function after CABG (before CABG: ms; 7-day follow-u: ms, versus before CABG; 4-month follow-u: ms, versus before CABG; Fig 3A). Surrisingly, atients undergoing CABG without CPB showed imrovement of cognitive P300 eak latencies (before CABG: ms; 7-day follow-u: ms, versus before

4 Ann Thorac Surg KILO ET AL 2001;72: P300 AUDITORY-EVOKED RESPONSE AFTER CABG 1929 Table 3. Univariate Linear Correlation Analysis of Individual Changes of P300 Peak Latencies (Cz) Preoerative to 1 Week Postoerative Pearson Correlation Coefficient Preoerative to 4 Months Postoerative Characteristic Pearson Correlation Coefficient Age Female sex Diseased vessels LVF imaired Diabetes mellitus Hyertension Carotid stenosis CABG with CPB Number of grafts Atrial fibrillation CABG coronary artery byass grafting; CPB cardioulmonary byass; LVF left ventricular function. CABG; 4-months follow-u: ms, versus before CABG). Preoeratively, atients oerated with and without CPB were comarable ( ). At 7-day follow-u, atients who had undergone the oeration without CPB erformed better than those who had undergone CABG with CPB ( ). Thereafter, both grous erformed comarably ( , Fig 3A). Characteristics of atients undergoing CABG with or without CPB are dislayed in Table 5. Interestingly, the resence of diabetes mellitus resulted in imairment of cognitive brain function reoeratively (diabetes: ms; no diabetes: ms, ; Fig 3B). At 7-day follow-u both atient grous erformed worse than reoeratively (diabetes: , versus before CABG; no diabetes: ms, versus before CABG; diabetes versus no diabetes, ). Most imortantly, diabetic atients showed significant imrovement in cognitive brain function at 4-month follow-u ( ms, versus 7-day follow-u). In contrast, nondiabetic atients showed worse cognitive brain function at 4-month follow-u as comared with reoeratively ( ms, ). The resence of significant carotid artery stenosis resulted in imairment of cognitive brain function reoeratively (carotid artery stenosis: ms; no carotid artery stenosis: ms, , Fig 3C). At 7-day follow-u atients without carotid artery stenosis erformed worse ( ms, versus before CABG). In contrast, concomitant reair of carotid artery stenosis did not affect P300 eak latencies ( ms, ; carotid artery stenosis versus no carotid artery stenosis, ). At 4-month follow-u cognitive brain function of atients with concomitant reair of carotid artery stenosis imroved ( ms, versus before CABG and concomitant carotid artery oeration). Patients without carotid artery stenosis remained unchanged ( ms, versus before CABG; carotid artery stenosis versus no carotid artery stenosis, , Fig 3C). In control ultrasound investigation, the carotid artery was atent in all atients. Comment Objective P300 auditory-evoked otential measurement revealed that cognitive brain function is imaired after CABG. The use of CPB turns out to be the only indeendent redictor of imaired cognitive brain function. In- Table 4. Multile Regression Analysis: Predictors of Individual Changes in P300 Peak Latency (Cz) Preoerative to 1 Week Postoerative Parameter Estimate Preoerative to 4 Months Postoerative Characteristic Parameter Estimate Diseased vessels Diabetes mellitus Carotid stenosis CABG with CPB Number of grafts Atrial fibrillation CABG coronary artery byass grafting; CPB cardioulmonary byass;... variable not entered on the 0.15 entrance level.

