Eur J Cardiothorac Surg 1999;16:513-518
© 1999 Elsevier Science NL
A contrastive analysis of release patterns of biochemical markers of brain damage after coronary artery bypass grafting and valve replacement and their association with the neurobehavioral outcome after cardiac surgery
Manfred Herrmanna,
Anne D. Eberta,
Dankmar Toberb,
Jakob Hannb,
Christof Huthc
a Division of Neuropsychology and Behavioral Neurology, Otto-von-Guericke University, Leipziger Strasse 44, D-39120 Magdeburg, Germany
b Department of Anaesthesiology and Critical Care Medicine, Otto-von-Guericke University, Leipziger Strasse 44, D-39120 Magdeburg, Germany
c Department of Thoracic and Cardiovascular Surgery, Otto-von-Guericke University, Leipziger Strasse 44, D-39120 Magdeburg, Germany
Corresponding author. Tel.: +49-391-67-15319; fax: +49-391-67-15216
e-mail: manfred.herrmann{at}medizin.uni-magdeburg.de
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Abstract
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Objective: The present study aimed at a comparative analysis of neurobiochemical markers of brain damage and the neurobehavioral outcome in patients undergoing either valve replacement (VR) or isolated coronary artery bypass surgery (CABG). In order to control for well known risk factors both samples were strictly matched according to age, sex and preoperative neuropsychological performance. Methods: We analysed neurone-specific enolase (NSE) and protein S-100B (S-100B) concentrations in serial venous blood samples taken preoperatively and 1, 6, 20 and 30 h postoperatively in 36 patients undergoing VR (N=18) or isolated CABG surgery (N=18). Mini Mental State Examination (MMS) was performed preoperatively, 3 and 7 days after surgery and 0.5 years later. Neuropsychiatric assessments were based on the diagnosis of postoperative delirium according to DMS-IIIR criteria and the Brief Psychiatric and the Delirium Rating Scale. Results: VR and CABG patients, respectively, showed an increase of both S-100B (exact two-tailed Wilcoxon signed ranks test: P=0.0001) and NSE (P=0.0001) concentrations followed by a decrease during the next 30 h. Whereas S-100B values did not differ between patients groups subjects undergoing VR surgery exhibited higher NSE values during the postoperative course. Furthermore, VR patients showed a higher decline in cognitive performance which was also detectable 0.5 years after surgery. We found a weak association between the degree of individual postoperative decline of cognitive performance and S-100B area under curve values. Conclusions: Our data indicate that – apart from patients’ age and preoperative neuropsychological performance – type of surgery remains a risk factor for postoperative neurobehavioral disorders. The different vulnerability of neurobehavioral disorders might be mirrored in different postoperative release patterns of NSE. We assume that both, NSE release and neurobehavioral disorders might be caused by a higher amount of intraoperative cerebral embolic events in VR patients.
Key Words: Cardiac surgery • Protein S-100B • NSE • Neuropsychology • Neuropsychiatry • Risk factor • Follow-up
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1. Introduction
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Neurologic and neurobehavioral disorders are a frequent complication of cardiac surgery under cardiopulmonary bypass (CPB) condition leading to disability and reduced postoperative quality of life [1–3]. Both disorders lengthen the stay in the Intensive Care Unit (ICU) or ward and cause additional in-hospital boarding costs [4]. Recent studies showed an association between release of neurobiochemical markers of brain damage and adverse neurological outcome after cardiac surgery under CPB condition or cardiac arrest [5,6]. Patients with neurological complications (such as stroke or seizures) or fatal outcome exhibit highly elevated concentrations of protein S-100B and neuron-specific enolase (NSE). Hitherto, a comparable association between neurobehavioral disorders and release patterns of neurobiochemical markers of brain damage has not been demonstrated.
Vast literature on risk factors of neurobehavioral disorders after cardiac surgery indicates that postoperative decrease of neuropsychological function seems to be associated with advanced age [7], lower preoperative cognitive performance [8], higher degree of proximal atherosclerosis [4] and length of cross clamp or perfusion time [7,9]. Furthermore, patients undergoing valve replacement surgery (VR) are reported to be more vulnerable for postoperative neurobehavioral disorders compared to patients with coronary artery bypass grafting (CABG) [10,11]. A recent retrospective study of neurologic complications after cardiac surgery [12] found more frequent neurologic disorders in isolated bypass than in valve replacement surgery. This finding, however, was interpreted as a result of the increasing age of patients who undergo CABG surgery. Advanced age does not only affect the neuropsychological outcome of cardiac surgery but also influences serum and CSF concentrations of neurobiochemical markers of brain damage such as protein S-100B [6,13,14]. A large number of factors influencing the outcome after cardiac surgery are confounded and studies which control for well-known risk factors of postoperative neuropsychological deficits are missing.
