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Ann Thorac Surg 2001;71:1433-1437
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

S100B as a predictor of size and outcome of stroke after cardiac surgery

^a Department of Cardiothoracic Surgery, University of Lund, Lund, Sweden
^b Oxford Heart Centre, Oxford, United Kingdom

Accepted for publication November 3, 2000.

Address reprint requests to Dr Jönsson, Department of Cardiothoracic Surgery, University Hospital Lund, SE-221 85 Lund, Sweden
e-mail: henrik.jonsson{at}thorax.lu.se

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Stroke after cardiac surgery is a clinical problem with often fatal or disabling outcome. To assess severity and probable outcome in affected patients only from clinical and radiological examinations is difficult. The glial-derived protein S100B has been suggested to be a marker of cerebral ischemia, and increased blood concentrations of S100B have been shown to correlate with size of lesion and prognosis after stroke. We studied the validity of S100B as a predictor of size of brain lesion and median term outcome in a consecutive group of patients suffering from stroke after cardiac surgery.

Methods. During a period of 17 months, 20 patients with clinical signs of postoperative stroke were investigated with S100B measurement, sampled at 5, 15 and 48 hours after surgery. All patients were examined with computed tomography or magnetic resonance imaging to confirm the diagnosis, and the size of cerebral infarction was estimated from the radiological examinations. The patients were followed up for survival 24 to 39 months after surgery.

Results. S100B concentration in blood 48 hours after surgery correlated with the size of infarcted brain tissue (r = 0.68, p < 0.001). Nine patients had S100B levels exceeding 0.5 µg/L and a 2-year mortality of 78%, whereas the 11 patients with S100B below 0.5 µg/L had a mortality of 18%.

Conclusions. Increased S100B in patients with a stroke following cardiac surgery correlate with the size of infarcted brain tissue. High S100B levels 48 hours after surgery have a negative predictive value for median term survival.

	Introduction

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Stroke is a devastating complication in cardiac surgery and often makes the patient unable to gain from the benefits of the operation. Large lesions may lead to extensive human suffering and substantial cost for society. In contrast, patients who have a small lesion with a favorable location can have a rapid recovery and end up without, or with only minor, sequelae. Incidence figures between 1.2% and 5.7% have been reported for stroke after cardiac surgery [1, 2]. These figures seem to be increasing every decade, probably due to the increasing patient age, which itself is a predictor for stroke [3, 4]. Given the severity and the incidence of the stroke complication, a new diagnostic tool for the assessment of the presence and magnitude of any damage to the brain would be of interest.

The glial protein S100B has been shown to be a valid serum marker after ischemic stroke in patients admitted to the emergency care units, where increased levels of S100B were found 1 to 7 days after the insult. In this setting, S100B levels correlated to clinical outcome and size of infarcted brain tissue [5–7]. We have earlier reported that increased S100B levels 24 to 48 hours after cardiac surgery were associated with postoperative stroke [8–11]. S100B levels in blood samples drawn very early after surgery are obscured by extracerebral contamination and have not been associated with cerebral ischemia [12, 13]. However, such early increase in S100B can be corrected for the contamination, and has then been associated with a decline in cognitive function after surgery [12].

The aim of this study was to investigate whether the serum concentration of S100B in patients with a postoperative stroke was correlated to the size of the brain infarction and if long-term outcome could be predicted.

	Material and methods

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In a consecutive series of 684 patients undergoing cardiac surgery, 20 patients with a clinically detected stroke (2.9%) after surgery were studied. Patients underwent operation at the division of Cardiothoracic Surgery, University Hospital Malmö, Malmö, Sweden from January 1996 to May 1997. Sixteen of the patients had coronary artery bypass grafting (CABG) as their sole procedure, 2 patients had aortic valve replacement, and 2 had replacement of the ascending aorta due to type A dissection or aneurysm.

Study protocol
Demographic, intraoperative and postoperative data on each patient was collected from patient records. Blood samples for the analysis of S100B were routinely drawn at 5, 15, and 48 hours after surgery.

All patients with clinical signs of postoperative stroke were examined by a neurologist and with computed tomography (CT) or magnetic resonance imaging (MRI) once or twice 2 to 8 days after surgery. All patients were followed up for mortality 2 years after the last patient was operated, giving a range between 24 to 39 months for the follow-up.

S100B assay
Blood samples were cooled and centrifuged within 5 hours. They were analyzed using a monoclonal two-site immunoradiometric assay (Sangtec 100, AB Sangtec Medical, Bromma, Sweden) [10]. The lower level of detection in this series was 0.2 µg/L.

