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J Thorac Cardiovasc Surg 2000;119:138-147
© 2000 Mosby, Inc.

CARDIOPULMONARY SUPPORT AND PHYSIOLOGY

PREDICTIVE VALUE OF S-100ß AND NEURON-SPECIFIC ENOLASE SERUM LEVELS FOR ADVERSE NEUROLOGIC OUTCOME AFTER CARDIAC SURGERY

From the University Departments of Neurology,^a Cardio-Thoracic Surgery,^d and Medical Statistics and Epidemiology,^b Halle/Saale, and of Clinical Chemistry and Laboratory Diagnostics,^c Jena, Germany.

Address for reprints: D. Georgiadis, MD, Department of Neurology, Martin-Luther-University at Halle-Wittenberg, Ernst Grube Str 40, 06097 Halle/Saale, Germany (E-mail: dimitrios.georgiadis{at}medizin.uni-halle.de).

	Abstract

Top Abstract Introduction Patients and methods Results Discussion References

 
Objectives: The aim of this study was to evaluate the time course of S-100ß and neuron-specific enolase serum levels after cardiac surgery and their clinical relevance in predicting postoperative adverse neurologic outcomes; the 2 proteins are only released in peripheral blood in association with nervous system lesions.
Methods: We neurologically assessed 190 consecutive patients undergoing elective cardiac operations for coronary artery bypass (n = 147), valve replacement (n = 29), or both (n = 14), before as well as after the operation. Postoperative outcome was classified as type I (uncomplicated), type II (confusion, agitation, disorientation, or epileptic seizures), or type III (stroke, stupor, or coma). Levels of S-100ß and neuron-specific enolase were evaluated in venous blood samples drawn preoperatively and then daily in the first 5 postoperative days.
Results: Levels of S-100ß and neuron-specific enolase differed significantly among the 3 groups (type III > type II > type I) throughout the postoperative period and had a diagnostic specificity and specificity of 89% and 79%, respectively, in identifying patients with type III outcome. S-100ß (but not neuron-specific enolase) levels were identified as significant independent predictors for type II and III outcomes (odds ratio 16.2, P < .0004). The same was true for duration of cardiopulmonary bypass (odds ratio 1.02, P < .006).
Conclusions: Serum levels of S-100ß are reliable markers for adverse neurologic outcomes after cardiac surgery.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

 
Despite substantial methodologic improvements over the past decades, cardiac surgery with extracorporeal circulation remains a hazard to the brain. Incidences of postoperative stroke and adverse cerebral outcomes were recently reported as 2% ¹ and 6.1%, ² respectively; the prevalence of postoperative neuropsychologic deficit thereby is far higher, ^3-5 reaching values of 79% ³ in single studies.

S-100 is an acidic calcium-binding protein, with a molecular weight of 21 kDa and a biologic half-life of approximately 2 hours. ⁶ This protein consists of 2 subunits: S-100 is predominantly found in the heart, kidney, and striated muscles, S-100ß in glial cells, and S-100ßß in astrocytes and Schwann cells. Thus the ß subunit of S-100 is specific for neuronal tissue. Neuron-specific enolase (NSE) has a molecular weight of 78 kDa and is mainly located in the cytoplasm of endocrine tissues and axonal processes. ⁷ Release of both proteins into peripheral blood suggests neuronal injury changing both cell membrane integrity and permeability of the blood-brain barrier. To date, elevation of S-100ß and/or NSE in peripheral blood has been reported in patients with a variety of cerebral lesions, including head injury, ^8,9 multiple sclerosis, ¹⁰ status epilepticus, ^11,12 brain tumors, ¹³ and stroke, ^14-18 as well as after circulatory arrest ¹⁹ and cardiac operations. ^20-24 Several of the above reports; suggested a clinical relevance of both proteins in predicting size of cerebral lesions and/or functional outcome. ^{8,9,14-17,23-25}

We undertook this study to evaluate the clinical relevance of S-100ß and NSE serum levels in patients undergoing elective cardiac operations. Additionally, the time course of potential changes in postoperative levels of both proteins was examined to evaluate the sampling time associated with the best predictive value for adverse neurologic outcomes.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

 
Patients
A total of 190 consecutive patients, 131 men and 59 women, aged 63 ± 1 years (mean ± standard error), undergoing elective cardiac surgery for coronary artery bypass grafting (CABG, n = 147), valve replacement (n = 29), or both (n = 14), were enrolled in this study after informed consent had been obtained.