The objective of the present study was (1) a comparison of pre and postoperative serum concentrations of NSE and protein S-100B (S-100B) in patients undergoing either isolated coronary bypass or valve replacement surgery; and (2) an analysis of the association between neurobiochemical markers of brain damage and postoperative neurobehavioral disorders in both patients groups. In order to control for factors influencing both neurobiochemical markers and neurobehavioral disorders CABG and VR patients were strictly matched for age, sex and the preoperative neuropsychological performance.
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2. Materials and methods
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2.1. Patients
Out of a consecutive series of 113 patients admitted to elective cardiac surgery at the Department of Thoracic and Cardiovascular Surgery, Magdeburg University, we retrospectively selected 18 patients with valve replacement (VR) and 18 patients with bypass surgery (CABG) matched by sex, age and the preoperative cognitive status (Mini Mental State Examination, MMS [15]). All patients were native German speakers and underwent routine surgery without simultaneous other surgery. Informed and written consent to participate at the study was obtained by all patients. Median number of bypass grafts in patients undergoing CABG was 4 (range 2–6). Seven patients received an aortal valve replacement, four patients a mitral valve replacement and three patients a combined surgery. In four patients valve replacement was combined with bypass surgery. Table 1 shows clinical and demographic variables of both patients groups. With the exception of more myocardial infarctions in CABG patients both groups did not differ with respect to medical history or risk factors, pre-, intra- or postoperative drug treatment as well as all operative parameters described in Table 1.
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Table 1. Demographic and clinical variables (exact two-sided P-values according to Mann–Whitney U- or  2 Fisher's exact tests)
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One patient who underwent valve replacement surgery suffered from left-sided hemiparesis due to cerebral infarction 11 years ago. All other patients had no history of neurological or psychiatric disorders.
Neurological and neurobehavioral assessments were performed on the last or next to the last preoperative (median 1 day, range 1–2 days), on the 3rd (median 3 days, range 2–3 days) and on the 7th postoperative day (median 7.5 days, range 5–11 days). Fifteen CABG and 12 VR patients could be re-evaluated 0.5 years after surgery (median 22 weeks, range 18–35 weeks).
2.2. Methods
2.2.1. Cardiac surgery
Standard cardiopulmonary bypass technique with membrane oxygenator, non-pulsatile flow and mean arterial pressure control was used. Patients were hypothermic at 29°C. Anesthesia consisted of pre-medication with flunitrazepame, induction with pancuronium, sufentanyl and propofol and maintenance with sufentanyl, propofol and an oxygen-air mixture. pCO2 was kept constant at 40 mmHg. Patients were extubated 8–12 h postoperatively and transferred from ICU between the 1st and 3rd postoperative day.
2.2.2. Neurobiochemistry
Serial venous blood samples were collected in all patients before surgery, 1 h (0.9±0.5 h), 6 h (5.8±1.5), 20 h (20.0±1.7), and 30 h (29.6±2.5) after skin closure. Blood was allowed to clot and after centrifugation within 30 min (1000xg, 10 min) serum was stored at -80°C for later analysis. Protein S-100B and NSE were analyzed using monoclonal sandwich immunoluminometric assay (Sangtec®). The S-100 assay measures the ß-subunit of protein S-100 as defined by three monoclonal antibodies and the detection limit of the kit is 0.02 µg/l. The range of S-100B serum concentrations in 95% of healthy subjects is below 0.12 µg/l. NSE measurement uses monoclonal antibodies which bind to the 
-subunit of the enzyme. The sensitivity is reported to be below 1.0 µg/l, the reference range of serum concentrations of healthy subjects is below 12.5 µg/l.
2.2.3. Neurobehavioral assessments
All patients were examined pre- and postoperatively with a standardized neurological assessment performed by an experienced neurologist.
