Markers of brain cell damage related to cardiac surgery

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S100 proteins belong to a family of many small proteins[1]. The isoform S100B₂ is 21kDa in size, consist of two B-chains, and is a so called EF-hand protein with the capacity to bind calcium. It is normally present in serum in very low concentrations 0.03–0.12 μg/l, but in high concentrations both extracellular and intracellular in the brain. It has been found both in glial cells and in neurones, but is believed to be synthesized only in glial cells. The protein is neurotrophic and takes part in healing and maturation processes, but can also be a trigger for apoptosis via stimulation of nitric oxide synthase (NOS) and lipid peroxidation pathways [2]. It can be analyzed in serum with a luminescence immunoassay (Sangtec100, AB Sangtec, Bromma, Sweden).

In brain damage from stroke, trauma or subarachnoidal haemorrhage, the serum concentration is associated with the volume of cellular damage and with outcome. In global anoxemia, as after successful (!) resuscitation, it is an early measure of prognosis [3]. S100 can be used, to evaluate the cellular involvement and prognosis in patients suffering from stroke and after cardiac surgery. In stroke, peak concentrations in serum occur after about 1–3 days, depending on the heterogeneity of cell damage in focal brain lesions. It has long been known that that S100 is released to the bloodstream during cardiopulmonary perfusion and that this release is associated to the duration of perfusion [4]. Whether cellular disruption is mandatory or only an impaired blood-brain barrier is sufficient for this release to occur is unclear. Expectations of a possible association between S100 levels and the neuropsychological deterioration occurring after cardiac surgery has increased the clinical interest in S100.

Reports of irregular peak levels and nonsystematical correlation's to risk factors for brain damage, perfusion times or neuropsychological results led us to doubt the specificity of the protein to brain tissue alone. It now seems clear that S100 is also present in fat or mediastinal tissue. This extracerebral source contaminates the S100 levels during operation if cardiotomy suckers are used, and after surgery due to the use of autotransfusion. The biological half-life of S100 in the circulation was earlier considered to be around 2 h, but has recently been reinvestigated and found to be only 25 min. Bearing this in mind, it is still possible to use early serum levels of S100 for assessment of brain damage in conjunction with cardiopulmonary perfusion.

Preliminary findings from a long-term follow up study of patients operated on in 1996 and 1997 suggested that S100 sampled 2 days after surgery is a strong predictor of late mortality. Patients who are dismissed from surgery without any suspicion of a cerebral complication, but with an elevation of S100, seem to have a shorter life expectancy. It can be speculated that the elevated S100 in these patients represents subclinical brain injury.

Neurone-specific enolase (NSE) is another suggested marker of cerebral injury. However, as enolase is present not only in neurones, but also in erythrocytes, early increases have to be interpreted with caution. The elimination rate of free hemoglobin from the circulation is much faster than that of NSE, which is why a simple measure of hemoglobin is hard to use for the estimation of hemolysis and erythrocytic contamination. Still, a number of reports have been published where NSE has been advocated to be a reliable marker, and I believe that there may be room for NSE as well. However, increased efforts to characterize the kinetics and possible erroneous contribution from erythrocytes have to be made first.

In children, we face other problems. The normal concentrations of S100 cannot be used in children. S100 levels are higher and it is not clear whether this is a function of imperfection of the blood-brain barrier or ongoing maturation processes in the brain. Likewise, there seem to be differences between cyanotic and acyanotic babies.

A biochemical marker of brain dysfunction/damage would of course make the evaluation of surgical techniques much easier, compared with 'the gold standard' of prospective neuropsychological or morphological investigations such as magnetic resonance imaging. However, it is not justified to expect congruent results with these three methods. One should instead see the three as complementary, although the biochemical marker would be an ideal and simpler screening method, both for the risk assessment in individual patients and for the assessment of new techniques. The number of published articles on the issue of biochemical markers is rapidly increasing. It is therefore reasonable to believe that some of the problems we face today will be overcome by increased research efforts.