Radiological examinations
CT or MRI were standard clinical examinations and were reviewed by a neuroradiologist (M.B.-I.), who was blinded for the S100B results. A linear semiquantitative measurement of the size of the lesion(s) was obtained by measuring the diameter for each lesion. If more than one lesion was found, the individual measures for each lesion were added to one measure. Old infarctions, consistent with parenchymal destruction, were not included.

Surgical technique
Anesthesia was induced with midazolam (Dormicum, Roche, Basel, Switzerland) or thiopentone (Pentothal, Abbott Laboratories, IL). It was subsequently maintained with fentanyl (Leptanal, Janssen Pharmaceutica, Beerse, Belgium), a continuous infusion of propofol (Diprivan, Zeneca Ltd, London, England), or inhalation of isoflurane (Forene, Abbot Laboratories, North Chicago, IL). Nitrous oxide (Aga Industries, Stockholm, Sweden) was used before cardiopulmonary bypass (CPB) but not during or after CPB.

Intermittent antegrade cold St. Thomas crystalloid cardioplegia (Cardioplegi, Pharmacia-Upjohn, Uppsala, Sweden) was used for myocardial protection. Perfusion was performed with roller pump (Cobe Industries, Denver, CO) and a membrane oxygenator (Cobe CML or Duo, both Cobe Industries). All circuits contained a heparin-coated 40 µm arterial filter (Cobe Sence, Cobe Industries). Perfusion flow was nonpulsatile with a flow rate of 2.4 l/min/m² at normothermia. Systematic cooling to approximately 32°C was used in all patients but the 2 with aortic graft surgery, where deep hypothermia and circulatory arrest with retrograde cerebral perfusion were used. Heparin (3 mg/kg bodyweight) was given prior to cannulation and reversed with a corresponding dose of protamine sulfate at decannulation.

Statistics
All results were analyzed with Statistica version 5.0 for PC. Results are presented as median (IQR [Inter Quartile Range]). For comparisons of means, a nonparametric test was used (Mann-Whitney). Regression analysis was performed with the least squares method with a casewise deletion of missing data. Kaplan-Meier curves were made to graphically show survival. For comparisons of survival between groups, odds ratio calculation was used. Results were considered significant if p was less than 0.05.

	Results

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Three patients died within 30 days and another 6 died during the following 2 years. The cause of death in the 9 deceased patients was due to, or directly related to, the stroke in 8 patients, whereas in 1 patient, the cause was congestive heart failure. Demographics for all patients are shown in Table 1. The S100B values and outcome are presented for each individual patient in Table 2, where patients are sorted in ascending order according to their S100B levels 48 hours after surgery.

View larger version (24K): [in this window] [in a new window]   Fig 1. The relation between infarct size, derived from computed tomographic (CT) scans and magnetic resonance imaging (MRI), and the serum level of S100B, 48 hours after surgery (r = 0.68, p < 0.001). Dotted lines denote a 95% confidence interval (CI) for the equation. Circles denote patients and the solid line denotes regression analysis.

View larger version (16K): [in this window] [in a new window]   Fig 2. S100B levels in patients suffering from stroke after cardiac surgery. Open boxes denote patients with < 0.5 µg/L 48 hours after surgery (n = 11); shaded boxes denote patients with S100B 0.5 µg/L, 48 hours after surgery (n = 9). **p < 0.01.

View larger version (27K): [in this window] [in a new window]   Fig 3. Kaplan-Meier survival curve for 20 patients suffering a postoperative stroke confirmed with computed tomography (CT) or magnetic resonance imaging (MRI). Patients divided into 2 groups: broken line denotes the group of patients with a serum S100B equal to, or higher than, 0.5 µg/L (n = 9); solid line denotes the group of patients with a serum S100B lower than 0.5 µg/L, 48 hours after surgery (n = 11); circles denote fatal outcome; and triangles denote patients alive at follow-up.

When the 9 patients who died during the study period were compared with the 11 survivors, the surviving patients had lower S100B levels at 48 hours after surgery (median 0.2 µg/L [IQR 0.2 to 0.38 µg/L] vs 0.6 µg/L [0.34 to 0.84 µg/L], p < 0.005). No difference was found in size of lesion (median survivors 2 [IQR 1 to 5] vs deceased 6 [2–11]), patient age, or perfusion time.

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
The principal finding of this study was a correlation between the S100B concentration in blood 48 hours after surgery and the size of the brain lesion in a consecutive group of patients who developed stroke after cardiac surgery. Furthermore, the risk of mortality after surgery increased with higher S100B levels; if the concentration exceeded 0.5 µg/L, the risk increased drastically.