The neuropsychological assessment consisted of the Mini Mental State Examination (MMS [15]) which provides a rough estimation of orientation and global cognitive function under ICU conditions but does not allow for subtle neuropsychological changes. We used three parallel and psychometrically evaluated test forms with a separate scoring for orientation (MMS-O) and cognitive status (MMS-C) as described in previous studies [8,16].
Neuropsychiatric assessments included the diagnosis of delirium based on DSM-IIIR criteria [17]. Furthermore, we applied the Delirium Rating Scale (DRS [18]) to analyze the severity of delirious symptoms and the Brief Psychiatric Rating Scale (BPRS [19]) in order to assess psychopathological changes.
2.2.4. Statistical analysis
Due to small sample sizes as well as expected ceiling effects and ordinal scaled data in behavioral measurements all statistical data evaluation was performed with non-parametrical procedures (2 and Fisher's exact tests, exact Mann–Whitney U-tests, exact Wilcoxon signed ranks tests, exact Friedman tests and rank correlations) with the SPSS program package. All levels of significance reported in the following sections are two-tailed values.
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3. Results
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3.1. Neurobiochemical markers of brain damage
Both, S-100B and NSE serum concentrations increased from the preoperative to the 1-h postoperative time of blood taking (Wilcoxon signed ranks test: NSE: P<0.0001; S-100B: P<0.0001) followed by a continuous decrease during the next 30 h (Friedman test: NSE: P<0.0001; S-100B: P<0.0001). Fig. 1 illustrates that postoperative NSE concentrations were higher in VR patients whereas S-100B values did not vary considerably between groups. In order to analyze differences in time patterns we calculated the area under curve (AUC) of both neurobiochemical markers. Patients with VR surgery exhibited longer and higher NSE concentration compared to patients with bypass surgery (Mann–Whitney U-test: P=0.0281). The AUC of protein S-100B release did not differ between VR and CABG patients (P=0.1797). Both, NSE and S-100B values were significantly correlated with cross-clamp time at the 1-h (Spearman's rho: NSE: r=0.43, P=0.0083; S-100B: r=0.43, P=0.0091) and 6-h (NSE: r=0.40, P=0.0184; S-100B: r=0.43, P=0.0102) time of blood sampling. Significant correlation between perfusion time and release of neurobiochemical markers were only found for the 1-h (r=0.39, P=0.0171) and 6-h (r=0.40, P=0.0182) NSE samples.
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Fig. 1. Release patterns of protein NSE and S-100B (means±95% CI for mean; exact two-tailed P-values according to Mann–Whitney U-tests; CABG, coronary artery bypass grafting; VR, valve replacement). The marked area indicates the respective reference range of 95% of healthy control subjects.
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3.2. Neurobehavioral performance
Except for a preexisting hemiparesis no patient showed marked focal neurological deficits, seizures or disturbances of consciousness at the postoperative neurologic examinations. Three patients with valve replacement (16.7%) exhibited delirium according to DSM-IIIR criteria at the first postoperative examination. NSE-values of all delirious patients and S-100B values in two of three delirious patients were found above the 75% percentiles 6 and 20 h after surgery. Patients groups did not differ with respect to DRS and BPRS-scores. CABG as well as VR patients exhibited a decrease in MMS-scores between the preoperative and the first postoperative assessment (Wilcoxon signed ranks test: CABG: P=0.0005; VR: P=0.0005) and a following increase from the first postoperative to the second postoperative examination (CABG: P=0.0002; VR: P=0.0951). Only the VR group, however, presented a lower MMS-performance one week after surgery compared to the preoperative results (CABG: P=0.5645; VR: P=0.0125). Six months after surgery, CABG as well as VR patients exhibited numerically lower MMS-scores than preoperatively. The difference, however, did not reach statistical significance. CABG and VR-patients did not differ with respect to the MMS-orientation part but VR patients showed lower MMS-C scores at all assessments of the follow-up examination (see Fig. 2).
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Fig. 2. Pre and postoperative performance in the MMS-cognition part (MMS-C, means±95% CI for mean; exact two-tailed P-values according to Mann–Whitney U-tests; CABG, coronary artery bypass grafting; VR, valve replacement).