The presence of peripheral vascular disease, diabetes mellitus, or arterial hypertension was documented in all cases. Left ventricular ejection fraction was evaluated during transthoracic echocardiography. Preoperative neurologic assessment included detailed clinical examination and screening of the brain-supplying arteries by means of extracranial continuous wave Doppler (n = 165) and/or duplex studies (n = 47). Carotid disease was classified as mild (stenosis < 50%), moderate (stenosis between 50% and 69%), severe (stenosis between 70% and 99%), or occlusion. In addition, duration of cardiopulmonary bypass (CPB), reperfusion, and total duration of the operative procedure (defined as time between skin incision and skin closure) were documented.

Neurologic assessment
For the purposes of the present study, all patients were neurologically assessed before the operation as well as on the fifth postoperative day. Patients referred to the neurologic service because of acute onset of neurologic symptoms were additionally evaluated on the day of referral and on subsequent occasions depending on their clinical course. Outcome was classified as type I (uncomplicated), type II (confusion, agitation, disorientation, or epileptic seizures), or type III (stroke, stupor, or coma). Patients with types II and III outcomes were neurologically reassessed before discharge and, in patients with persisting deficit, also in the fourth postoperative week. Cranial computed tomography (CCT) was routinely performed in all patients with type III and in selected patients with type II outcomes on the second postoperative day.

S-100ß and NSE evaluation
Venous blood was drawn before the operation and then daily in the first 5 postoperative days, immediately centrifuged at 4000g for 10 minutes, and stored at –30°C until batch evaluation. Serum S-100ß and NSE levels were measured by commercially available, monoclonal, 2-site immunoluminometric assays (LIA-mat and Sangtec 100 [S-100ß] and LIA-mat NSE and Prolifigen [NSE], Sangtec Medical AB, Bromma, Sweden). Visibly hemolyzed samples were not analyzed for NSE because hemolysis elevates NSE levels. ²⁶ Detection limits for S-100ß and NSE were 0.1 µg/L and 0.5 ng/L, respectively. In cases in which S-100ß levels were under the detection level, S-100ß values were set at 0.1 µg/L.

In addition to the aforementioned protocol, venous blood was drawn serially during the first 24 hours after the operation (at 3, 6, 12, and 24 hours) in 10 patients to evaluate potential short-term changes in S-100ß and NSE serum levels.

Surgical procedure
Midazolam and fentanyl dihydrogencitrate were used for anesthesia induction, pancuronium as a muscle relaxant, and isoflurane as an inhalation anesthetic. Surgery was performed under normothermic bypass (35°C-37°C) with membrane oxygenators (COBE CML Duo, COBE Cardiovascular Inc, Denver, Colo, and Dideco D 703 Compactflo, Dideco, Mirandola, Italy) with the tubing system including an arterial line filter (COBE 40 µ). A nonpulsatile blood flow pump was used (Stoeckert S3, Stoeckert, Germany). Temperature was measured intranasally, as well as in the pulmonary vein and in the arterial and venous lines of the extracorporeal system. Alpha-stat was used for pH maintenance.

Statistical analysis
Normally distributed data were expressed as mean ± standard deviation and compared with a 2-sample t test or 1-way analysis of variance; non-normally distributed data were expressed as median and 95% confidence intervals (CI) and were compared by the Mann-Whitney U, Kruskal-Wallis, or Wilcoxon tests as appropriate. Correlations of nonparametric data were examined by means of the Spearmann rank test; the ² test was used for comparison of frequencies. Relation between S-100ß and NSE levels and operative parameters (duration of CPB, reperfusion, and total operation time) was assessed by means of linear regression analysis. Receiver-operating characteristics (ROC) curves ²⁷ were used to evaluate the optimal cutoff values of S-100ß and NSE in predicting postoperative neurologic deficit.

Multivariable logistic regression analysis was performed to evaluate the value of relevant risk factors and S-100ß and NSE levels for predicting postoperative adverse neurologic outcomes. The following factors were included in this analysis: age; sex; presence of hypertension, diabetes mellitus, peripheral vascular disease, or carotid disease; history of previous stroke or previous cardiac surgery; left ventricular ejection fraction; duration of bypass, reperfusion, and total operation time; and serum levels of S-100ß and NSE on the first postoperative day. Concerning S-100ß and NSE, the cutoff values evaluated through ROC curves were used in this analysis. Thus the odds ratio for adverse neurologic outcomes when S-100ß and/or NSE exceeded a certain value were evaluated. Initial analysis was performed, including all potentially relevant factors, with a probability limit of 10% (P < .1). Subsequently, parameters failing to reach significance were excluded by means of conditional backward selection, and the odds ratios for remaining parameters were recalculated. Two models were used: model 1 evaluated the predictive value of relevant parameters in distinguishing between type I and type II/III outcomes and model 2 between type I/II and type III outcomes. Additionally, a separate logistic regression model was calculated; this model evaluated the probability of adverse neurologic outcome (type II or III outcome) depending on the S-100ß serum levels on the first postoperative day and relevant risk factors as evaluated in the initial multilinear regression analysis. S-100ß values were not dichotomized but rather retained as continuous values for the purposes of this model. Bonferroni correction was applied where appropriate.