5 1930 KILO ET AL Ann Thorac Surg P300 AUDITORY-EVOKED RESPONSE AFTER CABG 2001;72: Fig 3. (A) Serial recordings of P300 eak latencies before coronary artery byass grafting (CABG), at 7-day and at 4-month follow-u. Solid line P300 eak latencies of atients undergoing CABG with cardioulmonary byass (CPB). Dotted line P300 eak latencies of atients undergoing CABG without CPB. Imairment of P300 eak latencies, 0.05 versus before CABG. Imrovement of P300 eak latencies, 0.05 versus before CABG. *P300 eak latencies with versus without CPB, (B) Serial recordings of P300 eak latencies before CABG, at 7-day and at 4-month follow-u. Solid line P300 eak latencies of atients with diabetes mellitus. Dotted line P300 eak latencies of atients without diabetes mellitus. Imairment of P300 eak latencies, 0.05 versus before CABG. Imrovement of P300 eak latencies, 0.05 versus 7 days. *P300 eak latencies with versus without diabetes mellitus, (C) Serial recordings of P300 eak latencies reoerative, 7 days and 4 months ostoeratively. Solid line P300 eak latencies of atients with internal carotid artery stenosis. Dotted line P300 eak latencies of atients without internal carotid artery stenosis. Imairment of P300 eak latencies, 0.05 versus before CABG. Imrovement of P300 eak latencies, 0.05 versus before CABG. *P300 eak latencies with versus without internal carotid artery stenosis, terestingly, the resence of diabetes mellitus and concomitant reair of significant carotid artery stenosis were redictive of long-term cognitive benefit. Our results confirm what numerous studies have already shown: Cognitive brain dysfunction is a significant adverse event related to CABG (reorted from 20% to 80%), which may affect length of hosital stay, quality of life, the rehabilitation rocess, and work erformance [1 4]. Cognitive brain dysfunction after CABG has been demonstrated only by sychometric testing [1 4]. However, it is generally acceted that sychometric tests are not unbiased, for examle, because of the occasionally long erformance times, influence of sychomotor function, level of education, or learning effects [14]. Learning effects are of articular interest for follow-u studies [7]. Cognitive P300 evoked otentials, elicited by a tone Table 5. Characteristics of Patients Undergoing CABG With or Without CPB Characteristic With CPB Without CPB Number of atients (n) Age (years) Diseased vessels (n) Female sex (%) LVF imaired (%) Reoerations (%) Diabetes mellitus (%) Hyertension (%) Carotid stenosis (%) Renal dysfunction (%) CABG coronary artery byass grafting; byass; LVF left ventricular function. CPB cardioulmonary

6 Ann Thorac Surg KILO ET AL 2001;72: P300 AUDITORY-EVOKED RESPONSE AFTER CABG 1931 discrimination aradigm, reresent an objective and valid measure of cognitive brain function, registering brain activity required in the maintenance of working memory [6, 11]. P300 eak latencies increasing with age in healthy subjects [5] were shown to be related to cognitive imairment rating [6], raid evaluation of cognitive function testing, orienting, stimulus evaluation, selective attention, and digit san [15]. Additionally, P300 eak latencies were shown to be much more sensitive in the detection of metabolically induced cognitive brain dysfunction than sychometric tests or EEGs [5, 7, 9]. Furthermore, the low coefficient of intraindividual test retest variation of 2% in cognitive P300 auditory-evoked otential measurement, which is of articular imortance in follow-u assessments, demonstrates its usefulness in our study [5]. Based on P300 measurements we were able to show that cognitive brain function was markedly imaired after CABG. By means of objective P300 measurements, we were able to show that the use of CPB is the only redictor of imaired cognitive brain function after CABG. The role of CPB as a cause of cognitive imairment remains unclear, however. Susected mechanisms of cognitive imairment after CPB may be insufficient intraoerative cerebral erfusion [16, 17] or cerebral microembolism, caused by gas, biological aggregates, or articles of silicone or olyvinyl chloride [3, 18, 19]. It has therefore been hyothesized that CABG without CPB may reserve cognitive brain function after CABG [20 22]. By means of neurosychological testing, Taggart and colleagues [23] recently stated that the similar early decline and late recovery of cognitive brain function in atients undergoing CABG with and without CPB excludes CPB as the major cause of cognitive imairment. In contrast we