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3.3. Neurobiochemical markers and postoperative neurobehavioral disorders
In order to investigate whether serum concentrations of neurobiochemical markers were associated with the neurobehavioral outcome we calculated rank correlations between the individual differences of pre- and postoperative MMS-scores and S-100B and NSE release. With respect to the whole patients group we found a correlation between the S100BAUC values and the decrease in MMS-C scores at the first follow-up examination. Fig. 3 illustrates that patients with higher and longer S-100B release tend to show a higher decrease of cognitive performance (Spearman's rho: r=-0.44, P=0.0178). If the whole group was separated into CABG- and VR-patients, this weak effect was only significant for the VR-group (VR: r=-0.66, P=0.0184; CABG: r=-0.30, P=0.2520) and only at the early follow-up examination. No significant correlation between NSE release and decrease in neuropsychological performance at any time of assessment could be calculated. With respect to both the 1-week or 6-month follow-up and the neuropsychiatric data we found no association with release patterns of neurobiochemical markers.
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4. Discussion
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The present study focussed on two objectives. Firstly, we aimed at the comparative analysis of release patterns of NSE and protein S-100B after coronary bypass and valve replacement surgery and secondly, we focussed at the analysis of the association between the release of neurobiochemical markers of brain damage and the neurobehavioral outcome.
The present data demonstrate clearly distinct release patterns of NSE and S-100B after VR and CABG surgery. We found peak concentrations of both markers 1 h after the end of surgery and a continuous decline during the following 30 h. Patients with VR-surgery showed a numerically higher release of S-100B compared to CABG-patients but the difference did not reach statistical significance. These data are in contrast to the finding of Taggart and co-workers [6] who reported significantly higher S-100B values in patients undergoing intracardiac operations. Taggart and colleagues, however, reported a significant correlation between S-100B release and the age of patients and the patients undergoing intracardiac surgery were slightly older and showed a higher standard deviation of age. Contrary to this study, we strictly controlled for the age of patients. We found highly elevated postoperative NSE concentrations in patients undergoing VR surgery. Twenty hours after skin closure CABG patients reached mean NSE serum concentrations below the upper limit of the reference range of normal controls. Patients with valve replacement surgery, however, exhibited mean NSE concentrations above the reference value of 12.5 µg/l during the whole observation time. Because both patients groups were strictly matched with respect to age and gender these differences cannot be attributed to the respective sample characteristics [13]. They rather suggest different patterns of cerebral vulnerability during and after CABG and VR surgery. Protein S-100B forms part of a large and diverse family of Ca2+-binding proteins predominantly found in astrocyts and Schwann cells [20]. The protein is secreted predominantly by astroglial cells and its release is associated with functional disturbance of membrane integrity and increased permeability of the blood-brain-barrier [21]. Neurone-specific enolase (NSE) is a dimeric isoenzyme of the glycolytic enzyme enolase predominantly found in the cytoplasm of neurones and cells with neuroendocrine differentiation [22]. The cytoplasmatic enzyme is not secreted into the extracellular liquid by intact neurones but set free by cell destruction. Our data indicate that VR surgery might be associated with a higher degree of neuronal damage leading to a higher and longer release of NSE. Cell destruction may be caused by transient or outlasting hypoxia as a consequence of cerebral micro- or macroembolism. Grocott and coworkers [14] reported a significant correlation between serum S100-B concentrations and number of emboli between aortic cannulation to cross-clamp onset in patients undergoing CABG and considered cannulation as a high-risk time period for cerebral complications. Embolic events are more often detected in patients with valve replacement surgery compared to patients with bypass grafting [23] and a recent study [11] indicates an association between postoperative neuropsychological deficits and the number of intraoperative microembolic signals only in patients undergoing VR surgery.
Patients undergoing valve replacement exhibited more neuropsychological deficits 1 week after surgery and a slower recovery from disorders. Although both patients groups did not differ with respect to their preoperative cognitive performance postoperative differences were detectable even 0.5 years after surgery. Furthermore, only VR patients exhibited a delirious state according to DMS-IIIR criteria during the first 3 postoperative days and only VR patients showed an association between the individual degree of postoperative cognitive decline and S-100B release. Our data, therefore, corroborate recent findings which indicate a higher vulnerability of neurobehavioral disorders in patients with VR surgery [10,11,16] which also might be associated with the amount of emboli delivered during surgery [24,25].