	Results

Top Abstract Introduction Patients and methods Results Discussion References

 
Patient characteristics
Prevalence of relevant risk factors is listed in Table I. Carotid disease was mild in 10, moderate in 4, and severe in further 4 patients, and a carotid occlusion was diagnosed in 2 patients. Eight patients had had a stroke between 6 months and 5 years before admission; this was ischemic in 7 and hemorrhagic in 1 patient. Multiple ischemic strokes had occurred in 2 patients.

Five of the 10 patients with a type III outcome died. The cause of death was neurologic in 3 patients (brain swelling through ischemic infarction in all cases), multiple organ failure in 1, and cardiogenic shock in a further patient, who died on the second postoperative day. Creatinine levels were within normal range (<100 µmol/L) in 5 of the 10 patients with a type III outcome, whereas mild or moderate elevations were evident in the remaining patients (maximum values of 277, 238, 219, 181, and 137 µmol/L on the third, fourth, second, first, and second postoperative days, respectively). Deficit on discharge was mild in 2 patients (ataxia and discrete weakness of the right arm in 1 patient and discrete hemiparesis with complete functional independence in the other), moderate in 2 (moderate hemiparesis needing help for daily activities), and severe in 1 patient (severe hemiparesis, completely dependent).

CCT scans revealed multiple territory infarcts in 5 patients (bilateral middle cerebral artery, n = 1; middle and anterior cerebral arteries, n = 2; bilateral posterior cerebral artery, n = 1; middle and posterior cerebral arteries, n = 1) and single territory infarcts in 3 patients with type III outcomes (complete territory of the middle cerebral artery, n = 1; incomplete territory of the middle cerebral artery, n = 2). Repeat CCT scans were performed 2 to 4 days later in all patients and confirmed the initial findings. CCT of 1 patient with moderate hemiparesis disclosed no pathologic findings on the second postoperative day, and the test was not repeated. No CCT scan was performed in the patient who died on the second postoperative day. Infarction of the complete middle and anterior cerebral arterial territory was evident on necropsy. No watershed infarcts were diagnosed in any case.

S-100ß and NSE
A total of 12 scheduled samples (1%) were not obtained, and a further 25 NSE samples (2.1%) were discarded because of hemolysis. Elevations in the serum levels of both proteins were observed in 9 of 10 patients in whom blood was serially drawn during the first 24 postoperative hours. These reached statistical significance 3 hours after the operation and remained significantly elevated until the second postoperative day(Fig 1). Outcome was uncomplicated in all 10 patients.

View larger version (20K): [in this window] [in a new window]   Fig. 1. Time course of S-100ß and NSE levels at 3, 6, and 12 hours and in the first 5 postoperative days in 10 patients with uncomplicated postoperative outcome. Data are expressed as median, and error bars represent 95% confidence intervals.

Linear regression analysis revealed a significant relation between CPB duration and S-100ß and NSE levels, reaching its highest values for S-100ß on the second postoperative day (r = 0.41, P < .0001) and for NSE on the first postoperative day (r = 0.40, P < .0001)(Fig 2, A and B).

View larger version (17K): [in this window] [in a new window]   Fig. 2. A, Linear regression between CPB duration and S-100ß levels in 190 patients undergoing cardiac surgery. Interrupted lines represent 95% confidence intervals. r2 was 0.16 and Sy.x 0.62. The equation best matching the data was S-100ß (µg/L) = –0.3 + 0.007 x CPB duration (minutes). B, Linear regression between CPB duration and NSE levels in the first postoperative day in 190 patients undergoing cardiac surgery. Interrupted lines represent 95% confidence intervals. r2 was 0.16 and Sy.x 8. The equation best matching the data was NSE (ng/L) = 7.4 + 0.08 x CPB duration.

View larger version (16K): [in this window] [in a new window]   Fig. 3. A, Time course of S-100ß levels preoperatively (day 0) and in the first 5 postoperative days in neurologically asymptomatic patients (type I outcome), patients with postoperative confusion, agitation, and disorientation (type II outcome), and patients with postoperative stroke, stupor, or coma (type III outcome). Data are expressed as median, and error bars represent 95% confidence intervals. B, Time course of NSE levels preoperatively (day 0) and in the first 5 postoperative days in neurologically asymptomatic patients (type I outcome), patients with postoperative confusion, agitation, and disorientation (type II outcome), and patients with postoperative stroke, stupor, or coma (type III outcome). Data are expressed as median, and error bars represent 95% confidence intervals.