were able to demonstrate an association between ostoerative cognitive brain dysfunction and the use of CPB. However, in agreement with Taggart and colleagues [23], we, too, failed to detect any ostoerative cognitive changes using standard neurosychological testing. Therefore, cognitive decline in atients investigated by Taggart and colleagues [23] may have been missed because of the lower sensitivity of the neurosychological test battery. For the first time, our findings stress the use of CPB as the only indeendent redictor of cognitive brain dysfunction as revealed by multivariate analysis. We showed that the resence of diabetes mellitus was redictive of late imrovement in cognitive brain function after CABG. In noncardiac atients, various studies have shown that atients with a history of diabetes mellitus have cognitive imairment [12, 13, 24, 25]. A history of hyoglycemia does not correlate with cognitive dysfunction [24], whereas a history of hyerglycemia correlated with imaired cognitive function [25]. These findings suggest that cognitive dysfunction may be related to chronic hyerglycemia. Selnes and coworkers [26] identified diabetes mellitus as a redictor of cognitive decline after CABG. Their study, however, was based on neurosychological testing and diabetes mellitus roved to be redictive in only one of 16 erformed neurosychological tests. By means of P300 measurement, however, we found that atients with diabetes mellitus showed an imrovement in cognitive function at 4-month follow-u, thus suggesting otential cognitive benefit for atients with diabetes mellitus after successful CABG. Objective P300 auditory-evoked otential measurement revealed that concomitant reair of significant carotid artery stenosis is redictive of imrovement in brain function during follow-u. Our results agree with those of Madl and colleagues [9], who showed that cognitive brain function is imaired in atients with carotid artery stenosis. In a rosective study on atients either with or without concomitant carotid artery stenosis undergoing oen-heart oerations, Vingerhoets and colleagues [27] found no difference in cognitive function between the two atient grous. The variable results from different studies relating to the effect of carotid endarterectomy on cognitive brain function are discussed by Lunn and coworkers [28]. Irvine and colleagues [29] demonstrated that the controversy might be related to the methodologic bias of sychometric testing with less sensitivity. Based on objective P300 auditoryevoked otentials, we were able to demonstrate that atients with concomitant reair of carotid artery stenosis showed significant imrovement in cognitive brain function after CABG, robably because of better cerebral erfusion after CABG and carotid endarterectomy. The validity of our conclusions may be limited by several factors. First, the clinical relevance of cognitive dysfunction is still uncertain. Because investigation of cognitive brain function became a field of interest for the research community only a few years ago, data on this area are still rare. P300 measurement detects minute changes of cognitive function that have to be rimarily interreted as subclinical. The real clinical imact of cognitive dysfunction, esecially regarding quality of life and rehabilitation, needs to be confirmed by further investigations. Second, we did not use an external control grou but referred the cognitive changes to the reoerative base line cognitive state of the individual atient. This base line could erhas have been influenced by, for examle, reoerative anxiety. Therefore the reoerative values might not be true measurements of cognitive state. Another limitation to the study arises from the fact that we did not control myocardial erformance at follow-u. It is therefore imossible to determine whether imrovement of cognitive brain function may be related to imrovement of myocardial function. Additionally, we cannot exclude the ossibility that other unknown factors that did not enter our investigation may have influenced P300 measures. Furthermore, the follow-u time of 4 months is relatively short and changes in cognitive function after 4-month follow-u eriod may be lacking. Finally, the study was limited by the fact that we investigated nonrandomized atient grous, because the decision regarding the surgical strategy (with or without CPB) was left to the individual surgeon. When the above-mentioned limitations are taken into consideration, this study shows that the use of CPB is the