However, the analysis of the association between release patterns of neurobiochemical markers and neurobehavioral outcome showed no clear-cut result. We found a correlation between the individual postoperative decrease of cognitive performance and the S-100B area under curve values. The association between neurobehavioral disorders and neurobiochemical markers of brain damage obviously is much weaker than the association between severe postoperative neurological disorders and NSE or S-100B release [5]. In order to analyze the predictive value of neurobiochemical markers for neurobehavioral disorders after cardiac surgery we need studies including many more patients. In the present study the patients sample dropped to a small number due to the matching criteria of study groups and the dropouts at the follow-up examination 0.5 years after surgery. The present study, therefore, is mainly of exploratory nature and in addition to the small sample size the results are hampered by a variety of other limitations. We could only control for a limited range of variables possibly associated with the neurobehavioral outcome of cardiac surgery. Other variables which might affect the postoperative cognitive state (such as choice of surgeons, time of operation or a coexisting predementia process which might influence the long-term neuropsychological follow-up), obviously, cannot be controlled.
Despite the limitations outlined above, the present data indicate that – apart from patients’ age and preoperative neuropsychological performance – type of surgery remains a important risk factor for postoperative neurobehavioral disorders. Patients undergoing valve replacement surgery run a higher risk of postoperative neuropsychological dysfunction compared to patients with isolated bypass surgery. This finding is also reflected in the higher and longer release patterns of NSE. The question, however, whether neurobiochemical markers of brain damage have – apart from well known risk or causative factors – an additional value to predict neurobehavioral postoperative disorders remains the subject of further studies including more matched patients at the postacute and follow-up examinations.
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Acknowledgments
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This investigation was supported in part by the Federal Ministry of Education and Research and the State of Saxony-Anhalt. The authors wish to thank Dr Wunderlich for the analysis of neurobiochemical markers. Kits for the analysis of protein S-100B and NSE were provided by Byk-Sangtec Diagnostica, Dietzenbach, Germany.
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References
|
|---|
-
Shaw P.J., Bates D., Cartlidge N.E.F., French J.M., Heaviside D., Julian D.G., Shaw D.A. Early intellectual dysfunction following coronary bypass surgery. Q J Med 1986;58:59-68.[Abstract/Free Full Text]
-
McKhann G.M., Goldsborough M.A., Borowicz L.M., Selnes O.A., Mellits E.D., Enger C., Quaskey S.A., Baumgartner W.A., Cameron D.E., Stuart R.S., Gardner T.J. Cognitive outcome after coronary artery bypass: A one year prospective study. Ann Thorac Surg 1997;63:510-515.[Abstract/Free Full Text]
-
Newman S., Klinger L., Venn G., Smith P., Harrison M., Treasure T. The persistence of neuropsychological deficits twelve months after coronary artery bypass surgery. In: Willner A.E., Rodewald G., eds. Impact of cardiac surgery on the quality of life. New York: Plenum Press, 1990:173-179.
-
Roach G.W., Kanchuger M., Mangano C.M., Newman M., Nussmeier N., Wolman R., Aggarwal A., Marschall K., Graham S.H., Ley C., Ozanne G., Mangano D.T. Adverse cerebral outcomes after coronary bypass surgery. New Engl J Med 1996;335:1857-1863.[Abstract/Free Full Text]
-
Johnsson P., Lundqvist C., Lindgren A., Ferencz I., Alling C., Stahl E. Cerebral complications after cardiac surgery assessed by S-100 and NSE levels in blood. J Cardiothorac Vasc Anesth 1995;9:694-699.[Medline]
-
Taggart D.P., Mazel J.W., Bhattacharya K., Meston N., Standing S.J., Kay J.D.S., Pillai R., Johnsson P., Westaby S. Comparison of serum S-100ß levels during CABG and intracardiac operations. Ann Thorac Surg 1997;63:492-496.[Abstract/Free Full Text]
-
Hofsté W.J., Linssen C.A.M., Boezeman E.H.J.F., Hengeveld J.S., Leusink J.A., de Boer A. Delirium and cognitive disorders after cardiac operations: relationship to pre and intraoperative quantitative electroencephalogram. Int J Clin Monit Comput 1997;14:29-36.[Medline]
-
Walzer T., Herrmann M., Wallesch C.W. Neuropsychological disorders after coronary bypass surgery. J Neurol Neurosurg Psychiatry 1997;62:644-648.[Abstract/Free Full Text]
-
Smith P.L., Treasure T., Newman S.P., Joseph P., Ell P.J., Schneidau A., Harrison M.J.G. Cerebral consequences of cardiopulmonary bypass. Lancet 1986;8485:823-825.