The optimal cutoff values of S-100ß and NSE for predicting adverse neurologic outcomes were evaluated by means of ROC curves(Fig 4, A and B). Both NSE and S-100ß levels demonstrated high sensitivity and specificity in identifying patients with type III outcomes. Identification of all patients with adverse outcomes (types II and III) was also feasible, sensitivity and specificity of S-100ß levels being markedly higher than those obtained with the use of NSE levels. On the other hand, S-100ß levels below 1.1 µg/L on the first postoperative day had a specificity of 97.4% in excluding adverse neurologic outcomes. Similar results were obtained regarding NSE levels on the first postoperative day (86% of patients with a type I outcome had NSE levels < 20 ng/L).

View larger version (28K): [in this window] [in a new window]   Fig. 4. ROC curves for evaluation of the optimal cutoff values of A, S-100ß and B, NSE in the differentiation between patients with an uncomplicated outcome (type I) and those with type II or type III outcomes (upper curve) and between patients with types I/II and those with type III outcomes (lower curve). Optimal cutoff values and derived specificity and sensitivity are displayed.

The formula derived by the third multivariable linear regression model was as follows:
Probability = 1/(1/[exp (3.67 x S-100ß [µg/L] + 0.021 x bypass duration [min] - 0.0239 x LVEF [%] - 4.538)])
whereby mean bypass duration was calculated as 105.93 minutes and mean left ventricular ejection fraction (LVEF) as 60.49%. S-100ß values > 1.4 µg/L were related to an 80% probability of adverse neurologic outcome; this reached 90% when S-100ß levels exceeded 1.7 µg/L(Fig 5).

View larger version (17K): [in this window] [in a new window]   Fig. 5. Probability for adverse neurologic outcome (types II and III) depending on S-100ß values on the first postoperative day, calculated by means of a logistic regression model.

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

The high specificity and sensitivity of S-100ß serum levels in predicting adverse neurologic outcome is a major finding of the present study. Our results suggest that S-100ß levels 24 hours after the operation possess a sensitivity and specificity of approximately 90% in identifying patients with cerebral lesions, thus indicating the need for further examinations. The opposite statement was also found to be true, as specificity of S-100ß levels in excluding cerebral lesions was 97%. Additionally, the applied multivariable logistic regression model demonstrated that S-100ß serum levels possess a high predictive value for prediction of adverse neurologic outcomes, independently of other relevant risk factors. Serums levels of NSE were shown to possess a lower predictive value; sole increase of NSE was not predictive of adverse neurologic outcomes, and increase of both S-100ß and NSE levels only marginally improved the predictive value of a sole S-100ß increase. The demonstrated superiority of S-100ß in comparison with NSE levels is in agreement with most previous reports. We did not observe elevated NSE levels in the absence of elevated S-100ß levels in any of the symptomatic patients; thus routine evaluation of both proteins appears redundant and not cost effective.

The significant postoperative elevation of S-100ß and NSE serum levels irrespective of neurologic outcome suggests that cardiac surgery almost always results in brain injury. This remains unnoticed on clinical examination but can readily be detected by neuropsychologic testing. ^3-5 The close relation observed for duration of CPB with both elevation of S-100ß and NSE levels and outcome identifies this procedure as responsible for at least part of the postoperative deficit.

Recent reports suggested a correlation between S-100ß levels and lesion size on CCT. ^14-16 The size of our study, as well as the low number of patients with focal neurologic lesions, prohibited such analysis. Interestingly, vascular encephalopathy was diagnosed in 5 of 7 patients with postoperative disorientation who underwent CCT. This finding is in accordance with the results of Schmidt and associates, ²⁹ who identified ventricular width as the only risk factor for postoperative encephalopathy. We hypothesize that the pre-existing encephalopathy in our patients was exacerbated through microembolism and/or hypoperfusion during CPB, causing the aforementioned symptoms. We did not apply stroke scales to characterize functional outcome in our patients; this was due to the low number of patients in whom permanent deficit was observed.

We conclude that serum levels of S-100ß sampled on the first postoperative day are valid clinical predictors for adverse neurologic outcome in patients undergoing cardiac surgery and might prove useful in assessing the effect of alternative surgical techniques or neuroprotective treatment.

	References

Top Abstract Introduction Patients and methods Results Discussion References

 

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