There are several reasons for choosing 48 hours as sampling time. Studies in patients with stroke caused by other cerebrovascular events have shown that the highest levels of S100B were found 3 days after the injury, and the levels remained high up to 10 days after the injury [6, 7]. Only a few of our patients with large brain lesions were followed with S100B sampling for more than 48 hours; in those patients, increased concentrations were found up to 4 days after surgery. We and others have recently reported that results of S100B measurements early after cardiac surgery with the use of CPB are to some extent obscured by an extracerebral contamination [12, 13]. The infusion of shed mediastinal blood by means of cardiotomy suction and autotransfusion leads to an increase in the S100B levels. Even though the half-life of S100B is short, approximately 25 minutes [14], it would take approximately 3 hours to eliminate this contamination from shed blood. Since no autotransfusion was used after 20 hours after surgery in our study, the risk of obtaining increased levels of S100B from extracerebral sources 48 hours after surgery should be minimal although not excluded. Other sources of S100B release, eg, bone marrow, traumatized skin, and muscle, could contribute to late false-positive results, although it seems improbable that blood concentrations reaching 0.5 µg/L could emanate from such sources.

Another argument for choosing 48 hours after surgery as the sampling point can be deduced from the fact that after brain ischemia, the cell membranes start to disrupt at 24 to 48 hours after the injury, and intracellular content can flow out to the extracellular space [15]. In studies where cerebrospinal fluid was examined for S100B after stroke, increased levels were found 1 to 7 days after the insult with the maximum increase occurring at 1 to 2 days after the insult [5]. Furthermore, a release of S100B into the extracellular space in the brain can probably not be traced in the systemic circulation unless there is a damage to the blood brain barrier. Such injury to the barrier has been shown to occur in time frames of 3 to 5 and 24 to 48 hours after an ischemic event [16].

Based on this reasoning, we suggest that if S100B is to be used as a prognostic marker for brain injury after cardiac surgery, 48 hours after surgery is the earliest sampling time to be used in order to minimize the risk of false-positive results. However, false-negative results cannot be excluded at this time point since there are probably different release patterns due to different size and location of the brain lesions.

From Figure 2, it can be noted that the levels of S100B in the group with bad prognosis (0.5 µg/L at 48 hours after surgery) were significantly higher already at 15 hours after surgery. However, due to the possible inflow of S100B from mediastinal blood and possible resorption from the wound, the importance of this finding cannot be evaluated. Forty-six percent (r² = 0.46) of the S100B levels after surgery corresponded with radiological findings. This relation was probably lower than would have been the case if the morphological assessments could have been performed at the optimal time point. In the present study, this time point was determined by the clinical signs and the overall performance of the patients as well as by the availability of examination resources. An absolute optimization of the time points for the radiological examinations and sampling of S100B could therefore not be achieved. Furthermore, we were unable to perform direct measurements of the volume of the brain lesions. Instead, we choose a semiquantitative method, which measured the size of the lesion in one dimension. This methodological problem could affect the correlation in a negative way. Recent development in the techniques of radiological imaging of the brain may, in future studies, yield more reliable measurements of the size of infarctions.

Since the distribution of S100B in brain tissue is uneven, the highest levels are found in glial dense areas [17], and the amount of released S100B depends on both the size and the location of the lesion. This fact may offer yet another explanation to the reduced strength in correlation between the increase in S100B levels and radiological findings. A more correct measure of infarct size would be the cubed diameter, and when we used it, it yielded a better regression (r = 0.80, p < 0.0001).

The S100B cut of level of 0.5 µg/L was chosen based on our previous reports [8, 11]. Out of a total number of 515 patients undergoing CABG, 13% had levels above 0.2 µg/L; only 2.3% had levels of S100B greater than or equal to 0.5 µg/L. In the same cohort, 7% of the patients had adverse neurological outcome of different dignity. This difference might reflect silent ischemia or release from other unknown sources, and this discrepancy should be addressed in future studies. The technique of analyzing S100B has recently been improved and, with the new method, the lowest detection limit has been reported to be 0.02 µg/L [18]. Normal levels in a group of healthy blood donors were found to be 0.07 µg/L (range 0.03 to 0.12, AB Sangtec Medical). In theory small lesions to the brain caused by cardiac surgery could be diagnosed using this sensitive analysis of S100B. However, the risk of false-positive results would also increase, therefore studies are needed to measure S100B in patients with no clinical signs of brain lesions after cardiac surgery.

In conclusion, we found that in patients who developed localized cerebral lesions after cardiac surgery with the use of CPB, high levels of S100B 48 hours after surgery are correlated to the size of the brain lesion. Furthermore, patients with postoperative stroke and high levels of S100B have a shorter life expectancy.

	References

Top Abstract Introduction Material and methods Results Comment References

 

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