-
Slogoff S., Girgis K.Z., Keats A.S. Etiologic factors in neuropsychiatric complications associated with cardiopulmonary bypass. Anesth Analg 1982;61:903-911.[Abstract/Free Full Text]
-
Braekken S.K., Reinvang I., Russel D., Brucher R., Svennevig J.L. Association between intraoperative cerebral microembolic signals and postoperative neuropsychological deficit: comparison between patients with cardiac valve replacement and patients with coronary artery bypass grafting. J Neurol Neurosurg Psychiatry 1998;65:573-576.[Abstract/Free Full Text]
-
Kuroda Y., Uchimoto R., Kaieda R., Shinkura R., Shinohara K., Miyamoto S. Central nervous system complications after cardiac surgery: a comparison between coronary artery bypass grafting and valve surgery. Anesth Analg 1993;76:222-227.[Medline]
-
Nygaard O., Langbakk B., Romner B. Age- and sex-related changes of S100 protein concentrations in cerebrospinal fluid and serum in patients with no previous history of neurological disorder. Clin Chem 1997;43:541-543.[Free Full Text]
-
Grocott H.P., Croughwell N.D., Amory D.W., White D.N., Kirchner J.L., Newman M.F. Cerebral emboli and serum S100ß during cardiac operations. Ann Thorac Surg 1998;65:1645-1650.[Abstract/Free Full Text]
-
Folstein M.F., Folstein S.E., McHugh P.R. Mini-Mental-State. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198.[Medline]
-
Walzer T.A., Wallesch C.W., Starkstein S.E., Herrmann M. Neuropsychologische Defizite in der frühen postoperativen Phase nach kardiochirurgischen Eingriffen – Ein Vergleich zwischen Patienten mit Klappenersatz- und Bypass-Operationen. Z Neuropsychol 1998;9:123-132.
-
American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd edition, Revised. Washington, DC: American Psychiatric Association, 1987.
-
Trzepacz P.T., Baker R.W., Greenhouse J. A symptom rating scale for delirium. Psychiatr Res 1987;23:89-97.
-
Overall J.E., Gorham D.R. The brief psychiatric rating scale. Psychol Rep 1962;10:799-812.
-
Schäfer B.W., Heizmann C.W. The S100 family of EF-hand calcium-binding proteins: function and pathology. Trends Biochem Sci 1996;21:134-140.[Medline]
-
Westaby S., Johnsson P., Parry A.J., Blomqvist S., Solem J.O., Alling C., Pillai R., Taggart D.P., Grebenik C., Stahl E. Serum S100 protein: a potential marker for cerebral events during cardiopulmonary bypass. Ann Thorac Surg 1996;61:88-92.[Abstract/Free Full Text]
-
Marangos P.J. Neuron specific enolase: a clinically useful marker of neurons and neuroendocrine cells. Annu Rev Neurosci 1987;10:269-295.[Medline]
-
Thiel A., Zimmer M., Stertmann W.A., Kaps M., Hempelmann G. Microembolizations during heart surgery under extracorporeal circulation. Anaestesiol Intensivmed Notfallmed Schmerzther 1997;32:715-720.
-
Stump D.A., Rogers A.T., Hammon J.W., Newman S.P. Cerebral emboli and cognitive outcome after cardiac surgery. J Cardiothorac Vasc Anesth 1996;10:113-119.[Medline]
-
Newman M.F., Croughwell N.D., Blumenthal J.A., Lowry E., White W.D., Spillane W., Davis R.D., Glower D.D., Smith L.R., Mahanna E., Reves J.G. Predictors of cognitive decline after cardiac operation. Ann Thorac Surg 1995;59:1326-1330.[Abstract/Free Full Text]
Received May 3, 1999;
received in revised form June 28, 1999;
accepted July 7, 1999.
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Abstract
1. Introduction
MMS-C) two days after surgery and S-100B release (area under curve). 
indicate valve replacement and crosses coronary surgery patients.