7 1932 KILO ET AL Ann Thorac Surg P300 AUDITORY-EVOKED RESPONSE AFTER CABG 2001;72: only indeendent redictor of cognitive decline after CABG at 7-day and 4-month follow-u. Patients with reoeratively imaired cognitive function because of carotid artery stenosis or diabetes mellitus are those most likely to benefit from CABG. We thank Meinhard Ploner, MSc (Stat), for statistical analysis of the work. References 1. Sotaniemi KA, Mononen H, Hokkanen TE. Long-term cerebral outcome after oen-heart surgery. Stroke 1986;17: Sotaniemi KA. Long-term neurologic outcome after cardiac oeration. Ann Thorac Surg 1995;59: Mills SA. Cerebral Injury and cardiac oerations. Ann Thorac Surg 1993;56:S Selnes OA, Goldsborough MA, Borowicz LM, et al. Neurobehavioral sequelae of cardioulmonary byass. Lancet 1999;353: Grimm G, Stockenhuber F, Schneeweiss B, et al. Imrovement of brain function in hemodialysis atients treated with erythrooietin. Kidney Int 1990;38: Polich J, Ehlers CL, Otis S, et al. P300 latency reflects the degree of cognitive decline in dementing illness. Electroenceh Clin Neurohysiol 1986;63: Grimm G, Oder W, Prayer L, et al. Evoked otentials in assessment and follow-u of atients with Wilson s disease. Lancet 1990;336: Grimm G, Ferenci P, Katzenschlager R, et al. Imrovement of heatic encehaloathy treated with flumazenil. Lancet 1988;2: Madl C, Grimm G, Kramer L, et al. Cognitive brain function in non-demented atients with low-grade and high-grade carotid artery stenosis. Eur J Clin Invest 1994;24: Madl C, Grimm G, Kramer L, et al. Early rediction of individual outcome after cardioulmonary resuscitation. Lancet 1993;341: Picton TW. The P300 wave of the human event-related otential. J Clin Neurohysiol 1992;9: De Feo P, Gallai V, Mazzota G, et al. Modest decrements in lasma glucose concentration cause early imairment in cognitive function and later activation of glucose counterregulation in the absence of hyoglycemic symtoms in normal men. J Clin Invest 1988;82: Pozzessere G, Valle E, De Crignis S, et al. Abnormalities of cognitive function in IDDM revealed by P300 event-related otential analysis. Diabetes 1991;40: Teresi JA, Golden RR, Cross P, et al. Item bias in cognitive screening measures. J Clin Eidemiol 1995;48: Grimm M, Yeganehfar W, Laufer G, et al. Cyclosorine may affect imrovement of cognitive brain function after successful cardiac translantation. Circulation 1996;94: Hall RA, Fordyce DJ, Lee ME, et al. Brain SPECT imaging, and neurosychological testing in coronary artery byass atients. Ann Thorac Surg 1999;68: Newman MF, Croughwell ND, Blumenthal JA, et al. Predictors of cognitive decline after cardiac oeration. Ann Thorac Surg 1995;59: Moody DM, Brown WR, Challa VR, et al. Brain microemboli associated with cardioulmonary byass. Ann Thorac Surg 1995;59: Blauth CI. Macroemboli and microemboli during cardioulmonary byass. Ann Thorac Surg 1995;59: Lloyd CT, Ascione R, Underwood MJ, et al. Serum S-100 rotein release, and neurosychologic outcome during coronary revascularization on the beating heart. J Thorac Cardiovasc Surg 2000;119: Malheiros SM, Brucki SM, Gabbai AA, et al. Neurological outcome in coronary artery surgery with and without cardioulmonary byass. Acta Neurol Scand 1995;92: Diegeler A, Hirsch R, Schneider F, et al. Neuromonitoring and neurocognitive outcome in off-um versus conventional coronary byass oeration. Ann Thorac Surg 2000;69: Taggart DP, Browne SM, Halligan PW, et al. Is cardioulmonary byass still the cause of cognitive dysfunction after CABG? J Thorac Cardiovasc Surg 1999;118: Kramer L, Fasching P, Madl C, et al. Previous eisodes of hyoglycemic coma are not associated with ermanent cognitive brain dysfunction in IDDM atients on intensive insulin treatment. Diabetes 1998;47: Mochizuki Y, Oishi M, Hayakawa Y, et al. Imrovement of P300 latency by treatment in non-insulin-deendent diabetes mellitus. Clin Electroencehalogr 1998;29: Selnes OA, Goldsborough, Borowicz LM, Enger C, Quaskey SA, McKhann GM. Determinants of cognitive change after coronary artery byass surgery. Ann Thorac Surg 1999;67: Vingerhoets G, Van Nooten G, Jannes C. Effect of asymtomatic carotid artery disease on cognitive outcome after cardioulmonary byass. J Int Neurosychol Soc 1996;2: Lunn S, Crawley F, Harrison MJ, et al. Imact of carotid endarterectomy on cognitive functioning. Cerebrovasc Dis 1999;9: Irvine CD, Gardner FV, Davies AH, et al. Cognitive testing in atients undergoing carotid endarterectomy. Eur J Vasc Endovasc Surg 1998;15: